@article {pmid39046019,
year = {2024},
author = {Varela, ELP and Gomes, ARQ and Santos, ASBD and Cruz, JND and Carvalho, EP and Prazeres, BAPD and Dolabela, MF and Percario, S},
title = {Lycopene supplementation promoted increased survival and decreased parasitemia in mice with severe malaria: comparison with N-acetylcysteine.},
journal = {Anais da Academia Brasileira de Ciencias},
volume = {96},
number = {3},
pages = {e20230347},
doi = {10.1590/0001-3765202420230347},
pmid = {39046019},
issn = {1678-2690},
mesh = {Animals ; *Lycopene/therapeutic use/administration & dosage/pharmacology ; *Parasitemia/drug therapy ; Mice ; *Malaria/drug therapy ; *Acetylcysteine/administration & dosage/therapeutic use/pharmacology ; *Plasmodium berghei/drug effects ; *Antioxidants/therapeutic use/administration & dosage ; *Dietary Supplements ; Oxidative Stress/drug effects ; Carotenoids/therapeutic use/administration & dosage ; Male ; Disease Models, Animal ; Random Allocation ; },
abstract = {Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.},
}

Animals
*Lycopene/therapeutic use/administration & dosage/pharmacology
*Parasitemia/drug therapy
Mice
*Malaria/drug therapy
*Acetylcysteine/administration & dosage/therapeutic use/pharmacology
*Plasmodium berghei/drug effects
*Antioxidants/therapeutic use/administration & dosage
*Dietary Supplements
Oxidative Stress/drug effects
Carotenoids/therapeutic use/administration & dosage
Male
Disease Models, Animal
Random Allocation

@article {pmid39045541,
year = {2024},
author = {Wu, X and Zhang, G and Du, X},
title = {Cigarette Smoke Extract Induces MUC5AC Expression Through the ROS/ IP3R/Ca[2+] Pathway in Calu-3 Cells.},
journal = {International journal of chronic obstructive pulmonary disease},
volume = {19},
number = {},
pages = {1635-1647},
pmid = {39045541},
issn = {1178-2005},
mesh = {*Mucin 5AC/metabolism/genetics ; Humans ; *Reactive Oxygen Species/metabolism ; *Smoke/adverse effects ; *Inositol 1,4,5-Trisphosphate Receptors/metabolism/genetics ; *Mucin-5B/metabolism/genetics ; *Calcium Signaling/drug effects ; Up-Regulation ; Oxidative Stress/drug effects ; Protein Serine-Threonine Kinases/metabolism/genetics ; Cell Line, Tumor ; Nicotiana/adverse effects ; RNA Interference ; Endoplasmic Reticulum Stress/drug effects ; Epithelial Cells/metabolism/drug effects ; Acetylcysteine/pharmacology ; Cigarette Smoking/adverse effects ; Calcium/metabolism ; X-Box Binding Protein 1 ; Endoribonucleases ; },
abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is caused by exposure to noxious external particles, air pollution, and the inhalation of cigarette smoke. Airway mucus hypersecretion particularly mucin5AC (MUC5AC), is a crucial pathological feature of COPD and is associated with its initiation and progression. In this study, we aimed to investigate the effects of cigarette smoke extract (CSE) on MUC5AC expression, particularly the mechanisms by which reactive oxygen species (ROS) induce MUC5AC expression.

METHODS: The effects of CSE on the expression of MUC5AC and mucin5B (MUC5B) were investigated in vitro in Calu-3 cells. MUC5AC and MUC5B expression levels were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Total cellular levels of ROS and Ca[2+] were determined using DCFH-DA and Fluo-4 AM. Subsequently, the expression levels of IP3R, IRE1α, p-IRE1α and XBP1s were measured by Western blotting. Gene silencing was achieved by using small-interfering RNAs.

RESULTS: Our findings revealed that exposure to CSE increased MUC5AC levels and upregulated ROS, IP3R/Ca[2+] and unfolded protein response (UPR)-associated factors. In addition, knockdown of IP3R using siRNA decreased CSE-induced Ca[2+] production, UPR-associated factors, and MUC5AC expression. Furthermore, 10 mM N-acetyl-l-cysteine (NAC) treatment suppressed the effects of CSE, including ROS generation, IP3R/ Ca[2+], UPR activation, and MUC5AC overexpression.

CONCLUSION: Our results suggest that ROS regulates CSE-induced UPR and MUC5AC overexpression through IP3R/ Ca[2+] signaling. Additionally, we identified NAC as a promising therapeutic agent for mitigating CSE-induced MUC5AC overexpression.},
}

*Mucin 5AC/metabolism/genetics
Humans
*Reactive Oxygen Species/metabolism
*Smoke/adverse effects
*Inositol 1,4,5-Trisphosphate Receptors/metabolism/genetics
*Mucin-5B/metabolism/genetics
*Calcium Signaling/drug effects
Up-Regulation
Oxidative Stress/drug effects
Protein Serine-Threonine Kinases/metabolism/genetics
Cell Line, Tumor
Nicotiana/adverse effects
RNA Interference
Endoplasmic Reticulum Stress/drug effects
Epithelial Cells/metabolism/drug effects
Acetylcysteine/pharmacology
Cigarette Smoking/adverse effects
Calcium/metabolism
X-Box Binding Protein 1
Endoribonucleases

@article {pmid39044301,
year = {2024},
author = {Hao, WY and Wang, JX and Xu, XY and Chen, JL and Chen, Q and Li, YH and Zhu, GQ and Chen, AD},
title = {Chemerin in caudal division of nucleus tractus solitarius increases sympathetic activity and blood pressure.},
journal = {The European journal of neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1111/ejn.16475},
pmid = {39044301},
issn = {1460-9568},
support = {32071106//National Natural Science Foundation of China/ ; 31871148//National Natural Science Foundation of China/ ; 31571168//National Natural Science Foundation of China/ ; },
abstract = {Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses.},
}

@article {pmid39042563,
year = {2024},
author = {Jeon, M and Bae, S},
title = {In vitro effects of N-acetylcysteine in combination with antifungal agents against Malassezia pachydermatis isolated from canine otitis externa.},
journal = {Veterinary medicine and science},
volume = {10},
number = {5},
pages = {e1479},
doi = {10.1002/vms3.1479},
pmid = {39042563},
issn = {2053-1095},
mesh = {Animals ; Dogs ; *Malassezia/drug effects ; *Otitis Externa/veterinary/drug therapy/microbiology ; *Dog Diseases/drug therapy/microbiology ; *Antifungal Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Drug Therapy, Combination/veterinary ; *Microbial Sensitivity Tests/veterinary ; Male ; Female ; },
abstract = {BACKGROUND: Many clinicians prescribe antifungal agents to treat canine otitis externa (OE). However, studies evaluating the antifungal effects of N-acetylcysteine (NAC) and its combinations are limited.

HYPOTHESIS/OBJECTIVES: The aim of this study was to evaluate the antifungal effects of NAC alone and in combination with other antifungal agents against Malassezia pachydermatis isolated from canine OE.

MATERIALS AND METHODS: M. pachydermatis samples were collected from 13 dogs with OE. The final concentration of the inoculum suspensions of M. pachydermatis was 1-5 × 10[6] colony forming units/mL. The concentrations of the test compounds ketoconazole (KTZ), terbinafine (TER), nystatin (NYS) and NAC were 0.02-300 µg/mL, 0.04-80 µg/mL, 0.16-40 µg/mL and 1.25-20 mg/mL, respectively. The minimum inhibitory concentration (MIC) was measured to evaluate the susceptibility of the M. pachydermatis to KTZ, TER, NYS and NAC. The checkerboard testing method and fractional inhibitory concentration index were used to evaluate the effect of NAC in combination with KTZ, TER and NYS against M. pachydermatis.

RESULTS: The MIC90 values of M. pachydermatis were 4.6875-9.375 µg/mL, 1.25 µg/mL, 5-10 µg/mL and 10 mg/mL for KTZ, TER, NYS and NAC, respectively. The synergistic effects of KTZ, TER and NYS with NAC were identified in 0/13, 2/13 and 0/13 isolates, respectively.

NAC had an antifungal effect against M. pachydermatis but did not exert synergistic effects when used with KTZ, TER and NYS. Thus, the use of NAC alone as a topical solution could be considered an effective treatment option for canine OE involving M. pachydermatis.},
}

Animals
Dogs
*Malassezia/drug effects
*Otitis Externa/veterinary/drug therapy/microbiology
*Dog Diseases/drug therapy/microbiology
*Antifungal Agents/pharmacology
*Acetylcysteine/pharmacology
*Drug Therapy, Combination/veterinary
*Microbial Sensitivity Tests/veterinary
Male
Female

@article {pmid39040524,
year = {2024},
author = {Tomimoto, N and Takasaki, T and Sugiura, R},
title = {Arsenite treatment induces Hsp90 aggregatesdistinct from conventional stress granules in fission yeast.},
journal = {Microbial cell (Graz, Austria)},
volume = {11},
number = {},
pages = {242-253},
pmid = {39040524},
issn = {2311-2638},
abstract = {Various stress conditions, such as heat stress (HS) and oxidative stress, can cause biomolecular condensates represented by stress granules (SGs) via liquid-liquid phase separation. We have previously shown that Hsp90 forms aggregates in response to HS and that Hsp90 aggregates transiently co-localize with SGs as visualized by Pabp. Here, we showed that arsenite, one of the well-described SG-inducing stimuli, induces Hsp90 aggregates distinct from conventional SGs in fission yeast. Arsenite induced Hsp90 granules in a dose-dependent manner, and these granules were significantly diminished by the co-treatment with a ROS scavenger N-acetyl cysteine (NAC), indicating that ROS are required for the formation of Hsp90 granules upon arsenite stress. Notably, Hsp90 granules induced by arsenite do not overlap with conventional SGs as represented by eIF4G or Pabp, while HS-induced Hsp90 granules co-localize with SGs. Nrd1, an RNA-binding protein known as a HS-induced SG component, was recruited into Hsp90 aggregates but not to the conventional SGs upon arsenite stress. The non-phosphorylatable eIF2α mutants significantly delayed the Hsp90 granule formation upon arsenite treatment. Importantly, inhibition of Hsp90 by geldanamycin impaired the Hsp90 granule formation and reduced the arsenite tolerance. Collectively, arsenite stimulates two types of distinct aggregates, namely conventional SGs and a novel type of aggregates containing Hsp90 and Nrd1, wherein Hsp90 plays a role as a center for aggregation, and stress-specific compartmentalization of biomolecular condensates.},
}

@article {pmid39039898,
year = {2024},
author = {Yifu, P},
title = {A review of antioxidant N-acetylcysteine in addressing polycystic ovary syndrome.},
journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology},
volume = {40},
number = {1},
pages = {2381498},
doi = {10.1080/09513590.2024.2381498},
pmid = {39039898},
issn = {1473-0766},
mesh = {*Polycystic Ovary Syndrome/drug therapy/metabolism ; *Acetylcysteine/therapeutic use/pharmacology ; Humans ; Female ; *Antioxidants/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; },
abstract = {N-acetylcysteine (NAC), a compound known for its cysteine and glutathione precursor properties, has been used in therapeutic applications for many years. Recently, there has been increasing interest in exploring the potential benefits of NAC in addressing polycystic ovary syndrome (PCOS). However, the exact mechanisms underlying NAC's therapeutic and clinical uses remain not fully understood. This review aims to specifically investigate how NAC offers protection against PCOS. This involved an extensive systematic review of the literature, and it made use of PubMed, Embase, and Web of Science databases. By analyzing key findings from over 100 research papers, the potential mechanisms through which NAC produces its effects were explored and summarized. Most studies suggest that NAC, whether used on its own or in combination with other medications, has the potential to counteract oxidative stress, utilize its anti-inflammatory and anti-apoptotic properties, and offer benefits in managing PCOS. Moreover, NAC might have the potential to influence specific signaling pathways in insulin target cells and β cells. Diverse biological effects of NAC indicate its potential usefulness as a supplementary or therapeutic approach for managing PCOS. As a result, additional research is required to explore its potential in addressing PCOS.},
}

*Polycystic Ovary Syndrome/drug therapy/metabolism
*Acetylcysteine/therapeutic use/pharmacology
Humans
Female
*Antioxidants/therapeutic use/pharmacology
*Oxidative Stress/drug effects

@article {pmid39039306,
year = {2024},
author = {Chen, Y and Luo, X and Deng, C and Zhao, L and Gao, H and Zhou, J and Peng, L and Yang, H and Li, M and Zhang, W and Zhao, Y and Fei, Y},
title = {Immunometabolic alteration of CD4[+] T cells in the pathogenesis of primary Sjögren's syndrome.},
journal = {Clinical and experimental medicine},
volume = {24},
number = {1},
pages = {163},
pmid = {39039306},
issn = {1591-9528},
support = {3332022105//Fundamental Research Funds for the Central Universities/ ; 82172343//National Natural Science Foundation of China/ ; 81971545//National Natural Science Foundation of China/ ; 7242103//Beijing Natural Science Foundation Program/ ; 2022-PUMCH-C-039//National High Level Hospital Clinical Research Funding/ ; CIFMS 2023-I2M-C & T-B-006//Chinese Academy of Medical Science Innovation Fund/ ; },
mesh = {Humans ; *Sjogren's Syndrome/immunology/metabolism/pathology ; *CD4-Positive T-Lymphocytes/immunology/metabolism ; *Glycolysis ; *Reactive Oxygen Species/metabolism ; Female ; Middle Aged ; Male ; Adult ; Th17 Cells/immunology ; Cell Differentiation ; Interferon-gamma/metabolism ; Interleukin-17/metabolism ; Th1 Cells/immunology ; },
abstract = {Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4[+] T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4[+] T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4[+] T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4[+] T cells, conducted flow cytometry to assess the effector function and differentiation of CD4[+] T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4[+] T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4[+] T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4[+] T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4[+] T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4[+] T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4[+] T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.},
}

Humans
*Sjogren's Syndrome/immunology/metabolism/pathology
*CD4-Positive T-Lymphocytes/immunology/metabolism
*Glycolysis
*Reactive Oxygen Species/metabolism
Female
Middle Aged
Male
Adult
Th17 Cells/immunology
Cell Differentiation
Interferon-gamma/metabolism
Interleukin-17/metabolism
Th1 Cells/immunology

@article {pmid39038059,
year = {2024},
author = {Bandekar, M and Panda, D},
title = {Microtubule depolymerization induces ferroptosis in neuroblastoma cells.},
journal = {IUBMB life},
volume = {},
number = {},
pages = {},
doi = {10.1002/iub.2899},
pmid = {39038059},
issn = {1521-6551},
support = {JCB/2019/000016//Department of Science and Technology, Ministry of Science and Technology, India (The J.C. Bose fellowship)/ ; },
abstract = {Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.},
}

@article {pmid39037665,
year = {2024},
author = {Gao, C and Wang, L and Fu, K and Cheng, S and Wang, S and Feng, Z and Yu, S and Yang, Z},
title = {N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells.},
journal = {Inflammation},
volume = {},
number = {},
pages = {},
pmid = {39037665},
issn = {1573-2576},
support = {GSWS2021036//Gusu Talent Program/ ; SKY2022181//Science and Technology Project of Suzhou/ ; LGY2020045//Jiangsu Commission of Health/ ; SYH-32034-0103(2024007)//Jiangsu Medical Association Pediatric Medical Research Special Fund Project/ ; },
abstract = {Abstract-Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in neonates, and effective strategies to prevent and treat NEC are still lacking. Studies have shown that N-acetylcysteine (NAC) has protective effects against NEC, however, the specific mechanism underlying its effects on intestinal functions remains unclear. Recently, NAC has been shown to suppress ferroptosis in many diseases, while it is unclear whether the beneficial effects of NAC on NEC are related to ferroptosis. In this study, we revealed that ferroptosis was significantly induced in intestinal samples from infants with NEC. NAC alleviated intestinal inflammation, barrier damage and ferroptosis in multifactorial NEC models in vivo and in vitro. Sestrin2 (SESN2) was identified as an important mediator of NAC-induced ferroptosis resistance in intestinal epithelial cells. Furthermore, SESN2 knockdown inhibited the inflammatory response, alleviated barrier damage and ferroptosis in intestinal epithelial cells and enhanced the protective effects of NAC to a certain extent. Conversely, cells overexpressing SESN2 showed the opposite changes. In summary, our study demonstrated that NAC attenuates NEC progression by decreasing SESN2 expression to inhibit ferroptosis in intestinal epithelial cells, suggesting that NAC might be an effective clinical treatment for NEC.},
}

@article {pmid38639871,
year = {2024},
author = {Nakai, A and Fukushima, Y and Yamamoto, A and Amatsu, Y and Chen, X and Nishigori, M and Yoshioka, Y and Kaneko, M and Koshiba, T and Watanabe, T},
title = {Increased ROS levels in mitochondrial outer membrane protein Mul1-deficient oocytes result in abnormal preimplantation embryogenesis.},
journal = {FEBS letters},
volume = {598},
number = {14},
pages = {1740-1752},
doi = {10.1002/1873-3468.14876},
pmid = {38639871},
issn = {1873-3468},
support = {26291032//Japan Society for the Promotion of Science/ ; 17H03667//Japan Society for the Promotion of Science/ ; 23H02096//Japan Society for the Promotion of Science/ ; //Nara Women's University Intramural Grant for Project Research/ ; },
mesh = {Animals ; *Oocytes/metabolism ; *Reactive Oxygen Species/metabolism ; Female ; *Embryonic Development/genetics ; Mice ; *Ubiquitin-Protein Ligases/metabolism/genetics/deficiency ; DNA Damage ; Acetylcysteine/pharmacology ; Blastocyst/metabolism ; Mitochondrial Membranes/metabolism ; Mice, Knockout ; Mitochondrial Proteins/metabolism/genetics/deficiency ; Mitochondria/metabolism ; },
abstract = {Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N-acetyl-l-cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1-deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1-deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.},
}

Animals
*Oocytes/metabolism
*Reactive Oxygen Species/metabolism
Female
*Embryonic Development/genetics
Mice
*Ubiquitin-Protein Ligases/metabolism/genetics/deficiency
DNA Damage
Acetylcysteine/pharmacology
Blastocyst/metabolism
Mitochondrial Membranes/metabolism
Mice, Knockout
Mitochondrial Proteins/metabolism/genetics/deficiency
Mitochondria/metabolism

@article {pmid39034050,
year = {2024},
author = {Liyanage, W and Kale, N and Kannan, S and Kannan, RM},
title = {Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines.},
journal = {Advances in pharmacology (San Diego, Calif.)},
volume = {100},
number = {},
pages = {119-155},
doi = {10.1016/bs.apha.2024.05.003},
pmid = {39034050},
issn = {1557-8925},
mesh = {*Dendrimers/chemistry ; *Acetylcysteine/pharmacology/therapeutic use/chemistry ; Humans ; Animals ; *Nanomedicine/methods ; COVID-19 Drug Treatment ; Drug Delivery Systems/methods ; Drug Development/methods ; },
abstract = {Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances of clinical success for drugs. Yet, dendrimer-based drug products are still in their infancy. However, Hydroxyl polyamidoamine (PAMAM) dendrimers showed significant promise in drug discovery efforts, owning their remarkable potential to selectively target and deliver drugs specifically to activated microglia and astrocytes at the site of brain injury in several preclinical models. After a decade's worth of academic research and pre-clinical efforts, the hydroxyl PAMAM dendrimer-N-acetyl cysteine conjugate (OP-101) nanomedicine has made a significant advancement in the field of nanomedicine and targeted delivery. The OP-101 conjugate, primarily developed and validated in academic labs, has now entered clinical trials as a potential treatment for hyperinflammation in hospitalized adults with severe COVID-19 through Ashvattha Therapeutics. This chapter, we delve into the journey of the hydroxyl PAMAM dendrimer-N-acetylcysteine (NAC) OP-101 formulation from the laboratory to the clinic. It will specifically focus on the design, synthesis, preclinical, and clinical development of OP-101, highlighting the potential it holds for the future of medicine and the positive Phase 2a results for treating severe COVID-19.},
}

*Dendrimers/chemistry
*Acetylcysteine/pharmacology/therapeutic use/chemistry
Humans
Animals
*Nanomedicine/methods
COVID-19 Drug Treatment
Drug Delivery Systems/methods
Drug Development/methods

@article {pmid39031462,
year = {2024},
author = {Hsu, CS and Chang, SH and Yang, RC and Lee, CH and Lee, MS and Kao, JK and Shieh, JJ},
title = {Lipopolysaccharide-Induced Lysosomal Cell Death Through Reactive Oxygen Species in Rat Liver Cell Clone 9.},
journal = {Environmental toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1002/tox.24377},
pmid = {39031462},
issn = {1522-7278},
support = {NCHU-CCH-11007//National Chung Hsing University/Changhua Christian Hospital Joint Research Program/ ; TCVGH-1107304D//Taichung Veterans General Hospital Research Program/ ; MOST-109-2320-B-371-003//Ministry of Science and Technology, Taiwan/ ; },
abstract = {In sepsis, bacterial components, particularly lipopolysaccharide (LPS), trigger organ injuries such as liver dysfunction. Although sepsis induces hepatocyte damage, the mechanisms underlying sepsis-related hepatic failure remain unclear. In this study, we demonstrated that the LPS-treated rat hepatocyte cell line Clone 9 not only induced reactive oxygen species (ROS) generation and apoptosis but also increased the expression of the autophagy marker proteins LC3-II and p62, and decreased the expression of intact Lamp2A, a lysosomal membrane protein. Additionally, LPS increased lysosomal membrane permeability and galectin-3 puncta formation, and promoted lysosomal alkalization in Clone 9 cells. Pharmacological inhibition of caspase-8 and cathepsin D (CTSD) suppressed the activation of caspase-3 and rescued the viability of LPS-treated Clone 9 cells. Furthermore, LPS induced CTSD release associated with lysosomal leakage and contributed to caspase-8 activation. Pretreatment with the antioxidant N-acetylcysteine (NAC) not only diminished ROS generation and increased the cell survival rate, but also decreased the expression of activated caspase-8 and caspase-3 and increased the protein level of Lamp2A in LPS-treated Clone 9 cells. These results demonstrate that LPS-induced ROS causes lysosomal membrane permeabilization and lysosomal cell death, which may play a crucial role in hepatic failure in sepsis. Our results may facilitate the development of new strategies for sepsis management.},
}

@article {pmid39028629,
year = {2024},
author = {Ye, JJ and Chen, ZY and Wang, QH and Liao, XY and Wang, XY and Zhang, CC and Liu, LR and Wei, Q and Bao, YG},
title = {Current treatment for male infertility: an umbrella review of systematic reviews and meta-analyses.},
journal = {Asian journal of andrology},
volume = {},
number = {},
pages = {},
doi = {10.4103/aja202428},
pmid = {39028629},
issn = {1745-7262},
abstract = {This umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments for male infertility and assess the quality of evidence and possible biases. An umbrella review of systematic reviews and meta-analyses available in PubMed, Web of Science, and Scopus, covering studies published up to October 2023, was conducted. Sperm concentration, morphology, and motility were used as endpoints to evaluate the effectiveness of the treatments. Of 2998 studies, 18 published meta-analyses were extracted, yielding 90 summary effects on sperm concentration (n = 36), sperm morphology (n = 26), and sperm motility (n = 28) on 28 interventions. None of the meta-analyses were classified as having low methodological quality, whereas 12 (66.7%) and 6 (33.3%) had high and moderate quality, respectively. Of the 90 summary effects, none were rated high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23), and 21.1% (n = 19) were rated moderate, low, and very low, respectively. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (N-acetyl-cysteine, antioxidant therapy, aromatase inhibitors, selective estrogen receptor modulators, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (varicocele repair and redo varicocelectomy). In addition, vitamin supplementation had no significant positive effects on sperm concentration, motility, or morphology. Treatments for male infertility are increasingly diverse; however, the current evidence is poor because of the limited number of patients. Further well-designed studies on single treatment and high-quality meta-analysis of intertreatment comparisons are recommended.},
}

@article {pmid39028412,
year = {2024},
author = {Zolnourian, A and Garland, P and Holton, P and Arora, M and Rhodes, J and Uff, C and Birch, T and Howat, D and Franklin, S and Galea, I and Bulters, D},
title = {A Randomised Controlled Trial of SFX-01 After Subarachnoid Haemorrhage - The SAS Study.},
journal = {Translational stroke research},
volume = {},
number = {},
pages = {},
pmid = {39028412},
issn = {1868-601X},
abstract = {SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R[2] = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.},
}

@article {pmid39028033,
year = {2024},
author = {Arenhoevel, J and Kuppe, A and Addante, A and Wei, LF and Boback, N and Butnarasu, C and Zhong, Y and Wong, C and Graeber, SY and Duerr, J and Gradzielski, M and Lauster, D and Mall, MA and Haag, R},
title = {Thiolated polyglycerol sulfate as potential mucolytic for muco-obstructive lung diseases.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4bm00381k},
pmid = {39028033},
issn = {2047-4849},
abstract = {Increased disulfide crosslinking of secreted mucins causes elevated viscoelasticity of mucus and is a key determinant of mucus dysfunction in patients with cystic fibrosis (CF) and other muco-obstructive lung diseases. In this study, we describe the synthesis of a novel thiol-containing, sulfated dendritic polyglycerol (dPGS-SH), designed to chemically reduce these abnormal crosslinks, which we demonstrate with mucolytic activity assays in sputum from patients with CF. This mucolytic polymer, which is based on a reportedly anti-inflammatory polysulfate scaffold, additionally carries multiple thiol groups for mucolytic activity and can be produced on a gram-scale. After a physicochemical compound characterization, we compare the mucolytic activity of dPGS-SH to the clinically approved N-acetylcysteine (NAC) using western blot studies and investigate the effect of dPGS-SH on the viscoelastic properties of sputum samples from CF patients by oscillatory rheology. We show that dPGS-SH is more effective than NAC in reducing multimer intensity of the secreted mucins MUC5B and MUC5AC and demonstrate significant mucolytic activity by rheology. In addition, we provide data for dPGS-SH demonstrating a high compound stability, low cytotoxicity, and superior reaction kinetics over NAC at different pH levels. Our data support further development of the novel reducing polymer system dPGS-SH as a potential mucolytic to improve mucus function and clearance in patients with CF as well as other muco-obstructive lung diseases.},
}

@article {pmid38376368,
year = {2024},
author = {Ghani, H and Podwojniak, A and Tan, IJ and Fliorent, R and Jafferany, M},
title = {From tugs to treatments: a systematic review on pharmacological interventions for trichotillomania.},
journal = {Clinical and experimental dermatology},
volume = {49},
number = {8},
pages = {774-782},
doi = {10.1093/ced/llae052},
pmid = {38376368},
issn = {1365-2230},
mesh = {*Trichotillomania/drug therapy ; Humans ; *Acetylcysteine/therapeutic use ; *Selective Serotonin Reuptake Inhibitors/therapeutic use ; Aripiprazole/therapeutic use ; Behavior Therapy/methods ; },
abstract = {BACKGROUND: Trichotillomania (TTM) is a psychiatric disorder with dermatological consequences, characterized by recurrent hair pulling. It affects 1-3% of the population, and often coexists with other psychiatric disorders, leading to emotional distress. Effective management of TTM can be challenging because of underdiagnosis, symptom heterogeneity and stigma. Pharmacological interventions, including selective serotonin reuptake inhibitors and N-acetyl cysteine (NAC) are commonly used.

OBJECTIVES: To assess the existing literature on pharmacotherapy for TTM and identify potential avenues for future research and treatment advancements.

METHODS: A systematic review of the literature was performed using PubMed and Scopus databases within the past 10 years (PROSPERO: CRD42023454009). Included studies assessed pharmacotherapy for TTM and provided insights into current evidence and potential directions for future research and treatment advancements.

RESULTS: In total, 23 articles were identified that met inclusion criteria. The most successful interventions were NAC, aripiprazole and monoamine oxidase inhibitors. NAC was identified as the most impressive adjunctive therapy to selective serotonin reuptake inhibitors and behavioural therapies in treatment through its mechanism of decreased glutamate-induced excitatory neuronal damage, with adjunctive antioxidant properties. Most of the other therapeutics that were identified require further research and controlled trials to validate their findings.

CONCLUSIONS: Even if successful therapeutic outcomes are achieved, it is important to consider the patient's comorbidities and to combine pharmacological interventions with behavioural therapy interventions to comprehensively manage TTM.},
}

*Trichotillomania/drug therapy
Humans
*Acetylcysteine/therapeutic use
*Selective Serotonin Reuptake Inhibitors/therapeutic use
Aripiprazole/therapeutic use
Behavior Therapy/methods

@article {pmid39019252,
year = {2024},
author = {Rivera-Ingraham, GA and Martínez-Alarcón, D and Theuerkauff, D and Nommick, A and Lignot, JH},
title = {Two faces of one coin: Beneficial and deleterious effects of reactive oxygen species during short-term acclimation to hypo-osmotic stress in a decapod crab.},
journal = {Comparative biochemistry and physiology. Part A, Molecular & integrative physiology},
volume = {},
number = {},
pages = {111700},
doi = {10.1016/j.cbpa.2024.111700},
pmid = {39019252},
issn = {1531-4332},
abstract = {Exposure to environmental changes often results in the production of reactive oxygen species (ROS), which, if uncontrolled, leads to loss of cellular homeostasis and oxidative distress. However, at physiological levels these same ROS are known to be key players in cellular signaling and the regulation of key biological activities (oxidative eustress). While ROS are known to mediate salinity tolerance in plants, little is known for the animal kingdom. In this study, we use the Mediterranean crab Carcinus aestuarii, highly tolerant to salinity changes in its environment, as a model to test the healthy or pathological role of ROS due to exposure to diluted seawater (dSW). Crabs were injected either with an antioxidant [N-acetylcysteine (NAC), 150 mg·kg[-1]] or phosphate buffered saline (PBS). One hour after the first injection, animals were either maintained in seawater (SW) or transferred to dSW and injections were carried out at 12-h intervals. After ≈48 h of salinity change, all animals were sacrificed and gills dissected for analysis. NAC injections successfully inhibited ROS formation occurring due to dSW transfer. However, this induced 55% crab mortality, as well as an inhibition of the enhanced catalase defenses and mitochondrial biogenesis that occur with decreased salinity. Crab osmoregulatory capacity under dSW condition was not affected by NAC, although it induced in anterior (non-osmoregulatory) gills a 146-fold increase in Na[+]/K[+]/2Cl[-] expression levels, reaching values typically observed in osmoregulatory tissues. We discuss how ROS influences the physiology of anterior and posterior gills, which have two different physiological functions and strategies during hyper-osmoregulation in dSW.},
}

@article {pmid39006976,
year = {2024},
author = {Sadeghinejad, S and Mousavi, M and Zeidooni, L and Mansouri, E and Mohtadi, S and Khodayar, MJ},
title = {Ameliorative effects of umbelliferone against acetaminophen-induced hepatic oxidative stress and inflammation in mice.},
journal = {Research in pharmaceutical sciences},
volume = {19},
number = {1},
pages = {83-92},
pmid = {39006976},
issn = {1735-5362},
abstract = {BACKGROUND AND PURPOSE: Acetaminophen (APAP) is a commonly used antipyretic and pain reliever that its overdose causes acute liver toxicity. Umbelliferone (UMB) has many pharmacological effects. In this study, the hepatoprotective effect of UMB on acute hepatotoxicity induced by APAP was investigated.

EXPERIMENTAL APPROACH: Forty-nine male mice were separated into seven groups. The control received vehicle (i.p.), UMB group received UMB (120 mg/kg, i.p.), APAP group was treated with a single dose of APAP (350 mg/kg, i.p.), and pretreated groups received N-acetylcysteine (NAC, 200 mg/kg, i.p.) or different doses of UMB (30, 60, and 120 mg/kg, i.p.), respectively before APAP. Twenty-four hours after APAP injection, mice were sacrificed and blood and liver samples were collected. Then, serum and tissue samples were investigated for biochemical and histological studies.

FINDINGS/RESULTS: A single dose of APAP caused elevation in the serum liver enzymes, including alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. The amounts of thiobarbituric acid reactive substances, tumor necrosis factor-alpha, and nitric oxide increased in the mice's liver tissue. Moreover, the amount of total thiol and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) significantly diminished in the APAP group. Histological results confirmed the hepatotoxicity induced by APAP. However, UMB (more effective at 60 and 120 mg/kg) lessened APAP-induced hepatic injuries, which is comparable with NAC effects.

CONCLUSION AND IMPLICATIONS: The findings of this study provided evidence that UMB ameliorates liver injury induced by APAP through its antioxidant and anti-inflammatory effects.},
}

@article {pmid39005460,
year = {2024},
author = {Wellslager, B and Roberts, J and Chowdhury, N and Madan, L and Orellana, E and Yilmaz, Ö},
title = {Porphyromonas gingivalis activates Heat-Shock-Protein 27 to drive a LC3C-specific probacterial form of select autophagy that is redox sensitive for intracellular bacterial survival in human gingival mucosa.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.01.601539},
pmid = {39005460},
issn = {2692-8205},
abstract = {Porphyromonas gingivalis , a major oral pathobiont, evades canonical host pathogen clearance in human primary gingival epithelial cells (GECs) by initiating a non-canonical variant of autophagy consisting of Microtubule-associated protein 1A/1B-light chain 3 (LC3)-rich autophagosomes, which then act as replicative niches. Simultaneously, P. gingivalis inhibits apoptosis and oxidative-stress, including extracellular-ATP (eATP)-mediated reactive-oxygen-species (ROS) production via phosphorylating Heat Shock Protein 27 (HSp27) with the bacterial nucleoside-diphosphate-kinase (Ndk). Here, we have mechanistically identified that P. gingivalis -mediated induction of HSp27 is crucial for the recruitment of the LC3 isoform, LC3C, to drive the formation of live P. gingivalis -containing Beclin1-ATG14-rich autophagosomes that are redox sensitive and non-degrading. HSp27 depletions of both infected GECs and gingiva-mimicking organotypic-culture systems resulted in the collapse of P. gingivalis -mediated autophagosomes, and abolished P. gingivalis -induced LC3C-specific autophagic-flux in a HSp27-dependent manner. Concurrently, HSp27 depletion accompanied by eATP treatment abrogated protracted Beclin 1-ATG14 partnering and decreased live intracellular P. gingivalis levels. These events were only partially restored via treatments with the antioxidant N-acetyl cysteine (NAC), which rescued the cellular redox environment independent of HSp27. Moreover, the temporal phosphorylation of HSp27 by the bacterial Ndk results in HSp27 tightly partnering with LC3C, hindering LC3C canonical cleavage, extending Beclin 1-ATG14 association, and halting canonical maturation. These findings pinpoint how HSp27 pleiotropically serves as a major platform-molecule, redox regulator, and stepwise modulator of LC3C during P. gingivalis -mediated non-canonical autophagy. Thus, our findings can determine specific molecular strategies for interfering with the host-adapted P. gingivalis ' successful mucosal colonization and oral dysbiosis.},
}

@article {pmid38804152,
year = {2024},
author = {Wang, Y and Long, L and Luo, Q and Huang, X and Zhang, Y and Meng, X and Chen, D},
title = {Aflatoxin B1 induces ROS-dependent mitophagy by modulating the PINK1/Parkin pathway in HepG2 cells.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {135},
number = {2},
pages = {195-209},
doi = {10.1111/bcpt.14034},
pmid = {38804152},
issn = {1742-7843},
mesh = {Humans ; *Mitophagy/drug effects ; Hep G2 Cells ; *Reactive Oxygen Species/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Membrane Potential, Mitochondrial/drug effects ; *Protein Kinases/metabolism ; *Aflatoxin B1/toxicity ; *Adenosine Triphosphate/metabolism ; *NF-E2-Related Factor 2/metabolism/genetics ; Signal Transduction/drug effects ; Phosphoprotein Phosphatases/metabolism/genetics ; Mitochondria/drug effects/metabolism ; Acetylcysteine/pharmacology ; Mitochondrial Proteins/metabolism/genetics ; },
abstract = {Aflatoxin B1 (AFB1) is extremely harmful to both humans and animals. Mitophagy is a selective process of self-elimination and has an important role in controlling mitochondrial quality. The present study aimed to investigate the effect of reactive oxygen species (ROS) accumulation on AFB1-induced mitophagy in HepG2 cells to provide a new perspective from which to design novel therapeutic strategies to treat AFB1 poisoning. ROS release was induced in HepG2 cells with AFB1 (10 μmol/L). Cell autophagy activity, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) levels, Parkin translocation and both the transcription and expression of mitophagy-related proteins were measured when N-acetyl-L-cysteine (NAC) partially decreased the ROS level, while the knockdown of nuclear factor erythroid 2-related factor 2 (Nrf2) resulted in a large accumulation of ROS. The results reveal that NAC pretreatment ameliorated the decline in both the MMP and the ATP levels while also activating phosphoglycerate mutase 5 (PGAM5)-PTEN-induced kinase 1 (PINK1)/Parkin, while the Nrf2 knockdown group exhibited the opposite trend. These results suggest that AFB1-induced mitophagy in HepG2 cells depends on ROS, and proper ROS activates mitophagy to play a protective role.},
}

Humans
*Mitophagy/drug effects
Hep G2 Cells
*Reactive Oxygen Species/metabolism
*Ubiquitin-Protein Ligases/metabolism/genetics
*Membrane Potential, Mitochondrial/drug effects
*Protein Kinases/metabolism
*Aflatoxin B1/toxicity
*Adenosine Triphosphate/metabolism
*NF-E2-Related Factor 2/metabolism/genetics
Signal Transduction/drug effects
Phosphoprotein Phosphatases/metabolism/genetics
Mitochondria/drug effects/metabolism
Acetylcysteine/pharmacology
Mitochondrial Proteins/metabolism/genetics

@article {pmid39004668,
year = {2024},
author = {Erichsen, PA and Dalhoff, K and Andersen, MA},
title = {Should high-dose N-acetylcysteine be given in cases of massive paracetamol overdoses: A narrative review.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {},
number = {},
pages = {},
pmid = {39004668},
issn = {1742-7843},
abstract = {N-acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20-21 h). The subject is further complicated because "massive overdoses" and "high-risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high-dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49-3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08-0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high-dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high-dose NAC regimen should be included in clinical practice.},
}

@article {pmid39004152,
year = {2024},
author = {Chen, Q and Hu, R and Qiu, H and Li, S and Xiang, P and Lu, Y and Wang, X and Wang, T and Zhou, L and Zhang, W and Wen, E and Ma, L and Yu, C},
title = {REDD1 knockdown ameliorates endothelial cell senescence through repressing TXNIP-mediated oxidative stress.},
journal = {Mechanisms of ageing and development},
volume = {},
number = {},
pages = {111962},
doi = {10.1016/j.mad.2024.111962},
pmid = {39004152},
issn = {1872-6216},
abstract = {Endothelial cell senescence characterized by reactive oxygen species (ROS) accumulation and chronic inflammation is widely recognized as a key contributor to atherosclerosis (AS). Regulated in development and DNA damage response 1 (REDD1), a conserved stress-response protein that regulates ROS production, is involved in the pathogenesis of various age-related diseases. However, the role of REDD1 in endothelial cell senescence is still unclear. Here, we screened REDD1 as a differentially expressed senescence-related gene in the AS progression using bioinformatics methods, and validated the upregulation of REDD1 expression in AS plaques, senescent endothelial cells, and aging aorta by constructing AS mice, D-galactose (DG)-induced senescent endothelial cells and DG-induced accelerated aging mice, respectively. siRNA against REDD1 could improve DG-induced premature senescence of endothelial cells and inhibit ROS accumulation, similar to antioxidant N-Acetylcysteine (NAC) treatment. Meanwhile, NAC reduced the upregulation of REDD1 induced by DG, supporting the positive feedback loop between REDD1 and ROS contributes to endothelial cell senescence. Mechanistically, the regulatory effect of REDD1 on ROS might be related to the TXNIP-REDD1 interaction in DG-induced endothelial cell senescence. Collectively, experiments above provide evidence that REDD1 participates in endothelial cell senescence through repressing TXNIP-mediated oxidative stress, which may be involved in the progression of atherosclerosis.},
}

@article {pmid39003685,
year = {2024},
author = {Dharshini, KS and Ameen, F and Anbazhagan, V},
title = {Mechanistic Investigation on the Antibacterial Activity of Biogenic Silver Nanoparticles Prepared Using Root Extract of Sarsaparilla and Demonstrated their In Vivo Efficacy in Zebrafish Model.},
journal = {Current microbiology},
volume = {81},
number = {9},
pages = {268},
pmid = {39003685},
issn = {1432-0991},
mesh = {Animals ; *Zebrafish ; *Silver/pharmacology/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Metal Nanoparticles/chemistry ; *Plant Extracts/pharmacology/chemistry ; *Microbial Sensitivity Tests ; *Plant Roots/chemistry/microbiology ; Reactive Oxygen Species/metabolism ; Bacteria/drug effects ; },
abstract = {Antibiotic success rates are decreasing as drug-resistant bacteria become more prevalent, prompting the development of new therapeutic drugs. Herein, we demonstrated the antimicrobial activity of sarsaparilla root extract fabricated silver nanoparticles (sAgNPs). The UV-Visible spectra revealed that the surface Plasmon resonance maxima of sAgNPs were at 415 nm. Transmission electron microscopy confirms that the particles are spherical with size of 12-35 nm. The minimum inhibitory concentration (MIC) of sAgNPs against Escherichia coli, uropathogenic Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus was 62.5, 62.5, 62.5, 62.5, 125 and 125 µM, respectively. At 1X MIC, sAgNPs induces excess reactive oxygen species (ROS) production and disturbs the bacteria membrane intergity, causing cytoplamic membrane depolarization. Interestingly, antibacterial activity of sAgNPs was considerably reduced in the presence of an antioxidant, N-acetyl cysteine, suggesting that ROS-induced membrane damage is a plausible cause of cell death. In contrast to many studies that only report the in vitro activity of NPs, we determined the in vivo antibacterial efficacy using the zebrafish model. It was found that sAgNPs protect fish from infection by inhibiting bacterial growth and eliminating them from the fish. In addition, the catalytic potential of sAgNPs for wastewater decontamination was demonstrated by degrading organic pollutants such as methyl orange, congo red, reactive black, and acid blue. The pollutants degraded in less than 10 min, and the reaction follows pseudo-first-order kinetics. As a proof of concept, the catalytic potential of sAgNPs in degrading mixed dyes to satisfy industrial wastewater treatment needs was established. In summary, sAgNPs have the potential to act as nanocatalysts and nano-drugs, addressing key challenges in medical and environmental research.},
}

Animals
*Zebrafish
*Silver/pharmacology/chemistry
*Anti-Bacterial Agents/pharmacology/chemistry
*Metal Nanoparticles/chemistry
*Plant Extracts/pharmacology/chemistry
*Microbial Sensitivity Tests
*Plant Roots/chemistry/microbiology
Reactive Oxygen Species/metabolism
Bacteria/drug effects

@article {pmid38997833,
year = {2024},
author = {Shiozawa, A and Kajiwara, C and Ishii, Y and Tateda, K},
title = {Corrigendum to "N-acetyl-cysteine mediates protection against Mycobacterium avium through induction of human β-defensin-2" [Microb Infect 22 (10) (2020) 567-575].},
journal = {Microbes and infection},
volume = {},
number = {},
pages = {105388},
doi = {10.1016/j.micinf.2024.105388},
pmid = {38997833},
issn = {1769-714X},
}

@article {pmid38992233,
year = {2024},
author = {Glass, KA and Stoecker, ZR and LeRoy, J and Palmer, CL and Stipek, J and Boley, S},
title = {Investigating a Novel Two-Bag N-Acetylcysteine Regimen for Acetaminophen Toxicity.},
journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology},
volume = {},
number = {},
pages = {},
pmid = {38992233},
issn = {1937-6995},
abstract = {BACKGROUND: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors.

OBJECTIVE: We aimed to assess whether switching to a novel two-bag protocol (150 mg/kg over 1 h followed by 150 mg/kg over 20 h) reduced administration errors while not increasing liver injury or anaphylactoid reactions.

METHODS: This was a retrospective chart review of hospital encounters for patients with acetaminophen toxicity, comparing outcomes before and after the change from a three-bag protocol to a two-bag protocol at two affiliated institutions. The primary outcome was incidence of medication errors with secondary outcomes including acute liver injury (ALI) and incidence of non-anaphylactoid allergic reactions (NAAR). The study was approved by the health system's Institutional Review Board.

RESULTS: 483 encounters were included for analysis (239 in the three-bag and 244 in the two-bag groups). NAAR were identified in 11 patients with no difference seen between groups. Similarly, no differences were seen in ALI. Medication administration errors were observed significantly less often in the two-bag group (OR 0.24) after adjusting for confounders.

CONCLUSION: Transitioning to a novel two-bag NAC regimen decreased administration errors. This adds to the literature that two-bag NAC regimens are not only safe but also may have significant benefits over the traditional NAC protocol.},
}

@article {pmid38990380,
year = {2024},
author = {Lu, SH and Yun, TF and Kou, YR and Chang, YP},
title = {Preliminary evidence for therapeutic impact of intravesical glucosamine on protamine sulfate and potassium chloride-induced bladder overactivity in rat model.},
journal = {World journal of urology},
volume = {42},
number = {1},
pages = {405},
pmid = {38990380},
issn = {1433-8726},
support = {V105C-148//Taipei Veterans General Hospital/ ; },
mesh = {Animals ; *Urinary Bladder, Overactive/drug therapy ; Female ; *Rats, Sprague-Dawley ; Rats ; Administration, Intravesical ; *Protamines ; *Disease Models, Animal ; *Potassium Chloride ; *Glucosamine/pharmacology/therapeutic use/administration & dosage ; },
abstract = {PURPOSE: To investigate the protective effect of intravesical glucosamine in treating overactive bladder (OAB).

METHODS: Ninety-two female Sprague-Dawley (SD) rats were divided into 4 groups i.e. protamine sulfate (PS), N-acetylcysteine (NAC), and glucosamine-treated PS (GPS), and normal saline control (NC) were used. We induced hyperactivity in rats via intravesical infusion of PS and potassium chloride (KCl), whereas the NC group underwent a sustained intravesical saline infusion for 1 h. N-acetylcysteine (NAC), a potential antioxidant as well as anti-inflammatory agent was employed as positive control. Cystometrography (CMG) was then conducted to determine urodynamic parameters, i.e., leak point pressure (LPP, n = 48) and inter-contractile interval, the duration between two voids (ICI, n = 32).

RESULTS: LPP was significantly elevated in the GPS group (mean ± SD: 110.9 ± 6.2 mmHg) compared to the NC (81.0 ± 32.5 mmHg), PS (40.3 ± 10.9 mmHg), and NAC group (70.3 ± 19.4 mmHg). The cystometrogram data also reveals a prolonged ICI in the GPS group (241.3 ± 40.2 s) compared to the NC group (216.0 ± 41.7 s), PS group (128.8 ± 23.6 s), and NAC group (193.8 ± 28.3 s).

CONCLUSION: This preliminary study implies the ameliorative impact of GPS treatment on OAB in terms of improved urodynamic parameters, including LPP and ICI.},
}

Animals
*Urinary Bladder, Overactive/drug therapy
Female
*Rats, Sprague-Dawley
Rats
Administration, Intravesical
*Protamines
*Disease Models, Animal
*Potassium Chloride
*Glucosamine/pharmacology/therapeutic use/administration & dosage

@article {pmid38986690,
year = {2024},
author = {Li, Z and Li, H and Wang, D and Peng, X and Syed, BM and Liu, Q},
title = {S-glutathionylation in hepatocytes is involved in arsenic-induced liver fibrosis through activation of the NLRP3 inflammasome, an effect alleviated by NAC.},
journal = {The Science of the total environment},
volume = {},
number = {},
pages = {174534},
doi = {10.1016/j.scitotenv.2024.174534},
pmid = {38986690},
issn = {1879-1026},
abstract = {Arsenic, a toxicant widely distributed in the environment, is considered as a risk factor for liver fibrosis. At present, the underlying mechanism still needs to be explored. In the present study, we found that, for mice, chronic exposure to arsenic induced liver fibrosis, activated the NLRP3 inflammasome, and increased the levels of reactive oxygen species (ROS). After hepatocytes were co-cultured with hepatic stellate cells (HSCs), we observed the arsenic-activated NLRP3 inflammasome in hepatocytes, and the co-cultured HSCs were activated. Further, we found that, in livers of mice, arsenic disturbed GSH metabolism and promoted protein S-glutathionylation. A 3D molecular docking simulation suggested that NLRP3 binds with GSH, which was confirmed by immunoprecipitation experiments. N-acetylcysteine (NAC) increased the levels of GSH in hepatocytes, which suppressed the S-glutathionylation of NLRP3 and blocked arsenic-induced activation of the NLRP3 inflammasome. Mechanistically, an imbalance of the redox state induced by arsenic promotes the S-glutathionylation of NLRP3, which regulates activation of the NLRP3 inflammasome, leading into the activation of HSCs. Moreover, NAC increases the levels of GSH to block arsenic-induced S-glutathionylation of NLRP3, thereby blocking arsenic-induced liver fibrosis. Thus, via activating HSCs, the S-glutathionylation of NLRP3 in hepatocytes is involved in arsenic-induced liver fibrosis, and, for hepatocytes, NAC alleviates these effects by increasing the levels of GSH. These results reveal a new mechanism and provide a possible therapeutic target for the liver fibrosis induced by environmental factors.},
}

@article {pmid38985827,
year = {2024},
author = {Krause, BJ and Paz, AA and Garrud, TAC and Peñaloza, E and Vega-Tapia, F and Ford, SG and Niu, Y and Giussani, DA},
title = {Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP286266},
pmid = {38985827},
issn = {1469-7793},
support = {PG/10/99/28656/BHF_/British Heart Foundation/United Kingdom ; 1220421//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; },
abstract = {Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.},
}

@article {pmid38953310,
year = {2024},
author = {Choi, EJ and Oh, HT and Lee, SH and Zhang, CS and Li, M and Kim, SY and Park, S and Chang, TS and Lee, BH and Lin, SC and Jeon, SM},
title = {Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/15548627.2024.2374692},
pmid = {38953310},
issn = {1554-8635},
abstract = {Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca[2+]. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H[+]-translocating ATPase.},
}

@article {pmid38814824,
year = {2024},
author = {Zheng, F and Ye, C and Lei, JZ and Ge, R and Li, N and Bo, JH and Chen, AD and Zhang, F and Zhou, H and Wang, JJ and Chen, Q and Li, YH and Zhu, GQ and Han, Y},
title = {Intervention of Asprosin Attenuates Oxidative Stress and Neointima Formation in Vascular Injury.},
journal = {Antioxidants & redox signaling},
volume = {},
number = {},
pages = {},
doi = {10.1089/ars.2023.0383},
pmid = {38814824},
issn = {1557-7716},
abstract = {Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury.},
}

@article {pmid38973318,
year = {2024},
author = {Babu Balagopal, P and Kohli, R and Uppal, V and Averill, L and Shah, C and McGoogan, K and Di Guglielmo, M and Goran, M and Hossain, MJ},
title = {Effect of N-acetyl cysteine in children with metabolic dysfunction-associated steatotic liver disease-A pilot study.},
journal = {Journal of pediatric gastroenterology and nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1002/jpn3.12312},
pmid = {38973318},
issn = {1536-4801},
support = {1-14-CE-04//American Diabetes Association/ ; //Nemours Biomedical Research/ ; },
abstract = {BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction-associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N-acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and (LS) in children with obesity and biopsy-confirmed MASLD.

METHODS: Thirteen children (n = 13; age: 13.6 ± 2.8 years; NAS score >2) underwent a double-blind, placebo-controlled trial of NAC (either 600 or 1200 mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high-sensitivity c-reactive protein (hs-CRP), and interleukin-6 (IL-6) were also measured. HOMA-IR was calculated.

RESULTS: Sixteen-week NAC treatment improved (baseline adjusted between-group p < .05 for all) markers of inflammation (IL-6 and hs-CRP), oxidative stress (GSH), and insulin resistance (HOMA-IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes.

CONCLUSIONS: Sixteen-week NAC treatment was well tolerated in children with obesity and MASLD and led to improvements in oxidative stress, inflammation and IR and liver outcomes. The results from this pilot study support further investigation of NAC as a therapeutic agent in children with MASLD.},
}

@article {pmid38972409,
year = {2024},
author = {Huang, Y and Sun, Y and Huang, Q and Wu, S and Huang, Z and Hong, Y},
title = {Abamectin-induced behavioral alterations link to energy metabolism disorder and ferroptosis via oxidative stress in Chinese mitten crab, Eriocheir sinensis.},
journal = {The Science of the total environment},
volume = {},
number = {},
pages = {174558},
doi = {10.1016/j.scitotenv.2024.174558},
pmid = {38972409},
issn = {1879-1026},
abstract = {The increasing application of abamectin (ABM) in agriculture has raised concerns regarding its environmental safety and potential adverse effects on aquatic environment safety. In the present study, the toxic effects of ABM exposure on the adult Chinese mitten crab, Eriocheir sinensis were investigated, with a focus on locomotion impairment, behavioral changes, oxidative stress, energy metabolism disruption, and ferroptosis. Crabs were exposed to sublethal concentrations of ABM at 2, 20 and 200 μg/L. After 21 d chronic exposure to 200 μg/L, residual ABM in hepatopancreas and muscles were detected as 12.24 ± 6.67 and 8.75 ± 5.42 μg/Kg, respectively. By using acute exposure experiments (96 h), we observed significant locomotion and behavioral alterations, alongside biochemical evidences of oxidative stress and energy metabolism impairment. The presence of ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, was notably identified in the hepatopancreas. Functional tests with N-acetylcysteine (NAC) supplementation showed restored behavioral responses and decrease of ferroptosis levels. It suggests that mitigating oxidative stress could counteract ABM-induced toxicity. Our findings highlight the critical roles of oxidative stress and ferroptosis in mediating the toxic effects of ABM on E. sinensis, underscoring the need for strategies to mitigate environmental exposure to pesticides.},
}

@article {pmid38969277,
year = {2024},
author = {Shi, W and Gao, Y and Yang, H and Li, H and Liu, T and Zhao, J and Wei, Z and Li Lin, and Huang, Y and Guo, Y and Xu, A and Bai, Z and Xiao, X},
title = {Bavachinin, a main compound of Psoraleae Fructus, facilitates GSDMD-mediated pyroptosis and causes hepatotoxicity in mice.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111133},
doi = {10.1016/j.cbi.2024.111133},
pmid = {38969277},
issn = {1872-7786},
abstract = {Psoraleae Fructus (PF, Psoralea corylifolia L.), a traditional medicine with a long history of application, is widely used clinically for the treatment of various diseases. However, the reports of PF-related adverse reactions, such as hepatotoxicity, phototoxic dermatitis, and allergy, are increasing year by year, with liver injury being the mostly common. Our previous studies have demonstrated that PF and its preparations can cause liver injury in lipopolysaccharide (LPS)-mediated susceptibility mouse model, but the mechanism of PF-related liver injury is unclear. In this study, we showed that PF and bavachinin, a major component of PF, can directly induce the expression of caspase-1 and interleukin-1β (IL-1β), indicating that PF and bavachinin can directly triggered the activation of inflammasome. Furthermore, pretreatment with NLR family pyrin domain-containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome inhibitors, containing MCC950, ODN TTAGGG (ODN) and carnosol, all significantly reversed bavachinin-induced inflammasome activation. Mechanistically, bavachinin dose-dependently promote Gasdermin D (GSDMD) post-shear activation and then induce mitochondrial reactive oxygen species (mtROS) production and this effect is markedly inhibited by pretreatment with N-Acetylcysteine amide (NAC). In addition, combination treatment of LPS and bavachinin significantly induced liver injury in mice, but not LPS or bavachinin alone, and transcriptome analysis further validated these results. Thus, PF and bavachinin can induce the activation of inflammasome by promoting GSDMD cleavage and cause hepatotoxicity in mice. Therefore, PF, bavachinin, and PF-related preparations should be avoided in patients with inflammasome activation-associated diseases.},
}

@article {pmid38958792,
year = {2024},
author = {Yan, Y and Huang, W and Lu, X and Chen, X and Shan, Y and Luo, X and Li, Y and Yang, X and Li, C},
title = {Zinc oxide nanoparticles induces cell death and consequently leading to incomplete neural tube closure through oxidative stress during embryogenesis.},
journal = {Cell biology and toxicology},
volume = {40},
number = {1},
pages = {51},
pmid = {38958792},
issn = {1573-6822},
support = {2021A1515110232//Guangdong Basic and Applied Basic Research Foundation/ ; 202201011394//the Science and Technology Program of Guangzhou/ ; 2022KTSCX025//Guangdong Scientific Research Platform and Projects for the Higher-educational Institution/ ; 20211112//Research Project of Traditional Chinese Medicine Bureau of Guangdong/ ; No.29//2021 Guangdong Province Undergraduate College Teaching Quality and Teaching Reform Engineering Construction Project/ ; },
mesh = {*Zinc Oxide/toxicity ; Animals ; *Oxidative Stress/drug effects ; Chick Embryo ; *Embryonic Development/drug effects ; Mice ; *Neural Tube/drug effects/embryology/metabolism ; Humans ; *Neural Tube Defects/chemically induced/metabolism/embryology/pathology ; *Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Cell Death/drug effects ; Female ; Mitochondria/drug effects/metabolism ; Metal Nanoparticles/toxicity ; Autophagy/drug effects ; Cell Line, Tumor ; Nanoparticles/toxicity ; },
abstract = {The implementation of Zinc oxide nanoparticles (ZnO NPs) raises concerns regarding their potential toxic effects on human health. Although more and more researches have confirmed the toxic effects of ZnO NPs, limited attention has been given to their impact on the early embryonic nervous system. This study aimed to explore the impact of exposure to ZnO NPs on early neurogenesis and explore its underlying mechanisms. We conducted experiments here to confirm the hypothesis that exposure to ZnO NPs causes neural tube defects in early embryonic development. We first used mouse and chicken embryos to confirm that ZnO NPs and the Zn[2+] they release are able to penetrate the placental barrier, influence fetal growth and result in incomplete neural tube closure. Using SH-SY5Y cells, we determined that ZnO NPs-induced incomplete neural tube closure was caused by activation of various cell death modes, including ferroptosis, apoptosis and autophagy. Moreover, dissolved Zn[2+] played a role in triggering widespread cell death. ZnO NPs were accumulated within mitochondria after entering cells, damaging mitochondrial function and resulting in the over production of reactive oxygen species, ultimately inducing cellular oxidative stress. The N-acetylcysteine (NAC) exhibits significant efficacy in mitigating cellular oxidative stress, thereby alleviating the cytotoxicity and neurotoxicity brought about by ZnO NPs. These findings indicated that the exposure of ZnO NPs in early embryonic development can induce cell death through oxidative stress, resulting in a reduced number of cells involved in early neural tube closure and ultimately resulting in incomplete neural tube closure during embryo development. The findings of this study could raise public awareness regarding the potential risks associated with the exposure and use of ZnO NPs in early pregnancy.},
}

*Zinc Oxide/toxicity
Animals
*Oxidative Stress/drug effects
Chick Embryo
*Embryonic Development/drug effects
Mice
*Neural Tube/drug effects/embryology/metabolism
Humans
*Neural Tube Defects/chemically induced/metabolism/embryology/pathology
*Reactive Oxygen Species/metabolism
Apoptosis/drug effects
Cell Death/drug effects
Female
Mitochondria/drug effects/metabolism
Metal Nanoparticles/toxicity
Autophagy/drug effects
Cell Line, Tumor
Nanoparticles/toxicity

@article {pmid38958241,
year = {2024},
author = {Zuo, XS and Wang, QY and Wang, SS and Li, G and Zhan, LY},
title = {The role of N-acetylcysteine on adhesion and biofilm formation of Candida parapsilosis isolated from catheter-related candidemia.},
journal = {Journal of medical microbiology},
volume = {73},
number = {7},
pages = {},
doi = {10.1099/jmm.0.001848},
pmid = {38958241},
issn = {1473-5644},
mesh = {*Biofilms/drug effects/growth & development ; *Acetylcysteine/pharmacology ; Humans ; *Candida parapsilosis/drug effects/genetics/physiology ; *Catheter-Related Infections/microbiology ; *Candidemia/microbiology ; Fungal Proteins/genetics/metabolism ; Antifungal Agents/pharmacology ; },
abstract = {Objectives. Anti-fungal agents are increasingly becoming less effective due to the development of resistance. In addition, it is difficult to treat Candida organisms that form biofilms due to a lack of ability of drugs to penetrate the biofilms. We are attempting to assess the effect of a new therapeutic agent, N-acetylcysteine (NAC), on adhesion and biofilm formation in Candida parapsilosis clinical strains. Meanwhile, to detect the transcription level changes of adhesion and biofilm formation-associated genes (CpALS6, CpALS7, CpEFG1 and CpBCR1) when administrated with NAC in C. parapsilosis strains, furthermore, to explore the mechanism of drug interference on biofilms.Hypothesis/Gap statement. N-acetylcysteine (NAC) exhibits certain inhibitory effects on adhesion and biofilm formation in C. parapsilosis clinical strains from CRBSIs through: (1) down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections (CRBSIs), (2) regulating the metabolism and biofilm -forming factors of cell structure.Methods. To determine whether non-antifungal agents can exhibit inhibitory effects on adhesion, amounts of total biofilm formation and metabolic activities of C. parapsilosis isolates from candidemia patients, NAC was added to the yeast suspensions at different concentrations, respectively. Reverse transcription was used to detect the transcriptional levels of adhesion-related genes (CpALS6 and CpALS7) and biofilm formation-related factors (CpEFG1 and CpBCR1) in the BCR1 knockout strain, CP7 and CP5 clinical strains in the presence of NAC. To further explore the mechanism of NAC on the biofilms of C. parapsilosis, RNA sequencing was used to calculate gene expression, comparing the differences among samples. Gene Ontology (GO) enrichment analysis helps to illustrate the difference between two particular samples on functional levels.Results. A high concentration of NAC reduces the total amount of biofilm formation in C. parapsilosis. Following co-incubation with NAC, the expression of CpEFG1 in both CP7 and CP5 clinical strains decreased, while there were no significant changes in the transcriptional levels of CpBCR1 compared with the untreated strain. GO enrichment analysis showed that the metabolism and biofilm-forming factors of cell structure were all regulated after NAC intervention.Conclusions. The non-antifungal agent NAC exhibits certain inhibitory effects on clinical isolate biofilm formation by down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections.},
}

*Biofilms/drug effects/growth & development
*Acetylcysteine/pharmacology
Humans
*Candida parapsilosis/drug effects/genetics/physiology
*Catheter-Related Infections/microbiology
*Candidemia/microbiology
Fungal Proteins/genetics/metabolism
Antifungal Agents/pharmacology

@article {pmid38956487,
year = {2024},
author = {Saad, M and Flament, J},
title = {Paracetamol overdose causing acute kidney injury without hepatotoxicity: a case report.},
journal = {International journal of emergency medicine},
volume = {17},
number = {1},
pages = {81},
pmid = {38956487},
issn = {1865-1372},
abstract = {BACKGROUND: Paracetamol is a widely used analgesic and antipyretic. Paracetamol-induced hepatotoxicity is well known, but nephrotoxicity without hepatotoxicity is rarely seen.

CASE PRESENTATION: We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48 h after she had taken 10 g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20 mg/dL on admission, with a peak at 3.67 mg/dL 3 days later. The liver blood tests and blood paracetamol level were negative. She did not receive N-acetyl cysteine and was treated with intravenous fluid (crystalloid). The ultrasonography of the kidneys was normal. Her renal function returned almost to baseline 7 days after admission. It was concluded that the diagnosis was an acute kidney injury caused by acute tubular necrosis due to paracetamol overdose.

CONCLUSION: This case shows that nephrotoxicity can occur without hepatotoxicity in paracetamol overdose.},
}

@article {pmid38910554,
year = {2024},
author = {Shao, Y and Zhang, Y and Zou, S and Wang, J and Li, X and Qin, M and Sun, L and Yin, W and Chang, X and Wang, S and Han, X and Wu, T and Chen, F},
title = {(-)-Epigallocatechin 3-gallate protects pancreatic β-cell against excessive autophagy-induced injury through promoting FTO degradation.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/15548627.2024.2370751},
pmid = {38910554},
issn = {1554-8635},
abstract = {Excessive macroautophagy/autophagy leads to pancreatic β-cell failure that contributes to the development of diabetes. Our previous study proved that the occurrence of deleterious hyperactive autophagy attributes to glucolipotoxicity-induced NR3C1 activation. Here, we explored the potential protective effects of (-)-epigallocatechin 3-gallate (EGCG) on β-cell-specific NR3C1 overexpression mice in vivo and NR3C1-enhanced β cells in vitro. We showed that EGCG protects pancreatic β cells against NR3C1 enhancement-induced failure through inhibiting excessive autophagy. RNA demethylase FTO (FTO alpha-ketoglutarate dependent dioxygenase) caused diminished m[6]A modifications on mRNAs of three pro-oxidant genes (Tlr4, Rela, Src) and, hence, oxidative stress occurs; by contrast, EGCG promotes FTO degradation by the ubiquitin-proteasome system in NR3C1-enhanced β cells, which alleviates oxidative stress, and thereby prevents excessive autophagy. Moreover, FTO overexpression abolishes the beneficial effects of EGCG on β cells against NR3C1 enhancement-induced damage. Collectively, our results demonstrate that EGCG protects pancreatic β cells against NR3C1 enhancement-induced excessive autophagy through suppressing FTO-stimulated oxidative stress, which provides novel insights into the mechanisms for the anti-diabetic effect of EGCG.Abbreviation 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ad: adenovirus; ALD: aldosterone; AUC: area under curve; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; Ctrl: control; CHX: cycloheximide; DEX: dexamethasone; DHE: dihydroethidium; EGCG: (-)-epigallocatechin 3-gallate; FTO: FTO alpha-ketoglutarate dependent dioxygenase; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; HG: high glucose; i.p.: intraperitoneal; IOD: immunofluorescence optical density; KSIS: potassium-stimulated insulin secretion; m[6]A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NO: nitric oxide; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NAC: N-acetylcysteine; NC: negative control; PBS: phosphate-buffered saline; PI: propidium iodide; OCR: oxygen consumption rate; Palm.: palmitate; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RNA-seq: RNA sequencing; O2[.-]: superoxide anion; SRC: Rous sarcoma oncogene; ROS: reactive oxygen species; T2D: type 2 diabetes; TEM: transmission electron microscopy; TLR4: toll-like receptor 4; TUNEL: terminal dUTP nick-end labeling; UTR: untranslated region; WT: wild-type.},
}

@article {pmid38947789,
year = {2024},
author = {Gad, FA and Abdelghaffar Emam, M and Eldeeb, AA and Abdelhameed, AA and Soliman, MM and Alotaibi, KS and Albattal, SB and Abughrien, B},
title = {Mitigative Effects of l-Arginine and N-Acetyl Cysteine against Cisplatin-Induced Testicular Dysfunction and Toxicity through the Regulation of Antioxidant, Anti-inflammatory, and Antiapoptotic Markers: Role of miR-155 and miR-34c Expression.},
journal = {ACS omega},
volume = {9},
number = {25},
pages = {27680-27691},
pmid = {38947789},
issn = {2470-1343},
abstract = {Testicular dysfunction is a common adverse effect of cisplatin (CIS) administration as a chemotherapeutic drug. The current study has outlined the role of micro-RNAs (miR-155 and 34c) in CIS-induced testicular dysfunction and evaluated the protective effect of N-acetyl cysteine (NAC) and/or l-arginine (LA). Seven groups of Albino rats were used for this study. The control (C) group received physiological saline; the CIS group was injected CIS (7 mg/kg IP, once) on day 21 of the experiment; the NAC group was administered NAC (150 mg/kg intragastric, for 28 days); and the LA group was injected LA (50 mg/kg IP, for 28 days). NAC+CIS, LA+CIS, and NAC+LA+CIS groups received the above regime. CIS significantly reduced serum testosterone, LH, and FSH concentrations with decline of testicular enzyme activities. CIS caused significant elevation in testicular oxidative-stress biomarkers, inflammation-associated cytokines, and apoptosis markers, along with overexpression of miR-155 and low miR-34c expression. Additionally, marked testicular degenerative changes were observed in the examined histological section; a significant decrease in the expression of PCNA with significant increase in expressions of F4/80 and BAX was confirmed. The administration of NAC or LA upregulated testicular functions and improved histopathological and immunohistochemical changes as well as miRNA expression compared with the CIS-administered group. Rats receiving both NAC and LA showed a more significant ameliorative effect compared with groups receiving NAC or LA alone. In conclusion, NAC or LA showed an ameliorative effect against CIS-induced testicular toxicity and dysfunction through the regulation of antioxidant, anti-inflammatory, and antiapoptotic markers and via modulating miR-155 and miR-34c expression.},
}

@article {pmid38946815,
year = {2024},
author = {Aldaghi, N and Kamalabadi-Farahani, M and Alizadeh, M and Alizadeh, A and Salehi, M},
title = {Enhancing pressure ulcer healing and tissue regeneration by using N-acetyl-cysteine loaded carboxymethyl cellulose/gelatin/sodium alginate hydrogel.},
journal = {Biomedical engineering letters},
volume = {14},
number = {4},
pages = {833-845},
pmid = {38946815},
issn = {2093-985X},
abstract = {Prolonged pressure on the skin can result in pressure ulcers, which may lead to serious complications, such as infection and tissue damage. In this study, we evaluated the effect of a carboxymethyl cellulose/gelatin/sodium alginate (CMC/Gel/Alg) hydrogel containing N-acetyl-cysteine (NAC) on the healing of pressure ulcers. Pressure ulcers were induced by applying a magnet to the dorsum of rat skin. The wounds were then treated with sterile gauze, ChitoHeal Gel[®], and CMC/Gel/Alg hydrogel dressings with or without NAC for the other groups. We evaluated the morphology, weight loss, swelling, rheology, blood compatibility, cytocompatibility, antioxidant capacity, and wound scratch of the prepared hydrogel. MTT assay revealed that the optimum concentration of NAC was 5 mg/ml, which induced higher cell proliferation and viability. Results of the histopathological evaluation showed increased wound closure, and complete re-epithelialization in the hydrogel-containing NAC group compared to the other groups. The CMC/Gel/Alg/5 mg/ml NAC hydrogel dressing showed 84% wound closure at 14 days after treatment. Immunohistochemical results showed a decrease in the level of TNF-α on day 14 compared day 7. Results of the qPCR assay revealed that NAC hydrogel increased the expression of Collagen type I and TGF-β1 and decreased MMP2 and MMP9 mRNA on the 14th day. The results suggest that the CMC/Gel/Alg/5 mg/ml NAC hydrogel with antioxidant properties is an appropriate dressing for wound healing.},
}

@article {pmid38946388,
year = {2024},
author = {Sun, J and Zhang, X and Wang, L and Di Stefano, AFD and Zanin, V and Magrone, P and Yuan, Y},
title = {Author Correction: Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.},
journal = {European review for medical and pharmacological sciences},
volume = {28},
number = {12},
pages = {3806},
doi = {10.26355/eurrev_202406_36449},
pmid = {38946388},
issn = {2284-0729},
abstract = {Eur Rev Med Pharmacol Sci 2023; 27 (24): 12103-12111-DOI: 10.26355/eurrev_202312_34808-PMID: 38164872, published online on December 22, 2023. After publication, the authors found that Table III's legend was the same as that of Table II. Therefore, Table III's legend has been corrected as follows: Table III. Plasma PK parameters following repeat doses of IV NAC 600 mg (n = 24). There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34808.},
}

@article {pmid38873925,
year = {2024},
author = {Yin, Z and Zhang, J and Zhao, M and Liu, J and Xu, Y and Peng, S and Pan, W and Wei, C and Zheng, Z and Liu, S and Qin, JJ and Wan, J and Wang, M},
title = {EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/15548627.2024.2367191},
pmid = {38873925},
issn = {1554-8635},
abstract = {Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3[-/-]) mice and edil3[-/-] bone marrow chimeric mice exhibited a considerable exacerbation in β-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/β3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: β-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-β-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.},
}

@article {pmid38718420,
year = {2024},
author = {Gökalp, G and Nalbant, T and Bıcılıoğlu, Y},
title = {The Insidious Enemy of the Liver: The Situation in Childhood Acetaminophen Poisoning and Early N-AC Treatment.},
journal = {Pediatric emergency care},
volume = {40},
number = {7},
pages = {e89-e93},
doi = {10.1097/PEC.0000000000003176},
pmid = {38718420},
issn = {1535-1815},
mesh = {Humans ; *Acetaminophen/poisoning ; Retrospective Studies ; Female ; Male ; Cross-Sectional Studies ; Child ; Child, Preschool ; *Chemical and Drug Induced Liver Injury/etiology/epidemiology ; *Acetylcysteine/therapeutic use ; Infant ; Analgesics, Non-Narcotic/poisoning ; Drug Overdose ; Antidotes/therapeutic use ; Liver Transplantation ; Adolescent ; Liver ; },
abstract = {METHODS: This study was designed as a cross-sectional, observational, retrospective study. The variables of the study were paracetamol overdose, demographic information, poisoning mechanisms, clinical, laboratory findings, and clinical progression of the cases. The cases compared in whom treatment was initiated within the first 8 hours after poisoning and those in whom it was not. χ 2 , t test, and logistic regression analyses were conducted at appropriate facilities.

RESULTS: Three hundred forty-eight cases were included in the study. N-AC treatment was initiated within the first 8 hours after poisoning in 322 cases (92.5%), and 26 cases received N-AC treatment after 8 hours after poisoning. Liver toxicity developed in 6 cases (1.7%), and indications for liver transplantation were met in 36 cases (10.3%). Among the 26 cases for which treatment was not initiated within the first 8 hours, 18 cases (69.2%) had indications for liver transplantation (P < 0.01). It was found that N-AC within the first 8 hours reduced the risk by 43 times (P = 0.02) and being older than 6 years, being admitted to the intensive care unit, and having alanine aminotransferase values above 1000 U/L increased the risk significantly (P = 0.009, P = 0.005, P < 0.001). When a receiver operating characteristic curve was plotted for the 4th-hour blood acetaminophen level to predict liver transplantation, a value of 684.5 μg/mL emerged with 89% sensitivity and 93% specificity (area under the curve, 0.951).

CONCLUSIONS: As a result, this study demonstrates the protective effect of early-initiated N-AC therapy on liver toxicity in pediatric acetaminophen poisoning cases. It also highlights a significant impact of gastrointestinal decontamination methods.},
}

Humans
*Acetaminophen/poisoning
Retrospective Studies
Female
Male
Cross-Sectional Studies
Child
Child, Preschool
*Chemical and Drug Induced Liver Injury/etiology/epidemiology
*Acetylcysteine/therapeutic use
Infant
Analgesics, Non-Narcotic/poisoning
Drug Overdose
Antidotes/therapeutic use
Liver Transplantation
Adolescent
Liver

@article {pmid38944154,
year = {2024},
author = {Higham, CS and Shimano, KA and Kharbanda, S and Chu, J and Cisneros, GS and Winestone, LE and Dara, J and Huang, JN and Hermiston, ML and Long-Boyle, JR and Dvorak, CC},
title = {Cyclophosphamide and thiotepa increases risk of transplant-associated thrombotic microangiopathy.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2024.06.020},
pmid = {38944154},
issn = {2666-6367},
abstract = {BACKGROUND: Transplant associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic cell transplant (HCT) associated with endothelial injury resulting in severe end organ damage, acute and long-term morbidity, and mortality. Myeloablative conditioning is a known risk factor, though specific causative agents have not been identified. We hypothesized that the combination of cyclophosphamide and thiotepa (CY+TT) is particularly toxic to the endothelium, placing patients at elevated risk for TA-TMA.

METHODS: We conducted a retrospective review of pediatric and young adult patients who received conditioned autologous and allogeneic HCT between 2012 and August 2023 at UCSF Benioff Children's Hospital, San Francisco. We excluded patients undergoing gene therapy or triple tandem transplants for brain tumors. Neuroblastoma tandem transplants were classified a single transplant occurrence. High dose N-acetylcysteine (NAC) prophylaxis was incorporated into the institutional standard of care from December 2016-May 2019 and May 2022-August 2023. Defibrotide was given prophylactically to patients deemed high-risk for sinusoidal obstruction syndrome (SOS) per institutional guidelines or on clinical trial NCT#02851407 for SOS prophylaxis or NCT#03384693 for TA-TMA prophylaxis. Kaplan-Meier analysis was used to estimate the 1-year cumulative incidence of TA-TMA. Univariate analysis was performed for each of the potential risk factors of interest using log-rank tests and bivariate analysis with Cox regression models using backward selection and hazard ratios were built using all covariates with a univariate p-value <0.2 for allogeneic HCT. SPSS (v29) was used to estimate all summary statistics, cumulative incidences, and uni- and bi-variate analyses.

RESULTS: A total of 558 transplants were performed with 43 patients developing TA-TMA, for a 1-year cumulative incidence of 8.6% (95% CI, 5.9-11.3%) and 7.2% (95% CI, 2.9-11.5%) in allogeneic and autologous HCTs, respectively (p=0.62). In allogeneic recipients (n=417), the 1-year cumulative incidence of TA-TMA with CY+TT as part of conditioning was 35.7% (95% CI, 15.7-55.7%) compared to 11.7% (95% CI, 7.2-16.2%) with either CY or TT alone, and 1.2% (95% CI, 0-2.8%) if neither agent was included in the conditioning regimen (p<0.001). Use of either CY or TT (HR=10.14; p=0.002) or CY+TT (HR=35.93; p<0.001), viral infections (HR=4.3; p=0.017) and fungal infections (HR=2.98; p=0.027) were significant factors resulting in increased risk for developing TA-TMA. In subjects undergoing autologous HCT (n=141), the 1-year cumulative incidence of TA-TMA with CY+TT was 19.6% (95% CI, 8.8-30.6%) while TA-TMA did not occur in patients receiving either CY or TT alone or when neither were included (p<0.001). TA-TMA occurred only in patients with neuroblastoma receiving CY+TT as part of their conditioning. For autologous patients who received CY+TT, those who were CMV seronegative at the time of HCT had an incidence of TA-TMA of 6.7% (95% CI, 0.1-15.7%) compared to 38.1% (95% CI, 35-41.2%) for those CMV seropositive (p=0.007).

CONCLUSIONS: These data show that CY or TT alone or in combination as part of pre-transplant conditioning prior to HCT increase the incidence of TA-TMA. Alternative conditioning excluding the combination of CY+TT should be considered whenever possible to limit the development of TA-TMA.},
}

@article {pmid38943148,
year = {2024},
author = {Üstüner, E and Yıldırım, E and Macun, HC and Ekici, H and Şahin, Y and Güncüm, E and Anteplioğlu, T and Elifoğlu, TB and Bozkaya, E},
title = {Ultrasonographic and histopathological investigation of the effect of N-acetylcysteine on doxorubicin-induced ovarian and uterine toxicity in rats.},
journal = {Journal of ovarian research},
volume = {17},
number = {1},
pages = {135},
pmid = {38943148},
issn = {1757-2215},
mesh = {Animals ; Female ; *Doxorubicin/toxicity ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *Ovary/drug effects/pathology/diagnostic imaging ; *Ultrasonography ; *Uterus/drug effects/pathology/diagnostic imaging ; Antibiotics, Antineoplastic/toxicity/adverse effects ; },
abstract = {BACKGROUND: This study aimed to investigate the mitigating effect of N-acetylcysteine (NAC) on doxorubicin (DOX)-induced ovarian and uterine toxicity in rats using laboratory tests, ultrasonographic (US) imaging, and histopathology analysis.

METHODS: Forty-eight rats were divided into six groups (n = 8) as follows: Group A (control) (0.5 mL saline administered intraperitoneally [IP]), Group B (a single 10 mg/kg dose of DOX administered IP on day 1), Group C (a single 10 mg/kg dose of DOX administered IP 24 h before sacrifice), Group D (100 mg/kg of NAC administered IP for 21 days), Group E (a single 10 mg/kg dose of DOX administered IP on day 1 and 100 mg/kg of NAC administered IP for 21 days), and Group F (100 mg/kg of NAC administered IP for 21 days and a single 10 mg/kg dose of DOX administered IP 24 h before sacrifice). The ovaries were examined using B-mode US on days 1, 14, and 21, and the histopathological examinations of the ovaries and the uterus were undertaken after sacrifice on day 22.

RESULTS: Histomorphological analyses showed that ovarian weight decreased after DOX administration in Group B but not in Group E. US revealed a transient increase in ovarian size in Group B and E, reverting to baseline levels over time, as well as a progressive increase in peritoneal fluid in Groups B and E. Group B exhibited a significant decrease in the thickness of the endometrium and myometrium and uterine cornual length, which was not observed in Group E. Histopathological examination showed that DOX caused a decline in follicular count, especially in primordial, secondary, and Graafian follicles, and resulted in follicular atresia, predominantly in Group B. Destructive degeneration/necrosis and vascular changes were most prominently seen in the corpus luteum of Groups C and B. In NAC-treated rats (Groups E and F), although germ cell damage was present, atretic follicles and vascular changes, such as hyperemia and congestion, were reduced. The anti-müllerian hormone (AMH) level was the highest in Group F.

CONCLUSIONS: NAC, an antioxidant, attenuated DOX-induced gonadotoxicity in rats.},
}

Animals
Female
*Doxorubicin/toxicity
*Acetylcysteine/pharmacology/therapeutic use
Rats
*Ovary/drug effects/pathology/diagnostic imaging
*Ultrasonography
*Uterus/drug effects/pathology/diagnostic imaging
Antibiotics, Antineoplastic/toxicity/adverse effects

@article {pmid38936520,
year = {2024},
author = {Tang, M and Xia, W and Song, F and Liu, C and Wang, X and Zhou, H and Mai, K and He, G},
title = {Loss of Gcn2 exacerbates gossypol induced oxidative stress, apoptosis and inflammation in zebrafish.},
journal = {Fish & shellfish immunology},
volume = {},
number = {},
pages = {109727},
doi = {10.1016/j.fsi.2024.109727},
pmid = {38936520},
issn = {1095-9947},
abstract = {Gossypol, a naturally occurring compound found in cottonseed meal, shows promising therapeutic potential for human diseases. However, within the aquaculture industry, it is considered an antinutritional factor. The incorporation of cottonseed meal into fish feed introduces gossypol, which induces intracellular stresses and hinders overall health of farmed fish. The aim of this study is to determine the role of General control nonderepressible 2 (gcn2), a sensor for intracellular stresses in gossypol-induced stress responses in fish. In the present study, we established two gcn2 knockout zebrafish lines. A feeding trial was conducted to assess the growth-inhibitory effect of gossypol in both wild type and gcn2 knockout zebrafish. The results showed that in the absence of gcn2, zebrafish exhibited increased oxidative stress and apoptosis when exposed to gossypol, resulting in higher mortality rates. In feeding trial, dietary gossypol intensified liver inflammation in gcn2[-/-] zebrafish, diminishing their growth and feed conversion. Remarkably, administering the antioxidant N-acetylcysteine (NAC) was effective in reversing the gossypol induced oxidative stress and apoptosis, thereby increasing the gossypol tolerance of gcn2[-/-] zebrafish. Exposure to gossypol induces more severe mitochondrial stress in gcn2[-/-] zebrafish, thereby inducing metabolic disorders. These results reveal that gcn2 plays a protective role in reducing gossypol-induced oxidative stress and apoptosis, attenuating inflammation responses, and enhancing the survivability of zebrafish in gossypol-challenged conditions. Therefore, maintaining appropriate activation of Gcn2 may be beneficial for fish fed diets containing gossypol.},
}

@article {pmid38929087,
year = {2024},
author = {Dobariya, P and Xie, W and Rao, SP and Xie, J and Seelig, DM and Vince, R and Lee, MK and More, SS},
title = {Deletion of Glyoxalase 1 Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {13},
number = {6},
pages = {},
doi = {10.3390/antiox13060648},
pmid = {38929087},
issn = {2076-3921},
support = {R01-AG062469/NH/NIH HHS/United States ; NA//Center for Drug Design, Research Endowment Funds/ ; },
abstract = {Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose.},
}

@article {pmid38928002,
year = {2024},
author = {Dymanowska-Dyjak, I and Frankowska, K and Abramiuk, M and Polak, G},
title = {Oxidative Imbalance in Endometriosis-Related Infertility-The Therapeutic Role of Antioxidants.},
journal = {International journal of molecular sciences},
volume = {25},
number = {12},
pages = {},
doi = {10.3390/ijms25126298},
pmid = {38928002},
issn = {1422-0067},
support = {DS121//Medical University of Lublin/ ; },
mesh = {*Endometriosis/metabolism/drug therapy/complications ; Humans ; Female ; *Antioxidants/therapeutic use ; *Oxidative Stress/drug effects ; *Infertility, Female/etiology/metabolism/drug therapy ; Acetylcysteine/therapeutic use/pharmacology ; },
abstract = {Endometriosis in half of affected women is closely related to problems with fertility. Endometriosis-associated infertility is caused by a wide range of abnormalities affecting the female reproductive tract, from oocyte quality impairment to disturbances in the eutopic endometrium or mechanical abnormalities resulting from disease progression. Since supportive antioxidant therapies, in addition to surgical treatment or assisted reproductive techniques (ARTs), have overall been proven to be effective tools in endometriosis management, the objective of our review was to analyze the role of antioxidant substances, including vitamins, micronutrients, N-acetylcysteine (NAC), curcumin, melatonin, and resveratrol, in endometriosis-related infertility. Most of these substances have been proven to alleviate the systemic oxidant predominance, which has been expressed through decreased oxidative stress (OS) markers and enhanced antioxidative defense. In addition, we demonstrated that the predominant effect of the aforementioned substances is the inhibition of the development of endometriotic lesions as well as the suppression of pro-inflammatory molecules. Although we can undoubtedly conclude that antioxidants are beneficial in fertility support, further studies explaining the detailed pathways of their action are needed.},
}

*Endometriosis/metabolism/drug therapy/complications
Humans
Female
*Antioxidants/therapeutic use
*Oxidative Stress/drug effects
*Infertility, Female/etiology/metabolism/drug therapy
Acetylcysteine/therapeutic use/pharmacology

@article {pmid38923010,
year = {2024},
author = {Gong, Z and Yang, S and Ling, S and Wang, H and Xu, X and Lin, Z},
title = {Dermatopathological features and successful treatment with topical antioxidant for ichthyosiform lesions in Mitchell syndrome caused by an ACOX1 variant.},
journal = {The Journal of dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1111/1346-8138.17346},
pmid = {38923010},
issn = {1346-8138},
support = {82373459//National Natural Science Foundation of China/ ; 82373500//National Natural Science Foundation of China/ ; },
abstract = {Peroxisomal acyl-CoA oxidase 1 (ACOX1), is a peroxisomal enzyme that catalyzes β-oxidation of very-long-chain fatty acids (VLCFA). The gain-of-function variant p.Asn237Ser in ACOX1 has been shown to cause Mitchell syndrome (MITCH), a neurodegenerative disorder characterized by episodic demyelination, hearing loss, and polyneuropathy, through the overproduction of hydrogen peroxide. Only eight cases of MITCH have been reported. While all these patients experienced cutaneous abnormalities, detailed skin features and potential treatment have not been documented. Herein, we report two MITCH patients who harbored a de novo heterozygous variant p.Asn237Ser in ACOX1 and experienced progressive ichthyosiform erythroderma. Skin histopathology revealed hyperkeratosis and parakeratosis with focal hypogranulosis as well as dyskeratotic keratinocytes. Lipid accumulation in the epidermis was observed using Oil Red O staining. Both patients exhibited a remarkable response to treatment with the topical antioxidant N-acetylcysteine (NAC), with Patient 1 achieving complete recovery after 3 months of consistent treatment. This study provides the first comprehensive description of the clinicopathological characteristics and effective treatment of skin lesions in MITCH patients. The successful treatment with topical NAC suggests excessive reactive oxygen species might play a significant role in the pathogenesis of skin lesions in MITCH.},
}

@article {pmid38918702,
year = {2024},
author = {Kagemichi, N and Umemura, M and Ishikawa, S and Iida, Y and Takayasu, S and Nagasako, A and Nakakaji, R and Akimoto, T and Ohtake, M and Horinouchi, T and Yamamoto, T and Ishikawa, Y},
title = {Cytotoxic effects of the cigarette smoke extract of heated tobacco products on human oral squamous cell carcinoma: the role of reactive oxygen species and CaMKK2.},
journal = {The journal of physiological sciences : JPS},
volume = {74},
number = {1},
pages = {35},
pmid = {38918702},
issn = {1880-6562},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Mouth Neoplasms/metabolism/pathology ; Cell Line, Tumor ; *Smoke/adverse effects ; *Carcinoma, Squamous Cell/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism ; *Tobacco Products/adverse effects ; Apoptosis/drug effects ; Nicotiana/chemistry ; Calcium/metabolism ; Cell Survival/drug effects ; },
abstract = {BACKGROUND: The increasing prevalence of heated tobacco products (HTPs) has heightened concerns regarding their potential health risks. Previous studies have demonstrated the toxicity of cigarette smoke extract (CSE) from traditional tobacco's mainstream smoke, even after the removal of nicotine and tar. Our study aimed to investigate the cytotoxicity of CSE derived from HTPs and traditional tobacco, with a particular focus on the role of reactive oxygen species (ROS) and intracellular Ca[2+].

METHODS: A human oral squamous cell carcinoma (OSCC) cell line, HSC-3 was utilized. To prepare CSE, aerosols from HTPs (IQOS) and traditional tobacco products (1R6F reference cigarette) were collected into cell culture media. A cell viability assay, apoptosis assay, western blotting, and Fluo-4 assay were conducted. Changes in ROS levels were measured using electron spin resonance spectroscopy and the high-sensitivity 2',7'-dichlorofluorescein diacetate assay. We performed a knockdown of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) by shRNA lentivirus in OSCC cells.

RESULTS: CSE from both HTPs and traditional tobacco exhibited cytotoxic effects in OSCC cells. Exposure to CSE from both sources led to an increase in intracellular Ca[2+] concentration and induced p38 phosphorylation. Additionally, these extracts prompted cell apoptosis and heightened ROS levels. N-acetylcysteine (NAC) mitigated the cytotoxic effects and p38 phosphorylation. Furthermore, the knockdown of CaMKK2 in HSC-3 cells reduced cytotoxicity, ROS production, and p38 phosphorylation in response to CSE.

CONCLUSION: Our findings suggest that the CSE from both HTPs and traditional tobacco induce cytotoxicity. This toxicity is mediated by ROS, which are regulated through Ca[2+] signaling and CaMKK2 pathways.},
}

Humans
*Reactive Oxygen Species/metabolism
*Mouth Neoplasms/metabolism/pathology
Cell Line, Tumor
*Smoke/adverse effects
*Carcinoma, Squamous Cell/metabolism
*Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism
*Tobacco Products/adverse effects
Apoptosis/drug effects
Nicotiana/chemistry
Calcium/metabolism
Cell Survival/drug effects

@article {pmid38915482,
year = {2024},
author = {Mudambi, S and Fitzgerald, ME and Washington, DL and Pera, PJ and Huss, WJ and Paragh, G},
title = {Dual targeting of KDM1A and antioxidants is an effective anticancer strategy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.06.12.597953},
pmid = {38915482},
abstract = {Lysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen species (ROS) levels by increasing cellular glucose uptake, glycolysis, and endogenous antioxidants. The role of KDM1A in cellular ROS response has not previously been described. We determined the role of KDM1A in regulating the ROS response and the utility of KDM1A inhibitors in combination with ROS-inducing cancer therapies. Our results show that KDM1A inhibition sensitized cells to oxidative stress and increased total cellular ROS, which was mitigated by treatment with the antioxidant N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration and impaired induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Thus we found that increased sensitivity of ROS after KDM1A inhibition was mediated by HIF-1A and depletion of endogenous glutathione. We also show that KDM1A-specific inhibitor bizine synergized with antioxidant-depleting therapies, buthionine sulfoximine, and auranofin in rhabdomyosarcoma cell lines (Rh28 and Rh30). In this study, we describe a novel role for KDM1A in regulating HIF- 1A functions under oxidative stress and found that dual targeting of KDM1A and antioxidant systems may serve as an effective combination anticancer strategy.},
}

@article {pmid38904252,
year = {2024},
author = {Panja, S and Nahomi, RB and Rankenberg, J and Michel, CR and Nagaraj, RH},
title = {Thiol-Mediated Enhancement of N[ε]-Acetyllysine Formation in Lens Proteins.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.4c00174},
pmid = {38904252},
issn = {1554-8937},
abstract = {Lysine acetylation (AcK) is a prominent post-translational modification in eye lens crystallins. We have observed that AcK formation is preferred in some lysine residues over others in crystallins. In this study, we have investigated the role of thiols in such AcK formation. Upon incubation with acetyl-CoA (AcCoA), αA-Crystallin, which contains two cysteine residues, showed significantly higher levels of AcK than αB-Crystallin, which lacks cysteine residues. Incubation with thiol-rich γS-Crystallin resulted in higher AcK formation in αB-Crystallin from AcCoA. External free thiol (glutathione and N-acetyl cysteine) increased the AcK content in AcCoA-incubated αB-Crystallin. Reductive alkylation of cysteine residues significantly decreased (p < 0.001) the AcCoA-mediated AcK formation in αA-Crystallin. Introduction of cysteine residues within ∼5 Å of lysine residues (K92C, E99C, and V169C) in αB-Crystallin followed by incubation with AcCoA resulted in a 3.5-, 1.3- and 1.3-fold increase in the AcK levels when compared to wild-type αB-Crystallin, respectively. Together, these results suggested that AcK formation in α-Crystallin is promoted by the proximal cysteine residues and protein-free thiols through an S → N acetyl transfer mechanism.},
}

@article {pmid38899269,
year = {2024},
author = {Qadir, NA and Stachler, L and Reddy, AD and Diaz-Garcia, G and Sottile, E},
title = {Polysubstance-Induced Hepatotoxicity and the Role of Supportive Management.},
journal = {Cureus},
volume = {16},
number = {5},
pages = {e60649},
pmid = {38899269},
issn = {2168-8184},
abstract = {With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been widely documented in its association with salicylates or acetaminophen and the utility of using N-acetylcysteine (NAC) for its hepatoprotective effects. However, DILI caused by illicit drug use and guideline-directed management has had little research. We present the case of a 29-year-old female who presented with altered mental status. She was found to have a concomitant liver injury and was treated supportively without the use of NAC, with gradual improvement.},
}

@article {pmid38899149,
year = {2024},
author = {Zou, H and Boboltz, A and Cheema, Y and Song, D and Cahn, D and Duncan, GA},
title = {Synthetic mucus barrier arrays as a nanoparticle formulation screening platform.},
journal = {RSC pharmaceutics},
volume = {1},
number = {2},
pages = {218-226},
pmid = {38899149},
issn = {2976-8713},
abstract = {A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug delivery systems delivered to these sites may become trapped in mucus and subsequently cleared before they can reach target cells. As such, optimizing the properties of nanoparticle delivery vehicles, such as their surface chemistry and size, is essential to improving their penetration through the mucus barrier. In previous work, we developed a mucin-based hydrogel that has viscoelastic properties like that of native mucus which can be further tailored to mimic specific mucosal tissues and disease states. Using this biomimetic hydrogel system, a 3D-printed array containing synthetic mucus barriers was created that is compatible with a 96-well plate enabling its use as a high-throughput screening platform for nanoparticle drug delivery applications. To validate this system, we evaluated several established design parameters to determine their impact on nanoparticle penetration through synthetic mucus barriers. Consistent with the literature, we found nanoparticles of smaller size and coated with a protective PEG layer more efficiently penetrated through synthetic mucus barriers. In addition, we evaluated a mucolytic (tris(2-carboxyethyl) phosphine, TCEP) for use as a permeation enhancer for mucosal drug delivery. In comparison to N-acetyl cysteine (NAC), we found TCEP significantly improved nanoparticle penetration through a disease-like synthetic mucus barrier. Overall, our results establish a new high-throughput screening approach using synthetic mucus barrier arrays to identify promising nanoparticle formulation strategies for drug delivery to mucosal tissues.},
}

@article {pmid38897422,
year = {2024},
author = {Russell-Guzmán, J and Américo-Da Silva, L and Cadagan, C and Maturana, M and Palomero, J and Estrada, M and Barrientos, G and Buvinic, S and Hidalgo, C and Llanos, P},
title = {Activation of the ROS/TXNIP/NLRP3 pathway disrupts insulin-dependent glucose uptake in skeletal muscle of insulin-resistant obese mice.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2024.06.011},
pmid = {38897422},
issn = {1873-4596},
abstract = {Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.},
}

@article {pmid38892556,
year = {2024},
author = {Liu, M and You, Y and Zhu, H and Chen, Y and Hu, Z and Duan, J},
title = {N-Acetylcysteine Alleviates Impaired Muscular Function Resulting from Sphingosine Phosphate Lyase Functional Deficiency-Induced Sphingoid Base and Ceramide Accumulation in Caenorhabditis elegans.},
journal = {Nutrients},
volume = {16},
number = {11},
pages = {},
pmid = {38892556},
issn = {2072-6643},
support = {82171551//National Natural Science Foundation of China/ ; 20232ACB205002//Jiangxi Provincial Natural Science Foundation/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects ; *Acetylcysteine/pharmacology ; *Ceramides/metabolism ; *Aldehyde-Lyases/metabolism ; *Sphingolipids/metabolism ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology/metabolism ; Muscles/drug effects/metabolism ; RNA Interference ; Sphingosine/analogs & derivatives/metabolism ; },
abstract = {Sphingosine-1-phosphate lyase (SPL) resides at the endpoint of the sphingolipid metabolic pathway, catalyzing the irreversible breakdown of sphingosine-1-phosphate. Depletion of SPL precipitates compromised muscle morphology and function; nevertheless, the precise mechanistic underpinnings remain elusive. Here, we elucidate a model of SPL functional deficiency in Caenorhabditis elegans using spl-1 RNA interference. Within these SPL-deficient nematodes, we observed diminished motility and perturbed muscle fiber organization, correlated with the accumulation of sphingoid bases, their phosphorylated forms, and ceramides (collectively referred to as the "sphingolipid rheostat"). The disturbance in mitochondrial morphology was also notable, as SPL functional loss resulted in heightened levels of reactive oxygen species. Remarkably, the administration of the antioxidant N-acetylcysteine (NAC) ameliorates locomotor impairment and rectifies muscle fiber disarray, underscoring its therapeutic promise for ceramide-accumulation-related muscle disorders. Our findings emphasize the pivotal role of SPL in preserving muscle integrity and advocate for exploring antioxidant interventions, such as NAC supplementation, as prospective therapeutic strategies for addressing muscle function decline associated with sphingolipid/ceramide metabolism disruption.},
}

Animals
*Caenorhabditis elegans/drug effects
*Acetylcysteine/pharmacology
*Ceramides/metabolism
*Aldehyde-Lyases/metabolism
*Sphingolipids/metabolism
Reactive Oxygen Species/metabolism
Antioxidants/pharmacology/metabolism
Muscles/drug effects/metabolism
RNA Interference
Sphingosine/analogs & derivatives/metabolism

@article {pmid38892427,
year = {2024},
author = {Calderón Guzmán, D and Osnaya Brizuela, N and Ortíz Herrera, M and Valenzuela Peraza, A and Labra Ruíz, N and Juárez Olguín, H and Santamaria Del Angel, D and Barragán Mejía, G},
title = {N-Acetylcysteine Attenuates Cisplatin Toxicity in the Cerebrum and Lung of Young Rats with Artificially Induced Protein Deficiency.},
journal = {International journal of molecular sciences},
volume = {25},
number = {11},
pages = {},
pmid = {38892427},
issn = {1422-0067},
mesh = {Animals ; *Cisplatin/adverse effects/toxicity ; *Acetylcysteine/pharmacology ; Rats ; *Rats, Wistar ; *Lung/drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Male ; Cerebrum/drug effects/metabolism ; Glutathione/metabolism ; Neuroprotective Agents/pharmacology ; Antineoplastic Agents/adverse effects ; },
abstract = {Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP[®] 5 mg/kg or NAC[®] 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca[+2], and Mg[+2] ATPase using validated methods. TBARS, H2O2, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.},
}

Animals
*Cisplatin/adverse effects/toxicity
*Acetylcysteine/pharmacology
Rats
*Rats, Wistar
*Lung/drug effects/metabolism/pathology
Lipid Peroxidation/drug effects
Oxidative Stress/drug effects
Male
Cerebrum/drug effects/metabolism
Glutathione/metabolism
Neuroprotective Agents/pharmacology
Antineoplastic Agents/adverse effects

@article {pmid38892239,
year = {2024},
author = {Wrotek, A and Badyda, A and Jackowska, T},
title = {Molecular Mechanisms of N-Acetylcysteine in RSV Infections and Air Pollution-Induced Alterations: A Scoping Review.},
journal = {International journal of molecular sciences},
volume = {25},
number = {11},
pages = {},
pmid = {38892239},
issn = {1422-0067},
support = {501-1-020-19-23.//Centre of Postgraduate Medical Education in Warsaw/ ; },
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Respiratory Syncytial Virus Infections/drug therapy/virology/metabolism ; Animals ; *Air Pollution/adverse effects ; ErbB Receptors/metabolism ; },
abstract = {N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important etiological factors of lower respiratory tract infections, and exposure to air pollution appears to be additionally associated with higher RSV incidence and disease severity. We aimed to systematically review the existing literature to determine which molecular mechanisms mediate the effects of NAC in an RSV infection and air pollution, and to identify the knowledge gaps in this field. A search for original studies was carried out in three databases and a calibrated extraction grid was used to extract data on the NAC treatment (dose, timing), the air pollutant type, and the most significant mechanisms. We identified only 28 studies conducted in human cellular models (n = 18), animal models (n = 7), and mixed models (n = 3). NAC treatment improves the barrier function of the epithelium damaged by RSV and air pollution, and reduces the epithelial permeability, protecting against viral entry. NAC may also block RSV-activated phosphorylation of the epidermal growth factor receptor (EGFR), which promotes endocytosis and facilitates cell entry. EGFR also enhances the release of a mucin gene, MUC5AC, which increases mucus viscosity and causes goblet cell metaplasia; the effects are abrogated by NAC. NAC blocks virus release from the infected cells, attenuates the cigarette smoke-induced shift from necrosis to apoptosis, and reverses the block in IFN-γ-induced antiviral gene expression caused by the inhibited Stat1 phosphorylation. Increased synthesis of pro-inflammatory cytokines and chemokines is induced by both RSV and air pollutants and is mediated by the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that are activated in response to oxidative stress. MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, expressed and secreted by normal T cells) partially mediate airway hyperresponsiveness (AHR), and therapeutic (but not preventive) NAC administration reduces the inflammatory response and has been shown to reduce ozone-induced AHR. Oxidative stress-induced DNA damage and cellular senescence, observed during RSV infection and exposure to air pollution, can be partially reversed by NAC administration, while data on the emphysema formation are disputed. The review identified potential common molecular mechanisms of interest that are affected by NAC and may alleviate both the RSV infection and the effects of air pollution. Data are limited and gaps in knowledge include the optimal timing or dosage of NAC administration, therefore future studies should clarify these uncertainties and verify its practical use.},
}

Humans
*Acetylcysteine/pharmacology
*Respiratory Syncytial Virus Infections/drug therapy/virology/metabolism
Animals
*Air Pollution/adverse effects
ErbB Receptors/metabolism

@article {pmid38891420,
year = {2024},
author = {Alatta, A and Nassar, M and Gorduysus, M and Alkhatib, W and Sayed, M},
title = {In Vitro Investigation of the Effects of Various Reducing Agents on Dentin Treated with Hydrogen Peroxide.},
journal = {Polymers},
volume = {16},
number = {11},
pages = {},
pmid = {38891420},
issn = {2073-4360},
support = {Research Project (G20) ID (89).//This research was supported by the Office of Vice Chancellor for Research and Graduate Studies, University of Sharjah, Sharjah, United Arab Emirates./ ; },
abstract = {We assessed the effect of non-protein thiols (NPSH), reduced glutathione (GSH) and n-acetylcysteine (NAC), on resin shear bond strength (SBS) to hydrogen peroxide (H2O2)-treated dentin, and their effects on the characteristics of dentin in comparison to ascorbic acid (AA) and sodium thiosulfate (STS). H2O2-treated dentin was conditioned with 5% AA, GSH, NAC, or STS applied for 1 or 5 min. The positive control group received H2O2 without antioxidant application, and the first negative control group received distilled water (DW). The specimens received resin bonding immediately after treatment except for the second negative control group (delayed bonding). Microhardness, roughness, and topography were studied. The SBS values of all antioxidants were statistically greater than the positive control group (p < 0.05); however, NAC and AA applied for 1 min demonstrated the highest values, which were comparable to delayed bonding. All treatments removed the smear layer except DW, H2O2, and STS. The negative effect of H2O2 on resin-dentin bonding was mitigated by the application of the antioxidants; however, their efficiencies were dependent on the antioxidant type and time of application. NAC was more effective in optimizing resin bonding to bleached dentin compared to GSH at 1 min application and STS at both application times but was comparable to AA. Negligible negative effects on the substrate's roughness and microhardness were detected. The antioxidant properties of the agent and its capacity to remove the smear layer are the processes underpinning the ability of a certain antioxidant to reverse the effect of H2O2 on bonding.},
}

@article {pmid38885324,
year = {2024},
author = {Li, L and Xie, D and Yu, S and Ma, M and Fan, K and Chen, J and Xiu, M and Xie, K and Li, Y and Yong, G},
title = {WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma.},
journal = {Cancer research},
volume = {},
number = {},
pages = {},
doi = {10.1158/0008-5472.CAN-23-1167},
pmid = {38885324},
issn = {1538-7445},
abstract = {Cellular oxidative stress plays a key role in the development and progression of hepatocellular carcinoma (HCC). A better understanding of the processes that regulate reactive oxygen species (ROS) homeostasis could uncover improved strategies for treating HCC. Here, we identified WNK1 as an antioxidative factor and therapeutic target in HCC. In human HCC, WNK1 expression was increased and correlated with poor patient prognosis. WNK1 knockdown significantly inhibited cell proliferation and xenograft tumor growth. Mechanistically, WNK1 competed with NRF2 for binding to the partial Kelch domain of KEAP1, reducing NRF2 ubiquitination and promoting NRF2 accumulation and nuclear translocation to increase antioxidant response. WNK1 silencing increased H2O2-induced apoptosis and inhibited cell growth by elevating reactive oxygen species (ROS) levels, which could be rescued by treatment with the antioxidant N-acetylcysteine (NAC) and NRF2 activator tert-butylhydroquinone (tBHQ). Liver-specific WNK1 knockout mouse models of HCC substantiated that WNK1 promoted HCC development by regulating ROS levels. WNK463, an inhibitor of the WNK kinase family, suppressed HCC progression and altered the redox status. These findings suggest that WNK1 plays a critical role in HCC development and progression and that the WNK1-oxidative stress axis may be a promising therapeutic target for HCC.},
}

@article {pmid38885202,
year = {2024},
author = {Guo, X and Zhang, M and Li, Y and Ding, Z and Liu, M and Li, W and Peng, Y and Zheng, J},
title = {CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron.},
journal = {Chemical research in toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.chemrestox.3c00351},
pmid = {38885202},
issn = {1520-5010},
abstract = {Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or N-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an N-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.},
}

@article {pmid38884516,
year = {2024},
author = {Tang, W and Zhu, D and Wu, F and Xu, JF and Yang, JP and Deng, ZP and Chen, XB and Papi, A and Qu, JM},
title = {Author Correction: Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.},
journal = {European review for medical and pharmacological sciences},
volume = {28},
number = {11},
pages = {3697},
doi = {10.26355/eurrev_202406_36388},
pmid = {38884516},
issn = {2284-0729},
abstract = {Eur Rev Med Pharmacol Sci 2023; 27 (11): 5119-5127-DOI: 10.26355/eurrev_202306_32628-PMID: 37318485, published online on June 13, 2023. After publication, the authors have found some mistakes. This erratum corrects the following: In Figure 1, "4 withdrawal" has been corrected into "7 withdrawal" and "95 completed study" has been corrected into "97 corrected study" In the "Efficacy" paragraph at page 5123, "1.0 in the placebo group" has been corrected into "-1.0 in the placebo group". The legend of Table V has been corrected as follows: Table V. Published clinical studies of the mucolytic and expectorant efficacy of IV NAC in respiratory diseases. In Table V, the data regarding the Treatment groups (duration) by Grassi et al5 have been corrected as follows: NAC oral 200 mg TID NAC IM 300 mg BID NAC IV 500 mg OD (6 days) In Table V, the data regarding the Treatment groups (duration) by Henneghien et al8 have been corrected as follows: NAC oral 200 mg TID NAC IV 300 mg TID (3-10 days) NAC IV 500 mg BID (12 days) There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/32628.},
}

@article {pmid38880547,
year = {2024},
author = {Yakovlev, AV and Detterer, AS and Yakovleva, OV and Hermann, A and Sitdikova, GF},
title = {H2S prevents the disruption of the blood-brain barrier in rats with prenatal hyperhomocysteinemia.},
journal = {Journal of pharmacological sciences},
volume = {155},
number = {4},
pages = {131-139},
doi = {10.1016/j.jphs.2024.05.001},
pmid = {38880547},
issn = {1347-8648},
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Pregnancy ; *Hyperhomocysteinemia/metabolism ; Female ; *Hydrogen Sulfide/metabolism ; *Neuroprotective Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Cytokines/metabolism ; Homocysteine/blood/metabolism/analogs & derivatives ; Rats, Wistar ; Sulfides/pharmacology/administration & dosage ; Rats ; Male ; Pregnancy Complications ; Brain/metabolism ; L-Lactate Dehydrogenase/metabolism/blood ; Permeability ; Nitrites/metabolism/blood ; },
abstract = {Elevation of the homocysteine concentration in the plasma called hyperhomocysteinemia (hHCY) during pregnancy causes a number of pre- and postnatal developmental disorders. The aim of our study was to analyze the effects of H2S donors -NaHS and N-acetylcysteine (NAC) on blood-brain barrier (BBB) permeability in rats with prenatal hHCY. In rats with mild hHCY BBB permeability assessed by Evans Blue extravasation in brain increased markedly throughout life. Administration of NaHS or NAC during pregnancy attenuated hHCY-associated damage and increased endogenous concentrations of sulfides in brain tissues. Acute application of dl-homocysteine thiolactone induced BBB leakage, which was prevented by the NMDA receptor antagonist MK-801 or H2S donors. Rats with hHCY demonstrated high levels of NO metabolite - nitrites and proinflammatory cytokines (IL-1β, TNF-α, IL-6) in brain. Lactate dehydrogenase (LDH) activity in the serum was higher in rats with hHCY. Mitochondrial complex-I activity was lower in brain of hHCY rats. NaHS treatment during pregnancy restored levels of proinflammatory cytokines, nitrites and activity of the respiratory chain complex in brain as well as the LDH activity in serum. Our data suggest that H2S has neuroprotective effects against prenatal hHCY-associated BBB disturbance providing a potential strategy for the prevention of developmental impairments in newborns.},
}

Animals
*Blood-Brain Barrier/metabolism/drug effects
Pregnancy
*Hyperhomocysteinemia/metabolism
Female
*Hydrogen Sulfide/metabolism
*Neuroprotective Agents/pharmacology
*Acetylcysteine/pharmacology
*Cytokines/metabolism
Homocysteine/blood/metabolism/analogs & derivatives
Rats, Wistar
Sulfides/pharmacology/administration & dosage
Rats
Male
Pregnancy Complications
Brain/metabolism
L-Lactate Dehydrogenase/metabolism/blood
Permeability
Nitrites/metabolism/blood

@article {pmid38879122,
year = {2024},
author = {Cai, J and Huang, J and Li, D and Zhang, X and Shi, B and Liu, Q and Fang, C and Xu, S and Zhang, Z},
title = {Hippo-YAP/TAZ-ROS signaling axis regulates metaflammation induced by SelenoM deficiency in high-fat diet-derived obesity.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2024.06.005},
pmid = {38879122},
issn = {2090-1224},
abstract = {INTRODUCTION: Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined.

OBJECTIVES: We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet.

METHODS: Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue.

RESULTS: Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-κB) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation.

CONCLUSION: Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity.},
}

@article {pmid38876744,
year = {2024},
author = {Goedert, M and Griesinger, C and Outeiro, TF and Riek, R and Schröder, GF and Spillantini, MG},
title = {Abandon the NAC in α-synuclein.},
journal = {The Lancet. Neurology},
volume = {23},
number = {7},
pages = {669},
doi = {10.1016/S1474-4422(24)00176-5},
pmid = {38876744},
issn = {1474-4465},
mesh = {Humans ; *alpha-Synuclein/metabolism ; Parkinson Disease/drug therapy ; Acetylcysteine/therapeutic use ; Animals ; },
}

Humans
*alpha-Synuclein/metabolism
Parkinson Disease/drug therapy
Acetylcysteine/therapeutic use
Animals

@article {pmid38875923,
year = {2024},
author = {Bagri, KM and de Andrade Abraham, C and Santos, AT and da Silva, WS and Costa, ML and Mermelstein, C},
title = {Rotenone inhibits embryonic chick myogenesis in a ROS-dependent mechanism.},
journal = {Tissue & cell},
volume = {89},
number = {},
pages = {102423},
doi = {10.1016/j.tice.2024.102423},
pmid = {38875923},
issn = {1532-3072},
abstract = {Skeletal muscle function is highly dependent on the energy supply provided by mitochondria. Besides ATP production, mitochondria have several other roles, such as calcium storage, heat production, cell death signaling, autophagy regulation and redox state modulation. Mitochondrial function is crucial for skeletal muscle fiber formation. Disorders that affect mitochondria have a major impact in muscle development and function. Here we studied the role of mitochondria during chick skeletal myogenesis. We analyzed the intracellular distribution of mitochondria in myoblasts, fibroblasts and myotubes using Mitotracker labeling. Mitochondrial respiration was investigated in chick muscle cells. Our results show that (i) myoblasts and myotubes have more mitochondria than muscle fibroblasts; (ii) mitochondria are organized in long lines within the whole cytoplasm and around the nuclei of myotubes, while in myoblasts they are dispersed in the cytoplasm; (iii) the area of mitochondria in myotubes increases during myogenesis, while in myoblasts and fibroblasts there is a slight decrease; (iv) mitochondrial length increases in the three cell types (myoblasts, fibroblasts and myotubes) during myogenesis; (v) the distance of mitochondria to the nucleus increases in myoblasts and myotubes during myogenesis; (vi) Rotenone inhibits muscle fiber formation, while FCCP increases the size of myotubes; (vii) N-acetyl cysteine (NAC), an inhibitor of ROS formation, rescues the effects of Rotenone on muscle fiber size; and (viii) Rotenone induces the production of ROS in chick myogenic cells. The collection of our results suggests a role of ROS signaling in mitochondrial function during chick myogenesis.},
}

@article {pmid38870779,
year = {2024},
author = {Liu, J and Bai, Y and Feng, Y and Liu, X and Pang, B and Zhang, S and Jiang, M and Chen, A and Huang, H and Chen, Y and Ling, J and Mei, L},
title = {ABCC1 deficiency potentiated noise-induced hearing loss in mice by impairing cochlear antioxidant capacity.},
journal = {Redox biology},
volume = {74},
number = {},
pages = {103218},
doi = {10.1016/j.redox.2024.103218},
pmid = {38870779},
issn = {2213-2317},
abstract = {The ABCC1 gene belongs to the ATP-binding cassette membrane transporter superfamily, which plays a crucial role in the efflux of various endogenous and exogenous substances. Mutations in ABCC1 can result in autosomal dominant hearing loss. However, the specific roles of ABCC1 in auditory function are not fully understood. Through immunofluorescence, we found that ABCC1 was expressed in microvascular endothelial cells (ECs) of the stria vascularis (StV) in the murine cochlea. Then, an Abcc1 knockout mouse model was established by using CRISPR/Cas9 technology to elucidate the role of ABCC1 in the inner ear. The ABR threshold did not significantly differ between WT and Abcc1[-/-] mice at any age studied. After noise exposure, the ABR thresholds of the WT and Abcc1[-/-] mice were significantly elevated. Interestingly, after 14 days of noise exposure, ABR thresholds largely returned to pre-exposure levels in WT mice but not in Abcc1[-/-] mice. Our subsequent experiments showed that microvascular integrity in the StV was compromised and that the number of outer hair cells and the number of ribbons were significantly decreased in the cochleae of Abcc1[-/-] mice post-exposure. Besides, the production of ROS and the accumulation of 4-HNE significantly increased. Furthermore, StV microvascular ECs were cultured to elucidate the role of ABCC1 in these cells under glucose oxidase challenge. Notably, 30 U/L glucose oxidase (GO) induced severe oxidative stress damage in Abcc1[-/-] cells. Compared with WT cells, the ROS and 4-HNE levels and the apoptotic rate were significantly elevated in Abcc1[-/-] cells. In addition, the reduced GSH/GSSG ratio was significantly decreased in Abcc1[-/-] cells after GO treatment. Taken together, Abcc1[-/-] mice are more susceptible to noise-induced hearing loss, possibly because ABCC1 knockdown compromises the GSH antioxidant system of StV ECs. The exogenous antioxidant N-acetylcysteine (NAC) may protect against oxidative damage in Abcc1[-/-] murine cochleae and ECs.},
}

@article {pmid38867461,
year = {2024},
author = {Maxwell, MN and Marullo, AL and Valverde-Pérez, E and Slyne, AD and Murphy, BT and O'Halloran, KD},
title = {Chronic N-acetyl cysteine treatment does not improve respiratory system performance in the mdx mouse model of Duchenne muscular dystrophy.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP091862},
pmid = {38867461},
issn = {1469-445X},
support = {FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; },
abstract = {Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.},
}

@article {pmid38866114,
year = {2024},
author = {Khan, AQ and Al-Tamimi, M and Anver, R and Agha, MV and Anamangadan, G and Raza, SS and Ahmad, F and Ahmad, A and Allam, M and Buddenkotte, J and Steinhoff, M and Uddin, S},
title = {Targeting of S-phase kinase associated protein 2 stabilized tumor suppressors leading to apoptotic cell death in squamous skin cancer cells.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {167286},
doi = {10.1016/j.bbadis.2024.167286},
pmid = {38866114},
issn = {1879-260X},
abstract = {S-phase kinase-associated protein 2 (Skp2) is an F-box protein overexpressed in human cancers and linked with poor prognosis. It triggers cancer pathogenesis, including stemness and drug resistance. In this study, we have explored the potential role of Skp2 targeting in restoring the expression of tumor suppressors in human cutaneous squamous cell carcinoma (cSCC) cells. Our results showed that genetic and pharmacological Skp2 targeting markedly suppressed cSCC cell proliferation, colony growth, spheroid formation, and enhanced sensitization to chemotherapeutic drugs. Further, western blot results demonstrated restoration of tumor suppressor (KLF4) and CDKI (p21) and suppression of vimentin and survivin in Skp2-knocked-down cSCC cells. Importantly, we also explored that Skp2 targeting potentiates apoptosis of cSCC cells through MAPK signaling. Moreover, co-targeting of Skp2 and AKT resulted in increased cancer cell death. Interestingly, curcumin, a well-known naturally derived anticancer agent, also inhibits Skp2 expression with concomitant CDKI upregulation. In line, curcumin suppressed cSCC cell growth through ROS-mediated apoptosis, while the use of N-acetyl cysteine (NAC) reversed curcumin-induced cell death. Curcumin treatment also sensitized cSCC cells to conventional anticancer drugs, such as cisplatin and doxorubicin. Altogether, these data suggest that Skp2 targeting restores the functioning of tumor suppressors, inhibits the expression of genes associated with cell proliferation and stemness, and sensitizes cancer cells to anticancer drugs. Thus, genetic, and pharmacological ablation of Skp2 can be an important strategy for attenuating cancer pathogenesis and associated complications in skin squamous cell carcinoma.},
}

@article {pmid38862667,
year = {2024},
author = {Kang, F and Wu, J and Hong, L and Zhang, P and Song, J},
title = {Iodine-125 seed inhibits proliferation and promotes apoptosis of cholangiocarcinoma cells by inducing the ROS/p53 axis.},
journal = {Functional & integrative genomics},
volume = {24},
number = {3},
pages = {114},
pmid = {38862667},
issn = {1438-7948},
mesh = {*Cholangiocarcinoma/metabolism/radiotherapy/pathology/genetics/drug therapy ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Iodine Radioisotopes ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Humans ; Cell Line, Tumor ; Bile Duct Neoplasms/metabolism/pathology/genetics/radiotherapy ; Acetylcysteine/pharmacology ; Benzothiazoles/pharmacology ; Signal Transduction/drug effects ; },
abstract = {With advances in radioactive particle implantation in clinical practice, Iodine-125 ([125]I) seed brachytherapy has emerged as a promising treatment for cholangiocarcinoma (CCA), showing good prognosis; however, the underlying molecular mechanism of the therapeutic effect of [125]I seed is unclear. To study the effects of [125]I seed on the proliferation and apoptosis of CCA cells. CCA cell lines, RBE and HCCC-9810, were treated with reactive oxygen species (ROS) scavenger acetylcysteine (NAC) or the p53 functional inhibitor, pifithrin-α hydrobromide (PFTα). Cell counting kit-8 (CCK-8) assay, 5-bromo-2-deoxy-uridine (BrdU) staining, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry assay were performed to test the radiation-sensitivity of [125]I seed toward CCA cells at different radiation doses (0.4 mCi and 0.8 mCi). 2,7-dichlorofluorescein diacetate (DCF-DA) assay, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot analysis were performed to assess the effect of [125]I seed on the ROS/p53 axis. A dose-dependent inhibitory effect of [125]I seeds on the proliferation of CCA cells was observed. The [125]I seed promoted apoptosis of CCA cells and induced the activation of the ROS/p53 pathway in a dose-dependent manner. NAC or PFTα treatment effectively reversed the stimulatory effect of [125]I seed on the proliferation of CCA cells. NAC or PFTα suppressed apoptosis and p53 protein expression induced by the [125]I seed. [125]I seed can inhibit cell growth mainly through the apoptotic pathway. The mechanism may involve the activation of p53 and its downstream apoptotic pathway by up-regulating the level of ROS in cells.},
}

*Cholangiocarcinoma/metabolism/radiotherapy/pathology/genetics/drug therapy
*Tumor Suppressor Protein p53/metabolism/genetics
*Iodine Radioisotopes
*Reactive Oxygen Species/metabolism
*Apoptosis/drug effects
*Cell Proliferation/drug effects
Humans
Cell Line, Tumor
Bile Duct Neoplasms/metabolism/pathology/genetics/radiotherapy
Acetylcysteine/pharmacology
Benzothiazoles/pharmacology
Signal Transduction/drug effects

@article {pmid38858642,
year = {2024},
author = {Hao, J and Zhang, X and Hu, R and Lu, X and Wang, H and Li, Y and Cheng, K and Li, Q},
title = {Metabolomics combined with network pharmacology reveals a role for astragaloside IV in inhibiting enterovirus 71 replication via PI3K-AKT signaling.},
journal = {Journal of translational medicine},
volume = {22},
number = {1},
pages = {555},
pmid = {38858642},
issn = {1479-5876},
support = {81301426//the National Natural Science Foundation of China/ ; 201901D111329//the Provincial Natural Science Foundation of Shanxi/ ; 202102130501005//Key Research and Development Plan of Shanxi Province/ ; 2020SHFZ38//the Mega Research and Development Projects of Lüliang/ ; 2020ZDSYS17//the Key Laboratory Platform Construction Projects of Lüliang/ ; 2023SHFZ50//the Luliang City Social Development Key Research and Development Project/ ; 2022C25//the Shanxi Medical University Fenyang College Project/ ; },
mesh = {*Virus Replication/drug effects ; *Saponins/pharmacology ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *Triterpenes/pharmacology ; Humans ; *Phosphatidylinositol 3-Kinases/metabolism ; *Network Pharmacology ; *Metabolomics ; *Enterovirus A, Human/drug effects ; },
abstract = {BACKGROUND: Astragaloside IV (AST-IV), as an effective active ingredient of Astragalus membranaceus (Fisch.) Bunge. It has been found that AST-IV inhibits the replication of dengue virus, hepatitis B virus, adenovirus, and coxsackievirus B3. Enterovirus 71 (EV71) serves as the main pathogen in severe hand-foot-mouth disease (HFMD), but there are no specific drugs available. In this study, we focus on investigating whether AST-IV can inhibit EV71 replication and explore the potential underlying mechanisms.

METHODS: The GES-1 or RD cells were infected with EV71, treated with AST-IV, or co-treated with both EV71 and AST-IV. The EV71 structural protein VP1 levels, the viral titers in the supernatant were measured using western blot and 50% tissue culture infective dose (TCID50), respectively. Network pharmacology was used to predict possible pathways and targets for AST-IV to inhibit EV71 replication. Additionally, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was used to investigate the potential targeted metabolites of AST-IV. Associations between metabolites and apparent indicators were performed via Spearman's algorithm.

RESULTS: This study illustrated that AST-IV effectively inhibited EV71 replication. Network pharmacology suggested that AST-IV inhibits EV71 replication by targeting PI3K-AKT. Metabolomics results showed that AST-IV achieved these effects by elevating the levels of hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-hydroxy-1 H-indole-3- acetamide, oxypurinol, while reducing the levels of PC (14:0/15:0). Furthermore, AST-IV also mitigated EV71-induced oxidative stress by reducing the levels of MDA, ROS, while increasing the activity of T-AOC, CAT, GSH-Px. The inhibition of EV71 replication was also observed when using the ROS inhibitor N-Acetylcysteine (NAC). Additionally, AST-IV exhibited the ability to activate the PI3K-AKT signaling pathway and suppress EV71-induced apoptosis.

CONCLUSION: This study suggests that AST-IV may activate the cAMP and the antioxidant stress response by targeting eight key metabolites, including hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-Hydroxy-1 H-indole-3-acetamide, oxypurinol and PC (14:0/15:0). This activation can further stimulate the PI3K-AKT signaling to inhibit EV71-induced apoptosis and EV71 replication.},
}

*Virus Replication/drug effects
*Saponins/pharmacology
*Proto-Oncogene Proteins c-akt/metabolism
*Signal Transduction/drug effects
*Triterpenes/pharmacology
Humans
*Phosphatidylinositol 3-Kinases/metabolism
*Network Pharmacology
*Metabolomics
*Enterovirus A, Human/drug effects

@article {pmid38857427,
year = {2024},
author = {Zhang, R and Guan, S and Meng, Z and Deng, X and Lu, J},
title = {3-MCPD Induces Renal Cell Pyroptosis and Inflammation by Inhibiting ESCRT-III-Mediated Cell Repair and Mitophagy.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.4c01994},
pmid = {38857427},
issn = {1520-5118},
abstract = {3-Monochloropropane-1,2-diol (3-MCPD) is a chloropropyl alcohol contaminant mainly from the thermal processing of food and could affect kidneys. Pyroptosis is programmed cell death mediated by inflammasomes and gasdermins, and excessive cellular pyroptosis and inflammation can lead to tissue injury. In the present study, we found that 3-MCPD increased lactate dehydrogenase (LDH) levels in vitro and in vivo, increased the protein expression of NOD-like receptor family pyrin domain containing 3 (NLRP3), N-terminal domain of GSDMD (GSDMD-N), and cleaved caspase-1 and promoted the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), which induced renal cell pyroptosis and inflammation. Mechanistic studies indicated that the addition of N-acetylcysteine (NAC), a ROS scavenger, inhibited NLRP3 activation and attenuated pyroptosis. Furthermore, we revealed that 3-MCPD induced ROS accumulation by inhibiting ESCRT-III-mediated mitophagy. These results were further validated by the overexpression of charged multivesicular body protein 4B (CHMP4B), a key subunit of ESCRT-III, and the addition of the mitophagy activator carbonyl cyanide m-chlorophenylhydrazone (CCCP) and rapamycin (Rapa). Thus, our results showed that 3-MCPD could induce mitochondrial damage and produce ROS. 3-MCPD suppressed mitophagy, leading to the accumulation of damaged mitochondria and ROS, thereby activating NLRP3 and pyroptosis. Meanwhile, 3-MCPD-mediated suppression of ESCRT-III hindered the repair of GSDMD-induced cell membrane rupture, which further caused the occurrence of pyroptosis. Our findings provide new perspectives for studying the mechanisms underlying 3-MCPD-induced renal injury.},
}

@article {pmid38854233,
year = {2024},
author = {Shah, N and Campbell, H and Patel, V and Moormeier, J},
title = {A Clinical Course of Repeated Supratherapeutic Ingestion of Acetaminophen.},
journal = {Cureus},
volume = {16},
number = {5},
pages = {e59883},
pmid = {38854233},
issn = {2168-8184},
abstract = {Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as jaundice, confusion, and potentially life-threatening complications. Timely medical intervention, and, in severe instances, liver transplantation, are essential for enhancing outcomes and averting further deterioration. While the causes of ALF are multifaceted, in developed nations, it predominantly arises from drug-induced liver injury. Treatment primarily revolves around supportive measures, with severe cases necessitating liver transplantation. In instances where acute overdose with acetaminophen serves as the instigating factor, N-acetylcysteine (NAC) emerges as a pivotal component of management, as indicated by the Rumack-Matthew nomogram. The Rumack-Matthew nomogram guides treatment for acetaminophen overdose by correlating serum levels with the risk of liver damage. If levels exceed a set threshold, NAC is administered to prevent toxicity by replenishing glutathione. The decision to administer NAC is typically guided by this clinical tool, which aids healthcare providers in determining the appropriate course of action. NAC assumes a critical role in ameliorating the detrimental effects of acetaminophen overdose, particularly in averting liver damage, thus holding significant importance in patient care and recovery. While chronic acetaminophen overdose cases leading to ALF may also benefit from NAC, the supporting evidence remains weak. In this context, we present a case of ALF stemming from chronic acetaminophen ingestion, managed with NAC when liver transplantation was not a viable option.},
}

@article {pmid38847101,
year = {2024},
author = {Li, G and Li, M and Deng, Q and Yan, C and Lv, H and Zhao, G and Li, Y and Feng, Y and Sun, F and Fu, Y and Li, Y and Zhao, Z},
title = {Design, Synthesis and Preliminary Bioactivity Evaluation of N-acetylcysteine Derivatives as Antioxidative and Anti-inflammatory Agents.},
journal = {ChemMedChem},
volume = {},
number = {},
pages = {e202400110},
doi = {10.1002/cmdc.202400110},
pmid = {38847101},
issn = {1860-7187},
abstract = {N-acetylcysteine (NAC) is a commonly used mucolytic agent and antidote for acetaminophen overdose. For pulmonary diseases, NAC exhibits antioxidative properties, regulates cytokine production, reduces apoptosis of lung epithelial cells, and facilitates the resolution of inflammation. However, the efficacy of NAC in clinical trials targeting different pathological conditions is constrained by its short half-life and low bioavailability. In the present study, a series of NAC derivatives were designed and synthesized to further enhance its pharmacological activity. Structure-activity relationship (SAR) studies were conducted to optimize the activating groups. In vitro evaluations revealed that compounds 4r, 4t, 4w, and 4x exhibited superior antioxidative and anti-inflammatory activities compared to the positive controls of NAC and fudosteine. The ADME prediction analysis indicated that these compounds exhibited a favorable pharmacological profile. In-vivo experiments with compound 4r demonstrated that the high-dose group (80 mg/kg) exhibited improved therapeutic effects in reversing the HPY level in mice with pulmonary fibrosis compared to the NAC group (500 mg/kg), further proving its superior oral bioavailability and therapeutic effect compared to NAC.},
}

@article {pmid38845374,
year = {2024},
author = {Bhowmik, A and Chakraborty, S and Rohit, A and Chauhan, A},
title = {Transcriptomic responses of XDR Klebsiella pneumoniae to N-acetyl cysteine reveals suppression of major biogenesis pathways leading to bacterial killing and biofilm eradication.},
journal = {Journal of applied microbiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jambio/lxae136},
pmid = {38845374},
issn = {1365-2672},
abstract = {AIMS: Carbapenemase-producing K. pneumoniae is categorized as a "critical global priority-one" pathogen by WHO and new and efficient treatment options are warranted. This study aims to assess the antibacterial and antibiofilm potential of N-acetyl cysteine (NAC), against clinical isolates of extensively drug resistant (XDR) K. pneumoniae and elucidate the mechanism of killing.

METHODS AND RESULTS: XDR-K. pneumoniae were isolated from patients admitted to Madras Medical Mission Hospital, India. Antibiofilm activity of NAC was checked using in vitro continuous flow model and RNA sequencing was done using Illumina Novoseq. Data quality was checked using FastQC and MultiQC software. Our findings revealed that NAC at a concentration of 100 mg/mL was safe, and could inhibit the growth and completely eradicate mature biofilms of all XDR- K. pneumoniae isolates. Transcriptomic responses in XDR- K. pneumoniae to NAC showed significant downregulation of the genes associated with crucial biogenesis pathways including electron transport chain and oxidoreductase activity besides a specific cluster of genes linked to ribosomal proteins.

CONCLUSIONS: Our results indicate that NAC kills the XDR- K. pneumoniae clinical isolates by shutting the overall metabolism and hence, successfully eradicate in vitro biofilms formed on catheters.},
}

@article {pmid38843996,
year = {2024},
author = {Adiyeke, E and Bakan, N and Uvez, A and Arslan, DO and Kilic, S and Koc, B and Ozer, S and Saatci, O and Armutak, Eİ},
title = {THE EFFECT OF N- ACETYLCYSTEINE ON THE NEUROTOXICITY OF SEVOFLURANE IN DEVELOPING HIPPOCAMPUS CELLS.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuro.2024.05.006},
pmid = {38843996},
issn = {1872-9711},
abstract = {Sevoflurane, a common pediatric anesthetic, has been linked to neurodegeneration, raising safety concerns. This study explored N-acetylcysteine's protective potential against sevoflurane-induced neurotoxicity in rat hippocampi. Four groups were examined: Control: Received 6hours of 3l/min gas (air and 30% O2) and intraperitoneal saline. NAC: Received 6hours of 3l/min gas and 150mg/kg NAC intraperitoneally. Sev: Exposed to 6hours of 3l/min gas and 3% sevoflurane. Sev+NAC: Received 6hours of 3l/min gas, 3% sevoflurane, and 150mg/kg NAC. Protein levels of NRF-2, NLRP3, IL-1β, caspase-1, Beclin 1, p62, LC3A, and apoptosis markers were assessed. Sevoflurane and NAC alone reduced autophagy, while Sev+NAC group maintained autophagy levels. Sev group had elevated NRF-2, NLRP3, pNRF2, Caspase-1, and IL-1β, which were reduced in Sev+NAC. Apoptosis was higher in Sev, but Sev+NAC showed reduced apoptosis compared to the control. In summary, sevoflurane induced neurotoxicity in developing hippocampus, which was mitigated by N-acetylcysteine administration.},
}

@article {pmid38842239,
year = {2024},
author = {Hassan, AA and Ismail, NR and Rezk, AE and Elfeky, HM and Mady, AM and Allam, AG and Abbas, KS},
title = {Efficacy of N-acetylcysteine in reducing the risk of postoperative atrial fibrillation in cardiothoracic surgery: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Minerva cardiology and angiology},
volume = {},
number = {},
pages = {},
doi = {10.23736/S2724-5683.24.06482-2},
pmid = {38842239},
issn = {2724-5772},
abstract = {INTRODUCTION: New-onset postoperative atrial fibrillation (POAF) is a common complication following cardiac surgeries. N-acetylcysteine (NAC) showed a significant reduction in the incidence of POAF. This review aimed to systematically summarize and Meta-analyze data from previously published Randomized Controlled Trials (RCTs).

EVIDENCE ACQUISITION: Electronic databases: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched. Data was extracted and the quality of the included studies was assessed. A random-effects DerSimonian Laird model was employed for meta-analysis.

EVIDENCE SYNTHESIS: Fifteen RCTs were included in this study (NAC, N.=940; control, N.=935). In the NAC group, 16.38% developed POAF compared with 23.53% in the control group. NAC supplementation was associated with a decreased incidence of POAF in patients undergoing cardiothoracic surgery (RR 0.69; 95% CI 0.52, 0.91; P=0.008). Meta-regression of randomized trial data showed that the incidence of POAF was not related to the NAC dose (P=0.439). A subgroup analysis in terms of the time of NAC administration revealed that preoperative and postoperative NAC administration was the only subgroup that demonstrated a statistically significant difference (RR 0.48, 95% CI 0.32, 0.71; P=0.0003) compared with placebo and showed no heterogeneity.

CONCLUSIONS: Atrial fibrillation is a significant postoperative complication, particularly in cardiothoracic surgery. This study highlights the need for further research on optimal NAC dosing and timing, with evidence suggesting that preoperative and postoperative NAC administration may significantly decrease postoperative atrial fibrillation in cardiothoracic surgery patients, although limitations and variability in study designs need to be considered.},
}

@article {pmid38841121,
year = {2024},
author = {Jenkins, DD and Garner, SS and Brennan, A and Morris, J and Bonham, K and Adams, L and Hunt, S and Moss, H and Badran, BW and George, MS and Wiest, DB},
title = {Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.},
journal = {Frontiers in human neuroscience},
volume = {18},
number = {},
pages = {1373543},
pmid = {38841121},
issn = {1662-5161},
abstract = {OBJECTIVE: This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.

METHODS: We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone.

RESULTS: NAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM (p = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake.

CONCLUSION: In IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.},
}

@article {pmid38836732,
year = {2024},
author = {Chen, J and Zhu, Y and Zheng, C and Zhao, W and Liu, Q},
title = {Influence Factors of the Therapeutic Effect of Budesonide Combined with N-Acetylcysteine in Children with Mycoplasma Pneumoniae Infection Analyzed by Lasso-Logistic and Construction of a Nomogram Prediction Model.},
journal = {Alternative therapies in health and medicine},
volume = {},
number = {},
pages = {},
pmid = {38836732},
issn = {1078-6791},
abstract = {OBJECTIVE: This study aims to analyze the factors influencing the efficacy of budesonide (BUD) combined with N-acetylcysteine (NAC) treatment in children with Mycoplasma pneumoniae (MP) infection through Lasso-Logistic analysis, construct a Nomogram predictive model, and provide personalized treatment plans for clinicians. Additionally, it aims to fill the knowledge gap regarding the treatment of MP-infected children with BUD combined with NAC.

METHODS: We retrospectively analyzed clinical data from 96 children treated with BUD and NAC for MP infection at our hospital from January 2022 to May 2023. Treatment outcomes were categorized as good or poor. Logistic regression and Lasso-Logistic analysis were used to identify independent factors influencing outcomes and construct a predictive Nomogram model, which was validated through ROC curve analysis.

RESULTS: Logistic regression identified prolonged fever (≥7 days), high fever, and elevated levels of TNF-α, IL-6, and CRP as independent risk factors for poor outcomes. The Nomogram model, based on these factors, demonstrated excellent predictive accuracy with a C-index of 0.992 and AUC values of 0.987 and 0.948 in the modeling and validation cohorts, respectively.

CONCLUSION: The developed Nomogram model provides clinicians with a reliable tool to predict poor treatment outcomes in children with MP infection treated with BUD and NAC, supporting more personalized and effective treatment plans.},
}

@article {pmid38759847,
year = {2024},
author = {Shin, BJ and Kim, BJ and Paeng, EJ and Rifkin, JT and Moon, SH and Shin, SH and Ryu, BY},
title = {N-Acetyl-L-cysteine attenuates titanium dioxide nanoparticle (TiO2 NP)-induced autophagy in male germ cells.},
journal = {Environmental toxicology and pharmacology},
volume = {108},
number = {},
pages = {104466},
doi = {10.1016/j.etap.2024.104466},
pmid = {38759847},
issn = {1872-7077},
mesh = {*Titanium/toxicity ; Male ; *Autophagy/drug effects ; Animals ; *Acetylcysteine/pharmacology ; Mice ; *Reactive Oxygen Species/metabolism ; Cell Line ; *Cell Proliferation/drug effects ; *Metal Nanoparticles/toxicity ; Spermatogonia/drug effects ; Nanoparticles/toxicity ; },
abstract = {Titanium dioxide nanoparticles (TiO2 NPs) are widely used in consumer products, raising concerns about their impact on human health. This study investigates the effects of TiO2 NPs on male germ cells while focusing on cell proliferation inhibition and underlying mechanisms. This was done by utilizing mouse GC-1 spermatogonia cells, an immortalized spermatogonia cell line. TiO2 NPs induced a concentration-dependent proliferation inhibition with increased reactive oxygen species (ROS) generation. Notably, TiO2 NPs induced autophagy and decreased ERK phosphorylation. Treatment with the ROS inhibitor N-Acetyl-l-cysteine (NAC) alleviated TiO2 NPs-induced autophagy, restored ERK phosphorylation, and promoted cell proliferation. These findings call attention to the reproductive risks posed by TiO2 NPs while also highlighting NAC as a possible protective agent against reproductive toxins.},
}

*Titanium/toxicity
Male
*Autophagy/drug effects
Animals
*Acetylcysteine/pharmacology
Mice
*Reactive Oxygen Species/metabolism
Cell Line
*Cell Proliferation/drug effects
*Metal Nanoparticles/toxicity
Spermatogonia/drug effects
Nanoparticles/toxicity

@article {pmid38828636,
year = {2024},
author = {Lu, J and Zhao, P and Ding, X and Liu, Y and Li, H},
title = {N-Acetylcysteine assists muscle development in offspring of mice subjected to maternal heat stress during pregnancy.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.13620},
pmid = {38828636},
issn = {1097-0010},
support = {No.32172725//National Natural Science Foundation of China/ ; 2023AAC02013//Ningxia Natural Science Foundation of China/ ; 2021YFC2101403//National Key Research and Development Program of China/ ; },
abstract = {BACKGROUND: Heat stress (HS) has been shown to affect reproductive performance and muscle development negatively in animals. N-Acetylcysteine (NAC) plays a pivotal role in enhancing the antioxidant performance in animals as a recognized antioxidant. The present study assesses the potential of NAC to modulate the reproductive performance and antioxidant function in pregnant mice exposed to HS. The role of NAC in muscle development of offspring mice was also explored.

RESULTS: The results showed that NAC supplementation from day 12 to day 18 of gestation increased the number of litters and enhanced the antioxidant function in pregnant mice under HS exposure. It improved the weight and body condition significantly in the offspring mice (P < 0.05). The alleviation of HS-induced muscle impairment with NAC was consistent with the alleviation of apoptosis, the enrichment of the proliferation and differentiation in the offspring mice muscle. N-Acetylcysteine also reversed HS-induced reduction in the cross-sectional area of the leg muscle and increased the proportion of myosin heavy chain IIx (MYHCIIx) in the muscle fiber.

CONCLUSION: The results of the present study support the use of NAC at a dose of 100 mg kg[-1] body weight as supplement for protecting the offspring derived from pregnant mice exposed to HS from muscle impairment by accelerating proliferation and differentiation. © 2024 Society of Chemical Industry.},
}

@article {pmid38825302,
year = {2024},
author = {Zhang, Y and Qu, Y and Cai, R and Gao, J and Xu, Q and Zhang, L and Kang, M and Jia, H and Chen, Q and Liu, Y and Ren, F and Zhou, MS},
title = {Atorvastatin ameliorates diabetic nephropathy through inhibiting oxidative stress and ferroptosis signaling.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {176699},
doi = {10.1016/j.ejphar.2024.176699},
pmid = {38825302},
issn = {1879-0712},
abstract = {Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe[2+] accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe[2+] accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy.},
}

@article {pmid38821668,
year = {2024},
author = {Naser, H and Munn, K and Lawrence, R and Wright, R and Grewal, E and Williams, L and Doak, S and Jenkins, G},
title = {Human plasma can modulate micronucleus frequency in TK6 and OE33 cells in vitro.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {896},
number = {},
pages = {503766},
doi = {10.1016/j.mrgentox.2024.503766},
pmid = {38821668},
issn = {1879-3592},
mesh = {Humans ; *Micronucleus Tests ; *DNA Damage ; *Barrett Esophagus/pathology/genetics ; *Adenocarcinoma/pathology/genetics ; *Esophageal Neoplasms/genetics/pathology ; Plasma/metabolism ; Interleukin-8/metabolism/genetics ; Cell Line, Tumor ; Cell Cycle/drug effects ; Male ; Middle Aged ; Adult ; Cell Survival/drug effects ; Female ; Micronuclei, Chromosome-Defective ; Interferon-beta ; Aged ; },
abstract = {In this paper, we studied the potential genotoxic effects of human plasma from healthy volunteers, as well as patients with gastro-oesophageal reflux disease, Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) using the oesophageal adenocarcinoma cell line (OE33) and the lymphoblastoid cell line (TK6). Both TK6 and OE33 cells were treated with plasma (10 % volume, replacing foetal bovine serum (FBS) or horse serum (HS)) at different time points of 4 h (for the micronucleus (Mn) assay and the invasion assay) and 24 h (for the cell cycle studies). Plasma-induced effects on DNA damage levels, cell viability and the cell cycle were studied by the micronucleus assay, cytokinesis block proliferation index (CBPI) and flow cytometry respectively. The expression of IL-8 in supernatants of TK6 cells and IFN-β in OE33 cells was also analysed by enzyme-linked immunosorbent assay (ELISA). Finally, we carried out an assessment of cellular invasion of OE33 cells following plasma treatment. The results of the micronucleus assay confirmed the genotoxicity of direct plasma treatment from some participants through the increase in DNA damage in TK6 cells. Conversely, some individual patient plasma samples reduced background levels of TK6 cell Mn frequency, in an anti-genotoxic fashion. In TK6 cells, (on average) plasma samples from patients with Barrett's oesophagus induced higher micronucleus levels than healthy volunteers (p= 0.0019). There was little difference in Mn induction when using plasma versus serum to treat the cells in vitro. Cell cycle results showed that direct plasma treatment had a marked impact on OE33 cells at 24 h (p=0.0182 for BO and p=0.0320 for OAC) by decreasing the proportion of cells in the S phase, while plasma exposure was less impactful on the cell cycle of TK6 cells. Invasion of OE33 cells was also seen to be non-significantly affected by plasma treatment of OE33 cells. The addition of N-acetyl cysteine NAC in a dose-dependent matter did not alter the formation of Mn in TK6 cells, suggesting that reactive oxygen species (ROS) are not the root cause of plasma's genotoxicity. The concentration of IL-8 in TK6 cells and IFN-β in OE33 cells was significantly higher in cells treated with OAC-derived plasma than in the untreated negative control. Collectively, our results demonstrate that plasma-specific effects are detectable which helps us better understand some important aspects of the biology of blood-based biomarkers under development.},
}

Humans
*Micronucleus Tests
*DNA Damage
*Barrett Esophagus/pathology/genetics
*Adenocarcinoma/pathology/genetics
*Esophageal Neoplasms/genetics/pathology
Plasma/metabolism
Interleukin-8/metabolism/genetics
Cell Line, Tumor
Cell Cycle/drug effects
Male
Middle Aged
Adult
Cell Survival/drug effects
Female
Micronuclei, Chromosome-Defective
Interferon-beta
Aged

@article {pmid38821596,
year = {2024},
author = {Wang, YJ and Hao, YY and Lee, DH and Guo, XY and Sun, HN and Kwon, T},
title = {Hispidin Increases Cell Apoptosis and Ferroptosis in Prostate Cancer Cells Through Phosphatidylinositol-3-Kinase and Mitogen-activated Protein Kinase Signaling Pathway.},
journal = {Anticancer research},
volume = {44},
number = {6},
pages = {2533-2544},
doi = {10.21873/anticanres.17059},
pmid = {38821596},
issn = {1791-7530},
mesh = {Humans ; Male ; *Ferroptosis/drug effects ; *Prostatic Neoplasms/pathology/metabolism/drug therapy ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; MAP Kinase Signaling System/drug effects ; Cell Movement/drug effects ; Signal Transduction/drug effects ; Mitochondria/drug effects/metabolism ; Pyridones/pharmacology ; Phosphatidylinositol 3-Kinase/metabolism ; Pyrones ; },
abstract = {BACKGROUND/AIM: Chemotherapy is mainly used in the clinical treatment of prostate cancer. Different anticancer mechanisms can induce cell death in various cancers. Reactive oxygen species (ROS) play crucial roles in cell proliferation, differentiation, apoptosis, and signal transduction. It is widely accepted that ROS accumulation is closely related to chemical drug-induced cancer cell death.

MATERIALS AND METHODS: We utilized the MTT assay to detect changes in cell proliferation. Additionally, colony formation and wound healing assay were conducted to investigate the effect of hispidin on cell colony formation and migration ability. Fluorescence microscopy was used to detect intracellular and mitochondrial ROS levels, while western blot was used for detection of cell apoptosis.

RESULTS: Hispidin treatment significantly decreased viability of PC3 and DU145 cancer cells but exhibited no cytotoxicity in WPMY-1 cells. Furthermore, hispidin treatment inhibited cell migration and colony formation and triggered cellular and mitochondrial ROS accumulation, leading to mitochondrial dysfunction and mitochondrion-dependent apoptosis. Moreover, hispidin treatment induced ferroptosis in PC3 cells. Scavenging of ROS with N-acetyl cysteine significantly inhibited hispidin-induced apoptosis by altering the expression of apoptosis-related proteins, such as cleaved caspase-3, 9, Bax, and Bcl2. Furthermore, hispidin treatment dramatically up-regulated MAPK (involving p38, ERK, and JNK proteins) and NF-kB signaling pathways while down-regulating AKT phosphorylation. Hispidin treatment also inhibited ferroptosis signaling pathways (involving P53, Nrf-2, and HO-1 proteins) in PC3 cells. In addition, inhibiting these signaling pathways via treatment with specific inhibitors significantly reversed hispidin-induced apoptosis, cellular ROS levels, mitochondrial dysfunction, and ferroptosis.

CONCLUSION: Hispidin may represent a potential candidate for treating prostate cancer.},
}

Humans
Male
*Ferroptosis/drug effects
*Prostatic Neoplasms/pathology/metabolism/drug therapy
*Apoptosis/drug effects
*Reactive Oxygen Species/metabolism
Cell Line, Tumor
Cell Proliferation/drug effects
MAP Kinase Signaling System/drug effects
Cell Movement/drug effects
Signal Transduction/drug effects
Mitochondria/drug effects/metabolism
Pyridones/pharmacology
Phosphatidylinositol 3-Kinase/metabolism
Pyrones

@article {pmid38818810,
year = {2024},
author = {Li, X and Li, Y and Yu, H and Men, LL and Deng, G and Liu, Z and Du, JL},
title = {Oxidized LDL decreases the survival of bone marrow stem cells via inhibition of Bcl-2 expression.},
journal = {Tissue engineering. Part A},
volume = {},
number = {},
pages = {},
doi = {10.1089/ten.TEA.2024.0025},
pmid = {38818810},
issn = {1937-335X},
abstract = {Therapy with mesenchymal stem cells (MSCs) is considered an attractive strategy for the repair or regeneration of damaged tissues. However, low survival of MSCs limits their applications clinically. Oxidized low-density lipoprotein (ox-LDL) is significantly increased in patients with hyperlipidemia and decreases the survival of MSCs. Bcl-2 is critically involved in important cell functions including cell membrane integrity and cell survival. The present study was designed to test the hypothesis that ox-LDL attenuate the survival of MSCs via suppression of Bcl-2 expression. Bone marrow MSCs from C57BL/6 mice were cultured with ox-LDL at different concentrations (0-140 μg/ml) for 24 hours with native LDL as control. Ox-LDL treatment substantially decreased the survival of MSCs dose-dependently and enhanced the release of intracellular LDH in association with a significant decrease in Bcl-2 protein level without change in BAX protein expression in MSCs. Bcl-2 overexpression effectively protected MSCs against ox-LDL-induced damages with preserved cell numbers without significant increase in LDH release. Treatment with N-acetylcysteine (NAC) (1 mM) effectively preserved Bcl-2 protein expression in MSCs and significantly attenuated ox-LDL-induced decrease of cell number and increase in the release of intracellular LDH. These data indicated that ox-LDL treatment resulted in a significant damage of cell membrane and dramatically decreased the survival of MSCs dose-dependently through inhibition of Bcl-2 expression. NAC treatment significantly protected MSCs against the damage of cell membrane by ox-LDL and promoted the survival of MSCs in association with preserved Bcl-2 expression.},
}

@article {pmid38815788,
year = {2024},
author = {Ge, L and Liu, P and Tian, L and Li, Y and Chen, L},
title = {Se-methylselenocysteine inhibits the progression of non-small cell lung cancer via ROS-mediated NF-κB signaling pathway.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {114101},
doi = {10.1016/j.yexcr.2024.114101},
pmid = {38815788},
issn = {1090-2422},
abstract = {Se-methylselenocysteine (MSC) is recognized for its potential in cancer prevention, yet the specific effects and underlying processes it initiates within non-small cell lung cancer (NSCLC) remain to be fully delineated. Employing a comprehensive array of assays, including CCK-8, colony formation, flow cytometry, MitoSOX Red staining, wound healing, transwell, and TUNEL staining, we evaluated MSC's effects on A549 and 95D cell lines. Our investigation extended to the ROS-mediated NF-κB signaling pathway, utilizing western blot analysis, P65 overexpression, and the application of IκB-α inhibitor (BAY11-7082) or N-acetyl-cysteine (NAC) to elucidate MSC's mechanism of action. In vivo studies involving subcutaneous xenografts in mice further confirmed MSC's inhibitory effect on tumor growth. Our findings indicated that MSC inhibited the proliferation of A549 and 95D cells, arresting cell cycle G0/G1 phase and reducing migration and invasion, while also inducing apoptosis and increasing intracellular ROS levels. This was accompanied by modulation of key proteins, including the upregulation of p21, p53, E-cadherin, Bax, cleaved caspase-3, cleaved-PARP, and downregulation of CDK4, SOD2, GPX-1. MSC was found to inhibit the NF-κB pathway, as evidenced by decreased levels of P-P65 and P-IκBα. Notably, overexpression of P65 and modulation of ROS levels with NAC could attenuate MSC's effects on cellular proliferation and metastasis. Moreover, MSC significantly curtailed tumor growth in vivo and disrupted the NF-κB signaling pathway. In conclusion, our research demonstrates that MSC exhibits anticancer effects against NSCLC by modulating the ROS/NF-κB signaling pathway, suggesting its potential as a therapeutic agent in NSCLC treatment.},
}

@article {pmid38812790,
year = {2024},
author = {Chung, J and Jernigan, J and Menees, KB and Lee, JK},
title = {RGS10 mitigates high glucose-induced microglial inflammation via the reactive oxidative stress pathway and enhances synuclein clearance in microglia.},
journal = {Frontiers in cellular neuroscience},
volume = {18},
number = {},
pages = {1374298},
pmid = {38812790},
issn = {1662-5102},
abstract = {Microglia play a critical role in maintaining brain homeostasis but become dysregulated in neurodegenerative diseases. Regulator of G-protein Signaling 10 (RGS10), one of the most abundant homeostasis proteins in microglia, decreases with aging and functions as a negative regulator of microglia activation. RGS10-deficient mice exhibit impaired glucose tolerance, and high-fat diet induces insulin resistance in these mice. In this study, we investigated whether RGS10 modulates microglia activation in response to hyperglycemic conditions, complementing our previous findings of its role in inflammatory stimuli. In RGS10 knockdown (KD) BV2 cells, TNF production increased significantly in response to high glucose, particularly under proinflammatory conditions. Additionally, glucose uptake and GLUT1 mRNA levels were significantly elevated in RGS10 KD BV2 cells. These cells produced higher ROS and displayed reduced sensitivity to the antioxidant N-Acetyl Cysteine (NAC) when exposed to high glucose. Notably, both BV2 cells and primary microglia that lack RGS10 exhibited impaired uptake of alpha-synuclein aggregates. These findings suggest that RGS10 acts as a negative regulator of microglia activation not only in response to inflammation but also under hyperglycemic conditions.},
}

@article {pmid38812125,
year = {2024},
author = {Chu, CS and Chen, YT and Liang, WZ},
title = {Investigation of the mechanisms behind ochratoxin A-induced cytotoxicity in human astrocytes and the protective effects of N-acetylcysteine.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4652},
pmid = {38812125},
issn = {1099-1263},
support = {//Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University/ ; },
abstract = {Ochratoxin A (OTA) is a type of mycotoxin commonly found in raw and processed foods. It is essential to be aware of this toxin, as it can harm your health if consumed in high quantities. OTA can induce toxic effects in various cell models. However, a more comprehensive understanding of the harmful effects of OTA on human astrocytes is required. This study evaluated OTA's neurotoxic effects on the Gibco® Human Astrocyte (GHA) cell line, its underlying mechanisms, and the antioxidant N-acetylcysteine (NAC) ability to prevent them. OTA exposure within 5-30 μM has induced concentration-dependent cytotoxicity. In the OTA-treated cells, the levels of reactive oxygen species (ROS) were found to be significantly increased, while the glutathione (GSH) contents were found to decrease considerably. The western blotting of OTA-treated cells has revealed increased Bax, cleaved caspase-9/caspase-3 protein levels, and increased Bax/Bcl-2 ratio. In addition, exposure to OTA has resulted in the induction of antioxidant responses associated with the protein expressions of Nrf2, HO-1, and NQO1. On the other hand, the pretreatment with NAC has partially alleviated the significant toxic effects of OTA. In conclusion, our findings suggest that oxidative stress and apoptosis are involved in the OTA-induced cytotoxicity in GHA cells. NAC could act as a protective agent against OTA-induced oxidative damage.},
}

@article {pmid38810310,
year = {2024},
author = {Shen, P and Xue, M and Hu, Z and Han, L and Deng, X},
title = {Direct targeting of S100A9 with Icariin counteracted acetaminophen‑induced hepatotoxicity.},
journal = {International immunopharmacology},
volume = {136},
number = {},
pages = {112296},
doi = {10.1016/j.intimp.2024.112296},
pmid = {38810310},
issn = {1878-1705},
abstract = {Acetaminophen (APAP) is a widely used antipyretic and analgesic medication, but its overdose can induce acute liver failure with lack of effective therapies. Icariin is a bioactive compound derived from the herb Epimedium that displays hepatoprotective activities. Here, we explored the protective effects and mechanism of icariin on APAP-induced hepatotoxicity. Icariin (25/50 mg/kg) or N-Acetylcysteine (NAC, 300 mg/kg) were orally administered in wild-type C57BL/6 mice for 7 consecutive days before the APAP administration. Icariin attenuated APAP-induced acute liver injury in mice, as measured by alleviated serum enzymes activities and hepatic apoptosis. In vitro, icariin pretreatment significantly inhibited hepatocellular damage and apoptosis by reducing the BAX/Bcl-2 ratio as well as the expression of cleaved-caspase 3 and cleaved-PARP depended on the p53 pathway. Moreover, icariin attenuated APAP-mediated inflammatory response and oxidative stress via the Nrf2 and NF-κB pathways. Importantly, icariin reduced the expression of S100A9, icariin interacts with S100A9 as a direct cellular target, which was supported by molecular dynamics simulation and surface plasmon resonance assay (equilibrium dissociation constant, KD = 1.14 μM). In addition, the genetic deletion and inhibition of S100A9 not only alleviated APAP-induced injury but also reduced the icariin's protective activity in APAP-mediated liver injury. These data indicated that icariin targeted S100A9 to alleviate APAP-induced liver damage via the following signaling pathways NF-κB, p53, and Nrf2.},
}

@article {pmid38810283,
year = {2024},
author = {Zhu, Y and Zhang, S and Shao, Y and Tang, L and Zhang, C and Tang, S and Lu, H},
title = {Regulatory role of oxidative stress in retrorsine - Induced apoptosis and autophagy in primary rat hepatocytes.},
journal = {Ecotoxicology and environmental safety},
volume = {279},
number = {},
pages = {116515},
doi = {10.1016/j.ecoenv.2024.116515},
pmid = {38810283},
issn = {1090-2414},
abstract = {Pyrrolizidine alkaloids (PAs) are a group of naturally occurring alkaloids widely present in plants. PAs are highly hepatotoxic and have been documented to cause many incidents of human and animal poisoning. Retrorsine (RTS) is a pyrrolizidine alkaloid (PA) derived from the Compositae Senecio, which has been shown to cause hepatotoxicity. Human liver poisoning occurs through the consumption of RTS-contaminated food, and animals can also be poisoned by ingesting RTS-containing toxic plants. The mechanism of RTS-induced liver toxicity is not fully understood. In this study, we demonstrated that RTS-induced oxidative stress plays a pivotal role in RTS-induced liver toxicity involving apoptosis and autophagy. The results showed that RTS treatment in the cultured Primary rat hepatocytes caused cytotoxicity and release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in a time- and dose-dependent manner. Our study showed that treatment of RTS induced ROS and MDA (malondialdehyde, a lipid peroxidation marker) in the hepatocytes, and reduced antioxidant capacity (GSH content, SOD activity), suggesting RTS treatment caused oxidative stress response in the hepatocytes. Furthermore, we found that RTS induced apoptosis and autophagy in the hepatocytes, and RTS-induced apoptosis and autophagy could be alleviated by ROS scavenger N-acetylcysteine (NAC) and the MAPK pathway inhibitors suggesting ROS/MAPK signaling pathway plays a role in RTS induced apoptosis and autophagy. Collectively, this study reveals the regulatory mechanism of oxidative stress in RTS-induced apoptosis and autophagy in the hepatocytes, providing important insights of molecular mechanisms of hepatotoxicity induced by RTS and related pyrrolizidine alkaloids in liver. This mechanism provides a basis for the prevention and treatment of PA poisoning in humans and animals.},
}

@article {pmid38800031,
year = {2024},
author = {Raeeszadeh, M and Arvand, S and Shojaee Moghadam, D and Akradi, L},
title = {Evaluation of the influence of N-acetylcysteine and broccoli extract on systemic paraquat poisoning: Implications for biochemical, physiological, and histopathological parameters in rats.},
journal = {Iranian journal of basic medical sciences},
volume = {27},
number = {7},
pages = {895-903},
pmid = {38800031},
issn = {2008-3866},
abstract = {OBJECTIVES: Paraquat (PQ), a potent environmental herbicide, is recognized for inducing irreparable toxic damage to biological systems. This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) and broccoli extract, individually and in combination, in alleviating PQ poisoning in rats, leveraging the exceptional anti-oxidant, anti-inflammatory, and anti-apoptotic properties of broccoli.

MATERIALS AND METHODS: Seventy Wistar rats were categorized into seven groups: C (control, vehicle), PQ (paraquat at 40 mg/kg), BC (broccoli extract at 300 mg/kg), NC (N-acetylcysteine at the same dose of 300 mg/kg), and combined groups PQ+BC, PQ+NC, and NC+PQ+BC, all administered equivalent doses. After 42 days, blood samples were collected to evaluate liver and kidney parameters, proinflammatory biomarkers, caspase-3, and caspase-9. Lung tissues were excised, with one part preserved for hydroxyproline and oxidative stress parameter measurement and another sectioned and stained for histopathological analysis.

RESULTS: The PQ group exhibited the highest lung-to-body weight (LW/BW) ratio, while the PQ+BC+NC group demonstrated the lowest ratio. Results indicated an elevated lung hydroxyproline concentration and a significant reduction in anti-oxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase, and total anti-oxidant capacity) (P<0.001). The PQ+BC group showed modified malondialdehyde levels, reaching a peak in the PQ group. Additionally, a significant decrease in tumor necrosis factor, interleukin-1, caspase-3, and caspase-9 was observed in the PQ+BC+NC group (P<0.01). Pulmonary edema, hyperemia, and severe hemorrhage observed in the PQ group were notably reduced in the PQ+BC+NC group.

CONCLUSION: The combination of active compounds from broccoli and NAC demonstrated significant systemic and pulmonary effects in mitigating PQ-induced toxicity.},
}

@article {pmid38800015,
year = {2024},
author = {Fan, H and Le, JW and Sun, M and Zhu, JH},
title = {N-acetylcysteine protects septic acute kidney injury by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis.},
journal = {Iranian journal of basic medical sciences},
volume = {27},
number = {7},
pages = {850-856},
pmid = {38800015},
issn = {2008-3866},
abstract = {OBJECTIVES: To investigate the protective effect of N-acetylcysteine (NAC) on septic acute kidney injury (SAKI) via regulating Sirtuin3 (SIRT3)-mediated mitochondrial dysfunction and apoptosis.

MATERIALS AND METHODS: By constructing SIRT3 knockout mice and culturing kidney tubular epithelial cells (KTECs), we assessed the changes of renal function and detected the protein expression of adenine nucleotide translocator (ANT), cyclophilin (CypD) and voltage-dependent anion channel (VDAC) using western-blotting, and simultaneously detected toll-like receptor 4 (TLR4), inhibitor of kappa B kinase (IKKβ), inhibitor of Kappa Bα (IκBα), and p65 protein expression. We observed mitochondrial damage of KTECs using a transmission electron microscope and assessed apoptosis by TdT-mediated dUTP Nick-End Labeling and flow cytometry.

RESULTS: SIRT3 deficiency led to the deterioration of renal function, and caused a significant increase in inducible nitric oxide synthase production, a decrease in mitochondrial volume, up-regulation of TLR4, IκBα, IKKβ, and p65 proteins, and up-regulation of ANT, CypD and VDAC proteins. However, NAC significantly improved renal function and down-regulated the expression of TLR4, IκBα, IKKβ, and p65 proteins. Furthermore, SIRT3 deficiency led to a significant increase in KTEC apoptosis, while NAC up-regulated the expression of SIRT3 and inhibited apoptosis.

CONCLUSION: NAC has a significant protective effect on SAKI by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis of KTECs.},
}

@article {pmid38799536,
year = {2024},
author = {Jamalvi, SA and Rauf, SA and Sherali, A and Ali, SK and Shah, HH and Jamalvi, F and Yogeeta, F and Dave, T},
title = {COVID-19 presenting as severe acute hepatitis in a pediatric patient with thalassemia minor: A case report.},
journal = {Clinical case reports},
volume = {12},
number = {6},
pages = {e8955},
pmid = {38799536},
issn = {2050-0904},
abstract = {KEY CLINICAL MESSAGE: This case emphasizes the significance of COVID-19 in pediatric patients presenting with unusual hepatic manifestations, urging clinicians to broaden their diagnostic lens. The unexpected elevation of SARS-CoV-2 antibodies and the effective use of N-acetyl cysteine highlight the importance of adaptability in treatment strategies.

ABSTRACT: This case report presents a unique manifestation of severe hepatic involvement in a 4-year-old girl with thalassemia minor and COVID-19. Despite the absence of prominent respiratory symptoms, the patient exhibited jaundice, elevated liver enzymes, and coagulopathy. Initial suspicion of viral hepatitis was replaced by the discovery of significantly elevated SARS-CoV-2 antibodies. A multidisciplinary approach, including gastroenterology consultation and an extensive workup, was pivotal in ruling out alternative etiologies. Unconventional use of N-acetyl cysteine contributed to clinical improvement, highlighting the need for adaptable treatment strategies. This case underscores the importance of heightened awareness in recognizing atypical presentations of COVID-19 in pediatric patients, especially those with underlying health conditions. Further exploration into nuanced manifestations and treatment approaches is warranted for comprehensive clinical management.},
}

@article {pmid38798604,
year = {2024},
author = {Winterlind, EL and Malone, SG and Setzer, MR and Murphy, MA and Saunders, D and Gray, JC},
title = {N-acetylcysteine as a treatment for substance use cravings: A meta-analysis.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.05.13.24306839},
pmid = {38798604},
abstract = {N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. There were no between-group differences in risk of AEs. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.},
}

@article {pmid38797057,
year = {2024},
author = {Li, Y and Guo, M and Wang, Q and Zhou, H and Wu, W and Lin, H and Fan, H},
title = {Glaesserella parasuis serotype 5 induces pyroptosis via the RIG-I/MAVS/NLRP3 pathway in swine tracheal epithelial cells.},
journal = {Veterinary microbiology},
volume = {294},
number = {},
pages = {110127},
doi = {10.1016/j.vetmic.2024.110127},
pmid = {38797057},
issn = {1873-2542},
abstract = {Glaesserella parasuis (G. parasuis) is a common Gram-negative commensal bacterium in the upper respiratory tract of swine that can cause Glässer's disease under stress conditions. Pyroptosis is an important immune defence mechanism of the body that plays a crucial role in clearing pathogen infections and endogenous danger signals. This study aimed to investigate the mechanism of G. parasuis serotype 5 SQ (GPS5-SQ)-induced pyroptosis in swine tracheal epithelial cells (STECs). The results of the present study demonstrated that GPS5-SQ infection induces pyroptosis in STECs by enhancing the protein level of the N-terminal domain of gasdermin D (GSDMD-N) and activating the NOD-like receptor protein 3 (NLRP3) inflammasome. Furthermore, the levels of pyroptosis-related proteins, including GSDMD-N and cleaved caspase-1 were considerably decreased in STECs after the knockdown of retinoic acid inducible gene-I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). These results indicated that GPS5-SQ might trigger pyroptosis through the activation of the RIG-I/MAVS/NLRP3 signaling pathway. More importantly, the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) repressed the activation of the RIG-I/MAVS/NLRP3 signaling and rescued the decrease in Occludin and zonula occludens-1 (ZO-1) after GPS5-SQ infection. Overall, our findings show that GPS5-SQ can activate RIG-I/MAVS/NLRP3 signaling and destroy the integrity of the epithelial barrier by inducing ROS generation in STECs, shedding new light on G. parasuis pathogenesis.},
}

@article {pmid38791242,
year = {2024},
author = {Pascal, W and Smoliński, A and Gotowiec, M and Wojtkiewicz, M and Stachura, A and Pełka, K and Kopka, M and Quinn, KP and Woessner, AE and Grzelecki, D and Włodarski, P},
title = {Pre-Incisional and Multiple Intradermal Injection of N-Acetylcysteine Slightly Improves Incisional Wound Healing in an Animal Model.},
journal = {International journal of molecular sciences},
volume = {25},
number = {10},
pages = {},
pmid = {38791242},
issn = {1422-0067},
support = {1M15/NM1/17//Medical University of Warsaw/ ; MNiSW/2019/106/DIR/NN3//Polish Ministry of Science and Higher Education/ ; },
mesh = {Animals ; *Wound Healing/drug effects ; *Acetylcysteine/pharmacology/administration & dosage ; Rats ; *Rats, Sprague-Dawley ; Injections, Intradermal ; Disease Models, Animal ; Skin/drug effects/pathology/injuries ; Male ; Surgical Wound/drug therapy/pathology ; Collagen/metabolism ; Cicatrix/pathology/drug therapy ; },
abstract = {The objective of this study was to investigate if delivering multiple doses of N-acetylcysteine (NAC) post-surgery in addition to pre-incisional administration significantly impacts the wound healing process in a rat model. Full-thickness skin incisions were carried out on the dorsum of 24 Sprague-Dawley rats in six locations. Fifteen minutes prior to the incision, half of the sites were treated with a control solution, with the wounds on the contralateral side treated with solutions containing 0.015%, 0.03% and 0.045% of NAC. In the case of the NAC treated group, further injections were given every 8 h for three days. On days 3, 7, 14 and 60 post-op, rats were sacrificed to gather material for the histological analysis, which included histomorphometry, collagen fiber organization analysis, immunohistochemistry and Abramov scale scoring. It was determined that scars treated with 0.015% NAC had significantly lower reepithelization than the control at day 60 post-op (p = 0.0018). Scars treated with 0.045% NAC had a significantly lower collagen fiber variance compared to 0.015% NAC at day 14 post-op (p = 0.02 and p = 0.04) and a lower mean scar width than the control at day 60 post-op (p = 0.0354 and p = 0.0224). No significant differences in the recruitment of immune cells and histological parameters were found. The results point to a limited efficacy of multiple NAC injections post-surgery in wound healing.},
}

Animals
*Wound Healing/drug effects
*Acetylcysteine/pharmacology/administration & dosage
Rats
*Rats, Sprague-Dawley
Injections, Intradermal
Disease Models, Animal
Skin/drug effects/pathology/injuries
Male
Surgical Wound/drug therapy/pathology
Collagen/metabolism
Cicatrix/pathology/drug therapy

@article {pmid38788361,
year = {2024},
author = {Cao, W and Zeng, Y and Su, Y and Gong, H and He, J and Liu, Y and Li, C},
title = {The involvement of oxidative stress and the TLR4/NF-κB/NLRP3 pathway in acute lung injury induced by high-altitude hypoxia.},
journal = {Immunobiology},
volume = {229},
number = {3},
pages = {152809},
doi = {10.1016/j.imbio.2024.152809},
pmid = {38788361},
issn = {1878-3279},
abstract = {OBJECTIVE: This study investigated the effect of oxidative stress and the TLR4/NF-κB/NLRP3 pathway on the pathogenesis of acute lung injury (ALI) induced by high-altitude hypoxia.

METHODS: Rats were placed in an animal hyperbaric oxygen chamber to establish a rat model of ALI induced by high-altitude hypoxia after treatment with N-acetylcysteine (NAC; a reactive oxygen species [ROS] inhibitor) or/and MCC950 (an NLPR3 inflammasome inhibitor). After modeling, the wet-to-dry weight ratio (W/D) of rat lung tissues was calculated. In lung tissues, ROS levels were detected with immunofluorescence, the enzyme activity was tested with the kit, and the expression of TLR4/NF-κB/NLRP3 pathway-related genes and proteins was measured with western blotting and qRT-PCR. The levels of inflammatory factors in the serum were quantified with ELISA.

RESULTS: After modeling, rats showed significantly increased W/D, ROS levels, and Malondialdehyde (MDA) concentrations and markedly diminished Superoxide dismutase (SOD) and Glutathione (GSH) concentrations in lung tissues (all P < 0.01), accompanied by substantially enhanced serum levels of TNF-α, IL-6, and IL-1β, significantly reduced serum levels of IL-10, and remarkably augmented TLR4, NLRP3, p-NF-κB p65, NF-κB p65 mRNA, and Caspase-1 expression in lung tissues (all P < 0.01). Furthermore, treatment with NAC or MCC950 alone or in combination prominently lowered the W/D of lung tissues (P < 0.01), serum levels of TNF-α (P < 0.05), IL-6 (P < 0.05), and IL-1β (P < 0.01), and NF-κB p65 expression and phosphorylation (P < 0.05, P < 0.01) while significantly increasing SOD and GSH concentrations (P < 0.05, P < 0.01) and serum levels of IL-10 (P < 0.01) in modeled rats. Meanwhile, treatment of NAC alone or combined with MCC950 significantly reduced MDA concentration and ROS levels (P < 0.05, P < 0.01) in modeled rats, and treatment of MCC950 alone or combined with NAC considerably declined TLR4, NLRP3, and Caspase-1 expression in modeled rats (P < 0.05, P < 0.01).

CONCLUSION: Inhibition of oxidative stress and the TLR4/NF-κB/NLRP3 pathway can ameliorate ALI in rats exposed to high-altitude hypoxia.},
}

@article {pmid38785564,
year = {2024},
author = {Kobroob, A and Kumfu, S and Chattipakorn, N and Wongmekiat, O},
title = {Modulation of Sirtuin 3 by N-Acetylcysteine Preserves Mitochondrial Oxidative Phosphorylation and Restores Bisphenol A-Induced Kidney Damage in High-Fat-Diet-Fed Rats.},
journal = {Current issues in molecular biology},
volume = {46},
number = {5},
pages = {4935-4950},
pmid = {38785564},
issn = {1467-3045},
support = {075/2564//The Faculty of Medicine Endowment Fund for Medical Research, Chiang Mai University, Chiang Mai, Thailand/ ; },
abstract = {Bisphenol A (BPA) and high-fat diets (HFD) are known to adversely affect the kidneys. However, the combined effects of both cases on kidney health and the potential benefits of N-acetylcysteine (NAC) in mitigating these effects have not been investigated. To explore these aspects, male Wistar rats were fed with HFD and allocated to receive a vehicle or BPA. At week twelve, the BPA-exposed rats were subdivided to receive a vehicle or NAC along with BPA until week sixteen. Rats fed HFD and exposed to BPA showed renal dysfunction and structural abnormalities, oxidative stress, inflammation, and mitochondrial dysfunction, with alterations in key proteins related to mitochondrial oxidative phosphorylation (OXPHOS), bioenergetics, oxidative balance, dynamics, apoptosis, and inflammation. Treatment with NAC for 4 weeks significantly improved these conditions. The findings suggest that NAC is beneficial in protecting renal deterioration brought on by prolonged exposure to BPA in combination with HFD, and modulation of sirtuin 3 (SIRT3) signaling by NAC appears to play a key role in the preservation of homeostasis and integrity within the mitochondria by enhancing OXPHOS activity, maintaining redox balance, and reducing inflammation. This study provides valuable insights into potential therapeutic strategies for preserving kidney health in the face of environmental and dietary challenges.},
}

@article {pmid38781725,
year = {2024},
author = {Nagano, S and Unuma, K and Aki, T and Uemura, K},
title = {N-acetylcysteine alleviates arsenic trioxide-induced reductions in hepatic catalase gene expression both in vitro and in vivo.},
journal = {Legal medicine (Tokyo, Japan)},
volume = {69},
number = {},
pages = {102458},
doi = {10.1016/j.legalmed.2024.102458},
pmid = {38781725},
issn = {1873-4162},
abstract = {Arsenic trioxide (ATO), one of the oldest and most frequently used poisons, is well-known in forensic science for inducing hepatotoxicity. The regulation of peroxisomal antioxidative enzyme catalase (CAT) involves intricate mechanisms at both transcriptional and post-transcriptional levels. However, the molecular mechanisms underlying the regulation of CAT gene expression in hepatic cells remain elusive. Furthermore, the regulation of CAT gene expression evident in animals administered with ATO in vivo is not well-explored, although several studies have revealed ATO-induced reductions in CAT enzymatic activity in rat livers. In this study, we revealed ATO-dependent reductions in CAT gene expression in both rat liver and Huh-7 human hepatoma cells. Our results indicate that the decline in CAT enzymatic activity can be attributed, at least in part, to the downregulation of its gene expression. The ATO-induced reduction in CAT expression was concurrent with the reduction in peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator (PGC)-1α and inactivation of PPARγ, both considered as positive regulators of CAT gene expression. Moreover, antioxidant N-acetylcysteine (NAC) demonstrated the capability to alleviate the downregulation of CAT gene expression both in vivo and in vitro. Additionally, NAC played a role in alleviating ATO-induced hepatotoxicity, potentially by mitigating the transcriptional downregulation of the CAT gene. Altogether, these results indicate that ATO exerts toxicity by inhibiting the antioxidant defense mechanism, which may be useful for forensic diagnosis of arsenic poisoning and clinical treatment of mitigating ATO-induced hepatotoxicity.},
}

@article {pmid38775255,
year = {2024},
author = {Bolarinwa, AB and Oduwole, O and Okebe, J and Ogbenna, AA and Otokiti, OE and Olatinwo, AT},
title = {Antioxidant supplementation for sickle cell disease.},
journal = {The Cochrane database of systematic reviews},
volume = {5},
number = {5},
pages = {CD013590},
pmid = {38775255},
issn = {1469-493X},
mesh = {Humans ; *Anemia, Sickle Cell/drug therapy/blood ; *Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Bias ; *Dietary Supplements ; Oxidative Stress/drug effects ; Placebos/therapeutic use ; Quality of Life ; *Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the presence of an abnormal haemoglobin molecule called haemoglobin S (HbS). When subjected to oxidative stress from low oxygen concentrations, HbS molecules form rigid polymers, giving the red cell the typical sickle shape. Antioxidants have been shown to reduce oxidative stress and improve outcomes in other diseases associated with oxidative stress. Therefore, it is important to review and synthesize the available evidence on the effect of antioxidants on the clinical outcomes of people with SCD.

OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD.

SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023.

SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing antioxidant supplementation to placebo, other antioxidants, or different doses of antioxidants, in people with SCD.

DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed the risk of bias and certainty of the evidence, and reported according to Cochrane methodological procedures.

MAIN RESULTS: The review included 1609 participants in 26 studies, with 17 comparisons. We rated 13 studies as having a high risk of bias overall, and 13 studies as having an unclear risk of bias overall due to study limitations. We used GRADE to rate the certainty of evidence. Only eight studies reported on our important outcomes at six months. Vitamin C (1400 mg) plus vitamin E (800 mg) versus placebo Based on evidence from one study in 83 participants, vitamin C (1400 mg) plus vitamin E (800 mg) may not be better than placebo at reducing the frequency of crisis (risk ratio (RR) 1.18, 95% confidence interval (CI) 0.64 to 2.18), the severity of pain (RR 1.33, 95% CI 0.40 to 4.37), or adverse effects (AE), of which the most common were headache, nausea, fatigue, diarrhoea, and epigastric pain (RR 0.56, 95% CI 0.31 to 1.00). Vitamin C plus vitamin E may increase the risk of SCD-related complications (acute chest syndrome: RR 2.66, 95% CI 0.77 to 9.13; 1 study, 83 participants), and increase haemoglobin level (median (interquartile range) 90 (81 to 96) g/L versus 93.5 (84 to 105) g/L) (1 study, 83 participants) compared to placebo. However, the evidence for all the above effects is very uncertain. The study did not report on quality of life (QoL) of participants and their caregivers, nor on frequency of hospitalization. Zinc versus placebo Zinc may not be better than placebo at reducing the frequency of crisis at six months (rate ratio 0.62, 95% CI 0.17 to 2.29; 1 study, 36 participants; low-certainty evidence). We are uncertain whether zinc is better than placebo at improving sickle cell-related complications (complete healing of leg ulcers at six months: RR 2.00, 95% CI 0.60 to 6.72; 1 study, 34 participants; very low-certainty evidence). Zinc may be better than placebo at increasing haemoglobin level (g/dL) (MD 1.26, 95% CI 0.44 to 1.26; 1 study, 36 participants; low-certainty evidence). The study did not report on severity of pain, QoL, AE, and frequency of hospitalization. N-acetylcysteine versus placebo N-acetylcysteine (NAC) 1200 mg may not be better than placebo at reducing the frequency of crisis in SCD, reported as pain days (rate ratio 0.99 days, 95% CI 0.53 to 1.84; 1 study, 96 participants; low-certainty evidence). Low-certainty evidence from one study (96 participants) suggests NAC (1200 mg) may not be better than placebo at reducing the severity of pain (MD 0.17, 95% CI -0.53 to 0.87). Compared to placebo, NAC (1200 mg) may not be better at improving physical QoL (MD -1.80, 95% CI -5.01 to 1.41) and mental QoL (MD 2.00, 95% CI -1.45 to 5.45; very low-certainty evidence), reducing the risk of adverse effects (gastrointestinal complaints, pruritus, or rash) (RR 0.92, 95% CI 0.75 to 1.14; low-certainty evidence), reducing the frequency of hospitalizations (rate ratio 0.98, 95% CI 0.41 to 2.38; low-certainty evidence), and sickle cell-related complications (RR 5.00, 95% CI 0.25 to 101.48; very low-certainty evidence), or increasing haemoglobin level (MD -0.18 g/dL, 95% CI -0.40 to 0.04; low-certainty evidence). L-arginine versus placebo L-arginine may not be better than placebo at reducing the frequency of crisis (monthly pain) (RR 0.71, 95% CI 0.26 to 1.95; 1 study, 50 participants; low-certainty evidence). However, L-arginine may be better than placebo at reducing the severity of pain (MD -1.41, 95% CI -1.65 to -1.18; 2 studies, 125 participants; low-certainty evidence). One participant allocated to L-arginine developed hives during infusion of L-arginine, another experienced acute clinical deterioration, and a participant in the placebo group had clinically relevant increases in liver function enzymes. The evidence is very uncertain whether L-arginine is better at reducing the mean number of days in hospital compared to placebo (MD -0.85 days, 95% CI -1.87 to 0.17; 2 studies, 125 participants; very low-certainty evidence). Also, L-arginine may not be better than placebo at increasing haemoglobin level (MD 0.4 g/dL, 95% CI -0.50 to 1.3; 2 studies, 106 participants; low-certainty evidence). No study in this comparison reported on QoL and sickle cell-related complications. Omega-3 versus placebo Very low-certainty evidence shows no evidence of a difference in the risk of adverse effects of omega-3 compared to placebo (RR 1.05, 95% CI 0.74 to 1.48; 1 study, 67 participants). Very low-certainty evidence suggests that omega-3 may not be better than placebo at increasing haemoglobin level (MD 0.36 g/L, 95% CI -0.21 to 0.93; 1 study, 67 participants). The study did not report on frequency of crisis, severity of pain, QoL, frequency of hospitalization, and sickle cell-related complications.

AUTHORS' CONCLUSIONS: There was inconsistent evidence on all outcomes to draw conclusions on the beneficial and harmful effects of antioxidants. However, L-arginine may be better than placebo at reducing the severity of pain at six months, and zinc may be better than placebo at increasing haemoglobin level. We are uncertain whether other antioxidants are beneficial for SCD. Larger studies conducted on each comparison would reduce the current uncertainties.},
}

Humans
*Anemia, Sickle Cell/drug therapy/blood
*Antioxidants/therapeutic use
Ascorbic Acid/therapeutic use
Bias
*Dietary Supplements
Oxidative Stress/drug effects
Placebos/therapeutic use
Quality of Life
*Randomized Controlled Trials as Topic

@article {pmid38774197,
year = {2023},
author = {Sztolsztener, K and Dzięcioł, J and Chabowski, A},
title = {N-acetylcysteine acts as a potent anti-inflammatory agent altering the eicosanoid profile in the development of simple steatosis and its progression to hepatitis.},
journal = {Clinical and experimental hepatology},
volume = {9},
number = {4},
pages = {386-395},
pmid = {38774197},
issn = {2392-1099},
abstract = {AIM OF THE STUDY: We aimed to examine the influence of N-acetylcysteine (NAC) on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) in rats with a specific focus on the eicosanoid pathway.

MATERIAL AND METHODS: The experiment was conducted on male Wistar rats fed a standard diet or a high-fat diet (HFD) for eight weeks. In the entire experiment, half of rats from both groups received intragastrically NAC solution prepared in normal saline. H + E staining was used for the histological assessment of liver tissue. The gas-liquid chromatography (GLC) technique was used for the assessment of the activity of n-3 and n-6 polyunsaturated fatty acid (PUFA) pathways and arachidonic acid concentration. ELISA and multiplex immunoassay kits were applied for the measurement of eicosanoid, cytokine, and chemokine levels. The Western blot technique was applied to determine the expression of proteins involved in the inflammation pathway.

RESULTS: NAC decreased hepatic n-6 PUFA activity in all examined lipid pools and decreased the hepatic content of arachidonic acid as a pro-inflammatory precursor in each lipid pool, especially in the phospholipid fraction in rats with fatty lipid disease. NAC administration abolished 5-LOX expression, leading to a decrease in the content of pro-inflammatory leukotriene B4 and leukotriene C4. In rats with steatosis, NAC weakened NF-κB expression and raised Nrf-2 expression, inhibiting the synthesis of pro-inflammatory cytokines and chemokines.

CONCLUSIONS: NAC treatment significantly rate-limited the progression of simple hepatic steatosis to hepatitis in a rat model of MASLD.},
}