@article {pmid40111652, year = {2025}, author = {Bai, H and Chen, H and Du, S and Qiu, D and Li, S and Ma, T and Gao, R and Zhang, Z}, title = {N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40111652}, issn = {1559-1182}, support = {SYKJYB202302//Discipline Project of College of Veterinary Medicine/ ; NDYB2022-4//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; NDYB2022-7//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; 2023MS03035//Natural Science Foundation of Inner Mongolia Autonomous Region of china/ ; }, abstract = {Ketamine, an N-methyl-D-aspartate receptor antagonist with anesthetic and analgesic properties, is extensively utilized for the induction and maintenance of pediatric perioperative anesthesia. Increasing evidence suggests that prolonged exposure to ketamine may induce neurotoxicity in developing animals, adversely affecting their long-term cognitive function. N-acetylcysteine (NAC) is an organic sulfur compound in the Allium genus; however, the mechanisms through which it alleviates ketamine-induced neurotoxicity during developmental stages remain inadequately understood. Refine the investigation of the mechanisms by which Nac mitigates ketamine-induced neurotoxicity during development via ferroptosis and pyroptosis pathways. Postnatal day 7 in SD rats PC12 cells and HAPI cells were used in this study. The neuroprotective mechanism of Nac was elucidated through pathological, histological, and molecular biological methodologies to assess pyroptosis, ferroptosis, hippocampal tissue damage, and behavioral modifications in adulthood. The results suggest that prior administration of Nac reduced lipid peroxidation and mitochondrial injury, along with pyroptosis activated by the NLRP3/caspase-1 pathway, hippocampal damage, and cognitive deficits after exposure to ketamine. In summary, our findings from both in vivo and in vitro studies indicate that ROS plays a significant regulatory role in the neurotoxic effects of ketamine during development. Furthermore, Nac mitigates hippocampal damage and cognitive deficits associated with ketamine exposure by inhibiting ROS-mediated ferroptosis and pyroptosis.}, } @article {pmid40108283, year = {2025}, author = {Charoensappakit, A and Sae-Khow, K and Vutthikraivit, N and Maneesow, P and Sriprasart, T and Pachinburavan, M and Leelahavanichkul, A}, title = {Immune suppressive activities of low-density neutrophils in sepsis and potential use as a novel biomarker of sepsis-induced immune suppression.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {9458}, pmid = {40108283}, issn = {2045-2322}, support = {N41A640076, N34A660583//The National Research Council of Thailand (NRCT)/ ; RA-MF-18/65, RA-MF-15/66, and RA-MF-14/67//Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University/ ; B16F640175//The Program Management Unit for Human Resources, Institutional Development, Research, and Innovation/ ; }, mesh = {Humans ; *Sepsis/immunology ; *Neutrophils/immunology/metabolism ; *Biomarkers ; Male ; Middle Aged ; Female ; *B7-H1 Antigen/metabolism ; Aged ; T-Lymphocytes/immunology/metabolism ; Antigens, CD/metabolism ; Leukocytes, Mononuclear/metabolism/immunology ; Adult ; Phagocytosis ; Apoptosis ; }, abstract = {Data of low-density neutrophils (LDN), the neutrophils in the peripheral blood mononuclear cells (PBMC) fraction, in sepsis is still less. As such, LDN (CD66b-positive cells in PBMC) was highest in intensive care unit (ICU) patients with sepsis (n=24) compared with non-sepsis (n=10) and healthy control (n=20), with a negative correlation with lymphocyte count and could predict secondary infection and mortality with the area under the curve (AUC) at 0.79 and 0.84, respectively. Compared with sepsis normal-density neutrophils (NDN), sepsis-LDN demonstrated higher expression of CD66b, CD63, CD11b, and CD184, but lower expression of CD62L and CD182 and defects of effector functions, including phagocytosis and apoptosis. The t-distributed stochastic neighbor embedding (t-SNEs) demonstrated high program cell death ligand-1 (PD-L1) in sepsis-LDN. In sepsis samples, the T cell proliferation in PBMC (T cells with LDNs) was lower than that in the isolated T cells (T cells alone) and incubation of anti-PD-L1 neutralizing antibody, but not a reactive oxygen species (ROS) scavenger (N-acetyl cysteine), improved the T cell suppression. Additionally, 30 min lipopolysaccharide (LPS) activation altered healthy control NDN into LPS-LDN (reduced density) and LPS-NDN (maintain density) with similarly elevated CD66b, CD11B, and CD62L. However, LPS-LDN (in vitro LDN) showed lower expression of CD63, CD184, and PD-L1 compared with LDN from patients (sepsis-LDN), suggesting a partial LPS impact on LDN generation. From the microscopic-based method (Wright's staining in PBMC), sepsis-LDN demonstrated a mixed population of mature and immature cells with a good correlation with the flow-based analysis (Bland-Altman analysis and AUC). In conclusion, LDN in sepsis, partly generated by LPS activation, was associated with secondary infection and T cell suppression, mainly through the expression of PD-L1, which might be an immune suppression biomarker, especially with a less expensive microscopic-based method.}, } @article {pmid40106157, year = {2025}, author = {Zhang, F and Zhang, C and Sun, W and Xie, S and Wu, P and Zeng, G and Liu, X}, title = {Proteomic Profiling and Therapeutic Targeting of Oxidative Stress in Autoimmune Encephalitis.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {2}, pages = {38}, pmid = {40106157}, issn = {1559-1166}, support = {82360251//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Oxidative Stress ; Mice ; *Mice, Inbred C57BL ; Humans ; Female ; *Acetylcysteine/therapeutic use/pharmacology ; *Encephalitis/metabolism/drug therapy ; *Encephalomyelitis, Autoimmune, Experimental/metabolism/drug therapy/blood ; Biomarkers/blood ; Male ; Adult ; Hashimoto Disease/drug therapy/metabolism/blood ; Proteome/metabolism ; Antioxidants/therapeutic use/metabolism ; Middle Aged ; }, abstract = {Autoimmune encephalitis (AE) is an immune-mediated non-infectious disease, and novel and robust biomarkers are needed to improve the diagnosis and prognostic outcomes of AE. Oxidative stress is a ubiquitous cellular process causing damage to various biological molecules. The aim of our study was to understand the clinical implication and mechanism underlying oxidative stress in AE. Liquid chromatography-mass spectrometry analysis was conducted on the serum of eight patients with AE and seven healthy controls, and oxidative stress was characterized. Experimental autoimmune encephalitis (EAE) models were established in C57BL/6 and SJL mice for investigation of the therapeutic effect and mechanism of anti-oxidative stress N-acetylcysteine (NAC). We provided proteomic landscape in the serum of AE and identified antioxidant ALB, APOE, GPX3, and SOD3 as serum diagnostic markers of AE. The antioxidant markers were lowly expressed both in the serum of AE patients and central nervous system (CNS) of EAE mice. NAC administration improved clinical signs and motor function and alleviated nerve injury of EAE mice as well as lowered oxidative stress (decreased MDA content and ROS accumulation and elevated SOD activity and GSH content). ALB, APOE, GPX3, and SOD3 expressions were elevated by NAC in the CNS of EAE mice. Moreover, NAC reduced tissue-resident CD4[+] and CD8[+] T cells and GFAP-marked astrocytes and Iba-1-marked microglia in EAE mice, thus alleviating autoimmunity-mediated damage and neuroinflammation. Our findings facilitate the discovery of novel oxidative stress-related biomarkers for AE and reveal the promise of anti-oxidative stress for AE management.}, } @article {pmid40106010, year = {2025}, author = {Yuksel, C and Uz, YH}, title = {Protective effects of N-acetylcysteine against titanium dioxide nanoparticles-induced kidney damage in rats.}, journal = {Journal of molecular histology}, volume = {56}, number = {2}, pages = {112}, pmid = {40106010}, issn = {1567-2387}, support = {Project number: TUBAP 2022/57//Scientific Research Projects Coordination Unit of Trakya University, Turkey/ ; Project number: TUBAP 2022/57//Scientific Research Projects Coordination Unit of Trakya University, Turkey/ ; }, mesh = {Animals ; *Titanium/adverse effects/toxicity ; *Acetylcysteine/pharmacology ; Rats ; *Kidney/drug effects/pathology/metabolism ; Male ; Apoptosis/drug effects ; Nanoparticles ; NF-kappa B/metabolism ; Protective Agents/pharmacology ; Kidney Diseases/chemically induced/prevention & control/pathology ; Metal Nanoparticles ; Caspase 3/metabolism ; Rats, Sprague-Dawley ; }, abstract = {The objective of this study was to evaluate the potential protective effect of N-acetylcysteine (NAC) against kidney damage induced by titanium dioxide nanoparticles (TiO2NP) through biochemical, histological, and immunohistochemical analyses. Forty rats were randomly divided into four groups of 10 animals each. Saline was administered intragastrically to control group for 14 days. In NAC group, 150 mg/kg NAC was injected intraperitoneally for 21 days. In TiO2NP group, TiO2NP at a dose of 50 mg/kg/day, dissolved in saline, was administered intragastrically for 14 days. TiO2NP + NAC group received 50 mg/kg/day TiO2NP for 14 days and 150 mg/kg NAC for 21 days, starting 7 days before TiO2NP administration. At the end of experiment, rats were anesthetized, serum samples were collected for biochemical analysis, and kidney tissue was removed for histological and immunohistochemical analyses. There was no significant change in body weight, kidney weight, or serum urea-creatinine levels between the groups. TiO2NP caused a significant increase in vacuolization and brush border loss scores in tubular cells, as well as scores for congestion and leukocyte infiltration. However, NAC supplementation significantly ameliorated these impairments. Additionally, TiO2NP significantly increased NF-kB, TNF-α, and caspase-3 immunoreactivities, as well as the number of PCNA-positive and TUNEL-positive cells. NAC treatment decreased all immunoreactivities and TUNEL-positive cells, but did not change the number of PCNA-positive cells after TiO2NP exposure. The results of the study showed that the toxic effects of TiO2NP on the kidneys, commonly encountered in daily life, can be mitigated by the anti-inflammatory and anti-apoptotic properties of NAC.}, } @article {pmid40097764, year = {2025}, author = {Li, X and Li, W and Xie, X and Fang, T and Yang, J and Shen, Y and Wang, Y and Wang, H and Tao, L and Zhang, H}, title = {ROS Regulate Rotenone-induced SH-SY5Y Dopamine Neuron Death Through Ferroptosis-mediated Autophagy and Apoptosis.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {40097764}, issn = {1559-1182}, abstract = {Rotenone, a plant-derived natural insecticide, is widely used to induce Parkinson's disease (PD) models. However, the mechanisms of rotenone-induced cell death remain unclear. Here, we found that rotenone (0.01, 0.1, or 1 μmol/L) suppressed SH-SY5Y dopamine neuron viability and led to PD-like pathological changes, such as reduced tyrosine hydroxylase (TH) but increased α-synuclein. Rotenone increased the levels of intracellular reactive oxygen species (ROS) and mitochondrial ROS, as well as the levels of the antioxidants nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), ultimately resulting in oxidative stress. Moreover, rotenone significantly downregulated the expression of GPX4 and xCT but upregulated the expression of COX2 and NCOA4, which are markers of ferroptosis. Furthermore, rotenone decreased phosphorylated mTOR level but increased Beclin-1, ATG5, LC3 and p62 expression, suggesting that rotenone enhances autophagy and reduces autophagy flux. Additionally, rotenone reduced Bcl-2 levels and the mitochondrial membrane potential (MMP) while promoting BAX and Caspase-3 expression, thus initiating cell apoptosis. N-acetylcysteine (NAC), a ROS scavenger, and ferrostatin-1 (Fer-1) and deferoxamine (DFO), two ferroptosis inhibitors, significantly eliminated rotenone-induced autophagy and apoptosis. Moreover, ML385, a specific inhibitor of Nrf2, suppressed rotenone-induced ferroptosis. Our results demonstrated that ROS might mediate rotenone-induced PD-like pathological changes by regulating iron death, autophagy, and apoptosis. Inhibiting ferroptosis blocked the rotenone-induced increase in autophagy and apoptosis. Thus, the ability of ROS to regulate rotenone-induced death through autophagy and apoptosis is dependent on ferroptosis. The findings require validation in multiple neuronal cell lines and in vivo.}, } @article {pmid40094443, year = {2025}, author = {Smieško, L and Mažerik, J and Gondáš, E and Dohál, M and Jošková, M and Šutovská, M and Fraňová, S}, title = {N-Acetylcysteine and Its Therapeutic Potential in an Animal Model of Allergic Asthma.}, journal = {Journal of aerosol medicine and pulmonary drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.1089/jamp.2024.0049}, pmid = {40094443}, issn = {1941-2703}, abstract = {Background: N-acetylcysteine (NAC) is a classical mucolytic agent that, in addition to its mucolytic activity, also exhibits antioxidant activity. This could be beneficial in treating chronic inflammatory airway diseases, including asthma. Background: We evaluated the ability of NAC to modulate airway defense mechanisms, airway reactivity, inflammation, and remodeling after 10 days of administration [20 and 60 mg/(kg·d)] in an experimental guinea pig model of allergic inflammation. Methods: The concentrations of inflammatory cytokines (interleukins: IL-4, IL-5, IL-10, IL-12, and IL-13), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were measured in bronchoalveolar lavage fluid using a multiplex detection method. The concentration of remodeling marker transforming growth factor beta-1 (TGF-β1) was measured in lung homogenates using enzyme-linked immunosorbent assay. In vivo, changes in specific airway resistance and number of cough efforts were determined. Tracheal smooth muscle reactivity was evaluated in vitro. Ciliary beat frequency (CBF) indicated mucociliary clearance. Results: A 10-day administration of NAC at a higher dosage led to a significant decrease in the regulatory cytokines IL-4, IL-5, and GM-CSF. NAC, in both dosing schedules, decreased the levels of TGF-β1. NAC at a higher dosage reduced the number of chemically induced cough reflexes and CBF. NAC did not affect airway hyperreactivity parameters. Conclusion: NAC is a multifactorial drug, and under our experimental conditions of allergic inflammation, it showed positive effects on the levels of regulatory cytokines and growth factors, which probably led to a reduction in the intensity of airway defense mechanisms.}, } @article {pmid40094059, year = {2025}, author = {Yadav, N and Mondal, D and Raja, R and Ma, EL and Singh, KP and Sharma, DK and Das, AK}, title = {N-acetylcysteine enhances bone marrow activity in treating pancytopenia induced by canine hemoprotozoan diseases.}, journal = {Veterinary research forum : an international quarterly journal}, volume = {16}, number = {1}, pages = {1-10}, pmid = {40094059}, issn = {2008-8140}, abstract = {Canine hemoprotozoan diseases viz. ehrlichiosis and babesiosis are mostly associated with critical anemia and thrombocytopenia with pancytopenic changes, leading to multi-organ failure. For faster recovery of patients with complicated hemoprotozoan diseases, whole blood transfusion or bone marrow stimulating agents to produce more red blood cells (RBCs) and platelets might be helpful. Unfortunately, canine specific transfusion procedures are expensive and even not available in many developing countries. Development of alternate therapeutic modality by bone marrow stimulation to augment the production of RBCs and platelets and thus, to treat the critical pancytopenic patients is and an urgent necessity. N-acetylcysteine (NAC), acts as a precursor of reduced glutathione and increases the production of bone marrow B cells. It also improves viability and self-renewal capacity of stem cells and thus, boosts hematopoietic differentiation by protecting induced pluripotent stem cells. This study envisaged to develop alternate therapeutic approach to combat pancytopenia secondary to canine hemoprotozoan diseases. Bone marrow mediated aplastic pancytopenia was induced experimentally by administration of cyclophosphamide in rats. Bone marrow stimulating property of NAC was compared with desmopressin, another bone marrow stimulator, which revealed better in terms of hematobiochemical and histopathological changes. Results of rat model study were extrapolated in clinical canine hemoprotozoan cases having pancytopenia. Dogs treated with hemoprotozoan disease specific therapy along with NAC rendered favorable changes by haltering the progression of critical anemia and thrombocytopenia. Study revealed that supplementation of NAC along with canine hemoprotozoan specific therapy is beneficial to alleviate pancytopenia.}, } @article {pmid40092853, year = {2024}, author = {Wahab, A and Ganiger, C and Pawar, R and Phaphe, S and Ronad, Y}, title = {Anti-microbial and micro-leakage properties of orthodontic cement.}, journal = {Bioinformation}, volume = {20}, number = {10}, pages = {1368-1373}, pmid = {40092853}, issn = {0973-2063}, abstract = {Glass Ionomer Cement (GIC) is used for cementing orthodontic bands because of its anti-cariogenic property, which is attributed to the release of fluoride. Therefore, it is of interest to assess the antimicrobial property and micro-leakage of GIC incorporated with different concentration of N-acetylcysteine (N-AC) and copper nanoparticle (Cu-NP). Our study composed of 5 groups i.e. group I is control with different concentration of N-AC and Cu-NP involving each group with 8 samples. We found that, group V showed the highest zone of inhibition; while the micro-leakage was seen highest for group I with a score of 2.2 ± 1.09 and the least score was recorded for Group III (0.8± 0.37). Thus, addition of 2% Cu-NP and 15% N-AC resulted in minimal micro-leakage. We conclude that increase in concentration of N-AC and CU-NP antimicrobial property efficiency also increases; on the other hand, increase in the concentration of N-AC and CU-NP did not decrease the micro-leakage.}, } @article {pmid40084379, year = {2025}, author = {Yang, CC and Chen, WM and Shia, BC and Wu, SY}, title = {Impact of long-term N-acetylcysteine use on cancer risk.}, journal = {American journal of cancer research}, volume = {15}, number = {2}, pages = {618-630}, pmid = {40084379}, issn = {2156-6976}, abstract = {Chronic obstructive pulmonary disease (COPD) patients face an increased risk of developing various malignancies due to shared risk factors and underlying systemic inflammation. N-acetylcysteine (NAC) has shown potential anticancer properties in preclinical studies, but clinical evidence in COPD patients is limited. We conducted a nationwide propensity score-matched cohort study using data from Taiwan's National Health Insurance Research Database to evaluate the anticancer effects of NAC in COPD patients. Patients diagnosed with COPD between 2008 and 2019 were included, and those with pre-existing cancer were excluded. NAC use was defined as consistent administration for most days with an average dose exceeding 28 cumulative defined daily doses (cDDDs) annually. Cox regression models were adjusted for various covariates was employed. PSM yielded 91,546 patients, evenly distributed between NAC and non-NAC groups. Multivariate Cox regression analysis revealed a lower cancer risk in patients with long-term NAC use compared to non-users (adjusted hazard ratio [aHR] 0.69, 95% confidence interval [CI] 0.66-0.72; P<0.001). Dose-dependent relationships were observed, with higher daily NAC intake associated with reduced cancer risk. Time-varying Cox regression analysis demonstrated significant reductions in the risk of specific cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer, among NAC users compared to non-users. Our study provides clinical evidence supporting the potential anticancer effects of NAC in COPD patients. These findings highlight the importance of exploring NAC as a chemopreventive agent in high-risk populations and inform clinical practice and future research endeavors.}, } @article {pmid40083413, year = {2025}, author = {Hu, QL and Zhong, H and Wang, XR and Han, L and Ma, SS and Li, L and Wang, Y}, title = {Mitochondrial phosphate carrier plays an important role in virulence of Candida albicans.}, journal = {Mycology}, volume = {16}, number = {1}, pages = {369-381}, pmid = {40083413}, issn = {2150-1203}, abstract = {Candida albicans is a common fungal pathogen that can cause life-threatening infections. MIR1 is considered to be a mitochondrial phosphate carrier of C. albicans, while its role in virulence has not been fully elucidated. In this study, we found that mir1Δ/Δ mutant exhibited severe virulence defect in both nematode and murine models. Further mechanism studies revealed that the mir1Δ/Δ mutant grew more slowly than the wild-type strain and showed severe filamentation defects on the hypha-inducing agar media, including YPD + serum, Lee, Spider + glucose, SLAD, SLD, and YPS. Furthermore, the loss of MIR1 resulted in unfermentable carbon utilisation defect, ATP decrease, and reactive oxygen species (ROS) accumulation in C. albicans. Antioxidant proanthocyanidins, vitamin E, and N-acetyl cysteine (NAC) could reduce intracellular ROS levels and partially rescue the filamentation defects of the mir1Δ/Δ mutant. Accordingly, hypha-specific genes, as well as CEK1 and RIM101 were down-regulated in the mir1Δ/Δ mutant, and this down-regulation could be partially rescued by the addition of the antioxidant NAC. Collectively, MIR1 plays an important role in C. albicans mitochondrial function, filamentation and virulence, and would be a promising antifungal target.}, } @article {pmid40080083, year = {2025}, author = {Basaran, R and Efendioglu, M and Akça, M and Ceman, D and Demirtaş, C and Sürmeneli, YE and Yildirim, M}, title = {Antihyperalgesic effects of gabapentin and levetiracetam in a model of post-traumatic epilepsy.}, journal = {Physiology international}, volume = {}, number = {}, pages = {}, doi = {10.1556/2060.2025.00524}, pmid = {40080083}, issn = {2498-602X}, abstract = {OBJECTIVE: This study aimed to investigate the role of levetiracetam (LEV) and gabapentin (GBP) on mechanical and thermal pain thresholds, as well as n-acetylcysteine (NAC) as an adjuvant, in the pentylenetetrazol (PTZ)-induced post-traumatic epilepsy (PTE) model after mild-traumatic brain injury (TBI) in male Sprague-Dawley rats.

METHODS: Animals were randomly divided into 7 groups (Control, PTE, PTE+LEV, PTE+GBP, PTE+NAC, PTE+LEV+NAC and PTE+GBP+NAC). Rats received 50 mg kg-1 LEV, 100 mg kg-1 GBP, and combinations of these antiepileptics with 100 mg kg-1 NAC for 14 days after TBI.

RESULTS: While the thermal pain threshold decreased significantly in the PTE group (P < 0.05), it increased in the PTE+LEV, PTE+GBP, and PTE+LEV+NAC groups (P < 0.05, P < 0.001 and P < 0.01, respectively). Interestingly, NAC alone did not affect the thermal pain threshold, but the combination of PTE+LEV+NAC increased the thermal pain threshold. Furthermore, PTE+GBP+NAC administration prevented the effect of GBP on the thermal pain threshold.

CONCLUSIONS: The presented study is the first to examine the effect of LEV and GBP in PTE. It was found that PTE decreased the thermal pain threshold, but LEV and GBP applied for 14 days prevented the decrease in PTE-related pain threshold and increased the thermal pain threshold. NAC, which was used as an adjuvant to support antiepileptic drugs, did not influence the thermal pain threshold alone; however, it increased the pain threshold more by potentiating the effect of LEV. Both LEV and GBP have an antihyperalgesic effect in the PTE model facilitated by PTZ, and NAC further reinforces the antihyperalgesic effect of LEV.}, } @article {pmid40069676, year = {2025}, author = {Heydari, B and Aflatonian, M and Bagherizadeh, M and Hoseinzade, F and Saghafi, F}, title = {Evaluating the efficacy of N-acetylcysteine in diminishing the duration and frequency of rotavirus-induced gastroenteritis: a preliminary randomized, placebo-controlled, double-blind clinical trial.}, journal = {BMC pediatrics}, volume = {25}, number = {1}, pages = {186}, pmid = {40069676}, issn = {1471-2431}, support = {85//Shahid Sadoughi University of Medical Sciences/ ; }, mesh = {Humans ; Double-Blind Method ; *Rotavirus Infections/drug therapy/complications ; *Gastroenteritis/drug therapy/virology/complications ; *Acetylcysteine/therapeutic use ; Female ; Male ; Infant ; Child, Preschool ; *Diarrhea/drug therapy/etiology ; Treatment Outcome ; Time Factors ; Rotavirus ; }, abstract = {BACKGROUND: Globally, gastroenteritis stands as a primary contributor to child mortality, annually taking the lives of 3 million children under the age of 5 years. Rotavirus, a major factor in viral diarrhea among children aged 6 months to 2 years, presents with severe symptoms such as watery diarrhea and vomiting. Although mortality rates have decreased due to supportive care and vaccines, promising alternatives like N-acetylcysteine (NAC) show potential benefits in laboratory studies, indicating a possible supplementary strategy for managing rotavirus infections by reducing the duration and antigen excretion in feces.

METHODS: During this double-blind clinical trial, 71 patients, confirmed to have gastroenteritis resulting from rotavirus using a rapid diagnostic strip, were randomly allocated to two groups. One group was prescribed NAC at a dosage of 60 mg/kg/day, while the other received a placebo. The patient's progress was monitored daily until their gastroenteritis improved, and details regarding the duration of diarrhea and the frequency of bowel movements were recorded for each participant.

RESULTS: The average duration of diarrhea in the NAC group and the placebo group was 2 and 3 days, respectively, with a level of p = 0.121. During the diarrhea period, the number of bowel movements in the NAC group was recorded at 28.1 ± 21.6 times, whereas in the placebo group, it was 35.3 ± 33.1 times, yielding a p-value of 0.409.

CONCLUSIONS: Even though the effects of NAC were observed in lowering the duration of the period and decreasing the frequency of bowel movements in gastroenteritis, these results did not reach statistical significance. Hence, the data from this study suggest that NAC may not effectively reduce the duration of diarrhea and the frequency of bowel movements linked to gastroenteritis caused by rotavirus.

TRIAL REGISTRATION: IRCT20181208041882N13, 14-10-2023 (https://irct.behdasht.gov.ir/trial/68259).}, } @article {pmid40058751, year = {2025}, author = {Zhao, Y and Lv, R and He, Y and Dong, N and Wang, X and Pu, J and Yu, Q}, title = {The miR-21-5p/DUSP8/MAPK signaling pathway mediates inflammation and apoptosis in vascular endothelial cells induced by intermittent hypoxia and contributes to the protective effects of N-acetylcysteine.}, journal = {European journal of pharmacology}, volume = {997}, number = {}, pages = {177462}, doi = {10.1016/j.ejphar.2025.177462}, pmid = {40058751}, issn = {1879-0712}, abstract = {Obstructive sleep apnoea hypopnea syndrome (OSAHS) is a sleep disorder associated with significant cardiovascular complications, characterized by intermittent hypoxia (IH). IH causes endothelial dysfunction, an early event in cardiovascular disease. We investigated the role of dual-specificity phosphatase 8 (DUSP8), a key negative regulator of the mitogen-activated protein kinase (MAPK) signalling pathway, in IH-induced endothelial cell damage, and the therapeutic effects of N-acetylcysteine (NAC) by establishing IH models in human umbilical vein endothelial cells and C57BL/6 mice. DUSP8 and MAPK signalling pathway-related proteins were analysed by western blotting, and DUSP8 mRNA and miR-21-5p expression was assessed by RT-qPCR. Inflammatory cytokines were detected by an enzyme-linked immunosorbent assay, apoptosis-related proteins were analysed by western blotting, and apoptosis was assessed using flow cytometry. IH stimulation induced inflammation and apoptosis in endothelial cells, downregulated DUSP8 expression, and upregulated the phosphorylation of key molecules involved in the MAPK signalling pathway. However, DUSP8 overexpression alleviated IH-induced inflammation and apoptosis in endothelial cells and reduced the phosphorylation of key molecules in the MAPK signalling pathway. Bioinformatic analysis and dual-luciferase reporter assays confirmed that DUSP8 is a direct target of miR-21-5p. DUSP8 overexpression effectively reversed the damage caused by miR-21-5p upregulation under IH conditions. Furthermore, in cell and animal models of IH, NAC demonstrated protective effects against inflammation, apoptosis, and oxidative stress through a mechanism linked to the miR-21-5p/DUSP8/MAPK signalling pathway. Overall, this study elucidated the protective role of DUSP8 against IH-induced endothelial injury and confirmed the potential of NAC as a therapeutic agent for OSAHS-related diseases.}, } @article {pmid40057704, year = {2025}, author = {Qiu, X and Yang, S and Zhang, Y and Wang, Q and Kong, L and Zhou, L}, title = {Effect of N-acetylcysteine on antimicrobials induced nephrotoxicity: a meta-analysis.}, journal = {BMC nephrology}, volume = {26}, number = {1}, pages = {128}, pmid = {40057704}, issn = {1471-2369}, mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Acute Kidney Injury/chemically induced/prevention & control ; *Anti-Infective Agents/therapeutic use ; Randomized Controlled Trials as Topic ; Creatine/blood ; Creatinine/blood ; Blood Urea Nitrogen ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) has antioxidant effects in reducing acute kidney injury. This study systematically reviewed and assessed the efficacy of NAC in preventing antimicrobials induced nephrotoxicity.

METHODS: Pubmed, Embase, Web of Science, and the Cochrane Library were searched extensively for relevant studies that evaluating NAC on antimicrobials induced nephrotoxicity until June 1, 2024. Eligible records were screened according to the inclusion and exclusion criteria. The odds ratio (OR) was selected to evaluate the effect of NAC on nephrotoxicity. We pooled the extracted data using a random effects model.

RESULTS: Three randomized controlled trials were included in the analysis. The pooled results showed that NAC could reduce the incidence of antimicrobials induced nephrotoxicity (OR = 0.487, 95% CI = 0.258, 0.918, P = 0.03, I[2] = 0%). Serum creatine (Scr) on Day 2 was significantly decreased in the NAC group compared to the placebo group (SMD, - 0.298; 95%CI, - 0.585 to - 0.010; I[2] = 23%; P = 0.04). No difference was observed in blood urea nitrogen (BUN), and creatinine clearance (CrCl).

CONCLUSION: In this meta-analysis, NAC was associated with a benefit in the prevention of antimicrobials induced nephrotoxicity. However, large-scaled and well-designed RCTs are required in the future.}, } @article {pmid40057223, year = {2025}, author = {Maartens, M and Vlok, M and van de Vyver, M}, title = {Antioxidants improve the viability of diabetic bone marrow MSCs without rescuing their pro-regenerative secretome function.}, journal = {Molecular and cellular endocrinology}, volume = {601}, number = {}, pages = {112519}, doi = {10.1016/j.mce.2025.112519}, pmid = {40057223}, issn = {1872-8057}, abstract = {Bone marrow mesenchymal stem cell (BM-MSC) dysfunction and poor viability are prominent in diabetes and limit their therapeutic efficacy. A proteomic investigation was performed to assess disease associated alterations and the efficacy of antioxidants to rescue cellular function. BM-MSCs were isolated from obese diabetic mice (B6.Cg-Lep[ob]/J) cultured in the presence or absence of N-acetylcysteine (NAC) and ascorbic acid-2phosphate (AAP). Label free Liquid Chromatography and Mass Spectrometry (LC-MS) analysis detected 5079 proteins with 251 being differentially expressed between treatment groups. NAC/AAP improved cellular growth/viability post isolation by up-regulating proteins involved in redox status, ATP synthesis, Rho-GTPase signaling and modulated the immunophenotype of BM-MSCs. Despite a single application of the secretome not providing any advantage for wound bed regeneration in full thickness excisional diabetic wounds, the intracellular proteome illustrated the potential mechanisms of action by which NAC/AAP targeted the respiratory chain and modulated the immune phenotype of BM-MSCs. Given these observations, antioxidant supplementation might be more effective as prophylactic strategy to protect MSCs against functional decline instead of using it as a restorative agent and warrants further investigation.}, } @article {pmid40056000, year = {2025}, author = {Zanganeh, Z and Hezavehei, M and Halvaei, I and Sharafi, M}, title = {Beneficial Effects of N-Acetyl Cysteine in the Different Equilibration Times on Post-Thawed Rooster Sperm Quality.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {60}, number = {3}, pages = {e70035}, doi = {10.1111/rda.70035}, pmid = {40056000}, issn = {1439-0531}, support = {TMU8216//Tarbiat Modares University/ ; }, mesh = {Animals ; Male ; *Acetylcysteine/pharmacology ; *Semen Preservation/veterinary/methods ; *Cryopreservation/veterinary/methods ; *Chickens ; *Spermatozoa/drug effects/physiology ; *Sperm Motility/drug effects ; *Semen Analysis/veterinary ; Antioxidants/pharmacology ; Cryoprotective Agents/pharmacology ; Cell Membrane/drug effects ; Membrane Potential, Mitochondrial/drug effects ; }, abstract = {Cryopreservation is the best method for preserving rooster sperm, especially in declining indigenous breeds. Cryopreserved semen is significantly compromised due to equilibration time, cold shock and oxidative stress encountered during the freezing-thawing process. To improve the quality and fertility of thawed semen, it is essential to protect sperm cells from peroxidative damage. This study assessed the effects of N-acetyl cysteine (NAC), an antioxidant supplement, on the functional parameters of thawed rooster sperm after pre-freezing equilibration periods of 2 and 4 h. Samples were collected from 10 male Ross 308 broiler breeders and diluted with Beltsville extenders containing different concentrations of NAC (0, 0.1, 1 and 10 mM/mL) during equilibrium periods of 2 and 4 h before freezing. Our findings showed that NAC-0.1 and NAC-1 groups in 2 h increased significantly total and progressive motility (59.85 ± 3.73, 59.67 ± 3.73, 42.85 ± 2.64 and 42.80 ± 2.64, respectively), viability, and plasma membrane functionality (62.45 ± 3.51, 62.36 ± 3.51, 56.81 ± 3.51 and 56.82 ± 3.56, respectively) compared to the control groups. Furthermore, NAC-0.1-2 h and NAC-1-2 h demonstrated the lowest levels of apoptosis and intracellular reactive oxygen species (ROS), as well as the highest mitochondrial membrane potential in comparison to the control groups. These findings indicate that NAC-0.1 and NAC-1 are effective in maintaining the quality of thawed rooster sperm during a 2-h equilibration period.}, } @article {pmid40051733, year = {2025}, author = {Asgharzadeh, N and Diziche, AN and Amini-Khoei, H and Yazdanpanahi, N and Korrani, MS}, title = {N-acetyl cysteine through modulation of HDAC2 and GCN5 in the hippocampus mitigates behavioral disorders in the first and second generations of socially isolated mice.}, journal = {IBRO neuroscience reports}, volume = {18}, number = {}, pages = {350-359}, pmid = {40051733}, issn = {2667-2421}, abstract = {OBJECTIVES: Social isolation stress (SIS) in early life can lead to behavioral disorders. N-acetylcysteine (NAC), an antioxidant, may aid treatment. This study explored NAC's impact on behavior in first and second-generation mice after SIS, focusing on HDAC2 and GCN5 expression in the hippocampus.

MATERIALS AND METHODS: In this study, 24 male and 24 female mice were bred for one generation. The pups were divided into six (3male, 3female) groups (n = 20): 1- Control receiving normal saline, 2- SIS with normal saline, 3- SIS with NAC (150 mg/kg) IP for four weeks. Eight mice from each group underwent behavioral, histopathological, and molecular tests, while others were mated (4 males + 4 females) to produce second generations. These pups were divided into 9 groups (n = 8) for behavioral tests, including elevated plus maze, open field, forced swimming, and histopathological and molecular assessments (HDAC2 and GCN5 expression) in the hippocampus.

RESULTS: The SIS group showed increased HDAC2 and GCN5 expression. Following SIS, there was a decrease in open arm entries and passes in the open field test, alongside increased immobility in the forced swimming test and reduced CA1 and CA3 hippocampal diameters. NAC mitigated the adverse molecular, behavioral, and histopathological impacts of SIS across both generations.

CONCLUSION: NAC reduces behavioral disorders after SIS (first and second generation) by reducing the expression of GCN5 and HDAC2 and increasing neuronal diameter in the hippocampus. Future research should investigate the long-term therapeutic effects of NAC for behavioral disorders after SIS.}, } @article {pmid40050926, year = {2025}, author = {Tseng, TH and Chang, CH and Chen, CL and Chiang, H and Wang, JH and Young, TH}, title = {Enhanced antibiotic release and biocompatibility with simultaneous addition of N-acetylcysteine and vancomycin to bone cement: a potential replacement for high-dose antibiotic-loaded bone cement.}, journal = {Journal of orthopaedic surgery and research}, volume = {20}, number = {1}, pages = {246}, pmid = {40050926}, issn = {1749-799X}, mesh = {*Vancomycin/administration & dosage ; *Bone Cements/chemistry ; *Acetylcysteine/administration & dosage/pharmacology ; *Anti-Bacterial Agents/administration & dosage ; *Polymethyl Methacrylate ; Biocompatible Materials ; Animals ; Materials Testing/methods ; Mice ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Antibiotic-loaded bone cement (ALBC) is crucial for treating orthopedic infections, but its use is limited by suboptimal antibiotic release patterns and potential toxicity. This study explores the dual addition of N-acetylcysteine (NAC) and vancomycin to polymethylmethacrylate (PMMA) as a strategy to enhance the antibacterial efficacy and reduce toxicity.

METHODS: PMMA cement cylinders were loaded with varying combinations of NAC and vancomycin and tested for antibiotic release, cytotoxicity, and antibacterial activity over a 35-day period. Porosity of the cements was also evaluated as a measure of potential antibiotic release enhancement.

RESULTS: The addition of NAC improved vancomycin release, particularly after the initial burst release phase, and reduced cytotoxicity compared to high-dose vancomycin alone. The optimal combination was found to be 2 gm vancomycin with either 2 gm or 4 gm of NAC, which maintained effective antibacterial activity over 35 days without the toxicity seen with higher doses of vancomycin alone. Moreover, NAC alone did not demonstrate antibacterial properties, indicating its role primarily as a bioenhancer in this context.

CONCLUSION: Simultaneous inclusion of NAC and vancomycin in PMMA bone cement provides a more favorable release profile and biocompatibility than high-dose vancomycin alone, suggesting a potential strategy for enhancing the therapeutic efficacy of ALBC in treating prosthetic joint infections. This approach allows for lower doses of antibiotics, reducing potential cytotoxicity, systemic toxicity and enhancing the duration of antibacterial activity.

LEVEL OF EVIDENCE: Laboratory study.}, } @article {pmid40049439, year = {2025}, author = {Liu, JM and Lee, KI and Su, CC and Fang, KM and Liu, SH and Fu, SC and Kuo, CY and Chang, KC and Ke, JA and Chen, YW and Yang, CY and Huang, CF}, title = {Chlorpyrifos-oxon results in autophagic flux dysfunction contributing to neuronal apoptosis via a ROS/AMPK/CHOP activation pathway.}, journal = {Chemico-biological interactions}, volume = {}, number = {}, pages = {111452}, doi = {10.1016/j.cbi.2025.111452}, pmid = {40049439}, issn = {1872-7786}, abstract = {Chlorpyrifos (CPF) is a widely used organophosphate (OP) pesticide in agriculture and sanitation, known to elicit neurotoxic effects. Chlorpyrifos-oxon (CPO), a metabolite of CPF, is the primary neurotoxic agent, yet its mechanisms are less understood. In this study, we investigated the effects and underlying mechanisms of CPO-induced neurotoxicity. CPO exposure significantly induced cytotoxicity in Neuro-2a cells, alongside the activation of apoptosis, as evidenced by an increase in the apoptotic cell population, caspase-3 activity, and cleavage of caspaspe-3, -7, and PARP proteins. Furthermore, defective autophagy was observed in CPO-treated Neuro-2a cells, indicated by increased expression of Beclin-1, Atg5, LC3-II, and p62 proteins. 3-MA, an autophagy inhibitor, suppressed CPO-activated LC3-II and apoptotic marker proteins expression, but not p62. In contrast, chloroquine and bafilomycin A1, autophagic flux inhibitors, potentiated the CPO-induced elevation of LC3-II, p62, and cleaved caspase-3 and -7 protein levels. CPO exposure also upregulated CHOP protein expression. Transfection with CHOP-specific siRNA markedly reduced CHOP protein expression, autophagic flux dysfunction, and apoptosis. Additionally, CPO exposure significantly increased AMPKα phosphorylation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC), but not the AMPK inhibitor Compound C, effectively attenuated the CPO-induced ROS generation in neuronal cells, which was accompanied by the prevention of AMPKα activation, downstream CHOP expression, autophagic flux dysfunction, and apoptosis. Collectively, these findings suggest that CPO-induced neurotoxicity arises from autophagic flux dysfunction, contributing to apoptosis via the ROS-activated AMPK pathway, which regulates CHOP expression, ultimately leading to neuronal cell death. Targeting the ROS/AMPK/CHOP axis may offer a promising intervention to against CPO-induced neurotoxicity.}, } @article {pmid40048297, year = {2025}, author = {Flaherty, BF and Olsen, CS and Coon, ER and Srivastava, R and Cook, LJ and Keenan, HT}, title = {Patterns of Use of β-2 Agonists, Steroids, and Mucoactive Medications to Treat Bronchiolitis in the PICU: U.S. Pediatric Health Information System 2009-2022 Database Study.}, journal = {Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies}, volume = {26}, number = {3}, pages = {e294-e303}, pmid = {40048297}, issn = {1529-7535}, support = {UM1 TR004409/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Infant ; Retrospective Studies ; *Bronchiolitis/drug therapy ; *Intensive Care Units, Pediatric/statistics & numerical data ; Female ; Male ; United States/epidemiology ; *Length of Stay/statistics & numerical data ; *Adrenergic beta-2 Receptor Agonists/therapeutic use ; Expectorants/therapeutic use ; Infant, Newborn ; Databases, Factual ; Steroids/therapeutic use ; Child, Preschool ; Practice Patterns, Physicians'/statistics & numerical data ; Saline Solution, Hypertonic/therapeutic use/administration & dosage ; Acetylcysteine/therapeutic use ; Hospitalization/statistics & numerical data ; }, abstract = {OBJECTIVES: Describe β2-agonists, steroids, hypertonic saline (HTS), n-acetylcysteine (NAC), and dornase alfa (DA) use to treat bronchiolitis, factors associated with use, and associations between use and PICU length of stay (LOS).

DESIGN: Retrospective, multicenter cohort study.

SETTING: PICUs in the Pediatric Health Information System database.

PATIENTS: PICU admitted children 24 months young or younger with bronchiolitis.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: We analyzed 47,520 hospitalizations between July 1, 2018, and June 30, 2022. We calculated the rate of medication use overall and the median (range) rate for each hospital: β2-agonist (24,984/47,520 [52.6%]; median hospital, 51.7% [21.4-81.7%]), steroid (15,878/47,520 [33.4%]; median hospital, 33.4% [6.0-54.8%]), HTS (7,041/47,520 [14.8%]; median hospital, 10.5% [0-66.1%]), NAC (1,571/47,520 [3.3%]; median hospital, 0.8% [0-22.0%], and DA (840/47,520 [1.8%]; median hospital, 1.4% [0-13.6%]). Logistic regression using generalized estimating equations (GEEs) identified associations between concurrent asthma and β2-agonist (adjusted odds ratio [aOR], 8.68; 95% CI, 7.08-10.65; p < 0.001) and steroid (aOR, 10.10; 95% CI, 8.84-11.53; p < 0.001) use. Mechanical ventilation was associated with all medications: β2-agonists (aOR, 1.79; 95% CI, 1.57-2.04; p < 0.001), steroids (aOR, 2.33; 95% CI, 1.69-3.21; p < 0.001), HTS (aOR, 1.82; 95% CI, 1.47-2.25; p < 0.001), NAC (aOR, 3.29; 95% CI, 2.15-5.03; p < 0.001), and DA (aOR, 7.65; 95% CI, 4.30-13.61; p < 0.001). No medication was associated with decreased PICU LOS. To assess changes in medication use over time and associations with the 2014 American Academy of Pediatrics bronchiolitis guidelines, we expanded our analysis to 83,820 hospitalizations between July 1, 2009, and June 30, 2022. Logistic regression with GEEs found no change in β2-agonist use; steroid use increased after guideline publication (aOR, 1.05; 95% CI, 1.01-1.10; p = 0.02), HTS use changed from increasing prior to the guidelines (aOR, 1.32; 95% CI, 1.11-1.56; p = 0.001) to stable since guideline publication (aOR, 0.93; 95% CI, 0.81-1.07; p = 0.33).

CONCLUSIONS: β2-agonists, steroids, and HTS are commonly, but variably used for PICU bronchiolitis treatment. Medication use appears relatively stable over the last decade.}, } @article {pmid40043915, year = {2025}, author = {Chen, Y and Yang, X and Li, J and Luo, H and Huang, Q and Yang, W and Lei, T and Lui, S and Gong, Q and Li, H and Wu, H and Gao, H}, title = {A nasally administrated reactive oxygen species-responsive carrier-free gene delivery nanosystem for Alzheimer's disease combination therapy.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {}, number = {}, pages = {113604}, doi = {10.1016/j.jconrel.2025.113604}, pmid = {40043915}, issn = {1873-4995}, abstract = {Combination therapies targeting multiple pathways are needed in order to improve treatment outcomes in Alzheimer's disease (AD) due to its complex pathogenesis. Amyloid-β and microglia-mediated neuroinflammation significantly contribute to AD pathogenesis. Amyloid-β-related nucleic acid drugs have demonstrated considerable potential in AD treatment; however, their clinical translation is limited by complex synthesis processes and carrier toxicity. Herein, an intranasally administrated, reactive oxygen species (ROS)-responsive, carrier-free gene delivery nanosystem (FTBR-NAC) was constructed for re-polarizing microglia and decreasing amyloid-β expression. In this nanosystem, fingolimod was conjugated with biguanide via an ROS-responsive linker to form the carrier for β-secretase 1 siRNA (siBACE1) to form FTBR nanoparticles. The electropositivity of FTBR and mucolytic activity of N-acetylcysteine (NAC) together enhanced the brain entry of FTBR. Upon reaching the brain, FTBR responded to the elevated ROS at the pathological site, releasing siBACE1 and fingolimod. Administration of FTBR-NAC improved cognitive function in AD mice, demonstrating the high therapeutic efficacy of this relatively simple nanosystem.}, } @article {pmid40038825, year = {2025}, author = {Emara, SM and Fahmy, SF and AbdelSalam, MM and Wakeel, LME}, title = {Effect of high-dose N-acetyl cysteine on the clinical outcome of patients with diabetic peripheral neuropathy: a randomized controlled study.}, journal = {Diabetology & metabolic syndrome}, volume = {17}, number = {1}, pages = {79}, pmid = {40038825}, issn = {1758-5996}, abstract = {BACKGROUND: Diabetic peripheral neuropathy (DPN) is a vastly common and bothersome disorder with a clinically challenging course of treatment affecting patients with diabetes. This study aimed to evaluate the efficacy and safety of high dose oral N-acetyl cysteine (NAC) as adjuvant therapy on clinical outcome of DPN.

METHODS: A prospective, randomized, parallel, open label, controlled clinical trial. Ninety eligible DPN patients were randomly assigned to either control group receiving standard of care or NAC group receiving standard of care treatment and NAC at a dose of 2400 mg/day for 12 weeks. Glutathione peroxidase (GPx), nuclear factor erythoid-2 related factor (NRF-2) and tumor necrosis factor (TNF) were measured at baseline and after 12 weeks to assess anti-oxidant and anti-inflammatory properties. Michigan neuropathy screening instrument (MNSI), Toronto clinical neuropathy score (TCNS), Diabetic neuropathy score (DNS), Diabetes-39 quality of life questionnaire (DQOL) and pain score were assessed at baseline and after 12 weeks.

RESULTS: NAC group showed a significant increase (p < 0.05) in NRF-2 by 25.3% and GPx by 100% and a decline of 21.45% in TNF-alpha levels versus controls that reported a decline in NRF-2 and GPx and an increase in TNF-alpha. HgbA1C and AST levels significantly decreased in NAC versus controls (7.2 ± 1 vs 8 ± 1.1, p = 0.028 and 29.1 vs 55.4, p = 0.012) respectively. NAC administration resulted in a significant decline in MNSA, TCNS, DNS and pain scores versus controls that showed increase in all scores. The QOL total score and the anxiety and energy and mobility domain scores significantly decreased in the NAC group versus controls, p < 0.001.

CONCLUSION: High dose NAC administered for 12 weeks modulated inflammation by reducing TNF-alpha and increasing GPx and NRF2 versus controls. NAC improved clinical outcomes of DPN reflected by a decline in neuropathy and pain scores and an improvement in QOL.

NCT04766450.}, } @article {pmid40037730, year = {2025}, author = {Chen, S and Hou, Z and Xiao, M and Wu, P and Yang, Y and Han, S and Xia, J and Hu, J and Zhang, K and Yang, L}, title = {Quaternized chitosan-based photothermal antibacterial hydrogel with pro-vascularization and on-demand degradation properties for enhanced infected wound healing.}, journal = {Carbohydrate polymers}, volume = {355}, number = {}, pages = {123350}, doi = {10.1016/j.carbpol.2025.123350}, pmid = {40037730}, issn = {1879-1344}, mesh = {*Chitosan/chemistry/pharmacology ; *Wound Healing/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; Animals ; *Hydrogels/chemistry/pharmacology ; Humans ; *Staphylococcus aureus/drug effects ; *Human Umbilical Vein Endothelial Cells/drug effects ; Rats ; *Rats, Sprague-Dawley ; Microbial Sensitivity Tests ; Wound Infection/drug therapy/microbiology ; Staphylococcal Infections/drug therapy ; Male ; Copper/chemistry/pharmacology ; Photothermal Therapy/methods ; Neovascularization, Physiologic/drug effects ; }, abstract = {Compromised skin barrier fails to prevent pathogenic bacterial invasion, leading to wound infection and potentially severe tissue damage, for which conventional wound dressings provide inadequate therapeutic outcomes. Herein, we have developed a multifunctional injectable hydrogel (QCS-APA/P@D@C) based on quaternized chitosan (QCS) and aldehyde-modified aliphatic polycarbonate (APA), incorporating Prussian Blue (PB) @Polydopamine (PDA) @Cu (P@D@C) submicron particles (SPs). This novel hydrogel exhibits photothermal antibacterial properties, on-demand removal capability, and Cu[2+]-facilitated wound healing enhancement. The QCS-APA/P@D@C hydrogel, crosslinked via dynamic Schiff-base bonds, exhibits remarkable antibacterial efficacy (>99 %) against various bacteria, including multidrug-resistant (MDR) bacteria, through the synergistic effects of QCS, Cu[2+], and 808 nm near-infrared (NIR) photothermal effect. The hydrogel demonstrates rapid degradation (~12 min) upon exposure to N-acetylcysteine (NAC), facilitating on-demand removal and minimizing secondary trauma during dressing changes. Furthermore, the sustained release of Cu[2+] within 1-10 μM significantly enhances the migration and tube formation of human umbilical vein endothelial cells (HUVECs). In a Staphylococcus aureus (S. aureus)-infected wound model of Sprague-Dawley (SD) rats, the QCS-APA/P@D@C hydrogel demonstrated effectively modulating wound inflammation, promoting collagen deposition and angiogenesis, and accelerating wound closure. These findings demonstrate that the QCS-APA/P@D@C hydrogel can effectively promote the healing of bacterially infected wounds.}, } @article {pmid40037093, year = {2025}, author = {Pan, H and Zhai, G and Jing, Q and Fan, Y and Fang, C and Shi, F}, title = {Two-step metabolic activation to ortho-benzoquinone intermediate and its role in 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside-induced liver injury in mice.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {53}, number = {3}, pages = {100047}, doi = {10.1016/j.dmd.2025.100047}, pmid = {40037093}, issn = {1521-009X}, abstract = {2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is the most abundant constituent of Polygonum multiflorum and is exclusively found in this herb. This renowned herbal medicine has been documented to lead to liver damage in humans. The present study demonstrated that TSG underwent 2-step metabolic activation to generate a reactive metabolite, involving both intestinal and hepatic metabolisms. TSG was hydrolyzed to its aglycone 2,3,5,4'-tetrahydroxystilbene (TS) in the intestine, and then, the 2,3 catechol of 2,3,5,4'-tetrahydroxystilbene was metabolized to an ortho-benzoquinone intermediate in the liver. The reactive metabolite was characterized as the N-acetyl-cysteine conjugate both in vivo and in vitro. Its structure was verified by a combined isotope-labeling strategy using the [14]N/[15]N, H/D, and [79]Br/[81]Br isotope pattern-based mass shifts. Intestinal β-glucosidase and hepatic CYP3A4 and CYP2C9 contributed to the reactive metabolite formation. The reactive intermediate could covalently modify the hepatic proteins through cysteine in mice. Combined with the treatment with β-glucosidase, a single oral administration of 400 mg/kg TSG caused liver centrilobular necrosis and degeneration in mice. Selective CYP3A inhibitor ketoconazole protected TSG-induced liver injury, concurrently attenuating protein adduct formation modified by reactive metabolites. The results indicate that TSG does not exert hepatotoxic effects but that the reactive ortho-benzoquinone metabolite from the oxidation of the 2,3 catechol of aglycone is responsible for TSG-induced liver injury. The study also facilitates a better understanding of the principal hepatotoxic chemicals in Polygonum multiflorum. SIGNIFICANCE STATEMENT: 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) undergoes intestinal deglycosylation to generate its aglycone, and then, the 2,3 catechol of aglycone was metabolized to an ortho-benzoquinone intermediate in the liver. β-glucosidase potentiates TSG-induced liver injury and protein adduction by the reactive metabolite. The results indicate that the reactive metabolite of TSG exerts hepatotoxic effects rather than the parent compound.}, } @article {pmid40028879, year = {2025}, author = {Truwit, JD and Fleming, K and Nanchal, RS}, title = {Empowering Respiratory Therapists to Restrict Nebulized 3% Saline and N-Acetylcysteine During Mechanical Ventilation.}, journal = {Respiratory care}, volume = {}, number = {}, pages = {}, doi = {10.1089/respcare.12586}, pmid = {40028879}, issn = {1943-3654}, abstract = {Background: We previously implemented a policy that enabled respiratory therapists to reject orders for nebulized 3% hypertonic saline and/or N-acetylcysteine (HTS/NAC) that did not conform to the American Association for Respiratory Care (AARC) Clinical Practice Guideline. Outcomes of adhering to this more conservative approach are not well studied. We sought to determine if an approach conforming to guidelines is noninferior to a previously practiced more liberal approach. Methods: We performed a retrospective analysis of 2,272 subjects receiving mechanical ventilation ≥48 h within 5 adult ICUs between June 2020 and August 2023. The primary outcome was ventilator-free days at day 28 (VFD28). Secondary outcomes included ventilator days, ICU days, hospital stay, re-intubation rates, and mortality. Analysis was stratified by before and after policy implementation (see intervention) and by receiving HTS/NAC or not (ϕHTS/NAC). The latter was examined before and after propensity matching. The Δ for noninferiority was -0.5 days for VFD28 and +0.5 days for other continuous variables. As outcomes were not normally distributed, we analyzed them using Mann-Whitney U statistics. Results: Two thousand two hundred seventy-two subjects were evaluated. The mean age was 58.70 + 16.13 years and 929 (40.9%) subjects were women. HTS/NAC administration was reduced after policy implementation (40.2% before policy and 8.9% after policy; a reduction of 77.9%). The post-policy group and ϕHTS/NAC before and after propensity matching groups were all noninferior to the comparators. Subjects had significantly more VFD28 in the post-policy group, median (IQR), post 21 (0-25), pre: 20 (0-24), P = .02; and in the ϕHTS/NAC group, before matching ϕHTS/NAC: 21 (0-25), HTS/NAC: 18 (0-23), P < .001 and after propensity matching ϕHTS/NAC: 21 (0-25), HTS/NAC; 18 (0-23), P < .001. Conclusions: Restricting practice to conform to the AARC Clinical Practice Guideline was noninferior to more liberal use. The use of HTS/NAC in mechanically ventilated subjects does not appear efficacious and is both costly and time-consuming.}, } @article {pmid40023441, year = {2025}, author = {Yonatan, E and Shukha, ON and Golani, I and Abu-Ata, S and Awad-Igbaria, Y and Khatib, N and Ginsberg, Y and Palzur, E and Beloosesky, R and Shamir, A}, title = {Maternal N-acetylcysteine Supplementation in Lactation Ameliorates Metabolic and Cognitive Deficits in Adult Offspring Exposed to Maternal Obesity.}, journal = {Neuropharmacology}, volume = {}, number = {}, pages = {110390}, doi = {10.1016/j.neuropharm.2025.110390}, pmid = {40023441}, issn = {1873-7064}, abstract = {Maternal obesity in pregnancy and lactation is linked to metabolic disturbances and neurodevelopmental problems in offspring, increasing the risk of psychiatric disorders in adulthood. We proposed that maternal N-acetyl cysteine (NAC) supplementation during lactation, a critical period for neurodevelopment, potentially protects offspring from developing cognitive impairment in adulthood. Fifteen young female ICR mice were randomly allocated to different experimental groups: high-fat diet (HFD; 60.3% fat before mating, during pregnancy and lactation), HFD-NAC of 300 mg/Kg/day during lactation, CD (high-fat diet before mating, during pregnancy, and regular chow control diet of 8.2% fat during lactation), CD-NAC of 300 mg/Kg/day during lactation and control group consuming regular chow diet. The serum inflammatory markers of the offspring were evaluated post-weaning, while metabolic markers, microglial density, and cognitive performance were assessed in adulthood using the novel Object Recognition and Morris Water Maze tests. Our results demonstrate maternal obesity during gestation and lactation increased body weight, hepatic steatosis, and microglial cell density in the dentate gyrus (DG) and cortex. Furthermore, these offspring exhibited reduced spatial learning abilities in adulthood, regardless of sex. However, maternal NAC administration during lactation and maternal diet intervention significantly reduced brain microglial density and improved both male and female offspring metabolic profiles. More importantly, NAC supplementation during lactation, regardless of maternal diet, enhanced male offspring's learning ability in adulthood. Our findings indicate that administering NAC to obese mothers during the critical lactation period may offer protection against metabolic disturbances and cognitive deficits in adult offspring previously exposed to maternal obesity.}, } @article {pmid40023202, year = {2025}, author = {Pangrazzi, L and Cerilli, E and Balasco, L and Khurshid, C and Tobia, C and Dall'O', GM and Chelini, G and Perini, S and Filosi, M and Barbieri, A and Ravizza, T and Vezzani, A and Provenzano, G and Pastore, A and Weinberger, B and Rubert, J and Domenici, E and Bozzi, Y}, title = {The interplay between oxidative stress and inflammation supports autistic-related behaviors in Cntnap2 knockout mice.}, journal = {Brain, behavior, and immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbi.2025.02.030}, pmid = {40023202}, issn = {1090-2139}, abstract = {Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that oxidative stress and inflammation may contribute to ASD. Indeed, increased levels of oxygen radicals and pro-inflammatory molecules were described in the brain and peripheral blood of persons with ASD and mouse models. Despite this, a potential direct connection between oxidative stress and inflammation within specific brain areas and ASD-related behaviors has not been investigated in detail yet. Here, we used RT-qPCR, RNA sequencing, metabolomics, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2, a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress, inflammation, as well as motor and social impairments in Cntnap2[-/-] mice, concomitant with enhanced function of microglia cells in NAC-treated mutants. Intriguingly, social deficits, cerebellar inflammation, and microglia dysfunction were induced by NAC in Cntnap2[+/+] animals. Our findings suggest that the interplay between oxidative stress and inflammation accompanied by genetic vulnerability may underlie ASD-related behaviors in Cntnap2 mutant mice.}, } @article {pmid40022144, year = {2025}, author = {Okon, IA and Beshel, JA and Owu, DU and Orie, NN and Jim, AE and Edet, LI}, title = {Moderate aerobic exercise improves haematological indices without altering cardio-metabolic enzyme activities in sedentary healthy young adults.}, journal = {BMC sports science, medicine & rehabilitation}, volume = {17}, number = {1}, pages = {32}, pmid = {40022144}, issn = {2052-1847}, abstract = {BACKGROUND: Regular aerobic exercise regulates cardiorespiratory functions by its effect on specific enzyme activities. This study investigated the immediate effects of moderate aerobic exercise on haematological parameters and cardio-metabolic enzymes activity in healthy young male and female adults.

METHODS: Forty young healthy sedentary subjects, twenty males (25 ± 5.6 years; 65 ± 4.0 kg; 176.9 ± 2.5 cm) and twenty females (25 ± 4.5 years, 62 ± 2.9 kg, 175 ± 1.3 cm) volunteered for the study. The exercise regimen was of moderate intensity lasting for 20 min daily on a treadmill at incremental speed of 3 km/h to 13 km/h for 14 consecutive days. The weight and height of participants were measured. Blood sample was collected via antecubital vein for haematological and biochemical analysis. The haematological parameters namely red blood cell and indices, leukocyte and differential white blood cell count, platelet and platelet indices were assessed. Cardiac troponin-T, creatine kinase, lactate dehydrogenase and N-acetyl-cysteine activated creatine kinase activities were assessed before and after exercise.

RESULTS: The result showed a significant (p < 0.05) increase in RBC (males 7%, females 11%) haemoglobin (males 8%, females 8.3%), haematocrit (males 5%, females 14%) leukocyte (males 54%, females 40%) and monocyte count (males 68%, females 55%) after 14 days of exercise. The enzymatic activities of lactate dehydrogenase, N-acetyl-cysteine activated creatine kinase (CK-NAC), creatine kinase (CK-MB) and cardiac troponin-T showed no significant change after 14 days of exercise.

CONCLUSION: It is concluded that moderate aerobic exercise increased haematological parameters and maintained cardio-metabolic enzymes activities in young male and female adults.}, } @article {pmid40020975, year = {2025}, author = {Liu, ZH and Zhai, Y and Zhang, J and Huang, W and Li, W and Qin, W}, title = {Mitochondrial iron deficiency mediated inhibition of ecdysone synthesis underlies lead (Pb) induced developmental toxicity in Drosophila melanogaster.}, journal = {Toxicology and applied pharmacology}, volume = {497}, number = {}, pages = {117283}, doi = {10.1016/j.taap.2025.117283}, pmid = {40020975}, issn = {1096-0333}, abstract = {Lead (Pb) is a pervasive heavy metal possessing developmental toxicity, at least in part, by disrupting iron homeostasis. In this study, we aimed to elucidate the underlying mechanism of iron deficiency mediated developmental defects in Pb exposed Drosophila melanogaster, mainly focusing on iron-dependent synthesis of ecdysone signaling, which plays a key role in the development of insects. Herein, we found Pb exposure resulted in iron deficiency in mitochondria by inhibiting expression of mitoferrin (evidenced by qPCR assay), the mitochondrial iron importer. Further study demonstrated that biosynthesis of ecdysone, a hormone synthesized with the help of iron-containing cytochrome P450s in mitochondria, was inhibited following Pb exposure. Ecdysone supplementation, to some extent, rescued Pb induced developmental delay and reproductive defects in Drosophila melanogaster. Furthermore, we found that disruption of mitoferrin and ecdysone synthesis was restored by NAC (N-Acetylcysteine, a well-known ROS scavenger), suggesting that oxidative stress plays a key role in Pb mediated mitochondrial iron dys-homeostasis and developmental toxicity. This study therefore revealed that mitochondrial iron deficiency mediated inhibition of ecdysone synthesis is a key event associated with iron dys-homeostasis mediated developmental defects caused by Pb exposure. Meanwhile, our study indicated that mitochondria may act as an important target of Pb, thus providing potential protective strategies against Pb toxicity.}, } @article {pmid40020837, year = {2025}, author = {Yaseen, K and Ejaz, S and Imran, M}, title = {Surface engineering of biomedical catheters using N-acetyl cysteine functionalized carboxymethyl chitosan nanosystems to combat biofouling and device-associated infections.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {141516}, doi = {10.1016/j.ijbiomac.2025.141516}, pmid = {40020837}, issn = {1879-0003}, abstract = {Functionalized anti-biofouling nanosystems were developed to engineer the surface of silicone catheters for mitigating the incidence of device-associated infections (DAIs). These infections are typically a consequence of microbial biofilms and antimicrobial resistance (AMR) which lead to increased hospitalization costs and mortality rates. Covalent coupling of N-acetyl cysteine (NAC) with O-carboxymethyl chitosan (O-CMC) was optimized to develop NAC-functionalized CMC nanosystems (NAC-CMC-NS). The coupling was confirmed by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and 4, 6-trinitrobenzene sulfonic acid (TNBS) assay indicating 80 ± 2 % functionalization efficacy. Subsequently, meropenem-loaded NAC-CMC NS exhibited an average particle size of 273 ± 4.2 nm with 0.4 ± 0.03 polydispersity index (PDI), a zeta potential of -9.15 ± 0.5 mV and encapsulation efficiency (EE) of 67 ± 3.2 %. These functionalized NS employing the dual strategy of contact-killing and meropenem-release, exhibited exceptional antimicrobial activity leading to the 76 ± 1.5 % and 60 ± 1 % inhibition of E. coli and P. aeruginosa biofilms, respectively. After the successful grafting of functionalized NS onto silicone catheters, the resulting substrate remarkably reduced the bacterial colonization, offering a promising solution for reducing DAIs like ventilator-associated pneumonia (VAP) and catheter-associated urinary tract infections (CAUTI). Moreover, the excellent hemocompatibility and low cytotoxicity of these nanovesicles highlight their potential applications for clinical use.}, } @article {pmid40017063, year = {2025}, author = {Bikal, P and Bhardwaj, JK}, title = {N-Acetyl-L-Cysteine Mediated Attenuation of Cadmium Induced Oxidative Stress and Apoptosis in Ovarian Antral Follicles In Vitro.}, journal = {Environmental toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1002/tox.24505}, pmid = {40017063}, issn = {1522-7278}, support = {//CSIR (Council of Scientific and Industrial Research)/ ; }, abstract = {Female fertility has been demonstrated to be directly correlated with cadmium, a heavy metal contaminant that is widely present in the environment. N-acetyl cysteine (NAC), a powerful antioxidant, has been shown to have therapeutic effects for a number of ailments. NAC's potential to prevent ovarian toxicity caused by Cd is still unknown. Therefore, the objective of the current study was to evaluate the concentration- and time-dependent protective effect of NAC supplementation against Cd-induced granulosa cell toxicity in healthy caprine ovaries. The in vitro cultured ovaries/follicles were subjected to different cytotoxic (ethidium bromide and acridine orange [EB/AO] staining), histomorphological, and biochemical analyses during study. The results revealed that NAC treatment significantly attenuated the Cd-instigated cytotoxicity in granulosa cells, as evidenced by diminished apoptotic attributes in NAC co-supplemented groups compared to only Cd-exposed groups. Moreover, NAC markedly restored the decline in enzymatic activity of antioxidant enzymes (GST, SOD, and CAT), along with ferric reducing antioxidant power, further diminishing the formation of MDA in Cd exposed caprine ovary. The findings of this study indicated that Cd, being an ovarian toxicant, adversely affects the female reproductive system. However, simultaneous NAC administration significantly reduced the Cd-caused ovarian damage, indicating that NAC has therapeutic potential in controlling female gonadotoxicity due to gradually growing environmental Cd pollution.}, } @article {pmid40013897, year = {2025}, author = {Nakatsu, L and Lopez, JR and Garcia, CM and Cherian, M and Nash, J and Tofighi, D and Seifert, SA and Smolinske, S and Warrick, BJ}, title = {Comparison of two-bag and three-bag acetylcysteine regimens in the treatment of paracetamol poisoning: a systematic review and meta-analysis.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/15563650.2025.2456116}, pmid = {40013897}, issn = {1556-9519}, abstract = {INTRODUCTION: Worldwide, paracetamol poisoning is a common cause of acute liver failure and referral to transplant centers. Acetylcysteine has long been the mainstay of treatment, but recent literature suggests that a simplification of the "three-bag" method may decrease adverse effects. Our primary hypothesis is that a simplified dosing regimen (two-bag regimen) is non-inferior to the three-bag method in preventing liver injury. Our secondary hypothesis is that a simplified regimen will have lower rates of adverse effects.

METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched Medline/PubMed, Google, Google Scholar, Cochrane Library, Embase and Toxnet on May 23, 2022. The Medical Subject Headings terms were NAC, acetaminophen toxicity, acetyl-cysteine, N-acetylcysteine, paracetamol, APAP, 2-bag, and 3-bag. The Embase terms were acetylcysteine, NAC, 2-bag, two bag, 3-bag, three bag, simplified dosing, acetaminophen, Tylenol[®], paracetamol, APAP, drug overdose, poisoning, and overdose. Studies included both non-United States Food and Drug Administration-approved and United States Food and Drug Administration-approved acetylcysteine regimens. Case reports, review articles, and animal studies were excluded. Two authors independently reviewed each study using Rayyan QCRI to determine if the studies met search criteria while blinded to the selections of each other. The two authors discussed until reaching a consensus. We used a primary outcome of non-inferiority of hepatotoxicity. We used secondary outcomes of non-allergic anaphylactoid reactions and adverse events. We conducted a fixed-effect meta-analysis using R package meta. To visually summarize the meta-analysis results, we also produced forest plots. We used Cochran's Q test and I[2] statistical analysis to assess heterogeneity between the studies.

RESULTS: Our search resulted in 657 total citations, which were reduced to unique citations. Of the 643 studies, 46 met the criteria for full text review, and eight met the study criteria. Of the eight studies investigating a simplified acetylcysteine regimen, four studies utilized some form of a modified two-bag infusion regimen, varying in duration or dosing of infusions, and four studies shared the same "common" two-bag treatment, a regimen that delivers acetylcysteine 200 mg/kg over 4 h, followed by 100 mg/kg acetylcysteine over 16 h. The six studies comparing a two-bag dosing regimen to the three-bag technique were utilized for our random effect model meta-analysis. We found no significant heterogeneity amongst the six studies for either hepatotoxicity (Q(5) = 1.11; P = 0.95; I[2] = 0%; 95% CI: 0%-74.6%) or non-allergic anaphylactoid reactions and adverse events (Q(5) = 10.15; P = 0.07; I[2] = 50.7%; 95% CI: 0%-80.4%). Compared to the traditional three-bag dosing regimen, the two-bag method did not demonstrate a difference in relative risk for hepatotoxicity (OR: 0.88; 95% CI: 0.72-1.08; P = 0.23) but did demonstrate a significantly decreased likelihood of non-allergic anaphylactoid reactions and other adverse events (OR: 0.24; 95% CI: 0.17-0.35; P <0.0001).

DISCUSSION: The two-bag method is a safe and effective treatment for acute paracetamol poisoning. The two-bag regimen is correlated with a significant reduction in non-allergic anaphylactoid reactions, compared to the three-bag method, and is non-inferior with respect to hepatotoxicity. While we feel this information is practice changing for many, further research in the form of a randomized control trial would be beneficial to compare even more abbreviated methods such as a "single bag method."

CONCLUSION: Two-bag acetylcysteine dosing regimens appear to be non-inferior to the three-bag method with respect to hepatotoxicity, and result in fewer anaphylactoid, cutaneous, and gastrointestinal reactions.}, } @article {pmid40011998, year = {2025}, author = {Wu, CH and Chou, WC and Jou, IM and Tu, YK and Ma, CH and Tsai, KL}, title = {Cisplatin-induced oxidative stress, apoptosis, and pro-inflammatory responses in chondrocytes through modulating LOX-1.}, journal = {Journal of orthopaedic surgery and research}, volume = {20}, number = {1}, pages = {206}, pmid = {40011998}, issn = {1749-799X}, mesh = {*Cisplatin/pharmacology ; *Chondrocytes/drug effects/metabolism ; *Scavenger Receptors, Class E/metabolism ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Animals ; Humans ; Antineoplastic Agents/pharmacology ; NF-kappa B/metabolism ; Cells, Cultured ; Inflammation/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Cisplatin is a potent and efficacious anticancer medication. In pediatric cancer, the height of the growth plate's proliferating layer is known to be reduced by cisplatin, but researchers have not yet determined the specific mechanism behind this phenomenon. Lectin-like oxidized low-density lipoprotein receptor-1 is known to be involved in the development of osteoarthritis and atherosclerosis. The equilibrium of cartilage is regulated by LOX-1, but the function of LOX-1 in cisplatin-induced chondrocyte impairment remains unknown. Positive regulation of LOX-1 leads to increased cellular oxidative stress and cell damage. Research has shown that blocking of LOX-1 can reduce the chondrocyte damage and oxidative stress in cells induced by oxidized LDL treatment. However, the role of LOX-1 in cisplatin-mediated chondrocyte damage is still unclear. This study found that cisplatin increased ROS concentration and p38, ERK phosphorylation. Cisplatin activated NF-κB in chondrocytes. In addition, LOX-1 small interfering RNA transfection mitigated cisplatin-induced apoptosis in TC28a2 cells. Phosphorylated extracellular signal-regulated kinase and p38 were dose-dependently increased by administration of cisplatin. Silencing LOX-1 or MAPK inhibition reduces cisplatin-caused apoptosis. The findings suggest that cisplatin-induced growth plate dysfunction operates through the LOX-1/p38/NF-κB signaling pathway.}, } @article {pmid40009511, year = {2025}, author = {Kandel, H and Cruz, AR and Thom, RP and McDougle, CJ}, title = {N-Acetylcysteine for Nonsuicidal Self-Injurious Behavior in 3 Adults With Williams Syndrome: A Case Series.}, journal = {Journal of clinical psychopharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1097/JCP.0000000000001976}, pmid = {40009511}, issn = {1533-712X}, abstract = {BACKGROUND: Williams syndrome (WS) is a genetic disorder that results from a microdeletion of 25 to 27 genes on chromosome 7q11.23. Individuals with WS often exhibit comorbid neuropsychiatric symptoms, especially anxiety. To our knowledge, nonsuicidal self-injurious behavior (NSSIB) has not been reported in WS. N-acetylcysteine (NAC) is a safe and readily available drug that may modulate glutamate activity in the brain. NAC is effective for treating various neuropsychiatric symptoms and disorders. There are limited reports in the literature where NAC has been used to treat NSSIB effectively, but none in WS.

METHODS: This report describes using NAC to treat NSSIB in 3 adults with WS.

FINDINGS: Nonsuicidal self-injurious behavior was successfully treated in 3 adults with WS using NAC in doses ranging from 2400 to 3600 mg a day, resulting in significant improvement in their daily functioning. Additionally, NAC was well tolerated.

CONCLUSIONS: NAC was effective for treating NSSIB in 3 adults with WS. By addressing these challenging behaviors, NAC offers a promising pharmacological intervention that can significantly improve the quality of life for patients with WS who engage in NSSIB. Further research and clinical trials are necessary.}, } @article {pmid40007988, year = {2024}, author = {Habib, M}, title = {Combination of atorvastatin plus N-acetylcysteine versus atorvastatin alone to prevent contrast-induced nephropathy.}, journal = {Archives of medical sciences. Atherosclerotic diseases}, volume = {9}, number = {}, pages = {e207-e211}, pmid = {40007988}, issn = {2451-0629}, abstract = {INTRODUCTION: Contrast-induced acute renal injury is the third leading cause of hospital-acquired acute kidney injury. Our trial aimed to compare high-dose statin versus statin plus N-acetylcysteine (NAC) to prevent contrast-induced nephropathy.

MATERIAL AND METHODS: Randomized control trial included patients who undergoing elective percutaneous coronary intervention (PCI) at Alshifa Hospital in Gaza, the first group (statin: 50 patients) received 80 mg of atorvastatin orally once daily for 3 days. The second group (statin + NAC: 50 patients) received 80 mg of atorvastatin orally once daily for 3 days, plus NAC 1200 mg orally twice daily every 12 h for 2 days. All patients underwent measurement of serum creatinine and urea level before PCI and 2-3 days after the procedure. The primary endpoint was to compare development of contrast-induced nephropathy between the two groups.

RESULTS: The total group comprised 100 patients: 71 male patients and 29 female patients. Mean age was 59 ±9.8 years. After intervention serum creatinine decreased from 1.02 ±0.27 mg/dl to1.01 ±0.29 mg/dl in the statin group, while it decreased from 1.08 ±0.36 mg/dl to 0.92 ±0.13 mg/dl in the statin + NAC group. The difference between the two groups was significant (p = 0.048). Also, the urea plasma level in the statin group decreased from 34.5 ±9.7 mmol/l to 30.6 ±8.7 mmol/l after PCI, while in the statin + NAC group it decreased from 36.4 ±9.9 mmol/l to 26.2 ±10.6 mmol/l; the difference between the two groups was significant (p = 0.017). Contrast-induced nephropathy was seen in 9 (18%) patients in the statin group and in 2 (4%) patients in the statin + NAC group (p = 0.025).

CONCLUSIONS: The combination of high-dose atorvastatin plus NAC compared to atorvastatin alone was associated with a significant reduction of contrast-induced nephropathy in patients undergoing PCI.}, } @article {pmid40005451, year = {2025}, author = {Abdelbagi, O and Taha, M and Al-Kushi, AG and Alobaidy, MA and Baokbah, TAS and Sembawa, HA and Azher, ZA and Obaid, R and Babateen, O and Bokhari, BT and Qusty, NF and Malak, HA}, title = {Ameliorative Effect of N-Acetylcysteine Against 5-Fluorouracil-Induced Cardiotoxicity via Targeting TLR4/NF-κB and Nrf2/HO-1 Pathways.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {2}, pages = {}, pmid = {40005451}, issn = {1648-9144}, mesh = {Animals ; *Fluorouracil/adverse effects/pharmacology ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *NF-E2-Related Factor 2/metabolism ; *Cardiotoxicity/prevention & control/etiology/drug therapy ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Male ; Antimetabolites, Antineoplastic/adverse effects/toxicity ; Signal Transduction/drug effects ; }, abstract = {Background and Objectives: 5-Fluorouracil (5-FU) is a widely prescribed and effective chemotherapeutic drug, but its cardiotoxic side effects pose a significant challenge to its use. Identifying a protective agent that does not affect its anticancer efficacy is essential. Our study aimed to investigate the cardioprotective effect of N-acetyl cysteine (NAC) against 5-FU-induced cardiac injury and to elucidate the underlying mechanisms. Materials and Methods: This study included four experimental groups, each with eight rats (n = 8): Group I (control group), Group II (NAC group), Group III (5-FU group), and Group IV (combined group 5-FU+NAC). Cardiac enzymes, oxidative stress, inflammatory, and apoptotic markers were investigated, and cardiac sections from the different groups were histologically examined. Results: Co-treatment of 5-FU with NAC resulted in significantly lower levels of cardiac enzymes (alanine transaminase (ALT) by 62.1%, aspartate transaminase (AST) by 73.6%, lactate dehydrogenase (LDH) by 55.8%, and creatine kinase (CK) by 57.3%) compared to the 5-FU group, along with marked improvements in heart tissue histology. Additionally, NAC enhanced the activity of cardiac antioxidant enzymes (superoxide dismutase (SOD) by 295.6%, catalase (CAT) by 181%, and glutathione peroxidase (GPx) by 320.9%) while decreasing malondialdehyde (MDA) by 51.1%, a marker of membranous lipid peroxidation. This might be due to significant upregulation of the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway at the gene and protein levels. The combined treatment significantly decreased the gene expression of the toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) pathway. Furthermore, it downregulated the protein levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α) by 29.9%, interleukin-1 beta (IL-1β) by 21.9%, and interleukin-6 (IL-6) by 49.3%. Moreover, it upregulated the antiapoptotic marker B-cell lymphoma 2 (Bcl-2) protein levels by 269% and decreased apoptotic indicators Bcl-2-associated protein x (Bax) by 57.9% and caspase-3 by 30.6% compared to the 5-FU group. Conclusions: This study confirmed that NAC prevented the cardiotoxic effect of 5-FU through its antioxidant, anti-inflammatory, and antiapoptotic properties, suggesting its potential application as an adjuvant therapy in chemotherapy to alleviate 5-FU-induced cardiotoxicity.}, } @article {pmid40002497, year = {2025}, author = {Lomelí Martínez, SM and Pacheco Moisés, FP and Bitzer-Quintero, OK and Ramírez-Jirano, J and Delgado-Lara, DLC and Cortés Trujillo, I and Torres Jasso, JH and Salazar-Flores, J and Torres-Sánchez, ED}, title = {Effect of N-Acetyl Cysteine as an Adjuvant Treatment in Alzheimer's Disease.}, journal = {Brain sciences}, volume = {15}, number = {2}, pages = {}, doi = {10.3390/brainsci15020164}, pmid = {40002497}, issn = {2076-3425}, abstract = {Oxidative stress levels are exacerbated in Alzheimer's disease (AD). This phenomenon feeds back into the overactivation of oxidase enzymes, mitochondrial dysfunction, and the formation of advanced glycation end-products (AGEs), with the stimulation of their receptors (RAGE). These factors stimulate Aβ peptide aggregation and tau hyperphosphorylation through multiple pathways, which are addressed in this paper. The aim of this study was to evaluate the regulatory effect of N-acetyl cysteine (NAC) on oxidant/antioxidant balance as an adjuvant treatment in patients with AD. The results obtained showed that NAC supplementation produced improved cognitive performance, decreased levels of oxidative stress markers, lowered activities of oxidase enzymes, increased antioxidant responses, and attenuated inflammatory and apoptotic markers. Moreover, NAC reversed mitochondrial dysfunction, lowered AGEs-RAGE formation, attenuated Aβ peptide oligomerization, and reduced phosphorylation of tau, thereby halting the formation of neurofibrillary tangles and the progression of AD.}, } @article {pmid40002335, year = {2025}, author = {Chien, HJ and Hu, HM and Tsai, SJ and Lin, CL and Yang, SF and Chen, JK and Liu, CJ and Hsieh, YH}, title = {Licochalcone A Induces Uterine Leiomyoma Cell Apoptosis via the ROS-Mediated JNK Activation of the GRP78/NRF2 Pathway In Vitro and In Vivo.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, doi = {10.3390/antiox14020148}, pmid = {40002335}, issn = {2076-3921}, support = {CSMU-CCH-112-01//Chung Shan Medical University and Changhua Christian Hospital/ ; KMU-TC113A02//Kaohsiung Medical University Research Center Grant/ ; }, abstract = {Licochalcone A (LicoA) possesses anti-tumor properties. However, the potential therapeutic effect of LicoA on uterine leiomyomas (ULs) remains unknown. In this study, the effects of LicoA on the proliferation of ULs and its underlying mechanism were explored. LicoA treatment significantly decreased the viability of uterine smooth muscle cells (UtSMCs) and ELT3 cells in a dose-dependent manner. The induction of ELT3 cell apoptosis by LicoA was accompanied by the increased generation of reactive oxygen species (ROS), elevated endoplasmic reticulum (ER) stress (GRP78/IRE1α/ATF6/CHOP), and the increased expression of proapoptotic proteins (c-caspase-3, c-caspase-9, and c-PARP). The ability of Z-VAD-FMK (a caspase inhibitor) and n-acetylcysteine (NAC; a cell membrane permeable antioxidant) to reverse LicoA-induced ROS-mediated ER stress pathways also observed. Furthermore, GRP78 or JNK knockdown was involved in LicoA-induced ROS-mediated ER stress and apoptosis in ELT3 cells. In immunodeficient mice, LicoA significantly suppressed the growth of ELT3 tumor cells, without toxicity. This study is the first to show that LicoA exerts anti-leiomyoma effects via the modulation of ROS-mediated ER stress-induced apoptosis through the JNK/GRP78/NRF2 signaling pathway.}, } @article {pmid40002315, year = {2025}, author = {Ückert, AK and Suciu, I and Land, A and Spreng, AS and Welte, H and Herzog, D and Basler, M and Leist, M}, title = {Chemical and Biological Mechanisms Relevant to the Rescue of MG-132-Treated Neurons by Cysteine.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {2}, pages = {}, doi = {10.3390/antiox14020128}, pmid = {40002315}, issn = {2076-3921}, support = {TRR353//Deutsche Forschungsgemeinschaft/ ; 161L0243B//Federal Ministry of Education and Research/ ; 016LW0146K//Federal Ministry of Education and Research/ ; 964537//European Union/ ; 964518//European Union/ ; 101057014//European Union/ ; GP/EFSA/ED/2022/01//European Food Safety Authority/ ; }, abstract = {Proteasome dysfunctions are observed in many human pathologies. To study their role and potential treatment strategies, models of proteasome inhibition are widely used in biomedical research. One frequently used tool is the proteasome inhibitor MG-132. It triggers the degeneration of human neurons, and several studies show protection from pathological events by glutathione or its precursors. It has therefore been concluded that glutathione protects cells from proteasome dysfunction. However, an alternative explanation is that MG-132, which is a peptide aldehyde, is chemically inactivated by thiols, and the apparent protection by glutathione from proteasome dysfunction is an artefact. To clarify this issue, we examined the chemical inactivation of MG-132 by thiols and the role of such reactions for neuroprotection. Using mass spectrometry and nuclear magnetic resonance spectroscopy, we found that MG-132 reacted with L-cysteine to form a stable end product and with glutathione to form an unstable intermediate. Using a cell-free proteasome inhibition assay, we found that high concentrations of L-cysteine can scavenge a substantial fraction of MG-132 and thus reduce proteasome inhibition. Glutathione (or N-acetyl-cysteine) did not alter proteasome inhibition (even at high concentrations). In a final step, we studied human neuronal cultures. We exposed them to MG-132, supplemented the culture medium with various thiols, and assessed intracellular L-cysteine concentrations. The transcriptome response pattern also indicated an inhibition of the proteasome by MG-132 in the presence of L-cysteine. We conclude that thiol concentrations that can be reached in cells do not inactivate MG-132 in pathological models. They rather act in a cytoprotective way as antioxidants.}, } @article {pmid40001479, year = {2025}, author = {Zhao, M and Han, M and Guo, S and Tang, Z}, title = {CXCL12 as a Potential Hub Gene for N-Acetylcysteine Treatment of T1DM Liver Disease.}, journal = {Biomolecules}, volume = {15}, number = {2}, pages = {}, doi = {10.3390/biom15020176}, pmid = {40001479}, issn = {2218-273X}, support = {No. 31572585//National Natural Science Foundation of China/ ; }, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Chemokine CXCL12/genetics/metabolism ; *Diabetes Mellitus, Type 1/drug therapy/genetics/metabolism ; Dogs ; *Liver Diseases/drug therapy/genetics/metabolism ; Humans ; Liver/metabolism/drug effects ; Male ; Disease Models, Animal ; }, abstract = {The etiology of type 1 diabetes mellitus (T1DM) is intricate, leading to its classification as an autoimmune metabolic disorder. T1DM often coexists with various visceral diseases. N-acetylcysteine (NAC) is widely acknowledged for its potent antioxidant properties. Studies have demonstrated that the combination of NAC and insulin can effectively alleviate iron-induced nephropathy in T1DM and mitigate oxidative stress injury in skeletal muscle associated with the condition. However, the potential impact of NAC alone on liver disease in individuals with T1DM remains uncertain. In this study, a beagle model was established to simulate T1DM, enabling investigation into the role of NAC in liver disease using RNA-seq biogenic analysis and subsequent validation through molecular biological methods. The findings revealed suppressed expression of CXCL12 chemokine in the livers of individuals with T1DM, while treatment with NAC induced specific activation of CXCL12 within the liver affected by T1DM. These results suggest that CXCL12 may serve as a regulatory factor involved in the therapeutic effects of NAC on liver disease associated with TIDM. This discovery holds significant implications for utilizing NAC as an adjunctive therapy for managing complicated liver diseases accompanying type 1 diabetes mellitus.}, } @article {pmid40000992, year = {2025}, author = {Kumar, S and Das, B and Maurya, G and Dey, S and Gupta, P and Sarma, JD}, title = {Limonoid-rich fraction from Azadirachta indica A. Juss. (neem) stem bark triggers ROS-independent ER stress and induces apoptosis in 2D cultured cervical cancer cells and 3D cervical tumor spheroids.}, journal = {BMC cancer}, volume = {25}, number = {1}, pages = {334}, pmid = {40000992}, issn = {1471-2407}, support = {BT/MEDII/NIBMG/SYMEC/2014/Vol.II//Department of Biotechnology, Ministry of Science and Technology, India/ ; }, mesh = {Humans ; *Azadirachta/chemistry ; *Reactive Oxygen Species/metabolism ; *Uterine Cervical Neoplasms/drug therapy/pathology/metabolism ; *Limonins/pharmacology/chemistry/isolation & purification ; *Apoptosis/drug effects ; Female ; *Plant Bark/chemistry ; *Plant Extracts/pharmacology/chemistry ; HeLa Cells ; *Endoplasmic Reticulum Stress/drug effects ; *Spheroids, Cellular/drug effects ; Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; }, abstract = {BACKGROUND: The existing anticancer drugs in clinical practice show poor efficacy in cervical cancer patients and are associated with multiple side effects. Our previous study demonstrated the strong antineoplastic activity of crude extract prepared from the stem bark of Azadirachta indica (Neem) against cervical cancer. However, the active phytoconstituents of neem stem bark extract and its underlying anticancer mechanism are yet to be investigated. Thus, the present study aimed to identify the active fraction from crude neem stem bark extract to further dissect its anticancer mechanism and determine the active components.

METHODS: Dichloromethane (DCM) extract from neem stem bark was prepared and fractionated using thin-layer chromatography. The fractions obtained were screened against HeLa and ME-180 cervical cancer cell lines to identify the most active fraction, which was then selected for further studies. Clonogenic assay, cell cycle analysis, apoptosis assay, and reactive oxygen species (ROS) assay were performed to determine the cytotoxicity of the active fraction. Gene expression was analyzed using real-time PCR and western blot to determine the mechanism. Additionally, the HeLa cells-derived 3D spheroid model was used to determine the antitumor efficacy of the active fraction. Electrospray ionization-mass spectrometry, Fourier-transform infrared spectroscopy, and proton nuclear magnetic resonance were used to identify the phytoconstituents of the fraction.

RESULTS: Initial screening revealed fraction 2 (F2) as the most active fraction. Additionally, F2 showed the least cytotoxic effect on normal human fibroblast cells. Mechanistically, F2 induced cell cycle arrest and apoptosis in cervical cancer cells. F2 increased ROS levels, induced ER stress, and activated cell survival pathway. Treatment with N-acetyl cysteine revealed that F2 induced ROS-independent ER stress and apoptosis. 3D spheroid viability and growth delay experiments demonstrated the strong antitumor potential of F2. Finally, six compounds, including one flavonoid (nicotiflorin) and five limonoids, were identified in the F2 fraction.

CONCLUSION: This is the first study to identify the active fraction and its phytoconstituents from neem stem bark and demonstrate the anticancer mechanism against cervical cancer. Our study highlights the importance of investigating neem stem bark-derived limonoids and nicotiflorin as a potential source to develop new anticancer therapeutic agents.}, } @article {pmid39992072, year = {2025}, author = {Eid, SY and Koshak, MF and Elzubier, ME and Refaat, B and Almaimani, RA and Althubiti, M and Nour Eldin, EEM and Alahmadi, NH and Fatani, SH and Aslam, A and Khidir, EBA and Abdellatif, AA and El-Readi, MZ}, title = {Protective Effects of Oral Pharmaceutical Solution of Fucoxanthin Against Paracetamol-Induced Liver Injury: Modulation of Drug-Metabolizing Enzymes, Oxidative Stress, and Apoptotic Pathways in Rats.}, journal = {Drug development and industrial pharmacy}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/03639045.2025.2469808}, pmid = {39992072}, issn = {1520-5762}, abstract = {BACKGROUND: Paracetamol (PAC) overdose causes acute liver injury through oxidative stress, inflammation, and apoptosis. While N-acetyl cysteine (NAC) is the standard treatment, fucoxanthin (FUC), a carotenoid from brown seaweed, has shown hepatoprotective effects in animal studies, but its role in PAC toxicity is unclear.

OBJECTIVE: Compared to NAC, this study assessed the hepatoprotective potential of oral FUC solution towards PAC-induced injury to the rat's liver.

METHOD: FUC was formulated as a pharmaceutical solution and characterized via UV-VIS spectroscopy. Six groups of male Wistar rats each contain five animal which are in total thirty rats: negative control (NC), positive control (PC, 2 g/kg PAC), NAC (1200 mg/kg), and three oral FUC doses (100, 200, and 500 mg/kg) for seven days, with PAC administered on day-8. Liver tissues were analyzed for oxidative stress, gene expression, and histology.

RESULTS: FUC solution was clear with absorbance at 433 nm. PAC caused 30% mortality (p < 0.01 vs. others). NAC reduced ALT (56%), AST (78%), ALP (28%), and increased TP by 25% (p < 0.001 vs. PC). FUC at 500 mg/kg (F500) was superior, reducing ALT (82%), AST (93%), ALP (40%), and increasing TP (35%) (p < 0.001 vs. NAC). PAC increased oxidative stress, CYP2E1/CYP3A2 expression, apoptosis markers, and suppressed Nrf2/AMPK/AKT1. F500 improved antioxidants, reduced oxidative stress, and apoptosis, enhanced the Nrf2/AMPK pathway, and downregulated CYP2E1/CYP3A2 (p < 0.01).

CONCLUSION: FUC, particularly at 500 mg/kg, offers significant hepatoprotection against PAC-induced liver injury by modulating drug metabolizing enzymes and enhancing antioxidant defences, warranting further research.}, } @article {pmid39989173, year = {2025}, author = {Jiang, ZB and He, QH and Kang, LP and Jiang, S and Liu, JN and Xu, C and Wang, WJ and Wang, XR and Wu, QB and Huang, DH}, title = {Rutecarpine Suppresses Non-Small Cell Lung Cancer Progression Through Activating the STING Pathway and Elevating CD8+ T Cells.}, journal = {Chemical biology & drug design}, volume = {105}, number = {2}, pages = {e70070}, doi = {10.1111/cbdd.70070}, pmid = {39989173}, issn = {1747-0285}, support = {//Beijing Science and Technology Innovation Medical Development Foundation: KC2021-JX-0186-4/ ; //Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine (No.202303)/ ; //Guangdong Province-Provincial Chinese Medicine construction special fund named Traditional Chinese Medicine Inheritance Studio construction project Guangdong Chinese Medicine Office Letter [2023] 108/ ; //Guangdong Provincial Administration of Traditional Chinese Medicine (No. 20221361, No. 20251345, No. 20241285)/ ; //Zhuhai Science and Technology Innovation Bureau (No. 2420004000022, No. 2320004000290, No. 2420004000007)/ ; //China Postdoctoral Science Foundation (2022M713652 and 2022M721411)/ ; //Guangdong Basic and Applied Basic Research Foundation of China (2022A1515110790 and 2024A1515012478)/ ; //"Towards a New Horizon" Research Project of the Beijing Chao Enxiang Traditional Chinese Medicine Heritage and Development Foundation in 2023 (No. 2023CX03)/ ; }, mesh = {*Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/metabolism ; Animals ; Humans ; *CD8-Positive T-Lymphocytes/drug effects/metabolism ; *Lung Neoplasms/drug therapy/pathology/metabolism ; Mice ; Cell Line, Tumor ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Membrane Proteins/metabolism ; Signal Transduction/drug effects ; Antineoplastic Agents/pharmacology/chemistry ; Quinazolines/pharmacology/chemistry ; Cell Survival/drug effects ; }, abstract = {Globally, non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths. Rutecarpine (RUT), a quinazolinocarboline alkaloid that is naturally occurring and present in Chinese medicinal herbs, has been shown to have anticancer properties in several cancer cell lines. However, the specific antitumor mechanisms of RUT in NSCLC remain unclear. This study demonstrates that RUT induces apoptosis and significantly reduces the viability of NSCLC cell lines. This effect is achieved by stimulating intracellular ROS production, leading to mitochondrial dysfunction. The decreased cell viability observed with RUT treatment is attributed to the elimination of ROS and apoptosis through the suppression of ROS by N-acetylcysteine (NAC). Furthermore, RUT therapy elevated the production of CXCL10 and CCL5 in NSCLC cell lines and markedly activated the STING pathway in NSCLC cells. Mechanistically, RUT substantially decreased the levels of PD-L1 protein in NSCLC cells. Notably, in vivo experiments demonstrated that RUT significantly inhibits mouse NSCLC tumor growth in mice, exhibiting anti-tumor activity by elevating CD8[+] T cells. These findings strongly support RUT as a promising anti-cancer drug for NSCLC.}, } @article {pmid39988222, year = {2025}, author = {Xu, H and Mao, X and Mo, D and Lv, M}, title = {6PPD impairs growth performance by inducing intestinal oxidative stress and ferroptosis in zebrafish.}, journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP}, volume = {}, number = {}, pages = {110161}, doi = {10.1016/j.cbpc.2025.110161}, pmid = {39988222}, issn = {1532-0456}, abstract = {N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), a tire-derived pollutant, has gained increasing attention due to its potential toxicity to aquatic organisms. Although previous studies have revealed that 6PPD impacts early developmental stages of larval fish, its effects on adult fish, particularly on key organs, remain unclear. In this study, we observed that adult zebrafish exposed to 6PPD exhibited reduced growth performance and increased fecal output. Histological examination with hematoxylin and eosin (H&E) staining revealed damage to the intestinal villi and a reduction in goblet cell numbers, indicating that 6PPD impairs growth performance by disrupting the digestive system. Comparative transcriptomic analysis revealed that 6PPD caused significant changes in the expression of 727 genes in the intestine, of which 280 genes were up-regulated and 447 genes were down-regulated. These genes were primarily associated with nutrient digestion and absorption, energy metabolism, immune response, and redox regulation. Mechanistically, 6PPD induced oxidative stress and triggered ferroptosis in the intestine, leading to structural damage of the intestinal villi. Treatment with the antioxidant N-acetylcysteine (NAC) alleviated 6PPD-induced oxidative stress and ferroptosis, thereby improving intestinal villi structure and promoting fish growth. This study provides insights into the mechanisms by which 6PPD impairs growth in adult zebrafish and highlights NAC as a potential therapeutic strategy to mitigate its toxicity.}, } @article {pmid39985580, year = {2025}, author = {Shariati, S and Mohtadi, S and Khodayar, MJ and Salehcheh, M and Azadnasab, R and Mansouri, E and Moosavi, M}, title = {Quinic acid alleviates liver toxicity induced by acetaminophen in mice via anti-oxidative and anti-inflammatory effects.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39985580}, issn = {1432-1912}, support = {TRC-9924//Ahvaz Jundishapur University of Medical Sciences/ ; }, abstract = {Acetaminophen (N-acetyl-para-aminophenol: APAP)-induced hepatotoxicity is a common toxicity that is associated with oxidative stress and inflammation. Quinic acid (QA) is a naturally occurring metabolite that exhibits antioxidant and anti-inflammatory properties. In this research, the effect of QA on hepatotoxicity caused by APAP was investigated. The mice were divided into six groups: control, APAP (300 mg/kg, i.p.), QA (100 mg/kg, i.p.), N-acetylcysteine (NAC) (100 mg/kg, i.p.), and treatment groups, which pretreated with QA at two doses of 50 and 100 mg/kg. NAC and QA were injected for 7 days, and APAP was injected on the seventh day. On day 8, mice were euthanized, and serum factors, markers of oxidative stress, tumor necrosis factor-α (TNF-α), and expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and cytochrome P450 2E1 (CYP2E1) proteins were measured. The results showed that the APAP-treated group significantly increased the activity of serum enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase). APAP decreased hepatic total thiol content, as well as catalase, superoxide dismutase, and glutathione peroxidase activities, and increased thiobarbituric acid reactive substances and TNF-α levels. In addition, Nrf2 and CYP2E1 protein expression was upregulated in APAP-induced injury. Moreover, histopathological findings confirmed APAP hepatotoxicity. However, QA protected mice against the detrimental effects resulting from an imbalance in the oxidant/antioxidant system. QA ameliorated APAP-induced inflammation and histopathological changes and was able to upregulate the protein expression of Nrf2, while also reversing the increase in protein expression of CYP2E1 in APAP-intoxicated mice. These findings demonstrate the potential of QA in preventing APAP-induced hepatotoxicity, which is comparable to the effects of NAC.}, } @article {pmid39983406, year = {2025}, author = {Zhang, C and Peng, S and Zheng, Z and Chen, Z and Li, M and Huang, N and Liu, Z and Yang, MX and Chen, H}, title = {Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner.}, journal = {Bioorganic chemistry}, volume = {157}, number = {}, pages = {108286}, doi = {10.1016/j.bioorg.2025.108286}, pmid = {39983406}, issn = {1090-2120}, abstract = {Multidrug resistance (MDR) represents a bottleneck in the treatment of breast cancer. Although the potential of aldose reductase inhibitors (ARIs) as sensitizers against MDR has been explored in recent decades, the intrinsic mechanism still needs to be elucidated, and promising agents in the clinic need to be developed. In this study, three novel ARIs (5a-c), characterized by bis-pocket binding, were designed and synthesized. Inhibitory activity is positively correlated with antioxidation and benefits from rigid spacers. Only 5a with less activities in inhibition and antioxidation was demonstrated as a stronger sensitizer against doxorubicin (DOX)-resistant MCF-7 cells (MCF-7/ADR) than epalrestat (EPA). Either 5a or EPA may decrease GSH abundance and increase ROS, Fe[2+], and lipid peroxidation levels. The restorative effects of both ARIs may be blocked by N-acetyl cysteine (NAC). These data suggest that both 5a and EPA may restore the sensitivity of MCF-7/ADR cells to DOX by increasing ferroptosis activity. Furthermore, the inhibition of AKR1B1 by 5a, as well as by EPA, dramatically decreased both p-STAT3 and SLC7A11 expression. Gene knockdown of AKR1B1 has the same effects as AKR1B1 inhibition. This evidence indicates that both ARIs can suppress MCF-7/ADR cell growth via the upregulation of ferroptosis activity via the AKR1B1/STAT3/SLC7A11 axis. Additionally, 5a was found to increase the accumulation of intramolecular DOX by inhibiting ABCB1, but EPA did not. These results support that 5a is a promising sensitizing agent against multidrug resistance in breast cancer.}, } @article {pmid39981906, year = {2025}, author = {Chen, J and Cheng, Y and Cui, H and Li, S and Duan, L and Jiao, Z}, title = {N‑acetyl‑L‑cysteine protects rat lungs and RLE‑6TN cells from cigarette smoke‑induced oxidative stress.}, journal = {Molecular medicine reports}, volume = {31}, number = {4}, pages = {}, doi = {10.3892/mmr.2025.13462}, pmid = {39981906}, issn = {1791-3004}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; Rats ; *Lung/drug effects/metabolism/pathology ; Male ; Rats, Wistar ; Cell Line ; Apoptosis/drug effects ; Antioxidants/pharmacology ; Alveolar Epithelial Cells/metabolism/drug effects ; Smoke/adverse effects ; Malondialdehyde/metabolism ; Superoxide Dismutase/metabolism ; Cigarette Smoking/adverse effects ; }, abstract = {Cigarette smoke (CS) is a key contributor of chronic obstructive pulmonary disease (COPD); however, its role in the pathogenesis of COPD has not been fully elucidated. N‑acetyl‑L‑cysteine (NAC), as an antioxidant, has been used in the treatment of COPD; however, the mechanisms of action of NAC are not fully understood. Alveolar epithelial type 2 (ATII) cells serve an essential role in the maintenance of alveolar integrity. The aim of the present study was to identify the effect of CS on rat lungs and ATII cells. A subacute lung injury model of Wistar rats was established using CS exposure for 4 weeks. Interalveolar septa widening, infiltration of inflammatory cells, edema fluid in airspaces and abnormal enlargement of airspaces were observed through H&E staining. ELISA revealed that NAC could protect against CS‑induced increases in serum levels of malondialdehyde and decreases in serum levels of superoxide dismutase. Additionally, 8‑hydroxy‑deoxyguanosine was detected using immunohistochemical staining, and this was also expressed at increased levels in the lung tissue of the CS‑exposed group. In addition, the expression levels of Bcl‑2, BAX and caspase‑3 p12 in lung tissue were detected by western blotting or immunohistochemical staining. The expression levels of Bcl‑2 decreased and those of caspase3 p12 were increased in response to CS exposure when compared with those in the control group. These effects were prevented by treatment with NAC. In vitro, the effect of CS extract (CSE) on rat lung epithelial‑6‑T‑antigen negative (RLE‑6TN) cells was observed, flow cytometry was used to detect intracellular reactive oxygen species (ROS) levels and the occurrence of apoptosis, and the content of glutathione (GSH) was detected using a colorimetric assay. Additionally, the expression levels of heme oxygenase‑1 (HO‑1), p53 and Bcl‑2 were examined by western blotting, and HO‑1 mRNA expression was also examined using reverse transcription‑quantitative PCR. The results of the present study revealed that CSE induced apoptosis of RLE‑6TN cells, accompanied by increased levels of intracellular ROS and exhaustion of GSH. Significantly increased protein levels of HO‑1 and p53, as well as decreased protein levels of Bcl‑2 were also observed. These effects were prevented by administration of NAC. Overall, these findings suggested that CS could promote apoptosis in rat lung tissues and alveolar epithelial cells by inducing intracellular oxidative injury, and NAC may serve an antioxidant role by replenishing the intracellular GSH content.}, } @article {pmid39980679, year = {2025}, author = {Natali, PG and Piantelli, M and Sottini, A and Eufemi, M and Banfi, C and Imberti, L}, title = {A step forward in enhancing the health-promoting properties of whole tomato as a functional food to lower the impact of non-communicable diseases.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1519905}, pmid = {39980679}, issn = {2296-861X}, abstract = {Nutritional interventions facilitating the consumption of natural, affordable, and environment-compatible health-promoting functional foods are a promising strategy for controlling non-communicable diseases. Given that the complex of tomato micronutrients produces healthier outcomes than lycopene, its major antioxidant component, new strategies to improve the health-supporting properties of the berry are ongoing. In this context, a whole tomato food supplement (WTFS), enriched by 2% olive wastewater containing a complex of healthy nutrients with converging biologic activities, has recently been developed, which is superior to those present in tomato commodities or obtained with whole tomato conventional processing methods. WTFS equals the antioxidant activity of N-acetyl-cysteine and interferes with multiple inflammation and cellular transformation-sustaining metabolic pathways. In interventional studies, WTFS inhibits prostate experimental tumors and improves benign prostate hypertrophy-associated symptoms with no associated side-effects. Although WTFS may be susceptible to further improvements and clinical scrutiny, its composition embodies the features of advanced functional foods to ease adherence to dietary patterns, that is, the Mediterranean diet, aimed at contrasting and mitigating the low-grade inflammation, thus being interceptive or preventive of non-communicable diseases.}, } @article {pmid39980567, year = {2025}, author = {Ahn, CH and Myong, JS and Ahmed, KR and Rahman, MA and Fahim, MMH and Choi, M and Rahman, M and Choi, J and Kim, K and Moon, S and Dalli, M and Syahputra, RA and Shin, SW and Harrath, AH and Park, MN and Kim, B and Yoo, HS}, title = {A pharmacoinformatic approach for studying Atractylodes Lancea DC's anticancer potential and control ROS-mediated apoptosis against prostate cancer cells.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1471110}, pmid = {39980567}, issn = {2234-943X}, abstract = {INTRODUCTION: Prostate cancer (PCa) is a malignancy characterized by abnormal cell proliferation in the prostate gland, a critical component of the male reproductive system. Atractylodes lancea DC. (ALD), a medicinal herb commonly used in traditional Asian medicine, is highly regarded for its antioxidant, antidiabetic, and anticancer properties. Virtual docking stud-ies have identified Atractylenolide II and III as active components of ALD, demonstrating strong binding potential to inhibit androgen receptor (AR) activity, with docking scores of -8.9 and -9.3, respectively. These findings suggest that ALD may exert a synergistic effect comparable to or greater than that of enzalutamide (ENZ) in inhibiting AR. How-ever, its specific anticancer and anti-metastatic mechanisms in prostate cancer remain unclear.

METHODS: The cytotoxic effects of ALD were evaluated on PC3 and DU145 prostate cancer cells, as well as on the normal prostate cell line BPH-1. Cell viability was assessed using the EZ-Cytotoxic kit, while colony formation assays and TUNEL staining were used to meas-ure proliferation and apoptosis, respectively. Apoptosis was further analyzed through an-nexin V-FITC/PI staining and quantified by flow cytometry (FACS). Western blotting was performed to elucidate the underlying molecular mechanisms. Additionally, mito-chondrial membrane potential (ΔΨm) and intracellular calcium levels were measured to evaluate mitochondrial function, while reactive oxygen species (ROS) generation was assessed with and without pretreatment with N-acetylcysteine (NAC) .

RESULTS: ALD selectively reduced the viability of PC3 and DU145 prostate cancer cells while spar-ing BPH-1 normal prostate cells, demonstrating cancer-selective cytotoxicity. ALD dis-rupted mitochondrial function by reducing ΔΨm and increasing intracellular calcium lev-els. A concentration-dependent increase in ROS generation was observed in PC3 and DU145 cells, which was completely inhibited by NAC pretreatment, confirming a ROS-mediated mechanism. Colony formation assays revealed a significant reduction in prolif-eration, while TUNEL and annexin V-FITC/PI staining indicated enhanced apoptosis. Western blot analysis showed that ALD modulates critical survival pathways, leading to apoptotic cell death.

DISCUSSION: These findings demonstrate that ALD exerts potent anticancer effects against metastatic prostate cancer cells through ROS-mediated apoptosis and mitochondrial dysfunction, while exhibiting minimal cytotoxicity toward normal prostate cells. The presence of ac-tive compounds such as Atractylenolide II and III suggests a synergistic interaction that enhances AR inhibition and promotes apoptosis. ALD's ability to engage multiple path-ways highlights its therapeutic potential as a selective and multifaceted treatment for ag-gressive prostate cancer.}, } @article {pmid39979946, year = {2025}, author = {Rahman, FA and Graham, MQ and Adam, AM and Juracic, ES and Tupling, AR and Quadrilatero, J}, title = {Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.}, journal = {Journal of biomedical science}, volume = {32}, number = {1}, pages = {29}, pmid = {39979946}, issn = {1423-0127}, support = {RGPIN 258590//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN 2020-05632//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Animals ; *Mitophagy/drug effects ; *Muscular Atrophy/metabolism ; Mice ; *Hindlimb Suspension/adverse effects ; *Muscle, Skeletal/metabolism/drug effects/pathology ; Male ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.

METHODS: We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit autophagy.

RESULTS: Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.

CONCLUSION: These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.}, } @article {pmid39976169, year = {2025}, author = {Savaliya, BF and Kim, S and Veltman, T and Trott, DJ}, title = {Comparison of the in vitro antibiofilm activities of otic cleansers against canine otitis externa pathogens.}, journal = {Veterinary dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/vde.13331}, pmid = {39976169}, issn = {1365-3164}, support = {//Dermcare-Vet, Australia/ ; //University of Adelaide/ ; }, abstract = {BACKGROUND: Biofilm production by canine otitis externa (COE) pathogens and resistance development to multiple antimicrobials are commonly reported problems in veterinary practice. The use of adjuvants to disrupt biofilms may be a viable adjunctive therapy.

HYPOTHESIS/OBJECTIVES: To compare the in vitro antibiofilm activity against COE pathogens of three otic cleansers: PHMB-EDTA (poly [hexamethylene] biguanide hydrochloride and disodium edetate), N-acetylcysteine (NAC) and Triz-EDTA.

ANIMALS/ISOLATES: Thirty isolates of each species, including Staphylococcus pseudintermedius, Pseudomonas aeruginosa, Streptococcus canis, Proteus mirabilis, Escherichia coli, and Malassezia pachydermatis, were collected from COE cases and stored at -80°C until tested.

METHODS AND MATERIALS: Biofilm production was determined by Congo-red agar and microtitre plate-assay methods. Ten of the best biofilm-producing isolates per species were selected to determine minimum biofilm eradication concentration (MBEC) values. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined to compare MBEC/MIC and MBEC/MBC.

RESULTS: PHMB-EDTA possessed antibiofilm activity at low concentrations (MBEC range 3.9/2.3-500/300 μg/mL) against all tested COE pathogens. NAC demonstrated antibiofilm activity for all tested bacterial COE pathogens (MBEC range 4,925-19,700 μg/mL); however, most M. pachydermatis isolates exhibited MBEC values >20,000 μg/mL. Triz/EDTA at the highest concentration tested (3,025/19,520 μg/mL) did not demonstrate antibiofilm activity against most COE pathogens except for S. canis (94.5/610 μg/mL).

PHMB-EDTA had intrinsic antibiofilm activity at low concentrations against all COE pathogens. Therefore, it is likely to be a very effective adjuvant when used in conjunction with other antimicrobials for the treatment of COE caused by biofilm-producing pathogens.}, } @article {pmid39974683, year = {2025}, author = {Shenvi, S and Joshi, SB and Seal, M}, title = {A comparative evaluation of the decalcifying effects of ethylenediaminetetraacetic acid and N-acetyl cysteine on root canal dentin using energy-dispersive X-ray spectroscopy.}, journal = {Journal of conservative dentistry and endodontics}, volume = {28}, number = {1}, pages = {39-43}, pmid = {39974683}, issn = {2950-4708}, abstract = {BACKGROUND: Chelating agents used to remove the inorganic part of the smear layer from prepared canals can alter dentin mineral composition, potentially affecting the adhesion of resin-based root canal cement and sealers.

AIM: This study aimed to compare the decalcifying effects of 17% ethylenediaminetetraacetic acid (EDTA), 20% N-acetyl cysteine (NAC), and deionized water (control) on root canal dentin using energy-dispersive X-ray spectroscopy (EDXS).

MATERIALS AND METHODS: Sixty-nine extracted human mandibular premolars were randomly divided into three groups, yielding 138 root halves treated with either 17% EDTA, 20% NAC, or a control solution (n = 46). The mineral content was assessed using EDXS, and statistical analysis was conducted with the Kruskal-Wallis test, using an alpha level of 5%.

RESULTS: Twenty percent NAC and control groups retained more calcium, magnesium, and phosphorus than 17% EDTA, suggesting better mineral preservation, while 17% EDTA resulted in the lowest mineral content across all elements analyzed.

CONCLUSION: Twenty percent NAC exhibited milder decalcifying effects compared to EDTA while preserving mineral content. Twenty percent NAC could be a biocompatible alternative to EDTA for smear layer removal in endodontic treatments.}, } @article {pmid39972374, year = {2025}, author = {Muthmainah, M and Sketriene, D and Anversa, RG and Harris, E and Griffiths, S and Gogos, A and Sumithran, P and Brown, RM}, title = {Exploring the utility of N-acetylcysteine for loss of control eating: protocol of an open-label single-arm pilot study.}, journal = {Pilot and feasibility studies}, volume = {11}, number = {1}, pages = {19}, pmid = {39972374}, issn = {2055-5784}, abstract = {BACKGROUND: A sense of loss of control over eating, such that eating occurs despite the intent not to, is common in people with obesity and eating disorders such as binge eating disorder and bulimia nervosa. Currently, options for management of loss of control eating are limited. We recently determined that the pro-drug N-acetylcysteine (NAC) reduces compulsive-like eating in a rat model of diet-induced obesity. We will now conduct a single site, open-label pilot study to examine the feasibility of a randomized controlled trial (RCT) of NAC for loss of control eating in humans.

METHODS: Thirty-six adult volunteers with loss of control eating will be enrolled. All participants will receive NAC at a dose of 1200 mg orally twice daily for 12 weeks. Eating behaviors and triggers will be assessed before and after the NAC treatment period using questionnaires (Eating Loss of Control Scale, Palatable Eating Motives Scale: Coping Subscale, Food Craving Inventory, Reward-Based Eating Scale, Perceived Stress Scale, and Emotional Eating Scale) and ecological momentary assessment (EMA). The primary outcomes of this feasibility study are recruitment rate, participant retention rate at week 12, and medication adherence. The secondary outcome is change in Eating Loss of Control Scale score from baseline to week 12. Exploratory data will be collected on the change in eating behaviors from baseline to week 12. Although EMA can provide real-time data on eating behaviors compared with retrospective questionnaires, it relies on repeated daily measurement for long periods which can affect participant's adherence to study protocol. Therefore, this feasibility study will assess the performance of EMA versus retrospective questionnaires and will determine which approach suits the purposes of the research.

DISCUSSION: The results of this study will inform the feasibility of a RCT of NAC for loss of control eating using EMA.

TRIAL REGISTRATION: This study was prospectively registered with the Australian and New Zealand Clinical Trials Registry in June 2022 (ACTRN12622000902796).}, } @article {pmid39971251, year = {2025}, author = {Fu, H and Wang, Y and Huang, B and Liang, Z and Li, Y and Cao, Z and Wu, J and Zhao, Y}, title = {Tannic acid‑cerium nanoenzymes serve as broad-spectrum antioxidants to alleviate acute kidney injury by modulating macrophage polarization, mitophagy and endoplasmic reticulum stress.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jconrel.2025.02.038}, pmid = {39971251}, issn = {1873-4995}, abstract = {Acute kidney injury (AKI) is a critical condition marked by a rapid decline in renal function, primarily driven by oxidative stress, mitochondrial dysfunction, and inflammation. Despite extensive research, effective therapeutic strategies addressing the complex pathophysiology of AKI remain limited. In this study, we prepared a tannic acid‑cerium nanoenzyme (TA-Ce) and explored its potential for treating AKI. TA-Ce, synthesized via a one-pot method, demonstrated strong reactive oxygen species (ROS) scavenging, therapeutic efficacy, and biocompatibility in vitro and in vivo. TA-Ce, approximately 25.6 nm in size, was obtained by optimizing the molar ratios of TA to Ce and pH conditions, resulting in effective accumulation in the injured kidney. In addition, TA-Ce exhibited broad-spectrum antioxidant ability, capable of scavenging various ROS and alleviating oxidative stress. Notably, TA-Ce outperformed the conventional anti-inflammatory drug N-acetylcysteine (NAC) in both rhabdomyolysis-induced AKI (RM-AKI) and cisplatin-induced AKI (CP-AKI) mouse models. Mechanistic studies in RM-AKI revealed that TA-Ce disrupted the vicious cycle of oxidative stress, mitochondrial damage, endoplasmic reticulum stress, apoptosis, and inflammation. The nanoenzyme restored mitochondrial autophagic flux by inhibiting the P62-LC3 signaling pathway and alleviated endoplasmic reticulum stress by suppressing the IRE1-XBP1s pathway. Consequently, this prevented the downstream activation of the Bcl-2-Bax-Cyt-c-Cleaved Casp-3 apoptotic pathway and the NF-κB inflammatory pathway, ultimately ameliorating RM-AKI. This study lays a strong foundation for the development of metal-polyphenol nanomaterials as a therapeutic strategy for clinical AKI.}, } @article {pmid39968425, year = {2025}, author = {Aiad, M and Bhalala, HJ and Bagshaw, H and Starner, S and Saha, D}, title = {Severe Hepatotoxicity From Capmatinib: A Case Report and Therapeutic Approach.}, journal = {Cureus}, volume = {17}, number = {1}, pages = {e77652}, pmid = {39968425}, issn = {2168-8184}, abstract = {Capmatinib, a selective mesenchymal-epithelial transition (MET)-kinase inhibitor, is approved for treating metastatic non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping mutation. Although a known side effect, not much data is available on the management of capmatinib-induced liver injury. Here, we present a case of a 60-year-old male with MET exon mutated NSCLC who developed grade 4 liver injury after capmatinib initiation, which did not respond to drug discontinuation and eventually responded to N-acetyl cysteine (NAC) and ursodeoxycholic acid (ursodiol) therapy. This case demonstrates that NAC plus ursodiol can be an effective treatment strategy in such patients.}, } @article {pmid39961200, year = {2025}, author = {Cp, S and V, A and Tm, MK and S, M and K, B and Singh, ISB and Puthumana, J}, title = {BIF-induced ROS-mediated cytotoxicity and genotoxicity in embryonic cell culture of Daphnia magna.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {280}, number = {}, pages = {107285}, doi = {10.1016/j.aquatox.2025.107285}, pmid = {39961200}, issn = {1879-1514}, abstract = {Bifenthrin (BIF) is a widely used synthetic pyrethroid insecticide that poses significant risks to the environment, particularly to aquatic ecosystems. In the present study, the cytotoxic and genotoxic effects of BIF on Daphnia magna cells were evaluated using in vitro methods. To achieve this, we developed a novel embryonic cell culture system from D.magna using Modified Schneider's Insect Medium (MSIM), which demonstrated remarkable viability for over two months. The lethal concentration 50 (LC50) values of BIF were determined using this cell culture system through XTT (2,3-bis-(2‑methoxy-4-nitro-5-sulphenyl)-(2H)-tetrazolium-5-carboxanilide)assays, yielding values of 7.4 µg/mL and 4.3 µg/mL for 24 h and 48 h exposures, respectively. A fluorometric intracellular reactive oxygen species (ROS) assay was employed to measure ROS production, revealing that BIF exposure induced oxidative stress in a dose-dependent manner. The activities of Glutathione peroxidase (GPx), glutathione (GSH), and glutathione-S-transferase (GST) were significantly reduced, indicating oxidative damage. Co-treatment with N-acetylcysteine(NAC) mitigated these effects, restoring antioxidant enzyme activity and reducing (ROS) levels. Gene expression analysis via quantitative real-time PCR (qPCR) showed upregulation of stress-related genes (hsp70, hsp90) and antioxidant genes (Mn/ZnSod, cat) following exposure to LC50 concentrations of BIF. However, prolonged exposure led to a downregulation of these genes, suggesting cumulative effects over time. The comet assay confirmed that BIF caused genotoxicity, as evidenced by significant increases in comet and tail lengths. Co-treatment with NAC effectively mitigated these genotoxic effects. This study highlighted the cytotoxic and genotoxic potential of BIF in aquatic organisms and suggested the need for environmentally friendly pest control strategies. Also, the findings confirmed the reliability of D. magna embryonic cell cultures for assessing the toxicological effects of environmental pollutants, offering new possibilities for in vitro toxicity testing at cellular and molecular levels.}, } @article {pmid39960426, year = {2025}, author = {Roshdy, E and Taniguchi, H and Nakamura, Y and Takahashi, H and Kikuchi, Y and Celik, I and Mohammed, ESI and Ishihara, Y and Morioka, N and Abe, M}, title = {Design, Synthesis, and Biological Evaluation of BODIPY-Caged Resiquimod as a Dual-Acting Phototherapeutic.}, journal = {Journal of medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jmedchem.4c02606}, pmid = {39960426}, issn = {1520-4804}, abstract = {Resiquimod, an imidazoquinoline scaffold, exhibits potent immunotherapeutic activity but is associated with off-target effects, limiting its clinical utility. To address this limitation, we developed a novel BODIPY-caged resiquimod that is responsive to red light, combining photocaging and photodynamic therapy functionalities. Molecular docking studies guided identification of the optimal caging site for resiquimod, effectively masking its immune activity. BODIPY-caged resiquimod remained inactive under dark conditions, effectively masking resiquimod's immunostimulatory effects. However, red light irradiation precisely uncaged resiquimod, inducing robust immune activation, even in the presence of N-acetyl cysteine as an antioxidant. Notably, the attachment of resiquimod to BODIPY reduced the dark toxicity typically associated with BODIPY as a photosensitizer. In 3D spheroid models of HeLa and A549 cells, BODIPY-caged resiquimod demonstrated spatiotemporal control over cytotoxicity, significantly enhancing cell death only upon irradiation. This dual-function therapeutic approach highlights a "win-win" strategy: precise, red-light-mediated control of immune activation and photodynamic efficacy with reduced collateral toxicity.}, } @article {pmid39959616, year = {2025}, author = {Chaves, AS and Ventura, RD and Pacini, MF and Magalhães, NS and Silva, PMRE and Martins, MA and Pérez, AR and Carvalho, VF}, title = {Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands.}, journal = {Frontiers in endocrinology}, volume = {16}, number = {}, pages = {1500630}, pmid = {39959616}, issn = {1664-2392}, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; Male ; Mice ; *Hypothalamo-Hypophyseal System/drug effects/metabolism ; *Pituitary-Adrenal System/drug effects/metabolism ; *Acetylcysteine/pharmacology ; *Receptors, Glucocorticoid/metabolism ; *Pituitary Gland/metabolism/drug effects ; *Down-Regulation/drug effects ; Signal Transduction/drug effects ; Feedback, Physiological/drug effects ; Heme Oxygenase-1/metabolism ; Up-Regulation/drug effects ; Membrane Proteins ; }, abstract = {We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of the glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on the impairment of the negative feedback of the HPA axis induced by N-acetylcysteine (NAC). Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after the starting of NAC supplementation. NAC reduced the expression of Nrf2 in the pituitary of mice. Furthermore, NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in the GRα expression and an increase of GRβ expression in the pituitary gland. Treatment with CoPPIX reduced adrenal enlargement, systemic corticosterone levels, and GRβ expression in the pituitary gland of mice supplemented with NAC, besides increasing the expression of GRα. CoPPIX treatment also restored the failure in the negative feedback of the HPA axis induced by NAC. In conclusion, these findings showed that NAC reduced the Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis.}, } @article {pmid39959017, year = {2024}, author = {Subiksha, K and Jena, A and Sarangi, P and Mohanty, S and Sahoo, S and Mallick, RR}, title = {Comparative evaluation of antibacterial efficacy of N-acetylcysteine, Aegle marmelos, and chitosan as intracanal medicaments against Enterococcus faecalis biofilm - An in vitro study.}, journal = {Journal of conservative dentistry and endodontics}, volume = {27}, number = {12}, pages = {1246-1250}, pmid = {39959017}, issn = {2950-4708}, abstract = {CONTEXT: The main objective of root canal treatment is the removal of bacteria. Established medicaments and their combinations have been compromised in efficacy against Enterococcus faecalis, causing the need to explore novel intracanal medicaments.

AIM: The aim of the study was to evaluate the antibacterial efficacy of chitosan, N-acetylcysteine (NAC), and Aegle marmelos as intracanal medicaments against E. faecalis biofilm.

MATERIALS AND METHODOLOGY: Minimum inhibitory concentration and susceptibility of medicaments determined. Two hundred and forty dentin disc specimens were prepared and inoculated with E. faecalis for 21 days. Samples were divided into four groups (A - N-acetylcysteine; B - Aegle marmelos; C - Chitosan; D -Control) (n = 60), and two subgroups (n = 30) based on the duration of medicament placed (subgroup 1: 24 h, subgroup 2: 7 days). Thereafter, dentinal shavings were retrieved, incubated in agar plate, visible colonies counted, and statistically analyzed.

RESULTS: At 24 h Group C1 exhibited the lowest CFUs, followed by Group A1, Group B, and Group D1. On the 7[th] day, Group B2 showed the lowest CFUs, followed by Group A2, Group C2, and Group D2.

CONCLUSIONS: Against E. faecalis, NAC has the highest antimicrobial properties closely followed by Aegle marmelos and both provide promising novel possibilities for use as intracanal medicaments.}, } @article {pmid39954867, year = {2025}, author = {Wang, J and Zhao, R and Ma, J and Qin, J and Zhang, H and Guo, J and Chang, X and Zhang, W}, title = {Biallelic FDXR mutations induce ferroptosis in a rare mitochondrial disease with ataxia.}, journal = {Free radical biology & medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2025.02.012}, pmid = {39954867}, issn = {1873-4596}, abstract = {Biallelic mutations in the FDXR are known to cause rare mitochondrial diseases. However, the underlying pathogenic mechanisms remain elusive. This study investigated a patient affected by optic atrophy, ataxia, and peripheral neuropathy resulting from compound heterozygous mutations in FDXR. Structural abnormalities in mitochondria were observed in muscle and nerve tissues. Lymphoblastic cell lines (LCLs) and muscle samples from the patient exhibited signs of mitochondrial dysfunction, iron overload, oxidative stress, and lipid peroxidation. Dysregulation of the glutathione peroxidase-4 was noted in the LCLs. Furthermore, treatment with deferoxamine, N-acetyl-cysteine, and ferrostatin-1 effectively alleviated oxidative stress and cell death. Cortical neurons demonstrate that FDXR deficiency impacts the morphogenesis of neurites. Collectively, these findings suggest that ferroptosis plays a significant role in the pathogenesis of FDXR-associated diseases. Additionally, idebenone appeared to have protective effects against various cellular injuries induced by FDXR mutations, providing novel insights and therapeutic approaches for the treatment of FDXR-associated diseases.}, } @article {pmid39954761, year = {2025}, author = {Kumar, S and D'Souza, LC and Shaikh, FH and Rathor, P and Ratnasekhar, CH and Sharma, A}, title = {Multigenerational immunotoxicity assessment: A three-generation study in Drosophila melanogaster upon developmental exposure to triclosan.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {}, number = {}, pages = {125860}, doi = {10.1016/j.envpol.2025.125860}, pmid = {39954761}, issn = {1873-6424}, abstract = {Triclosan (TCS) is widely used as an antibacterial agent, nevertheless, its presence in different environmental matrices and its persistent environmental nature pose a significant threat to the organism, including humans. Numerous studies showed that TCS exposure could lead to multiple toxicities, including immune dysfunction. However, whether parental TCS exposure could impair the offspring's immune response remains limited. Maintaining the immune homeostasis is imperative to neutralize the pathogen and crucial for tissue repair and the organism's survival. Thus, this study aimed to assess the multigenerational immune response of TCS using Drosophila melanogaster. TCS was administered to organisms (1.0, 10, and 100.0 μg/mL) over three generations during their developing phases, and its effect on the immunological response of the unexposed progeny was evaluated. Total circulatory hemocyte (immune cells) count, crystal cell count, phagocytic activity, clotting time, gene expression related to immune response and epigenetics, ROS generation, and cell death were assessed in the offspring. A concentration-dependent decline in total hemocytes, crystal cells, phagocytic activity, and increased clotting time in the subsequent generations was observed. Furthermore, parental TCS exposure enhanced the ROS levels, induced cell death, and altered the expression of antimicrobial peptides drosomycin, diptericin, and inflammatory genes upd1, upd2, and upd3, in the offspring's hemocytes across successive generations. The upregulation of reaper hid, and grim suggests that TCS promotes apoptotic death in the offspring's hemocytes. Notably, the increased mRNA expression of epigenetic regulators dnmt2 and g9a in the hemocytes of the offspring indicates epigenetic modifications. Further, we also observed that the antioxidant N-acetylcysteine (NAC) supplementation to the parents alleviated TCS toxicity and improved immunological functions in the progeny, indicating the role of ROS in the TCS-induced multigenerational immune toxicity. This finding provides valuable insights into the potential immune risk of prenatal TCS exposure to their offspring in the higher organism.}, } @article {pmid39954094, year = {2025}, author = {Zhou, Y and Yuan, X and Guo, M}, title = {Unlocking NAC's potential ATF4 and m6A dynamics in rescuing cognitive impairments in PTSD.}, journal = {Metabolic brain disease}, volume = {40}, number = {2}, pages = {129}, pmid = {39954094}, issn = {1573-7365}, support = {ZDYF2022SHFZ110//Key R&D Plan of Hainan Province in 2022/ ; ZDYF2022SHFZ110//Key R&D Plan of Hainan Province in 2022/ ; }, mesh = {Animals ; *Cognitive Dysfunction/metabolism ; *Activating Transcription Factor 4/metabolism ; *Acetylcysteine/pharmacology/therapeutic use ; Mice ; *Stress Disorders, Post-Traumatic/metabolism/drug therapy ; Male ; *Hippocampus/metabolism/drug effects ; Mice, Inbred C57BL ; Apoptosis/physiology/drug effects ; Neurons/metabolism ; Disease Models, Animal ; }, abstract = {In this study, we investigated the therapeutic potential of N-acetylcysteine (NAC) in a mouse model of post-traumatic stress disorder (PTSD) induced by a single prolonged stress (SPS) protocol. Our findings demonstrate that NAC treatment significantly improved cognitive function and mitigated hippocampal neuronal apoptosis in PTSD model mice. These positive effects were accompanied by a reduction in m6A methylation levels and activating transcription factor 4 (ATF4) expression. Silencing ATF4 further attenuated hippocampal neuronal apoptosis and cognitive dysfunction, while ATF4 overexpression partially reversed the beneficial effects of NAC. It suggests that NAC's efficacy in PTSD may be mediated by its regulation of ATF4 expression and m6A methylation levels. Overall, our study provides valuable insights into the potential mechanism of action for NAC in PTSD treatment, offering promising avenues for future therapeutic strategies.}, } @article {pmid39954037, year = {2025}, author = {Zhu, X and Yuan, F and Sun, Q and Yang, C and Jiang, H and Xiang, X and Zhang, X and Sun, Z and Wei, Y and Chen, Q and Cai, L}, title = {N-acetylcysteine remodels the tumor microenvironment of primary and recurrent mouse glioblastoma.}, journal = {Journal of neuro-oncology}, volume = {}, number = {}, pages = {}, pmid = {39954037}, issn = {1573-7373}, support = {NO. 82303647//the National Natural Science Foundation of China/ ; NO.82203624//the National Natural Science Foundation of China/ ; NO. 2022CFB635//the Natural Science Foundation of Hubei Province/ ; }, abstract = {PURPOSE: Glioblastoma (GBM) exhibits a high ROS character, giving rise to an immunosuppressive microenvironment and tumor vascular abnormality. This study investigated the potential effect of N-acetylcysteine (NAC), an antioxidant, on primary and recurrent mouse brain tumors.

METHODS: We measured reactive oxygen species (ROS)/ glutathione (GSH) levels in human GBM. Additionally, we conducted NAC trials on primary mouse brain tumor models (GL261-Luc, CT2A-Luc) and a recurrent mouse GBM model (GL261-iCasp9-Luc). After brain tumor inoculation, mice received a daily 100 mg/kg NAC treatment, and the tumor volume was monitored via IVIS imaging. The efficacy of NAC was evaluated through survival time, tumor volume, ROS/GSH levels, M1/M2 macrophages, immune cells infiltration, and tumor vascularization.

RESULTS: Human GBM suffered from significant oxidative stress. With NAC treatment, mouse brain tumors exhibited a lower ROS level, more M1-like tumor-associated macrophages/microglia (TAMs), more CD8 + T cell infiltration, and a normalized vascular character. NAC inhibited tumor growth and suppressed recurrence in mouse brain tumor models.

CONCLUSION: NAC is a promising adjunctive drug to remodel the brain tumors microenvironment.}, } @article {pmid39950481, year = {2025}, author = {Liu, X and Zhong, D and Tang, CZ and Xu, X and Lan, H and Diao, X}, title = {In vitro and In vivo Drug Metabolism Analysis of BPI-460372 - A Covalent TEAD1/3/4 Inhibitor.}, journal = {Current drug metabolism}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892002351556250123105344}, pmid = {39950481}, issn = {1875-5453}, abstract = {BACKGROUND: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations.

OBJECTIVE: This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372.

METHODS: The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).

RESULTS: BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree.

CONCLUSION: This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.}, } @article {pmid39949804, year = {2025}, author = {Qian, X and Liu, Y and Chen, W and Zheng, S and Lu, Y and Qiu, P and Ke, X and Tang, H and Zhang, X}, title = {Paris saponin VII induces Caspase-3/GSDME-dependent pyroptosis in pancreatic ductal adenocarcinoma cells by activating ROS/Bax signaling.}, journal = {Chinese herbal medicines}, volume = {17}, number = {1}, pages = {94-107}, pmid = {39949804}, issn = {2589-3610}, abstract = {OBJECTIVE: Paridis Rhizoma (Chonglou in Chinese), a traditional Chinese herbal medicine, has been shown have strong anti-tumor effects. Paris saponin VII (PSVII), an active constituent isolated from Paridis Rhizoma, was demonstrated to significantly suppress the proliferation of BxPC-3 cells in our previous study. Here, we aimed to elucidate the anti-pancreatic ductal adenocarcinoma (PDAC) effect of PSVII and the underlying mechanism.

METHODS: Cell viability was determined by CCK-8, colony formation, and cell migration assays. Cell apoptosis and reactive oxygen species (ROS) production were measured by flow cytometry with annexin V/propidine iodide (Annexin V/PI) and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), respectively. Pyroptosis was evaluated by morphological features, Hoechst 33342/PI staining assay, and release of lactate dehydrogenase (LDH). JC-1 fluorescent dye was employed to measure mitochondrial membrane potential. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to determine the levels of proteins or mRNAs. The effect in vivo was assessed by a xenograft tumor model.

RESULTS: PSVII inhibited the viability of PDAC cells (BxPC-3, PANC-1, and Capan-2 cells) and induced gasdermin E (GSDME) cleavage, as well as the simultaneous cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP). Knockdown of GSDME shifted PSVII-induced pyroptosis to apoptosis. Additionally, the effect of PSVII was significantly attenuated by Z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone (Z-DEVD-FMK), on the induction of GSDME-dependent pyroptosis. PSVII also elevated intracellular ROS accumulation and stimulated Bax and Caspase-3/GSDME to conduct pyroptosis in PDAC cells. The ROS scavenger N-acetyl cysteine (NAC) suppressed the release of LDH and inhibited Caspase-9, Caspase-3, and GSDME cleavage in PDAC cells, ultimately reversing PSVII-induced pyroptosis. Furthermore, in a xenograft tumor model, PSVII markedly suppressed the growth of PDAC tumors and induced pyroptosis.

CONCLUSION: These results demonstrated that PSVII exerts therapeutic effects through Caspase-3/GSDME-dependent pyroptosis and may constitute a novel strategy for preventing chemotherapeutic resistance in patients with PDAC in the future.}, } @article {pmid39947664, year = {2025}, author = {Lee, SO and Joo, SH and Park, J and Khong, QT and Seo, SY and Yoon, G and Park, JW and Na, M and Shim, JH}, title = {Deoxybouvardin Glucoside Induces Apoptosis in Oxaliplatin-Sensitive and -Resistant Colorectal Cancer Cells via Reactive Oxygen Species-Mediated Activation of JNK and p38 MAPK.}, journal = {Journal of microbiology and biotechnology}, volume = {35}, number = {}, pages = {e2410008}, doi = {10.4014/jmb.2410.10008}, pmid = {39947664}, issn = {1738-8872}, mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Colorectal Neoplasms/drug therapy/metabolism ; *Oxaliplatin/pharmacology ; *Membrane Potential, Mitochondrial/drug effects ; *Drug Resistance, Neoplasm/drug effects ; HCT116 Cells ; Antineoplastic Agents/pharmacology ; Glucosides/pharmacology ; Cell Survival/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; JNK Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation/drug effects ; Organoplatinum Compounds/pharmacology ; }, abstract = {The roots of Rubia spp. (Rubiaceae) have been employed to treat hematemesis, inflammatory disease, and tumor. Cyclohexapeptides derived from Rubia spp. have been reported to have antitumor potential; however, the mechanism of action for their antitumor activity remains unclear. We aimed to examine the antitumor effect of deoxybouvardin glucoside (DBG), a cyclohexapeptide from Rubia spp. on oxaliplatin (Ox)-resistant human HCT116 colorectal cancer (CRC) cells. Cell viability in the presence of DBG was monitored using an MTT viability assay, and flow cytometry was used to analyze changes in apoptosis, cell cycle, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) activity. The antiproliferative activity involved apoptosis and phosphorylation of JNK and p38 MAPK. Inhibition of JNK and p38 MAPK by specific inhibitors prevented DBG-induced apoptosis, underscoring the close involvement of these kinases. Further, DBG induced cell cycle arrest in CRC cells at the G2/M phase by regulating the p21, p27, cyclin B1, and cdc2 proteins. DBG-induced apoptosis was accompanied mitochondrial membrane depolarization, resulting in cytochrome c release into the cytoplasm and caspase activation. Remarkably, DBG induced apoptosis by generating high ROS levels. The mediation of apoptosis by increased ROS generation was confirmed by pretreatment with the ROS scavenger N-acetyl cysteine (NAC). Collectively, DBG exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, inducing cell cycle arrest, elevating cellular ROS levels, and disrupting MMP. This study suggests that DBG has the potential to be utilized as a therapeutic agent for treating Ox-resistant CRC.}, } @article {pmid39944180, year = {2025}, author = {Bellone, S and Siegel, ER and Santin, AD}, title = {N-acetylcysteine (NAC) supplementation improves dyspnea and may normalize von Willebrand plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID.}, journal = {Gynecologic oncology reports}, volume = {57}, number = {}, pages = {101682}, pmid = {39944180}, issn = {2352-5789}, abstract = {OBJECTIVES: A subset of COVID-infected cancer patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC). While LC is considered multifactorial in its pathogenesis, growing evidence suggests that persistent microvascular inflammation (ie, spike-induced endotheliosis) causing chronically elevated levels of clotting factors including von Willebrand factor (vWF), clumping/clotting of red blood cells and platelets, and thrombotic complications may be at the root of PASC/LC symptoms. N-Acetylcysteine (NAC), a precursor of glutathione, is an inexpensive FDA-approved drug/supplement endowed with mucolytic, antioxidant, anti-inflammatory and thrombolytic properties. Multiple reports have recently demonstrated the potential clinical activity of NAC in COVID-19 patients. We retrospectively evaluated responses to NAC supplementation in a total of 9 PASC/LC patients, 3 of which reporting regular use of NAC, followed in our Gynecologic Oncology clinic.

METHODS: Gynecologic patients using NAC supplement (3 patients) vs controls (6 patients) with persistent LC/PASC symptoms and with elevated plasmatic vWF levels were identified in our Gynecologic Oncology clinic database and evaluated for improvement/normalization in LC/PASC symptoms and vWF levels.

RESULTS: Subjective improvement in shortness of breath, brain fog and fatigue with normalization of vWF levels were noted in 3 out of 3 PASC/LC patients using oral NAC (600-1200 mg BID) vs none of the randomly selected cancer control patients with PASC/LC (Fisher's exact P = 0.0119).

CONCLUSIONS: These preliminary results suggest that NAC may represent an inexpensive, safe and potentially effective supplement to improve many PASC/LC-related symptoms. Prospective randomized studies with NAC in PASC/LC patients are needed to confirm these findings.}, } @article {pmid39942681, year = {2025}, author = {Iciek, M and Bilska-Wilkosz, A and Górny, M and Bednarski, M and Zygmunt, M and Miller, A and Nicosia, N and Lombardo, GP and Zammit, P and Kotańska, M}, title = {The Effect of Disulfiram and N-Acetylcysteine, Potential Compensators for Sulfur Disorders, on Lipopolysaccharide-Induced Neuroinflammation Leading to Memory Impairment and the Metabolism of L-Cysteine Disturbance.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {3}, pages = {}, doi = {10.3390/molecules30030578}, pmid = {39942681}, issn = {1420-3049}, support = {N41/DBS/001389.//Jagiellonian University, Medical College Krakow/ ; }, mesh = {Animals ; *Disulfiram/pharmacology ; *Acetylcysteine/pharmacology ; *Lipopolysaccharides ; Rats ; *Memory Disorders/drug therapy/chemically induced/metabolism ; *Cysteine/pharmacology/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Male ; Rats, Wistar ; Cerebral Cortex/metabolism/drug effects ; Sulfur/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Reactive Oxygen Species/metabolism ; Nitric Oxide/metabolism ; Disease Models, Animal ; }, abstract = {BACKGROUND: The role of sulfur-containing drugs, disulfiram (DSF) and N-acetylcysteine (NAC), in alleviating neuroinflammation is poorly understood. The objective of this study was to examine the effect of DSF and NAC on memory and on the metabolism of L-cysteine and inflammation-related parameters in the cerebral cortex of rats in a model of neuroinflammation induced by the administration of lipopolysaccharide (LPS).

METHODS: All the treatments were administered intraperitoneally for 10 days (LPS at a dose of 0.5 mg/kg b.w., DSF at a dose of 100 mg/kg b.w, and NAC at a dose of 100 mg/kg b.w.). Behavior was evaluated by the novel object recognition (NOR) test and object location (OL) test, and the level of brain-derived neurotrophic factor (BDNF) was assayed to evaluate neuronal functioning. Cerebral cortex homogenates were tested for hydrogen sulfide (H2S), sulfane sulfur, sulfates, non-protein sulfhydryl groups (NPSH), nitric oxide (NO), and reactive oxygen species (ROS) by biochemical analysis.

RESULTS: Neither DSF nor NAC alleviated LPS-induced memory disorders estimated by the NOR test and OL test. The studied compounds also did not affect significantly the levels of BDNF, ROS, NO, H2S, and sulfane sulfur in the cerebral cortex. However, we observed an increase in sulfate concentration in brain tissues after LPS treatment, while DSF and NAC caused an additional increase in sulfate concentration. On the other hand, our study showed that the administration of DSF or NAC together with LPS significantly enhanced the cortical level of NPSH, of which glutathione is the main component.

CONCLUSIONS: Our study did not confirm the suggested potential of DSF and NAC to correct memory disorders; however, it corroborated the notion that they reduced oxidative stress induced by LPS by increasing the NPSH level. Additionally, our study showed an increase in sulfate concentration in the brain tissues after LPS treatment, which means the upregulation of sulfite and sulfate production in inflammatory conditions.}, } @article {pmid39941974, year = {2025}, author = {Lee, SH and Park, GS and Lee, R and Hong, S and Han, S and Lee, YM and Nah, SY and Han, SG and Oh, JW}, title = {Gintonin-Enriched Panax ginseng Extract Induces Apoptosis in Human Melanoma Cells by Causing Cell Cycle Arrest and Activating Caspases.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {3}, pages = {}, doi = {10.3390/foods14030381}, pmid = {39941974}, issn = {2304-8158}, support = {2022//Korean Ginseng Corporation/ ; }, abstract = {Gintonin, a non-saponin glycolipoprotein from Panax ginseng, acts as a lysophosphatidic acid ligand. However, its anticancer effects, especially in melanoma, remain unclear. This study investigated the anti-proliferative effects and intracellular signaling mechanisms of a gintonin-enriched fraction (GEF) from Panax ginseng in human melanoma cell lines. In vitro, GEF treatment significantly inhibited cell proliferation, reduced clonogenic potential, and delayed wound healing in melanoma cells. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining showed that GEF induced apoptosis, as evidenced by increased apoptotic cell populations and nuclear changes. GEF also caused cell cycle arrest in the G1 phase for A375 cells and the G2/M phase for A2058 cells. It triggered apoptotic signaling via activation of caspase-3, -9, poly (ADP-ribose) polymerase cleavage, and downregulation of B cell lymphoma-2 (Bcl-2). GEF treatment also raised intracellular reactive oxygen species (ROS) levels and mitochondrial stress, which were mitigated by N-acetyl cysteine (NAC), an ROS inhibitor. In vivo, GEF suppressed tumor growth in A375- and A2058-xenografted mice without toxicity. These findings suggest that GEF from Panax ginseng has potential antitumor effects in melanoma by inducing apoptosis and cell cycle arrest, presenting a promising therapeutic avenue.}, } @article {pmid39934594, year = {2025}, author = {Mishra, AK and Hossain, MM and Sata, TN and Pant, K and Yadav, AK and Sah, AK and Gupta, P and Ismail, M and Nayak, B and Shalimar, and Venugopal, SK}, title = {ALR inhibits HBV replication and autophagosome formation by ameliorating HBV-induced ROS production in hepatic cells.}, journal = {Virus genes}, volume = {}, number = {}, pages = {}, pmid = {39934594}, issn = {1572-994X}, abstract = {HBV has a small genome and thrives in the infected hepatocytes by hijacking the cellular machinery and cellular pathways. HBV induces incomplete autophagy for its replication and survival. This study showed that HBV replication induces Reactive oxygen species (ROS) production, which in turn augments the formation of autophagosomes. Augmenter of liver regeneration (ALR) is a sufhydryl oxidase and has an anti-oxidative property. We sought to determine the interplay between HBV and antioxidant protein ALR. We showed that HBV downregulated ALR expression in hepatic cells. There was increased ROS production in HBV-infected cells while ALR downregulated ROS levels and expression of NADPH oxidase NOX4. N-acetyl cysteine, a ROS scavenger, downregulated ROS level and autophagosome formation in HBV-expressing cells. ALR overexpression in HBV-expressing cells downregulated the expression of autophagy marker proteins while upregulated the expression of p-MTOR. ALR overexpression decreased the expression of HBx, HBsAg, and total HBV load. This study showed that HBx relieved ALR-mediated inhibition by upregulating the miR-181a expression in HBV-infected cells, which in turn downregulated ALR expression.}, } @article {pmid39933948, year = {2025}, author = {Kwon, MJ and Raut, PK and Jang, JH and Chun, KS}, title = {Isoliquiritigenin Induces Apoptosis via ROS-Mediated Inhibition of p38/mTOR/STAT3 Pathway in Human Melanoma Cells.}, journal = {Biomolecules & therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.4062/biomolther.2024.118}, pmid = {39933948}, issn = {1976-9148}, abstract = {Isoliquiritigenin (ISL), a phenolic compound derived from licorice, exhibits various biological activities, including anti-inflammatory, anti-viral, anti-tumor, and antioxidant effects. However, the molecular mechanisms underlying its anti-cancer effects are not well understood in SK-MEL-28 melanoma cells. Melanoma, a highly aggressive and treatment-resistant cancer, remains a significant health challenge. This study investigates the anti-cancer effects of ISL, focusing on identifying reactive oxygen species (ROS)-mediated apoptosis mechanisms on SK-MEL-28 melanoma cells. Our results show that ISL treatment induces apoptosis in SK-MEL-28 cells, as evidenced by the cleavage of caspase-9, -7, -3, and PARP. ISL increased Bax expression, decreased Bcl-2 expression, and promoted cytochrome C release into the cytosol. ISL also reduced the expression of cell cycle markers, including cyclin D1, D3, and survivin. Notably, ISL treatment markedly increased intracellular ROS levels and pretreatment with N-acetyl cysteine, a ROS scavenger, abrogated the ISL-induced inhibition of the p38/mTOR/STAT3 pathway and prevented apoptosis. Moreover, ISL significantly diminished the constitutive phosphorylation of mTOR and STAT3 in SK-MEL-28 cells by blocking the phosphorylation of p38 MAPK, an upstream kinase of mTOR. Pharmacological inhibition of mTOR attenuated the STAT3 signaling, indicating that mTOR acts as an upstream kinase of STAT3 in these cells. Collectively, these findings demonstrate that ISL inhibits SK-MEL-28 cell growth by downregulating cell survival proteins and inducing apoptosis through ROS generation.}, } @article {pmid39933827, year = {2025}, author = {Lee, SO and Joo, SH and Cho, SS and Yoon, G and Choi, YH and Park, JW and Weon, KY and Shim, JH}, title = {Licochalcone D Exerts Antitumor Activity in Human Colorectal Cancer Cells by Inducing ROS Generation and Phosphorylating JNK and p38 MAPK.}, journal = {Biomolecules & therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.4062/biomolther.2024.123}, pmid = {39933827}, issn = {1976-9148}, abstract = {Anticancer activities of Licochalcone D (LCD) in human colorectal cancer (CRC) cells HCT116 and oxaliplatin-resistant HCT116 (HCT116-OxR) were determined. Cell viability assay and soft agar assay were used to analyze antiproliferative activity of LCD. Flow cytometry was performed to determine effects of LCD on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. Western blot analysis was used to monitor levels of proteins involved in cell cycle and apoptosis signaling pathways. LCD suppressed the growth and anchorageindependent colony formation of both HCT116 and HCT116-OxR cells. Cell cycle analysis by flow cytometry indicated that LCD induced cell cycle arrest and increased cells in sub-G1 phase. In parallel with the antiproliferative effect of LCD, LCD up-regulated levels of p21 and p27 while downregulating cyclin B1 and cdc2. In addition, phosphorylation levels of JNK and p38 mitogen-activated protein kinase (MAPK) were increased by LCD. Inhibition of these kinases somehow prevented the antiproliferative effect of LCD. Moreover, LCD increased ROS and deregulated mitochondrial membrane potential, leading to the activation of multiple caspases. An ROS scavenger N-acetyl-cysteine (NAC) or pan-caspase inhibitor Z-VAD-FMK prevented the antiproliferative effect of LCD, supporting that ROS generation and caspase activation mediated LCD-induced apoptosis in CRC cells. In conclusion, LCD exerted antitumor activity in CRC cells by inducing ROS generation and phosphorylation of JNK and p38 MAPK. These results support that LCD could be further developed as a chemotherapeutic agent for treating CRC.}, } @article {pmid39923905, year = {2025}, author = {Kim, YH and Kim, JB and Bae, JE and Park, NY and Kim, SH and Park, D and So, JH and Lee, JM and Jeong, K and Choi, DK and Jo, DS and Cho, DH}, title = {ZLDI-8 facilitates pexophagy by ROS-mediated activation of TFEB and ATM in HeLa cells.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {}, number = {}, pages = {130130}, doi = {10.1016/j.bmcl.2025.130130}, pmid = {39923905}, issn = {1464-3405}, abstract = {Autophagy-mediated organelle quality control is vital for cellular homeostasis. However, the mechanisms underlying selective autophagy of peroxisomes, known as pexophagy, are less well understood than those of other organelles, such as mitochondria. In this study, we screened a phosphatase inhibitor library using a cell-based system and identified several potent pexophagy inducers, including ZLDI-8, a known inhibitor of lymphoid-specific tyrosine phosphatase. Notably, treatment with ZLDI-8 selectively induces the loss of peroxisomes without affecting other organelles, such as mitochondria, the endoplasmic reticulum, or the Golgi apparatus. The peroxisome loss induced by ZLDI-8 was significantly blocked in ATG5-knockout HeLa cells, confirming its dependence on autophagy. We further found that ZLDI-8 treatment increases both cellular and peroxisomal reactive oxygen species (ROS), which were effectively scavenged by N-acetylcysteine (NAC). The increase in peroxisomal ROS leads to the activation of ATM kinase and the dephosphorylation of TFEB. Moreover, ROS scavenging prevents all of these processes. Taken together, these findings demonstrate that ZLDI-8 induces pexophagy through a mechanism involving peroxisomal ROS-mediated activation of TFEB and ATM. This study provides valuable insights into the molecular mechanisms regulating selective peroxisome degradation and potential therapeutic strategies for targeting pexophagy.}, } @article {pmid39921193, year = {2025}, author = {Lin, KA and Su, CC and Lee, KI and Liu, SH and Fang, KM and Tang, CH and Lia, WC and Kuo, CY and Chang, KC and Huang, CF and Chen, YW and Yang, CY}, title = {The herbicide 2,4-dichlorophenoxyacetic acid induces pancreatic β-cell death via oxidative stress-activated AMPKα signal downstream-regulated apoptotic pathway.}, journal = {Toxicology letters}, volume = {405}, number = {}, pages = {16-29}, doi = {10.1016/j.toxlet.2025.01.009}, pmid = {39921193}, issn = {1879-3169}, abstract = {2,4-Dichlorophenoxyacetic acid (2,4-D) is one of commonly and widely used organic herbicides in agriculture. It has been reported that 2,4-D can induce adverse effects in mammalian cells. Epidemiological and animal studies have indicated that exposure to 2,4-D is associated with poorer glycemic control and impaired pancreatic β-cell function. However, limited information is available on 2,4-D-induced toxicological effects in β-cells, with the underlying toxicological mechanisms remains unclear. Herein, our results showed that 2,4-D exposure (30-500 μg/mL) significantly reduced cell viability, induced mitochondria dysfunction (including the mitochondrial membrane potential (MMP) loss, the increase in cytosolic cytochrome c release, and the change in Bcl-2 and Bax protein expression), and triggered apoptotic events (including the increased population of apoptotic cells, caspase-3 activity, and caspase-3/-7 and PAPR activation) in RIN-m5F β-cells, accompanied with insulin secretion inhibition. Exposure of cells to 2,4-D could also evoke JNK, ERK1/2, p38, and AMP-activated protein kinase (AMPK)α activation as well as reactive oxygen species (ROS) generation. Pretreatment of cells with compound C (an AMPK inhibitor) and the antioxidantN-acetylcysteine (NAC), but not that SP600125/PD98059/SB203580 (the inhibitors of JNK/ERK/p38, respectively), obviously attenuated the 2,4-D-triggered AMPKα phosphorylation, MMP loss, apoptotic events, and insulin secretion dysfunction,as similar effects with the transfection with AMPKα1-specific siRNA. Of note, buffering the ROS production with NAC obviously prevented the 2,4-D-induced ROS generation as well as AMPKα activation, but the either compound C and AMPKα1-specific siRNA transfection could not effectively reduce 2,4-D-induced ROS generation. Collectively, these findings indicate that the induction of oxidative stress-activated AMPKα signaling is a crucial mechanism underlying 2,4-D-triggered mitochondria-dependent apoptosis, ultimately leading to β-cell death.}, } @article {pmid39920835, year = {2025}, author = {Roe, T and Talbot, T and Terrington, I and Johal, J and Kemp, I and Saeed, K and Webb, E and Cusack, R and Grocott, MPW and Dushianthan, A}, title = {Physiology and pathophysiology of mucus and mucolytic use in critically ill patients.}, journal = {Critical care (London, England)}, volume = {29}, number = {1}, pages = {68}, pmid = {39920835}, issn = {1466-609X}, mesh = {Humans ; *Mucus/physiology/metabolism ; *Critical Illness/therapy ; *Expectorants/therapeutic use ; *Mucociliary Clearance/physiology/drug effects ; }, abstract = {Airway mucus is a highly specialised secretory fluid which functions as a physical and immunological barrier to pathogens whilst lubricating the airways and humifying atmospheric air. Dysfunction is common during critical illness and is characterised by changes in production rate, chemical composition, physical properties, and inflammatory phenotype. Mucociliary clearance, which is determined in part by mucus characteristics and in part by ciliary function, is also dysfunctional in critical illness via disease related and iatrogenic mechanisms. The consequences of mucus dysfunction are potentially devastating, contributing to prolonged ventilator dependency, increased risk of secondary pneumonia, and worsened lung injury. Mucolytic therapies are designed to decrease viscosity, improve expectoration/suctioning, and thereby promote mucus removal. Mucolytics, including hypertonic saline, dornase alfa/rhDNase, nebulised heparin, carbocisteine/N-Acetyl cysteine, are commonly used in critically ill patients. This review summarises the physiology and pathophysiology of mucus and the existing evidence for the use of mucolytics in critically ill patients and speculates on journey to individualised mucolytic therapy.}, } @article {pmid39917036, year = {2025}, author = {Henaidy, MF and Ghanem, M and Shehata, SF and Shouair, AM and Mabrouk, RR}, title = {Therapeutic effects of NAC and CoQ10 on aluminium phosphide poisoning as an adjuvant therapy: A Pilot study.}, journal = {Toxicology reports}, volume = {14}, number = {}, pages = {101907}, pmid = {39917036}, issn = {2214-7500}, abstract = {UNLABELLED: In aluminium phosphide (AlP) poisoning, death is mainly due to acute heart failure. There is some evidence showing that N-acetylcysteine (NAC) and coenzyme Q10 have antioxidant and cardioprotective effects. This study investigated a new approach for treating acute AlP poisoning by using NAC and Co-Q10 as adjuvant therapy.

SUBJECTS AND METHODS: The study design was a retrospective-prospective study. It was conducted in the poisoning unit of Kafer Eldwar General Hospital. Sixty patients with acute aluminium phosphide poisoning were included. The patients were divided into two groups. The first group (standard protocol) considered the control group received the standard supportive care, and their data were collected from the medical records. The second group (new protocol) in addition to the standard supportive care received the NAC and CoQ10 regimen, and all data were collected in a specially designed sheet.

RESULTS: The results showed that the highest percentage of patients in both groups were aged 18-25, followed by those under 18, and females outnumbered the males. The systolic (SBP) and diastolic (DBP) blood pressure showed significant improvement in the new protocol group. A significant statistical difference was found between the two groups regarding mechanical ventilation (p = 0.015), where mechanical ventilation was used in 20 % of patients in the new protocol group and 50 % in the standard group. Regarding the outcome of patients, the survival rate reached 73.3 % upon using the new protocol, compared to 50 % who received the standard protocol.

CONCLUSION: The data imply that further investigation in using the NAC and CoQ10 regimen is warranted. It gave an improvement of the survival rate and decrease the need for mechanical ventilation in AlP.}, } @article {pmid39912999, year = {2025}, author = {Li, M and Hu, Y and Wu, X and Tong, J and Tao, J and Tang, A and Ji, Y and Yao, Y and Tao, F and Liang, C}, title = {Placental Ferroptosis May Be Involved in Prenatal Arsenic Exposure Induced Cognitive Impairment in Offspring.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {39912999}, issn = {1559-0720}, support = {U22A20361//the National Natural Science Foundation of China/ ; YJS20230151//Postgraduate Innovation Research and Practice Program of Anhui Medical University/ ; }, abstract = {The association between prenatal arsenic (As) exposure and offspring's cognition is still unclear, and the underlying etiology has also not been elucidated. Based on the Ma'anshan Birth Cohort (MABC) study in China, 1814 mother-child pairs were included in this study, and the association of As levels in cord serum with preschoolers' intelligence scores was explored. To validate the results from population study, in vivo models were adopted to observe the association between prenatal As exposure and spatial learning and memory abilities of mice offsprings. The As-exposure induced ferroptosis in the placenta of human beings as well as C57BL/6 J mice and HTR-8/SVneo cells was explored in order to clarify the potential cause of impairment of offspring's cognition related to As exposure, respectively. In the population study, we observed a significant inverse association between natural logarithm transformed (ln) As levels and preschoolers' intelligence scores, especially for the fluid reasoning index (FRI) [(β (95%CI): - 1.07 (- 1.98, - 0.16)] and working memory index (WMI) [β (95%CI): - 1.51 (- 2.76, - 0.25)]. Meanwhile, the data from in vivo models revealed that the learning and memory abilities of offspring mice decreased after prenatal As exposure. The occurrence of ferroptosis-like characteristics in the placenta and HTR-8/SVneo cells after As exposure was observed, accompanying with evident oxidative stress, iron accumulation, mitochondrial damage, and decreased protein levels of GPX4, xCT, and FTH1 (or FPN1). Notably, the ferroptosis-like alterations induced by NaAsO2 can be effectively alleviated by N-acetylcysteine (NAC) and ferrostatin-1 (Fer-1) treatment in HTR-8/SVneo cells, respectively. In conclusion, prenatal As exposure associates with impairment of offspring's cognition, and placental ferroptosis may be involved in the association. Further studies are needed to confirm the findings.}, } @article {pmid39855039, year = {2025}, author = {Wang, Y and Wang, Q and Ji, Q and An, P and Wang, X and Ju, Y and Li, R and Ruan, Y and Zhao, J and Cao, M and Chen, X}, title = {Supplementation with N-Acetyl-L-cysteine during in vitro maturation improves goat oocyte developmental competence by regulating oxidative stress.}, journal = {Theriogenology}, volume = {235}, number = {}, pages = {221-230}, doi = {10.1016/j.theriogenology.2025.01.016}, pmid = {39855039}, issn = {1879-3231}, mesh = {Animals ; *Goats/physiology ; *In Vitro Oocyte Maturation Techniques/veterinary/methods ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; *Oocytes/drug effects ; Female ; Antioxidants/pharmacology ; Embryonic Development/drug effects ; Reactive Oxygen Species/metabolism ; Embryo Culture Techniques/veterinary ; }, abstract = {Oocyte quality can affect mammal fertilization rate, early embryonic development, pregnancy maintenance, and fetal development. Oxidative stress induced by reactive oxygen species (ROS) is one of the most important causes of poor oocyte maturation in vitro. To reduce the degree of cellular damage caused by ROS, supplementation with the antioxidant N-Acetyl-L-cysteine (NAC) serves as an effective pathway to alleviate glutathione (GSH) depletion during oxidative stress. This study investigated the effects of NAC supplementation during in vitro maturation of goat oocytes and explored the molecular mechanisms of maturation by transcriptome sequencing of MⅡ oocytes. The results showed that 1.5 mM NAC significantly increased the rates of oocyte maturation and cumulus cell expansion and improved the subsequent development of embryos. During the subsequent culture of parthenogenetically activated embryos, 1.5 mM NAC significantly increased the division rate of oocytes and blastocyst rate. It also reduced the accumulation of ROS, increased the level of GSH, alleviated oxidative stress, and enhanced the antioxidant capacity and cell metabolic activity. Transcriptome sequencing results revealed that NAC treatment significantly increased the expression of SIRT1, GGCT, and MITF genes related to the cellular antioxidant system, as well as the IDH3G gene related to energy metabolism, and decreased the expression of CASP8, FOS, and MMP1 genes related to apoptosis and cell invasion, as well as the CCL2. and CXCL8 genes related to the inflammatory response. In conclusion, the findings suggest that NAC supplementation significantly reduces oxidative stress, improves antioxidant capacity and metabolic activity, promotes oocyte maturation, and improves oocyte quality.}, } @article {pmid39912676, year = {2025}, author = {Sui, B and Li, X and Li, N and Tao, Y and Wang, L and Xu, Y and Hou, Y and Hu, B and Tan, D}, title = {Synergistic action of mucoactive drugs and phages against Pseudomonas aeruginosa and Klebsiella pneumoniae.}, journal = {Microbiology spectrum}, volume = {}, number = {}, pages = {e0160124}, doi = {10.1128/spectrum.01601-24}, pmid = {39912676}, issn = {2165-0497}, abstract = {N-acetylcysteine (NAC) and ambroxol hydrochloride (AMB) are commonly prescribed alongside antibiotics to alleviate sputum retention in lower respiratory tract infections, which are often caused by bacterial pathogens. With the rising threat of antibiotic resistance, phage therapy has emerged as a promising alternative alongside. However, no studies have explored the potential interactions between phages and these mucoactive agents despite their frequent concurrent use during phage therapy. Therefore, investigating the potential synergy and its subsequent impact on phage infection dynamics could enhance clinical strategies for treating bacterial infections with phages. Our study utilized Pseudomonas aeruginosa strain ZS-PA-35 and Klebsiella pneumoniae strain Kp36, alongside their respective phages, to investigate their interactions in the presence of NAC or AMB. Our findings indicate that, under specific conditions, these mucoactive agents can function as adjuvants to lytic phages, enhancing bacterial susceptibility to phage infection and facilitating subsequent phage proliferation. Our study revealed that these synergistic interactions are strongly influenced by the physiological characteristics of the phages, the surrounding microenvironments, and the physiology of host tissues, as varying outcomes of phage-host interactions were observed among different phages and across distinct media. Taken together, our results emphasize the complexity of interactions between phages and NAC or AMB, underscoring the need for caution when using combination treatments.IMPORTANCEN-acetylcysteine (NAC) and ambroxol hydrochloride (AMB) are used in medical treatment of patients with acute and chronic bronchitis. Often, the choice of NAC or AMB is empirically determined by physicians. However, the potential impact of combining NAC or AMB with phage therapy remains unclear. To address this gap, a comprehensive understanding of their interplay is crucial to determine any potential synergistic effects. This study aims to elucidate how NAC or AMB influence phages targeting different receptors, thereby affecting their antibacterial activity against Pseudomonas aeruginosa and Klebsiella pneumoniae. Our results suggest that, under certain conditions, NAC or AMB provides an adjuvant effect by rendering the cells more susceptible to phage infection. These results contribute to advancing our understanding of the clinical combination of mucoactive agents and phage therapy, offering insights for optimizing treatment efficacy.}, } @article {pmid39905500, year = {2025}, author = {Tawalbeh, M and Ibrahim, RM and Al-Saraireh, T and Khreesha, L and Rawashdeh, BA}, title = {Intratympanic N-acetylcysteine in the prevention of cisplatin-induced ototoxicity: a systematic review and meta-analysis of randomized controlled trials.}, journal = {BMC pharmacology & toxicology}, volume = {26}, number = {1}, pages = {26}, pmid = {39905500}, issn = {2050-6511}, mesh = {*Acetylcysteine/therapeutic use/administration & dosage ; *Cisplatin/adverse effects ; Humans ; *Randomized Controlled Trials as Topic ; *Antineoplastic Agents/adverse effects ; *Ototoxicity/prevention & control ; Injection, Intratympanic ; }, abstract = {OBJECTIVE: To evaluate the efficacy of the otoprotective transtympanic application of N-acetylcysteine in preventing chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy.

DATA SOURCES: PubMed, Scopus, Web of Science, Cochrane Central, and ClinicalTrials.gov were searched for the following concepts: (("Acetylcysteine" [Mesh]) AND ("Ototoxicity" [Mesh]) AND ("Cisplatin" [Objective: To evaluate the efficacy of otoprotective transtympanic application of N-acetylcysteine in the prevention of chemotherapy-induced ototoxicity in patients subjected to platinum-based chemotherapy. [Mesh]).

STUDY SELECTION: Inclusion: randomized controlled trials, Exclusion: (1) case reports or case series; (2) thesis; (3) review articles; (4) conference abstracts; (5) animal studies; (6) non-english studies; (7) studies whose population was other than patients on platinum-based chemotherapy.

DATA EXTRACTION: changes in hearing thresholds measured by pure tone tympanometry, covering high and low frequencies: 250, 500, 1000, 2000, 4000, and 8000 Hz. We used RevMan (Review Manager) version 5.3 to conduct the meta-analysis and GRADE to assess the quality of the evidence.

DATA SYNTHESIS: The literature search yielded 277 unique articles. After reviewing six full-text articles, three RCTs provided data available for meta-analysis. A total of 88 cisplatin-based chemotherapy candidates were included for final analysis. Hearing thresholds showed a significant threshold difference between the ear treated with N-acetylcysteine and the control ear (ear not treated with N-acetylcysteine), especially at high frequencies as high as 8000 Hz (pooled effect size - 10.67, 95% CI [-12.33, -9.02], P < 0.00001). The data favored the Nac group in all frequencies as well, at 4000 Hz (pooled effect size - 2.13, 95% CI [-3.49, -0.77], P = 0.002), at 2000 Hz (pooled effect size - 1.38, 95% CI [-2.69, -0.06], P = 0.04), at 1000 Hz (pooled effect size - 1.58, 95% CI [-2.63, -0.53], P = 0.003), at 500 Hz (pooled effect size - 1.58, 95% CI [-2.62, -0.54], P = 0.003), and at the low frequency of 250 after solving the heterogeneity (pooled effect size - 0.96, 95% CI [-2.88, 0.95], P = 0.32).

CONCLUSIONS: Current data justifies the transtympanic administration of N-acetylcysteine for otoprotection in chemotherapy patients, minimizing the enduring consequences of cisplatin-induced ototoxicity and auditory impairment. Given the results' emphasis on the Sarafraz et al. (2018) study, more randomized controlled trials are necessary with an expanded sample size and standardization of N-acetylcysteine concentration, study population, and assessed outcomes.}, } @article {pmid39903949, year = {2025}, author = {Sun, M and Lu, Z and Chen, WM and Lv, S and Fu, N and Yang, Y and Wang, Y and Miao, M and Wu, SY and Zhang, J}, title = {N-acetylcysteine therapy reduces major adverse cardiovascular events in patients with type 2 diabetes mellitus.}, journal = {Atherosclerosis}, volume = {402}, number = {}, pages = {119117}, doi = {10.1016/j.atherosclerosis.2025.119117}, pmid = {39903949}, issn = {1879-1484}, abstract = {BACKGROUND: Effective preventive strategies for major adverse cardiovascular events (MACE) in T2DM patients are limited. Recent studies have explored the cardiovascular benefits of N-Acetylcysteine (NAC), an antioxidant with endothelial protective properties. This study investigates the long-term effects of NAC on MACE risk in T2DM patients, focusing on its potential as an adjunctive therapy.

METHODS: This population-based cohort study used data from Taiwan's National Health Insurance Research Database (NHIRD) and included 46,718 T2DM patients diagnosed between 2008 and 2018, with follow-up until December 31, 2021. Propensity score matching (PSM) ensured balanced comparisons between NAC users and non-users. Cox regression and time-dependent Cox hazards models assessed MACE risk, adjusting for multiple covariates.

RESULTS: In the matched cohort of 23,359 NAC users and 23,359 non-users, NAC users had a significantly lower incidence of MACE (41.74 % vs. 46.87 %, P < .0001). Adjusted Hazard Ratios (aHRs) indicated a consistent protective effect of NAC against overall MACE (aHR: 0.84; 95 % CI: 0.81-0.86, P < .0001). Higher cumulative defined daily doses (cDDD) of NAC correlated with reduced MACE risk, with the highest quartile (Q4) showing an aHR of 0.61 (95 % CI: 0.58-0.64, P < .0001).

CONCLUSION: This study underscores the significant reduction in MACE risk among T2DM patients with long-term NAC therapy. Notably, the findings emphasize NAC's dose-dependent effectiveness in diminishing MACE incidence, indicating its potential as a valuable adjunctive therapy for managing cardiovascular risk in T2DM patients.}, } @article {pmid39663676, year = {2025}, author = {Ge, S and Sun, A and Zhou, X and Niu, P and Chen, Y and Bao, X and Yu, M and Zhong, Z and Sun, J and Li, G}, title = {Functionalized Nanozyme Microcapsules Targeting Deafness Prevention via Mitochondrial Homeostasis Remodeling.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {37}, number = {5}, pages = {e2413371}, doi = {10.1002/adma.202413371}, pmid = {39663676}, issn = {1521-4095}, support = {82271180//National Natural Science Foundation of China/ ; YZ2023137//Social Development Foundation of Yangzhou/ ; SJCX23_2023//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; }, mesh = {*Mitochondria/metabolism/drug effects ; *Homeostasis/drug effects ; Animals ; *Deafness/metabolism/prevention & control ; *Capsules/chemistry ; Polymers/chemistry ; Mice ; Metal-Organic Frameworks/chemistry ; Indoles/chemistry/pharmacology ; Acetylcysteine/chemistry/pharmacology ; Humans ; Hydrogels/chemistry ; Gelatin/chemistry ; }, abstract = {Mitochondrial dysfunction, which is the primary mechanism underlying cisplatin-induced hearing loss, can potentially be mitigated by modulating the redox balance and reprogramming the energy metabolism to remodel mitochondrial homeostasis. Herein, N-acetyl-l-cysteine-derived carbonized polymer dots (NAC CPDs) are embedded into manganese porphyrin-doped metal-organic frameworks and encapsulated using a polydopamine (PDA) coating and gelatin methacryloyl (GelMA) hydrogel to afford functionalized nanozyme microcapsules. Owing to their injectability and adhesion properties, these microcapsules exhibit the advantages of prolonged retention in the middle ear and sustained release in the inner ear. The synergy between the manganese porphyrin and polymer dots results in excellent antioxidant properties. The developed nanozymes activate the PI3K-AKT pathway, reprogramming the energy supply mechanism, and inhibiting the oligomerization of BAX in mitochondria to prevent the leakage of mitochondrial DNA and cytochrome c. Therapeutic efficacy and related mechanisms are validated in vivo. Thus, this study on mitochondrial homeostasis remodeling by nanozyme microcapsules opens a new chapter in the treatment of hearing loss.}, } @article {pmid39902830, year = {2025}, author = {Chamberlain, SR and Ioannidis, K and Grant, JE}, title = {Trait Impulsivity Predicts Treatment Response in Gambling Disorder.}, journal = {Clinical neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1097/WNF.0000000000000622}, pmid = {39902830}, issn = {1537-162X}, abstract = {OBJECTIVES: Impulsivity is thought to be a core feature of gambling disorder, yet little is known as to whether trait impulsivity predicts treatment response.

METHODS: Data were pooled from 2 previous randomized controlled pharmacological trials using naltrexone and N-acetyl cysteine.

RESULTS: Trait impulsivity statistically explained variation in medication treatment response (P = 0.0260, R2 = 0.26). Higher baseline motor impulsiveness was associated with greater treatment response (P = 0.009).

CONCLUSIONS: Measures of impulsivity may thus be important to include in future large-scale datasets, in trial settings but also routine clinical gambling clinic practice, toward building predictive algorithms that may ultimately help to inform optimal treatment choices and improve outcomes.}, } @article {pmid39901768, year = {2025}, author = {Lu, YT and Chen, TY and Lin, HH and Chen, YW and Lin, YX and Le, DC and Huang, YH and Wang, AH and Lee, CC and Ling, TY}, title = {Small Extracellular Vesicles Engineered Using Click Chemistry to Express Chimeric Antigen Receptors Show Enhanced Efficacy in Acute Liver Failure.}, journal = {Journal of extracellular vesicles}, volume = {14}, number = {2}, pages = {e70044}, doi = {10.1002/jev2.70044}, pmid = {39901768}, issn = {2001-3078}, mesh = {*Extracellular Vesicles/metabolism ; *Liver Failure, Acute/therapy ; Animals ; Humans ; *Receptors, Chimeric Antigen ; *Click Chemistry/methods ; Mice ; *Mesenchymal Stem Cells/metabolism ; Asialoglycoprotein Receptor/metabolism ; Acetaminophen ; Male ; }, abstract = {Acetaminophen (APAP) overdose can cause severe liver injury and life-threatening conditions that may lead to multiple organ failure without proper treatment. N-acetylcysteine (NAC) is the accepted and prescribed treatment for detoxification in cases of APAP overdose. Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)-based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC-derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC-derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor-modified sEVs (CAR-sEVs) for the treatment. First, we engineered azido-modified sEVs (N3-sEVs) through metabolic glycoengineering by treating MSCs with the azide-containing monosaccharide N-azidoacetyl-mannosamine (Ac4ManNAz). Next, we conjugated N3-sEVs with a dibenzocyclooctyne (DBCO)-tagged single-chain variable fragment (DBCO-scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR-sEVs for precise liver targeting. The efficacy of CAR-sEV therapy in ALF models by targeting ASGR1 was validated. MSC-derived CAR-sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP-induced injury. Overall, CAR-sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell-free targeted therapy.}, } @article {pmid39900950, year = {2025}, author = {El-Abassy, OM and Fawzy, MG and Kamel, EB}, title = {Two chromatographic methods for analyzing paracetamol in spiked human plasma with its toxic metabolite, N-acetyl parabenzoquinone imine and its antidote, N-acetyl-L-cysteine.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {4119}, pmid = {39900950}, issn = {2045-2322}, mesh = {*Acetaminophen/blood ; Humans ; *Acetylcysteine ; *Imines ; *Benzoquinones/metabolism/blood ; Chromatography, High Pressure Liquid/methods ; *Antidotes ; Limit of Detection ; }, abstract = {Acetaminophen, also known as paracetamol (APAP), is a highly utilized pharmaceutical agent on a global scale, particularly in the field of pediatrics. Regrettably, an overdose of APAP, resulting from the predominant oxidation, has the potential to trigger acute liver injury. The study's goal was to find an easy, accurate, and selective way to measure APAP, N-acetyl para benzoquinone imine (NAPQI) (an APAP metabolite that is harmful), and N-acetyl-L-cysteine (NAC) (an antidote). Two different chromatographic methods were used. The HPTLC method, which used silica gel 60 F254 as a stationary phase and a developing liquid made up of methanol, ethyl acetate, and glacial acetic acid (8:2:0.2, v/v/v) and a UV detection at 254 nm. The HPLC method was developed using a mobile phase consisting of water, methanol, and formic acid in a proportion of (70:30:0.15, v/v/v). The stationary phase used in the approach was a C18 column. Analytes quantification was established utilizing a UV detector operating at a wavelength of 254 nm. The present methods make it possible to measure the amount of APAP in plasma samples. When it comes to pharmacokinetics or medication levels in children's plasma, for example, this may be also very helpful. The current methods can quantify NAPQI, which is helpful in figuring out drug concentrations in individuals with APAP intoxication diagnoses. Additionally, the current approaches can estimate NAC as an antidote; as a result, this study is a complete study because it can analyse drug, toxic metabolite, and antidote in one analytical run. Using the innovative blue applicability grade index software, which measures the practicality of procedures, both methodologies were compared with a reported methods. Additionally, the achievement of the eco-friendliness profile of the designed procedures was assessed. Both techniques passed the ICH validation tests.}, } @article {pmid39898945, year = {2025}, author = {Supervía, A and Gispert, MªÀ and Puiguriguer, J and Álvarez Zabala, PB and Martínez Sánchez, L and Olmos, S and Calderón, B and Paz Picornell, R and Nogué, S and Córdoba, F}, title = {Paracetamol poisoning: a prospective comparison of 2 protocols for N-acetylcysteine treatment.}, journal = {Emergencias : revista de la Sociedad Espanola de Medicina de Emergencias}, volume = {37}, number = {1}, pages = {39-43}, doi = {10.55633/s3me/100.2024}, pmid = {39898945}, issn = {2386-5857}, mesh = {Humans ; *Acetylcysteine/therapeutic use/administration & dosage ; Female ; Prospective Studies ; Male ; Adult ; *Acetaminophen/poisoning ; *Antidotes/administration & dosage/therapeutic use ; Young Adult ; Middle Aged ; Adolescent ; *Length of Stay/statistics & numerical data ; Clinical Protocols ; Analgesics, Non-Narcotic/poisoning ; Emergency Service, Hospital ; }, abstract = {OBJECTIVE: Paracetamol poisoning can be serious and require treatment with N-acetylcysteine (NAC). A dose of 300 mg/kg is usually given in 3 fractions over 21 hours. An alternative regimen, the Scottish and Newcastle Acetylcysteine Protocol (SNAP), specifies the same total dose given in 2 intravenous injections over 12 hours. This study aimed to compare the 2 regimens in terms of effectiveness, adverse events, and lengths of emergency department (ED) and hospital stays.

METHODS: Prospective multicenter study to compare outcomes associated with the traditional NAC regimen vs SNAP. We enrolled all patients with paracetamol poisoning requiring NAC treatment in the participating hospital EDs from 2021 through 2023. Data related to referrals, poisoning episodes, and discharge destinations were collected. Patients were studied in 2 groups according to the protocol assigned in the EDs.

RESULTS: A total of 165 patients were treated (SNAP, 103; traditional protocol, 62). The mean (SD) age was 28.1 (19.7) years, and most were female (70.5%). No differences in peak transaminase levels were observed. SNAP-treated patients had significantly fewer adverse effects as well as shorter stays both in the ED (17.8 [15.2] hours vs 25.9 [17.1] hours; P = .001) and on the ward (2.6 [2.3] days vs 4.4 [3.6] days; P = .019).

CONCLUSIONS: Fewer adverse events occurred with the SNAP approach. The 2 protocols were similarly effective. The SNAP-treated patients spent less time in the ED, and those who were admitted to hospital had shorter stays.}, } @article {pmid39894191, year = {2025}, author = {Amini, H and Shirpoor, A and Naderi, R}, title = {Nandrolone decanoate induces heart injury via oxidative damage and mitochondrial apoptotic pathway by regulation of TLR4/NF-κB/NLRP3 axis in male rats: The rescue effect of N-acetylcysteine.}, journal = {Steroids}, volume = {}, number = {}, pages = {109563}, doi = {10.1016/j.steroids.2025.109563}, pmid = {39894191}, issn = {1878-5867}, abstract = {Myocardial apoptosis is a leading cause of damage in cardiac tissues of nandrolone (ND) treatment. However, its molecular mechanism is not fully understood. This study aims to investigate the effect of ND with or without N -acetylcysteine (NAC) treatment on oxidative damage and TLR4/NF-κB /NLRP3 signaling pathway in the heart of male rats. Eighteen male Wistar rats with a weight range of 220 ± 10 g were selected. They were divided into three groups (n = 6): control (C) group, ND group, NAC + ND group. After six weeks of treatment, the TUNEL staining indicated that ND increased the number of apoptotic cells in the hearts of male rats. The molecular analysis demonstrated that ND exposure resulted in increased protein levels of cytochrome c, c-Caspase-3/p-Caspase-3 ratio, p53, TLR4, NF-κB, NLRP3, and 8-OHdG with a concomitant up-regulation of LDH and CK-MB enzymes activity in the heart tissue compared to the C group. Our findings suggested that ND can cause damage to heart tissue via induction of DNA damage, apoptosis, and probably TLR4/NF-κB/NLRP3 signaling pathway plays a crucial role in this process. It also demonstrates that these negative effects of ND can be reduced by using NAC treatment as an antioxidant and anti-inflammatory agent.}, } @article {pmid39893616, year = {2025}, author = {Abu Hasna, A and Khoury, RD and Mendes, GV and Carvalho, CAT and Bresciani, E and Valera, MC}, title = {N-acetylcysteine antimicrobial action against endodontic pathogens-systematic review and meta-analysis.}, journal = {Odontology}, volume = {}, number = {}, pages = {}, pmid = {39893616}, issn = {1618-1255}, abstract = {Effective root canal disinfection is crucial for the success of endodontic treatment. N-acetylcysteine (NAC), known for its antimicrobial properties, has recently been investigated as a potential endodontic irrigant or intracanal medication. This systematic review aims to assess the antimicrobial efficacy of NAC in comparison to sodium hypochlorite, chlorhexidine, and calcium hydroxide against endodontic pathogens. A comprehensive search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, and LILACS databases up to April 2024, without language or date restrictions. The PICO strategy for this review were as follows: population-teeth requiring endodontic treatment; intervention-NAC used as an endodontic irrigant or intracanal medication; comparison-sodium hypochlorite, chlorhexidine, and calcium hydroxide; Outcomes: reduction in microbial load, encompassing clinical and in vitro studies. Risks of bias assessment and data extraction were conducted with two reviewers independently selecting studies, extracting data, and assessing risk of bias. A general meta-analysis was performed across all included studies, with additional meta-analyses evaluating different exposure times, NAC concentrations, control groups and evaluation methods. After removing duplicates, 9170 studies were initially identified, and seven in vitro studies were included in the systematic review, of which five were included in the meta-analysis. Data were compared using standardized mean differences within a random-effects model. No clinical studies using NAC as an antimicrobial agent were identified. The overall meta-analysis demonstrated that NAC effectively reduced Enterococcus faecalis. Further meta-analyses revealed that exposure time, NAC concentration and choice of control group significantly influenced NAC's effectiveness. NAC effectively reduced Enterococcus faecalis, showing comparable antimicrobial activity to CHX and NaOCl, especially at concentrations of 25-50 mg/mL over a 7-day exposure. Despite significant heterogeneity across studies, NAC demonstrated satisfactory antimicrobial effects in vitro. This suggests that NAC merits reconsideration as an effective intracanal medication for clinical use.}, } @article {pmid39892016, year = {2025}, author = {Gong, L and Chang, L and Chen, S and Wei, X and Du, H and Cheng, J and Chen, X and Yuan, Z and Zhao, P and Geng, M and Yang, H and Cai, K and Dai, L}, title = {Multifunctional injectable hydrogel with self-supplied H2S release and bacterial inhibition for the wound healing with enhanced macrophages polarization via interfering with PI3K/Akt pathway.}, journal = {Biomaterials}, volume = {318}, number = {}, pages = {123144}, doi = {10.1016/j.biomaterials.2025.123144}, pmid = {39892016}, issn = {1878-5905}, abstract = {Hydrogen sulfide (H2S) gas therapy is beneficial for accelerating wound healing and alleviating the inflammatory process, but is seriously hindered by insufficient delivery and unsustainable release in vivo. This study presents a multifunctional injectable hydrogel, OC@ε-PL-SATO, composed of oxidized hyaluronic acid and N-acetylcysteine (NAC) as an initiator, carboxymethyl chitosan and S-aroylthiooxime modified ε-Poly-(l-lysine) (ε-PL-SATO). ε-PL-SATO is a NAC-responsive H2S donor. OC@ε-PL-SATO hydrogel is designed for the desired wound healing process, with rapid gelation (<30 s) and a sustained H2S release. After mixing and gelling, H2S could be long-term released from the hydrogel and effectively drives macrophages toward M2 polarization, thereby ameliorating the inflammatory response. Revealed by transcriptome analysis, the underlying mechanism is that OC@ε-PL-SATO hydrogel releasing H2S inhibits LPS-mediated inflammatory responses in RAW264.7 cells by interfering with phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling and NF-κB activation. Furthermore, the OC@ε-PL-SATO hydrogel effectively eliminates the bacterial burden and alleviates the accompanying inflammation in a rat model of cutaneous wound infection. Importantly, the sustained generation of H2S gas significantly promotes angiogenesis and collagen deposition, ultimately accelerating the wound repair. In conclusion, this study provides a multifunctional injectable hydrogel with rapid gelatinization and continuous H2S release for accelerating the infected wound healing.}, } @article {pmid39887038, year = {2025}, author = {Sharma, P and Kumar, R and Bari, A and Singh, SK}, title = {N-Acetyl Cysteine and Vitamin C Modulate the Antibiotic Efficacy Against Escherichia coli Cells.}, journal = {Microbial drug resistance (Larchmont, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1089/mdr.2024.0135}, pmid = {39887038}, issn = {1931-8448}, abstract = {Supplements with their own beneficial effect on hosts are consumed by us. N-acetyl cysteine (NAC) and Vitamin C (Vit C) are antioxidants and supplements, consumed for their beneficial properties. The present investigation evaluates the effect of their antioxidant property on antibiotic efficacy against Escherichia coli cells from different physiological states, including exponential and stationary-phase, cell aggregates, and in-vitro stress-induced persister cells. Survival was measured in cfu/mL by cfu (colony-forming unit) counting, with efficacy determined by log-fold change in survival by comparing CFUs in antibiotics alone and antibiotic + antioxidant combinations. Fluoroquinolones in the presence of NAC reduced ∼1 log CFUs of log-phase and persister cells, while Vit C reduced CFUs (∼1-3-log increase) of cells from all physiological states. Aminoglycosides results were inconclusive; streptomycin's activity declined (∼1-3-log increase in survival), whereas amikacin's activity potentiated (∼1-log reduction in cfu/mL). Rifampicin's showed reduced activity (∼2-3 log increase in survival) with Vit C in all the states and a ∼1-2 log increase with NAC, especially in cell aggregates and persisters. Beta-lactams activity showed variability, with amoxicillin and ampicillin not being influenced, but ceftriaxone showed significant reduction of efficacy (∼2-3-log increase in survival) in all the treatments. The findings suggest that the overall impact of antioxidants on antibiotic efficacy varies depending on the antibiotic class.}, } @article {pmid39885970, year = {2025}, author = {Brites, GS and Ferreira, I and Sebastião, AI and Sousa, C and Silva, A and Carrascal, M and Oliveira, RC and Gonçalo, M and Vitorino, C and Neves, BM and Cruz, MT}, title = {Blocking the adverse outcome pathway of skin sensitization through a N-acetyl cysteine and lysine-loaded hydrogel.}, journal = {Journal of pharmaceutical analysis}, volume = {15}, number = {1}, pages = {101071}, pmid = {39885970}, issn = {2214-0883}, abstract = {Image 1.}, } @article {pmid39884079, year = {2025}, author = {Chen, K and Li, J and Chen, Z and Shen, C and Li, X and Li, Y and Song, D and Li, X and Wang, X and Xia, Y and Yu, X and Wang, Y and Shen, Y and Tong, J}, title = {Notoginsenoside R1 alleviates blue light-induced corneal injury and wound healing delay by binding to and inhibiting TRIB1.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {138}, number = {}, pages = {156399}, doi = {10.1016/j.phymed.2025.156399}, pmid = {39884079}, issn = {1618-095X}, abstract = {BACKGROUND: With the escalating use of digital devices, blue light (BL) exposure has emerged as a critical concern due to its potential to cause ocular damage. This study explores the protective effects of notoginsenoside R1 (NR1), a bioactive compound from Panax notoginseng (Burkill) F.H. Chen (Sanqi), against BL-induced corneal epithelial injury.

PURPOSE: This research aims to investigate the protective effects of NR1 on BL-induced corneal injury and wound healing delay.

METHODS: Human corneal epithelial cells (hCECs) were pretreated with NR1 (0-50 μM) or N-acetylcysteine (NAC, 10 mM), then exposed to BL (570 μW/cm²) for 24 h. Cell viability, proliferation, migration, and ROS levels were assessed using various techniques. In mice, NR1 (25 μM and 50 μM) and NAC (0.3 %) eye drops were administered during BL exposure. Corneal injury, healing rates, cell proliferation, migration, ROS, and inflammation were evaluated. RNA-sequencing, bioinformatics, and molecular binding validation identified tribbles homolog 1 (TRIB1) as a key molecule mitigating BL damage with NR1. Functional studies via gene silencing, overexpression, and pharmacological modulation further explored TRIB1's role in BL exposure.

RESULTS: NR1 significantly reduced BL-induced inflammation, ROS production, and inhibited migration and proliferation in hCECs and murine corneas. It also alleviated BL-induced corneal injury and delayed healing in mice. NR1 inhibited TRIB1 upregulation, a marker of BL-induced injury and healing delay. Overexpression of TRIB1 negated NR1's therapeutic effects on hCECs, while TRIB1 silencing mitigated functional impairment. In mice, increased Trib1 expression caused corneal injury and delayed healing, reversed by NR1 treatment.

CONCLUSION: NR1 shows potential as a therapeutic agent by inhibiting TRIB1 elevation in response to BL exposure, providing a novel promising target for corneal injury and wound healing delay induced by BL, and offering a comprehensive strategy for clinical pharmacological intervention.}, } @article {pmid39882502, year = {2024}, author = {Biering, V and Bellouard, R and Martin, M and Dailly, É and Monteil-Ganière, C and Le Carpentier, EC}, title = {N-acetylcysteine use in a cocaine-induced liver failure: a case report.}, journal = {Frontiers in toxicology}, volume = {6}, number = {}, pages = {1502716}, pmid = {39882502}, issn = {2673-3080}, abstract = {BACKGROUND: Cocaine intoxication and abuse is a worldwide problem that can be the cause of numerous acute medical complications, including severe acute hepatitis. Although these cases are scarce, they are extremely serious and may lead to liver transplantation or death. Management of toxic hepatitis, once the causative agent has been discontinued, is essentially symptomatic, based on clinical and biological monitoring and prevention of complications related to acute hepatitis.

CASE DETAILS: We present a case of a 28-year-old woman admitted to the emergency department for acute hepatitis due to cocaine intoxication. In addition to a sharp rise in her liver enzymes, the patient also presented metabolic acidosis, renal failure, and rhabdomyolysis. Treatment consisted of administering N-acetylcysteine (NAC), dialysis, and additional supportive measures. An improvement in the liver function with a decrease in transaminases occurred after the NAC administration. The toxicokinetics of major cocaine metabolites and clinical chemistry concentrations were monitored.

CONCLUSION: In addition to the usual management measures for acute hepatitis, the administration of N-acetylcysteine should be investigated further, although it is currently used only in cases of acetaminophen acute toxic hepatitis.}, } @article {pmid39877352, year = {2024}, author = {Ruths, L and Hengge, J and Teixeira, GQ and Haffner-Luntzer, M and Ignatius, A and Riegger, J}, title = {Terminal complement complex deposition on chondrocytes promotes premature senescence in age- and trauma-related osteoarthritis.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1470907}, pmid = {39877352}, issn = {1664-3224}, mesh = {Animals ; *Chondrocytes/metabolism ; *Osteoarthritis/metabolism/etiology/immunology ; Humans ; *Cellular Senescence ; Mice ; Male ; *Cartilage, Articular/metabolism/pathology ; Mice, Knockout ; Mice, Inbred C57BL ; Complement Membrane Attack Complex/metabolism ; Swine ; Aging ; Disease Models, Animal ; Cells, Cultured ; }, abstract = {BACKGROUND: The complement system is locally activated after joint injuries and leads to the deposition of the terminal complement complex (TCC). Sublytic TCC deposition is associated with phenotypical alterations of human articular chondrocytes (hAC) and enhanced release of inflammatory cytokines. Chronic inflammation is a known driver of chondrosenescence in osteoarthritis (OA). Therefore, we investigated whether TCC deposition contributes to stress-induced premature senescence (SIPS) during aging in vivo and after ex vivo cartilage injury.

METHODS: Femoral condyles of male 13-week-old and 72-week-old CD59-ko (higher TCC deposition), C6-deficient (insufficient TCC formation), and C57BL/6 (WT) mice were collected to assess age-related OA. Furthermore, macroscopically intact human and porcine cartilage explants were traumatized and cultured with/without 30% human serum (HS) to activate the complement system. Explants were additionally treated with clusterin (CLU, TCC inhibitor), N-acetylcysteine (NAC, antioxidant), Sarilumab (IL-6 receptor inhibitor), STAT3-IN-1 (STAT3 inhibitor), or IL-1 receptor antagonist (IL-1RA) in order to investigate the consequences of TCC deposition. Gene and protein expression of senescence-associated markers such as CDKN1A and CDKN2A was determined.

RESULTS: In the murine aging model, CD59-ko mice developed after 72 weeks more severe OA compared to C6-deficient and WT mice. mRNA analysis revealed that the expression of Cdkn1a, Cdkn2a, Tp53, Il1b, and Il6 was significantly increased in the cartilage of CD59-ko mice. In human cartilage, trauma and subsequent stimulation with HS increased mRNA levels of CDKN1A, CDKN2A, and IL6, while inhibition of TCC formation by CLU reduced the expression. Antioxidative therapy with NAC had no anti-senescent effect. In porcine tissue, HS exposure and trauma had additive effects on the number of CDKN2A-positive cells, while Sarilumab, STAT-IN-1, and IL-1RA reduced CDKN2A expression by trend.

CONCLUSION: Our results demonstrate that complement activation and consequent TCC deposition is associated with chondrosenescence in age-related and trauma-induced OA. We provided evidence that the SIPS-like phenotype is more likely induced by TCC-mediated cytokine release rather than oxidative stress. Overall, targeting TCC formation could be a future approach to attenuate OA progression.}, } @article {pmid39876989, year = {2025}, author = {Song, M and Han, M and Zhang, H and Yang, Y and Tian, Y and Li, J and Zhao, J}, title = {The Effective Compound Combination of Bufei Yishen Formula III Improves the Mitochondrial Dysfunction via Inhibiting JNK/Sab Pathway in COPD Mice.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {525-538}, pmid = {39876989}, issn = {1177-8881}, mesh = {Animals ; Mice ; *Pulmonary Disease, Chronic Obstructive/drug therapy/metabolism ; *Mitochondria/drug effects/metabolism ; *Mice, Inbred BALB C ; *Drugs, Chinese Herbal/pharmacology/chemistry ; Male ; Disease Models, Animal ; MAP Kinase Signaling System/drug effects ; }, abstract = {PURPOSE: The effective compound combination of Bufei Yishen formula III (ECC-BYF III) has shown protective effects against chronic obstructive pulmonary disease (COPD). However, its effect on mitochondrial dysfunction remains unclear. The current study aimed to investigate the effect of ECC-BYF III on mitochondrial dysfunction in COPD mice and elucidate its potential mechanisms.

METHODS: Twenty-eight BALB/c mice were randomized into four groups: control, model, ECC-BYF III, and NAC (N-acetylcysteine) groups. A COPD model was established using cigarette smoke and Klebsiella pneumoniae for 8 weeks. The mice in the ECC-BYF III group were treated with ECC-BYF III (7.7 mg/kg/d), and the NAC group was treated with NAC (78 mg/kg/d) for eight weeks. Mice in the control and model groups were administered with 0.5% sodium carboxymethyl cellulose (25 mL/kg/d) for eight weeks. Then pulmonary function, histopathology, inflammatory factor levels, mitochondrial ultrastructure and function, and immunoblotting analyses were evaluated.

RESULTS: Compared with the model, ECC-BYF III significantly improved the decline in pulmonary function and histopathological changes. Furthermore, ECC-BYF III ameliorated mitochondrial dysfunction by restoring the mitochondrial membrane potential, increasing mitochondrial complex I activity, and decreasing tumor necrosis factor-α (TNF-α) level and protein expressions of SH3BP5 (Sab), Phospho-JNK (P-JNK), and cleaved CASP3.

CONCLUSION: The results suggest that the potential therapeutic benefit of ECC-BYF III against mitochondrial dysfunction in COPD is due to the inhibition of the JNK/Sab pathway, which will help to further understand the potential mechanisms of ECC-BYF III in the treatment of COPD.}, } @article {pmid39873044, year = {2025}, author = {Komatsu, K and Chao, D and Matsuura, T and Kido, D and Ogawa, T}, title = {Advancing osseointegration research: A dynamic three-dimensional (3D) in vitro culture model for dental implants.}, journal = {Journal of dental sciences}, volume = {20}, number = {1}, pages = {350-360}, pmid = {39873044}, issn = {2213-8862}, abstract = {BACKGROUND/PURPOSE: In-vitro studies are essential for understanding cellular responses, but traditional culture systems often neglect the three-dimensional (3D) structure of real implants, leading to limitations in cellular recruitment and behavior largely governed by gravity. The objective of this study was to pioneer a novel 3D dynamic osteoblastic culture system for assessing the biological capabilities of dental implants in a more clinically and physiologically relevant manner.

MATERIALS AND METHODS: Rat bone marrow-derived osteoblasts were cultured in a 24-well dish with a vertically positioned dental implant. Controlled rotation using a 3D rotator with 3° tilts was applied. Cell attachment, proliferation, and differentiation on implant surfaces were evaluated in response to different surface topographies, physicochemical properties, and local environments.

RESULTS: Among the tested rotational speeds (0, 10, 30, 50 rpm), optimal osteoblast attachment and proliferation were observed at 30 rpm. A linear correlation was found between cell attachment and rotation speed up to 30 rpm, declining at 50 rpm. Alkaline phosphatase (ALP) activity and mineralized matrix formation were elevated on newly acid-etched, hydrophilic surfaces compared to their 4-week-old hydrophobic surfaces. Sandblasted implants showed higher ALP activity and matrix mineralization. Adding N-acetyl cysteine to the culture medium increased ALP activity and mineralization.

CONCLUSION: Osteoblasts successfully attached, proliferated, and mineralized on dental implants in vitro under optimized dynamic conditions. This system differentiated the biological capabilities of implants with varying surface topographies, wettability, and biochemically modulated environments. These findings support developing a 3D dynamic dental implant culture model, advancing osseointegration research and innovating dental implant designs.}, } @article {pmid39872815, year = {2024}, author = {Li, F and Deng, L and Xu, T and Xu, L and Xu, Z and Lai, S and Ai, Y and Wang, Y and Yan, G and Zhu, L}, title = {Getah virus triggers ROS-mediated autophagy in mouse Leydig cells.}, journal = {Frontiers in microbiology}, volume = {15}, number = {}, pages = {1519694}, pmid = {39872815}, issn = {1664-302X}, abstract = {INTRODUCTION: Getah virus (GETV) is a zoonotic virus transmitted via a mosquito-vertebrate cycle. While previous studies have explored the epidemiology and pathogenicity of GETV in various species, its molecular mechanisms remain largely unexplored.

METHODS: This study investigated the impact of GETV infection and associated molecular mechanisms on reactive oxygen species (ROS) and autophagy levels in mouse Leydig cells both in vivo and in vitro. The male mice and TM3 cells were treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels. Rapamycin (Rapa) and 3-Methyladenine (3- MA) were used to change autophagy in both infected and uninfected TM3 cells.

RESULTS AND DISCUSSION: The findings revealed that GETV infection in mouse testes speciffcally targeted Leydig cells and induced oxidative stress while enhancing autophagy in testicular tissue. Using TM3 cells as an in vitro model, the study confirmed GETV replication in this cell line, triggering increased ROS and autophagy levels. Treatment with N-acetylcysteine (NAC) to reduce cellular ROS levels markedly reduced autophagy in testicular tissue and TM3 cells infected with GETV. Interestingly, the use of rapamycin (Rapa) and 3-Methyladenine (3- MA) led to autophagy change in both infected and uninfected TM3 cells, with no signiffcant alterations in cellular ROS levels. These results indicate that GETV infection elevates ROS levels, subsequently inducing autophagy in mouse Leydig cells. We also found that autophagy plays an important role in GETV replication. When autophagy levels were reduced using NAC and 3-MA, a corresponding decrease in TCID50 was observed. Conversely, upregulation of autophagy using Rapa resulted in an increase in TCID50 of GETV. Therefore, we speculate that GETV may exploit the autophagy pathway to facilitate its replication. These ffndings illuminate the interplay between GETV and host cells, providing valuable insights for therapeutic strategies targeting autophagy in GETV infections.}, } @article {pmid39864434, year = {2025}, author = {Pfau, K and Callizo, J and Rossouw, P and Gabrani, C and Holz, F and Charbel Issa, P and Kellner, U and Strauss, R and Kühlewein, L and Stingl, K and Feltgen, N and Pfau, M}, title = {[Not Available].}, journal = {Klinische Monatsblatter fur Augenheilkunde}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2525-4419}, pmid = {39864434}, issn = {1439-3999}, } @article {pmid39872876, year = {2023}, author = {McLaughlin, RM and Top, I and Laguna, A and Hernandez, C and Katz, H and Livi, LL and Kramer, L and Zambuto, SG and Hoffman-Kim, D}, title = {Cortical Spheroid Model for Studying the Effects of Ischemic Brain Injury.}, journal = {In vitro models}, volume = {2}, number = {1-2}, pages = {25-41}, pmid = {39872876}, issn = {2731-3441}, abstract = {PURPOSE: Ischemic brain injury occurs when there is reduced or complete disruption of blood flow to a brain region, such as in stroke or severe traumatic brain injury. Even short interruptions can lead to devastating effects including excitotoxicity and widespread cell death. Despite many decades of research, there are still very few therapeutic options for patients suffering from brain ischemia.

METHODS: We developed an in vitro brain ischemia model using our previously established 3D spheroids derived from primary postnatal rat cortex. These spheroids provide an in vivo-relevant model containing a similar cellular composition to the native cortex and a cell-synthesized extracellular matrix. This model is cost-effective, highly reproducible, and can be produced in a high-throughput manner, making it an ideal candidate for screening potential therapeutics. To study the cellular and molecular mechanisms of stroke in this model, spheroids were deprived of glucose, oxygen, or both oxygen and glucose for 24 h.

RESULTS: Both oxygen and oxygen-glucose deprived spheroids demonstrated many of the hallmarks of ischemic brain injury, including a decrease in metabolism, an increase in neural dysfunction, breakdown in the neurovascular unit, and an increase in reactive astrocytes. Pretreatment of spheroids with the antioxidant agent N-acetylcysteine (NAC) mitigated the decrease in ATP after oxygen-glucose deprivation, was partially neuroprotective, and enhanced the expression of laminin.

CONCLUSION: This 3D cortical spheroid model provides a platform for studying ischemic injury and has the potential for screening therapeutics.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44164-023-00046-z.}, } @article {pmid39861915, year = {2025}, author = {Nabipur, L and Mouawad, M and Venketaraman, V}, title = {Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV-M.tb Co-Infection in the Central Nervous System: A Systematic Review.}, journal = {Viruses}, volume = {17}, number = {1}, pages = {}, doi = {10.3390/v17010127}, pmid = {39861915}, issn = {1999-4915}, mesh = {*Glutathione/metabolism ; Humans ; *HIV Infections/complications/drug therapy ; *Coinfection/drug therapy ; Animals ; *Mycobacterium tuberculosis/drug effects ; *Tuberculosis/drug therapy ; *Antitubercular Agents/therapeutic use/pharmacology ; Central Nervous System/drug effects ; Treatment Outcome ; Disease Models, Animal ; Anti-Bacterial Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction.

METHODS: Relevant studies were identified through systematic searches of PubMed, Elsevier, WHO, and related databases. Inclusion criteria focused on preclinical and clinical research examining GSH or its precursors in HIV, TB, or co-infection, with emphasis on microbial control, immune modulation, and CNS-related outcomes.

RESULTS: Preclinical studies showed that GSH improves macrophage antimicrobial function, reduces oxidative stress, and limits Mycobacterium tuberculosis (M.tb) growth. Animal models demonstrated reduced bacterial burden in the lungs, liver, and spleen with GSH supplementation, along with enhanced granuloma stability. Clinical studies highlighted increased TH1 cytokine production, reduced inflammatory markers, and improved CD4+ T cell counts in HIV-M.tb co-infected patients. N-acetylcysteine (NAC), a GSH precursor, was shown to significantly enhance the efficacy of first-line TB antibiotics and mitigate treatment-associated toxicity.

DISCUSSION: GSH shows promise as an adjunct therapy for HIV-M.tb co-infection, particularly for cases involving the CNS, where it may improve immune recovery and reduce inflammation. However, evidence is limited by small sample sizes and a lack of randomized trials. Future research should focus on developing CNS-directed GSH formulations and evaluating its integration into current treatment protocols to address the dual burden of HIV and TB, ultimately improving patient outcomes.}, } @article {pmid39861414, year = {2025}, author = {Viña, I and Viña, JR and Carranza, M and Mariscal, G}, title = {Efficacy of N-Acetylcysteine in Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis.}, journal = {Nutrients}, volume = {17}, number = {2}, pages = {}, doi = {10.3390/nu17020284}, pmid = {39861414}, issn = {2072-6643}, mesh = {*Polycystic Ovary Syndrome/drug therapy/blood ; Humans ; *Acetylcysteine/therapeutic use ; Female ; *Metformin/therapeutic use ; Clomiphene/therapeutic use ; Progesterone/blood ; Treatment Outcome ; Endometrium/drug effects/pathology ; Antioxidants/therapeutic use ; Adult ; }, abstract = {BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age and requires better treatment. N-acetylcysteine (NAC) is known to be beneficial under such conditions owing to its antioxidant potential and insulin-sensitizing properties. The effect of NAC on the reproductive outcomes of PCOS patients was examined in this meta-analysis.

METHODS: In accordance with PRISMA standards, this meta-analysis included studies that compared N-acetylcysteine, metformin, clomiphene citrate, and a placebo in patients with POCS. The main indicators were follicular growth, endometrial thickness, and hormone level. The risk of bias was evaluated using the Cochrane ROB2 tool.

RESULTS: Twenty-two studies (n = 2515) were included. NAC was associated with a statistically significant increase in progesterone (SMD 0.95, 95% CI: 0.13-1.77, p = 0.02) and endometrial thickness (SMD 0.58, 95% CI: 0.10-1.06, p = 0.02) compared to the placebo and other drugs (SMD 0.71, 95% CI: 0.48-0.94, p < 0.0001). LH levels were significantly increased by NAC compared to metformin (SMD 0.67, 95% CI: 0.23-1.12, p = 0.003). However, no significant differences were observed in the estradiol, SHBG, or FSH levels.

CONCLUSIONS: NAC had a major effect on progesterone, endometrial thickness, and LH levels in women with PCOS. Therefore, it may be a potential treatment option.}, } @article {pmid39860053, year = {2025}, author = {Sanduzzi Zamparelli, S and Sanduzzi Zamparelli, A and Bocchino, M}, title = {Immune-Boosting and Antiviral Effects of Antioxidants in COVID-19 Pneumonia: A Therapeutic Perspective.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, doi = {10.3390/life15010113}, pmid = {39860053}, issn = {2075-1729}, abstract = {The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.}, } @article {pmid39857691, year = {2025}, author = {Vorwerk, J and Liu, L and Stadler, TH and Frank, D and Ahmed, HMM and Patnana, PK and Kebenko, M and Dazert, E and Opalka, B and von Bubnoff, N and Khandanpour, C}, title = {Germline Single-Nucleotide Polymorphism GFI1-36N Causes Alterations in Mitochondrial Metabolism and Leads to Increased ROS-Mediated DNA Damage in a Murine Model of Human Acute Myeloid Leukemia.}, journal = {Biomedicines}, volume = {13}, number = {1}, pages = {}, doi = {10.3390/biomedicines13010107}, pmid = {39857691}, issn = {2227-9059}, support = {17R/2018//Deutsche José Carreras Leukämie-Stiftung/ ; 70112392//German Cancer Aid/ ; KH331/2-3//Deutsche Forschungsgemeinschaft/ ; Kha2/002/20//Interdisziplinäres Zentrum für Klinische Forschung Münster/ ; }, abstract = {Background/Objectives: GFI1-36N represents a single-nucleotide polymorphism (SNP) of the zinc finger protein Growth Factor Independence 1 (GFI1), in which the amino acid serine (S) is replaced by asparagine (N). The presence of the GFI1-36N gene variant is associated with a reduced DNA repair capacity favoring myeloid leukemogenesis and leads to an inferior prognosis of acute myeloid leukemia (AML) patients. However, the underlying reasons for the reduced DNA repair capacity in GFI1-36N leukemic cells are largely unknown. Since we have demonstrated that GFI1 plays an active role in metabolism, in this study, we investigated whether increased levels of reactive oxygen species (ROS) could contribute to the accumulation of genetic damage in GFI1-36N leukemic cells. Methods: We pursued this question in a murine model of human AML by knocking in human GFI1-36S or GFI1-36N variant constructs into the murine Gfi1 gene locus and retrovirally expressing MLL-AF9 to induce AML. Results: Following the isolation of leukemic bone marrow cells, we were able to show that the GFI1-36N SNP in our model is associated with enhanced oxidative phosphorylation (OXPHOS), increased ROS levels, and results in elevated γ-H2AX levels as a marker of DNA double-strand breaks (DSBs). The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in GFI1-36N leukemic cells. Conclusions: We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.}, } @article {pmid39857416, year = {2025}, author = {Cusato, J and Mulasso, A and Ferrara, M and Manca, A and Accardo, G and Palermiti, A and Antonucci, M and Bianco, G and Chiara, F and Mula, J and Tettoni, MC and Cuomo, S and Trevisan, G and Bonora, S and Di Perri, G and Lupo, C and Rainoldi, A and D'Avolio, A}, title = {How Antiretroviral Drug Concentrations Could Be Affected by Oxidative Stress, Physical Capacities and Genetics: A Focus on Dolutegravir Treated Male PLWH.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {1}, pages = {}, doi = {10.3390/antiox14010082}, pmid = {39857416}, issn = {2076-3921}, support = {CUSJ_RILO_21_01//Medical Sciences Department University of Turin/ ; }, abstract = {High levels of reactive oxygen species (ROS) are present in people living with HIV (PLWH), produced by intense physical activity; in response, our body produces antioxidant molecules. ROS influence the expression of gene-encoding enzymes and transporters involved in drug biotransformation. In addition, pharmacogenetics can influence transporter activity, and thus drug exposure. Currently, no studies concerning this topic are present in the literature. The aim of this study was to investigate whether some antioxidant molecules, physical exercise, and genetic variants could affect dolutegravir (DTG) concentrations in PLWH, switching from triple to dual therapy. Thirty PLWH were recruited and analyzed at baseline (triple therapy), and 6 months after (dual therapy). Physical capacities were investigated using validated tools. Drug concentrations and oxidative stress biomarkers levels were evaluated through liquid chromatography coupled with tandem mass spectrometry, while genetic variants through real-time PCR. No statistical differences were suggested for drug concentrations, with the exception of intracellular DTG (p = 0.047). Statistically significant correlations between DTG plasma concentrations and white blood cells (p = 0.011; S = 0.480) and cytoplasmic N-acetyl-cysteine (p = 0.033; S = -0.419) were observed. Finally, white blood cells and BMI remained in the final multivariate regression model as predictors of DTG concentrations. This is the first study showing possible factors related to oxidative stress impacting DTG exposure.}, } @article {pmid39852136, year = {2024}, author = {Cimmino, A and Gioia, M and Clementi, ME and Faraoni, I and Marini, S and Ciaccio, C}, title = {Polydatin-Induced Shift of Redox Balance and Its Anti-Cancer Impact on Human Osteosarcoma Cells.}, journal = {Current issues in molecular biology}, volume = {47}, number = {1}, pages = {}, doi = {10.3390/cimb47010021}, pmid = {39852136}, issn = {1467-3045}, support = {MUR Prin 2022PFFPBL//Italian Ministry of University and Research/ ; }, abstract = {Cancer cells demonstrate remarkable resilience by adapting to oxidative stress and undergoing metabolic reprogramming, making oxidative stress a critical target for cancer therapy. This study explores, for the first time, the redox-dependent anticancer effects of Polydatin (PD), a glucoside derivative of resveratrol, on the human Osteosarcoma (OS) cells SAOS-2 and U2OS. Using cell-based biochemical assays, we found that cytotoxic doses of PD (100-200 µM) promote ROS production, deplete glutathione (GSH), and elevate levels of both total iron and intracellular malondialdehyde (MDA), which are key markers of ferroptosis. Notably, the ROS scavenger N-acetylcysteine (NAC) and the ferroptosis inhibitor ferrostatin-1 (Fer-1) partially reverse PD's cytotoxic effects. Interestingly, PD's ability to hinder cell adhesion and migration appears independent of its pro-oxidant effect. Analysis of the oxidative stress regulators SIRT1 and Nrf2 at the gene and protein levels using real-time PCR and Western blot indicates an early oxidative response to PD treatment. PD remains effective under tumor-like conditions of hypoxia and serum starvation, and sensitizes OS cells to ROS-inducing chemotherapeutics like doxorubicin (DOX) and cisplatin (CIS). Importantly, PD exhibits minimal toxicity to non-tumorigenic cells (hFOB), suggesting a favorable therapeutic profile. Overall, our findings underscore that PD-induced redox imbalance plays a crucial role in its anti-OS effects, warranting further exploration into the molecular mechanisms behind its pro-oxidant activity.}, } @article {pmid39765110, year = {2025}, author = {Farhadi, M and Sohbatzadeh, F and Moghaddam, AH and Firouzjaei, Y and Cheng, C}, title = {Enhancing the efficacy of low doses of N-acetyl-L-cysteine in mitigating CCl4-induced hepatotoxicity in animal model using physical cold plasma.}, journal = {Ecotoxicology and environmental safety}, volume = {289}, number = {}, pages = {117642}, doi = {10.1016/j.ecoenv.2024.117642}, pmid = {39765110}, issn = {1090-2414}, mesh = {Animals ; *Acetylcysteine/pharmacology ; Rats ; Male ; *Chemical and Drug Induced Liver Injury/prevention & control ; *Carbon Tetrachloride/toxicity ; *Oxidative Stress/drug effects ; *Plasma Gases ; *Liver/drug effects/pathology ; *Antioxidants ; Glutathione/metabolism ; Kidney/drug effects/pathology ; Disease Models, Animal ; Rats, Sprague-Dawley ; Rats, Wistar ; }, abstract = {Liver diseases have become widespread especially due to various factors of modern life. Although the effect of N-acetyl-L-cysteine (NAC) is investigated in the recovery of liver damage, gas plasma therapy can be identified as a promising candidate. Our study aimed to enhance the effectiveness of ineffective doses of NAC in stopping CCl4-induced hepatotoxicity in rats by physical cold plasma. The plasma-treated NAC (PTN) structural changes were investigated through FTIR and LCMS/MS analysis. It was observed that the PTN consists of various chemical bioproducts with different molecular weights. We investigated an ineffective dose of NAC and its parallel effect through the administration of PTN on liver and kidney morphology and several biochemical factors including ALT, AST, and ALP. Additionally, we examined oxidative stress, antioxidant parameters, and glutathione (GSH) levels. Results showed that PTN exhibited greater antioxidant properties and increased GSH levels, contributing to its therapeutic effects. Also, the antioxidant enzymes and oxidative stress activities improved after receiving PTN. It also enhanced histological parameters, although various damages were detected in both liver and kidney tissues after CCl4 injection, PTN remarkably prevented the tissue changes caused by CCl4. PTN could protect against liver damage even at a very low dose of NAC, acting as a prophylactic drug with a high margin of safety for hepatotoxicity.}, } @article {pmid39847829, year = {2025}, author = {Moka, MK and George, M and Rathakrishnan, D and Jagadeeshwaran, V and D K, S}, title = {Trends in drug repurposing: Advancing cardiovascular disease management in geriatric populations.}, journal = {Current research in translational medicine}, volume = {73}, number = {2}, pages = {103496}, doi = {10.1016/j.retram.2025.103496}, pmid = {39847829}, issn = {2452-3186}, abstract = {Drug repurposing is a promising strategy for managing cardiovascular disease (CVD) in geriatric populations, offering efficient and cost-effective solutions. CVDs are prevalent across all age groups, with a significant increase in prevalence among geriatric populations. The middle-age period (40-65 years) is critical due to factors like obesity, sedentary lifestyle, and psychosocial stress. In individuals aged 65 and older, the incidence of CVDs is highest due to age-related physiological changes and prolonged exposure to risk factors. In this review we find that certain drugs, such as non-cardiovascular drugs like anakinra, probenecid, N-acetyl cysteine, quercetin, resveratrol, rapamycin, colchicine, bisphosphonates, hydroxychloroquine, SGLT-2i drugs, GLP-1Ras drugs and sildenafil are recommended for drug repurposing to achieve cardiovascular benefits in geriatric patients. However, agents such as canakinumab, methotrexate, ivermectin, erythromycin, capecitabine, carglumic acid, chloroquine, and furosemide are constrained in their therapeutic use and warrant meticulous consideration, rendering them less favorable for this specific application. This review emphasizes the importance of exploring alternative therapeutic strategies to improve outcomes in geriatric populations and suggests drug repurposing as a promising avenue to enhance treatment efficacy.}, } @article {pmid39843512, year = {2025}, author = {Candela, ME and Addison, M and Aird, R and Man, TY and Cartwright, JA and Ashmore-Harris, C and Kilpatrick, AM and Starkey Lewis, PJ and Drape, A and Barnett, M and Mitchell, D and McLean, C and McGowan, N and Turner, M and Dear, JW and Forbes, SJ}, title = {Cryopreserved human alternatively activated macrophages promote resolution of acetaminophen-induced liver injury in mouse.}, journal = {NPJ Regenerative medicine}, volume = {10}, number = {1}, pages = {5}, pmid = {39843512}, issn = {2057-3995}, support = {MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; MR/T044802/1//RCUK | Medical Research Council (MRC)/ ; }, abstract = {Acute liver failure is a rapidly progressing, life-threatening condition most commonly caused by an overdose of acetaminophen (paracetamol). The antidote, N-acetylcysteine (NAC), has limited efficacy when liver injury is established. If acute liver damage is severe, liver failure can rapidly develop with associated high mortality rates. We have previously demonstrated that alternatively, activated macrophages are a potential therapeutic option to reverse acute liver injury in pre-clinical models. In this paper, we present data using cryopreserved human alternatively activated macrophages (hAAMs)-which represent a potential, rapidly available treatment suitable for use in the acute setting. In a mouse model of APAP-induced injury, peripherally injected cryopreserved hAAMs reduced liver necrosis, modulated inflammatory responses, and enhanced liver regeneration. hAAMs were effective even when administered after the therapeutic window for NAC. This cell therapy approach represents a potential treatment for APAP overdose when NAC is ineffective because liver injury is established.}, } @article {pmid39843023, 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}, doi = {10.1186/s12576-024-00928-1}, pmid = {39843023}, issn = {1880-6562}, mesh = {Humans ; Apoptosis/drug effects ; Calcium/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism ; *Carcinoma, Squamous Cell/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; *Mouth Neoplasms/metabolism/pathology ; *Reactive Oxygen Species/metabolism ; *Smoke/adverse effects ; *Tobacco Products/adverse 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. GRAPHICAL ABSTRACT.}, } @article {pmid39842600, year = {2025}, author = {Gu, D and Zhou, L and Zhang, Y and Jin, H and Nie, W and Zhang, M and Dong, Y}, title = {N-acetylcysteine and chitosan conjugate modified dexamethasone nanostructured lipid carriers: Enhanced permeability, precorneal retention and lower inflammation for the treatment of dry eye syndrome.}, journal = {International journal of biological macromolecules}, volume = {}, number = {}, pages = {140123}, doi = {10.1016/j.ijbiomac.2025.140123}, pmid = {39842600}, issn = {1879-0003}, abstract = {Dexamethasone (Dex) is a primary medication for treating dry eye syndrome, and tobramycin-dexamethasone eye drops are commercially available. However, the eye's complex physiological environment reduces its bioavailability, and repeated use can lead to significant systemic toxicity and side effects. This study introduces a novel conjugate of chitosan (CS) and N-acetylcysteine (NAC), a bioadhesive material, which was grafted onto the surface of a Dex-supported nanostructured lipid carrier (NLC) to develop an innovative nanoparticle lipid ocular drug delivery system (CS-NAC@Dex-NLC). The enhancements afforded by CS-NAC, such as adhesion, osmotic, and targeting properties, address the limitations of traditional eye drops. NMR characterization confirmed the successful synthesis of the copolymer (CS-NAC). Particle size (PS), zeta potential, and transmission electron microscopy (TEM) verified the proper formation of the CS-NAC@Dex-NLC system. Cytotoxicity tests confirmed its excellent biocompatibility and safety. Cellular uptake studies showed that CS-NAC@Dex-NLC achieved the highest efficiency. Pharmacokinetic assessments revealed a significant increase in Dex's bioavailability in tears and aqueous humor. In vitro corneal penetration and in vivo imaging experiments demonstrated effective corneal penetration and retention, enhancing the drug's duration on the ocular surface and overcoming the barrier effect. Pharmacodynamic studies in rabbits with dry eye syndrome indicated that CS-NAC@Dex-NLC effectively alleviates symptoms, repairs corneal damage, and stabilizes the tear film. ELISA results showed a reduction in inflammation caused by dry eye. These findings suggest that CS-NAC@Dex-NLC is a promising vector for dry eye treatment, offering significant clinical relevance.}, } @article {pmid39832189, year = {2024}, author = {Mishra, S and Botlagunta, M and Rajasekaran, S}, title = {Arsenic-Induced Inflammatory Response via ROS-Dependent Activation of ERK/NF-kB Signaling Pathways: Protective Role of Natural Polyphenol Tannic Acid.}, journal = {Journal of applied toxicology : JAT}, volume = {}, number = {}, pages = {}, doi = {10.1002/jat.4748}, pmid = {39832189}, issn = {1099-1263}, support = {ICMR-NIREH/BPL/IMP-PJ-40/2021-22/473//Indian Council of Medical Research (ICMR)-Intramural funding of the National Institute for Research in Environmental Health (NIREH)/ ; }, abstract = {Arsenic (As), a highly toxic metalloid, is present throughout our environment as a result of both natural and human-related activities. Furthermore, As exposure could lead to a persistent inflammatory response, which may facilitate the pathogenesis of several diseases in various organs. This study was performed to investigate the As-induced inflammatory response and the underlying molecular mechanisms in vitro. Further, the anti-inflammatory effects of a natural dietary polyphenol tannic acid (TA) were also explored. In human normal bronchial (BEAS-2B), adenocarcinoma alveolar basal (A549), and murine macrophages (J774) cell lines, a trivalent form of As (as As[3+]) exposure markedly induced the expression of various pro-inflammatory mediators (cytokines and chemokines). Additionally, it was found that As[3+] exposure induced reactive oxygen species (ROS) generation and activation of the nuclear factor-kappa B (NF-kB) p65 and extracellular signal-regulated kinase (ERK)1/2 pathways in BEAS-2B cells. As expected, the blockade of either ERK1/2 (PD98059) or NF-kB p65 (IMD0354), or both pathways attenuated As[3+]-induced pro-inflammatory mediators release. Interestingly, pre-treatment with ROS inhibitor N-acetylcysteine (NAC) attenuated activation of ERK/NF-kB pathways, suggesting that ROS have a critical role in pathway's activation and subsequent inflammatory response. Further, TA pre-treatment effectively attenuated As[3+]-induced inflammatory response by suppressing ROS production and ERK/NF-kB signaling pathways activation. Therefore, this study provides scientific evidence for the anti-inflammatory activities of TA and the underlying molecular mechanisms.}, } @article {pmid39830891, year = {2025}, author = {Shri, P and Singh, KP and Rani, V and Nagar, DP and Acharya, J and Bhaskar, ASB}, title = {N-acetylcysteine prevents cholinergic and non-cholinergic toxic effects induced by nerve agent poisoning in rats.}, journal = {Toxicology research}, volume = {14}, number = {1}, pages = {tfae223}, doi = {10.1093/toxres/tfae223}, pmid = {39830891}, issn = {2045-452X}, abstract = {OBJECTIVE: Organophosphorus Nerve Agent, VX [(O-Ethyl S-diisopropylaminomethyl) methylphosphonothioate] compound interferes with acetylcholine signaling by targeting the AChE enzyme. Studies suggest that in nerve agents poisoning, non-cholinergic effects are also responsible for damage in peripheral tissues including long term damage in brain. Present study reports cholinergic and non-cholinergic effects of VX poisoning and their prevention by use of N-acetylcysteine (NAC) in addition to conventional antidotes atropine sulphate and 2-PAM chloride as an antioxidant. NAC was chosen being an approved drug for medical conditions including oxidative damage and as mucolytic.

RESULTS: Results of the study showed that after 1x LD 50 exposure to VX and standard atropine and oxime therapy resulted in recovery of cholinesterase activity up to 51%, while additional NAC administration resulted in increased recovery up to 89% in brain cholinesterase activity. NAC also helped in maintaining intracellular and tissue GSH level, reduced ROS generation and lipid peroxidation. NAC treatment could able to reduce the lipid peroxidation (MDA) levels in liver of NAC administered groups as compared to standard treatment of atropine sulphate and PAM chloride at 10 LD 50 VX. Likewise, a 20% higher level of GSH was found in NAC treated group at 1x LD 50 dose in brain. Cell cycle analysis and histopathological results showed that NAC prevents VX induced damage.

CONCLUSION: it was found that use of antioxidant agent NAC along with standard atropine-oxime treatment is helpful in reducing the cholinergic and oxidative stress mediated toxicity induced by VX.}, } @article {pmid39830885, year = {2025}, author = {Abd El-Khalek, SH and Amin, SA and El-Ebiary, AA and Elfeky, A and Kandeel, F}, title = {The potential role of N-acetylcysteine as an adjuvant therapy in acute aluminum phosphide poisoning: a randomized clinical trial.}, journal = {Toxicology research}, volume = {14}, number = {1}, pages = {tfae210}, doi = {10.1093/toxres/tfae210}, pmid = {39830885}, issn = {2045-452X}, abstract = {OBJECTIVE: Aluminum phosphide (AP) intoxication is a life-threatening emergency with no available effective antidote. This study evaluated the efficacy and safety of N-acetylcysteine (NAC) infusion in cases of acute AP poisoning.

METHODS: This randomized, single-blinded, parallel-group, controlled, clinical trial enrolled 96 patients with acute AP poisoning. The patients were allocated to two groups and received either conventional treatment (control group) or conventional treatment plus NAC infusion (NAC group). The patients were subjected to full clinical evaluation, routine laboratory investigations, silver nitrate test, and evaluation of the oxidative markers, malondialdehyde (MDA) and total antioxidant capacity (TAC), at admission and after 24 h treatment. The primary outcome was mortality, and the secondary outcomes were the arterial blood pressure, the length of hospital stay, and the need for intubation or mechanical ventilation.

RESULTS: Compared to the control group, the NAC group showed significantly lower MDA (median [interquartile range (IQR)]: 4.6 [1.9-10.6] vs. 6.8 [3.5-17.4] nmol/mL, P = 0.014) and higher TAC levels (median [IQR]: 0.7 [0.6-0.7] vs. 0.6 [0.6-06] mM/L, P < 0.001). The mortality rate and the need for mechanical ventilation were comparable in both groups (P = 0.601 and 0.505, respectively). However, the NAC group showed significant improvements of both systolic and diastolic blood pressure values (both P = 0.030). The duration of hospitalization was significantly shorter in the NAC group (P = 0.017). No adverse events were reported in patients who received NAC infusion.

CONCLUSION: In patients with acute AP poisoning, the use of NAC mitigates oxidative stress and partially enhances clinical manifestations without inducing noticeable adverse effects.}, } @article {pmid39825811, year = {2024}, author = {Linares-Ramírez, JD and Córdoba, AC and Calderón-Franco, CH and Aponte-Martín, DM and Dávila, F and Sabbagh, LC}, title = {Premedication in upper gastrointestinal endoscopy to improve mucosal visualization. A systematic review.}, journal = {Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru}, volume = {44}, number = {4}, pages = {346-353}, pmid = {39825811}, issn = {1609-722X}, mesh = {Humans ; *Premedication ; *Endoscopy, Gastrointestinal/methods ; Expectorants/therapeutic use ; Simethicone/therapeutic use/administration & dosage ; Antifoaming Agents/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: This review aims to evaluate the efficacy and safety of premedication comprising mucolytics and/or defoaming agents to improve the quality of visualization during elective upper digestive endoscopy (elective upper GI endoscopy) procedure.

MATERIALS AND METHODS: A systematic review of the literature contained in electronic databases (Medline/Pubmed, Embase, and Lilacs) was performed to identify randomized controlled trials and systematic reviews that assessed patients undergoing upper gastrointestinal endoscopy (elective upper GI Endoscopy) under sedation, after being premedicated with mucolytics and/or defoaming agents for mucous clearance. A meta-analysis was conducted to determine the relative efficacy and safety profile of such premedication.

RESULTS: In patients undergoing an elective procedure, premedication with defoaming and/or mucolytic agents improved the visibility score of the gastric antrum during upper GI endoscopy. The use of combined agents such as simethicone vs. water and N-acetyl cysteine (NAC) vs. water showed significant differences in favor of the active substance; however, no significant differences were found between the use of simethicone alone vs. simethicone + NAC. The use of pronase and dimethylpolysiloxane, among others, produced no significant difference (additive effect) in the visualization score. This is associated with the limited number of studies that performed similar comparisons and the heterogeneity of the outcomes. No major adverse effects were reported in the studies that were included regarding safety outcomes (i.e., volume of fluids required for clearance, risk of bronchoaspiration, and disinfection of equipment).

CONCLUSIONS: The results of this review evidence that premedication with simethicone (a drug registered in Colombia for use against functional gastrointestinal disorders; ATC group A03A) is safe and effective for improving the quality of visualization during elective upper GI endoscopy procedures. However, no significant differences were observed in the visualization quality with the use or addition of other agents. The use simethicone should be set as off-label use and should be implemented at the prescriber's discretion. The use of simethicone as a premedication is recommended to improve the endoscopic visualization score in elective procedures.}, } @article {pmid39825593, year = {2025}, author = {Wang, J and Yang, Y and Ma, J and Li, P and Li, Y and Yang, C and Zhao, B and Zhao, Z and Ding, X and Chen, H and Huo, S and Yang, Y and Luo, W}, title = {Molecular Mechanism of N-Acetylcysteine Regulating Proliferation and Hormone Secretion of Granulosa Cells in Sheep.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {60}, number = {1}, pages = {e70006}, doi = {10.1111/rda.70006}, pmid = {39825593}, issn = {1439-0531}, support = {32460907//National Natural Science Foundation of China/ ; 20240036//Plateau Animal Disease Innovation Team/ ; 2022-2-44//Lanzhou Science and Technology Plan Project/ ; }, mesh = {Animals ; Female ; *Granulosa Cells/drug effects/metabolism ; *Cell Proliferation/drug effects ; *Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Sheep, Domestic ; Phosphatidylinositol 3-Kinases/metabolism ; Sheep ; Antioxidants/pharmacology/metabolism ; Progesterone/metabolism ; Cells, Cultured ; Signal Transduction/drug effects ; Estradiol/metabolism/pharmacology ; }, abstract = {Granulosa cells (GCs) are pivotal in the development of ovarian follicles, serving not only as supportive cells but also as the primary producers of steroid hormones. The proliferation of these cells and the synthesis of steroid hormones are crucial for follicular development and atresia. In our study, GCs were isolated using follicular fluid aspiration and subsequently identified through immunofluorescence. We investigated the impact of varying concentrations of N-acetylcysteine (NAC) at 50, 100, 500, and 1000 μmol/L on sheep GCs, focusing on antioxidant levels, proliferation, apoptosis, and steroid hormone secretion. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 was used to explore the molecular mechanism of NAC on GCs proliferation and steroid hormone secretion in sheep. Our findings indicate that all concentrations of NAC tested promoted GC proliferation and suppressed apoptosis in sheep GCs. Notably, 100 μmol/L NAC exhibited the most pronounced effect on GC proliferation after 48 h. The expression levels of CCND1, CDK4, and Bcl-2 were significantly elevated in all NAC concentration groups, whereas Bax expression was notably reduced. Furthermore, all NAC concentrations led to a significant reduction in reactive oxygen species (ROS) levels and an increase in the expression of CAT and SOD1. NAC also significantly enhanced the expression of CYP19A1 and 3β-HSD, as well as the secretion of estradiol (E2) and progesterone (P4) by GCs. In summary, NAC activates the PI3K/AKT signalling pathway, thereby promoting the proliferation of GCs and the secretion of E2 and P4 by sheep GCs in vitro.}, } @article {pmid39821896, year = {2025}, author = {Zarowin, DH and Buros Stein, A and Sheppard, SE and Treat, JR}, title = {A Retrospective Review of Oral N-Acetylcysteine for Habit-Driven Cutaneous Disorders.}, journal = {Pediatric dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/pde.15852}, pmid = {39821896}, issn = {1525-1470}, support = {ZIA-HD009003-01//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //Pediatric Dermatology Research Alliance/ ; }, abstract = {Oral N-acetylcysteine (NAC) has shown efficacy for debilitating habit-driven and neuropsychiatric disorders in small, mostly adult studies. We retrospectively evaluated the therapeutic use and safety of oral NAC in 93 children from the Children's Hospital of Philadelphia. This study supports the use of oral NAC for habit-driven skin, hair, and nail abnormalities in pediatric patients.}, } @article {pmid39817046, year = {2025}, author = {Shishodia, S and Rinnert, H and Balan, L and Jasniewski, J and Bruyère, S and Medjahdi, G and Gries, T and Schneider, R}, title = {Microwave-assisted synthesis of highly photoluminescent core/shell CuInZnSe/ZnS quantum dots as photovoltaic absorbers.}, journal = {Nanoscale advances}, volume = {}, number = {}, pages = {}, pmid = {39817046}, issn = {2516-0230}, abstract = {Water-dispersible core/shell CuInZnSe/ZnS (CIZSe/ZnS) quantum dots (QDs) were efficiently synthesized under microwave irradiation using N-acetylcysteine (NAC) and sodium citrate as capping agents. The photoluminescence (PL) emission of CIZSe/ZnS QDs can be tuned from 593 to 733 nm with varying the Zn : Cu molar ratio in the CIZSe core. CIZSe/ZnS QDs prepared with a Zn : Cu ratio of 0.5 exhibit the highest PL quantum yield (54%) and the longest PL lifetime (515 ns) originating from the recombination of donor-acceptor pairs. The potential of CIZSe/ZnS QDs as photoabsorbers in QD-sensitized solar cells was also evaluated. An adequate type-II band alignment is observed between TiO2 and CIZSe/ZnS QDs, indicating that photogenerated electrons in CIZSe/ZnS QDs could efficiently be injected into TiO2.}, } @article {pmid39815362, year = {2025}, author = {Jing, Q and Wu, Y and Li, Y and Zhou, C and Zhang, J and Xia, J and Li, K and Shen, Y and Yao, H and Tong, X and Du, J and Yu, L and Wang, Y}, title = {Bi-targeting of thioredoxin 1 and telomerase by thiotert promotes cell death of myelodysplastic syndromes and lymphoma.}, journal = {Biology direct}, volume = {20}, number = {1}, pages = {7}, pmid = {39815362}, issn = {1745-6150}, support = {ZRY2020B001//Outstanding Youth Foundation of Zhejiang Provincial People's Hospital/ ; LBY23H080004, LBY23H080005//Zhejiang Province Public Welfare Technology Application Research Project/ ; 82102938//National Natural Science Foundation of China/ ; }, mesh = {*Thioredoxins/metabolism/genetics ; *Telomerase/metabolism/genetics ; *Myelodysplastic Syndromes/drug therapy/metabolism ; Humans ; Mice ; Animals ; *Lymphoma/drug therapy/metabolism ; Cell Line, Tumor ; Cell Death/drug effects ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; }, abstract = {Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment.}, } @article {pmid39813214, year = {2025}, author = {Fatima, S}, title = {N-acetyl-L-cysteine and lauric acid; effective antioxidant and antimicrobial feed additives for juvenile Pacific white shrimp (Litopenaeus vannamei) cultured at high stocking density.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0315819}, doi = {10.1371/journal.pone.0315819}, pmid = {39813214}, issn = {1932-6203}, mesh = {Animals ; *Penaeidae/drug effects/immunology/growth & development ; *Lauric Acids/pharmacology ; *Antioxidants/metabolism/pharmacology ; *Acetylcysteine/pharmacology ; *Animal Feed/analysis ; Dietary Supplements ; Anti-Infective Agents/pharmacology ; Aquaculture/methods ; }, abstract = {Present study aimed at improving the immune and antioxidant response of Pacific white shrimp (Litopenaeus vannamei) cultured at high stocking density fed with 0.2% supplementation of lauric acid (LA) and N-acetyl-L-cysteine (NAC). Shrimp (initial average weight = 0.65 g; n = 270) were grown at low stocking density (LSD) (n = 10/0.80 ft3 per replicate) and high stocking density (HSD) (n = 20/0.80 ft3 per replicate). They were randomly distributed into five groups (T1: negative control at LSD, T2: positive control at HSD, T3: at HSD and fed with LA supplement diet, T4: at HSD and fed with NAC supplemented diet, T5: at HSD and fed with combination of LA and NAC). All these five treatments were studied in triplicates and study continued for eight weeks. Better growth and higher levels of glucose, total protein, total hemocyte count and phagocytic index were observed in shrimp fed with NAC and LA supplemented diets. Observed survival rate and feed conversion ratio in all treatments was 75-89% and < 0.82, respectively. All parameters indicating stress were observed to be higher in T1 as compared to T2. Improved expression of superoxide dismutase and glutathione peroxidase and lower levels of malondialdehyde genes in T3, T4 and T5 showed that supplementation with these nutraceuticals can improve antioxidant response at high stocking density. A parallel increase was observed in the profiles of prophenoloxidase and lysozyme, underscoring the immune-boosting effects of both NAC and LA. This finding was further supported by higher expression of innate immune signaling pathway-related gene, toll like receptor-2 in T3, T4 and T5. In conclusion, NAC and LA, can possibly improve the resistance of white pacific shrimp against oxidative stress and pathogens when cultured in intensive production system.}, } @article {pmid39810570, year = {2025}, author = {Baraldi, F and Bigoni, T and Foschino Barbaro, MP and Micheletto, C and Scioscia, G and Vatrella, A and Papi, A}, title = {Mucus production and chronic obstructive pulmonary disease, a possible treatment target: zooming in on N-acetylcysteine.}, journal = {Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace}, volume = {}, number = {}, pages = {}, doi = {10.4081/monaldi.2025.3159}, pmid = {39810570}, issn = {2532-5264}, abstract = {Mucus hypersecretion is a trait of chronic obstructive pulmonary disease (COPD) associated with poorer outcomes. As it may be present before airway obstruction, its early treatment may have a preventive role. This narrative review of the literature presents the role of mucus dysfunction in COPD, its pathophysiology, and the rationale for the use of N-acetylcysteine (NAC). NAC can modify mucus rheology, improving clearance and reducing damage induced MUC5AC expression. It exerts a direct and indirect (glutathione replenishment) antioxidant mechanism; it interferes with inflammatory molecular pathways, including inhibition of nuclear factor-kB activation in epithelial airway cells and reduction in the expression of cytokine tumor necrosis factor α, interleukin (IL)-6, and IL-10. Some clinical experiences suggest that the adjunctive use of NAC may reduce symptoms and improve outcomes for patients with COPD. In conclusion, NAC may be a candidate drug for the early treatment of subjects at risk of COPD development.}, } @article {pmid39809659, year = {2025}, author = {Finotti, M and Zanetto, A and Vitale, A and Rodriguez-Davalos, M and Burra, P and Cillo, U and D'Amico, F}, title = {N-Acetylcysteine and Liver Transplant. Advantages of its Administration in Multi-Organ Donors Especially During World-Economical-Crisis. Long-Term Sub-Group Analysis in a Randomized Study.}, journal = {Transplantation proceedings}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.transproceed.2024.11.038}, pmid = {39809659}, issn = {1873-2623}, abstract = {BACKGROUND: Liver transplantation (LT) is the main indication for the treatment of end-stage liver disease but have to face organ shortages. Using marginal donors is an option to increase the donor pool. Previous studies showed that the graft procured using N-acetylcysteine (NAC) provides a longer survival compared to perfusion with standard solutions, especially in marginal liver donors. We now evaluate the effect of NAC perfusion compared to control (no NAC protocol) at a 5-year follow-up, with a special focus on the overall survival (OS) and graft survival.

METHODS: Single-center, retrospective review of the OS and graft survival among NAC and control group, with a sub-stratification based on the LT indication.

RESULTS: 140 donors were enrolled: 69 in the NAC protocol and 71 in the control group. The 5-year OS was 84% in the NAC protocol compared to 63% in the control (P = .0045). In LT for HCC, the OS at 5 years was 80% and 55% in the study group and control group, respectively (P = .04), with no statistical difference in the RFS (P = .46). Furthermore, in cost analysis, the resources needed for the NAC protocol is negligible compared to the control group. Beneficial tendency of NAC protocol application has been seen in the other organs (lungs, hearts, pancreas, kidney and intestine) CONCLUSION: The application of NAC infusion in liver donors improves the overall survival of the recipient, especially in the HCC and HCV LT indications.}, } @article {pmid39802290, year = {2025}, author = {Tanadi, C and Pajala, FB and Supranoto, YTN and Tandarto, K and Stella, MM and Adiwinata, R and Simadibrata, P and Simadibrata, M}, title = {Simethicone with or without N-acetylcysteine as premedication in esophagogastroduodenoscopy: a systematic review and meta-analysis.}, journal = {Annals of gastroenterology}, volume = {38}, number = {1}, pages = {28-40}, pmid = {39802290}, issn = {1108-7471}, abstract = {BACKGROUND: The impairment of gastrointestinal mucosa visibility during esophagogastroduodenoscopy (EGD), due to the presence of foam and bubbles, may lead to reduced quality in the EGD results. The combination of simethicone, a defoaming agent, along with N-acetylcysteine (NAC), which has mucolytic properties, has been proposed to improve the visibility of the mucosa. This study aimed to evaluate the effectiveness of pre-procedural administration of simethicone and N-acetylcysteine in improving mucosal visibility, procedure time and mucosal cleansing volume needed during EGD.

METHODS: We conducted a comprehensive literature search from inception to November 23, 2023, in PubMed, CENTRAL, ProQuest, SAGE, and JSTOR. We included randomized clinical trials that investigated the effects of simethicone with or without NAC as premedication in EGD. For the quantitative analysis, standardized mean difference (SMD) was used to assess continuous outcomes and risk ratio for dichotomous outcomes. The Cochrane risk of bias 2 tool was used to evaluate the risk of bias.

RESULTS: This meta-analysis comprised a total of 20 studies and found that simethicone with or without NAC improved mucosal visibility compared with control (SMD -1.27, 95% confidence interval [CI] -1.74 to -0.81, P<0.001). The combination of simethicone and NAC was significantly better than simethicone alone (SMD -0.68, 95%CI -1.08 to -0.28, P=0.001). Simethicone with or without NAC also shortened the procedure time compared to control (MD -1.40, 95%CI -2.67 to -0.12, P=0.03). The risk of bias was low with a moderate grade of certainty.

CONCLUSION: The administration of simethicone with or without NAC may improve EGD quality.}, } @article {pmid39801742, year = {2025}, author = {Ford, JW and VanNatta, JM and Mondal, D and Lin, CM and Deng, Y and Bai, R and Hamel, E and Trawick, ML and Pinney, KG}, title = {Drug-Linker Constructs Bearing Unique Dual-Mechanism Tubulin Binding Payloads Tethered through Cleavable and Non-Cleavable Linkers.}, journal = {Tetrahedron}, volume = {171}, number = {}, pages = {}, pmid = {39801742}, issn = {0040-4020}, abstract = {Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels. These payloads have been incorporated into a variety of drug-linker constructs utilizing the clinically relevant cathepsin B cleavable Val-Cit dipeptide linker, employed within several FDA approved ADCs, along with other non-cleavable constructs. Various synthetic strategies were evaluated to prepare these drug-linker constructs. Aniline-based payloads were incorporated utilizing the Val-Cit dipeptide linker similar to FDA approved ADCs such as Adcetris[®] (brentuximab vedotin). An additional self-immolative group, previously described in the literature for related model systems, was employed to tether the phenolic payloads. A variety of drug-linker constructs (with each bearing a unique dual mechanism payload) were synthesized and evaluated biologically for their enzyme-mediated release of payload and inhibition of tubulin polymerization. Following deactivation of the highly electrophilic maleimido terminus as its corresponding N-acetyl cysteine (NAC) derivative, the most promising construct (NAC-4) demonstrated approximately 90% release of an aniline-functionalized payload (1) upon treatment with cathepsins B or L over 90 minutes. Building on these promising results, future studies will examine the conjugation of drug-linker construct 4 to selected antibodies and engineered proteins and evaluate the biological activity of the resultant antibody-drug conjugates (ADCs).}, } @article {pmid39790357, year = {2025}, author = {Mohammed, SS and Zaaqoq, A and Talaat, S and Abdelkader, SI}, title = {A randomized, clinical trial of intravenous N-acetylcysteine as an antioxidant therapy in acute organophosphorus pesticide poisoning.}, journal = {Toxicology research}, volume = {14}, number = {1}, pages = {tfae234}, pmid = {39790357}, issn = {2045-452X}, abstract = {The incidence of acute organophosphate (OP) poisoning has steadily increased in developing countries. Many studies showed that oxidative stress could have a significant role in its mechanism. The current study aimed to evaluate the role of N acetylcysteine (NAC) as an antioxidant in acute OP poisoned. A randomized, controlled, parallel-group trial was conducted in the period from the beginning of January 2022 to the end of June 2022. The study included 56 acute OP poisoned patients admitted to the intensive care unit (ICU) at the Poison Control Center of Ain Shams University Hospitals within 6 h after the exposure. The patients were randomly allocated in two equal groups; group (A): received the standard treatment plus NAC in a total dose of 300 mg/kg administered intravenously (IV) while group (B) received the standard treatment. Then both groups were compared as regards clinical parameters, laboratory investigations, ECG, and outcomes. Baseline parameters were comparable between the groups. However, NAC treatment significantly elevated concentrations of both serum catalase and glutathione peroxidase levels at 24 h, it did not significantly affect the total dose of atropine required, duration of atropine and oximes treatment or need for mechanical ventilation, and length of hospital stay. Mortality was lower in the NAC group (2 out of 28) than the standard treatment-only group (5 out of 28) but the difference was not statistically significant. This trial found that NAC improved antioxidant enzyme levels including serum CAT and GPX but did not affect clinically relevant outcomes.}, } @article {pmid39783394, year = {2024}, author = {Kang, Y and Chen, JJ and Mah, E and Survilla, K and Vieira, D and Herrmann, N and Gallagher, D and Andreazza, AC and Black, SE and Oh, PI and Swardfager, W and Graham, SJ and Ramirez, J and Marzolini, S and Lanctôt, KL}, title = {Developing Topics.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {20 Suppl 8}, number = {}, pages = {e095550}, doi = {10.1002/alz.095550}, pmid = {39783394}, issn = {1552-5279}, mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction ; *Oxidative Stress/physiology/drug effects ; Double-Blind Method ; Neuropsychological Tests/statistics & numerical data ; Acetylcysteine/therapeutic use ; Middle Aged ; Biomarkers/blood ; Antioxidants ; Aldehydes/blood ; Dinoprost/analogs & derivatives/blood ; Dementia, Vascular/blood ; }, abstract = {BACKGROUND: Oxidative stress (OS) has been a target of interest for vascular dementia, given its implications in pathogenesis. OS may be important in prodromal stage, such as vascular mild cognitive impairment (vMCI), and examining OS markers in vMCI may help better understand biological processes in the onset of cognitive impairment. Our study compared OS levels in vMCI vs controls, and explored whether OS markers predicted the response to antioxidant treatments in vMCI.

METHOD: Cardiac rehabilitation patients with cardiovascular risk factors (CVRFs) were recruited as vMCI (1SD below norms in executive function (EF), memory, processing speed or working memory) or cognitively-healthy controls. vMCI patients were classified as probable vMCI if they had neuroimaging evidence of vascular pathology. vMCI patients were randomized to 2400mg N-acetylcysteine (NAC) or placebo in a 24-week, double-blind trial. Serum 8-isoprostane (8ISO), 4-hydroxynonenal (4HNE) and lipid hydroperoxides (LPH) collection and cognitive assessments were done at three time points. ANCOVA models adjusting for age, sex and CVRFs compared OS markers between groups at baseline. Linear mixed-effects models were used for longitudinal analyses.

RESULT: LPH levels were significantly lower in vMCI (n = 60) compared to controls (n = 16) (0.86±0.45 vs 1.18±0.31, F(1,62) = 7.0, p = 0.011). 4HNE were significantly higher in vMCI compared to controls (1.03±0.06 vs 0.99±0.04, F(1,70) = 6.6, p = 0.012). vMCI patients had significantly higher 4HNE/LPH (0.17±0.44 vs -0.18±0.29, F(1,62) = 9.3, p = 0.003) and (8ISO+4HNE)/LPH ratio (0.41±0.45 vs 0.13±0.38, F(1,62) = 5.9, p = 0.018) compared to controls. In probable vMCI group (n = 25), there was significant decreases in 4HNE/LPH (β = -0.68, SE = 0.27, p = 0.02) and (8ISO+4HNE)/LPH ratio (β = -0.65, SE = 0.28, p = 0.028) after NAC treatment. A significant time by baseline 8ISO effect on EF in the NAC group was observed (β = 0.78, SE = 0.26, p<0.01) after adjusting for age, sex and education.

CONCLUSION: This study showed that the ratios of late- to early-phase lipid peroxidation markers were significantly elevated in vMCI groups compared to controls. This aligns with existing literature that altered lipid peroxidation may be implicated in vMCI. Antioxidant treatments decreased OS in probable vMCI groups, and higher baseline 8ISO was associated with greater improvement in EF in the NAC group, suggesting that probable vMCI patients with high OS may be appropriately targeted for antioxidant treatments.}, } @article {pmid39780844, year = {2024}, author = {Nemetova, U and Önem, AN and Er, A and Çelik, S and Özel, AE and Akyüz, S and Özyürek, M and Şahinler Ayla, S}, title = {A fast and responsive turn-on fluorescent probe based on a quinone conjugated alkoxy derivative for biothiols and a cellular imaging study.}, journal = {Turkish journal of chemistry}, volume = {48}, number = {6}, pages = {830-842}, pmid = {39780844}, issn = {1300-0527}, abstract = {The detection of intracellular biothiols (cysteine, N-acetyl cysteine, and glutathione) with high selectivity and sensitivity is important to reveal biological functions. In this study, a 2-(2-methoxy-4-methylphenoxy)-3-chloro-5,8-dihydroxynaphthalene-1,4-dione (DDN-O) compound (3) was newly synthesized and used as a fluorogenic probe (detector molecule) in the fluorometric method for the rapid, highly selective, and sensitive determination of biothiols. The intensity values (λex = 260 nm, λem = 620 nm) of the product were measured by adding biothiols to the reaction medium at varying concentrations and the glutathione equivalent thiol content values of each biothiol were calculated. Using compound 3, glutathione as the reference biothiol was detected in the linear concentration range of 10-70 μM and the LOD value was found to be 0.11 μM. Biothiol detection with structurally simple compound 3 was performed at the cellular level within 1 min and the probe was also successfully used in bioimaging with low cytotoxicity. It was concluded that this probe can serve as an alternative to existing fluorescence-based biothiol probes with applications in rapid biothiol detection at the cellular level for biological functions. To evaluate the molecular structure of 3, conformational analysis was performed using the PM3 semiempirical method. The most stable obtained molecular geometry was then optimized at the DFT/wb97xd/6-311++G(d,p) level of theory. Frontier molecular orbitals (HOMO and LUMO) and molecular electrostatic potential map analyses were performed for the optimized structure. Molecular docking studies demonstrated the interactions of 3 with HAS (1AO6) and FhGST (2FHE) target proteins.}, } @article {pmid39700869, year = {2025}, author = {Poudel, SB and Kim, MH and Bhattarai, G and So, HS and Kook, SH and Lee, JC}, title = {n-acetyl-l-cysteine stimulates bone healing by recovering the age-associated degenerative complications relative to osteoblastic Wntless ablation.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {182}, number = {}, pages = {117761}, doi = {10.1016/j.biopha.2024.117761}, pmid = {39700869}, issn = {1950-6007}, mesh = {Animals ; *Acetylcysteine/pharmacology ; *Osteoblasts/drug effects/metabolism ; Mice ; *Oxidative Stress/drug effects ; Osteogenesis/drug effects ; Bone Regeneration/drug effects ; Wnt Signaling Pathway/drug effects ; Aging ; Mice, Inbred C57BL ; Male ; Antioxidants/pharmacology ; Receptors, G-Protein-Coupled ; }, abstract = {Dysregulated Wnt signaling causes age-related characteristics such as oxidative stress, stem cell senescence, and abnormal bone homeostasis. Here we explored whether supplemental n-acetyl-l-cysteine (NAC) recovers the age-associated complications relative to osteoblastic Wntless (Wls) ablation and examined the possible mechanisms therein. For this work, we administered Col2.3-Cre;Wls[fl/fl] mutant and littermate control (Wls[fl/fl]) mice (14 weeks of age) with NAC (40 mM)-supplemented or NAC-free water for four weeks. A proportion of these mice received non-critical-sized femoral defects at 16 weeks of age. Blood, bone, and bone marrow (BM) samples were collected and adjusted for in vivo, ex vivo, and in vitro analyses. Osteoblastic Wls deletion delayed bone mass accrual and the healing of bone defects, stimulated osteoclastic activation and inflammatory factor expression, and decreased antioxidant enzyme activity in the BM. Osteoblastic Wls deletion also promoted oxidative stress, apoptosis, and senescence in BM stromal cells (BMSCs) and decreased BMSC' multipotencies. Supplementation of Wls[fl/fl] mice with NAC enhanced bone mass accrual and regenerative bone healing via a Wnt signal-associated osteogenic activation. However, supplemental NAC induced new bone formation in the mutant mice by inhibiting the age-related complications of BM/BMSCs, as well as by restoring endogenous antioxidant system without any alterations in Wnt ligand secretion, hematopoiesis, and expression of osteogenic and growth factors. This study indicates that supplemental NAC protects mice against Wnt deficiency-mediated and age-associated degenerative complications. Overall, this study highlights the therapeutic potency of NAC for restoring the antioxidant system, stem cell function, and regenerative bone homeostasis in osteoblastic Wls-dispensable manner.}, } @article {pmid39779606, year = {2025}, author = {Li, P and Tang, W and Wen, H and Zhou, S and Cao, H}, title = {Senkyunolide I prevent chondrocytes from oxidative stress through Nrf2/HO-1 signaling pathway.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39779606}, issn = {1432-1912}, support = {2042023kf0049//the Fundamental Research Funds for the Central Universities/ ; }, abstract = {Osteoarthritis (OA) is a degenerative musculoskeletal disease, featured by the destruction of articular cartilage. Oxidative stress, one of the drivers of the extracellular matrix degradation in cartilage, plays a vital role in OA pathogenesis. Senkyunolide I (SEI) is a natural compound with a prominent anti-oxidative stress property against multiple diseases. However, the protective effect of SEI on OA has not been explored. Here, we aimed to elucidate the effect of SEI on OA in vitro. Our results showed that SEI suppressed the expression of senescence-related markers such as P16 and P21 in IL-1β-induced chondrocytes. Besides, SEI alleviated IL-1β-induced the degradation of extracellular matrix (ECM) by suppressing the matrix proteinase like MMP13 and ATAMDS5 while promoting matrix synthesis regulated biomarkers like COL2A1 and ACAN in chondrocytes. Mechanically, the mitochondrial dysfunction and overproduction of intracellular reactive oxygen species (ROS) in chondrocytes induced by IL-1β were reversed by SEI. Additionally, the ROS inhibitor N-acetylcysteine (NAC) synergistically enhanced the biological effect of SEI in IL-1β-induced chondrocytes. Moreover, it was also found that the expression of Nrf2 and HO-1 was increased by the treatment of SEI in IL-1β-stimulated chondrocytes, while the Nrf2 inhibitor ML385 reversed the protective effect of SEI on OA chondrocytes. In conclusion, SEI could inhibit senescence, the degradation of ECM, and the production of ROS through activating Nrf2/ HO-1 signaling pathway, which provide a novel candidate for OA treatment.}, } @article {pmid39775338, year = {2025}, author = {Hamed, S and Emara, M and Tohidifar, P and Rao, CV}, title = {N-Acetyl cysteine exhibits antimicrobial and anti-virulence activity against Salmonella enterica.}, journal = {PloS one}, volume = {20}, number = {1}, pages = {e0313508}, doi = {10.1371/journal.pone.0313508}, pmid = {39775338}, issn = {1932-6203}, mesh = {*Salmonella enterica/drug effects/pathogenicity ; *Acetylcysteine/pharmacology ; *Microbial Sensitivity Tests ; Virulence/drug effects ; *Anti-Bacterial Agents/pharmacology ; Animals ; Mice ; Salmonella Infections/microbiology/drug therapy ; Humans ; Drug Resistance, Multiple, Bacterial/drug effects ; }, abstract = {Salmonella enterica is a common foodborne pathogen that causes intestinal illness varying from mild gastroenteritis to life-threatening systemic infections. The frequency of outbreaks due to multidrug-resistant Salmonella has been increased in the past few years with increasing numbers of annual deaths. Therefore, new strategies to control the spread of antimicrobial resistance are required. In this work, we found that N-acetyl cysteine (NAC) inhibits S. enterica at MIC of 3 mg ml-1 and synergistically activates the bactericidal activities of common antibiotics from three-fold for ampicillin and apramycin up to1000-fold for gentamycin. In addition, NAC inhibits the expression of virulence genes at sub-inhibitory concentrations in a dose-dependent manner. The whole-genome sequencing revealed that continuous exposure of S. enterica to NAC leads to the development of resistance; these resistant strains are attenuated for virulence. These results suggest that NAC may be a promising adjuvant to antibiotics for treating S. enterica in combination with other antibiotics.}, } @article {pmid39773189, year = {2025}, author = {Wang, K and Qu, H and Hu, R and Lassègue, B and Eaton, DC and Song, C and Mu, J and Griendling, KK and Hernandes, MS}, title = {Polymerase delta-interacting protein 2 mediates brain vascular permeability by regulating ROS-mediated ZO-1 phosphorylation and localization at the interendothelial border.}, journal = {Cell communication and signaling : CCS}, volume = {23}, number = {1}, pages = {9}, pmid = {39773189}, issn = {1478-811X}, mesh = {Animals ; Phosphorylation ; *Zonula Occludens-1 Protein/metabolism ; *Reactive Oxygen Species/metabolism ; *Capillary Permeability ; Mice ; Humans ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Mice, Knockout ; Nuclear Proteins/metabolism/genetics ; Brain Ischemia/metabolism ; Endothelial Cells/metabolism ; Tight Junctions/metabolism ; }, abstract = {BACKGROUND: Polymerase delta-interacting protein 2 (Poldip2) is a novel regulator of vascular permeability that has been shown to be involved in aggravating blood-brain barrier (BBB) disruption following stroke; however, the underlying mechanisms are unknown. While endothelial tight junctions (TJ) are critical mediators of BBB permeability, the effect of Poldip2 on TJ function has not been elucidated yet. Here, we aim to define the mechanism by which Poldip2 mediates BBB disruption, specifically focusing on phosphorylation and stabilization of the TJ integral protein ZO-1.

METHODS AND RESULTS: Cerebral ischemia was induced in endothelial-specific Poldip2 knockout mice and controls. Cerebral vascular permeability was assessed by Evans blue dye extravasation. Endothelial-specific Poldip2 deletion abolished Evans blue dye extravasation after ischemia induction. In vitro permeability assays demonstrated that Poldip2 knockdown suppressed TNF-α-induced endothelial cell (EC) permeability. Immunofluorescence staining showed that Poldip2 depletion prevented TNF-α-induced ZO-1 disruption at interendothelial junctions. Conversely, Poldip2 overexpression increased endothelial permeability, loss of ZO-1 localization at cell-cell junctions and enhanced reactive oxygen species (ROS) production. Treatment with the antioxidant N-acetyl cysteine (NAC) reduced Poldip2-induced ZO-1 disruption at inter interendothelial junctions. Immunoprecipitation studies demonstrated Poldip2 overexpression induced tyrosine phosphorylation of ZO-1, which was prevented by treatment with NAC or MitoTEMPO, a mitochondrial ROS scavenger.

CONCLUSIONS: These data reveal a novel mitochondrial ROS-driven mechanism by which Poldip2 induces ZO-1 tyrosine phosphorylation and promotes EC permeability following cerebral ischemia.}, } @article {pmid39772929, year = {2025}, author = {La Mensa, A and Buscetta, M and Woldhuis, RR and Cimino, M and Giuffrè, MR and Cristaldi, M and Dino, P and Fiore, L and Fucarino, A and Lo Iacono, G and Bertani, A and Brandsma, CA and Bucchieri, F and Cipollina, C}, title = {Caspase Inhibition Restores Collagen I α1 and Fibronectin Release in Cigarette Smoke Extract-Exposed Human Lung Fibroblasts.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {}, number = {}, pages = {}, doi = {10.1152/ajplung.00214.2024}, pmid = {39772929}, issn = {1522-1504}, support = {G78I18000930007//Sicilian Region/ ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by obstructed airflow, airway remodeling, and inflammation, with cigarette smoke (CS) exposure being the main risk factor. While CS extract (CSE) has been shown to activate caspases in various cell types, the role of caspases in human lung fibroblasts (hLFs), in COPD remains poorly understood. Recent studies have linked caspases to extracellular matrix (ECM) remodeling in skin and kidney fibrosis. Caspase activation can be triggered by oxidative stress, with active caspase-3 executing the pore-forming protein gasdermin E (GSDME) in the cleaved N-terminal form GSDME-NT. We investigated whether CSE activates caspases and GSDME in hLFs, and their role in ECM remodeling. MRC-5 lung fibroblasts were treated with CSE with or without the antioxidant N-acetyl cysteine (NAC), and the caspase-8 inhibitor z-IETD-fmk. We measured the effects on caspase-1-8-3/7 activation, GSDME cleavage, ECM remodeling (procollagen Iα1, COLIα1, and fibronectin, FN), and mitochondrial superoxide (mSOX) generation. Key findings were validated in patient-derived hLFs (phLFs). Our results showed that CSE induced caspase-1-8-3/7 activation, mSOX generation, and decreased COLIα1 and FN levels in MRC-5. CSE caused caspase-8-dependent activation of caspase-3, leading to the GSDME cleavage. Treatment with NAC inhibited mSOX and caspase activation. Inhibition of caspase-8 and mSOX restored FN and COLIα1 levels. In phLFs, we confirmed caspase-1 and -8 activation, mSOX increase, COLIα1/FN decrease, and the effects of NAC. Our findings highlight the role of the axis caspase-8-3/7-GSDME and mSOX in regulating ECM protein, suggesting that these pathways may contribute to remodeling in COPD.}, } @article {pmid39770941, year = {2024}, author = {Kim, TW and Ko, SG}, title = {Anti-Inflammatory and Anticancer Effects of Kaurenoic Acid in Overcoming Radioresistance in Breast Cancer Radiotherapy.}, journal = {Nutrients}, volume = {16}, number = {24}, pages = {}, doi = {10.3390/nu16244320}, pmid = {39770941}, issn = {2072-6643}, support = {2018R1D1A1B07048556//NRF/ ; 2020R1A5A2019413//NRF/ ; }, mesh = {Animals ; *Breast Neoplasms/radiotherapy/drug therapy/pathology ; Humans ; Female ; Mice ; *Anti-Inflammatory Agents/pharmacology ; *Diterpenes/pharmacology ; *PPAR gamma/metabolism ; *Apoptosis/drug effects ; Radiation Tolerance/drug effects ; MCF-7 Cells ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Endoplasmic Reticulum Stress/drug effects/radiation effects ; Antineoplastic Agents/pharmacology ; Reactive Oxygen Species/metabolism ; Cytokines/metabolism ; Mice, Inbred BALB C ; }, abstract = {Background/Objectives: Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in mediating anti-inflammatory and anticancer effects in the tumor microenvironment. Kaurenoic acid (KA), a diterpene compound isolated from Sphagneticola trilobata (L.) Pruski, has been demonstrated to exert anti-inflammatory, anticancer, and antihuman immunodeficiency virus effects. Methods: In this study, we identified KA as a novel activator of PPARγ with potent anti-inflammatory and antitumor effects both in vitro and in vivo. Given the potential of PPARγ regulators in overcoming radioresistance and chemoresistance in cancer therapies, we hypothesized that KA may enhance the efficacy of breast cancer radiotherapy. Results: In a lipopolysaccharide (LPS)-induced mouse inflammation model, KA treatment reduced the levels of pro-inflammatory cytokines, including COX-2, IL-6, IL-1β, and TNFα. In a xenograft mouse mode of breast cancer, KA treatment inhibited tumor growth. Specifically, KA treatment enhanced caspase-3 activity and cytotoxicity against MDA-MB-231 and MCF-7 breast cancer cells. When KA was co-treated with a caspase inhibitor, Z-VAD-FMK, caspase-dependent apoptosis was suppressed in these cells. KA was found to induce the generation of cytosolic calcium ions (Ca[2+]) and reactive oxygen species (ROS), triggering endoplasmic reticulum (ER) stress via the PERK-ATF4-CHOP axis. Hence, the ER stressor thapsigargin (TG) synergized with KA treatment to enhance apoptosis in these cells, while the loss of the PERK or CHOP function inhibited this phenomenon. KA treatment was shown to induce oxidative stress via the NADPH oxidase 4 (NOX4) and stimulate ROS production. Specifically, NOX4 knockdown (KD) and antioxidant treatment (N-acetyl cysteine or diphenyleneiodonium) suppressed such ER stress-mediated apoptosis by inhibiting KA-enhanced caspase-3 activity, cytotoxicity, and intracellular ROS production in the treated cells. In radioresistant MDA-MB-231R and MCF-7R cells, KA combined with 2 Gy radiation overcame radioresistance by upregulating PPARγ and modulating epithelial-mesenchymal transition (EMT) markers, such as E-cadherin, N-cadherin, and vimentin. In PPARγ KD MDA-MB-231R and MCF-7R cells, this phenomenon was inhibited due to reduced PPARγ and NOX4 expression. Conclusions: In conclusion, these findings demonstrated KA as a novel PPARγ regulator with promising potential to enhance the efficacy of breast cancer radiotherapy.}, } @article {pmid39770034, year = {2024}, author = {Karwowski, BT}, title = {A Comparison of the Electronic Properties of Selected Antioxidants Vitamin C, Uric Acid, NAC and Melatonin with Guanosine Derivatives: A Theoretical Study.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {24}, pages = {}, doi = {10.3390/molecules29245944}, pmid = {39770034}, issn = {1420-3049}, support = {503/3-045-02/503-31-002//Medical University of Lodz/ ; }, mesh = {*Melatonin/chemistry/pharmacology ; *Antioxidants/chemistry/pharmacology ; *Ascorbic Acid/chemistry/pharmacology ; *Uric Acid/chemistry ; *Acetylcysteine/chemistry/pharmacology ; *Guanosine/chemistry ; Electrons ; Humans ; Oxidation-Reduction ; Models, Theoretical ; }, abstract = {Each cell in the human body is continually exposed to harmful external and internal factors. During evolution, cells have developed various defence systems, divided into enzymatic and non-enzymatic types, to which low-weight molecule antioxidants belong. In this article, the ionisation potential and electron affinity, as well as global reactivity descriptors of Vitamin C, Melatonin, Uric Acids, and N-acetyl-L-cysteine, were theoretically investigated at the MP-2/aug-cc-pVTZ level of theory in the condensed (aqueous) phase. The vertical ionisation potential and electron affinity are discussed in terms of non-equilibrated and equilibrated solvent-solute interactions. Additionally, at the same theoretical level, the electronic properties of canonical and oxidised derivatives of guanine were analysed. The presented results indicate that the selected antioxidants for this study (Vitamin C, Uric Acid, NAC, and Melatonin) exhibit the highest adiabatic electron affinity, while guanine derivatives (Gua, [OXO]Gua, Guo, dGuo, [OXO]Guo, [OXO]dGuo) are more prone to adiabatic radical cation formation. A red-ox balance (redox homeostasis) is crucial for intracellular signalling pathways that are reactive oxygen and nitrogen species (RO/NS)-dependent. Should this gentle balance be disrupted, either by an overload or deficit of species, physiological consequences may result, which in turn lead to pathological outcomes. On the other hand, maintaining the stability of the above balance of antioxidants/radicals may result in the improved effectiveness and safety of anticancer radiotherapy/chemotherapy or combined therapies with a subsequent increase in a patient's quality of life.}, } @article {pmid39765760, year = {2024}, author = {Martin, V and Trus, M and Atlas, D}, title = {Thiol-Based Redox Molecules: Potential Antidotes for Acrylamide Toxicity.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {12}, pages = {}, doi = {10.3390/antiox13121431}, pmid = {39765760}, issn = {2076-3921}, support = {MYP G5852//North Atlantic Treaty Organization/ ; }, abstract = {Acrylamide (ACR) is a low-molecular weight, non-aromatic reagent, widely used in industry, such as in the manufacture of paper, textiles, plastics, cosmetics, and dyes. ACR is formed during the cooking of starchy food and its toxicity results mainly by conferring oxidative stress by elevating reactive oxygen species (ROS). To identify potential antidotes for ACR toxicity, we evaluated the efficacy of several thiol-based molecules known for ROS-scavenging, disulfide-reducing properties, and inhibition of oxidative stress-induced activation of the mitogen-activated protein kinases (MAPKs): the extracellular-signal-regulated-kinases (ERK1/2), p38-mitogen-activated-protein-kinases (p38[MAPK]), and c-Jun-N-terminal-kinases (JNKs). We established a reproducible assay testing N-acetylcysteine (NAC), AD4/NACA, and the N-and C-blocked tri- and tetra-thioredoxin-mimetic (TXM) peptides, in PC12 cells. Our results demonstrate that these compounds exhibited high efficacy in suppressing ACR-induced MAPK activation, either prior to or subsequent to ACR exposure. The inhibition by single cysteine (Cys) residue, NAC and AD4/NACA (NAC-amide), 2 Cys peptides TXM-CB30, AcDCys-Gly-DCysNH2, TXM-CB20, AcCys-Gly-CysNH2, SuperDopa (SD, Ac-CysL-Levodopa-CysNH2, TXM-CB13, AcCys-Met-Lys-CysNH2, and a 3-Cys peptide, TXM-CB16, AcCys-γGlu-Cys-CysNH2 was dose-dependent and potency displayed a direct correlation with the number of Cys residues. Cellular proteolysis of SD, which consists of levodopa flanked by two Cys, may suppress the manifestation of Parkinson's disease (PD)-like symptoms mediated by chronic ACR exposure not only through lowering oxidative stress but also by replenishing cellular levels of dopamine. Overall, these results could advance the clinical application of TXM peptides as potential treatments for acute and/or chronic exposure to ACR and show promise as antidotes for preventing ACR-triggered PD-like neurotoxic symptoms.}, } @article {pmid39760429, year = {2025}, author = {Li, X and Duan, Z and Zhao, Z and Zhang, X and Cheng, W and Guo, W and Wang, B}, title = {Mercury(II)-Triggered Targeted and NIR-II Fluorescence/Photoacoustic Imaging Probe for High-Sensitivity Early Diagnosis and Evaluating Drug against Acute Liver and Kidney Injury.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.4c06622}, pmid = {39760429}, issn = {1520-6882}, abstract = {Mercury ions (Hg[2+]) have been found to disrupt the body's antioxidant defense mechanisms, leading to oxidative stress and physiological dysfunction. Early diagnosis and real-time monitoring of Hg[2+] fluctuations in organ damage are crucial but limited due to the lack of noninvasive and deep tissue imaging probes. Herein, a Hg[2+]-triggered targeted and NIR-II fluorescence/photoacoustic (PA) dual-mode molecular probe (NHG-2) was developed for real-time monitoring Hg[2+] fluctuations in Hg[2+]-induced acute liver and kidney injury mice. NHG-2 was designed through rational adjustment of the conjugated ring structure and further screening processes, enabling it to sensitively recognize Hg[2+] and subsequently open mitochondrial targeting, producing NIR-II fluorescence/PA signals. This probe allowed for noninvasive NIR-II fluorescence/PA imaging for real-time monitoring of Hg[2+]-induced acute liver and kidney injury, demonstrating excellent detection sensitivity. Furthermore, NHG-2 can be utilized to evaluate the efficacy of N-acetylcysteine (NAC) in Hg[2+]-induced liver and kidney injury through dual signal indication. Mechanism studies suggested that NAC activated the antioxidant Akt/Nrf2 signaling pathway, reversed the changes of related biomarkers, and restored mitochondrial membrane potential. Thus, this study not only presents the first specific NIR-II fluorescence/PA dual-mode probe for Hg[2+] but also provides a potential tool for early diagnosis and treatment evaluation and potential pathogenesis study.}, } @article {pmid39756697, year = {2025}, author = {Mapamba, DA and Sabi, I and Lalashowi, J and Sauli, E and Buza, J and Olomi, W and Mtafya, B and Kibona, M and Bakhuli, A and Rachow, A and Velen, K and Hoelscher, M and Ntinginya, NE and Charalambous, S and Churchyard, G and Wallis, RS and , }, title = {N-acetylcysteine modulates markers of oxidation, inflammation and infection in tuberculosis.}, journal = {The Journal of infection}, volume = {}, number = {}, pages = {106379}, doi = {10.1016/j.jinf.2024.106379}, pmid = {39756697}, issn = {1532-2742}, abstract = {BACKGROUND: Half the global tuberculosis health burden is due to post-tuberculosis lung disease. Host-directed therapies have been proposed to reduce this burden. N-acetylcysteine (NAC) provides the conditionally essential amino acid cysteine required for synthesis of glutathione, an antioxidant thiol. We recently reported clinical outcomes of a trial of adjunctive NAC in patients with pulmonary tuberculosis, finding that NAC improved the secondary endpoint of recovery of lung function. Here we report the effects of NAC on biomarkers of oxidation, inflammation, and infection in that trial.

METHODS: 140 adults with moderate or far-advanced pulmonary tuberculosis were randomly assigned to standard tuberculosis treatment with or without NAC 1200mg twice daily for months 1-4. Sputum and blood samples were obtained at specified intervals to measure total glutathione, MTB-induced cytokines, haemoglobin, whole blood mycobactericidal activity (WBA), and sputum MTB burden.

RESULTS: NAC treatment rapidly increased total glutathione (P<.0001), but levels did not reach those of healthy volunteers (P<.001). NAC reduced MTB-induced TNF-α (P =.011) without affecting IL-10, and accelerated the recovery of hemoglobin in participants with low values on entry. NAC did not affect killing in ex vivo whole blood culture but did slow the clearance of MTB from sputum (P=0.003).

CONCLUSION: Adjunctive NAC showed antioxidant and anti-inflammatory effects consistent with the amelioration of immunopathology seen in preclinical models. Two biomarkers of antimicrobial activity showed discordant results; neither demonstrated the enhanced antimicrobial effects seen preclinically. The reduction of oxidative stress and inflammation by NAC may explain its effects on the recovery of lung function post-TB.}, } @article {pmid39753298, year = {2025}, author = {Sun, E and Torices, S and Osborne, OM and Toborek, M}, title = {Microvascular dysfunction, mitochondrial reprogramming, and inflammasome activation as critical regulators of ischemic stroke severity induced by chronic exposure to prescription opioids.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1523/JNEUROSCI.0614-24.2024}, pmid = {39753298}, issn = {1529-2401}, abstract = {The opioid epidemic endangers not only public health but also social and economic welfare. Growing clinical evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke and negatively impact post-stroke recovery. In addition, NLRP3 inflammasome activation has been related to several cerebrovascular diseases, including ischemic stroke. Interestingly, an increase in NLRP3 inflammasome activation has also been reported in chronic opioid exposure. Given the pivotal roles of the blood-brain barrier (BBB) and oxidative stress in ischemic stroke pathophysiology, this study focuses on the impact of chronic exposure to prescription opioids on the integrity of cerebrovascular microvasculature, endothelial mitochondrial homeostasis, and the outcomes of ischemic stroke in male wild type and NLRP3-deficient mice. Our results demonstrate that chronic opioid exposure can compromise the integrity of the BBB and elevate the generation of reactive oxygen species (ROS), resulting in endothelial mitochondrial dysfunction and apoptosis activation. We also provide evidence that opioid exposure enhances inflammasome activation, inflammatory responses, and increases the severity of an ischemic stroke. The antioxidant N-acetylcysteine (NAC) ameliorated these opioid-induced alterations and accelerated the post-stroke tissue restoration and functional recovery processes in opioid-exposed mice. Importantly, there was also a significant decrease in ischemic stroke damage in the NLRP3-deficient mice with chronic opioid exposure as compared to wild-type controls. These findings indicate that chronic exposure to prescription opioids impacts the outcome of ischemic stroke by damaging microvascular cerebral integrity through inflammasome activation and mitochondrial dysfunction.Significance Statement Misuse of opioids has become one of the most important public health problems. Growing evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke, and negatively impact post-stroke recovery. In the present study, we hypothesize that microvascular dysfunction can underlie the impact of prescription opioid on an ischemic stroke. Our novel results demonstrate that opioid exposure leads to mitochondrial dysfunction in the brain microvascular endothelium, compromised blood-brain barrier integrity, enhanced inflammatory responses, and more severe effects of an ischemic stroke. Importantly, the NLRP3 inflammasome-deficient mice or treatment with N-acetylcysteine attenuated these alterations and enhanced post-stroke tissue and functional recovery, providing valuable therapeutic options for people with opioid use disorder.}, } @article {pmid39752784, year = {2024}, author = {Lin, J and Zhang, T and Zhang, L}, title = {Arsenite-induced liver apoptosis via oxidative stress and the MAPK signaling pathway in marine medaka.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {279}, number = {}, pages = {107226}, doi = {10.1016/j.aquatox.2024.107226}, pmid = {39752784}, issn = {1879-1514}, abstract = {Arsenic (As) is widely recognized for its hazards to aquatic organisms; however, its toxicological impacts on apoptosis in marine fish remain inadequately explored. This study investigated the effects of in vivo dietary exposure to 50 or 500 mg/kg AsIII (as NaAsO2) over 28 days in marine medaka, alongside in vitro exposure to 50-750 μg/L AsIII for 48 h in a hepatic cell line derived from marine medaka, to elucidate the toxicity and underlying molecular mechanisms. In vivo, As significantly accumulated in liver tissue (1.79-fold compared to the control), causing hepatic lesions and increased apoptosis (4.85 ± 0.56 % and 9.29 ± 1.82 %, respectively). Gene expression analysis showed downregulation of bcl2l1 and upregulation of bax, caspase-3 and caspase-9, indicating mitochondrial pathway-mediated apoptosis. In vitro, As exposure induced hepatocyte morphological changes, reactive oxygen species (ROS) production, and apoptosis. Additionally, mapk1 and mapk3 (ERK pathway) were downregulated both in vivo and in vitro, while mapk14a (P38 pathway), mapk8b and mapk9 (JNK pathway) were upregulated exclusively in hepatocytes. Furthermore, n-acetyl cysteine (NAC) attenuated As-induced apoptosis and modulated the expression of MAPK signaling pathway genes, including mapk3 and mapk8b, suggesting that As-induced oxidative stress regulates apoptosis via the MAPK signaling pathway. In contrast, phenylbutyric acid (PBA) was ineffective in preventing apoptosis. Overall, these results demonstrate that As induces endogenous apoptosis through oxidative stress and the MAPK signaling pathway in marine medaka.}, } @article {pmid39748984, year = {2024}, author = {Shokoohi, M and Khaki, AA and Roshangar, L and Nasr Esfahani, MH and Soltani, GG and Alihemmati, A}, title = {The impact of N-acetylcysteine on hypoxia-induced testicular apoptosis in male rats: TUNEL and IHC findings.}, journal = {Heliyon}, volume = {10}, number = {22}, pages = {e40097}, pmid = {39748984}, issn = {2405-8440}, abstract = {The present study aimed to evaluate the impact of N-acetylcysteine (NAC) on testicular hypoxia caused by varicocele, focusing specifically on the regulation of genes related to apoptosis and oxidative stress in the testes of mature Wistar rats. Thirty-two rats were divided into four groups: Control (Sham), hypoxia, testicular hypoxia treated with NAC (Hypoxia + NAC), and healthy animals treated with NAC. After the 8-week treatment period, testicular histopathology and the levels of oxidative stress markers-superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA)-in serum were examined. The expression of Bax and Bcl-2 mRNA was analyzed using immunocytochemistry and RT-qPCR assays, while the apoptosis rate was determined using the TUNEL method. Histopathological evaluations showed that parameters such as Johnsen's score, epithelium width, and seminiferous tubule diameter indicated significant improvement in the Hypoxia + NAC group compared to the Hypoxia group. NAC administration resulted in elevated serum levels of GPx and SOD, accompanied by a reduction in MDA levels (p < 0.003). Furthermore, the study revealed that NAC decreased Bax expression and enhanced Bcl-2 gene and protein expression compared to the varicocele group (p < 0.05). Additionally, NAC administration significantly decreased the rate of apoptosis in germ cells (p < 0.05). These findings suggest that NAC administration can mitigate testicular damage induced by hypoxia from varicocele in rats, primarily due to its antioxidant properties.}, } @article {pmid39747891, year = {2025}, author = {Bahramibanan, F and Rad, MV and Ranjbar, A and Karbasi, A and Abbasifard, A}, title = {Comparison of oxidative stress status in the kidney tissue of male rats treated with paraquat and nanoparaquat.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {389}, pmid = {39747891}, issn = {2045-2322}, mesh = {Animals ; *Paraquat/toxicity ; *Oxidative Stress/drug effects ; Male ; *Kidney/metabolism/drug effects ; *Rats, Wistar ; Rats ; *Lipid Peroxidation/drug effects ; *Antioxidants/metabolism ; Malondialdehyde/metabolism ; Herbicides/toxicity ; Nanoparticles ; Acetylcysteine/pharmacology ; }, abstract = {The study aimed to compare the oxidative stress status in the kidney tissue of rats treated with paraquat and nanoparaquat. The levels of oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (TAC), and thiol groups (TTG), were measured in the kidney tissue samples. A total of forty male Wistar rats were randomly assigned to eight groups, each consisting of five rats: a control group, a paraquat (PQ) group, an N-acetylcysteine (NAC) group, groups receiving nanoparaquat α and β (α and β), groups receiving PQ and NAC (PQ + NAC), and groups receiving nanoparaquat α and β with NAC (+ NACα and β). Paraquat, a widely used herbicide, induces severe oxidative damage in kidneys through radical formation and cellular stress. Newly developed nanoparaquat formulations may modify its toxicity profile and tissue distribution patterns. The results revealed that rats treated with paraquat showed a significant increase in Lipid Peroxidation Oxidation (LPO) levels compared to the control group and those treated with NAC. However, treatment with nanoparaquat α and β resulted in a decrease in LPO levels compared to the paraquat-treated group. Additionally, when nanoparaquat α and β were administered in combination with NAC, a further reduction in LPO levels was observed compared to the PQ treated group. Regarding TAC levels, the PQ group exhibited a significant decrease compared to the control group and the NAC-treated group. However, treatment with nanoparaquat β resulted in higher TAC levels compared to the PQ group. Moreover, when nanoparaquat α and β were administered in combination with NAC, there was an increase in TAC levels compared to the PQ group. In terms of TTG levels, the PQ group showed a significant decrease compared to the control group and the NAC group. However, treatment with nanoparaquat β led to an increase in TTG levels compared to the PQ group. Furthermore, when nanoparaquat α and β were administered in combination with NAC, there was an increase in TTG levels compared to the PQ group. Overall, the results suggest that treatment with nanoparaquat, especially nanoparaquat β, may have a protective effect against oxidative stress induced by PQ toxicity in the kidney tissue of rats. Further studies are warranted to elucidate the underlying mechanisms and potential therapeutic implications of nanoparaquat in oxidative stress-related kidney disorders.}, } @article {pmid39742610, year = {2024}, author = {Yang, X and Li, Y and Shen, R and Song, R and Duan, Y and Zhang, X and Shi, H and Kong, X and Hua, Y and Zhang, L}, title = {New insights into the tenderization pattern of yak meat by ROS-ERS: Promotion of ERS-associated apoptosis through feedback regulation of PERK/IRE1/ATF6 and caspase-12 activity.}, journal = {Food chemistry}, volume = {470}, number = {}, pages = {142705}, doi = {10.1016/j.foodchem.2024.142705}, pmid = {39742610}, issn = {1873-7072}, abstract = {This study aimed to investigate the molecular mechanisms of reactive oxygen species (ROS)-induced endoplasmic reticulum stress (ERS) in apoptosis and meat tenderization during postmortem aging. Yak longissimus dorsi muscle was incubated with N-acetylcysteine (NAC), 4-phenylbutyric acid (4-PBA) and NAC + 4-PBA, respectively, and stored at 4 °C for 0 h, 12 h, 24 h, 72 h, 120 h and 168 h. The results showed that NAC and 4-PBA treatments significantly reduced ROS content and endoplasmic reticulum stress levels. Meanwhile, the specific inhibitory effect of 4-PBA affected Ca[2+] content, caspase-12 activity, endoplasmic reticulum apoptotic cascade reaction and meat tenderization by preventing myogenic fiber degradation. Additionally, the combined treatment of NAC + 4-PBA had a more significant effect than the other groups, confirming the necessity of targeted regulation of the ROS-ERS axis. Overall, our findings provide new insights into the critical role of ROS-mediated ERS in caspase-12-dependent apoptosis and yak meat tenderization during yak meat postmortem.}, } @article {pmid39739120, year = {2024}, author = {Essam, R and Nasr, M and Khater, MW and Fayez, B and Anis, N}, title = {Anti-microbial impact of non-antibiotic agents; salicylic acid, N-acetylcysteine, and isotretinoin against Cutibacterium acnes in patients with acne vulgaris.}, journal = {Archives of dermatological research}, volume = {317}, number = {1}, pages = {155}, pmid = {39739120}, issn = {1432-069X}, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Young Adult ; *Acetylcysteine/pharmacology/therapeutic use ; *Acne Vulgaris/drug therapy/microbiology ; Anti-Bacterial Agents/pharmacology/therapeutic use ; *Biofilms/drug effects ; *Isotretinoin/therapeutic use/pharmacology ; Microbial Sensitivity Tests ; Propionibacterium acnes/drug effects/isolation & purification ; *Salicylic Acid ; }, abstract = {There are two main strategies to eliminate Cutibacterium acnes and to reduce antibiotic resistance in acne treatment. The first is to target the pathogenic bacteria and the second is to change the environment for their growth. The present study aimed to evaluate the anti-microbial role of non-antibiotic agents against Cutibacterium acnes (C. acnes) in acne vulgaris patients. The three agents of interest in the study were isotretinoin, salicylic acid, and N-acetylcysteine (NAC). The study included forty-eight patients with acne vulgaris with ages ranging from 16 to 30 years, and they had different grades of the disease. Azithromycin and Doxycycline sensitivity and the ability of biofilm formation of C. acnes isolated from all patients were assessed before and after adding the 3 agents. Azithromycin and Doxycycline sensitivity was improved after adding the 3 agents and the ability of biofilm formation of C. acnes was also reduced. Isotretinoin, salicylic acid, and NAC can be promising adjuvants in treating acne vulgaris by their anti-microbial effect in reducing biofilm formation and improving antibiotic sensitivity. Clinical Trial NCT06179056.}, } @article {pmid39738092, year = {2024}, author = {Higazy, D and Ahmed, MN and Ciofu, O}, title = {The impact of antioxidant-ciprofloxacin combinations on the evolution of antibiotic resistance in Pseudomonas aeruginosa biofilms.}, journal = {NPJ biofilms and microbiomes}, volume = {10}, number = {1}, pages = {156}, pmid = {39738092}, issn = {2055-5008}, mesh = {*Biofilms/drug effects/growth & development ; *Ciprofloxacin/pharmacology ; *Pseudomonas aeruginosa/drug effects/genetics/physiology ; *Antioxidants/pharmacology ; *Microbial Sensitivity Tests ; *Anti-Bacterial Agents/pharmacology ; *Mutation ; *Drug Resistance, Bacterial ; Whole Genome Sequencing ; Bacterial Proteins/genetics/metabolism ; Acetylcysteine/pharmacology ; Oxidative Stress/drug effects ; DNA-Binding Proteins ; Transcription Factors ; }, abstract = {The evolution of antimicrobial resistance (AMR) in biofilms, driven by mechanisms like oxidative stress, is a major challenge. This study investigates whether antioxidants (AOs) such as N-acetyl-cysteine (NAC) and Edaravone (ED) can reduce AMR in Pseudomonas aeruginosa biofilms exposed to sub-inhibitory concentrations of ciprofloxacin (CIP). In vitro experimental evolution studies were conducted using flow cells and glass beads biofilm models. Results showed that combining CIP with antioxidants (CIP-AOs) effectively reduced the development of CIP resistance. Isolates from biofilms treated with CIP-AO had significantly lower minimum inhibitory concentrations (MICs) of CIP compared to those treated with CIP alone. Whole-genome sequencing (WGS) revealed mutations in the negative regulators of efflux pumps, nfxB, and nalC, in CIP-only treated biofilm populations. The occurrence of nfxB mutations was significantly lower in flow cell biofilms treated with CIP-AO compared to CIP alone. These findings suggest that antioxidants could play a role in mitigating AMR development in biofilms.}, } @article {pmid39737962, year = {2024}, author = {Xing, T and Hu, LJ and Zhao, HY and Li, CY and Wang, ZK and Shen, MZ and Lyu, ZS and Wang, J and Wang, Y and Jiang, H and Jiang, Q and Chang, YJ and Zhang, XH and Kong, Y and Huang, XJ}, title = {Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.}, journal = {Nature communications}, volume = {15}, number = {1}, pages = {10832}, pmid = {39737962}, issn = {2041-1723}, mesh = {*Leukemia, Myeloid, Acute/pathology/drug therapy ; Animals ; *Hematopoiesis ; Humans ; *Endothelial Progenitor Cells/metabolism ; Mice ; *Acetylcysteine/pharmacology ; *Remission Induction ; Male ; Female ; Bone Marrow/pathology ; Mice, Inbred C57BL ; Hematopoietic Stem Cells/metabolism ; Tumor Microenvironment ; Reactive Oxygen Species/metabolism ; Middle Aged ; Adult ; Disease Models, Animal ; }, abstract = {Although acute myeloid leukemia (AML) affects hematopoietic stem cell (HSC)-supportive microenvironment, it is largely unknown whether leukemia-modified bone marrow (BM) microenvironment can be remodeled to support normal hematopoiesis after complete remission (CR). As a key element of BM microenvironment, endothelial progenitor cells (EPCs) provide a feasible way to investigate BM microenvironment remodeling. Here, we find reduced and dysfunctional BM EPCs in AML patients, characterized by impaired angiogenesis and high ROS levels, could be partially remodeled after CR and improved by N-acetyl-L-cysteine (NAC). Importantly, HSC-supporting ability of BM EPCs is partially recovered, whereas leukemia-supporting ability is decreased in CR patients. Mechanistically, the transcriptome characteristics of leukemia-modified BM EPCs return to near-normal after CR. In a classic AML mouse and chemotherapy model, BM vasculature and normal hematopoiesis are reversed after CR. In summary, we provide further insights into how leukemia-modified BM microenvironment can be remodeled to support normal hematopoiesis after CR, which can be further improved by NAC.}, } @article {pmid39737637, year = {2025}, author = {Coşkun, Ç and Aksu, T and Gülhan, B and Düzova, A and Ünal, Ş}, title = {Plasma Exchange and N-Acetylcysteine Therapy in a Case of Congenital Thrombotic Thrombocytopenic Purpura Presenting With Acute Renal Failure.}, journal = {Journal of pediatric hematology/oncology}, volume = {47}, number = {1}, pages = {e65-e67}, doi = {10.1097/MPH.0000000000002963}, pmid = {39737637}, issn = {1536-3678}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Acute Kidney Injury/etiology/therapy ; ADAM Proteins/genetics ; *ADAMTS13 Protein/deficiency/genetics ; Mutation ; *Plasma Exchange ; *Purpura, Thrombotic Thrombocytopenic/therapy/drug therapy/genetics/complications ; Child ; }, abstract = {Congenital thrombotic thrombocytopenic purpura (cTTP), which is associated with mutations in the gene for a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13), is a chronic and lifelong disease. The clinical course is variable. Regularly using ADAMTS13-containing products such as fresh frozen plasma (FFP) for long-term prophylaxis is the most important treatment to prevent thrombotic microangiopathy (TMA) episodes. Here, we identified novel pathogenic mutations of ADAMTS13 in our patients who experienced severe acute renal failure. Infections can trigger acute hemolytic episodes, and if the initiation of FFP therapy is delayed, this leads to severe organ dysfunction, as in our case. We have shown that regular use of products containing ADAMTS13 can reverse TMA episodes and long-term morbidity and mortality. When severe acute renal failure occurs, daily plasma exchange and N-acetylcysteine (NAC) are useful.}, } @article {pmid39736315, year = {2024}, author = {Mao, K and Huang, Y and Liu, Z and Sui, W and Liu, C and Li, Y and Zeng, J and Qian, X and Ma, X and Lin, X and Lou, B}, title = {Oxidative stress mediates retinal damage after corneal alkali burn through the activation of the cGAS/STING pathway.}, journal = {Experimental eye research}, volume = {}, number = {}, pages = {110228}, doi = {10.1016/j.exer.2024.110228}, pmid = {39736315}, issn = {1096-0007}, abstract = {Retinal damage accounts for irreversible vision loss following ocular alkali burn (OAB), but the underlying mechanisms remain largely unexplored. Herein, using an OAB mouse model, we examined the impact of oxidative stress (OS) in retinal damage and its molecular mechanism. Results revealed that OS in the retina was enhanced soon after alkali injury. Antioxidant therapy with N-acetylcysteine (NAC) preserved the retinal structure, suppressed cell apoptosis and decreased retinal inflammation, confirming the role of OS. Moreover, enhanced OS was linked to mitochondrial dysfunction, mtDNA leakage and initiation of the cytosolic DNA-sensing signaling. The activation of the major DNA sensors cyclic GMP-AMP Synthase (cGas) and cGAS-Stimulator of Interferon Genes (cGAS/STING) pathway was then identified. Notably, inhibiting cGAS/STING signaling with C-176 markedly reduced inflammation and cell apoptosis and ultimately protected the retina against OAB. Overall, our study reveals the vital function of OS in the occurence of OAB-induced retinal damage and the involvement of cGAS/STING activation. Furthermore, our provides preclinical validation of the use of an antioxidant or a STING inhibitor as a potential therapeutic approach to protect the retina after OAB.}, } @article {pmid39734022, year = {2024}, author = {Li, Z and Nie, J and Zhou, R and Huang, H and Li, X and Wang, L and Lv, L and Ren, S and Zhao, M}, title = {Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress.}, journal = {Toxicology and applied pharmacology}, volume = {495}, number = {}, pages = {117221}, doi = {10.1016/j.taap.2024.117221}, pmid = {39734022}, issn = {1096-0333}, abstract = {Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Due to the poor therapeutic efficacy of CRC treatments and poor prognosis of the disease, effective treatment strategies are urgently needed. As long-term proteotoxic stress is a major cause of cell death, agents that induce proteotoxic stress offer a promising strategy for cancer intervention. Thiostrepton is a natural antibiotic derived from the Streptomyces genus. In the present study, we found that thiostrepton triggered apoptosis, reduced the migration of CRC cells, and inhibited xenograft tumour growth in vivo. Mechanistically, thiostrepton reduced proteasome activity; induced the aggregation of ubiquitinated proteins; caused endoplasmic reticulum (ER) stress, which was characterized by increased protein levels of GRP78, ATF4, P-eIF2α, and CHOP and cytosolic calcium release; and ultimately resulted in cell death. Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant N-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer.}, } @article {pmid39731665, year = {2024}, author = {Rasheed, H and Ijaz, M and Ahmed, A and Ali, MM}, title = {Antimicrobial resistance, virulence profiling, and drug repurposing analysis of Staphylococcus aureus from camel mastitis.}, journal = {Veterinary research communications}, volume = {49}, number = {1}, pages = {59}, pmid = {39731665}, issn = {1573-7446}, mesh = {Animals ; *Camelus ; Female ; *Staphylococcus aureus/drug effects/genetics/pathogenicity ; *Mastitis/veterinary/microbiology/drug therapy ; *Staphylococcal Infections/veterinary/microbiology/drug therapy ; *Anti-Bacterial Agents/pharmacology ; *Drug Resistance, Bacterial ; Virulence/genetics ; Drug Repositioning ; Virulence Factors/genetics ; Microbial Sensitivity Tests/veterinary ; Methicillin-Resistant Staphylococcus aureus/drug effects/genetics/pathogenicity ; Phylogeny ; }, abstract = {Camel mastitis especially caused by Staphylococcus aureus (S. aureus), is a major risk to animal health and milk production. The current investigation evaluated the antibiotic susceptibility and virulence factors of S. aureus isolates from subclinical mastitis in camels. A total of 384 milk samples were collected and submitted to isolate S. aureus. The S. aureus isolates exhibiting resistance to Penicillin and Cefoxitin disc on Kirby-Bauer disc diffusion method were considered as β-lactam resistant S. aureus (BRSA) and methicillin-resistant S. aureus (MRSA) which were further confirmed by PCR targeting blaZ and mecA genes, respectively. The results showed that S. aureus was found in 57.06% of subclinical (SCM) positive camel milk samples. A high molecular prevalence of BRSA and MRSA were found to be 48.51% and 46.53% respectively depicting that treating these infections is challenging due to their high resistance levels. The phylogenetic analysis revealed a significant resemblance of the study isolates with each other and with already reported sequences from different countries which shows the potential for the spread of pathogen. Virulence profiling of antibiotic resistance strains showed the presence of virulence markers (nuc and coag genes), intercellular adhesion genes (icaA, icaD), Panton-Valentine leukocidin (pvl) gene, and enterotoxin-producing genes including sea, seb, sec, and sed. In-vitro antibiotic susceptibility testing revealed that the most resistant antibiotic group was penicillin followed by aminoglycosides and cephalosporins. Drug repurposing analysis of different non-antibiotics for combination therapies with resistant antibiotics was done to combat the S. aureus isolates harboring the mecA and blaZ genes. The results revealed the synergistic effect of amoxicillin, sulfamethoxazole, gentamicin, and doxycycline with ketoprofen, amikacin with flunixin meglumine, and gentamicin with N-acetylcysteine (NAC) against study isolates. The current investigation provides the status of antibiotic-resistant strains and virulence factors of S. aureus in the udder of dromedary camels. The combinational therapy of resistant antibiotics with non-antibiotics provides a potential therapeutic option for the treatment of resistant strains.}, } @article {pmid39730568, year = {2024}, author = {Li, M and Liu, Z and Cao, X and Xiao, W and Wang, S and Zhao, C and Zhao, Y and Xie, Y}, title = {[Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {30924}, pmid = {39730568}, issn = {2045-2322}, support = {81670742//National Natural Science Foundation of China/ ; SKJY2021082//Suzhou Municipal Health Commission/ ; ML12301323//Conversion Base - Endocrinology and Metabolism/ ; }, mesh = {Humans ; *Sirtuins/metabolism ; *Cellular Senescence/drug effects ; *Glucose/metabolism ; *Reactive Oxygen Species/metabolism ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; }, abstract = {High glucose (HG) induced endothelial senescence is related to endothelial dysfunction and cardiovascular complications in diabetic patients. Humanin, a member of mitochondrial derived peptides (MDPs), is thought to contribute to aging-related cardiovascular protection. The goal of the study is to explore the pathogenesis of HG-induced endothelial senescence and potential anti-senescent effects of Humanin. Human umbilical vein endothelial cells (HUVECs) were exposed to glucose to induce senescence, determined by β-galactosidase staining and the expressions of p21, p53, and p16. A clinically relevant dose of HG (15 mM, HG) induced endothelial senescence after 72 h incubation without elevated apoptosis. HG-induced senescence was attributed to the induction of reactive oxygen species (ROS) caused by SIRT6 downregulation, as ROS inhibitor N-acetyl cysteine blocked HG-induced senescence, while inactivation of SIRT6 increased ROS levels and promoted senescence. Strikingly. pretreatment with [Gly14]-Humanin (HNG) antagonized the downregulation of SIRT6 in response to HG and alleviated ROS production and cell senescence. HG-induced reduction of SIRT6 results in ROS overproduction and endothelial senescence. Humanin protects against HG-induced endothelial senescence via SIRT6. This study provides new directions for biological products related to Humanin to be a potential candidate for the prevention of vascular aging in diabetes.}, } @article {pmid39729531, year = {2024}, author = {Muhammad, W and Liang, M and Wang, B and Xie, J and Ahmed, W and Gao, C}, title = {NAC-Grafted ROS-Scavenging Polymer Nanoparticles for Modulation of Acute Lung Injury Microenvironment In Vivo.}, journal = {Biomacromolecules}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.biomac.4c01290}, pmid = {39729531}, issn = {1526-4602}, abstract = {N-Acetyl cysteine (NAC) is an essential molecule that boosts acute lung injury (ALI) defense via its direct antioxidant capability. Nevertheless, the therapeutic use of NAC is limited due to its poor bioavailability and short half-life. In this study, NAC was grafted to the polyurethane consisting of poly(propylene fumarate), poly(thioketal), and 1,6-hexamethylene diisocyanate (PFTU) to reduce excessive oxidative stress and inflammatory factors in ALI. The NAC-grafted polymer nanoparticles (NPT@NPs) were prepared as a drug delivery system, which could effectively scavenge free radicals and reduce inflammation in vitro. The administration of NPT@NPs exhibited notable efficacy in ameliorating pulmonary edema, attenuating the presence of inflammatory cells, suppressing myeloperoxidase expression, diminishing the levels of pro-inflammatory cytokines, and reversing cell apoptosis in an ALI model induced by lipopolysaccharide (LPS). The NPT@NPs demonstrated significantly better efficacy compared to the free NAC in mitigating the deleterious effects of LPS on pulmonary tissue, thereby providing more effective protection against pulmonary inflammation.}, } @article {pmid39727662, year = {2024}, author = {Alrashed, M and Alyousef, A and Badreldin, HA and Bin Saleh, K and Al Harbi, S and Albekairy, AM and Alghamdi, A and Al-Nahdi, A and Alonazi, D and Alnuhait, M and Alshammari, A and Alqahtani, T}, title = {Comparison of Three-Bag Method Acetylcysteine Versus Two-Bag Method Acetylcysteine for the Treatment of Acetaminophen Toxicity: An Updated Systematic Review and Meta-Analysis.}, journal = {Diseases (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, doi = {10.3390/diseases12120332}, pmid = {39727662}, issn = {2079-9721}, abstract = {BACKGROUND: Acetaminophen is generally considered safe when used according to the recommended guidelines. Consumption in excessive doses can lead to severe liver damage and, in critical cases, may even result in death. To reduce the effects of acetaminophen overdose, N-acetylcysteine (NAC) has been established as the preferred intervention to prevent liver damage.

OBJECTIVES: The purpose of this updated systematic review and meta-analysis is to evaluate the potential benefits of a two-bag N-acetylcysteine (NAC) dosing regimen compared to the traditional three-bag protocol in the treatment of acetaminophen-induced liver toxicity.

METHODS: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The research team utilized the PubMed and Cochrane databases to perform a thorough and comprehensive search of the relevant literature from the inception of these databases up until January 2024.

RESULTS: Nine studies were included. The overall use of two-bag NAC was associated with lower anaphylactic reactions and gastrointestinal symptoms compared to the three-bag method. The rate of liver toxicity resolution was the same between the two treatment groups.

CONCLUSIONS: The two-bag NAC regimen can be considered a safe and effective method for managing acetaminophen toxicity.}, } @article {pmid39726479, year = {2024}, author = {Ntchana, A and Muhumza, R}, title = {Use of N-Acetylcysteine in the Management of Isoniazid-Induced Liver Injury in a Tuberculosis Patient: A Case Report.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e74445}, pmid = {39726479}, issn = {2168-8184}, abstract = {Drug-induced liver injury (DILI) is a rare but significant cause of acute liver failure, often challenging to diagnose due to its clinical similarity to other liver conditions. Since most drugs are metabolized by liver enzymes, the liver is at risk for hepatotoxicity. Although DILI has a low incidence in clinical practice, it remains a critical consideration for patients on potentially hepatotoxic medications. Acetaminophen is the most commonly implicated drug in DILI cases and is prioritized in toxicology screenings. Effective management of DILI requires the prompt discontinuation of the offending drug and supportive care. This case report discusses a 65-year-old male patient who developed elevated liver enzymes three weeks after starting tuberculosis treatment, raising suspicion of DILI. This report explores the diagnostic process, management strategies, and therapeutic role of N-acetylcysteine (NAC), emphasizing its mechanism of action, current clinical applications, and potential future uses in treating DILI.}, } @article {pmid39725121, year = {2024}, author = {Khanal, S and Shin, EJ and Yoo, CJ and Kim, J and Choi, DY}, title = {Inosine exerts dopaminergic neuroprotective effects via mitigation of NLRP3 inflammasome activation.}, journal = {Neuropharmacology}, volume = {266}, number = {}, pages = {110278}, doi = {10.1016/j.neuropharm.2024.110278}, pmid = {39725121}, issn = {1873-7064}, abstract = {Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD. Inosine has been shown to exert anti-inflammatory effects in various disease models. In this study, we evaluated inosine's inhibitory effects on the microglial NLRP3 inflammasome, which may be related to the dopaminergic neuroprotective effects of inosine. Inosine suppresses lipopolysaccharides (LPS)-induced NLRP3 inflammasome activation in BV-2 microglial cells dose dependently. When SH-SY5Y cells were treated with conditioned medium from BV-2 cells treated with LPS and inosine, an NLRP3 inhibitor, or a caspase-1 inhibitor, the viability of SH-SY5Y cells was reduced indicating that LPS-induced microglial inflammasome activation could contribute to neuronal death. Inosine's modulatory effect on NLRP3 inflammasome activity appears to rely on the adenosine A2A and A3 receptors activation, as A2A or A3 receptor antagonists reversed the amelioration of NLRP3 activation by inosine. In addition, inosine treatment attenuated intracellular and mitochondrial ROS production mediated by LPS and this effect might be related to attenuation of NLRP3 inflammasome activity, as the antioxidant, N-acetyl cysteine ameliorated LPS-induced activation of the inflammasome. Finally, we assessed the inosine's neuroprotective effects via inflammasome activity modulation in mice receiving an intranigral injection of LPS. Immunohistochemical analysis revealed that LPS caused a significant loss of nigral dopaminergic neurons, which was mitigated by inosine treatment. LPS increased NLRP3 expression in IBA1-positive microglial cells, which was attenuated by inosine injection. These findings indicate that inosine can rescue neurons from LPS-induced injury by ameliorating NLRP3 inflammasome activity. Therefore, inosine could be applied as an intervention for neuroinflammatory diseases such as Parkinson's disease.}, } @article {pmid39724484, year = {2024}, author = {Kokurcan, A and Sandıkçı, F and Yılmaz, MŞ and Öztürk, U and Doğan, K and Yılmazer, D and Aydın, FN and Yalçındağ, A and İmamoğlu, A}, title = {Protective effects of tadalafil and N-acetyl cysteine therapy on cisplatin-induced testicular toxicity.}, journal = {International urology and nephrology}, volume = {}, number = {}, pages = {}, pmid = {39724484}, issn = {1573-2584}, abstract = {PURPOSE: To investigate whether tadalafil (TAD) and N-acetyl cysteine (NAC) can prevent cisplatin (CIS)-induced testicular toxicity.

METHODS: Forty Wistar-Albino rats were divided into five groups: Control group, CIS group, TAD group, NAC group and TAD + NAC group. All groups were compared regarding body and testicular weights, testicular volumes, blood testosterone levels, testicular tissue malondialdehyde (MDA) levels, histopathological features, and testicular Cosentino and Johnsen scores.

RESULTS: There was no significant difference between the groups regarding body weights and Johnsen scores. It was observed that TAD and NAC affected the apoptotic index, and Cosentino scores were lower in these groups than in the control group. This effect was most prominent in the TAD + NAC group. The CIS treatment led to a decrease in serum testosterone levels. While testosterone levels were higher in the TAD Group, no statistically significant difference was found between the groups. Combination therapy and NAC did not affect blood testosterone levels.

CONCLUSIONS: Cisplatin has adverse effects on the testicular tissue. The histopathological changes caused by this agent can be prevented by TAD + NAC combination therapy.}, } @article {pmid39721495, year = {2024}, author = {Zhu, Y and Dutta, S and Han, Y and Choi, D and Polverino, F and Owen, CA and Somanath, PR and Wang, X and Zhang, D}, title = {Oxidative stress promotes lipid-laden macrophage formation via CYP1B1.}, journal = {Redox biology}, volume = {79}, number = {}, pages = {103481}, doi = {10.1016/j.redox.2024.103481}, pmid = {39721495}, issn = {2213-2317}, abstract = {Emerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or H2O2 significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 (CYP1B1) was highly upregulated in lung macrophages from chronic obstructive pulmonary disease (COPD) patients and CSE-treated macrophages. Functionally, CYP1B1 contributes to the CSE-induced lipid accumulation and LLM formation. CYP1B1 expression and LLM formation were effectively suppressed by antioxidant N-acetylcysteine (NAC) and carvedilol. The formation of LLM was also associated with classically activated M1 but not the M2 state. CSE-induced LLM showed time-dependent alterations in inflammatory response and phagocytic ability. In summary, our study highlights the role of oxidative stress in LLM formation. CYP1B1 contributes to ROS-induced LLM formation and may serve as a therapeutic target for reducing LLM-induced lung damage.}, } @article {pmid39720578, year = {2024}, author = {Qiu, X and Yao, Y and Chen, Y and Li, Y and Sun, X and Zhu, X}, title = {TRPC5 Promotes Intermittent Hypoxia-Induced Cardiomyocyte Injury Through Oxidative Stress.}, journal = {Nature and science of sleep}, volume = {16}, number = {}, pages = {2125-2141}, pmid = {39720578}, issn = {1179-1608}, abstract = {PURPOSE: Intermittent hypoxia (IH), a defining feature of obstructive sleep apnea (OSA), is associated with heart damage and linked to transient receptor potential canonical channel 5 (TRPC5). Nonetheless, the function of TRPC5 in OSA-induced cardiac injury remains uncertain. For this research, we aimed to explore the role and potential mechanism of TRPC5 in cardiomyocyte injury induced by intermittent hypoxia.

METHODS: 30 patients with newly diagnosed OSA and 30 patients with primary snoring(PS) were included in this study. Participants were subjected to polysomnography (PSG) for OSA diagnosis. Echocardiography was used to evaluate the structure and function of the heart, while peripheral blood samples were obtained. Additionally, RT-qPCR was utilized to quantify the relative expression level of TRPC5 mRNA in peripheral blood. H9c2 cells experienced IH or normoxia. TRPC5 levels in H9c2 cells were determined via RT-qPCR and Western blotting (WB) methods. H9c2 cells overexpressing TRPC5 were subjected to either normoxic or intermittent hypoxia conditions. Cell viability was determined by CCK8, the apoptosis rate, reactive oxygen species(ROS) levels, and Ca[2+] concentration were assessed by flow cytometry, and the protein levels of TRPC5, Bcl-2, Bax, and Caspase-3 were analyzed by WB. Mitochondrial membrane potential(MMP), mitochondrial membrane permeability transition pore(mPTP), and transmission electron microscopy(TEM) were employed to observe mitochondrial function and structure. After inhibiting ROS with N-acetylcysteine (NAC), apoptosis, mitochondrial function and structure, and the concentration of Ca[2+] were further detected.

RESULTS: TRPC5 and left atrial diameter (LAD) were higher in OSA individuals, while the E/A ratio was lower(all P<0.05). IH impaired cell viability, triggered cell apoptosis, and enhanced TRPC5 expression in H9c2 cells(all P<0.05). The effects of IH on apoptosis, cell viability, mitochondrial function and structure damage, and oxidative stress (OxS) in H9c2 cells were accelerated by the overexpression of TRPC5(all P<0.05). Furthermore, cell apoptosis and mitochondrial structural and functional damage caused by overexpression of TRPC5 were attenuated by ROS inhibition.

CONCLUSION: TRPC5 is associated with structural and functional cardiac damage in patients with OSA, and TRPC5 promotes IH-induced apoptosis and mitochondrial damage in cardiomyocytes through OxS. TRPC5 may be a novel target for the diagnosis and treatment of OSA-induced myocardial injury.}, } @article {pmid39710209, year = {2024}, author = {Xu, M and Yu, S and Li, P and Chen, Y and Chen, Y and Pan, J and Deng, X and Hu, H}, title = {Tailored multilayer nanoparticles against resistant P. aeruginosa by disrupting the thickened mucus, dense biofilm and hyperinflammation.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {378}, number = {}, pages = {588-604}, doi = {10.1016/j.jconrel.2024.12.040}, pmid = {39710209}, issn = {1873-4995}, abstract = {Therapeutic challenges of chronic pulmonary infections caused by multidrug-resistant Pseudomonas aeruginosa (MDRP. aeruginosa) biofilms due to significantly enhanced antibiotic resistance. This resistance is driven by reduced outer membrane permeability, biofilm barriers, and excessive secretion of virulence factors. Thickened mucus in the airways exacerbates the problem by impeding antibiotic penetration, providing a breeding ground for biofilms, consequently aggravating infection. Moreover, biofilms recruit numerous immune cells, resulting in chronic inflammation and lung tissue damage. In turn, damaged airway further facilitates bacterial colonization and elevated mucus production. To thoroughly disintegrate the stubborn triad of "thickened mucus & dense biofilm & excessive inflammation" and address drug resistance, tailored multilayer nanoparticles (NPVC/PBIP NPs) were developed. NPVC/PBIP NPs were engineered through self-assembly of vanillin-chitosan amphiphilic polymer loading polymyxin B-linoleic acid ion pairs in. Then polyaspartic acid and N-acetylcysteine-ε-poly-l-lysine were coated by layer-by-layer on the surface of vanillin-chitosan NPs via electrostatic interactions. As expected, the NAC units on NPVC/PBIP NPs effectively thinned human clinical sputum and porcine sputum, resulting in rapid sputum penetration followed by biofilm permeation. NPVC/PBIP NPs achieved over 99 % eradication of mature biofilms in vitro. Furthermore, they effectively inhibited virulence factors production and bacteria re-adhesion (biofilm reformation) while exhibiting superior anti-inflammatory and antioxidant activities. In a chronic pulmonary infection model, NPVC/PBIP NPs remarkably thinned airway mucus, reduced bacterial burden by 99.7 %, alleviated inflammatory cell infiltration, and minimized lung tissue damage. In summary, the NPVC/PBIP NPs represent a novel and promising strategy to manage MDRP. aeruginosa biofilms associated infections by disintegrating the stubborn triad of "thickened mucus & dense biofilm & excessive inflammation".}, } @article {pmid39710118, year = {2024}, author = {Luo, G and Yang, W and Geng, Z and Cheng, Y and Xu, Y and Xiao, Y and Liu, J}, title = {Molecular mechanism of GSH metabolism and autophagy in NAC-promoted recombinant human serum albumin and follicle stimulating hormone beta fusion protein secretion in Pichia pastoris.}, journal = {Journal of biotechnology}, volume = {398}, number = {}, pages = {146-157}, doi = {10.1016/j.jbiotec.2024.12.006}, pmid = {39710118}, issn = {1873-4863}, abstract = {The Pichia pastoris expression system is a favorable platform for production of pharmaceutical proteins. Treatment of strains with N-acetyl-L-cysteine (NAC) has been shown to enhance the yield of recombinant proteins, thereby contributing to a reduction in production costs. However, the specific mechanism of action of NAC remains unclear. Previous research has indicated that glutathione (GSH) and autophagy are involved in the increased production of human serum albumin and porcine follicle-stimulating hormone β (HSA-pFSHβ) by NAC. This study investigated the potential interaction between GSH and autophagy in the production of HSA-pFSHβ. The findings indicated that sulfhydryl-free antioxidants such as melatonin, vitamin C, or vitamin E did not exhibit similar effects to NAC in enhancing HSA-pFSHβ yield. Moreover, NAC was found to enhance HSA-pFSHβ production by modulating GSH metabolism to reduce GSH consumption, increase total GSH levels, as well as glutathione peroxidase (GSH-Px) and glutathione reductase (GR) activities. Additionally, inhibition of autophagy through disruption of autophagy scaffolding proteins Atg1 or Atg11 led to an increase in recombinant HSA-pFSHβ production. Furthermore, NAC significantly decreased the phosphorylation of Slt2, and the absence of the SLT2 gene influenced the effect of NAC on HSA-pFSHβ secretion by modulating mitophagy and GSH metabolism. In conclusion, these results suggest a complex interplay between GSH metabolism and autophagy in the regulation of NAC-induced HSA-pFSHβ secretion.}, } @article {pmid39707625, year = {2024}, author = {Jiang, ZB and Xu, C and Xu, P and Huang, DH and Kang, LP}, title = {Lycorine Suppresses Non-Small-Cell Lung Cancer Progression Through Activating STING Pathway and Stimulating an Antitumor Immune Response.}, journal = {Chemical biology & drug design}, volume = {104}, number = {6}, pages = {e70036}, doi = {10.1111/cbdd.70036}, pmid = {39707625}, issn = {1747-0285}, support = {2022M713650//China Postdoctoral Science Foundation/ ; 2022A1515110790//Guangdong Basic and Applied Basic Research Foundation of China/ ; 2024A1515012478//Guangdong Basic and Applied Basic Research Foundation of China/ ; 20221361//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20241290//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20241285//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; No.20251345//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 2320004000290//Zhuhai Science and Technology Bureau/ ; 2420004000007//Zhuhai Science and Technology Bureau/ ; 2420004000022//Zhuhai Science and Technology Bureau/ ; }, mesh = {*Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/pathology ; Humans ; Animals ; *Lung Neoplasms/drug therapy/pathology/metabolism ; *Membrane Proteins/metabolism ; Mice ; Cell Line, Tumor ; *Amaryllidaceae Alkaloids/pharmacology/chemistry/therapeutic use ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Phenanthridines/pharmacology/chemistry/therapeutic use ; Cell Proliferation/drug effects ; Signal Transduction/drug effects ; Antineoplastic Agents/pharmacology/chemistry ; }, abstract = {Non-small-cell lung cancer (NSCLC) stands as a primary contributor to cancer-related deaths worldwide. It has been demonstrated that Lycorine (LYD), a naturally occurring active sesquiterpene present in Chinese medicinal plants, exhibits anti-cancer properties across various cancer cell lines. However, the underlying mechanisms of LYD-induced anti-tumor in NSCLC are not fully known. This study demonstrated that LYD significantly reduced the proliferation of NSCLC and induced apoptosis by increasing intracellular ROS levels. The inhibition of ROS using N-acetylcysteine (NAC) eliminated the apoptosis effects of LYD, resulting in increased cell viability. Additionally, LYD treatment significantly activated the STING pathway in NSCLC and induced the expression of CXCL10, CXCL9 and CCL5 in NSCLC cells. Mechanistically, LYD was found to significantly reduce the protein levels of P70S6K and S6K, which are key proteins involved in cell growth and survival. Notably, in vivo experiments demonstrated that LYD significantly inhibited the growth of H358 xenograft and LLC1 tumor, exhibiting anti-tumor activity by elevating CD8[+] T cells in the NSCLC mouse model. Our findings suggest that LYD possesses potent anti-cancer properties in NSCLC by inducing apoptosis through ROS generation and modulating the STING pathway and key chemokines. Furthermore, LYD also exerts its antitumor effects by inhibiting crucial proteins involved in cell growth. Overall, LYD shows promise as a potential therapeutic agent for NSCLC treatment.}, } @article {pmid39707526, year = {2024}, author = {Yang, C and Fu, J and Zheng, F and Fu, Y and Duan, X and Zuo, R and Zhu, J}, title = {Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.}, journal = {Journal of cardiothoracic surgery}, volume = {19}, number = {1}, pages = {665}, pmid = {39707526}, issn = {1749-8090}, support = {202301AY070001-213//the Kunming medical joint special project-surface project/ ; }, mesh = {*Aconitine/pharmacology/analogs & derivatives ; *Autophagy/drug effects ; *Reactive Oxygen Species/metabolism ; *Myocytes, Cardiac/drug effects/metabolism/pathology ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Rats ; *NF-E2-Related Factor 2/metabolism ; Animals ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; MAP Kinase Signaling System/drug effects/physiology ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: Aconitine has cardiotoxicity, but the mechanism of cardiotoxicity induced by aconitine is limited. The aim of this study was to investigate the mechanism of myocardial injury induced by aconitine.

METHODS: Using aconitine, ROS inhibitor N-acetylcysteine(NAC), the autophagy activitor Rapamycin (Rap) or the P38/MAPK pathway activitor Dehydrocorydaline treats H9C2 cells. CCK-8 assay was used to assay cell proliferation activity. Flow Cytometry was used to detect cell apoptosis. Dichloro-dihydrofluorescein diacetate was used to detect ROS levels. The expression of LC3 was detected by Immunofluorescence Staining. Western blotting detected the expression of related proteins. The mRNA levels of inflammatory factors were detected by RT-qPCR.

RESULTS: Aconitine inhibits cardiomyocyte proliferation, induces apoptosis and secretion of inflammatory factors. Aconitine activates the P38/MAPK/Nrf2 pathway, induces ROS increase, and promotes autophagy. NAC can inhibit proliferation inhibition, apoptosis, inflammation and P38/MAPK/Nrf2 pathway activation induced by aconitine. Rap and P38 activators can partially recover the effects of NAC on proliferation, apoptosis, inflammation and autophagy of cardiomyocytes.

CONCLUSION: Aconitine promotes ROS-activated P38/MAPK/Nrf2 pathway to inhibit autophagy and promote myocardial injury.}, } @article {pmid39706252, year = {2024}, author = {Lomeli, N and Pearre, DC and Lepe, J and Argueta, DA and Arellano, MA and Ricks-Oddie, JL and Gupta, K and Bota, DA}, title = {N-acetylcysteine prevents cisplatin-induced cognitive impairments in an ovarian cancer rat model.}, journal = {Cancer letters}, volume = {611}, number = {}, pages = {217405}, doi = {10.1016/j.canlet.2024.217405}, pmid = {39706252}, issn = {1872-7980}, abstract = {Cancer-related cognitive impairment (CRCI) is prevalent among cancer patients. A critical disparity in the CRCI field is that most pre-clinical studies have been conducted on young cancer-free male rodents, although CRCI predominantly affects breast cancer and ovarian cancer women survivors. Since oxidative stress is widely implicated in the development of CRCI, we developed an ovarian cancer xenograft rat model of CRCI in Cr:NIH-RNU female rats to examine whether administration of the antioxidant N-acetylcysteine (NAC) prevents cisplatin-induced CRCI without altering its anti-cancer efficacy. In vitro, delayed treatment with NAC (10 h) following cisplatin treatment in the human ovarian cancer cell line SKOV3.ip1 did not decrease cisplatin's anti-cancer efficacy while mitigating hippocampal dendritic branching damage and neuronal apoptosis. Rats received subcutaneous and intraperitoneal implantation of SKOV3.ip1 cells. Rats received one cisplatin (5 mg/kg) injection every two weeks for a total of four cycles, with or without NAC (250 mg/kg/day), given for five consecutive days during cisplatin treatment. NAC was administered 10 h after cisplatin, based on our in vitro data. Cognitive testing was performed six to seven weeks after treatment cessation. In vivo, cognitive impairments were observed in tumor-bearing rats in the vehicle and cisplatin-treatment groups, while delayed NAC prevented cognitive impairments. Delayed NAC administration did not affect cisplatin-induced tumor volume reduction. Our study supports using NAC to mitigate cisplatin-induced CRCI through the novel development of an ovarian cancer rodent model. This study highlights the importance of developing clinically relevant tumor-bearing models to elucidate the underlying mechanisms associated with CRCI, which will aid in identifying potential therapeutic agents for preventing CRCI.}, } @article {pmid39705849, year = {2024}, author = {Jog, E and Jainarayanan, AK and La Ferlita, A and Chakraborty, A and Dalwai, A and Yahya, S and Shivashankar, A and Choudhary, BS and Chandramouli, A and Kazi, M and Jain, D and Khapare, N and B, A and Khan, BK and Gera, P and Patil, P and Thorat, R and Verma, N and Sehgal, L and Saklani, A and Kamat, SS and Dalal, SN and Chaudhary, N}, title = {Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer.}, journal = {Redox biology}, volume = {79}, number = {}, pages = {103458}, doi = {10.1016/j.redox.2024.103458}, pmid = {39705849}, issn = {2213-2317}, abstract = {A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy resistance and relapse in CRC is associated with the formation of lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, the molecular mechanisms underlying the increase in DNL and the susceptibility to DNL-targeted therapies remain unclear. Our study demonstrates that colorectal drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), which facilitates the sequestration of free fatty acids into LDs. The increased expression is mediated by the ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking the conversion of free fatty acids into LDs by treatment with statins or inhibiting lipin1 expression disrupts lipid homeostasis, leading to lipotoxicity and ferroptotic cell death in both DTPs and patient-derived organoids (PDOs) in vitro. Ferroptosis inhibitors or N-acetylcysteine (NAC) can alleviate lipid ROS and cell death resulting from lipin1 inhibition. This strategy also significantly reduces tumor growth in CRC DTP mouse xenograft and patient-derived xenograft (PDX) models. Our findings highlight a new metabolic vulnerability in CRC DTPs, PDO, and PDX models and provide a framework for the rational repurposing of statins. Targeting the phosphatidic acid (PA) to diacylglycerol (DAG) conversion to prevent lipid droplet formation could be an effective therapeutic approach for therapy-resistant CRC.}, } @article {pmid39704007, year = {2024}, author = {Braunreuther, M and Arenhoevel, J and Bej, R and Moose, C and Mall, MA and Haag, R and Fuller, GG}, title = {Magnetic microwire rheometer reveals differences in hydrogel degradation via disulfide reducing agents.}, journal = {Soft matter}, volume = {}, number = {}, pages = {}, doi = {10.1039/d4sm01118j}, pmid = {39704007}, issn = {1744-6848}, abstract = {Mucus is composed of a complex network of mucin polymers connected by disulfide bonds. In muco-obstructive diseases, an increase in mucin disulfide crosslinks contributes to pathologic mucus formation, characterized by an increase in mucus viscosity and stiffness. Reducing agents that break down the disulfide bonds between mucins can be used to treat pathologic mucus and restore healthy mucus flow properties. Here, we compare three reducing agents via a rheological assay. A mucus-mimetic disulfide-crosslinked hyaluronic acid hydrogel was treated with thiolated dendritic polyglycerol sulfate (dPGS-SH), N-acetylcysteine (NAC), or dithiothreitol (DTT). A magnetic microwire rheometer was used to track the rheology of the hydrogel over time as the treatment degraded the sample. This nondestructive and minimally invasive technique reveals differences in the degradation mechanism between these reducing agents, with potential implications for drug delivery and the treatment of muco-obstructive diseases.}, } @article {pmid39701936, year = {2024}, author = {Chen, S and Cao, Y and Fan, Z and Xu, L and Pan, Z and Gao, Y and Wei, L and Wei, Q and Tian, Y and Zhang, X and Liu, M and Ren, F}, title = {Depressed TFAM promotes acetaminophen-induced hepatotoxicity regulated by DDX3X-PGC1α-NRF2 signaling pathway.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {30}, number = {1}, pages = {246}, pmid = {39701936}, issn = {1528-3658}, support = {82002243, 82100653//National Natural Science Foundation of China/ ; 82002243, 82100653//National Natural Science Foundation of China/ ; KZ202010025035//Key Projects of the Beijing Municipal Education Commission's Science and Technology Plan/ ; QML20201702//Beijing Hospitals Authority Youth Programme/ ; DFL20221503//Talent Cultivation plan of "Climbing the peak" of Beijing Municipal Hospital Administration/ ; Subject leaders-02-13//High-level public health technical personnel construction Project/ ; BJMB0012022028021//2022 Chronic disease prevention and health education research project/ ; PX2021065//Beijing Municipal Administration of Hospitals Incubating Program/ ; YARCKB2022008//Beijing You'an Hospital Construction of Talent Pool Program/ ; CX24PY23//Chinese Institutes for Medical Research/ ; L234046//Beijing Natural Science Foundation-Changping Innovation Joint Fund/ ; CCMU2023ZKYXZ003//Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University/ ; }, mesh = {*Acetaminophen/adverse effects ; Animals ; *Signal Transduction/drug effects ; Humans ; *Chemical and Drug Induced Liver Injury/metabolism/etiology/genetics ; Mice ; Male ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism/genetics ; *Transcription Factors/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Mitochondrial Proteins/metabolism/genetics ; *NF-E2-Related Factor 2/metabolism/genetics ; *DEAD-box RNA Helicases/metabolism/genetics ; Disease Models, Animal ; Mice, Inbred C57BL ; Female ; Gene Expression Regulation/drug effects ; High Mobility Group Proteins ; }, abstract = {BACKGROUND: Acetaminophen (APAP)-induced acute liver injury (AILI) is the most prevalent cause of acute liver failure and mitochondrial dysfunction plays a dominant role in the pathogenesis of AILI. Mitochondrial transcription factor A (TFAM) is an important marker for maintaining mitochondrial functional homeostasis, but its functions in AILI are unclear. This study aimed to investigate the function of TFAM and its regulatory molecular mechanism in the progression of AILI.

METHODS: The roles of TFAM and DEAD (Asp-Glu-Ala-Asp) box polypeptide 3 X-linked (DDX3X) in AILI were determined with TFAM overexpression and DDX3X knockdown, respectively.

RESULTS: TFAM expression was suppressed in AILI patients. TFAM overexpression alleviated liver necrosis and mitochondrial dysfunction. Treatment of the AILI mice model with N-acetylcysteine (NAC), a drug used to treat APAP overdose, resulted in significant TFAM activation. In vivo experiments confirmed that TFAM expression was negatively regulated by DDX3X. Mechanistic studies showed that nuclear respiratory factor 2 (NRF-2), a key regulator of TFAM, was selectively activated after DDX3X knockdown via activated peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α), in vivo and in vitro.

CONCLUSIONS: This study demonstrates that depressed hepatic TFAM plays a key role in the pathogenesis of AILI, which is regulated by the DDX3X-PGC1α-NRF2 signaling pathway.}, } @article {pmid39688969, year = {2024}, author = {Flaherty, BF and Olsen, CS and Coon, ER and Srivastava, R and Cook, LJ and Keenan, HT}, title = {Patterns of Use of β-2 Agonists, Steroids, and Mucoactive Medications to Treat Bronchiolitis in the PICU: U.S. Pediatric Health Information System 2009-2022 Database Study.}, journal = {Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies}, volume = {}, number = {}, pages = {}, doi = {10.1097/PCC.0000000000003670}, pmid = {39688969}, issn = {1529-7535}, abstract = {OBJECTIVES: Describe β2-agonists, steroids, hypertonic saline (HTS), n-acetylcysteine (NAC), and dornase alfa (DA) use to treat bronchiolitis, factors associated with use, and associations between use and PICU length of stay (LOS).

DESIGN: Retrospective, multicenter cohort study.

SETTING: PICUs in the Pediatric Health Information System database.

PATIENTS: PICU admitted children 24 months young or younger with bronchiolitis.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: We analyzed 47,520 hospitalizations between July 1, 2018, and June 30, 2022. We calculated the rate of medication use overall and the median (range) rate for each hospital: β2-agonist (24,984/47,520 [52.6%]; median hospital, 51.7% [21.4-81.7%]), steroid (15,878/47,520 [33.4%]; median hospital, 33.4% [6.0-54.8%]), HTS (7,041/47,520 [14.8%]; median hospital, 10.5% [0-66.1%]), NAC (1,571/47,520 [3.3%]; median hospital, 0.8% [0-22.0%], and DA (840/47,520 [1.8%]; median hospital, 1.4% [0-13.6%]). Logistic regression using generalized estimating equations (GEEs) identified associations between concurrent asthma and β2-agonist (adjusted odds ratio [aOR], 8.68; 95% CI, 7.08-10.65; p < 0.001) and steroid (aOR, 10.10; 95% CI, 8.84-11.53; p < 0.001) use. Mechanical ventilation was associated with all medications: β2-agonists (aOR, 1.79; 95% CI, 1.57-2.04; p < 0.001), steroids (aOR, 2.33; 95% CI, 1.69-3.21; p < 0.001), HTS (aOR, 1.82; 95% CI, 1.47-2.25; p < 0.001), NAC (aOR, 3.29; 95% CI, 2.15-5.03; p < 0.001), and DA (aOR, 7.65; 95% CI, 4.30-13.61; p < 0.001). No medication was associated with decreased PICU LOS. To assess changes in medication use over time and associations with the 2014 American Academy of Pediatrics bronchiolitis guidelines, we expanded our analysis to 83,820 hospitalizations between July 1, 2009, and June 30, 2022. Logistic regression with GEEs found no change in β2-agonist use; steroid use increased after guideline publication (aOR, 1.05; 95% CI, 1.01-1.10; p = 0.02), HTS use changed from increasing prior to the guidelines (aOR, 1.32; 95% CI, 1.11-1.56; p = 0.001) to stable since guideline publication (aOR, 0.93; 95% CI, 0.81-1.07; p = 0.33).

CONCLUSIONS: β2-agonists, steroids, and HTS are commonly, but variably used for PICU bronchiolitis treatment. Medication use appears relatively stable over the last decade.}, } @article {pmid39687604, year = {2025}, author = {Gupta, K and Chen, D and Wells, RG}, title = {Microcystin-RR is a biliary toxin selective for neonatal extrahepatic cholangiocytes.}, journal = {JHEP reports : innovation in hepatology}, volume = {7}, number = {1}, pages = {101218}, pmid = {39687604}, issn = {2589-5559}, support = {P30 DK050306/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND & AIMS: Biliary atresia is a fibrosing cholangiopathy affecting neonates that is thought to result from a prenatal environmental insult to the bile duct. Biliatresone, a plant toxin with an α-methylene ketone group, was previously implicated in biliary atresia in Australian livestock, but is found in a limited location and is unlikely to be a significant human toxin. We hypothesized that other unsaturated carbonyl compounds, some with the potential for significant human exposure, might also be biliary toxins.

METHODS: We focused on the family of microcystins, cyclic peptide toxins from blue-green algae that are found worldwide, particularly during harmful algal blooms. We used primary extrahepatic cholangiocyte spheroids and extrahepatic bile duct explants from both neonatal [a total of 86 postnatal day (P) 2 mouse pups and 18 P2 rat pups (n = 8-10 per condition for both species)] and adult rodents [a total of 31 P15-18 mice (n = 10 or 11 per condition)] to study the biliary toxicity of microcystins and potential mechanisms involved.

RESULTS: Results showed that 400 nM microcystin (MC)-RR, but not six other microcystins or the related algal toxin nodularin, caused >80% lumen closure in cell spheroids made from extrahepatic cholangiocytes isolated from 2-3-day-old mice (p <0.0001). By contrast, 400 nM MC-RR resulted in less than an average 5% lumen closure in spheroids derived from neonatal intrahepatic cholangiocytes or cells from adult mice (p = 0.4366). In addition, MC-RR caused occlusion of extrahepatic bile duct explants from 2-day-old mice (p <0.0001), but not 18-day-old mice. MC-RR also caused a 2.3-times increase in reactive oxygen species in neonatal cholangiocytes (p <0.0001), and treatment with N-acetyl cysteine partially prevented microcystin-RR-induced lumen closure (p = 0.0004), suggesting a role for redox homeostasis in its mechanism of action.

CONCLUSIONS: We identified MC-RR as a selective neonatal extrahepatic cholangiocyte toxin and suggest that it acts by increasing redox stress.

IMPACT AND IMPLICATIONS: The plant toxin biliatresone causes a biliary atresia-like disease in livestock and vertebrate animal model systems. We tested the widespread blue-green algal toxin, microcystin-RR, another highly electrophilic unsaturated carbonyl compound that is released during harmful algal blooms, and found that it was also a biliary toxin with specificity for neonatal extrahepatic cholangiocytes. This work should drive further animal studies and, ultimately, studies to determine whether human exposure to microcystin-RR causes biliary atresia.}, } @article {pmid39687303, year = {2024}, author = {Mahmoud, NM and Elshazly, SM and El-Shaarawy, F and Zaitone, SA and Aldahish, AA and Ahmed, GA and Fawzy, MS and Aloyouni, SY and Abed, SY and Saeedi, T and El-Sayed, SS}, title = {Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1491249}, pmid = {39687303}, issn = {1663-9812}, abstract = {OBJECTIVES: Hepatotoxicity is a severe outcome of methotrexate (MTX) therapy, limiting its clinical use and contributing to its related morbidity and mortality. This study investigated the hepatoprotective effects of nitazoxanide (NTZ), an antiprotozoal drug, against MTX-induced hepatotoxicity and whether endoplasmic reticulum (ER) stress-modulation underlies the expected beneficial effects of NTZ.

METHODS: Thirty-six rats were allocated to six groups, one control group and five MTX groups, where induction of hepatotoxicity was achieved via injecting MTX (20 mg/kg). Groups were assigned as MTX-vehicle, NTZ-100, and NTZ-200 groups (at 100 and 200 mg/kg/day, gavage, respectively), N-acetyl cysteine (NAC) group (500 mg/kg), and 4-phenyl butyric acid (4-PBA) group (150 mg/kg, i.p). Liver function enzymes in serum, hepatic oxidative stress, proinflammatory cytokines, apoptosis, and ER-stress biomarkers were assessed. A histopathological examination was performed.

RESULTS: Treatment with NTZ lessened the serum liver enzymes, reduced malondialdehyde (lipid peroxidation product), enhanced antioxidant capacity, attenuated proinflammatory cytokines, and suppressed apoptosis. The protective effect of NTZ was dose-dependent, and the findings observed with the high-dose NTZ were similar to those obtained with the ER-stress inhibitor (4-PBA).

CONCLUSION: NTZ exerted a hepatoprotective effect in MTX-challenged rats that is mediated via modulation of ER stress and inhibiting apoptosis.}, } @article {pmid39683654, year = {2024}, author = {Bognár, G and Kenari, F and Pintér, Z and Borges, ID and Camargo, AJ and Oliveira, HCB and Sanches-Neto, FO and Carvalho-Silva, VH and Napolitano, HB and Perjési, P}, title = {(E)-2-Benzylidenecyclanones: Part XX-Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Unexpected Increased Reactivity of 4-Chromanone- Compared to 1-Tetralone Analogs in Thia-Michael Reactions.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {23}, pages = {}, pmid = {39683654}, issn = {1420-3049}, mesh = {Humans ; *Sulfhydryl Compounds/chemistry ; Chromones/chemistry/pharmacology ; Tetralones/chemistry/pharmacology ; Chalcones/chemistry/pharmacology ; Glutathione/metabolism/chemistry ; Molecular Structure ; Models, Molecular ; Cell Line, Tumor ; Acetylcysteine/chemistry/pharmacology ; Chromatography, High Pressure Liquid ; }, abstract = {In vitro relative cytotoxicity (IC50 (IIb)/IC50 (IIIb) of (E)-3-(4'-methylbenzylidene)-4-chromanone (IIIb) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (IIb). On the other hand, such an increase was not observed in the analogous 4-OCH3 (IIc and IIIc) derivatives. In order to study whether thiol reactivity-as a possible basis of the mechanism of action-correlates with the observed cytotoxicities, the kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of IIIb and IIIc were investigated. The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the unexpectedly higher thiol reactivity of the chromanones (III) compared to the carbocyclic analog tetralones (II). The results indicate the possible role of spontaneous thiol reactivity of compounds III in their recorded biological effects.}, } @article {pmid39682737, year = {2024}, author = {Dorcas Aremu, T and Ramírez Ortega, D and Blanco Ayala, T and González Esquivel, DF and Pineda, B and Pérez de la Cruz, G and Salazar, A and Flores, I and Meza-Sosa, KF and Sánchez Chapul, L and Rangel-López, E and Gómez-Manzo, S and Márquez Navarro, A and Roldán Roldán, G and Pérez de la Cruz, V}, title = {Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats.}, journal = {Cells}, volume = {13}, number = {23}, pages = {}, pmid = {39682737}, issn = {2073-4409}, support = {IN207025//PAPIIT DGAPA-UNAM/ ; }, mesh = {Animals ; *Kynurenic Acid/metabolism ; Female ; *Acetylcysteine/pharmacology ; *Rats, Wistar ; *Cognitive Dysfunction/drug therapy/metabolism/prevention & control ; Rats ; *Brain/drug effects/metabolism/pathology ; *Cisplatin/adverse effects/pharmacology ; *Muscle Weakness/metabolism/drug therapy/pathology ; }, abstract = {Cisplatin (CIS) is a potent chemotherapeutic agent primarily used to treat hematologic malignancies and solid tumors, including lymphomas, sarcomas, and some carcinomas. Patients receiving this treatment for tumors outside the nervous system develop cognitive impairment. Alterations in the kynurenine pathway (KP) following CIS treatment suggest that certain KP metabolites may cross the blood-brain barrier, leading to increased production of the neuromodulator kynurenic acid (KYNA), which is associated with cognitive impairment. This study aimed to evaluate the effects of modulating brain KYNA levels by the administration of N-acetylcysteine (NAC), an inhibitor of kynurenine aminotransferase II (KATII), an enzyme responsible for KYNA biosynthesis on the cognitive and neuromuscular deficits induced by CIS. Female Wistar rats were divided into four groups: control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p/5 days), and NAC + CIS (both treatments co-administered in parallel). Seven days after the last CIS administration, cognitive performance, muscle strength, brain KYNA levels, KATII activity, and brain tissue redox profile (lipid peroxidation and oxidized/reduced glutathione (GSH/GSSG) ratio) were assessed. CIS did not affect short-term memory but induced long-term memory deficits and reduced muscle strength, effects which were prevented by NAC co-administration. CIS decreased the GSH/GSSG ratio and the number of cells in the brain cortex while it increased lipid peroxidation, KYNA levels, and marginal KATII activity. All these effects were attenuated by the co-administration of NAC. These findings suggest that NAC mitigates the side effects of CIS, such as chemo-brain and muscle weakness, by improving the redox imbalance and modulating KYNA levels by limiting its non-enzymatic production by reactive oxygen species (ROS).}, } @article {pmid39677988, year = {2024}, author = {Roy, S and Saleem, H}, title = {Mushroom Poisoning and Acute Liver Injury: A Case-Based Review.}, journal = {Cureus}, volume = {16}, number = {12}, pages = {e75706}, pmid = {39677988}, issn = {2168-8184}, abstract = {Mushrooms have always found their way into our dining plates due to their exotic looks and edibility. It is also one of the food items that can lead to fatal hepatotoxicity if the wrong species is picked up. Mushroom poisoning is frequently seen in forest adventure seekers and presents with variable time frames, mainly with acute gastrointestinal symptoms. Here we discuss a case of mushroom poisoning in a lady in her early sixties who presented with acute liver injury after 6 hours of wild toxic mushroom intake, having severely raised INR (International Normalized Ratio). She was managed with N-acetylcysteine (NAC), vitamin K, and regular benzylpenicillin in the liver-intensive therapy unit (ITU). The data regarding the treatment of mushroom poisoning is not tested in conventional rigorous randomized control trials. However, the role of good supportive care in liver-ITU, the addition of NAC, and benzylpenicillin in some cases, is reassuring. And if that fails, then liver transplant is a viable option. Her case underscores the critical importance of early diagnosis and immediate initiation of supportive care, including the addition of NAC and regular benzylpenicillin in selected cases. For those not responding to these conventional therapies, the possibility of a liver transplant, as a last resort, must be considered.}, } @article {pmid39674107, year = {2024}, author = {Wang, X and Luo, J and Cao, M and Ju, Y and Long, Q and Yang, R and Ji, Q and Zhou, G and Zhang, J and Li, R and Chen, X}, title = {Effects of different concentrations of N-acetylcysteine on the sperm quality, antioxidant enzyme activity, and antioxidant gene expression of cryopreserved goat semen.}, journal = {Theriogenology}, volume = {234}, number = {}, pages = {101-109}, doi = {10.1016/j.theriogenology.2024.12.009}, pmid = {39674107}, issn = {1879-3231}, abstract = {During cryopreservation, spermatozoa produce excess reactive oxygen species (ROS), which attack the plasma membrane, disrupt the physiological structure of the sperm, and ultimately decrease semen quality. This study investigated the effects of different N-acetylcysteine (NAC) concentrations on the cryopreservation of semen from Qianbei Ma goats. Semen samples were collected from five bucks with motility rates above 80 %. The treatment groups were diluted 20-fold in extenders containing 3 or 9 mM NAC and cryopreserved in liquid nitrogen, whereas the control group did not include NAC. After thawing, the sperm motility, antioxidant gene expression, enzyme activity, and cell structure were analysed. The NAC-treated groups showed improved post-thaw sperm motility. The 9 mM NAC group presented the highest catalase (CAT) and glutathione peroxidase activities, lowest ROS levels, and fewest apoptotic sperms. Moreover, the 3 mM NAC group presented the highest superoxide dismutase activity and L-cysteine levels and the lowest malondialdehyde levels. Additionally, sperm membrane integrity and mitochondrial membrane potential were significantly higher in the NAC-treated group than that in the control. Further analysis of antioxidant and apoptotic gene expression in the treated sperm revealed that the 9 mM NAC group presented significantly greater CAT and GPX4 expression than the control and 3 mM NAC groups, whereas the apoptotic genes BAX and Caspase3 were elevated in the control group compared to both the NAC groups. In summary, adding NAC to semen extenders enhanced antioxidant gene expression, increased enzyme activity, and improved post-thaw semen quality, with the 9 mM NAC treatment showing the optimal effects.}, } @article {pmid39674082, year = {2024}, author = {Tsuji, Y and Ninomiya-Tsuji, J and Shen, MYF and DiFrancesco, BR}, title = {Modulation of iron metabolism by new chemicals interacting with the iron regulatory system.}, journal = {Redox biology}, volume = {79}, number = {}, pages = {103444}, pmid = {39674082}, issn = {2213-2317}, abstract = {Despite the vital role of iron and vulnerability of iron metabolism in disease states, it remains largely unknown whether chemicals interacting with cellular proteins are responsible for perturbation of iron metabolism. We previously demonstrated that cisplatin was an inhibitor of the iron regulatory system by blocking IRP2 (iron regulatory protein 2) binding to an iron-responsive element (IRE) located in the 3'- or 5'-UTR (untranslated region) of key iron metabolism genes such as transferrin receptor 1 (TfR1) and ferritin mRNAs. To guide the development of new chemical probes to modulate the IRP-IRE regulatory system, we used an artificial intelligence (AI)-based ligand design and screened a chemical library composed of cysteine-reactive warheads. Using wild type and mutant IRE-luciferase reporter cells, we identified new IRP-IRE inhibitors such as V004-0872 harboring chloroacetamide, while its analog V011-6261 with chloropropanamide completely lost the inhibitory activity. V004-0872 inhibited the human IRP2 via Cys512 and caused decreased iron levels through reciprocal TfR1 downregulation and ferritin upregulation. V004-0872 increased production of mitochondrial reactive oxygen species (ROS) and exhibited cytotoxicity that was inhibited by N-acetyl cysteine but not the ferroptosis inhibitor ferrostatin-1. Furthermore, we found that widely used haloketone protease inhibitors and acetamide herbicides inhibit the IRP-IRE system. Since IRP2 overexpression is responsible for iron excess conditions to promote growth of several cancers and exacerbation of iron-overload diseases, these results and new compounds lay the groundwork for new reagents and strategies to limit the availability of iron and oxidative stress in iron-overloaded disease conditions.}, } @article {pmid39672615, year = {2024}, author = {Ju, Z and Bi, Y and Gao, M and Yin, Y and Xu, T and Xu, S}, title = {Emamectin benzoate and nanoplastics induce PANoptosis of common carp (Cyprinus carpio) gill through MAPK pathway.}, journal = {Pesticide biochemistry and physiology}, volume = {206}, number = {}, pages = {106202}, doi = {10.1016/j.pestbp.2024.106202}, pmid = {39672615}, issn = {1095-9939}, mesh = {Animals ; *Carps/metabolism ; *Gills/drug effects/metabolism ; *Ivermectin/analogs & derivatives/toxicity ; *MAP Kinase Signaling System/drug effects ; Microplastics/toxicity ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Water Pollutants, Chemical/toxicity ; Nanoparticles/toxicity ; }, abstract = {Emamectin benzoate (EMB) is a pesticide that is frequently used. Nanoplastics (NPs) are a recently identified class of pollutants that are ubiquitous in the environment. In the aquatic environment, NPs can appear together with EMB, which may exacerbates the damage to water and aquatic organisms. However, the damage and mechanism of EMB and NPs to the gill tissue of common carp (Cyprinus carpio) remain unclear. Therefore, an EMB or/NPs exposure model was constructed to explore the mechanism of EMB or/NPs exposure on carp gill damage. This study was done by immunofluorescence, RT-qPCR, Western blot and other methods. Both in vitro and in vivo data indicated that EMB or NPs exposure could lead to gill tissue destruction, oxidative stress with the increased of ROS fluorescence intensity, MDA and H2O2 content, and the decreased CAT and GSH-PX activity, and the activation of MAPK pathway. Subsequently, PANoptosomes were activated with the up-regulated mRNA and protein expression of RIPK-1, Caspase-1,NLRP3, ACS, RIPK-3, Caspase-8, resulting in PANoptosis including the increased GSDMD, Caspase-3, MLKL expression. Notably, the results following combined exposure were more pronounced than those observed following exposure alone. The addition of N-acetylcysteine (NAC) and 3-methylindole (3-MI) further evidenced that EMB or/and NPs exposure can induce gill damage via the ROS/MAPK/PANoptosis pathway. Therefore, the present study reveals that EMB or/NPs exposure induces PANoptosis in carp gill by activating ROS/p38/MAPK signaling.}, } @article {pmid39669379, year = {2024}, author = {Letras-Luna, DE and Rosas-Murrieta, NH and Pazos-Salazar, NG and Flores-Hernández, J and Castelán, F and Venegas, B and Díaz, A and Treviño, S and Juárez-Serrano, D and García-Suastegui, WA and Handal-Silva, A and Morán-Perales, JL}, title = {Efficacy of Local N-Acetylcysteine Administration in Mitigating OHSS Parameters: A Comparative Analysis With Dopaminergic Agonist in the OHSS Model.}, journal = {International journal of endocrinology}, volume = {2024}, number = {}, pages = {1634072}, pmid = {39669379}, issn = {1687-8337}, abstract = {In this study, we evaluated the effects of intrabursal administration of cabergoline and N-acetylcysteine on ovarian hyperstimulation syndrome (OHSS) in an immature rat model. The study assessed body, ovarian, and uterine weights, as well as the concentrations of vascular endothelial growth factor A (VEGF-A). Moreover, levels of MDA, 4-HDA, and nitrites were assessed in ovarian homogenates, and vascular permeability was quantified in the peritoneal cavity. Ovarian morphology was characterized using histology and hematoxylin-eosin staining, determining the count of ovarian follicles and corpus luteum. Our results demonstrated a significant increase in lipoperoxidation, nitrite levels, and VEGF-A concentrations in the OHSS group compared to the control group. These biochemical alterations corroborate the successful induction of OHSS in the experimental model. Direct injection into the ovarian bursa resulted in reduced vascular permeability and VEGF-A levels, suggesting that the effects of cabergoline are predominantly ovarian. Particularly, cabergoline did not significantly alter other parameters such as ovarian weight, lipoperoxidation, nitrite levels, or morphology. Conversely, low concentrations of N-acetylcysteine (25-50 µg/kg) significantly reduced ovarian and uterine weights, VEGF-A levels, and vascular permeability. Interestingly, this dose-response relationship was not observed at higher NAC concentrations (100-200 μg/kg), suggesting a potential threshold beyond which NAC loses efficacy in these specific parameters. Our results suggest that the localized administration of N-acetylcysteine shows promise as a therapeutic strategy for OHSS by modulating key parameters associated with the syndrome. These promising results warrant further investigation into its mechanisms and efficacy, potentially expanding therapeutic options for OHSS management.}, } @article {pmid39662870, year = {2024}, author = {Eker, A and Eraslan, G}, title = {Single and combined effect of chrysin and N-acetylcysteine against deltamethrin exposure in rats.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {196}, number = {}, pages = {115191}, doi = {10.1016/j.fct.2024.115191}, pmid = {39662870}, issn = {1873-6351}, abstract = {Effects of chrysin and N-acetylcysteine on deltamethrin exposure in rats were investigated. Eighty male Wistar Albino rats, weighing between 150 and 200 g and aged 2-3 months, were used and evenly allocated into eight groups. The control group of rats received a corn oil vehicle. Chrysin (50 mg/kg.bw), N-acetylcysteine (50 mg/kg.bw), a combination of chrysin and N-acetylcysteine, deltamethrin (10 mg/kg.bw), deltamethrin combined with chrysin, deltamethrin combined with N-acetylcysteine, and a combination of deltamethrin, chrysin, and N-acetylcysteine were administered via oral gavage for a duration of 21 days. Tissue (liver, kidney, brain, testis, heart, lung) and blood of oxidative stress markers (MDA, NO, GSH, SOD, CAT, GSH-Px, GR, GST, G6PD), hepatic caspase 3, 9 and p53 protein levels, biochemical parameters (glucose, triglyceride, cholesterol, BUN, creatinine, uric acid, total protein, albumin, LDH, AST, ALT, ALP, PChE activities/levels), as well as rat body/organ weights and plasma/liver deltamethrin concentrations. The administration of chrysin and N-acetylcysteine independently did not alter the assessed parameters. Significant differences were observed in most parameters assessed in the deltamethrin-alone group compared to the control group, whereas the parameter values in the groups treated with chrysin, NAC, or their combination with deltamethrin were similar to those of the control.}, } @article {pmid39643123, year = {2024}, author = {Zhang, D and Chen, Y and Sun, Y and Xu, H and Wei, R and Zhou, Y and Li, F and Li, J and Wang, J and Chen, P and Xi, L}, title = {Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells.}, journal = {Biochemical pharmacology}, volume = {232}, number = {}, pages = {116695}, doi = {10.1016/j.bcp.2024.116695}, pmid = {39643123}, issn = {1873-2968}, abstract = {Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities. However, whether GA induces pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian cancer (OC) has not yet been reported. This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines. Typical pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a caspase-3 inhibitor could switch GA-induced cell death from pyroptosis to apoptosis, indicating GA induced caspase-3/GSDME-dependent pyroptosis. Furthermore, this research indicated that GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment. Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues. Notably, the expressions of GSDME-N, cleaved caspase-3 and other proteins were increased in tumor tissues with high-dose GA groups. These findings demonstrate that GA-treated OC cells could induce GSDME-mediated pyroptosis through the ROS/p53/mitochondria signaling pathway and caspase-3/-9 activation. Thus, GA is a promising therapeutic agent for OC treatment.}, } @article {pmid39641827, year = {2024}, author = {Yang, Y and Ren, D and Peng, B and Huang, J and Yang, B}, title = {The role of FOXM1 in acetylcysteine improving diabetic periodontitis.}, journal = {Journal of molecular histology}, volume = {56}, number = {1}, pages = {34}, pmid = {39641827}, issn = {1567-2387}, support = {2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; 2023NSFSC1515//This study is supported by Sichuan Provincial Natural Science Foundation/ ; }, mesh = {Animals ; Mice ; *Forkhead Box Protein M1/metabolism/genetics ; *Acetylcysteine/pharmacology ; *Periodontitis/metabolism/pathology/genetics/complications ; *Diabetes Mellitus, Experimental/metabolism/complications ; Reactive Oxygen Species/metabolism ; Male ; Osteoclasts/metabolism ; Macrophages/metabolism ; Disease Models, Animal ; Oxidative Stress ; Diabetes Complications/metabolism ; Cell Differentiation ; RAW 264.7 Cells ; }, abstract = {Diabetic periodontitis (DP) stems from hyperglycemia-driven oxidative stress amplification and chronic inflammation, leading to periodontal tissue breakdown. Misregulated forkhead box protein M1 (FOXM1) play key roles in this process, exacerbating both inflammation and oxidative stress. In light of N-Acetylcysteine (NAC)'s potent anti-oxidative capacity and anti-inflammatory potential, understanding how it modulates these central pathways to alleviate DP holds high scientific and clinical importance. An animal model of diabetic mice periodontitis was established, and the model mice were injected with FOXM 1 adenovirus to enrich FOXM 1, and the periodontal pathological histology of each group was evaluated by HE staining. Western blotting and RT-PCR evaluated the expression levels of factors involved in bone destruction. ELISA evaluated the amount of inflammatory factors in mice serum. FOXM 1 over-expression and NAC were treated in murine macrophages, and the intracellular reactive oxygen species(ROS) levels in macrophages were measured using a DCFH-DA probe. Receptor activator of NF-κB ligand (RANKL) and lipopolysaccharide (LPS) were used to establish the macrophage osteoclast differentiation model and test the expression level of osteoclast differentiation factors after giving NAC. Hydrogen peroxide was used to establish a peroxidation environment, the plasmid silenced C-JUN, and the DNA binding activity of activating protein-1(AP1) was detected by EMSA. The effect of peroxidation on the osteoclast differentiation level was determined by WB. Mice with DP model had epithelial damage and inflammatory infiltration in periodontal tissues, and in the FOXM1 enriched group, the periodontal epithelial damage was repaired and inflammation was alleviated. FOXM1 enrichment resulted in DP model lower expression of RANKL (P < 0.01), macrophage colony-stimulating factor (M-CSF) (P < 0.01) and elevated expression of osteoprotegerin (OPG) (P < 0.001). Serum levels of pro-inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were elevated in DP mice (P < 0.001), and anti-inflammatory factor IL-10 was reduced(P < 0.001),, and FOXM1 enrichment significantly reversed inflammatory factor levels (P < 0.01). Overexpression of FOXM1 reduced ROS content in macrophages (P < 0.001), and NAC was performed to further reduce ROS content (P < 0.01). Silencing of FOXM1 elevated the expression of osteoclast-specific genes NFATc1, TRAP and OSCAR (P < 0.01), and the addition of NAC on top of silencing of FOXM1 markedly suppressed the expression level of osteoclast-specific genes (P < 0.01). ROS increased the transcriptional activity of AP1 (P < 0.001), which promoted osteoclast-specific gene expression (P < 0.001), and osteoclast-specific gene expression was decreased after silencing C-JUN (P < 0.01). FOXM1 relieve diabetic periodontitis inflammation and promote bone formation, regulates ROS production and ROS increases the transcriptional activity of AP1 and affects the osteoclastic differentiation of macrophages, which plays a positive role in bone protection in diabetic periodontitis.}, } @article {pmid39632267, year = {2024}, author = {Sadowski, M and Zawieja, E and Chmurzynska, A}, title = {The impact of N-acetylcysteine on lactate, biomarkers of oxidative stress, immune response, and muscle damage: A systematic review and meta-analysis.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {23}, pages = {e70198}, pmid = {39632267}, issn = {1582-4934}, support = {//Ministerstwo Edukacji i Nauki/ ; }, mesh = {*Acetylcysteine/pharmacology ; *Biomarkers ; Humans ; *Oxidative Stress/drug effects ; *Lactic Acid/metabolism ; Glutathione/metabolism ; Muscle, Skeletal/drug effects/metabolism ; Dietary Supplements ; Myalgia/drug therapy ; Tumor Necrosis Factor-alpha/metabolism/blood ; Exercise ; Immunity/drug effects ; Interleukin-6/metabolism/blood ; }, abstract = {N-acetylcysteine (NAC) is a compound whose mechanism of action is intricately linked to the provision of cysteine for glutathione synthesis. It has been used in medicine and has also made significant inroads into sports, as it can modify the levels of several biomarkers, including those of oxidative processes, inflammation and muscle damage after exercise. Because the effectiveness of NAC supplementation is unclear, the primary objective of the present study was to perform a meta-analysis elucidating how NAC supplementation alters the concentrations of GSH (glutathione), GSSG (glutathione disulfide), TBARS (thiobarbituric acid reactive substances), IL-6 (interleukin 6), TNF-α (tumour necrosis factor alpha), CK (creatine kinase), lactate, and muscle soreness after physical exertion. Suitable studies were searched for from February to September 2023, and the results of those included (n = 20) indicate that NAC supplementation significantly diminishes both muscle soreness (p = 0.03; the mean difference (MD) of NAC's effect was -0.43 with a 95% confidence interval (CI), -0.81, -0.04) and lactate concentrations after exercise (p = 0.03; the MD -0.56 mmol/L; 95% CI, -1.07, -0.06). A substantial decrease was observed in concentrations of IL-6 (p = 0.03; the standardized MD (SMD) was -1.71; 95% CI, -3.26, -0.16) and TBARS (p = 0.02; SMD was -1.03, 95% CI, -1.90, -0.15). Furthermore, an elevation in GSH concentration was observed following supplementation. However, we saw no significant effect of NAC on TNF-α, CK or GSSG concentrations. NAC supplementation holds promise for attenuating muscle soreness, lactate, TBARS and IL-6 concentrations and increasing GSH level following physical exertion.}, } @article {pmid39631278, year = {2024}, author = {Li, G and Wu, M and Chen, K and Xu, Y and Zhang, X and Chen, Y and Zhang, H and Zhang, R and Huang, X}, title = {ROS-mediated M1 polarization-necroptosis crosstalk involved in Di-(2-ethylhexyl) phthalate-induced chicken liver injury.}, journal = {Poultry science}, volume = {104}, number = {1}, pages = {104558}, pmid = {39631278}, issn = {1525-3171}, abstract = {The widespread use of plasticizers poses a serious threat to the environment and poultry health. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer that can cause liver damage with prolonged exposure. Oxidative stress is closely associated with DEHP toxicity. Macrophage polarization plays an important role in many physiological and pathological processes and regulates disease development. This study aims to elucidate the mechanism of chronic DEHP exposure leading to chicken liver injury through oxidative stress-induced M1 polarization-necroptosis. In this study, the DEHP exposure model of chicken liver and the single and co-culture model of LMH and HD11 cells were established. With increasing dose and time, DEHP decreased body weight, increased liver coefficient, raised activities of liver function indicators and caused pathological liver damage in chickens. Further studies revealed the increase of reactive oxygen species (ROS) level and malonaldehyde (MDA) content, and the decrease of total antioxidant capacity (T-AOC) level, total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) activities, which led to excessive oxidative stress in the liver. In addition, there was increased infiltration of liver macrophages (CD68), upregulation of M1 polarization indicators (CD86, iNOS, IL-1β, TNF-α) and downregulation of M2 polarization indicators (CD163, Arg-1, IL-10, TGF-β) and appearance of necroptosis (RIPK1, RIPK3, MLKL). The vitro experiments confirmed the addition of N-acetylcysteine (NAC) inhibited M1 polarization and necroptosis. Besides, M1 polarization of HD11 cells promoted necroptosis of LMH cells in the HD11-LMH co-culture system. In brief, ROS-mediated M1 polarization-necroptosis is involved in DEHP-induced liver injury. This study provides a reference for environmental toxicant exposure in livestock and poultry farming.}, } @article {pmid39628758, year = {2024}, author = {Ejubović, M and Kapic, D and Custovic, S and Lazović Salčin, E and Lepara, O and Kurtović, A and Jahić, R and Kulo Cesic, A and Paralija, B and Ziga Smajic, N and Jagodić Ejubović, A and Hasanbegovic, S and Katica, M and Besic, A and Djesevic, E and Fajkić, A}, title = {Therapeutic Potential of N-acetylcysteine and Glycine in Reducing Pulmonary Injury in Diabetic Rats.}, journal = {Cureus}, volume = {16}, number = {11}, pages = {e72902}, pmid = {39628758}, issn = {2168-8184}, abstract = {INTRODUCTION: Diabetes mellitus is associated with systemic complications, including the development of pulmonary injury, characterized mainly by excessive accumulation of extracellular matrix components and inflammatory cell infiltration in lung tissue. This process is driven by oxidative stress and chronic inflammation, both caused and exacerbated by hyperglycemia. N-acetylcysteine (NAC) and glycine, known for their antioxidant and anti-inflammatory effects, offer potential therapeutic benefits in mitigating diabetes-induced lung injury.

OBJECTIVE: The study aimed to investigate the effects of supplementation by either NAC or glycine or their combination on reducing lung injury in rats with type 1 diabetes Materials and methods: The study used 30 adult Wistar albino rats (10 weeks old, weighing between 180 g and 380 g). Six of them were used as controls, while 24 adult rats (10 weeks old, 180-380 g) with type 1 diabetes, induced through a single intraperitoneal injection of streptozotocin (STZ) at a dose of 55 mg/kg, were randomly assigned to four experimental groups: control (CTL), diabetic (Db), NAC treatment (diabetic+NAC), glycine treatment (diabetic+glycine), and combined NAC and glycine treatment (diabetic+NAC+glycine). NAC (100 mg/kg) and glycine (250 mg/kg) were administered orally for 12 weeks. At the end of the study, lung tissues were collected for histopathological examination. Qualitative, semi-quantitative, and stereological histological analysis was used to analyze structural changes in the lung tissue. Semi-quantitative scoring was carried out to evaluate the extent of inflammation, while stereological analysis was performed to determine the volume density of alveolar spaces and septal connective tissue. The semi-quantitative scoring included scores ranging from 0 (absent), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe).

RESULTS: Qualitative histological analysis revealed pronounced inflammation and fibrosis in the lungs of untreated diabetic rats, characterized by thickened alveolar septa and immune cell infiltration. Both treatments with NAC and glycine individually reduced inflammation and fibrosis compared to untreated diabetic rats. The greatest improvement was observed in the NAC+glycine group, where the alveolar structure appeared almost normal, with minimal inflammation. Semiquantitative analysis showed statistically significant differences in peribronchial and peribrochiolar infiltrates between the diabetic group (2.16±0.47) and the control group (0.33±0.21, p=0.026). The combination of NAC and glycine significantly reduced peribronchial and peribronchiolar infiltrates (0.33±0.33, p=0.026) compared to the diabetic group. Similarly, septal inflammatory infiltrates were significantly lower in the NAC+glycine group (1±0.36) compared to diabetic rats (3.33±0.33, p=0.004). Total airway inflammatory infiltration was also significantly reduced in the NAC+glycine group (1.33±0.33, p=0.002) compared to the diabetic group (5.5±0.5).

CONCLUSION: As the combination of NAC and glycine demonstrated protective effects against lung inflammation and fibrosis in diabetic rats, a synergistic effect of NAC and glycine in mitigating pulmonary complications associated with type 1 diabetes may be suggested. These findings warrant further exploration of the combination for managing diabetic lung disease and potentially other fibrotic conditions.}, } @article {pmid39626181, year = {2025}, author = {Sivasinprasasn, S and Chattipakorn, K and Pratchayasakul, W and Chattipakorn, SC and Chattipakorn, N}, title = {N-Acetylcysteine enhances low-dose estrogen efficacy against ischemia-reperfusion injury in estrogen-deprived obese insulin-resistant rats.}, journal = {Menopause (New York, N.Y.)}, volume = {32}, number = {1}, pages = {81-90}, pmid = {39626181}, issn = {1530-0374}, mesh = {Animals ; Female ; *Insulin Resistance ; *Rats, Wistar ; *Acetylcysteine/pharmacology/administration & dosage ; Rats ; *Obesity/drug therapy/complications ; *Estrogens/administration & dosage/pharmacology ; *Ovariectomy ; *Myocardial Reperfusion Injury/drug therapy/prevention & control ; *Estradiol/blood/pharmacology/administration & dosage ; Diet, High-Fat/adverse effects ; Ventricular Function, Left/drug effects ; Reperfusion Injury/drug therapy/prevention & control ; Disease Models, Animal ; }, abstract = {OBJECTIVES: Postmenopausal women are at higher risk of metabolic syndrome and cardiovascular disease, which are aggravated by obesity. Although estrogen provides cardiometabolic protection, chronic high-dose treatment could be harmful. This study investigated the efficacy of combined N-acetylcysteine (NAC) and low-dose estrogen treatment against cardiometabolic dysfunction in female estrogen-deprived obese rats with cardiac ischemia-reperfusion (I/R) injury.

METHODS: Bilateral ovariectomized (O) female Wistar rats were fed a high-fat diet (H) for 12 weeks. Then, rats were treated for 4 weeks with one of the following: vehicle (OH; sesame oil), regular-dose estrogen (E; 50 μg/kg/d), low-dose estrogen (e; 25 μg/kg/d), NAC (N; 100 mg/kg/d), or combined low-dose estradiol with NAC (eN). All rats then underwent cardiac I/R injury, and the left ventricle (LV) function and mitochondrial function were investigated (n = 6/group). Statistical analysis was performed by one-way ANOVA followed by Fisher's least significant difference post hoc test.

RESULTS: Body weight, visceral fat, plasma glucose, and plasma cholesterol were significantly increased with impaired LV function and heart rate variability in OH rats. OH-E rats had decreased plasma insulin and Homeostatic Model Assessment for Insulin Resistance index. Both OH-E and OH-eN rats had similarly improved heart rate variability and LV function. During cardiac I/R, OH-E and OH-eN rats had preserved left ventricular ejection fraction, stroke volume, and attenuated arrhythmias. Impaired cardiac mitochondrial function and infarct size were similarly reduced in OH-E and OH-eN rats.

CONCLUSIONS: Combined NAC and low-dose estrogen treatment shares similar efficacy as regular-dose estrogen in attenuating cardiac dysfunction, cardiac mitochondrial dysfunction, and protecting the heart against I/R injury in estrogen-deprived obese insulin-resistant rats.}, } @article {pmid39624277, year = {2024}, author = {Maurer, S and Fuchs, M and Brenner, RE and Riegger, J}, title = {Glutathione has cell protective and anti-catabolic effects in articular cartilage without impairing the chondroanabolic phenotype.}, journal = {Heliyon}, volume = {10}, number = {22}, pages = {e40368}, pmid = {39624277}, issn = {2405-8440}, abstract = {Joint injuries and consequent oxidative stress is a high-risk factor for developing post-traumatic osteoarthritis (OA). While antioxidative therapy using N-acetylcysteine (NAC) has cell- and chondroprotective effects following cartilage injury, it strongly impairs matrix synthesis. Consequently, direct application of Glutathione (GSH) was tested as an alternative therapeutic approach using an ex vivo cartilage trauma model and isolated chondrocytes, with comparison to NAC. Porcine cartilage explants were traumatized using a drop tower with an impact energy of 0.47 J and afterwards treated with 0.5-2 mM GSH or 2 mM NAC for 4 days according to a standardized protocol. The effects of antioxidative treatment on the chondrogenic phenotype were tested in a 3D pellet culture for 28 days. Our results demonstrated that both antioxidants had cell protective effects after cartilage trauma. GSH was most effective at a concentration of 0.5 mM, as confirmed in experiments with isolated human chondrocytes exposed to H2O2. At this concentration, GSH did not impair cell proliferation or hyaline cartilage matrix synthesis, while NAC suppressed the chondrogenic phenotype in pellet culture. Both, NAC and GSH elevated the intracellular GSH concentration, indicating an efficient uptake of the antioxidants. Furthermore, both therapeutics inhibited the activity of the matrix degrading enzyme MMP-2. Our results demonstrated cell- and chondroprotective effects by NAC and GSH therapy after cartilage trauma, with GSH demonstrating advantages in preserving the chondrogenic phenotype.}, } @article {pmid39624161, year = {2024}, author = {Zhang, D and Qin, C and Meng, F and Han, X and Guo, X}, title = {N-Acetylcysteine Treats Spinal Cord Injury by Inhibiting Astrocyte Proliferation.}, journal = {Analytical cellular pathology (Amsterdam)}, volume = {2024}, number = {}, pages = {6624283}, pmid = {39624161}, issn = {2210-7185}, mesh = {Animals ; *Spinal Cord Injuries/pathology/metabolism/drug therapy ; *Astrocytes/drug effects/metabolism/pathology ; *Cell Proliferation/drug effects ; *Acetylcysteine/pharmacology ; *Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Rats ; Janus Kinases/metabolism ; STAT Transcription Factors/metabolism ; Connexin 43/metabolism ; Male ; Glial Fibrillary Acidic Protein/metabolism ; Disease Models, Animal ; }, abstract = {Astrocyte proliferation commonly occurs after spinal cord injury (SCI). N-Acetylcysteine (NAC) has a regulatory effect on many diseases. In this study, we investigated the effect and underlying mechanism of NAC on astrocytes in SCI. We isolated rat primary astrocytes and stimulated with lipopolysaccharide to induce cell proliferation and degeneration. A rat model of SCI was also established, and the Basso-Beattie-Bresnahan score was determined. The localization of glial fibrillary acidic protein in the cells and tissues was determined using TUNEL staining and immunofluorescence, while that of connexin 43 was assessed via immunofluorescence. Pathological changes associated with SCI were detected using hematoxylin and eosin staining, and inflammatory factors were detected using enzyme-linked immunosorbent assay. Additionally, JAK/STAT expression was evaluated using western blotting and quantitative reverse transcription polymerase chain reaction. NAC downregulated the glial fibrillary acidic protein abundance and connexin 43 in reactive astrocytes and SCI rat models while inhibiting the abundance of secreted proteins DSPG, HSPG, KSPG, tenascin C, vimentin, CSPG, ephrin-B2, and nestin. NAC also regulated the JAK/STAT signaling pathway by downregulating the expression of JAK2, STAT5, STAT3, STAT1, PIM1, NFATc1, COL1, COL3, TGF-β, SMAD1, CTGF, CyCD1, and CDK4, thus alleviating SCI. Finally, NAC exhibited durable effects, with no SCI recurrence within 60 days. Therefore, NAC relieves SCI by inhibiting the proliferation of reactive astrocytes and suppressing the expression of secretory and JAK/STAT pathway proteins.}, } @article {pmid39618229, year = {2024}, author = {He, T and Ren, K and Xiang, L and Yao, H and Huang, Y and Gao, Y}, title = {Efficacy of N-Acetylcysteine as an Adjuvant Therapy for Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {British journal of hospital medicine (London, England : 2005)}, volume = {85}, number = {11}, pages = {1-16}, doi = {10.12968/hmed.2024.0560}, pmid = {39618229}, issn = {1750-8460}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Arthritis, Rheumatoid/drug therapy ; *Randomized Controlled Trials as Topic ; Antioxidants/therapeutic use ; Blood Sedimentation ; Treatment Outcome ; }, abstract = {Aims/Background Rheumatoid arthritis (RA) is an inflammatory autoimmune disease and N-acetylcysteine (NAC) is considered a potential therapeutic agent for RA due to strong antioxidant and anti-inflammatory properties. Therefore, this systematic review and meta-analysis aimed to evaluate the efficacy of NAC as an adjuvant therapy for RA. Methods A systematic search was conducted across five databases from inception to 1 August 2024, including CINAHL, Cochrane Library, EMBASE, PubMed, and Web of Science. The Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the included studies. Sensitivity analysis was performed when significant heterogeneity was identified. Results Four studies involving 204 patients were included in our meta-analysis. The results indicated that NAC alleviated disease activity in RA patients (Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR): mean difference (MD) = 0.54). Additionally, NAC reduced inflammatory markers (erythrocyte sedimentation rate (ESR): MD = 3.00). However, the beneficial effects of NAC on oxidative stress in RA patients were not observed. Conclusion This meta-analysis demonstrated the efficacy of NAC in reducing inflammatory markers, improving joint tenderness, and swelling in patients with RA.}, } @article {pmid39617257, year = {2025}, author = {Wang, L and Chen, JH and Zhang, YJ and Zhang, MB and Zeng, T}, title = {PPARβ/δ agonist GW0742 mitigates acute liver damage induced by acetaminophen overdose in mice.}, journal = {Toxicology and applied pharmacology}, volume = {494}, number = {}, pages = {117180}, doi = {10.1016/j.taap.2024.117180}, pmid = {39617257}, issn = {1096-0333}, mesh = {Animals ; *Acetaminophen/toxicity ; *PPAR-beta/agonists ; Male ; *PPAR delta/agonists ; *Chemical and Drug Induced Liver Injury/pathology/prevention & control/drug therapy/etiology ; Mice ; *Mice, Inbred C57BL ; *Thiazoles/pharmacology ; Oxidative Stress/drug effects ; Drug Overdose/drug therapy ; Liver/drug effects/pathology/metabolism ; Kupffer Cells/drug effects/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/agonists ; Inflammasomes/metabolism ; Phenols ; Sulfhydryl Compounds ; }, abstract = {Liver damage caused by acetaminophen (APAP) overdose remains a worldwide medical problem. New therapeutic medicines for APAP poisoning are needed as the efficacy of the only antidote, N-acetyl-cysteine (NAC), significantly decreases if administered after 8 h of APAP intake and massive APAP overdose remains to induce hepatotoxicity despite the timely administration of NAC. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) possesses versatile roles including regulation of lipid homeostasis and anti-inflammation in the liver. This study aimed to investigate the effects of GW0742, one specific PPARβ/δ agonist, on APAP-caused liver damage in mice. We found that GW0742 (40 mg/kg, i.p.) pretreatment completely blocked the increase of serum aminotransferase activities, hepatocyte necrosis, oxidative stress, and liver inflammation in mice exposed to 300 mg/kg APAP (i.p.). Mechanistically, GW0742 pretreatment significantly suppressed the M1 polarization of liver Kupffer cells and activation of NLRP3 inflammasome. Interestingly, GW0742 remained effective when administered 6 h after APAP exposure, although its efficacy was less pronounced than that administered 6 h before the APAP challenge. Notably, GW0742 exhibited a more profound effect than NAC evidenced by the lower serum alanine transaminase (ALT) level and the improved histopathological manifestation. Furthermore, exposure to APAP for 6 h had resulted in dramatic liver inflammation, while pretreatment with GW0742 prior to APAP exposure did not influence the increase in serum aminotransferase activity and oxidative stress at 2 h after APAP exposure. These results highlight that PPARβ/δ may be a promising therapeutic target for treating APAP-caused acute liver damage probably acting on liver macrophages.}, } @article {pmid39616487, year = {2024}, author = {Su, R and Qiao, M and Gao, T and Gao, J and Nie, L and Li, S and Wang, Y and Pang, Y and Li, Q}, title = {Effect of N-acetylcysteine on apoptosis and autophagy of macrophages infected with Mycobacterium tuberculosis.}, journal = {Journal of infection in developing countries}, volume = {18}, number = {10}, pages = {1566-1575}, doi = {10.3855/jidc.19372}, pmid = {39616487}, issn = {1972-2680}, mesh = {*Autophagy/drug effects ; *Acetylcysteine/pharmacology ; *Macrophages/drug effects/microbiology ; *Apoptosis/drug effects ; *Mycobacterium tuberculosis/drug effects ; Humans ; *Reactive Oxygen Species/metabolism ; *Oxidative Stress/drug effects ; Bacterial Load/drug effects ; }, abstract = {INTRODUCTION: The purpose of this study was to observe the effect of N-acetylcysteine (NAC) on oxidative stress (OS), intracellular Mycobacterium tuberculosis (MTB) load, apoptosis, and autophagy of macrophages infected with H37Rv MTB. In addition, we explored the possible mechanism of action, to provide a rationale for the use of NAC in the treatment of tuberculosis.

METHODOLOGY: We divided THP-1 macrophages into four groups: control, control + NAC, H37Rv, and H37Rv + NAC. OS, apoptosis, autophagy and intracellular MTB colony-forming unit (CFU) indexes were measured at 0, 4, 24, and 48 hours, respectively. Then, various indicator changes were systematically compared.

RESULTS: The levels of reactive oxygen species (ROS), malondialdehyde (MDA), apoptosis rate, and LC3II/ β-actin ratio in the H37Rv group increased at 4 hours and reached their peak at 48 hours. The ROS and MDA in the H37Rv + NAC group were lower than those in the H37Rv group. CFU in the H37Rv + NAC group increased at 24 hours and decreased at 48 hours after treatment with NAC, relative to the H37Rv group. In addition, the H37Rv + NAC group showed a decrease in LC3II/β-actin ratio 48 hours after NAC treatment, compared to the H37Rv group.

CONCLUSIONS: MTB infection can lead to an increase in macrophage OS, apoptosis, and autophagy levels. However, after treatment with NAC, the growth of MTB in macrophages is inhibited, and OS and autophagy levels are reduced. The antioxidant effect and inhibitory effect of NAC on MTB are related to MTB-mediated macrophage OS and autophagy.}, } @article {pmid39616350, year = {2024}, author = {Zhang, H and Pertiwi, H and Michiels, J and Gaublomme, D and Majdeddin, M and Hou, Y and Boone, M and Elewaut, D and Josipovic, I and Degroote, J}, title = {Improvement of antioxidant capability by dietary N-acetyl cysteine supplementation alleviates bone loss induced by chronic heat stress in finisher broilers.}, journal = {Journal of animal science and biotechnology}, volume = {15}, number = {1}, pages = {158}, pmid = {39616350}, issn = {1674-9782}, abstract = {BACKGROUND: Heat stress (HS) incidence is associated with the accumulation of reactive substances, which might be associated with bone loss. N-Acetylcysteine (NAC) exhibits strong antioxidants due to its sulfhydryl group and being as the precursor for endogenous glutathione synthesis. Therefore, interplay between oxidative stress and bone turnover of broilers and the effects of dietary NAC inclusion on antioxidant capability and "gut-bone" axis were evaluated during chronic HS.

RESULTS: Implementing cyclic chronic HS (34 °C for 7 h/d) evoked reactive oxygen species excessive production and oxidant stress, which was accompanied by compromised tibia mass. The RNA-seq of proximal tibia also revealed the enrichment of oxidation-reduction process and inflammatory outbursts during HS. Although no notable alterations in the growth performance and cecal microbiota were found, the diet contained 2 g/kg NAC enhanced the antioxidant capability of heat-stressed broiler chickens by upregulating the expression of Nrf2 in the ileum, tibia, and bone marrow. Simultaneously, NAC tended to hinder NF-κB pathway activation and decreased the mRNA levels of the proinflammatory cytokines in both the ileum and bone marrow. As a result, NAC suppressed osteoclastogenesis and osteoclast activity, thereby increasing osteocyte-related gene expression. Furthermore, the inclusion of NAC tended to increase the ash content and density of the whole tibia, as well as improve cortical thickness and bone volume of the diaphysis.

CONCLUSIONS: These findings HS-mediated outburst of oxidant stress accelerates bone resorption and negatively regulates the bone quality of tibia, which is inhibited by NAC in broilers.}, } @article {pmid39615429, year = {2024}, author = {Antwi-Baah, R and Acquah, MEE and Dapaah, MF and Chen, X and Walker, J and Liu, H}, title = {Juxtaposing the antibacterial activities of different ZIFs in photodynamic therapy and their oxidative stress approach.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {247}, number = {}, pages = {114397}, doi = {10.1016/j.colsurfb.2024.114397}, pmid = {39615429}, issn = {1873-4367}, abstract = {Instigating oxidative stress is a crucial aspect of antibacterial therapy. Yet, its behavior is poorly understood in the context of zeolitic imidazolate frameworks (ZIFs) - a group of highly promising antibacterial agents. To address this gap, a series of ZIF@Ce6 particles were synthesized to investigate the impact of particle shape, size, and metal ion type on oxidative stress and bactericidal activity. For the first time, the interplay between the physicochemical properties and antibacterial activities of different ZIF@Ce6 particles is demonstrated, while unearthing their oxidative stress strategy in photodynamic therapy. Notably, the incorporation of chlorin e6 (Ce6), combined with light irradiation, amplified the bactericidal effect of the ZIFs and achieved a rare minimum inhibition concentration (MIC) of 12.5 µgmL[-1] for ZIF-8. We discovered that singlet oxygen ([1]O2) production varies with particle shape and size, while photodynamic activity reshuffles the antibacterial performance sequence from pristine to modified ZIF-8. Interestingly, reactive oxygen species (ROS) accumulation and glutathione depletion tests revealed that oxidative stress in pristine ZIF-8 is predominantly induced by ROS, whereas both ROS and glutathione contribute to the oxidative stress in ZIF@Ce6 and pristine ZIF-67. When bacteria are preincubated with the antioxidant N-acetyl cysteine, the bactericidal activity of ZIF@Ce6 increases while the activity of pristine ZIF-8 is reduced and that of ZIF-67 remains unchanged. This study deepens our understanding of the antibacterial properties of ZIFs and their oxidative stress paths, paving way for the fabrication of ZIF-based materials with enriched and targeted antibacterial properties.}, } @article {pmid39607014, year = {2024}, author = {Esezobor, CI and Bhatt, GC and Effa, EE and Hodson, EM}, title = {Fenoldopam for preventing and treating acute kidney injury.}, journal = {The Cochrane database of systematic reviews}, volume = {11}, number = {11}, pages = {CD012905}, pmid = {39607014}, issn = {1469-493X}, mesh = {*Fenoldopam/therapeutic use ; Humans ; *Acute Kidney Injury/prevention & control ; *Randomized Controlled Trials as Topic ; Child ; Adult ; *Bias ; *Dopamine Agonists/therapeutic use ; Postoperative Complications/prevention & control ; Cardiac Surgical Procedures/adverse effects ; Sepsis/prevention & control/complications ; }, abstract = {BACKGROUND: Fenoldopam is a short-acting benzazepine selective dopaminergic A1 (DA1) receptor agonist with increased activity at the D1 receptor compared with dopamine. Activation of the DA1 receptors increases kidney blood flow because of dilatation of the afferent and efferent arterioles. Previous reviews have been published on the efficacy and safety of fenoldopam for acute kidney injury (AKI); however, they either combined data on its effect on both prevention and treatment of AKI, focused on only those undergoing cardiac surgery and/or excluded children.

OBJECTIVES: This review aimed to assess the benefits and harms of fenoldopam for the prevention or treatment of AKI in children and adults.

SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating fenoldopam for the prevention or treatment of AKI in children and adults following surgery, radiocontrast exposure or sepsis.

DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility, assessed the studies for risk of bias and extracted data from the studies. Dichotomous outcomes were presented as relative risk (RR) with 95% confidence intervals (CI). For continuous outcomes, the mean difference (MD) with 95% CI was used. Statistical analysis was performed using the random-effects model. We assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.

MAIN RESULTS: We identified 25 RCTs, including 3339 randomised participants. Twenty-three studies used fenoldopam for preventing AKI and two for the treatment of AKI. Nine studies included participants undergoing cardiac surgery, and one included children. The risks of bias for sequence generation and concealment were low in 11 and 13 studies, respectively. Only 13 and 18 studies were at low risk of performance bias and detection bias, respectively. The risk of attrition bias and selective reporting were judged to be at low risk of bias in 17 and 10 studies, respectively. We included data in the meta-analyses from eight of the 14 studies comparing fenoldopam with placebo or saline, all six studies comparing fenoldopam with dopamine, all five studies comparing fenoldopam with N-acetylcysteine (NAC) for the prevention of AKI and from the two studies comparing fenoldopam with placebo or saline for the treatment of AKI. Compared with placebo or saline fenoldopam probably results in fewer participants developing AKI (RR 0.72, 95% CI 0.53 to 0.98; 8 studies, 1147 participants; I[2] = 48%; moderate certainty) but may make little or no difference to the number requiring kidney replacement therapy (KRT) (RR 0.81, 95% CI 0.31 to 2.15; 7 studies, 835 participants; I[2] = 17%), risk of death (RR 0.76, 95% CI: 0.58 to 1.00; 7 studies, 944 participants; I[2] = 0%) or change in urine output (SMD 0.20, 95% CI -0.44 to 0.84; 2 studies, 58 participants; I[2] = 34%; all low certainty). Fenoldopam may result in a shorter stay in the ICU (MD -1.81 days; 95% CI -2.41 to -1.21; 4 studies, 403 participants; I[2] = 0%). It is uncertain whether adverse events (hypotension, myocardial infarction, drug intolerance, cardiac arrhythmias) differed between the treatment groups as the certainty of the evidence was very low. In patients undergoing cardiac surgery, fenoldopam, compared to placebo or saline, may make little or no difference to the prevention of AKI, the need for KRT or death. Compared with dopamine, fenoldopam may make little or no difference to the prevention of AKI (RR 0.62, 95% CI 0.23 to 1.68; 4 studies, 398 participants; I[2] = 78%), the number requiring KRT (RR 0.74, 95% CI 0.29 to 1.87; 4 studies, 434 participants; I[2] = 0%) or the risk of death (RR 1.27, 95% CI 0.36 to 4.50; 2 studies, 174 participants; I[2] = 0%) (all low certainty). It is uncertain whether participants receiving fenoldopam were more likely to develop hypotension compared with those receiving dopamine (RR 3.00, 95% CI 1.06 to 8.52; 1 study, 80 participants; very low certainty). Change in urine output was not reported. It is uncertain whether fenoldopam compared with NAC prevents AKI (RR 1.68, 95% CI 0.79 to 3.56; 3 studies, 359 participants; I[2] = 38%), reduces the need for KRT (RR 0.96, 95% CI 0.15 to 6.26; 2 studies, 137 participants; I[2] = 0%), or the risk of death (RR 1.05, 95% CI 0.07 to 15.66; 1 study, 39 participants) (all very low certainty). It is uncertain whether hypotension was more frequent with fenoldopam (RR 5.10, 95% CI 0.25, 104.94; 1 study, 192 participants; very low certainty). Change in urine output was not reported. In participants with established AKI, it is uncertain whether fenoldopam compared to placebo or half saline reduces the numbers needing KRT (RR: 0.91, 95% CI 0.54 to 1.54; 2 studies, 822 participants; I[2] = 58%; very low certainty) or the risk of death (RR 0.81, 95% CI 0.44 to 1.48; 2 studies, 822 participants; I[2] = 66%; very low certainty), or if it increases the risk of hypotension (RR 1.65, 95% CI 1.22 to 2.22; 2 studies, 822 participants; I[2] = 0%; very low certainty).

AUTHORS' CONCLUSIONS: Fenoldopam administration in patients at risk of AKI is probably associated with a lower risk of developing AKI and shorter ICU stay when compared with placebo or saline, but has little or no effect on the need for KRT or the risk of death. In those undergoing cardiac surgery, fenoldopam may not confer any benefits compared with placebo or saline. Furthermore, it remains unclear whether fenoldopam is more or less effective than either dopamine or NAC in reducing the risk for AKI or the need for KRT. Further well-designed and adequately powered studies are required to evaluate the efficacy and safety of fenoldopam in preventing or treating AKI.}, } @article {pmid39600278, year = {2024}, author = {Zhang, J and Chen, A and Song, Y}, title = {Propofol Triggers Cell Death in Lung Cancer Cells by Increasing PANX1 Expression, Activating the Mitochondrial Cell Death Pathway, and Enhancing ROS Levels.}, journal = {Discovery medicine}, volume = {36}, number = {190}, pages = {2231-2243}, doi = {10.24976/Discov.Med.202436190.205}, pmid = {39600278}, issn = {1944-7930}, mesh = {Humans ; *Propofol/pharmacology ; *Reactive Oxygen Species/metabolism ; *Connexins/metabolism/genetics ; *Lung Neoplasms/pathology/metabolism/drug therapy/genetics ; *Mitochondria/drug effects/metabolism ; A549 Cells ; *Nerve Tissue Proteins/metabolism/genetics ; Apoptosis/drug effects ; Cell Death/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Membrane Potential, Mitochondrial/drug effects ; }, abstract = {BACKGROUND: Lung cancer treatment remains a global challenge due to tumor cell resistance. Propofol, traditionally used as an anesthetic, has demonstrated potential anti-tumor properties. This study seeks to elucidate how propofol induces cell death in lung cancer cells by upregulating Pannexin 1 (PANX1) expression, activating the mitochondrial cell death pathway, and augmenting reactive oxygen species (ROS) production.

METHODS: In this study, the A549 lung cancer cell line was employed as the experimental model. Cells underwent exposure to varying propofol concentrations and were pre-treated with H2O2 and N-acetylcysteine (NAC) to simulate oxidative stress and antioxidant conditions. Various techniques, including 5-Ethynyl-2'-deoxyuridine (EdU), colony formation, Transwell, 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL), and JC-1 (5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide) probes, were employed to evaluate propofol's effects on lung cancer cell viability, growth, invasion, ROS levels, apoptosis, and mitochondrial membrane potential. Western blot analysis was used to measure PANX1, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, and Cytochrome C (Cyt C) protein levels. Additionally, PANX1's influence on propofol-induced apoptosis was investigated through siRNA interference.

RESULTS: The experiment unveiled propofol's dose-dependent inhibition of A549 lung cancer cell growth, coupled with decreased cell proliferation and invasion attributable to heightened ROS production. Notably, propofol treatment significantly elevated mitochondrial membrane potential, signifying activation of the mitochondrial cell death pathway (p < 0.01). Furthermore, propofol upregulated PANX1 expression (p < 0.01), thereby intensifying apoptosis signaling, whereas PANX1 inhibition ameliorated propofol-induced apoptosis (p < 0.01). These findings underscore the pivotal role of PANX1 upregulation and ROS augmentation in propofol-induced apoptosis in lung cancer cells.

CONCLUSION: This study provides evidence that propofol induces cell death in lung cancer cells by upregulating PANX1, activating the mitochondrial apoptosis pathway, and increasing ROS production. These findings suggest that targeting PANX1 and ROS could enhance the anti-cancer efficacy of propofol in lung cancer.}, } @article {pmid39599590, year = {2024}, author = {Poulios, A and Papanikolaou, K and Draganidis, D and Tsimeas, P and Chatzinikolaou, A and Tsiokanos, A and Jamurtas, AZ and Fatouros, IG}, title = {The Effects of Antioxidant Supplementation on Soccer Performance and Recovery: A Critical Review of the Available Evidence.}, journal = {Nutrients}, volume = {16}, number = {22}, pages = {}, pmid = {39599590}, issn = {2072-6643}, mesh = {*Antioxidants/pharmacology ; Humans ; *Dietary Supplements ; *Soccer ; *Athletic Performance/physiology ; Oxidative Stress/drug effects ; Muscle, Skeletal/drug effects/metabolism ; Sports Nutritional Physiological Phenomena ; }, abstract = {Background Soccer is linked to an acute inflammatory response and the release of reactive oxygen species (ROS). Antioxidant supplements have shown promising effects in reducing muscle damage and oxidative stress and enhancing the recovery process after eccentric exercise. This critical review highlights the influence of antioxidant supplements on performance and recovery following soccer-related activity, training, or competition. Methods: English-language publications from the main databases that examine how antioxidant-based nutrition and supplements affect the recovery process before, during, and after soccer practice or competition were used. Results:Coenzyme Q10 (CoQ10), astaxanthin (Asx), red orange juice (ROJS), L-carnitine (LC), N-acetyl cysteine (NAC), beetroot (BET), turmeric root, and tangeretin reduce muscle damage (creatine kinase, myoglobin, cortisol, lactate dehudrogenase, muscle soreness). Tangeretin, docosahexaenoic acid (DHA), turmeric root, and aronia melanocarpa restrict inflammation (leukocytes, prostalagdin E2, C-reactive protein, IL-6 and 10). Q10, DHA, Asx, tangeretin, lippia citriodora, quercetin, allopurinol, turmeric root, ROJS, aronia melanocarpa, vitamins C-E, green tea (GTE), and sour tea (STE) reduce oxidative stress (malondialdehude, glutathione, total antioxidant capacity, superoxide dismutases, protein carbonyls, ascorbate, glutathione peroxidase, and paraoxonase 1). BET and NAC reinforce performance (endurance, jump, speed, strength). Conclusions: Further research is needed to determine the main mechanism and the acute and long-term impacts of antioxidant supplements in soccer.}, } @article {pmid39598577, year = {2024}, author = {Scialabba, C and Craparo, EF and Bonsignore, S and Cabibbo, M and Cavallaro, G}, title = {Lipid-Polymer Hybrid Nanoparticles in Microparticle-Based Powder: Evaluating the Potential of Methylprednisolone Delivery for Future Lung Disease Treatment via Inhalation.}, journal = {Pharmaceutics}, volume = {16}, number = {11}, pages = {}, pmid = {39598577}, issn = {1999-4923}, support = {B73C22001250006//Italian Ministry of University and Research under PNRR/ ; G71I22000950001//POC SICILIA 14-20/ ; }, abstract = {BACKGROUND: Lipid-polymer hybrid nanoparticles (LPHNPs) offer a promising method for delivering methylprednisolone (MePD) to treat lung inflammation, addressing aggregation issues seen with polymer-only formulations.

OBJECTIVES: This study aimed to develop LPHNPs for MePD delivery, assessing their physicochemical properties, drug loading, cytocompatibility, and release profiles, ultimately enabling inhalable microparticle-based powder.

METHODS: The nanoparticles were formulated using α,β-poly(N-2-hydroxyethyl)-DL-aspartamide-g-Rhodamine B-g-poly(lactic acid) (PHEA-g-RhB-g-PLA) and phospholipids DPPC, DOTAP, and DSPE-PEG2000 in a 45:30:25 weight ratio. Their size, redispersion after freeze-drying, drug loading (DL%), and controlled release were evaluated. Cytocompatibility was assessed on 16-HBE cell lines, measuring anti-inflammatory effects via IL-6 and IL-8 levels. Spray drying was optimized to produce microparticles using mannitol (MAN), leucine (LEU), and N-acetylcysteine (NAC).

RESULTS: The nanoparticles had a size of 186 nm and a DL% of 2.9% for MePD. They showed good cytocompatibility, significantly reducing IL-6 and IL-8 levels. Spray drying yielded microparticles with a fine particle fraction (FPF) of 62.3% and a mass median aerodynamic diameter (MMAD) of 3.9 µm. Inclusion of LPHNPs@MePD (0.25% w/v) resulted in FPF and MMAD values of 56.7% and 4.4 µm. In conclusion, this study described the production of novel inhalable powders as carriers for MePD-loaded nanostructures with favorable physicochemical properties, cytocompatibility, and promising aerosol performance, indicating their potential as an effective inhalable therapy for lung inflammation with corticosteroids, especially for treating chronic diseases.}, } @article {pmid39598160, year = {2024}, author = {Singh, M and Kim, A and Young, A and Nguyen, D and Monroe, CL and Ding, T and Gray, D and Venketaraman, V}, title = {The Mechanism and Inflammatory Markers Involved in the Potential Use of N-acetylcysteine in Chronic Pain Management.}, journal = {Life (Basel, Switzerland)}, volume = {14}, number = {11}, pages = {}, pmid = {39598160}, issn = {2075-1729}, abstract = {N-acetylcysteine (NAC) has established use as an antidote for acetaminophen overdose and treatment for pulmonary conditions and nephropathy. It plays a role in regulating oxidative stress and interacting with various cytokines including IL-1β, TNFα, IL-8, IL-6, IL-10, and NF-κB p65. The overexpression of reactive oxygen species (ROS) is believed to contribute to chronic pain states by inducing inflammation and accelerating disease progression, favoring pain persistence in neuropathic and musculoskeletal pain conditions. Through a comprehensive review, we aim to explore the mechanisms and inflammatory pathways through which NAC may manage neuropathic and musculoskeletal pain. Evidence suggests NAC can attenuate neuropathic and musculoskeletal pain through mechanisms such as inhibiting matrix metalloproteinases (MMPs), reducing reactive oxygen species (ROS), and enhancing glutamate transport. Additionally, NAC may synergize with opioids and other pain medications, potentially reducing opioid consumption and enhancing overall pain management. Further research is needed to fully elucidate its therapeutic potential and optimize its use in pain management. As an adjuvant therapy, NAC shows potential for chronic pain management, offering significant benefits for public health.}, } @article {pmid39596166, year = {2024}, author = {Lee, MM and Chou, YX and Huang, SH and Cheng, HT and Liu, CH and Huang, GJ}, title = {Renoprotective Effects of Brown-Strain Flammulina velutipes Singer in Chronic Kidney Disease-Induced Mice Through Modulation of Oxidative Stress and Inflammation and Regulation of Renal Transporters.}, journal = {International journal of molecular sciences}, volume = {25}, number = {22}, pages = {}, pmid = {39596166}, issn = {1422-0067}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Flammulina/chemistry ; Mice ; *Renal Insufficiency, Chronic/drug therapy/metabolism/chemically induced/pathology ; *Cisplatin/adverse effects ; *Kidney/drug effects/metabolism/pathology ; *Mice, Inbred C57BL ; Male ; Inflammation/drug therapy/metabolism/pathology ; Antioxidants/pharmacology ; Disease Models, Animal ; Apoptosis/drug effects ; Plant Extracts/pharmacology/chemistry ; }, abstract = {Cisplatin, widely used in chemotherapy, acts through mechanisms such as oxidative stress to damage the DNA and cause the apoptosis of cancer cells. Although effective, cisplatin treatment is associated with considerable side effects including chronic kidney disease (CKD). Studies on brown-strain Flammulina velutipes Singer (FVB) have shown its significant antioxidant and immunomodulatory effects. High-performance liquid chromatography (HPLC) confirmed that the FVB extract contained gallic acid and quercetin. This study investigated whether FVB extract can improve and protect against cisplatin-induced CKD in mice. C57BL/6 mice were used as an animal model, and CKD was induced through intraperitoneal cisplatin injection. FVB was orally administered to the mice for 14 consecutive days. N-acetylcysteine (NAC) was administered in the positive control group. Organ pathology and serum biochemical analyses were conducted after the mice were sacrificed. Significant dose-dependent differences were discovered in body mass, kidney mass, histopathology, renal function, inflammatory factors, and antioxidant functions among the different groups. FVB extract reduced the severity of cisplatin-induced CKD in pathways related to inflammation, autophagy, apoptosis, fibrosis, oxidative stress, and organic ion transport proteins; FVB extract, thus, displays protective physiological activity in kidney cells. Additionally, orally administered high doses of the FVB extract resulted in significantly superior renal function, inflammatory factors, antioxidative activity, and fibrotic pathways. This study establishes a strategy for future clinical adjunctive therapy using edible-mushroom-derived FVB extract to protect kidney function.}, } @article {pmid39594532, year = {2024}, author = {Pangrazzi, L and Cerilli, E and Balasco, L and Dall'O', GM and Chelini, G and Pastore, A and Weinberger, B and Bozzi, Y}, title = {N-Acetylcysteine Counteracts Immune Dysfunction and Autism-Related Behaviors in the Shank3b Mouse Model of Autism Spectrum Disorder.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594532}, issn = {2076-3921}, support = {2020//university of Trento/ ; 2021//Autism Research Institute/ ; }, abstract = {Autism spectrum disorder (ASD) includes a range of neurodevelopmental disabilities characterized by social interaction deficits, communication impairments, and repetitive behaviors. Previous studies have shown that pro-inflammatory conditions play a key role in ASD. Despite this, how oxidative stress and inflammation may contribute to ASD-related behaviors is still poorly understood. Here, we reported that increased levels of molecules related to inflammation are present in the cerebellum and peripheral blood (PB) of mice lacking Shank3b, an established model of syndromic ASD. In parallel, immune dysfunction was documented in the bone marrow (BM) and spleens of mutant mice. N-acetylcysteine (NAC) treatment rescued inflammation in the cerebellum and PB and impaired the production of pro-inflammatory molecules in the BM and spleen. In addition, social impairment was counteracted in NAC-treated Shank3b[-/-] animals. Taken together, our results provide clear evidence of the key role of cerebellar oxidative stress and inflammation in the establishment of ASD-related behaviors. Furthermore, our findings underscore the importance of considering ASD as a systemic disorder.}, } @article {pmid39594521, year = {2024}, author = {Aitken, RJ and Wilkins, A and Harrison, N and Kobarfard, K and Lambourne, S}, title = {Towards the Development of Novel, Point-of-Care Assays for Monitoring Different Forms of Antioxidant Activity: The RoXsta[TM] System.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594521}, issn = {2076-3921}, support = {G2201336//Memphasys Ltd/ ; }, abstract = {(1) Background: This study set out to develop a series of simple, novel, rapid methods for assessing different forms of antioxidant activity. (2) Methods: An ABTS platform was used to engineer: (i) an electrochemical post-activation assay to assess free radical scavenging activity; (ii) an electrochemical pre-activation strategy to assesses the suppression of free radical formation; (iii) a horseradish peroxidase-mediated oxidation system to monitor hydrogen peroxide scavenging activity and (iv) a cumene peroxide-hematin system to determine the ability of samples to scavenge the mixture of organic peroxides and peroxyl and alkoxyl radicals generated in the presence of these reagents. Each assay was assessed against a panel of candidate antioxidant compounds to determine their relative activities and specificities. In addition, human semen samples were analyzed to determine how the results of these antioxidant assays correlated with semen quality. (3) Results: All 4 assays revealed dose-dependent antioxidant activity on the part of vitamin C, N-acetyl cysteine, hypotaurine, BSA, melatonin, glutathione, resveratrol and epigallocatechin gallate. The other compounds tested either completely lacked antioxidant activity or were only active in one of the assays. Using unfractionated human semen as an exemplar of biological fluids rich in antioxidants, the outputs from the individual assays were found to reflect different aspects of semen quality. When the data from all 4 assays were combined, accurate predictions were generated reflecting the importance of oxidative stress in defining semen quality as reflected by sperm count, seminal lipid aldehyde content, sperm DNA damage and free radical generation by the sperm mitochondria. (4) Conclusions: The methodologies described in this paper constitute the basis for rapid, point-of-care assessments of oxidative stress.}, } @article {pmid39594437, year = {2024}, author = {Wang, Y and Lv, J and Liu, G and Yao, Q and Wang, Z and Liu, N and He, Y and Il, D and Tusupovich, JI and Jiang, Z}, title = {ZnO NPs Impair the Viability and Function of Porcine Granulosa Cells Through Autophagy Regulated by ROS Production.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {39594437}, issn = {2076-3921}, abstract = {The zinc oxide nanoparticles (ZnO NPs) is one of the most extensively utilized metal oxide nanoparticles in biomedicine, human food, cosmetics and livestock farming. However, growing evidence suggests that there is a potential risk for humans and animals because of the accumulation of ZnO NPs in cells, which leads to cell death through several different pathways. Nevertheless, the effects of ZnO NPs on porcine granulosa cells (PGCs) and how ZnO NPs regulate the follicular cells are unknown. In this study, we aimed to elucidate the role of ZnO NPs in the porcine ovary by using PGCs. Firstly, we identified the characterization of ZnO NPs used in this study and the results showed that the size of ZnO NPs was 29.0 nm. The results also demonstrated that ZnO NPs impaired cell viability and decreased steroid hormone secretion in PGCs. In addition, ZnO NPs induced reactive oxygen species (ROS) production, leading to oxidative stress of PGCs. Meanwhile, ZnO NPs also triggered autophagy in PGCs by increasing the ratio of LC3-II/LC3-I, along with the expression of SQSTM1 and ATG7. Finally, the results from N-acetylcysteine (NAC) addition suggested that ZnO NPs promoted autophagy through the enhancement of ROS production. In summary, this study demonstrates that ZnO NPs impair the viability and function of PGCs through autophagy, which is regulated by ROS production.}, } @article {pmid39591907, year = {2024}, author = {Bajpai, A and Bharathi, V and Kumawat, R and Tomar, RS and Patel, BK}, title = {Activation of the yeast MAP kinase, Slt2, protects against TDP-43 and TDP-25 toxicity in the Saccharomyces cerevisiae proteinopathy model.}, journal = {Biochemical and biophysical research communications}, volume = {741}, number = {}, pages = {151062}, doi = {10.1016/j.bbrc.2024.151062}, pmid = {39591907}, issn = {1090-2104}, mesh = {*Saccharomyces cerevisiae/metabolism/genetics ; *Saccharomyces cerevisiae Proteins/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Unfolded Protein Response/drug effects ; *Mitogen-Activated Protein Kinases/metabolism/genetics ; TDP-43 Proteinopathies/metabolism/genetics/pathology ; Humans ; Enzyme Activation ; Oxidative Stress/drug effects ; }, abstract = {TDP-43 proteinopathy is observed in human neurodegenerative diseases like ALS. Heterologous TDP-43 expression in the yeast model also mimics several proteinopathy features such as cytotoxicity, cytoplasmic mis-localization and oxidative stress. Among the pathways implicated in modulating the TDP-43 toxicity in yeast, the unfolded protein response (UPR) activation was also identified. Here, we examine the role of stress-regulated yeast MAP kinase, Slt2, which also links cellular stress with UPR activation, in modulating the toxicities of the full-length TDP-43 and its 25 kDa C-terminal fragment, TDP-25. We find enhancement in the cytotoxicity of TDP-43, as well as TDP-25, in the yeast cells deleted for the MAP kinase, Slt2, but not in those lacking other yeast MAP kinases, Kss1 and Fus3. Unlike in the wild-type yeast, upon treatment with an antioxidant N-acetyl cysteine, the TDP-43 toxicity could not be mitigated in the slt2Δ yeast but the TDP-25 toxicity was significantly rescued suggesting oxidative stress as an important contributor to the TDP-25 toxicity. Notably, TDP-43 as well as TDP-25 expressions could cause significant phosphorylation of Slt2 suggesting activation of this MAP Kinase due to their toxicities. Interestingly, in the slt2Δ cells, lacking the MAP Kinase activity, a treatment with low concentrations of an UPR activator molecule, DTT, caused significant reduction in the toxicities of both TDP-43 as well as TDP-25. Taken together, these findings suggest that TDP-43 and TDP-25 toxicity-induced stress-mediated activation of the MAP kinase Slt2 helps in mitigating their toxicities in the yeast model possibly through UPR activation.}, } @article {pmid39590959, year = {2024}, author = {Li, T and Bian, B and Ji, R and Zhu, X and Wo, X and Song, Q and Li, Z and Wang, F and Jia, Y}, title = {Polyethylene Terephthalate Microplastic Exposure Induced Reproductive Toxicity Through Oxidative Stress and p38 Signaling Pathway Activation in Male Mice.}, journal = {Toxics}, volume = {12}, number = {11}, pages = {}, pmid = {39590959}, issn = {2305-6304}, support = {42377430//National Natural Science Foundation of China/ ; 2021MS08046//Natural Science Foundation of Inner Mongolia/ ; BYJJ-DXK2022018//Scientific research Fund of Baotou Medical College/ ; HLJH202418//Bud plan of Baotou Medical College/ ; }, abstract = {Polyethylene terephthalate (PET) is a type of polymer plastic that is often used to make plastic bags, bottles, and clothes. However, the waste of such plastic products is decomposed into microplastics (MPs), which are plastic fragments smaller than 5 mm, by various external forces such as wind, UV radiation, mechanical wear, and biodegradation. PET MPs have been widely detected in the environment and human tissue samples; however, the toxicity and mechanism of PET MPs in mammals are still unclear. In this study, we investigated the male reproductive toxicity of PET MPs and their underlying mechanism. A total of 80 male mice were orally exposed to 0.01, 0.1, and 1 mg/d of PET MPs (with a diameter of 1 μm) for 42 days. The results showed that 1 μm PET MPs induced different degrees of pathological damage to testicular tissues, decreased sperm quality, and increased the apoptosis of spermatogenic cells via oxidative stress and p38 signaling pathway activation. To further illustrate and verify the mechanistic pathway, oxidative stress was antagonized using N-acetylcysteine (NAC), and the activation of the p38 signaling pathway was blocked using SB203580. The results revealed that the male reproductive injury effects after exposure to PET MPs were significantly ameliorated. Specifically, the testicular tissue lesions were relieved, the sperm quality improved, and the apoptosis of spermatogenic cells decreased. These results demonstrated that PET MP exposure induced male reproductive toxicity through oxidative stress and the p38 signaling pathway. This study provides new insights into the reproductive toxicity of MPs in males, as well as valuable references for public health protection strategies.}, } @article {pmid39582278, year = {2024}, author = {Zheng, Y and Tian, Q and Yang, H and Cai, Y and Zhang, J and Wu, Y and Zhu, S and Qiu, Z and Lin, Y and Hong, J and Zhang, Y and Dockrell, D and Ma, S}, title = {Identification of Nicotinic Acetylcholine Receptor for N-Acetylcysteine to Rescue Nicotine-induced Injury Using Beating Cilia in Primary Tissue Derived Airway Organoids.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2407054}, doi = {10.1002/advs.202407054}, pmid = {39582278}, issn = {2198-3844}, support = {2023B0909020003//Department of Science and Technology of Guangdong Province/ ; 32371470//National Natural Science Foundation of China/ ; 82341019//National Natural Science Foundation of China/ ; 82111530212//National Natural Science Foundation of China/ ; 2021B1515020092//Natural Science Foundation of Guangdong Province/ ; RCYX20200714114736146//Shenzhen Science and Technology Innovation Commission/ ; 2022QNA095//Health Committee of Fujian Province/ ; JC2022007//Cross-disciplinary Research and Innovation Fund of Tsinghua SIGS/ ; }, abstract = {Smoking is one of the major contributors to airway injuries. N-acetylcysteine (NAC) has been proposed as a treatment or preventive measure for such injuries. However, the exact nature of the smoking-induced injury and the protective mechanism of NAC are not yet fully understood. Here, patient tissue-derived airway organoids for modeling smoking-induced injury, therapeutic investigation, and mechanism studies are developed. Airway organoids consist mainly of ciliated cells, together with basal cells, goblet cells, and myofibroblast-like cells. The organoids display apical-out and basal-in polarity and are enriched in beating cilia, which are sensitive to smoking challenge and NAC treatment. An algorithm is developed to measure ciliary beating activity by analyzing the altered beating pattern of cilia in response to nicotine challenge and NAC treatment. Nicotinic acetylcholine receptors (nAChRs) expressed by airway organoids are involved in the mechanisms of nicotine-induced injury through the nicotine-nAChR pathway. In contrast to the common understanding that NAC has an antioxidative effect that mitigates airway damage, it is elucidated that NAC binding to nicotine can abolish the binding capacity of nicotine to nAChRs and thus prevent nicotine-induced injury. This study focuses on the advances and potential of humanized organoids in understanding biological processes, mechanisms, and identifying therapeutic targets.}, } @article {pmid39580917, year = {2024}, author = {Najjar, RS and Grace, WW and Siqueira, APS and Setka, AM and Lu, W and Wang, S and Feresin, RG}, title = {Polyphenols have unique cellular effects that are distinct from antioxidant function in Toll-like receptor 4-mediated inflammation in RAW264.7 macrophage-like cells.}, journal = {Nutrition research (New York, N.Y.)}, volume = {132}, number = {}, pages = {136-151}, doi = {10.1016/j.nutres.2024.10.007}, pmid = {39580917}, issn = {1879-0739}, mesh = {Animals ; *Polyphenols/pharmacology ; Mice ; *Antioxidants/pharmacology ; *Toll-Like Receptor 4/metabolism ; *Macrophages/drug effects/metabolism ; RAW 264.7 Cells ; *Lipopolysaccharides ; *Inflammation/metabolism/drug therapy ; Signal Transduction/drug effects ; Plant Extracts/pharmacology ; Spin Labels ; Cyclic N-Oxides/pharmacology ; Oxidation-Reduction ; Acetylcysteine/pharmacology ; }, abstract = {Plant polyphenols are bioactive compounds touted for their antioxidant effects, and this is often the primary attribute used to explain their health benefits. However, we hypothesize that polyphenols have molecular properties independent of antioxidant function. The objective of this study was to investigate whether polyphenols had distinct molecular effects compared to pure antioxidants. RAW 264.7 macrophages were pretreated with either TEMPOL, a superoxide scavenger, N-acetyl cysteine, a hydroxyl radical and hydrogen peroxide scavenger, or polyphenol extracts from blackberry, blueberry, raspberry, strawberry, kale, and baru nut. After 1 hour of pretreatment, cells were treated with lipopolysaccharides (100 ng/mL) for an additional 6 hour. Antioxidants and polyphenol extracts elicited antioxidant effects in vitro; however, polyphenols regulated redox proteins in a distinct, protective manner, whereas antioxidants, TEMPOL, and N-acetyl cysteine, did not. Additionally, distinct effects were observed in downstream Toll-like receptor 4 signaling and transcriptional activity of inflammatory proteins. We conclude that polyphenols have unique molecular effects that are independent of just their free radical scavenging capacity. This work advances our molecular understanding of how polyphenols act to target inflammation.}, } @article {pmid39579577, year = {2024}, author = {Li, WL and Li, K and Chang, WG and Shi, H and Zhang, WX and Wang, Z and Li, W}, title = {20(R)-ginsenoside Rg3 alleviates diabetic retinal injury in T2DM mice by attenuating ROS-mediated ER stress through the activation of the Nrf2/HO-1 axis.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {135}, number = {}, pages = {156202}, doi = {10.1016/j.phymed.2024.156202}, pmid = {39579577}, issn = {1618-095X}, mesh = {Animals ; *Ginsenosides/pharmacology ; *NF-E2-Related Factor 2/metabolism ; *Endoplasmic Reticulum Stress/drug effects ; *Diabetic Retinopathy/drug therapy/metabolism ; Male ; *Diabetes Mellitus, Experimental/drug therapy/complications ; *Heme Oxygenase-1/metabolism ; *Reactive Oxygen Species/metabolism ; Mice ; Humans ; *Mice, Inbred C57BL ; Endothelial Cells/drug effects/metabolism ; Retina/drug effects/metabolism ; Panax/chemistry ; Diabetes Mellitus, Type 2/drug therapy/metabolism ; Diet, High-Fat/adverse effects ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; Membrane Proteins ; }, abstract = {BACKGROUND: Although our previous work confirmed 20(R)-ginsenoside Rg3 (R-Rg3), which is an active ingredient in the Panax Ginseng C.A. Meyer, to have good anti-diabetic activity, its beneficial effect on diabetic retinal injury was found to be limited.

PURPOSE: This study aims to investigate the protective effects of R-Rg3 on diabetes-induced retinal injury and the associated molecular mechanisms of action.

METHODS: Diabetic retinal injury was induced in mice using a combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). R-Rg3 (10 and 20 mg/kg) was subsequently administered for 6 weeks. The human retinal endothelial cells (HRECs) were subjected to high glucose (HG)-induced injury for the in vitro analysis and treated with R-Rg3 (4, 8, 16 μM), antioxidant N-Acetylcysteine (NAC, 1 mM) and Nrf2 inhibitor ML385 (5 μM). The mice retinas then underwent functional and histopathological analysis. Expression levels of proteins related to the Nrf2/HO-1 axis, tight junction proteins, endoplasmic reticulum (ER) stress and the apoptosis in retinal tissue and HRECs were determined by western blot. Expressions of ZO-1 and Nrf2 in the retina and HRECs were assessed by immunofluorescence. Additional evaluations included measuring body weights, fasting blood glucose (FBG), lipid levels and oxidative markers.

RESULTS: The results showed 6 weeks of R-Rg3 treatment significantly restored the functional changes and redox system imbalance that was induced by HFD/STZ in mice. R-Rg3 was also found to significantly reduce retinal barrier damage and thickness changes resulting from hyperglycaemia exposure. At the same time, R-Rg3 also protected HRECs from HG-induced damage. R-Rg3 could also activate Nrf2/HO-1 axis and inhibit endoplasmic reticulum stress as a means of alleviating retinal endothelial cells apoptosis. The molecular docking results also demonstrated that R-Rg3 had a good binding ability with Nrf2.

CONCLUSION: Our study suggested Nrf2/HO-1 axis might be crucial for the ability of R-Rg3 to prevent diabetic retinal injury.}, } @article {pmid39574249, year = {2024}, author = {Fong, KM and Ng, GWY and Leung, AKH and Lai, KY}, title = {High-dose Intravenous N-Acetylcysteine in Mechanically Ventilated Patients with COVID-19 Pneumonia: A Propensity-Score Matched Cohort Study.}, journal = {Journal of intensive care medicine}, volume = {}, number = {}, pages = {8850666241299391}, doi = {10.1177/08850666241299391}, pmid = {39574249}, issn = {1525-1489}, abstract = {BACKGROUND: Current therapies for severe COVID-19, such as steroids and immunomodulators are associated with various side effects. N-acetylcysteine (NAC) has emerged as a potential adjunctive therapy with minimal side effects for patients with cytokine storm due to COVID-19. However, evidence supporting high-dose intravenous NAC in severe COVID-19 pneumonia requiring mechanical ventilation is limited.

METHODS: We conducted a retrospective analysis of consecutive patients aged ≥ 18 who were admitted for acute respiratory failure (PaO2/FiO2 ratio <300) with SARS-CoV-2 infection to the Intensive Care Unit (ICU) of Queen Elizabeth Hospital from fifth July 2020 to 31[st] October 2022. Inclusion was limited to patients who required mechanical ventilation. High-dose NAC refers to a dosage of 10 g per day. The primary outcome was all-cause mortality within 28 days. Propensity-score matched analysis using logistic regression was performed.

RESULTS: Among the 136 patients analyzed, 42 (40.3%) patients received NAC. The unmatched NAC patients displayed a higher day-28 mortality (12 (28.6%) versus 4 (6.5%), p = 0.005) and fewer ventilator-free days (18.5 (0-23.0) versus 22.0 (18.3-24.0), p = 0.015). No significant differences were observed in ICU and hospital length of stays among survivors. In patients who were not treated with tocilizumab, those receiving NAC exhibited a trend toward a quicker reduction in C-reactive protein compared to those who did not receive NAC.After propensity score matching which included 64 patients with 33 (51.6%) receiving NAC, no significant differences were found in 28-day mortality, ventilator-free days, or ICU and hospital length of stay. After adjusting for potential confounders, logistic regression of the propensity score-matched population did not demonstrate that the use of NAC independently affected 28-day mortality.

CONCLUSIONS: In patients with COVID-19 pneumonia requiring mechanical ventilation and receiving standard COVID-19 treatment, the addition of high-dose NAC did not lead to improved clinical outcomes.}, } @article {pmid39570044, year = {2024}, author = {Saha, M and Qiu, L and Han-Hallett, Y and Welch, CJ and Cooks, RG}, title = {Simultaneous Quantitation of Multiple Biological Thiols Using Reactive Ionization and Derivatization with Charged Mass Tags.}, journal = {Analytical chemistry}, volume = {96}, number = {49}, pages = {19414-19421}, doi = {10.1021/acs.analchem.4c03807}, pmid = {39570044}, issn = {1520-6882}, mesh = {*Sulfhydryl Compounds/chemistry/analysis/blood ; Humans ; Chromatography, High Pressure Liquid ; Mass Spectrometry/methods ; Oxidation-Reduction ; Animals ; Cysteine/blood/analysis/chemistry ; Homocysteine/analysis/blood ; }, abstract = {The biologically important thiols (cysteine, homocysteine, N-acetyl cysteine, and glutathione) are key species in redox homeostasis, and there is a clinical need to measure them rapidly, accurately, and simultaneously at low levels in complex biofluids. The solution to the challenge presented here is based on a new derivatizing reagent that combines a thiol-selective unit to optimize the chemical transformation and a precharged pyridinium unit chosen to maximize sensitivity in mass spectrometry. Derivatization is performed simultaneously with ionization ("reactive ionization"), and mass spectrometry is used to record and characterize the thiol reaction products. The method is applicable over the concentration range from 1 μM to 10 mM and is demonstrated for 25 blood serum, 1 plasma, and 3 types of tissue samples. The experiment is characterized by limited sample preparation (<4 min) and short analysis time (<1 min). High precision and accuracy (both better than 8%) are validated using independent HPLC-MS analysis. Cystine-cysteine redox homeostasis can be monitored by introducing an additional reduction step, and the accuracy and precision of these results are also validated by HPLC-MS.}, } @article {pmid39565530, year = {2024}, author = {Jiang, J and Li, D and Li, F and Li, H and Zhang, X and Feng, L}, title = {Catechin promotes endoplasmic reticulum stress-mediated gastric cancer cell apoptosis via NOX4-induced reactive oxygen species.}, journal = {Molecular and cellular biochemistry}, volume = {}, number = {}, pages = {}, pmid = {39565530}, issn = {1573-4919}, abstract = {Catechin, a polyphenolic compound in various foods and beverages, shows strong anti-cancer effects against gastric cancer (GC) cells. This study explored the effect of catechin on GC cell apoptosis and endoplasmic reticulum (ER) stress. GC cells were treated with different catechin concentrations to assess effects on cell viability, LDH release, invasion, migration, apoptosis, intracellular calcium (Ca[2][+]), ER stress markers, and reactive oxygen species (ROS). siRNA knockdown targeted GRP78, PERK, CHOP, and NOX4 to examine their roles in catechin-induced ER stress and apoptosis. Catechin treatment significantly reduced GC cell viability, increased LDH release, and induced apoptosis dose-dependently. Catechins elevated intracellular Ca[2][+] and ER stress markers. Co-treatment with thapsigargin (TG) intensified these effects, implicating ER stress in apoptosis. Knocking down GRP78, PERK, and CHOP mitigated catechin-induced apoptosis and restored viability. Additionally, catechins raised ROS levels, while co-treatment with Diphenyleneiodonium (DPI) or N-acetylcysteine (NAC) lowered ROS, cell damage, and ER stress markers. NOX4 knockdown countered catechin-induced viability loss and upregulated CHOP and cleaved caspase-3. Catechin induces apoptosis in GC cells through ER stress and ROS generation. Key mediators include GRP78, PERK, CHOP, and NOX4, suggesting potential therapeutic targets for enhancing catechin efficacy in GC treatment.}, } @article {pmid39564655, year = {2024}, author = {AbhijnaKrishna, R and Lu, YH and Wu, SP and Velmathi, S}, title = {Sensitive Detection of Sulfur Mustard Poisoning via N-Salicylaldehyde Naphthyl Thiourea Probe and Investigation into Detoxification Scavengers.}, journal = {ACS applied bio materials}, volume = {7}, number = {12}, pages = {8341-8350}, doi = {10.1021/acsabm.4c01143}, pmid = {39564655}, issn = {2576-6422}, mesh = {*Mustard Gas/poisoning/analogs & derivatives ; Animals ; *Zebrafish ; *Thiourea/chemistry ; Aldehydes/chemistry ; Molecular Structure ; Biocompatible Materials/chemistry ; Materials Testing ; Particle Size ; Chemical Warfare Agents/poisoning ; Humans ; }, abstract = {Sulfur mustard (SM), a blister agent and toxic chemical warfare compound, leads to injuries in the skin, eyes, and lungs, with early diagnosis being difficult because of its incubation period. Developing scavengers for sulfur mustard (SM) and its simulant, 2-chloroethylsulfide (CEES), is essential due to the severe and long-lasting toxic effects these compounds have on the human body. Existing scavengers like cysteine, sodium hydrosulfide (NaHS), and sodium thiosulfate cannot cross the blood-brain barrier (BBB), rendering them ineffective for detoxifying SM in the brain and highlighting the need for lipophilic scavengers. In this study, an N-salicylaldehyde naphthyl thiourea probe (NCrHT) was developed for detecting SM simulant CEES and its in vivo and in vitro imaging capabilities were evaluated. Additionally, the detoxification potential of scavengers was tested under similar conditions, and we introduced N-acetyl cysteine, which is lipophilic in nature, as an effective scavenger for detoxifying CEES in the zebrafish brain.}, } @article {pmid39556483, 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 = {Addiction biology}, volume = {29}, number = {11}, pages = {e70001}, pmid = {39556483}, issn = {1369-1600}, support = {R01 AA030041/AA/NIAAA NIH HHS/United States ; HU0001-22-2-0066//Department of Defense/ ; R01AA030041/AA/NIAAA NIH HHS/United States ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Craving/drug effects ; Randomized Controlled Trials as Topic ; *Substance-Related Disorders/drug therapy ; }, 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 this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with 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 in June and July of 2023 to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analysed 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 the treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests and funnel plot tests were conducted to examine the 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. Overall, our findings are contrary to those of prior meta-analyses, suggesting a 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 {pmid39555580, year = {2024}, author = {Schuch, JB and Hansen, F and Hartmann, T and Benzano, D and Gomes, HM and Moreira, JCF and Pechansky, F and Kessler, FHP and Galland, F and Silvello, D and Sordi, AO and von Diemen, L}, title = {A randomized, double-blind, placebo-controlled trial of N-acetylcysteine as an adjuvant treatment for alcohol use disorder.}, journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}, volume = {}, number = {}, pages = {}, doi = {10.47626/1516-4446-2024-3541}, pmid = {39555580}, issn = {1809-452X}, support = {08129.011787/2015-95/SENAD/Secretaria Nacional de Políticas Sobre Drogas/Brazil ; 2015-0488/FIPE/HCPA/Fundo de Incentivo à Pesquisa e Eventos/Hospital de Clínicas de Porto Alegre/Brazil ; 001/CAPES/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/Brazil ; }, abstract = {OBJECTIVE: We aimed to assess the effect of N-acetylcysteine (NAC), as an adjuvant treatment, on treatment adherence (primary outcome), in peripheral biomarkers and clinical improvement (secondary outcomes) in alcohol use disorders (AUD) patients.

METHODS: A 9-week randomized, double-blind, placebo-controlled trial (RCT) was conducted on 53 (n=25 NAC, n=28 placebo) inpatients with AUD. Neuropeptide Y (NPY), oxidative stress and inflammatory biomarkers, and hepatic parameters were analyzed in three-time moments.

RESULTS: Seventeen (60.7%) subjects in placebo and sixteen (64%) in the NAC group completed the RCT. Levels of hepatic biomarkers significantly changed over time (p<0.001). Oxidized glutathione (GSSG) levels at admission were lower in NAC group ((ppairwise=0.043). By the end of the study, both groups had similar GSSG levels (p=0.868), showing a reduction in GSSG levels in the placebo group. In the NAC group, a decrease in superoxide dismutase (SOD) activity and an increase in NPY levels in the end of the intervention were observed. Both groups showed similar mean survival time to relapse, treatment adherence and clinical improvement.

CONCLUSION: Our findings reinforce the alcohol effects on oxidative stress and NPY parameters. However, our sample size may limit the generalizability of the results, especially for clinical outcomes. Future RCTs with less severe alcoholics and longer follow-up may be necessary to test if NAC could be helpful to reduce the mental health burden related to AUD.}, } @article {pmid39549915, year = {2025}, author = {Higashi, Y and Nishida, C and Izumi, H and Sato, K and Kawai, N and Tomonaga, T and Morimoto, T and Yamasaki, K and Wang, KY and Higashi, H and Moriyama, A and Takeshita, JI and Kojima, T and Sakurai, K and Yatera, K and Morimoto, Y}, title = {Inhalation exposure to cross-linked polyacrylic acid induces pulmonary disorders.}, journal = {Toxicology}, volume = {510}, number = {}, pages = {154001}, doi = {10.1016/j.tox.2024.154001}, pmid = {39549915}, issn = {1879-3185}, mesh = {Animals ; Male ; *Acrylic Resins/toxicity/administration & dosage ; *Rats, Inbred F344 ; *Inhalation Exposure/adverse effects ; *Acetylcysteine/pharmacology/administration & dosage ; *Bronchoalveolar Lavage Fluid/cytology/chemistry ; Lung/drug effects/pathology/metabolism ; Rats ; Lung Diseases/chemically induced/pathology ; Oxidative Stress/drug effects ; Dose-Response Relationship, Drug ; Heme Oxygenase-1/metabolism ; Chemokine CXCL1/metabolism ; }, abstract = {Organic polymers, widely used in food, daily necessities, and medicines, include cross-linked polyacrylic acid (CL-PAA), which has been reported to induce severe lung disease. While previous studies mainly used intratracheal instillation, our research focused on inhalation exposure to corroborate these findings. We conducted 5-day (short-term) and 13-week (subchronic) inhalation exposure studies with CL-PAA. In the short-term study, male F344 rats inhaled CL-PAA at 0.2, 2.0, or 20 mg/m[3] for 6 hours/day over 5 days. Rats were dissected 3 days and 1 month post-exposure. In the subchronic study, rats inhaled CL-PAA at 0.2 or 2.0 mg/m[3] for 6 hours/day, 5 days/week for 13 weeks, with dissections from 3 days to 6 months post-exposure. To investigate the mechanism of pulmonary disorders, an additional short-term study with 20 mg/m[3] CL-PAA included intraperitoneal injections of the antioxidant N-acetylcysteine (NAC) (200 mg/kg) with dissection the day after exposure. Short-term exposure led to concentration-dependent increases in neutrophil influx, cytokine-induced neutrophil chemoattractant (CINC), total protein, lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Histopathology showed concentration-dependent neutrophil infiltration. Subchronic exposure caused persistent increases in BALF total protein and lung HO-1, with ongoing neutrophil infiltration and fibrosis. NAC administration reduced neutrophils, total protein, LDH, and CINC in BALF, and HO-1 in lung tissue, improving histopathological findings. Inhalation of CL-PAA caused concentration-dependent lung inflammation and persistent fibrosis. The no observed adverse effect level (NOAEL) for chronic pulmonary disorders was 0.2 mg/m[3]. Oxidative stress linked to CL-PAA-induced inflammation was mitigated by NAC administration.}, } @article {pmid39549861, year = {2025}, author = {Li, Y and Yu, M and Wei, Y and Zhou, Z and Guo, Y and Yuan, M and Jin, J and Li, J and Shen, H and Wu, D}, title = {Risk assessment of developmental and neurotoxicity by the flavoring agent perillaldehyde: NAC (N-acetylcysteine) mitigation of oxidative stress-mediated inhibition of the Nrf2 pathway.}, journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP}, volume = {288}, number = {}, pages = {110071}, doi = {10.1016/j.cbpc.2024.110071}, pmid = {39549861}, issn = {1532-0456}, mesh = {Animals ; *Zebrafish ; *Oxidative Stress/drug effects ; *NF-E2-Related Factor 2/metabolism/genetics ; *Acetylcysteine/pharmacology ; Flavoring Agents/toxicity ; Acrolein/toxicity/analogs & derivatives ; Risk Assessment ; Zebrafish Proteins/metabolism/genetics ; Neurotoxicity Syndromes/prevention & control ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Embryo, Nonmammalian/drug effects ; Animals, Genetically Modified ; Antioxidants/pharmacology ; Monoterpenes ; }, abstract = {Perillaldehyde (PAE), a prevalent flavoring agent, has raised safety concerns due to conflicting evidence regarding its toxicity. This study provides a comprehensive assessment of the developmental and neurotoxic effects of PAE in zebrafish, elucidating the underlying mechanisms of its toxicity. Results showed that PAE affected the viability and hatching rate of zebrafish at 96 h postfertilization with the 50 % lethal concentration (LC50) of 7.975 mg/L. Furthermore, exposed‌ to a non-lethal concentration of 4 mg/L PAE induced a spectrum of morphological abnormalities, such as pericardial edema, delayed yolk sac absorption, reduced body length, and microphthalmia. Behavioral observations revealed that PAE reduced motor ability, and was accompanied by an increase in spontaneous turning angle and angular velocity. Using the TG(elav13:EGFP) transgenic model, we observed the number of newborn neurons was reduced, indicating that PAE induced obvious neurotoxic effects. Additionally, this concentration facilitated the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), concomitantly decreasing the activity of antioxidant enzymes. QRT-PCR analysis revealed that PAE down-regulated Nestin and Neurogenin1 gene expression, up-regulated Glipr1a and Nox1 gene expression, and inhibited the Nrf2/HO-1 pathway. Notably, co-administration of N-acetylcysteine (NAC), an inhibitor of oxidative stress, mitigated oxidative stress levels and partially ameliorated the neurotoxicity. These findings suggest that oxidative stress is the primary mediator of PAE-induced neurotoxicity. This study provides crucial insights for the safe application of PAE.}, } @article {pmid39549856, year = {2024}, author = {Scioscia, G and Baraldi, F and Bigoni, T and Papi, A and Vatrella, A and Micheletto, C and Foschino Barbaro, MP}, title = {The precision medicine strategy to treat COPD pulmonary traits in clinical practice: The role of N-acetylcysteine.}, journal = {Respiratory medicine}, volume = {235}, number = {}, pages = {107865}, doi = {10.1016/j.rmed.2024.107865}, pmid = {39549856}, issn = {1532-3064}, mesh = {Humans ; *Pulmonary Disease, Chronic Obstructive/drug therapy/physiopathology ; *Acetylcysteine/therapeutic use ; *Precision Medicine/methods ; Expectorants/therapeutic use ; Cough/drug therapy ; Disease Progression ; Bronchitis, Chronic/drug therapy/physiopathology ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a progressive lung condition and a leading cause of physical decline and death. COPD prevalence is expected to increase steadily in the coming years, and as a result, the healthcare and social burden of this condition will intensify. In this scenario, a patient-centric approach, the treatable trait (TT) strategy, based on the identification of traits that are clinically relevant, identifiable, monitorable and treatable, has emerged. The TT strategy, which considers behavioral/risk factors, as well as pulmonary and extrapulmonary traits, has shown to be a promising strategy in COPD management. This work reviews the TT strategy in COPD, giving special attention to the most relevant pulmonary traits, such as frequent productive cough, chronic bronchitis, type 2 inflammation, neutrophilic inflammation, lung hyperinflation, bronchiectasis, exacerbations and non-reversible airflow limitation. N-acetylcysteine (NAC), a widely used mucolytic agent, might be a major player in this strategy. Indeed, through a thorough review of the literature, it has been possible to highlight that, besides being essential in the treatment of frequent productive cough, NAC could bring benefits in case of airflow limitations, airways inflammation, exacerbations and bronchiectasis. A clinical case in which the TT strategy was able to reduce symptoms and improve lung function and quality of life, minimizing unnecessary medication and side effects, is also presented. The identification of TTs and their proper treatment through personalized medicine remarkably ameliorates COPD management. Of note, the mucolytic, antioxidant, and anti-inflammatory activities of NAC might have beneficial effects on several TTs.}, } @article {pmid39549062, year = {2024}, author = {Rajabian, F and Razavi, BM and Mehri, S and Amouian, S and Ghasemzadeh Rahbardar, M and Khajavi Rad, A and Hosseinzadeh, H}, title = {Evaluation of pathways involved in the protective effect of trans sodium crocetinate against contrast-induced nephropathy in rats.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39549062}, issn = {1432-1912}, support = {995678//National Institutes for Medical Research Development (NIMAD), Tehran, Iran/ ; 981809//Vice Chancellor of Research, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran/ ; }, abstract = {Contrast-induced nephropathy (CIN) is the most important side effect following contrast media application. The purpose of this study was to investigate the nephroprotective effects of trans sodium crocetinate (TSC) against sodium amidotrizoate/meglumine amidotrizoate (SAMA). Wistar rats were classified into eight groups (n = 6, male, 220-250 g) including (1) sham, injection of solvents (intraperitoneally; i.p.), (2) premedication-control, N(ω)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.) + indomethacin (IND, 10 mg/kg, i.p.), (3) model (L-NAME + IND + SAMA (12.5 ml/kg, i.p.)), (4-6) TSC 10, 20, and 40 mg/kg/day, 7 days, i.p., and L-NAME + IND + SAMA, (7) N-acetylcysteine (NAC, 125 mg/kg/day, 7 days, i.p.) and L-NAME + IND + SAMA, (8) TSC alone (40 mg/kg/day, 7 days, i.p.). Rats were injected with L-NAME, IND, and SAMA 40 h after water deprivation. SAMA caused the enhancement of histopathological damage in kidney tissue, biochemical factors (serum blood urea nitrogen and creatinine), and oxidative stress. Moreover, SAMA increased inflammation (TNF-α), apoptosis proteins (Caspase 3-cleaved and Bax/Bcl-2 ratio), and autophagy markers (Beclin-1 and LC3 II/I ratio). TSC declined biochemical factors and oxidative stress. Also, TSC 40 mg/kg decreased histopathological damage, inflammation, apoptosis, and autophagy markers. This study demonstrated that TSC has nephroprotective effects through anti-oxidant, anti-inflammatory, and anti-apoptotic properties, as well as regulating autophagy.}, } @article {pmid39548866, year = {2024}, author = {Vaneev, AN and Gorelkin, PV and Barykin, EP and Kolmogorov, VS and Timoshenko, RV and Mitkevich, VA and Petrushanko, IY and Varshavskaya, KB and Salikhov, SV and Klyachko, NL and Makarov, AA and Erofeev, AS}, title = {Impact of Antioxidants on Mechanical Properties and ROS Levels of Neuronal Cells Exposed to β-Amyloid Peptide.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {}, number = {}, pages = {e202400786}, doi = {10.1002/cbic.202400786}, pmid = {39548866}, issn = {1439-7633}, support = {075-15-2022-264//Ministry of Science and Higher Education of the Russian Federation/ ; }, abstract = {This study aims to investigate the potential role of antioxidants in oxidative stress and its consequent impact on the mechanical properties of neuronal cells, particularly the stress induced by amyloid-beta (1-42) (Aβ42) aggregates. A key aspect of our research involved using scanning ion-conductance microscopy (SICM) to assess the mechanical properties (Young's modulus) of neuronal cells under oxidative stress. Reactive oxygen species (ROS) level was measured in single-cell using the electrochemical method by low-invasive Pt nanoelectrode. We investigated the effects of the low molecular weight antioxidant N-acetylcysteine (NAC) and the antioxidant enzyme superoxide dismutase 1 (SOD1) on the physiological and mechanical properties of neuronal cells using SICM. Using electrochemical method and SICM, NAC effectively reduces oxidative stress and restores Young's Modulus in SH-SY5Y cells exposed to hydrogen peroxide and Aβ42 oligomers. Our study first examined the influence of SOD1 on intracellular ROS levels in the presence of Aβ oligomers. The investigation into the effects of SOD1 and its nanoparticle form SOD1 on SH-SY5Y cells reveals impacts on mechanical properties and oxidative stress. The combined use of SICM and electrochemical measurements provided a comprehensive understanding of how oxidative stress, including that triggered by the Aβ oligomers affects the mechanical properties of cells.}, } @article {pmid39547318, year = {2024}, author = {Koo, J and Sim, WJ and Lim, W and Lim, TG}, title = {Activation of mixed lineage kinase 3 by fine particulate matter induces skin inflammation in human keratinocytes.}, journal = {Toxicology letters}, volume = {402}, number = {}, pages = {38-43}, doi = {10.1016/j.toxlet.2024.11.002}, pmid = {39547318}, issn = {1879-3169}, mesh = {Humans ; *Particulate Matter/toxicity ; *Keratinocytes/drug effects/metabolism ; Phosphorylation ; *Reactive Oxygen Species/metabolism ; *Dinoprostone/metabolism ; *MAP Kinase Kinase Kinases/metabolism ; *Cyclooxygenase 2/metabolism ; *Mitogen-Activated Protein Kinase Kinase Kinase 11 ; HaCaT Cells ; Signal Transduction/drug effects ; Air Pollutants/toxicity ; Enzyme Activation ; Dermatitis/pathology ; Cell Line ; MAP Kinase Signaling System/drug effects ; Particle Size ; Proto-Oncogene Proteins ; }, abstract = {Fine particulate matter (PM2.5) induces a range of diseases, including skin disorders, through inflammatory responses. In this study, we investigated the novel mechanisms by which PM2.5 causes skin inflammation in human keratinocytes HaCaT. We observed increased protein expression of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) in PM2.5-treated HaCaT cells. To identify the pathways promoting the expression of these inflammatory proteins, we conducted a phospho-kinase antibody array and confirmed that the phosphorylation levels of JNK and p38 were increased by PM2.5-treated HaCaT cells. Further investigation of the phosphorylation levels of mitogen-activated protein kinases (MAPKs) and upstream signals revealed that PM2.5 activated the MKK4/7-JNK-c-Jun and MKK3/6-p38-p70[S6K] signaling pathways, while the phosphorylation level of ERK1/2 remained unchanged. HaCaT cells treated with PM2.5 phosphorylated Mixed-lineage kinase 3 (MLK3), an upstream regulator of p38 and JNK. Furthermore, inhibition of ROS production by N-Acetylcysteine (NAC) treatment inhibited MLK3 phosphorylation. Taken together, ROS production induced by PM2.5 activated the MLK3 signaling pathway and induced skin inflammation.}, } @article {pmid39547016, year = {2024}, author = {Guo, S and Tong, J and Liu, Y and Qin, D and Yan, J and Peng, H and Sun, L and Jing, X and Wu, X and Li, B}, title = {Synthesis of Eucommia ulmoides-derived carbon dots for anti-inflammatory and accelerated wound healing.}, journal = {International immunopharmacology}, volume = {143}, number = {Pt 3}, pages = {113606}, doi = {10.1016/j.intimp.2024.113606}, pmid = {39547016}, issn = {1878-1705}, mesh = {Animals ; *Wound Healing/drug effects ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Eucommiaceae/chemistry ; Rats ; *Carbon/chemistry ; Male ; Humans ; Rats, Sprague-Dawley ; Acetylcysteine/pharmacology/therapeutic use ; Cytokines/metabolism ; Skin/drug effects/pathology ; Mice ; Quantum Dots/chemistry ; Inflammation/drug therapy ; }, abstract = {Inflammation affects the pathology of wound healing and is strongly associated with many chronic wounds that do not heal. Natural herbs with anti-inflammatory effects have received much attention in clinical treatment because they are inexpensive, readily available, safe, and effective. In this study, EUO-NAC-CDs were prepared using a hydrothermal method in which Eucommia ulmoides (EUO) and n-acetylcysteine (NAC) were used as carbon sources. EUO-NAC-CDs have a small particle size distribution with an average particle size of 2.84 nm, emit stable blue-green fluorescence, and are biocompatible. EUO-NAC-CDs have been used for in vitro bioimaging, where high anti-inflammatory activity and accelerated wound healing have been demonstrated in vivo and in vitro. Additionally, EUO-NAC-CDs significantly decreased the expression of TNF-α, IL-6, and IL-1β and increased the expression of IL-10, suggesting that EUO-NAC-CDs had good anti-inflammatory effects. In a rat model of skin defects, EUO-NAC-CDs promoted wound healing, stimulated the formation of blood vessels and tissue regeneration near the wound, increased the expression of CD31, VEGF, and CD206, and decreased the expression of INOS, further demonstrating the therapeutic function of CDs. Therefore, fluorescent EUO-NAC-CDs can be effective in clinical wound treatment as imaging tools and functional wound dressings.}, } @article {pmid39546096, year = {2024}, author = {Xu, B and Wang, G and Xu, L and Ding, L and Li, S and Han, Y}, title = {Vitamin C ameliorates D-galactose-induced senescence in HEI-OC1 cells by inhibiting the ROS/NF-κB pathway.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1157}, pmid = {39546096}, issn = {1573-4978}, mesh = {*Galactose/pharmacology/metabolism ; *Reactive Oxygen Species/metabolism ; *Cellular Senescence/drug effects ; *Ascorbic Acid/pharmacology/metabolism ; *NF-kappa B/metabolism ; Animals ; *Signal Transduction/drug effects ; Cell Line ; *Hair Cells, Auditory/drug effects/metabolism ; Mice ; Cell Survival/drug effects ; Acetylcysteine/pharmacology ; }, abstract = {BACKGROUND: Cochlear hair cell senescence is one of the major causes of age-related hearing loss (ARHL) and is significantly related to reactive oxygen species (ROS) accumulation. Research shows that vitamin C (VC) can inhibit ROS accumulation; however, its association with cochlear hair cell senescence remains elusive.

METHODS AND RESULTS: Firstly, a cellular senescence model was established using D-galactose (D-gal) induced HEI-OC1 cells for 24 h. Senescent HEI-OC1 cells were then continued to be treated with the addition of VC or ROS inhibitor (N-acetylcysteine; NAC) for another 24 h, and explored the impact of VC on senescent cochlear hair cell and the potential regulatory mechanisms. The results indicated that D-gal-induced senescent HEI-OC1 cells, manifested as decreased cell viability, increased β-galactosidase activity and p21 protein level, and ROS and pro-inflammatory factors were upregulated, and NF-κB p65 phosphorylation was enhanced. However, the use of VC or NAC can significantly ameliorate these effects and improve HEI-OC1 cell senescence.

CONCLUSIONS: This research indicates that VC can ameliorate D-gal-induced senescence of HEI-OC1 cochlear hair cells, and its protective effect may be related to the inhibition of the ROS/NF-κB pathway, which provides a new research direction for the prevention and treatment of ARHL.}, } @article {pmid39541698, year = {2024}, author = {Jin, L and Yang, Q and Li, J and Li, X and Xia, Y and Chen, Z and Wen, Y and Wang, L and Wang, X and Tong, J and Shen, Y and Chen, K}, title = {The ROS/AKT/S6K axis induces corneal epithelial dysfunctions under LED blue light exposure.}, journal = {Ecotoxicology and environmental safety}, volume = {287}, number = {}, pages = {117345}, doi = {10.1016/j.ecoenv.2024.117345}, pmid = {39541698}, issn = {1090-2414}, mesh = {*Reactive Oxygen Species/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Epithelium, Corneal/drug effects/radiation effects ; Humans ; Animals ; *Light/adverse effects ; *Apoptosis/drug effects/radiation effects ; Mice ; Cell Movement/drug effects/radiation effects ; Cell Survival/drug effects/radiation effects ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction/drug effects ; Epithelial Cells/drug effects/radiation effects ; Acetylcysteine/pharmacology ; Blue Light ; Acetates ; Benzopyrans ; }, abstract = {In recent years, concerns have escalated regarding eye health problems arising from Light-emitting diode (LED), which emits high-energy blue light (BL), potentially causing corneal epithelial dysfunctions (CEpD). Nevertheless, the mechanisms underlying this damage remain poorly comprehended. This study endeavors to explore the specific mechanisms through which BL exposure induces CEpD. The study carried out diverse assays and treatments to investigate the toxicological effects of BL exposure. 48 hours (h) of 440 nm of BL exposure decreased the migration of human corneal epithelial cells (hCEpCs) while augmenting reactive oxygen species (ROS) production and apoptosis. RNA-Sequencing and bioinformatic analysis indicated that cellular oxidation and reduction equilibrium, wound healing, the positive regulation of the apoptotic process, and the Phosphoinositide 3-kinase (PI3K)/AKT pathway were significantly influenced by BL exposure. Treatment with N-acetylcysteine (NAC), a ROS scavenger, restored cell viability and AKT/S6 kinase (S6K) activation, suggesting the involvement of ROS in BL-induced damage. NAC also reversed BL-induced apoptosis and migration. Blocking AKT/S6K replicated detrimental effects, while pre-treatment with SC79 (SC), an AKT activator, alleviated the changes caused by BL exposure in hCEpCs. Furthermore, in mice, the combination of AKT inhibition and BL exposure led to CEpD. However, treatment with SC and NAC restored CEpD caused by BL exposure. These results imply that the regulation of the ROS/PI3K/AKT/S6K axis is implicated in BL-induced CEpD. Collectively, this study offers insights into the molecular mechanisms of BL-induced CEpD and proposes targeting the ROS/PI3K/AKT/S6K cascade as a potential therapeutic approach. The findings contribute to ocular health knowledge and establish the basis for developing interventions to safeguard the cornea from the detrimental effects of excessive BL exposure.}, } @article {pmid39540528, year = {2024}, author = {Yamauchi, K and Tsutsumi, Y and Kobayashi, T and Komura, JI}, title = {The effects of antioxidant administration in the early stages of radiation-induced tumorigenesis.}, journal = {Radiation protection dosimetry}, volume = {200}, number = {16-18}, pages = {1594-1597}, doi = {10.1093/rpd/ncae145}, pmid = {39540528}, issn = {1742-3406}, support = {//Aomori Prefecture, Japan/ ; }, mesh = {Animals ; Mice ; *Antioxidants/pharmacology ; *Neoplasms, Radiation-Induced/etiology ; Female ; *Gamma Rays/adverse effects ; *Acetylcysteine/pharmacology ; Male ; Carcinogenesis/radiation effects/drug effects ; Whole-Body Irradiation ; Mice, Inbred C57BL ; Intestinal Neoplasms/etiology ; Dose-Response Relationship, Radiation ; Adenomatous Polyposis Coli ; }, abstract = {ApcMin/+ mouse was a model mouse for human familial adenomatous polyposis, and irradiation at an early age increases tumors in the small and large intestine. To study the effects of antioxidant administration on tumor incidence after continuous whole-body exposure to gamma rays, ApcMin/+ mice were exposed to a medium-dose-rate, 200 mGy/d, from postnatal Day 0 to 21 of age or a high-dose-rate of 0.65 Gy/min (total dose 4.2 Gy) on postnatal Day 7. The dams and pups were supplied with the N-acetylcysteine (NAC) in drinking water (7 g/L), from gestation Day 15 until weaning (21 days-old). A significant increase in the number of intestinal tumors were observed in ApcMin/+ mice irradiated with high dose-rate gamma rays as compared with the non-irradiated controls, but there was no significant difference in tumor counts between the non-irradiated controls and the medium-dose rate irradiation groups. NAC administration did not have any significant effect at least at this dose. These results suggest that the supplementation of anti-oxidant at the early stage of tumorigenesis does not suppress the formation of irradiation-induced small intestinal tumors.}, } @article {pmid39539442, year = {2024}, author = {Xiang, C and Lu, Y and Hao, R and Wei, Y and Hu, Y and Yu, G}, title = {Catalpol alleviates amyloid- generation and neuronal oxidative stress injury via activating the Keap1-Nrf2/ARE signaling pathway in the immortalized lymphocytes from patients with late-onset Alzheimer's disease and SKNMC cells co-culture model.}, journal = {Iranian journal of basic medical sciences}, volume = {27}, number = {12}, pages = {1547-1557}, pmid = {39539442}, issn = {2008-3866}, abstract = {OBJECTIVES: To assess the effect of catalpol, the major bioactive constituents of Rehmannia glutinosa, on our Alzheimer's disease (AD) in vitro model.

MATERIALS AND METHODS: We employed the immortalized lymphocytes (lymphoblastoid cell line, LCL) from late-onset AD patients and co-cultured "them" to mimic the pathological process of late-onset AD and investigated the effect of catalpol on our AD in vitro model.

RESULTS: In the co-culture model, AD-derived LCL triggered excessive Aβ1-42 in SKNMC cells due to its high levels of oxidative stress and resulted in neuronal oxidative stress injury through inhibiting Keap1-Nrf2/ARE signaling pathway. Treatment with catalpol and N-acetylcysteine (NAC), an antioxidant, prevented the AD LCL-induced Aβ1-42 overproduction and reduced the level of β-site amyloid precursor protein cleaving enzyme-1 (BACE1) and amyloid precursor protein (APP)-C99. Catalpol and NAC also enhanced the antioxidant capacity and reduced apoptosis in SKNMC cells co-cultured with AD LCL. The anti-oxidative effect of catalpol was antagonized by ML385, the Nrf2 inhibitor. Therefore, we speculate that the antioxidant and anti-apoptotic effects of catalpol are mediated by activating the Keap1-Nrf2/ARE signaling pathway.

CONCLUSION: Catalpol affects the anti-Aβ generation and the antioxidative and antiapoptotic properties in the AD co-cultured model. So, it might be a novel natural drug and offer a potential therapeutic approach for AD.}, } @article {pmid39537820, year = {2024}, author = {Morales Fénero, C and Sacksteder, RE and Diamos, AG and Kimmey, JM}, title = {Heat-inactivated Streptococcus pneumoniae augments circadian clock gene expression in zebrafish cells.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {27805}, pmid = {39537820}, issn = {2045-2322}, support = {Pew Biomedical Scholars//Pew Charitable Trusts/ ; R35GM147509/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Zebrafish/microbiology ; *Circadian Clocks/genetics ; *Streptococcus pneumoniae/genetics ; *Zebrafish Proteins/genetics/metabolism ; Gene Expression Regulation/radiation effects ; Period Circadian Proteins/genetics/metabolism ; Hot Temperature ; Light ; Cell Line ; Cryptochromes/genetics/metabolism ; }, abstract = {The circadian clock is a cell-autonomous process that regulates daily internal rhythms by interacting with environmental signals. Reports across species show that infection can alter the expression of circadian genes; however, in teleosts, these effects are influenced by light exposure. Currently, no reports analyze the direct effects of bacterial exposure on the zebrafish clock. Using zebrafish Z3 cells, we demonstrate that exposure to heat-killed Streptococcus pneumoniae (HK-Spn) augments the expression of core repressive factors in a light- and time-dependent manner. In constant darkness, HK-Spn highly upregulated cry1a, per3, and per1b expression. In the presence of light, HK-Spn exposure rapidly and strongly upregulated per2 and cry1a, and this was proportionally increased with light intensity. The combinatorial effect of light and HK-Spn on per2 and cry1a was not duplicated with H2O2, a known byproduct of light exposure. However, the ROS inhibitor N-acetyl cysteine was sufficient to block HK-Spn augmentation of per2, cry1a, and per3. These findings demonstrate that exposure to an inactive bacteria influences the expression of zebrafish clock genes under different light conditions.}, } @article {pmid39531327, year = {2024}, author = {Monti, DA and Faezeh, V and Zabrecky, G and Alizadeh, M and Wintering, N and Bazzan, AJ and Mohamed, FB and Newberg, AB}, title = {Changes in Resting-State Functional Connectivity and Cognitive-Affective Symptoms in Patients With Post-Concussion Syndrome Treated With N-Acetyl Cysteine.}, journal = {The Journal of head trauma rehabilitation}, volume = {}, number = {}, pages = {}, pmid = {39531327}, issn = {1550-509X}, abstract = {OBJECTIVE: Concussion accounts for more than 80% of people experiencing traumatic brain injury. Acute concussion is associated with characteristic cognitive and functional deficits that may persist for weeks to months. A subgroup of these patients (from 10% to 50%) have persistent symptoms referred to as chronic post-concussion syndrome (PCS). There are limited treatment options for these patients and the pathophysiology is poorly understood, though oxidative stress is thought to be a contributing factor. The purpose of this study was to evaluate whether an antioxidant, N-acetylcysteine (NAC), might be beneficial in patients with PCS.

SETTING: Outpatient medicine center.

PARTICIPANTS: Fifty patients with chronic PCS for at least 3 months post injury.

DESIGN: The patients with PCS were enrolled in this randomized unblinded clinical trial to receive the antioxidant NAC as a combination of daily oral and weekly intravenous infusions, or assigned to a waitlist control group where they would continue to receive standard of care.

MAIN MEASURES: Resting-state functional connectivity (FC) magnetic resonance imaging (rsFC-MRI) was performed pre and post either NAC or the waitlist period along with cognitive, emotional, and sensory symptom assessments.

RESULTS: The results demonstrated significant (P < .05) improvements in symptoms as determined by the Rivermead Post-Concussion Symptoms Questionnaire, Spielberger State-Trait Anxiety Inventory, and Profile of Mood Scale in the PCS group receiving NAC as compared to patients receiving ongoing standard care. Importantly, there were significant (P< .01) changes in FC in the NAC group, particularly in networks such as the default mode network, salience network, and executive control network. These changes in FC also correlated with improvements in symptoms.

CONCLUSIONS: In patients with chronic PCS, NAC treatment was associated with significant changes in resting state FC and improvement in a variety of symptoms, particularly cognitive and affective symptoms.}, } @article {pmid39530276, year = {2024}, author = {Gaffney, PJ and Shetty, KR and Yuksel, S and Kaul, VF}, title = {Antioxidant Therapies in the Treatment of Aminoglycoside-Induced Ototoxicity: A Meta-Analysis.}, journal = {The Laryngoscope}, volume = {}, number = {}, pages = {}, doi = {10.1002/lary.31902}, pmid = {39530276}, issn = {1531-4995}, abstract = {OBJECTIVE: A feared complication of aminoglycoside treatment is ototoxicity, which is theorized to be attributed to the production of aminoglycoside-induced reactive oxygen species. Previous studies using animal models have suggested that numerous therapies targeting reducing oxidative stress may prevent ototoxicity from aminoglycosides. However, few clinical studies have been conducted on these antioxidants. This systematic review and meta-analysis examines the effectiveness of antioxidant therapies in the treatment of aminoglycoside-induced ototoxicity.

DATA SOURCES: PubMed, Embase, Web of Science, and ClinicalTrials.gov.

REVIEW METHOD: A literature search was conducted in August 2024. This review sought randomized controlled trials to be conducted on humans to examining otologic outcomes in aminoglycoside-induced ototoxicity following administration of medications intended to reduce oxidative stress.

RESULTS: A systematic review yielded 2037 results, of which seven studies met inclusion criteria. N-acetylcysteine (NAC) was investigated in four studies, aspirin in two studies, and vitamin E in one study. Six studies examined the benefit of antioxidant treatments for up to 8 weeks after administration while one study tested subjects' hearing after 1 year. In pooled analysis, two studies assessing NAC showed the greatest reduction in ototoxicity (RR 0.112, 95% CI, 0.032-0.395; p = 0.0007; I[2] = 18%), followed by two studies examining aspirin (RR 0.229, 95% CI, 0.080-0.650; p = 0.0057; I[2] = 0%). One study performed with vitamin E did not find a reduction in ototoxicity compared to the placebo (RR 0.841, 95% CI, 0.153-4.617; p = 0.8416).

CONCLUSIONS: Multiple studies have shown that NAC and aspirin are effective in reducing ototoxicity from treatment with aminoglycosides. However, there is a lack of high-quality evidence. Additional studies should examine whether aspirin and N-acetylcysteine provide long-term benefit, and which of the other promising antioxidants translate from animal models.

LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.}, } @article {pmid39526680, year = {2025}, author = {Baune, BT and Fromme, SE}, title = {The role of immunomodulators in severe mental disorders: future perspectives.}, journal = {Current opinion in psychiatry}, volume = {38}, number = {1}, pages = {41-47}, doi = {10.1097/YCO.0000000000000976}, pmid = {39526680}, issn = {1473-6578}, mesh = {Humans ; *Immunologic Factors/therapeutic use ; Schizophrenia/drug therapy/immunology ; Immunomodulating Agents/therapeutic use ; Mental Disorders/drug therapy/immunology ; Bipolar Disorder/drug therapy/immunology ; }, abstract = {PURPOSE OF REVIEW: The immune system is of pivotal importance with regard to the development and maintenance of mental illness. Aberrant cytokine levels are significant immune markers, and research is increasingly focusing on the complement system and the gut-brain axis. The efficacy and safety of immunomodulatory interventions are currently the subject of clinical studies. Hence, this review is timeline and relevant to evaluate the latest evidence on the clinical value of immunomodulatory treatments from studies over the past 18 months in schizophrenia, bipolar disorder and unipolar depression.

RECENT FINDINGS: While conventional psychotropic drugs (antidepressants, antipsychotics, lithium) appear to have immunomodulatory adverse effects, antibiotics (minocycline), nonsteroid anti-inflammatory drugs (celecoxib) and anti-inflammatory therapeutics in particular are the subject of ongoing clinical trials. Integrative medical interventions such as nutritional supplements (e.g., N -acetyl- l -cysteine, polyunsaturated fatty acids) and exercise interventions (e.g., running, yoga) are being evaluated for their immunomodulatory effects and clinical value.

SUMMARY: No evidence-based recommendation can be made for the immunomodulatory treatment of depression, although celecoxib appears to be more effective than minocycline and omega-3 fatty acid. N -acetylcysteine (NAC) may be beneficial for the treatment of bipolar and schizophrenia disorders. However, further translational research is required to confirm these findings.}, } @article {pmid39510433, year = {2025}, author = {Jiang, W and Ma, X and Li, B and Jiang, T and Jiang, H and Chen, W and Gao, J and Mao, Y and Sun, X and Ye, Z and Zhao, S and Huang, S and Chen, Y}, title = {Role of the PGAM5-CypD mitochondrial pathway in methylglyoxal-induced bone loss in diabetic osteoporosis.}, journal = {Bone}, volume = {190}, number = {}, pages = {117322}, doi = {10.1016/j.bone.2024.117322}, pmid = {39510433}, issn = {1873-2763}, mesh = {Animals ; *Pyruvaldehyde/metabolism ; Mice ; *Mitochondria/metabolism/drug effects ; *Osteoporosis/metabolism/pathology ; *Osteoblasts/metabolism/drug effects ; *Peptidyl-Prolyl Isomerase F/metabolism ; *Apoptosis/drug effects ; Phosphoprotein Phosphatases/metabolism ; Cell Differentiation/drug effects ; Cyclophilins/metabolism ; Osteogenesis/drug effects ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Male ; Membrane Potential, Mitochondrial/drug effects ; Cell Line ; Signal Transduction/drug effects ; Bone Resorption/pathology/metabolism ; Diabetes Complications/pathology/metabolism ; }, abstract = {Diabetic osteoporosis (DOP) is a skeletal complication with a high rate of disability. It results in a great burden to the patient's family and society. Methylglyoxal (MG) is a toxic by-product of the glycolytic process that occurs during diabetic conditions. It causes osteoblastic injury and con-tributes to the initiation and development of DOP. Disruption of mitochondrial homeostasis has been implicated as a cause of dysregulated osteo-blastogenesis, an essential step in bone formation. It is unclear whether mitochondrial dysfunction is involved in MG-induced osteoblast dysfunction. In this study, we showed that mitochondrial dysfunction contributes to MG-induced MC3T3-E1 cell apoptosis and impaired differentiation. A significant reduction of mitochondrial membrane potential (MMP) and ATP production occurred in MG-induced osteoblasts as well as increasing mitochondrial reactive oxygen species (mtROS) and intracellular Ca[2+]. Classical antioxidant N-Acetylcysteine (NAC) significantly attenuated mitochondrial dysfunction as well as osteoblast apoptosis and osteogenic differentiation damage induced by MG. More importantly, we found that activating phosphoglycerate mutase family member 5 (PGAM5) and cyclophilin D (CypD), which contributes to mitochondrial homeostasis, is involved in MG-induced osteoblast injury. Both PGAM5 and CypD knockdown effectively reversed osteoblast viability and function, whereas PGAM5 or CypD overexpression aggravated osteoblast injury caused by MG. Moreover, the result of co-transfection revealed that PGAM5 is an upstream signaling molecule of CypD. By constructing type I diabetes mouse models, we further found that the expression of PGAM5 and CypD were both increased in the femur along with a reduction of ATP and increased TUNEL-positive cells. These results, for the first time, suggest that MG-induced mitochondrial dysfunction induces osteoblast injury through the PGAM5-CypD pathway. This study provides insight into the prevention and treatment of DOP. LAY SUMMARY: This study highlights the role of mitochondria in regulating osteoblast viability and function under conditions of diabetic osteoporosis (DOP). We found that the PGAM5-CypD mitochondrial pathway is activated following glycolytic by-product methylglyoxal (MG) treatment, which contributes to mitochondrial dysfunction and osteogenic dysfunction. This mechanism implicates mitochondria as a potential therapeutic target for osteoporosis.}, } @article {pmid39506899, year = {2024}, author = {Zhao, K and Zhu, GZ and Li, HZ and Gao, JW and Tu, C and Wu, DZ and Huang, YS and Han, D and Chen, XY and Wu, LY and Zhong, ZM}, title = {Accumulation of Advanced Oxidation Protein Products Promotes Age-Related Decline of Type H Vessels in Bone.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {80}, number = {1}, pages = {}, doi = {10.1093/gerona/glae271}, pmid = {39506899}, issn = {1758-535X}, support = {81871819//National Natural Science Foundation of China/ ; 2023A1515011943//Guangdong Provincial Basic and Applied Basic Research Fund Natural Science Foundation Project/ ; 2022-YB1273//Technology Project of Ganzhou/ ; 202310843//Technology Project of Health Commission of Jiangxi Province/ ; GJJ2201444//Youth Project of Foundation of Jiangxi/ ; //President Foundation of Nanfang Hospital/ ; 2022B026//Southern Medical University/ ; }, mesh = {Animals ; Mice ; *Advanced Oxidation Protein Products/metabolism ; *Aging/physiology/metabolism ; Bone and Bones/metabolism/blood supply ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; Male ; Neovascularization, Physiologic/drug effects/physiology ; NADPH Oxidases/metabolism ; Cell Proliferation/drug effects ; Osteogenesis/drug effects/physiology ; }, abstract = {Type H vessels have been proven to couple angiogenesis and osteogenesis. The decline of type H vessels contributes to bone loss in the aging process. Aging is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, whether AOPP accumulation is involved in age-related decline of type H vessels is unclear. Here, we show that the increase of AOPP levels in plasma and bone was correlated with the decline of type H vessels and loss of bone mass in old mice. Exposure of microvascular endothelial cells to AOPPs significantly inhibited cell proliferation, migration, and tube formation; increased NADPH oxidase activity and excessive reactive oxygen species generation; upregulated the expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1; and eventually impaired angiogenesis, which was alleviated by redox modulator N-acetylcysteine and NADPH oxidase inhibitor apocynin. Furthermore, reduced AOPP accumulation by NAC treatment was able to alleviate significantly the decline of type H vessels, bone mass loss, and deterioration of bone microstructure in old mice. Collectively, these findings suggest that AOPPs accumulation contributes to the decline of type H vessels in the aging process, and illuminate a novel potential mechanism underlying age-related bone loss.}, } @article {pmid39506442, year = {2024}, author = {Barlattani, T and Celenza, G and Cavatassi, A and Minutillo, F and Socci, V and Pinci, C and Santini, R and Pacitti, F}, title = {Neuropsychiatric Manifestations of COVID-19 Disease and Post Covid Syndrome: The Role of N Acetyl-cysteine and Acetyl-L-carnitine.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X343115241030094848}, pmid = {39506442}, issn = {1875-6190}, abstract = {COVID-19 is associated with neuropsychiatric symptoms, such as anosmia, anxiety, depression, stress-related reactions, and psychoses. The illness can cause persistent cognitive impairment and "brain fog", suggesting chronic brain involvement. Clinical entities of ongoing symptomatic COVID-19 and Post COVID Syndrome (PCS) mainly present neuropsychiatric symptoms such as dysgeusia, headache, fatigue, anxiety, depression, sleep disturbances, and post-traumatic stress disorder. The pathophysiology of COVID-19-related brain damage is unclear, but it is linked to various mechanisms such as inflammation, oxidative stress, immune dysregulation, impaired glutamate homeostasis, glial and glymphatic damage, and hippocampal degeneration. Noteworthy is that the metabotropic receptor mGluR2 was discovered as a mechanism of internalisation of SARS-CoV-2 in Central Nervous System (CNS) cells. N-acetylcysteine (NAC) and acetyl-L-carnitine (ALC) are two supplements that have already been found effective in treating psychiatric conditions. Furthermore, NAC showed evidence in relieving cognitive symptomatology in PCS, and ALC was found effective in treating depressive symptomatology of PCS. The overlapping effects on the glutamatergic system of ALC and NAC could help treat COVID-19 psychiatric symptoms and PCS, acting through different mechanisms on the xc-mGluR2 network, with potentially synergistic effects on chronic pain and neuro-astrocyte protection. This paper aims to summarise the current evidence on the potential therapeutic role of NAC and ALC, providing an overview of the underlying molecular mechanisms and pathophysiology. It proposes a pathophysiological model explaining the effectiveness of NAC and ALC in treating COVID-19-related neuropsychiatric symptoms.}, } @article {pmid39504621, year = {2024}, author = {Peng, TR and Lin, HH and Tseng, TL and Huang, YH and Tsai, PY and Lin, CY and Lee, MC and Chen, SM}, title = {Efficacy of N-acetylcysteine for patients with depression: An updated systematic review and meta-analysis.}, journal = {General hospital psychiatry}, volume = {91}, number = {}, pages = {151-159}, doi = {10.1016/j.genhosppsych.2024.10.018}, pmid = {39504621}, issn = {1873-7714}, mesh = {*Acetylcysteine/administration & dosage/therapeutic use ; Humans ; Outcome Assessment, Health Care ; Depressive Disorder, Major/drug therapy ; Depressive Disorder/drug therapy ; }, abstract = {BACKGROUND: Results on whether N-acetylcysteine (NAC) ameliorates depression in patients with psychiatric problems, such as bipolar disorder and major depressive disorder, remain inconsistent, and several new studies have recently been published. Thus, we conducted an uptodated meta-analysis to evaluate the efficacy of NAC against depression.

METHODS: This systematic review and meta-analysis included randomized controlled trials where NAC was used to treat depression. The present study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase (Ovid), and Cochrane were searched for relevant articles. A random-effects model was used to evaluate the primary outcome-efficacy of NAC in ameliorating depression.

RESULTS: This review included 12 studies (904 patients with depression). The daily dose of NAC in the included studies ranged from 1000 to 3000 mg. The duration of NAC treatment ranged from 8 to 24 weeks. A significant difference was noted between NAC and placebo in terms of the change in mean depression score from baseline to treatment conclusion (standardized mean difference = -0.24; 95 % confidence interval (CI) = -0.44 to -0.05; I[2] = 45 %; P = .02).

CONCLUSION: Our findings indicate that adjunctive NAC can ameliorate depressive symptoms in patients with psychiatric problems, particularly bipolar disorder. However, large-scale clinical trials were needed to substantiate our results due to the wide CI value.}, } @article {pmid39500660, year = {2024}, author = {Xie, R and Yang, Y and Jiang, X and Gao, L and Sun, J and Yang, J}, title = {The effect of modulating platelet reactive oxygen species by the addition of antioxidants to prevent clearance of cold-stored platelets.}, journal = {Hematology, transfusion and cell therapy}, volume = {46 Suppl 6}, number = {}, pages = {S272-S283}, doi = {10.1016/j.htct.2024.09.2479}, pmid = {39500660}, issn = {2531-1387}, abstract = {BACKGROUND: It is known that the rapid clearance of cold-stored platelets is attributed to various storage lesions, including an abnormal increase in reactive oxygen species when platelets are exposed to cold temperatures. As an antioxidant, N-acetylcysteine exhibits some significant effects on scavenging various reactive oxygen species and inhibiting cell damage and apoptosis.

AIMS: This study aimed to investigate the effects of N-acetylcysteine on reducing reactive oxygen species production and protecting cold-stored platelets from phagocytosis and clearance, and to determine the optimal concentration of N-acetylcysteine.

METHODS: Platelet concentrates were divided into three groups: room-temperature-stored platelets, cold-stored platelets, and cold-stored platelets with the addition of different concentrations of N-acetylcysteine. After five days of storage, reactive oxygen species production, lipid peroxidation levels, activation marker expressions, GPIb/ɑ desialylation with exposure of glycan residues and other quality parameters of platelets were measured and compared between the groups. Phagocytosis of platelets was detected by phorbol 12-myristate 13-acetate-activated THP-1 or Hep G2 cells. Moreover, the recovery of infused platelets was measured in severe combined immunodeficient mice at different timepoints.

RESULTS: After 5 days of storage, cytoplasmic reactive oxygen species significantly increased in chilled compared to non-chilled platelets; they were notably reduced with the addition of N-acetylcysteine, particularly at a concentration of 5 mM. Compared with chilled platelets, the P-selectin and phosphatidylserine expressions, as well as exposure of GPIb/ɑ glycan residues, were significantly reduced with 5 mM of N-acetylcysteine. Phagocytosis of platelets by THP-1 or Hep G2 cells was significantly lower in 5 mM of N-acetylcysteine compared to cold-stored platelets without N-acetylcysteine.

CONCLUSIONS: This study demonstrated correlations between reactive oxygen species production and their pro-oxidant effects on platelet clearance after cold storage. The addition of N-acetylcysteine at an appropriate concentration do not only protects chilled platelets from storage lesions caused by reactive oxygen species overproduction but also prevents platelet phagocytosis in vitro and clearance in vivo, thereby extending circulating time.}, } @article {pmid39497872, year = {2024}, author = {Jain, E and Alex, R and Coutinho, T and Narula, N}, title = {Utility of N-acetylcysteine in Non-Acetaminophen-Induced Liver Injury Secondary to Influenza A Infection.}, journal = {Cureus}, volume = {16}, number = {10}, pages = {e70900}, pmid = {39497872}, issn = {2168-8184}, abstract = {Influenza A, which belongs to the Orthomyxoviridae viral family, is a known causative agent of respiratory illness and systemic inflammation. Annual influenza immunizations are crucial in reducing the incidence and severity of the flu. Intravenous (IV) N-acetylcysteine (NAC) is a pharmaceutical agent indicated for hepatic injury, particularly to address oxidative stress and inflammation secondary to acetaminophen toxicity. The authors present a case of a young female with acute liver injury and impending liver failure in the setting of viral influenza A infection, successfully treated with IV-NAC.}, } @article {pmid39497389, year = {2024}, author = {, }, title = {[Guidelines for diagnosis and management of drug-induced liver injury caused by anti-tuberculosis drugs (2024 version)].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {47}, number = {11}, pages = {1069-1090}, doi = {10.3760/cma.j.cn112147-20240614-00338}, pmid = {39497389}, issn = {1001-0939}, support = {2023ZX10003001//National Key Research and Development Program/ ; 2023-2025//Shanghai Three-Year/ ; GWVI-11.1-05//Action Plan to Strengthen the Public Health System/ ; }, mesh = {*Chemical and Drug Induced Liver Injury/diagnosis/etiology/prevention & control/therapy ; Humans ; *Antitubercular Agents/adverse effects ; China ; Tuberculosis/drug therapy/diagnosis ; }, abstract = {Drug-induced liver injury (DILI) is one of the most common adverse reactions of anti-tuberculosis treatment. To improve the diagnosis and management of anti-tuberculosis drug-induced liver injury (ATB-DILI) for clinicians and tuberculosis control workers, the Chinese Medical Association Tuberculosis Branch has developed guidelines for the diagnosis and treatment of ATB-DILI. These guidelines summarized recent research progress in relevant fields and provide detailed explanations, recommendations, and quality assessments related to ATB-DILI, covering aspects such as definition, risk factors, mechanisms, pathological manifestations, clinical classification, diagnosis, and management. The key recommendations are as follows.Recommendation 1: Risk factors: NAT2 slow acetylation genotype, GSTM1 gene variation, advanced age, hepatitis virus infection or concurrent acute/chronic liver disease, HIV infection, malnutrition, and alcohol (ethanol) intake are risk factors for ATB-DILI (2, B).Recommendation 2: R-value calculation: Calculate the R-value for suspected ATB-DILI patients at different time points during the course of the disease. ALT and ALP values should be obtained on the same day, with a maximum interval of no more than 48 hours. This helps to accurately determine the clinical type and prognosis of DILI (2, C).Recommendation 3: Comprehensive medical history collection: Collect information on past medication history, clinical features, dynamic changes in liver biochemical markers, drug rechallenge reactions, comorbidities, and underlying liver diseases (4, B).Recommendation 4: Liver biochemical tests: Include at least ALT, AST, ALP, GGT, TBil, DBil, and albumin. If necessary, measure prothrombin time or international normalized ratio (INR) (3, B).Recommendation 5: Abdominal imaging: Routine abdominal imaging should be performed for suspected ATB-DILI patients (3, B).Recommendation 6: Liver histopathological examination: Histology of liver biopsies aids in the diagnosis and differential diagnosis of DILI (4, B).Recommendation 7: Biochemical diagnostic criteria for acute ATB-DILI: Liver biochemical tests should meet one of the following criteria: ALT≥3×ULN and/or TBil≥2×ULN; simultaneous elevation of AST, ALP, and TBil, with at least one parameter≥2×ULN (4, C).Recommendation 8: Diagnostic criteria for ATB-DILI: Diagnosis requires:(1) A history of exposure to anti-tuberculosis drugs that can cause liver injury;(2)Rapid normalization of abnormal liver biochemical markers after drug discontinuation: For patients with hepatocellular injury, a decrease in the peak serum ALT level of at least 50% within 8 days is highly suggestive, while a decrease of at least 50% within 30 days is considered important. For patients with cholestatic injury, a serum ALP or TBil peak level that decreases by at least 50% within 180 days is also considered important;(3) Exclusion of other causes of liver injury;(4) Positive rechallenge reaction. Meeting three of the above criteria confirms ATB-DILI, whereas meeting (1) and (2) criteria indicates a suspected case. In practice, the vast majority of ATB-DILI are suspected cases (3, B).Recommendation 9: Avoid re-exposure: Minimize re-exposure to the same suspected drug, especially if the initial exposure caused severe liver injury (4, B).Recommendation 10: Causality assessment: Use the RUCAM scale as the primary method for assessing causality. In cases involving multiple hepatotoxic drugs, concurrent liver disease, or new drug clinical trials, combine expert opinions for reliable assessment (3, B).Recommendation 11: Baseline testing: All patients are recommended to undergo baseline liver biochemistry, HBsAg (if HBsAg is positive, further HBV DNA testing), anti-HCV testing, and abdominal imaging before starting anti-TB treatment (3, B).Recommendation 12: Monitoring frequency: Patients without high-risk factors should have monthly liver biochemical monitoring (4, C);high-risk patients or those using hepatotoxic drugs should be monitored every 2 weeks during the first 2 months of anti-tuberculosis treatment, then monthly (2, B).Recommendation 13: Avoid concurrent hepatotoxic drugs: Evaluate the benefit-risk ratio of using other hepatotoxic drugs or traditional Chinese medicine (4, C).Recommendation 14: Antiviral treatment: In ATB-DILI patients with viral hepatitis, consider prompt antiviral therapy if indicated (3, B).Recommendation 15: NAT2 genotyping: Guide isoniazid dosing based on NAT2 gene polymorphism (4, C).Recommendation 16: Application of preventive hepatoprotective drugs: People with high risk factors for liver damage may consider it (4, C); however, routine use in the general population is not recommended (2, B).Recommendation 17: Immediate discontinuation: In the case of ATB-DILI, suspected drugs should be discontinued immediately (4, A).Recommendation 18: N-acetylcysteine (NAC): Early intravenous administration of NAC is beneficial for acute liver failure and subacute liver failure induced by drugs in adults (4, D).Recommendation 19: Glucocorticoids: Use with caution;not recommended as routine treatment for ATB-DILI(4, C);may be considered for immune-mediated DILI with hypersensitivity and autoimmune features (3, B).Recommendation 20: For acute hepatocellular injury or mixed DILI with significantly elevated ALT/AST, bicyclol and/or magnesium isoglycyrrhizinate are recommended (2, B).Recommendation 21: For mild to moderate hepatocellular injury type DILI with elevated ALT/AST, reasonable choices include ammonium glycyrrhizinate, compound glycyrrhizin, and other glycyrrhizic acid derivatives, glutathione, silymarin, polyenylphosphatidylcholine, and other drugs (4, C); For cholestatic DILI with elevated ALP/GGT/TBil, ursodeoxycholic acid or S-adenosylmethionine may be selected (4, C); the combined use of two or more drugs that mainly reduce ALT is not recommended (4, B).Recommendation 22: Treatment of severe patients: For severe patients such as those with drug-induced liver failure, liver transplantation is recommended (2, B); artificial liver (high-volume plasma exchange, dual plasma molecular adsorption system, etc.) may be a beneficial option (4, C); ornithine aspartate may help reduce blood ammonia levels in patients with severe disease or liver failure (4, C).Recommendation 23: Rational drug use during the recovery period: During or after liver function recovery, clinicians should comprehensively assess the patient's liver injury severity, presence of liver injury-related risk factors, and tuberculosis severity. Based on this assessment, anti-tuberculosis drugs should be selected rationally (4, C). These recommendations provide clinical evidence and decision-making guidance for the standardized diagnosis and treatment of ATB-DILI.}, } @article {pmid39494844, year = {2024}, author = {Hassanzadeh, E and Sedighi Pashaki, A and Akbari Hamed, E and Mehrpooya, M and Mohammadian, K and Bayani, R and Sheikhi, K and Ranjbar, H and Abbasi, M}, title = {Evaluating N-acetylcysteine as a Protective Agent Against Chemotherapy-induced Neuropathy in Breast Cancer: A Triple-blind, Randomized Clinical Trial.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/COC.0000000000001153}, pmid = {39494844}, issn = {1537-453X}, abstract = {OBJECTIVES: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant clinical issue that affects patients' quality of life and can limit the dosing of chemotherapeutic agents. N-acetylcysteine (NAC) has been proposed as a potential chemoprotective agent against CIPN due to its antioxidant properties. This study aimed to investigate the efficacy of oral NAC in preventing and controlling taxane-induced neuropathy in patients with breast cancer.

METHODS: This randomized, triple-blind, placebo-controlled trial included 80 breast cancer patients undergoing taxane-based chemotherapy. Participants were divided into 2 groups: an intervention group receiving 1200 mg of oral NAC in divided doses per day and a placebo group. Patients were evaluated for neuropathy grade and functional status at 1 and 12 weeks postintervention.

RESULTS: Our analysis revealed no significant difference in the incidence and severity of neuropathy between the intervention and placebo groups at 1 (P=0.328) and 12 weeks (P=0.569) postchemotherapy. Baseline characteristics such as age, number of treatment cycles, and disease stage were similar between groups, indicating a homogeneous population.

CONCLUSIONS: Oral NAC at a dose of 1200 mg per day did not significantly reduce the incidence or severity of taxane-induced neuropathy. These findings suggest that the oral bioavailability of NAC may be insufficient to exert a protective effect and that future studies should consider alternative dosing strategies or routes of administration. The need for further research to optimize NAC's chemoprotective role in CIPN remains evident.}, } @article {pmid39494328, year = {2024}, author = {Kim, HB and Kim, YJ and Lee, YJ and Yoo, JY and Choi, Y and Kim, EM and Suh, SW and Woo, RS}, title = {N-Acetylcysteine Alleviates Depressive-Like Behaviors in Adolescent EAAC1[-/-] Mice and Early Life Stress Model Rats.}, journal = {International journal of biological sciences}, volume = {20}, number = {14}, pages = {5450-5473}, pmid = {39494328}, issn = {1449-2288}, mesh = {Animals ; *Acetylcysteine/therapeutic use/pharmacology ; Male ; Female ; Mice ; *Depression/drug therapy/metabolism ; Rats ; *Excitatory Amino Acid Transporter 3/metabolism ; *Stress, Psychological/drug therapy ; Hippocampus/metabolism/drug effects ; Oxidative Stress/drug effects ; Mice, Knockout ; Disease Models, Animal ; Rats, Sprague-Dawley ; Behavior, Animal/drug effects ; Maternal Deprivation ; }, abstract = {Exposure to adverse experiences during early life is associated with an increased risk of psychopathology during adolescence. In a previous study, we demonstrated that neonatal maternal separation (NMS) combined with social isolation led to impulsive and depressive-like behaviors in male adolescents. Additionally, it significantly reduced the expression of excitatory amino acid carrier 1 (EAAC1) in the hippocampus. Building upon this work, we investigated the effects of N-acetylcysteine (NAC), a precursor to glutathione, in early-life stress (ELS) model rats and in EAAC1[-/-] mice. EAAC1 plays a dual role in transporting both glutamate and cysteine into neurons. Our findings revealed that female adolescents subjected to in the ELS model also exhibited behavioral defects similar to those of males. NAC injection rescued depressive-like behaviors in both male and female NMS models, but it improved impulsive behavior only in males. Furthermore, we observed increased reactive oxidative stress (ROS) and neuroinflammation in the ventral hippocampus (vHPC) and prefrontal cortex of NMS model rats, which were mitigated by NAC treatment. Notably, NAC reversed the reduced expression of EAAC1 in the vHPC of NMS model rats. In EAAC1[-/-] mice, severe impulsive and depressive-like behaviors were evident, and the NAC intervention improved only depressive-like behaviors. Collectively, our results suggest that ELS contributes to depression and impulsive behaviors during adolescence. Moreover, the cysteine uptake function of EAAC1 in neurons may be specifically related to depression rather than impulsive behavior.}, } @article {pmid39493971, year = {2024}, author = {Xu, C and Chen, Y and Zhou, Z and Yan, Y and Fu, W and Zou, P and Ni, D}, title = {ML385, an Nrf2 Inhibitor, Synergically Enhanced Celastrol Triggered Endoplasmic Reticulum Stress in Lung Cancer Cells.}, journal = {ACS omega}, volume = {9}, number = {43}, pages = {43697-43705}, pmid = {39493971}, issn = {2470-1343}, abstract = {Lung cancer is one of the leading causes of death. Celastrol is a natural product that has shown anticancer activity but has not yet been applied in clinical settings due to its narrow therapeutic window. In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol. At the same time, celastrol upregulated the expression of cytoprotective transcription factor Nrf2 and its downstream proteins, which are effective in preventing the oxidative damage caused by ROS accumulation. Notably, we found that the overexpression of Nrf2 enhances the tolerance of lung cancer cells to celastrol and that lung cancer cells H460 with a Keap1 mutation are insensitive to celastrol. This indicates that the increase in Nrf2 contributes to the survival of lung cancer cells. Thus, we brought in an Nrf2 inhibitor ML385 to suppress the activation of Nrf2. We found that when ML385 and celastrol were added together the survival rates of lung cancer cells decreased more and the detected ROS level became much higher compared to treatment with celastrol alone. We also discovered that ML385 suppressed the expression of HO-1 and GCLC, which amplified celastrol-induced ATF4/CHOP-dependent endoplasmic reticulum stress (ER stress). Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.}, } @article {pmid39493366, year = {2024}, author = {Rogliani, P and Manzetti, GM and Gholamalishahi, S and Cazzola, M and Calzetta, L}, title = {Impact of N-Acetylcysteine on Mucus Hypersecretion in the Airways: A Systematic Review.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {19}, number = {}, pages = {2347-2360}, pmid = {39493366}, issn = {1178-2005}, mesh = {Animals ; Humans ; *Acetylcysteine/pharmacology/therapeutic use ; *Expectorants/pharmacology/therapeutic use ; *Goblet Cells/drug effects/metabolism ; Hyperplasia ; *Lung/drug effects/metabolism ; Mucin 5AC/metabolism/genetics ; Mucin-5B/metabolism/genetics ; Mucociliary Clearance/drug effects ; *Mucus/metabolism ; *Pulmonary Disease, Chronic Obstructive/drug therapy/metabolism/physiopathology ; }, abstract = {Mucus clearance is crucial for airway protection, and its dysfunction leads to chronic obstructive pulmonary disease (COPD) characterized by mucus hypersecretion (MHS) and impaired clearance. MUC5AC and MUC5B mucin proteins are key components of airway mucus, with MUC5AC being particularly responsive to environmental stimuli, making it a potential COPD biomarker. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance, but its precise mechanisms in COPD remain unclear. This systematic review evaluated the impact of NAC on MHS in the airways, reporting significant inhibitory effects on MUC5AC and MUC5B gene and protein expression, as well as a reduction in the number of goblet cells. NAC has demonstrated efficacy in vitro and in animal models of MHS, including COPD models, but data on human bronchial tissue are lacking. This systematic review suggests that NAC acts as a mucolytic and a mucoregulator, directly inhibiting mucus secretion and goblet cell hyperplasia. Given the critical role of MHS in COPD progression, exacerbations, and mortality, these findings highlight the potential of NAC as a targeted therapy for hypersecretion COPD phenotypes. However, further studies are needed to confirm the results of this systematic review, even in human bronchial tissue, to provide translatable evidence in clinical settings. Understanding the intimate mechanism of NAC versus MHS regulation may pave the way for more effective treatments targeting airway mucus dysfunction in COPD, ultimately improving patient outcomes and reducing morbidity and mortality associated with chronic mucus hypersecretion.}, } @article {pmid39493346, year = {2024}, author = {Pastore, A and Badolati, N and Manfrevola, F and Sagliocchi, S and Laurenzi, V and Musto, G and Porreca, V and Murolo, M and Chioccarelli, T and Ciampaglia, R and Vellecco, V and Bucci, M and Dentice, M and Cobellis, G and Stornaiuolo, M}, title = {N-acetyl-L-cysteine reduces testis ROS in obese fathers but fails in protecting offspring from acquisition of epigenetic traits at cyp19a1 and IGF11/H19 ICR loci.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1450580}, pmid = {39493346}, issn = {2296-634X}, abstract = {INTRODUCTION: Paternal nutrition before conception has a marked impact on offspring's risk of developing metabolic disorders during adulthood. Research on human cohorts and animal models has shown that paternal obesity alters sperm epigenetics (DNA methylation, protamine-to-histone replacement, and non-coding RNA content), leading to adverse health outcomes in the offspring. So far, the mechanistic events that translate paternal nutrition into sperm epigenetic changes remain unclear. High-fat diet (HFD)-driven paternal obesity increases gonadic Reactive Oxygen Species (ROS), which modulate enzymes involved in epigenetic modifications of DNA during spermatogenesis. Thus, the gonadic pool of ROS might be responsible for transducing paternal health status to the zygote through germ cells.

METHODS: The involvement of ROS in paternal intergenerational transmission was assessed by modulating the gonadic ROS content in male mice. Testicular oxidative stress induced by HFD was counterbalanced by N-acetylcysteine (NAC), an antioxidant precursor of GSH. The sires were divided into four feeding groups: i) control diet; ii) HFD; iii) control diet in the presence of NAC; and iv) HFD in the presence of NAC. After 8 weeks, males were mated with females that were fed a control diet. Antioxidant treatment was then evaluated in terms of preventing the HFD-induced transmission of dysmetabolic traits from obese fathers to their offspring. The offspring were weaned onto a regular control diet until week 16 and then underwent metabolic evaluation. The methylation status of the genomic region IGFII/H19 and cyp19a1 in the offspring gDNA was also assessed using Sanger sequencing and methylation-dependent qPCR.

RESULTS: Supplementation with NAC protected sires from HFD-induced weight gain, hyperinsulinemia, and glucose intolerance. NAC reduced oxidative stress in the gonads of obese fathers and improved sperm viability. However, NAC did not prevent the transmission of epigenetic modifications from father to offspring. Male offspring of HFD-fed fathers, regardless of NAC treatment, exhibited hyperinsulinemia, glucose intolerance, and hypoandrogenism. Additionally, they showed altered methylation at the epigenetically controlled loci IGFII/H19 and cy19a1.

CONCLUSION: Although NAC supplementation improved the health status and sperm quality of HFD-fed male mice, it did not prevent the epigenetic transmission of metabolic disorders to their offspring. Different NAC dosages and antioxidants other than NAC might represent alternatives to stop the intergenerational transmission of paternal dysmetabolic traits.}, } @article {pmid39492659, year = {2024}, author = {Angelini, A and Garcia Marquez, G and Malovannaya, A and Fiorotto, ML and Saltzman, A and Jain, A and Trial, JA and Taffet, GE and Cieslik, KA}, title = {Sex Differences in Response to Diet Enriched with Glutathione Precursors in the Aging Heart.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glae258}, pmid = {39492659}, issn = {1758-535X}, abstract = {Common features of the aging heart are dysregulated metabolism, inflammation, and fibrosis. Elevated oxidative stress is another hallmark of cardiac aging that can exacerbate each of these conditions. We hypothesize that by increasing natural antioxidant levels (glutathione), we will improve cardiac function. Twenty-one-month-old mice were fed Glycine and N-Acetyl Cysteine (GlyNAC) (glutathione precursors)-supplemented or control diets for 12 weeks. Heart function was monitored longitudinally, and the exercise performance was determined at the end of the study. We found that the GlyNAC diet was beneficial for old male but not old female mice, leading to an increase of Ndufb8 expression (a subunit of the mitochondrial respiratory chain complex), and higher enzymatic activity for CPT1b and CrAT, two carnitine acyltransferases that are critical to cardiomyocyte metabolism. Although no quantifiable change of collagen turnover was detected, hearts from GlyNAC-fed old males exhibited a slight but significant enrichment in Fmod, a protein that can inhibit collagen fibril formation, possibly reducing extracellular matrix (ECM) stiffness and thus improving diastolic function. Cardiac diastolic function was modestly improved in males but not females, and surprisingly GlyNAC-fed female mice showed a decline in exercise performance. In summary, our work supports the concept that aged male and female hearts are phenotypically different. These basic differences may affect the response to pharmacological and diet interventions, including antioxidants.}, } @article {pmid39490995, year = {2024}, author = {Zhao, E and Liang, R and Li, P and Lu, D and Chen, S and Tan, W and Qin, Y and Zhang, Y and Zhang, Y and Zhang, Q and Liu, Q}, title = {Mesenchymal stromal cells alleviate APAP-induced liver injury via extracellular vesicle-mediated regulation of the miR-186-5p/CXCL1 axis.}, journal = {Stem cell research & therapy}, volume = {15}, number = {1}, pages = {392}, pmid = {39490995}, issn = {1757-6512}, support = {81971526 and 82370629//the National Natural Science Foundation of China/ ; 2022A1515012223//the Natural Science Foundation of Guangdong Province/ ; 202201020398, 202201020430//the Science and Technology Program of Guangzhou/ ; }, mesh = {*Mesenchymal Stem Cells/metabolism/cytology ; *MicroRNAs/metabolism/genetics ; *Chemokine CXCL1/metabolism/genetics ; *Extracellular Vesicles/metabolism ; Animals ; *Chemical and Drug Induced Liver Injury/metabolism/therapy ; Mice ; *Acetaminophen/adverse effects ; Humans ; Male ; Mice, Inbred C57BL ; Mesenchymal Stem Cell Transplantation/methods ; }, abstract = {BACKGROUND: Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury (DILI). N-acetylcysteine (NAC) is the first-line agent used in the clinic. However, it rarely benefits patients with advanced APAP toxicity. Mesenchymal stromal cells (MSCs) have demonstrated potential in treating DILI. However, the specific mechanism by which MSCs protect against APAP-induced liver injury remains unclear.

METHODS: APAP was injected intraperitoneally to induce a liver injury model. We then detected histopathology, biochemical indices, and inflammatory cytokine levels to assess the efficacy of MSCs and MSC extracellular vesicles (MSC-EVs). Flow cytometry was performed to reveal the immunoregulatory effects of MSCs and MSC-EVs on the neutrophils. RNA sequencing (RNA-Seq) of liver tissues was used to identify critical target genes for MSC treatment.

RESULTS: MSC and MSC-EV treatment effectively alleviated APAP-induced liver injury and inhibited neutrophil infiltration. RNA-Seq analysis and ELISA data indicated that C-X-C motif chemokine 1 (CXCL1), a chemoattractant for neutrophils, was a key molecule in the MSC-mediated amelioration of APAP-induced liver damage. In addition, neutralization of CXCL1 reduced APAP-induced liver damage, which was accompanied by decreased neutrophil infiltration. Importantly, we verified that MSC-EV-derived miR-186-5p directly binds to the 3'-UTR of Cxcl1 to inhibit its expression in hepatocytes. The agomir miR-186-5p showed excellent potential for the treatment of DILI.

CONCLUSIONS: Our findings suggest that MSCs and MSC-EVs are an effective approach to mitigate DILI. Targeting the miR-186-5p/CXCL1 axis is a promising approach to improve the efficacy of MSCs and MSC-EVs in the treatment of DILI.}, } @article {pmid39489865, year = {2024}, author = {Har-Zahav, A and Tobar, A and Fried, S and Sivan, R and Wilkins, BJ and Russo, P and Shamir, R and Wells, RG and Gurevich, M and Waisbourd-Zinman, O}, title = {Oral N-acetylcysteine ameliorates liver fibrosis and enhances regenerative responses in Mdr2 knockout mice.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {26513}, pmid = {39489865}, issn = {2045-2322}, support = {72-12//PSC Partners Seeking a Cure/ ; 1879/21//The Israeli Science Foundation/ ; }, mesh = {Animals ; Male ; Mice ; *Acetylcysteine/pharmacology/administration & dosage ; Administration, Oral ; *ATP Binding Cassette Transporter, Subfamily B/genetics/metabolism ; *ATP-Binding Cassette Sub-Family B Member 4 ; Disease Models, Animal ; Liver/drug effects/metabolism/pathology ; *Liver Cirrhosis/drug therapy/pathology/metabolism ; Liver Regeneration/drug effects ; Mice, Knockout ; }, abstract = {Cholangiopathies are poorly understood disorders with no effective therapy. The extrahepatic biliary tree phenotype is less studied compared to the intrahepatic biliary injury in both human disease and Mdr2[-/-] mice, the established cholestatic mouse model. This study aimed to characterize the extra hepatic biliary tree of Mdr2[-/-] mice at various ages and to determine if injury can be repaired with the antioxidant and glutathione precursor N-acetyl-L-Cysteine treatment (NAC). We characterized extra hepatic bile ducts (EHBD)s at various ages from 2 to 40 weeks old FVB/N and Mdr2[-/-] mice. We examined the therapeutic potential of local NAC ex vivo using EHBD explants at early and late stages of injury; and systematic therapy by in vivo oral administration for 3 weeks. EHBD and liver sections were assessed by histology and immunofluorescent stains. Serum liver enzyme activities were analyzed, and liver spatial protein expression analysis was performed. Mdr2[-/-] mice developed progressive EHBD injury, similar to extrahepatic PSC. NAC treatment of ex vivo EHBD explants led to improved duct morphology. In vivo, oral administration of NAC improved liver fibrosis, and decreased liver enzyme activities. Spatial protein analysis revealed cell-type specific differential response to NAC, collectively indicating a transition from pro-apoptotic into proliferative state. NAC treatment should be further investigated as a potential therapeutic option for human cholangiopathies.}, } @article {pmid39489186, year = {2024}, author = {Chen, C and Wang, T and Gao, TY and Chen, YL and Lu, YB and Zhang, WP}, title = {Ablation of NAMPT in dopaminergic neurons leads to neurodegeneration and induces Parkinson's disease in mouse.}, journal = {Brain research bulletin}, volume = {218}, number = {}, pages = {111114}, doi = {10.1016/j.brainresbull.2024.111114}, pmid = {39489186}, issn = {1873-2747}, mesh = {Animals ; *Nicotinamide Phosphoribosyltransferase/metabolism ; *Dopaminergic Neurons/metabolism/pathology/drug effects ; Mice ; *Rotenone/toxicity/pharmacology ; Parkinson Disease/metabolism/pathology ; Cytokines/metabolism ; Substantia Nigra/metabolism/pathology/drug effects ; NAD/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Humans ; Mitochondria/metabolism/drug effects ; Disease Models, Animal ; Male ; Cell Line, Tumor ; }, abstract = {Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the salvaging synthesize pathway of nicotinamide adenine dinucleotide (NAD). The neuroprotective roles of NAMPT on neurodegeneration have been explored in aging brain and Alzheimer's Disease. However, its roles in Parkinson's Disease (PD) remain to be elucidated. We found that the dopaminergic neurons in substantia nigra expressed higher levels of NAMPT than the other types of neurons. Using conditional knockout of the Nampt gene in dopaminergic neurons and utilizing a NAMPT inhibitor in the substantia nigra of mice, we found that the NAMPT deficiency triggered the time-dependent loss of dopaminergic neurons, the impairment of the dopamine nigrostriatal pathway, and the development of PD-like motor dysfunction. In the rotenone-induced PD mouse model, nicotinamide ribose (NR), a precursor of NAD, rescued the loss of dopaminergic neurons, the impairment of dopamine nigrostriatal pathway, and mitigated PD-like motor dysfunction. In SH-SY5Y cells, NAD suppression induced the accumulation of reactive oxygen species (ROS), mitochondrial impairment, and cell death, which was reversed by N-acetyl cysteine, an antioxidant and ROS scavenger. Rotenone decreased NAD level, induced the accumulation of ROS and the impairment of mitochondria, which was reversed by NR. In summary, our findings show that the ablation of NAMPT in dopaminergic neurons leads to neurodegeneration and contributes to the development of PD. The NAD precursors have the potential to protect the degeneration of dopaminergic neurons, and offering a therapeutic approach for the treatment of PD.}, } @article {pmid39488036, year = {2024}, author = {Joseph, JP and Kumar, T and Ramteke, NS and Chatterjee, K and Nandi, D}, title = {High intracellular calcium amounts inhibit activation-induced proliferation of mouse T cells: Tert-butyl hydroquinone as an additive enhancer of intracellular calcium.}, journal = {International immunopharmacology}, volume = {143}, number = {Pt 3}, pages = {113501}, doi = {10.1016/j.intimp.2024.113501}, pmid = {39488036}, issn = {1878-1705}, mesh = {Animals ; *Hydroquinones/pharmacology ; *Calcium/metabolism ; *Cell Proliferation/drug effects ; *T-Lymphocytes/drug effects/immunology/metabolism ; Mice ; *Lymphocyte Activation/drug effects ; *Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Colitis/drug therapy/chemically induced/immunology ; Cells, Cultured ; Ionomycin/pharmacology ; Dextran Sulfate ; NF-E2-Related Factor 2/metabolism/genetics ; Tetradecanoylphorbol Acetate/pharmacology ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism/genetics ; Female ; }, abstract = {Optimal T cell activation is critical to orchestrate adaptive immune responses. Calcium is critical for T cell activation and integrates signaling pathways necessary to activate key transcription factors. In fact, patients with calcium channelopathies are immunodeficient. Here, we investigated the effects of different concentrations of intracellular calcium on activation of mouse T cells. High intracellular calcium amounts inhibited in vitro T cell proliferation as evidenced by a decreased cell cycling-to-hypodiploidy ratio in two models of activation: the combination of phorbol 12-myristate 13-acetate (PMA) and Ionomycin (an ionophore)/Thapsigargin (a SERCA inhibitor) or plate bound anti-CD3 and anti-CD28. High intracellular calcium amounts increased the production of reactive oxygen species (ROS) in T cells activated with PMA and Ionomycin and scavenging excess ROS using N-acetyl cysteine (NAC) rescued the decrease in cycling-to-hypodiploidy ratio. To test the universality of our observations, we studied the effects of tert-Butylhydroquinone (tBHQ), a SERCA inhibitor and Nrf2 activator. tBHQ alone did not increase intracellular calcium amounts but the intracellular calcium amounts increased when tBHQ was used in combination with PMA. Also, tBHQ inhibited T cell activation in a dose-dependent manner in both in vitro models of T cell activation. Importantly, intraperitoneal injection of tBHQ ameliorated Dextran Sodium Sulfate (DSS)-induced colitis in mice as evidenced by rescue of colon length shortening and lower disease activity index. Overall, this study identifies high calcium amounts as a potential target to lower T cell activation. The implications of these observations are discussed in the context of calcium modulating drugs that are used to treat various diseases.}, } @article {pmid39479839, year = {2024}, author = {Yang, B and Zhao, LL and DU, JH and Yan, Y and Dai, KS}, title = {[Regulation of Reactive Oxygen Species on Platelet Activation and Apoptosis].}, journal = {Zhongguo shi yan xue ye xue za zhi}, volume = {32}, number = {5}, pages = {1503-1508}, doi = {10.19746/j.cnki.issn.1009-2137.2024.05.031}, pmid = {39479839}, issn = {1009-2137}, mesh = {*Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Humans ; *Blood Platelets/metabolism ; *Membrane Potential, Mitochondrial ; *Platelet Activation ; *P-Selectin/metabolism ; *Thrombin/pharmacology ; *Platelet Aggregation ; Signal Transduction ; Acetylcysteine/pharmacology ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; }, abstract = {OBJECTIVE: To investigate how reactive oxygen species (ROS) regulates the signal transduction of platelet activation and apoptosis, and to explore the relationship between platelet activation and apoptosis.

METHODS: Platelets were directly stimulated with thrombin or pretreated with ROS inhibitor N-acetylcysteine (NAC) before being stimulated with thrombin, and then flow cytometry was used to detect the effects of thrombin and NAC on P-selectin expression, αⅡbβ3 activation, mitochondrial membrane potential depolarization, phosphatidylserine (PS) externalization, ROS expression and platelet aggregation.

RESULTS: Thrombin could induce the production of ROS in platelets in a concentration- and time-dependent manner. 0.01 U thrombin induced ROS-dependent high degree of integrin αⅡbβ3 activation, P-selectin expression, and platelet aggregation. The platelets induced by different concentration gradients of thrombin exhibited ROS-dependent mitochondrial membrane potential depolarization and PS externalization in platelets. After induction with thrombin for 30 min, the activation of integrin αⅡbβ3 in platelets reached its maximum level, and after 60 minutes, the depolarization of mitochondrial membrane potential in platelets reached its maximum level. However, the expression of P-selectin, depolarization of mitochondrial membrane potential, and platelet aggregation function were all inhibited to a certain extent when the platelets were pretreated with ROS inhibitor NAC and then induced with thrombin.

CONCLUSION: When platelets are induced by thrombin, ROS first regulates the activation of platelets, and then regulates the apoptosis of platelets. Both platelet activation and apoptosis depend on the production of ROS in platelets, and the signals of activation and apoptosis occur orderly. Inhibiting the ROS signal in platelets can effectively inhibit the activation and apoptosis of platelets.}, } @article {pmid39478327, year = {2024}, author = {Ma, Y and Chen, M and Huang, K and Chang, W}, title = {The impact of cysteine on lifespan in three model organisms: A systematic review and meta-analysis.}, journal = {Aging cell}, volume = {}, number = {}, pages = {e14392}, doi = {10.1111/acel.14392}, pmid = {39478327}, issn = {1474-9726}, support = {MYRG2022-00251-FHS//Universidade de Macau/ ; 0061/2022/A//Fundo para o Desenvolvimento das Ciências e da Tecnologia/ ; 0077/2020/A2//Fundo para o Desenvolvimento das Ciências e da Tecnologia/ ; 0099/2022/AFJ//Fundo para o Desenvolvimento das Ciências e da Tecnologia/ ; }, abstract = {Cysteine is an amino acid present in thiol proteins and often dictates their secondary structures. Although considered nonessential, cysteine may be essential for patients with certain metabolic diseases and can reduce the requirement for dietary methionine. Cysteine and some of its derivatives, such as N-acetylcysteine, are considered antioxidants and widely used in animal aging studies. To provide insights into the potential anti-aging effects of cysteine, we systematically reviewed and performed a meta-analysis to investigate the impact of cysteine supplementation on lifespan using three model organisms: mice, nematodes, and fruit flies. A total of 13 mouse studies, 13 C. elegans studies, and 5 Drosophila studies were included in the analysis. The findings revealed that cysteine supplementation significantly reduced the risk of mortality in mice and C. elegans. Subgroup analysis showed consistent results across different starting times and administration methods and revealed adverse effects of high doses on worms and a lack of effect in nondisease mouse models. Similar to mice, the effects of cysteine supplementation on Drosophila were not statistically significant, except in transgenic flies. The study identified certain limitations, including the quality of the included studies and the potential for publication bias. We also discussed uncertainties in the underlying molecular mechanisms and the clinical application of dietary cysteine.}, } @article {pmid39474327, year = {2024}, author = {Guo, Y and Yang, Y and Zhou, Z and Zhao, C and Li, Y and Zhou, H and Ren, S and Gu, Y and Gao, Z}, title = {Propylparaben Induces Reproductive Toxicity in Human Extravillous Trophoblast Cells via Apoptosis and Cell Cycle Pathways.}, journal = {Environment & health (Washington, D.C.)}, volume = {2}, number = {5}, pages = {301-310}, pmid = {39474327}, issn = {2833-8278}, abstract = {Parabens (PBs), especially propylparaben, commonly used in consumer products, pose environmental and health concerns. This study explored propylparaben's cytotoxicity on HTR-8/SVneo human trophoblast cells, revealing significant dose-dependent cytotoxic effects, particularly post 48-h exposure. Elevated propylparaben levels triggered apoptosis, evidenced by increased Bax and activated Caspase-3, and induced the G0/G1 cell cycle arrest. Concurrently, an increase in reactive oxygen species and reduced mitochondrial membrane potential indicated oxidative stress and mitochondrial dysfunction. Although N-acetylcysteine (NAC) treatment reduced oxidative stress, cell invasiveness persisted, suggesting propylparaben might affect cell migration through nonoxidative mechanisms. Integrated transcriptome analysis through RNA sequencing revealed 3488 differentially expressed genes affected by propylparaben, highlighting changes in pathways like apoptosis and cell cycle regulation and identifying seven hub genes as potential biomarkers for pregnancy-related complications. This study comprehensively demonstrates the cytotoxic effects of propylparaben on human trophoblast cells, notably through apoptosis induction and cell cycle disruption, thereby providing crucial insights into its potential risks for reproductive health.}, } @article {pmid39473642, year = {2024}, author = {Mendes Abreu, J and Quitério, A and Cerqueira, É and Ribeiro, R and Nunes, T and Figueiredo, JP and Corte Real, A}, title = {Evaluating the Impact of Different Treatments on the Quality of Life in Patients With Burning Mouth Syndrome: A Scoping Review.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e70419}, pmid = {39473642}, issn = {2168-8184}, abstract = {The profound impact of burning mouth syndrome (BMS) on patients' quality of life (QoL) highlights the critical need to identify effective treatments for this condition. This study aims to evaluate and compare the health-related quality of life (HRQoL) and oral health-related quality of life (OHRQoL) among individuals diagnosed with BMS, focusing on different treatment modalities. For that purpose, a scoping review was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for scoping review reporting guidelines and the registration with the International Prospective Register of Systematic Reviews (PROSPERO). An electronic search was then conducted in March 2024, encompassing the following databases: PubMed, Embase, Cochrane, Web of Science, and Trip Database. Publications were deemed eligible if they assessed the impact of different treatments for BMS on health-related and oral health-related QoL. Out of the initial 5400, only 13 studies were considered suitable to be included in this review. The instrument used to evaluate HRQoL was the 36-Item Short Form Survey (SF-36). For OHRQoL, the preferred tools were the Oral Health Impact Profile (OHIP) and the Geriatric Oral Health Assessment Index (GOHAI). Literature reported improvements in patients' HRQoL across the majority of analyzed treatment modalities. However, low-level laser therapy (LLLT) and n-acetylcysteine (NAC) plus clonazepam were the most effective in improving OHRQoL. This review highlights several promising treatment options for improving both HRQoL and OHRQoL in individuals with BMS. Nevertheless, the variability among the studies analyzed underscores the need for further research to identify and establish consistently effective treatments for this condition, reflecting the need for consistent trial designs to accurately assess the true impact of treatments on the disease.}, } @article {pmid39472133, year = {2024}, author = {Li, WK and Zhang, Y and Qu, XY and Lin, YQ and Zhao, YZ and Liu, N}, title = {[N-acetylcysteine regulates NF-κB signaling pathway alleviates the pulmonary toxicity induced by indium-tin oxide nanoparticles in rats].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {42}, number = {10}, pages = {721-729}, doi = {10.3760/cma.j.cn121094-20230919-00061}, pmid = {39472133}, issn = {1001-9391}, support = {H2024209031//Natural Science Foundation of Hebei Province/ ; 24130225C//Tangshan Science and Technology Project/ ; }, mesh = {Animals ; Rats ; Male ; *NF-kappa B/metabolism ; *Rats, Sprague-Dawley ; *Signal Transduction/drug effects ; *Acetylcysteine/pharmacology ; *Tin Compounds/toxicity ; *Oxidative Stress/drug effects ; *Lung/metabolism/drug effects/pathology ; Nanoparticles/toxicity ; Pulmonary Alveolar Proteinosis/metabolism ; }, abstract = {Objective: The current study aimed to evaluate the possible protective effects of N-acetylcysteine (NAC) against Indum-tin oxide (ITO) nanoparticle (Nano-ITO) -induced pulmonary alveolar proteinosis (PAP) in rats, especially via modulation of nuclear factor kappa B (NF-κB) signaling. Methods: In October 2019, 50 adult male Sprague-Dawley rats were randomly allocated into five groups (10 rats each) as follows: blank control group, saline control group, NAC control group (200 mg/kg), Nano-ITO group (receiving a repeated intratracheal dose of 6 mg/kg Nano-ITO) and NAC intervention group (pre-treated intraperitoneally with 200 mg/kg NAC 1.5 h before the administration of an intratracheal dose of 6 mg/kg Nano-ITO). The rats were exposed twice a week for 12 weeks. Rats were then euthanized under anesthesia, and their lungs were removed for histopathological and immunohistochemical analysis. The comparison of indicators reflecting oxidative stress and pulmonary inflammation among groups was conducted using one-way analysis of variance (ANOVA) and Bonferroni's test. The effect of NAC on Nano-ITO induced NF-κB signaling pathway in rats was analyzed. Results: Histopathological examination of Nano-ITO exposed rats revealed diffuse alveolar damage, including PAP, cholesterol crystals, alveolar fibrosis, pulmonary fibrosis, and alveolar emphysema. Immunohistochemical results of Nano-ITO exposed rats showed strong positive for nuclear factor κB p65 (NF-κB p65) and nuclear factor Kappa B inhibitory factor kinase (IKK-β) and weak positive for nuclear factor κB inhibitory protein α (IκB-α) in the nuclei of bronchiolar and alveolar epithelial cells. Compared with blank control group, saline control group and NAC control group, the level of total protein (TP) in bronchoalveolar lavage fluid of rats in Nano-ITO group was significantly increased (P<0.05), and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) were significantly increased (P<0.05), the levels of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were significantly increased (P<0.05), and the levels of NF-κB p65, IKK-β, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) in lung tissue were significantly increased (P<0.05). Compared with Nano-ITO group, the levels of TP, T-AOC, MDA and TNF-α in bronchoalveolar lavage fluid of rats in NAC intervention group were significantly decreased (P<0.05), and the levels of NF-κB p65 and ROS in lung tissue were significantly decreased (P<0.05). Western blot results showed that compared with the control groups, the protein expressions of NF-κB p65 and IKK-β in the lung tissue of Nano-ITO group were increased, while the protein expression of IκB-α was decreased (P<0.05). Compared with Nano-ITO group, the protein expressions of NF-κB p65 and IKK-β in lung tissue of rats in NAC intervention group were decreased, while the protein expression of IκB-α was increased (P<0.05) . Conclusion: The study demonstrated that Nano-ITO might induce pulmonary toxicity through the activation of NF-κB signaling pathway, and NAC could antagonize the pulmonary toxicity of Nano-ITO by inhibiting the NF-κB signaling pathway.}, } @article {pmid39471200, year = {2024}, author = {Quintanilla, ME and Morales, P and Santapau, D and Gallardo, J and Rebolledo, R and Riveras, G and Acuña, T and Herrera-Marschitz, M and Israel, Y and Ezquer, F}, title = {Morphine self-administration is inhibited by the antioxidant N-acetylcysteine and the anti-inflammatory ibudilast; an effect enhanced by their co-administration.}, journal = {PloS one}, volume = {19}, number = {10}, pages = {e0312828}, pmid = {39471200}, issn = {1932-6203}, mesh = {Animals ; *Acetylcysteine/pharmacology/administration & dosage ; *Antioxidants/pharmacology/administration & dosage ; *Rats, Wistar ; Rats ; *Morphine/pharmacology/administration & dosage ; Male ; *Oxidative Stress/drug effects ; *Pyridines/pharmacology/administration & dosage ; *Self Administration ; *Anti-Inflammatory Agents/pharmacology/administration & dosage ; Morphine Dependence/drug therapy/metabolism ; Excitatory Amino Acid Transporter 2/metabolism ; Hippocampus/metabolism/drug effects ; Nucleus Accumbens/metabolism/drug effects ; Indolizines ; Pyrazoles ; }, abstract = {BACKGROUND: The treatment of opioid addiction mainly involves the medical administration of methadone or other opioids, aimed at gradually reducing dependence and, consequently, the need for illicit opioid procurement. Thus, initiating opioid maintenance therapy with a lower level of dependence would be advantageous. There is compelling evidence indicating that opioids induce brain oxidative stress and associated glial activation, resulting in the dysregulation of glutamatergic homeostasis, which perpetuates drug intake. The present study aimed to determine whether inhibiting oxidative stress and/or neuroinflammation reduces morphine self-administration in an animal model of opioid dependence.

METHODS: Morphine dependence, assessed as voluntary morphine self-administration, was evaluated in Wistar-derived UChB rats. Following an extended period of morphine self-administration, animals were administered either the antioxidant N-acetylcysteine (NAC; 40 mg/kg/day), the anti-inflammatory ibudilast (7.5 mg/kg/day) or the combination of both agents. Oxidative stress and neuroinflammation were evaluated in the hippocampus, a region involved in drug recall that feeds into the nucleus accumbens, where the levels of the glutamate transporters GLT-1 and xCT were further assessed.

RESULTS: Daily administration of either NAC or ibudilast led to a mild reduction in voluntary morphine intake, while the co-administration of both therapeutic agents resulted in a marked inhibition (-57%) of morphine self-administration. The administration of NAC or ibudilast markedly reduced both the oxidative stress induced by chronic morphine intake and the activation of microglia and astrocytes in the hippocampus. However, only the combined administration of NAC + ibudilast was able to restore the normal levels of the glutamate transporter GLT-1 in the nucleus accumbens.

CONCLUSION: Separate or joint administration of an antioxidant and anti-inflammatory agent reduced voluntary opioid intake, which could have translational value for the treatment of opioid use disorders, particularly in settings where the continued maintenance of oral opioids is a therapeutic option.}, } @article {pmid39469595, year = {2024}, author = {Khoury, RD and Abu Hasna, A and Gagliardi, CF and Marinho, RMM and Carvalho, CAT and Bresciani, E and Valera, MC}, title = {Antimicrobial and anti-endotoxin activity of N-acetylcysteine, calcium hydroxide and their combination against Enterococcus faecalis, Escherichia coli and lipopolysaccharides.}, journal = {PeerJ}, volume = {12}, number = {}, pages = {e18331}, pmid = {39469595}, issn = {2167-8359}, mesh = {*Enterococcus faecalis/drug effects ; *Calcium Hydroxide/pharmacology ; *Acetylcysteine/pharmacology ; *Escherichia coli/drug effects ; Humans ; *Lipopolysaccharides/pharmacology ; Dental Pulp Cavity/microbiology/drug effects ; Anti-Infective Agents/pharmacology ; Biofilms/drug effects ; Anti-Bacterial Agents/pharmacology ; Root Canal Irrigants/pharmacology ; }, abstract = {BACKGROUND: The management of endodontic infections is a complex challenge, mainly due to the involvement of diverse microorganisms and their by-products. This study aimed to evaluate the efficacy of N-acetylcysteine (NAC), calcium hydroxide (Ca(OH)2), and their combined application as intracanal medications in combating Enterococcus faecalis, Escherichia coli, and lipopolysaccharides (LPS) from E. coli.

METHODS: A total of 60 single-rooted human teeth were carefully selected and divided into six groups. These tooth canals were deliberately exposed to E. faecalis (ATCC 29212) and E. coli (ATCC 25922) to induce biofilm formation. Subsequently, the specimens were treated with NAC, Ca(OH)2, or a combination of both substances. Three samples of the root canals were collected at three moments: the first sample (S1) was to confirm the initial contamination, the second sample (S2) was immediately post-instrumentation, and the third sample (S3) was collected after the use of the intracanal medication. The antimicrobial efficacy of these intracanal medications was assessed by enumerating colony-forming units per milliliter (CFU/mL). In addition to this, the kinetic chromogenic Limulus Amebocyte Lysate (LAL) assay by Lonza was used to quantify LPS from E. coli. Data tested for normality; then, Kruskal-Wallis and Friedman tests were used, and Dunn's for multiple comparisons.

RESULTS: The findings of this study showed significant reductions in the microbial load of E. faecalis and E. coli by S3. Notably, there were no statistically significant differences among the treatment groups concerning these microorganisms. However, it was observed that only the combination of NAC and Ca(OH)2 led to a noteworthy decrease in the quantity of E. coli's LPS after 7-days, demonstrating a statistically significant difference from the other treatment groups. NAC + Ca(OH)2 combination, applied for a duration of 7-days, proved to be more suitable in reducing the presence of E. faecalis, E. coli, and LPS from E. coli within the context of endodontic infections.}, } @article {pmid39467998, year = {2024}, author = {Zhang, M and Dai, GC and Zhang, YW and Lu, PP and Wang, H and Li, YJ and Rui, YF}, title = {Enhancing osteogenic differentiation of diabetic tendon stem/progenitor cells through hyperoxia: Unveiling ROS/HIF-1α signalling axis.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {20}, pages = {e70127}, pmid = {39467998}, issn = {1582-4934}, support = {BK20221462//Natural Science Foundation of Jiangsu Province/ ; No.81871812//National Natural Science Foundation of China/ ; YL20220525//Winfast Charity Foundation Project/ ; CZXM-GSP-RC46//Research Personnel Cultivation Programme of Zhongda Hospital Southeast University/ ; }, mesh = {*Osteogenesis ; Animals ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Stem Cells/metabolism/cytology ; *Signal Transduction ; *Cell Differentiation ; Rats ; *Tendons/metabolism/pathology ; Male ; *Diabetes Mellitus, Experimental/metabolism/pathology ; Rats, Sprague-Dawley ; Hyperoxia/metabolism ; Acetylcysteine/pharmacology ; }, abstract = {Diabetic calcific tendinopathy is the leading cause of chronic pain, mobility restriction, and tendon rupture in patients with diabetes. Tendon stem/progenitor cells (TSPCs) have been implicated in the development of diabetic calcified tendinopathy, but the molecular mechanisms remain unclear. This study found that diabetic tendons have a hyperoxic environment, characterized by increased oxygen delivery channels and carriers. In hyperoxic environment, TSPCs showed enhanced osteogenic differentiation and increased levels of reactive oxygen species (ROS). Additionally, hypoxia-inducible factor-1a (HIF-1a), a protein involved in regulating cellular responses to hyperoxia, was decreased in TSPCs by the ubiquitin-proteasome system. By intervening with antioxidant N-acetyl-L-cysteine (NAC) and overexpressing HIF-1a, we discovered that blocking the ROS/HIF-1a signalling axis significantly inhibited the osteogenic differentiation ability of TSPCs. Animal experiments further confirmed that hyperoxic environment could cause calcification in the Achilles tendon tissue of rats, while NAC intervention prevented calcification. These findings demonstrate that hyperoxia in diabetic tendons promotes osteogenic differentiation of TSPCs through the ROS/HIF-1a signalling axis. This study provides a new theoretical basis and research target for preventing and treating diabetic calcified tendinopathy.}, } @article {pmid39461063, year = {2025}, author = {Jin, Y and Zhang, J and Chen, X and Li, F and Xue, T and Yi, K and Xu, Y and Wang, H and Lao, YH and Chan, HF and Shao, D and Li, M and Tao, Y}, title = {3D printing incorporating gold nanozymes with mesenchymal stem cell-derived hepatic spheroids for acute liver failure treatment.}, journal = {Biomaterials}, volume = {315}, number = {}, pages = {122895}, doi = {10.1016/j.biomaterials.2024.122895}, pmid = {39461063}, issn = {1878-5905}, mesh = {*Gold/chemistry ; *Liver Failure, Acute/therapy ; *Printing, Three-Dimensional ; *Mesenchymal Stem Cells/cytology ; *Spheroids, Cellular/drug effects ; Animals ; *Hydrogels/chemistry ; Hepatocytes/cytology/drug effects ; Metal Nanoparticles/chemistry ; Humans ; Reactive Oxygen Species/metabolism ; Male ; Tissue Scaffolds/chemistry ; Mice ; Alginates/chemistry ; }, abstract = {Acute liver failure (ALF) is a highly fatal disease, necessitating the advancement and optimization of alternative therapeutic strategies to benefit patients awaiting liver transplantation. In this study, we innovatively established the antioxidant nanozyme-hepatocyte-like cells (HLCs) microtissue sheets (HS/N-Au@composite) for ALF therapy. We first prepared a 3D-printed hyaluronic acid/gelatin/sodium alginate scaffold with N-acetylcysteine (NAC)-capped gold nanoclusters (NAC-Au NCs), forming the N-Au@hydrogel. For the encapsulation of HLC spheroids, we used a biocompatible hybrid hydrogel composed of decellularized extracellular matrix (dECM), thrombin, and fibrinogen, resulting in the HS@dECM hydrogel. Utilizing 3D printing technology, we integrated the N-Au@hydrogel with the HS@dECM hydrogel to create the HS/N-Au@composite for in situ transplantation to treat ALF. Our results demonstrated that NAC-Au NCs effectively mitigated reactive oxygen species (ROS)-induced liver necrosis in ALF. Additionally, the N-Au@hydrogel provided mechanical support, ensuring the proper landing and effective functioning of the transplanted HLC spheroids. The HS/N-Au@composite synergistically decreased serum transaminase levels, reduced the accumulation of pro-inflammatory cytokines, accelerated liver function recovery, and promoted liver regeneration in ALF treatment. This combination of HLC spheroids and NAC-Au NCs nanozymes via 3D-printed composite scaffolds represents a promising strategy for enhancing hepatocyte transplantation and advancing stem cell regenerative medicine in ALF therapy.}, } @article {pmid39456416, year = {2024}, author = {Yun, HM and Kim, SH and Kwon, YJ and Park, KR}, title = {Effect of Spicatoside a on Anti-Osteosarcoma MG63 Cells through Reactive Oxygen Species Generation and the Inhibition of the PI3K-AKT-mTOR Pathway.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {39456416}, issn = {2076-3921}, support = {K412000//Korea Basic Science Institute/ ; 2022R1C1C1003491//National Research Foundation of Korea/ ; }, abstract = {Osteosarcoma is a primary malignant tumor found in the bones of children and adolescents. Unfortunately, many patients do not respond well to treatment and succumb to the illness. Therefore, it is necessary to discover novel bioactive compounds to overcome therapeutic limitations. Liriope platyphylla Wang et Tang is a well-known herb used in oriental medicine. Studies have shown that metabolic diseases can be clinically treated using the roots of L. platyphylla. Recent studies have demonstrated the anticarcinoma potential of root extracts; however, the exact mechanism remains unclear. The aim of this study was to examine the anti-osteosarcoma activity of a single compound extracted from the dried roots of L. platyphylla. We purified Spicatoside A (SpiA) from the dried roots of L. platyphylla. SpiA significantly inhibited the proliferation of human osteosarcoma MG63 cells in a dose- and time-dependent manner. SpiA also regulated the expression of various downstream proteins that mediate apoptosis (PARP, Bcl-2, and Bax), cell growth (cyclin D1, Cdk4, and Cdk6), angiogenesis (VEGF), and metastasis (MMP13). The Proteome Profiler Human Phospho-Kinase Array Kit showed that the AKT signaling protein was a target of SpiA in osteosarcoma cells. We also found that SpiA suppressed the constitutive activation of the PI3K-AKT-mTOR-p70S6K1 signaling pathway. We further validated the effects of SpiA on the AKT signaling pathway. SpiA induced autophagosome formation and suppressed necroptosis (a form of programmed cell death). SpiA increased the generation of reactive oxygen species (ROS) and led to the loss of mitochondrial membrane potential. N-acetylcysteine (NAC)-induced inhibition of ROS generation reduced SpiA-induced AKT inhibition, apoptotic cell death, and anti-metastatic effects by suppressing cell migration and invasion. Overall, these results highlight the anti-osteosarcoma effect of SpiA by inhibiting the AKT signaling pathway through ROS generation, suggesting that SpiA may be a promising compound for the treatment of human osteosarcoma.}, } @article {pmid39452251, year = {2024}, author = {Recinella, L and Pinti, M and Libero, ML and Di Lodovico, S and Veschi, S and Piro, A and Generali, D and Acquaviva, A and Nilofar, N and Orlando, G and Chiavaroli, A and Ferrante, C and Menghini, L and Di Simone, SC and Brunetti, L and Di Giulio, M and Leone, S}, title = {Beneficial Effects Induced by a Proprietary Blend of a New Bromelain-Based Polyenzymatic Complex Plus N-Acetylcysteine in Urinary Tract Infections: Results from In Vitro and Ex Vivo Studies.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {39452251}, issn = {2079-6382}, abstract = {Background/Objectives: Urinary tract infections (UTIs) are infections that involve the urethra, bladder, and, in much more severe cases, even kidneys. These infections represent one of the most common diseases worldwide. Various pathogens are responsible for this condition, the most common being Escherichia coli (E. coli). Bromelain is a proteolytic complex obtained from the stem and stalk of Ananas comosus (L.) Merr. showing several beneficial activities. In addition to bromelain, N-acetylcysteine (NAC) has also been used. Methods: The purpose of this experiment was to evaluate the antibacterial, anti-motility, and anti-biofilm effects of a new polyenzymatic complex (DIF17BRO[®]) in combination with NAC (the Formulation) on various strains of E. coli isolated from patients with UTIs. Subsequently, the anti-inflammatory and antioxidant effects of the Formulation were studied in an ex vivo model of cystitis, using bladder samples from mice exposed to E. coli lipopolysaccharide (LPS). Results: Our results showed that the Formulation significantly affects the capability of bacteria to form biofilm and reduces the bacteria amount in the mature biofilm. Moreover, it combines the interesting properties of NAC and a polyenzyme plant complex based on bromelain in a right dose to affect the E. coli adhesion capability. Finally, the Formulation exhibited protective effects, as confirmed by the inhibitory activities on multiple inflammatory and oxidative stress-related pathways on bladder specimens exposed to LPS. Conclusions: This blend of active compounds could represent a promising and versatile approach to use to overcome the limitations associated with conventional therapies.}, } @article {pmid39450216, year = {2024}, author = {Yahia, Z and Yahia, A and Abdelaziz, T}, title = {N-acetylcysteine Clinical Applications.}, journal = {Cureus}, volume = {16}, number = {10}, pages = {e72252}, pmid = {39450216}, issn = {2168-8184}, abstract = {This study aims to evaluate the therapeutic application of N-acetylcysteine (NAC) as a treatment or adjunct therapy for various medical conditions. While its efficacy in treating acetaminophen overdose, cystic fibrosis, and chronic obstructive pulmonary disease is well-established, emerging evidence suggests that NAC may also benefit a broader spectrum of illnesses due to its safety, simplicity, and affordability. A comprehensive review was conducted by searching PubMed, relevant books, and conference proceedings for publications discussing NAC about the specified health conditions. The clinically relevant data were analysed using the American Family Physician Evidence-Based Medicine Toolkit, following a standard integrated review methodology. NAC shows potential as an adjunctive treatment for a wide range of medical conditions, particularly chronic diseases. It may be beneficial for polycystic ovary syndrome, endometriosis, male infertility, cataracts, glaucoma, dry eye syndrome, parkinsonism, multiple sclerosis, Alzheimer's disease, stroke outcomes, non-acetaminophen-induced acute liver failure, Crohn's disease, ulcerative colitis, schizophrenia, bipolar disorder, and obsessive-compulsive disorder. Although evidence for some conditions is less robust, NAC's therapeutic potential warrants further investigation. Given the aging population and the decline in glutathione levels, the use of NAC should be considered across a variety of medical conditions. This paper suggests that NAC supplementation could play a significant role in reducing morbidity and mortality associated with numerous chronic diseases.}, } @article {pmid39447843, year = {2024}, author = {Zheng, M and Song, W and Huang, P and Huang, Y and Lin, H and Zhang, M and He, H and Wu, J}, title = {Drug conjugates crosslinked bioresponsive hydrogel for combination therapy of diabetic wound.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {376}, number = {}, pages = {701-716}, doi = {10.1016/j.jconrel.2024.10.046}, pmid = {39447843}, issn = {1873-4995}, mesh = {Animals ; *Wound Healing/drug effects ; *Fibroblast Growth Factor 2/administration & dosage/chemistry ; *Hydrogels/chemistry/administration & dosage ; *Acetylcysteine/administration & dosage ; Antioxidants/administration & dosage/chemistry/pharmacology ; Male ; Diabetes Mellitus, Experimental/drug therapy ; Oxidative Stress/drug effects ; Drug Liberation ; Rats, Sprague-Dawley ; Mice ; Cross-Linking Reagents/chemistry ; }, abstract = {Basic fibroblast growth factor (bFGF) has proved to be effective for wound healing, yet its effectiveness is extremely retarded in diabetic wounds due to the severe oxidative stress in wound beds. To solve this issue, herein a novel combination therapy of bFGF and N-acetylcysteine (NAC, antioxidant) was devised for improved diabetic wound repair. To avoid rapid loss of both drugs in the wound beds, a bioresponsive hydrogel (bFGF-HSPP-NAC) was engineered by incorporating bFGF and NAC into polymer-drug conjugates (HSPP) via thiol-disulfide exchange reactions. In response to oxidative stress (e.g., reactive oxygen species), the disulfide bonds (SS) within the hydrogel are broken into thiol groups (-S-H), thereby promoting hydrogel degradation and enabling controlled drug release. Initially, NAC is released to scavenge free radicals and ameliorate oxidative damage. Subsequently, bFGF is released to expedite tissue regeneration. This combinatorial strategy is tailored to the specific characteristics of the wound microenvironment at various stages of diabetic wound healing, thereby achieving therapeutic efficacy. The results indicate that the bFGF-HSPP-NAC hydrogel markedly enhances re-epithelialization, collagen deposition, hair follicle regeneration, and neovascularization. In conclusion, the bioresponsive bFGF-HSPP-NAC hydrogel demonstrates significant potential for application in combinatorial therapeutic approaches for diabetic wound healing.}, } @article {pmid39436429, year = {2024}, author = {Galicia-Moreno, M and Monroy-Ramirez, HC and Caloca-Camarena, F and Arceo-Orozco, S and Muriel, P and Sandoval-Rodriguez, A and García-Bañuelos, J and García-González, A and Navarro-Partida, J and Armendariz-Borunda, J}, title = {A new opportunity for N-acetylcysteine. An outline of its classic antioxidant effects and its pharmacological potential as an epigenetic modulator in liver diseases treatment.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {39436429}, issn = {1432-1912}, abstract = {Liver diseases represent a worldwide health problem accountable for two million deaths per year. Oxidative stress is critical for the development of these diseases. N-acetyl cysteine (NAC) is effective in preventing liver damage, both in experimental and clinical studies, and evidence has shown that the pharmacodynamic mechanisms of NAC are related to its antioxidant nature and ability to modulate key signaling pathways. Here, we provide a comprehensive description of the beneficial effects of NAC in the treatment of liver diseases, addressing the first evidence of its role as a scavenger and precursor of reduced glutathione, along with studies showing its immunomodulatory action, as well as the ability of NAC to modulate epigenetic hallmarks. We searched the PubMed database using the following keywords: oxidative stress, liver disease, epigenetics, antioxidants, NAC, and antioxidant therapies. There was no time limit to gather all available information on the subject. NAC has shown efficacy in treating liver damage, exerting mechanisms of action different from those of free radical scavengers. Like different antioxidant therapies, its effectiveness and safety are related to the administered dose; therefore, designing new pharmacological formulations for this drug is imperative to achieve an adequate response. Finally, there is still much to explore regarding its effect on epigenetic marker characteristics of liver damage, turning it into a drug with broad therapeutic potential. According to the literature reviewed, NAC could be an appropriate option in clinical studies related to hepatic injury and, in the future, a repurposing alternative for treating liver diseases.}, } @article {pmid39430194, year = {2024}, author = {Hernández-Cruz, EY and Aparicio-Trejo, OE and Hammami, FA and Bar-Shalom, D and Tepel, M and Pedraza-Chaverri, J and Scholze, A}, title = {N-acetylcysteine in Kidney Disease: Molecular Mechanisms, Pharmacokinetics, and Clinical Effectiveness.}, journal = {Kidney international reports}, volume = {9}, number = {10}, pages = {2883-2903}, pmid = {39430194}, issn = {2468-0249}, abstract = {N-acetylcysteine (NAC) has shown beneficial effects in both acute kidney disease and chronic kidney disease (CKD) in preclinical and clinical studies. Different dosage and administration forms of NAC have specific pharmacokinetic properties that determine the temporal pattern of plasma concentrations of NAC and its active metabolites. Especially in acute situations with short-term NAC administration, appropriate NAC and glutathione (GSH) plasma concentrations should be timely ensured. For oral dosage forms, bioavailability needs to be established for the respective NAC formulation. Kidney function influences NAC pharmacokinetics, including a reduction of NAC clearance in advanced CKD. In addition, mechanisms of action underlying beneficial NAC effects depend on kidney function as well as comorbidities, both involving GSH deficiency, alterations in nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent signaling, oxidative stress, mitochondrial dysfunction, and disturbed mitochondrial bioenergetics. This also applies to nonrenal NAC mechanisms. The timing of preventive NAC administration in relation to potential injury is important. NAC administration seems most effective either preceding, or preceding and paralleling conditions that induce tissue damage. Furthermore, studies suggest that very high concentrations of NAC should be avoided because they could exert reductive stress. Delayed administration of NAC might interfere with endogenous repair mechanisms. In conclusion, studies on NAC treatment regimens need to account for both NAC pharmacokinetics and NAC molecular effects. Kidney function of the patient population and pathomechanisms of the kidney disease should guide rational NAC trial design. A targeted trial approach and biomarker-guided protocols could pave the way for the use of NAC in precision medicine.}, } @article {pmid39423623, year = {2024}, author = {Liu, M and Gao, M and Shi, X and Yin, Y and Liu, H and Xie, R and Huang, C and Zhang, W and Xu, S}, title = {Quercetin attenuates SiO2-induced ZBP-1-mediated PANoptosis in mouse neuronal cells via the ROS/TLR4/NF-κb pathway.}, journal = {Journal of environmental management}, volume = {370}, number = {}, pages = {122948}, doi = {10.1016/j.jenvman.2024.122948}, pmid = {39423623}, issn = {1095-8630}, mesh = {Animals ; Mice ; *Silicon Dioxide/toxicity ; *Toll-Like Receptor 4/metabolism ; *NF-kappa B/metabolism ; *Quercetin/pharmacology ; *Reactive Oxygen Species/metabolism ; *Neurons/drug effects ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; }, abstract = {With the increasing development of the society, silicon dioxide (SiO2) has been used in various fields, such as agriculture, food industry, etc., and its residues can pose a potential health threat to organisms. Quercetin (Que) is a potent free radical scavenger commonly found in plants. C57BL/6 mice were chosen to established a mouse model of SiO2 exposure and Que antagonism to investigate the mechanism of action of Que in rescuing the toxic damage of SiO2 on mouse cerebellum tissue. The results showed that cytoplasmic vacuolization, and inflammatory cell infiltration caused by SiO2 were alleviated by the addition of Que, and reduced oxidative stress in mouse cerebellum, alleviated the activation of TLR4 pathway induced by SiO2, and substantially reduced the occurrence of ZBP-1-mediated PANoptosis induced by SiO2 exposure in mouse cerebellum. In NS20Y cells, the oxidative stress activator (Elesclomol) and inhibitor N-acetyl cysteine (NAC), and the NF-κB activator 2 (NA2) were added. Elesclomol and NAC confirm the involvement of ROS in regulating the TLR4/NF-κB pathway, the TLR4/NF-κB pathway regulated ZBP-1-mediated PANoptosis in cerebellum and NS20Y cells induced by SiO2 exposure. In conclusion, the present experimental data suggest that Que mitigates the onset of ZBP-1-mediated PANoptosis in neuronal cells induced by SiO2 through the ROS/TLR4/NF-κB pathway. The present experimental findings help to understand the detoxification effect of Que in more tissues and provide an important reference for the rescue of organisms in long-term SiO2 environment.}, } @article {pmid39420342, year = {2024}, author = {Zhou, W and Qu, M and Yue, Y and Zhong, Z and Nan, K and Sun, X and Wu, Q and Zhang, J and Chen, W and Miao, C}, title = {Acetylcysteine synergizes PD-1 blockers against colorectal cancer progression by promoting TCF1[+]PD1[+]CD8[+] T cell differentiation.}, journal = {Cell communication and signaling : CCS}, volume = {22}, number = {1}, pages = {503}, pmid = {39420342}, issn = {1478-811X}, mesh = {Animals ; *Colorectal Neoplasms/pathology/drug therapy/immunology/metabolism ; *CD8-Positive T-Lymphocytes/immunology/drug effects ; *Cell Differentiation/drug effects ; *Programmed Cell Death 1 Receptor/metabolism/antagonists & inhibitors/immunology ; Mice ; *Acetylcysteine/pharmacology ; *Hepatocyte Nuclear Factor 1-alpha/metabolism/genetics ; *Disease Progression ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; Humans ; Cell Line, Tumor ; Mice, Inbred C57BL ; Drug Synergism ; }, abstract = {BACKGROUND: Programmed cell death protein 1 (PD-1) blockade is essential in treating progressive colorectal cancer (CRC). However, some patients with CRC do not respond well to immunotherapy, possibly due to the exhaustion of CD8[+] T cells in the tumor microenvironment. N-Acetylcysteine (NAC) can reduce CD8[+] T cell exhaustion in vitro and induce their differentiation into long-lasting phenotypes, thus enhancing the anti-tumor effect of adoptive T cell transfer. However, whether NAC can be combined with PD-1 blockade in CRC treatment and how NAC regulates CD8[+] T cell differentiation remain unclear. Hence, in this study, we aimed to investigate whether NAC has a synergistic effect with PD-1 blockers against CRC progression.

METHODS: We constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8 + T cell differentiation and its potential mechanism were explored using cell flow assay and other studies in vitro and ex vivo.

RESULTS: We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model mediated by CD8[+] T cells. We further found that NAC can induce TCF1[+]PD1[+]CD8[+] T cell differentiation and reduce the formation of exhausted T cells in vitro and in vivo. Moreover, NAC enhanced the expression of Glut4 in CD8[+] T cells, promoting the differentiation of TCF1[+]PD1[+]CD8[+] T cells.

CONCLUSIONS: Our study provides a novel idea for immunotherapy for clinically progressive CRC and suggests that Glut4 may be a new immunometabolic molecular target for regulating CD8[+] T cell differentiation.}, } @article {pmid39415242, year = {2024}, author = {Fang, YQ and Ding, H and Li, T and Zhao, XJ and Luo, D and Liu, Y and Li, Y}, title = {N-acetylcysteine supplementation improves endocrine-metabolism profiles and ovulation induction efficacy in polycystic ovary syndrome.}, journal = {Journal of ovarian research}, volume = {17}, number = {1}, pages = {205}, pmid = {39415242}, issn = {1757-2215}, mesh = {*Polycystic Ovary Syndrome/drug therapy/metabolism ; Female ; *Acetylcysteine/pharmacology/therapeutic use ; Animals ; Mice ; Humans ; *Ovulation Induction/methods ; Adult ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; Pregnancy ; Dietary Supplements ; Antioxidants/pharmacology/therapeutic use ; Ovary/drug effects/metabolism ; Metformin/pharmacology/therapeutic use ; Insulin Resistance ; Letrozole/pharmacology ; }, abstract = {BACKGROUND: Polycystic ovary syndrome (PCOS) affects 6-20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS.

METHODS: Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups.

RESULTS: Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p < 0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p < 0.005).

CONCLUSION: NAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS.}, } @article {pmid39409801, year = {2024}, author = {Ninković, M and Žutić, J and Tasić, A and Arsić, S and Bojkovski, J and Zdravković, N}, title = {An Innovative Approach: The Usage of N-Acetylcysteine in the Therapy of Pneumonia in Neonatal Calves.}, journal = {Animals : an open access journal from MDPI}, volume = {14}, number = {19}, pages = {}, pmid = {39409801}, issn = {2076-2615}, support = {451-03-66/2024-03/200030//This research was funded by the Serbian Ministry of Science, Technological Development and In-novation, grant numbers 451-03-66/2024-03/200030 and Collaborative Grant Scheme Program Call (ID: 50404) of the Innovation Found of The Republic of Serbia./ ; }, abstract = {NAC has mucolytic, antioxidant, and antimicrobial effects in living organisms. However, the therapeutic effects of NAC on clinical recovery among neonatal calves with respiratory diseases have not yet been studied. Our study represents the first investigation of the effects of NAC in neonatal calves with pneumonia. The objective of this work was to observe the effects of NAC in the treatment of neonatal pneumonia, including its ability to reduce the clinical score, shorten the duration of the treatment, and improve the overall health condition of neonatal calves. For this study, calves were divided into two groups: a treatment group that received NAC and amoxicillin with clavulanic acid, and a control group that received amoxicillin with clavulanic acid (antimicrobial only). The findings of this study indicate that NAC treatment significantly shortened the time to resolution (p < 0.001), compared to the results in the group without NAC treatment. Generally, NAC-supplemented therapy reduced the recovery time by more than 27 h (or slightly more than one day), compared to that in the antimicrobial-only group. Our study presents the first reported usage of NAC in therapy for respiratory disorders.}, } @article {pmid39409186, year = {2024}, author = {Lien, TS and Sun, DS and Wu, WS and Chang, HH}, title = {Dengue Envelope Protein as a Cytotoxic Factor Inducing Hemorrhage and Endothelial Cell Death in Mice.}, journal = {International journal of molecular sciences}, volume = {25}, number = {19}, pages = {}, pmid = {39409186}, issn = {1422-0067}, support = {104-2320-B-320 -009 -MY3, 107-2311-B-320-002-MY3, 111-2320-B320-006-MY3, 112-2320-B-320-007//National Science and Technology Council, Taiwan/ ; TCMMP104-06, TCMMP108-04, TCMMP 111-01, TCAS111-02, TCAS-112-02, TCAS113-04, TCRD112-033, TCRD113-041//Tzu-Chi Medical Foundation/ ; }, mesh = {Animals ; Mice ; *Dengue Virus ; Humans ; *Endothelial Cells/drug effects/metabolism ; *Viral Envelope Proteins/metabolism ; *Apoptosis/drug effects ; *Severe Dengue/pathology/drug therapy ; *Hemorrhage/drug therapy ; Caspase 3/metabolism ; Disease Models, Animal ; Dengue/drug therapy/pathology ; Cell Line ; Cell Death/drug effects ; }, abstract = {Dengue virus (DENV) infection, prevalent in tropical and subtropical regions, can progress to dengue hemorrhagic fever (DHF), which increases mortality during secondary infections. DHF is characterized by endothelial damage and vascular leakage. Despite its severity, no specific antiviral treatments exist, and the viral factors responsible for endothelial damage remain unclear. This study examines the role of the DENV envelope protein domain III (EIII) in inducing endothelial apoptosis using a mouse model. Additionally, we aim to explore whether cell death-inducing pathways could serve as drug targets to ameliorate EIII-induced endothelial injury and hemorrhage. In vitro experiments using human endothelial HMEC-1 cells demonstrated that both recombinant EIII (rEIII) and DENV markedly induced caspase-3-mediated endothelial cell death, an effect that was attenuated by co-treatment with chondroitin sulfate B (CSB), N-acetyl cysteine (NAC), and the caspase-3 inhibitor z-DEVD-FMK. In vivo, sequential injections of rEIII and anti-platelet immunoglobulin in mice, designed to mimic the clinical phase of DHF with peak viremia followed by an increase in DENV-induced Ig, including autoantibodies, revealed that these dual treatments markedly triggered caspase-3-dependent apoptosis in vascular endothelial cells at hemorrhage sites. Treatments with z-DEVD-FMK effectively reduced DHF-like symptoms such as thrombocytopenia, hemorrhage, inflammation, hypercoagulation, and endothelial damage. Additionally, CSB and NAC alleviated hemorrhagic symptoms in the mice. These results suggest that targeting EIII, reactive oxygen species, and caspase-3-mediated apoptosis could offer potential therapeutic strategies for addressing EIII-induced hemorrhagic pathogenesis.}, } @article {pmid39396855, year = {2024}, author = {Gago, S and Diaz-Muñoz, J and Mogas, T}, title = {Impact of N-acetyl-L-cysteine on spindle morphology and reactive oxygen species in vitrified/warmed in vitro matured bovine oocytes.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {59 Suppl 3}, number = {}, pages = {e14619}, doi = {10.1111/rda.14619}, pmid = {39396855}, issn = {1439-0531}, support = {PID2020-116531RB-I00//Ministerio de Ciencia e Innovación/ ; 2021 SGR 00900//Generalitat de Catalunya/ ; }, mesh = {Animals ; Cattle ; *Acetylcysteine/pharmacology ; *Oocytes/drug effects ; *Reactive Oxygen Species/metabolism ; *In Vitro Oocyte Maturation Techniques/veterinary/methods ; *Vitrification ; Female ; *Spindle Apparatus/drug effects ; Antioxidants/pharmacology ; Cryopreservation/veterinary ; }, abstract = {Low developmental potential of vitrified in vitro matured (IVM) bovine oocytes is frequently attributed to high levels of reactive oxygen species (ROS) and abnormal spindle assembly. This study aimed to evaluate the efficacy of N-acetyl-L-cysteine (NAC), a cell-permeating antioxidant, added to IVM medium in reducing ROS and preserving spindle configuration of vitrified/warmed IVM bovine oocytes. Oocytes collected from abattoir ovaries were either cultured in IVM medium or in IVM medium supplemented with 1 mM NAC for the initial 8 h of IVM. Half of the oocytes of each group were vitrified/warmed, and spindle morphology and ROS production were assessed at 24 h of IVM. Results indicated that fresh oocytes IVM with NAC improved spindle configuration, with significantly lower ROS levels compared to the control group. Vitrification resulted in lower percentages of bovine oocytes reaching the metaphase II stage but similar ROS levels to non-vitrified oocytes, regardless of NAC supplementation. However, the supplementation of NAC during maturation had no effect on spindle or chromosome configuration of vitrified oocytes. These findings emphasize NAC's potential in enhancing the quality of IVM bovine oocytes but its addition at 1 mM for 8 h to IVM medium did not decrease levels of ROS nor improve spindle assembly after vitrification.}, } @article {pmid39395220, year = {2024}, author = {Xiang, RH and Wang, JQ and Li, ZG}, title = {Crosstalk of methylglyoxal and calcium signaling in maize (Zea mays L.) thermotolerance through methylglyoxal-scavenging system.}, journal = {Journal of plant physiology}, volume = {303}, number = {}, pages = {154362}, doi = {10.1016/j.jplph.2024.154362}, pmid = {39395220}, issn = {1618-1328}, mesh = {*Zea mays/physiology/drug effects/metabolism/genetics ; *Pyruvaldehyde/metabolism ; *Calcium Signaling ; *Thermotolerance/physiology ; Seedlings/physiology/drug effects ; Calcium/metabolism ; Heat-Shock Response/physiology ; Plant Proteins/metabolism/genetics ; Gene Expression Regulation, Plant/drug effects ; }, abstract = {Methylglyoxal (MG) and calcium ion (Ca[2+]) can increase multiple-stress tolerance including plant thermotolerance. However, whether crosstalk of MG and Ca[2+] exists in the formation of maize thermotolerance and underlying mechanism still remain elusive. In this paper, maize seedlings were irrigated with MG and calcium chloride alone or in combination, and then exposed to heat stress (HS). The results manifested that, compared with the survival percentage (SP, 45.3%) of the control seedlings, the SP of MG and Ca[2+] alone or in combination was increased to 72.4%, 74.2%, and 83.4% under HS conditions, indicating that Ca[2+] and MG alone or in combination could upraise seedling thermotolerance. Also, the MG-upraised SP was separately weakened to 42.2%, 40.3%, 52.1%, and 39.4% by Ca[2+] chelator (ethylene glycol tetraacetic acid, EGTA), plasma membrane Ca[2+] channel blocker (lanthanum chloride, LaCl3), intracellular Ca[2+] channel blocker (neomycin, NEC), and calmodulin (CaM) antagonist (trifluoperazine, TFP). However, significant effect of MG scavengers N-acetylcysteine (NAC) and aminoguanidine (AG) on Ca[2+]-induced thermotolerance was not observed. Similarly, an endogenous Ca[2+] level in seedlings was increased by exogenous MG under non-HS and HS conditions, while exogenous Ca[2+] had no significant effect on endogenous MG. These data implied that Ca[2+] signaling, at least partly, mediated MG-upraised thermotolerance in maize seedlings. Moreover, the activity and gene expression of glyoxalase system (glyoxalase I, glyoxalase II, and glyoxalase III) and non-glyoxalase system (MG reductase, aldehyde reductase, aldo-keto reductase, and lactate dehydrogenase) were up-regulated to a certain extent by Ca[2+] and MG alone in seedlings under non-HS and HS conditions. The up-regulated MG-scavenging system by MG was enhanced by Ca[2+], while impaired by EGTA, LaCl3, NEC, or TFP. These data suggest that the crosstalk of MG and Ca[2+] signaling in maize thermotolerance through MG-scavenging system. These findings provided a theoretical basis for breeding climate-resilient maize crop and developing smart agriculture.}, } @article {pmid39394703, year = {2024}, author = {Meng, T and Guo, HJ and Yao, Y and Mi, ZH and Tian, Y and Yu, JZ}, title = {[Study on the molecular mechanism of autophagy and apoptosis induced by ultrafine carbon black in human bronchial epithelial cells and the intervention effect of N-acetylcysteine].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {42}, number = {9}, pages = {656-667}, doi = {10.3760/cma.j.cn121094-20231010-00080}, pmid = {39394703}, issn = {1001-9391}, support = {81502845//National Natural Science Foundation for Young Scholars of China/ ; 2021XM17//Four "Batches" Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province/ ; 202103021224311//Fundamental Research Program of Shanxi Province/ ; 20220808, XDC2021135//Innovation and Entrepreneurship Training Program for College Students/ ; }, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; *Autophagy/drug effects ; *Epithelial Cells/drug effects/metabolism ; *Bronchi/cytology ; *Soot/toxicity ; *Oxidative Stress/drug effects ; Cell Line ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Malondialdehyde/metabolism ; Catalase/metabolism ; bcl-2-Associated X Protein/metabolism/genetics ; Glutathione Peroxidase/metabolism ; Cell Survival/drug effects ; }, abstract = {Objective: To investigate the molecular mechanism of autophagy and apoptosis induced by ultrafine carbon black in human bronchial epithelial cells (BEAS-2B cells), and to study the intervention effect and mechanism of N-acetylcysteine (NAC) on ultrafine carbon black-induced oxidative damage in BEAS-2B cells. Methods: In March 2023, BEAS-2B cells were used as research object, an in vitro airway model exposed to ultrafine carbon black was constructed. A control group and three carbon black exposure groups (50, 100, 200 μg/ml) were set up, and the cells were treated with corresponding concentrations of ultrafine carbon black for 24 hours. In addition, the experiment was divided into control group, NAC+ control group, 100 μg/ml carbon black exposure group and NAC+ exposure group. The corresponding groups were treated with 2 mmol/L NAC for 1 h and 100 μg/ml ultrafine carbon black for 24 h, respectively. Cell viability was measured by CCK-8 assay. Intracellular reactive oxygen species (ROS) level was detected by chemical fluorescence method. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), as well as the content of malondialdehyde (MDA) were detected by colorimetry. The mRNA and protein expressions of autophagy-related genes[Atg5, Atg7, Beclin1, microtubule-associated protein light chain 3B (LC3B), p62 and lysosome-associated membrane protein 2 (LAMP2) ] and apoptosis-related genes [B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase3, Caspase9 and poly (ADP-ribose) polymerase 1 (PARP1) ] were determined by fluorescence quantitative PCR and Western blot. Cell apoptosis was determined by flow cytometry. Results: Compared with the control group, the relative survival rates of BEAS-2B cells in 50, 100, 200 μg/ml carbon black exposure groups were significantly decreased, the levels of ROS and MDA were significantly increased, and the activities of SOD, GSH-Px and CAT were significantly decreased (P<0.05). The relative survival rate, ROS and MDA levels, SOD, GSH-Px and CAT activities were significantly correlated with the exposure dose of ultrafine carbon black (r(s)=-0.755, 0.826, 0.934, -0.810, -0.880, -0.840, P<0.05). Compared with the control group, the relative expression levels of Atg5, Atg7, Beclin1, LC3B, p62, LAMP2, Bax, Caspase3, Caspase9, PARP1 mRNA and Atg5, Atg7, Beclin1, LC3BⅡ, p62, LAMP2, Bax, cleaved Caspase3 (C-Caspase3), cleaved Caspase9 (C-Caspase9), cleaved PARP1 (C-PARP1) protein and the ratio of LC3BⅡ/LC3BⅠ in 50, 100 and 200 μg/ml carbon black exposure groups were significantly increased, while the relative expression levels of Bcl-2 mRNA and protein were significantly decreased (P<0.05). The changes of the above indexes were significantly correlated with the exposure dose of carbon black (r(s)=0.892, 0.879, 0.944, 0.892, 0.828, 0.880, 0.814, 0.794, 0.931, 0.918, 0.813, 0.866, 0.774, 0.695, 0.918, 0.761, 0.794, 0.944, 0.833, 0.866, 0.905, -0.886, -0.748, P<0.05). Compared with 100 μg/ml carbon black exposure group, the relative survival rate, the activities of SOD, GSH-Px and CAT in NAC+exposure group were significantly increased, while the levels of ROS and MDA were significantly decreased, and the relative expression levels of LC3B, p62 and Caspase3 mRNA and protein as well as the ratio of LC3BⅡ/LC3BⅠ were significantly decreased, and the differences were statistically significant (P<0.05). Compared with the control group, the apoptosis rates of BEAS-2B cells in 50, 100, 200 μg/ml carbon black exposure groups were significantly increased (P<0.05), and there was a significant positive correlation between ultrafine carbon black exposure dose and cell apoptosis rate (r(s)=0.944, P<0.05). While compared with 100 μg/ml carbon black exposure group, the apoptosis rate of NAC+exposure group was significantly decreased, and the difference was statistically significant (P<0.05) . Conclusion: Cell autophagy and apoptosis may be important pathophysiological mechanisms of ultrafine carbon black-induced oxidative damage in BEAS-2B cells. NAC can alleviate the occurrence of BEAS-2B cell damage caused by ultrafine carbon black by regulating oxidative stress and the cascading autophagy and apoptosis pathways.}, } @article {pmid39393575, year = {2024}, author = {Feng, J and Liu, H and Jiang, K and Gong, X and Huang, R and Zhou, C and Mao, J and Chen, Y and Xu, H and Zhang, X and Yang, X and Zhao, D}, title = {Enhanced oxidative stress aggravates BLM-induced pulmonary fibrosis by promoting cellular senescence through enhancing NLRP3 activation.}, journal = {Life sciences}, volume = {358}, number = {}, pages = {123128}, doi = {10.1016/j.lfs.2024.123128}, pmid = {39393575}, issn = {1879-0631}, mesh = {Animals ; *Bleomycin/toxicity ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Cellular Senescence/drug effects ; Mice ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Mice, Inbred C57BL ; Humans ; *Pulmonary Fibrosis/metabolism/chemically induced/pathology ; A549 Cells ; Male ; Inflammasomes/metabolism ; Disease Models, Animal ; Idiopathic Pulmonary Fibrosis/metabolism/pathology/chemically induced ; Transforming Growth Factor beta/metabolism ; }, abstract = {AIMS: Idiopathic pulmonary fibrosis (IPF) is a disease associated with aging, where increased oxidative stress accelerates the progression of pulmonary fibrosis (PF). The specific mechanisms through which oxidative stress intensifies PF are still not fully understood.

MATERIALS AND METHODS: In this study, we used bleomycin (BLM)-induced PF mouse model and TGF-β-induced collagen deposition cells for in vivo and in vitro experiments, respectively. Additionally, we employed BSO, a glutathione synthesis inhibitor, to induce excess reactive oxygen species (ROS).

KEY FINDINGS: Our findings revealed that heightened ROS production significantly exacerbated PF development in mice and increased collagen deposition in A549 cells. We also showed that cellular senescence was further intensified by the combined treatment of BSO with BLM or TGF-β, as indicated by the increased levels of p53 and p21, along with an increase in β-galactosidase-positive cells. Moreover, inflammatory responses, including inflammatory cells, inflammatory cytokines, and ROS levels were dramatically increased with the BSO and BLM or TGF-β combination. Mechanistically, we found that NLRP3 inflammasome was activated more significantly by the combined treatments of BSO with BLM or TGF-β. Inhibition of NLRP3 ameliorated the aging-related phenotype and reduced p53 and p21 expression. Furthermore, we showed that N-acetylcysteine (NAC) treatment significantly attenuated BLM or BLM plus BSO-enhanced PF in vivo.

SIGNIFICANCE: Our study demonstrates that elevated ROS levels contribute to the development of PF via NLRP3-mediated cellular senescence. We also provide that targeting oxidative stress might be an effective strategy for treating PF.}, } @article {pmid39389326, year = {2025}, author = {Qiao, J and Du, D and Wang, Y and Xi, L and Zhu, W and Morigen, }, title = {Uncovering the effects of non-lethal oxidative stress on replication initiation in Escherichia coli.}, journal = {Gene}, volume = {933}, number = {}, pages = {148992}, doi = {10.1016/j.gene.2024.148992}, pmid = {39389326}, issn = {1879-0038}, mesh = {*Oxidative Stress/drug effects ; *Escherichia coli/genetics/metabolism/drug effects ; *Escherichia coli Proteins/genetics/metabolism ; *DNA Replication/drug effects ; *Hydrogen Peroxide/pharmacology ; Superoxide Dismutase/metabolism/genetics ; Protease La/metabolism/genetics ; Bacterial Proteins/genetics/metabolism ; DNA Glycosylases/genetics/metabolism ; Endopeptidase Clp/genetics/metabolism ; Acetylcysteine/pharmacology ; Catalase ; }, abstract = {Cell cycle adaptability assists bacteria in response to adverse stress. The effect of oxidative stress on replication initiation in Escherichia coli remains unclear. This work examined the impact of exogenous oxidant and genetic mutation-mediated oxidative stress on replication initiation. We found that 0-0.5 mM H2O2 suppresses E. coli replication initiation in a concentration-dependent manner but does not lead to cell death. Deletion of antioxidant enzymes SodA-SodB, KatE, or AhpC results in delayed replication initiation. The antioxidant N-acetylcysteine (NAC) promotes replication initiation in ΔkatE and ΔsodAΔsodB mutants. We then explored the factors that mediate the inhibition of replication initiation by oxidative stress. MutY, a base excision repair DNA glycosylase, resists inhibition of replication initiation by H2O2. Lon protease deficiency eliminates inhibition of replication initiation mediated by exogenous H2O2 exposure but not by katE or sodA-sodB deletion. The absence of clpP and hslV further delays replication initiation in the ΔktaE mutant, whereas hflK deletion promotes replication initiation in the ΔkatE and ΔsodAΔsodB mutants. In conclusion, non-lethal oxidative stress inhibits replication initiation, and AAA+ proteases are involved and show flexible regulation in E. coli.}, } @article {pmid39384146, year = {2024}, author = {Zeng, Q and Lv, C and Qi, L and Wang, Y and Hao, S and Li, G and Sun, H and Du, L and Li, J and Wang, C and Zhang, Y and Wang, X and Ma, R and Wang, T and Li, Q}, title = {Sodium selenite inhibits cervical cancer progression via ROS-mediated suppression of glucose metabolic reprogramming.}, journal = {Life sciences}, volume = {357}, number = {}, pages = {123109}, doi = {10.1016/j.lfs.2024.123109}, pmid = {39384146}, issn = {1879-0631}, mesh = {Humans ; Animals ; *Reactive Oxygen Species/metabolism ; *Uterine Cervical Neoplasms/drug therapy/pathology/metabolism ; Female ; Mice ; *Mice, Nude ; *Glucose/metabolism ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; *Sodium Selenite/pharmacology ; *Xenograft Model Antitumor Assays ; HeLa Cells ; Glycolysis/drug effects ; Mice, Inbred BALB C ; Membrane Potential, Mitochondrial/drug effects ; Cell Line, Tumor ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Disease Progression ; Metabolic Reprogramming ; }, abstract = {AIMS: This study aims to explore the inhibitory effect of selenium on cervical cancer through suppression of glucose metabolic reprogramming and its underlying mechanisms.

METHODS: Sodium selenite (SS) treated HeLa and SiHa cells were assessed for proliferation using the CCK-8 assay and immunofluorescence. DNA synthesis was measured with the EdU assay. A nude mouse xenograft model evaluated SS's anti-cervical cancer effects. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured using flow cytometry, DCFH-DA, and JC-1 probes, respectively. Apoptosis was detected via Annexin V/PI staining and Western blot. Glucose uptake, lactate production, and ATP generation were determined using 2-NBDG probes and assay kits. The mRNA and protein levels of glycolysis-related genes HK2, GLUT1, and PDK1 were measured using RT-qPCR and Western blot.

KEY FINDINGS: SS inhibited HeLa and SiHa cells viability in a dose- and time-dependent manner. Intraperitoneal injection of SS in nude mice significantly inhibited HeLa cell xenograft growth without evident hepatotoxicity or nephrotoxicity. SS inhibited glucose metabolic reprogramming in cancer cells primarily via ROS-mediated AKT/mTOR/HIF-1α pathway inhibition. Pretreatment with N-acetylcysteine (NAC) or MHY1485 (an mTOR activator) partially reversed the inhibitory effects of SS on glucose metabolic reprogramming, cell proliferation, and migration, as well as its pro-apoptotic effects.

SIGNIFICANCE: SS exhibited anti-cervical cancer effects, likely through the induction of ROS generation and inhibition of glucose metabolic reprogramming in cervical cancer cells, thereby inhibiting cell proliferation and promoting apoptosis. These findings provide new insights into understanding the molecular mechanisms underlying SS for potential new drug development for cervical cancer.}, } @article {pmid39381531, year = {2024}, author = {Ghazaiean, M and Aliasgharian, A and Karami, H and Ghasemi, MM and Darvishi-Khezri, H}, title = {Antioxidative effects of N-acetylcysteine in patients with β-thalassemia: A quick review on clinical trials.}, journal = {Health science reports}, volume = {7}, number = {10}, pages = {e70096}, pmid = {39381531}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Several studies have highlighted the potent antioxidant properties of N-acetyl cysteine (NAC). This review aimed to assess the impact of NAC on oxidative stress biomarkers in patients with β-thalassemia.

METHODS: The review included articles published before 2024 that investigated the effects of NAC on oxidative stress in individuals with β-thalassemia. A comprehensive search was conducted across various databases, including Scopus, PubMed, Web of Science, Trip, and CENTRAL. Only English-language clinical trials were considered for inclusion in this review. Besides, the number needed to treat (NNT) was calculated based on the included studies.

RESULTS: Ninety-nine articles were retrieved from electronic databases, and after a thorough review, eight articles were selected for comprehensive text analysis. The highest dose of NAC administered was 10 mg/kg/day (equivalent to 600 mg/day) over a period of 3-6 months. All the studies assessing the impact of NAC on oxidative stress indicators in β-thalassemia patients demonstrated positive effects during the 3-month follow-up period. Most estimated NNTs fell into 1-5, suggesting significant clinical therapeutic value in this context.

CONCLUSION: The current potency of NAC alone appears to be effective in ameliorating oxidative stress in patients with β-thalassemia major. While a 3-month duration seems adequate to demonstrate the antioxidant properties of NAC in this population, larger and well-designed clinical trials are warranted. Current clinical evidence possesses a high risk of bias.}, } @article {pmid39377544, year = {2024}, author = {Formato, A and Salbini, M and Orecchini, E and Pellegrini, M and Buccarelli, M and Vitiani, LR and Giannetti, S and Pallini, R and D'Alessandris, QG and Lauretti, L and Martini, M and De Falco, V and Levi, A and Falchetti, ML and Mongiardi, MP}, title = {N-Acetyl-L-Cysteine (NAC) Blunts Axitinib-Related Adverse Effects in Preclinical Models of Glioblastoma.}, journal = {Cancer medicine}, volume = {13}, number = {19}, pages = {e70279}, pmid = {39377544}, issn = {2045-7634}, support = {A0375-2020-36524//Gruppi di Ricerca 2020-POR-FESR Lazio 2014-2020/ ; IG 2021#25664//Associazione Italiana per la Ricerca sul Cancro/ ; RF-2019-12368786//Ministero della Salute/ ; }, mesh = {*Axitinib/pharmacology/therapeutic use ; Animals ; *Glioblastoma/drug therapy/pathology/metabolism ; Humans ; Mice ; *Acetylcysteine/pharmacology/therapeutic use ; *Xenograft Model Antitumor Assays ; *Brain Neoplasms/drug therapy/pathology/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Protein Kinase Inhibitors/pharmacology/adverse effects/therapeutic use ; Cellular Senescence/drug effects ; }, abstract = {OBJECTIVE: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH-wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo-angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib-dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells.

METHODS: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N-Acetyl-L-Cysteine (NAC) might be used to reduce senescence-associated adverse effects of axitinib treatment without altering its anti-tumor activity.

RESULTS: We demonstrate that the use of the antioxidant molecule N-Acetyl-Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib-dependent toxicity.

CONCLUSION: Overall, we found that NAC co-treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib-dependent toxicity.}, } @article {pmid39376972, year = {2024}, author = {Eghdami, S and Eissazade, N and Heidari Mokarar, M and Boroon, M and Orsolini, L and Shalbafan, M}, title = {The safety and efficacy of N-acetylcysteine as an augmentation in the treatment of obsessive-compulsive disorder in adults: a systematic review and meta-analysis of randomized clinical trials.}, journal = {Frontiers in psychiatry}, volume = {15}, number = {}, pages = {1421150}, pmid = {39376972}, issn = {1664-0640}, abstract = {BACKGROUND: Obsessive-compulsive disorder (OCD) ranks as the fourth most prevalent psychiatric disorder, with selective serotonin reuptake inhibitors (SSRIs) as its mainstay pharmacological treatment. However, approximately 40 to 60% of patients do not adequately respond to initial treatment, highlighting the need for alternative options. N-acetylcysteine (NAC) is one of the several medications that have been used in augmentation with SSRIs to enhance their efficacy.

OBJECTIVES: We aimed to investigate the safety and efficacy of NAC, a glutamate-modulating agent, as an augmentation in the treatment of moderate to severe OCD.

METHOD: We conducted a thorough search across PubMed, Scopus, Web of science, and ProQuest to identify relevant trials published until December 2023. The primary outcome of interest was the mean difference between the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores before and after administrating augmented NAC among patients with moderate to severe OCD. Furthermore, we compared the occurrence of adverse drug events between the experimental and control groups.

RESULTS: We included six randomized controlled trials with 195 patients. The results of our study indicated a positive outcome for the experimental group in terms of the total Y-BOCS score when using the medication for a period of five to eight weeks (p-Value = 0.05). However, no significant difference was observed for durations shorter than five weeks or longer than 12 weeks. Additionally, no significant difference was found between the two groups in terms of the obsession and compulsion Y-BOCS scores. Furthermore, no significant differences were observed in terms of adverse events.

CONCLUSION: Augmentation of NAC with SSRIs may benefit patients with moderate to severe OCD. However, it is necessary to conduct additional multi-center trials over extended periods to develop a comprehensive strategy for action.

https://www.crd.york.ac.uk/prospero/, identifier CRD42023463683.}, } @article {pmid39371865, year = {2024}, author = {Gupta, M and Sharma, A and Kumaran, MS}, title = {An Insight Into Adolescent Dermatitis Artefacta: A Case Report.}, journal = {Cureus}, volume = {16}, number = {9}, pages = {e68682}, pmid = {39371865}, issn = {2168-8184}, abstract = {Dermatitis artefacta (DA) is a rare and challenging-to-diagnose factitious dermatological disorder, most commonly affecting late adolescents and young adults. This case report presents a 17-year-old girl with a history of unexplained linear lesions on her face and abdomen persisting for 11 months, leading to significant school absenteeism. The dermatological examination was otherwise unremarkable except for multiple well-defined excoriations, erosions, and scarring, suggestive of DA. Dermoscopic examination supported this diagnosis, showing characteristic features. The patient was treated with N-acetyl cysteine and referred for psychiatric evaluation, highlighting the intricate nature of managing DA, particularly in young individuals who may have underlying psychological distress. The case underscores the importance of a multidisciplinary approach in diagnosing and treating DA, given its overlap with other neuropsychiatric and dermatological disorders.}, } @article {pmid39366552, year = {2024}, author = {Ishtiaq, A and Mushtaq, I and Rehman, H and Mushtaq, I and Mushtaq, I and Abbasi, SW and Liaqat, F and Rasheed, A and Ahmad, S and Akhtar, Z and Murtaza, I}, title = {Tetra aniline-based polymers ameliorate BPA-induced cardiotoxicity in Sprague Dawley rats, in silico and in vivo analysis.}, journal = {Life sciences}, volume = {358}, number = {}, pages = {123104}, doi = {10.1016/j.lfs.2024.123104}, pmid = {39366552}, issn = {1879-0631}, mesh = {Animals ; *Phenols/pharmacology/toxicity ; *Rats, Sprague-Dawley ; *Benzhydryl Compounds/toxicity ; Rats ; *Cardiotoxicity/metabolism/prevention & control ; *Aniline Compounds/pharmacology/toxicity ; *Molecular Docking Simulation ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Polymers ; Male ; MicroRNAs/metabolism/genetics ; Antioxidants/pharmacology ; Computer Simulation ; Apoptosis/drug effects ; }, abstract = {AIMS: Bisphenol A (BPA), xenoestrogen, is an environmental toxicant, that generates oxidative stress leading to cardiotoxicity. The oxidative stress can be neutralized by natural and synthetic antioxidants. The present study elucidates the highly selective antioxidative potential of synthetic tetra aniline polymers Es-37 and L-37 against Bisphenol A-induced cardiac cellular impairments and the role of miRNA-15a-5p in the regulation of different apoptotic proteins.

MATERIALS AND METHODS: The molecular docking of L-37 and Es-37 with three proteins (p53, Cytochrome c, and Bcl-2) were performed. The dose of 1 mg/kg BW of BPA, 1 mg/kg BW Es-37 and L-37 and 50 mg/kg BW N-acetyl cysteine (NAC) was administered to Sprague Dawley rats. The miRNA and target gene expression were confirmed by qRt-PCR and Immunoblotting.

KEY FINDINGS: In our results, BPA administration significantly elevated the reactive oxygen species (ROS), p53, cytochrome c, and particularly miRNA-15a-5p expression; however: these changes were notably reversed by Es-37 and L-37 treatment. Additionally, molecular docking of synthetic polymers validated that L-37 has a greater binding affinity with the target proteins compared to Es-37, with the highest binding values reported for the enzymatic protein cytochrome c.

SIGNIFICANCE: These results suggest that both synthetic polymers Es-37 and L-37 have the potential to scavenge free radicals, boost-up antioxidant enzyme activities, and avert (BPA-induced) toxicity, thus, may serve as cardioprotective agents. Moreover, this study first time proposes that miRNA-15a-5p overexpression is associated with oxidative stress and coincides with BPA induced cardiotoxicity, thus may serve as potential therapeutic target in future.}, } @article {pmid39365130, year = {2024}, author = {Ram Kiran, KS and Trivedi, V and Rajesh, VSP and Sharma, M and Haranal, M and Pandya, H}, title = {Role of Prophylactic N-Acetylcysteine Supplementation on Postoperative Outcomes in Patients Undergoing Elective Double-Valve Replacement (Aortic and Mitral Valve).}, journal = {Annals of cardiac anaesthesia}, volume = {27}, number = {4}, pages = {324-329}, pmid = {39365130}, issn = {0974-5181}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Double-Blind Method ; Female ; Male ; Prospective Studies ; *Postoperative Complications/prevention & control/epidemiology ; *Heart Valve Prosthesis Implantation/methods ; Middle Aged ; *Mitral Valve/surgery ; *Aortic Valve/surgery ; Treatment Outcome ; Adult ; Free Radical Scavengers/therapeutic use ; Length of Stay/statistics & numerical data ; Liver Function Tests ; Aged ; Elective Surgical Procedures ; Liver Diseases/prevention & control ; }, abstract = {AIMS AND OBJECTIVES: The incidence of postoperative liver dysfunction is high in patients undergoing double-valve replacement - mitral and aortic valve replacement (DVR). This study aims to evaluate N-acetylcysteine's free radical scavenging property (NAC) to prevent postoperative liver dysfunction in these patients, thus affecting overall clinical outcomes.

METHODS: A single-center, prospective, randomized, double-blinded interventional study of 60 patients divided into two groups of 30 each. Group N received prophylactic intravenous NAC, and Group C received volume-matched 5% dextrose. Data comprised demographics, liver function tests (LFT), renal function tests (RFT), vasoactive-inotropic scores (VIS) score, and C-reactive protein (CRP) at various time intervals. Postoperative parameters such as ventilation duration, length of stay in ICU (LOS-ICU), length of hospital stay (LOHS), atrial fibrillation (AF), acute kidney injury (AKI) requiring hemodialysis, and mortality were noted. Statistical analysis was performed with the Student's t-test and Chi-square test (SPSS 22 software).

RESULTS: All postoperative LFT parameters (total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), and alkaline phosphatase (ALP)) were significantly lower (P < 0.05) at 24, 48, and 72 hours in Group N compared to Group C. RFT and VIS scores were lower in Group N; however, were not statistically significant except for Serum Creatinine at 48 hours (P = 0.0478). Ventilation duration (P = 0.0465) and LOS-ICU (P = 0.0431) were significantly lower in Group N. Other outcomes like AF, LOHS, and mortality were lower in Group N but were not statistically significant.

CONCLUSION: Our study showed that prophylactic administration of NAC in patients undergoing DVR is associated with a reduction in the incidence of postoperative liver dysfunction with a positive impact on postoperative outcomes.}, } @article {pmid39365126, year = {2024}, author = {Kapoor, MC}, title = {N-acetyl Cysteine to Mitigate Liver Damage in Patients with Deranged Liver Function Undergoing Surgery on Cardiopulmonary Bypass.}, journal = {Annals of cardiac anaesthesia}, volume = {27}, number = {4}, pages = {299-300}, pmid = {39365126}, issn = {0974-5181}, mesh = {Humans ; *Cardiopulmonary Bypass/adverse effects ; *Acetylcysteine/therapeutic use ; Liver Diseases ; Liver Function Tests ; Liver/drug effects ; Male ; Female ; }, } @article {pmid39363690, year = {2024}, author = {Li, K and Jiang, L and Wei, Y and Li, Z}, title = {Identification of the metabolites of nimbolide in rat by liquid chromatography combined with quadrupole/orbitrap mass spectrometry.}, journal = {Biomedical chromatography : BMC}, volume = {38}, number = {12}, pages = {e6012}, doi = {10.1002/bmc.6012}, pmid = {39363690}, issn = {1099-0801}, mesh = {Animals ; Rats ; Male ; *Microsomes, Liver/metabolism ; *Rats, Sprague-Dawley ; *Limonins/metabolism/pharmacokinetics/chemistry/urine/analysis ; Chromatography, High Pressure Liquid/methods ; Tandem Mass Spectrometry/methods ; Bile/chemistry/metabolism ; }, abstract = {Nimbolide is a major furanoid compound isolated from Azadirachta indica. The aim of this study was to characterize the metabolites of nimbolide in rats and to propose the metabolic pathways. The metabolites were generated by incubating nimbolide (10 μM) with rat liver microsomes, nicotinamide adenine dinucleotide phosphate (NADPH), and nucleophiles (glutathione [GSH] or N-acetyl-lysine [NAL]) at 37°C for 60 min. For the in vivo study, nimbolide was intravenously administered to rats at a single dose of 10 mg/kg, and the bile and urine were collected. The metabolites were identified by ultra-high-performance liquid chromatography-quadrupole/orbitrap mass spectrometry (UPLC-Q/Orbitrap-MS) using electrospray ionization in positive ion mode. Totally, nine metabolites were detected, and their identities were characterized by accurate MS and MS/MS data. In GSH-supplemented liver microsomes, GSH conjugation was the primary elimination pathway. The furan ring was bioactivated into cis-butene-1,4-dial that can be trapped by GSH. In NAL-supplemented liver microsomes, two NAL conjugates (M4 and M5) derived from cis-butene-1,4-dial were observed. In rat bile and urine, N-acetyl-cysteine, cysteine-glycine, and GSH conjugate were also found. The current study provides an overview of the metabolism and the bioactivation profiles of nimbolide in rats, which aids in understanding its safety and activity.}, } @article {pmid39360368, year = {2024}, author = {D'Agostino Gennari, J and Deveza, GBH and Ribeiro, CT and Seguro, AC and Aikawa, NE and Shimizu, MHM and Leon, EP and Guedes, LKN and Kupa, LVK and Silva, CAA and Bonfa, E and Pasoto, SG}, title = {Efficacy of N-acetylcysteine for treating dryness symptoms of Sjögren's disease: randomised placebo-controlled double-blind clinical study.}, journal = {Clinical and experimental rheumatology}, volume = {42}, number = {12}, pages = {2427-2436}, doi = {10.55563/clinexprheumatol/dmd5dv}, pmid = {39360368}, issn = {0392-856X}, mesh = {Humans ; *Acetylcysteine/therapeutic use/administration & dosage ; *Sjogren's Syndrome/drug therapy/complications/diagnosis/blood ; Double-Blind Method ; Female ; Middle Aged ; Adult ; Treatment Outcome ; *Xerostomia/drug therapy/etiology ; Glutathione/blood ; Thiobarbituric Acid Reactive Substances/metabolism ; Aged ; Biomarkers/blood ; Time Factors ; }, abstract = {OBJECTIVES: N-acetylcysteine (NAC) is used in Sjögren's disease (SjD) based on limited evidence. The aim of this study was to assess the efficacy of NAC for relieving dryness symptoms in SjD.

METHODS: In this placebo-controlled double-blind trial, 60 adult SjD females (with low disease activity) were randomised to receive NAC (1,200 mg/day orally) or placebo. At baseline (D0), 30 days (D30) and 90 days (D90), all participants underwent the following evaluations: EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Ocular Surface Disease Index (OSDI), Xerostomia Inventory (XI), Leicester Cough Questionnaire (LCQ), unstimulated/stimulated salivary flow, Schirmer's test, and plasma levels of thiobarbituric acid reactive substances (TBARS), glutathione and NAC.

RESULTS: At inclusion, both groups were balanced for age, ethnicity, disease duration, ESSPRI, OSDI, XI, Schirmer's test, salivary flow, ESSDAI and topical/systemic treatments (p>0.05). No significant differences were observed between NAC and placebo groups on D30 and D90 regarding ESSPRI, XI, OSDI, LCQ, Schirmer's test, stimulated salivary flow, ESSDAI and topical/systemic treatments (p>0.05). Unstimulated salivary flow was significantly higher in the placebo group on D90 (p=0.018). NAC blood concentrations were significantly higher in the NAC group on D30 (p=0.018) and D90 (p<0.001), however, no differences were found in TBARS and glutathione. Further analysis showed decrease≥1 in ESSPRI in the NAC compared with placebo group on D30 (p=0.045), a result not found on D90 (p=0.696).

CONCLUSIONS: NAC is recommended as a rescue therapy for SjD. However, our well-designed study provides novel evidence demonstrating its inefficacy for improving dryness symptoms or reducing oxidative stress.

CLINICALTRIALS: gov-NCT04793646.}, } @article {pmid39357253, year = {2025}, author = {Huang, W and He, M and Chen, S and Yin, G and Gan, Y and Li, H and Wu, C and Yin, P}, title = {Dual-Channel fluorescent detection of Biothiols: A novel probe for Distinguishing Cysteine, Homocysteine, Glutathione, and N-Acetylcysteine in cellular environments.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {326}, number = {}, pages = {125221}, doi = {10.1016/j.saa.2024.125221}, pmid = {39357253}, issn = {1873-3557}, mesh = {*Fluorescent Dyes/chemistry ; *Acetylcysteine/chemistry ; *Glutathione/analysis/blood ; *Homocysteine/analysis/blood ; Humans ; *Cysteine/analysis/blood ; *Spectrometry, Fluorescence/methods ; Sulfhydryl Compounds/analysis/chemistry/blood ; Limit of Detection ; Optical Imaging ; Coumarins/chemistry ; }, abstract = {Biothiols, including cysteine (Cys), homocysteine (Hcy), glutathione (GSH), and N-acetylcysteine (NAC), possess similar chemical structures and properties but play crucial, distinct roles in biological cells and blood serum. Imbalances in the concentrations of these biothiols are associated with various diseases, highlighting the importance of precise discrimination, especially between Cys and other biothiols. Owing to the similarity of the chemical properties of Cys, Hcy, GSH, and NAC, developing an effective methodology to differentiate these thiol compounds is challenging. In this study, we designed and synthesized a novel dual-channel fluorescent probe, hereafter referred to as CNTC, by integrating coumarin and acrylonitrile. This probe enabled the simultaneous discrimination of Cys from Hcy, GSH, and NAC, producing distinct fluorescent signals: blue for Cys and green for Hcy, GSH, and NAC. CNTC exhibited rapid response kinetics (within 30 min) and impressive detection limits of 0.31, 0.11, 0.029, and 0.032 μM for Cys, Hcy, GSH, and NAC, respectively. Furthermore, CNTC was successfully applied in the fluorescence imaging of both exogenous and endogenous Cys, Hcy, GSH, and NAC in living cells. The remarkable analytical and bioimaging capabilities of CNTCin vivo establish it as a promising tool for elucidating the pathophysiological roles of biothiols, particularly Cys, Hcy, GSH, and NAC.}, } @article {pmid39353794, year = {2024}, author = {Rajaratnam, G and Baldwin, AJ}, title = {"To BAL or not to BAL, that is the question": Variations in smoke inhalation injury guidelines from burn units and centres in England, Scotland and Wales.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {50}, number = {9}, pages = {107273}, doi = {10.1016/j.burns.2024.09.012}, pmid = {39353794}, issn = {1879-1409}, mesh = {Humans ; *Smoke Inhalation Injury/therapy ; Cross-Sectional Studies ; *Practice Guidelines as Topic ; Wales ; Scotland ; England ; *Burn Units ; *Bronchoscopy/methods ; Bronchoalveolar Lavage/methods ; Adult ; Carbon Monoxide Poisoning/therapy ; Carboxyhemoglobin/analysis ; Guideline Adherence/statistics & numerical data ; Acetylcysteine/therapeutic use ; }, abstract = {AIM: To evaluate variations in diagnostic criteria and management recommendations for smoke inhalation injury (SII) amongst the burn networks of England, Scotland, and Wales.

METHODS: A descriptive cross-sectional study examining SII guidelines provided by adult burn units and centres in England, Scotland and Wales.

RESULTS: All 16 adult burn units and centres responded. Fourteen (87.5 %) had guidelines. Due to sharing of guidelines, ten unique guidelines were assessed. Diagnostic criteria showed variability with no universal criterion shared amongst guidelines. Bronchoscopy was recommended by 90 % of guidelines, but the timing varied. The use of bronchoscopic scoring systems was recommended by four guidelines. Bronchoalveolar lavage (BAL) was recommended by four, with considerable variation in frequency and choice of lavage fluid. All guidelines advised at least one nebulised agent: heparin (n = 8); N-acetyl cysteine (NAC) (n = 8); or salbutamol (n = 8). All guidelines included advice on carbon monoxide poisoning; however, carboxyhaemoglobin (COHb) cut-off levels for treatment varied (5 % [n-4], 10 % [n = 3], 15 % [n = 1]). All recommended high-flow oxygen. Seven (70 %) guidelines offered guidance on cyanide poisoning. Reduced/altered consciousness was the only consistent diagnostic criterion. Five (50 %) guidelines provided intubation guidance, emphasising the role of a 'senior clinician' as the intubator. Ventilatory guidance appeared in eight guidelines, focusing on lung protective ventilation (n = 8); oxygenation goals (n = 3); and permissive hypercapnia (n = 3). Within lung-protective ventilation, advice on tidal volume (6, or 6-8 ml/kg) and plateau pressures (>30 cmH2O) were presented most commonly (n = 7).

CONCLUSION: This study has outlined the substantial variations in guidance for the management of SII. The results underscore the need for a national guideline outlining a standardised approach to the diagnosis and management of SII, within the limitations of the current evidence.}, } @article {pmid39351494, year = {2024}, author = {Li, P and Zhou, H and Yang, Y and Wu, M and Zhao, D and Wang, L and Yi, D and Hou, Y}, title = {Dietary supplementation with N-acetylcysteine confers a protective effect on muscle and liver in lipopolysaccharide-challenged piglets.}, journal = {Frontiers in nutrition}, volume = {11}, number = {}, pages = {1458912}, pmid = {39351494}, issn = {2296-861X}, abstract = {N-acetylcysteine (NAC) is a well-established antioxidant that offers exciting opportunities for intestinal health in weaned piglets, while the effects of NAC on muscle and liver has not been fully characterized. Therefore, the present study was performed to investigate the effects of dietary supplementation with NAC on muscle and liver in weaned piglets challenged with lipopolysaccharide (LPS). Twenty-four piglets (24-day-old) were randomly assigned to three treatment groups, the piglets in the control (CTR) and LPS- challenged (LPS) groups were fed the basal diet and those in the LPS+ NAC group was fed the basal diet supplemented with 500 mg/kg NAC. The animal trial lasted for 21 days. At the end of the trial, piglets in the LPS and LPS+ NAC groups were injected intraperitoneally with LPS (100 μg/kg body weight) and piglets in the CTR group were administrated with an equal volume of normal saline. 3 h later, the blood was collected and tissue samples were obtained after 6 h of LPS or normal saline treatment. The results showed that the level of IL-1β, and the mRNA levels of C-X-C motif chemokine receptor 3 (CXCR3) and interferon-γ (IFN-γ) in the liver were up-regulated, and the mRNA levels of insulin-like growth factor 1 (IGF-1), total glutathione (T-GSH), and the ratio of total protein to DNA in the liver were decreased under LPS challenge (P < 0.05). At the same time, LPS increased the level of H2O2 and decreased the content of T-GSH and DNA in the longissimus dorsi and gastrocnemius muscles (P < 0.05). In addition, the percentage of monocytes and the level of epidermal growth factor (EGF) were down-regulated in the LPS treatment (P < 0.05). Interestingly, dietary NAC supplementation reversed the above changes induced by LPS (P < 0.05). Furthermore, NAC might alleviate the muscle and liver injury in LPS-challenged piglets by regulating the expression of genes related to the type I interferon signaling pathway, as well as hypoxia inducible factor 1 (HIF1) and nuclear factor erythroid-2 related factor 2 (Nrf-2). Our findings suggested that dietary supplementation with NAC could benefit the health of muscle and liver in LPS-challenged weaned piglets.}, } @article {pmid39349423, year = {2024}, author = {Wang, SH and Lee, DS and Kim, TH and Kim, JE and Kang, TC}, title = {Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.}, journal = {Cell death & disease}, volume = {15}, number = {9}, pages = {707}, pmid = {39349423}, issn = {2041-4889}, support = {2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; 2021R1A2C4002003//National Research Foundation of Korea (NRF)/ ; }, mesh = {Animals ; *Mitochondrial Dynamics/drug effects ; *Oxidative Stress/drug effects ; *Dynamins/metabolism/genetics ; *Glutathione Peroxidase GPX1 ; *NF-kappa B/metabolism ; *Signal Transduction ; *Parvalbumins/metabolism ; *Cyclin-Dependent Kinase 5/metabolism/genetics ; *Glutathione Peroxidase/metabolism/genetics ; *Down-Regulation/drug effects ; Neurons/metabolism/drug effects ; Male ; Mice ; Quinazolinones/pharmacology ; Phosphorylation/drug effects ; Buthionine Sulfoximine/pharmacology ; Mitochondria/metabolism/drug effects ; }, abstract = {Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.}, } @article {pmid39348347, year = {2024}, author = {Komal, W and Fatima, S and Minahal, Q and Liaqat, R and Hussain, AS}, title = {Assessing the effects of N-acetyl cysteine on growth, antioxidant and immune response in tilapia (Oreochromis niloticus) under different regimes of stocking densities.}, journal = {PloS one}, volume = {19}, number = {9}, pages = {e0307212}, pmid = {39348347}, issn = {1932-6203}, mesh = {Animals ; *Antioxidants/metabolism/pharmacology ; *Acetylcysteine/pharmacology ; *Dietary Supplements ; Hydrocortisone/metabolism ; Cichlids/growth & development/immunology/metabolism ; Superoxide Dismutase/metabolism ; Animal Feed/analysis ; Catalase/metabolism ; Tilapia/growth & development/immunology/metabolism ; Aquaculture/methods ; Glutathione Peroxidase/metabolism ; }, abstract = {The study investigated the impact of N-acetyl cysteine on growth, immune response, and antioxidant activity in tilapia (Oreochromis niloticus). Fish were reared at three densities (1.50, 3.00, and 4.50 kg/m3) with four levels of N-acetyl cysteine supplementation (0, 2, 4, and 6 mg/kg) over 60 days. Better growth was observed at low density, but at all densities, fish fed the highest N-acetyl cysteine level (6 mg/kg) showed improved growth. Chemical composition of fish and activity of amylase, lipase and protease in all treatments were noted to be insignificant. The levels of antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) and cortisol in HD treatments were high as compared to LD and MD treatment. However, fish fed with N3 diet in each density treatment showed the lowest level of antioxidant enzymes as well as cortisol. Similarly, the levels of malondialdehyde were noted to be high at HD treatments as compared to that in LD and MD. Its levels were lower in fish fed with N3 diets in all density treatments. Expression of somatostatins-1 did not increase in MD and HD treatments in response to high stocking density when compared with LD treatment. However, pro-opiomelanocortin-α level was reduced after N3 diet in HD treatment and interleukin 1-β expression increased after N3 supplement in HD treatment. In conclusion, N-acetyl cysteine supplementation improved growth and antioxidant response in tilapia. The most optimum dose of N-acetyl cysteine was noted to be 6 mg/kg at high stocking, suggesting the potential role of this nutraceutical in tilapia intensive culture.}, } @article {pmid39342748, year = {2024}, author = {Zhang, S and Wang, D and Ding, Y and Li, Y and Wang, Y and Zeng, J}, title = {Inhibition of calpain reduces oxidative stress and attenuates pyroptosis and ferroptosis in Clostridium perfringens Beta-1 toxin-induced macrophages.}, journal = {Microbiological research}, volume = {289}, number = {}, pages = {127916}, doi = {10.1016/j.micres.2024.127916}, pmid = {39342748}, issn = {1618-0623}, mesh = {*Pyroptosis/drug effects ; *Ferroptosis/drug effects ; *Macrophages/drug effects/metabolism ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Bacterial Toxins/metabolism/toxicity ; Mice ; Animals ; *Calpain/metabolism ; Humans ; Clostridium perfringens/drug effects/metabolism ; Hydrogen Peroxide/metabolism ; Mitochondrial Proton-Translocating ATPases/metabolism ; RAW 264.7 Cells ; Acetylcysteine/pharmacology/metabolism ; Inflammation/metabolism ; }, abstract = {Clostridium perfringens Beta-1 toxin (CPB1) is a lethal toxin, which can lead to necrotic enteritis, but the pathological mechanism has not been elucidated. We investigated whether reactive oxygen species (ROS) participated in CPB1-induced pyroptosis and ferroptosis, and investigated the effects of calpain on CPB1-induced oxidative stress and inflammation. Scavenging ROS by N-Acetyl-L cysteine (NAC) led to the reduction of ROS, inhibited the death of macrophages, cytoplasmic swelling and membrane rupture, the expression of pyroptosis-related proteins and proinflammatory factor, while increased the expression of anti-inflammatory factors in cells treated with rCPB1. Adenosine triphosphate (ATP) synthase, H[+] transporting, mitochondrial F1 complex, alpha subunit 1 (ATP5A1) was identified specifically interact with rCPB1. Silencing ATP5A1 inhibited accumulation of ATP and ROS, leaded to less cytoplasmic swelling and membrane rupture, attenuated pyroptosis and inflammation in rCPB1-treated cells. We also found that rCPB1 induces ferroptosis in macrophages, and the level of ferroptosis was similar with H2O2. Of note, H2O2 is a major ROS source, indicated that ROS production may play a major role in the regulation of ferroptosis in macrophages treated with rCPB1. This finding was further corroborated in rCPB1- induced human acute monocytic leukemia cells, which were treated with NAC. In addition, the inhibition of ferroptosis using liproxstatin-1 inhibited the shriveled mitochondrial morphology, increased the expression of glutathione peroxidase 4, nicotinamide adenine dinucleotide (phosphate) hydrogen: quinone oxidoreductase 1 and cysteine/glutamic acid reverse transport solute carrier family 7 members 11, decreased the expression of heme oxygenase 1, nuclear receptor coactivator 4 and transferrin receptor proteins, reduced malondialdehyde and lipid peroxidation levels, and increased intracellular L-glutathione levels in cells treated with rCPB1. Furthermore, calpain inhibitor PD151746 was used to investigate how pyroptosis and ferroptosis were involved simultaneously in rCPB1-treated macrophages. We showed that PD151746 inhibited ATP and ROS production, reversed the representative pyroptosis/ferroptosis indicators and subsequently reduced inflammation. The above findings indicate that rCPB1 might lead to macrophage pyroptosis and ferroptosis through the large and sustained increase in intracellular calpain and oxidative stress, further lead to inflammation.}, } @article {pmid39339978, year = {2024}, author = {Wang, Y and Luan, T and Wang, L and Feng, D and Dong, Y and Li, S and Yang, H and Chen, Y and Fei, Y and Lin, L and Pan, J and Zhong, Z and Zhao, W}, title = {N-Acetylcysteine Inhibits Coxsackievirus B3 Replication by Downregulating Eukaryotic Translation Elongation Factor 1 Alpha 1.}, journal = {Viruses}, volume = {16}, number = {9}, pages = {}, pmid = {39339978}, issn = {1999-4915}, mesh = {Animals ; Humans ; Male ; Mice ; *Acetylcysteine/pharmacology ; Antiviral Agents/pharmacology ; Cell Line ; *Coxsackievirus Infections/drug therapy/virology ; *Down-Regulation/drug effects ; *Enterovirus B, Human/drug effects/physiology ; Myocarditis/virology/drug therapy ; *Peptide Elongation Factor 1/metabolism/genetics ; *Virus Replication/drug effects ; }, abstract = {Group B Coxsackieviruses (CVB) are one of the causative pathogens of myocarditis, which may progress to cardiomyopathy. The pathogenesis of CVB is not fully understood, and effective antiviral therapy is not available. N-acetylcysteine (NAC), the classic antioxidant, has been used in clinical practice for several decades to treat various medical conditions. In this study, the anti-CVB effect of NAC was investigated. We show that NAC dramatically suppressed viral replication and alleviated cardiac injury induced by CVB3. To further study the antiviral mechanism of NAC, RNA-sequencing was performed for CVB3-infected cells with NAC treatment. We found that eukaryotic elongation factor 1 alpha 1 (EEF1A1) is one of the most upregulated genes in CVB3-infected cells. However, EEF1A2, the highly homologous isoform of EEF1A1, remains unchanged. EEF1A1 expression was significantly suppressed by NAC treatment in CVB3-infected cells, while EEF1A2 was not affected. eEF1A1 knockdown significantly inhibited CVB3 replication, implicating that eEF1A1 facilitates viral replication. Importantly, we show that eEF1A1, which was not expressed in the myocardia of newborn mice, was significantly upregulated by CVB3 infection. NAC markedly downregulated the expression of eEF1A1 but not eEF1A2 in the myocardia of CVB3-infected mice. Furthermore, NAC accelerated eEF1A1 degradation by promoting autophagy in CVB3-infected cells. We show that p62, one of the critical adaptors of autophagic targets, interacts with eEF1A1 and was downregulated in CVB3-infected cells upon NAC treatment. Taken together, this study demonstrated that NAC shows a potent anti-CVB effect through the downregulation of eEF1A1.}, } @article {pmid39339161, year = {2024}, author = {Alam, MI and Paget, T and Moosa, NY and Alghurairy, H and Elkordy, AA}, title = {Liposomal Drug Delivery against Helicobacter pylori Using Furazolidone and N-Acetyl Cysteine in Augmented Therapy.}, journal = {Pharmaceutics}, volume = {16}, number = {9}, pages = {}, pmid = {39339161}, issn = {1999-4923}, abstract = {Helicobacter pylori (H. pylori) infection is a significant global health concern, affecting approximately 50% of the world's population and leading to gastric ulcers, gastritis, and gastric cancer. The increase in antibiotic resistance has compromised the efficacy of existing therapeutic regimens, necessitating novel approaches for effective eradication. This study aimed to develop a targeted liposomal drug delivery system incorporating furazolidone and N-acetylcysteine (NAC) to enhance mucopenetration and improve Helicobacter pylori eradication. Liposomes were formulated with furazolidone, NAC, and Pluronic F-127 using a modified reverse-phase evaporation technique. The formulations were categorized based on charge as neutral, negative, and positive and tested for mucopenetration using a modified silicon tube method with coumarin-6 as a fluorescent marker. The encapsulation efficiency and particle size were analyzed using HPLC and an Izon q-nano particle size analyzer. The results indicated that charged liposomes showed a higher encapsulation efficiency than neutral liposomes with Pluronic F-127. Notably, combining furazolidone with 1% NAC achieved complete eradication of H. pylori in 2.5 h, compared to six hours without NAC. The findings of this study suggest that incorporating NAC and Pluronic F-127 into liposomal formulations significantly enhances mucopenetration and antimicrobial efficacy.}, } @article {pmid39337681, year = {2024}, author = {Zhang, M and Chai, ZH and Zhang, C and Chen, L}, title = {Unbalanced Expression of Structural Genes in Carotenoid Pathway Contributes to the Flower Color Formation of the Osmanthus Cultivar 'Yanzhi Hong'.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337681}, issn = {1422-0067}, support = {BK20200786//Natural Science Foundation of Jiangsu Province/ ; 2019M651839//China Postdoctoral Science Foundation/ ; CX2019029//Innovation Fund for Young Scholars of Nanjing Forestry University/ ; 32071782//National Natural Science Foundation of China/ ; }, mesh = {*Carotenoids/metabolism ; *Flowers/genetics/metabolism/growth & development ; *Gene Expression Regulation, Plant ; *Pigmentation/genetics ; *Oleaceae/genetics/metabolism/growth & development ; Plant Proteins/genetics/metabolism ; Gene Expression Profiling/methods ; }, abstract = {Carotenoids are important natural pigments that are responsible for the fruit and flower colors of many plants. The composition and content of carotenoid can greatly influence the color phenotype of plants. However, the regulatory mechanism underling the divergent behaviors of carotenoid accumulation, especially in flower, remains unclear. In this study, a new cultivar Osmanthus fragrans 'Yanzhi Hong' was used to study the regulation of carotenoid pigmentation in flower. Liquid chromatograph-mass spectrometer (LC-MS) analysis showed that β-carotene, phytoene, lycopene, γ-carotene, and lutein were the top five pigments enriched in the petals of 'Yanzhi Hong'. Through transcriptome analysis, we found that the expression of the structural genes in carotenoid pathway was imbalanced: most of the structural genes responsible for lycopene biosynthesis were highly expressed throughout the flower developmental stages, while those for lycopene metabolism kept at a relatively lower level. The downregulation of LYCE, especially at the late developmental stages, suppressed the conversion from lycopene to α-carotene but promoted the accumulation of β-carotene, which had great effect on the carotenoid composition of 'Yanzhi Hong'. Ethylene response factor (ERF), WRKY, basic helix-loop-helix (bHLH), v-myb avian myeloblastosis viral oncogene homolog (MYB), N-Acetylcysteine (NAC), auxin response factor (ARF), and other transcription factors (TFs) have participated in the flower color regulation of 'Yanzhi Hong', which formed co-expression networks with the structural genes and functioned in multiple links of the carotenoid pathway. The results suggested that the cyclization of lycopene is a key link in determining flower color. The modification of the related TFs will break the expression balance between the upstream and downstream genes and greatly influence the carotenoid profile in flowers, which can be further used for creating colorful plant germplasms.}, } @article {pmid39337474, year = {2024}, author = {Stachura, A and Sobczak, M and Kędra, K and Kopka, M and Kopka, K and Włodarski, PK}, title = {The Influence of N-Acetylcysteine-Enriched Hydrogels on Wound Healing in a Murine Model of Type II Diabetes Mellitus.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337474}, issn = {1422-0067}, support = {1MN/2/MG/N/20//Medical University of Warsaw/ ; }, mesh = {Animals ; *Acetylcysteine/pharmacology/administration & dosage ; *Hydrogels/chemistry ; *Wound Healing/drug effects ; Mice ; *Diabetes Mellitus, Type 2/drug therapy ; *Disease Models, Animal ; Skin/drug effects/pathology ; Male ; Cell Proliferation/drug effects ; Antioxidants/pharmacology ; Diabetes Mellitus, Experimental/drug therapy ; }, abstract = {Diabetes mellitus (DM) severely impairs skin wound healing capacity, yet few treatment options exist to enhance this process. N-acetylcysteine (NAC) is an antioxidant that improves cellular proliferation and enhances wound healing in healthy animals, yet its use in the context of type II DM has not been studied. The aim of our research was to investigate the effect of topically applied NAC-enriched hydrogels on wound healing in a leptin-deficient murine wound model. Four excisional wounds were created on the backs of 20 db/db mice and were subsequently treated with hydrogels containing NAC at concentrations of 5%, 10% and 20% or placebo (control). Healing was monitored for 28 days; photographs of the wounds were taken on every third day. Wound tissues were harvested on days 3, 7, 14 and 28 to undergo histological examinations. Wounds treated with 5% NAC showed improved wound closure speed accompanied by an increased dermal proliferation area on microscopic assessment compared with other groups. Higher concentrations of NAC failed to show a beneficial effect on wound healing. 5% NAC improved early stages of wound healing in a murine model of type II DM by increasing wound closure speed, likely mediated by improved dermal proliferation.}, } @article {pmid39337344, year = {2024}, author = {Morabito, C and Di Sinno, N and Mariggiò, MA and Guarnieri, S}, title = {Impact of Extremely Low-Frequency Electromagnetic Fields on Skeletal Muscle of Sedentary Adult Mice: A Pilot Study.}, journal = {International journal of molecular sciences}, volume = {25}, number = {18}, pages = {}, pmid = {39337344}, issn = {1422-0067}, mesh = {Animals ; *Electromagnetic Fields/adverse effects ; Mice ; Male ; Pilot Projects ; *Muscle, Skeletal/metabolism/radiation effects ; *Oxidative Stress/radiation effects ; *Mice, Inbred C57BL ; *Superoxide Dismutase-1/metabolism ; Acetylcysteine/pharmacology ; Myosin Heavy Chains/metabolism ; Antioxidants/metabolism ; PAX7 Transcription Factor/metabolism ; Sedentary Behavior ; Muscle Strength/radiation effects ; Catalase/metabolism ; }, abstract = {Extremely low-frequency electromagnetic fields (ELF-EMFs) are ubiquitous in industrialized environments due to the continuous use of electrical devices. Our previous studies demonstrated that ELF-EMFs affect muscle cells by modulating oxidative stress and enhancing myogenesis. This pilot study investigated these effects on the skeletal muscles of sedentary adult mice, assessing physiological responses to ELF-EMF exposure and potential modulation by antioxidant supplementation. Male C57BL/6 mice were exposed to ELF-EMFs (0.1 or 1.0 mT) for 1 h/day for up to 5 weeks and fed a standard diet without or with N-acetyl-cysteine (NAC). The results showed transient increases in muscle strength (after 2 weeks of exposure at 1.0 mT), potentially linked to muscle fiber recruitment and activation, revealed by higher PAX7 and myosin heavy chain (MyH) expression levels. After ELF-EMF exposure, oxidative status assessment revealed transient increases in the expression levels of SOD1 and catalase enzymes, in total antioxidant capacity, and in protein carbonyl levels, markers of oxidative damage. These effects were partially reduced by NAC. In conclusion, ELF-EMF exposure affects skeletal muscle physiology and NAC supplementation partially mitigates these effects, highlighting the complex interactions between ELF-EMFs and antioxidant pathways in vivo. Further investigations on ELF-EMFs as a therapeutic modality for muscle health are necessary.}, } @article {pmid39332540, year = {2024}, author = {Yao, Z and Xue, K and Chen, J and Zhang, Y and Zhang, G and Zheng, Z and Li, Z and Li, Z and Wang, F and Sun, X and Shen, L and Mao, C and Lin, C}, title = {Biliverdin improved angiogenesis and suppressed apoptosis via PI3K/Akt-mediated Nrf2 antioxidant system to promote ischemic flap survival.}, journal = {Free radical biology & medicine}, volume = {225}, number = {}, pages = {35-52}, doi = {10.1016/j.freeradbiomed.2024.09.042}, pmid = {39332540}, issn = {1873-4596}, mesh = {*NF-E2-Related Factor 2/metabolism/genetics ; Humans ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; *Apoptosis/drug effects ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism/genetics ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *Neovascularization, Physiologic/drug effects ; *Surgical Flaps ; *Ischemia/metabolism/drug therapy/pathology ; *Biliverdine/metabolism/pharmacology ; *Antioxidants/pharmacology ; Hydrogen Peroxide/metabolism ; Mice ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Oxidative Stress/drug effects ; Male ; Angiogenesis ; }, abstract = {Plastic and reconstructive surgeons frequently utilize random skin flap transplantation to repair skin defects. However, the procedure carries a substantial risk of necrosis. Previous research has suggested that Biliverdin (Bv), the main component of Calculus Bovis, possessed potent anti-ischemic properties, making it a potential therapeutic agent for skin flap survival. Hence, in this study, the potential of Bv in promoting flap survival has been comprehensively investigated. Network pharmacology analysis revealed that the pharmacological effects of Bv on ischemic diseases may be attributed to its modulation of various signaling molecules, including the PI3K-Akt pathway. In vitro results demonstrated that Bv treatment significantly promoted angiogenesis in human umbilical vein endothelial cells (HUVEC), even in the presence of H2O2. This was evident by the increased cell proliferation, enhanced migration, and improved tube formation. Bv also effectively attenuated the intracellular generation of reactive oxygen species (ROS) induced by H2O2, which was achieved by suppressing mitochondrial ROS production through the PI3K/Akt-mediated activation of Nrf2/HO-1 signaling pathway. Consequently, Bv treatment led to a significant reduction in apoptosis and an increase in cell viability of HUVEC. Furthermore, in vivo experiment demonstrated that Bv treatment vastly elevated flap survival through enhancing angiogenesis while decreasing oxidative stress and apoptosis, which was comparable to the results of positive control of N-acetylcysteine (Nac). In conclusion, this study not only established a solid foundation for future study on therapeutic potential of Bv, but also proposed a promising treatment approach for enhancing the success rate of flap transplants and other ischemic-related tissue repair.}, } @article {pmid39331828, year = {2024}, author = {Moraes, LGDS and Oliveira, VC and Macedo, AP and Freiria de Oliveira, CA and Watanabe, E and Pagnano, VO}, title = {Enhancing Removable Partial Dentures Hygiene: Investigating Mucolytic Agents and Biocides for Disrupting Biofilms and Improving Antimicrobial Efficacy.}, journal = {The International journal of prosthodontics}, volume = {0}, number = {0}, pages = {1-25}, doi = {10.11607/ijp.9133}, pmid = {39331828}, issn = {1942-4426}, abstract = {PURPOSE: This study evaluates the antibiofilm action of 2.5 mg/mL peracetic acid (PA), 0.5 mg/mL cetylpyridinium chloride (CPC), and 160 mg/mL N-Acetylcysteine (NAC) against multispecies biofilm of Streptococcus mutans, Staphylococcus aureus, Candida albicans, and Candida glabrata, developed on surfaces of heat-polymerizing acrylic resin (AR) and cobaltchromium (Co-Cr) alloy.

MATERIALS AND METHODS: A multispecies biofilm was grown on the surface of AR and Co-Cr specimens (Ø 12×3mm). After biofilm maturation, the specimens were immersed in experimental solutions and evaluated through biofilm viability (CFU) (n=9), biofilm metabolic activity (XTT) (n=9), biofilm-covered areas (Live/Dead) (n=2), effects on the extracellular polymeric substance (EPS) (n=2) and biofilm morphology (n=1). Data were analyzed by ANOVA and the Tukey post-test or Kruskal-Wallis followed by the Dunn post-test (α=.05).

RESULTS: Overall, all evaluated solutions impacted biofilm viability. PA presented wider activity by reducing CFU of all microorganisms on both surfaces, XTT (P<.001) and Live/Dead (P<.001). NAC had a notorious effect in reducing the viability of bacteria without affecting the yeasts. NAC reduced XTT on AR (P=.006) and Co-Cr (P=.003) but did not reduce the aggregated biofilm layer. CPC had distinct effect according to the surface, being most effective in reducing CFU on AR than the Co-Cr surface. However, it did not influence XTT, and the amount of residual aggregated biofilm.

CONCLUSIONS: PA provided the greatest antibiofilm action, while CPC and NAC showed intermediate action. Nonetheless, no solution was able to completely remove the biofilm adhered to the surfaces of heat-polymerizing AR and Co-Cr alloy.}, } @article {pmid39319193, year = {2024}, author = {Attiq, A and Afzal, S and Wahab, HA and Ahmad, W and Kandeel, M and Almofti, YA and Alameen, AO and Wu, YS}, title = {Cytokine Storm-Induced Thyroid Dysfunction in COVID-19: Insights into Pathogenesis and Therapeutic Approaches.}, journal = {Drug design, development and therapy}, volume = {18}, number = {}, pages = {4215-4240}, pmid = {39319193}, issn = {1177-8881}, mesh = {Humans ; *COVID-19/complications ; *Cytokine Release Syndrome/drug therapy/etiology ; *SARS-CoV-2 ; *COVID-19 Drug Treatment ; Cytokines/metabolism ; Thyroid Diseases/drug therapy/metabolism ; Angiotensin-Converting Enzyme 2/metabolism ; Thyroid Gland/metabolism/physiopathology ; }, abstract = {Angiotensin-converting enzyme 2 receptors (ACE2R) are requisite to enter the host cells for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). ACE2R is constitutive and functions as a type I transmembrane metallo-carboxypeptidase in the renin-angiotensin system (RAS). On thyroid follicular cells, ACE2R allows SARS-CoV-2 to invade the thyroid gland, impose cytopathic effects and produce endocrine abnormalities, including stiff back, neck pain, muscle ache, lethargy, and enlarged, inflamed thyroid gland in COVID-19 patients. Further damage is perpetuated by the sudden bursts of pro-inflammatory cytokines, which is suggestive of a life-threatening syndrome known as a "cytokine storm". IL-1β, IL-6, IFN-γ, and TNF-α are identified as the key orchestrators of the cytokine storm. These inflammatory mediators upregulate transcriptional turnover of nuclear factor-kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK), paving the pathway for cytokine storm-induced thyroid dysfunctions including euthyroid sick syndrome, autoimmune thyroid diseases, and thyrotoxicosis in COVID-19 patients. Targeted therapies with corticosteroids (dexamethasone), JAK inhibitor (baricitinib), nucleotide analogue (remdesivir) and N-acetyl-cysteine have demonstrated effectiveness in terms of attenuating the severity and frequency of cytokine storm-induced thyroid dysfunctions, morbidity and mortality in severe COVID-19 patients. Here, we review the pathogenesis of cytokine storms and the mechanisms and pathways that establish the connection between thyroid disorder and COVID-19. Moreover, cross-talk interactions of signalling pathways and therapeutic strategies to address COVID-19-associated thyroid diseases are also discussed herein.}, } @article {pmid39313073, year = {2025}, author = {Fort, TD and Azuma, MC and Laux, DA and Cain, ME}, title = {Environmental enrichment and sex, but not n-acetylcysteine, alter extended-access amphetamine self-administration and cue-seeking.}, journal = {Behavioural brain research}, volume = {476}, number = {}, pages = {115261}, pmid = {39313073}, issn = {1872-7549}, support = {P20 GM113109/GM/NIGMS NIH HHS/United States ; R15 DA035435/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; *Cues ; Male ; Female ; *Amphetamine/pharmacology/administration & dosage ; *Self Administration ; *Acetylcysteine/pharmacology/administration & dosage ; *Rats, Sprague-Dawley ; *Central Nervous System Stimulants/pharmacology/administration & dosage ; *Environment ; Drug-Seeking Behavior/drug effects/physiology ; Rats ; Nucleus Accumbens/drug effects/metabolism ; Astrocytes/drug effects/metabolism ; Sex Characteristics ; Prefrontal Cortex/drug effects/metabolism ; }, abstract = {There are no approved therapeutics for psychostimulant use and recurrence of psychostimulant use. However, in preclinical rodent models environmental enrichment can decrease psychostimulant self-administration of low unit doses and cue-induced amphetamine seeking. We have previously demonstrated that glutamate-dependent therapeutics are able to alter amphetamine seeking to amphetamine-associated cues only in enriched rats. In the current experiment, we will determine if enrichment can attenuate responding and cue-induced amphetamine seeking during extended access to a high dose of intravenous amphetamine. We will also determine if N-acetylcysteine (NAC), a glutamate dependent therapeutic, can attenuate amphetamine seeking in differentially reared rats. Female and male Sprague-Dawley rats were reared in enriched, isolated, or standard conditions from postnatal day 21-51. Rats were trained to self-administer intravenous amphetamine (0.1 mg/kg/infusion) during twelve 6-hour sessions. During the abstinence period, NAC (100 mg/kg) or saline was administered daily. Following a cue-induced amphetamine-seeking test, astrocyte densities within regions of the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb) were quantified using immunohistochemistry. Environmental enrichment decreased responding for amphetamine and during the cue-induced amphetamine-seeking test. NAC did not attenuate cue-induced amphetamine seeking or alter astrocyte density. Across all groups, female rats self-administered less amphetamine but responded more during cue-induced amphetamine seeking than male rats. While amphetamine increased astrocyte densities within the ACb and mPFC, it did not alter mPFC astrocyte densities in female rats. The results suggest that enrichment can attenuate responding during extended access to a high dose of amphetamine and the associated cues. Sex alters amphetamine-induced changes to astrocyte densities in a regionally specific matter.}, } @article {pmid39312385, year = {2024}, author = {Dinç, M and Soydemir, ÖC}, title = {Efficacy of N-acetylcysteine in reducing inflammation and oxidative stress to prevent complex regional pain syndrome type 1.}, journal = {Medicine}, volume = {103}, number = {38}, pages = {e39742}, pmid = {39312385}, issn = {1536-5964}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Female ; Male ; *Oxidative Stress/drug effects ; Middle Aged ; *Reflex Sympathetic Dystrophy/drug therapy/blood ; Retrospective Studies ; Aged ; Inflammation/blood/prevention & control ; Radius Fractures ; Antioxidants/therapeutic use ; Biomarkers/blood ; Cytokines/blood ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) in preventing complex regional pain syndrome type 1 (CRPS-1) by reducing proinflammatory cytokines and oxidative stress markers in patients with distal radius fractures. A retrospective single-center study at Bursa City Hospital involves patients over 50 years of age with distal radius fractures treated between January 2021 and December 2023. A total of 60 patients (mean age, 62.8 ± 5.1 years; 26 males and 34 females) were analyzed. Patients were divided into 2 groups: the NAC group (31 patients receiving 600-mg NAC daily for 3 months) and the control group (29 patients with no prophylactic medication). CRPS-1 diagnosis was based on Budapest criteria during multiple follow-up visits. Serum levels of interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha (TNF-α), total oxidant status (TOS), and total antioxidant status (TAS) were measured at baseline and study end point. CRPS-1 positive patients had significantly higher levels of IL-6, TNF-α, and IL-1 (P < .001 for all), higher TOS (P < .001) and oxidative stress index (P < .001), and lower TAS (P < .001) compared with CRPS-1 negatives. The incidence of CRPS-1 was significantly lower in the NAC group (9.7%) compared with the control group (31.0%; P = .039). Logistic regression indicated a 78% reduction in CRPS-1 odds ratio with NAC treatment (odds ratio, 0.219 [95% confidence interval, 0.053-0.895]; P = .0322). NAC significantly reduced end-point levels and changes in IL-6 (P < .001), TNF-α (P < .001), and IL-1 (P = .038) and improved oxidative stress markers, showing higher TAS (P < .001), lower TOS (P < .001), and oxidative stress index (P < .001) compared with controls. NAC significantly reduced the risk of developing CRPS-1 by decreasing levels of proinflammatory cytokines and oxidative stress. This study highlights NAC's potential as a preventive treatment for CRPS-1 and emphasizes the importance of early intervention.}, } @article {pmid39312076, year = {2024}, author = {Xue, Y and Bian, H and Bai, S and Bao, Z and Wang, L and Wang, S and Zhao, B and Wu, X and Chen, Y}, title = {N-acetylcysteine mitigates oxidative damage to the ovary in D-galactose-induced ovarian failure in rabbits.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {1008}, pmid = {39312076}, issn = {1573-4978}, support = {CARS-43-A-1//China Agriculture Research System of MOF and MARA/ ; 2022//Qing Lan Project of Yangzhou university/ ; }, mesh = {Animals ; Rabbits ; Female ; *Acetylcysteine/pharmacology ; *Galactose/adverse effects/pharmacology ; *Oxidative Stress/drug effects ; *Ovary/drug effects/metabolism/pathology ; Primary Ovarian Insufficiency/chemically induced/metabolism/pathology ; Granulosa Cells/metabolism/drug effects ; Antioxidants/pharmacology/metabolism ; Superoxide Dismutase/metabolism ; Glutathione/metabolism ; Catalase/metabolism ; Disease Models, Animal ; }, abstract = {BACKGROUND: Oxidative damage to the ovaries is the primary cause of impaired reproductive functions in female animals. This study aimed to investigate the protective role of N-Acetyl-L-cysteine (NAC) in reducing oxidative damage in the ovaries of female rabbits.

METHODS AND RESULTS: Female rabbit ovaries were treated in vitro with varying concentrations of D-galactose (D-gal): 0, 5, 10, and 15 mg/mL, and it was found that 10 mg/mL D-gal significantly disrupted follicular structures, causing disarray in granulosa cell arrangements and significantly reducing T-SOD and GSH levels (p < 0.01). Consequently, we selected 10 mg/mL D-gal to establish an ovarian failure model. These models were treated with multiple doses of NAC (0, 0.1, 0.3, 0.5 mg/mL). The results revealed that the disruption in granulosa cell arrangement caused by 10 mg/mL D-gal was effectively alleviated by 0.1 mg/mL NAC compared to the D-gal treatment group. Furthermore, 10 mg/mL D-gal significantly (p < 0.01) reduced GSH, T-SOD, and catalase (CAT) levels in the ovaries. However, 0.1 mg/mL NAC effectively (p < 0.01) suppressed these adverse effects. Moreover, the current results showed that 10 mg/mL D-gal alone significantly (p < 0.01) downregulated the expression of Nrf2, GPX, PRDX4, GSR, SOD1, and TAF4B, whereas 0.1 mg/mL NAC counteracted these suppressive effects (p < 0.01).

CONCLUSIONS: It could be concluded that NAC may delay ovarian failure by reducing D-gal-induced ovarian oxidative damage in female rabbit, suggested NAC could be a promising therapeutic agent for protecting against ovarian failure and potentially delaying ovarian failure in female rabbits.}, } @article {pmid39309000, year = {2024}, author = {Cuocina, M and Aiello, G and Cutrufelli, P and Rampello, M and Rapisarda, L and Rodolico, A and Cantarella, G and Signorelli, MS and Bernardini, R}, title = {Effect of N-acetylcysteine on craving in substance use disorders (SUD): a meta-analysis of randomized controlled trials.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1462612}, pmid = {39309000}, issn = {1663-9812}, abstract = {BACKGROUND: N-acetyl cysteine (NAC) appears promising as a treatment in patients with substance use disorder (SUD) as it helps rebalance glutamate levels in the central nervous system (CNS). Basal concentrations of glutamate are indeed reduced in SUD patients but increased during craving.

MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether NAC reduce craving rating as compared to a placebo in SUD patients. Secondary outcomes were withdrawal symptoms (WS), side effects (SE) and drop-outs. Estimates are presented as standardized mean differences (SMD) or risk ratio (RR) with 95% confidence interval (CI).

RESULTS: Eleven RCTs were included. NAC reduced craving rating (SMD -0.61 (-1.17, -0.06), p = 0.03, I2 = 85%), with no differences in the subgroup analysis according to the drug addiction (alcohol, cocaine, poly-drugs, amphetamine, nicotine) (p = 0.98). Among the secondary outcomes, for WS data showed no significant difference between groups (SMD -0.18 (-0.43, 0.08), p = 0.17); for SE no substantial difference was observed between the two treatment groups (RR = 1.06 (0.89-1.27), p = 0.52, I2 = 0%); for dropouts the results are in favor of the placebo but no statistically significant (RR 1.17 (0.85, 1.61), p = 0.34; I2 = 0%).

CONCLUSION: NAC seem to reduce craving rating in SUD patients, but evidence is weak. More studies are needed to confirm this finding.}, } @article {pmid39302378, year = {2024}, author = {Park, J and Oh, JP and Ku, K and Jin, Y and Kim, EJ and Lee, JH}, title = {Preventing Donepezil-Induced Adverse Effects Through N-acetylcysteine Co-Administration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {101}, number = {4}, pages = {1281-1292}, doi = {10.3233/JAD-240709}, pmid = {39302378}, issn = {1875-8908}, mesh = {*Donepezil/pharmacology ; Animals ; *Acetylcysteine/pharmacology ; *Rats, Sprague-Dawley ; Male ; *Cholinesterase Inhibitors/pharmacology ; Female ; Rats ; *Reactive Oxygen Species/metabolism ; Calcium/metabolism ; Indans/pharmacology ; Piperidines/pharmacology ; }, abstract = {BACKGROUND: Drug-induced adverse symptoms affect patients' quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer's disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL.

OBJECTIVE: Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and investigate the underlying mechanisms.

METHODS: Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes.

RESULTS: High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+]i levels in muscle cells.

CONCLUSIONS: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients.}, } @article {pmid39301637, year = {2024}, author = {Jin, J and Nan, J and Si, Y and Chen, X and Wang, H and Wang, X and Huang, J and Guo, T}, title = {Exploring the therapeutic potential of rabdoternin E in lung cancer treatment: Targeting the ROS/p38 MAPK/JNK signaling pathway.}, journal = {Molecular medicine reports}, volume = {30}, number = {5}, pages = {}, pmid = {39301637}, issn = {1791-3004}, mesh = {Humans ; *Reactive Oxygen Species/metabolism ; Animals ; *Lung Neoplasms/drug therapy/metabolism/pathology ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *MAP Kinase Signaling System/drug effects ; Mice ; A549 Cells ; *Apoptosis/drug effects ; Xenograft Model Antitumor Assays ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Ferroptosis/drug effects ; Mice, Nude ; Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Lung cancer has the highest incidence and mortality rates of all cancer types in China and therefore represents a serious threat to human health. In the present study, the mechanism of rabdoternin E against the proliferation of the lung cancer cell line A549 was explored. It was found that rabdoternin E caused the accumulation of large amounts of reactive oxygen species (ROS), promoted cell S phase arrest by reducing the expression of CDK2 and cyclin A2, induced apoptosis by increasing the Bax/Bcl‑2 ratio and promoted the phosphorylation of proteins in the ROS/p38 MAPK/JNK signaling pathway, which is associated with apoptosis and ferroptosis. In addition, it was also found that Z‑VAD‑FMK (an apoptosis inhibitor), ferrostatin‑1 (ferroptosis inhibitor) and N‑acetylcysteine (a ROS inhibitor) could partially or greatly reverse the cytotoxicity of rabdoternin E to A549 cells. Similarly, NAC (N‑acetylcysteine) treatment notably inhibited the rabdoternin E‑stimulated p38 MAPK and JNK activation. Furthermore, in vivo experiments in mice revealed that Rabdoternin E markedly reduced tumor volume and weight and regulated the expression levels of apoptosis and ferroptosis‑related proteins (including Ki67, Bcl‑2, Bax, glutathione peroxidase 4, solute carrier family 7 member 11 and transferrin) in the tumor tissues of mice. Histopathological observation confirmed that the number of tumor cells decreased markedly after administration of rabdoternin E. Taken together, rabdoternin E induced apoptosis and ferroptosis of A549 cells by activating the ROS/p38 MAPK/JNK signaling pathway. Therefore, the results of the present study showed that rabdoternin E is not toxic to MCF‑7 cells (normal lung cells), had no significant effect on body weight and was effective and therefore may be a novel therapeutic treatment for lung cancer.}, } @article {pmid39299599, year = {2024}, author = {da Silva, AM and Murillo, DM and Anbumani, S and von Zuben, AA and Cavalli, A and Obata, HT and Fischer, ER and de Souza E Silva, M and Bakkers, E and Souza, AA and Carvalho, HF and Cotta, MA}, title = {N-acetylcysteine effects on extracellular polymeric substances of Xylella fastidiosa: A spatiotemporal investigation with implications for biofilm disruption.}, journal = {International journal of antimicrobial agents}, volume = {64}, number = {5}, pages = {107340}, doi = {10.1016/j.ijantimicag.2024.107340}, pmid = {39299599}, issn = {1872-7913}, mesh = {*Biofilms/drug effects ; *Xylella/drug effects/physiology ; *Acetylcysteine/pharmacology ; *Extracellular Polymeric Substance Matrix/drug effects/metabolism ; Bacterial Adhesion/drug effects ; Anti-Bacterial Agents/pharmacology ; Spatio-Temporal Analysis ; }, abstract = {BACKGROUND: The matrix of extracellular polymeric substances (EPS) present in biofilms greatly amplifies the problem of bacterial infections, protecting bacteria against antimicrobial treatments and eventually leading to bacterial resistance. The need for alternative treatments that destroy the EPS matrix becomes evident. N-acetylcysteine (NAC) is one option that presents diverse effects against bacteria; however, the different mechanisms of action of NAC in biofilms have yet to be elucidated.

OBJECTIVES: In this work, we performed microscopy studies at micro and nano scales to address the effects of NAC at single cell level and early-stage biofilms of the Xylella fastidiosa phytopathogen.

METHODS: We show the physical effects of NAC on the adhesion surface and the different types of EPS, as well as the mechanical response of individual bacteria to NAC concentrations between 2 and 20 mg/mL.

RESULTS: NAC modified the conditioning film on the substrate, broke down the soluble EPS, resulting in the release of adherent bacteria, decreased the volume of loosely bound EPS, and disrupted the biofilm matrix. Tightly bound EPS suffered structural alterations despite no solid evidence of its removal. In addition, bacterial force measurements upon NAC action performed with InP nanowire arrays showed an enhanced momentum transfer to the nanowires due to increased cell mobility resulting from EPS removal.

CONCLUSIONS: Our results clearly show that conditioning film and soluble EPS play a key role in cell adhesion control and that NAC alters EPS structure, providing solid evidence that NAC actuates mainly on EPS removal, both at single cell and biofilm levels.}, } @article {pmid39295440, year = {2024}, author = {Brand, F and Bale, E and Tsiachristas, A and Hawton, K}, title = {Self-poisoning with paracetamol in England: short report of characteristics of individuals and their overdoses according to source of tablets.}, journal = {BJPsych open}, volume = {10}, number = {5}, pages = {e155}, pmid = {39295440}, issn = {2056-4724}, support = {//Department of Health and Social Care/ ; //National Institute for Health and Care Research Applied Research Collaboration Oxford and Thames Valley/ ; }, abstract = {Self-poisoning with paracetamol is the most frequently used overdose method in the UK. Psychosocial assessments were conducted by mental health clinicians with 127 consecutive individuals who presented with pure paracetamol overdoses to a large general hospital over 8 months, including asking about the source of the tablets and scoring the patients' acts on the Beck Suicide Intent scale (BSI). Patients were predominantly female (86%) and young (79% aged 12-24 years). Most had used paracetamol which was available in the home (77%). Those who purchased paracetamol for the act took double the number of tablets compared with those who used paracetamol available in the home (37 v. 18), had higher suicidal intent (mean BSI: 11 v. 7) and more often required treatment with N-acetyl cysteine (71% v. 43%). These results highlight the need for safer home storage of paracetamol and consideration of reducing pack size limits on paracetamol that can be purchased.}, } @article {pmid39281865, year = {2024}, author = {Bishop, A and Romero, JC and Tonapi, S and Parihar, M and Loranc, E and Miller, H and Lawrence, L and Bassani, N and Robledo, D and Cao, L and Nie, J and Kanda, K and Stoja, A and Garcia, N and Gorthi, A and Stoveken, B and Lane, A and Fan, T and Cassel, T and Zha, S and Musi, N}, title = {ATM phosphorylation of CD98HC increases antiporter membrane localization and prevents chronic toxic glutamate accumulation in Ataxia telangiectasia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {39281865}, issn = {2693-5015}, support = {T32 AG021890/AG/NIA NIH HHS/United States ; R01 CA241554/CA/NCI NIH HHS/United States ; F31 AG072902/AG/NIA NIH HHS/United States ; TL1 TR002647/TR/NCATS NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; K22 ES012264/ES/NIEHS NIH HHS/United States ; P30 CA177558/CA/NCI NIH HHS/United States ; T32 CA148724/CA/NCI NIH HHS/United States ; }, abstract = {Ataxia telangiectasia (A-T) is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in A-T, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of A-T is not understood. CD98HC chaperones cystine/glutamate (xc [-]) and cationic/neutral amino acid (y[+]L) antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on SLC family antiporters relevant to A-T phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes) with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance both in ATM-deficient cells and mouse models. These findings provide new insight into the long-known benefits of N-acetyl cysteine to A-T cells beyond oxidative stress through removing excess glutamate by production of glutathione.}, } @article {pmid39278392, year = {2024}, author = {Wang, Z and Guo, L and Zhu, C and Li, J and Guo, J and Zhu, X and Li, J and Cui, L and Dong, J and Liu, K and Meng, X and Zhu, G and Wang, H}, title = {NLRP3 targets HMGB1 to exacerbate the pyroptosis of canine corneal epithelial cells infected with Staphylococcus pseudintermedius.}, journal = {Experimental eye research}, volume = {248}, number = {}, pages = {110096}, doi = {10.1016/j.exer.2024.110096}, pmid = {39278392}, issn = {1096-0007}, mesh = {Animals ; *Pyroptosis ; *HMGB1 Protein/metabolism/genetics ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Dogs ; *Epithelium, Corneal/metabolism/microbiology/drug effects ; *Reactive Oxygen Species/metabolism ; *Staphylococcus ; Staphylococcal Infections/microbiology/metabolism ; Eye Infections, Bacterial/microbiology/metabolism ; Cells, Cultured ; Blotting, Western ; Gene Expression Regulation ; RNA, Messenger/genetics/metabolism ; }, abstract = {PURPOSE: This study focused on the mechanisms of pyroptosis and oxidative damage exacerbation by NOD-like receptor thermal protein domain associated protein 3 (NLRP3) during the infection of canine corneal epithelial cells (CCECs) with Staphylococcus pseudintermedius.

METHODS: The CCECs treated with dimethyl fumarate (DMF), recombinant high mobility group protein 1 (HMGB1), or N-acetylcysteine (NAC). The gasdermin (GSDM) family and HMGB1 mRNA expression levels were detected using quantitative reverse transcription polymerase chain reaction. Lactate dehydrogenase activity, bacterial counts, the pyroptosis rate, reactive oxygen species (ROS) content, and antioxidant enzyme activity were used to reflect pyroptosis and oxidation level.

RESULTS: Regulation of NLRP3 significantly affected the pyroptosis rate and GSDMD-N expression levels during S. pseudintermedius infection. Inhibition of GSDMD-N protein activation by DMF reversed the exacerbation of pyroptosis induced by NLRP3 overexpression and reduced the levels of cleaved interleukin-1β (IL-1β), cleaved cysteinyl aspartate-specific protease-1, and NLRP3. In addition, NLRP3 was found to target the HMGB1 promoter and regulate its protein expression, to increase ROS accumulation and GSDMD-N expression levels, and activate the NLRP3-HMGB1-ROS-GSDMD signaling axis to aggravate pyroptosis during infection.

CONCLUSIONS: NLRP3 aggravates pyroptosis and oxidative damage associated with the activation of NLRP3-GSDMD and NLRP3-HMGB1-ROS-GSDMD signaling pathways during the infection of CCECs with S. pseudintermedius.}, } @article {pmid39276051, year = {2024}, author = {Cong, X and Chen, T and Li, S and Wang, Y and Zhou, L and Li, X and Zhang, P and Sun, X and Zhao, S}, title = {[Dihydroartemisinin enhances sensitivity of nasopharyngeal carcinoma HNE1/DDP cells to cisplatin-induced apoptosis by promoting ROS production].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {44}, number = {8}, pages = {1553-1560}, pmid = {39276051}, issn = {1673-4254}, mesh = {Humans ; *Cisplatin/pharmacology ; *Artemisinins/pharmacology ; *Apoptosis/drug effects ; *Nasopharyngeal Carcinoma/metabolism/pathology/drug therapy ; *Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; *Nasopharyngeal Neoplasms/metabolism/pathology/drug therapy ; *Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Antineoplastic Agents/pharmacology ; }, abstract = {OBJECTIVE: To investigate the effect of dihydroartemisinin (DHA) for enhancing the inhibitory effect of cisplatin (DDP) on DDP-resistant nasopharyngeal carcinoma cell line HNE1/DDP and explore the mechanism.

METHODS: CCK-8 method was used to assess the survival rate of HNE1/DDP cells treated with DHA (0, 5, 10, 20, 40, 80, and 160 μmol/L) and DDP (0, 4, 8, 16, 32, 64, 128 μmol/L) for 24 or 48 h, and the combination index of DHA and DDP was calculated using Compusyn software. HNE1/DDP cells treated with DHA, DDP, or their combination for 24 h were examined for cell viability, proliferation and colony formation ability using CCK-8, EdU and colony-forming assays. Flow cytometry was used to detect cell apoptosis and intracellular reactive oxygen species (ROS). The expression levels of apoptosis-related proteins cleaved PARP, cleaved caspase-9 and cleaved caspase-3 were detected by Western blotting. The effects of N-acetyl-cysteine (a ROS inhibitor) on proliferation and apoptosis of HNE1/DDP cells with combined treatment with DHA and DDP were analyzed.

RESULTS: Different concentrations of DHA and DDP alone both significantly inhibited the viability of HNE1/DDP cells. The combination index of DHA (5 μmol/L) combined with DDP (8, 16, 32, 64, 128 μmol/L) were all below 1. Compared with DHA or DDP alone, their combined treatment more potently decreased the cell viability, colony-forming ability and the number of EdU-positive cells, and significantly increased the apoptotic rate, intracellular ROS level, and the expression levels of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 in HNE1/DDP cells. N-acetyl-cysteine pretreatment obviously attenuated the inhibitory effect on proliferation and apoptosis-inducing effect of DHA combined with DDP in HNE1/DDP cells (P<0.01).

CONCLUSION: DHA enhances the growth-inhibitory and apoptosis-inducing effect of DDP on HNE1/DDP cells possibly by promoting accumulation of intracellular ROS.}, } @article {pmid39275957, year = {2024}, author = {}, title = {RETRACTION "Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats,".}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {10}, pages = {e23852}, doi = {10.1002/jbt.23852}, pmid = {39275957}, issn = {1099-0461}, abstract = {M. F. Nagoor Meeran and P. S. Mainzen Prince, Journal of Biochemical and Molecular Toxicology 25, no. 3 (2011): 151-157, https://doi.org/10.1002/jbt.20371. The above article, published online on 23 November 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Hari K. Bhat; and Wiley Periodicals, LLC. The retraction has been agreed due to duplication of several Western blot bands observed in Figure 2. The authors did not provide an explanation or their raw data. The editors consider the results and conclusion reported in this article unreliable.}, } @article {pmid39272966, year = {2024}, author = {Gupta, KB and Taylor, TL and Panda, SS and Thangaraju, M and Lokeshwar, BL}, title = {Curcumin-Dichloroacetate Hybrid Molecule as an Antitumor Oral Drug against Multidrug-Resistant Advanced Bladder Cancers.}, journal = {Cancers}, volume = {16}, number = {17}, pages = {}, pmid = {39272966}, issn = {2072-6694}, support = {HT9425-23-1-0761//US Department of Defense Army Research program/ ; }, abstract = {Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.}, } @article {pmid39268103, year = {2024}, author = {Zheng, J and Zhao, L and Liu, Y and Chen, M and Guo, X and Wang, J}, title = {N-acetylcysteine, a small molecule scavenger of reactive oxygen species, alleviates cardiomyocyte damage by regulating OPA1-mediated mitochondrial quality control and apoptosis in response to oxidative stress.}, journal = {Journal of thoracic disease}, volume = {16}, number = {8}, pages = {5323-5336}, pmid = {39268103}, issn = {2072-1439}, abstract = {BACKGROUND: Oxidative stress-induced mitochondrial damage is the major cause of cardiomyocyte dysfunction. Therefore, the maintenance of mitochondrial function, which is regulated by mitochondrial quality control (MQC), is necessary for cardiomyocyte homeostasis. This study aimed to explore the underlying mechanisms of N-acetylcysteine (NAC) function and its relationship with MQC.

METHODS: A hydrogen peroxide-induced oxidative stress model was established using H9c2 cardiomyocytes treated with or without NAC prior to oxidative stress stimulation. Autophagy with light chain 3 (LC3)-green fluorescent protein (GFP) assay, reactive oxygen species (ROS) with the 2',7'-dichlorodi hydrofluorescein diacetate (DCFH-DA) fluorescent, lactate dehydrogenase (LDH) release assay, adenosine triphosphate (ATP) content assay, and a mitochondrial membrane potential detection were used to evaluate mitochondrial dynamics in H2O2-treated H9c2 cardiomyocytes, with a focus on the involvement of MQC regulated by NAC. Cell apoptosis was analyzed using caspase-3 activity assay and Annexin V-fluorescein isothiocyanate (V-FITC)/propidium iodide (PI) double staining.

RESULTS: We observed that NAC improved cell viability, reduced ROS levels, and partially restored optic atrophy 1 (OPA1) protein expression under oxidative stress. Following transfection with a specific OPA1-small interfering RNA, the mitophagy, mitochondrial dynamics, mitochondrial functions, and cardiomyocyte apoptosis were evaluated to further explore the mechanisms of NAC. Our results demonstrated that NAC attenuated cardiomyocyte apoptosis via the ROS/OPA1 axis and protected against oxidative stress-induced mitochondrial damage via the regulation of OPA1-mediated MQC.

CONCLUSIONS: NAC ameliorated the injury to H9c2 cardiomyocytes caused by H2O2 by promoting the expression of OPA1, consequently improving mitochondrial function and decreasing apoptosis.}, } @article {pmid39265983, year = {2025}, author = {Sun, J and Ding, J and Yue, H and Xu, B and Sodhi, A and Xue, K and Ren, H and Qian, J}, title = {Hypoxia-induced BNIP3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming.}, journal = {Autophagy}, volume = {21}, number = {1}, pages = {191-209}, pmid = {39265983}, issn = {1554-8635}, mesh = {*Melanoma/pathology/metabolism ; *Membrane Proteins/metabolism ; Humans ; *Uveal Neoplasms/pathology/metabolism ; *Mitophagy/physiology ; Animals ; *Disease Progression ; *Proto-Oncogene Proteins/metabolism ; Cell Line, Tumor ; *Neoplasm Metastasis ; *Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mitochondria/metabolism ; Oxidative Phosphorylation ; Reactive Oxygen Species/metabolism ; Mice ; Glycolysis ; Cell Hypoxia ; Mice, Nude ; Metabolic Reprogramming ; Uveal Melanoma ; }, abstract = {Uveal melanoma (UM) is an aggressive intraocular malignancy derived from melanocytes in the uvea tract of the eye. Up to 50% of patients with UM develop distant metastases which is usually fatal within one year; preventing metastases is therefore essential. Metabolic reprogramming plays a critical role in UM progression and metastasis. However, the metabolic phenotype of UM cells in the hypoxic tumor is not well understood. Here, we report that hypoxia-induced BNIP3 reprograms tumor cell metabolism, promoting their survival and metastasis. In response to hypoxia, BNIP3-mediated mitophagy alleviates mitochondrial dysfunction and enhances mitochondrial oxidative phosphorylation (OXPHOS) while simultaneously reducing mitochondrial reactive oxygen species (mtROS) production. This, in turn, impairs HIF1A/HIF-1α protein stability and inhibits glycolysis. Inhibition of mitophagy significantly suppresses BNIP3-induced UM progression and metastasis in vitro and in vivo. Collectively, these observations demonstrate a novel mechanism whereby BNIP3 promotes UM metabolic reprogramming and malignant progression by mediating hypoxia-induced mitophagy and suggest that BNIP3 could be an important therapeutic target to prevent metastasis in patients with UM.Abbreviations: AOD: average optical density; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine; CoCl2: cobalt chloride; GEPIA: Gene Expression Profiling Interactive Analysis; HIF1A: hypoxia inducible factor 1, alpha subunit; IHC: immunohistochemistry; mtROS: mitochondrial reactive oxygen species; NAC: N-acetylcysteine; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; TCGA: The Cancer Genome Atlas; UM: uveal melanoma.}, } @article {pmid39265812, year = {2024}, author = {Pazarci, Ö and Hümeyra Taşkin Kafa, A and Taş, A and Keklikcioğlu Çakmak, N and Hasbek, M and Kilinç, S and Tunçbilek, Z}, title = {Assessment of the antimicrobial and antibiofilm activity of the combination of N-acetyl cysteine and carvacrol against Staphylococcus aureus, the most common orthopedic infectious agent.}, journal = {Microbial pathogenesis}, volume = {196}, number = {}, pages = {106934}, doi = {10.1016/j.micpath.2024.106934}, pmid = {39265812}, issn = {1096-1208}, mesh = {*Biofilms/drug effects ; *Cymenes/pharmacology ; *Acetylcysteine/pharmacology ; *Microbial Sensitivity Tests ; *Staphylococcus aureus/drug effects ; *Drug Synergism ; *Anti-Bacterial Agents/pharmacology ; Staphylococcal Infections/drug therapy/microbiology ; Monoterpenes/pharmacology ; Humans ; Methicillin-Resistant Staphylococcus aureus/drug effects ; Cell Line ; }, abstract = {BACKGROUND: The increasing prevalence of antibiotic-resistant bacterial infections has led to the search for new approaches.

OBJECTIVE: This study aimed to evaluate the effects of carvacrol and N-acetyl cysteine, both individually and in combination, on the planktonic cells and biofilm formations of Staphylococcus aureus, including methicillin-resistant and methicillin-sensitive strains. Additionally, the study sought to perform cytotoxicity tests and chemical characterization to further understand the properties and potential applications of these substances.

METHODS: A total of 19 S. aureus strains were included in the study. Minimum inhibitory concentration and minimum bactericidal concentration were determined by assays. Synergy analysis tests were carried out. Cytotoxicity tests were conducted on the fibroblast cell line. Characterization test was performed.

RESULTS: While Minimum inhibitory concentration and minimum bactericidal concentration values for carvacrol varied between 250 and 500 μg/ml, these values were in the range of 32-64 mg/ml for N-acetyl cysteine. Biofilm formation activities were identified. A total of eight strains, including six clinical and two standard strains with the highest biofilm-forming ability, were selected for combination studies. The combination of Carvacrol and N-acetyl cysteine exhibited synergistic and partially synergistic effects on the tested planktonic and biofilm strains, and these effects were dose-dependent. Carvacrol was found to be the most active drug at the end of 24, 48, and 72 h. Regarding the synergistic effect of N-acetyl cysteine + carvacrol, it was revealed to exhibit higher activity than N-acetyl cysteine and lower activity than carvacrol.

CONCLUSION: The combination of carvacrol and N-acetyl cysteine demonstrated synergistic and partially synergistic effects against both planktonic and biofilm forms of Staphylococcus aureus. These results suggest potential for novel approaches in managing orthopedic infections, warranting further research to explore their therapeutic applications.}, } @article {pmid39263473, year = {2024}, author = {Li, YL and Wang, G and Wang, BW and Li, YH and Ma, YX and Huang, Y and Yan, WT and Xie, P}, title = {The potential treatment of N-acetylcysteine as an antioxidant in the radiation-induced heart disease.}, journal = {Cardiovascular diagnosis and therapy}, volume = {14}, number = {4}, pages = {509-524}, pmid = {39263473}, issn = {2223-3652}, abstract = {BACKGROUND: Radiation-induced heart disease (RIHD) is a serious complication of thoracic tumor radiotherapy that substantially affects the quality of life of cancer patients. Oxidative stress plays a pivotal role in the occurrence and progression of RIHD, which prompted our investigation of an innovative approach for treating RIHD using antioxidant therapy.

METHODS: We used 8-week-old male Sprague-Dawley (SD) rats as experimental animals and H9C2 cells as experimental cells. N-acetylcysteine (NAC) was used as an antioxidant to treat H9C2 cells after X-ray irradiation in this study. In the present study, the extent of cardiomyocyte damage caused by X-ray exposure was determined, alterations in oxidation/antioxidation levels were assessed, and changes in the expression of genes related to mitochondria were examined. The degree of myocardial tissue and cell injury was also determined. Dihydroethidium (DHE) staining, reactive oxygen species (ROS) assays, and glutathione (GSH) and manganese superoxide dismutase (Mn-SOD) assays were used to assess cell oxidation/antioxidation. Flow cytometry was used to determine the mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening. High-throughput transcriptome sequencing and bioinformatics analysis were used to elucidate the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure. Polymerase chain reaction (PCR) was used to verify the expression of differentially expressed genes.

RESULTS: X-ray irradiation damaged myocardial tissue and cells, resulting in an imbalance of oxidative and antioxidant substances and mitochondrial damage. NAC treatment increased cell counting kit-8 (CCK-8) levels (P=0.02) and decreased lactate dehydrogenase (LDH) release (P=0.02) in cardiomyocytes. It also reduced the level of ROS (P=0.002) and increased the levels of GSH (P=0.04) and Mn-SOD (P=0.01). The mitochondrial membrane potential was restored (P<0.001), and mPTP opening was inhibited (P<0.001). Transcriptome sequencing and subsequent validation analyses revealed a decrease in the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure, but antioxidant therapy did not reverse the related DNA damage.

CONCLUSIONS: Antioxidants mitigated radiation-induced myocardial damage to a certain degree, but these agents did not reverse the associated DNA damage. These findings provide a new direction for future investigations by our research group, including exploring the treatment of RIHD-related DNA damage.}, } @article {pmid39262205, year = {2024}, author = {González-Guzmán, D and Andrade-Castellanos, CA and Ponce-Gallegos, MA and Mesina-Estarrón, I and Mora-Almanza, JG and Ruelas-Moreno, HE and Rodríguez-González, D and Eguia-Ortega, O and Colunga-Lozano, LE}, title = {N-acetyl-cysteine in Intensive Care Unit Patients with Acute Respiratory Distress Syndrome due to COVID-19: A Retrospective Cohort Study.}, journal = {Journal of intensive care medicine}, volume = {}, number = {}, pages = {8850666241281281}, doi = {10.1177/08850666241281281}, pmid = {39262205}, issn = {1525-1489}, abstract = {PURPOSE: We assessed the potential association between N-acetyl-cysteine (NAC) and clinical outcomes in critically ill subjects with COVID-19-related ARDS.

MATERIAL AND METHODS: We included subjects with confirmed COVID-19 who were admitted to our ICU between March 1, 2020, and January 31, 2021, due to ARDS and necessitating invasive mechanical ventilation (IMV). Subjects who received standard of care (SOC) were compared with subjects who additionally received NAC 600 mg bid orally.

RESULTS: A total of 243 subjects were included in this study. The results indicate significantly improved survival rates in the NAC plus SOC group, both in the unadjusted analysis and after adjusting for confounding factors such as ARDS severity (HR 0.48, 95% CI 0.32-0.70).

CONCLUSIONS: We found that oral administration of NAC was associated with reduced mortality in critically ill patients with COVID-19 related ARDS.}, } @article {pmid39260547, year = {2024}, author = {Das, S and Mukherjee, U and Biswas, S and Banerjee, S and Karmakar, S and Maitra, S}, title = {Unravelling bisphenol A-induced hepatotoxicity: Insights into oxidative stress, inflammation, and energy dysregulation.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {362}, number = {}, pages = {124922}, doi = {10.1016/j.envpol.2024.124922}, pmid = {39260547}, issn = {1873-6424}, mesh = {Animals ; *Phenols/toxicity ; *Benzhydryl Compounds/toxicity ; Mice ; Male ; *Oxidative Stress/drug effects ; *Inflammation/chemically induced/metabolism ; Endocrine Disruptors/toxicity ; Reactive Oxygen Species/metabolism ; Liver/metabolism/drug effects ; NF-kappa B/metabolism ; Inflammasomes/metabolism ; Chemical and Drug Induced Liver Injury/metabolism ; Energy Metabolism/drug effects ; }, abstract = {Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1β, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1β) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.}, } @article {pmid39258904, year = {2024}, author = {Chae, IG and Jung, J and Kim, DH and Choi, JS and Chun, KS}, title = {EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells.}, journal = {Free radical research}, volume = {58}, number = {10}, pages = {596-605}, doi = {10.1080/10715762.2024.2396909}, pmid = {39258904}, issn = {1029-2470}, mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Colorectal Neoplasms/metabolism/drug therapy/pathology ; *Receptors, Prostaglandin E, EP4 Subtype/agonists/metabolism ; *HSP90 Heat-Shock Proteins/metabolism ; Mice ; Animals ; Up-Regulation/drug effects ; HCT116 Cells ; Mice, Nude ; }, abstract = {Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and β isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.}, } @article {pmid39257692, year = {2024}, author = {De Felice, M and Szkudlarek, HJ and Uzuneser, TC and Rodríguez-Ruiz, M and Sarikahya, MH and Pusparajah, M and Galindo Lazo, JP and Whitehead, SN and Yeung, KK and Rushlow, WJ and Laviolette, SR}, title = {The Impacts of Adolescent Cannabinoid Exposure on Striatal Anxiety- and Depressive-Like Pathophysiology Are Prevented by the Antioxidant N-Acetylcysteine.}, journal = {Biological psychiatry global open science}, volume = {4}, number = {6}, pages = {100361}, pmid = {39257692}, issn = {2667-1743}, abstract = {BACKGROUND: Exposure to Δ[9]-tetrahydrocannabinol (THC) is an established risk factor for later-life neuropsychiatric vulnerability, including mood- and anxiety-related symptoms. The psychotropic effects of THC on affect and anxiogenic behavioral phenomena are known to target the striatal network, particularly the nucleus accumbens, a neural region linked to mood and anxiety disorder pathophysiology. THC may increase neuroinflammatory responses via the redox system and dysregulate inhibitory and excitatory neural balance in various brain circuits, including the striatum. Thus, interventions that can induce antioxidant effects may counteract the neurodevelopmental impacts of THC exposure.

METHODS: In the current study, we used an established preclinical adolescent rat model to examine the impacts of adolescent THC exposure on various behavioral, molecular, and neuronal biomarkers associated with increased mood and anxiety disorder vulnerability. Moreover, we investigated the protective properties of the antioxidant N-acetylcysteine against THC-related pathology.

RESULTS: We demonstrated that adolescent THC exposure induced long-lasting anxiety- and depressive-like phenotypes concomitant with differential neuronal and molecular abnormalities in the two subregions of the nucleus accumbens, the shell and the core. In addition, we report for the first time that N-acetylcysteine can prevent THC-induced accumbal pathophysiology and associated behavioral abnormalities.

CONCLUSIONS: The preventive effects of this antioxidant intervention highlight the critical role of redox mechanisms underlying cannabinoid-induced neurodevelopmental pathology and identify a potential intervention strategy for the prevention and/or reversal of these pathophysiological sequelae.}, } @article {pmid39251120, year = {2024}, author = {Wood, JPM and Chidlow, G and Wall, GM and Casson, RJ}, title = {N-acetylcysteine amide and di- N-acetylcysteine amide protect retinal cells in culture via an antioxidant action.}, journal = {Experimental eye research}, volume = {248}, number = {}, pages = {110074}, doi = {10.1016/j.exer.2024.110074}, pmid = {39251120}, issn = {1096-0007}, mesh = {Animals ; *Acetylcysteine/pharmacology/analogs & derivatives ; Rats ; *Oxidative Stress/drug effects ; Cells, Cultured ; *Retinal Ganglion Cells/drug effects/metabolism ; *Antioxidants/pharmacology ; *Reactive Oxygen Species/metabolism ; Glutathione/metabolism ; Cell Survival/drug effects ; Neuroglia/drug effects/metabolism ; Retina/drug effects/metabolism ; Dose-Response Relationship, Drug ; }, abstract = {Reactive oxygen species (ROS) play a significant role in toxicity to the retina in a variety of diseases. N-acetylcysteine (NAC), N-acetylcysteine amide (NACA) and the dimeric di-N-acetylcysteine amide (diNACA) were evaluated in terms of protecting retinal cells, in vitro, in a variety of stress models. Three types of rat retinal cell cultures were utilized in the study: macroglial-only cell cultures, neuron-only retinal ganglion cell (RGC) cultures, and mixed cultures containing retinal glia and neurons. Ability of test agents to attenuate oxidative stress in all cultures was ascertained. In addition, capability of agents to protect against a variety of alternate clinically-relevant stressors, including excitotoxins and mitochondrial electron transport chain inhibitors, was also evaluated. Capacity of test agents to elevate cellular levels of reduced glutathione under normal and compromised conditions was also determined. NAC, NACA and diNACA demonstrated concentration-dependent cytoprotection against oxidative stress in all cultures. These three compounds, however, had differing effects against a variety of alternate insults to retinal cells. The most protective agent was NACA, which was most potent against the most stressors (including oxidative stress, mitochondrial impairment by antimycin A and azide, and glutamate-induced excitotoxicity). Similar to NAC, NACA increased glutathione levels in non-injured cells, although diNACA did not, suggesting a different, unknown mechanism of antioxidant activity for the latter. In support of this, diNACA was the only agent to attenuate rotenone-induced toxicity in mitochondria. NAC, NACA and diNACA exhibited varying degrees of antioxidant activity, i.e., protected cultured rat retinal cells from a variety of stressors which were designed to mimic aspects of the pathology of different retinal diseases. A general rank order of activity was observed: NACA ≥ diNACA > NAC. These results warrant further exploration of NACA and diNACA as antioxidant therapeutics for the treatment of retinal diseases, particularly those involving oxidative stress. Furthermore, we have defined the battery of tests carried out as the "Wood, Chidlow, Wall and Casson (WCWC) Retinal Antioxidant Indices"; we believe that these are of great value for screening molecules for potential to reduce retinal oxidative stress in a range of retinal diseases.}, } @article {pmid39251036, year = {2024}, author = {Moyano, P and Flores, A and San Juan, J and García, J and Anadón, MJ and Plaza, JC and Naval, MV and Fernández, MC and Guerra-Menéndez, L and Del Pino, J}, title = {Imidacloprid unique and repeated treatment produces cholinergic transmission disruption and apoptotic cell death in SN56 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {193}, number = {}, pages = {114988}, doi = {10.1016/j.fct.2024.114988}, pmid = {39251036}, issn = {1873-6351}, mesh = {Animals ; *Apoptosis/drug effects ; *Acetylcholinesterase/metabolism ; *Neonicotinoids/toxicity ; *tau Proteins/metabolism/genetics ; Mice ; NF-E2-Related Factor 2/metabolism/genetics ; Synaptic Transmission/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism/genetics ; Insecticides/toxicity ; Reactive Oxygen Species/metabolism ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Cholinergic Neurons/drug effects/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Oxidative Stress/drug effects ; Cell Line ; Proteasome Endopeptidase Complex/metabolism/drug effects ; Amyloid Precursor Protein Secretases/metabolism/genetics ; Aspartic Acid Endopeptidases/metabolism/genetics ; Nitro Compounds ; }, abstract = {Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), β-amyloid-precursor-protein (βAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3β), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 μM-800 μM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aβ and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aβ and Tau accumulation through BACE1, GSK3β, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.}, } @article {pmid39248027, year = {2024}, author = {Thakkar, Y and Kobets, T and Api, AM and Duan, JD and Williams, GM}, title = {Assessment of genotoxic potential of fragrance materials in the chicken egg assays.}, journal = {Environmental and molecular mutagenesis}, volume = {65}, number = {8}, pages = {261-274}, doi = {10.1002/em.22627}, pmid = {39248027}, issn = {1098-2280}, mesh = {Animals ; *Chickens ; *Micronucleus Tests/methods ; *Mutagenicity Tests/methods ; *DNA Damage/drug effects ; *Perfume/toxicity ; Mutagens/toxicity ; Aldehydes/toxicity ; Ovum/drug effects ; Acrolein/toxicity/analogs & derivatives ; }, abstract = {The genotoxic and clastogenic/aneugeneic potentials of four α,β-unsaturated aldehydes, 2-phenyl-2-butenal, nona-2-trans-6-cis-dienal, 2-methyl-2-pentenal, and p-methoxy cinnamaldehyde, which are used as fragrance materials, were assessed using the Chicken Egg Genotoxicity Assay (CEGA) and the Hen's egg micronucleus (HET-MN) assay, respectively. Selection of materials was based on their chemical structures and the results of their previous assessment in the regulatory in vitro and/or in vivo genotoxicity test battery. Three tested materials, 2-phenyl-2-butenal, nona-2-trans-6-cis-dienal, and 2-methyl-2-pentenal, were negative in both, CEGA and HET-MN assays. These findings were congruent with the results of regulatory in vivo genotoxicity assays. In contrast, p-methoxy cinnamaldehyde, which was also negative in the in vivo genotoxicity assays, produced evidence of DNA damage, including DNA strand breaks and DNA adducts in CEGA. However, no increase in the micronucleus formation in blood was reported in the HET-MN study. Such variation in responses between the CEGA and HET-MN assay can be attributed to differences in the dosing protocols. Pretreatment with a glutathione precursor, N-acetyl cysteine, negated positive outcomes produced by p-methoxy cinnamaldehyde in CEGA, indicating that difference in response observed in the chicken egg and rodent models can be attributed to rapid glutathione depletion. Overall, our findings support the conclusion that CEGA and/or HET-MN can be considered as a potential alternative to animal testing as follow-up strategies for assessment of genotoxic potential of fragrance materials with evidence of genotoxicity in vitro.}, } @article {pmid39246710, year = {2024}, author = {Abolfazli, S and Foroumand, S and Mohammadi, E and Ahangar, N and Kheirandish, A and Fathi, H and Mohammadi, H}, title = {Brain mitochondrial damage attenuation by quercetin and N-acetyl cysteine: peripheral and central antiemetic effects.}, journal = {Toxicology research}, volume = {13}, number = {5}, pages = {tfae139}, pmid = {39246710}, issn = {2045-452X}, abstract = {Nausea serves as a protective mechanism in organisms to prevent excessive consumption of toxic substances. Due to the adverse effects of chemical anti-nausea drugs, there is a growing interest in using herbal remedies and natural antioxidants. In this study, we evaluated the neuroprotective effects of quercetin (QU) and N-acetylcysteine (NAC) against oxidative damage induced by nausea. Emesis was induced in chickens using ipecac and copper sulfate (600 and 60 mg/kg, orally, respectively). QU and NAC (with doses of 50, 100, 200 mg/kg), and their combination were administered, along with a standard therapy (metoclopramide; MET 2 mg/kg) for one-time. Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC), glutathione level (GSH), and reactive oxygen species (ROS) as oxidative damage biomarkers were evaluated in the chicken's brain mitochondria. QU and NAC significantly reduced emesis induced by copper sulfate and ipecac compared to the control group (P < 0.001). Significant differences in oxidative damage were observed in the groups received of copper sulfate and ipecac compared with control group. Levels of LPO, ROS, and PC were significantly decreased after the administration of QU and NAC in emesis induced by copper sulfate and ipecac. While, mitochondrial function and GSH levels were increased after the administration of QU and NAC. Combination therapy with QU and NAC yielded the most effective results. This study suggests that QU and NAC possess antiemetic effects through both peripheral and central mechanisms and exhibit neuroprotective effects against oxidative brain damage induced by emesis by increasing plasma antioxidants or scavenging free radicals.}, } @article {pmid39245438, year = {2024}, author = {Lee, TL and Shen, WC and Chen, YC and Lai, TC and Lin, SR and Lin, SW and Yu, IS and Yeh, YH and Li, TK and Lee, IT and Lee, CW and Chen, YL}, title = {Mir221- and Mir222-enriched adsc-exosomes mitigate PM exposure-exacerbated cardiac ischemia-reperfusion injury through the modulation of the BNIP3-MAP1LC3B-BBC3/PUMA pathway.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/15548627.2024.2395799}, pmid = {39245438}, issn = {1554-8635}, abstract = {Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Mir221 and Mir222. The present study investigated the effects of PM exposure on I/R-induced cardiac injury through mitophagy and apoptosis, as well as the potential role of Mir221 and Mir222 in ADSC-Exos. Wild-type, mir221- and mir222-knockout (KO), and Mir221- and Mir222-overexpressing transgenic (TG) mice were intratracheally injected with PM (10 mg/kg). After 24 h, mice underwent left coronary artery ligation for 30 min, followed by 3 h of reperfusion (I/R). H9c2 cardiomyocytes were cultured under 1% O2 for 6 h, then reoxygenated for 12 h (hypoxia-reoxygenation [H/R]). PM aggravated I/R (or H/R) cardiac injury by increasing ROS levels and causing mitochondrial dysfunction, which increased the expression of mitochondrial fission-related proteins (DNM1L/Drp1 and MFF) and mitophagy-related proteins (BNIP3 and MAP1LC3B/LC3B) in vivo and in vitro. Treatment with ADSC-Exos or Mir221- and Mir222-mimics significantly reduced PM+I/R-induced cardiac injury. Importantly, ADSC-Exos contain Mir221 and Mir222, which directly targets BNIP3, MAP1LC3B/LC3B, and BBC3/PUMA, decreasing their expression and ultimately reducing cardiomyocyte mitophagy and apoptosis. The present data showed that ADSC-Exos treatment regulated mitophagy and apoptosis through the Mir221 and Mir222-BNIP3-MAP1LC3B-BBC3/PUMA pathway and significantly reduced the cardiac damage caused by PM+I/R. The present study revealed the novel therapeutic potential of ADSC-Exos in alleviating PM-induced exacerbation of myocardial I/R injury.Abbreviation: ADSC-Exos: adipose-derived stem cell exosomes; AL: autolysosome; ATP: adenosine triphosphate; BBC3/PUMA: BCL2 binding component 3; BNIP3: BCL2/adenovirus E1B interacting protein 3; CASP3: caspase 3; CASP9: caspase 9; CDKN1B/p27: cyclin dependent kinase inhibitor 1B; CVD: cardiovascular disease; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DHE: dihydroethidium; DNM1L/Drp1: dynamin 1-like; EF: ejection fraction; FS: fractional shortening; H/R: hypoxia-reoxygenation; I/R: ischemia-reperfusion; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFF: mitochondrial fission factor; miRNA: microRNA; NAC: N-acetylcysteine; OCR: oxygen consumption rate; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PM: particulate matter; PRKAA1/AMPK: protein kinase AMP-activated catalytic subunit alpha 1; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TRP53/p53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.}, } @article {pmid39245103, year = {2024}, author = {Mondal, S and Hazra, A and Paul, P and Saha, B and Roy, S and Bhowmick, P and Bhowmick, M}, title = {Formulation and evaluation of n-acetyl cysteine loaded bi-polymeric physically crosslinked hydrogel with antibacterial and antioxidant activity for diabetic wound dressing.}, journal = {International journal of biological macromolecules}, volume = {279}, number = {Pt 4}, pages = {135418}, doi = {10.1016/j.ijbiomac.2024.135418}, pmid = {39245103}, issn = {1879-0003}, mesh = {*Acetylcysteine/pharmacology/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Wound Healing/drug effects ; *Antioxidants/pharmacology/chemistry ; *Hydrogels/chemistry/pharmacology ; *Bandages ; Animals ; Humans ; Alginates/chemistry ; Microbial Sensitivity Tests ; Candida albicans/drug effects ; Drug Liberation ; Plant Gums/chemistry ; Escherichia coli/drug effects ; Rats ; Drug Compounding ; Mannans/chemistry/pharmacology ; }, abstract = {Diabetic wounds have become a serious global health concern, with a growing number of patients each year. Diabetic altered wound healing physiology, as well as resulting complications, make therapy difficult. Hence, diabetic wound healing necessitates a multidisciplinary strategy. This study focused on the formulation, statistical optimization, ex vivo, and in vitro evaluation of a diabetic wound healing by n-acetyl cysteine (NAC) loaded hydrogel. The objective of the study is to formulate n-acetyl loaded hydrogel with different ratio (1:1, 1:2, 1:3, 2:1) of sodium alginate and guar gum. The antibacterial and antifungal assessment against the viability of Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), and Staphylococcus aureus (S.aureus) and Candida albicans (C. albicans) was conducted after determining the in vitro drug release profile. The results of the experiment demonstrated that the formulation F3 was an optimal formulation on triplicate measurement with a pH of 6.2 ± 0.168, and a density of 1.026 ± 0.21. In vitro cell line study exhibited F3 has potential role in cell adhesion and proliferation might be beneficial to tissue regeneration and wound healing. The results imply that F3 may be helpful for the quick healing of diabetic wounds by promoting angiogenesis and also by scavenging free oxygen radicals.}, } @article {pmid39239906, year = {2024}, author = {Guo, J and Xu, Q and Zhong, Y and Su, Y}, title = {N-acetylcysteine promotes doxycycline resistance in the bacterial pathogen Edwardsiella tarda.}, journal = {Virulence}, volume = {15}, number = {1}, pages = {2399983}, pmid = {39239906}, issn = {2150-5608}, mesh = {*Edwardsiella tarda/drug effects/genetics ; *Doxycycline/pharmacology ; *Anti-Bacterial Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Drug Resistance, Bacterial ; Reactive Oxygen Species/metabolism ; Enterobacteriaceae Infections/microbiology/drug therapy ; Animals ; Glutathione/metabolism ; Proteomics ; Bacterial Proteins/genetics/metabolism ; Humans ; Microbial Sensitivity Tests ; }, abstract = {Bacterial resistance poses a significant threat to both human and animal health. N-acetylcysteine (NAC), which is used as an anti-inflammatory, has been shown to have distinct and contrasting impacts on bacterial resistance. However, the precise mechanism underlying the relationship between NAC and bacterial resistance remains unclear and requires further investigation. In this study, we study the effect of NAC on bacterial resistance and the underlying mechanisms. Specifically, we examine the effects of NAC on Edwardsiella tarda ATCC15947, a pathogen that exhibits resistance to many antibiotics. We find that NAC can promote resistance of E. tarda to many antibiotics, such as doxycycline, resulting in an increase in the bacterial survival rate. Through proteomic analysis, we demonstrate that NAC activates the amino acid metabolism pathway in E. tarda, leading to elevated intracellular glutathione (GSH) levels and reduced reactive oxygen species (ROS). Additionally, NAC reduces antibiotic influx while enhancing efflux, thus maintaining low intracellular antibiotic concentrations. We also propose that NAC promotes protein aggregation, thus contributing to antibiotic resistance. Our study describes the mechanism underlying E. tarda resistance to doxycycline and cautions against the indiscriminate use of metabolite adjuvants.}, } @article {pmid39232832, year = {2024}, author = {Duan, H and Wang, F and Wang, K and Yang, S and Zhang, R and Xue, C and Zhang, L and Ma, X and Du, X and Kang, J and Zhang, Y and Zhao, X and Hu, J and Xiao, L}, title = {Quercetin ameliorates oxidative stress-induced apoptosis of granulosa cells in dairy cow follicular cysts by activating autophagy via the SIRT1/ROS/AMPK signaling pathway.}, journal = {Journal of animal science and biotechnology}, volume = {15}, number = {1}, pages = {119}, pmid = {39232832}, issn = {1674-9782}, abstract = {BACKGROUND: Follicular cysts contribute significantly to reproductive loss in high-yield dairy cows. This results from the death of follicular granulosa cells (GCs) caused by oxidative stress. Quercetin is known to have significant antioxidant and anti-apoptotic effects. However, the effect of quercetin on follicular cysts has yet been elucidated. Therefore, this study aimed to explore the anti-oxidant and anti-apoptosis effects and potential molecular mechanisms of quercetin in H2O2-induced primary cow GCs and 3-nitropropionic acid (3-NPA)-induced mouse model of oxidative stress and thus treat ovarian cysts in dairy cows.

RESULTS: In this study, compared with estrus cows, cows with follicular cysts showed heightened levels of oxidative stress and increased follicular cell apoptosis, while autophagy levels were reduced. A model of oxidative stress was induced in vitro by H2O2 and showed significant increases in apoptosis together with reduced autophagy. These effects were significantly ameliorated by quercetin. Effects similar to those of quercetin were observed after treatment of cells with the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC). Further investigations using chloroquine (autophagy inhibitor), rapamycin (autophagy activator), selisistat (SIRT1 inhibitor), and compound C (AMPK inhibitor) showed that chloroquine counteracted the effects of quercetin on oxidative stress-induced apoptosis, while rapamycin had the same effect as quercetin. In addition, the SIRT1/AMPK pathway inhibitors antagonized quercetin-mediated mitigation of the effects of oxidative stress on increased apoptosis and reduced autophagy. Consistent with the results in vitro, in mouse ovarian oxidative stress model induced by 3-NPA, quercetin activated autophagy through the SIRT1/AMPK signaling pathway, while alleviating oxidative stress damage and inhibiting apoptosis in mouse ovaries.

CONCLUSIONS: These findings indicate that quercetin can inhibit apoptosis in GCs and restore ovarian function by activating autophagy through the SIRT1/ROS/AMPK signaling pathway, suggesting a new direction for the treatment of ovarian follicular cysts in high-yield dairy cows.}, } @article {pmid39225404, year = {2025}, author = {Chinnapaka, S and Bakthavachalam, V and Dasari, S and Kannan, J and Sapkota, S and Kumar, R and Munirathinam, G}, title = {Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells.}, journal = {BioFactors (Oxford, England)}, volume = {51}, number = {1}, pages = {e2117}, doi = {10.1002/biof.2117}, pmid = {39225404}, issn = {1872-8081}, mesh = {Humans ; Male ; *Apoptosis/drug effects ; Black or African American/genetics ; Cell Line, Tumor ; *Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; *Prostatic Neoplasms/pathology/drug therapy/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Receptors, Androgen/metabolism/genetics ; *Signal Transduction/drug effects ; Thioredoxin Reductase 2/metabolism/genetics ; *Vitamin K 3/pharmacology ; }, abstract = {Prostate cancer (PCa) is the second critical cause of cancer-related deaths, with African Americans dying at higher rates in the U.S. The main reasons for the higher mortality rate are ethnic differences and lack of understanding of prostate cancer biology and affordable treatments, as well as the financial burden of African American men to obtain the most effective and safe treatments. The effect of micronutrients, including Vitamin K, on various cancer cell lines has been widely studied, but the potential anticancer effect of VK3-OCH3, an analog of vitamin K3 (Menadione), on African American prostate cancer has not been evaluated. In this study, we compared the anticancer effect of VK3-OCH3 on targeting African American derived PCa cell lines namely RC77-T and MDA-PCa-2b. Our results show that VK3-OCH3 significantly inhibits the proliferation of both RC77-T and MDA-PCa-2b African American PCa cells and promotes apoptosis, and the underlying mechanism of cell death appears to be similar in both the cell lines. Notably, VK3-OCH3 inhibits colony-forming ability and induces apoptosis by blocking the cell cycle at G0 in African American PCa cells. VK3-OCH3 also acts as an anti-metastatic agent by inhibiting the migration ability of the metastatic properties of African American PCa cells. The cell death of African American PCa cells mediated by VK3-OCH3 is associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS). Interestingly, antioxidants such as N-Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3-OCH3 on PCa cell lines derived from African American patients. Of note, VK3-OCH3 reduces androgen receptor and prostate-specific antigen expression in these PCa cells. Furthermore, molecular dynamic studies reiterated that VK3-OCH3 strongly binds to the androgen receptor, suggesting that the androgen receptor is the potential molecular target of VK3-OCH3. In addition, Western blot analysis showed that VK3-OCH3 reduces the expression of androgen receptor, TRX2, and anti-apoptotic signaling molecules such as Bcl-2 and TCTP in the MDA-PCa-2b metastatic PCa cellular model. In conclusion, our results suggested that VK3-OCH3 is a promising anticancer agent that could potentially reduce the mortality rates of African American PCa patients, warranting further preclinical and translational studies.}, } @article {pmid39223526, year = {2024}, author = {Rhee, CK and Lim, SY and Lee, WY and Jung, JY and Park, YB and Lee, CY and Hwang, YI and Song, JW and Choi, WI and Yoo, KH and Kim, KU and Kim, YI and Kim, TH and Park, SJ and Shin, KC and Um, SJ and Yoon, HK and Lee, HS and Kim, DK and Leem, AY and , }, title = {The effect of nebulized N-acetylcysteine on the phlegm of chronic obstructive pulmonary disease: the NEWEST study.}, journal = {BMC pulmonary medicine}, volume = {24}, number = {1}, pages = {434}, pmid = {39223526}, issn = {1471-2466}, mesh = {Humans ; *Acetylcysteine/administration & dosage ; *Pulmonary Disease, Chronic Obstructive/drug therapy/physiopathology ; Male ; Female ; Aged ; Prospective Studies ; *Nebulizers and Vaporizers ; Middle Aged ; Forced Expiratory Volume/drug effects ; Administration, Inhalation ; Vital Capacity/drug effects ; Expectorants/administration & dosage/adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND: Phlegm is prevalent symptom in patients with chronic obstructive pulmonary disease (COPD). Few studies have investigated the effectiveness of N-acetylcysteine (NAC) nebulizer therapy in COPD patients. We evaluated the effect of nebulized NAC on the improvement of phlegm symptom in COPD patients.

METHODS: This was a 12-week, prospective, single-arm, open-label, phase IV multi-center trial (NCT05102305, Registration Date: 20-October-2021). We enrolled patients aged ≥ 40 years with post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC) < 0.7 and COPD assessment test (CAT) phlegm score ≥ 2; the patients were current or ex-smoker with smoking pack-years ≥ 10. The primary endpoint was to determine the change in CAT phlegm score at 12 weeks compared to the baseline. Patients were assessed at baseline, 4, 8, and 12 weeks of treatment using the CAT score.

RESULTS: In total, 100 COPD patients were enrolled from 10 hospitals. The mean age of the patients was 71.42 ± 8.20 years, with 19.78% being current-smokers and 80.22% being ex-smokers. The mean smoking pack-years was 40.32 ± 35.18. The mean FVC, FEV1, and FEV1/FVC were 3.94 L (75.44%), 2.22 L (58.50%), and 0.53, respectively. The CAT phlegm score at baseline was 3.47 ± 1.06, whereas after 12 weeks of nebulized NAC it significantly decreased to 2.62 ± 1.30 (p < 0.01). More than half (53.5%) of the patients expressed satisfaction with the effects of nebulized NAC therapy. Adverse events occurred in 8 (8.0%) patients. Notably, no serious adverse drug reactions were reported.

CONCLUSION: In this study, we have established the effectiveness and safety of nebulized NAC over 12 weeks.}, } @article {pmid39214451, year = {2024}, author = {Kim, JE and Lee, DS and Wang, SH and Kim, TH and Kang, TC}, title = {GPx1-ERK1/2-CREB pathway regulates the distinct vulnerability of hippocampal neurons to oxidative stress via modulating mitochondrial dynamics following status epilepticus.}, journal = {Neuropharmacology}, volume = {260}, number = {}, pages = {110135}, doi = {10.1016/j.neuropharm.2024.110135}, pmid = {39214451}, issn = {1873-7064}, mesh = {Animals ; *Oxidative Stress/drug effects/physiology ; Male ; *Neurons/metabolism/drug effects ; *Glutathione Peroxidase/metabolism ; *Glutathione Peroxidase GPX1 ; *Hippocampus/metabolism/drug effects/pathology ; *Mitochondrial Dynamics/drug effects/physiology ; *Status Epilepticus/chemically induced/metabolism/pathology ; *Cyclic AMP Response Element-Binding Protein/metabolism ; Rats ; *MAP Kinase Signaling System/drug effects/physiology ; *Rats, Sprague-Dawley ; }, abstract = {Glutathione peroxidase-1 (GPx1) and cAMP/Ca[2+] responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics.}, } @article {pmid39208656, year = {2024}, author = {Xue, A and Zhang, H and Song, S and Yu, X}, title = {Effects of N-Acetylcysteine combined with Ambroxol Hydrochloride on clinical symptoms, CRP, and PCT in children with pneumonia.}, journal = {Clinics (Sao Paulo, Brazil)}, volume = {79}, number = {}, pages = {100476}, pmid = {39208656}, issn = {1980-5322}, mesh = {Humans ; *Ambroxol/therapeutic use/administration & dosage ; *C-Reactive Protein/analysis ; *Acetylcysteine/therapeutic use ; Female ; Male ; *Procalcitonin/blood ; Child, Preschool ; *Expectorants/therapeutic use/adverse effects ; *Drug Therapy, Combination ; *Pneumonia/drug therapy ; Child ; Treatment Outcome ; Infant ; Blood Gas Analysis ; }, abstract = {OBJECTIVE: This study investigated the effects of N-Acetylcysteine (NAC) combined with Ambroxol Hydrochloride (AH) on clinical symptoms, C-Reactive Protein (CRP), and Procalcitonin (PCT) levels in children with pneumonia.

METHODS: A total of 98 children with pneumonia were assigned to the control group and observation group by random number table method. NAC was administered to the observation group and AH was given to the control group. The therapeutic effect was observed, the disappearance time of clinical symptoms and levels of inflammatory factors, lung function parameters, blood gas analysis parameters, and immunoglobulin were measured. The incidence of adverse reactions was statistically analyzed.

RESULTS: A higher effective rate was observed in the observation group than in the control group (p < 0.05). Antipyretic time, cough disappearance time, and lung rale disappearance time in the observation group were shorter than those in the control group (p < 0.05). After treatment, CRP and PCT were lower (p < 0.05), FVC, FEV1, and FEV1/FVC were higher, PaCO2 was lower, PaO2 and SaO2 were higher, and IgA, IgG, IgM, and C3 were higher in the observation group than those in the control group (p < 0.05). The incidence of adverse reactions between the two groups was not significantly different (p > 0.05).

CONCLUSION: NAC combined with AH is effective in the treatment of pediatric pneumonia by effectively alleviating clinical symptoms, reducing inflammatory factors, and improving lung function and immune function.}, } @article {pmid39208572, year = {2024}, author = {Chen, C and Chen, Y and Zhai, H and Xiao, Y and Xu, J and Gu, Y and Han, X and Wang, C and Chen, Q and Lu, H}, title = {Cadmium exposure induces skeletal muscle insulin resistance through the reactive oxygen species-mediated PINK1/Parkin pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {284}, number = {}, pages = {116954}, doi = {10.1016/j.ecoenv.2024.116954}, pmid = {39208572}, issn = {1090-2414}, mesh = {Animals ; Male ; Rats ; *Cadmium/toxicity ; *Insulin Resistance ; Mitophagy/drug effects ; Muscle Fibers, Skeletal/drug effects/pathology ; *Muscle, Skeletal/drug effects ; Oxidative Stress/drug effects ; Protein Kinases/metabolism ; Rats, Sprague-Dawley ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Epidemiological studies have suggested a positive association between environmental cadmium (Cd) exposure and type 2 diabetes mellitus (T2DM). Skeletal muscle insulin resistance (IR) plays a critical role in the pathogenesis of T2DM. This study aimed to investigate the effects of chronic low-level Cd exposure on skeletal muscle IR and its potential mechanism. Rats were exposed to drinking water containing 2 or 10 mg/L Cd for 24 weeks. Differentiated L6 myotubes were treated with Cd for 72 h. Immunofluorescence, flow cytometry assay, RNA-sequencing, and Seahorse analysis were conducted to determine the effects of Cd and its underlying mechanism on relevant parameters, including insulin sensitivity, glucose uptake, oxidative stress, mitophagy, and mitochondrial function in skeletal muscle and L6 myotubes. N-acetyl-cysteine (NAC), a scavenger of reactive oxygen species (ROS), and mitophagy inhibitor Cyclosporin A (CsA) were used to confirm the role of oxidative stress in mitophagy and mitochondrial dysfunction caused by Cd. We found that rats exposed to 10 mg/L Cd exhibited hyperglycemia and skeletal muscle IR. Cd markedly increased IRS-1 phosphorylation at Ser612, while decreased levels of phosphorylated PI3K, Akt, AS160, inhibited GLUT4 translocation and glucose uptake. Mechanistically, Cd increased the intracellular ROS, hydrogen peroxide, and malondialdehyde levels and decreased antioxidase activity in L6 myotubes. Furthermore, Cd upregulated the mRNA and protein levels of LC3II/I, PINK1, and Parkin. In addition, Cd induced the formation of mitophagosomes, reduced the mitochondrial membrane potential, decreased the adenosine triphosphate content, and impaired the mitochondrial respiratory capacity. Strikingly, NAC ameliorated oxidative stress, excessive mitophagy, and the associated reduction in myotube insulin sensitivity, while inhibition of mitophagy by CsA alleviated skeletal muscle IR. In conclusion, this study reveals a previously unrecognized mechanism that chronic low-level Cd exposure may induce mitophagy by activating the PINK1/Parkin signal pathway by increasing ROS, thus causing skeletal muscle IR and elevated blood glucose.}, } @article {pmid39204746, year = {2024}, author = {Carlucci, V and Ponticelli, M and Russo, D and Labanca, F and Costantino, V and Esposito, G and Milella, L}, title = {Nutraceutical Valorization of Exhausted Olive Pomace from Olea europaea L. Using Advanced Extraction Techniques.}, journal = {Plants (Basel, Switzerland)}, volume = {13}, number = {16}, pages = {}, pmid = {39204746}, issn = {2223-7747}, support = {CUP: G49J19001350004//Regione Basilicata/ ; CUP: C31G18000210002//Regione Basilicata/ ; }, abstract = {Exhausted olive pomace (EOP) represents the principal residue of olive pomace. Several studies have optimized the extraction of specialized metabolites from the EOP of Olea europaea L., but a comparison between different extractive methods has not been made. For this reason, the present investigation aims to compare four different extractive methods by using water and 15% ethanol/water as extractive solvents. Specifically, based on extract antioxidant activity, the methods compared were maceration (MAC), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), and Accelerated Solvent Extraction (ASE). Between these, the UAE and ASE hydroalcoholic EOP extracts were demonstrated to have the highest antioxidant activity. Subsequently, these extracts were investigated for their hypoglycemic and antiradical activity using in vitro cell-free and cell-based assays, respectively. ASE hydroalcoholic EOP extract demonstrated the greatest ability to inhibit the α-amylase enzyme and an in vitro antioxidant activity comparable to N-acetyl cysteine in HepG2 cells. UAE and ASE extracts' phytochemical characterization was also performed, identifying seven phenolic compounds, including 3-hydroxytyrosol, tyrosol, and, for the first time, salidroside. The ASE hydroalcoholic EOP extract was the richest from a phytochemical point of view, thus confirming its major biological activity. Therefore, ASE and 15% ethanol/water may represent the best extractive method for EOP nutraceutical valorization.}, } @article {pmid39196852, year = {2024}, author = {Zhao, Q and Hu, Z and Wang, A and Ding, Z and Zhao, G and Wang, X and Li, W and Peng, Y and Zheng, J}, title = {Correlation of Vanillin-Induced Cytotoxicity with CYP3A-Mediated Metabolic Activation.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {36}, pages = {20064-20076}, doi = {10.1021/acs.jafc.4c03060}, pmid = {39196852}, issn = {1520-5118}, mesh = {Animals ; *Benzaldehydes/metabolism/pharmacology ; *Hepatocytes/metabolism/drug effects ; Rats ; Male ; *Cytochrome P-450 CYP3A/metabolism/genetics ; *Microsomes, Liver/metabolism/drug effects ; *Rats, Sprague-Dawley ; *Activation, Metabolic ; Glutathione/metabolism ; Flavoring Agents/metabolism/chemistry/toxicity ; }, abstract = {Vanillin (VAN) is a common flavoring agent that can cause liver damage when ingested in large amounts. Nevertheless, the precise processes responsible for its toxicity remain obscure. The present research aimed to examine the metabolic activation of VAN and establish a potential correlation between its reactive metabolites and its cytotoxicity. In rat liver microsomes incubated with VAN, reduced glutathione/N-acetylcysteine (GSH/NAC), and nicotinamide adenine dinucleotide phosphate (NADPH), two conjugates formed from GSH and one conjugate derived from NAC were identified. We also discovered one GSH conjugate in both the bile obtained from rats and the rat primary hepatocytes that were subjected to VAN exposure. Additionally, the NAC conjugate exerted in the urine of VAN-treated rats was observed. These results indicate that a quinone intermediate was produced from VAN both in vitro and in vivo. Next, we identified CYP3A as the main enzyme that initiated the bioactive pathway of VAN. After the activity of CYP3A was selectively inhibited by ketoconazole (KTZ), the generation of the GSH conjugate declined in hepatocytes exposed to VAN. Furthermore, the vulnerability to VAN-induced toxicity was alleviated by KTZ in hepatocytes. Thus, we propose that the cytotoxicity of VAN may derive from metabolic activation triggered by CYP3A.}, } @article {pmid39195722, year = {2024}, author = {Wang, Z and Wang, Q and Gong, X}, title = {Unveiling the Mysteries of Contrast-Induced Acute Kidney Injury: New Horizons in Pathogenesis and Prevention.}, journal = {Toxics}, volume = {12}, number = {8}, pages = {}, pmid = {39195722}, issn = {2305-6304}, support = {No.82074387//National Natural Science Foundation of China/ ; No.81873280//National Natural Science Foundation of China/ ; No.20Y21902200//Shanghai Science and Technology Development Foundation/ ; }, abstract = {The utilization of contrast media (CM) in clinical diagnostic imaging and interventional procedures has escalated, leading to a gradual increase in the incidence of contrast-induced acute kidney injury (CI-AKI). Presently, the scarcity of effective pharmacological treatments for CI-AKI poses significant challenges to clinical management. Firstly, we explore the pathogenesis of CI-AKI in this review. Beyond renal medullary ischemia and hypoxia, oxidative stress, cellular apoptosis, and inflammation, emerging mechanisms such as ferroptosis, release of neutrophil extracellular traps (NETs), and nitrosative stress, which offer promising avenues for the management of CI-AKI, are identified. Secondly, a comprehensive strategy for the early prevention of CI-AKI is introduced. Investigating the risk factors associated with CI-AKI is essential for the timely identification of high-risk groups. Additionally, exploring early sensitive biomarkers is crucial for early diagnosis. A synergistic approach that combines these sensitive biomarkers, CI-AKI risk factors, and disease risk prediction models enhances both the accuracy and efficiency of early diagnostic processes. Finally, we explore recent pharmacological and non-pharmacological interventions for the management of Cl-AKI. Beyond the traditional focus on the antioxidant N-acetylcysteine (NAC), we look at active compounds from traditional Chinese medicine, including tetramethylpyrazine (TMP), salvianolic acid B (Sal B), as well as emerging preventive medications like N-acetylcysteine amide (NACA), alprostadil, and others, which all showed potential benefits in animal and clinical studies for CI-AKI prevention. Furthermore, innovative strategies such as calorie restriction (CR), enhanced external counterpulsation (EECP), and mesenchymal stem cell therapy are highlighted as providing fresh insights into Cl-AKI prevention and management.}, } @article {pmid39195687, year = {2024}, author = {Podobnik, B and Demšar, L and Šarc, L and Jerin, A and Osredkar, J and Trontelj, J and Roškar, R and Brvar, M}, title = {N-Acetylcysteine Ineffective in Alleviating Hangover from Binge Drinking: A Clinical Study.}, journal = {Toxics}, volume = {12}, number = {8}, pages = {}, pmid = {39195687}, issn = {2305-6304}, support = {P3-0019//Slovenian Research Agency grants/ ; 20200175//University Medical Centre Ljubljana/ ; }, abstract = {Alcohol hangover (veisalgia) is a fairly common phenomenon. The pathogenesis of veisalgia is not understood and treatment has not yet been established. Occasionally, students take N-acetylcysteine (NAC) before binge drinking to alleviate hangover. The aim of this study was to evaluate the effect of NAC on serum levels of electrolytes, enzymes, oxidative stress biomarkers and symptoms of veisalgia in binge drinking. In this randomized, double-blind, placebo-controlled study, healthy students were randomly assigned into two groups: one receiving NAC and the other receiving a placebo. Blood samples were taken before drinking, 30 min after a 1.5 h long drinking session, and the subsequent morning. Serum levels of electrolytes, urea, enzymes, ethanol, 8-Hydroxydeoxyguanosine (8-OHdG) and N-epsilon-hexanoyl-lysine were measured. The participants completed the Acute Hangover Severity Scale (AHSS) assessment based on symptoms, and 40 students (20 male), aged 23 ± 2 years, were included in the study. Their mean blood ethanol concentration was 1.4 g/kg. Serum sodium levels were increased after drinking, and urea decreased the following morning compared to their levels before drinking in both groups. Serum 8-OHdG levels were increased after drinking and remained elevated until the following morning, compared to the levels before drinking, in both groups. NAC had no effect on sodium, urea and 8-OHdG levels or the symptoms of veisalgia. In conclusion, binge drinking causes a transient increase in serum sodium and as a prolonged increase in oxidative marker 8-OHdG levels. NAC had no effect on the sodium and 8-OHdG levels.}, } @article {pmid39192169, year = {2024}, author = {Sun, C and Wang, Q and Li, P and Dong, R and Lei, Y and Hu, Y and Yan, Y and Song, G}, title = {The ROS Mediates MCUb in Mitochondria-Regulated Apoptosis of TM4 Cells Induced by Titanium Dioxide Nanoparticles.}, journal = {Biological trace element research}, volume = {}, number = {}, pages = {}, pmid = {39192169}, issn = {1559-0720}, support = {2023AB049//Corps Science and Technology Planning Project/ ; 2023AB049//Corps Science and Technology Planning Project/ ; 2023AB049//Corps Science and Technology Planning Project/ ; 2023AB049//Corps Science and Technology Planning Project/ ; 2023AB049//Corps Science and Technology Planning Project/ ; 2023AB049//Corps Science and Technology Planning Project/ ; 2023AB049//Corps Science and Technology Planning Project/ ; 2023AB049//Corps Science and Technology Planning Project/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 21966027, 81560536, and 32060125//National Natural Science Foundation of China/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; 2023CB008-18//Youth Science and Technology Innovation Talents Project of Xinjiang Production and Construction Corps/ ; }, abstract = {Titanium dioxide nanoparticles (TiO2 NPs) can cause mitochondrial apoptosis of TM4 cells associated with reactive oxygen species (ROS) accumulation and Ca[2+] overload, but the relations among these processes remain unclear. This study aimed to evaluate whether the accumulation of ROS caused by TiO2 NPs inhibits MCUb expression, leading to mitochondrial calcium overload and subsequent cell apoptosis through the mitochondrial pathway. TM4 cells were exposed to different concentrations of TiO2 NPs (0, 25, 50, 75, 100 μg/mL) for 24 h. We assessed cell viability, ROS level, MCUb and VDAC1 expression, mitochondrial and cytoplasmic Ca[2+] levels, mitochondrial membrane potential (MMP), apoptosis rate, and key proteins related to mitochondrial apoptosis (Bcl-2, Bax, Caspase 3, Caspase 9, p53 and Cyt c). Additionally, the effect of N-acetylcysteine (NAC) on MCUb expression, calcium homeostasis, and cell apoptosis was evaluated. Compared to control group, TiO2 NPs significantly increased ROS level, downregulated MCUb expression, elevated Ca[2+] levels in mitochondria and cytoplasm, and enhanced mitochondria-regulated apoptosis, starting from the 50 μg/mL TiO2 NPs group. However, NAC significantly increased MCUb expression, attenuated Ca[2+] levels in mitochondria and cytoplasm, and reduced mitochondria-related apoptosis. In conclusion, TiO2 NPs induced ROS accumulation, which inhibited the expression of MCUb. The decreased MCUb level led to Ca[2+] overload in mitochondria, causing TM4 cell apoptosis via the mitochondrial pathway. This research elucidates, for the first time, the role of MCUb and its relation with ROS in apoptosis of TM4 cells induced by TiO2 NPs, which supplementing the molecular mechanism of cell apoptosis caused by TiO2 NPs.}, } @article {pmid39189858, year = {2024}, author = {Wallis, RS and Sabi, I and Lalashowi, J and Bakuli, A and Mapamba, D and Olomi, W and Siyame, E and Ngaraguza, B and Chimbe, O and Charalambous, S and Rachow, A and Ivanova, O and Zurba, L and Myombe, B and Kunambi, R and Hoelscher, M and Ntinginya, N and Churchyard, G}, title = {Adjunctive N-Acetylcysteine and Lung Function in Pulmonary Tuberculosis.}, journal = {NEJM evidence}, volume = {3}, number = {9}, pages = {EVIDoa2300332}, doi = {10.1056/EVIDoa2300332}, pmid = {39189858}, issn = {2766-5526}, mesh = {Humans ; *Acetylcysteine/administration & dosage/therapeutic use ; Male ; *Tuberculosis, Pulmonary/drug therapy ; Female ; Adult ; Prospective Studies ; *Antitubercular Agents/therapeutic use/administration & dosage ; *Glutathione/blood ; Middle Aged ; Lung/drug effects/microbiology/physiopathology ; Sputum/microbiology ; Treatment Outcome ; Respiratory Function Tests ; Young Adult ; }, abstract = {BACKGROUND: Tuberculosis remains a global health concern, and half of cured patients have permanent lung injury. N-acetylcysteine (NAC) has shown beneficial antimicrobial, antioxidant, and immunomodulatory effects in preclinical tuberculosis models. We examined its effects on tuberculosis treatment outcomes.

METHODS: This prospective, randomized, controlled trial nested within the TB SEQUEL cohort study enrolled 140 adults with moderate or far-advanced tuberculosis. Participants were randomly assigned 1:1 to standard therapy with or without 1200 mg of oral NAC twice daily for days 1 to 112. Clinical evaluations, sputum culture, and spirometry were performed at specified intervals through day 168, after which participants returned to the TB SEQUEL cohort. The primary outcome was culture conversion. Secondary outcomes included whole-blood glutathione levels and lung function.

RESULTS: Participants were predominantly young, male, and human immunodeficiency virus 1-negative and had heavy sputum Mycobacterium tuberculosis (MTB) infection burdens. NAC increased glutathione levels (NAC × day interaction, 8.48; 95% confidence interval [CI], 1.93 to 15.02) but did not increase stable culture conversion (hazard ratio, 0.84; 95% CI, 0.59 to 1.20; P=0.33). NAC treatment was associated with improved recovery of lung function (NAC × month, 0.49 [95% CI, 0.02 to 0.95] and 0.42 [95% CI, -0.06 to 0.91] for forced vital capacity and forced expiratory volume in the first second, respectively, as percentages of predicted values). The effects of NAC on lung function were greatest in participants with severe baseline lung impairment and appeared to persist beyond the period of NAC administration. Rates of serious or grade 3 to 4 nonserious adverse events did not differ between the groups.

CONCLUSIONS: Despite increasing whole-blood glutathione levels, NAC did not affect eradication of MTB infection in adults with pulmonary tuberculosis that was moderate to far advanced. Secondary outcomes of lung function showed changes that merit further investigation. (Funded by TB SEQUEL grant 01KA1613 of the German Ministry for Education and Research, the Health Africa Project, and the German Center for Infection Research; ClinicalTrials.gov number, NCT03702738.).}, } @article {pmid39189572, year = {2024}, author = {Sarıtaş, TB and Ertürk, C and Büyükdoğan, H and Yıldırım, B and Gündüz, N and Selek, Ş}, title = {Effects of N-acetylcysteine on sciatic nerve healing: A histopathological, functional, and biochemical study of the rat sciatic nerve.}, journal = {Joint diseases and related surgery}, volume = {35}, number = {3}, pages = {618-627}, pmid = {39189572}, issn = {2687-4792}, mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Rats, Wistar ; Male ; *Sciatic Nerve/drug effects/pathology/injuries ; *Nerve Regeneration/drug effects ; Rats ; Antioxidants/pharmacology ; Disease Models, Animal ; Wound Healing/drug effects ; Peripheral Nerve Injuries/drug therapy/pathology ; Recovery of Function/drug effects ; }, abstract = {OBJECTIVES: This study aims to evaluate the histopathological, biochemical, and functional effects of N-acetylcysteine (NAC), which has antioxidant, anti-inflammatory, and cytoprotective activity, on nerve regeneration in rats with sciatic nerve crush (axonotmesis) injury.

MATERIALS AND METHODS: This study used 16 male Wistar rats, which were divided into treatment and control groups. A standard axonotmesis-type surgical injury was induced in the left sciatic nerves of all rats. The treatment group was given 300 mg/kg of intraperitoneal NAC once a day, whereas the control group received an equal volume of saline solution. After conducting gait analyses, the sciatic functional index (SFI) was used for functional assessment. After gait analysis, all animals were euthanized. Blood samples were examined biochemically. The left sciatic nerves and left triceps surae muscles were examined histopathologically.

RESULTS: Histopathologically, the thickness of the perineurium, axonal degeneration, axonolysis, edema, inflammation, muscle atrophy, and muscle degeneration were all significantly lower in the treatment group (p<0.05). Functionally, SFI-1, SFI-2, and SFI-3 were significantly higher in the treatment group (p<0.05). Biochemically, while the native thiol level and native thiol/total thiol ratio were significantly higher in the treatment group (p<0.003), the disulfide/total thiol ratio was significantly higher in the control group (p<0.005). Significant correlations were found between six of the seven gait parameters and the histopathological findings (p<0.05).

CONCLUSION: Our study results suggest that NAC may contribute positively to the histopathological and functional recovery of sciatic nerve injury in rats. Furthermore, NAC may have an antioxidant effect on thiol-disulfide homeostasis at a biochemical level. We believe that NAC has a stimulatory effect on healing following nerve injuries.}, } @article {pmid39189388, year = {2024}, author = {Adel, O and El-Sherbiny, HR and M Shahat, A and Ismail, ST}, title = {N-Acetylcysteine Supplementation Improves Testicular Haemodynamics, Testosterone Levels, Seminal Antioxidant Capacity and Semen Quality in Heat-Stressed Goat Bucks.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {59}, number = {8}, pages = {e14709}, doi = {10.1111/rda.14709}, pmid = {39189388}, issn = {1439-0531}, mesh = {Male ; Animals ; *Goats/physiology ; *Testis/drug effects ; *Testosterone/blood ; *Acetylcysteine/pharmacology/administration & dosage ; *Antioxidants/pharmacology ; *Semen Analysis/veterinary ; *Hemodynamics/drug effects ; *Dietary Supplements ; *Semen/drug effects ; Nitric Oxide/metabolism ; Hot Temperature ; }, abstract = {Heat stress (HS) disrupts testicular homeostasis because of oxidative stress. N-acetylcysteine (NAC) is a thiol compound with antioxidants, anti-inflammatory and anti-apoptotic properties. As a sequel, this research aimed to assess the ameliorative effects of NAC supplementation on the reproductive performance of goat bucks kept under environmental HS. Primarily, Doppler examination as well as semen collection and evaluation were conducted on 12 mature bucks for 2 weeks (W) as pre-heat stress control (W1 and W2) during winter (February 2023). The temperature-humidity index (THI) was 63.4-64.3 (winter season). Then during summer HS conditions (from the beginning of July till the end of August 2023) bucks were assessed before NAC supplementation (W0), afterwards they were arbitrarily assigned into two groups. The control group (CON; n = 6) received the basal diet while the NAC group (n = 6) received the basal diet in addition to oral NAC daily for 7 weeks (W1-W7). The THI was 78.1-81.6 (summer season). Testicular blood flow parameters, serum concentration of nitric oxide (NO) and testosterone were measured. Additionally, total antioxidant capacity (TAC) and malondialdehyde (MDA) content in seminal plasma and semen quality parameters were evaluated. There were marked reductions (p < 0.05) in the resistive index (RI; W1, W4 and W5), pulsatility index (PI; W2 and W4-W7), and systolic/diastolic ratio (S/D; W4-W7) in the NAC group compared to the CON group. Furthermore, testosterone and NO levels were higher (p < 0.01 and p < 0.05, respectively) in the NAC group (W2, W3, W5 and W3-W5, respectively). Seminal plasma TAC increased (p < 0.05) and MDA decreased (p < 0.05) in the NAC group (W2, W4 and W5) compared to the CON group. Moreover, there were marked improvements (p < 0.05) in semen quality parameters (mass motility, total motility, viability and normal morphology) in the NAC group. In conclusion, oral NAC supplementation could be used to enhance the reproductive performance of goat bucks during HS conditions which is supported by remarkable enhancement in testicular haemodynamics, NO, testosterone levels and semen quality parameters.}, } @article {pmid39182712, year = {2024}, author = {Jiang, P and Hu, S and Zheng, C and Liu, Y and Zhang, Q and Dou, L}, title = {Cryopreservation of human teeth using vitrification method with cryoprotectant cocktails and N-acetylcysteine for banking and clinical applications.}, journal = {Cryobiology}, volume = {117}, number = {}, pages = {104959}, doi = {10.1016/j.cryobiol.2024.104959}, pmid = {39182712}, issn = {1090-2392}, mesh = {Humans ; *Cryopreservation/methods ; *Cryoprotective Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Periodontal Ligament/cytology/drug effects ; *Vitrification/drug effects ; *Cell Survival/drug effects ; Animals ; Rats ; Tooth/drug effects ; Cell Differentiation/drug effects ; Male ; Superoxide Dismutase/metabolism ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Cells, Cultured ; Catalase/metabolism/genetics ; Osteogenesis/drug effects ; Female ; }, abstract = {Preserving freshly-extracted healthy human teeth offers an optional resource for potential tooth transplantation and cell therapy. This study aimed to assess the impact of vitrification, utilizing a blend of cryoprotectant agents and N-acetylcysteine (NAC), on the cryopreservation of periodontal ligament tissues, and investigate the underlying mechanisms of NAC on the tooth cryopreservation. Periodontal ligament cells were isolated from freshly-extracted healthy human permanent teeth, and cell sheets of PDLCs were fabricated. The samples including cell sheets, freshly-extracted human and rat teeth were cryopreserved with or without NAC for three months. The viability, ROS level, gene expressions and microstructure of PDLCs within cell sheets were assessed. The expression of SOD-2, Caspase3, LC3A/B and Catalase were evaluated through western blotting. Histological assessments of cryopreserved cell sheets and teeth were conducted. PDLCs were isolated from cryopreserved teeth, and their immunophenotype and differentiation ability were evaluated. The data was analyzed using one-way analysis of variance. The vitrification method showed good performance in preserving the viability and differentiation potential of PDLCs. Cryopreservation supplemented with NAC improved the survival rate of PDLCs, enhanced osteogenic differentiation ability, upregulated the expression of SOD-2 and Catalase, and inhibited cell apoptosis. Additionally, mRNA sequencing analysis revealed a significant activation of the PI3K-AKT pathway following cryopreservation via vitrification. Adding a PI3K-AKT activator improved the survival rates of PDLCs post-cryopreservation. The vitrification strategy combining various CPAs and NAC proved to be feasible for tooth cryopreservation. Targeting the PI3K-AKT pathway may improve the efficacy of tooth cryopreservation.}, } @article {pmid39182421, year = {2024}, author = {Lu, J and Zhao, P and Ding, X and Li, H}, title = {N-acetylcysteine stimulates the proliferation and differentiation in heat-stressed skeletal muscle cells.}, journal = {Journal of thermal biology}, volume = {124}, number = {}, pages = {103958}, doi = {10.1016/j.jtherbio.2024.103958}, pmid = {39182421}, issn = {0306-4565}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Heat-Shock Response/drug effects ; *Cell Proliferation/drug effects ; *Cell Differentiation/drug effects ; Mice ; *Oxidative Stress/drug effects ; Cell Line ; Apoptosis/drug effects ; HSP70 Heat-Shock Proteins/metabolism/genetics ; Muscle, Skeletal/drug effects/cytology/metabolism ; Antioxidants/pharmacology ; }, abstract = {N-acetylcysteine (NAC) is known for its beneficial effects on health due to its antioxidant and antiapoptotic properties. This study explored the protective effects of NAC against oxidative stress in heat-stressed (HS) skeletal muscle cells and its role in promoting muscle development. NAC reduced the heat shock response by decreasing the expression of heat shock protein 70 (HSP70) in HS-induced muscle cells during proliferation and differentiation. NAC also mitigated HS-induced oxidative stress via increasing the antioxidant enzyme levels and reducing oxidant enzyme levels. Treatment with NAC at 2 mM increased cell viability from 43.68% ± 5.14%-66.69% ± 14.43% and decreased the apoptosis rate from 7.89% ± 0.53%-5.17% ± 0.11% in skeletal muscle cells. Additionally, NAC promoted the proliferation and differentiation of HS-induced skeletal muscle cells by upregulating the expression of PAX7, MYF5, MRF4 and MYHC. These findings suggest that NAC alleviates HS-induced oxidative damage in skeletal muscle cells and support muscle development.}, } @article {pmid39182400, year = {2025}, author = {Feng, Y and Yuan, J and Yang, X and Ma, X and Cheng, Z}, title = {Developing an off-on fluorescence sensor based on red copper nanoclusters wrapped by sulfhydryl and polymer double ligands for sensitive detection of N-acetyl-L-cysteine.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {324}, number = {}, pages = {125008}, doi = {10.1016/j.saa.2024.125008}, pmid = {39182400}, issn = {1873-3557}, mesh = {*Acetylcysteine/chemistry/urine ; *Copper/chemistry/analysis ; *Spectrometry, Fluorescence/methods ; *Sulfhydryl Compounds/chemistry/analysis ; Ligands ; *Metal Nanoparticles/chemistry ; *Limit of Detection ; Mercury/analysis/urine ; Humans ; Fluorescent Dyes/chemistry ; Povidone/chemistry ; Benzoates/chemistry ; Polymers/chemistry ; }, abstract = {N-acetyl-L-cysteine (NAC) as a class of thiols is commonly used in the treatment of lung diseases, detoxification and prevention of liver damage. In this paper, 4-mercaptobenzoic acid (4-MBA) coated and polyvinylpyrrolidone (PVP) attached copper nanoclusters (4-MBA@PVP-CuNCs) were successfully synthesized using a simple one-pot method with an absolute quantum yield of 10.98 %, and its synthetic conditions (like effects of single/double ligands and temperature) were studied intensively. Then Hg[2+] could quench the fluorescence of the 4-MBA@PVP-CuNCs and its fluorescence was restored with the addition of NAC. Based on the above principles, an off-on switching system was established to detect NAC. That is, the 4-MBA@PVP-CuNCs-Hg probe was prepared by adding Hg[2+] to switch off the fluorescence of the CuNCs by static quenching, and then NAC was added to switch on the fluorescence of the probe based on the chelation of NAC and Hg[2+]. Moreover, the effects of metal ion types and mercury ion doses for the probe construction were also further discussed. The method showed excellent linearity in the range of 0.05-1.25 µM and low detection limit of 16 nM. Meanwhile, good recoveries in real urine, tablets and pellets were observed, which proved the reliability of the method and provided a convenient, fast and sensitive method for NAC detection.}, } @article {pmid39180519, year = {2024}, author = {Yang, H and Liu, Y and Wang, C and Hussain, M and Ettayri, K and Chen, Y and Wang, K and Long, L and Qian, J}, title = {Ultrastable NAC-Capped CdZnTe Quantum Dots Encapsulated within Dendritic Mesoporous Silica As an Exceptional Tag for Anti-Interference Fluorescence Aptasensor with Signal Amplification.}, journal = {Analytical chemistry}, volume = {96}, number = {36}, pages = {14550-14559}, doi = {10.1021/acs.analchem.4c02826}, pmid = {39180519}, issn = {1520-6882}, mesh = {*Quantum Dots/chemistry ; *Silicon Dioxide/chemistry ; *Tellurium/chemistry ; *Cadmium Compounds/chemistry ; *Biosensing Techniques/methods ; *Aptamers, Nucleotide/chemistry ; Porosity ; Acetylcysteine/chemistry ; Fluorescence ; Spectrometry, Fluorescence ; Limit of Detection ; Cadmium ; Zinc ; }, abstract = {In this work, we explored the potential of thiol-capped CdZnTe quantum dots (QDs) as an exceptional signal tag for fluorescence aptasensing applications. Employing a one-pot hydrothermal approach, we modulated the terminal functional groups of CdZnTe QDs using l-cysteine (Lcys), 3-mercaptopropionic acid (MPA), and N-acetyl-l-cysteine (NAC) as ligands. Our comparative analysis revealed that NAC-capped CdZnTe QDs (NAC-CdZnTe QDs) exhibited superior anti-interference capabilities and storage stability across various temperatures, pH levels, and storage durations. Encouraged by these promising results, we further optimized the use of ultrastable NAC-CdZnTe QDs encapsulated in dendritic mesoporous silica nanoparticles (DMSN@QDs) as an exceptional tag for the development of an advanced anti-interference fluorescence aptasensor for aflatoxin B1 (AFB1) detection. The developed aptasensor using DMSN@QDs as signal tags achieved a remarkable signal amplification of approximately 10.2 fold compared to the NAC-CdZnTe QDs coated silica (SiO2@QDs) labeled fluorescence aptasensor. This aptasensor was able to detect AFB1 within a wide range of 1 pg mL[-1] to 200 ng mL[-1], achieving a limit of detection as low as 0.41 pg mL[-1] (S/N = 3). Crucially, the specific binding affinity between the aptamer and the target enabled the aptasensor to be easily customized for various targets by simply replacing the aptamer sequence with the desired one. The exceptional potential of NAC-CdZnTe QDs, particularly when encapsulated in DMSNs, leads to the development of highly sensitive and selective anti-interference fluorescence aptasensors for various targets, thereby, paving the way for advancements in a diverse range of applications.}, } @article {pmid39178962, year = {2024}, author = {Zhao, Z and Yi, S and E, H and Jiang, L and Zhou, C and Zhao, X and Yang, L}, title = {α-amanitin induce inflammatory response by activating ROS/NF-κB-NLRP3 signaling pathway in human hepatoma HepG2 cells.}, journal = {Chemosphere}, volume = {364}, number = {}, pages = {143157}, doi = {10.1016/j.chemosphere.2024.143157}, pmid = {39178962}, issn = {1879-1298}, mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *Reactive Oxygen Species/metabolism ; Hep G2 Cells ; *Alpha-Amanitin/toxicity ; *Inflammation/chemically induced/metabolism ; Inflammasomes/metabolism ; Carcinoma, Hepatocellular/metabolism ; Liver Neoplasms/metabolism ; Oxidative Stress/drug effects ; Cytokines/metabolism ; Malondialdehyde/metabolism ; }, abstract = {α-amanitin (AMA) is a hepatotoxic mushroom toxin responsible for over 90% of mushroom poisoning fatalities worldwide, seriously endangering human life and health. Few evidences have indicated that AMA leads to inflammatory responses and inflammatory infiltration in vitro and in vivo. However, the molecular mechanism remains unknown. In this study, human hepatocellular carcinomas cells (HepG2) were exposed to AMA at various concentrations for short period of times. Results revealed that AMA increased ROS production and elevated the releases of malondialdehyde (MDA) and lactate dehydrogenase (LDH), resulting in oxidative damage in HepG2 cells. Also, AMA exposure significantly increased the secreted levels of inflammatory cytokines and activated the NLRP3 inflammasome. The inflammatory responses were reversed by NLRP3 inhibitor MCC950 and NF-κB inhibitor Bay11-7082. Additionally, N-acetylcysteine (NAC) blocked the upregulation of the NF-κB/NLRP3 signaling pathway and remarkably alleviated the inflammatory response. These results demonstrated that AMA could induce inflammation through activating the NLRP3 inflammasome triggered by ROS/NF-κB signaling pathway. Our research provides new insights into the molecular mechanism of AMA-induced inflammation damage and may contribute to establish new prevention strategies for AMA hepatotoxicity.}, } @article {pmid39178616, year = {2024}, author = {Zhang, C and Sun, X and Wu, D and Wang, G and Lan, H and Zheng, X and Li, S}, title = {IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.}, journal = {Theriogenology}, volume = {229}, number = {}, pages = {147-157}, doi = {10.1016/j.theriogenology.2024.08.023}, pmid = {39178616}, issn = {1879-3231}, mesh = {Animals ; *Inositol 1,4,5-Trisphosphate Receptors/metabolism/genetics ; Swine ; *Mitochondria/metabolism/physiology ; *Meiosis/physiology ; *Oxidative Stress ; *Calcium/metabolism ; *Embryonic Development/physiology ; Reactive Oxygen Species/metabolism ; Oocytes/physiology ; Female ; }, abstract = {Calcium ions (Ca[2+]) regulate cell proliferation and differentiation and participate in various physiological activities of cells. The calcium transfer protein inositol 1,4,5-triphosphate receptor (IP3R), located between the endoplasmic reticulum (ER) and mitochondria, plays an important role in regulating Ca[2+] levels. However, the mechanism by which IP3R1 affects porcine meiotic progression and embryonic development remains unclear. We established a model in porcine oocytes using siRNA-mediated knockdown of IP3R1 to investigate the effects of IP3R1 on porcine oocyte meiotic progression and embryonic development. The results indicated that a decrease in IP3R1 expression significantly enhanced the interaction between the ER and mitochondria. Additionally, the interaction between the ER and the mitochondrial Ca[2+] ([Ca[2+]]m) transport network protein IP3R1-GRP75-VDAC1 was disrupted. The results of the Duolink II in situ proximity ligation assay (PLA) revealed a weakened pairwise interaction between IP3R1-GRP75 and VDAC1 and a significantly increased interaction between GRP75 and VDAC1 after IP3R1 interference, resulting in the accumulation of large amounts of [Ca[2+]]m. These changes led to mitochondrial oxidative stress, increased the levels of reactive oxygen species (ROS) and reduced ATP production, which hindered the maturation and late development of porcine oocytes and induced apoptosis. Nevertheless, after treat with [Ca[2+]]m chelating agent ruthenium red (RR) or ROS scavenger N-acetylcysteine (NAC), the oocytes developmental abnormalities, oxidative stress and apoptosis caused by Ca[2+] overload were improved. In conclusion, our results indicated IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.}, } @article {pmid39175643, year = {2024}, author = {Sabbaghziarani, F and Soleimani, P and Eynshikh, FR and Zafari, F and Aali, E}, title = {Reduced ischemia-reperfusion oxidative stress injury by melatonin and N-acetylcysteine in the male rat brain.}, journal = {IBRO neuroscience reports}, volume = {17}, number = {}, pages = {131-137}, pmid = {39175643}, issn = {2667-2421}, abstract = {Middle cerebral artery occlusion (MCAO) is a model for inducing ischemic stroke in rodents, leading to devastating brain damage. Oxidative stress (OS) plays a crucial role in the pathogenesis of ischemia. In this study, the effect of melatonin and N-acetylcysteine on ischemia-reperfusion-induced oxidative stress injury in the cerebral cortex of male rats was investigated. 30 male Wistar rats were divided into sham, ischemic, NAC, melatonin and NAC + melatonin groups. All groups, except the sham group, underwent MCAO on the left side, and the treatment groups received intraperitoneal injections of either 50 mg/kg N-acetylcysteine (NAC) or 5 mg/kg melatonin or a combination of both 24 and 48 hours later. At 24 and 72 hours after surgery, the animals were examined for sensory and motor activity. The cerebral cortex was dissected after sacrificing the rats, infarct volume estimated and the concentrations of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and nuclear factor erythroid-2 related factor 2 (Nrf2) were analyzed by enzyme-linked immunosorbent assay (ELISA). The results indicate that the NAC + melatonin group exhibited elevated sensory-motor activity and a reduced infarct volume rate in comparison to the ischemic group (p≤ 0.05). Compared to the ischemic group, the NAC + melatonin group showed a significant increase in SOD concentration and a significant decrease in MDA (p≤ 0.05). It can therefore be concluded that the simultaneous administration of NAC and melatonin can reduce the cerebral infarction volume, and improve neurological functions by modulating SOD and MDA.}, } @article {pmid39166871, year = {2024}, author = {Wilson, PR and Bridges, KH and Scofield, M and Wilson, SH}, title = {Perioperative N-acetylcysteine: evidence and indications.}, journal = {Pain management}, volume = {14}, number = {7}, pages = {385-396}, pmid = {39166871}, issn = {1758-1877}, mesh = {Humans ; *Acetylcysteine/administration & dosage ; *Perioperative Care/methods ; Pain, Postoperative/drug therapy/prevention & control ; Analgesics, Non-Narcotic/adverse effects/administration & dosage/pharmacology ; }, abstract = {Nonopioid analgesics serve to improve analgesia and limit side effects and risks of perioperative opioids. N-acetylcysteine (NAC), the primary treatment of acetaminophen toxicity, may have perioperative indications, including analgesia. NAC impacts glutathione synthesis, oxidant scavenging, glutamate receptor modulation and neuroinflammation. Potential perioperative benefits include arrhythmia prevention after cardiac surgery, decreased contrast-induced nephropathy, improved post-transplant liver function and superior pulmonary outcomes with general anesthesia. NAC may improve perioperative analgesia, with some studies displaying a reduction in postoperative opioid use. NAC is generally well tolerated with an established safety profile. NAC administration may predispose to gastrointestinal effects, while parenteral administration may carry a risk of anaphylactoid reactions, including bronchospasm. Larger randomized trials may clarify the impact of NAC on perioperative analgesic outcomes.}, } @article {pmid39159553, year = {2024}, author = {Kim, NY and Dukanya, D and Sethi, G and Girimanchanaika, SS and Yang, J and Nagaraja, O and Swamynayaka, A and Vishwanath, D and Venkantesha, K and Basappa, S and Chinnathambi, A and Alharbi, SA and Madegowda, M and Sukhorukov, A and Pandey, V and Lobie, PE and Basappa, B and Ahn, KS}, title = {Oxazine drug-seed induces paraptosis and apoptosis through reactive oxygen species/JNK pathway in human breast cancer cells.}, journal = {Translational oncology}, volume = {49}, number = {}, pages = {102101}, pmid = {39159553}, issn = {1936-5233}, abstract = {Small molecule-driven JNK activation has been found to induce apoptosis and paraptosis in cancer cells. Herein pharmacological effects of synthetic oxazine (4aS, 7aS)-3-((4-(4‑chloro-2-fluorophenyl)piperazin-1-yl)methyl)-4-phenyl-4, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[e] [1,2]oxazine (FPPO; BSO-07) on JNK-driven apoptosis and paraptosis has been demonstrated in human breast cancer (BC) MDA-MB231 and MCF-7 cells respectively. BSO-07 imparted significant cytotoxicity in BC cells, induced activation of JNK, and increased intracellular reactive oxygen species (ROS) levels. It also enhanced the expression of apoptosis-associated proteins like PARP, Bax, and phosphorylated p53, while decreasing the levels of Bcl-2, Bcl-xL, and Survivin. Furthermore, the drug altered the expression of proteins linked to paraptosis, such as ATF4 and CHOP. Treatment with N-acetyl-cysteine (antioxidant) or SP600125 (JNK inhibitor) partly reversed the effects of BSO-07 on apoptosis and paraptosis. Advanced in silico bioinformatics, cheminformatics, density Fourier transform and molecular electrostatic potential analysis further demonstrated that BSO-07 induced apoptosis and paraptosis via the ROS/JNK pathway in human BC cells.}, } @article {pmid39158930, year = {2024}, author = {Li, J and Jiang, L and Zhao, K and Tang, Y and Yuan, X and Xu, Y}, title = {MYELOID-DERIVED TLR4-TRIF SIGNALING PATHWAY MEDIATES OXIDATIVE STRESS IN LPS/D-GALN-INDUCED ACUTE LIVER FAILURE.}, journal = {Shock (Augusta, Ga.)}, volume = {62}, number = {4}, pages = {582-587}, doi = {10.1097/SHK.0000000000002438}, pmid = {39158930}, issn = {1540-0514}, mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; *Adaptor Proteins, Vesicular Transport/metabolism ; *Oxidative Stress ; *Liver Failure, Acute/metabolism ; *Signal Transduction/drug effects ; Mice ; *Lipopolysaccharides/toxicity ; *Galactosamine ; *Mice, Knockout ; Male ; Mice, Inbred C57BL ; }, abstract = {Background: Acute liver failure (ALF) is a severe clinical syndrome characterized by massive hepatocyte death in a short time due to viruses, drugs, alcohol, or other factors. Oxidative stress is an important pathogenic mechanism of ALF. LPS-induced internalization of toll-like receptor 4 (TLR4) and the subsequent activation of the toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF) signaling pathway widely mediate inflammatory responses in a series of diseases. However, whether the TLR4-TRIF signaling pathway contributes to ALF by mediating oxidative stress processes remains unclear. Methods: An ALF mouse model was induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN). TLR4-TRIF systemic knockout mice and TLR4 conditional knockout mice were used to determine the role of the TLR4-TRIF signaling pathway in ALF. The effects of TLR4 or TRIF deficiency on oxidative stress were investigated. In addition, we examined the protective role of the clodronate liposomes (macrophage scavengers) and the antioxidant N-acetylcysteine (NAC) in ALF. Results: TLR4 or TRIF deficiency significantly alleviated LPS/D-GalN-induced lethality, hepatic dysfunction, and hepatic pathologic injury, which was dependent on myeloid-derived TLR4. Hence, macrophage clearance exhibits a similar protective effect. Mechanically, TLR4 or TRIF deficiency was observed to inhibit oxidative stress by increasing glutathione, while decreasing malondialdehyde, 8-hydroxy-2-deoxyguanosine, and γ-H2AX. Therefore, the pharmacologic antioxidant NAC exhibited significant hepato-protective effects. Conclusions: Targeting myeloid-derived TLR4-TRIF signaling pathway or antioxidant therapy may be a potential therapeutic direction to treat ALF.}, } @article {pmid39148391, year = {2024}, author = {Yang, K and Wu, Y and Zhang, R and Lei, XP and Kang, L and Dong, WB}, title = {[Role of reactive oxygen species/silent information regulator 1 in hyperoxia-induced bronchial epithelial cell injury].}, journal = {Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics}, volume = {26}, number = {8}, pages = {852-860}, pmid = {39148391}, issn = {1008-8830}, mesh = {*Sirtuin 1/metabolism/physiology/genetics ; Humans ; *Reactive Oxygen Species/metabolism ; *Hyperoxia/complications/metabolism ; *Epithelial Cells/metabolism ; *Bronchi/metabolism ; Mitochondria/metabolism ; Cells, Cultured ; Cell Line ; }, abstract = {OBJECTIVES: To investigate the effect of reactive oxygen species (ROS)/silent information regulator 1 (SIRT1) on hyperoxia-induced mitochondrial injury in BEAS-2B cells.

METHODS: The experiment was divided into three parts. In the first part, cells were divided into H0, H6, H12, H24, and H48 groups. In the second part, cells were divided into control group, H48 group, H48 hyperoxia+SIRT1 inhibitor group (H48+EX 527 group), and H48 hyperoxia+SIRT1 agonist group (H48+SRT1720 group). In the third part, cells were divided into control group, 48-hour hyperoxia+N-acetylcysteine group (H48+NAC group), and H48 group. The ROS kit was used to measure the level of ROS. Western blot and immunofluorescent staining were used to measure the expression levels of SIRT1 and mitochondria-related proteins. Transmission electron microscopy was used to observe the morphology of mitochondria.

RESULTS: Compared with the H0 group, the H6, H12, H24, and H48 groups had a significantly increased fluorescence intensity of ROS (P<0.05), the H48 group had significant reductions in the expression levels of SIRT1 protein and mitochondria-related proteins (P<0.05), and the H24 and H48 groups had a significant reduction in the fluorescence intensity of mitochondria-related proteins (P<0.05). Compared with the H48 group, the H48+SRT1720 group had significant increases in the expression levels of mitochondria-related proteins and the mitochondrial aspect ratio (P<0.05), and the H48+EX 527 group had a significant reduction in the mitochondrial area (P<0.05). Compared with the H48 group, the H48+NAC group had a significantly decreased fluorescence intensity of ROS (P<0.05) and significantly increased levels of SIRT1 protein, mitochondria-related proteins, mitochondrial area, and mitochondrial aspect ratio (P<0.05).

CONCLUSIONS: The ROS/SIRT1 axis is involved in hyperoxia-induced mitochondrial injury in BEAS-2B cells.}, } @article {pmid39148029, year = {2024}, author = {Wu, C and Li, Y and Liu, S and Wang, L and Wang, X}, title = {Catalpol inhibits HHcy-induced EndMT in endothelial cells by modulating ROS/NF-κB signaling.}, journal = {BMC cardiovascular disorders}, volume = {24}, number = {1}, pages = {431}, pmid = {39148029}, issn = {1471-2261}, support = {SB201901060;YJSCX202290Y//Medical Science and Technology Tackling Program of Henan Province (SB201901060) and Postgraduate research innovation program (YJSCX202290Y)./ ; SB201901060;YJSCX202290Y//Medical Science and Technology Tackling Program of Henan Province (SB201901060) and Postgraduate research innovation program (YJSCX202290Y)./ ; }, mesh = {Animals ; Humans ; Antigens, CD/metabolism ; Antioxidants/pharmacology ; *Atherosclerosis/drug therapy/etiology/pathology ; Cadherins/metabolism ; Cells, Cultured ; Disease Models, Animal ; *Endothelial-Mesenchymal Transition/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism/drug effects/pathology ; *Hyperhomocysteinemia/drug therapy/metabolism/complications ; *Iridoid Glucosides/pharmacology/therapeutic use ; Mice, Inbred C57BL ; *NF-kappa B/metabolism ; Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Transcription Factor RelA/metabolism ; Mice ; }, abstract = {BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis (AS). Endothelial mesenchymal transition (EndMT) refers to the process in which endothelial cells lose endothelial cell morphology and characteristic gene expression, and acquire phenotypic characteristics and gene expression related to mesenchymal cells. Numerous studies have confirmed that EndMT is involved in the formation of atherosclerosis. Catalpol is one of the active components of Rehmannia, which has antioxidant, anti-inflammatory, anti-tumor, neuroprotective and other biological activities. Studies have shown that catalpol can reduce atherosclerotic plaque induced by high sugar or fat. However, the effect of catalpol on HHCY-induced EndMT is unclear.

METHODS AND RESULTS: In vitro HHcy-treated primary human umbilical vein endothelial cells (HUVECs) were used to construct a cell model, and the antioxidants N-acetylcysteine (NAC) and catalase alcohol were administered. In vivo C57BL/6N mice were given a diet fed with 4.4% high methionine chow to construct a HHcy mice model and were treated with catalpol. The results showed that hhcy could induce morphological transformation of endothelial cells into mesenchymal cells, increase intracellular ROS content, up-regulate α-SMA, N-cadherin, p-p65 protein expression, down-regulate VE-cadherin, CD31 protein expression, induce pathological changes of aortic root endothelium, and increase aortic endothelial ROS content. Catalpol reversed these hhcy induced outcomes.

CONCLUSIONS: Catalpol inhibits HHcy-induced EndMT, and the underlying mechanism may be related to the ROS/NF-κB signaling pathway. Catalpol may be a potential drug for the treatment of HHcy-related AS.}, } @article {pmid39146674, year = {2024}, author = {Wu, H and Huo, H and Li, H and Zhang, H and Li, X and Han, Q and Liao, J and Tang, Z and Guo, J}, title = {N-acetylcysteine combined with insulin therapy can reduce myocardial injury induced by type 1 diabetes through the endoplasmic reticulum pathway.}, journal = {Tissue & cell}, volume = {90}, number = {}, pages = {102515}, doi = {10.1016/j.tice.2024.102515}, pmid = {39146674}, issn = {1532-3072}, mesh = {Animals ; *Diabetes Mellitus, Type 1/drug therapy/metabolism/pathology/complications ; *Insulin/pharmacology/metabolism ; Dogs ; *Endoplasmic Reticulum/metabolism/drug effects ; *Acetylcysteine/pharmacology ; *Myocardium/metabolism/pathology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Apoptosis/drug effects ; Male ; Signal Transduction/drug effects ; }, abstract = {With the development of Type 1 diabetes mellitus (T1DM), various complications can be caused. Hyperglycemia affects the microenvironment of cardiomyocytes, changes endoplasmic reticulum homeostasis, triggers unfolding protein response and eventually promotes myocardial apoptosis. However, insulin therapy alone cannot effectively combat the complications caused by T1DM. Forty adult beagles were randomly divided into five groups: control group, diabetes mellitus group, insulin group, insulin combined with NAC group, and NAC group. 24-hour blood glucose, 120-day blood glucose, 120-day body weight, and serum FMN content were observed, furthermore, hematoxylin-eosin staining, Periodic acid Schiff reagent staining, and Sirius red staining of the myocardium were evaluated. The protein expressions of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase 3, Bcl2, and Bax were detected. Results of the pathological section of myocardial tissue indicated that insulin combined with NAC therapy could improve myocardial pathological injury and glycogen deposition. Additionally, insulin combined with NAC therapy down-regulates the expression of GRP78, ATF6, IRE1, PERK, JNK, CHOP, caspase3, and Bax. These findings suggest that NAC has a phylactic effect on myocardial injury in beagles with T1DM, and the mechanism may be related to the improvement of endoplasmic reticulum stress-induced apoptosis.}, } @article {pmid39144112, year = {2024}, author = {Husain, MO and Chaudhry, IB and Khoso, AB and Husain, MI and Ansari, MA and Mehmood, N and Naqvi, HA and Nizami, AT and Talib, U and Rajput, AH and Bassett, P and Foussias, G and Deakin, B and Husain, N}, title = {Add-on Sodium Benzoate and N-Acetylcysteine in Patients With Early Schizophrenia Spectrum Disorder: A Multicenter, Double-Blind, Randomized Placebo-Controlled Feasibility Trial.}, journal = {Schizophrenia bulletin open}, volume = {5}, number = {1}, pages = {sgae004}, pmid = {39144112}, issn = {2632-7899}, abstract = {BACKGROUND AND HYPOTHESIS: Oxidative stress pathways may play a role in schizophrenia through direct neuropathic actions, microglial activation, inflammation, and by interfering with NMDA neurotransmission. N-acetylcysteine (NAC) has been shown to improve negative symptoms of schizophrenia, however, results from trials of other compounds targeting NMDA neurotransmission have been mixed. This may reflect poor target engagement but also that risk mechanisms act in parallel. Sodium Benzoate (NaB) could have an additive with NAC to act on several pathophysiological mechanisms implicated in schizophrenia.

STUDY DESIGN: A multicenter, 12 weeks, 2 × 2 factorial design, randomized double-blind placebo-controlled feasibility trial of NaB and NAC added to standard treatment in 68 adults with early schizophrenia. Primary feasibility outcomes included recruitment, retention, and completion of assessments as well as acceptability of the study interventions. Psychosis symptoms, functioning, and cognitive assessments were also assessed.

STUDY RESULTS: We recruited our desired sample (n = 68) and retained 78% (n = 53) at 12 weeks, supporting the feasibility of recruitment and retention. There were no difficulties in completing clinical outcome schedules. Medications were well tolerated with no dropouts due to side effects. This study was not powered to detect clinical effect and as expected no main effects were found on the majority of clinical outcomes.

CONCLUSIONS: We demonstrated feasibility of conducting a clinical trial of NaB and NAC. Given the preliminary nature of this study, we cannot draw firm conclusions about the clinical efficacy of either agent, and a large-scale trial is needed to examine if significant differences between treatment groups emerge.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT03510741.}, } @article {pmid39144108, year = {2024}, author = {Wasserthal, S and Muthesius, A and Hurlemann, R and Ruhrmann, S and Schmidt, SJ and Hellmich, M and Schultze-Lutter, F and Klosterkötter, J and Müller, H and Meyer-Lindenberg, A and Poeppl, TB and Walter, H and Hirjak, D and Koutsouleris, N and Fallgatter, AJ and Bechdolf, A and Brockhaus-Dumke, A and Mulert, C and Philipsen, A and Kambeitz, J}, title = {N-Acetylcysteine and a Specialized Preventive Intervention for Individuals at High Risk for Psychosis: A Randomized Double-Blind Multicenter Trial.}, journal = {Schizophrenia bulletin open}, volume = {5}, number = {1}, pages = {sgae005}, pmid = {39144108}, issn = {2632-7899}, abstract = {BACKGROUND AND HYPOTHESIS: Clinical high risk for psychosis (CHR-P) offers a window of opportunity for early intervention and recent trials have shown promising results for the use of N-acetylcysteine (NAC) in schizophrenia. Moreover, integrated preventive psychological intervention (IPPI), applies social-cognitive remediation to aid in preventing the transition to the psychosis of CHR-P patients.

STUDY DESIGN: In this double-blind, randomized, controlled multicenter trial, a 2 × 2 factorial design was applied to investigate the effects of NAC compared to placebo (PLC) and IPPI compared to psychological stress management (PSM). The primary endpoint was the transition to psychosis or deterioration of CHR-P symptoms after 18 months.

STUDY RESULTS: While insufficient recruitment led to early trial termination, a total of 48 participants were included in the study. Patients receiving NAC showed numerically higher estimates of event-free survival probability (IPPI + NAC: 72.7 ± 13.4%, PSM + NAC: 72.7 ± 13.4%) as compared to patients receiving PLC (IPPI + PLC: 56.1 ± 15.3%, PSM + PLC: 39.0 ± 17.4%). However, a log-rank chi-square test in Kaplan-Meier analysis revealed no significant difference of survival probability for NAC vs control (point hazard ratio: 0.879, 95% CI 0.281-2.756) or IPPI vs control (point hazard ratio: 0.827, 95% CI 0.295-2.314). The number of adverse events (AE) did not differ significantly between the four groups.

CONCLUSIONS: The superiority of NAC or IPPI in preventing psychosis in patients with CHR-P compared to controls could not be statistically validated in this trial. However, results indicate a consistent pattern that warrants further testing of NAC as a promising and well-tolerated intervention for CHR patients in future trials with adequate statistical power.}, } @article {pmid39142116, year = {2024}, author = {Wang, Y and Guo, AL and Xu, Y and Xu, X and Yang, L and Yang, Y and Chao, L}, title = {EHDPP induces proliferation inhibition and apoptosis to spermatocyte: Insights from transcriptomic and metabolomic profiles.}, journal = {Ecotoxicology and environmental safety}, volume = {284}, number = {}, pages = {116878}, doi = {10.1016/j.ecoenv.2024.116878}, pmid = {39142116}, issn = {1090-2414}, mesh = {Male ; Animals ; *Apoptosis/drug effects ; Mice ; *Cell Proliferation/drug effects ; *Spermatocytes/drug effects ; *Transcriptome/drug effects ; Cell Line ; Humans ; Oxidative Stress/drug effects ; Metabolome/drug effects ; Sperm Motility/drug effects ; Reactive Oxygen Species/metabolism ; DNA Damage ; Spermatogenesis/drug effects ; Testis/drug effects/metabolism ; }, abstract = {BACKGROUND: 2-ethylhexyldiphenyl phosphate (EHDPP) was used widespread in recent years and it was reported to impair reproductive behaviors and decrease fertility in male Japanese medaka. However, whether EHDPP causes spermatogenesis disturbance remains uncertain.

OBJECTIVES: We aimed to study the male reproductive toxicity of EHDPP and its related mechanism.

METHODS: Human spermatocyte cell line GC-2 was treated with 10 µM, 50 µM or 100 µM EHDPP for 24 h. Male CD-1 mice aged 6 weeks were given 1, 10, or 100 mg/kg/d EHDPP daily for 42 days and then euthanized to detect sperm count and motility. Proliferation, apoptosis, oxidative stress was detected in mice and cell lines. Metabolome and transcriptome were used to detect the related mechanism. Finally, anti-oxidative reagent N-Acetylcysteine was used to detect whether it could reverse the side-effect of EHDPP both in vivo and in vitro.

RESULTS: Our results showed that EHDPP inhibited proliferation and induced apoptosis in mice testes and spermatocyte cell line GC-2. Metabolome and transcriptome showed that nucleotide metabolism disturbance and DNA damage was potentially involved in EHDPP-induced reproductive toxicity. Finally, we found that excessive ROS production caused DNA damage and mitochondrial dysfunction; NAC supplement reversed the side effects of EHDPP such as DNA damage, proliferation inhibition, apoptosis and decline in sperm motility.

CONCLUSION: ROS-evoked DNA damage and nucleotide metabolism disturbance mediates EHDPP-induced germ cell proliferation inhibition and apoptosis, which finally induced decline of sperm motility.}, } @article {pmid39139444, year = {2024}, author = {Hanafy, DA and Willim, HA and Suwatri, WT and Sani, AA and Khouw, H and Susanti, EI and Sugisman, }, title = {Efficacy of N-acetylcysteine for Prevention of Postoperative Atrial Fibrillation Following Coronary Artery Bypass Grafting: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {Reviews in cardiovascular medicine}, volume = {25}, number = {7}, pages = {243}, pmid = {39139444}, issn = {2153-8174}, abstract = {BACKGROUND: As the prevalence of coronary artery disease rises, the demand for coronary artery bypass grafting (CABG) increases. A common complication after CABG is postoperative atrial fibrillation (POAF), which is linked to adverse clinical outcomes. N-acetylcysteine (NAC), an antioxidant, may mitigate oxidative stress and reduce the incidence of POAF. This meta-analysis aims to investigate the efficacy of NAC in preventing POAF after CABG.

METHODS: The meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched multiple databases, including PubMed, Cochrane Library, ProQuest, and ScienceDirect, to identify relevant randomized controlled trials (RCTs). The intervention groups received perioperative NAC therapy, while the control groups received a placebo. The outcomes assessed were POAF incidence, all-cause mortality, and hospital length of stay (LOS). Review Manager 5.3 was used to conduct the meta-analysis.

RESULTS: Eleven RCTs involving 648 patients were included. The NAC group comprised 326 patients, while the control group comprised 322 patients. In the pooled analysis, patients in the NAC group had a significantly lower incidence of POAF (odds ratios (OR) = 0.57; 95% confidence intervals (CI) = 0.33 to 0.97; p = 0.04) and a shorter hospital LOS (weighted mean differences (WMD) = -0.66; 95% CI = -1.22 to -0.10; p = 0.02) compared to the control group. However, there was no significant difference in all-cause mortality.

CONCLUSIONS: The perioperative administration of NAC can effectively reduce the incidence of POAF and hospital LOS in CABG patients. However, larger RCTs are needed to confirm these findings.}, } @article {pmid39139367, year = {2024}, author = {Tasci, T and Orta-Yilmaz, B and Aydin, Y and Caliskan, M}, title = {N-acetylcysteine attenuates sodium arsenite-induced oxidative stress and apoptosis in embryonic fibroblast cells.}, journal = {Toxicology research}, volume = {13}, number = {4}, pages = {tfae128}, pmid = {39139367}, issn = {2045-452X}, abstract = {In recent years, the increase in environmental pollutants has been one of the most important factors threatening human and environmental health. Arsenic, a naturally occurring element found in soil, water, and air, easily enters the human body and leads to many metabolic disorders. In this study, we focused on the possible protective effects of N-acetylcysteine (NAC) against sodium arsenite (As)-induced toxic effects on embryonic fibroblast cells. The effects of As and NAC treatment on cells were evaluated, including cytotoxicity, oxidative stress, and apoptosis. Embryonic fibroblast cells were exposed to As (ranging from 0.01 μM to 10 μM) and NAC (at a concentration of 2 mM) for 24 h. The assessment of cytotoxicity markers, such as cell viability and lactate dehydrogenase (LDH), showed that As significantly reduced cell viability and increased LDH levels. Furthermore, we observed that As increased the amount of reactive oxygen species (ROS) in the cell, decreased the activity of antioxidant enzymes, and triggered apoptosis in cells. Additionally, our research revealed that the administration of NAC mitigates the detrimental effects of As. The results showed that As exerted hazardous effects on embryonic fibroblast cells through the induction of oxidative stress and apoptosis. In this context, our study provides evidence that NAC may have a protective effect against the toxicity of As in embryonic fibroblast cells.}, } @article {pmid39131009, year = {2024}, author = {Roghani, SH and Arif, MA and Niazi, R and Mansoor, S}, title = {Naphthalene or Mothball Poisoning Manifesting as Acute Intravascular Hemolysis and Acquired Methemoglobinemia.}, journal = {Cureus}, volume = {16}, number = {7}, pages = {e64325}, pmid = {39131009}, issn = {2168-8184}, abstract = {Naphthalene is a major component of mothballs. Domestically, people use mothballs as an insect repellent. Its deliberate or accidental ingestion leading to toxicity has rarely been reported in the medical literature, despite its widespread use in Southeast Asia. Naphthalene, or mothball poisoning, is a rare but serious condition that can have detrimental effects on human health. This case report presents the clinical course of a 22-year-old male who ingested six naphthalene balls, resulting in severe symptoms including fever, abdominal pain, vomiting, jaundice, and dark-colored urine. Laboratory investigations were suggestive of acute intravascular hemolysis and methemoglobinemia. The patient was promptly admitted to the hospital, where he received supportive care along with specific treatment in the form of red blood cell transfusions, intravenous methylene blue, ascorbic acid, and N-acetyl cysteine. Through this report, the importance of raising awareness about the dangers of naphthalene poisoning and the specific treatment options available is highlighted.}, } @article {pmid39128732, year = {2024}, author = {Lu, X and Wu, S and Ai, H and Wu, R and Cheng, Y and Yun, S and Chang, M and Liu, J and Meng, J and Cheng, F and Feng, C and Cao, J}, title = {Sparassis latifolia polysaccharide alleviated lipid metabolism abnormalities in kidney of lead-exposed mice by regulating oxidative stress-mediated inflammation and autophagy based on multi-omics.}, journal = {International journal of biological macromolecules}, volume = {278}, number = {Pt 1}, pages = {134662}, doi = {10.1016/j.ijbiomac.2024.134662}, pmid = {39128732}, issn = {1879-0003}, mesh = {Animals ; *Oxidative Stress/drug effects ; Mice ; *Autophagy/drug effects ; *Lipid Metabolism/drug effects ; *Polysaccharides/pharmacology ; *Kidney/drug effects/metabolism/pathology ; *Inflammation/drug therapy/metabolism ; *Lead/toxicity ; Male ; Lipidomics ; Multiomics ; }, abstract = {Lead is a common environmental pollutant which can accumulate in the kidney and cause renal injury. However, regulatory effects and mechanisms of Sparassis latifolia polysaccharide (SLP) on lipid metabolism abnormality in kidney exposed to lead are not clarified. In this study, mice were used to construct an animal model to observe the histopathological changes in kidney, measure lead content, damage indicators, differentially expressed metabolites (DEMs) and genes (DEGs) in key signaling pathways that cause lipid metabolism abnormalities based on lipidomics and transcriptomics, which were later validated using qPCR and western blotting. Co-treatment of Pb and N-acetylcysteine (NAC) were used to verify the link between SLP and oxidative stress. Our results indicated that treatment with SLP identified 276 DEMs (including metabolism of glycerophospholipid, sphingolipid, glycerolipid and fatty acid) and 177 DEGs (including genes related to oxidative stress, inflammation, autophagy and lipid metabolism). Notably, regulatory effects of SLP on abnormal lipid metabolism in kidney were mainly associated with oxidative stress, inflammation and autophagy; SLP could regulate abnormal lipid metabolism in kidney by reducing oxidative stress and affecting its downstream-regulated autophagy and inflammatory to alleviate renal injury caused by lead exposure. This study provides a theoretical basis for SLP intervention in lead injury.}, } @article {pmid39128490, year = {2025}, author = {Isaguliants, M and Zhitkevich, A and Petkov, S and Gorodnicheva, T and Mezale, D and Fridrihsone, I and Kuzmenko, Y and Kostyushev, D and Kostyusheva, A and Gordeychuk, I and Bayurova, E}, title = {Enzymatic activity of HIV-1 protease defines migration of tumor cells in vitro and enhances their metastatic activity in vivo.}, journal = {Biochimie}, volume = {228}, number = {}, pages = {32-43}, doi = {10.1016/j.biochi.2024.08.009}, pmid = {39128490}, issn = {1638-6183}, mesh = {Animals ; *Cell Movement ; Mice ; Female ; Cell Line, Tumor ; *Mice, Inbred BALB C ; *Neoplasm Metastasis ; HIV Protease/metabolism/genetics ; Epithelial-Mesenchymal Transition ; Reactive Oxygen Species/metabolism ; HIV-1 ; Humans ; Breast Neoplasms/pathology/metabolism/enzymology ; }, abstract = {Overexpression of aspartic proteases, as cathepsin D, is an independent marker of poor prognosis in breast cancer, correlated with the incidence of clinical metastasis. We aimed to find if HIV-1 aspartic protease (PR) can play a similar role. Murine adenocarcinoma 4T1luc2 cells were transduced with lentivirus encoding inactivated drug-resistant PR, generating subclones PR20.1 and PR20.2. Subclones were assessed for production of reactive oxygen species (ROS), expression of epithelial-mesenchymal transition (EMT) factors, and in vitro migratory activity in the presence or absence of antioxidant N-acetyl cysteine and protease inhibitors. Tumorigenic activity was evaluated by implanting cells into BALB/c mice and following tumor growth by calipering and bioluminescence imaging in vivo, and metastases, by organ imaging ex vivo. Both subclones expressed PR mRNA, and PR20.2, also the protein detected by Western blotting. PR did not induce production of ROS, and had no direct effect on cell migration rate, however, treatment with inhibitors of drug-resistant PR suppressed the migratory activity of both subclones. Furthermore, expression of N-cadherin and Vimentin in PR20.2 cells and their migration were enhanced by antioxidant treatment. Sensitivity of in vitro migration to protease inhibitors and to antioxidant, known to restore PR activity, related the effects to the enzymatic activity of PR. In vivo, PR20.2 cells demonstrated higher tumorigenic and metastatic activity than PR20.1 or parental cells. Thus, HIV-1 protease expressed in breast cancer cells determines their migration in vitro and metastatic activity in vivo. This effect may aggravate clinical course of cancers in people living with HIV-1.}, } @article {pmid39125554, year = {2024}, author = {Wee, JH and Park, JH and Park, MW and Choi, YS and Jung, HJ}, title = {Sinus Irrigation with N-Acetylcysteine after Endoscopic Sinus Surgery for Chronic Rhinosinusitis: A Preliminary Report of a Single-Blind Randomized Controlled Trial.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {14}, number = {15}, pages = {}, pmid = {39125554}, issn = {2075-4418}, support = {2022101232//Chungbuk National University/ ; }, abstract = {Nasal irrigation is crucial following endoscopic sinus surgery (ESS), especially for managing chronic rhinosinusitis (CRS). This study assessed the effectiveness of N-acetylcysteine (NAC) irrigation during the post-ESS period of patients with CRS without nasal polyposis. In this prospective, single-blind randomized controlled trial, 49 patients (NAC, n = 24; saline, n = 25) undergoing ESS were assigned to receive either NAC or saline irrigations twice daily for a month. The preoperative and postoperative assessments conducted included Lund-Macka (LM) and Lund-Kennedy (LK) endoscopic scores, the Nasal Obstruction Symptom Evaluation (NOSE) scale, and the Sino-Nasal Outcome Test-20 (SNOT-20). At 2 weeks, 1 month, and 3 months after the operation, endoscopic findings and symptoms were evaluated. Both groups showed no differences in age, sex, LM and LK scores, NOSE scale, and SNOT-20 preoperatively. In terms of the endoscopic findings regarding the sinonasal mucosa after ESS, the NAC group had slightly lower scores 2 weeks, 1 month, and 3 months after the operation, but this difference was not statistically significant. The NAC group showed significant improvement in VAS scores, namely, postnasal drip (1.0, p = 0.041), smell dysfunction (0.8, p = 0.003), and crust (1.5, p = 0.034), compared to the control group's scores of 2.6, 4.7, and 3.6, respectively, 2 weeks after the operation, although no significant differences were observed in VAS scores for any symptoms 1 and 3 months after the operation. NAC was well tolerated, and no adverse events were reported. NAC irrigation showed benefits over saline irrigation in terms of improving postnasal drip, smell dysfunction, and crust after ESS for CRS without nasal polyposis in the immediate postoperative period.}, } @article {pmid39121982, year = {2024}, author = {Liu, DD and Liu, XL and Zheng, TF and Li, X and Zhao, YC and Pan, JC and Yuan, C and Wang, QQ and Zhang, M}, title = {Dapagliflozin alleviates right heart failure by promoting collagen degradation by reducing ROS levels.}, journal = {European journal of pharmacology}, volume = {981}, number = {}, pages = {176875}, doi = {10.1016/j.ejphar.2024.176875}, pmid = {39121982}, issn = {1879-0712}, mesh = {Animals ; *Glucosides/pharmacology/therapeutic use ; *Benzhydryl Compounds/pharmacology/therapeutic use ; *Heart Failure/drug therapy/metabolism/physiopathology ; *Reactive Oxygen Species/metabolism ; Rats ; *Collagen/metabolism ; Male ; *Rats, Sprague-Dawley ; *Fibrosis ; Fibroblasts/drug effects/metabolism/pathology ; Matrix Metalloproteinase 9/metabolism ; Hypertension, Pulmonary/drug therapy/metabolism/pathology ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use ; Matrix Metalloproteinase 2/metabolism ; Disease Models, Animal ; }, abstract = {BACKGROUND: Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms.

METHODS: We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-β) to investigate the effect of DAPA.

RESULTS: In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels.

CONCLUSIONS: In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.}, } @article {pmid39113878, year = {2024}, author = {Wong, G and Wu, SY and Chen, WM and Hsu, PJ and Chou, TC and Chiang, MF and Wu, MS and Lee, MC and Soong, RS}, title = {Effects of N-acetylcysteine on hepatocellular carcinoma in chronic hepatitis C.}, journal = {American journal of cancer research}, volume = {14}, number = {7}, pages = {3533-3544}, pmid = {39113878}, issn = {2156-6976}, abstract = {Hepatitis C virus (HCV) infection significantly contributes to global hepatocellular carcinoma (HCC) incidence. N-Acetylcysteine (NAC), known for its antioxidant properties, is a potential therapeutic agent. However, evidence on its efficacy in reducing HCC risk among HCV patients is limited. A retrospective cohort analysis using Taiwan's National Health Insurance Research Database (2008-2018) included ≥18-year-old HCV patients. NAC usage (≥28 cumulative defined daily doses [cDDDs]) was assessed for its association with HCC risk using Cox regression models and propensity score matching. The study comprised 269,647 HCV patients, with detailed NAC dosage characterization and hazard ratios (HRs) for HCC risk. Post-matching, NAC usage emerged as the significant predictor of reduced HCC risk (adjusted HR: 0.39, 95% CI: 0.37-0.41, P<0.0001). Dose-response analysis showed reduced HCC risk with increasing cDDDs of NAC (P<0.0001). Higher daily NAC dosage (≥1 DDD) was associated with significantly lower HCC risk (adjusted HR: 0.33, 95% CI: 0.31-0.36, P<0.0001). The study provides compelling evidence for NAC's potential in reducing HCC risk among HCV patients. Insights into dose-dependent effects and optimal daily intensity thresholds offer valuable directions for future therapeutic strategies and clinical trials targeting HCC burden in HCV-infected individuals.}, } @article {pmid39113864, year = {2024}, author = {Wu, SY and Chen, WM and Hsu, PJ and Chou, TC and Chiang, MF and Wu, MS and Lee, MC and Soong, RS}, title = {Protective effect of N-acetylcysteine against hepatocellular carcinoma in hepatitis B virus carriers.}, journal = {American journal of cancer research}, volume = {14}, number = {7}, pages = {3639-3651}, pmid = {39113864}, issn = {2156-6976}, abstract = {Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC), contributing to cancer development through direct genomic integration and chronic inflammation. N-acetylcysteine (NAC), known for its antioxidant properties, is widely utilized in cancer prevention. However, clinical evidence regarding its protective effect against HCC in HBV carriers remains sparse. In this retrospective cohort study spanning 2008 to 2018, we utilized Taiwan's National Health Insurance Research Database (NHIRD) to include 1,061,174 chronic HBV carriers. Participants were stratified into NAC users and non-users using Propensity Score Matching. We assessed the incidence of HCC in both cohorts, examining the relationship between NAC usage duration and HCC incidence, and evaluating the dose-response effect. NAC users exhibited a significantly lower risk of developing HCC (adjusted hazard ratio [aHR]: 0.38; 95% confidence interval [CI]: 0.36-0.40; P < 0.0001). A dose-response relationship was evident, with higher cumulative defined daily doses (cDDDs) of NAC correlating with reduced HCC risk, revealing a significant trend (P < 0.0001). Notably, a daily NAC intensity of > 1.4 DDDs was associated with a decreased risk of HCC in HBV patients. Our results demonstrate that the use of NAC, in a dose-dependent manner, is intricately linked with a diminished incidence of HCC in individuals chronically infected with the HBV.}, } @article {pmid39112929, year = {2024}, author = {Xu, X and Wu, Y and Zhao, Y and Liu, A and Yi, C and Zhang, A and Wang, X}, title = {Inhibition of Macrophage Pyroptosis─A New Therapeutic Strategy to Alleviate T-2 Toxin-Induced Subacute Liver Injury by Directly Competing with the Key Target.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {33}, pages = {18670-18681}, doi = {10.1021/acs.jafc.4c03340}, pmid = {39112929}, issn = {1520-5118}, mesh = {*Pyroptosis/drug effects ; Animals ; Mice ; *T-2 Toxin/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/genetics ; *Macrophages/drug effects/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Humans ; NF-kappa B/genetics/metabolism ; Cell Line ; Male ; Berberine/pharmacology ; Mice, Inbred C57BL ; Liver/drug effects/metabolism ; }, abstract = {Multiple compounds are related to the development of liver injury, such as toxins, drugs, and environmental pollutants. Although there are reports that the T-2 toxin can cause liver injury, its toxic mechanism remains unclear, which further impedes the development of effective antidotes. In this study, CRISPR-Cas9 genome-wide screening technology was used to identify transformation-related protein 53 inducible nuclear protein 1 (trp53inp1) as a toxic target of the T-2 toxin. Mechanism studies have shown that the T-2 toxin induced pyroptosis of macrophages (J774A.1 cells) by activating the trp53inp1/NF-κB/NLRP3/GSDMD-N pathway, leading to a subacute liver injury. Also, the new drug berberine (BER) identified through virtual screening significantly alleviated the subacute liver injury by competitively binding trp53inp1 via His224; the effect was better than those of the positive control drugs N-acetylcysteine (NAC) and disulfiram (DSF). In summary, the above results indicate that trp53inp1 is a key target for T-2 toxin to induce subacute liver injury and that inhibiting macrophage pyroptosis is a new method for treating liver injury. In addition, this study provides a new method and strategy for the discovery of key disease targets and the search for effective drugs.}, } @article {pmid39108325, year = {2024}, author = {Kwok, WC and Chan, SKS and Chiang, KY and Ho, CMJ}, title = {A double-blind randomized controlled trial of N-acetylcysteine (NAC) for the treatment of acute exacerbation of chronic obstructive pulmonary disease.}, journal = {Respirology case reports}, volume = {12}, number = {8}, pages = {e01449}, pmid = {39108325}, issn = {2051-3380}, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with acute exacerbation (AECOPD) being a common sequalae which negatively impact health status, rates of hospitalization and readmission, and disease progression. N-acetylcysteine (NAC) has been studied in COPD in both stable state and acute exacerbations, which has been shown to have small beneficial effects in stable COPD, as well as AECOPD. Yet, there has been lack of study with well-designed protocol to assess the role of NAC in more objective outcomes in AECOPD.

METHODS: This is a double-blind randomized controlled trial. Patients will be randomized in 1:1 ratio to receive oral NAC at 600 mg twice daily or placebo twice daily with standard of care. Partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2) and the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FiO2) will be measured on days 1 and 7. The following will be measure at baseline and on day 4 and 7: Forced expiratory volume in one second (FEV1), 24-hour sputum volume, oxygen saturation (SaO2), end-tidal CO2, Leicester Cough Questionnaire (LCQ) score, COPD Assessment Test (CAT) score, grading of wheeze and grade of dyspnoea; blood inflammatory markers (leucocyte count, neutrophil count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and high sensitivity CRP (hs-CRP)). Patients will be randomized to oral NAC at 600 mg twice daily or placebo for 7 days. The main outcome measures include: The difference in PaO2 on day 7. Secondary outcome: Change in following parameters on day 4/7 from baseline: FEV1, sputum volume, CAT score, LCQ score, SaO2, grade of wheeze; mMRC Dyspnoea Scale, end-tidal CO2, blood inflammatory marker, change in PaO2/FiO2 ratio from baseline to day 7, PaCO2 on day 7, 28 and 90 days' mortality, time to wean off supplemental oxygen, length of stay.Primary and secondary outcomes will be compared among the two treatment groups with two-sample t-test.

DISCUSSION: We hypothesize that NAC use in COPD exacerbation can provide benefits in clinical and laboratory parameters.

TRIAL REGISTRATION: Name of the registry : ClinicalTrials.gov Trial registration number : NCT05706402. URL of the trial registry record for this trial : https://classic.clinicaltrials.gov/ct2/show/NCT05706402 Date of registration : Registered on 11th January 2023 Funding of the trial : The Health and Medical Research Fund (HMRF). Name and contact information for the trial sponsor : Wang Chung Kwok, Clinical Assistant Professor, Honorary Associate Consultant, Queen Mary Hospital, The University of Hong Kong, Hong Kong. Role of sponsor : The funder is not involved in the planning of the study, gathering, analysing, and interpreting the data, or in preparing the manuscript.}, } @article {pmid39103770, year = {2024}, author = {Junqueira, A and Gomes, MJ and Lima, ARR and Pontes, THD and Rodrigues, EA and Damatto, FC and Depra, I and Paschoareli, GL and Pagan, LU and Fernandes, AAH and Oliveira-Jr, SA and Pacagnelli, FL and Okoshi, MP and Okoshi, K}, title = {Effects of concurrent training and N-acetylcysteine supplementation on cardiac remodeling and oxidative stress in middle-aged spontaneously hypertensive rats.}, journal = {BMC cardiovascular disorders}, volume = {24}, number = {1}, pages = {409}, pmid = {39103770}, issn = {1471-2261}, support = {307703/2022-3//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 307280/2022-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 2021/10923-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {Animals ; *Rats, Inbred SHR ; Male ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; *Ventricular Remodeling/drug effects ; *Hypertension/physiopathology/drug therapy/metabolism ; *NADPH Oxidases/metabolism/genetics ; Rats ; Antioxidants/pharmacology ; Physical Conditioning, Animal ; Disease Models, Animal ; NADPH Oxidase 2/metabolism/genetics ; NADPH Oxidase 4/metabolism/genetics ; Membrane Glycoproteins/metabolism/genetics ; Myocardium/metabolism/pathology ; Lipid Peroxides/metabolism ; Ventricular Function, Left/drug effects ; Dietary Supplements ; Hypertrophy, Left Ventricular/physiopathology/prevention & control/metabolism ; }, abstract = {BACKGROUND: This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR).

METHODS: Six-month-old male SHR were divided into sedentary (S, n = 12), concurrent training (T, n = 13), sedentary supplemented with NAC (SNAC, n = 13), and concurrent training with NAC supplementation (TNAC, n = 14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120 mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal-Wallis and Dunn.

RESULTS: Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40 ± 0.04; T 0.39 ± 0.03; SNAC 0.40 ± 0.04; TNAC 0.43 ± 0.04 *; * p < 0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50 ± 0.12; T 1.52 ± 0.10; SNAC 1.56 ± 0.12; TNAC 1.62 ± 0.14 * mm; * p < 0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4 ± 5.01; T 36.4 ± 2.96; SNAC 39.7 ± 3.44; TNAC 41.6 ± 3.57 * mm/s; * p < 0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210 ± 48; T 182 ± 43; SNAC 159 ± 33 *; TNAC 110 ± 23 *[#] nmol/g tissue; * p < 0.05 vs S, [#] p < 0.05 vs T and SNAC). Nox 2 and p22 phox expression was higher and p47 phox lower in T than S [S 1.37 (0.66-1.66); T 0.78 (0.61-1.04) *; SNAC 1.07 (1.01-1.38); TNAC 1.06 (1.01-1.15) arbitrary units; * p < 0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups.

CONCLUSION: N-acetylcysteine supplementation alone reduces oxidative stress in untreated spontaneously hypertensive rats. The combination of N-acetylcysteine and concurrent exercise further decreases oxidative stress. However, the lower oxidative stress does not translate into improved cardiac remodeling and function in untreated spontaneously hypertensive rats.}, } @article {pmid39103611, year = {2024}, author = {Leite, G and Rezaie, A and Morales, W and Weitsman, S and de Freitas Germano, J and Barlow, GM and Parodi, G and Pimentel, ML and Villanueva-Millan, MJ and Sanchez, M and Ayyad, S and Mathur, R and Pimentel, M}, title = {Low dose rifaximin combined with N-acetylcysteine is superior to rifaximin alone in a rat model of IBS-D: a randomized trial.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {18140}, pmid = {39103611}, issn = {2045-2322}, mesh = {Animals ; *Rifaximin/pharmacology/therapeutic use ; *Acetylcysteine/pharmacology/administration & dosage ; Rats ; *Escherichia coli/drug effects ; *Disease Models, Animal ; *Diarrhea/drug therapy/microbiology ; *Irritable Bowel Syndrome/drug therapy/microbiology ; Male ; Rats, Sprague-Dawley ; Drug Therapy, Combination ; }, abstract = {Rifaximin is FDA-approved for treatment of irritable bowel syndrome with diarrhea (IBS-D), but poor solubility may limit its efficacy against microbes in the mucus layer, e.g. Escherichia coli. Here we evaluate adding the mucolytic N-acetylcysteine (NAC) to improve rifaximin efficacy. In a resazurin checkerboard assay, combining rifaximin with NAC had significant synergistic effects in reducing E. coli levels. The optimal rifaximin + NAC combination was then tested in a validated rat model of IBS-D (induced by cytolethal distending toxin [CdtB] inoculation). Rats were inoculated with vehicle and treated with placebo (Control-PBS) or rifaximin + NAC (Control-Rif + NAC, safety), or inoculated with CdtB and treated with placebo (CdtB-PBS), rifaximin (CdtB-Rifaximin), or rifaximin + NAC (CdtB-Rif + NAC) for 10 days. CdtB-inoculated rats (CdtB-PBS) developed wide variability in stool consistency (P = 0.0014) vs. controls (Control-PBS). Stool variability normalized in rats treated with rifaximin + NAC (CdtB-Rif + NAC) but not rifaximin alone (CdtB-Rifaximin). Small bowel bacterial levels were elevated in CdtB-PBS rats but normalized in CdtB-Rif + NAC but not CdtB-Rifaximin rats. E. coli and Desulfovibrio spp levels (each associated with different IBS-D microtypes) were also elevated in CdtB-inoculated (CdtB-PBS) but normalized in CdtB-Rif + NAC rats. Cytokine levels normalized only in CdtB-Rif + NAC rats, in a manner predicted to be associated with reduced diarrhea driven by reduced E. coli. These findings suggest that combining rifaximin with NAC may improve the percentage of IBS-D patients responding to treatment.}, } @article {pmid39102049, year = {2024}, author = {Logge, WB and Haber, PS and Hurzeler, TP and Towers, EE and Morley, KC}, title = {The effects of N-acetyl cysteine on intrinsic functional connectivity and neural alcohol cue reactivity in treatment-seeking individuals with alcohol use disorder: a preliminary study.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {39102049}, issn = {1432-2072}, abstract = {N-acetyl cysteine (NAC) is a potential pharmacotherapy for alcohol use disorder (AUD), but it is not known whether it modulates neural activation to alcohol cues or intrinsic functional connectivity. We investigated whether NAC attenuates (i) alcohol cue-elicited activation, and (ii) intrinsic functional connectivity compared to placebo in patients with AUD. In this preliminary study, twenty-three individuals (7 females) with moderate-severe AUD received daily NAC (2400 mg/day, n = 9), or a placebo (n = 14) for at least 2 weeks. Participants completed a pre-treatment functional magnetic resonance imaging session (T0) and a post-treatment session (T1) comprising resting-state and visual alcohol cue reactivity task acquisitions. Activation differences between sessions, treatment, and session-by-treatment interaction were assessed. Resting-state functional connectivity examined using 377 node ROI-to-ROIs evaluated whether NAC reduced intrinsic functional connectivity after treatment. There were no differences in alcohol cue reactivity for brain activation or subjective craving between NAC and placebo during treatment or across sessions, or significant interaction. A significant treatment-by-time interaction, with reduced intrinsic connectivity was observed after treatment (T1) for NAC-treated compared to placebo-treated patients in the posterior cingulate node (9, left hemisphere) of the dorsal attentional network and connections to salience, ventral-attentional, somatosensory, and visual-peripheral networks implicated in AUD. NAC reduced intrinsic functional connectivity in patients with moderate-severe AUD after treatment compared to placebo, but did not attenuate alcohol cue-elicited activation. However, the absence of cue reactivity findings may result from low power, rather than the absence of cue reactivity findings associated with NAC. These results provide preliminary evidence that NAC treatment may modulate intrinsic functional connectivity brain activation in patients with alcohol use disorder, but replication in larger studies are required to determine the strength of this effect and any associations with clinical outcomes. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT03879759.}, } @article {pmid39101446, year = {2024}, author = {Cavalcanti, BC and Magalhães, IL and Rodrigues, DS and Cabral, VPF and Barbosa, AD and Valente Sá, LGDA and da Silva, LJ and de Andrade Neto, JB and da Silva, CR and de Moraes, MO and Dos Santos, CC and Nobre Júnior, HV}, title = {Anticandidal activity of Croton heliotropiifolius Kunth essential oil is enhanced by N-acetylcysteine and itraconazole.}, journal = {Future microbiology}, volume = {19}, number = {15}, pages = {1309-1320}, pmid = {39101446}, issn = {1746-0921}, mesh = {*Croton/chemistry ; *Oils, Volatile/pharmacology/chemistry ; *Itraconazole/pharmacology ; *Antifungal Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Microbial Sensitivity Tests ; *Biofilms/drug effects ; *Candida/drug effects ; Drug Synergism ; Animals ; Cell Line ; Fluconazole/pharmacology ; Cricetinae ; }, abstract = {Aim: Evaluate the anticandidal effect of Croton heliotropiifolius Kunth essential oil and its interaction with azoles and N-acetylcysteine (NAC) against planktonic cells and biofilms.Materials & methods: Broth microdilution and checkerboard methods were used to evaluate the individual and combined activity with fluconazole and itraconazole (ITRA). The antibiofilm effect of the oil was assessed in 96-well plates alone and combined with ITRA and NAC, and cytotoxicity determined by MTT.Results: The oil inhibited all Candida species growth. The activity was enhanced when associated with ITRA and NAC for planktonic cells and biofilms in formation. The effective concentrations were lower than the toxic ones to V79 cells.Conclusion: C. heliotropiifolius Kunth essential oil is an anticandidal alternative, and can be associated with ITRA and NAC.}, } @article {pmid39101362, year = {2024}, author = {Koh, A and Wong, T and Adiamah, A and Sanyal, S}, title = {Systematic review and meta-analysis of the effect of N-acetylcysteine on outcomes after liver resection.}, journal = {ANZ journal of surgery}, volume = {94}, number = {10}, pages = {1693-1701}, doi = {10.1111/ans.19183}, pmid = {39101362}, issn = {1445-2197}, mesh = {Humans ; *Acetylcysteine/administration & dosage ; Blood Transfusion/statistics & numerical data ; *Hepatectomy/adverse effects ; Length of Stay/statistics & numerical data ; *Postoperative Complications/epidemiology/prevention & control ; Randomized Controlled Trials as Topic ; Reperfusion Injury/epidemiology/prevention & control ; Treatment Outcome ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) is a recognized antioxidative agent that facilitates the conjugation of toxic metabolites. In recent years, NAC has been routinely used to limit ischaemia-reperfusion injury in liver transplantation. There remains, however, contradictory evidence on its effectiveness in liver resection. This meta-analysis examines the effectiveness of NAC in improving outcomes following hepatectomy.

METHODS: A comprehensive search of the MEDLINE, EMBASE, and Cochrane databases was performed to identify relevant randomized controlled trials (RCTs) published since database inception until November 2023. The outcomes of Day 1 biochemical markers (lactate, ALT, bilirubin, and INR), length of stay, transfusion rates, and morbidity were extracted. Quantitative pooling of data was based on a random-effects model. The study protocol was registered on PROSPERO (Registration no: CRD42023442429).

RESULTS: Five RCTs reporting on 388 patients undergoing hepatectomy were included in the analysis. There were no significant differences in patient demographics between groups. Post-operative lactate was lower in patients receiving NAC (WMD -0.61, 95% CI -1.19 to -0.04, I[2] = 67%). There were, however, no differences in the post-operative INR (WMD -0.04, 95% CI -0.19 to 0.12, I[2] = 96%) and ALT (WMD -94.94, 95% CI -228.46 to 40.38; I[2] = 67%). More importantly, there were no statistically significant differences in length of stay, transfusion rates, and morbidity between the two groups.

CONCLUSION: The administration of NAC in liver resection did not alter important biochemical parameters suggesting any real effectiveness in reducing hepatic dysfunction. There were no improvements in the clinical outcomes of length of stay, transfusion rates, and overall morbidity.}, } @article {pmid39100861, year = {2024}, author = {Zhang, R and Yang, A and Fu, J and Zhang, L and Yin, L and Xu, T and Dai, C and Su, W and Shen, W}, title = {Budesonide and N-acetylcysteine inhibit activation of the NLRP3 inflammasome by regulating miR-381 to alleviate acute lung injury caused by the pyroptosis-mediated inflammatory response.}, journal = {Toxicology research}, volume = {13}, number = {4}, pages = {tfae115}, pmid = {39100861}, issn = {2045-452X}, abstract = {BACKGROUND: The anti-inflammatory effects of budesonide (BUN) and N-acetylcysteine (NAC) attenuate acute lung injury (ALI). The aim of this study was to investigate the effects of combination therapy consisting of BUN and NAC on ALI and the underlying mechanisms.

METHODS: In vitro and in vivo models of ALI were generated by LPS induction. Western blotting was used to detect the expression levels of pyroptosis-related proteins and inflammation-related factors, and RT-qPCR was used to detect the expression of miR-381. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. ELISA was used to detect the levels of inflammation-related factors. HE staining was used to detect lung injury.

RESULTS: The results showed that LPS effectively induced pyroptosis in cells and promoted the expression of pyroptosis-related proteins (Caspase1, Gasdermin D and NLRP3) and inflammatory cytokines (TNF-α, IL-6 and IL-1β). The combination of BUN and NAC significantly alleviated LPS-induced pyroptosis and inflammation. In addition, the combination of BUN and NAC effectively promoted miR-381 expression. Transfection of miR-381 mimics effectively alleviated LPS-induced pyroptosis and inflammation, while transfection of miR-381 inhibitors had the opposite effect. miR-381 negatively regulates NLRP3 expression. Treatment with a miR-381 inhibitor or pc-NLRP3 reversed the effects of the combination of BUN and NAC. In a mouse model of ALI, the combination of BUN and NAC effectively improved lung injury, while treatment with a miR-381 inhibitor or pc-NLRP3 effectively reversed this effect.

CONCLUSION: Overall, this study revealed that BUN + NAC inhibits the activation of NLRP3 by regulating miR-381, thereby alleviating ALI caused by pyroptosis-mediated inflammation.}, } @article {pmid39094650, year = {2024}, author = {Ma, N and Liu, X and Zhao, L and Liu, Y and Peng, X and Ma, D and Ma, L and Kiyama, R and Dong, S}, title = {Bisphenol P induces increased oxidative stress in renal tissues of C57BL/6 mice and human renal cortical proximal tubular epithelial cells, resulting in kidney injury.}, journal = {The Science of the total environment}, volume = {949}, number = {}, pages = {175159}, doi = {10.1016/j.scitotenv.2024.175159}, pmid = {39094650}, issn = {1879-1026}, mesh = {Animals ; Humans ; Mice ; Apoptosis/drug effects ; Benzhydryl Compounds/toxicity ; Endocrine Disruptors/toxicity ; *Epithelial Cells/drug effects ; Kidney/cytology/drug effects/pathology ; Kidney Tubules, Proximal/cytology/drug effects/pathology ; *Mice, Inbred C57BL ; *Oxidative Stress/drug effects ; *Phenols/toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Bisphenol P (BPP) has been detected in human biological samples; however studies on its nephrotoxicity are scarce. Given the susceptibility of kidneys to endocrine-disrupting chemicals, there is an urgent need to investigate the renal toxicity of BPP. This study aimed to evaluate the effects of different concentrations of BPPs on the kidneys of C57BL/6 mice and elucidate the underlying mechanisms of renal damage using a combination of mouse renal transcriptomic data and human renal proximal tubular epithelial cells (HK-2). Mice were exposed to BPP (0, 0.3, 30, 3000 μg/kg bw/d) via gavage for 5 weeks. Renal injury was assessed based on changes in body and kidney weights, serum renal function indices, and histopathological examination. Transcriptomic analysis identified differentially expressed genes and pathways, whereas cellular assays were used to measure cell viability, reactive oxygen species (ROS), apoptosis, and the expression of key genes and proteins. The results show that BPP exposure induces renal injury, as evidenced by increased body weight, abnormal renal function indices, and renal tissue damage. Transcriptomic analysis revealed alterations in genes and pathways related to oxidative stress, p53 signaling, autophagy, and apoptosis. Cellular experiments confirmed that BPP induces oxidative stress and apoptosis. Furthermore, BPP exposure significantly inhibits autophagy, potentially exacerbating apoptosis and contributing to kidney injury. Treatment with a ROS inhibitor (N-Acetylcysteine, NAC) mitigated BPP-induced autophagy inhibition and apoptosis, implicating oxidative stress as a key factor. BPP exposure may lead to renal injury through excessive ROS accumulation, oxidative stress, inflammatory responses, autophagy inhibition, and increased apoptosis. The effects of NAC highlight the role of oxidative stress in BPP-induced nephrotoxicity. These findings enhance our understanding of BPP-induced nephrotoxicity and underscore the need to control BPP exposure to prevent renal disease. This study emphasized the importance of evaluating the safety of new Bisphenol A analogs, including BPP, in environmental toxicology.}, } @article {pmid39094233, year = {2024}, author = {Lu, WM and Ji, HN and Yang, RH and Cheng, KL and Yang, XL and Zeng, HL and Tao, K and Yin, DM and Wu, DH}, title = {A rat model of cerebral small vascular disease induced by ultrasound and protoporphyrin.}, journal = {Biochemical and biophysical research communications}, volume = {735}, number = {}, pages = {150451}, doi = {10.1016/j.bbrc.2024.150451}, pmid = {39094233}, issn = {1090-2104}, mesh = {Animals ; *Cerebral Small Vessel Diseases/pathology/diagnostic imaging ; *Disease Models, Animal ; *Protoporphyrins/pharmacology ; Male ; Rats ; *Rats, Sprague-Dawley ; Brain/pathology/drug effects/metabolism/diagnostic imaging ; Ultrasonic Waves ; Acetylcysteine/pharmacology ; Microspheres ; }, abstract = {Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 μm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.}, } @article {pmid39089892, year = {2024}, author = {Canbaz, FA and Yurtçu, M and Oltulu, P and Taştekin, G and Kocabaş, R and Doğan, M}, title = {Investigation of the Effects of N-acetylcysteine and Selenium on Vesicoureteral Reflux Nephropathy: An Experimental Study.}, journal = {Journal of pediatric surgery}, volume = {59}, number = {11}, pages = {161616}, doi = {10.1016/j.jpedsurg.2024.06.024}, pmid = {39089892}, issn = {1531-5037}, mesh = {*Vesico-Ureteral Reflux/complications/drug therapy ; Animals ; *Acetylcysteine/therapeutic use/pharmacology ; Rabbits ; *Selenium/therapeutic use ; Disease Models, Animal ; Kidney/drug effects ; Kidney Diseases/etiology/drug therapy/prevention & control ; Malondialdehyde/metabolism/analysis/urine ; Technetium Tc 99m Dimercaptosuccinic Acid ; Antioxidants/therapeutic use/administration & dosage/pharmacology ; Escherichia coli Infections/drug therapy/complications ; Male ; Cicatrix/prevention & control/etiology ; }, abstract = {INTRODUCTION: This study aimed to investigate the effects of N-acetylcysteine (NAC) and selenium (Se) on vesicoureteral reflux (VUR) nephropathy.

METHODS: A total of 44 rabbits in 7 groups, namely group 1 (Control), group 2 (VUR + sterile urine), group 3 (VUR + sterile urine + NAC), group 4 (VUR + sterile urine + Se), group 5 (VUR + infected urine), group 6 (VUR + infected urine + NAC) and group 7 (VUR + infected urine + Se), were used. [99m]Tc Dimercaptosuccinic acid renal scan (DMSA), cystogram and urine culture were performed both at the beginning and end of the study. Left VUR was created surgically, and E. coli was inoculated in infected urine groups. NAC and Se were administered daily for 21 days. Malondialdehyde (MDA) measurement, inflammatory response scores (IRSs), and cicatrization response scores (CRSs) in renal tissues were evaluated.

RESULTS: VUR did not reduce left renal uptake values in neither group 2 nor group 5. MDA levels of the left kidney were significantly higher in group 5 compared to group 1 (p = 0.001). There was no significant difference in MDA levels between group 5 and group 6, and between group 5 and group 7. Left kidney IRSs were found to be higher in all other groups except group 2 compared to the control group (p < 0.001). Left kidney CRSs were significantly higher in group 5 compared to group 2 (p = 0.026), group 6 (p < 0.001) and group 7 (p = 0.006).

CONCLUSION: A decrease in renal functions was not observed in VUR, even if there was infection. When CRSs were evaluated, NAC and Se had protective effects in terms of scar formation in VUR nephropathy.

TYPE OF STUDY: Experimental animal study.

LEVELS OF EVIDENCE: N/A.}, } @article {pmid39089052, year = {2024}, author = {Zhang, X and Qiu, W and Huang, J and Pang, X and Su, Y and Ye, J and Zhou, S and Tang, Z and Wang, R and Su, R}, title = {Insulin combined with N-acetylcysteine attenuates type 1 diabetes-induced splenic inflammatory injury in canines by inhibiting the MAPKs-NF-κB signaling pathway and pyroptosis.}, journal = {Journal of diabetes and its complications}, volume = {38}, number = {9}, pages = {108805}, doi = {10.1016/j.jdiacomp.2024.108805}, pmid = {39089052}, issn = {1873-460X}, mesh = {Animals ; Dogs ; *Acetylcysteine/pharmacology/therapeutic use ; *Diabetes Mellitus, Type 1/complications/drug therapy ; *Insulin ; *NF-kappa B/metabolism ; *Pyroptosis/drug effects ; *Diabetes Mellitus, Experimental/complications/drug therapy ; *Signal Transduction/drug effects ; Male ; *Drug Therapy, Combination ; *Spleen/drug effects/pathology ; Hypoglycemic Agents/pharmacology/therapeutic use ; Splenic Diseases/drug therapy/etiology/complications ; MAP Kinase Signaling System/drug effects ; }, abstract = {PURPOSE: Type 1 diabetes (T1DM) is a chronic metabolic disorder that can cause damage to multiple organs including the spleen. Sole insulin therapy is not satisfactory. This study aims to investigate the effects and mechanisms of combined treatment with insulin and N-acetylcysteine (NAC) on spleen damage in T1DM canines, in order to identify drugs that may better assist patients in the management of diabetes and its complications.

METHODS: The canine model of T1DM was established by intravenous injection of alloxan (ALX) and streptozotocin (STZ). The therapeutic effects of insulin and NAC were evaluated by clinical manifestations, spleen protein and mRNA expression.

RESULTS: The results indicate that the combined treatment of insulin and NAC can alleviate hyperglycemia and hematologic abnormalities, improve splenic histopathological changes, prevent fibrous tissue proliferation, and glycogen deposition. In addition, we observed that this combination treatment significantly suppressed the protein expression of p-P65/P65 (17.6 %, P < 0.05), NLRP3 (46.8 %, P < 0.05), and p-P38/P38 (37.1 %, P < 0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0 %, P < 0.01), TNF-α (30.3 %, P < 0.05), and NLRP3 (43.3 %, P < 0.05).

CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-κB pathway and pyroptosis. These findings provide a reference for the treatment strategies of diabetes and its complications.}, } @article {pmid39073694, year = {2024}, author = {Cheng, R and Jiang, Y and Zhang, Y and Ismail, M and Zhang, L and Jiang, Z and Yu, Q}, title = {Proteasome activity inhibition mediates endoplasmic reticulum stress-apoptosis in triptolide/lipopolysaccharide-induced hepatotoxicity.}, journal = {Cell biology and toxicology}, volume = {40}, number = {1}, pages = {60}, pmid = {39073694}, issn = {1573-6822}, support = {81973562//The research was supported by National Natural Science Foundation of China/ ; 82274200//The research was supported by National Natural Science Foundation of China/ ; CPU2018GY33//"Double First-Class" University project/ ; }, mesh = {*Phenanthrenes/pharmacology/toxicity ; *Diterpenes/pharmacology/toxicity ; *Endoplasmic Reticulum Stress/drug effects ; *Apoptosis/drug effects ; *Lipopolysaccharides/toxicity ; *Epoxy Compounds/toxicity/pharmacology ; Animals ; *Reactive Oxygen Species/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; *Endoplasmic Reticulum Chaperone BiP ; *Proteasome Inhibitors/pharmacology ; *Acetylcysteine/pharmacology ; Activating Transcription Factor 4/metabolism ; Phenylbutyrates/pharmacology ; Mice ; Chemical and Drug Induced Liver Injury/metabolism/pathology ; Liver/drug effects/pathology/metabolism ; Caspase 3/metabolism ; Male ; Leupeptins ; }, abstract = {Triptolide (TP) is a major active and toxic composition of the Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), exhibiting various therapeutic bioactivities. Among the toxic effects, the hepatotoxicity of TP deserves serious attention. Previously, our research group proposed a new view of TP-related hepatotoxicity: hepatic hypersensitivity under lipopolysaccharide (LPS) stimulation. However, the mechanism of TP/LPS-induced hepatic hypersensitivity remains unclear. In this study, we investigated the mechanism underlying TP/LPS-induced hypersensitivity from the perspective of the inhibition of proteasome activity, activated endoplasmic reticulum stress (ERS)-related apoptosis, and the accumulation of reactive oxygen species (ROS). Our results showed that N-acetylcysteine (NAC), a common ROS inhibitor, decreased the expression of cleaved caspase-3 and cleaved PARP, which are associated with FLIP enhancement. Moreover, 4-phenylbutyric acid (4-PBA), an ERS inhibitor, was able to alleviate TP/LPS-induced hepatotoxicity by reducing ERS-related apoptosis protein expression (GRP78, p-eIF2α/eIF2α, ATF4, CHOP, cleaved caspase-3 and cleaved PARP) and ROS levels, with ATF4 being an indispensable mediator. In addition, the proteasome activity inhibitor MG-132 further aggravated ERS-related apoptosis, which indicated that the inhibition of proteasome activity also plays an important role in TP/LPS-related liver injuries. In summary, we propose that TP/LPS may upregulate the activation of ERS-associated apoptosis by inhibiting proteasome activity and enhancing ROS production through ATF4.}, } @article {pmid39072707, year = {2024}, author = {Dino, P and Giuffrè, MR and Buscetta, M and Di Vincenzo, S and La Mensa, A and Cristaldi, M and Bucchieri, F and Lo Iacono, G and Bertani, A and Pace, E and Cipollina, C}, title = {Release of IL-1β and IL-18 in human primary bronchial epithelial cells exposed to cigarette smoke is independent of NLRP3.}, journal = {European journal of immunology}, volume = {54}, number = {10}, pages = {e2451053}, doi = {10.1002/eji.202451053}, pmid = {39072707}, issn = {1521-4141}, support = {G78I18000930007//Progetto "SeNSO/ ; //P.O. FESR Regione Siciliana/ ; //Fondazione Ri.MED./ ; }, mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Interleukin-18/metabolism ; *Interleukin-1beta/metabolism ; *Epithelial Cells/metabolism ; *Bronchi/cytology/pathology/metabolism ; *Inflammasomes/metabolism ; Cells, Cultured ; Smoke/adverse effects ; Caspase 1/metabolism ; Cigarette Smoking/adverse effects ; }, abstract = {Cigarette smoke (CS) is a major risk factor for chronic lung diseases and promotes activation of pattern recognition receptors in the bronchial epithelium. NOD-like receptor family, pyrin domain-containing 3 (NLRP3) is a pattern recognition receptor whose activation leads to caspase-1 cleavage, maturation/release of IL-1β and IL-18, and eventually pyroptosis. Whether the NLRP3 inflammasome participates in CS-induced inflammation in bronchial epithelial cells is still unclear. Herein, we evaluated the involvement of NLRP3 in CS-induced inflammatory responses in human primary bronchial epithelial cells. To this purpose, human primary bronchial epithelial cells were stimulated with CS extracts (CSE) and lytic cell death, caspase activation (-1, -8, -3/7), cytokine release (IL-1β, IL-18, and IL-8), NLRP3, pro-IL-1β/pro-IL-18 mRNA, and protein expression were measured. The impact of inhibitors of NLRP3 (MCC950), caspases, and the effect of the antioxidant N-acetyl cysteine were evaluated. We found that CSE increased pro-IL-1β expression and induced activation of caspase-1 and release of IL-1β and IL-18. These events were independent of NLRP3 and we found that NLRP3 was not expressed. N-acetyl cysteine reverted CSE-induced caspase-1 activation. Overall, our findings support that the bronchial epithelium may play a central role in the release of IL-1 family cytokines independently of NLRP3 in the lungs of smokers.}, } @article {pmid39070434, year = {2024}, author = {Awaji, AA and Bakhamees, BH and Alalshaikh, NK and Albelwi, NM and Al-Zahrani, MM and Alshammari, KF and Almutairi, SD and Siraj, IM and Aljaber, TN and Alnajdi, RS and Al-Majnooni, SS and Alserhani, AS}, title = {Vitamin E for the Prevention of Contrast-Induced Nephropathy: A Systematic Review and Meta-Analysis.}, journal = {Cureus}, volume = {16}, number = {6}, pages = {e63256}, pmid = {39070434}, issn = {2168-8184}, abstract = {Contrast-induced nephropathy (CIN) is a serious condition that may develop in patients undergoing diagnostic radiologic procedures. Several treatments have been assessed to prevent CIN development. This study aims to assess the efficacy and safety of vitamin E in the prevention of CIN compared to intravenous (IV) saline hydration. The literature search included MEDLINE/PubMed, Cochrane Central Register of Controlled Trials, the Web of Science, ProQuest, and Scopus for articles published until May 11, 2024, without language or time limits. The outcomes included the incidence of CIN, new-onset dialysis, and death (primary), as well as the change in serum creatinine and glomerular filtration rate (GFR) (secondary). Numerical and dichotomous outcomes were presented as standardized mean difference (SMD) and risk ratio (RR), respectively, with 95% confidence intervals (CI). Six clinical trials were included. Vitamin E was administered orally in varying doses, but one study used IV infusion. Vitamin E decreased the risk of developing CIN by 59% (n=5; pooled RR: 0.41; 95% CI: 0.25, 0.65; P<0.001) compared to IV hydration. None of the patients required renal replacement therapy. One patient on vitamin E died due to the occurrence of acute coronary syndrome. Vitamin E is a promising effective prophylaxis against CIN. However, the number of included studies and their sample sizes are small. The studies showed several limitations. There is a need for further high-quality clinical trials to ascertain the effectiveness of vitamin E compared to IV hydration and to compare vitamin E to other therapies, such as N-acetyl cysteine.}, } @article {pmid39066381, year = {2024}, author = {Bufan, B and Arsenović-Ranin, N and Živković, I and Ćuruvija, I and Blagojević, V and Dragačević, L and Kovačević, A and Kotur-Stevuljević, J and Leposavić, G}, title = {Modulation of T-Cell-Dependent Humoral Immune Response to Influenza Vaccine by Multiple Antioxidant/Immunomodulatory Micronutrient Supplementation.}, journal = {Vaccines}, volume = {12}, number = {7}, pages = {}, pmid = {39066381}, issn = {2076-393X}, support = {451-03-65/2024-03/ 200161, 451-03-66/2024-03/ 200161, and 451-03-66/2024-03.//Ministry of Science, Technological Development and Innovation, Republic of Serbia/ ; }, abstract = {Notwithstanding prevalence gaps in micronutrients supporting immune functions, the significance of their deficits/supplementation for the efficacy of vaccines is underinvestigated. Thus, the influence of supplementation combining vitamins C and D, zinc, selenium, manganese, and N-acetyl cysteine on immune correlates/surrogates of protection conferred by a quadrivalent influenza vaccine (QIV) in mice was investigated. The supplementation starting 5 days before the first of two QIV injections given 28 days apart increased the serum titres of total and neutralizing IgG against each of four influenza strains from QIV. Accordingly, the frequencies of germinal center B cells, follicular CD4+ T helper (Th) cells, and IL-21-producing Th cells increased in secondary lymphoid organs (SLOs). Additionally, the supplementation improved already increased IgG response to the second QIV injection by augmenting not only neutralizing antibody production, but also IgG2a response, which is important for virus clearance, through favoring Th1 differentiation as indicated by Th1 (IFN-γ)/Th2 (IL-4) signature cytokine level ratio upon QIV restimulation in SLO cell cultures. This most likely partly reflected antioxidant action of the supplement as indicated by splenic redox status analyses. Thus, the study provides a solid scientific background for further research aimed at repurposing the use of this safe and inexpensive micronutrient combination to improve response to the influenza vaccine.}, } @article {pmid39064168, year = {2024}, author = {Santus, P and Signorello, JC and Danzo, F and Lazzaroni, G and Saad, M and Radovanovic, D}, title = {Anti-Inflammatory and Anti-Oxidant Properties of N-Acetylcysteine: A Fresh Perspective.}, journal = {Journal of clinical medicine}, volume = {13}, number = {14}, pages = {}, pmid = {39064168}, issn = {2077-0383}, abstract = {N-acetyl-L-cysteine (NAC) was initially introduced as a treatment for mucus reduction and widely used for chronic respiratory conditions associated with mucus overproduction. However, the mechanism of action for NAC extends beyond its mucolytic activity and is complex and multifaceted. Contrary to other mucoactive drugs, NAC has been found to exhibit antioxidant, anti-infective, and anti-inflammatory activity in pre-clinical and clinical reports. These properties have sparked interest in its potential for treating chronic lung diseases, including chronic obstructive pulmonary disease (COPD), bronchiectasis (BE), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF), which are associated with oxidative stress, increased levels of glutathione and inflammation. NAC's anti-inflammatory activity is noteworthy, and it is not solely secondary to its antioxidant capabilities. In ex vivo models of COPD exacerbation, the anti-inflammatory effects have been observed even at very low doses, especially with prolonged treatment. The mechanism involves the inhibition of the activation of NF-kB and neurokinin A production, resulting in a reduction in interleukin-6 production, a cytokine abundantly present in the sputum and breath condensate of patients with COPD and correlates with the number of exacerbations. The unique combination of mucolytic, antioxidant, anti-infective, and anti-inflammatory properties positions NAC as a safe, cost-effective, and efficacious therapy for a plethora of respiratory conditions.}, } @article {pmid39063017, year = {2024}, author = {Kenari, F and Pintér, Z and Molnár, S and Borges, ID and Camargo, AJ and Napolitano, HB and Perjési, P}, title = {(E)-2-Benzylidenecyclanones: Part XIX. Reaction of (E)-2-(4'-X-Benzylidene)-1-tetralones with Cellular Thiols: Comparison of Thiol Reactivities of Open-Chain Chalcones and Their Six- and Seven-Membered Cyclic Analogs.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39063017}, issn = {1422-0067}, support = {EFOP-3.6.1.-16-2016-00004//European Union/ ; }, mesh = {Humans ; *Chalcones/chemistry/pharmacology ; *Sulfhydryl Compounds/chemistry ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology/chemistry ; Chromatography, High Pressure Liquid ; Glutathione/metabolism/chemistry ; Kinetics ; Benzylidene Compounds/chemistry ; }, abstract = {Non-enzyme-catalyzed thiol addition onto the α,β-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds.}, } @article {pmid39062784, year = {2024}, author = {Salanci, Š and Vilková, M and Martinez, L and Mirossay, L and Michalková, R and Mojžiš, J}, title = {The Induction of G2/M Phase Cell Cycle Arrest and Apoptosis by the Chalcone Derivative 1C in Sensitive and Resistant Ovarian Cancer Cells Is Associated with ROS Generation.}, journal = {International journal of molecular sciences}, volume = {25}, number = {14}, pages = {}, pmid = {39062784}, issn = {1422-0067}, support = {VEGA 1/0539/21//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Repub-lic/ ; VEGA 1/0498/23//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Repub-lic/ ; APVV-16-0446//Slovak Research and Development Agency/ ; ITMS2014+: 313011V455//EDRF/ ; ITMS2014 + 313011D103//EDRF/ ; }, mesh = {Humans ; *Reactive Oxygen Species/metabolism ; Female ; *Apoptosis/drug effects ; *Ovarian Neoplasms/metabolism/pathology/drug therapy ; *Drug Resistance, Neoplasm/drug effects ; *G2 Phase Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; *Chalcones/pharmacology ; Antineoplastic Agents/pharmacology ; Chalcone/pharmacology/analogs & derivatives ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Signal Transduction/drug effects ; DNA Damage/drug effects ; }, abstract = {Ovarian cancer ranks among the most severe forms of cancer affecting the female reproductive organs, posing a significant clinical challenge primarily due to the development of resistance to conventional therapies. This study investigated the effects of the chalcone derivative 1C on sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines. Our findings revealed that 1C suppressed cell viability, induced cell cycle arrest at the G2/M phase, and triggered apoptosis in both cell lines. These effects are closely associated with generating reactive oxygen species (ROS). Mechanistically, 1C induced DNA damage, modulated the activity of p21, PCNA, and phosphorylation of Rb and Bad proteins, as well as cleaved PARP. Moreover, it modulated Akt, Erk1/2, and NF-κB signaling pathways. Interestingly, we observed differential effects of 1C on Nrf2 levels between sensitive and resistant cells. While 1C increased Nrf2 levels in sensitive cells after 12 h and decreased them after 48 h, the opposite effect was observed in resistant cells. Notably, most of these effects were suppressed by the potent antioxidant N-acetylcysteine (NAC), underscoring the crucial role of ROS in 1C-induced antiproliferative activity. Moreover, we suggest that modulation of Nrf2 levels can, at least partially, contribute to the antiproliferative effect of chalcone 1C.}, } @article {pmid39062322, year = {2024}, author = {De Rose, DU and Landolfo, F and Pugnaloni, F and Giliberti, P and Santisi, A and Columbo, C and Martini, L and Ronchetti, MP and Schingo, PM and Salvatori, G and Fusaro, F and Bagolan, P and Dotta, A and Capolupo, I and Conforti, A}, title = {Use of N-Acetylcysteine in Preterm Neonates with Enteral Feeding Intolerance and Intestinal Obstruction: A Case Series and Review of the Literature.}, journal = {Children (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {39062322}, issn = {2227-9067}, support = {Current Research funds//Ministero della Salute/ ; }, abstract = {(1) Background: The use of N-acetylcysteine (NAC) to relieve meconium obstruction of prematurity in the first days of life has been reported, with NAC reducing the viscosity of luminal contents by cleaving the disulfide bonds of mucoproteins. However, its use in this population should be further explored since it has been associated with hypernatremia and transient increase in transaminases and bilirubin. (2) Methods: In this retrospective study, we included neonates admitted because of enteral feeding intolerance and intestinal obstruction from 2019 to 2021 who received NAC as a rescue therapy before explorative laparotomy. (3) Results: We summarized the clinical presentation of six preterm neonates with enteral feeding intolerance and intestinal obstruction who received NAC as a rescue therapy. Four infants (66.7%) gradually improved without the need for explorative laparotomy, whereas two infants (33.3%) underwent the creation of an ileostomy. No cases of hypernatremia or hepatic derangement associated with NAC therapy were observed. (4) Conclusions: We described the use of NAC treatment by nasogastric tube and/or rectal enemas in preterm infants with enteral feeding intolerance and intestinal obstruction after a multidisciplinary assessment, but the limited sample size did not allow us to obtain definitive conclusions and further research is needed in this field, given the limited evidence about NAC treatment in preterm infants.}, } @article {pmid39062036, year = {2024}, author = {Orban, C and Agapie, M and Bratu, A and Jafal, M and Duțu, M and Popescu, M}, title = {No Significant Beneficial Effects of Intravenous N-Acetylcysteine on Patient Outcome in Non-Paracetamol Acute Liver Failure: A Meta-Analysis of Randomized Controlled Trials.}, journal = {Biomedicines}, volume = {12}, number = {7}, pages = {}, pmid = {39062036}, issn = {2227-9059}, abstract = {Acute liver failure is a life-threatening organ dysfunction with systemic organ involvement and is associated with significant mortality and morbidity unless specific management is undertaken. This meta-analysis aimed to assess the effects of intravenous N-acetylcysteine (NAC) on mortality and the length of hospital stay in patients with non-acetaminophen acute liver failure. Two hundred sixty-six studies from four databases were screened, and four randomized control trials were included in the final analysis. Our results could not demonstrate increased overall survival (OR 0.70, 95% CI [0.34, 1.44], p = 0.33) or transplant-free survival (OR 0.90, 95% CI [0.25, 3.28], p = 0.87) in patients treated with intravenous NAC. We observed an increased overall survival in adult patients treated with NAC (OR 0.59, 95% CI [0.35, 0.99], p = 0.05) compared to pediatric patients, but whether this is attributed to the age group or higher intravenous dose administered remains unclear. We did not observe a decreased length of stay in NAC-treated patients (OR -5.70, 95% CI [-12.44, 1.05], p = 0.10). In conclusion, our meta-analysis could not demonstrate any significant benefits on overall and transplant-free patient survival in non-acetaminophen ALF. Future research should also focus on specific etiologies of ALF that may benefit most from the use of NAC.}, } @article {pmid39061932, year = {2024}, author = {Ebbert, L and von Montfort, C and Wenzel, CK and Reichert, AS and Stahl, W and Brenneisen, P}, title = {A Combination of Cardamonin and Doxorubicin Selectively Affect Cell Viability of Melanoma Cells: An In Vitro Study.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061932}, issn = {2076-3921}, support = {BR1551/7-1//Deutsche Forschungsgemeinschaft/ ; }, abstract = {Treatment of the most aggressive and deadliest form of skin cancer, the malignant melanoma, still has room for improvement. Its invasive nature and ability to rapidly metastasize and to develop resistance to standard treatment often result in a poor prognosis. While the highly effective standard chemotherapeutic agent doxorubicin (DOX) is widely used in a variety of cancers, systemic side effects still limit therapy. Especially, DOX-induced cardiotoxicity remains a big challenge. In contrast, the natural chalcone cardamonin (CD) has been shown to selectively kill tumor cells. Besides its anti-tumor activity, CD exhibits anti-oxidative, anti-inflammatory and anti-bacterial properties. In this study, we investigated the effect of the combinational treatment of DOX with CD on A375 melanoma cells compared to normal human dermal fibroblasts (NHDF) and rat cardiac myoblasts (H9C2 cells). DOX-induced cytotoxicity was unselective and affected all cell types, especially H9C2 cardiac myoblasts, demonstrating its cardiotoxic effect. In contrast, CD only decreased the cell viability of A375 melanoma cells, without harming normal (healthy) cells. The addition of CD selectively protected human dermal fibroblasts and rat cardiac myoblasts from DOX-induced cytotoxicity. While no apoptosis was induced by the combinational treatment in normal (healthy) cells, an apoptosis-mediated cytotoxicity was demonstrated in A375 melanoma cells. CD exhibited thiol reactivity as it was able to directly interact with N-acetylcysteine (NAC) in a cell-free assay and to induce heme oxygenase-1 (HO-1) in all cell types. And that took place in a reactive oxygen species (ROS)-independent manner. DOX decreased the mitochondrial membrane potential (Δψm) in all cell types, whereas CD selectively decreased mitochondrial respiration, affecting basal respiration, maximal respiration, spare respiratory capacity and ATP production in A375 melanoma cells, but not in healthy cardiac myoblasts. The DOX-induced cytotoxicity seen in melanoma cells was ROS-independent, whereas the cytotoxic effect of CD was associated with CD-induced ROS-formation and/or its thiol reactivity. This study highlights the beneficial properties of the addition of CD to DOX treatment, which might protect patients from DOX-induced cardiotoxicity. Future experiments with other tumor cell lines or a mouse model should substantiate this hypothesis.}, } @article {pmid39061900, year = {2024}, author = {Tsai, MS and Liou, GG and Liao, JW and Lai, PY and Yang, DJ and Wu, SH and Wang, SH}, title = {N-acetyl Cysteine Overdose Induced Acute Toxicity and Hepatic Microvesicular Steatosis by Disrupting GSH and Interfering Lipid Metabolisms in Normal Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061900}, issn = {2076-3921}, support = {NSTC 109-2320-B-040-005 and NSTC 110-2320-B-040-008//National Science and Technology Council Taiwan/ ; }, abstract = {N-acetyl cysteine (NAC) is a versatile drug used in various conditions, but the limitations and toxicities are not clear. The acute toxicity and toxicological mechanisms of an intraperitoneal injection of NAC in normal mice were deciphered. The LD50 for male and female BALB/cByJNarl mice were 800 mg/kg and 933 mg/kg. The toxicological mechanisms of 800 mg/kg NAC (N800) were investigated. The serum biomarkers of hepatic and renal indices dramatically increased, followed by hepatic microvesicular steatosis, renal tubular injury and necrosis, and splenic red pulp atrophy and loss. Thus, N800 resulted in mouse mortality mainly due to acute liver, kidney, and spleen damages. The safe dose (275 mg/kg) of NAC (N275) increased hepatic antioxidant capacity by increasing glutathione levels and catalase activity. N275 elevated the hepatic gene expressions of lipid transporter, lipid synthesis, β-oxidation, and ketogenesis, suggesting a balance between lipid production and consumption, and finally, increased ATP production. In contrast, N800 increased hepatic oxidative stress by decreasing glutathione levels through suppressing Gclc, and reducing catalase activity. N800 decreased the hepatic gene expressions of lipid transporter, lipid synthesis, and interferred β-oxidation, leading to lipid accumulation and increasing Cyp2E1 expression, and finally, decreased ATP production. Therefore, NAC doses are limited for normal individuals, especially via intraperitoneal injection or similar means.}, } @article {pmid39061896, year = {2024}, author = {Xie, B and Liu, Y and Chen, C and Velkov, T and Tang, S and Shen, J and Dai, C}, title = {Colistin Induces Oxidative Stress and Apoptotic Cell Death through the Activation of the AhR/CYP1A1 Pathway in PC12 Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061896}, issn = {2076-3921}, support = {2023YFD1802300//National Key R&D Program/ ; 32102724//National Natural Science Foundation of China/ ; }, abstract = {Colistin is commonly regarded as the "last-resort" antibiotic for combating life-threatening infections caused by multidrug-resistant (MDR) gram-negative bacteria. Neurotoxicity is a potential adverse event associated with colistin application in clinical settings, yet the exact molecular mechanisms remain unclear. This study examined the detrimental impact of colistin exposure on PC12 cells and the associated molecular mechanisms. Colistin treatment at concentrations of 0-400 μM decreased cell viability and induced apoptotic cell death in both time- and concentration-dependent manners. Exposure to colistin triggered the production of reactive oxygen species (ROS) and caused oxidative stress damage in PC12 cells. N-acetylcysteine (NAC) supplementation partially mitigated the cytotoxic and apoptotic outcomes of colistin. Evidence of mitochondrial dysfunction was observed through the dissipation of membrane potential. Additionally, colistin treatment upregulated the expression of AhR and CYP1A1 mRNAs in PC12 cells. Pharmacological inhibition of AhR (e.g., using α-naphthoflavone) or intervention with the CYP1A1 gene significantly decreased the production of ROS induced by colistin, subsequently lowering caspase activation and cell apoptosis. In conclusion, our findings demonstrate, for the first time, that the activation of the AhR/CYP1A1 pathway contributes partially to colistin-induced oxidative stress and apoptosis, offering insights into the cytotoxic effects of colistin.}, } @article {pmid39061830, year = {2024}, author = {Carles, L and Gibaja, A and Scheper, V and Alvarado, JC and Almodovar, C and Lenarz, T and Juiz, JM}, title = {Efficacy and Mechanisms of Antioxidant Compounds and Combinations Thereof against Cisplatin-Induced Hearing Loss in a Rat Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {7}, pages = {}, pmid = {39061830}, issn = {2076-3921}, support = {PID2020-117266RB-C22-1, EXC 2177/1, ID:390895286, SBPLY/17/180501/000544.//Ministerio de Ciencia Innovación, MCINN, Gobierno de España, Plan Estatal de I+D+i, PID2020-117266RB-C22-1, Cluster of Excellence "Hearing4All" EXC 2177/1, ID:390895286, part of the Germany´s Excellence Strategy of the German Research Foundation, DFG. Co/ ; }, abstract = {Cisplatin is an election chemotherapeutic agent used for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. Here, we show evidence that a cocktail of vitamins A, C, and E along with Mg[++] (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in rats. The addition of 500 mg N-acetylcysteine (NAC), which, administered individually, also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation results in functional degradation of ACEMg otoprotection. Mg[++] administered alone, as MgSO4, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection is also greatly degraded. Increasing the dose of NAC to 1000 mg also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet-to-be-defined "antioxidation threshold", results in unrecoverable redox imbalance with loss of otoprotectant activity.}, } @article {pmid39060756, year = {2024}, author = {Doi, K and Inoue, J and Ninomiya, M and Sano, A and Tsuruoka, M and Sato, K and Onuki, M and Sawahashi, S and Ouchi, K and Masamune, A}, title = {Three consecutive cases of acute liver failure in young women due to acetaminophen overdose: insights into Japanese social issues and transplantation landscape.}, journal = {Clinical journal of gastroenterology}, volume = {17}, number = {5}, pages = {948-954}, pmid = {39060756}, issn = {1865-7265}, mesh = {Humans ; Female ; *Acetaminophen/poisoning ; *Liver Failure, Acute/chemically induced/surgery ; *Drug Overdose ; Japan ; Young Adult ; *Liver Transplantation ; *Nonprescription Drugs/poisoning ; Analgesics, Non-Narcotic/poisoning ; Acetylcysteine/therapeutic use/administration & dosage ; Chemical and Drug Induced Liver Injury/etiology ; East Asian People ; }, abstract = {Acetaminophen (APAP) is an over-the-counter (OTC) drug known worldwide for its safety and efficacy. However, in Japan, OTC drug overdose has become a prominent social problem in recent years due to stricter regulations for other drugs, especially among young people, and APAP is an increasing cause of acute liver injury due to overdose. This report describes three consecutive cases of acute liver failure in young women (22, 22 and 19 years old) due to APAP overdose in December 2023. Despite severe liver injury, indicated by high ALT levels and coagulopathy, these cases recovered without requiring liver transplantation. This report discusses three cases of acute liver failure in young Japanese women following APAP overdose, reflecting a national increase in such cases due to increased misuse of OTC drugs and societal factors. Key findings include the need for early treatment with N-acetylcysteine (NAC) and the importance of mental health assessment in the management of overdose patients. The cases underscore the need for prompt team-based care to prevent serious outcomes and highlight the complexity of liver transplantation decisions in Japan, highlighting the need for comprehensive strategies to address the escalating problem of APAP overdose.}, } @article {pmid39055649, year = {2024}, author = {Zheng, H and Liu, J and Sun, L and Meng, Z}, title = {The role of N-acetylcysteine in osteogenic microenvironment for bone tissue engineering.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1435125}, pmid = {39055649}, issn = {2296-634X}, abstract = {Bone defect is a common clinical symptom which can arise from various causes. Currently, bone tissue engineering has demonstrated positive therapeutic effects for bone defect repair by using seeding cells such as mesenchymal stem cells and precursor cells. N-acetylcysteine (NAC) is a stable, safe and highly bioavailable antioxidant that shows promising prospects in bone tissue engineering due to the ability to attenuate oxidative stress and enhance the osteogenic potential and immune regulatory function of cells. This review systematically introduces the antioxidant mechanism of NAC, analyzes the advancements in NAC-related research involving mesenchymal stem cells, precursor cells, innate immune cells and animal models, discusses its function using the classic oral microenvironment as an example, and places particular emphasis on the innovative applications of NAC-modified tissue engineering biomaterials. Finally, current limitations and future prospects are proposed, with the aim of providing inspiration for targeted readers in the field.}, } @article {pmid39053861, year = {2024}, author = {Yu, H and Xie, Y and Lan, L and Ma, S and Mok, SWF and Wong, IN and Wang, Y and Zhong, G and Yuan, L and Zhao, H and Hu, X and Macrae, VE and He, S and Chen, G and Zhu, D}, title = {Sirt7 protects against vascular calcification via modulation of reactive oxygen species and senescence of vascular smooth muscle cells.}, journal = {Free radical biology & medicine}, volume = {223}, number = {}, pages = {30-41}, doi = {10.1016/j.freeradbiomed.2024.07.021}, pmid = {39053861}, issn = {1873-4596}, mesh = {Animals ; *Vascular Calcification/pathology/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Muscle, Smooth, Vascular/metabolism/pathology ; Mice ; *Cellular Senescence ; *Sirtuins/metabolism/genetics ; *Myocytes, Smooth Muscle/metabolism/pathology ; *Oxidative Stress ; Humans ; NF-E2-Related Factor 2/metabolism/genetics ; Male ; Cholecalciferol/pharmacology ; Renal Insufficiency, Chronic/pathology/metabolism/genetics ; Mice, Inbred C57BL ; Cells, Cultured ; }, abstract = {Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD[+]-dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D3 (vD3). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification.}, } @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.}, } @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.}, } @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 = {60}, number = {5}, pages = {4830-4842}, 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/ ; }, mesh = {Animals ; *Solitary Nucleus/drug effects/physiology/metabolism ; Male ; *Rats, Sprague-Dawley ; *Chemokines/metabolism ; *Blood Pressure/drug effects/physiology ; *Sympathetic Nervous System/physiology/drug effects ; Rats ; Receptors, Chemokine/metabolism ; Heart Rate/drug effects/physiology ; Intercellular Signaling Peptides and Proteins/pharmacology/administration & dosage ; NADPH Oxidases/metabolism ; Superoxides/metabolism ; }, 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}, 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.}, } @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.}, } @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.}, } @article {pmid39038059, year = {2024}, author = {Bandekar, M and Panda, D}, title = {Microtubule depolymerization induces ferroptosis in neuroblastoma cells.}, journal = {IUBMB life}, volume = {76}, number = {12}, pages = {1186-1198}, 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)/ ; }, mesh = {*Ferroptosis/drug effects ; Humans ; *Neuroblastoma/pathology/metabolism/drug therapy ; *Microtubules/metabolism/drug effects ; *Reactive Oxygen Species/metabolism ; *Lipid Peroxidation/drug effects ; Cell Line, Tumor ; Deferoxamine/pharmacology ; Iron/metabolism ; Cell Proliferation/drug effects ; Glutathione/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; Nocodazole/pharmacology ; Vinblastine/pharmacology ; }, 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 {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.}, } @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 = {39}, number = {11}, pages = {5008-5018}, 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/ ; }, mesh = {Animals ; *Lipopolysaccharides/pharmacology/toxicity ; *Reactive Oxygen Species/metabolism ; Rats ; *Lysosomes/drug effects/metabolism ; *Hepatocytes/drug effects/metabolism ; Cell Line ; Cathepsin D/metabolism ; Caspase 3/metabolism ; Caspase 8/metabolism ; Cell Survival/drug effects ; Apoptosis/drug effects ; Lysosomal-Associated Membrane Protein 2/metabolism ; Cell Death/drug effects ; }, 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 = {26}, number = {6}, pages = {645-652}, pmid = {39028629}, issn = {1745-7262}, mesh = {Humans ; Male ; Antioxidants/therapeutic use ; *Infertility, Male/diagnosis/therapy ; Meta-Analysis as Topic ; Sperm Count ; Sperm Motility ; Systematic Reviews as Topic ; }, 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 = {12}, number = {17}, pages = {4376-4385}, doi = {10.1039/d4bm00381k}, pmid = {39028033}, issn = {2047-4849}, mesh = {Humans ; *Glycerol/chemistry ; *Polymers/chemistry/pharmacology ; *Sputum/metabolism/chemistry ; *Sulfhydryl Compounds/chemistry/pharmacology ; Cystic Fibrosis/metabolism/drug therapy ; Mucin 5AC/metabolism ; Lung Diseases, Obstructive/drug therapy/metabolism ; Mucin-5B/metabolism ; Sulfates/chemistry/pharmacology ; Expectorants/pharmacology/chemistry ; Mucus/metabolism/chemistry ; Rheology ; Acetylcysteine/pharmacology/chemistry ; Viscosity ; }, 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 {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 = {296}, number = {}, pages = {111700}, doi = {10.1016/j.cbpa.2024.111700}, pmid = {39019252}, issn = {1531-4332}, mesh = {Animals ; *Reactive Oxygen Species/metabolism ; *Brachyura/physiology/metabolism/drug effects ; *Salinity ; *Acclimatization ; Osmotic Pressure ; Acetylcysteine/pharmacology ; Seawater ; Antioxidants/metabolism ; Oxidative Stress/drug effects ; Gills/metabolism/drug effects ; Osmoregulation ; }, 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 {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 = {135}, number = {3}, pages = {285-294}, pmid = {39004668}, issn = {1742-7843}, mesh = {*Acetylcysteine/administration & dosage/therapeutic use ; Humans ; *Acetaminophen/poisoning/administration & dosage ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury/etiology/prevention & control ; Analgesics, Non-Narcotic/poisoning/administration & dosage ; Antidotes/administration & dosage/therapeutic use ; Dose-Response Relationship, Drug ; Observational Studies as Topic ; }, 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 = {221}, number = {}, pages = {111962}, doi = {10.1016/j.mad.2024.111962}, pmid = {39004152}, issn = {1872-6216}, mesh = {*Cellular Senescence/drug effects ; Animals ; *Oxidative Stress/drug effects ; Mice ; Humans ; *Transcription Factors/metabolism/genetics ; *Atherosclerosis/metabolism/pathology/genetics ; *Carrier Proteins/metabolism/genetics ; *Endothelial Cells/metabolism ; *Reactive Oxygen Species/metabolism ; Thioredoxins/metabolism/genetics ; Human Umbilical Vein Endothelial Cells/metabolism ; Gene Knockdown Techniques ; }, 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.}, } @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 = {26}, number = {8}, 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 = {20}, number = {4}, pages = {381-388}, pmid = {38992233}, issn = {1937-6995}, mesh = {Humans ; *Acetylcysteine/therapeutic use/administration & dosage ; *Acetaminophen ; Retrospective Studies ; Female ; Male ; Adult ; *Chemical and Drug Induced Liver Injury/etiology/prevention & control ; Middle Aged ; *Medication Errors/prevention & control ; Analgesics, Non-Narcotic ; Antidotes/administration & dosage/adverse effects/therapeutic use ; Treatment Outcome ; Drug Administration Schedule ; Drug Packaging ; }, 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.}, } @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 = {947}, number = {}, pages = {174534}, doi = {10.1016/j.scitotenv.2024.174534}, pmid = {38986690}, issn = {1879-1026}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Liver Cirrhosis/chemically induced ; Mice ; *Hepatocytes/drug effects ; Animals ; *Inflammasomes/metabolism ; *Glutathione/metabolism ; *Arsenic/toxicity ; Acetylcysteine/pharmacology ; Reactive Oxygen Species/metabolism ; }, 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 = {602}, number = {15}, pages = {3833-3852}, doi = {10.1113/JP286266}, pmid = {38985827}, issn = {1469-7793}, support = {1220421//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; PG/10/99/28656/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Animals ; *Hydrogen Sulfide/metabolism ; *Acetylcysteine/pharmacology ; Chick Embryo ; Humans ; *Epigenesis, Genetic ; Female ; Pregnancy ; *Fetal Growth Retardation/metabolism/genetics/physiopathology ; *Hypoxia/metabolism/physiopathology ; DNA Methylation ; Cystathionine gamma-Lyase/genetics/metabolism ; Vasodilation/drug effects ; Placenta/metabolism/blood supply ; Umbilical Arteries/metabolism ; }, 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 {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 = {79}, number = {3}, pages = {652-660}, doi = {10.1002/jpn3.12312}, pmid = {38973318}, issn = {1536-4801}, support = {1-14-CE-04//American Diabetes Association/ ; //Nemours Biomedical Research/ ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Pilot Projects ; Male ; Female ; Child ; Double-Blind Method ; *Non-alcoholic Fatty Liver Disease/drug therapy/complications/metabolism ; Adolescent ; *Oxidative Stress/drug effects ; *Insulin Resistance ; *Biomarkers/blood ; Liver/metabolism/diagnostic imaging/drug effects ; Pediatric Obesity/complications/drug therapy ; Treatment Outcome ; }, 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 liver stiffness (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. homeostasis model assessment for insulin resistance (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 IR (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 = {947}, number = {}, pages = {174558}, doi = {10.1016/j.scitotenv.2024.174558}, pmid = {38972409}, issn = {1879-1026}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Ivermectin/toxicity/analogs & derivatives ; *Brachyura/drug effects/physiology ; *Energy Metabolism/drug effects ; *Water Pollutants, Chemical/toxicity ; *Ferroptosis/drug effects ; Behavior, Animal/drug effects ; }, 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 {pmid38971422, year = {2024}, author = {Guo, Z and Wu, J and Hu, Y and Zhou, J and Li, Q and Zhang, Y and Zhang, J and Yang, L and Wang, S and Zhang, H and Yang, J}, title = {Exogenous iron caused osteocyte apoptosis, increased RANKL production, and stimulated bone resorption through oxidative stress in a murine model.}, journal = {Chemico-biological interactions}, volume = {399}, number = {}, pages = {111135}, doi = {10.1016/j.cbi.2024.111135}, pmid = {38971422}, issn = {1872-7786}, mesh = {Animals ; *Osteocytes/drug effects/metabolism ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *RANK Ligand/metabolism ; *Mice, Inbred C57BL ; *Bone Resorption/metabolism/pathology ; Mice ; *Iron/metabolism ; Disease Models, Animal ; Male ; Iron Overload/metabolism/pathology/chemically induced ; Osteoprotegerin/metabolism ; Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing ; }, abstract = {Iron overload is a risk factor for osteoporosis due to its oxidative toxicity. Previous studies have demonstrated that an excessive amount of iron increases osteocyte apoptosis and receptor activator of nuclear factor κ-B ligand (RANKL) production, which stimulates osteoclast differentiation in vitro. However, the effects of exogenous iron supplementation-induced iron overload on osteocytes in vivo and its role in iron overload-induced bone loss are unknown. This work aimed to develop an iron overloaded murine model of C57BL/6 mice by intraperitoneal administration of iron dextran for two months. The iron levels in various organs, bone, and serum, as well as the microstructure and strength of bone, apoptosis of osteocytes, oxidative stress in bone tissue, and bone formation and resorption, were assessed. The results showed that 2 months of exogenous iron supplementation significantly increased iron levels in the liver, spleen, kidney, bone tissue, and serum. Iron overload negatively affected bone microstructure and strength. Osteocyte apoptosis and empty lacunae rate were elevated by exogenous iron. Iron overload upregulated RANKL expression but had no significant impact on osteoprotegerin (OPG) and sclerostin levels. Static and dynamic histologic analyses and serum biochemical assay showed that iron overload increased bone resorption without significantly affecting bone formation. Exogenous iron promoted oxidative stress in osteocytes in vivo and in vitro. Additional supplementation of iron chelator (deferoxamine) or N-acetyl-l-cysteine (NAC) partially alleviated bone loss, osteocyte apoptosis, osteoclast formation, and oxidative stress due to iron overload. These findings, in line with prior in vitro studies, suggest that exogenous iron supplementation induces osteoclastogenesis and osteoporosis by promoting osteocyte apoptosis and RANKL production via oxidative stress.}, } @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 Lin, L 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 = {400}, number = {}, pages = {111133}, doi = {10.1016/j.cbi.2024.111133}, pmid = {38969277}, issn = {1872-7786}, mesh = {Animals ; *Pyroptosis/drug effects ; Mice ; *Phosphate-Binding Proteins/metabolism/genetics ; *Psoralea/chemistry ; *Inflammasomes/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Chemical and Drug Induced Liver Injury/metabolism/pathology ; Mice, Inbred C57BL ; Lipopolysaccharides/toxicity ; Liver/drug effects/metabolism/pathology ; Flavonoids/pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Caspase 1/metabolism ; Interleukin-1beta/metabolism ; Gasdermins ; }, 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 {pmid38962807, year = {2024}, author = {Lv, H and Yang, H and Duan, Y and Yan, C and Li, G and Zhao, G and Sun, F and Feng, Y and Li, Y and Fu, Y and Li, Y and Zhao, Z and Jia, X}, title = {S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine for the treatment of non-small cell lung cancer through regulating NF-κB signalling pathway without neurotoxicity.}, journal = {Journal of drug targeting}, volume = {32}, number = {9}, pages = {1111-1124}, doi = {10.1080/1061186X.2024.2374037}, pmid = {38962807}, issn = {1029-2330}, mesh = {Animals ; Humans ; Mice ; A549 Cells ; Acetylcysteine/pharmacology ; *Antineoplastic Agents/pharmacology/administration & dosage ; Apoptosis/drug effects ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Ditiocarb/pharmacology ; Epithelial-Mesenchymal Transition/drug effects ; *Lung Neoplasms/drug therapy/pathology ; Mice, Inbred BALB C ; Mice, Nude ; NF-kappa B/metabolism ; *Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {The discovery of novel targeted agents for non-small cell lung cancer (NSCLC) remains an important research landscape due to the limited efficacy, side effects and drug resistance of current treatment options. Among many repurposed drugs, disulphiram (DSF) has shown the potential to target tumours. However, its unpleasant neurotoxicity greatly limits its use. A DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine (DS-NAC), was synthesised against NSCLC. The therapeutic effects, mechanism and toxicities of DS-NAC were evaluated in A549 and H460 cells and the mouse model of in situ lung cancer. The in vitro results exhibited that DS-NAC had potent anti-proliferation, apoptotic, anti-metastasis and epithelial-mesenchymal transition (EMT) inhibition effects. In the orthotopic lung cancer mouse model, therapeutic effects of DS-NAC were better than those of DSF and were similar to docetaxel (DTX). Also, results from western blot and immunohistochemistry showed that DS-NAC in combination with copper exerted therapeutic effects via regulating NF-κB signalling pathway and ROS-related proteins such as HIF-1α, Nrf2 and PKC-δ rather than regulating ROS level directly. Moreover, the safety evaluation study showed that DS-NAC had low haematologic and hepatic toxicities in comparison with DTX as well as low neurological toxicity compared with DSF. DS-NAC could be a promising anti-lung cancer agent with a favourable safety profile.}, } @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.}, } @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 = {}, 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.}, } @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 {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 = {20}, number = {11}, pages = {2490-2510}, pmid = {38953310}, issn = {1554-8635}, mesh = {*NF-E2-Related Factor 2/metabolism ; *Sequestosome-1 Protein/metabolism ; Animals ; Humans ; *AMP-Activated Protein Kinases/metabolism ; *Antioxidants/metabolism ; *Stress, Physiological ; *Feedback, Physiological ; Mice ; Phosphorylation ; Protein Serine-Threonine Kinases/metabolism/genetics ; Lysosomes/metabolism ; Autophagy/physiology/genetics ; }, 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 {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 {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 = {30}, number = {9}, pages = {931.e1-931.e10}, doi = {10.1016/j.jtct.2024.06.020}, pmid = {38944154}, issn = {2666-6367}, mesh = {Humans ; *Thiotepa/administration & dosage/therapeutic use ; *Thrombotic Microangiopathies/epidemiology/etiology ; *Cyclophosphamide/adverse effects/therapeutic use ; Male ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Retrospective Studies ; Adolescent ; Child ; Young Adult ; *Transplantation Conditioning/adverse effects ; Child, Preschool ; Adult ; Risk Factors ; Infant ; }, abstract = {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. 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 < .2 for allogeneic HCT. SPSS (v29) was used to estimate all summary statistics, cumulative incidences, and uni- and bi-variate analyses. 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 = .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 < .001). Use of either CY or TT (HR = 10.14; P = .002) or CY + TT (HR = 35.93; P < .001), viral infections (HR = 4.3; P = .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 < .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 = .007). 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.}, } @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 = {151}, number = {}, pages = {109727}, doi = {10.1016/j.fsi.2024.109727}, pmid = {38936520}, issn = {1095-9947}, mesh = {Animals ; *Zebrafish ; *Gossypol/toxicity/pharmacology/administration & dosage ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Inflammation/chemically induced ; Animal Feed/analysis ; Zebrafish Proteins/genetics/metabolism ; Diet/veterinary ; Fish Diseases/chemically induced/immunology ; Protein Serine-Threonine Kinases/genetics/metabolism ; }, 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 = {}, pmid = {38929087}, issn = {2076-3921}, support = {R01 AG062469/AG/NIA NIH HHS/United States ; 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 = {}, 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.}, } @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 ; 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.}, } @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 = {}, pmid = {38915482}, issn = {2692-8205}, support = {P30 CA016056/CA/NCI NIH HHS/United States ; }, 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 {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 = {20}, number = {11}, pages = {2460-2477}, pmid = {38910554}, issn = {1554-8635}, mesh = {Animals ; *Catechin/analogs & derivatives/pharmacology ; *Autophagy/drug effects/physiology/genetics ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism/genetics ; *Insulin-Secreting Cells/metabolism/drug effects ; Mice ; Oxidative Stress/drug effects ; Proteolysis/drug effects ; Protective Agents/pharmacology ; Mice, Inbred C57BL ; }, 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 {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 = {19}, number = {7}, pages = {1495-1505}, doi = {10.1021/acschembio.4c00174}, pmid = {38904252}, issn = {1554-8937}, mesh = {*Lysine/metabolism/chemistry ; *Sulfhydryl Compounds/chemistry/metabolism ; Acetylation ; Crystallins/metabolism/chemistry ; Lens, Crystalline/metabolism ; Protein Processing, Post-Translational ; Humans ; Acetyl Coenzyme A/metabolism/chemistry ; }, 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 = {222}, number = {}, pages = {187-198}, doi = {10.1016/j.freeradbiomed.2024.06.011}, pmid = {38897422}, issn = {1873-4596}, mesh = {Animals ; Male ; Mice ; *Carrier Proteins/metabolism/genetics ; *Diet, High-Fat/adverse effects ; Furans/pharmacology ; *Glucose/metabolism ; Indenes/pharmacology ; Inflammasomes/metabolism ; Insulin/metabolism ; *Insulin Resistance ; Mice, Inbred C57BL ; Mice, Obese ; *Muscle, Skeletal/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Obesity/metabolism/pathology ; *Oxidative Stress ; *Reactive Oxygen Species/metabolism ; *Signal Transduction ; Sulfonamides ; *Thioredoxins/metabolism/genetics ; }, 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 {pmid38896955, year = {2024}, author = {Zhao, Q and Liu, G and Ding, Q and Zheng, F and Shi, X and Lin, Z and Liang, Y}, title = {The ROS/TXNIP/NLRP3 pathway mediates LPS-induced microglial inflammatory response.}, journal = {Cytokine}, volume = {181}, number = {}, pages = {156677}, doi = {10.1016/j.cyto.2024.156677}, pmid = {38896955}, issn = {1096-0023}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Microglia/metabolism/drug effects ; *Lipopolysaccharides/pharmacology ; *Carrier Proteins/metabolism ; Animals ; Mice ; *Reactive Oxygen Species/metabolism ; *Caspase 1/metabolism ; *Signal Transduction/drug effects ; *Inflammasomes/metabolism ; *Inflammation/metabolism/pathology ; Cell Line ; Acetylcysteine/pharmacology ; Calcium-Binding Proteins/metabolism ; Interleukin-1beta/metabolism ; Interleukin-18/metabolism ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Microfilament Proteins/metabolism ; Thioredoxins/metabolism ; CARD Signaling Adaptor Proteins/metabolism ; Sepsis-Associated Encephalopathy/metabolism/pathology ; CD68 Molecule ; }, abstract = {BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction activated by microglia. The potential pathological changes of SAE are complex, and the cellular pathophysiological characteristics remains unclear. This study aims to explore the ROS/TXNIP/NLRP3 pathway mediated lipopolysaccharide (LPS)-induced inflammatory response in microglia.

METHODS: BV-2 cells were pre-incubated with 10 μM N-acetyl-L-cysteine (NAC) for 2 h, which were then reacted with 1 μg/mL LPS for 24 h. Western blot assay examined the protein levels of IBA1, CD68, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. The contents of inflammatory factor were detected by ELISA assay. The co-immunoprecipitation assay examined the interaction between TXNIP and NLRP3.

RESULTS: LPS was confirmed to promote the positive expressions of IBA1 and CD68 in BV-2 cells. The further experiments indicated that LPS enhanced ROS production and NLRP3 inflammasome activation in BV-2 cells. Moreover, we also found that NAC partially reversed the facilitation of LPS on the levels of ROS, IL-1β, IL-18, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. NAC treatment also notably alleviated the interaction between TXNIP and NLRP3 in BV-2 cells.

CONCLUSION: ROS inhibition mediated NLRP3 signaling inactivation by decreasing TXNIP expression.}, } @article {pmid38894680, year = {2024}, author = {Rieckher, M and Gallrein, C and Alquezar-Artieda, N and Bourached-Silva, N and Vaddavalli, PL and Mares, D and Backhaus, M and Blindauer, T and Greger, K and Wiesner, E and Pontel, LB and Schumacher, B}, title = {Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging.}, journal = {Nucleic acids research}, volume = {52}, number = {14}, pages = {8271-8285}, pmid = {38894680}, issn = {1362-4962}, support = {PID2022-136694NB-I00 FEDER//MCIN/AEI/10.13039/501100011033/ ; RYC2021-032395-I//European Union NextGenerationEU/PRTR/ ; 2021 SGR 01309//Generalitat de Catalunya/ ; 61734//John Templeton Foundation/ ; 70114555//Deutsche Krebshilfe/ ; 496650118//Deutsche Forschungsgemeinschaft/ ; DJCLS 04 R/2023//José Carreras Leukämie-Stiftung/ ; }, mesh = {*DNA Repair ; *Caenorhabditis elegans/genetics/drug effects/growth & development ; *Formaldehyde/toxicity ; Animals ; *Reproduction/drug effects/genetics ; *Aging/genetics ; *DNA Damage ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Aldehyde Dehydrogenase/genetics/metabolism ; Mutation ; Humans ; Transcription, Genetic/drug effects ; Acetylcysteine/pharmacology ; Aldehyde Oxidoreductases ; }, abstract = {Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences.}, } @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.}, } @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.}, } @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.}, } @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 {pmid38885551, year = {2024}, author = {Bresson, SE and Ruzzin, J}, title = {Persistent organic pollutants disrupt the oxidant/antioxidant balance of INS-1E pancreatic β-cells causing their physiological dysfunctions.}, journal = {Environment international}, volume = {190}, number = {}, pages = {108821}, doi = {10.1016/j.envint.2024.108821}, pmid = {38885551}, issn = {1873-6750}, mesh = {*Insulin-Secreting Cells/drug effects/metabolism ; *Antioxidants/metabolism ; *Polychlorinated Biphenyls/toxicity ; *Reactive Oxygen Species/metabolism ; *Receptors, Aryl Hydrocarbon/metabolism/genetics ; *Polychlorinated Dibenzodioxins/toxicity ; *Persistent Organic Pollutants ; *Cell Survival/drug effects ; Receptors, Cytoplasmic and Nuclear/metabolism/genetics ; Constitutive Androstane Receptor ; Insulin/metabolism ; Dichlorodiphenyl Dichloroethylene/toxicity ; Oxidative Stress/drug effects ; Oxidants/toxicity ; Cell Line ; Humans ; Acetylcysteine/pharmacology ; Animals ; Rats ; Pregnane X Receptor/metabolism/genetics ; }, abstract = {BACKGROUND: Persistent organic pollutants (POPs) have emerged as potent diabetogenic agents, but their mechanisms of action remain poorly identified.

OBJECTIVES: In this study, we aim to determine the mechanisms regulating the damaging effects of POPs in pancreatic β-cells, which have a central role in the development of diabetes.

METHODS: We treated INS-1E pancreatic β-cells with PCB-153, p,p'-DDE, PCB-126, or TCDD at doses ranging from 1 × 10[-15]to 5 × 10[-6]M. We measured insulin content and secretion, cell viability and assessed the mRNA expression of the xenobiotic nuclear receptors Nr1i2 and Nr1i3, and the aryl hydrocarbon receptor (Ahr). In addition, we evaluated the antioxidant defense and production of reactive oxygen species (ROS). Finally, we studied the ability of the antioxidant N-acetyl-L-cysteine (NAC) to counteract the effects of POPs in INS-1E cells.

RESULTS: When exposed to environmental POP levels, INS-1E cells had impaired production and secretion of insulin. These defects were observed for all tested POPs and were paralleled by reduced Ins1 and Ins2 mRNA expression. While POP treatment for 3 days did not affect INS-1E cell viability, longer treatment progressively killed the cells. Furthermore, we found that the xenobiotic detoxification machinery is poorly expressed in the INS-1E cells, as characterized by the absence of Nr1i2 and Nr1i3 and their respective downstream targets Cyp3a1/Cyp3a2 and Cyp2b1/Cyp2b3, and the weak functionality of the Ahr/Cyp1a1 signaling. Interestingly, POPs dysregulated key antioxidant enzymes such as glutathione peroxidases, peroxiredoxins, thioredoxins, and catalases. In parallel, the production of intracellular ROS, including superoxide anion (O2[•-]) and hydrogen peroxide (H2O2), was increased by POP exposure. Improving the oxidant scavenging capacity of INS-1E cells by NAC treatment restored the production and secretion of insulin.

CONCLUSION: By promoting oxidative stress and impairing the ability of INS-1E cells to produce and secrete insulin, this study reveals how POPs can mechanistically act as diabetogenic agents, and provides new scientific evidence supporting the concept that POPs are fueling the diabetes epidemics.}, } @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 = {37}, number = {7}, pages = {1104-1112}, doi = {10.1021/acs.chemrestox.3c00351}, pmid = {38885202}, issn = {1520-5010}, mesh = {Animals ; Rats ; *Cytochrome P-450 CYP3A/metabolism ; Humans ; *Hepatocytes/drug effects/metabolism ; Male ; *Microsomes, Liver/metabolism ; Rats, Sprague-Dawley ; Activation, Metabolic ; Cell Survival/drug effects ; Cells, Cultured ; Molecular Structure ; Herbicides/toxicity/metabolism ; Dose-Response Relationship, Drug ; }, 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.}, } @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 ; }, } @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}, mesh = {Animals ; *Reactive Oxygen Species/metabolism ; *Muscle Development/drug effects ; Chick Embryo ; *Rotenone/pharmacology ; *Muscle Fibers, Skeletal/metabolism/drug effects/cytology ; *Myoblasts/metabolism/drug effects/cytology ; Fibroblasts/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; }, 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 {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 = {20}, number = {11}, pages = {2405-2425}, pmid = {38873925}, issn = {1554-8635}, mesh = {Animals ; Mice ; *Aortic Dissection/pathology/metabolism ; *Apoptosis/drug effects ; *Muscle, Smooth, Vascular/metabolism/pathology ; *Mice, Knockout ; *Phagocytosis/drug effects/physiology ; Macrophages/metabolism ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Myocytes, Smooth Muscle/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Calcium-Binding Proteins/metabolism ; Male ; Autophagy/physiology/drug effects ; }, 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 {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}, pmid = {38870779}, issn = {2213-2317}, mesh = {Animals ; Mice ; *Multidrug Resistance-Associated Proteins/metabolism/genetics ; *Cochlea/metabolism/pathology ; *Hearing Loss, Noise-Induced/metabolism/genetics ; *Mice, Knockout ; *Antioxidants/metabolism ; *Oxidative Stress ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Endothelial Cells/metabolism ; }, 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 = {109}, number = {8}, pages = {1370-1384}, pmid = {38867461}, issn = {1469-445X}, support = {FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; }, mesh = {Animals ; *Acetylcysteine/pharmacology ; *Mice, Inbred mdx ; *Muscular Dystrophy, Duchenne/drug therapy/physiopathology ; Male ; Mice ; *Disease Models, Animal ; *Diaphragm/drug effects/physiopathology ; Mice, Inbred C57BL ; Respiratory Muscles/drug effects/physiopathology ; Respiration/drug effects ; Antioxidants/pharmacology ; Respiratory System/drug effects/physiopathology/metabolism ; }, 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 Alam, 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 = {1870}, number = {7}, pages = {167286}, doi = {10.1016/j.bbadis.2024.167286}, pmid = {38866114}, issn = {1879-260X}, mesh = {Humans ; *S-Phase Kinase-Associated Proteins/metabolism/genetics ; *Apoptosis/drug effects ; *Skin Neoplasms/pathology/metabolism/genetics/drug therapy ; *Carcinoma, Squamous Cell/pathology/metabolism/genetics/drug therapy ; Cell Line, Tumor ; *Kruppel-Like Factor 4/metabolism ; Cell Proliferation/drug effects ; Curcumin/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; }, 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 PI3K/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.}, } @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.}, } @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 = {19}, number = {18}, pages = {e202400110}, doi = {10.1002/cmdc.202400110}, pmid = {38847101}, issn = {1860-7187}, support = {2018CXGC1411//Key R&D Programs of Shandong Province/ ; 2021CXGC010514//Key R&D Programs of Shandong Province/ ; }, mesh = {*Acetylcysteine/pharmacology/chemistry/chemical synthesis ; Animals ; *Drug Design ; Structure-Activity Relationship ; *Antioxidants/pharmacology/chemical synthesis/chemistry ; Mice ; Molecular Structure ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/chemical synthesis/chemistry ; Dose-Response Relationship, Drug ; Pulmonary Fibrosis/drug therapy/chemically induced/pathology ; Male ; Humans ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; }, 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 4 r, 4 t, 4 w, and 4 x 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 4 r 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 extensively drug resistant 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 = {135}, number = {6}, pages = {}, doi = {10.1093/jambio/lxae136}, pmid = {38845374}, issn = {1365-2672}, support = {//UGC/ ; F.30-487/2019//BSR/ ; //DST/ ; OMI/20/2020-ECD-1//ICMR/ ; CRG/2021/001974//SERB/ ; //Department of Biotechnology/ ; }, mesh = {*Biofilms/drug effects ; *Klebsiella pneumoniae/drug effects/genetics ; *Anti-Bacterial Agents/pharmacology ; *Acetylcysteine/pharmacology ; Humans ; *Drug Resistance, Multiple, Bacterial/genetics ; *Transcriptome ; Klebsiella Infections/microbiology ; Microbial Sensitivity Tests ; India ; Bacterial Proteins/genetics/metabolism ; }, abstract = {AIMS: Carbapenemase-producing Klebsiella 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 = {103}, number = {}, pages = {96-104}, doi = {10.1016/j.neuro.2024.05.006}, pmid = {38843996}, issn = {1872-9711}, mesh = {*Sevoflurane/toxicity ; Animals ; *Acetylcysteine/pharmacology ; *Hippocampus/drug effects/metabolism/pathology ; *Anesthetics, Inhalation/toxicity ; Rats ; *Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Autophagy/drug effects ; Rats, Sprague-Dawley ; Male ; Neurons/drug effects/pathology/metabolism ; }, 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 6 hours of 3 l/min gas (air and 30 % O2) and intraperitoneal saline. NAC: Received 6 hours of 3 l/min gas and 150 mg/kg NAC intraperitoneally. Sev: Exposed to 6 hours of 3 l/min gas and 3 % sevoflurane. Sev+NAC: Received 6 hours of 3 l/min gas, 3 % sevoflurane, and 150 mg/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}, support = {P20 GM109040/GM/NIGMS NIH HHS/United States ; P2C HD086844/HD/NICHD NIH HHS/United States ; }, 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 = {30}, number = {9}, pages = {112-117}, pmid = {38836732}, issn = {1078-6791}, mesh = {Humans ; *Nomograms ; *Acetylcysteine/therapeutic use ; Female ; Male ; Child ; *Pneumonia, Mycoplasma/drug therapy ; Retrospective Studies ; *Budesonide/therapeutic use/administration & dosage ; Child, Preschool ; Drug Therapy, Combination ; Logistic Models ; Mycoplasma pneumoniae/drug effects ; Treatment Outcome ; Adolescent ; }, 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 {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 = {104}, number = {13}, pages = {7895-7906}, 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/ ; }, mesh = {Animals ; *Acetylcysteine/administration & dosage/pharmacology ; Female ; Mice ; Pregnancy ; *Muscle Development/drug effects ; Male ; *Heat-Shock Response/drug effects ; *Muscle, Skeletal/metabolism/drug effects/growth & development ; Antioxidants/metabolism ; Prenatal Exposure Delayed Effects ; Humans ; Dietary Supplements/analysis ; }, 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 = {976}, number = {}, pages = {176699}, doi = {10.1016/j.ejphar.2024.176699}, pmid = {38825302}, issn = {1879-0712}, mesh = {*Ferroptosis/drug effects ; Animals ; *Diabetic Nephropathies/drug therapy/metabolism/pathology/prevention & control ; *Oxidative Stress/drug effects ; *Atorvastatin/pharmacology/therapeutic use ; Male ; *Signal Transduction/drug effects ; Mice ; *Reactive Oxygen Species/metabolism ; Diabetes Mellitus, Experimental/drug therapy/metabolism/complications ; Mice, Inbred C57BL ; Humans ; Kidney/drug effects/metabolism/pathology ; Cell Line ; Phenylenediamines/pharmacology/therapeutic use ; }, 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 receptor 1 (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.}, } @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.}, } @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 Low-Density Lipoprotein 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 attenuates the survival of MSCs through 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 h with native LDL as control. Ox-LDL treatment substantially decreased the survival of MSCs dose-dependently and enhanced the release of intracellular lactate dehydrogenase (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 = {440}, number = {1}, pages = {114101}, doi = {10.1016/j.yexcr.2024.114101}, pmid = {38815788}, issn = {1090-2422}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/metabolism/pathology/drug therapy ; Animals ; *Lung Neoplasms/pathology/metabolism/drug therapy ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; *NF-kappa B/metabolism ; *Selenocysteine/analogs & derivatives/pharmacology ; *Cell Proliferation/drug effects ; Mice ; *Apoptosis/drug effects ; Cell Movement/drug effects ; Mice, Nude ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; A549 Cells ; Organoselenium Compounds/pharmacology ; Mice, Inbred BALB C ; }, 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 {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 = {41}, number = {7-9}, pages = {488-504}, doi = {10.1089/ars.2023.0383}, pmid = {38814824}, issn = {1557-7716}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Neointima/metabolism/pathology ; Mice ; *Fibrillin-1/metabolism/genetics ; *Cell Proliferation/drug effects ; *Muscle, Smooth, Vascular/metabolism/cytology ; *Cell Movement/drug effects ; *Vascular System Injuries/metabolism/pathology ; Myocytes, Smooth Muscle/metabolism ; NF-E2-Related Factor 2/metabolism ; Male ; Toll-Like Receptor 4/metabolism ; Disease Models, Animal ; }, 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. Antioxid. Redox Signal. 41, 488-504.}, } @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}, support = {R21 NS118224/NS/NINDS NIH HHS/United States ; }, 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 = {44}, number = {9}, pages = {1454-1465}, 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/ ; }, mesh = {*Ochratoxins/toxicity ; Humans ; *Astrocytes/drug effects ; *Acetylcysteine/pharmacology ; *Reactive Oxygen Species/metabolism ; Cell Line ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Glutathione/metabolism ; Cell Survival/drug effects ; Antioxidants/pharmacology ; NF-E2-Related Factor 2/metabolism ; Caspase 3/metabolism ; Heme Oxygenase-1/metabolism ; bcl-2-Associated X Protein/metabolism ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; }, 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}, mesh = {Animals ; *Flavonoids/pharmacology/therapeutic use ; *Acetaminophen ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; *Mice, Inbred C57BL ; Male ; Mice ; *Calgranulin B/metabolism/genetics ; Apoptosis/drug effects ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Liver/drug effects/pathology/metabolism ; Humans ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/metabolism/genetics ; }, 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}, mesh = {Animals ; *Oxidative Stress/drug effects ; *Hepatocytes/drug effects ; *Apoptosis/drug effects ; *Autophagy/drug effects ; *Pyrrolizidine Alkaloids/toxicity ; Rats ; Male ; Reactive Oxygen Species/metabolism ; Rats, Sprague-Dawley ; Cells, Cultured ; Aspartate Aminotransferases ; Alanine Transaminase ; }, 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 {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.}, } @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 = {}, pmid = {38798604}, support = {R01 AA030041/AA/NIAAA NIH HHS/United States ; }, 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 in June and July of 2023 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. 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}, mesh = {Animals ; *Pyroptosis ; *Epithelial Cells/microbiology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; Swine ; *Signal Transduction ; Haemophilus parasuis/pathogenicity/genetics ; Trachea/microbiology/cytology ; Swine Diseases/microbiology ; Serogroup ; Adaptor Proteins, Signal Transducing/metabolism/genetics ; Inflammasomes/metabolism/genetics ; DEAD Box Protein 58/genetics/metabolism ; Haemophilus Infections/veterinary/microbiology ; }, 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 = {P20 GM139768/GM/NIGMS NIH HHS/United States ; 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.}, } @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}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Toll-Like Receptor 4/metabolism ; *Acute Lung Injury/etiology/metabolism ; Rats ; *Oxidative Stress ; *NF-kappa B/metabolism ; *Signal Transduction ; Male ; *Disease Models, Animal ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Cytokines/metabolism ; Hypoxia/metabolism ; Inflammasomes/metabolism ; Lung/metabolism/pathology ; Altitude ; Sulfonamides/pharmacology ; }, 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}, mesh = {*Arsenic Trioxide/pharmacology ; *Acetylcysteine/pharmacology ; Animals ; *Catalase/metabolism/genetics ; Rats ; *Liver/metabolism/drug effects ; *Oxides ; Male ; Arsenicals ; Humans ; Gene Expression/drug effects ; Antioxidants/pharmacology/metabolism ; }, 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.}, } @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.}, } @article {pmid38770316, year = {2024}, author = {Huang, HL and Cheng, N and Zhou, CX and Liang, J}, title = {Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.}, journal = {Heliyon}, volume = {10}, number = {10}, pages = {e30947}, pmid = {38770316}, issn = {2405-8440}, abstract = {Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.}, } @article {pmid38769217, year = {2024}, author = {Takahashi, K and Tanaka, T and Ishihara, A and Ohta, T}, title = {Strobilurin X acts as an anticancer drug by inhibiting protein synthesis and suppressing mitochondrial respiratory chain activity.}, journal = {Discover oncology}, volume = {15}, number = {1}, pages = {177}, pmid = {38769217}, issn = {2730-6011}, abstract = {PURPOSE: Strobilurins act as antifungal agents by inhibiting the mitochondrial respiratory chain. The cytotoxic activity of strobilurins, focusing on its anticancer activities, has been reported. However, the mechanisms involved in these activities remain unclear.

METHODS: The cytotoxic effects of strobilurin X isolated from the mycelium of Mucidula. venosolamellata were examined in human cancer cell lines (A549 and HeLa) and normal fibroblasts (WI-38).

RESULTS: Strobilurin X significantly decreased the viability of A549 and HeLa cells compared to that in the WI-38 cells after 48 h of exposure. The EC50 values for cytotoxicity in the A549, HeLa, and WI-38 cells were 3.4, 5.4, and 16.8 μg/mL, respectively. Strobilurin X inhibited the mitochondrial respiratory chain and enhanced the release of lactate in the A549 cells. The IC50 value of strobilurin X against the mitochondrial respiratory chain complex III activity was 139.8 ng/mL. The cytotoxicity induced by strobilurin X was not completely rescued after adding uridine, methyl pyruvate, or N-acetyl cysteine. Furthermore, pharmacological approaches demonstrated that strobilurin X failed to modulate the mitogen-activated protein kinase family and phosphoinositide 3-kinase-Akt pathways; alternatively, it suppressed protein synthesis independent of uridine.

CONCLUSION: Strobilurin X induced cytotoxicity by blocking the mitochondrial respiratory chain and suppressing protein synthesis. These findings may aid in the development of novel anticancer drugs using strobilurins.}, } @article {pmid38762757, year = {2024}, author = {Qi, Z and Yang, W and Xue, B and Chen, T and Lu, X and Zhang, R and Li, Z and Zhao, X and Zhang, Y and Han, F and Kong, X and Liu, R and Yao, X and Jia, R and Feng, S}, title = {ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.}, journal = {Autophagy}, volume = {20}, number = {9}, pages = {2000-2016}, pmid = {38762757}, issn = {1554-8635}, mesh = {*Bleomycin/pharmacology ; *Cellular Senescence/drug effects ; *Reactive Oxygen Species/metabolism ; *Lysosomes/metabolism/drug effects ; *Autophagy/drug effects/physiology ; Animals ; Humans ; Mice ; Intracellular Membranes/metabolism/drug effects ; Permeability/drug effects ; Mice, Inbred C57BL ; }, abstract = {Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.}, } @article {pmid38761382, year = {2024}, author = {Li, X and Xin, L and Yang, L and Yang, Y and Li, W and Zhang, M and Liao, Y and Sun, C and Li, W and Peng, Y and Zheng, J}, title = {Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo.}, journal = {Chemical research in toxicology}, volume = {37}, number = {6}, pages = {935-943}, doi = {10.1021/acs.chemrestox.4c00008}, pmid = {38761382}, issn = {1520-5010}, mesh = {Animals ; *Amitriptyline/metabolism ; Rats ; *Cytochrome P-450 CYP3A/metabolism ; *Microsomes, Liver/metabolism ; *Hepatocytes/drug effects/metabolism ; Male ; *Rats, Sprague-Dawley ; *Epoxy Compounds/metabolism/toxicity/chemistry ; Glutathione/metabolism ; Cells, Cultured ; }, abstract = {Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.}, } @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.}, } @article {pmid38754743, year = {2024}, author = {Nguyen, UTT and Youn, E and Le, TAN and Ha, NM and Tran, SH and Lee, S and Cha, JW and Park, JS and Kwon, HC and Kang, K}, title = {Photodynamic treatment increases the lifespan and oxidative stress resistance of Caenorhabditis elegans.}, journal = {Free radical biology & medicine}, volume = {221}, number = {}, pages = {98-110}, doi = {10.1016/j.freeradbiomed.2024.05.023}, pmid = {38754743}, issn = {1873-4596}, mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism/genetics ; *Oxidative Stress/drug effects ; *Longevity/drug effects ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Photochemotherapy/methods ; *Photosensitizing Agents/pharmacology ; *Reactive Oxygen Species/metabolism ; *Transcription Factors/metabolism/genetics ; *Perylene/analogs & derivatives/pharmacology ; Anthracenes/pharmacology ; Forkhead Transcription Factors/metabolism/genetics ; DNA-Binding Proteins/metabolism/genetics ; Superoxide Dismutase/metabolism/genetics ; NF-E2-Related Factor 2/metabolism/genetics ; Gene Expression Regulation/drug effects ; Light ; Acetylcysteine/pharmacology ; }, abstract = {Photodynamic therapy is a noninvasive treatment in which specific photosensitizers and light are used to produce high amounts of reactive oxygen species (ROS), which can be employed for targeted tissue destruction in cancer treatment or antimicrobial therapy. However, it remains unknown whether lower amounts of ROS produced by mild photodynamic therapy increase lifespan and stress resistance at the organism level. Here, we introduce a novel photodynamic treatment (PDTr) that uses 20 μM hypericin, a photosensitizer that originates from Hypericum perforatum, and orange light (590 nm, 5.4 W/m[2], 1 min) to induce intracellular ROS formation (ROS), thereby resulting in lifespan extension and improved stress resistance in C. elegans. The PDTr-induced increase in longevity was abrogated by N-acetyl cysteine, suggesting the hormetic response was driven by prooxidative mechanisms. PDTr activated the translocation of SKN-1/NRF-2 and DAF-16/FOXO, leading to elevated expression of downstream oxidative stress-responsive genes, including ctl-1, gst-4, and sod-3. In summary, our findings suggest a novel PDTr method that extends the lifespan of C. elegans under both normal and oxidative stress conditions through the activation of SKN-1 and DAF-16 via the involvement of many antioxidant genes.}, } @article {pmid38751162, year = {2024}, author = {Roydeva, A and Beleva, G and Gadzhakov, D and Milanova, A}, title = {Pharmacokinetics of N-acetyl-l-cysteine in chickens.}, journal = {Journal of veterinary pharmacology and therapeutics}, volume = {47}, number = {5}, pages = {403-415}, doi = {10.1111/jvp.13452}, pmid = {38751162}, issn = {1365-2885}, support = {BG-RRP-2.004-0006-C02//Bulgarian Ministry of Education and Science (MES)/ ; }, mesh = {Animals ; *Chickens/metabolism ; *Acetylcysteine/pharmacokinetics/administration & dosage ; Administration, Oral ; Male ; Half-Life ; Area Under Curve ; Injections, Intravenous/veterinary ; Biological Availability ; Female ; }, abstract = {N-acetyl-l-cysteine (NAC) has been suggested as an antioxidant that can alleviate the negative effects of stress conditions in broilers. However, knowledge of its pharmacokinetics (PK) in this avian species is very limited. Therefore, the study aimed to shed more light on the PK properties of NAC in chickens. Broilers were subjected to single intravenous (i.v.) or oral (p.o.) treatment or multiple NAC administrations via the feed. Drug concentrations were determined by LC-MS/MS, and the data were subjected to non-compartmental analysis and modeled by non-linear mixed effect approach. NAC was eliminated in a short time after i.v. treatment, with a t 1/2el of 0.93 (0.59-2.09) h. It showed limited distribution with population mean of volumes of distribution in the central and peripheral compartments V 1 of 0.148 L/kg and V 2 of 0.199 L/kg, respectively, and V darea of 0.39 (0.258-0.635) L/kg. The value of MRT was 1.76 h (range of 0.96-2.69, p < .05) after single p.o. treatment, indicating a twofold increase if compared to i.v. administration (0.87 h, 0.55-1.78). Both methods of Pk analysis revealed very limited bioavailability, <10%. Feeding behavior led to a later achievement of lower maximum plasma concentrations (5.74, range of 3.44-9.32 μg/mL, p < .05), which were maintained during the 5 days of treatment.}, } @article {pmid38750444, year = {2024}, author = {Li, YS and Xia, J and Chen, CY and Ren, SH and He, MR}, title = {Upregulated dual oxidase 1-induced oxidative stress and caspase-1-dependent pyroptosis reflect the etiologies of heart failure.}, journal = {BMC molecular and cell biology}, volume = {25}, number = {1}, pages = {16}, pmid = {38750444}, issn = {2661-8850}, support = {ZK2019A07//Songjiang District New round of Medical key discipline Construction Project (Cardiology Department)/ ; }, mesh = {Humans ; Caspase 1/metabolism ; Cell Line ; Doxorubicin/pharmacology ; *Dual Oxidases/metabolism/genetics ; *Heart Failure/chemically induced/genetics/metabolism ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; *Oxidative Stress ; *Pyroptosis ; *Reactive Oxygen Species/metabolism ; Up-Regulation ; }, abstract = {BACKGROUND: Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was designed to evaluate the potential role of DUOX1 in heart failure.

MATERIALS AND METHODS: AC16 cells were treated with 2 µmol/L of doxorubicin (DOX) for 12, 24, and 48 h to construct a heart failure model. DUOX1 overexpression and silencing in AC16 cell were established. DUOX1 expression was detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Pyroptosis and reactive oxygen species (ROS) production were measured by flow cytometry.

RESULTS: Increased DUOX1 expression levels were observed after DOX treatment for 24 h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1β, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1β, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors.

CONCLUSION: These results suggest that DUOX1-derived genotoxicity could promote heart failure development. In the process, oxidative stress and pyroptosis may be involved in the regulation of DUOX1 in heart failure.}, } @article {pmid38749218, year = {2024}, author = {Han, YK and Lim, HJ and Jang, G and Jang, SY and Park, KM}, title = {Kidney ischemia/reperfusion injury causes cholangiocytes primary cilia disruption and abnormal bile secretion.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1870}, number = {6}, pages = {167225}, doi = {10.1016/j.bbadis.2024.167225}, pmid = {38749218}, issn = {1879-260X}, mesh = {Animals ; *Reperfusion Injury/metabolism/pathology ; *Cilia/metabolism/pathology ; Mice ; *Bile/metabolism ; Male ; Acute Kidney Injury/metabolism/pathology ; Mice, Inbred C57BL ; Glutathione/metabolism ; Mice, Knockout ; Liver/pathology/metabolism ; Hepatocytes/metabolism/pathology ; Cystathionine gamma-Lyase/metabolism/genetics ; Kidney/metabolism/pathology ; Hydrogen Sulfide/metabolism/pharmacology ; Bile Ducts/pathology/metabolism ; Epithelial Cells/metabolism/pathology ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle).

METHODS: Cystathione γ-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC).

RESULTS: KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione β-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion.

CONCLUSIONS: These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.}, } @article {pmid38740632, year = {2024}, author = {Boppana, TK and Mittal, S and Madan, K and Tiwari, P and Mohan, A and Hadda, V}, title = {Antioxidant therapies for obstructive sleep apnea: A systematic review and meta-analysis.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {28}, number = {4}, pages = {1513-1522}, pmid = {38740632}, issn = {1522-1709}, mesh = {*Sleep Apnea, Obstructive/drug therapy ; Humans ; *Antioxidants/therapeutic use ; *Oxidative Stress/drug effects/physiology ; }, abstract = {PURPOSE: Obstructive sleep apnea (OSA) is a common clinical problem that is associated with adverse cardiovascular outcomes attributed to the oxidative stress due to sympathetic overstimulation. Treatment approaches targeting oxidative stress have been tried by multiple investigators. This systematic review and meta-analysis evaluated the efficacy and safety of such approaches.

METHODS: Pubmed and Embase databases were searched for human studies evaluating the utility of antioxidant therapies in patients with OSA.

RESULTS: A total of six studies (five randomized trials and one case-control study) were included, including 160 patients with OSA using N-acetyl cysteine, vitamin C, carbocysteine, superoxide dismutase, vitamin E, allopurinol, and their combinations. There was a significant improvement in flow-mediated dilatation (FMD) following antioxidants, with the pooled effect being 2.16 % (95% CI 1.65-2.67) using the random-effects model (I2 = 0% and p<0.001). It was also associated with a significant reduction in malondialdehyde levels and an increase in reduced glutathione (GSH) levels. There was also a significant improvement in the Epworth sleepiness scale, oxygen desaturation index, and minimum oxygen saturation during sleep without any significant adverse effects.

CONCLUSION: Antioxidant therapy in patients with OSA is associated with improved endothelial function, reduced oxidative stress, and improved sleep parameters. These results call for future multicentre studies with longer follow-ups to assess the utility of antioxidant therapy in patients with OSA.}, } @article {pmid38735462, year = {2024}, author = {Li, M and Tang, S and Velkov, T and Shen, J and Dai, C}, title = {Copper exposure induces mitochondrial dysfunction and hepatotoxicity via the induction of oxidative stress and PERK/ATF4 -mediated endoplasmic reticulum stress.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {352}, number = {}, pages = {124145}, doi = {10.1016/j.envpol.2024.124145}, pmid = {38735462}, issn = {1873-6424}, mesh = {*Endoplasmic Reticulum Stress/drug effects ; Animals ; *Oxidative Stress/drug effects ; Humans ; Mice ; *Activating Transcription Factor 4/metabolism/genetics ; *Mitochondria/drug effects/metabolism ; Hep G2 Cells ; *eIF-2 Kinase/metabolism/genetics ; *Endoplasmic Reticulum Chaperone BiP ; *Mice, Inbred C57BL ; Copper/toxicity ; Chemical and Drug Induced Liver Injury/metabolism ; Copper Sulfate/toxicity ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Male ; Liver/drug effects/metabolism ; Cell Survival/drug effects ; }, abstract = {Copper is an essential trace element, and excessive exposure could result in hepatoxicity, however, the underlying molecular mechanisms remain incompletely understood. The present study is aimed to investigate the molecular mechanisms of copper sulfate (CuSO4) exposure-induced hepatoxicity both in vivo and in vitro. In vitro, HepG2 and L02 cells were exposed to various doses of CuSO4 for 24 h. Cell viability, ROS production, oxidative stress biomarkers, mitochondrial functions, ultrastructure, intracellular calcium (Ca[2+)] concentration, and the expression of proteins related to mitochondrial apoptosis and endoplasmic reticulum (ER) stress were assessed. In vivo, C57BL/6 mice were treated with CuSO4 at doses of 10 and 30 mg/kg BW/day and co-treated with 4-PBA at 100 mg/kg BW/day for 35 days. Subsequently, liver function, histopathological features, and protein expression were evaluated. Results found that exposure to CuSO4 at concentrations of 100-400 μM for 24 h significantly decreased the viabilities of HepG2 and L02 cells and it was in a dose-dependent manner. Additionally, CuSO4 exposure induced significant oxidative stress and mitochondrial dysfunction in HepG2 cells, which were partially ameliorated by the antioxidant N-acetylcysteine (NAC). Furthermore, CuSO4 exposure prominently triggered ER stress, as evidenced by the upregulation of GRP94, GRP78, phosphorylated forms of PERK and eIF2α, and CHOP proteins in livers of mice and HepG2 cells. NAC treatment significantly inhibited CuSO4 exposure -induced ER stress in HepG2 cells. Pharmacological inhibition of ER stress through co-treatment with 4-PBA and the PERK inhibitor GSK2606414, as well as genetic knockdown of ATF4, partially mitigated CuSO4-induced cytotoxicity in HepG2 cells by reducing mitochondrial dysfunction and inhibiting the mitochondrial apoptotic pathway. Moreover, 4-PBA treatment significantly attenuated CuSO4-induced caspase activation and hepatoxicity in mice. In conclusion, these results reveal that CuSO4-induced hepatotoxicity involves mitochondrial dysfunction and ER stress by activating oxidative stress induction and PERK/ATF4 pathway.}, } @article {pmid38735082, year = {2024}, author = {Yu, N and Wu, X and Zhang, C and Qin, Q and Gu, Y and Ke, W and Liu, X and Zhang, Q and Liu, Z and Chen, M and Wang, K}, title = {NADPH and NAC synergistically inhibits chronic ocular hypertension-induced neurodegeneration and neuroinflammation through regulating p38/MAPK pathway and peroxidation.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116711}, doi = {10.1016/j.biopha.2024.116711}, pmid = {38735082}, issn = {1950-6007}, mesh = {Animals ; *NADP/metabolism ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Ocular Hypertension/metabolism/drug therapy/pathology ; *Acetylcysteine/pharmacology ; Rats ; Male ; *Retinal Ganglion Cells/drug effects/metabolism/pathology ; *Rats, Sprague-Dawley ; Glaucoma/metabolism/pathology/drug therapy ; Neuroinflammatory Diseases/drug therapy/metabolism ; Humans ; Ependymoglial Cells/drug effects/metabolism/pathology ; Disease Models, Animal ; MAP Kinase Signaling System/drug effects ; Apoptosis/drug effects ; Chronic Disease ; Neuroprotective Agents/pharmacology ; Cells, Cultured ; Lipid Peroxidation/drug effects ; }, abstract = {Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.}, } @article {pmid38733769, year = {2024}, author = {Wang, R and Zhong, L and Wang, T and Sun, T and Yang, J and Liu, X and Wu, Y and Guo, Q and Gao, Y and Zhao, K}, title = {Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production.}, journal = {Neoplasia (New York, N.Y.)}, volume = {53}, number = {}, pages = {101004}, pmid = {38733769}, issn = {1476-5586}, mesh = {Humans ; Cell Line, Tumor ; A549 Cells ; HEK293 Cells ; Animals ; Mice ; Mice, Nude ; *Thioredoxin Reductase 1/antagonists & inhibitors ; Male ; Female ; Middle Aged ; Aged ; *Antineoplastic Agents/chemistry/pharmacology ; Apoptosis/drug effects ; Heterografts ; *Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred BALB C ; *Lung Neoplasms/drug therapy ; Auranofin/pharmacology ; }, abstract = {Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.}, } @article {pmid38732054, year = {2024}, author = {Padalhin, A and Abueva, C and Ryu, HS and Yoo, SH and Seo, HH and Park, SY and Chung, PS and Woo, SH}, title = {Impact of Thermo-Responsive N-Acetylcysteine Hydrogel on Dermal Wound Healing and Oral Ulcer Regeneration.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38732054}, issn = {1422-0067}, support = {RS-2020-KD000027//Ministry of Science and ICT/ ; RS-2023-00247651//National Research Foundation of Korea/ ; NRF-2020R1A6A1A03043283//National Research Foundation of Korea/ ; }, mesh = {*Wound Healing/drug effects ; *Acetylcysteine/pharmacology ; Animals ; Rats ; Humans ; *Hydrogels/chemistry/pharmacology ; *Rats, Sprague-Dawley ; *Oral Ulcer/drug therapy/pathology ; Regeneration/drug effects ; Fibroblasts/drug effects ; Male ; Temperature ; Cell Survival/drug effects ; }, abstract = {This study investigates the efficacy of a thermo-responsive N-acetylcysteine (NAC) hydrogel on wound healing and oral ulcer recovery. Formulated by combining NAC with methylcellulose, the hydrogel's properties were assessed for temperature-induced gelation and cell viability using human fibroblast cells. In vivo experiments on Sprague Dawley rats compared the hydrogel's effects against saline, NAC solution, and a commercial NAC product. Results show that a 5% NAC and 1% methylcellulose solution exhibited optimal outcomes. While modest improvements in wound healing were observed, significant enhancements were noted in oral ulcer recovery, with histological analyses indicating fully regenerated mucosal tissue. The study concludes that modifying viscosity enhances NAC retention, facilitating tissue regeneration. These findings support previous research on the beneficial effects of antioxidant application on damaged tissues, suggesting the potential of NAC hydrogels in improving wound care and oral ulcer treatment.}, } @article {pmid38731862, year = {2024}, author = {Yi, LX and Tan, EK and Zhou, ZD}, title = {Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38731862}, issn = {1422-0067}, support = {CS-IRG, OF-IRG, HLCA2022, STaR, OF-LCG 000207//National Medical Research Council/ ; Collaboration pilot grant//Duke-NUS Medical School/ ; }, mesh = {Animals ; Humans ; Dopamine/metabolism ; *Dopamine Agonists/therapeutic use/pharmacology ; Dopaminergic Neurons/drug effects/metabolism ; Drug Therapy, Combination ; Enzyme Inhibitors/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Tyrosine 3-Monooxygenase/antagonists & inhibitors/metabolism ; }, abstract = {There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.}, } @article {pmid38730615, year = {2024}, author = {Forbes, M and Kempa, R and Mastrobuoni, G and Rayman, L and Pietzke, M and Bayram, S and Arlt, B and Spruessel, A and Deubzer, HE and Kempa, S}, title = {L-Glyceraldehyde Inhibits Neuroblastoma Cell Growth via a Multi-Modal Mechanism on Metabolism and Signaling.}, journal = {Cancers}, volume = {16}, number = {9}, pages = {}, pmid = {38730615}, issn = {2072-6694}, abstract = {Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and [13]C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment.}, } @article {pmid38729599, year = {2024}, author = {Wang, Z and Hu, Q and Tian, C and Wang, R and Jiao, Q and Chen, F and Wu, T and Wang, J and Zhu, Y and Liu, A and Zhang, W and Li, J and Shen, H}, title = {Prophylactic Effects of n-Acethylcysteine on Inflammation-induced Depression-like Behaviors in Mice.}, journal = {Neuroscience}, volume = {549}, number = {}, pages = {42-54}, doi = {10.1016/j.neuroscience.2024.05.005}, pmid = {38729599}, issn = {1873-7544}, mesh = {Animals ; Male ; *Depression/drug therapy/etiology/metabolism/prevention & control ; *Acetylcysteine/pharmacology ; *Mice, Inbred C57BL ; Mice ; *Brain-Derived Neurotrophic Factor/metabolism ; *Inflammation/drug therapy/metabolism ; *Lipopolysaccharides/pharmacology ; *Neuronal Plasticity/drug effects ; Receptors, AMPA/metabolism ; Excitatory Postsynaptic Potentials/drug effects/physiology ; Synaptic Transmission/drug effects ; Behavior, Animal/drug effects ; Disease Models, Animal ; Neurons/drug effects/metabolism ; }, abstract = {Depression, affecting individuals worldwide, is a prevalent mental disease, with an increasing incidence. Numerous studies have been conducted on depression, yet its pathogenesis remains elusive. Recent advancements in research indicate that disturbances in synaptic transmission, synaptic plasticity, and reduced neurotrophic factor expression significantly contribute to depression's pathogenesis. In our study, we utilized adult male C57BL/6J mice. Lipopolysaccharide (LPS) can induce both chronic and acute depression-like symptoms in mice, a widely used model for studying depression associated with inflammation. N-acetylcysteine (NAC) exhibits anti-inflammatory and ameliorative effects on depressive symptoms. This study sought to determine whether NAC use could mitigate inflammatory depressive behavior through the enhancement of synaptic transmission, synaptic plasticity, and increasing levels of brain-derived neurotrophic factor (BDNF). In this study, we discovered that in mice modeled with depression-like symptoms, the expression levels of dendrites, BDNF, and miniature excitatory postsynaptic potential (mEPSC) in glutamatergic neurons, as well as the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPARs) GluA1 and GluA2 subunits, were significantly decreased. These findings suggest an impairment in the synaptic transmission of glutamatergic neurons. Following treatment with NAC, the previously mentioned levels improved, indicating an enhancement in both synaptic transmission and synaptic plasticity. Our results suggest that NAC exerts a protective effect on mouse models of inflammatory depression, potentially through the enhancement of synaptic transmission and plasticity, as well as the restoration of neurotrophic factor expression. These findings offer vital animal experimental evidence supporting NAC's role in mitigating inflammatory depressive behaviors.}, } @article {pmid38726279, year = {2024}, author = {Zhao, MM and Wang, B and Huang, WX and Zhang, L and Peng, R and Wang, C}, title = {Verteporfin suppressed mitophagy via PINK1/parkin pathway in endometrial cancer.}, journal = {American journal of cancer research}, volume = {14}, number = {4}, pages = {1935-1946}, pmid = {38726279}, issn = {2156-6976}, abstract = {Endometrial cancer (EC) is a malignancy that poses a threat to woman's health worldwide. Building upon prior work, we explored the inhibitory effect of verteporfin on EC. We showed that verteporfin can damage the mitochondria of EC cells, leading to a decrease of mitochondrial membrane potential and an increase in ROS (reactive oxygen species). In addition, verteporfin treatment was shown to inhibit the proliferation and migration of EC cells, promote apoptosis, and reduce the expression of mitophagy-related proteins PINK1/parkin and TOM20. The ROS inhibitor N-Acetyl Cysteine was able to rescue the expression of PINK1/parkin proteins. This suggests that verteporfin may inhibit mitophagy by elevating ROS levels, thereby inhibiting EC cell viability. The effect of verteporfin on mitophagy supports further investigation as a potential therapeutic option for EC.}, } @article {pmid38718763, year = {2024}, author = {Behtaj, D and Ghorbani, A and Eslamian, G and Malekpour Alamdari, N and Abbasi, M and Zand, H and Shakery, A and Shimi, G and Sohouli, MH and Fazeli Taherian, S}, title = {Ex vivo Anti-Senescence Activity of N-Acetylcysteine in Visceral Adipose Tissue of Obese Volunteers.}, journal = {Obesity facts}, volume = {17}, number = {4}, pages = {355-363}, pmid = {38718763}, issn = {1662-4033}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Intra-Abdominal Fat/metabolism/drug effects ; *Cellular Senescence/drug effects ; Adult ; Male ; *beta-Galactosidase/metabolism ; *Interleukin-6/metabolism ; *Tumor Necrosis Factor-alpha/metabolism ; Female ; *Obesity/metabolism/drug therapy ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Middle Aged ; Tumor Suppressor Protein p53/metabolism ; Antioxidants/pharmacology/metabolism ; Oxidative Stress/drug effects ; Inflammation/metabolism ; }, abstract = {INTRODUCTION: Excessive visceral adiposity is known to drive the onset of metabolic derangements, mostly involving oxidative stress, prolonged inflammation, and cellular senescence. N-acetylcysteine (NAC) is a synthetic form of l-cysteine with potential antioxidant, anti-inflammatory, and anti-senescence properties. This ex-vivo study aimed to determine the effect of NAC on some markers of senescence including β-galactosidase activity and p16, p53, p21, IL-6, and TNF-α gene expressions in visceral adipose tissue in obese adults.

METHODS: This ex-vivo experimental study involved 10 obese participants who were candidates for bariatric surgery. Duplicate biopsies from the abdominal visceral adipose tissue were obtained from the omentum. The biopsies were treated with or without NAC (5 and 10 mm). To evaluate adipose tissue senescence, beta-galactosidase (β-gal) activity and the expression of P16, P21, P53, IL-6, and TNF-α were determined. ANOVA test was employed to analyze the varying markers of cellular senescence and inflammation between treatment groups.

RESULTS: The NAC at concentrations of 5 mm and 10 mm resulted in a noteworthy reduction β-gal activity compared to the control group (p < 0.001). Additionally, the expression of P16, P21, and IL-6 was significantly reduced following treatment with NAC (5 mm) and NAC (10 mm) compared to the control group (All p < 0.001).

DISCUSSION/CONCLUSION: Taken together, these data suggest the senotherapeutic effect of NAC, as it effectively reduces the activity of SA-β-gal and the expression of IL-6, P16, and P21 genes in the visceral adipose tissue of obese individuals.}, } @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.}, } @article {pmid38715671, year = {2024}, author = {Zhao, W and Wang, K and Yu, L and Guo, Y and Li, Z}, title = {Dasatinib-induced pleural effusions, pericardial effusion and pulmonary arterial hypertension: a case report.}, journal = {Translational pediatrics}, volume = {13}, number = {4}, pages = {673-681}, pmid = {38715671}, issn = {2224-4344}, abstract = {BACKGROUND: Pleural effusion, pericardial effusion, and pulmonary arterial hypertension have been shown to have potential associations with the use of dasatinib in adults. However, due to the limited data regarding the efficacy and safety of tyrosine kinase inhibitors (TKIs) in pediatric patients necessities reliance on clinical experience gained from treating adults.

CASE DESCRIPTION: We present a case of a 12-year-old female patient with chronic myelogenous leukemia (CML) who developed significant right-sided pleural effusion, moderate pericardial effusion, and pulmonary arterial hypertension during dasatinib therapy. Dasatinib was promptly discontinued upon identification of these adverse events. This was followed by the use of bosentan for pulmonary hypertension, furosemide and spironolactone diuretics, prednisone anti-inflammatory, and especially a bold attempt to improve pulmonary endothelial permeability with acetyl cysteine aerosolization. At the same time, according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data reported by the patient and combined with the actual situation, the appropriate TKI was selected for the patient to continue the CML treatment.

CONCLUSIONS: FAERS data gathered on OpenVigil indicates that the signal associated with pericardial effusion is stronger among individuals under the age of 18 when imatinib is used instead of dasatinib (exactly the reverse of the results in the adult group). However, this does not imply that dasatinib is safer for the smaller group. In our situation, dasatinib-induced adverse effects include pericardial effusion. As a result, while administering TKIs to pediatric patients, we still need to increase monitoring-particularly for pulmonary and cardiovascular toxicity-and take swift action in the event that a major adverse reaction occurs. In addition, it is important to report these adverse effects as much as possible in order to give pediatric patients utilizing TKIs more helpful information.}, } @article {pmid38713059, year = {2024}, author = {Vargas-Barona, A and Bernáldez-Sarabia, J and Castro-Ceseña, AB}, title = {Lipid-polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease.}, journal = {Journal of materials chemistry. B}, volume = {12}, number = {21}, pages = {5085-5097}, doi = {10.1039/d4tb00521j}, pmid = {38713059}, issn = {2050-7518}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Nanoparticles/chemistry ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; *Acetylcysteine/chemistry/pharmacology ; *Astrocytes/drug effects/metabolism ; Polymers/chemistry/pharmacology ; Lipids/chemistry ; Biomarkers/metabolism ; Particle Size ; Neuroinflammatory Diseases/drug therapy ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in the brain, increasing the secretion of proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD is considered a global health priority. The main limitations are the low drug bioavailability and impermeability of the blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as a promising field for the development of new nanosystems for the controlled and targeted delivery of drugs to the brain. Therefore, in this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated with transferrin (Tf) to facilitate crossing the BBB and loaded with N-acetylcysteine (NAC) for its anti-inflammatory effect were synthesized, and their physicochemical characterization was carried out. Subsequently, an in vitro model involving human astrocytes derived from induced pluripotent stem cells (iPSC) from an AD-diagnosed patient was developed, which was brought to a reactive state by stimulation with lipopolysaccharides (LPSs). The cell culture was treated with either Tf-conjugated LPHNPs loaded with NAC (NAC-Tf-LPHNPs) at 0.25 mg mL[-1], or free NAC at 5 mM. The results showed that NAC-Tf-LPHNPs favorably modulated the expression of proinflammatory genes such as interleukin-1β (IL-1β), amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). In addition, they reduced the secretion of the proinflammatory cytokines interleukin 6 (IL-6), IL-1β and interferon-gamma (INF-γ). Results for both cases were compared to the group of cells that did not receive any treatment. In contrast, free NAC only had this effect on the expression of IL-1β and the secretion of the cytokines IL-6 and INF-γ. These results indicate the potential of NAC-Tf-LPHNPs for AD treatment.}, } @article {pmid38704503, year = {2024}, author = {Wajih, N and Erali, RA and Forsythe, SD and Schaaf, CR and Shen, P and Levine, EA and Soker, S and Morris, DL and Votanopoulos, KI}, title = {Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.}, journal = {Annals of surgical oncology}, volume = {31}, number = {8}, pages = {5377-5389}, pmid = {38704503}, issn = {1534-4681}, support = {R01 CA249087/CA/NCI NIH HHS/United States ; R01 CA258692/CA/NCI NIH HHS/United States ; CA249087//Foundation for the National Institutes of Health/ ; CA258692//Foundation for the National Institutes of Health/ ; }, mesh = {*Bromelains/pharmacology ; Humans ; *Appendiceal Neoplasms/pathology/therapy/drug therapy ; *Hyperthermic Intraperitoneal Chemotherapy ; *Cisplatin/pharmacology/administration & dosage ; Male ; Female ; Middle Aged ; Apoptosis/drug effects ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Tumor Cells, Cultured ; Mitomycin/pharmacology/administration & dosage ; Aged ; Cell Proliferation/drug effects ; Cytoreduction Surgical Procedures ; Adenocarcinoma, Mucinous/pathology/therapy/drug therapy/metabolism ; Prognosis ; Follow-Up Studies ; }, abstract = {INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line.

PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment.

RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs.

CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.}, } @article {pmid38703034, year = {2024}, author = {Mato, S and Municio, S and Alonso, JL and Alonso, ER and León, I}, title = {Impact of the Acetyl Group on Cysteine: A Study of N-Acetyl-Cysteine through Rotational Spectroscopy.}, journal = {Chemphyschem : a European journal of chemical physics and physical chemistry}, volume = {25}, number = {15}, pages = {e202400191}, doi = {10.1002/cphc.202400191}, pmid = {38703034}, issn = {1439-7641}, support = {PID2019-111396GB-I00//Ministerio de Ciencia e Innovación/ ; VA244P20//Junta de Castilla y León/ ; 23CO1/002570//Ministerio de Ciencia e Innovación for a postgraduate fellowship/ ; }, mesh = {*Acetylcysteine/chemistry ; Cysteine/chemistry ; Rotation ; Spectrum Analysis/methods ; Molecular Conformation ; Microwaves ; }, abstract = {Herein, we report a spectroscopic study of N-acetyl-L-cysteine, an important antioxidant drug, using Fourier-transform microwave techniques and in isolated conditions. Two conformers are observed, where most stable structure adopts a cis disposition, and the second conformer has a lower abundance and adopts a trans disposition. The rotational constants and the barriers to methyl internal rotation are determined for each conformer, allowing a precise conformation identification. The results show that the cis form adopts an identical structure in the crystal, solution, and gas phases. Additionally, the structures are contrasted against those of cysteine.}, } @article {pmid38702594, year = {2024}, author = {Sohouli, MH and Eslamian, G and Ardehali, SH and Raeissadat, SA and Shimi, G and Pourvali, K and Zand, H}, title = {Effects of N-acetylcysteine on the expressions of UCP1 and factors related to thyroid function in visceral adipose tissue of obese adults: a randomized, double-blind clinical trial.}, journal = {Genes & nutrition}, volume = {19}, number = {1}, pages = {8}, pmid = {38702594}, issn = {1555-8932}, abstract = {BACKGROUND: Evidences have shown that obesity is influenced by various factors, including various hormones such as thyroid hormones and the body's metabolism rate. It seems that practical solutions such as weight loss diets and common drugs can affect these potential disorders. In this study, we investigate one of these common drugs, N-Acetylcysteine (NAC), on expressions of UCP1 and factors related to thyroid function in adults with obesity.

METHODS AND ANALYSIS: The current investigation was carried out as a randomized clinical trial (RCT) including 43 adults with obesity who were potential candidates for bariatric surgery. These individuals were randomly divided into two groups: 600 mg of NAC (n = 22) or placebo (n = 21) for a duration of 8 weeks. Visceral adipose tissue was utilized in the context of bariatric surgery to investigate the gene expression of UCP1 and thyroid function. Polymerase chain reaction (PCR) was performed in duplicate for UCP1, DIO2, DIO3, THRα and β, and 18s RNA (as an internal control) using the provided instructions to investigate the expression of the respective genes.

RESULTS: Our findings revealed that after 8 weeks compared to placebo, NAC caused a significant decrease in the expression of the DIO3 gene as one of the genes related to thyroid function and metabolism. However, regarding other related genes, no statistically significant was found (despite the increase in UCP1, DIO2, and THRα expression and decrease in THRβ expression). In addition, after adjustment of possible confounders, no significant effect was observed on anthropometric factors and serum levels of thyroid hormones.

CONCLUSION: The results of this study indicate that, following an 8-week period, NAC effectively decreases the expression of the DIO3 gene in the visceral fat tissue, in comparison to the placebo.}, } @article {pmid38702220, year = {2024}, author = {Hodgson, S and Abouchedid, R and Cleary, K and Tile, N and Wong, A}, title = {Acute arsenic exposure secondary to deliberate self-poisoning with sheep dip.}, journal = {The American journal of emergency medicine}, volume = {80}, number = {}, pages = {226.e1-226.e3}, doi = {10.1016/j.ajem.2024.04.050}, pmid = {38702220}, issn = {1532-8171}, mesh = {Male ; Humans ; Middle Aged ; *Suicide, Attempted ; *Arsenic Poisoning ; *Acetylcysteine/therapeutic use ; *Arsenicals ; Arsenic Trioxide/poisoning ; Oxides/poisoning ; Antidotes/therapeutic use ; Unithiol/therapeutic use ; }, abstract = {A 53-year-old male patient presented to a regional hospital Emergency Department approximately 2 h post an intentional ingestion of Coopers Instant Wetting Powder Sheep Dip (66% arsenic trioxide, 23% sulphur and 0.42% rotenone), mixed in 600 mL water, as a suicide attempt. On arrival to the Emergency Department, the patient had nausea, vomiting and diarrhoea. Seven hours post ingestion, hypotension developed (BP 90/60 mmHg) and intravenous fluids were commenced. He later developed QTc prolongation. He was treated with 2,3-Dimercapto-1-propanesulfonic acid (DMPS) and N-acetylcysteine and improved without development of neurology. Further investigation of NAC efficacy in humans in the setting of acute arsenic poisoning is required and the optimal duration of treatment and dosing needs to be established. This case highlights an uncommon poisoning which presented to the Emergency Department, the acute symptoms of arsenic toxicity and considerations for management.}, } @article {pmid38700012, year = {2024}, author = {Abouelgreed, TA and Amer, MA and Mamdouh, H and El-Sherbiny, AF and Aboelwafa, H and Fahmy, SF and Omar, OA and Abdelshakour, M and Elesawy, M and Sonbol, M and Maawad, AN and Elsayed, OK}, title = {The influence of oral antioxidants on men with infertility: a systemic review.}, journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica}, volume = {96}, number = {2}, pages = {12323}, doi = {10.4081/aiua.2024.12323}, pmid = {38700012}, issn = {2282-4197}, mesh = {Humans ; Male ; *Antioxidants/administration & dosage/therapeutic use ; *Infertility, Male/drug therapy/etiology ; Administration, Oral ; Randomized Controlled Trials as Topic ; Semen Analysis ; Dietary Supplements ; }, abstract = {OBJECTIVE: This study aims to investigate the current evidence regarding the impact of oral antioxidant supplementation on semen parameters of infertile men.

MATERIALS AND METHODS: We conducted a systematic search of PubMed, and Cochrane electronic databases, adhering to modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The focus was on studies exploring the effects of antioxidant therapy on infertile men, with an examination of antioxidants in terms of types, doses, rationale for use, and their impact on semen parameters measures.

RESULTS: A total of 18 studies that met the inclusion criteria were included in this study. Out of these, 14 studies reported a significantly positive influence of antioxidant therapy on basic semen parameters and advanced sperm function. These comprised 11 randomized clinical trials and 7 prospective studies. Commonly utilized antioxidants included Vitamin E, Vitamin C, carnitines, co-enzyme Q10, N-acetyl cysteine, zinc, selenium, folic acid, and lycopene.

CONCLUSIONS: Overall, antioxidants generally demonstrate a favorable effect on semen parameters of infertile men. However, further research is necessary to pinpoint the optimal antioxidant regimen that can be applied safely and effectively in clinical practice.}, } @article {pmid38693878, year = {2024}, author = {Pandey, R and Pinon, V and Garren, M and Maffe, P and Mondal, A and Brisbois, EJ and Handa, H}, title = {N-Acetyl Cysteine-Decorated Nitric Oxide-Releasing Interface for Biomedical Applications.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {19}, pages = {24248-24260}, pmid = {38693878}, issn = {1944-8252}, support = {R01 HL134899/HL/NHLBI NIH HHS/United States ; R01 HL157587/HL/NHLBI NIH HHS/United States ; }, mesh = {*Acetylcysteine/chemistry/pharmacology ; *Nitric Oxide/chemistry/metabolism/pharmacology ; *Staphylococcus aureus/drug effects ; *Escherichia coli/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Biofilms/drug effects ; Polyethyleneimine/chemistry/pharmacology ; Biocompatible Materials/chemistry/pharmacology ; Microbial Sensitivity Tests ; Polyvinyl Chloride/chemistry ; Nitric Oxide Donors/chemistry/pharmacology ; }, abstract = {Biomedical devices are vulnerable to infections and biofilm formation, leading to extended hospital stays, high expenditure, and increased mortality. Infections are clinically treated via the administration of systemic antibiotics, leading to the development of antibiotic resistance. A multimechanistic strategy is needed to design an effective biomaterial with broad-spectrum antibacterial potential. Recent approaches have investigated the fabrication of innately antimicrobial biomedical device surfaces in the hope of making the antibiotic treatment obsolete. Herein, we report a novel fabrication strategy combining antibacterial nitric oxide (NO) with an antibiofilm agent N-acetyl cysteine (NAC) on a polyvinyl chloride surface using polycationic polyethylenimine (PEI) as a linker. The designed biomaterial could release NO for at least 7 days with minimal NO donor leaching under physiological conditions. The proposed surface technology significantly reduced the viability of Gram-negative Escherichia coli (>97%) and Gram-positive Staphylococcus aureus (>99%) bacteria in both adhered and planktonic forms in a 24 h antibacterial assay. The composites also exhibited a significant reduction in biomass and extra polymeric substance accumulation in a dynamic environment over 72 h. Overall, these results indicate that the proposed combination of the NO donor with mucolytic NAC on a polymer surface efficiently resists microbial adhesion and can be used to prevent device-associated biofilm formation.}, } @article {pmid38693516, year = {2024}, author = {Ozawa, K and Packwood, W and Muller, MA and Qi, Y and Xie, A and Varlamov, O and McCarty, OJ and Chung, D and López, JA and Lindner, JR}, title = {Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {412}, pmid = {38693516}, issn = {1479-5876}, support = {R35 HL145262/HL/NHLBI NIH HHS/United States ; NIH R01-HL078610/NH/NIH HHS/United States ; NIH R01-HL165422/NH/NIH HHS/United States ; R35-HL145262/NH/NIH HHS/United States ; R01 HL130046/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *von Willebrand Factor/metabolism ; *Myocardial Infarction/pathology/complications ; *ADAMTS13 Protein/metabolism ; Vascular Cell Adhesion Molecule-1/metabolism ; Mice ; Plaque, Atherosclerotic/pathology ; P-Selectin/metabolism ; Endothelial Cells/metabolism/drug effects ; Male ; Molecular Imaging ; Aorta/pathology/drug effects ; Acetylcysteine/pharmacology/therapeutic use ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI).

METHODS: Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21.

RESULTS: Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p < 0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by > 50% (p < 0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p < 0.05), approximately 20-fold greater platelet adhesion (p < 0.05), and increased staining for markers of platelet transforming growth factor-β1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology.

CONCLUSIONS: Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.}, } @article {pmid38691522, year = {2024}, author = {Gao, X and Hu, Z and Wang, Y and Zhao, G and Shen, Y and Zhou, H and Liao, Y and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {19}, pages = {10897-10908}, doi = {10.1021/acs.jafc.4c00400}, pmid = {38691522}, issn = {1520-5118}, mesh = {Animals ; Rats ; Male ; *Hepatocytes/metabolism/drug effects ; *Cytochrome P-450 CYP3A/metabolism/genetics ; *Rats, Sprague-Dawley ; *Activation, Metabolic ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; Insecticides/toxicity/metabolism ; Alkaloids/metabolism ; }, abstract = {Gramine (GRM), which occurs in Gramineae plants, has been developed to be a biological insecticide. Exposure to GRM was reported to induce elevations of serum ALT and AST in rats, but the mechanisms of the observed hepatotoxicity have not been elucidated. The present study aimed to identify reactive metabolites that potentially participate in the toxicity. In rat liver microsomal incubations fortified with glutathione or N-acetylcysteine, one oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetylcysteine conjugate (M3) were detected after exposure to GRM. The corresponding conjugates were detected in the bile and urine of rats after GRM administration. CYP3A was the main enzyme mediating the metabolic activation of GRM. The detected GSH and NAC conjugates suggest that GRM was metabolized to a quinone imine intermediate. Both GRM and M1 showed significant toxicity to rat primary hepatocytes.}, } @article {pmid38688172, year = {2024}, author = {Chen, Y and Xu, M and Liu, XM and Wang, JX and Sun, MF and Song, JX and Guan, P and Ji, ES and Wang, N}, title = {Mechanistic study of Huangqi Guizhi Wuwu decoction amelioration of doxorubicin-induced cardiotoxicity by reducing oxidative stress and inhibiting cellular pyroptosis.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {175}, number = {}, pages = {116653}, doi = {10.1016/j.biopha.2024.116653}, pmid = {38688172}, issn = {1950-6007}, mesh = {Animals ; *Doxorubicin/toxicity ; *Pyroptosis/drug effects ; *Drugs, Chinese Herbal/pharmacology ; *Oxidative Stress/drug effects ; *Cardiotoxicity/drug therapy/metabolism/prevention & control ; Rats ; Male ; *Rats, Sprague-Dawley ; Myocytes, Cardiac/drug effects/metabolism/pathology ; Cell Line ; Network Pharmacology ; }, abstract = {Huangqi Guizhi Wuwu Decoction (HQGZWWD) has shown promising potential in treating various cardiovascular diseases. This study aimed to elucidate the molecular basis and therapeutic role of HQGZWWD in the treatment of doxorubicin (DOX)-induced myocardial injury. The HPLC fingerprint of HQGZWWD was used to analyze the active components. A DOX-induced myocardial damage rat model was developed, and the therapeutic effects of HQGZWWD were evaluated using echocardiography, myocardial enzyme levels, and hematoxylin and eosin staining. Network pharmacology was used to screen treatment targets, and western blotting and immunohistochemistry were performed to assess cellular pyroptosis levels. Oxidative stress levels were measured using assay kits, and mitochondrial damage was examined using transmission electron microscopy. An in vitro model of DOX-induced cell damage was established, and treatment was administered using serum containing HQGZWWD and N-acetylcysteine (NAC). Oxidative stress levels were detected using assay kits and DCFH-DA, whereas cellular pyroptosis levels were assessed through WB, immunofluorescence, and ELISA assays. HQGZWWD ameliorated DOX-induced myocardial injury. Network pharmacology identified IL-1β and IL-18 as crucial targets. HQGZWWD downregulated the protein levels of the inflammatory factors IL-1β and IL-18, inhibited the expression of GSDMD-NT, and simultaneously suppressed the synthesis of Caspase-1, ASC, NLRP3, and Caspase-11. Additionally, HQGZWWD inhibited oxidative stress, and the use of NAC as an oxidative stress inhibitor resulted in significant inhibition of the GSDMD-NT protein in H9C2 cells. These findings highlight the myocardial protective effects of HQGZWWD by inhibiting oxidative stress and suppressing both canonical and non-canonical pyroptotic pathways.}, } @article {pmid38687644, year = {2024}, author = {Manhas, A and Arnold, CG and Bush, AM}, title = {Underreporting Supplements: A Case of Drug-induced Liver Injury Due to a Testosterone Booster.}, journal = {Military medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/milmed/usae136}, pmid = {38687644}, issn = {1930-613X}, abstract = {Acute liver injuries (ALIs) are caused by a wide range of etiologies, and determining the cause can often be challenging. Detailed history taking is essential in patients with liver injuries to promptly determine the underlying source of injury and for timely treatment and prognosis. A 27-year-old active duty man presented to the emergency department (ED) with jaundice. On medication reconciliation, he only reported taking acetaminophen for a recent upper respiratory infection. The patient had an ALI and was treated with N-acetyl cysteine for presumed acetaminophen toxicity. Initially, his liver-associated enzymes (LAEs) improved, but 2 weeks after discharge, he returned to the ED upon referral from ship medical for jaundice and worsening liver injury. Repeated query into the patient's history revealed that he was using a testosterone booster supplement for 6 months preceding initial hospitalization. After evaluation of other etiologies for liver injury returned negative, drug-induced liver injury from the testosterone booster was determined to be the underlying etiology. With discontinuation of the supplement, his liver injury improved. Hepatotoxicity is a major concern in supplement use; however, it is largely underreported. Supplements are often not recognized or reported as medications by patients, leading to failure to identify them as potential toxicants. This case highlights the importance of including supplement education and questioning in the evaluation of ALI and maintaining a high index of suspicion when other common etiologies of liver disease are negative.}, } @article {pmid38687431, year = {2024}, author = {Giri, S and Anirvan, P and Vaidya, A and Praharaj, DL}, title = {Dengue-related acute liver failure-A scoping review.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {43}, number = {2}, pages = {407-424}, pmid = {38687431}, issn = {0975-0711}, mesh = {Humans ; *Liver Failure, Acute/etiology/epidemiology/therapy ; *Dengue/complications/epidemiology ; Risk Factors ; Liver Transplantation ; Female ; Male ; Child ; India/epidemiology ; Adult ; Incidence ; }, abstract = {Infection by dengue virus is common in tropical countries. Hepatic involvement in dengue can range from asymptomatic elevation of transaminases to life-threatening acute liver failure (ALF). Dengue-related ALF (DALF) is responsible for significant morbidity and mortality, especially in Southeast Asia. However, there is a scarcity of literature on DALF, necessitating a thorough examination of its clinical determinants and management strategies. All relevant studies related to DALF were reviewed until December 2023. Case reports, case series and studies reporting ALF in dengue infection were included. Demographics, clinical profiles, management and outcomes of DALF cases were analyzed, which revealed a predominance of DALF incidence in pediatric patients (1.1% to 15.8%) and an upward trend over the years, particularly in India. The proportion of ALF cases attributable to dengue was also higher among pediatric ALF patients (6.7% to 34.3%). Age ≤ 40 years, persistent nausea, vomiting and elevated serum bilirubin and alkaline phosphatase (ALP) with aspartate aminotransferase (AST) > 1000 IU/mL within the first five days of illness, more than 10% of atypical lymphocytes in peripheral blood, platelet count of < 50,000/cu·mm, severe hepatitis at presentation and baseline model for end-stage liver disease (MELD) > 15 were the risk factors for the development of DALF. Histopathological features of DALF included multi-lobular hepatic necrosis, steatosis and occasional cholestasis. Mortality in DALF ranged from 0% to 80%; admission pH and lactate strongly predicted mortality, while mortality was found to be significantly higher in patients with cirrhosis. N-Acetyl cysteine (NAC) has been used as a treatment modality with varying results. There is limited evidence regarding the use of extra-corporeal support systems, while candidate selection for liver transplantation (LT) in DALF remains poorly defined.}, } @article {pmid38686842, year = {2024}, author = {Hamsho, M and Ranneh, Y and Fadel, A}, title = {Comments on "A Meta-Analysis of the Efficacy of L-Carnitine/L-Acetyl-Carnitine or N-Acetyl-Cysteine in Men with Idiopathic Asthenozoospermia".}, journal = {American journal of men's health}, volume = {18}, number = {2}, pages = {15579883241249109}, pmid = {38686842}, issn = {1557-9891}, mesh = {Humans ; Male ; *Acetylcysteine/therapeutic use/administration & dosage ; *Asthenozoospermia/drug therapy ; *Carnitine/therapeutic use ; Meta-Analysis as Topic ; Acetylcarnitine/therapeutic use ; Treatment Outcome ; }, } @article {pmid38686557, year = {2024}, author = {Yang, L and Wang, X and Ma, Z and Sui, Y and Liu, X}, title = {Fangchinoline inhibits growth and biofilm of Candida albicans by inducing ROS overproduction.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {9}, pages = {e18354}, pmid = {38686557}, issn = {1582-4934}, support = {20220505041ZP//the Science and Technology Development Plan Project of Jilin Province/ ; 20200201595JC//Natural Science Foundation of Jilin Province/ ; JJKH20231220KJ//the Education Department of Jilin Province/ ; }, mesh = {*Biofilms/drug effects/growth & development ; *Candida albicans/drug effects/growth & development ; *Antifungal Agents/pharmacology ; *Reactive Oxygen Species/metabolism ; *Benzylisoquinolines/pharmacology ; *Microbial Sensitivity Tests ; Hyphae/drug effects/growth & development ; }, abstract = {Infections caused by Candida species, especially Candida albicans, threaten the public health and create economic burden. Shortage of antifungals and emergence of drug resistance call for new antifungal therapies while natural products were attractive sources for developing new drugs. In our study, fangchinoline, a bis-benzylisoquinoline alkaloid from Chinese herb Stephania tetrandra S. Moore, exerted antifungal effects on planktonic growth of several Candida species including C. albicans, with MIC no more than 50 μg/mL. In addition, results from microscopic, MTT and XTT reduction assays showed that fangchinoline had inhibitory activities against the multiple virulence factors of C. albicans, such as adhesion, hyphal growth and biofilm formation. Furthermore, this compound could also suppress the metabolic activity of preformed C. albicans biofilms. PI staining, followed by confocal laser scanning microscope (CLSM) analysis showed that fangchinoline can elevate permeability of cell membrane. DCFH-DA staining suggested its anti-Candida mechanism also involved overproduction of intracellular ROS, which was further confirmed by N-acetyl-cysteine rescue tests. Moreover, fangchinoline showed synergy with three antifungal drugs (amphotericin B, fluconazole and caspofungin), further indicating its potential use in treating C. albicans infections. Therefore, these results indicated that fangchinoline could be a potential candidate for developing anti-Candida therapies.}, } @article {pmid38682430, year = {2024}, author = {Chen, HX and Wang, XY and Yu, B and Feng, CL and Cheng, GF and Zhang, L and Wang, JJ and Wang, Y and Guo, RW and Ji, XM and Xie, WJ and Chen, WL and Song, C and Zhang, X}, title = {Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.}, journal = {Zoological research}, volume = {45}, number = {3}, pages = {478-491}, pmid = {38682430}, issn = {2095-8137}, mesh = {*Acetaminophen/toxicity ; Animals ; Mice ; *Chemical and Drug Induced Liver Injury ; *Drug Overdose ; *Analgesics, Non-Narcotic/toxicity ; Oxidative Stress/drug effects ; Male ; Magnetic Fields ; Acetylcysteine/therapeutic use/pharmacology ; }, abstract = {Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.}, } @article {pmid38678953, year = {2024}, author = {Dou, M and Zhu, D and Cui, G and Li, H and Di, L and Wang, L}, title = {Euphorbia helioscopia L. exhibits promising therapeutic effects on hemangioendothelioma and melanoma through angiogenesis inhibition.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {129}, number = {}, pages = {155666}, doi = {10.1016/j.phymed.2024.155666}, pmid = {38678953}, issn = {1618-095X}, mesh = {Animals ; *Euphorbia/chemistry ; *Hemangioendothelioma/drug therapy ; *Reactive Oxygen Species/metabolism ; *Angiogenesis Inhibitors/pharmacology ; Humans ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Mice ; *Plant Extracts/pharmacology ; *Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Melanoma/drug therapy ; Plant Leaves/chemistry ; Melanoma, Experimental/drug therapy ; Neovascularization, Pathologic/drug therapy ; Mice, Inbred C57BL ; Male ; Angiogenesis ; }, abstract = {BACKGROUND: Euphorbia helioscopia L (EHL), a widely used medicinal plant in traditional Chinese medicine, has shown promising effects on certain cancers. However, previous studies on EHL did not elucidate the underlying molecular mechanisms. Herein, for the first time, we present the strong therapeutic potential of EHL extracts on malignant hemangioendothelioma, a rare type of vascular tumor.

PURPOSE: To investigate the potential anti-tumor mechanism of extracts of EHL on hemangioendothelioma and melanoma.

METHODS: The dried stems and leaves of EHL were extracted with Ethyl Acetate and n-Butyl alcohol, yielding two crude extracts Ethyl Acetate fraction (EA) and n-Butyl alcohol fraction (Bu). EA and Bu were prepared to assess the potential mechanism by assays for cell proliferation, cell cycle, apoptosis, colony formation, tube formation, cellular metabolic activity, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, RNA expression and western blot. To further confirm the anti-tumor effect of EHL in vivo, we established hemangioendothelioma and melanoma tumor-bearing mouse model using node mice and administered with EA and Bu, tracked alterations in tumor volume and survival rate. Furthermore, tissue samples were obtained for histological, protein, and genetic investigations.

RESULTS: We demonstrate that the injection of EA and Bu, significantly inhibits tumor growth and prolongs the lifespan of tumor-bearing mice. Bu treatment exhibited a remarkable 33 % healing effect on the primary hemangioendothelioma tumor, bringing the survival rate to a level comparable to that of healthy mice. Mechanically, both EA and Bu impair respiratory chain complexes, leading to mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), resulting in DNA damage, cell apoptosis, and finally blocked angiogenesis. While EA demonstrates robust inhibitory effects on cancer cell growth and a broader impact on metabolism in vitro, the in vivo effect of Bu surpasses that of EA in terms of strength. EA and Bu also exhibit potent anti-tumor effects on a primary melanoma model by inhibiting angiogenesis. Importantly, when compared to other compounds used in the treatment of hemangioendothelioma, EA and Bu demonstrate more profound anti-tumor effects.

CONCLUSION: For the first time, our findings reveal that EHL extracts, especially the high polarity compounds, exhibit potent anti-tumor effects by targeting cellular metabolism, specifically through the inhibition of mitochondria-related metabolic activities. This leads to the accumulation of ROS and effectively suppresses abnormal angiogenesis.}, } @article {pmid38675591, year = {2024}, author = {Zigová, M and Miškufová, V and Budovská, M and Michalková, R and Mojžiš, J}, title = {Exploring the Antiproliferative and Modulatory Effects of 1-Methoxyisobrassinin on Ovarian Cancer Cells: Insights into Cell Cycle Regulation, Apoptosis, Autophagy, and Its Interactions with NAC.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {8}, pages = {}, pmid = {38675591}, issn = {1420-3049}, support = {APVV-16-0446//Slovak Research and Development Agency/ ; VEGA 1/0653/19//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Repub-lic/ ; VEGA 1/0498/23//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Republic/ ; VEGA 1/0446/22//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Republic/ ; ITMS2014+: 313011V455//ERDF/ ; }, mesh = {Female ; Humans ; *Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology/chemistry ; *Apoptosis/drug effects ; *Autophagy/drug effects ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor/drug effects ; *Cell Proliferation/drug effects ; Cisplatin/pharmacology ; DNA Damage/drug effects ; Drug Resistance, Neoplasm/drug effects ; *Ovarian Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; *Phytoalexins/pharmacology ; *Indoles/pharmacology ; Thiocarbamates/pharmacology ; }, abstract = {Ovarian cancer, a highly lethal malignancy among reproductive organ cancers, poses a significant challenge with its high mortality rate, particularly in advanced-stage cases resistant to platinum-based chemotherapy. This study explores the potential therapeutic efficacy of 1-methoxyisobrassinin (MB-591), a derivative of indole phytoalexins found in Cruciferae family plants, on both cisplatin-sensitive (A2780) and cisplatin-resistant ovarian cancer cells (A2780 cis). The findings reveal that MB-591 exhibits an antiproliferative effect on both cell lines, with significantly increased potency against cisplatin-sensitive cells. The substance induces alterations in the distribution of the cell cycle, particularly in the S and G2/M phases, accompanied by changes in key regulatory proteins. Moreover, MB-591 triggers apoptosis in both cell lines, involving caspase-9 cleavage, PARP cleavage induction, and DNA damage, accompanied by the generation of reactive oxygen species (ROS) and mitochondrial dysfunction. Notably, the substance selectively induces autophagy in cisplatin-resistant cells, suggesting potential targeted therapeutic applications. The study further explores the interplay between MB-591 and antioxidant N-acetylcysteine (NAC), in modulating cellular processes. NAC demonstrates a protective effect against MB-591-induced cytotoxicity, affecting cell cycle distribution and apoptosis-related proteins. Additionally, NAC exhibits inhibitory effects on autophagy initiation in cisplatin-resistant cells, suggesting its potential role in overcoming resistance mechanisms.}, } @article {pmid38672493, year = {2024}, author = {Kamenshchyk, A and Belenichev, I and Oksenych, V and Kamyshnyi, O}, title = {Combined Pharmacological Modulation of Translational and Transcriptional Activity Signaling Pathways as a Promising Therapeutic Approach in Children with Myocardial Changes.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672493}, issn = {2218-273X}, mesh = {Humans ; *Signal Transduction/drug effects ; Child ; Animals ; Myocardium/metabolism/pathology ; Transcription, Genetic/drug effects ; Protein Biosynthesis/drug effects ; Cardiomegaly/drug therapy/metabolism/genetics ; }, abstract = {Myocardial hypertrophy is the most common condition that accompanies heart development in children. Transcriptional gene expression regulating pathways play a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy, and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed the downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pumps, and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs make combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.}, } @article {pmid38672280, year = {2024}, author = {Altay, O and Yang, H and Yildirim, S and Bayram, C and Bolat, I and Oner, S and Tozlu, OO and Arslan, ME and Hacimuftuoglu, A and Shoaie, S and Zhang, C and Borén, J and Uhlén, M and Turkez, H and Mardinoglu, A}, title = {Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {12}, number = {4}, pages = {}, pmid = {38672280}, issn = {2227-9059}, support = {72110//Knut and Alice Wallenberg Foundation/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate.

METHODS: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations.

FINDINGS: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals.

INTERPRETATION: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.}, } @article {pmid38672256, year = {2024}, author = {Chen, R and Zheng, Y and Zhou, C and Dai, H and Wang, Y and Chu, Y and Luo, J}, title = {N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress.}, journal = {Biomedicines}, volume = {12}, number = {4}, pages = {}, pmid = {38672256}, issn = {2227-9059}, abstract = {(1) Background: Sepsis-induced muscle atrophy is characterized by a loss of muscle mass and function which leads to decreased quality of life and worsens the long-term prognosis of patients. N-acetylcysteine (NAC) has powerful antioxidant and anti-inflammatory properties, and it relieves muscle wasting caused by several diseases, whereas its effect on sepsis-induced muscle atrophy has not been reported. The present study investigated the effect of NAC on sepsis-induced muscle atrophy and its possible mechanisms. (2) Methods: The effect of NAC on sepsis-induced muscle atrophy was assessed in vivo and in vitro using cecal ligation and puncture-operated (CLP) C57BL/6 mice and LPS-treated C2C12 myotubes. We used immunofluorescence staining to analyze changes in the cross-sectional area (CSA) of myofibers in mice and the myotube diameter of C2C12. Protein expressions were analyzed by Western blotting. (3) Results: In the septic mice, the atrophic response manifested as a reduction in skeletal muscle weight and myofiber cross-sectional area, which is mediated by muscle-specific ubiquitin ligases-muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1). NAC alleviated sepsis-induced skeletal muscle wasting and LPS-induced C2C12 myotube atrophy. Meanwhile, NAC inhibited the sepsis-induced activation of the endoplasmic reticulum (ER) stress signaling pathway. Furthermore, using 4-Phenylbutyric acid (4-PBA) to inhibit ER stress in LPS-treated C2C12 myotubes could partly abrogate the anti-muscle-atrophy effect of NAC. Finally, NAC alleviated myotube atrophy induced by the ER stress agonist Thapsigargin (Thap). (4) Conclusions: NAC can attenuate sepsis-induced muscle atrophy, which may be related to downregulating ER stress.}, } @article {pmid38671944, year = {2024}, author = {Kim, RJ and Park, HB}, title = {Protective and Regenerative Effects of Reconstituted HDL on Human Rotator Cuff Fibroblasts under Hypoxia: An In Vitro Study.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {4}, pages = {}, pmid = {38671944}, issn = {2076-3921}, support = {2021R1A2C1008931//National Research Foundation of Korea/ ; }, abstract = {Hypoxia and hypo-high-density lipoproteinemia (hypo-HDLemia) are proposed risk factors for rotator cuff tear. HDL is recognized for its potential benefits in ischemia-driven angiogenesis and wound healing. Nevertheless, research on the potential benefits of reconstituted HDL (rHDL) on human rotator cuff fibroblasts (RCFs) under hypoxia is limited. This study investigates the cytoprotective and regenerative effects of rHDL, as well as N-acetylcysteine (NAC), vitamin C (Vit C), and HDL on human RCFs under hypoxic conditions. Sixth-passage human RCFs were divided into normoxia, hypoxia, and hypoxia groups pretreated with antioxidants (NAC, Vit C, rHDL, HDL). Hypoxia was induced by 1000 µM CoCl2. In the hypoxia group compared to the normoxia group, there were significant increases in hypoxia-inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), and Bcl-2/E1B-19kDa interacting protein 3 (BNIP3) expressions, along with reduced cell viability, elevated reactive oxygen species (ROS) production, apoptosis rate, expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors (VEGF), and matrix metalloproteinase-2 (MMP-2), as well as decreased collagen I and III production, and markedly lower cell proliferative activity (p ≤ 0.039). These responses were significantly mitigated by pretreatment with rHDL (p ≤ 0.046). This study suggests that rHDL can enhance cell proliferation and collagen I and III production while reducing apoptosis in human RCFs under hypoxic conditions.}, } @article {pmid38671832, year = {2024}, author = {Cai, J and Li, Y and Zhao, B and Bao, Z and Li, J and Sun, S and Chen, Y and Wu, X}, title = {N-Acetylcysteine Alleviates D-Galactose-Induced Injury of Ovarian Granulosa Cells in Female Rabbits by Regulating the PI3K/Akt/mTOR Signaling Pathway.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {4}, pages = {}, pmid = {38671832}, issn = {2076-3921}, abstract = {The ovary plays a crucial role in the reproductive system of female animals. Ovarian problems such as ovarian insufficiency, premature aging, polycystic ovary syndrome, and ovarian cysts may lead to ovulation disorders, abnormal hormone secretion, or luteal dysfunction, thereby increasing the risk of infertility and abortion. Only when the ovarian function and other organs in the reproductive system remain healthy and work normally can female animals be ensured to carry out reproductive activities regularly, improve the pregnancy rate and litter size, promote the healthy development of the fetus, and then improve their economic value. The follicle, as the functional unit of the ovary, is composed of theca cells, granulosa cells (GCs), and oocytes. GCs are the largest cell population and main functional unit in follicles and provide the necessary nutrients for the growth and development of follicles. N-acetylcysteine (NAC) is a prevalent and cell-permeable antioxidant molecule that effectively prevents apoptosis and promotes cellular survival. Over the past few years, its function in boosting reproductive performance in animals at the cellular level has been widely acknowledged. However, its specific role and mechanism in influencing GCs is yet to be fully understood. The objective of this study was to examine the effects of NAC on ovarian damage in female rabbits. For this purpose, D-galactose (D-gal) was first used to establish a model of damaged GCs, with exposure to 1.5 mg/mL of D-gal leading to substantial damage. Subsequently, varying concentrations of NAC were introduced to determine the precise mechanism through which it influences cell damage. Based on the results of the Cell Counting Kit-8 assay, flow cytometry, and Western blotting, it was found that 0.5 mg/mL of NAC could significantly suppress cell apoptosis and promote proliferation. In particular, it decreased the expression levels of Bax, p53, and Caspase-9 genes, while concurrently upregulating the expression of the BCL-2 gene. Moreover, NAC was found to alleviate intracellular oxidative stress, suppress the discharge of mitochondrial Cytochrome c, and boost the enzymatic activities of CAT (Catalase), GSH (Glutathione), and SOD (Superoxide dismutase). RNA sequencing analysis subsequently underscored the critical role of the PI3K/Akt/mTOR pathway in governing proliferation and apoptosis within GCs. These findings demonstrated that NAC could significantly influence gene expression within this pathway, thereby clarifying the exact relationship between the PI3K/Akt/mTOR signaling cascade and the underlying cellular processes controlling proliferation and apoptosis. In conclusion, NAC can reduce the expression of Bax, p53, and Caspase-9 genes, inhibit the apoptosis of GCs, improve cell viability, and resist D-gal-induced oxidative stress by increasing the activity of CAT, GSH, and SOD. The molecular mechanism of NAC in alleviating D-gal-induced ovarian GC injury in female rabbits by regulating the PI3K/Akt/mTOR signaling pathway provides experimental evidence for the effect of NAC on animal reproductive function at the cellular level.}, } @article {pmid38670497, year = {2024}, author = {Liang, WZ and Chia, YY and Sun, HJ and Sun, GC}, title = {Exploration of beauvericin's toxic effects and mechanisms in human astrocytes and N-acetylcysteine's protective role.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {243}, number = {}, pages = {107734}, doi = {10.1016/j.toxicon.2024.107734}, pmid = {38670497}, issn = {1879-3150}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Astrocytes/drug effects ; *Oxidative Stress/drug effects ; *Depsipeptides/toxicity ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Cell Line ; Antioxidants/pharmacology ; }, abstract = {Beauvericin (BEA) is a newly identified mycotoxin produced by various Fusarium species, and its contamination in food and animal feed is widespread globally. This mycotoxin demonstrates cytotoxic effects by inducing oxidative stress in multiple models. Furthermore, evidence indicates that BEA possesses diverse toxic activities, making it a promising candidate for toxicological research. Recent studies have highlighted the ability of BEA to traverse the blood-brain barrier, suggesting its potential neurotoxicity. However, limited information is available regarding the neurotoxic effects of BEA on human astrocytes. Therefore, this study aimed to assess the neurotoxic effects of BEA on the Gibco® Human Astrocyte (GHA) cell line and elucidate the underlying mechanisms. Additionally, the study aimed to investigate the protective effects of the antioxidant N-acetylcysteine (NAC) against BEA-induced toxicity. The data show that exposure to BEA within the 2.5-15 μM concentration range resulted in concentration-dependent cytotoxicity. BEA-treated cells exhibited significantly increased levels of reactive oxygen species (ROS), while intracellular glutathione (GSH) content was significantly reduced. Western blot analysis of cells treated with BEA revealed altered protein levels of Bax, cleaved caspase-9, and caspase-3, along with an increased Bax/Bcl-2 ratio, indicating the induction of apoptosis. Additionally, BEA exposure triggered antioxidant responses, as evidenced by increased protein expression of Nrf2, HO-1, and NQO1. Significantly, pretreatment with NAC partially attenuated the significant toxic effects of BEA. In conclusion, our findings suggest that BEA-induced cytotoxicity in GHA cells involves oxidative stress-associated apoptosis. Furthermore, NAC demonstrates potential as a protective agent against BEA-induced oxidative damage.}, } @article {pmid38670245, year = {2024}, author = {Lu, W and Cheng, S and Xu, J and Xiao, Z and Yu, Y and Xie, Q and Fang, Y and Chen, R and Shen, B and Xie, Y and Ding, X}, title = {Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy.}, journal = {Toxicology letters}, volume = {396}, number = {}, pages = {81-93}, doi = {10.1016/j.toxlet.2024.04.005}, pmid = {38670245}, issn = {1879-3169}, mesh = {Animals ; *Receptors, Aryl Hydrocarbon/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Uremia/metabolism ; *Myocytes, Cardiac/metabolism/drug effects/pathology ; *Signal Transduction ; *Indican/toxicity ; Humans ; *Cardiomyopathies/metabolism/pathology ; Rats ; Male ; *Rats, Sprague-Dawley ; Cell Line ; Basic Helix-Loop-Helix Transcription Factors/metabolism/genetics ; Oxidative Stress ; Disease Models, Animal ; Renal Insufficiency, Chronic/metabolism/pathology ; }, abstract = {PURPOSE: Uremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury.

METHODS: UCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2',7'-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1 s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC).

RESULTS: UCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy.

CONCLUSION: This study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.}, } @article {pmid38669982, year = {2024}, author = {An, K and Fan, J and Lin, B and Han, Y}, title = {A lysosome-targeted fluorescent probe for fluorescence imaging of hypochlorous acid in living cells and in vivo.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {316}, number = {}, pages = {124316}, doi = {10.1016/j.saa.2024.124316}, pmid = {38669982}, issn = {1873-3557}, mesh = {*Hypochlorous Acid/analysis/metabolism ; *Lysosomes/metabolism/chemistry ; *Fluorescent Dyes/chemistry/chemical synthesis ; Animals ; *Zebrafish ; *Optical Imaging ; Humans ; RAW 264.7 Cells ; Mice ; Boron Compounds/chemistry ; Spectrometry, Fluorescence ; Pyridines/chemistry ; Limit of Detection ; }, abstract = {Lysosomes, as crucial acidic organelles in cells, play a significant role in cellular functions. The levels and distribution of hypochlorous acid (HOCl) within lysosomes can profoundly impact their biological functionality. Hence, real-time monitoring of the concentration of HOCl in lysosomes holds paramount importance for further understanding various physiological and pathological processes associated with lysosomes. In this study, we developed a bodipy-based fluorescent probe derived from pyridine and phenyl selenide for the specific detection of HOCl in aqueous solutions. Leveraging the probe's sensitive photoinduced electron transfer effect from phenyl selenide to the fluorophore, the probe exhibited satisfactory high sensitivity (with a limit of detection of 5.2 nM and a response time of 15 s) to hypochlorous acid. Further biological experiments confirmed that the introduction of the pyridine moiety enabled the probe molecule to selectively target lysosomes. Moreover, the probe successfully facilitated real-time monitoring of HOCl in cell models stimulated by N-acetylcysteine (NAC) and lipopolysaccharide (LPS), as well as in a normal zebrafish model. This provides a universal method for dynamically sensing HOCl in lysosomes.}, } @article {pmid38665380, year = {2024}, author = {Gangadharan Nambiar, G and Gonzalez Szachowicz, S and Zirbes, CF and Hill, JJ and Powers, LS and Meyerholz, DK and Thornell, IM and Stoltz, DA and Fischer, AJ}, title = {Pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines.}, journal = {Frontiers in pediatrics}, volume = {12}, number = {}, pages = {1387171}, pmid = {38665380}, issn = {2296-2360}, abstract = {INTRODUCTION: Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.

METHODS: We collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 °C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.

RESULTS AND DISCUSSION: In CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405 nm after submersion in saline over approximately 8 h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.}, } @article {pmid38657455, year = {2024}, author = {Zhang, L and Xu, F and Yang, Y and Yang, L and Wu, Q and Sun, H and An, Z and Li, J and Wu, H and Song, J and Wu, W}, title = {PM2.5 exposure upregulates pro-inflammatory protein expression in human microglial cells via oxidant stress and TLR4/NF-κB pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {277}, number = {}, pages = {116386}, doi = {10.1016/j.ecoenv.2024.116386}, pmid = {38657455}, issn = {1090-2414}, mesh = {Humans ; Air Pollutants/toxicity ; *Brain-Derived Neurotrophic Factor/metabolism ; Cell Line ; *Cyclooxygenase 2/metabolism ; *Interleukin-6/metabolism ; *Microglia/drug effects/metabolism ; NF-kappa B/metabolism ; *Oxidative Stress/drug effects ; *Particulate Matter/toxicity ; *Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 4/metabolism ; Up-Regulation/drug effects ; }, abstract = {Exposure to ambient PM2.5 is associated with neurodegenerative disorders, in which microglia activation plays a critical role. Thus far, the underlying mechanisms for PM2.5-induced microglia activation have not been well elucidated. In this study, a human microglial cell line (HMC3) was used as the in vitro model to examine the inflammatory effect (hall marker of microglia activation) of PM2.5 and regulatory pathways. The expression of inflammatory mediators including interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) as well as the brain derived neurotrophic factor (BDNF) were determined by ELISA and/or real-time PCR, respectively. Flow cytometry was used to measure the production of intracellular reactive oxygen species (ROS). Western blot was used to measure protein levels of Toll-like receptor 4 (TLR4), NF-κB inhibitor α (IκBα) and COX-2. It was shown that PM2.5 stimulation increased IL-6 and COX-2 expression but decreased BDNF expression in a dose-dependent manner. Further studies showed that PM2.5 triggered the formation of ROS and pre-treatment with the ROS scavenger acetylcysteine (NAC) significantly suppressed PM2.5-induced IL-6 and COX-2 expression. Moreover, the nuclear factor kappa B (NF-κB) inhibitor BAY11-7085 or the TLR4 neutralizing antibody markedly blocked PM2.5-induced IL-6 and COX-2 expression. However, NAC or BAY11-7085 exhibited minimal effect on PM2.5-induced BDNF down-regulation. In addition, pre-treatment with BAY11-7085 or TLR4 neutralizing antibody reduced ROS production induced by PM2.5, and NAC pre-treatment inhibited TLR4 expression and NF-κB activation induced by PM2.5. Collectively, PM2.5 treatment induced IL-6 and COX-2 but suppressed BDNF expression. PM2.5-induced IL-6 and COX-2 expression was mediated by interactive oxidative stress and TLR4/NF-κB pathway.}, } @article {pmid38647950, year = {2024}, author = {Zhou, D and Yang, Y and Chen, J and Zhou, J and He, J and Liu, D and Zhang, A and Yuan, B and Jiang, Y and Xia, W and Han, R and Xia, Z}, title = {N-acetylcysteine Protects Against Myocardial Ischemia-Reperfusion Injury Through Anti-ferroptosis in Type 1 Diabetic Mice.}, journal = {Cardiovascular toxicology}, volume = {24}, number = {5}, pages = {481-498}, pmid = {38647950}, issn = {1559-0259}, support = {81970247//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Myocardial Reperfusion Injury/prevention & control/pathology/metabolism/physiopathology ; *Acetylcysteine/pharmacology ; *Diabetes Mellitus, Experimental/drug therapy/complications ; Male ; *Diabetes Mellitus, Type 1/complications/drug therapy/metabolism ; *Antioxidants/pharmacology ; *Ferroptosis/drug effects ; *Mice, Inbred C57BL ; Myocardial Infarction/prevention & control/pathology/metabolism/physiopathology/drug therapy ; Time Factors ; Myocardium/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; }, abstract = {The hearts of subjects with diabetes are vulnerable to ischemia-reperfusion injury (IRI). In contrast, experimentally rodent hearts have been shown to be more resistant to IRI at the very early stages of diabetes induction than the heart of the non-diabetic control mice, and the mechanism is largely unclear. Ferroptosis has recently been shown to play an important role in myocardial IRI including that in diabetes, while the specific mechanisms are still unclear. Non-diabetic control (NC) and streptozotocin-induced diabetic (DM) mice were treated with the antioxidant N-acetylcysteine (NAC) in drinking water for 4 week starting at 1 week after diabetes induction. Mice were subjected to myocardial IRI induced by occluding the coronary artery for 30 min followed by 2 h of reperfusion, subsequently at 1, 2, and 5 week of diabetes induction. The post-ischemic myocardial infarct size in the DM mice was smaller than that in NC mice at 1 week of diabetes but greater than that in the NC mice at 2 and 5 week of diabetes, which were associated with a significant increase of ferroptosis at 2 and 5 week but a significant reduction of ferroptosis at 1 week of diabetes. NAC significantly attenuated post-ischemic ferroptosis as well as oxidative stress and reduced infarct size at 2 and 5 week of diabetes. Application of erastin, a ferroptosis inducer, reversed the cardioprotective effects of NAC. It is concluded that increased oxidative stress and ferroptosis are the major factors attributable to the increased vulnerability to myocardial IRI in diabetes and that attenuation of ferroptosis represents a major mechanism whereby NAC confers cardioprotection against myocardial IRI in diabetes.}, } @article {pmid38647195, year = {2024}, author = {Picchi, SC and Rebelatto, D and Martins, PMM and Blumer, S and Mesquita, GL and Hippler, FWR and Mattos, D and Boaretto, RM and Machado, MA and Takita, MA and Coletta-Filho, HD and de Souza, AA}, title = {N-acetylcysteine absorption and its potential dual effect improve fitness and fruit yield in Xylella fastidiosa infected plants.}, journal = {Pest management science}, volume = {80}, number = {9}, pages = {4333-4343}, doi = {10.1002/ps.8137}, pmid = {38647195}, issn = {1526-4998}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; }, mesh = {*Xylella/drug effects/physiology ; *Acetylcysteine/pharmacology ; *Plant Diseases/microbiology/prevention & control ; Citrus/microbiology ; Fruit/microbiology ; }, abstract = {BACKGROUND: Xylella fastidiosa is a multi-host bacterium that can be detected in hundreds of plant species including several crops. Diseases caused by X. fastidiosa are considered a threat to global food production. The primary method for managing diseases caused by X. fastidiosa involves using insecticides to control the vector. Hence, it is necessary to adopt new and sustainable disease management technologies to control not only the insect but also the bacteria and plant health. We demonstrated that N-acetylcysteine (NAC), a low-cost cysteine analogue, is a sustainable molecule that can be used in agriculture to decrease the damage caused by X. fastidiosa and improve plant health.

RESULTS: Using [15]N-NAC we proved that this analogue was absorbed by the roots and transported to different parts of the plant. Inside the plant, NAC reduced the bacterial population by 60-fold and the number of xylem vessels blocked by bacterial biofilms. This reflected in a recovery of 0.28-fold of the daily sap flow compared to health plants. In addition, NAC-treated citrus variegated chlorosis (CVC) plants decreased the oxidative stress by improving the activity of detoxifying enzymes. Moreover, the use of NAC in field conditions positively contributed to the increase in fruit yield of CVC-diseased plants.

CONCLUSION: Our research not only advances the understanding of NAC absorption in plants, but also indicates its dual effect as an antimicrobial and antioxidant molecule. This, in turn, negatively affects bacterial survival while improving plant health by decreasing oxidative stress. Overall, the positive field-based evidence supports the viability of NAC as a sustainable agricultural application. © 2024 Society of Chemical Industry.}, } @article {pmid38643270, year = {2024}, author = {Bates, JN and Baby, SM and Getsy, PM and Coffee, GA and Hsieh, YH and Knauss, ZT and Dahan, A and Bubier, JA and MacFarlane, PM and Mueller, D and Lewis, SJ}, title = {L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {9091}, pmid = {38643270}, issn = {2045-2322}, support = {R01 DA048890/DA/NIDA NIH HHS/United States ; R01 DA059060/DA/NIDA NIH HHS/United States ; U01 DA051373/DA/NIDA NIH HHS/United States ; U01DA051373/DA/NIDA NIH HHS/United States ; }, mesh = {Rats ; Male ; Animals ; Fentanyl/pharmacology ; Acetylcysteine/*analogs & derivatives ; Rats, Sprague-Dawley ; *Substance Withdrawal Syndrome ; Naloxone/pharmacology ; Narcotic Antagonists/pharmacology ; *Morphine Dependence ; Lysine/*analogs & derivatives ; }, abstract = {N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 μmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 μg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.}, } @article {pmid38641841, year = {2024}, author = {Sajedi, F and Abdi, A and Mehrpooya, M and Faramarzi, V and Mohammadi, Y and Sheida, F}, title = {Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial.}, journal = {Clinical diabetes and endocrinology}, volume = {10}, number = {1}, pages = {15}, pmid = {38641841}, issn = {2055-8260}, support = {IR.UMSHA.REC.1397.137//Hamadan University of Medical Sciences/ ; }, abstract = {OBJECTIVES: Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN.

METHODS: One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.

RESULTS: NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC.

DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects.

TRIAL REGISTRATION: The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).}, } @article {pmid38641701, year = {2024}, author = {Hassan, YF and Shabaan, DA}, title = {Effect of N-acetylcysteine on hair follicle changes in mouse model of cyclophosphamide-induced alopecia: histological and biochemical study.}, journal = {Histochemistry and cell biology}, volume = {161}, number = {6}, pages = {477-491}, pmid = {38641701}, issn = {1432-119X}, mesh = {Animals ; *Cyclophosphamide ; *Alopecia/chemically induced/drug therapy/pathology/metabolism ; Mice ; *Hair Follicle/metabolism/drug effects/pathology ; Female ; *Acetylcysteine/pharmacology ; *Mice, Inbred C57BL ; *Disease Models, Animal ; Antineoplastic Agents, Alkylating ; }, abstract = {Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP & NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6-16, and group IV (NAC) received NAC from day 6-16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy.}, } @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 ; Female ; Mice ; Acetylcysteine/pharmacology ; Blastocyst/metabolism ; DNA Damage ; *Embryonic Development/genetics ; Mice, Knockout ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/metabolism/genetics/deficiency ; *Oocytes/metabolism ; *Reactive Oxygen Species/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics/deficiency ; }, 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.}, } @article {pmid38636660, year = {2024}, author = {Boeglin, WE and Stec, DF and Noguchi, S and Calcutt, MW and Brash, AR}, title = {The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {5}, pages = {107293}, pmid = {38636660}, issn = {1083-351X}, mesh = {*Glutathione/chemistry/metabolism ; *Sulfhydryl Compounds/chemistry ; Mass Spectrometry/methods ; Chromatography, High Pressure Liquid/methods ; Chromatography, Liquid/methods ; Mercaptoethanol/chemistry ; Liquid Chromatography-Mass Spectrometry ; }, abstract = {Unsaturated fatty acid ketones with αβ,γδ conjugation are susceptible to Michael addition of thiols, with unresolved issues on the site of adduction and precise structures of the conjugates. Herein we reacted 13-keto-octadecadienoic acid (13-oxo-ODE or 13-KODE) with glutathione (GSH), N-acetyl-cysteine, and β-mercaptoethanol and identified the adducts. HPLC-UV analyses indicated none of the products exhibit a conjugated enone UV chromophore, a result that conflicts with the literature and is relevant to the mass spectral interpretation of 1,4 versus 1,6 thiol adduction. Aided by the development of an HPLC solvent system that separates the GSH diastereomers and thus avoids overlap of signals in proton NMR experiments, we established the two major conjugates are formed by 1,6 addition of GSH at the 9-carbon of 13-oxo-ODE with the remaining double bond α to the thiol in the 10,11 position. N-acetyl cysteine reacts similarly, while β-mercaptoethanol gives equal amounts of 1,4 and 1,6 addition products. Equine glutathione transferase catalyzed 1,6 addition of GSH to the two major diastereomers in 44:56 proportions. LC-MS in positive ion mode gives a product ion interpreted before as evidence of 1,4-thiol adduction, whereas here we find this ion using the authentic 1,6 adduct. LC-MS with negative ion APCI gave a fragment selective for 1,4 adduction. These results clarify the structures of thiol conjugates of a prototypical unsaturated keto-fatty acid and have relevance to the application of LC-MS for the structural analysis of keto-fatty acid glutathione conjugation.}, } @article {pmid38634668, year = {2024}, author = {Hakimi, F and Karimi Torshizi, MA and Hezavehei, M and Sharafi, M}, title = {Protective Effect of N-Acetylcysteine on Rooster Semen Cryopreservation.}, journal = {Biopreservation and biobanking}, volume = {22}, number = {6}, pages = {609-615}, pmid = {38634668}, issn = {1947-5543}, mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; *Cryopreservation/methods ; *Semen Preservation/methods/veterinary ; *Chickens ; *Membrane Potential, Mitochondrial/drug effects ; *Sperm Motility/drug effects ; *Lipid Peroxidation/drug effects ; Spermatozoa/drug effects ; Semen/drug effects/metabolism ; Antioxidants/pharmacology ; Cryoprotective Agents/pharmacology ; Semen Analysis ; Cell Survival/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Cryopreservation of avian semen is a useful reproductive technique in the poultry industry. However, during cooling, elevated reactive oxygen species (ROS) levels have destructive effects on both quality and function of thawed sperm. The aim of the current study is to investigate the antioxidant effects of N-acetylcysteine (NAC) during rooster semen cryopreservation. Semen samples were collected from ten Ross 308 broiler breeder roosters (32 weeks) and mixed. The mixed samples were divided into five equal parts and cryopreserved in Lake Buffer extender that contained different concentrations (0, 0.01, 0.1, 1, and 10 mM) of NAC. The optimum concentration of NAC was determined based on quality parameters of mobility, viability, membrane integrity, acrosome integrity, lipid peroxidation, and mitochondrial membrane potential after the freeze-thaw process. There was a higher percentage (p < 0.05) of total motility (TM) (60.9 ± 2.4%) and progressive motility (PM) (35.6 ± 1.9%) observed with the NAC-0.1 group compared to the other groups. Significantly higher percentages of viability (74.4 ± 2.3% and 71 ± 2.3%), membrane integrity (76.4 ± 1.5% and 74.7 ± 1.5%) and mitochondrial membrane potential (67.1 ± 1.6% and 66.3 ± 1.6%) were observed in the NAC-0.1 and NAC-1 groups compared to the other frozen groups (p < 0.05). The lowest percentage of lipid peroxidation and nonviable sperm was found in the NAC-0.1 and NAC-1 groups compared to the other groups (p < 0.05). The average path velocity (VAP), straight line velocity (VSL), curvilinear velocity (VCL), and acrosome integrity, were not affected by different concentrations of NAC in the thawed sperm (p > 0.05). Both NAC-0.1 and NAC-1 appear to be beneficial for maintaining the quality of rooster sperm after thawing.}, } @article {pmid38633147, year = {2024}, author = {Shams, G and Allah, SA and Ezzat, R and Said, MA}, title = {Ameliorative effects of berberine and selenium against paracetamol-induced hepatic toxicity in rats.}, journal = {Open veterinary journal}, volume = {14}, number = {1}, pages = {292-303}, pmid = {38633147}, issn = {2218-6050}, mesh = {Humans ; Rats ; Male ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Acetaminophen/pharmacology ; *Selenium/pharmacology ; *Berberine/pharmacology/therapeutic use ; Oxidative Stress ; Rats, Wistar ; }, abstract = {BACKGROUND: Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities.

AIM: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats.

METHODS: This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies.

RESULTS: Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-α, and TGF-β1 levels, and marked elevation in the IgM levels.

CONCLUSION: Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.}, } @article {pmid38629620, year = {2024}, author = {Kim, SH and Kang, DW and Kwon, D and Jung, YS}, title = {Critical role of endoplasmic reticulum stress on bisphenol A-induced cytotoxicity in human keratinocyte HaCaT cells.}, journal = {Environmental toxicology}, volume = {39}, number = {8}, pages = {4091-4104}, doi = {10.1002/tox.24290}, pmid = {38629620}, issn = {1522-7278}, support = {2022R1I1A1A01070024//National Research Foundation of Korea/ ; //Korean Government (MSIT)/ ; 20014436//Technology Innovation Program/ ; //Ministry of Trade, Industry & Energy (MOTIE, Korea)/ ; }, mesh = {*Benzhydryl Compounds/toxicity ; *Phenols/toxicity ; Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Keratinocytes/drug effects ; *Reactive Oxygen Species/metabolism ; *Cell Survival/drug effects ; Oxidative Stress/drug effects ; Taurochenodeoxycholic Acid/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; HaCaT Cells ; Acetylcysteine/pharmacology ; Cell Line ; }, abstract = {Bisphenol A (BPA) is widely used in plastic and paper products, and its exposure can occur through skin contact or oral ingestion. The hazardous effects of BPA absorbed through the skin may be more severe; however, few studies have investigated the skin toxicity of BPA. This study investigated the effects of BPA on human epidermal keratinocyte cell lines, which is relevant for skin exposure. BPA treatment reduced cell viability in a time- and concentration-dependent manner and elevated oxidative and endoplasmic reticulum (ER) stress. N-acetylcysteine (NAC), an oxidative stress inhibitor, reduced BPA-induced reactive oxygen species (ROS) levels. However, only 10% of the decreased cell viability was restored at the highest NAC concentration. Treatment with tauroursodeoxycholic acid (TUDCA), which is an ER stress inhibitor, effectively countered the increase in ER stress-related proteins induced by BPA. Moreover, TUDCA treatment led to a reduction in oxidative stress, as demonstrated by the decrease in ROS levels, maintenance of mitochondrial membrane potential, and modulation of stress signaling proteins. Consequently, TUDCA significantly improved BPA-induced cytotoxicity in a concentration-dependent manner. Notably, combined treatment using TUDCA and NAC further reduced the BPA-induced ROS levels; however, no significant difference in cell viability was observed compared with that for TUDCA treatment alone. These findings indicated that the oxidative stress observed following BPA exposure was exacerbated by ER stress. Moreover, the principal factor driving BPA-induced cytotoxicity was indeed ER stress, which has potential implications for developing therapeutic strategies for diseases associated with similar stress responses.}, } @article {pmid38622261, year = {2024}, author = {Liu, C and Zha, J and Sun, T and Kong, L and Zhang, X and Wang, D and Ni, G}, title = {Cold atmospheric plasma attenuates skin cancer via ROS induced apoptosis.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {518}, pmid = {38622261}, issn = {1573-4978}, mesh = {Animals ; *Skin Neoplasms/drug therapy/pathology ; *Carcinoma, Squamous Cell/drug therapy/pathology ; Reactive Oxygen Species/pharmacology ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 9/genetics ; *Plasma Gases/pharmacology ; Proliferating Cell Nuclear Antigen/genetics ; bcl-2-Associated X Protein ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; }, abstract = {BACKGROUND: Cold atmospheric plasma (CAP) has been widely used in biomedical research, especially in vitro cancer therapy. Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor originating from epidermal keratinocytes. However, the mechanism of CAP therapy on CSCC remains unclear.

METHODS AND RESULTS: The animal models of CSCC induced by 7,12-dimethylbenz(a) anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) were constructed. For the CAP treatment group, after each TPA application, CAP was administered for 3 min twice weekly after drying. HE staining were used to detect the pathological status of tumor tissue in each group. The levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 were evaluated by western blot and qPCR. TUNEL staining were used to detect apoptosis in tumor tissues. In vivo, serum samples were used for ELISA of total ROS. MTT assay was used to detect the viability of A431 cells. Western blot and qPCR were used to detect the levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 in A431 cells. A431 cell proliferation was examined by colony formation assay. The proportions of apoptosis of A431 cells were detected by flow cytometry. Transwell assessed the ability of A431 cells migration and proliferation. We found that CAP could induce skin cancer cells apoptosis and inhibit the progress of skin cancer. Through experiments in vitro, reactive oxygen species (ROS) generated by N-acetylcysteine (NAC) and CAP inhibited the proliferation and migration of A431 skin cancer cells while promoting apoptosis.

CONCLUSIONS: These evidences suggest the protective effect of CAP in CSCC, and CAP has the potential clinical application of CSCC.}, } @article {pmid38618504, year = {2024}, author = {Ameri, A and Rahmati, A and Soroushfar, S and Lalehzari, M and Dehghani, T and Haghi-Aminjan, H and Shamseddin, J and Omidi, M}, title = {The Protective Effect of N-acetylcysteine against Deltamethrin-Induced Hepatotoxicity in Mice.}, journal = {Avicenna journal of medical biotechnology}, volume = {16}, number = {2}, pages = {88-94}, pmid = {38618504}, issn = {2008-2835}, abstract = {BACKGROUND: Exposure to pesticides is of concern to public health officials worldwide. Deltamethrin is a synthetic pyrethroid pesticide which is widely used in agriculture and veterinary medicine. Deltamethrin poisoning is always one of the concerns in medical centers due to the deltamethrin induced hepatotoxicity. This study evaluated the hepato-protective effects of N-acetylcysteine (NAC) against deltamethrin induced hepatotoxicity in mice.

METHODS: A total of 40 BALB/c male mice were randomly divided into four groups; the first group was used as a control (0.5 ml normal saline); Groups 2-4 were treated with NAC [160 mg/kg Body Weight (BW)], deltamethrin (50 mg/kg BW), and NAC plus deltamethrin. At 1 and 24 hr after treatment, the animals were sacrificed and blood and liver samples were obtained for analysis and the liver/body ration, hepatic enzymes as Aspartate aminotransferase (AST), Alanine Transaminase (ALT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Glutathione (GSH) content and Reactive Oxygen Species (ROS) level were measured. For comparison between more than two experimental groups, one-way ANOVA following Tukey test was used by SPSS software.

RESULTS: The deltamethrin significantly increased AST, ALT, ALP, and the level of ROS level at the end of 1 and 24 hr after treatment; while the LDH level and GSH content were decreased. Mice in the deltamethrin treated group had a higher liver/body weight ratio than in other treated groups after 24 hr. On the other hand, NAC in combination with deltamethrin significantly reduced the activities of AST, ALT, ALP, and increased GSH levels.

CONCLUSION: This study demonstrated that NAC has a hepatoprotective role against deltamethrin-induced toxicity.}, } @article {pmid38611747, year = {2024}, author = {Abdelkader, I and Guisán, JM and Sayari, A and Fernández-Lorente, G}, title = {Various Strategies for the Immobilization of a Phospholipase C from Bacillus cereus for the Modulation of Its Biochemical Properties.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {7}, pages = {}, pmid = {38611747}, issn = {1420-3049}, mesh = {*Bacillus cereus ; Sepharose ; *Acetylcysteine ; Enzymes, Immobilized ; Type C Phospholipases ; *Glyoxylates ; }, abstract = {In this study, the effect of various immobilization methods on the biochemical properties of phospholipase C (PLC) from Bacillus cereus obtained from the oily soil located in Sfax, Tunisia, was described. Different supports were checked: octyl sepharose, glyoxyl agarose in the presence of N-acetyl cysteine, and Q-sepharose. In the immobilization by hydrophobic adsorption, a hyperactivation of the PLCBc was obtained with a fold of around 2 times. The recovery activity after immobilization on Q-sepharose and glyoxyl agarose in the presence of N-acetyl cysteine was 80% and 58%, respectively. Furthermore, the biochemical characterization showed an important improvement in the three immobilized enzymes. The performance of the various immobilized PLCBc was compared with the soluble enzyme. The derivatives acquired using Q-sepharose, octyl sepharose, and glyoxyl agarose were stable at 50 °C, 60 °C, and 70 °C. Nevertheless, the three derivatives were more stable in a large range of pH than the soluble enzyme. The three derivatives and the free enzyme were stable in 50% (v/v) ethanol, hexane, methanol, and acetone. The glyoxyl agarose derivative showed high long-term storage at 4 °C, with an activity of 60% after 19 days. These results suggest the sustainable biotechnological application of the developed immobilized enzyme.}, } @article {pmid38608750, year = {2024}, author = {Salas, G and Litta, AA and Medeot, AC and Schuck, VS and Andermatten, RB and Miszczuk, GS and Ciriaci, N and Razori, MV and Barosso, IR and Sánchez Pozzi, EJ and Roma, MG and Basiglio, CL and Crocenzi, FA}, title = {NADPH oxidase-generated reactive oxygen species are involved in estradiol 17ß-d-glucuronide-induced cholestasis.}, journal = {Biochimie}, volume = {223}, number = {}, pages = {41-53}, doi = {10.1016/j.biochi.2024.04.002}, pmid = {38608750}, issn = {1638-6183}, mesh = {Animals ; *NADPH Oxidases/metabolism ; *Reactive Oxygen Species/metabolism ; Rats ; *Hepatocytes/metabolism/drug effects ; *Estradiol/pharmacology/metabolism/analogs & derivatives ; Female ; Cholestasis/chemically induced/metabolism/pathology ; Rats, Wistar ; Acetophenones/pharmacology ; Oxidative Stress/drug effects ; Acetylcysteine/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; Multidrug Resistance-Associated Proteins/metabolism ; MAP Kinase Signaling System/drug effects ; Cells, Cultured ; Antioxidants/pharmacology/metabolism ; Cholestasis, Intrahepatic ; Pregnancy Complications ; ATP-Binding Cassette Transporters ; }, abstract = {The endogenous metabolite of estradiol, estradiol 17β-D-glucuronide (E17G), is considered the main responsible of the intrahepatic cholestasis of pregnancy. E17G alters the activity of canalicular transporters through a signaling pathway-dependent cellular internalization, phenomenon that was attributed to oxidative stress in different cholestatic conditions. However, there are no reports involving oxidative stress in E17G-induced cholestasis, representing this the aim of our work. Using polarized hepatocyte cultures, we showed that antioxidant compounds prevented E17G-induced Mrp2 activity alteration, being this alteration equally prevented by the NADPH oxidase (NOX) inhibitor apocynin. The model antioxidant N-acetyl-cysteine prevented, in isolated and perfused rat livers, E17G-induced impairment of bile flow and Mrp2 activity, thus confirming the participation of reactive oxygen species (ROS) in this cholestasis. In primary cultured hepatocytes, pretreatment with specific inhibitors of ERK1/2 and p38MAPK impeded E17G-induced ROS production; contrarily, NOX inhibition did not affect ERK1/2 and p38MAPK phosphorylation. Both, knockdown of p47phox by siRNA and preincubation with apocynin in sandwich-cultured rat hepatocytes significantly prevented E17G-induced internalization of Mrp2, suggesting a crucial role for NOX in this phenomenon. Concluding, E17G-induced cholestasis is partially mediated by NOX-generated ROS through internalization of canalicular transporters like Mrp2, being ERK1/2 and p38MAPK necessary for NOX activation.}, } @article {pmid38608558, year = {2024}, author = {Madhu, M and Santhoshkumar, S and Tseng, WB and Kumar, ASK and Tseng, WL}, title = {Synthesis of rhenium disulfide nanodots exhibiting pH-dependent fluorescence and phosphorescence for anticounterfeiting and hazardous gas detection.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {315}, number = {}, pages = {124240}, doi = {10.1016/j.saa.2024.124240}, pmid = {38608558}, issn = {1873-3557}, abstract = {The synthesis and characterization of ReS2 nanodots (NDs) are detailed, by highlighting their structure, morphological, and optical properties. ReS2 NDs were synthesized using NH4ReO4 as a rhenium source, thiourea as a sulfur source, and N-acetyl cysteine as a capping agent. The synthesis involved the hydrothermal reaction of these precursors, leading to the nucleation and growth of ReS2 NDs. Characterization techniques including transmission electron microscopy, energy dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy confirmed the formation of ReS2 NDs with a spherical morphology, crystalline structure, and rich sulfur sites. The fluorescence behavior of ReS2 NDs was found to be influenced by the solution pH, with fluorescence intensity increasing with rising pH values. This pH-dependent fluorescence response was attributed to the dissociation of functional groups and the subsequent impact on the excited-state proton transfer process. The fluorescence intensity of ReS2 NDs showed a correlation with solution pH, enabling pH detection from 3.0 to 12.5 with an interval of 0.5 pH unit. Additionally, the incorporation of ReS2 NDs into a polyvinyl alcohol (PVA) matrix resulted in pH-sensitive phosphorescence, offering a new avenue for pH sensing. The strong interaction between PVA and ReS2 NDs was proposed to enhance phosphorescence intensity and trigger a blue shift in the phosphorescent peak at high pH. The ReS2 NDs/PVA-deposited filter paper exhibited pH-sensitive fluorescence and phosphorescence, which could be utilized as unique identifiers or authentication markers. Moreover, the ReS2 NDs/PVA-deposited filter paper showed potential for discriminating between hydrogen chloride and ammonia, based on their distinct fluorescence and phosphorescence responses.}, } @article {pmid38591866, year = {2024}, author = {Monou, PK and Andriotis, E and Tzetzis, D and Tzimtzimis, E and Panteris, E and Andreadis, D and Demiri, E and Vizirianakis, IS and Fatouros, DG}, title = {Evaluation of 3D-Printed Solid Microneedles Coated with Electrosprayed Polymeric Nanoparticles for Simultaneous Delivery of Rivastigmine and N-Acetyl Cysteine.}, journal = {ACS applied bio materials}, volume = {7}, number = {5}, pages = {2710-2724}, doi = {10.1021/acsabm.3c00750}, pmid = {38591866}, issn = {2576-6422}, mesh = {*Acetylcysteine/chemistry/pharmacology ; *Rivastigmine/chemistry/pharmacology/administration & dosage ; Humans ; *Printing, Three-Dimensional ; *Needles ; *Nanoparticles/chemistry ; *Biocompatible Materials/chemistry/pharmacology ; *Materials Testing ; *Particle Size ; Drug Delivery Systems ; Skin/metabolism ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Cell Survival/drug effects ; }, abstract = {In the current study, coated microneedle arrays were fabricated by means of digital light processing (DLP) printing. Three different shapes were designed, printed, and coated with PLGA particles containing two different actives. Rivastigmine (RIV) and N-acetyl-cysteine (NAC) were coformulated via electrohydrodynamic atomization (EHDA), and they were incorporated into the PLGA particles. The two actives are administered as a combined therapy for Alzheimer's disease. The printed arrays were evaluated regarding their ability to penetrate skin and their mechanical properties. Optical microscopy and scanning electron microscopy (SEM) were employed to further characterize the microneedle structure. Confocal laser microscopy studies were conducted to construct 3D imaging of the coating and to simulate the diffusion of the particles through artificial skin samples. Permeation studies were performed to investigate the transport of the drugs across human skin ex vivo. Subsequently, a series of tape strippings were performed in an attempt to examine the deposition of the APIs on and within the skin. Light microscopy and histological studies revealed no drastic effects on the membrane integrity of the stratum corneum. Finally, the cytocompatibility of the microneedles and their precursors was evaluated by measuring cell viability (MTT assay and live/dead staining) and membrane damages followed by LDH release.}, } @article {pmid38583854, year = {2024}, author = {Kim, NY and Shivanne Gowda, SG and Lee, SG and Sethi, G and Ahn, KS}, title = {Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells.}, journal = {Chemico-biological interactions}, volume = {394}, number = {}, pages = {110995}, doi = {10.1016/j.cbi.2024.110995}, pmid = {38583854}, issn = {1872-7786}, mesh = {Humans ; *Autophagy/drug effects ; Beclin-1/metabolism ; *Cannabidiol/pharmacology ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/drug effects/metabolism ; *Ferroptosis/drug effects ; *Glioblastoma/metabolism/pathology/drug therapy ; MAP Kinase Signaling System/drug effects ; *Reactive Oxygen Species/metabolism ; }, abstract = {Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells). CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS. Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.}, } @article {pmid38583502, year = {2024}, author = {Kim, SG and Jeon, JH and Shin, SH and Varias, DC and Moon, SH and Ryu, BY}, title = {Inhibition of reactive oxygen species generation by N-Acetyl Cysteine can mitigate male germ cell toxicity induced by bisphenol analogs.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {188}, number = {}, pages = {114652}, doi = {10.1016/j.fct.2024.114652}, pmid = {38583502}, issn = {1873-6351}, mesh = {*Reactive Oxygen Species/metabolism ; Male ; *Phenols/toxicity ; Animals ; *Benzhydryl Compounds/toxicity ; *Acetylcysteine/pharmacology ; Mice ; *Cell Proliferation/drug effects ; *Apoptosis/drug effects ; Sesquiterpenes/pharmacology ; Cell Line ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Spermatogonia/drug effects/metabolism ; TOR Serine-Threonine Kinases/metabolism ; NF-kappa B/metabolism ; }, abstract = {The estrogen-like effect of bisphenol A (BPA) disrupting the maintenance of functional male germ cells is associated with male sub-fertility. This study investigated toxicity of male germ cells induced by four bisphenol analogs: BPA, BPAF, BPF, and BPS. The investigation of bisphenol analogs' impact on male germ cells included assessing proliferation, apoptosis induction, and the capacity to generate reactive oxygen species (ROS) in GC-1 spermatogonia (spg) cells, specifically type B spermatogonia. Additionally, the therapeutic potential and protective effects of N-Acetyl Cysteine (NAC) and NF-κB inhibitor parthenolide was evaluated. In comparison to BPA, BPF and BPS, BPAF exhibited the most pronounced adverse effect in GC-1 spg cell proliferation. This effect was characterized by pronounced inhibition of phosphorylation of PI3K, AKT, and mTOR, along with increased release of cytochrome c and subsequent cleavages of caspase 3, caspase 7, and poly (ADP-ribose) polymerase. Both NAC and parthenolide were effective reducing cellular ROS induced by BPAF. However, only NAC demonstrated a substantial recovery in proliferation, accompanied by a significant reduction in cytochrome c release and cleaved PARP. These results suggest that NAC supplementation may play an effective therapeutic role in countering germ cell toxicity induced by environmental pollutants with robust oxidative stress-generating capacity.}, } @article {pmid38576186, year = {2024}, author = {Lopes, AR and Costa Silva, DG and Rodrigues, NR and Kemmerich Martins, I and Paganotto Leandro, L and Nunes, MEM and Posser, T and Franco, J}, title = {Investigating the impact of Psidium guajava leaf hydroalcoholic extract in improving glutamatergic toxicity-induced oxidative stress in Danio rerio larvae.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {87}, number = {11}, pages = {457-470}, doi = {10.1080/15287394.2024.2337366}, pmid = {38576186}, issn = {1528-7394}, mesh = {Animals ; Glutamates/toxicity ; Oxidative Stress ; Plant Extracts/pharmacology/therapeutic use ; Plant Leaves ; *Psidium ; *Zebrafish ; }, abstract = {Glutamate is one of the predominant excitatory neurotransmitters released from the central nervous system; however, at high concentrations, this substance may induce excitotoxicity. This phenomenon is involved in numerous neuropathologies. At present, clinically available pharmacotherapeutic agents to counteract glutamatergic excitotoxicity are not completely effective; therefore, research to develop novel compounds is necessary. In this study, the main objective was to determine the pharmacotherapeutic potential of the hydroalcoholic extract of Psidium guajava (PG) in a model of oxidative stress-induced by exposure to glutamate utilizing Danio rerio larvae (zebrafish) as a model. Data showed that treatment with glutamate produced a significant increase in oxidative stress, chromatin damage, apoptosis, and locomotor dysfunction. All these effects were attenuated by pre-treatment with the classical antioxidant N-acetylcysteine (NAC). Treatment with PG inhibited oxidative stress responsible for cellular damage induced by glutamate. However, exposure to PG failed to prevent glutamate-initiated locomotor damage. Our findings suggest that under conditions of oxidative stress, PG can be considered as a promising candidate for treatment of glutamatergic excitotoxicity and consequent neurodegenerative diseases.}, } @article {pmid38565435, year = {2024}, author = {Liu, JJ and Zhang, X and Cai, BL and Qi, MM and Chi, YB and Peng, B and Zhang, DH}, title = {Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells.}, journal = {Journal of integrative medicine}, volume = {22}, number = {3}, pages = {286-294}, doi = {10.1016/j.joim.2024.03.007}, pmid = {38565435}, issn = {2095-4964}, mesh = {Humans ; Hep G2 Cells ; *Pentacyclic Triterpenes/pharmacology ; *Insulin Resistance ; *Ferroptosis/drug effects ; Triterpenes/pharmacology ; Cyclohexylamines/pharmacology ; Acetylcysteine/pharmacology ; Phenylenediamines/pharmacology ; Molecular Docking Simulation ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/metabolism ; }, abstract = {OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity.

METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48 h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis.

RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells.

CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; 22(3): 286-294.}, } @article {pmid38556154, year = {2024}, author = {Teixeira-Fonseca, JL and Souza, DS and Conceição, MRL and Marques, LP and Durço, AO and Silva, PLD and Joviano-Santos, JV and Santos-Miranda, A and Roman-Campos, D}, title = {In vivo tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: involvement of reactive oxygen species.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {187}, number = {}, pages = {114596}, doi = {10.1016/j.fct.2024.114596}, pmid = {38556154}, issn = {1873-6351}, mesh = {Humans ; Rats ; Animals ; Male ; Reactive Oxygen Species ; Rats, Wistar ; *Dobutamine ; *Arrhythmias, Cardiac/chemically induced ; Acetylcysteine ; Myocytes, Cardiac ; *Triazoles ; }, abstract = {Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a vehicle (control) revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.}, } @article {pmid38555190, year = {2024}, author = {Papi, A and Alfano, F and Bigoni, T and Mancini, L and Mawass, A and Baraldi, F and Aljama, C and Contoli, M and Miravitlles, M}, title = {N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses.}, journal = {Archivos de bronconeumologia}, volume = {60}, number = {5}, pages = {269-278}, doi = {10.1016/j.arbres.2024.03.010}, pmid = {38555190}, issn = {1579-2129}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Bronchitis, Chronic/drug therapy ; Disease Progression ; Expectorants/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; *Quality of Life ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. Oxidative stress is a key pathogenic mechanism in chronic respiratory conditions such as COPD and chronic bronchitis (CB). In these meta-analyses we investigated the efficacy of NAC in subjects with COPD or CB, the latter being a potential pre-COPD condition (CB/pre-COPD).

METHODS: The meta-analyses were conducted according to PRISMA guidelines. Exacerbations were assessed using total number of exacerbations. Improvement in patients' respiratory symptoms and/or patients quality of life (QoL) were measured by validated tools or assessed at the end of the study.

RESULTS: Twenty studies were included, of which seven evaluated NAC in patients with symptoms of CB/pre-COPD as entry criterion. NAC treated patients showed a significant reduction of the incidence of exacerbations as compared to placebo both in COPD (IRR=0.76; 95% confidence interval (CI) 0.59-0.99) and CB/pre-COPD (IRR=0.81; 95% CI 0.69-0.95). Sensitivity analyses in studies with duration higher than 5 months, confirmed the overall results. CB/pre-COPD patients treated with NAC were significantly more likely to experience an improvement in symptoms and/or QoL compared to placebo (odds ratio (OR)=3.47; 95% CI 1.92-6.26). A similar trend was observed in the few COPD studies evaluable. Sensitivity analyses showed a significant association of NAC with improvement in symptoms and/or QoL both in CB/pre-COPD and COPD patients.

CONCLUSIONS: These findings provide novel data of NAC on the improvement in symptoms and QoL in addition to prevention of exacerbations in COPD and CB/pre-COPD. PROSPERO registry no. CRD42023468154.}, } @article {pmid38554666, year = {2024}, author = {Sriwastava, S and Elkhooly, M and Amatya, S and Shrestha, K and Kagzi, Y and Bhatia, D and Gupta, R and Jaiswal, S and Lisak, RP}, title = {Recent advances in the treatment of primary and secondary progressive Multiple Sclerosis.}, journal = {Journal of neuroimmunology}, volume = {390}, number = {}, pages = {578315}, doi = {10.1016/j.jneuroim.2024.578315}, pmid = {38554666}, issn = {1872-8421}, mesh = {Animals ; Humans ; *Multiple Sclerosis, Chronic Progressive/drug therapy ; *Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; }, abstract = {BACKGROUND: The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS).

OBJECTIVES: The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments.

METHODS: We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010.

RESULTS: BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity.

CONCLUSIONS: SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.}, } @article {pmid38551724, year = {2024}, author = {Adelusi, OB and Akakpo, JY and Eichenbaum, G and Sadaff, E and Ramachandran, A and Jaeschke, H}, title = {The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.}, journal = {Archives of toxicology}, volume = {98}, number = {6}, pages = {1843-1858}, pmid = {38551724}, issn = {1432-0738}, support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; DK102142/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Male ; Mice ; *Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Cell Proliferation/drug effects ; *Chemical and Drug Induced Liver Injury/prevention & control/drug therapy ; Hepatocytes/drug effects ; *Liver/drug effects/metabolism/pathology ; *Liver Regeneration/drug effects ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Pyrazoles/pharmacology ; Receptors, Thrombopoietin/metabolism ; *Thrombopoietin/pharmacology ; }, abstract = {Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42-48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.}, } @article {pmid38547615, year = {2024}, author = {Li, Z and Bao, Z and Tan, J and Chen, G and Ye, B and Zhao, J and Zhang, L and Xu, H}, title = {Neobractatin induces pyroptosis of esophageal cancer cells by TOM20/BAX signaling pathway.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {128}, number = {}, pages = {155547}, doi = {10.1016/j.phymed.2024.155547}, pmid = {38547615}, issn = {1618-095X}, mesh = {Animals ; Humans ; Male ; Mice ; *bcl-2-Associated X Protein/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; *Esophageal Neoplasms/drug therapy/metabolism ; *Gasdermins ; Mice, Nude ; Mitochondria/drug effects/metabolism ; *Mitochondrial Precursor Protein Import Complex Proteins ; Phosphate-Binding Proteins/metabolism ; *Pyroptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; Up-Regulation/drug effects ; }, abstract = {BACKGROUND: Emerging evidence suggests that pyroptosis, a form of programmed cell death, has been implicated in cancer progression. The involvement of specific proteins in pyroptosis is an area of growing interest. TOM20, an outer mitochondrial membrane protein, has recently garnered attention for its potential role in pyroptosis. Our previous study found that NBT could induce pyroptosis by ROS/JNK pathway in esophageal cancer cells.

PURPOSE: This study aims to investigate whether NBT induces pyroptosis and verify whether such effects are involved in up-regulation of TOM20 in esophageal cancer cells.

METHODS: The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) was used to analyze the clinical significance of GSDME in esophageal cancer. MTT assay, morphological observation and Western blot were performed to verify the roles of TOM20 and BAX in NBT-induced pyroptosis after CRISPR-Cas9-mediated knockout. Immunofluorescence was used to determine the subcellular locations of BAX and cytochrome c. MitoSOX Red was employed to assess the mitochondrial reactive oxygen species (ROS) level. KYSE450 and TOM20 knockout KYSE450-/- xenograft models were established to elucidate the mechanisms involved in NBT-induced cell death.

RESULTS: In this study, NBT effectively upregulated the expression of TOM20 and facilitated the translocation of BAX to mitochondria, which promoted the release of cytochrome c from mitochondria to the cytoplasm, leading to the activation of caspase-9 and caspase-3, and finally induced pyroptosis. Knocking out TOM20 by CRISPR-Cas9 significantly inhibited the expression of BAX and the downstream BAX/caspase-3/GSDME pathway, which attenuated NBT-induced pyroptosis. The elevated mitochondrial ROS level was observed after NBT treatment. Remarkably, the inhibition of ROS by N-acetylcysteine (NAC) effectively suppressed the activation of TOM20/BAX pathway. Moreover, in vivo experiments demonstrated that NBT exhibited potent antitumor effects in both KYSE450 and TOM20 knockout KYSE450-/- xenograft models. Notably, the attenuated antitumor effects and reduced cleavage of GSDME were observed in the TOM20 knockout model.

CONCLUSION: These findings reveal that NBT induces pyroptosis through ROS/TOM20/BAX/GSDME pathway, which highlight the therapeutic potential of targeting TOM20 and GSDME, providing promising prospects for the development of innovative and effective treatment approaches for esophageal cancer.}, } @article {pmid38547333, year = {2024}, author = {Smith, JE and Rockey, DC}, title = {Update on ischemic hepatitis.}, journal = {Current opinion in gastroenterology}, volume = {40}, number = {3}, pages = {143-147}, pmid = {38547333}, issn = {1531-7056}, mesh = {Humans ; *Hepatitis/complications ; Acetylcysteine/therapeutic use ; }, abstract = {PURPOSE OF REVIEW: Ischemic hepatitis (IH) refers to diffuse liver injury secondary to hypoperfusion. The condition is usually seen in the critical care setting and is associated with significant mortality. IH typically occurs in the setting of systemic hypotension superimposed on some form of underlying cardiac dysfunction. This review aims to report what is known and what is new about the etiology, pathophysiology, and clinical features associated with IH.

RECENT FINDINGS: In recent years, studies on IH have largely confirmed earlier reports regarding etiologies, comorbid conditions, and associated mortality. Recent study has also shed light on the potential treatment of IH with N -acetyl-cysteine (NAC).

SUMMARY: IH is typically associated with underlying cardiac disease, and patients with IH have a very high mortality rate. Treatment remains largely supportive, although the utility of agents such as NAC are being explored.}, } @article {pmid38541080, year = {2024}, author = {Russo, C and Rusciano, D and Santangelo, R and Malaguarnera, L}, title = {Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {3}, pages = {}, pmid = {38541080}, issn = {1648-9144}, mesh = {Humans ; Edaravone/pharmacology ; Antioxidants/pharmacology ; Oxidative Stress ; *Eye Diseases ; *Retinal Diseases/drug therapy ; Ophthalmic Solutions ; }, abstract = {Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.}, } @article {pmid38539819, year = {2024}, author = {Islam, A and Chang, YC and Tsao, NW and Wang, SY and Chueh, PJ}, title = {Calocedrus formosana Essential Oils Induce ROS-Mediated Autophagy and Apoptosis by Targeting SIRT1 in Colon Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, pmid = {38539819}, issn = {2076-3921}, abstract = {Colorectal cancer is the most common cancer that affects both sexes and has a poor prognosis due to aggressiveness and chemoresistance. Essential oils isolated from Calocedrus formosana (CF-EOs) have been shown to demonstrate anti-termite, antifungal, anti-mosquito, and anti-microbial activities. However, the anticancer effects of CF-EOs are not yet fully understood. Therefore, the present study aimed to explore the molecular mechanism underlying CF-EOs-mediated anti-proliferative activity in colon cancer cells. Here, cell impedance measurements showed that CF-EOs inhibit proliferation in colon cancer cells with wild-type or mutant p53. Flow cytometry revealed that CF-EOs at 20, 50 µg/mL significantly induced ROS generation and autophagy in both HCT116 p53-wt and HCT116 p53-null cell lines, whereas pretreatment with the ROS scavenger N-acetyl cysteine (NAC) markedly attenuated these changes. CF-EOs also induced apoptosis at 50 µg/mL in both lines, as determined by flow cytometry. Protein analysis showed that CF-EOs markedly induced apoptosis markers, including Trail, cleaved caspase-3, cleaved caspase-9, and cleaved PARP, as well as autophagy markers, such as the levels of ULK1, Atg5, Atg6, Atg7, and the conversion of LC3-I to LC3-II. CF-EOs were further found to inhibit the activity and expression of the NAD[+]-dependent deacetylase SIRT1 to increase the levels of acetylated p53 (Ac-p53) in p53-wt cells and acetylated c-Myc (Ac-c-Myc) in p53-null cells, ultimately inducing apoptosis in both lines. Interestingly, suppression of SIRT1 by CF-EOs enhanced the acetylation of ULK1, which in turn prompted ROS-dependent autophagy in colon cancer cells. The induction of apoptosis and autophagy by CF-EOs suggests that they may have potential as a promising new approach for treating cancer. Collectively, our results suggest that essential oils isolated from Calocedrus formosana act as a promising anticancer agent against colon cancer cells by targeting SIRT1 to induce ROS-mediated autophagy and apoptosis.}, } @article {pmid38537439, year = {2024}, author = {Chen, X and Zhu, N and Wu, Y and Zhang, Y and Zhang, Y and Jin, K and Zhou, Z and Chen, G and Wang, J}, title = {Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {128}, number = {}, pages = {155317}, doi = {10.1016/j.phymed.2023.155317}, pmid = {38537439}, issn = {1618-095X}, mesh = {*Withanolides/pharmacology ; *Endoplasmic Reticulum Stress/drug effects ; Humans ; *Carcinoma, Hepatocellular/drug therapy ; *Reactive Oxygen Species/metabolism ; *Liver Neoplasms/drug therapy ; Animals ; *DNA Damage/drug effects ; *Drug Synergism ; *Sorafenib/pharmacology ; Cell Line, Tumor ; *Apoptosis/drug effects ; *Mice, Nude ; Thioredoxin Reductase 1/metabolism ; Mice, Inbred BALB C ; Cell Proliferation/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Activating Transcription Factor 4/metabolism ; }, abstract = {BACKGROUND: Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera, Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC.

METHODS: Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts.

RESULTS: Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro. Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo, Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues.

CONCLUSION: Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.}, } @article {pmid38536095, year = {2024}, author = {Aragona, SE and Fabbri, C and Cammarota, G and Ciprandi, G and , }, title = {Probiotic mixture in patients after Helicobacter pylori eradication: a real-life experience.}, journal = {Minerva gastroenterology}, volume = {70}, number = {2}, pages = {197-207}, doi = {10.23736/S2724-5985.24.03634-9}, pmid = {38536095}, issn = {2724-5365}, mesh = {Humans ; *Probiotics/therapeutic use ; *Helicobacter Infections/drug therapy ; Male ; Female ; *Helicobacter pylori ; Middle Aged ; Adult ; Lacticaseibacillus rhamnosus ; Acetylcysteine/therapeutic use ; Treatment Outcome ; Aged ; Dysbiosis ; Dietary Supplements ; }, abstract = {BACKGROUND: Eradication for Helicobacter pylori usually induces digestive dysbiosis that, in turn, elicits symptoms. Consequently, probiotic supplementation may counterbalance the disturbed microbiota after this procedure. So, probiotics may restore microbiota homeostasis quickly relieve complaints.

METHODS: The current study evaluated the efficacy and safety of Abivisor[®], a food supplement containing Lacticaseibacillus rhamnosus LR06 (3 billion living cells), Lactiplantibacillus pentosus LPS01(100 million living cells), Lactiplantibacillus plantarum LP01 (1 billion living cells), and N-acetyl cysteine (60 mg). Patients were randomized into two groups (2:1). Group A took one stick/daily for 60 days after eradication. Group B was considered as control. Patients were evaluated at baseline (T0) and after 15 (T1), 30 (T2), and 60 (T3) days. The severity of digestive symptoms was measured by patients using a Visual Analog Scale. The percentage of patients with each symptom was also evaluated.

RESULTS: Abivisor[®] has significantly and progressively diminished intestinal symptoms' presence and severity at T1, T2, and even more at T3. Accordingly, the percentage of symptomatic patients diminished more rapidly and significantly in group A than in B. All patients well tolerated the food supplement.

CONCLUSIONS: The present study suggests that Abivisor[®] may be an effective and safe therapeutic option for managing patients undergoing H. pylori eradication.}, } @article {pmid38535516, year = {2024}, author = {Tamur, S and Alyahya, B and Alsani, F and Bahauddin, AA and Aljaid, M and Al-Malki, S and Alzahrani, A and Khayat, A and Shams, A and Chalut, DS}, title = {Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.}, journal = {Pediatric reports}, volume = {16}, number = {1}, pages = {232-242}, pmid = {38535516}, issn = {2036-749X}, abstract = {BACKGROUND: Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents.

METHODS: At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results.

RESULTS: A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate.

CONCLUSIONS: The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.}, } @article {pmid38534586, year = {2024}, author = {Domínguez-Martínez, J and López-Sánchez, J and García-Galván, F and Serrano, A and Barranco, V and Galván, JC and Rodríguez de la Fuente, Ó and Carmona, N}, title = {Eco-Friendly Sol-Gel Coatings with Organic Corrosion Inhibitors for Lightweight AZ61 Alloy.}, journal = {Gels (Basel, Switzerland)}, volume = {10}, number = {3}, pages = {}, pmid = {38534586}, issn = {2310-2861}, support = {PID2019-104717RB-I00//Spanish Ministry of Economics Affairs and Digital Transformation/ ; PID2021-122980OB-C51//Spanish Ministry of Economic Affairs and Digital Transformation (MINECO)/ ; RYC2022-035912-I and RYC2021-031236-I//MCIN "Ramón y Cajal" Program/ ; }, abstract = {The latest advances in technology and materials science have catalyzed a transformative shift towards the adoption of environmentally conscious and lightweight materials across key sectors such as aeronautics, biomedical, and automotive industries. Noteworthy among these innovations are the magnesium-aluminum (Mg-Al) alloys employed in aeronautical applications, contributing to the overall reduction in aircraft weight and subsequently diminishing fuel consumption and mitigating atmospheric emissions. The present work delves into a study of the anti-corrosive properties inherent in various sol-gel coatings, leveraging a range of environmentally friendly corrosion inhibitors, specifically tailored for samples of the AZ61 alloy. Methodologically, the work involves the synthesis and application of sol-gel coatings on AZ61 alloy containing eco-friendly inhibitors: L-cysteine, N-acetyl-cysteine, curcumin and methylene blue. Subsequently, an accelerated corrosion test in a simulated saline environment is performed. Through microstructural and compositional analyses, the best inhibitors responses are achieved with inhibitors containing S, N heteroatoms and conjugated double bonds in their structure, probably due to the creation of a continuous MgCl2 layer. This research contributes to the ongoing discourse on protective eco-coatings, aligning with the broader paradigm shift towards sustainable and lightweight materials in key industries.}, } @article {pmid38525131, year = {2024}, author = {Dong, G and Li, Q and Yu, C and Wang, Q and Zuo, D and Li, X}, title = {n-Acetylcysteine protects against diazinon-induced histopathological damage and apoptosis in renal tissue of rats.}, journal = {Toxicological research}, volume = {40}, number = {2}, pages = {285-295}, pmid = {38525131}, issn = {1976-8257}, abstract = {Diazinon (DZN) is a member of organophosphorus insecticides that has cytotoxic effects on different organs. n-Acetyl cysteine (NAC) is a widely used antioxidant in clinical, in vivo and in vitro studies. We evaluated the protective role of NAC against DZN-induced toxicity in kidney tissue of Wistar rats. 30 male Wistar rats were divided into 5 groups of control, single dose of DZN, continuous dose of DZN, single doses of DZN + NAC and continuous doses of DZN + NAC. Kidney function test (blood urea nitrogen, creatinine and uric acid) was provided. Levels of malondialdehyde (MDA), total antioxidant capacity (TAC) and total sulfhydryl (T-SH) were determined in renal tissues. Renal cells apoptosis was detected using TUNEL assay. The mRNA expressions of apoptosis, oxidative stress and inflammatory mediators, including B-cell lymphoma-2 (Bcl2), Bcl-2-associated X protein (Bax), superoxide dismutase (SOD), catalase (CAT), Interleukin 10 (IL-10), Tumor necrosis factor-α (TNF-α), Caspase-3 and Caspase-8 were analyzed in kidney tissues using Real Time PCR method. Chronic exposure to DZN was associated with severe morphological changes in the kidney, as well as impairment of its function and decreased kidney weights. Continues treatment with DZN significantly decreased the percentage of renal apoptotic cells as compared to rats treated with continuous dose of DZN alone (17.69 ± 3.67% vs. 39.46% ± 2.44%; p < 0.001). Continuous exposure to DZN significantly decreased TAC and T-SH contents, as well as SOD and CAT expression, but increased MDA contents in the kidney tissues (p < 0.001). A significant increase was observed in mRNA expression of Bax, Caspase-3, Caspase-8, as well as TNF-α following exposure to DZN, but the expression of IL-10 and Bcl2 was significantly decreased. NAC can protect kidney tissue against DZN-induced toxicity by elevating antioxidants capacity, mitigating oxidative stress, inflammation and apoptosis.}, } @article {pmid38524728, year = {2024}, author = {Khasnavis, S and Belliveau, T and Arnsten, A and Fesharaki-Zadeh, A}, title = {Combined Use of Guanfacine and N-Acetylcysteine for the Treatment of Cognitive Deficits After Traumatic Brain Injury.}, journal = {Neurotrauma reports}, volume = {5}, number = {1}, pages = {226-231}, pmid = {38524728}, issn = {2689-288X}, abstract = {Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, N-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI.}, } @article {pmid38522494, year = {2024}, author = {Mabrouk, NEL and Mastouri, M and Lizard, G and Aouni, M and Harizi, H}, title = {In vitro immunotoxicity effects of carbendazim were inhibited by n-acetylcysteine in microglial BV-2 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {97}, number = {}, pages = {105812}, doi = {10.1016/j.tiv.2024.105812}, pmid = {38522494}, issn = {1879-3177}, mesh = {*Acetylcysteine/pharmacology ; *Microglia ; Lipopolysaccharides/toxicity ; Benzimidazoles/toxicity ; Nitric Oxide ; *Carbamates ; }, abstract = {Carbendazim (CBZ) is a benzimidazole fungicide widely used worldwide in industrial, agricultural, and veterinary practices. Although, CBZ was found in all brain tissues causing serious neurotoxicity, its impact on brain immune cells remain scarcely understood. Our study investigated the in vitro effects of CBZ on activated microglial BV-2 cells. Lipopolysaccharide (LPS)-stimulated BV-2 cells were exposed to increasing concentrations of CBZ and cytokine release was measured by ELISA, and Cytometric Bead Array (CBA) assays. Mitochondrial superoxide anion (O2[·-]) generation was evaluated by Dihydroethidium (DHE) and nitric oxide (NO) was assessed by Griess reagent. Lipid peroxidation was evaluated by measuring the malonaldehyde (MDA) levels. The transmembrane mitochondrial potential (ΔΨm) was detected by cytometry analysis with dihexyloxacarbocyanine iodide (DiOC6(3)) assay. CBZ concentration-dependently increased IL-1β, IL-6, TNF-α and MCP-1 by LPS-activated BV-2 cells. CBZ significantly promoted oxidative stress by increasing NO, O2[·-] generation, and MDA levels. In contrast, CBZ significantly decreased ΔΨm. Pre-treatment of BV-2 cells with N-acetylcysteine (NAC) reversed all the above mentioned immunotoxic parameters, suggesting a potential protective role of NAC against CBZ-induced immunotoxicity via its antioxidant and anti-inflammatory effects on activated BV-2 cells. Therefore, microglial proinflammatory over-activation by CBZ may be a potential mechanism by which CBZ could induce neurotoxicity and neurodegenerative disorders.}, } @article {pmid38520518, year = {2024}, author = {Cao, W and Zhang, J and Yu, S and Gan, X and An, R}, title = {N-acetylcysteine regulates oxalate induced injury of renal tubular epithelial cells through CDKN2B/TGF-β/SMAD axis.}, journal = {Urolithiasis}, volume = {52}, number = {1}, pages = {46}, pmid = {38520518}, issn = {2194-7236}, support = {No.81370803//National Natural Science Foundation of China/ ; No.81370803//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Male ; Rats ; Acetylcysteine/pharmacology ; Calcium Oxalate/metabolism ; Epithelial Cells/metabolism ; *Hyperoxaluria/chemically induced/metabolism ; *Oxalates/metabolism ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Transforming Growth Factor beta1/metabolism ; }, abstract = {This study was aimed to investigate the preventive effects of N-acetyl-L-cysteine (NAC) against renal tubular cell injury induced by oxalate and stone formation and further explore the related mechanism. Transcriptome sequencing combined with bioinformatics analysis were performed to identify differentially expressed gene (DEG) and related pathways. HK-2 cells were pretreated with or without antioxidant NAC/with or silencing DEG before exposed to sodium oxalate. Then, the cell viability, oxidative biomarkers of superoxidase dismutase (SOD) and malondialdehyde (MDA), apoptosis and cell cycle were measured through CCK8, ELISA and flow cytometry assay, respectively. Male SD rats were separated into control group, hyperoxaluria (HOx) group, NAC intervention group, and TGF-β/SMAD pathway inhibitor group. After treatment, the structure changes and oxidative stress and CaOx crystals deposition were evaluated in renal tissues by H&E staining, immunohistochemical and Pizzolato method. The expression of TGF-β/SMAD pathway related proteins (TGF-β1, SMAD3 and SMAD7) were determined by Western blot in vivo and in vitro. CDKN2B is a DEG screened by transcriptome sequencing combined with bioinformatics analysis, and verified by qRT-PCR. Sodium oxalate induced declined HK-2 cell viability, in parallel with inhibited cellular oxidative stress and apoptosis. The changes induced by oxalate in HK-2 cells were significantly reversed by NAC treatment or the silencing of CDKN2B. The cell structure damage and CaOx crystals deposition were observed in kidney tissues of HOx group. Meanwhile, the expression levels of SOD and 8-OHdG were detected in kidney tissues of HOx group. The changes induced by oxalate in kidney tissues were significantly reversed by NAC treatment. Besides, expression of SMAD7 was significantly down-regulated, while TGF-β1 and SMAD3 were accumulated induced by oxalate in vitro and in vivo. The expression levels of TGF-β/SMAD pathway related proteins induced by oxalate were reversed by NAC. In conclusion, we found that NAC could play an anti-calculus role by mediating CDKN2B/TGF-β/SMAD axis.}, } @article {pmid38518686, year = {2024}, author = {Kumar, S and Dhiman, M}, title = {Helicobacter pylori secretary Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation.}, journal = {Cellular immunology}, volume = {399-400}, number = {}, pages = {104811}, doi = {10.1016/j.cellimm.2024.104811}, pmid = {38518686}, issn = {1090-2163}, mesh = {Humans ; *Helicobacter pylori/immunology ; *Oxidative Stress ; *Reactive Oxygen Species/metabolism ; *Helicobacter Infections/immunology/metabolism ; *Inflammasomes/metabolism/immunology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Macrophages/metabolism/immunology ; Bacterial Proteins/metabolism ; Reactive Nitrogen Species/metabolism ; THP-1 Cells ; NADPH Oxidases/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Cell Differentiation/immunology ; }, abstract = {Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91[phox] (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91[phox] expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS. This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.}, } @article {pmid38518383, year = {2024}, author = {Sun, X and Qin, X and Liang, G and Chang, X and Zhu, H and Zhang, J and Zhang, D and Sun, Y and Feng, S}, title = {Manganese dioxide nanoparticles provoke inflammatory damage in BV2 microglial cells via increasing reactive oxygen species to activate the p38 MAPK pathway.}, journal = {Toxicology and industrial health}, volume = {40}, number = {5}, pages = {244-253}, doi = {10.1177/07482337241242508}, pmid = {38518383}, issn = {1477-0393}, mesh = {*Microglia ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Cell Line ; *Oxides ; *Manganese Compounds ; }, abstract = {With the widespread use of manganese dioxide nanoparticles (nano MnO2), health hazards have also emerged. The inflammatory damage of brain tissues could result from nano MnO2, in which the underlying mechanism is still unclear. During this study, we aimed to investigate the role of ROS-mediated p38 MAPK pathway in nano MnO2-induced inflammatory response in BV2 microglial cells. The inflammatory injury model was established by treating BV2 cells with 2.5, 5.0, and 10.0 μg/mL nano MnO2 suspensions for 12 h. Then, the reactive oxygen species (ROS) scavenger (20 nM N-acetylcysteine, NAC) and the p38 MAPK pathway inhibitor (10 μM SB203580) were used to clarify the role of ROS and the p38 MAPK pathway in nano MnO2-induced inflammatory lesions in BV2 cells. The results indicated that nano MnO2 enhanced the expression of pro-inflammatory cytokines IL-1β and TNF-α, elevated intracellular ROS levels and activated the p38 MAPK pathway in BV2 cells. Controlling intracellular ROS levels with NAC inhibited p38 MAPK pathway activation and attenuated the inflammatory response induced by nano MnO2. Furthermore, inhibition of the p38 MAPK pathway with SB203580 led to a decrease in the production of inflammatory factors (IL-1β and TNF-α) in BV2 cells. In summary, nano MnO2 can induce inflammatory damage by increasing intracellular ROS levels and further activating the p38 MAPK pathway in BV2 microglial cells.}, } @article {pmid38513962, year = {2024}, author = {Liang, Z and Sun, G and Zhang, J and Zhang, Q and Li, X and Qin, S and Lv, S and Ding, J and Zhang, Q and Xia, Y and Lu, D}, title = {Protein phosphatase 4 mediates palmitic acid-induced endothelial dysfunction by decreasing eNOS phosphorylation at serine 633 in HUVECs.}, journal = {Experimental cell research}, volume = {437}, number = {1}, pages = {113998}, doi = {10.1016/j.yexcr.2024.113998}, pmid = {38513962}, issn = {1090-2422}, mesh = {Humans ; Phosphorylation ; *Nitric Oxide Synthase Type III/metabolism ; Palmitic Acid/pharmacology ; Serine/metabolism ; Reactive Oxygen Species ; Cells, Cultured ; Protein Phosphatase 2/metabolism ; *Vascular Diseases ; Nitric Oxide/metabolism ; *Phosphoprotein Phosphatases ; }, abstract = {Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the mechanism underlying saturated FFA-induced ED remains unclear. This study demonstrated that palmitic acid (PA) induced ED by activating the NADPH oxidase (NOX)/ROS signaling pathway to activate protein phosphatase 4 (PP4) and protein phosphatase 2A (PP2A), thereby reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser633 and Ser1177, respectively. Okadaic acid (OA) and fostriecin (FST), which are inhibitors of PP2A, inhibited the PA-induced decreases in eNOS phosphorylation at Ser633 and Ser1177. The antioxidants N-acetylcysteine (NAC) and apocynin (APO) or knockdown of gp91phox or p67phox (NOX subunits) restored PA-mediated downregulation of PP4R2 protein expression and eNOS Ser633 phosphorylation. Knockdown of the PP4 catalytic subunit (PP4c) specifically increased eNOS Ser633 phosphorylation, while silencing the PP2A catalytic subunit (PP2Ac) restored only eNOS Ser1177 phosphorylation. Furthermore, PA dramatically decreased the protein expression of the PP4 regulatory subunit R2 (PP4R2) but not the other regulatory subunits. PP4R2 overexpression increased eNOS Ser633 phosphorylation, nitric oxide (NO) production, cell migration and tube formation but did not change eNOS Ser1177 phosphorylation levels. Coimmunoprecipitation (Co-IP) suggested that PP4R2 and PP4c interacted with the PP4R3α and eNOS proteins. In summary, PA decreases PP4R2 protein expression through the Nox/ROS pathway to activate PP4, which contributes to ED by dephosphorylating eNOS at Ser633. The results of this study suggest that PP4 is a novel therapeutic target for ED and ED-associated vascular diseases.}, } @article {pmid38513858, year = {2024}, author = {Li, S and Gu, X and Zhang, M and Jiang, Q and Xu, T}, title = {Di (2-ethylhexyl) phthalate and polystyrene microplastics co-exposure caused oxidative stress to activate NF-κB/NLRP3 pathway aggravated pyroptosis and inflammation in mouse kidney.}, journal = {The Science of the total environment}, volume = {926}, number = {}, pages = {171817}, doi = {10.1016/j.scitotenv.2024.171817}, pmid = {38513858}, issn = {1879-1026}, mesh = {Animals ; Mice ; Antioxidants/metabolism ; *Diethylhexyl Phthalate/toxicity/metabolism ; Inflammation/chemically induced ; Kidney/metabolism ; *Microplastics/metabolism/toxicity ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Oxidative Stress ; *Phthalic Acids ; Plasticizers/toxicity/metabolism ; Plastics/metabolism/toxicity ; Polystyrenes/toxicity/metabolism ; *Pyroptosis ; }, abstract = {Polystyrene microplastic (PS-MPs) contamination has become a worldwide hotspot of concern, and its entry into organisms can cause oxidative stress resulting in multi-organ damage. The plasticizer di (2-ethylhexyl) phthalate (DEHP) is a common endocrine disruptor, these two environmental toxins often occur together, but their combined toxicity to the kidney and its mechanism of toxicity are unknown. Therefore, in this study, we established PS-MPS and/or DEHP-exposed mouse models. The results showed that alone exposure to both PS-MPs and DEHP caused inflammatory cell infiltration, cell membrane rupture, and content spillage in kidney tissues. There were also down-regulation of antioxidant enzyme levels, increased ROS content, activated of the NF-κB pathway, stimulated the levels of heat shock proteins (HSPs), pyroptosis, and inflammatory associated factors. Notably, the co-exposure group showed greater toxicity to kidney tissues, the cellular assay further validated these results. The introduction of the antioxidant n-acetylcysteine (NAC) and the NLRP3 inhibitor (MCC950) could mitigate the changes in the above measures. In summary, co-exposure of PS-MPs and DEHP induced oxidative stress that activated the NF-κB/NLRP3 pathway and aggravated kidney pyroptosis and inflammation, as well as that HSPs are also involved in this pathologic injury process. This study not only enriched the nephrotoxicity of plasticizers and microplastics, but also provided new insights into the toxicity mechanisms of multicomponent co-pollution in environmental.}, } @article {pmid38513841, year = {2024}, author = {Malaviya, R and Meshanni, JA and Sunil, VR and Venosa, A and Guo, C and Abramova, EV and Vayas, KN and Jiang, C and Cervelli, JA and Gow, AJ and Laskin, JD and Laskin, DL}, title = {Role of macrophage bioenergetics in N-acetylcysteine-mediated mitigation of lung injury and oxidative stress induced by nitrogen mustard.}, journal = {Toxicology and applied pharmacology}, volume = {485}, number = {}, pages = {116908}, doi = {10.1016/j.taap.2024.116908}, pmid = {38513841}, issn = {1096-0333}, support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; R01 ES032553/ES/NIEHS NIH HHS/United States ; T32 ES007148/ES/NIEHS NIH HHS/United States ; U54 AR055073/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; *Mechlorethamine/toxicity ; Male ; *Energy Metabolism/drug effects ; Rats ; *Lung Injury/chemically induced/metabolism/pathology ; Rats, Sprague-Dawley ; Lung/drug effects/metabolism/pathology ; Macrophages/drug effects/metabolism ; Acute Lung Injury/chemically induced/metabolism/pathology ; Macrophages, Alveolar/drug effects/metabolism ; Chemical Warfare Agents/toxicity ; }, abstract = {Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.}, } @article {pmid38508437, year = {2024}, author = {Liu, H and Wang, X and He, K and Chen, Z and Li, X and Ren, J and Zhao, X and Liu, S and Zhou, T and Chen, H}, title = {Oxidized DJ-1 activates the p-IKK/NF-κB/Beclin1 pathway by binding PTEN to induce autophagy and exacerbate myocardial ischemia-reperfusion injury.}, journal = {European journal of pharmacology}, volume = {971}, number = {}, pages = {176496}, doi = {10.1016/j.ejphar.2024.176496}, pmid = {38508437}, issn = {1879-0712}, mesh = {Animals ; Humans ; Rats ; Autophagy ; Beclin-1 ; Cysteine/pharmacology ; *Myocardial Reperfusion Injury/metabolism ; *NF-kappa B/metabolism ; PTEN Phosphohydrolase ; Rats, Sprague-Dawley ; }, abstract = {Patients with myocardial infarction have a much worse prognosis when they have myocardial ischemia-reperfusion (I/R) injury. Further research into the molecular basis of myocardial I/R injury is therefore urgently needed, as well as the identification of novel therapeutic targets and linkages to interventions. Three cysteine residues are present in DJ-1 at amino acids 46, 53, and 106 sites, with the cysteine at position 106 being the most oxidation-prone. This study sought to understand how oxidized DJ-1(C106) contributes to myocardial I/R damage. Rats' left anterior descending branches were tied off to establish a myocardial I/R model in vivo. A myocardial I/R model in vitro was established via anoxia/reoxygenation (A/R) of H9c2 cells. The results showed that autophagy increased after I/R, accompanied by the increased expression of oxidized DJ-1 (ox-DJ-1). In contrast, after pretreatment with NAC (N-acetylcysteine, a ROS scavenger) or Comp-23 (Compound-23, a specific antioxidant binding to the C106 site of DJ-1), the levels of ox-DJ-1, autophagy and LDH release decreased, and cell survival rate increased. Furthermore, the inhibition of interaction between ox-DJ-1 and PTEN could increase PTEN phosphatase activity, inhibit the p-IKK/NF-κB/Beclin1 pathway, reduce injurious autophagy, and alleviate A/R injury. However, BA (Betulinic acid, a NF-κB agonist) was able to reverse the protective effects produced by Comp-23 pretreatment. In conclusion, ox-DJ-1 could activate detrimental autophagy through the PTEN/p-IKK/NF-κB/Beclin1 pathway and exacerbate myocardial I/R injury.}, } @article {pmid38507470, year = {2024}, author = {Yin, J and Ge, X and Ding, F and He, L and Song, K and Shi, Z and Ge, Z and Zhang, J and Ji, J and Wang, X and Zhao, N and Shu, C and Lin, F and Wang, Q and Zhou, Q and Cao, Y and Liu, W and Ye, D and Rich, JN and Wang, X and You, Y and Qian, X}, title = {Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly.}, journal = {Science translational medicine}, volume = {16}, number = {739}, pages = {eadg5553}, doi = {10.1126/scitranslmed.adg5553}, pmid = {38507470}, issn = {1946-6242}, mesh = {Humans ; *Glioblastoma/drug therapy ; Iron/metabolism ; *Glioma/drug therapy ; *Brain Neoplasms/drug therapy ; Neoplastic Stem Cells/pathology ; Sulfur/metabolism/therapeutic use ; Fumarates ; Cell Line, Tumor ; PTEN Phosphohydrolase/metabolism ; }, abstract = {Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.}, } @article {pmid38505087, year = {2024}, author = {Liang, Z and Chen, Q and Pan, L and She, X and Chen, T}, title = {Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer.}, journal = {Journal of thoracic disease}, volume = {16}, number = {2}, pages = {1412-1423}, pmid = {38505087}, issn = {2072-1439}, abstract = {BACKGROUND: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell.

METHODS: Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed in vivo to investigate the role of MBZ in NSCLC tumor growth.

RESULTS: The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC in vivo.

CONCLUSIONS: In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.}, } @article {pmid38503729, year = {2024}, author = {Rodrigues, ACBDC and Silva, SLR and Dias, IRSB and Costa, RGA and Oliveira, MS and Soares, MBP and Dias, RB and Valverde, LF and Rocha, CAG and Johnson, EM and Pina, C and Bezerra, DP}, title = {Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {147}, pmid = {38503729}, issn = {2058-7716}, abstract = {Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34[+] leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.}, } @article {pmid38503013, year = {2024}, author = {Li, Y and Long, W and Zhang, H and Zhao, M and Gao, M and Guo, W and Yu, L}, title = {Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.}, journal = {International immunopharmacology}, volume = {131}, number = {}, pages = {111844}, doi = {10.1016/j.intimp.2024.111844}, pmid = {38503013}, issn = {1878-1705}, mesh = {Mice ; Animals ; Male ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Diabetic Nephropathies/drug therapy/metabolism ; Irbesartan/therapeutic use ; NF-E2-Related Factor 2/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; Glucose ; *Diabetes Mellitus ; }, abstract = {OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure.

METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1β and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation.

CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.}, } @article {pmid38500894, year = {2024}, author = {Harlivasari, AD and Susanto, AD and Taufik, FF and Ginting, TT}, title = {The Role of Twice-Daily N-acetylcysteine (NAC) 2400 mg in Smoking Cessation: A Randomized, Placebo-Controlled Trial in Indonesia.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54322}, pmid = {38500894}, issn = {2168-8184}, abstract = {INTRODUCTION: Tobacco smoking remains a health concern, especially in developing countries. Nicotine is significantly linked to many cancers and even second-hand exposure. Hence, smoking can increase the risk of lung and heart disease. This makes quitting smoking important and challenging. Success tends to rise by achieving abstinence with assisted pharmacology. These treatments aim to reduce symptoms of nicotine withdrawal. This is a preclinical trial on glutamate modulator in N-acetylcysteine (NAC) as a new potential treatment for smoking cessation. It is based on the administration of NAC related to elevated levels of dopamine in the central nervous system to accomplish successful smoking cessation.

AIM: This study evaluated the efficacy and tolerability of NAC for smoking cessation. The primary outcome was abstinence rate and the secondary outcomes of the study were to assess carbon monoxide exhalation value (COexh), the withdrawal symptoms, craving score, safety, and tolerability associated with the administration of NAC.

METHODS: This is a randomized clinical trial. Eligible smokers were treated with NAC 2400 mg twice daily (BID) or placebo to obtain a potential effective abstinence rate. Subjects recruited from the smoking cessation clinic were screened for eligibility and were randomized to either the NAC or placebo group. The trial consisted of a four-week treatment phase and participants were evaluated each week with a brief counseling. Intention to treat data analysis was performed from 2018 to 2019. Smoking cessation status was verified by measuring the amount of carbon monoxide exhaled and by documenting their smoking habits. Adverse events (AEs) have also been observed on each visit.

RESULTS: A total of 90 male smokers with a mean (SD) age of 38.7 (11) years were randomized into two groups to receive NAC (n=45) and placebo (n=45). The primary outcome revealed that the abstinence rate was significantly higher for the NAC group than the placebo group (37.7% vs 6.6%; p=0.02). These findings were supported by data comparison between the NAC group and placebo group of COexh (ppm) (9.59 ±7.4 vs 13,4 ±6.1; p=0.04) and cigarette consumption/week (10 vs 46; p <0.001), which were statistically significant. Comparison of withdrawal with the Minnesota Nicotine Withdrawal Score between the NAC group and the placebo group showed lower values (8 (1-31) vs 11 (0-43); p=0.178), respectively, even though not statistically significant. Compared to the placebo group, the craving score (6 (2-29) vs 12 (6-31); p=0.04) in the NAC group was significantly lower. The most common adverse event was mild gastrointestinal effects (28.9%) and arthralgia (2.2%). No serious adverse events were detected.

CONCLUSIONS:  Despite a small sample size, the data demonstrate the potential benefits of NAC that may help elevate abstinence rates and promote successful smoking cessation pharmacotherapy. Comprehensive treatment combining pharmacologic therapy and counseling increases smoking cessation success rates. It is essential to conduct a randomized multicenter study with a large population to support a sustained abstinence rate using NAC.}, } @article {pmid38500550, year = {2024}, author = {Takasaki, T and Hamabe, Y and Touchi, K and Khandakar, GI and Ueda, T and Okada, H and Sakai, K and Nishio, K and Tanabe, G and Sugiura, R}, title = {ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2024}, number = {}, pages = {7683793}, pmid = {38500550}, issn = {1942-0994}, mesh = {Humans ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Reactive Oxygen Species/metabolism ; *Melanoma/drug therapy ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; *Pancreatic Neoplasms/drug therapy ; }, abstract = {The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identified an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identified nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine significantly attenuated the anticancer activity of ACA-28. Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28. Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1. Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28.}, } @article {pmid38498979, year = {2024}, author = {El-Habta, R and Af Bjerkén, S and Virel, A}, title = {N-acetylcysteine increases dopamine release and prevents the deleterious effects of 6-OHDA on the expression of VMAT2, α-synuclein, and tyrosine hydroxylase.}, journal = {Neurological research}, volume = {46}, number = {5}, pages = {406-415}, doi = {10.1080/01616412.2024.2325312}, pmid = {38498979}, issn = {1743-1328}, mesh = {*Vesicular Monoamine Transport Proteins/metabolism ; Humans ; *Oxidopamine/toxicity ; *alpha-Synuclein/metabolism ; *Dopamine/metabolism ; *Acetylcysteine/pharmacology ; *Tyrosine 3-Monooxygenase/metabolism ; Cell Line, Tumor ; Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; }, abstract = {OBJECTIVES: Current treatments for Parkinson's disease using pharmacological approaches alleviate motor symptoms but do not prevent neuronal loss or dysregulation of dopamine neurotransmission. In this article, we have explored the molecular mechanisms underlying the neuroprotective effect of the antioxidant N-acetylcysteine (NAC) on the damaged dopamine system.

METHODS: SH-SY5Y cells were differentiated towards a dopaminergic phenotype and exposed to 6-hydroxydopamine (6-OHDA) to establish an in vitro model of Parkinson's disease. We examined the potential of NAC to restore the pathological effects of 6-OHDA on cell survival, dopamine synthesis as well as on key proteins regulating dopamine metabolism. Specifically, we evaluated gene- and protein expression of tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and α-synuclein, by using qPCR and Western blot techniques. Moreover, we quantified the effect of NAC on total dopamine levels using a dopamine ELISA assay.

RESULTS: Our results indicate that NAC has a neuroprotective role in SH-SY5Y cells exposed to 6-OHDA by maintaining cell proliferation and decreasing apoptosis. Additionally, we demonstrated that NAC treatment increases dopamine release and protects SH-SY5Y cells against 6-OHDA dysregulations on the proteins TH, VMAT2, and α-synuclein.

CONCLUSIONS: Our findings contribute to the validation of compounds capable to restore dopamine homeostasis and shed light on the metabolic pathways that could be targeted to normalize dopamine turnover. Furthermore, our results highlight the effectiveness of the antioxidant NAC in the prevention of dopaminergic neurodegeneration in the present model.

ABBREVIATIONS: DAT, dopamine transporter; 6-OHDA, 6-hydroxydopamine; NAC, N-acetylcysteine; PARP, poly (ADP-ribose) polymerase; RA; retinoic acid; ROS, reactive oxygen species; TH, tyrosine hydroxylase; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; VMAT2, vesicle monoamine transporter 2.}, } @article {pmid38497734, year = {2024}, author = {Li, X and Zou, J and Lin, A and Chi, J and Hao, H and Chen, H and Liu, Z}, title = {Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus.}, journal = {Antioxidants & redox signaling}, volume = {40}, number = {16-18}, pages = {968-989}, pmid = {38497734}, issn = {1557-7716}, support = {RF1 NS132279/NS/NINDS NIH HHS/United States ; R01 HL148196/HL/NHLBI NIH HHS/United States ; R01 HL130845/HL/NHLBI NIH HHS/United States ; R01 HL162367/HL/NHLBI NIH HHS/United States ; R01 HL137229/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/metabolism/drug therapy/complications ; *Acetylcysteine/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; Animals ; *Endothelium, Vascular/metabolism/drug effects/pathology ; *Antioxidants/therapeutic use/pharmacology/metabolism ; Cardiovascular Diseases/metabolism/drug therapy/etiology ; }, abstract = {Significance: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) dysfunction with substantially increased risk for CVDs. Recent Advances: Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to EC dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In this review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in T2DM. Critical Issues: Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Future Directions: Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well-designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents and effective personalized strategies will be developed for the management of endothelial dysfunction in DM.}, } @article {pmid38496055, year = {2024}, author = {R, R and Routray, M}, title = {Management of Yellow Phosphorus-Induced Acute Liver Failure: A Case Report and Review of Literature.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54223}, pmid = {38496055}, issn = {2168-8184}, abstract = {Three percent (3%) of yellow phosphorus is the active component of the rodenticide Ratol[®]. It is a potent hepatotoxin that leads to acute liver failure (ALF) with high mortality. There is no antidote available; the only definitive management is liver transplantation. Therapeutic plasma exchange, or plasmapheresis, appears to help these patients by removing the toxin, its metabolite, or the inflammatory mediators released in the body in response to the toxin. Here, we report a case of a 19-year-old male with an alleged history of Ratol[®] ingestion and ALF with acute kidney injury. He had a complete reversal of his condition with timely intervention in the form of plasmapheresis.}, } @article {pmid38495889, year = {2024}, author = {Gupta, A and Song, MH and Youn, DH and Ku, D and Sasidharan Nair, V and Oh, K}, title = {Prolyl hydroxylase inhibition protects against murine MC903-induced skin inflammation by downregulating TSLP.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1330011}, pmid = {38495889}, issn = {1664-3224}, mesh = {Animals ; Mice ; *Prolyl Hydroxylases ; Interleukin-33 ; Reactive Oxygen Species ; *Dermatitis/drug therapy/etiology/prevention & control ; Anti-Inflammatory Agents ; Inflammation ; Calcitriol/*analogs & derivatives ; }, abstract = {Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation.}, } @article {pmid38494703, year = {2024}, author = {Miyake, K and Mikami, Y and Asayama, T and Toriumi, T and Shinozuka, K and Tonogi, M and Yonehara, Y and Tsuda, H}, title = {Reactive oxygen species generation required for autophagy induction during butyrate- or propionate-induced release of damage-associated molecular patterns from dying gingival epithelial Ca9-22 cells.}, journal = {Journal of oral science}, volume = {66}, number = {2}, pages = {125-129}, doi = {10.2334/josnusd.23-0421}, pmid = {38494703}, issn = {1880-4926}, mesh = {Humans ; *Butyrates/pharmacology ; *Propionates/pharmacology ; Reactive Oxygen Species/metabolism ; Fatty Acids, Volatile/pharmacology ; Autophagy/physiology ; }, abstract = {PURPOSE: Bacterial cells in mature dental plaque produce a high concentration of short-chain fatty acids (SCFAs) such as butyrate and propionate. SCFA-treatment on human gingival epithelial Ca9-22 cells induced cell death. However, the exact mechanism underlying cell death remains unclear. In this study, the relationship between reactive oxygen species (ROS) and autophagy induction during SCFA-induced cell death was examined.

METHODS: Human gingival epithelial Ca9-22 cells were treated with butyrate or propionate to induce cell death and the number of dead cells were measured using SYTOX-green dye. A siRNA for ATG5 and N-acetylcysteine (NAC) were used for autophagy reduction and ROS-scavenging, respectively. Release of damage-associated molecular patterns (DAMPs) such as Sin3A-associated protein 130 (SAP130) and high-mobility group box 1 (HMGB1) were detected using western blot.

RESULTS: Reducing autophagy significantly suppressed SCFA-induced Ca9-22 cell death. ROS generation was observed upon SCFA treatment, and scavenging ROS with NAC decreased cell death. NAC also reduced the SCFA-induced increase in microtubule-associated protein 1 light chain 3B (LC3B)-I and LC3B-II, and mitigated the release of DAMPs.

CONCLUSION: The findings suggest that ROS generation is necessary for autophagy, which is required for SCFA-induced cell death and accompanying DAMP release.}, } @article {pmid38488660, year = {2024}, author = {Cao, S and Yin, H and Li, X and Zeng, X and Liu, J}, title = {Nickel induces epithelial-mesenchymal transition in pulmonary fibrosis in mice via activation of the oxidative stress-mediated TGF-β1/Smad signaling pathway.}, journal = {Environmental toxicology}, volume = {39}, number = {6}, pages = {3597-3611}, doi = {10.1002/tox.24229}, pmid = {38488660}, issn = {1522-7278}, support = {22zx7153//Natural Science Foundation of Southwest University of Science and Technology/ ; }, mesh = {Animals ; Male ; Mice ; *Epithelial-Mesenchymal Transition/drug effects ; Lung/drug effects/pathology/metabolism ; *Nickel/toxicity ; *Oxidative Stress/drug effects ; *Pulmonary Fibrosis/chemically induced/metabolism/pathology ; *Signal Transduction/drug effects ; Smad Proteins/metabolism ; Transforming Growth Factor beta1/metabolism ; }, abstract = {Nickel (Ni) is recognized as a carcinogenic metal, and its widespread use has led to severe environmental and health problems. Although the lung is among the main organs affected by Ni, the precise mechanisms behind this effect remain poorly understood. This study aimed to elucidate the physiological mechanisms underlying Ni-induced pulmonary fibrosis (PF), using various techniques including histopathological detection, biochemical analysis, immunohistochemistry, western blotting, and quantitative real-time PCR. Mice were treated with nickel chloride (NiCl2), which induced PF (detected by Masson staining), up-regulation of α-smooth muscle actin (α-SMA), and collagen-1 mRNA and protein expression. NiCl2 was found to induce PF by: activation of the epithelial-mesenchymal transition (EMT) and the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway; up-regulation of protein and mRNA expression of TGF-β1, p-Smad2, p-Smad3, vimentin, and N-cadherin; and down-regulation of protein and mRNA expression of E-cadherin. In addition, NiCl2 treatment increased malondialdehyde content while inhibiting antioxidant activity, as indicated by decreased catalase, total antioxidant capacity, and superoxide dismutase activities, and glutathione content. Co-treatment with the effective antioxidant and free radical scavenger N-acetyl cysteine (NAC) plus NiCl2 was used to study the effects of oxidative stress in NiCl2-induced PF. The addition of NAC significantly mitigated NiCl2-induced PF, and reversed activation of the TGF-β1/Smad signaling pathway and EMT. NiCl2-induced PF was therefore shown to be due to EMT activation via the TGF-β1/Smad signaling pathway, mediated by oxidative stress.}, } @article {pmid38480798, year = {2024}, author = {Zhu, C and Lu, Y and Wang, S and Song, J and Ding, Y and Wang, Y and Dong, C and Liu, J and Qiu, W and Qi, W}, title = {Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {6050}, pmid = {38480798}, issn = {2045-2322}, support = {No. 202003030451//Science and Technology Development Plan of Shandong Province/ ; No. KC2021-JX-0186-145//Beijing Science and Technology Innovation Medical Development Foundation/ ; No.202103030554//Health Science and Technology Development Plan Project/ ; }, mesh = {Mice ; Animals ; Humans ; Reactive Oxygen Species/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; Nortriptyline/pharmacology ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; *Stomach Neoplasms/drug therapy ; Drug Repositioning ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Oxidative Stress ; Apoptosis ; }, abstract = {Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)-NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.}, } @article {pmid38474543, year = {2024}, author = {Beloglazkina, EK and Moiseeva, AA and Tsymbal, SA and Guk, DA and Kuzmin, MA and Krasnovskaya, OO and Borisov, RS and Barskaya, ES and Tafeenko, VA and Alpatova, VM and Zaitsev, AV and Finko, AV and Ol'shevskaya, VA and Shtil, AA}, title = {The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {5}, pages = {}, pmid = {38474543}, issn = {1420-3049}, support = {19-29-08007//Russian Foundation for Basic Research/ ; }, mesh = {Copper/chemistry ; Reducing Agents ; *Antineoplastic Agents/chemistry ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; *Coordination Complexes/chemistry ; Ligands ; }, abstract = {Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu[2+] to Cu[1+] triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu[+2] → Cu[+1] redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.}, } @article {pmid38472735, year = {2024}, author = {Farouk, F and Shebl, RI}, title = {LC-MS/MS determination of pyocyanin-N-acetyl cysteine adduct: application for understanding Pseudomonas aeruginosa virulence factor neutralization.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {40}, number = {5}, pages = {891-905}, pmid = {38472735}, issn = {1348-2246}, mesh = {*Acetylcysteine/chemistry/pharmacology ; Anti-Bacterial Agents/pharmacology/chemistry ; Liquid Chromatography-Mass Spectrometry ; *Pseudomonas aeruginosa/drug effects ; *Pyocyanine/metabolism/antagonists & inhibitors/analysis/chemistry ; *Virulence Factors/antagonists & inhibitors/metabolism ; }, abstract = {Combating Pseudomonas aeruginosa infection is challenging. It secretes pyocyanin (PCN) pigment that contributes to its virulence. Neutralizing PCN via reaction with thiol-containing compounds may represent a potential therapeutic option. This study investigates the neutralization reaction between PCN and N-acetyl cysteine (NAC) for bacterial inhibition and explores its mechanism of action. The neutralization adduct (PCN-NAC) was synthesized by reacting the purified PCN and NAC. The adduct was analyzed and its structure was elucidated. LC-MS/MS method was developed for the determination of PCN-NAC in P. aeruginosa cultures post-treatment with NAC (0-5 mg/mL). The corresponding anti-bacterial potential was estimated and compared to nanoparticles (NPs) alone and under stress conditions. In silico studies were performed to support explaining the mechanism of action. Results revealed that PCN-NAC was exclusively detected in NAC-treated cultures in a concentration-dependent manner. PCN-NAC concentration (230-915 µg/mL) was directly proportional to the reduction in the bacterial viable count (28.3% ± 7.1-87.5% ± 5.9) and outperformed all tested NPs, where chitosan NPs induced 56.9% ± 7.9 inhibition, followed by zinc NPs (49.4% ± 0.9) and gold NPs (17.8% ± 7.5) even post-exposure to different stress conditions. A concomitant reduction in PCN concentration was detected. In silico studies revealed possible interactions between key bacterial proteins and PCN-NAC rather than the NAC itself. These results pose NAC as a potential choice for the management of P. aeruginosa infection, where it neutralizes PCN via the formation of PCN-NAC adduct.}, } @article {pmid38470079, year = {2024}, author = {Atefi, N and Ziaeifar, E and Seirafianpour, F and Sadeghzadeh-Bazargan, A and Amin, NG and Mozafarpoor, S and Abouie, A and Jafari, MA and Goodarzi, A}, title = {Evaluation of efficacy and safety of vitiligo treatment with micro-needling combined with N-Acetylcysteine and micro-needling alone: A double-blinded randomized controlled clinical trial.}, journal = {Journal of cosmetic dermatology}, volume = {23}, number = {6}, pages = {2220-2230}, doi = {10.1111/jocd.16274}, pmid = {38470079}, issn = {1473-2165}, mesh = {Humans ; *Vitiligo/therapy/drug therapy ; *Acetylcysteine/administration & dosage/adverse effects/therapeutic use ; Double-Blind Method ; Female ; Adult ; Male ; Middle Aged ; Treatment Outcome ; Combined Modality Therapy/adverse effects/methods ; Young Adult ; Severity of Illness Index ; Dry Needling/adverse effects/methods ; Needles/adverse effects ; Adolescent ; Skin Pigmentation/drug effects ; }, abstract = {INTRODUCTION: Vitiligo is a skin pigmentation disorder caused by the selective degradation of melanocytes. This study investigates the therapeutic effects of microneedling with and without N-acetylcysteine (NAC) in patients with persistent and limited vitiligo.

METHOD: This research employed a clinical trial design with double-blind randomization. Individuals affected by vitiligo and seeking treatment at Rasool Akram Medical Complex were divided into two separate treatment groups. In the intervention group, 24 affected areas underwent meso-microneedling using 5% NAC ampoules over six sessions, in addition to the application of 4.7% NAC cream once daily on the specified area. Conversely, the control group, consisting of 22 lesions, underwent microneedling using distilled water during six sessions. The severity of lesions and the extent of repigmentation were gauged using the Modified VETI Score. Assessment of treatment efficacy was determined through both physician evaluations and patient feedback.

RESULTS: Twenty patients with a mean age of 36.4 years were recruited. The mean percentage of lesions and their intensity were significantly improved 2 weeks after the third session and 1 month after the end of the treatment (p < 0.01). There was no statistically significant difference between the intervention and control groups. Gender, age, family history, duration of disease, duration of disease stability, and history of hypothyroidism had no statistically significant relationship with patients' treatment outcomes (p > 0.05).

CONCLUSION: Microneedling with or without the application of NAC appears to be an effective treatment option for persistent vitiligo lesions. However, despite the higher improvement rate with the application of NAC, the difference was not significant.}, } @article {pmid38469128, year = {2024}, author = {Gautam, N and Shrestha, N and Bhandari, S and Thapaliya, S}, title = {Severe dengue infection unmasking drug-induced liver injury: Successful management with N-acetylcysteine.}, journal = {Clinical case reports}, volume = {12}, number = {3}, pages = {e8578}, pmid = {38469128}, issn = {2050-0904}, abstract = {KEY CLINICAL MESSAGE: Clinicians in tuberculosis and dengue endemic regions should have heightened vigilance for drug-induced liver injury (DILI) overlapping with active infections, enabling prompt recognition and life-saving conservative management.

ABSTRACT: Severe dengue and drug-induced liver injury (DILI) are significant independent risk factors for acute liver failure. The co-occurrence of these conditions significantly complicates clinical management. Here, we describe the case of a 21-year-old Nepali female who developed acute liver failure during antitubercular therapy (ATT). The patient, presenting with fever and nausea after 3 weeks of ATT, subsequently received a diagnosis of severe dengue. Laboratory evidence indicated markedly elevated transaminases (AST 4335 U/L, ALT 1958 U/L), total bilirubin (72 μmol/L), and INR (>5). Prompt discontinuation of first-line ATT, initiation of a modified ATT regimen, and N-acetylcysteine (NAC) infusion facilitated the patient's recovery after a week of intensive care. This case underscores the potential for synergistic hepatotoxicity in regions where multiple endemic illnesses coincide. Early recognition of DILI, cessation of offending agents, and comprehensive intensive care are crucial interventions. While the definitive efficacy of NAC remains under investigation, its timely administration in these complex cases warrants exploration for its potential lifesaving benefits.}, } @article {pmid38467612, year = {2024}, author = {Zhang, L and Shi, X and Zhang, L and Mi, Y and Zuo, L and Gao, S}, title = {A first-in-class TIMM44 blocker inhibits bladder cancer cell growth.}, journal = {Cell death & disease}, volume = {15}, number = {3}, pages = {204}, pmid = {38467612}, issn = {2041-4889}, support = {81902565//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Mice ; Animals ; Humans ; *Signal Transduction ; Proto-Oncogene Proteins c-akt/metabolism ; Mice, Nude ; Urinary Bladder/metabolism ; Cell Proliferation ; *Urinary Bladder Neoplasms/drug therapy/genetics/metabolism ; Apoptosis ; Adenosine Triphosphate/pharmacology ; Cell Line, Tumor ; Mammals ; Mitochondrial Precursor Protein Import Complex Proteins ; }, abstract = {Mitochondria play a multifaceted role in supporting bladder cancer progression. Translocase of inner mitochondrial membrane 44 (TIMM44) is essential for maintaining function and integrity of mitochondria. We here tested the potential effect of MB-10 (MitoBloCK-10), a first-in-class TIMM44 blocker, against bladder cancer cells. TIMM44 mRNA and protein expression is significantly elevated in both human bladder cancer tissues and cells. In both patient-derived primary bladder cancer cells and immortalized (T24) cell line, MB-10 exerted potent anti-cancer activity and inhibited cell viability, proliferation and motility. The TIMM44 blocker induced apoptosis and cell cycle arrest in bladder cancer cells, but failed to provoke cytotoxicity in primary bladder epithelial cells. MB-10 disrupted mitochondrial functions in bladder cancer cells, causing mitochondrial depolarization, oxidative stress and ATP reduction. Whereas exogenously-added ATP and the antioxidant N-Acetyl Cysteine mitigated MB-10-induced cytotoxicity of bladder cancer cells. Genetic depletion of TIMM44 through CRISPR-Cas9 method also induced robust anti-bladder cancer cell activity and MB-10 had no effect in TIMM44-depleted cancer cells. Contrarily, ectopic overexpression of TIMM44 using a lentiviral construct augmented proliferation and motility of primary bladder cancer cells. TIMM44 is important for Akt-mammalian target of rapamycin (mTOR) activation. In primary bladder cancer cells, Akt-S6K1 phosphorylation was decreased by MB-10 treatment or TIMM44 depletion, but enhanced after ectopic TIMM44 overexpression. In vivo, intraperitoneal injection of MB-10 impeded bladder cancer xenograft growth in nude mice. Oxidative stress, ATP reduction, Akt-S6K1 inhibition and apoptosis were detected in MB-10-treated xenograft tissues. Moreover, genetic depletion of TIMM44 also arrested bladder cancer xenograft growth in nude mice, leading to oxidative stress, ATP reduction and Akt-S6K1 inhibition in xenograft tissues. Together, targeting overexpressed TIMM44 by MB-10 significantly inhibits bladder cancer cell growth in vitro and in vivo.}, } @article {pmid38467037, year = {2024}, author = {Gakuba, C and Dumitrascu, AD and Marsan, PE and Legallois, D and Hanouz, JL and Vivien, D and Martinez de Lizarrondo, S and Gauberti, M and Cerasuolo, D}, title = {N-Acetylcysteine to Reduce Mortality for Patients Requiring Cardiac Catheterization or Cardiac Surgery: A Systematic Review and Meta-analysis.}, journal = {Journal of cardiovascular pharmacology}, volume = {83}, number = {6}, pages = {580-587}, doi = {10.1097/FJC.0000000000001551}, pmid = {38467037}, issn = {1533-4023}, mesh = {Humans ; *Cardiac Catheterization/adverse effects/mortality ; *Hospital Mortality ; *Acetylcysteine/adverse effects/therapeutic use/administration & dosage ; *Cardiac Surgical Procedures/adverse effects/mortality ; Treatment Outcome ; Risk Factors ; Risk Assessment ; Female ; Randomized Controlled Trials as Topic ; Male ; Aged ; Middle Aged ; }, abstract = {Multimers of von Willebrand factor play a critical role in various processes inducing morbidity and mortality in cardiovascular-risk patients. With the ability to reduce von Willebrand factor multimers, N-acetylcysteine (NAC) could reduce mortality in patients undergoing coronary catheterization or cardiac surgery. However, its impact in perioperative period has never been studied so far in regard of its potential cardiovascular benefits. Then, 4 databases were searched for randomized controlled trials that compared in-hospital mortality between an experimental group, with NAC, and a control group without NAC, in patients undergoing coronary catheterization or cardiac surgery. The primary efficacy outcome was in-hospital mortality. Secondary outcomes were the occurrence of thrombotic events, major cardiovascular events, myocardial infarction, and contrast-induced nephropathy. The safety outcome was occurrence of hemorrhagic events. Nineteen studies totaling 3718 patients were included. Pooled analysis demonstrated a reduction of in-hospital mortality associated with NAC: odds ratio, 0.60; 95% confidence interval, 0.39-0.92; P = 0.02. The occurrence of secondary outcomes was not significantly reduced with NAC except for contrast-induced nephropathy. No difference was reported for hemorrhagic events. Subgroup analyses revealed a life-saving effect of NAC in a dose-dependent manner with reduction of in-hospital mortality for the NAC high-dose group, but not for the NAC standard-dose (<3500-mg) group. In conclusion, without being able to conclude on the nature of the mechanism involved, our review suggests a benefit of NAC in cardiovascular-risk patients in perioperative period in terms of mortality and supports prospective confirmatory studies.}, } @article {pmid38465147, year = {2024}, author = {Martinez-Ortega, JI and Perez Hernandez, FJ and Ortegon Blanco, AE}, title = {Acro-Ischemia Associated With SARS-CoV-2: A Case Report.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e53798}, pmid = {38465147}, issn = {2168-8184}, abstract = {COVID-19 is known to cause various cutaneous lesions, including acro-ischemic lesions (AIL), which are associated with poor prognosis. Anticoagulant therapy has shown positive responses in AIL patients. However, in this case study, we present a fatal AIL case despite anticoagulant therapy. We propose different treatment approaches based on the limited current data on acro-ischemia pathogenesis related to SARS-CoV-2. The clinical case involved a 59-year-old male with severe COVID-19 symptoms, including acrocyanosis and right hemiparesis. Despite receiving anticoagulant therapy, the patient's condition worsened, leading to necrosis in the left foot. The discussion focuses on the high-risk nature of AIL, the potential link between angiotensin-converting enzyme 2 (ACE2) receptors and vasculitis or thromboembolic manifestations, and the role of immune clots in AIL pathogenesis. Behçet syndrome is referenced as a model of inflammation-induced thrombosis, guiding the suggestion for immunosuppressant-based treatment in addition to anticoagulants. Additionally, three substances, N-acetyl cysteine, sulodexide, and hydroxychloroquine, are proposed.}, } @article {pmid38460408, year = {2024}, author = {Liu, YL and Liu, JY and Zhu, XX and Wei, JH and Mi, SL and Liu, SY and Li, XL and Zhang, WW and Zhao, LL and Wang, H and Xu, DX and Gao, L}, title = {Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.}, journal = {Ecotoxicology and environmental safety}, volume = {274}, number = {}, pages = {116191}, doi = {10.1016/j.ecoenv.2024.116191}, pmid = {38460408}, issn = {1090-2414}, mesh = {Animals ; Male ; Mice ; Apoptosis ; Cell Proliferation ; DNA Breaks, Double-Stranded/drug effects ; DNA Repair ; *Marine Toxins/metabolism/toxicity ; Mice, Inbred ICR ; *Microcystins/metabolism/toxicity ; Semen ; *Sirtuins/drug effects/metabolism ; *Spermatogonia/drug effects/metabolism ; }, abstract = {The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 μg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.}, } @article {pmid38460098, year = {2024}, author = {Nam, Y and Na, J and Ma, SX and Park, H and Park, H and Lee, E and Kim, H and Jang, SM and Ko, HS and Kim, S}, title = {DJ-1 protects cell death from a mitochondrial oxidative stress due to GBA1 deficiency.}, journal = {Genes & genomics}, volume = {46}, number = {5}, pages = {519-529}, pmid = {38460098}, issn = {2092-9293}, support = {2022R1C1C1009937//National Research foundation of korea/ ; }, mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; Hydrogen Peroxide ; *Neuroblastoma ; Oxidative Stress ; Cell Death/physiology ; Mice, Knockout ; Protein Deglycase DJ-1/genetics/metabolism ; *Parkinson Disease ; }, abstract = {BACKGROUND: GBA1 mutations are the most common genetic risk factor for development of Parkinson's disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown.

OBJECTIVE: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction.

METHODS: GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice.

RESULTS: We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction.

CONCLUSION: Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations.}, } @article {pmid38455771, year = {2024}, author = {Aulakh, G and Singh, A}, title = {A Case Report Demonstrating the Favorable Outcomes of Using N-acetylcysteine (NAC) in Managing Hepatic Injury Induced by Amphetamine-Related Drug Toxicity: Do We Underestimate Its Potential?.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e53697}, pmid = {38455771}, issn = {2168-8184}, abstract = {A 59-year-old male with a history of alcohol abuse presented with altered mental status. Upon examination, he was hypertensive and lethargic, and laboratory results revealed severe transaminitis, coagulopathy, and lactic acidosis, despite having normal serum alcohol levels. Additionally, his urine drug screen tested positive for methamphetamine. Following the exclusion of infectious, autoimmune, and other common causes of acute hepatitis, a diagnosis of methamphetamine-induced acute hepatitis was established. A non-acetaminophen toxicity N-acetylcysteine (NAC) protocol was initiated, resulting in a positive response with improvement in mentation and a decrease in liver enzyme levels. This case emphasizes the potential effectiveness of NAC in treating amphetamine-induced liver injury, supported by the limited available literature on the subject.}, } @article {pmid38455596, year = {2024}, author = {Alkhattabi, NA and Khalifa, FK and Doghaither, HAA and Al-Ghafari, AB and Tarbiah, NI and Sabban, A}, title = {Protective effects of N-acetylcysteine and S-adenosyl-Lmethionine against nephrotoxicity and immunotoxicity induced by ochratoxin A in rats.}, journal = {International journal of health sciences}, volume = {18}, number = {2}, pages = {17-24}, pmid = {38455596}, issn = {1658-3639}, abstract = {OBJECTIVE: The present study was designed to investigate the nephroprotective and immunoprotective effects of S-adenosyl-L-methionine (SAMe) in comparison to N-acetylcysteine (NAC) against ochratoxin A (OTA) - intoxication.

METHODS: Forty-eight adult male Sprague-Dawley rats were categorized into four groups: Control; OTA intoxication (5 mg OTA/kg diet); OTA + NAC, rats received 200 mg NAC/day before feeding balanced diet contaminated with OTA; and (OTA + SAMe). Rats received 200 mg SAMe/day dissolved in distilled water orally just before feeding a balanced diet contaminated with OTA.

RESULTS: OTA administration altered serum kidney function biomarkers. These effects were pronouncedly alleviated by treatment with NAC. Results revealed a correlation between OTA-induced immunotoxicity and the reduced white blood cell (WBC) count. Treatments with SAMe significantly improved the WBCs count and hemoglobin concentration.

CONCLUSION: NAC and SAMe have a protective role against nephrotoxicity and immunotoxicity induced by continuous administration of OTA. NAC was more effective in reducing OTA nephrotoxicity, whereas SAMe was more potent than NAC in reducing OTA immunotoxicity.}, } @article {pmid38451349, year = {2024}, author = {Revand, R and Dontham, A and Sarkar, S and Patil, A}, title = {Subacute Exposure to Gaseous Pollutants from Diesel Engine Exhaust Attenuates Capsaicin-Induced Cardio-Pulmonary Reflex Responses Involving Oxidant Stress Mechanisms in Adult Wistar Rats.}, journal = {Cardiovascular toxicology}, volume = {24}, number = {4}, pages = {396-407}, pmid = {38451349}, issn = {1559-0259}, mesh = {Rats ; Male ; Animals ; Rats, Wistar ; Vehicle Emissions/toxicity ; Capsaicin/pharmacology ; *Environmental Pollutants ; Gases ; Cysteine ; *Air Pollutants/toxicity ; Reflex ; }, abstract = {Intravenous injection of capsaicin produces vagal-mediated protective cardio-pulmonary (CP) reflexes manifesting as tachypnea, bradycardia, and triphasic blood pressure (BP) response in anesthetized rats. Particulate matter from diesel engine exhaust has been reported to attenuate these reflexes. However, the effects of gaseous constituents of diesel exhaust are not known. Therefore, the present study was designed to investigate the effects of gaseous pollutants in diesel exhaust, on capsaicin-induced CP reflexes in rat model. Adult male rats were randomly assigned to three groups: Non-exposed (NE) group, filtered diesel exhaust-exposed (FDE) group and N-acetyl cysteine (NAC)-treated FDE group. FDE group of rats (n = 6) were exposed to filtered diesel exhaust for 5 h a day for 5 days (D1-D5), and were taken for dissection on day 6 (D6), while NE group of rats (n = 6) remained unexposed. On D6, rats were anesthetized, following which jugular vein was cannulated for injection of chemicals, and femoral artery was cannulated to record the BP. Lead II electrocardiogram and respiratory movements were also recorded. Results show that intravenous injection of capsaicin (0.1 ml; 10 µg/kg) produced immediate tachypneic, hyperventilatory, hypotensive, and bradycardiac responses in both NE and FDE groups of rats. However, these capsaicin-induced CP responses were significantly attenuated in FDE group as compared to the NE group of rats. Further, FDE-induced attenuation of capsaicin-evoked CP responses were diminished in the N-acetyl cysteine-treated FDE rats. These findings demonstrate that oxidant stress mechanisms could possibly be involved in inhibition of CP reflexes by gaseous pollutants in diesel engine exhaust.}, } @article {pmid38450909, year = {2024}, author = {Yan, H and Ding, J and Li, X and Li, S and Zhang, D}, title = {Arecoline induces neurotoxicity in HT22 cells via the promotion of endoplasmic reticulum stress and downregulation of the Nrf2/HO-1 pathway.}, journal = {Environmental toxicology}, volume = {39}, number = {6}, pages = {3410-3424}, doi = {10.1002/tox.24194}, pmid = {38450909}, issn = {1522-7278}, support = {202301AY070001-262//Science and Technology Foundation of Yunnan Provincial/ ; 2023Y0617//Scientific Research Foundation of the Education Department of Yunnan Province/ ; }, mesh = {Animals ; Mice ; *Apoptosis/drug effects ; *Arecoline/toxicity ; Calcium/metabolism ; Cell Line ; Down-Regulation/drug effects ; *Endoplasmic Reticulum Stress/drug effects ; Heme Oxygenase-1/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; }, abstract = {Arecoline, the predominant bioactive substance extracted from areca nut (AN), is the world's fourth most frequently used psychoactive material. Research has revealed that chewing AN can affect the central nervous system (CNS) and may lead to neurocognitive deficits that are possibly linked to the action of arecoline. However, the mechanism behind the neurotoxicity caused by arecoline remains unclear. This study aimed to investigate the neurotoxic effects of arecoline and its underlying mechanism. The results showed that arecoline caused cytotoxicity against HT22 cells in a dose-dependent manner and induced apoptosis by upregulating the expression of pro-apoptotic caspase and Bcl-2 family proteins. Furthermore, arecoline escalated intracellular reactive oxygen species (ROS) levels and Ca[2+] concentration with increasing doses, thereby motivating endoplasmic reticulum stress (ERS) and ERS-associated apoptotic protein expression. Additionally, the study found that arecoline attenuates intracellular antioxidant defense by inhibiting the translocation of NF-E2-related factor-2 (Nrf2) into the nucleus and decreasing downstream Heme oxygenase-1 (HO-1) levels. The specific inhibitor Sodium 4-phenylbutyrate (4-PBA) can dramatically attenuate arecoline-mediated cell apoptosis and ERS-associated apoptotic pathway expression by blocking ERS. The antioxidant N-Acetylcysteine (NAC) also effectively reverses the arecoline-mediated increase of ERS-related apoptotic pathway protein levels by scavenging intracellular ROS accumulation. In conclusion, this study suggests that arecoline induces neurotoxicity in HT22 cells via ERS mediated by oxidative stress- and Ca[2+] disturbance, as well as by downregulation of the Nrf2/HO-1 pathway.}, } @article {pmid38446318, year = {2024}, author = {Yang, R and Yan, F and Shen, J and Wang, T and Li, M and Ni, H}, title = {Geraniol attenuates oxygen-glucose deprivation/reoxygenation-induced ROS-dependent apoptosis and permeability of human brain microvascular endothelial cells by activating the Nrf-2/HO-1 pathway.}, journal = {Journal of bioenergetics and biomembranes}, volume = {56}, number = {3}, pages = {193-204}, pmid = {38446318}, issn = {1573-6881}, mesh = {Humans ; *Apoptosis/drug effects ; *Acyclic Monoterpenes/pharmacology ; *Reactive Oxygen Species/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Endothelial Cells/metabolism/drug effects ; *Glucose/metabolism ; *Heme Oxygenase-1/metabolism ; Oxygen/metabolism ; Brain/metabolism/blood supply ; Microvessels/metabolism/pathology/drug effects ; }, abstract = {Blood-brain barrier breakdown and ROS overproduction are important events during the progression of ischemic stroke aggravating brain damage. Geraniol, a natural monoterpenoid, possesses anti-apoptotic, cytoprotective, anti-oxidant, and anti-inflammatory activities. Our study aimed to investigate the effect and underlying mechanisms of geraniol in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced human brain microvascular endothelial cells (HBMECs). Apoptosis, caspase-3 activity, and cytotoxicity of HBMECs were evaluated using TUNEL, caspase-3 activity, and CCK-8 assays, respectively. The permeability of HBMECs was examined using FITC-dextran assay. Reactive oxygen species (ROS) production was measured using the fluorescent probe DCFH-DA. The protein levels of zonula occludens-1 (ZO-1), occludin, claudin-5, β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were determined by western blotting. Geraniol showed no cytotoxicity in HBMECs. Geraniol and ROS scavenger N-acetylcysteine (NAC) both attenuated OGD/R-induced apoptosis and increase of caspase-3 activity and the permeability to FITC-dextran in HBMECs. Geraniol relieved OGD/R-induced ROS accumulation and decrease of expression of ZO-1, occludin, claudin-5, and β-catenin in HBMECs. Furthermore, we found that geraniol activated Nrf2/HO-1 pathway to inhibit ROS in HBMECs. In conclusion, geraniol attenuated OGD/R-induced ROS-dependent apoptosis and permeability in HBMECs through activating the Nrf2/HO-1 pathway.}, } @article {pmid38445814, year = {2024}, author = {Iepsen, UW and Hjortdal, AR and Thuesen, AD and Finsen, SH and Hansen, PBL and Mortensen, SP}, title = {The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.}, journal = {Experimental physiology}, volume = {109}, number = {5}, pages = {779-790}, pmid = {38445814}, issn = {1469-445X}, support = {ID 101390//TrygFonden (Tryg Foundation)/ ; ID 20045//TrygFonden (Tryg Foundation)/ ; //The Capital Region of Denmark/ ; //The Beckett Foundation/ ; //The Ehrenreich Foundation/ ; //Dansk Selskab for Anaestesiologi og Intensiv Medicin (DASAIM)/ ; //The Region of Southern Denmark/ ; //The Danish Medical Research Council/ ; //Dansk Selskab for Anæstesiologi og Intensiv Medicin (DASAIM)/ ; }, mesh = {Humans ; Male ; *Calcium Channels, T-Type/metabolism/drug effects ; Aged ; *Calcium Channel Blockers/pharmacology ; *Nifedipine/pharmacology ; Pilot Projects ; Double-Blind Method ; *Endothelium, Vascular/drug effects/metabolism/physiology ; Dihydropyridines/pharmacology ; Vasodilation/drug effects/physiology ; Vasodilator Agents/pharmacology ; Blood Pressure/drug effects/physiology ; Regional Blood Flow/drug effects/physiology ; Organophosphorus Compounds/pharmacology ; Acetylcholine/pharmacology ; Leg/blood supply ; Nitroprusside/pharmacology ; Middle Aged ; *Nitrophenols ; }, abstract = {Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.}, } @article {pmid38444903, year = {2024}, author = {Williams, EE and Quach, D and Daigh, A}, title = {Massive acetaminophen ingestion managed successfully with N-acetylcysteine, fomepizole, and renal replacement therapy.}, journal = {Clinical nephrology. Case studies}, volume = {12}, number = {}, pages = {22-25}, pmid = {38444903}, issn = {2196-5293}, abstract = {Acetaminophen ingestion is routinely managed with the antidote, N-acetylcysteine (NAC). Massive acetaminophen poisoning has been treated successfully with adjunctive therapies such as fomepizole and hemodialysis. Fomepizole functions by inhibiting cytochrome p560, which prevents tylenol from forming its toxic metabolite, NAPQI. Prior cases have demonstrated favorable outcomes and a significant drop in acetaminophen levels after a single session of intermittent hemodialysis and continuous veno-venous hemofiltration (CVVH). However, the recommended dosage adjustments of NAC and fomepizole while a patient is undergoing CVVH has not been well reported. We present a case of an 18-year-old male who presented after ingesting 125 g of tylenol. His 4-hour acetaminophen level was 738.6 µg/mL. He was treated with NAC, fomepizole, and a single 4-hour session of hemodialysis. His acetaminophen level remained elevated at 730 µg/mL despite the hemodialysis session. CVVH was initiated, and he was given intravenous NAC at 12.5 mg/kg/h, oral NAC at 70 mg/kg every 4 hours, and intravenous fomepizole at 10 mg/kg every 6 hours. His tylenol levels became undetectable 57 hours after ingestion, and he did not develop permanent liver toxicity. This case encourages the use of CVVH for massive tylenol ingestion when a single run of intermittent hemodialysis is not effective in lowering the tylenol level. NAC, fomepizole, and CVVH can prevent unfavorable outcomes in massive acetaminophen ingestion when provided at an appropriate dose and frequency.}, } @article {pmid38444704, year = {2023}, author = {Rostamabadi, H and Samandari Bahraseman, MR and Esmaeilzadeh-Salestani, K}, title = {Froriepia subpinnata Leaf Extract-Induced Apoptosis in the MCF-7 Breast Cancer Cell Line by Increasing Intracellular Oxidative Stress.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {22}, number = {1}, pages = {e136643}, pmid = {38444704}, issn = {1726-6890}, abstract = {BACKGROUND: Froriepia subpinnata is one of the plants used in the diet of Iranian people. Previous studies have investigated the antioxidant and antibacterial effects of this plant extract, but no study has been conducted on its anticancer properties.

OBJECTIVES: In this study, we investigated the effect of F. subpinnata extract on MCF-7 breast cancer cells.

METHODS: The inhibitory effect of F. subpinnata leaf extract was determined on the growth of cancer cells by the MTT test. The ROS (reactive oxygen species) test was used to investigate the impact of the extract on intracellular oxidative stress. Flow cytometry and real-time PCR tests were used to investigate the apoptosis-related molecular processes. The GC-MS analysis was performed to determine the most abundant components.

RESULTS: The GC-MS analysis showed that phytol, mono-ethylhexyl phthalate (MEHP), cinnamaldehyde, and neophytadiene constituted 60% of the extracted content. The MTT assay demonstrated that F. subpinnata leaf extract caused 50% lethality at a 400 μg/mL dose in MCF7 cells. The F. subpinnata extract at low doses decreased the ROS level for 24 hours in MCF-7, but by increasing the concentration, the ROS levels increased. At the IC50 dose (inhibitory concentration (IC) associated with 50% impact), the ROS level increased 3.5 times compared to the control group. Examining the effect of N-acetyl cysteine (NAC) showed that this antioxidant agent could prevent the lethal impact of the extract and eliminate the ROS increase in MCF7 cells. Flow cytometry and real-time PCR results showed that the extract specifically induced apoptosis through the internal apoptosis pathway in this cancer cell line.

CONCLUSIONS: The F. subpinnata extract induced apoptosis by increasing ROS in MCF-7 cancer cells and can be considered for further studies.}, } @article {pmid38438412, year = {2024}, author = {Park, WH}, title = {Propyl gallate induces cell death in human pulmonary fibroblast through increasing reactive oxygen species levels and depleting glutathione.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5375}, pmid = {38438412}, issn = {2045-2322}, mesh = {Humans ; *Propyl Gallate/pharmacology ; Antioxidants/pharmacology ; Reactive Oxygen Species ; Catalase ; Cell Death ; Fibroblasts ; Glutathione ; Buthionine Sulfoximine/pharmacology ; *Chrysanthemum ; RNA, Small Interfering/genetics ; }, abstract = {Propyl gallate (PG) exhibits an anti-growth effect on various cell types. The present study investigated the impact of PG on the levels of reactive oxygen species (ROS) and glutathione (GSH) in primary human pulmonary fibroblast (HPF) cells. Moreover, the effects of N-acetyl cysteine (NAC, an antioxidant), L-buthionine sulfoximine (BSO, a GSH synthesis inhibitor), and small interfering RNA (siRNAs) against various antioxidant genes on ROS and GSH levels and cell death were examined in PG-treated HPF cells. PG (100-800 μM) increased the levels of total ROS and O2[·-] at early time points of 30-180 min and 24 h, whereas PG (800-1600 μM) increased GSH-depleted cell number at 24 h and reduced GSH levels at 30-180 min. PG downregulated the activity of superoxide dismutase (SOD) and upregulated the activity of catalase in HPF cells. Treatment with 800 μM PG increased the number of apoptotic cells and cells that lost mitochondrial membrane potential (MMP; ΔΨm). NAC treatment attenuated HPF cell death and MMP (ΔΨm) loss induced by PG, accompanied by a decrease in GSH depletion, whereas BSO exacerbated the cell death and MMP (ΔΨm) loss without altering ROS and GSH depletion levels. Furthermore, siRNA against SOD1, SOD2, or catalase attenuated cell death in PG-treated HPF cells, whereas siRNA against GSH peroxidase enhanced cell death. In conclusion, PG induced cell death in HPF cells by increasing ROS levels and depleting GSH. NAC was found to decrease HPF cell death induced by PG, while BSO enhanced cell death. The findings shed light on how manipulating the antioxidant system influence the cytotoxic effects of PG in HPF cells.}, } @article {pmid38435146, year = {2024}, author = {Khan, S and Hughes, S and Hill, O}, title = {N-acetyl Cysteine Supplementation to Alleviate Skin Picking Disorder: A Case Report.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e53440}, pmid = {38435146}, issn = {2168-8184}, abstract = {There are body-focused repetitive behaviors, such as skin picking, trichotillomania, or nail biting, for which therapeutic interventions are available and can be tried, but unfortunately, there are no FDA-approved medications specifically for them. These disorders can cause functional impairment, disrupt activities of daily living, and be burdensome for both the patients and their loved ones. This case report will discuss an over-the-counter vitamin supplement, N-acetyl cysteine (NAC), that can be used safely but is often overlooked.}, } @article {pmid38434559, year = {2024}, author = {Zeng, H and Zou, P and Chen, Y and Zhang, P and Shao, L}, title = {NOX4 aggravates doxorubicin-induced cardiomyocyte pyroptosis by increasing reactive oxygen species content and activating the NLRP3 inflammasome.}, journal = {Cardiovascular diagnosis and therapy}, volume = {14}, number = {1}, pages = {84-100}, pmid = {38434559}, issn = {2223-3652}, abstract = {BACKGROUND: Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)-mediated reactive oxygen species (ROS) has been reported to induce cardiomyocyte apoptosis, but its effect on pyroptosis of cardiomyocytes has been rarely reported. This paper aimed to explore the effects of NOX4-mediated ROS production on doxorubicin (DOX)-induced myocardial injury and pyroptosis through nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome.

METHODS: HL-1 cells were treated with DOX or mice (30 mice were divided into five groups with six mice/group) underwent intraperitoneal injection with DOX (5 mg/kg, once a week, five times) to induce myocardial injury, followed by assessment of NOX4 and NLRP3 expression in cell supernatant and myocardial tissues. In cardiomyocyte HL-1 cells, cell proliferation was tested by MTT assay and the activity of ROS by probes. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and glutathione (GSH) activity were evaluated by kits. The expression of pyroptosis proteins was assessed by western blotting. Subsequently, the expression of NOX4 or NLRP3 was altered to determine the effect of NOX4 or NLRP3 expression on cardiomyocyte injury and pyroptosis. The animal models were utilized to evaluate the changes in the cardiac function of mice using an echocardiographic system, with these parameters measured including left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular end-diastolic diameter (LVEDD). Furthermore, the content of myocardial injury markers and the protein expression of pyroptosis proteins were determined to evaluate myocardial injury in the mice.

RESULTS: DOX treatment led to cardiomyocyte injury and pyroptosis, as evidenced by weakened LVEF, LVFS, and cell proliferation (P<0.05), elevated LVEDD, ROS, and MDA (P<0.05), increased expression of pyroptosis proteins (P<0.05), and decreased SOD and GSH (P<0.05). Additionally, NOX4 and NLRP3 were highly-expressed (P<0.05) in cell supernatant and myocardial tissues. In DOX-induced HL-1 cells, the overexpression of NOX4 intensified ROS levels to aggravate cardiomyocyte injury and pyroptosis, which was reversed by treatment of the ROS scavenger N-acetyl-cysteine. Furthermore, it was revealed that the combination of short hairpin RNA (sh)-NOX4 and overexpressed (oe)-NLRP3 reversed the cardioprotective effects of sh-NOX4 and increased myocardial tissue or cell injury and pyroptosis in vitro and in vivo. No mice died during the animal experiments, and only two were ruled out due to a weight loss greater than 20%.

CONCLUSIONS: NOX4-mediated ROS production activated NLRP3 inflammasome, thereby aggravating DOX-induced myocardial injury in vitro and in vivo.}, } @article {pmid38432679, year = {2024}, author = {Roydeva, A and Milanova, A}, title = {LC-MS/MS determination of N-acetyl-l-cysteine in chicken plasma.}, journal = {Biomedical chromatography : BMC}, volume = {38}, number = {6}, pages = {e5854}, doi = {10.1002/bmc.5854}, pmid = {38432679}, issn = {1099-0801}, support = {BG-RRP-2.004-0006-C02//Bulgarian Ministry of Education and Science (MES) in the frames of Bulgarian National Recovery and Resilience Plan, Component "Innovative Bulgaria"/ ; //Trakia University, Bulgaria/ ; }, mesh = {Animals ; *Acetylcysteine/blood ; *Chickens ; Limit of Detection ; Linear Models ; Liquid Chromatography-Mass Spectrometry ; Reproducibility of Results ; Tandem Mass Spectrometry ; }, abstract = {N-acetyl-l-cysteine (NAC) shows beneficial effects in cases of aflatoxicosis and heat stress in poultry but little is known about its pharmacokinetics in chickens. Therefore, the study aimed to develop and validate a sensitive LC-MS/MS analytical method for quantitative analysis of NAC in chicken plasma. A split calibration curve approach was used for determination of NAC in chicken plasma. Standard curves for low (0.05-2.5 μg/ml) and high (2.5-100 μg/ml) ranges of concentrations were prepared. The standard curves for low (r[2] = 0.9987) and high (r[2] = 0.9899) concentrations were linear within the tested range. The limits of detection (LOD) and of quantification (LOQ) for the standard at low concentrations were 0.093 and 0.28 μg/ml, respectively. The accuracy was from 97.35 to 101.33%. The values of LOD and LOQ for the standard at high concentrations were 0.76 and 2.30 μg/ml, respectively. The accuracy was between 99.77 and 112.14%. The intra- and inter-day precisions for all concentrations from both standards did not exceed 8.57% and 10.69%, respectively. The recovery for all concentrations was between 92.45 and 105.52%. The validated method for determination of NAC in chicken plasma can be applied in future pharmacokinetic studies in chickens without dilution of samples and their repeated analysis.}, } @article {pmid38431210, year = {2024}, author = {Stewart, GW}, title = {Pyroglutamate acidosis 2023. A review of 100 cases.}, journal = {Clinical medicine (London, England)}, volume = {24}, number = {2}, pages = {100030}, pmid = {38431210}, issn = {1473-4893}, mesh = {Humans ; *Pyrrolidonecarboxylic Acid ; *Acetaminophen/adverse effects ; *Acidosis/diagnosis/chemically induced ; Floxacillin/adverse effects/therapeutic use ; Anti-Bacterial Agents/adverse effects/therapeutic use ; }, abstract = {This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.}, } @article {pmid38422239, year = {2024}, author = {Tuncer, G and Aktas, Z and Basaran, S and Cagatay, A and Eraksoy, H}, title = {Effect of N-acetyl cysteine, rifampicin, and ozone on biofilm formation in pan-resistant Klebsiella pneumoniae: an experimental study.}, journal = {Sao Paulo medical journal = Revista paulista de medicina}, volume = {142}, number = {4}, pages = {e2023113}, pmid = {38422239}, issn = {1806-9460}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Ozone/pharmacology ; Rifampin/pharmacology ; Klebsiella pneumoniae ; Biofilms ; }, abstract = {BACKGROUND: To the best of our knowledge, this is the first study to evaluate the effectiveness of specific concentrations of antibiofilm agents, such as N-acetyl cysteine (NAC), rifampicin, and ozone, for the treatment of pan-resistant Klebsiella pneumoniae (PRKp).

OBJECTIVES: We evaluated the effectiveness of antibiofilm agents, such as NAC, rifampicin, and ozone, on biofilm formation in PRKp at 2, 6, 24, and 72 h.

DESIGN AND SETTING: This single-center experimental study was conducted on June 15, 2017, and July 15, 2018, at Istanbul Faculty of Medicine, Istanbul University, Turkey.

METHODS: Biofilm formation and the efficacy of these agents on the biofilm layer were demonstrated using colony counting and laser-screened confocal microscopy.

RESULTS: NAC at a final concentration of 2 μg/mL was administered to bacteria that formed biofilms (24 h), and no significant decrease was detected in the bacterial counts of all isolates (all P > 0.05). Rifampicin with a final concentration of 0.1 μg/mL was administered to bacteria that formed biofilm (24 h), and no significant decrease was detected in bacterial count (all P > 0.05). Notably, ozonated water of even 4.78 mg/L concentration for 72 h decreased the bacterial count by ≥ 2 log10.

CONCLUSION: Different approaches are needed for treating PRKp isolates. We demonstrate that PRKp isolates can be successfully treated with higher concentrations of ozone.}, } @article {pmid38420829, year = {2024}, author = {Liao, L and Tao, P and Xu, Q and Chen, W and Chen, J and Liu, W and Liu, W and Hu, J and Lu, J}, title = {TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {2}, pages = {58}, doi = {10.31083/j.fbl2902058}, pmid = {38420829}, issn = {2768-6698}, support = {NSFC-82074261//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Interleukin-18/metabolism/pharmacology ; Pyroptosis ; Interleukin-6/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Signal Transduction ; Inflammation ; Acetylcysteine/metabolism/pharmacology ; Superoxide Dismutase/metabolism ; Epithelial Cells/metabolism ; Glutathione Peroxidase/metabolism/pharmacology ; Ubiquitination ; Malondialdehyde/metabolism ; RNA, Messenger/metabolism ; *Tripartite Motif Proteins ; *Ubiquitin-Protein Ligases ; }, abstract = {BACKGROUND: Pyroptosis is a critical form of cell death during the development of chronic kidney disease (CKD). Tripartite motif 6 (TRIM6) is an E3-ubiquitin ligase that participates in the progression renal fibrosis (RF). The aim of this study was to investigate the roles of TRIM6 and Glutathione peroxidase 3 (GPX3) in oxidative stress-induced inflammasome activation and pyroptosis in Ang-II treated renal tubular epithelial cells.

METHODS: To study its role in RF, TRIM6 expression was either reduced or increased in human kidney-2 (HK2) cells using lentivirus, and Ang-II, NAC and BMS-986299 were served as reactive oxygen species (ROS) inducer, ROS scavenger and NLRP3 agonist respectively. Pyroptosis and mitochondrial ROS were measured by flow cytometry. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined using commercial kits, while the levels of IL-1β, IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Co-immunoprecipitation (Co-IP) assay was used to evaluate the interaction between TRIM6 and GPX3. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to measure mRNA and protein expression, respectively.

RESULTS: Treatment with Angiotensin II (Ang II) increased the protein and mRNA levels of TRIM6 in HK2 cells. Ang II also increased mitochondrial ROS production and the malondialdehyde (MDA) level, but decreased the levels of GSH and SOD. In addition, Ang II enhanced HK2 cell pyroptosis, increased the levels of IL-1β, IL-18, IL-6, and TNF-α, and promoted the expression of active IL-1β, NLRP3, caspase-1, and GSDMD-N proteins. These effects were reversed by knockdown of TRIM6 and by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. BMS-986299, an NLRP3 agonist treatment, did not affect ROS production in HK2 cells exposed to Ang II combined with NAC, but cell pyroptosis and inflammation were aggravated. Moreover, the overexpression of TRIM6 in HK2 cells resulted in similar effects to Ang II. NAC and GPX3 overexpression in HK2 cells could reverse ROS production, inflammation, and pyroptosis induced by TRIM6 overexpression. TRIM6 overexpression decreased the GPX3 protein level by promoting its ubiquitination, without affecting the GPX3 mRNA level. Thus, TRIM6 facilitates GPX3 ubiquitination, contributing to increased ROS levels and pyroptosis in HK2 cells.

CONCLUSIONS: TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF.}, } @article {pmid38420067, year = {2024}, author = {Ahmed Attari, MB and Zaman, T and Amjad, A and Khan, MH and Waqar, Z and Jabeen, S}, title = {Comparative Analysis of Outcomes in Acute Organophosphate Poisoning With and Without N-acetyl Cysteine Intervention.}, journal = {Cureus}, volume = {16}, number = {1}, pages = {e53155}, pmid = {38420067}, issn = {2168-8184}, abstract = {INTRODUCTION: Organophosphorus poisoning (OPP) stands as a significant health concern in numerous regions, especially in developing nations. Despite the rising complexities and case fatalities associated with exposure, the treatment approach has remained unchanged for many years. Based on clinical insights, certain pharmacologic agents have demonstrated utility in enhancing outcomes and reducing complications arising from this type of exposure.

OBJECTIVES: The objective of this study is to compare the outcome of N-acetyl cysteine in the treatment of acute organophosphate poisoning cases. In terms of a) its impact on the requirement of atropine, b) Length of hospital stay, and mortality.

METHODS: The study was conducted in the intensive care unit (ICU) of the General Hospital Lahore. Thirty patients with a history and clinical presentation indicative of acute organophosphorus poisoning were randomly divided into two groups in a 1:1 ratio. The treatment group received parenteral administration of atropine, pralidoxime, and N-acetylcysteine (NAC) as an adjuvant, and the control group received standard treatment for acute organophosphate (OP) toxicity.

RESULT: Throughout the study duration, 30 patients suffering acute organophosphate (OP) toxicity (14 men, 16 women) were examined, with an age mean of (25.83±11.59) years. In the interventional group, only four patients required ICU admission, but in the control group, eight patients were admitted to ICU. The correlation result between the dose of atropine and length of hospital stays was not statistically significant between both study groups (<0.005). Plasma Cholinesterase (PChE) level (KU L-1) and total dose of Pralidoxime (g) were statistically significant in the length of hospital stay. The data was not normally distributed, so the non-parametric tests were applied. The Wilcoxon ranked test showed significant improvement in both the controlled and interventional groups because the p-value was (<0.005). Intergroup comparison analyzed by using the Mann-Whitney U test showed a significant reduction in the severity and other associated symptoms in the interventional group because the p-value was (0.001).

CONCLUSION: The outcome demonstrated that the NAC group had a decreased demand for atropine rather than Pralidoxime. In the NAC group, the length of hospital stay and mortality was decreased. The administration of NAC to the present study procedure for acute organophosphate (OP) poisoning is suggested.}, } @article {pmid38417537, year = {2024}, author = {Yang, Y and Zhou, M and Huang, Y and Ye, X and Mo, Y and Huang, Y and Wang, S}, title = {LCP1-mediated cytoskeleton alterations involve in arsenite-triggered malignant phenotype of human immortalized prostate stromal cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {186}, number = {}, pages = {114548}, doi = {10.1016/j.fct.2024.114548}, pmid = {38417537}, issn = {1873-6351}, mesh = {Male ; Humans ; Cell Line ; Prostate ; Reactive Oxygen Species ; *Arsenic ; *Arsenites/toxicity ; Stromal Cells ; *Prostatic Neoplasms ; Phenotype ; Cytoskeleton ; Tumor Microenvironment ; Microfilament Proteins ; HMGB Proteins ; }, abstract = {The connection between continuous arsenic exposure and prostate cancer is already established. However, the exact mechanisms of arsenic tumorigenesis are far from clear. Here, we employed human prostate stromal immortalized cells (WPMY-1) continuous exposure to 1 and 2 μM arsenite for 29 weeks to identify the malignant phenotype and explore the underlying molecular mechanism. As expected, continuous low-dose arsenite exposure led to the malignant phenotype of WPMY-1 cells. Quantitative proteomics identified 517 differentially expressed proteins (DEPs), of which the most remarkably changed proteins (such as LCP1 and DDX58, etc.) and the bioinformatic analysis were focused on the regulation of cytoskeleton, cell adhesion, and migration. Further, cell experiments showed that continuous arsenite exposure altered cytoskeleton structure, enhanced cell adhesive capability, and raised the levels of reactive oxygen species (ROS), ATM, p-ATM, p-ERK1/2, and LCP1 proteins. N-acetylcysteine (NAC) treatment antagonized the increase of LCP1 proteins, and LCP1 knockdown partially restored F-actin organization caused by arsenic. Overall, the results demonstrated that ROS-ATM-ERK1/2 signaling pathway was involved in the activation of LCP1, leading to cytoskeleton alterations. These alterations are believed to play a significant role in arsenite-triggered tumor microenvironment cell-acquired malignant phenotype, which could provide potential biomarkers with therapeutic implications for prostate cancer.}, } @article {pmid38414064, year = {2024}, author = {Smabers, LP and Wensink, E and Verissimo, CS and Koedoot, E and Pitsa, KC and Huismans, MA and Higuera Barón, C and Doorn, M and Valkenburg-van Iersel, LB and Cirkel, GA and Brousali, A and Overmeer, R and Koopman, M and Braat, MN and Penning de Vries, B and Elias, SG and Vries, RG and Kranenburg, O and Boj, SF and Roodhart, JM}, title = {Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.}, journal = {Journal of experimental & clinical cancer research : CR}, volume = {43}, number = {1}, pages = {61}, pmid = {38414064}, issn = {1756-9966}, mesh = {Humans ; Irinotecan/pharmacology/therapeutic use ; Oxaliplatin/pharmacology/therapeutic use ; *Colorectal Neoplasms/drug therapy/genetics ; Acetylcysteine/therapeutic use ; Precision Medicine ; Fluorouracil/pharmacology/therapeutic use ; *Colonic Neoplasms/drug therapy ; Organoids ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; }, abstract = {BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies.

METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness.

RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003).

CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.}, } @article {pmid38408632, year = {2024}, author = {Guan, S and Qu, X and Wang, J and Zhang, D and Lu, J}, title = {3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {186}, number = {}, pages = {114525}, doi = {10.1016/j.fct.2024.114525}, pmid = {38408632}, issn = {1873-6351}, mesh = {Humans ; *alpha-Chlorohydrin/toxicity/*analogs & derivatives ; Reactive Oxygen Species/metabolism ; Necroptosis ; Esters/toxicity ; Hep G2 Cells ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; }, abstract = {3-monochloropropane-1,2-diol esters (3-MCPDE) are toxic substances that form in food thermal processing and have a diverse range of toxicities. In this study, we found that 3-MCPDE triggered necroptosis by RIPK1/RIPK3/MLKL pathway in HepG2 cells. Previous studies have shown that ROS is an important activator of RIPK1 and RIPK3. The data showed that 3-MCPDE induced excessive ROS production through mitochondrial damage. After treatment with ROS inhibitor N-acetylcysteine (NAC), 3-MCPDE-induced necroptosis was relieved. Further, we explored how 3-MCPDE destroys mitochondria. The data suggested that 3-MCPDE induced mitochondrial dysfunction through the CTSB/TFAM pathway. Overall, the results indicated that 3-MCPDE induced necroptosis through CTSB/TFAM/ROS pathway in HepG2 cells. Our study provided a new mechanism for 3-MCPDE hepatotoxicity.}, } @article {pmid38408264, year = {2024}, author = {Doumi, I and Lang, L and Vileno, B and Deponte, M and Faller, P}, title = {Glutathione Protects other Cellular Thiols against Oxidation by Cu[II]-Dp44mT.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {21}, pages = {e202304212}, doi = {10.1002/chem.202304212}, pmid = {38408264}, issn = {1521-3765}, support = {ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ITI-CSC-PFA-22//ITI LabEx Chimie des Systèmes Complexes/ ; DE 1431/20-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Copper/metabolism ; Sulfhydryl Compounds ; Oxidation-Reduction ; *Thiosemicarbazones ; Glutathione/metabolism ; Penicillamine/metabolism ; Acetylcysteine/metabolism ; }, abstract = {Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)-di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (Cu[II]-Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of Cu[II]-Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, Cu[II]-Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of Cu[II]-Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L-cysteine (Cys), N-acetylcysteine (NAC), D-penicillamine (D-Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. Cu[II]-Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D-Pen>Cys≫NAC>GSH and Trx>Grx. Cu[II]-Dp44mT was more efficient than Cu[II] chloride for the oxidation of NAC and GSH, but not D-Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with Cu[II]-Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by Cu[II]-Dp44mT.}, } @article {pmid38407768, year = {2024}, author = {Jimenez-Chavez, A and Pedroza-Herrera, G and Betancourt-Reyes, I and De Vizcaya Ruiz, A and Masuoka-Ito, D and Zapien, JA and Medina-Ramirez, IE}, title = {Aluminum enhances the oxidative damage of ZnO NMs in the human neuroblastoma SH-SY5Y cell line.}, journal = {Discover nano}, volume = {19}, number = {1}, pages = {36}, pmid = {38407768}, issn = {2731-9229}, support = {Fordecyt-Pronaces/568494/2020 and C-104/2021//CONAHCYT/ ; }, abstract = {Bare and doped zinc oxide nanomaterials (ZnO NMs) are of great interest as multifunctional platforms for biomedical applications. In this study, we systematically investigate the physicochemical properties of Aluminum doped ZnO (AZO) and its bio-interactions with neuroblastoma (SH-SY5Y) and red blood (RBCs) cells. We provide a comprehensive chemical and structural characterization of the NMs. We also evaluated the biocompatibility of AZO NMs using traditional toxicity assays and advanced microscopy techniques. The toxicity of AZO NMs towards SH-SY5Y cells, decreases as a function of Al doping but is higher than the toxicity of ZnO NMs. Our results show that N-acetyl cysteine protects SH-SY5Y cells against reactive oxygen species toxicity induced by AZO NMs. ZnO and AZO NMs do not exert hemolysis in human RBCs at the doses that cause toxicity (IC50) in neuroblastoma cells. The Atomic force microscopy qualitative analysis of the interaction of SH-SY5Y cells with AZO NMs shows evidence that the affinity of the materials with the cells results in morphology changes and diminished interactions between neighboring cells. The holotomographic microscopy analysis demonstrates NMs' internalization in SH-SY5Y cells, changes in their chemical composition, and the role of lipid droplets in the clearance of toxicants.}, } @article {pmid38405665, year = {2024}, author = {Abdallah, R and Shaito, AA and Badran, A and Baydoun, S and Sobeh, M and Ouchari, W and Sahri, N and Eid, AH and Mesmar, JE and Baydoun, E}, title = {Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1331843}, pmid = {38405665}, issn = {1663-9812}, abstract = {Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z. nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers.}, } @article {pmid38399445, year = {2024}, author = {Lu, HI and Chen, KL and Yen, CY and Chen, CY and Chien, TM and Shu, CW and Chen, YH and Jeng, JH and Chen, BH and Chang, HW}, title = {Michelia compressa-Derived Santamarine Inhibits Oral Cancer Cell Proliferation via Oxidative Stress-Mediated Apoptosis and DNA Damage.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399445}, issn = {1424-8247}, support = {MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 112-P06//National Sun Yat-sen University-KMU Joint Research Project/ ; 111CM-KMU-05, 112CM-KMU-05//Chimei-KMU jointed project/ ; KMU-DK(A)112008//Kaohsiung Medical University/ ; KMU-TC112A04//Kaohsiung Medical University Research Center/ ; }, abstract = {The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow-Glickman; S-G) cells. SAMA selectively inhibits oral cancer cell viability more than normal cells, reverted by the oxidative stress remover N-acetylcysteine (NAC). The evidence of oxidative stress generation, such as the induction of reactive oxygen species (ROS) and mitochondrial superoxide and the depletion of mitochondrial membrane potential and glutathione, further supports this ROS-dependent selective antiproliferation. SAMA arrests oral cancer cells at the G2/M phase. SAMA triggers apoptosis (annexin V) in oral cancer cells and activates caspases 3, 8, and 9. SAMA enhances two types of DNA damage in oral cancer cells, such as γH2AX and 8-hydroxy-2-deoxyguanosine. Moreover, all of these anticancer mechanisms of SAMA are more highly expressed in oral cancer cells than in normal cells in concentration and time course experiments. These above changes are attenuated by NAC, suggesting that SAMA exerts mechanisms of selective antiproliferation that depend on oxidative stress while maintaining minimal cytotoxicity to normal cells.}, } @article {pmid38397782, year = {2024}, author = {Tuell, D and Ford, G and Los, E and Stone, W}, title = {The Role of Glutathione and Its Precursors in Type 2 Diabetes.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {38397782}, issn = {2076-3921}, support = {C06RR0306551/NH/NIH HHS/United States ; }, abstract = {Type 2 diabetes (T2D) is a major worldwide health crisis affecting about 6.2% of the world's population. Alarmingly, about one in five children in the USA have prediabetes. Glutathione (GSH) and its precursors play a promising role in the prevention and management of type T2D. Oxidative stress (OxS) is a probable factor in both T2D initiation and progression. GSH is the major cytosolic water-soluble chemical antioxidant and emerging evidence supports its role in improving T2D outcomes. Dietary supplementation with N-acetyl-cysteine (NAC) and/or glycine (GLY), which are GSH precursors, has also been studied for possible beneficial effects on T2D. This review will focus on the underlying pathophysiological and molecular mechanisms linking GSH and its precursors with T2D and OxS. In addition to their traditional antioxidant roles, the in vivo effects of GSH/NAC/GLY supplements will be evaluated for their potential abilities to modulate the complex pro-oxidant pathophysiological factors (e.g., hyperglycemia) driving T2D progression. Positive feedback loops that amplify OxS over long time intervals are likely to result in irreversible T2D micro- and macro-vascular damage. Most clinical studies with GSH/NAC/GLY have focused on adults or the elderly. Future research with pediatric populations should be a high priority since early intervention is critical.}, } @article {pmid38397769, year = {2024}, author = {Khan, S and Wang, T and Cobo, ER and Liang, B and Khan, MA and Xu, M and Qu, W and Gao, J and Barkema, HW and Kastelic, JP and Liu, G and Han, B}, title = {Antioxidative Sirt1 and the Keap1-Nrf2 Signaling Pathway Impair Inflammation and Positively Regulate Autophagy in Murine Mammary Epithelial Cells or Mammary Glands Infected with Streptococcus uberis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {38397769}, issn = {2076-3921}, support = {32172928//National Natural Science Foundation of China/ ; 31772813//National Natural Science Foundation of China/ ; G2022108009L//High-end Foreign Experts Recruitment Program/ ; 2019BBF02027//Ningxia Key Development Programs/ ; 6222031//Beijing Natural Science Foundation/ ; }, abstract = {Streptococcus uberis mastitis in cattle infects mammary epithelial cells. Although oxidative responses often remove intracellular microbes, S. uberis survives, but the mechanisms are not well understood. Herein, we aimed to elucidate antioxidative mechanisms during pathogenesis of S. uberis after isolation from clinical bovine mastitis milk samples. S. uberis's in vitro pathomorphology, oxidative stress biological activities, transcription of antioxidative factors, inflammatory response cytokines, autophagosome and autophagy functions were evaluated, and in vivo S. uberis was injected into the fourth mammary gland nipple of each mouse to assess the infectiousness of S. uberis potential molecular mechanisms. The results showed that infection with S. uberis induced early oxidative stress and increased reactive oxygen species (ROS). However, over time, ROS concentrations decreased due to increased antioxidative activity, including total superoxide dismutase (T-SOD) and malondialdehyde (MDA) enzymes, plus transcription of antioxidative factors (Sirt1, Keap1, Nrf2, HO-1). Treatment with a ROS scavenger (N-acetyl cysteine, NAC) before infection with S. uberis reduced antioxidative responses and the inflammatory response, including the cytokines IL-6 and TNF-α, and the formation of the Atg5-LC3II/LC3I autophagosome. Synthesis of antioxidants determined autophagy functions, with Sirt1/Nrf2 activating autophagy in the presence of S. uberis. This study demonstrated the evasive mechanisms of S. uberis in mastitis, including suppressing inflammatory and ROS defenses by stimulating antioxidative pathways.}, } @article {pmid38396357, year = {2024}, author = {Kamel, AA and Nassar, AY and Meligy, FY and Omar, YA and Nassar, GAY and Ezzat, GM}, title = {Acetylated oligopeptide and N-acetylcysteine protect against iron overload-induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO-1 and downregulation of MMP-9/TIMP-1 and GFAP.}, journal = {Cell biochemistry and function}, volume = {42}, number = {2}, pages = {e3958}, doi = {10.1002/cbf.3958}, pmid = {38396357}, issn = {1099-0844}, mesh = {Animals ; Male ; Rats ; *Acetylcysteine/pharmacology/metabolism ; Caspases/metabolism ; Claudins/genetics ; Dentate Gyrus/metabolism/pathology ; Dextrans/metabolism/pharmacology ; Down-Regulation ; Glutathione/metabolism ; Hippocampus/metabolism/pathology ; Iron/metabolism/pharmacology ; *Iron Overload/complications/drug therapy ; Matrix Metalloproteinase 9/genetics/metabolism/pharmacology ; Nestin/genetics/metabolism/pharmacology ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism/pharmacology ; Up-Regulation ; *Oligopeptides/pharmacology ; Heme Oxygenase-1/drug effects ; Glial Fibrillary Acidic Protein/drug effects/metabolism ; }, abstract = {Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.}, } @article {pmid38392216, year = {2024}, author = {Shih, LJ and Hsu, PC and Chuu, CP and Shui, HA and Yeh, CC and Chen, YC and Kao, YH}, title = {Epigallocatechin-3-gallate Synergistically Enhanced Arecoline-Induced Cytotoxicity by Redirecting Cycle Arrest to Apoptosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {2}, pages = {1516-1529}, pmid = {38392216}, issn = {1467-3045}, support = {MOST106-2320-B-008-008-MY3, MOST109-2320-B-008-001-MY3//National Science and Technology Council/ ; 11001-62-021, TPCH-110-05//Taipei City Hospital; Department of Health, Taipei City Government/ ; TYAFGH-E-111053, TYAFGH-E-112050//Taoyuan Armed Forces General Hospital/ ; MND-MAB-110-025, MND-MAB-C-11107-111026//National Defense Medical Center/ ; }, abstract = {Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.}, } @article {pmid38390944, year = {2024}, author = {Alvarez, IA and Lee, M and Eshaq, RS and Leskova, W and Harris, NR}, title = {High Glucose Induces Oxidative Stress That Alters Glycocalyx Proteoglycan Levels in Primary Rat Retinal Microvascular Endothelial Cells and in Isolated Ophthalmic Arteries.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {1}, pages = {89-99}, pmid = {38390944}, issn = {1873-149X}, support = {R01 EY025632/EY/NEI NIH HHS/United States ; NEI EY025632/NH/NIH HHS/United States ; }, abstract = {Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx.}, } @article {pmid38385491, year = {2024}, author = {Zhao, X and Shan, G and Xing, D and Gao, H and Xiong, Z and Hui, W and Gong, M}, title = {UBE2L3 Promotes Oxidative Stress-regulated Necroptosis to Accelerate Osteosarcoma Progression.}, journal = {Recent patents on anti-cancer drug discovery}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115748928297557240212112531}, pmid = {38385491}, issn = {2212-3970}, abstract = {BACKGROUND: Osteosarcoma is a highly invasive bone marrow stromal tumor with limited treatment options. Oxidative stress plays a crucial role in the development and progression of tumors, but the underlying regulatory mechanisms are not fully understood. Recent studies have revealed the significant involvement of UBE2L3 in oxidative stress, but its specific role in osteosarcoma remains poorly investigated.

OBJECTIVE: This study aimed to explore the molecular mechanisms by which UBE2L3 promotes oxidative stress-regulated necroptosis to accelerate the progression of osteosarcoma using in vitro cell experiments.

METHODS: Human osteoblast hFOB1.19 cells and various human osteosarcoma cell lines (MG-63, U2OS, SJSA-1, HOS, and 143B) were cultured in vitro. Plasmids silencing UBE2L3 and negative control plasmids were transfected into U2OS and HOS cells. The cells were divided into the following groups: U2OS cell group, HOS cell group, si-NC-U2OS cell group, si-UBE2L3-U2OS cell group, si-NC-HOS cell group, and si-UBE2L3-HOS cell group. Cell viability and proliferation capacity were measured using the Tunnel method and clonogenic assay. Cell migration and invasion abilities were assessed by Transwell and scratch assays. Cell apoptosis was analyzed by flow cytometry, and ROS levels were detected using immunofluorescence. The oxidative stress levels in various cell groups and the expression changes of necroptosis-related proteins were assessed by PCR and WB. Through these experiments, we aim to evaluate the impact of oxidative stress on necroptosis and uncover the specific mechanisms by which targeted regulation of oxidative stress promotes tumor cell necroptosis as a potential therapeutic strategy for osteosarcoma.

RESULTS: The mRNA expression levels of UBE2L3 in human osteosarcoma cell lines were significantly higher than those in human osteoblast hFOB1.19 cells (p <0.01). UBE2L3 expression was significantly decreased in U2OS and HOS cells transfected with si-UBE2L3, indicating the successful construction of stable cell lines with depleted UBE2L3. Tunnel assay results showed a significant increase in the number of red fluorescent-labeled cells in si-UBE2L3 groups compared to si-NC groups in both cell lines, suggesting a pronounced inhibition of cell viability. Transwell assay demonstrated a significant reduction in invasion and migration capabilities of si-UBE2L3 groups in osteosarcoma cells. The clonogenic assay revealed significant suppression of proliferation and clonogenic ability in both U2OS and HOS cells upon UBE2L3 knockdown. Flow cytometry confirmed that UBE2L3 knockdown significantly enhanced apoptosis in U2OS and HOS cells. Immunofluorescence results showed that UBE2L3 silencing promoted oxidative stress levels in osteosarcoma cells and facilitated tumor cell death. WB analysis indicated a significant increase in phosphorylation levels of necroptosis-related proteins, RIP1, RIP3, and MLKL, in both osteosarcoma cell lines after UBE2L3 knockdown. In addition, the expression of necrosis-associated proteins was inhibited by the addition of the antioxidant N-acetylcysteine (NAC).

CONCLUSION: UBE2L3 is upregulated in osteosarcoma cells, and silencing of UBE2L3 promotes oxidative stress in these cells, leading to enhanced necroptosis and delayed progression of osteosarcoma.}, } @article {pmid38381146, year = {2024}, author = {Rasouli, H and Razavi, BM and Ghasemzadeh Rahbardar, M and Sadeghian, H and Tabatabaee Yazdi, SA and Hosseinzadeh, H}, title = {Hepatoprotective effect of amifostine and WR-1065 on acetaminophen-induced liver toxicity on Wistar rats.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {8}, pages = {6001-6015}, pmid = {38381146}, issn = {1432-1912}, support = {910351//Pharmaceutical Research Center and the Vice-Chancellor of Research, Mashhad University of Medical Sciences/ ; }, mesh = {Animals ; *Acetaminophen/toxicity ; *Amifostine/pharmacology ; *Chemical and Drug Induced Liver Injury/prevention & control/pathology/metabolism/drug therapy ; *Rats, Wistar ; Male ; *Liver/drug effects/metabolism/pathology ; Mercaptoethylamines/pharmacology ; Acetylcysteine/pharmacology ; Rats ; Antioxidants/pharmacology ; Analgesics, Non-Narcotic/toxicity ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Protective Agents/pharmacology/therapeutic use ; }, abstract = {PURPOSE: The most important problem with acetaminophen is its hepatotoxicity. N-acetylcysteine (NAC) is used to treat the hepatotoxicity of acetaminophen. Due to the structural similarities of this compound with amifostine, we decided to test the effect of this substance and its metabolite, WR-1065, on the hepatotoxicity of acetaminophen.

METHODS: The single-dose method contained 1. Control; 2. Acetaminophen (1 g/kg, gavage); 3-5. Acetaminophen + amifostine (100, 200, 400 mg/kg, i.p.); 6-8. Acetaminophen + WR-1065 (50, 100, 200 mg/kg, i.p.); and 9. Acetaminophen + NAC (100, 200 mg/kg, i.p.). The multiple-dose method included the same groups: amifostine (50, 100, 200 mg/kg), WR-1065 (25, 50, 100 mg/kg), and NAC (100 mg/kg). Then, animals were sacrificed, and blood samples were collected for measuring ALT, AST, ALP, and T-Bil, liver tissue for histopathological examination, MDA, and GSH amounts.

RESULTS: Acetaminophen increased the levels of MDA, T-Bil, ALT, AST, and ALP, decreased GSH levels, and augmented necrosis, neutrophils, lymphocytes, and macrophages in the port space in single-dose and multiple-dose studies. Amifostine and WR-1065 significantly reduced the levels of MDA, T-Bil, ALT, AST, ALP, increased GSH content, and ameliorated histopathological alterations in a single-dose and multiple-dose method compared to the acetaminophen group. Moreover, NAC caused a significant decrease in the levels of MDA, T-Bil, ALT, AST, and ALP, and reduced GSH amounts in single-dose and multiple-dose studies.

CONCLUSION: Amifostine and WR-1065 as antioxidant and hepatoprotective compounds are effective in reducing acetaminophen-induced hepatotoxicity with a similar effect to NAC and can be administered as an adjunct in the treatment of acetaminophen overdose.}, } @article {pmid38379848, year = {2024}, author = {Lee, KI and Fang, KM and Kuo, CY and Huang, CF and Liu, SH and Liu, JM and Lai, WC and Chang, KC and Su, CC and Chen, YW}, title = {Roles of oxidative stress/JNK/ERK signals in paraquat-triggered hepatic apoptosis.}, journal = {Current research in toxicology}, volume = {6}, number = {}, pages = {100155}, pmid = {38379848}, issn = {2666-027X}, abstract = {Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome c release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant N-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.}, } @article {pmid38376812, year = {2024}, author = {Radan, M and Abol Nejadian, F and Bayati, V and Hemmati, AA and Hoseinynejad, K and Mard, SA}, title = {N-acetyl cysteine augments adipose tissue-derived stem cell efficacy on inflammatory markers and regulatory T cell system balance in an allergic asthma model.}, journal = {The Journal of asthma : official journal of the Association for the Care of Asthma}, volume = {61}, number = {9}, pages = {1029-1041}, doi = {10.1080/02770903.2024.2321296}, pmid = {38376812}, issn = {1532-4303}, mesh = {Animals ; *Acetylcysteine/pharmacology/administration & dosage ; *Asthma/drug therapy/immunology/therapy ; *T-Lymphocytes, Regulatory/immunology/drug effects ; *Rats, Sprague-Dawley ; Rats ; *Adipose Tissue/cytology ; Disease Models, Animal ; Bronchoalveolar Lavage Fluid/cytology/immunology ; Male ; Cytokines/metabolism ; Lung/immunology/pathology ; Immunoglobulin E/blood ; }, abstract = {BACKGROUND: Allergic asthma is a destructive inflammatory process in the respiratory system. The anti-inflammatory and antioxidant effects of N-acetylcysteine (NAC) have been reported in patients with obstructive pulmonary disease. On the other hand, several studies have shown the modulatory effects of mesenchymal stem cells on the immune system and inflammatory responses. Accordingly, the purpose of the current study was to evaluate the effect of administration of adipose tissue-derived stem cells (ADSCs) plus NAC on regulatory T cell system balance in an allergic asthma model.

METHODS: Eighty Sprague- Dawley rats were randomly divided into the following groups: Control, Plasmalite, Allergic asthma, Allergic asthma + ADSCs, NAC, Allergic asthma + NAC, Allergic asthma + ADSCs + NAC and Allergic asthma + Prednisolone. at the end of the experiment, arterial blood gas analysis, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokine concentration, total IgE and specific OVA-IgE levels, gene expression levels of CD4+-T cell subsets, pulmonary indicators, edema, and lung histopathology were evaluated in all groups.

RESULTS: Administration of NAC plus ADSCs demonstrated a significant decrease in total WBC and eosinophil counts, which was in line with remarkable decrease in IL-17 and TNF-α concentrations and increases in IL-10 level compared with other treated groups. NAC plus ADSC treatment showed significant increases in Treg gene expression, although Th17 and Th2 expression significantly decreased compared with that in prednisolone- treated rats.

CONCLUSION: The results of the present study documented that the administration of ADSCs plus NAC has an inhibitory effect on the inflammation caused by allergic asthma in a rat model. The improvement of inflammatory indexes was significantly higher than that with prednisolone treatment.}, } @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.}, } @article {pmid38373369, year = {2024}, author = {Yuce, M and Yildirim, E and Ekinci, M and Turan, M and Ilhan, E and Aydin, M and Agar, G and Ucar, S}, title = {N-acetyl-cysteine mitigates arsenic stress in lettuce: Molecular, biochemical, and physiological perspective.}, journal = {Plant physiology and biochemistry : PPB}, volume = {207}, number = {}, pages = {108390}, doi = {10.1016/j.plaphy.2024.108390}, pmid = {38373369}, issn = {1873-2690}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Arsenic/toxicity ; Lactuca ; Hydrogen Peroxide/metabolism ; Antioxidants/metabolism ; Soil ; }, abstract = {Agricultural land contaminated with heavy metals such as non-biodegradable arsenic (As) has become a serious global problem as it adversely affects agricultural productivity, food security and human health. Therefore, in this study, we investigated how the administration of N-acetyl-cysteine (NAC), regulates the physio-biochemical and gene expression level to reduce As toxicity in lettuce. According to our results, different NAC levels (125, 250 and 500 μM) significantly alleviated the growth inhibition and toxicity induced by As stress (20 mg/L). Shoot fresh weight, root fresh weight, shoot dry weight and root dry weight (33.05%, 55.34%, 17.97% and 46.20%, respectively) were decreased in plants grown in As-contaminated soils compared to lettuce plants grown in soils without the addition of As. However, NAC applications together with As stress increased these growth parameters. While the highest increase in shoot fresh and dry weight (58.31% and 37.85%, respectively) was observed in 250 μM NAC application, the highest increase in root fresh and dry weight (75.97% and 63.07%, respectively) was observed in 125 μM NAC application in plants grown in As-polluted soils. NAC application decreased the amount of ROS, MDA and H2O2 that increased with As stress, and decreased oxidative damage by regulating hormone levels, antioxidant and enzymes involved in nitrogen metabolism. According to gene expression profiles, LsHIPP28 and LsABC3 genes have shown important roles in reducing As toxicity in leaves. This study will provide insight for future studies on how NAC applications develop resistance to As stress in lettuce.}, } @article {pmid38369618, year = {2024}, author = {Sun, C and Zhang, M and Guan, C and Li, W and Peng, Y and Zheng, J}, title = {In vitro and in vivo metabolic activation and hepatotoxicity of chlorzoxazone mediated by CYP3A.}, journal = {Archives of toxicology}, volume = {98}, number = {4}, pages = {1095-1110}, pmid = {38369618}, issn = {1432-0738}, mesh = {Humans ; Rats ; Animals ; *Chlorzoxazone ; Cytochrome P-450 CYP3A/metabolism ; Activation, Metabolic ; Rats, Sprague-Dawley ; Microsomes, Liver/metabolism ; *Chemical and Drug Induced Liver Injury/etiology/metabolism ; Epoxy Compounds/metabolism ; Glutathione/metabolism ; }, abstract = {Chlorzoxazone (CZX), a benzoxazolone derivative, has been approved for the treatment of musculoskeletal disorders to relieve localized muscle spasm. However, its idiosyncratic toxicity reported in patients brought attention, particularly for hepatotoxicity. The present study for the first time aimed at the relationship between CZX-induced hepatotoxicity and identification of oxirane intermediate resulting from metabolic activation of CZX. Two N-acetylcysteine (NAC) conjugates (namely M1 and M2) and two glutathione (GSH) conjugates (namely M3 and M4) were detected in rat & human microsomal incubations with CZX (200 μM) fortified with NAC or GSH, respectively. The formation of M1-M4 was NADPH-dependent and these metabolites were also observed in urine or bile of SD rats given CZX intragastrically at 10 mg/kg or 25 mg/kg. NAC was found to attach at C-6' of the benzo group of M1 by sufficient NMR data. CYPs3A4 and 3A5 dominated the metabolic activation of CZX. The two GSH conjugates were also observed in cultured rat primary hepatocytes after exposure to CZX. Inhibition of CYP3A attenuated the susceptibility of hepatocytes to the cytotoxicity of CZX (10-400 μM). The in vitro and in vivo studies provided solid evidence for the formation of oxirane intermediate of CZX. This would facilitate the understanding of the underlying mechanisms of toxic action of CZX.}, } @article {pmid38369538, year = {2024}, author = {Wu, T and Liu, W and Chen, H and Hou, L and Ren, W and Zhang, L and Hu, J and Chen, H and Chen, C}, title = {Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {4008}, pmid = {38369538}, issn = {2045-2322}, support = {2023M731448//China Postdoctoral Science Foundation/ ; 2023M731011//China Postdoctoral Science Foundation/ ; 82203878//National Science Foundation of China/ ; U2102203//National Science Foundation of China/ ; 2023J01385//the Natural Science Foundation of Fujian Province/ ; 2020YFA0112300//National Key R&D Program of China/ ; 202302AA310046//Biomedical Projects of Yunnan Key Science and Technology Program/ ; 202101AS070050//Yunnan Fundamental Research Projects/ ; YSZJGZZ-2020025//Yunnan (Kunming) Academician Expert Workstation/ ; }, mesh = {Humans ; *Triple Negative Breast Neoplasms/genetics ; Reactive Oxygen Species/metabolism ; Cell Proliferation ; Cell Line, Tumor ; Apoptosis ; DNA Damage ; *Pyrimidinones ; *Triazines ; }, abstract = {Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.}, } @article {pmid38363806, year = {2024}, author = {Wu, T and Zhang, H and Zhang, P and James, TD and Sun, X}, title = {A Rationally Designed Prodrug for the Fluorogenic Labeling of Albumin and Theranostic Effects on Drug-Induced Liver Injury.}, journal = {Analytical chemistry}, volume = {96}, number = {8}, pages = {3498-3507}, doi = {10.1021/acs.analchem.3c05272}, pmid = {38363806}, issn = {1520-6882}, mesh = {Humans ; Antioxidants/pharmacology ; *Prodrugs/pharmacology/chemistry ; Precision Medicine ; Serum Albumin/chemistry ; Acetylcysteine ; Serum Albumin, Human ; *Chemical and Drug Induced Liver Injury ; }, abstract = {The development of small-molecular fluorogenic tools for the chemo-selective labeling of proteins in live cells is important for the evaluation of intracellular redox homeostasis. Dynamic imaging of human serum albumin (HSA), an antioxidant protein under oxidative stress with concomitant release of antioxidant drugs to maintain redox homeostasis, affords potential opportunities for disease diagnosis and treatment. In this work, we developed a nonfluorogenic prodrug named TPA-NAC, by introducing N-acetyl-l-cysteine (NAC) into a conjugated acceptor skeleton. Through combined thiol and amino addition, coupling with HSA results in fluorescence turn-on and drug release. It was reasoned that the restricted intramolecular motion of the probe under an HSA microenvironment after covalent bonding inhibited the nonradiative transitions. Furthermore, the biocompatibility and photochemical properties of TPA-NAC enabled it to image exogenous and endogenous HSA in living cells in a wash-free manner. Additionally, the released drug evoked upregulation of superoxide dismutase (SOD), which synergistically eliminated reactive oxygen species in a drug-induced liver injury model. This study provides insights into the design of new theranostic fluorescent prodrugs for chemo-selective protein labeling and disease treatments.}, } @article {pmid38363133, year = {2024}, author = {Guzman, RM and Savolainen, NG and Hayden, OM and Lee, M and Osbron, CA and Liu, Z and Yang, H and Shaw, DK and Omsland, A and Goodman, AG}, title = {Drosophila melanogaster Sting mediates Coxiella burnetii infection by reducing accumulation of reactive oxygen species.}, journal = {Infection and immunity}, volume = {92}, number = {3}, pages = {e0056022}, pmid = {38363133}, issn = {1098-5522}, support = {R01 AI139051/AI/NIAID NIH HHS/United States ; R01 AI162819/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Coxiella burnetii ; Drosophila melanogaster/genetics/metabolism ; NF-kappa B/metabolism ; *Q Fever/microbiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The Gram-negative bacterium Coxiella burnetii is the causative agent of query fever in humans and coxiellosis in livestock. C. burnetii infects a variety of cell types, tissues, and animal species including mammals and arthropods, but there is much left to be understood about the molecular mechanisms at play during infection in distinct species. Human stimulator of interferon genes (STING) induces an innate immune response through the induction of type I interferons (IFNs), and IFN promotes or suppresses C. burnetii replication, depending on tissue type. Drosophila melanogaster contains a functional STING ortholog (Sting) which activates NF-κB signaling and autophagy. Here, we sought to address the role of D. melanogaster Sting during C. burnetii infection to uncover how Sting regulates C. burnetii infection in flies. We show that Sting-null flies exhibit higher mortality and reduced induction of antimicrobial peptides following C. burnetii infection compared to control flies. Additionally, Sting-null flies induce lower levels of oxidative stress genes during infection, but the provision of N-acetyl-cysteine (NAC) in food rescues Sting-null host survival. Lastly, we find that reactive oxygen species levels during C. burnetii infection are higher in Drosophila S2 cells knocked down for Sting compared to control cells. Our results show that at the host level, NAC provides protection against C. burnetii infection in the absence of Sting, thus establishing a role for Sting in protection against oxidative stress during C. burnetii infection.}, } @article {pmid38361325, year = {2024}, author = {Angeli, SI and Brown, CS and Holcomb, MA and Velandia, SL and Eshraghi, AA and Chiossone-Kerdel, JA and Hoffer, ME and Sanchez, C and Telischi, FF}, title = {Functional Hearing Preservation in Cochlear Implantation: The Miami Cocktail Effect.}, journal = {Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology}, volume = {45}, number = {4}, pages = {376-385}, doi = {10.1097/MAO.0000000000004134}, pmid = {38361325}, issn = {1537-4505}, mesh = {Adult ; Humans ; Child ; *Cochlear Implantation/methods ; Case-Control Studies ; Prednisone ; Acetylcysteine ; Retrospective Studies ; Auditory Threshold ; Audiometry, Pure-Tone ; Hearing ; *Cochlear Implants ; Treatment Outcome ; }, abstract = {OBJECTIVE: To investigate if pharmacological treatment with prednisone and L-N-acetylcysteine (STE + NAC) influence functional hearing preservation in cochlear implant (CI) surgery.

STUDY DESIGNS: Preimplantation and postimplantation longitudinal case-control study.

SETTING: Tertiary referral center.

PATIENTS: Pediatric and adult recipients of CI with preimplantation functional hearing defined as an average of air-conducted thresholds at 125, 250, and 500 Hz (low-frequency pure-tone average [LFPTA]) <80 dB.

INTERVENTIONS: Preimplantation and postimplantation audiometry. Weight-adjusted oral prednisone and L-N-acetylcysteine starting 2 days before surgery (Miami cocktail). Prednisone was continued for 3 days and L-N-acetylcysteine for 12 days after surgery, respectively. Cochlear implantation with conventional length electrodes.

MAIN OUTCOME MEASURES: Proportion of patients with LFPTA <80 dB, and LFPTA change at 1-year postimplantation.

RESULTS: All 61 patients received intratympanic and intravenous dexamethasone intraoperatively, with 41 patients receiving STE + NAC and 20 patients not receiving STE + NAC. At 1-year postimplantation, the proportion of functional hearing preservation was 83% in the STE + NAC group compared with 55% of subjects who did not receive STE + NAC (p = 0.0302). The median LFPTA change for STE + NAC-treated and not treated subjects was 8.33 dB (mean, 13.82 ± 17.4 dB) and 18.34 dB (mean, 26.5 ± 23.4 dB), respectively (p = 0.0401, Wilcoxon rank test). Perioperative STE + NAC treatment resulted in 10 dB of LFPTA better hearing than when not receiving this treatment. Better low-frequency preimplantation hearing thresholds were predictive of postimplantation functional hearing. No serious side effects were reported.

CONCLUSION: Perioperative STE + NAC, "The Miami Cocktail," was safe and superior to intraoperative steroids alone in functional hearing preservation 1-year after cochlear implantation.}, } @article {pmid38359293, year = {2024}, author = {Noch, EK and Palma, L and Yim, I and Bullen, N and Barnett, D and Walsh, A and Bhinder, B and Benedetti, E and Krumsiek, J and Gurvitch, J and Khwaja, S and Atlas, D and Elemento, O and Cantley, LC}, title = {Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {8}, pages = {e2317343121}, pmid = {38359293}, issn = {1091-6490}, support = {R35 CA197588/CA/NCI NIH HHS/United States ; S10 RR027699/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; Hydrogen Peroxide ; Peroxides ; *Glioblastoma/drug therapy/genetics/metabolism ; Proteomics ; Acetylcysteine/pharmacology ; Glucose ; Cell Line, Tumor ; *Brain Neoplasms/drug therapy/genetics ; }, abstract = {Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.}, } @article {pmid38357896, year = {2024}, author = {Mestre-Bach, G and Potenza, MN}, title = {Pharmacological management of gambling disorder: an update of the literature.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {4}, pages = {391-407}, doi = {10.1080/14737175.2024.2316833}, pmid = {38357896}, issn = {1744-8360}, mesh = {Humans ; *Gambling/drug therapy ; Naltrexone/therapeutic use ; *Behavior, Addictive/drug therapy/psychology ; Narcotic Antagonists/therapeutic use ; Selective Serotonin Reuptake Inhibitors ; }, abstract = {INTRODUCTION: Gambling disorder (GD) is a mental health condition characterized by persistent and problematic betting behavior. GD generates distress and impairment, and treatment options include psychological and pharmacological interventions.

AREAS COVERED: This narrative review explores existing pharmacological treatments for GD. The following classes of medications were considered: opioid-receptor antagonists (e.g. naltrexone and nalmefene), serotonin reuptake inhibitors (e.g. fluvoxamine, paroxetine, sertraline, escitalopram, and citalopram), glutamatergic agents (e.g. N-acetylcysteine (NAC), acamprosate, and memantine), mood stabilizers (e.g. topiramate, carbamazepine, lithium), and other medications (e.g. modafinil, nefazodone, olanzapine, haloperidol, tolcapone, and bupropion).

EXPERT OPINION: Due to the limitations of the studies reviewed, solid conclusions regarding the optimal choice of pharmacotherapy for individuals with GD are challenging to draw at this time. Despite some medications, such as naltrexone and nalmefene, showing promising results, efficacy has varied across studies. The review highlights current gaps/limitations, including small sample sizes, limited diversity in participant demographics, the need for exploring different gambling subtypes and treatment responses, high placebo response rates, lack of longer-term longitudinal information, limited investigation of neurobiological correlates and co-occurring disorders, and the importance of implementation research. Further research is needed to address these gaps and explore additional medications, as well as interventions like neuromodulation.}, } @article {pmid38357503, year = {2024}, author = {Raas, Q and Wood, A and Stevenson, TJ and Swartwood, S and Liu, S and Kannan, RM and Kannan, S and Bonkowsky, JL}, title = {Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model.}, journal = {Frontiers in pediatrics}, volume = {12}, number = {}, pages = {1326886}, pmid = {38357503}, issn = {2296-2360}, abstract = {BACKGROUND: Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults.

METHODS: We report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts.

RESULTS: The patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes.

CONCLUSIONS: We developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.}, } @article {pmid38354685, year = {2024}, author = {Cheng, C and Li, W and Ye, Y and Zhu, Y and Tang, M and Hu, Z and Su, H and Dang, C and Wan, J and Liu, Z and Gong, Y and Yao, LH}, title = {Lactate induces C2C12 myoblasts differentiation by mediating ROS/p38 MAPK signalling pathway.}, journal = {Tissue & cell}, volume = {87}, number = {}, pages = {102324}, doi = {10.1016/j.tice.2024.102324}, pmid = {38354685}, issn = {1532-3072}, mesh = {Reactive Oxygen Species/metabolism ; *Lactic Acid/metabolism/pharmacology ; Cell Differentiation ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Myoblasts/metabolism ; }, abstract = {Lactate serves not merely as an energy substrate for skeletal muscle but also regulates myogenic differentiation, leading to an elevation of reactive oxygen species (ROS) levels. The present study was focused on exploring the effects of lactate and ROS/p38 MAPK in promoting C2C12 myoblasts differentiation. Our results demonstrated that lactate increased C2C12 myoblasts differentiation at a range of physiological concentrations, accompanied by enhanced ROS contents. We used n-acetylcysteine (NAC, a ROS scavenger) pretreatment and found that it delayed lactate-induced C2C12 myoblast differentiation by upregulating Myf5 expression on days 5 and 7 and lowering MyoD and MyoG expression. The finding implies that lactate accompanies ROS-dependent manner to promote C2C12 myoblast differentiation. Additionally, lactate significantly increased p38 MAPK phosphorylation to promote C2C12 cell differentiation, but pretreatment with SB203580 (p38 MAPK inhibitor) reduced lactate-induced C2C12 myoblasts differentiation. whereas lactate pretreatment with NAC inhibited p38 MAPK phosphorylation in C2C12 cells, demonstrating that lactate mediated ROS and regulated the p38 MAPK signalling pathway to promote C2C12 cell differentiation. In conclusion, our results suggest that the promotion of C2C12 myoblasts differentiation by lactate is dependent on ROS and the p38 MAPK signalling pathway. These observations reveal a beneficial role for lactate in increasing myogenesis through ROS-sensitive mechanisms as well as providing new ideas regarding the positive impact of ROS in improving the function of skeletal muscle.}, } @article {pmid38347533, year = {2024}, author = {Yang, Y and Wang, L and Huang, Z and Ge, L and Shi, J}, title = {N-acetylcysteine as a novel methacrylate-based resin cement component: effect on cell apoptosis and genotoxicity in human gingival fibroblasts.}, journal = {BMC oral health}, volume = {24}, number = {1}, pages = {222}, pmid = {38347533}, issn = {1472-6831}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Methacrylates/toxicity ; Resin Cements ; Reactive Oxygen Species ; Apoptosis ; DNA/pharmacology ; Fibroblasts ; Cell Survival ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) reduces the cytotoxicity and genotoxicity induced by monomers leached from dental composite resins. Herein, we investigated the effects of methacrylate-based resin cement used in dental implant restoration on apoptosis and genotoxicity, as well as the antiapoptotic and antigenotoxic capabilities of its component, NAC.

METHODS: The antioxidant NAC (0.1 or 1 wt.%) was experimentally incorporated into the methacrylate-based dental resin cement Premier®. The Premier® + NAC (0.1 or 1 wt.%) mixture was subsequently immersed into Dulbecco's modified Eagle's medium for 72 h, and used to treat human gingival fibroblasts (HGFs). The viability of HGFs was determined using the XTT assay. The formation of deoxyribonucleic acid (DNA) double-strand breaks (DNA-DSBs) was determined using a γ-H2AX assay. Reactive oxygen species (ROS), apoptosis, necrosis, and cell cycles were detected and analyzed using flow cytometry.

RESULTS: The eluate of Premier® significantly inhibited HGF proliferation in vitro by promoting a G1-phase cell cycle arrest, resulting in cell apoptosis. Significant ROS production and DNA-DSB induction were also found in HGFs exposed to the eluate. Incorporating NAC (1 wt.%) into Premier® was found to reduce cell cytotoxicity, the percentage of G1-phase cells, cell apoptosis, ROS production, and DNA-DSB induction.

CONCLUSION: Incorporating NAC (1 wt.%) into methacrylate-based resin cement Premier® decreases the cell cytotoxicity, ROS production, and DNA-DSBs associated with resin use, and further offers protective effects against the early stages of cell apoptosis and G1-phase cell cycle arrest in HGFs. Overall, our in vitro results indicate that the addition of NAC into methacrylate-based resin cements may have clinically beneficial effects on the cytotoxicity and genotoxicity of these materials.}, } @article {pmid38340270, year = {2024}, author = {Ali, J and Thompson, M and Mackenzie, C}, title = {Assessing the frequency and types of errors involved in the use of a modified intravenous N-acetylcysteine protocol for acetaminophen overdose.}, journal = {CJEM}, volume = {26}, number = {3}, pages = {174-178}, pmid = {38340270}, issn = {1481-8043}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; Antidotes ; *Drug Overdose/drug therapy/epidemiology ; *Poisons/therapeutic use ; Retrospective Studies ; }, abstract = {BACKGROUND: Acetaminophen overdose is a leading cause of acute liver failure in developing countries. N-acetylcysteine (NAC) is a highly effective antidote for acetaminophen hepatotoxicity, typically initiated in the emergency department. Due to a known high rate of errors with the standard three-bag IV NAC protocol, in 2019, the Ontario Poison Center changed to a modified 3% IV NAC one-bag protocol. This study was undertaken to determine the frequency and types of errors associated with the use of this protocol.

METHODS: Data were gathered via chart review of Ontario Poison Centre electronic medical record cases identified as receiving IV NAC for acetaminophen overdose between August 1 and September 30, 2022. 218 total charts were identified, and 188 were deemed eligible based on inclusion and exclusion criteria.

RESULTS: Errors were identified in 25% of charts, consisting of dosing errors in 11.7%, stopping errors in 9.0%, initiation errors in 3.7%, and interruptions in therapy in 3.2%. Dosing errors were the most common type of error (44.4%), with overdoses occurring three times more than underdoses. Errors were identified at 39% of geographic locations in the charts reviewed, with similar frequency in Ontario, Manitoba, and Nunavut. Clinical outcomes were similar in charts with and without errors.

INTERPRETATION: The rate of errors identified with this 3% IV NAC one-bag protocol is lower than reported for the standard three-bag protocol, but remains high due to dosing errors. Previously reported issues with prolonged interruptions in therapy with the standard three-bag protocol were low with the current 3% one-bag protocol. Although severe outcomes are rare, IV NAC overdose can be fatal. Identifying local factors in emergency departments that can contribute to administration errors (i.e., dose calculation, pump programming issues) can enhance the safety of this important antidote.}, } @article {pmid38336380, year = {2024}, author = {Sams, MP and Iansavitchous, J and Astridge, M and Rysan, H and Xu, LS and Rodrigues de Oliveira, B and DeKoter, RP}, title = {N-Acetylcysteine Alters Disease Progression and Increases Janus Kinase Mutation Frequency in a Mouse Model of Precursor B-Cell Acute Lymphoblastic Leukemia.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {389}, number = {1}, pages = {40-50}, doi = {10.1124/jpet.123.002000}, pmid = {38336380}, issn = {1521-0103}, support = {//CIHR/Canada ; }, mesh = {Child ; Humans ; Mice ; Animals ; Child, Preschool ; Acetylcysteine/pharmacology/therapeutic use ; Janus Kinases ; Mutation Rate ; Reactive Oxygen Species/metabolism ; Precursor Cells, B-Lymphoid/metabolism ; *Drinking Water ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Janus Kinase 1/genetics/metabolism ; Mutation ; Janus Kinase 3/genetics/metabolism ; Disease Progression ; }, abstract = {B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreΔPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-CreΔPB mice with NAC in drinking water significantly reduced the frequency of CD19[+] pre-B-ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by a median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared with control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. SIGNIFICANCE STATEMENT: In a mouse model of precursor B-cell acute lymphoblastic leukemia associated with high levels of reactive oxygen species, treatment with N-acetylcysteine did not delay disease progression but instead selected for leukemic clones with activating R653H mutations in Janus kinase 3.}, } @article {pmid38335769, year = {2024}, author = {Świętek, M and Marková, I and Malínská, H and Hüttl, M and Miklánková, D and Černá, K and Konefał, R and Horák, D}, title = {Tannic acid- and N-acetylcysteine-chitosan-modified magnetic nanoparticles reduce hepatic oxidative stress in prediabetic rats.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {235}, number = {}, pages = {113791}, doi = {10.1016/j.colsurfb.2024.113791}, pmid = {38335769}, issn = {1873-4367}, mesh = {Rats ; Animals ; Antioxidants/pharmacology/metabolism ; Acetylcysteine/pharmacology ; *Chitosan/pharmacology ; *Magnetite Nanoparticles ; *Prediabetic State/metabolism ; Silicon Dioxide/pharmacology ; Glutathione/metabolism ; Rats, Wistar ; Oxidative Stress ; Liver ; Superoxide Dismutase/metabolism ; *Polyphenols ; }, abstract = {Magnetic nanoparticles (MNPs) modified with tannic acid (TA) have shown remarkable success as an antioxidant and antimicrobial therapeutic agent. Herein, we report a synthetic procedure for the preparation of silica-coated MNPs modified with N-acetylcysteine-modified chitosan and TA. This was achieved by free-radical grafting of NAC onto chitosan (CS), a layer-by-layer technique for modifying negatively charged MNP@SiO2 nanoparticles with positively charged CS-NAC, and crosslinking CS with TA. The antioxidant and metabolic effects of MNP@SiO2-CS-NAC and MNP@SiO2-CS-NAC-TA nanoparticles were tested in a model of prediabetic rats with hepatic steatosis, the hereditary hypertriglyceridemic rats (HHTg). The particles exhibited significant antioxidant properties in the liver, increasing the activity of the antioxidant enzymes superoxide dismutase (SOD), glutathione reductase (GR) and glutathione peroxidase (GPx), decreasing the concentration of the lipoperoxidation product malondialdehyde (MDA), and improving the antioxidant status determined as the ratio of reduced to oxidized glutathione; in particular, TA increased some antioxidant parameters. MNPs carrying antioxidants such as NAC and TA could thus represent a promising therapeutic agent for the treatment of various diseases accompanied by increased oxidative stress.}, } @article {pmid38330258, year = {2024}, author = {Mao, X and Zhao, G and Wang, Q and He, J and Liu, Y and Liu, T and Li, W and Peng, Y and Zheng, J}, title = {Chelerythrine Chloride is an Affinity-Labeling Inactivator of CYP3A4 by Modification of Cysteine239.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {4}, pages = {2802-2811}, doi = {10.1021/acs.jmedchem.3c01943}, pmid = {38330258}, issn = {1520-4804}, mesh = {Cytochrome P-450 CYP3A ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; *Alkaloids ; *Antineoplastic Agents ; *Benzophenanthridines ; }, abstract = {Chelerythrine chloride (CHE) is a quaternary benzo[c]phenanthridine alkaloid with an iminium group that was found to cause time- and concentration-dependent inhibition of CYP3A4. The loss of CYP3A4 activity was independent of NADPH. CYP3A4 competitive inhibitor ketoconazole and nucleophile N-acetylcysteine (NAC) slowed the inactivation. No recovery of CYP3A4 activity was observed after dialysis. Dihydrochelerythrine hardly inhibited CYP3A4, suggesting that the iminium group was primarily responsible for the inactivation. UV spectral analysis revealed that the maximal absorbance of CHE produced a significant red-shift after being mixed with NAC, suggesting that 1,2-addition possibly took place between the sulfhydryl group of NAC and iminium group of CHE. Molecular dynamics simulation and site-direct mutagenesis studies demonstrated that modification of Cys239 by the iminium group of CHE attributed to the inactivation. In conclusion, CHE is an affinity-labeling inactivator of CYP3A4. The observed enzyme inactivation resulted from the modification of Cys239 of CYP3A4 by the iminium group of CHE.}, } @article {pmid38325272, year = {2024}, author = {Tian, T and Pang, H and Li, X and Ma, K and Liu, T and Li, J and Luo, Z and Li, M and Hou, Q and Hao, H and Dong, J and Du, H and Liu, X and Sun, Z and Zhao, C and Song, X and Jin, M}, title = {The role of DRP1 mediated mitophagy in HT22 cells apoptosis induced by silica nanoparticles.}, journal = {Ecotoxicology and environmental safety}, volume = {272}, number = {}, pages = {116050}, doi = {10.1016/j.ecoenv.2024.116050}, pmid = {38325272}, issn = {1090-2414}, mesh = {Adenosine Triphosphate ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; *Dynamins/metabolism ; *Mitophagy ; *Nanoparticles/toxicity ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; *Silicon Dioxide/pharmacology ; Superoxide Dismutase/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Animals ; Mice ; Cell Line, Tumor ; }, abstract = {Silica nanoparticles (SiNPs) are widely used in the biomedical field and can enter the central nervous system through the blood-brain barrier, causing damage to hippocampal neurons. However, the specific mechanism remains unclear. In this experiment, HT22 cells were selected as the experimental model in vitro, and the survival rate of cells under the action of SiNPs was detected by MTT method, reactive oxygen species (ROS), lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and adenosine triphosphate (ATP) were tested by the kit, the ultrastructure of the cells was observed by transmission electron microscope, membrane potential (MMP), calcium ion (Ca[2+]) and apoptosis rate were measured by flow cytometry, and the expressions of mitochondrial functional protein, mitochondrial dynein, mitochondrial autophagy protein as well as apoptosis related protein were detected by Western blot. The results showed that cell survival rate, SOD, CAT, GSH-Px, ATP and MMP gradually decreased with the increase of SiNPs concentration, while intracellular ROS, Ca[2+], LDH and apoptosis rate increased with the increase of SiNPs concentration. In total cellular proteins,the expressions of mitochondrial functional proteins VDAC and UCP2 gradually increased, the expression of mitochondrial dynamic related protein DRP1 increased while the expressions of OPA1 and Mfn2 decreased. The expressions of mitophagy related proteins PINK1, Parkin and LC3Ⅱ/LC3Ⅰ increased and P62 gradually decreased, as well as the expressions of apoptosis related proteins Apaf-1, Cleaved-Caspase-3, Caspase-3, Caspase-9, Bax and Cyt-C. In mitochondrial proteins, the expressions of mitochondrial dynamic related proteins DRP1 and p-DRP1 were increased, while the expressions of OPA1 and Mfn2 were decreased. Expressions of mitochondrial autophagy associated proteins PINK1, Parkin, LC3II/LC3I increased, P62 decreased gradually, as well as the expressions of apoptosis related proteins Cleaved-Caspase-3, Caspase-3, and Caspase-9 increased, and Cyt-C expressions decreased. To further demonstrate the role of ROS and DRP1 in HT22 cell apoptosis induced by SiNPs, we selected the ROS inhibitor N-Acetylcysteine (NAC) and Dynamin-related protein 1 (DRP1) inhibitor Mdivi-1. The experimental results indicated that the above effects were remarkably improved after the use of inhibitors, further confirming that SiNPs induce the production of ROS in cells, activate DRP1, cause excessive mitochondrial division, induce mitophagy, destroy mitochondrial function and eventually lead to apoptosis.}, } @article {pmid38325270, year = {2024}, author = {Xiong, A and He, X and Liu, S and Ran, Q and Zhang, L and Wang, J and Jiang, M and Niu, B and Xiong, Y and Li, G}, title = {Oxidative stress-mediated activation of FTO exacerbates impairment of the epithelial barrier by up-regulating IKBKB via N6-methyladenosine-dependent mRNA stability in asthmatic mice exposed to PM2.5.}, journal = {Ecotoxicology and environmental safety}, volume = {272}, number = {}, pages = {116067}, doi = {10.1016/j.ecoenv.2024.116067}, pmid = {38325270}, issn = {1090-2414}, mesh = {Animals ; Mice ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics/metabolism ; *Asthma/chemically induced/genetics ; *I-kappa B Kinase/metabolism ; Obesity ; Oxidative Stress/genetics ; Particulate Matter/toxicity ; RNA Stability ; RNA, Messenger/metabolism ; }, abstract = {In order to comprehend the underlying mechanisms contributing to the development and exacerbation of asthma resulting from exposure to fine particulate matter (PM2.5), we established an asthmatic model in fat mass and obesity-associated gene knockdown mice subjected to PM2.5 exposure. Histological analyses using hematoxylin-eosin (HE) and Periodic Acid-Schiff (PAS) staining revealed that the down-regulation of the fat mass and obesity-associated gene (Fto) expression significantly ameliorated the pathophysiological alterations observed in asthmatic mice exposed to PM2.5. Furthermore, the down-regulation of Fto gene expression effectively attenuated damage to the airway epithelial barrier. Additionally, employing in vivo and in vitro models, we elucidated that PM2.5 modulated FTO expression by inducing oxidative stress. Asthmatic mice exposed to PM2.5 exhibited elevated Fto expression, which correlated with increased levels of reactive oxygen species. Similarly, when cells were exposed to PM2.5, FTO expression was up-regulated in a ROS-dependent manner. Notably, the administration of N-acetyl cysteine successfully reversed the PM2.5-induced elevation in FTO expression. Concurrently, we performed transcriptome-wide Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) analysis subsequent to PM2.5 exposure. Through the implementation of Gene Set Enrichment Analysis and m6A-IP-qPCR, we successfully identified inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) as a target gene regulated by FTO. Interestingly, exposure to PM2.5 led to increased expression of IKBKB, while m6A modification on IKBKB mRNA was reduced. Furthermore, our investigation revealed that PM2.5 also regulated IKBKB through oxidative stress. Significantly, the down-regulation of IKBKB effectively mitigated epithelial barrier damage in cells exposed to PM2.5 by modulating nuclear factor-kappa B (NF-κB) signaling. Importantly, we discovered that decreased m6A modification on IKBKB mRNA facilitated by FTO enhanced its stability, consequently resulting in up-regulation of IKBKB expression. Collectively, our findings propose a novel role for FTO in the regulation of IKBKB through m6A-dependent mRNA stability in the context of PM2.5-induced oxidative stress. Therefore, it is conceivable that the utilization of antioxidants or inhibition of FTO could represent potential therapeutic strategies for the management of asthma exacerbated by PM2.5 exposure.}, } @article {pmid38323079, year = {2024}, author = {Hashmi, HZ and Khowaja, A and Moheet, A}, title = {Experimental pharmacological approaches to reverse impaired awareness of hypoglycemia-a review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1349004}, pmid = {38323079}, issn = {1663-9812}, abstract = {The colossal global burden of diabetes management is compounded by the serious complication of hypoglycemia. Protective physiologic hormonal and neurogenic counterregulatory responses to hypoglycemia are essential to preserve glucose homeostasis and avert serious morbidity. With recurrent exposure to hypoglycemic episodes over time, these counterregulatory responses to hypoglycemia can diminish, resulting in an impaired awareness of hypoglycemia (IAH). IAH is characterized by sudden neuroglycopenia rather than preceding cautionary autonomic symptoms. IAH increases the risk of subsequent sudden and severe hypoglycemic episodes in patients with diabetes. The postulated causative mechanisms behind IAH are complex and varied. It is therefore challenging to identify a single effective therapeutic strategy. In this review, we closely examine the efficacy and feasibility of a myriad of pharmaceutical interventions in preventing and treating IAH as described in clinical and preclinical studies. Pharmaceutical agents outlined include N-acetyl cysteine, GABA A receptor blockers, opioid receptor antagonists, AMP activated protein kinase agonists, potassium channel openers, dehydroepiandrosterone, metoclopramide, antiadrenergic agents, antidiabetic agents and glucagon.}, } @article {pmid38318818, year = {2024}, author = {Liu, J and Li, SM and Tang, YJ and Cao, JL and Hou, WS and Wang, AQ and Wang, C and Jin, CH}, title = {Jaceosidin induces apoptosis and inhibits migration in AGS gastric cancer cells by regulating ROS-mediated signaling pathways.}, journal = {Redox report : communications in free radical research}, volume = {29}, number = {1}, pages = {2313366}, pmid = {38318818}, issn = {1743-2928}, mesh = {Humans ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Flavonoids/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Stomach Neoplasms/drug therapy/metabolism/pathology ; }, abstract = {Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3β, N-cadherin, and β-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.}, } @article {pmid38318025, year = {2024}, author = {Liu, TH and Wu, JY and Huang, PY and Tsai, YW and Hsu, WH and Chuang, MH and Tang, HJ and Lai, CC}, title = {Clinical efficacy of N-acetylcysteine for COVID-19: A systematic review and meta-analysis of randomized controlled trials.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e25179}, pmid = {38318025}, issn = {2405-8440}, abstract = {BACKGROUND: The association between N-acetylcysteine (NAC) and COVID-19 remains undetermined; therefore, this meta-analysis assessed the clinical efficacy of NAC in the treatment of patients with COVID-19.

METHODS: This study searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for studies published from their inception to December 17, 2022. Only randomized controlled trials (RCTs) that assessed the clinical efficacy of NAC for patients with COVID-19 were included.

RESULTS: Five RCTs involving 651 patients were included. There was no significant difference in mortality between the study group receiving NAC and the control group (15.6 % [50/320] vs. 32.3 %, [107/331]; risk ratio [RR]: 0.58; 95 % confidence interval [CI]: 0.24-1.40). In addition, the two groups did not differ with respect to the incidence of invasive mechanical ventilation (RR: 0.93; 95 % CI: 0.65-1.33), the risk of intensive care unit (ICU) admission (RR: 0.86; 95 % CI: 0.62-1.21), the length of hospital stay (mean difference [MD]: 0.17 days; 95 % CI: -0.67-1.01), and the length of ICU stay (MD: -0.77 days; 95 % CI: -2.97-1.42).

CONCLUSIONS: The administration of NAC did not improve the clinical outcomes of patients with COVID-19; its routine use is not recommended for patients with SARS-CoV-2 infections.}, } @article {pmid38317753, year = {2024}, author = {Jerome, RN and Zahn, LA and Abner, JJ and Joly, MM and Shirey-Rice, JK and Wallis, RS and Bernard, GR and Pulley, JM}, title = {Repurposing N-acetylcysteine for management of non-acetaminophen induced acute liver failure: an evidence scan from a global health perspective.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {2}, pmid = {38317753}, issn = {2415-1289}, support = {UL1 TR002243/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: The World Health Organization (WHO)'s Essential Medicines List (EML) plays an important role in advocating for access to key treatments for conditions affecting people in all geographic settings. We applied our established drug repurposing methods to one EML agent, N-acetylcysteine (NAC), to identify additional uses of relevance to the global health community beyond its existing EML indication (acetaminophen toxicity).

METHODS: We undertook a phenome-wide association study (PheWAS) of a variant in the glutathione synthetase (GSS) gene in approximately 35,000 patients to explore novel indications for use of NAC, which targets glutathione. We then evaluated the evidence regarding biologic plausibility, efficacy, and safety of NAC use in the new phenotype candidates.

RESULTS: PheWAS of GSS variant R418Q revealed increased risk of several phenotypes related to non-acetaminophen induced acute liver failure (ALF), indicating that NAC may represent a therapeutic option for treating this condition. Evidence review identified practice guidelines, systematic reviews, clinical trials, retrospective cohorts and case series, and case reports. This evidence suggesting benefit of NAC use in this subset of ALF patients. The safety profile of NAC in this literature was also concordant with existing evidence on safety of this agent in acetaminophen-induced ALF.

CONCLUSIONS: This body of literature indicates efficacy and safety of NAC in non-acetaminophen induced ALF. Given the presence of NAC on the EML, this medication is likely to be available across a range of resource settings; promulgating its use in this novel subset of ALF can provide healthcare professionals and patients with a valuable and safe complement to supportive care for this disease.}, } @article {pmid38315254, year = {2024}, author = {Rodrigues, JP and da Costa Silva, JR and Ferreira, BA and Veloso, LI and Quirino, LS and Rosa, RR and Barbosa, MC and Rodrigues, CM and Gaspari, PBF and Beletti, ME and Goulart, LR and Corrêa, NCR}, title = {Development of collagenous scaffolds for wound healing: characterization and in vivo analysis.}, journal = {Journal of materials science. Materials in medicine}, volume = {35}, number = {1}, pages = {12}, pmid = {38315254}, issn = {1573-4838}, mesh = {Animals ; Mice ; *Acetylcysteine ; *Anti-Infective Agents/pharmacology ; Biocompatible Materials/chemistry ; *Chitosan/chemistry ; Collagen/chemistry ; Tissue Scaffolds/chemistry ; Wound Healing ; Polylysine/chemistry ; }, abstract = {The development of wound dressings from biomaterials has been the subject of research due to their unique structural and functional characteristics. Proteins from animal origin, such as collagen and chitosan, act as promising materials for applications in injuries and chronic wounds, functioning as a repairing agent. This study aims to evaluate in vitro effects of scaffolds with different formulations containing bioactive compounds such as collagen, chitosan, N-acetylcysteine (NAC) and ε-poly-lysine (ε-PL). We manufactured a scaffold made of a collagen hydrogel bioconjugated with chitosan by crosslinking and addition of NAC and ε-PL. Cell viability was verified by resazurin and live/dead assays and the ultrastructure of biomaterials was evaluated by SEM. Antimicrobial sensitivity was assessed by antibiogram. The healing potential of the biomaterial was evaluated in vivo, in a model of healing of excisional wounds in mice. On the 7th day after the injury, the wounds and surrounding skin were processed for evaluation of biochemical and histological parameters associated with the inflammatory process. The results showed great cell viability and increase in porosity after crosslinking while antimicrobial action was observed in scaffolds containing NAC and ε-PL. Chitosan scaffolds bioconjugated with NAC/ε-PL showed improvement in tissue healing, with reduced lesion size and reduced inflammation. It is concluded that scaffolds crosslinked with chitosan-NAC-ε-PL have the desirable characteristics for tissue repair at low cost and could be considered promising biomaterials in the practice of regenerative medicine.}, } @article {pmid38314899, year = {2024}, author = {Li, L and Chen, D and Lin, X and Luo, J and Tan, J and Ding, D and Li, P}, title = {Antioxidative Stress-Induced Destruction to Cochlear Cells Caused by Blind Antioxidant Therapy.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {170}, number = {5}, pages = {1421-1429}, doi = {10.1002/ohn.659}, pmid = {38314899}, issn = {1097-6817}, mesh = {*Antioxidants/pharmacology ; *Acetylcysteine/pharmacology ; *Ubiquinone/*analogs & derivatives/pharmacology/therapeutic use ; *Cell Survival/drug effects ; Animals ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Mice ; Cochlea/drug effects/pathology ; Hair Cells, Auditory/drug effects/pathology ; Cell Count ; *Oligopeptides ; }, abstract = {OBJECTIVE: Verification that blind and excessive use of antioxidants leads to antioxidant stress which exacerbates cochlear cell damage.

STUDY DESIGN: Basic research.

SETTING: The Third Affiliated Hospital of Sun Yat-Sen University.

METHODS: We compared and quantified hair cell-like house ear institute-organ of corti 1 (HEI-OC1) cell density, cell viability, and apoptosis caused by different concentrations of N-acetylcysteine (NAC) via Hoechst staining, Cell Counting Kit 8, Hoechst with propidium iodide staining, and Annexin V with propidium iodide (PI) staining. Apoptosis induced by high concentrations of M40403 and coenzyme Q10 in cochlear explants was analyzed and compared by cochlear dissection and activated caspase 3 labeling.

RESULTS: With the increase of NAC concentration (0-1000 μmol/L), cell density decreased consequently and reached the lowest at 1000 μmol/L (****P ≤ .0001). Cell viability is also declining (**P < .01). The number of Annexin V-fluorescein isothiocyanate-labeled cells and PI-labeled cells increased with increasing NAC concentration after treatment of HEI-OC1 cells for 48 hours. The proportion of apoptotic cells also rose (*P < .05, **P < .01). Cochlear hair cells (HCs) treated with low concentrations of M40403 and coenzyme Q10 for 48 hours showed no damage. When the concentrations of M40403 and coenzyme Q10 were increased (concentrations>30 μmol/L), HC damage began, followed by a dose-dependent increase in HC loss (*P < .001, **P < .0001). Activated caspase-3 was clearly apparent in cochlear explants treated with 50 μmol/L M40403 and coenzyme Q10 compared with cochlear explants without added M40403 and coenzyme Q10.

CONCLUSION: These experimental results suggest that inappropriate application of antioxidants can cause severe damage to normal cochlear HCs.}, } @article {pmid38309383, year = {2024}, author = {La Sala, L and Carlini, V and Conte, C and Macas-Granizo, MB and Afzalpour, E and Martin-Delgado, J and D'Anzeo, M and Pedretti, RFE and Naselli, A and Pontiroli, AE and Cappato, R}, title = {Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?.}, journal = {Pharmacological research}, volume = {201}, number = {}, pages = {107083}, doi = {10.1016/j.phrs.2024.107083}, pmid = {38309383}, issn = {1096-1186}, mesh = {Humans ; *MicroRNAs/genetics/therapeutic use ; *Non-alcoholic Fatty Liver Disease/drug therapy/genetics ; *Diabetes Mellitus, Type 2/drug therapy/genetics ; *Metabolic Diseases/drug therapy/genetics ; *Heart Diseases ; Oligonucleotides, Antisense/therapeutic use ; }, abstract = {Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.}, } @article {pmid38305139, year = {2024}, author = {Frasson, I and Diamante, L and Zangrossi, M and Carbognin, E and Pietà, AD and Penna, A and Rosato, A and Verin, R and Torrigiani, F and Salata, C and Dizanzo, MP and Vaccaro, L and Cacchiarelli, D and Richter, SN and Montagner, M and Martello, G}, title = {Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern.}, journal = {Journal of molecular cell biology}, volume = {16}, number = {3}, pages = {}, pmid = {38305139}, issn = {1759-4685}, support = {PRIN-2020KSY3KL//Ministry of Education, University and Research/ ; RCR-2019 23669115//Italian Ministry of Health/ ; OPP1097238/GATES/Bill & Melinda Gates Foundation/United States ; PO-FESR 2014-2020/ERC_/European Research Council/International ; 871029//European Union's Horizon 2020 Research and Innovation Programme/ ; OPP1035881//Bill and Melinda Gates Foundation/ ; TCP13013//Telethon Foundation/ ; NewTarCoV2//CaRiPaRo Foundation/ ; 615879//ERC/ ; }, mesh = {*SARS-CoV-2/genetics/drug effects/physiology/metabolism ; Humans ; Animals ; *Virus Replication/drug effects ; *COVID-19/virology ; *Antiviral Agents/pharmacology ; Mice ; COVID-19 Drug Treatment ; Reactive Oxygen Species/metabolism ; Chlorocebus aethiops ; Acetylcysteine/pharmacology ; Vero Cells ; Host-Pathogen Interactions/genetics/drug effects ; Drug Repositioning ; Mutation/genetics ; }, abstract = {The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors, e.g. cellular proteins required for viral replication, would help prevent the development of resistance. However, it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors. To this end, we compared three variants of concern and found that the host transcriptional response was conserved, differing only in kinetics and magnitude. Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection. Most of the genes were shared by multiple variants. We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs. All the drugs were highly active against all the tested variants, including new variants that emerged during the study (Delta and Omicron). Mechanistically, we identified reactive oxygen species production as a key step in early viral replication. Antioxidants such as N-acetyl cysteine (NAC) were effective against all the variants in both human lung cells and a humanized mouse model. Our study supports the use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.}, } @article {pmid38304461, year = {2023}, author = {Balmuri, SR and Noaman, S and Usman, H and Niepa, THR}, title = {Altering the interfacial rheology of Pseudomonas aeruginosa and Staphylococcus aureus with N-acetyl cysteine and cysteamine.}, journal = {Frontiers in cellular and infection microbiology}, volume = {13}, number = {}, pages = {1338477}, pmid = {38304461}, issn = {2235-2988}, mesh = {Humans ; Acetylcysteine/pharmacology/metabolism ; *Cystic Fibrosis/complications/microbiology ; Staphylococcus aureus ; Pseudomonas aeruginosa ; Cysteamine/pharmacology/metabolism ; *Staphylococcal Infections/microbiology ; Anti-Bacterial Agents/pharmacology ; Biofilms ; Lung ; *Pseudomonas Infections/microbiology ; *Cysts ; }, abstract = {INTRODUCTION: Chronic lung infection due to bacterial biofilms is one of the leading causes of mortality in cystic fibrosis (CF) patients. Among many species colonizing the lung airways, Pseudomonas aeruginosa and Staphylococcus aureus are two virulent pathogens involved in mechanically robust biofilms that are difficult to eradicate using airway clearance techniques like lung lavage. To remove such biological materials, glycoside hydrolase-based compounds are commonly employed for targeting and breaking down the biofilm matrix, and subsequently increasing cell susceptibility to antibiotics.

MATERIALS AND METHODS: In this study, we evaluate the effects of N-acetyl cysteine (NAC) and Cysteamine (CYST) in disrupting interfacial bacterial films, targeting different components of the extracellular polymeric substances (EPS). We characterize the mechanics and structural integrity of the interfacial bacterial films using pendant drop elastometry and scanning electron microscopy.

RESULTS AND DISCUSSION: Our results show that the film architectures are compromised by treatment with disrupting agents for 6 h, which reduces film elasticity significantly. These effects are profound in the wild type and mucoid P. aeruginosa, compared to S. aureus. We further assess the effects of competition and cooperation between S. aureus and P. aeruginosa on the mechanics of composite interfacial films. Films of S. aureus and wild-type P. aeruginosa cocultures lose mechanical strength while those of S. aureus and mucoid P. aeruginosa exhibit improved storage modulus. Treatment with NAC and CYST reduces the elastic property of both composite films, owing to the drugs' ability to disintegrate their EPS matrix. Overall, our results provide new insights into methods for assessing the efficacy of mucolytic agents against interfacial biofilms relevant to cystic fibrosis infection.}, } @article {pmid38299014, year = {2024}, author = {Vedaei, F and Newberg, AB and Alizadeh, M and Zabrecky, G and Navarreto, E and Hriso, C and Wintering, N and Mohamed, FB and Monti, D}, title = {Treatment effects of N-acetyl cysteine on resting-state functional MRI and cognitive performance in patients with chronic mild traumatic brain injury: a longitudinal study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1282198}, pmid = {38299014}, issn = {1664-2295}, abstract = {Mild traumatic brain injury (mTBI) is a significant public health concern, specially characterized by a complex pattern of abnormal neural activity and functional connectivity. It is often associated with a broad spectrum of short-term and long-term cognitive and behavioral symptoms including memory dysfunction, headache, and balance difficulties. Furthermore, there is evidence that oxidative stress significantly contributes to these symptoms and neurophysiological changes. The purpose of this study was to assess the effect of N-acetylcysteine (NAC) on brain function and chronic symptoms in mTBI patients. Fifty patients diagnosed with chronic mTBI participated in this study. They were categorized into two groups including controls (CN, n = 25), and patients receiving treatment with N-acetyl cysteine (NAC, n = 25). NAC group received 50 mg/kg intravenous (IV) medication once a day per week. In the rest of the week, they took one 500 mg NAC tablet twice per day. Each patient underwent rs-fMRI scanning at two timepoints including the baseline and 3 months later at follow-up, while the NAC group received a combination of oral and IV NAC over that time. Three rs-fMRI metrics were measured including fractional amplitude of low frequency fluctuations (fALFF), degree centrality (DC), and functional connectivity strength (FCS). Neuropsychological tests were also assessed at the same day of scanning for each patient. The alteration of rs-fMRI metrics and cognitive scores were measured over 3 months treatment with NAC. Then, the correlation analysis was executed to estimate the association of rs-fMRI measurements and cognitive performance over 3 months (p < 0.05). Two significant group-by-time effects demonstrated the changes of rs-fMRI metrics particularly in the regions located in the default mode network (DMN), sensorimotor network, and emotional circuits that were significantly correlated with cognitive function recovery over 3 months treatment with NAC (p < 0.05). NAC appears to modulate neural activity and functional connectivity in specific brain networks, and these changes could account for clinical improvement. This study confirmed the short-term therapeutic efficacy of NAC in chronic mTBI patients that may contribute to understanding of neurophysiological effects of NAC in mTBI. These findings encourage further research on long-term neurobehavioral assessment of NAC assisting development of therapeutic plans in mTBI.}, } @article {pmid38294834, year = {2024}, author = {Feng, R and Fan, Y and Zhang, X and Chen, L and Zhong, ZF and Wang, Y and Yu, H and Zhang, QW and Li, G}, title = {A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.}, journal = {ACS nano}, volume = {18}, number = {7}, pages = {5951-5964}, pmid = {38294834}, issn = {1936-086X}, abstract = {Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.}, } @article {pmid38291912, year = {2024}, author = {Akakpo, JY and Olivos, H and Shrestha, B and Midey, A and Jaeschke, H and Ramachandran, A}, title = {Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {198}, number = {2}, pages = {328-346}, pmid = {38291912}, issn = {1096-0929}, support = {R01 DK102142/DK/NIDDK NIH HHS/United States ; TL1 TR002368/TR/NCATS NIH HHS/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; Acetaminophen/toxicity/metabolism ; Fomepizole/therapeutic use ; Glutathione/metabolism ; Mice, Inbred C57BL ; Kidney/metabolism ; Mass Spectrometry ; Spatial Analysis ; *Acute Kidney Injury/chemically induced ; *Chemical and Drug Induced Liver Injury/drug therapy ; }, abstract = {Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent APAP-induced AKI. We have previously demonstrated the renal metabolism of APAP and identified fomepizole (4-methylpyrazole, 4MP) as a therapeutic option to prevent APAP-induced nephrotoxicity. However, the kidney has several functionally distinct regions, and the dose-dependent effects of APAP on renal response and regional specificity of APAP metabolism are unknown. These aspects were examined in this study using C57BL/6J mice treated with 300-1200 mg/kg APAP and mass spectrometry imaging (MSI) to provide spatial cues relevant to APAP metabolism and the effects of 4MP. We find that renal APAP metabolism and generation of the nonoxidative (APAP-GLUC and APAP-SULF) and oxidative metabolites (APAP-GSH, APAP-CYS, and APAP-NAC) were dose-dependently increased in the kidney. This was recapitulated on MSI which revealed that APAP overdose causes an accumulation of APAP and APAP GLUC in the inner medulla and APAP-CYS in the outer medulla of the kidney. APAP-GSH, APAP-NAC, and APAP-SULF were localized mainly to the outer medulla and the cortex where CYP2E1 expression was evident. Interestingly, APAP also induced a redistribution of reduced GSH, with an increase in oxidized GSH within the kidney cortex. 4MP ameliorated these region-specific variations in the formation of APAP metabolites in renal tissue sections. In conclusion, APAP metabolism has a distinct regional distribution within the kidney, the understanding of which provides insight into downstream mechanisms of APAP-induced nephrotoxicity.}, } @article {pmid38290605, year = {2024}, author = {He, J and Ma, Y and Niu, X and Pei, J and Yan, R and Xu, F and Ma, J and Ma, X and Jia, S and Ma, W}, title = {Silver nanoparticles induce endothelial cytotoxicity through ROS-mediated mitochondria-lysosome damage and autophagy perturbation: The protective role of N-acetylcysteine.}, journal = {Toxicology}, volume = {502}, number = {}, pages = {153734}, doi = {10.1016/j.tox.2024.153734}, pmid = {38290605}, issn = {1879-3185}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Silver/toxicity ; *Metal Nanoparticles/toxicity ; Autophagy ; Human Umbilical Vein Endothelial Cells ; Lysosomes/metabolism ; Mitochondria/metabolism ; Cell Survival ; }, abstract = {Silver nanoparticles (AgNPs) are used increasingly often in the biomedical field, but their potential deleterious effects on the cardiovascular system remain to be elucidated. The primary aim of this study was to evaluate the toxic effects, and the underlying mechanisms of these effects, of AgNPs on human umbilical vein endothelial cells (HUVECs), as well as the protective role of N-acetylcysteine (NAC) against cytotoxicity induced by AgNPs. In this study, we found that exposure to AgNPs affects the morphology and function of endothelial cells which manifests as decreased cell proliferation, migration, and angiogenesis ability. Mechanistically, AgNPs can induce excessive cellular production of reactive oxygen species (ROS), leading to damage to cellular sub-organs such as mitochondria and lysosomes. More importantly, our data suggest that AgNPs causes autophagy defect, inhibits mitophagy, and finally activates the mitochondria-mediated apoptosis signaling pathway and evokes cell death. Interestingly, treatment with ROS scavenger-NAC can effectively suppress AgNP-induced endothelial damage.Our results indicate that ROS-mediated mitochondria-lysosome injury and autophagy dysfunction are potential factors of endothelial toxicity induced by AgNPs. This study may provide new evidence for the cardiovascular toxicity of AgNPs and serve as a reference for the safe use of nanoparticles(NPs) in the future.}, } @article {pmid38290315, year = {2024}, author = {Li, L and Xu, H and Wang, Y and Zhang, Y and Ye, R and Li, W and Yang, J and Wu, J and Li, J and Jin, E and Cao, M and Li, X and Li, S and Liu, C}, title = {From inflammation to pyroptosis: Understanding the consequences of cadmium exposure in chicken liver cells.}, journal = {Ecotoxicology and environmental safety}, volume = {272}, number = {}, pages = {116004}, doi = {10.1016/j.ecoenv.2024.116004}, pmid = {38290315}, issn = {1090-2414}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Inflammasomes/metabolism ; Pyroptosis ; Cadmium/toxicity ; Chickens/metabolism ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2 ; *Chemical and Drug Induced Liver Injury, Chronic ; Inflammation/chemically induced ; }, abstract = {Hepatotoxicity is frequently observed following acute cadmium (Cd) exposure in chicken. Oxidative stress and subsequent inflammation are regarded as the main reasons for cadmium-induced liver injury. NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome-induced pyroptosis is involved in various inflammatory diseases, including liver injury. Poultry are more susceptible to harmful effects of heavy metals. However, the mechanism of cadmium-induced liver injury in chicken is still elusive. In this study, the effect of cadmium on chicken liver cells and the underlying mechanisms were investigated. The results showed mitochondria was damaged and excessive reactive oxygen species (ROS) were generated in chicken liver cell line LMH after cadmium exposure. Furthermore, cadmium-induced NLRP3 inflammasome activation and the cell membrane rupture indicated LMH cells pyroptosis. The ROS scavengers, acetylcysteine (NAC) and Mito-TEMPO prevented pyroptosis in LMH cells, suggesting that ROS were responsible for the activation of the NLRP3 inflammasome induced by cadmium. Additionally, anti-oxidative transcription factor Nrf2 was inhibited after cadmium exposure, explaining the excessive ROS generation. In summary, our study showed that cadmium leads to ROS generation by inducing mitochondrial damage and inhibiting Nrf2 activity, which promotes NLRP3 inflammasome activation and eventually induces pyroptosis in LMH cells.}, } @article {pmid38288173, year = {2023}, author = {Shuka, N and Hasimi, E and Kristo, A and Simoni, L and Gishto, T and Shirka, E and Zaimi Petrela, E and Goda, A}, title = {Contrast-Induced Nephropathy in Interventional Cardiology: Incidence, Risk Factors, and Identification of High-Risk Patients.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51283}, pmid = {38288173}, issn = {2168-8184}, abstract = {AIM: This study aimed to study contrast-induced nephropathy (CIN) or more recent nomenclature contrast-associated acute kidney injury (CI-AKI) in patients undergoing percutaneous coronary procedures, evaluating CIN incidence, risk factors (RFs), and high-risk patients with CIN. Methods: This is a prospective, observational, unicentric trial of patients who underwent coronary angiography and/or percutaneous coronary intervention (PCI) in the University Hospital Center (UHC) "Mother Teresa" in Tirana, Albania, during 2016-2018. CIN was defined as an increase of 25% and/or by 0.5 mg/dL of serum creatinine (SCr) and high-risk patients with CIN as an increase by 50% and/or by 2 mg/dL and/or need for dialysis compared to the basal pre-procedural values. We evaluated RFs for CIN: preexisting renal lesion (PRL), heart failure (HF), age, diabetes mellitus (DM), anemia, and contrast quantity. Results: The incidence of CIN resulted in 14.4%. HF, PRL, and age ≥65 years resulted in independent RFs for CIN, whereas anemia, DM, and contrast quantity >100 mL did not. PRL proved to be the most important RF for CIN, whereas HF was the only independent RF for high-risk CIN patients.

CONCLUSIONS: The incidence of CIN coincides with the results in the literature. PRL, HF, and age ≥65 years resulted in independent RFs for CIN; more and larger trials are needed to evaluate DM, anemia, and contrast quantity related to their impact on CIN. High-risk patients with CIN represent the most problematic patients of this pathology.}, } @article {pmid38287817, year = {2024}, author = {Patil, K and Khan, AQ and Ahmad, F and Kuttikrishnan, S and Anver, R and Mateo, JM and Ahmad, A and Bhat, AA and Buddenkotte, J and Steinhoff, M and Uddin, S}, title = {Sanguinarine Triggers Apoptosis in Cutaneous Squamous Cell Carcinoma Cells through Reactive Oxygen Species-Dependent c-Jun N-Terminal Kinase Signaling Pathway.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {1}, pages = {40}, doi = {10.31083/j.fbl2901040}, pmid = {38287817}, issn = {2768-6698}, support = {MRC-01-23-065//Medical Research Center, Hamad Medical Corporation/ ; }, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Benzophenanthridines/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Carcinoma, Squamous Cell/drug therapy ; *Skin Neoplasms/drug therapy ; Signal Transduction ; Apoptosis ; MAP Kinase Signaling System ; Cell Line, Tumor ; *Anthracenes ; *Isoquinolines ; }, abstract = {BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action.

METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (ΔΨm) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids.

RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, ΔΨm depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids.

CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.}, } @article {pmid38283455, year = {2023}, author = {Mohammed, HMI and Ahmad, F}, title = {Mushroom Poisoning: A Rare Etiology of Acute Liver Failure.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51144}, pmid = {38283455}, issn = {2168-8184}, abstract = {Acute liver failure is defined as a rapid deterioration in liver function, manifested by symptoms and signs of hepatic encephalopathy and disturbed synthetic function in a patient without Pre-existing cirrhosis and with an illness of less than 26 weeks duration. Mushroom poisoning as a cause of acute liver injury is rare but associated with deadly outcomes if not early recognized and treated. The mortality is very high in the case of amatoxin-containing mushrooms ingestion and liver transplantation is the only lifesaving option. Therefore, early recognition of a suspected patient who came with features of mushroom-related food poisoning, timely referral to a liver transplantation center, and adequate supportive management remain the main approaches of management in a patient with acute liver injury. We present a patient with gastroenteritis who ingested wild mushroom 14 hours prior to hospital admission with subsequent severe acute liver failure due to mushroom poisoning, successfully treated with urgent liver transplantation. This case study highlighted that careful evaluation of the symptoms and signs of acute liver failure in a patient with a history of mushroom ingestion can result in early referral to a liver transplant center, especially if the patient is systemically unwell.}, } @article {pmid38282602, year = {2024}, author = {Park, HR and Harris, SM and Boldenow, E and Aronoff, DM and Rea, M and Xi, C and Loch-Caruso, R}, title = {The antioxidant N-acetyl cysteine inhibits cytokine and prostaglandin release in human fetal membranes stimulated ex vivo with lipoteichoic acid or live group B streptococcus.}, journal = {American journal of reproductive immunology (New York, N.Y. : 1989)}, volume = {91}, number = {1}, pages = {e13807}, pmid = {38282602}, issn = {1600-0897}, support = {P42 ES017198/ES/NIEHS NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; R01 ES007062/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; R00 ES029548/ES/NIEHS NIH HHS/United States ; UL1 TR000433/TR/NCATS NIH HHS/United States ; UM1 TR004404/TR/NCATS NIH HHS/United States ; }, mesh = {Pregnancy ; Female ; Infant, Newborn ; Humans ; Cytokines/metabolism ; Lipopolysaccharides/pharmacology ; Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology/metabolism ; Dinoprostone/metabolism ; Prostaglandins/metabolism ; Streptococcus agalactiae ; Extraembryonic Membranes/metabolism ; *Chorioamnionitis ; *Streptococcal Infections ; *Teichoic Acids ; }, abstract = {BACKGROUNDS: Infection during pregnancy is a significant public health concern due to the increased risk of adverse birth outcomes. Group B Streptococcus or Streptococcus agalactiae (GBS) stands out as a major bacterial cause of neonatal morbidity and mortality. We aimed to explore the involvement of reactive oxygen species (ROS) and oxidative stress pathways in pro-inflammatory responses within human fetal membrane tissue, the target tissue of acute bacterial chorioamnionitis.

METHODS: We reanalyzed transcriptomic data from fetal membrane explants inoculated with GBS to assess the impact of GBS on oxidative stress and ROS genes/pathways. We conducted pathway enrichment analysis of transcriptomic data using the Database for Annotation, Visualization and Integrated Discovery (DAVID), a web-based functional annotation/pathway enrichment tool. Subsequently, we conducted ex vivo experiments to test the hypothesis that antioxidant treatment could inhibit pathogen-stimulated inflammatory responses in fetal membranes.

RESULTS: Using DAVID analysis, we found significant enrichment of pathways related to oxidative stress or ROS in GBS-inoculated human fetal membranes, for example, "Response to Oxidative Stress" (FDR = 0.02) and "Positive Regulation of Reactive Oxygen Species Metabolic Process" (FDR = 2.6*10[-4]). There were 31 significantly changed genes associated with these pathways, most of which were upregulated after GBS inoculation. In ex vivo experiments with choriodecidual membrane explants, our study showed that co-treatment with N-acetylcysteine (NAC) effectively suppressed the release of pro-inflammatory cytokines (IL-6, IL-8, TNF-α) and prostaglandin PGE2, compared to GBS-treated explants (p < .05 compared to GBS-treated samples without NAC co-treatment). Furthermore, NAC treatment inhibited the release of cytokines and PGE2 stimulated by lipoteichoic acid (LTA) and lipopolysaccharide (LPS) in whole membrane explants (p < .05 compared to LTA or LPS-treated samples without NAC co-treatment).

CONCLUSIONS: Our study sheds light on the potential roles of ROS in governing the innate immune response to GBS infection, offering insights for developing strategies to mitigate GBS-related adverse outcomes.}, } @article {pmid38279215, year = {2024}, author = {Castro, MC and Villagarcía, HG and Di Sarli Gutiérrez, L and Arbeláez, LG and Schinella, G and Massa, ML and Francini, F}, title = {Akt Signaling and Nitric Oxide Synthase as Possible Mediators of the Protective Effect of N-acetyl-L-cysteine in Prediabetes Induced by Sucrose.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38279215}, issn = {1422-0067}, support = {CONICET (PIP-2021/2023)//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; M-231//National University of La Plata - Argentina/ ; PICT 2017-2993//FONCYT/ ; }, mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/metabolism ; *Prediabetic State/drug therapy ; Rats, Wistar ; *Diabetes Mellitus, Type 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Sucrose/pharmacology ; *Insulin Resistance ; Oxidative Stress ; Insulin/metabolism ; Signal Transduction ; Glucose/pharmacology ; Nitric Oxide/metabolism ; }, abstract = {The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).}, } @article {pmid38274165, year = {2024}, author = {Sun, YL and Chang, HF and Chiang, PH and Lin, MW and Lin, CH and Kuo, CM and Lin, TC and Lin, CS}, title = {Fabrication and application of glutathione biosensing SPCE strips with gold nanoparticle modification.}, journal = {RSC advances}, volume = {14}, number = {6}, pages = {3808-3819}, pmid = {38274165}, issn = {2046-2069}, abstract = {Glutathione (GSH) is a major antioxidant in organisms. An alteration in GSH concentration has been implicated in a number of pathological conditions. Therefore, GSH sensing has become a critical issue. In this study, a disposable strip used for tyrosinase-modified electrochemical testing was fabricated for the detection of GSH levels in vivo. The system is based on tyrosinase as a biorecognition element and a screen-printed carbon electrode (SPCE) as an amperometric transducer. On the tyrosinase-SPCE strips, the oxidation reaction from catechol to o-quinone was catalyzed by tyrosinase. The tyrosinase-SPCE strips were modified with gold nanoparticles (AuNPs). In the presence of AuNPs of 25 nm diameter, the cathodic peak current of cyclic voltammetry (CV) was significantly enhanced by 5.2 fold. Under optimized conditions (250 μM catechol, 50 mM phosphate buffer, and pH 6.5), the linear response of the tyrosinase-SPCE strips ranged from 31.25 to 500 μM GSH, with a detection limit of approximately 35 μM (S/N > 3). The tyrosinase-SPCE strips have been used to detect real samples of plasma and tissue homogenates in a mouse experiment. The mice were orally administrated with N-acetylcysteine (NAC) 100 mg kg[-1] once a day for 7 days; the plasma GSH significantly enhanced 2.8 fold as compared with saline-treated mice (1123 vs. 480 μM μg[-1] protein). NAC administration also could alleviate the adverse effect of GSH reduction in the mice treated with doxorubicin.}, } @article {pmid38270755, year = {2024}, author = {Zhang, H and Huang, Y}, title = {Genome-wide identification and characterization of greenbug-inducible NAC transcription factors in sorghum.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {207}, pmid = {38270755}, issn = {1573-4978}, mesh = {*Sorghum/genetics ; Edible Grain ; Genotype ; Acetylcysteine ; }, abstract = {BACKGROUND: Sorghum (Sorghum bicolor) is an important cereal crop grown worldwide because of its multipurpose uses such as food, forage, and bioenergy feedstock and its wide range of adaption even in marginal environments. Greenbug can cause severe damage to sorghum plants and yield loss. Plant NAC transcription factors (TFs) have been reported to have diverse functions in plant development and plant defense but has not been studied in sorghum yet.

METHODS AND RESULTS: In this study, a comprehensive analysis of the sorghum NAC (SbNAC) gene family was conducted through genome-wide analysis. A total of 112 NAC genes has been identified in the sorghum genome. These SbNAC genes are phylogenetically clustered into 15 distinct subfamilies and unevenly distribute in clusters at the telomeric ends of each chromosome. Twelve pairs of SbNAC genes are possibly involved in the segmental duplication among nine chromosomes except chromosome 10. Structure analysis showed the diverse structures with a highly variable number of exons in the SbNAC genes. Furthermore, most of the SbNAC genes showed specific temporal and spatial expression patterns according to the results of RNA-seq analysis, suggesting their diverse functions during sorghum growth and development. We have also identified nine greenbug-inducible SbNAC genes by comparing the expression profiles between two sorghum genotypes (susceptible BTx623 and resistant PI607900) in response to greenbug infestation.

CONCLUSIONS: Our systematic analysis of the NAC gene expression profiles provides both a preliminary survey into their roles in plant defense against insect pests and a useful reference for in-depth characterization of the SbNAC genes and the regulatory network that contributes genetic resistance to aphids.}, } @article {pmid38269219, year = {2023}, author = {Schaefer, J and Khanna, D}, title = {Nutritional and Wellness Strategies for Neurological and Psychiatric Recovery From Post-COVID Syndrome and Post-acute Sequelae of COVID-19.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51076}, pmid = {38269219}, issn = {2168-8184}, abstract = {The post-COVID syndrome was officially recognized as a disability under the Americans with Disabilities Act, indicating that this syndrome has made a significant impact on our populace. Also, post-acute sequelae of COVID-19 (PASC) is a term that describes the long-term health problems that some people experience after being infected with the virus that causes COVID-19. These problems can last for weeks, months, or even years, and can affect various parts of the body, such as the heart, lungs, brain, and blood vessels. This narrative review paper utilized the PubMed database to explore the pathophysiology of post-COVID syndrome's neurological and psychiatric symptoms and PASC and make therapeutic connections to the known mechanisms of various nutritional, supplemental, and wellness approaches. Searches were queried on the PubMed database between March 29 and April 16, 2022, using the phrases "long-covid," "post-COVID syndrome," "Vitamin D covid," "vitamin C covid," "omega-3 covid," "kynurenine covid," "whole-body hyperthermia," "mushrooms immunity," "n-acetyl cysteine covid," "mushrooms cognition," "sugar consumption inflammation," and "covid microbiome." Articles were screened for their relevance to the discussion of post-COVID syndrome's neurological and psychiatric pathophysiology at the discretion of the principal researcher. There were no limitations regarding publication years, but articles from 2005 to April 2022 were cited. Micro-ischemic disease, neuropathy, autoimmune processes, mast-cell activation, and impaired blood-brain barriers have all been implicated in the pathological processes of this syndrome with varying degrees of supportive evidence. The common denominators, however, are inflammation and oxidative stress. Therefore, a beneficial approach to dealing with the complications of post-COVID syndrome would be to reduce the exacerbations of these common denominators with lifestyle and nutritional changes. Replenishing nutritional deficiencies, supplementing with N-acetylcysteine, decreasing consumption of refined sugars, preventing dysbiosis of the microbiome, performing exercises, increasing dietary intake of mushrooms, utilizing beneficial herbs such as rosemary, and increasing the core body temperature through whole-body hyperthermia seem to show potential for efficacy in this pursuit. Considering the safety and evidence-based connections of the therapies explored for dealing with the post-Covid syndrome, it could be of great benefit and of little harm to our patients to include these considerations in formulating post-Covid treatment plans.}, } @article {pmid38250216, year = {2024}, author = {Zavala-Valencia, AC and Velasco-Hidalgo, L and Martínez-Avalos, A and Castillejos-López, M and Torres-Espíndola, LM}, title = {Effect of N-Acetylcysteine on Cisplatin Toxicity: A Review of the Literature.}, journal = {Biologics : targets & therapy}, volume = {18}, number = {}, pages = {7-19}, pmid = {38250216}, issn = {1177-5475}, abstract = {N-acetylcysteine (NAC) is a membrane-permeable cysteine precursor capable of enhancing the intracellular cysteine pool, enhancing cellular glutathione (GSH) synthesis, and thus potentiating the endogenous antioxidant mechanism. Late administration of NAC after cisplatin has been shown in different in vivo studies to reduce the side effects caused by various toxicities at different levels without affecting the antitumor efficacy of platinum, improving total and enzymatic antioxidant capacity and decreasing oxidative stress markers. These characteristics provide NAC with a rationale as a potentially effective chemo protectant in cisplatin-based therapeutic cycles. NAC represents a potential candidate as a chemoprotective agent to decrease toxicities secondary to cisplatin treatment. It suggests that it could be used in clinical trials, whereby the effective dose, timing, and route should be adjusted to optimize chemoprotection. This review provides an overview of the effect of NAC on cisplatin toxicity, a drug widely used in the clinic in adults and children.}, } @article {pmid38247538, year = {2024}, author = {Sun, J and Chen, Y and Wang, T and Ali, W and Ma, Y and Liu, Z and Zou, H}, title = {Role of Mitochondrial Reactive Oxygen Species-Mediated Chaperone-Mediated Autophagy and Lipophagy in Baicalin and N-Acetylcysteine Mitigation of Cadmium-Induced Lipid Accumulation in Liver.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {38247538}, issn = {2076-3921}, support = {31872533//National Natural Science Foundation of China/ ; 32072933//National Natural Science Foundation of China/ ; 32273086//National Natural Science Foundation of China/ ; }, abstract = {Cadmium (Cd) is a major health concern globally and can accumulate and cause damage in the liver for which there is no approved treatment. Baicalin and N-acetylcysteine (NAC) have been found to have protective effects against a variety of liver injuries, but it is not clear whether their combined use is effective in preventing and treating Cd-induced lipid accumulation. The study found that Cd increased the production of mitochondrial reactive oxygen species (mROS) and elevated the level of chaperone-mediated autophagy (CMA). Interestingly, mROS-mediated CMA exacerbates the Cd-induced inhibition of lipophagy. Baicalin and NAC counteracted inhibition of lipophagy by attenuating Cd-induced CMA, suggesting an interplay between CMA elevation, mitochondrial destruction, and mROS formation. Maintaining the stability of mitochondrial structure and function is essential for alleviating Cd-induced lipid accumulation in the liver. Choline is an essential component of the mitochondrial membrane and is responsible for maintaining its structure and function. Mitochondrial transcriptional factor A (TFAM) is involved in mitochondrial DNA transcriptional activation and replication. Our study revealed that the combination of baicalin and NAC can regulate choline metabolism through TFAM and thereby maintain mitochondrial structure and functionality. In summary, the combination of baicalin and NAC plays a more beneficial role in alleviating Cd-induced lipid accumulation than the drug alone, and the combination of baicalin and NAC can stabilize mitochondrial structure and function and inhibit mROS-mediated CMA through TFAM-choline, thereby promoting lipophagy to alleviate Cd-induced lipid accumulation.}, } @article {pmid38247506, year = {2024}, author = {Kyriakou, S and Demosthenous, N and Amery, T and Stewart, KJ and Winyard, PG and Franco, R and Pappa, A and Panayiotidis, MI}, title = {Naturally Derived Phenethyl Isothiocyanate Modulates Induction of Oxidative Stress via Its N-Acetylated Cysteine Conjugated form in Malignant Melanoma.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {38247506}, issn = {2076-3921}, abstract = {Phenethyl isothiocyanate (PEITC) is a secondary metabolic product yielded upon the hydrolysis of gluconasturtiin and it is highly accumulated in the flowers of watercress. The aim of the current study was to assess the role of a naturally derived PEITC-enriched extract in the induction of oxidative stress and to evaluate its anti-melanoma potency through the regulation of its metabolism with the concurrent production of the N-acetyl cysteine conjugated by-product. For this purpose, an in vitro melanoma model was utilized consisting of human primary (A375) cells as well as metastatic (COLO-679) malignant melanoma cells together with non-tumorigenic immortalized keratinocytes (HaCaT). Cytotoxicity was assessed via the Alamar Blue assay whereas the antioxidant/prooxidant activity of PEITC was determined via spectrophotometric assays. Finally, kinetic characterization of the end-product of PEITC metabolism was monitored via UPLC coupled to a tandem mass spectrometry (MS/MS). Our results indicate that although PhEF showed very minor antioxidant activity in a cell-free system, in a cell-based system, it can modulate the activity of key enzyme(s) involved in cellular antioxidant defense mechanism(s). In addition, we have shown that PhEF induces lipid and protein oxidation in a concentration-dependent manner, while its cytotoxicity is not only dependent on PEITC itself but also on its N-acetylated cysteine conjugated form.}, } @article {pmid38246558, year = {2024}, author = {Hao, X and Liu, M and Zhang, X and Yu, H and Fang, Z and Gao, X and Chen, M and Shao, Q and Gao, W and Lei, L and Song, Y and Li, X and Liu, G and Du, X}, title = {Thioredoxin-2 suppresses hydrogen peroxide-activated nuclear factor kappa B signaling via alleviating oxidative stress in bovine adipocytes.}, journal = {Journal of dairy science}, volume = {107}, number = {6}, pages = {4045-4055}, doi = {10.3168/jds.2023-23465}, pmid = {38246558}, issn = {1525-3198}, mesh = {Animals ; Cattle ; *Hydrogen Peroxide/pharmacology/metabolism ; *Oxidative Stress/drug effects ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *Adipocytes/drug effects/metabolism ; *Thioredoxins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Female ; }, abstract = {During the periparturient period, both oxidative stress, and inflammation of adipose tissue are considered high risk factors for metabolic disorder of dairy cows. Oxidative stress can activate transcription factor nuclear factor kappa B (NF-κB), which lead to the upregulation of genes involved in inflammatory pathways. Thioredoxin-2 (TXN2) is a mitochondrial protein that regulates cellular redox by suppressing mitochondrial reactive oxygen species (ROS) generation in nonruminant, whereas the function of TXN2 in bovine adipocytes was unclear. Thus, the objective of this study was to evaluate how or by which mechanisms TXN2 regulates oxidative stress and NF-κB signaling pathway in bovine adipocytes. Bovine pre-adipocytes isolated from 5 healthy Holstein cows were differentiated and used for (1) treatment with different concentrations of hydrogen peroxide (H2O2; 0, 25, 50, 100, 200, or 400 μM) for 2 h; (2) transfection with or without TXN2 small interfering RNA (si-TXN2) for 48 h and then treated with or without 200 μM H2O2 for 2 h; (3) transfection with scrambled negative control siRNA (si-control) or si-TXN2 for 48 h, and then treatment with or without 10 mM N-acetylcysteine (NAC) for 2 h; (4) transfection with or without TXN2-overexpressing plasmid for 48 h and then treatment with or without 200 μM H2O2 for 2 h. High concentrations of H2O2 (200 and 400 μM) decreased protein and mRNA abundance of TXN2, reduced total antioxidant capacity (T-AOC) and ATP content in adipocytes. Moreover, 200 and 400 μM H2O2 reduced protein abundance of inhibitor of kappa B α (IκBα), increased phosphorylation of NF-κB and upregulated mRNA abundance of tumor necrosis factor-α (TNFA) and interleukin-1B (IL-1B), suggesting that H2O2-induced oxidative stress and activated NF-κB signaling pathway. Silencing of TXN2 increased intracellular ROS content, phosphorylation of NF-κB and mRNA abundance of TNFA and IL-1B, decreased ATP content and protein abundance of IκBα in bovine adipocytes. Knockdown of TXN2 aggravated H2O2-induced oxidative stress and inflammation. In addition, treatment with antioxidant NAC ameliorated oxidative stress and inhibited NF-κB signaling pathway in adipocytes transfected with si-TXN2. In bovine adipocytes treated with H2O2, overexpression of TXN2 reduced the content of ROS and elevated the content of ATP and T-AOC. Overexpression of TXN2 alleviated H2O2-induced inflammatory response in adipocytes, as demonstrated by decreased expression of phosphorylated NF-κB, TNFA, IL-1B, as well as increased expression of IκBα. Furthermore, the protein and mRNA abundance of TXN2 was lower in adipose tissue of dairy cows with clinical ketosis. Overall, our studies contribute to the understanding of the role of TXN2 in adipocyte oxidative stress and inflammatory response.}, } @article {pmid38245726, year = {2024}, author = {Lee, JH and Jaiswal, MS and Jang, YS and Choi, JH and Kim, GC and Hong, JW and Hwang, DS}, title = {No-ozone cold plasma induces apoptosis in human neuroblastoma cell line via increased intracellular reactive oxygen species (ROS).}, journal = {BMC complementary medicine and therapies}, volume = {24}, number = {1}, pages = {46}, pmid = {38245726}, issn = {2662-7671}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; *Plasma Gases/pharmacology/therapeutic use ; *Ozone/pharmacology/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use ; Cell Line, Tumor ; Apoptosis ; *Neuroblastoma/drug therapy/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: This study aimed to evaluate the effect of argon-based No-ozone Cold Plasma (NCP) on neuroblastoma cancer cell apoptosis.

METHODS: Experiments were performed with SK-N-SH and HS 68. Cell cultures were treated with NCP for 1, 3, and 5 min. NCP was applied using three different strategies: direct NCP application to cell cultures, to only media, and to only cells. Evaluation of cell viability and the level of the reactive oxygen species (ROS) was performed. N-acetyl-L-cysteine (NAC) was also used to antagonize intracellular ROS. Cleaved caspase 3, PARP, aquaporin (AQP) 3 and 8 were detected.

RESULTS: NCP induced a gradual decrease in the SK-N-SH cell viability. In contrast, the viability of HS 68 cells did not change. SK-N-SH cells viability was reduced the most when the only media-NCP application strategy was employed. Intracellular ROS levels were significantly increased with time. Cleaved caspase 3 and PARP were increased at 6 h after NCP application. SK-N-SH cells remained viable with NAC after NCP application. AQP 3 and 8 were over-expressed in SK-N-SH cells.

CONCLUSION: These findings demonstrate the anti-cancer effect of NCP on neuroblastoma cells. NCP enhanced the selective apoptosis of neuroblastoma cells due to the increased intracellular ROS.}, } @article {pmid38236790, year = {2024}, author = {Tavanaeimanesh, H and Alinia, Z and Sadeghian Chaleshtori, S and Moosavian, H and Mohebi, Z and Daneshi, M}, title = {The efficacy of N-acetylcysteine in decreasing airway inflammation and mucus accumulation in horses with 18 hours of head confinement.}, journal = {Journal of veterinary internal medicine}, volume = {38}, number = {2}, pages = {1224-1231}, pmid = {38236790}, issn = {1939-1676}, mesh = {Animals ; *Acetylcysteine/therapeutic use ; Bronchoalveolar Lavage Fluid ; *Horse Diseases/drug therapy/prevention & control ; Horses ; Inflammation/drug therapy/veterinary ; Mucus ; Prospective Studies ; Trachea ; Cross-Over Studies ; }, abstract = {BACKGROUND: During transportation many horses develop post-transportation infection, which can be life-threatening and end their sport career. Preventing mucus accumulation and inflammation during transportation is vital, emphasizing the need for effective strategies to enhance overall horse health welfare.

OBJECTIVES: Assess the impact of N-acetylcysteine (NAC) on mucus accumulation and inflammation in horses subjected to 18 hours of head confinement.

ANIMALS: Six healthy crossbred horses, 5.3 ± 2.1 years of age and weighing 387 ± 30 kg.

METHODS: Prospective placebo-controlled cross-over design study. The horses' heads were restrained in their stalls for a period of 18 hours. They were studied under 4 conditions: Not confined (NC): before head confinement, placebo (P), and confined head (CH): 18 hours of head confinement without treatment, and N-Acetylcysteine (NAC): 18 hours of head confinement treated with NAC before confinement (15 mg/kg/day NAC PO for 3 days). Bronchoalveolar lavage (BAL) was performed in each condition. Mucus accumulation along the trachea was evaluated by endoscopy.

RESULTS: Endoscopic scores were significantly different between CH and other conditions, whereas no significant differences were found among NC, P, and NAC. The BAL cell count (34 291 ± 2624 cells/μL), neutrophil and lymphocyte count (18 601 ± 3193 cells/μL and 3337.4 ± 593 cells/μL, respectively) in CH were significantly higher compared to NAC. Neutrophil percentage was significantly higher in CH (53.8 ± 8%) compared to horses that received NAC (20.08 ± 8%). Conversely, in comparison to NAC (66.33 ± 9%), the percentage of macrophages was significantly lower in CH (35.7 ± 10%).

CONCLUSIONS: N-acetylcysteine was found to significantly decrease mucus accumulation and inflammatory cell counts in horses with head confinement.}, } @article {pmid38236698, year = {2024}, author = {Li, C and Li, X and Fan, A and He, N and Wu, D and Yu, H and Wang, K and Jiao, W and Zhao, X}, title = {Evidence for cytochrome P450 3A4-mediated metabolic activation of SCO-267.}, journal = {Biopharmaceutics & drug disposition}, volume = {45}, number = {1}, pages = {30-42}, doi = {10.1002/bdd.2381}, pmid = {38236698}, issn = {1099-081X}, mesh = {Humans ; Rats ; Animals ; *Cytochrome P-450 CYP3A/metabolism ; Activation, Metabolic ; *Diabetes Mellitus, Type 2/metabolism ; Quinones/metabolism ; Imines/metabolism ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; *Piperidines ; *Pyridines ; *Benzoquinones ; }, abstract = {SCO-267 is a potent G-protein-coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO-267 in vitro and in vivo. Three SCO-267-derived glutathione (GSH) conjugates (M1-M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1-M2) together with two N-acetyl-cysteine conjugates (M4-M5) were detected in the bile of rats receiving SCO-267 at 10 mg/kg. The identified conjugates suggested the generation of quinone-imine and ortho-quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO-267. In addition, SCO-267 concentration-, time-, and NADPH-dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with KI and kinact values of 4.91 μM and 0.036 min[-1] , respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO-267-induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO-267 undergoes a facile CYP3A4-catalyzed bioactivation with the generation of quinone-imine and ortho-quinone intermediates, which were assumed to be involved in SCO-267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO-267. Further studies are needed to evaluate the influence of SCO-267 metabolism on the safety of this drug in vivo.}, } @article {pmid38234666, year = {2024}, author = {Yalçin, T and Kuloğlu, T and Tektemur, NK and Tektemur, A and Ozan, İE}, title = {Effects of N-acetylcysteine on spexin immunoreactivity in kidney tissues of rats treated with adriamycin.}, journal = {Iranian journal of basic medical sciences}, volume = {27}, number = {2}, pages = {233-240}, pmid = {38234666}, issn = {2008-3866}, abstract = {OBJECTIVES: Due to its negative side effects, mainly nephrotoxicity, adriamycin (ADR) is used fairly infrequently. The purpose of this study is to investigate the effects of N-acetyl cysteine (NAC) on the immunoreactivity of spexin (SPX) in the kidney tissues of rats given ADR.

MATERIALS AND METHODS: A total of 28 male Sprague-Dawley rats were randomly assigned to four groups (n=7): control (no intervention), NAC (150 mg/kg/day, administered intraperitoneally), ADR (single dose of 15 mg/kg, administered intraperitoneally), and ADR+NAC (single dose of 15 mg/kg ADR + 150 mg/kg/day NAC, both administered intraperitoneally). The experiment was concluded on the 15[th] day.

RESULTS: The administration of ADR resulted in biochemical and histopathological alterations in the kidney. It was found that ADR treatment led to elevated levels of TOS (total oxidative stress), apoptosis, and SPX. Conversely, when NAC was administered as a treatment, it effectively reduced TOS, apoptosis, and SPX levels. These findings suggest that SPX may contribute to the development of ADR-induced kidney damage.

CONCLUSION: Further investigations are warranted to gain a comprehensive understanding of kidney damage, and specifically to elucidate the role of SPX in this context. Additionally, these studies can pave the way for exploring novel therapeutic strategies targeting SPX to prevent and/or treat the development of kidney damage.}, } @article {pmid38233317, year = {2024}, author = {Jung, E and Romero, R and Suksai, M and Gotsch, F and Chaemsaithong, P and Erez, O and Conde-Agudelo, A and Gomez-Lopez, N and Berry, SM and Meyyazhagan, A and Yoon, BH}, title = {Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.}, journal = {American journal of obstetrics and gynecology}, volume = {230}, number = {3S}, pages = {S807-S840}, pmid = {38233317}, issn = {1097-6868}, support = {Z01 HD002400/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Female ; Infant, Newborn ; Pregnancy ; Humans ; *Chorioamnionitis/diagnosis/drug therapy/etiology ; Clarithromycin/therapeutic use ; *Postpartum Hemorrhage/drug therapy ; *Neonatal Sepsis/diagnosis/drug therapy ; Anti-Bacterial Agents/therapeutic use ; Amniotic Fluid/microbiology ; Inflammation/metabolism ; Tachycardia ; }, abstract = {Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.}, } @article {pmid38230777, year = {2024}, author = {Nili-Ahmadabadi, A and Abdpour, S and Omidifar, N and Hashemi, SA and Mousavi, SM and Ahmadabadi, MN}, title = {Therapeutic potentials of N-acetylcysteine immobilized polyrhodanine nanoparticles toward acetaminophen-induced acute hepatotoxicity in rat.}, journal = {Chemical biology & drug design}, volume = {103}, number = {1}, pages = {e14430}, doi = {10.1111/cbdd.14430}, pmid = {38230777}, issn = {1747-0285}, support = {//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; }, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; Acetaminophen/toxicity ; Antioxidants/pharmacology/therapeutic use ; Saline Solution/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Liver ; *Nanoparticles ; Sulfhydryl Compounds ; }, abstract = {N-acetylcysteine (NAC) is a recommended drug for treating acetaminophen (APAP) intoxication. Due to NAC's low bioavailability, this study aimed to use polyrhodanine (PR) nanoparticles (NPs) as a drug carrier to improve the effectiveness of NAC. After preparation and characterization of NAC loaded on PR, 30 rats were randomly divided into five groups of six. The first group (control) received normal saline. Groups 2-5 were treated with normal saline, PR, NAC, and NAC loaded on PR, respectively. The treatments were started 4 h after oral administration of APAP (2000 mg kg[-1]). After 48 h, the animals were anesthetized, and liver function indices and oxidative stress were measured in tissue and serum samples. The APAP administration can increase aminotransferases and alkaline phosphatase enzymes in serum, decreasing the total antioxidant capacity and thiol groups and increasing lipid peroxidation in liver tissue. Administration of PR-NAC could effectively improve the level of serum-hepatic enzymes, total antioxidant capacity and thiol groups, lipid peroxidation, and pathological changes in liver tissue in animals poisoned with APAP. PR-NAC has a significant therapeutic effect on preventing acute hepatotoxicity caused by APAP, and its effectiveness can be associated with an improvement in the oxidant/antioxidant balance of liver tissue.}, } @article {pmid38230207, year = {2024}, author = {Wang, Q and Lin, B and Wei, H and Wang, X and Nie, X and Shi, Y}, title = {AQP3 Promotes the Invasion and Metastasis in Cervical Cancer by Regulating NOX4-derived H2O2 Activation of Syk/PI3K/Akt Signaling Axis.}, journal = {Journal of Cancer}, volume = {15}, number = {4}, pages = {1124-1137}, pmid = {38230207}, issn = {1837-9664}, abstract = {Unrestrained chronic inflammation leads to the abnormal activity of NOX4 and the subsequent production of excessive hydrogen peroxide (H2O2). Excessive H2O2 signaling triggered by prolonged inflammation is thought to be one of the important reasons for the progression of some types of cancer including cervical cancer. Aquaporin 3 (AQP3) is a member of the water channel protein family, and it remains unknown whether AQP3 can regulate the transmembrane transport of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)-derived H2O2 induced by the stimulation of inflammatory factors to facilitate the malignant progression in cervical cancer. In this study, cervical cancer HeLa cell line was respectively treated with diphenyleneiodonium (DPI), N-Acetylcysteine (NAC) or lentivirus-shRNA- AQP3. Plate cloning, cell migration or transwell invasion assays, etc. were performed to detect the invasive and migration ability of the cells. Western blot and CO-IP were used to analyze the mechanism of AQP3 regulating H2O2 conduction. Finally, in vivo assays were performed for validation in nude mice. AQP3 Knockdown, DPI or NAC treatments all reduced intracellular H2O2 influx, and the activation of Syk/PI3K/Akt signal axis was inhibited, the migration and invasive ability of the cells was attenuated. In vivo assays confirmed that the excessive H2O2 transport through AQP3 enhanced the infiltration and metastasis of cervical cancer. These results suggest that AQP3 activates H2O2/Syk/PI3K/Akt signaling axis through regulating NOX4-derived H2O2 transport to contribute to the progression of cervical cancer, and AQP3 may be a potential target for the clinical treatment of advanced cervical cancer.}, } @article {pmid38216781, year = {2024}, author = {Zhao, Q and Yu, M and Li, J and Guo, Y and Wang, Z and Hu, K and Xu, F and Liu, Y and Li, L and Wan, D and Zhao, Y and Shang, J and Zhang, J}, title = {GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis.}, journal = {Discover oncology}, volume = {15}, number = {1}, pages = {8}, pmid = {38216781}, issn = {2730-6011}, support = {No. 212102310124//the Key Scientific and Technological Project of Henan Province/ ; No. 222102310083//the Key Scientific and Technological Project of Henan Province/ ; No. 222300420306//the Natural Science Foundation of Henan/ ; No. 2023BP0206//the Project of Basic Research Fund of Henan Institute of Medical and Pharmacological Sciences/ ; }, abstract = {Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was firstly examined and presented as that both the protein and mRNA levels were down-regulated in tumor tissues compared to the normal liver tissues. GLUD1 overexpression significantly inhibited HCC cells proliferation, migration, invasion and tumor growth both in vitro and in vivo, while GLUD1 knocking-down promoted HCC progression. Metabolomics study of GLUD1 overexpressing and control HCC cells showed that 129 differentially expressed metabolites were identified, which mainly included amino acids, bases, and phospholipids. Moreover, metabolites in mitochondrial oxidative phosphorylation system (OXPHOS) were differentially expressed in GLUD1 overexpressing cells. Mechanistic studies showed that GLUD1 overexpression enhanced mitochondrial respiration activity and reactive oxygen species (ROS) production. Excessive ROS lead to mitochondrial apoptosis that was characterized by increased expression levels of p53, Cytochrome C, Bax, Caspase 3 and decreased expression level of Bcl-2. Furthermore, we found that the p38/JNK MAPK pathway was activated in GLUD1 overexpressing cells. N-acetylcysteine (NAC) treatment eliminated cellular ROS and blocked p38/JNK MAPK pathway activation, as well as cell apoptosis induced by GLUD1 overexpression. Taken together, our findings suggest that GLUD1 inhibits HCC progression through regulating cellular metabolism and oxidative stress state, and provide that ROS generation and p38/JNK MAPK pathway activation as promising methods for HCC treatment.}, } @article {pmid38216081, year = {2024}, author = {Zhu, G and Zeng, Y and Peng, W and Lu, C and Cai, H and Abuduxukuer, Z and Chen, Y and Chen, K and Song, X and Song, Y and Ye, L and Wang, J and Jin, M}, title = {Edaravone alleviated allergic airway inflammation by inhibiting oxidative stress and endoplasmic reticulum stress.}, journal = {European journal of pharmacology}, volume = {966}, number = {}, pages = {176317}, doi = {10.1016/j.ejphar.2024.176317}, pmid = {38216081}, issn = {1879-0712}, mesh = {Mice ; Animals ; *Immunity, Innate ; Edaravone/pharmacology/therapeutic use ; Cytokines/metabolism ; Endoribonucleases/metabolism ; Hydrogen Peroxide/pharmacology ; Lymphocytes ; Protein Serine-Threonine Kinases/metabolism ; *Asthma/metabolism ; Lung ; Inflammation/drug therapy/metabolism ; Oxidative Stress ; Oxidants/pharmacology ; Pyroglyphidae/metabolism ; Disease Models, Animal ; }, abstract = {Oxidative stress and endoplasmic reticulum stress (ERS) was associated with the development of asthma. Edaravone (EDA) plays a classical role to prevent the occurrence and development of oxidative stress-related diseases. Herein, we investigated the involvement and signaling pathway of EDA in asthma, with particular emphasis on its impact on type 2 innate lymphoid cells (ILC2) and CD4[+]T cells, and then further elucidated whether EDA could inhibit house dust mite (HDM)-induced allergic asthma by affecting oxidative stress and ERS. Mice received intraperitoneally injection of EDA (10 mg/kg, 30 mg/kg), dexamethasone (DEX) and N-acetylcysteine (NAC), with the latter two used as positive control drugs. DEX and high dose of EDA showed better therapeutic effects in alleviating airway inflammation and mucus secretion in mice, along with decreasing eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) than NAC. Further, the protein levels of IL-33 in lung tissues were inhibited by EDA, leading to reduced activation of ILC2s in the lung. EDA treatment alleviated the activation of CD4[+] T cells in lung tissues of HDM-induced asthmatic mice and reduced Th2 cytokine secretion in BALF. ERS-related markers (p-eIF2α, IRE1α, CHOP, GRP78) were decreased after treatment of EDA compared to HDM group. Malondialdehyde (MDA), glutathione (GSH), hydrogen peroxide (H2O2), and superoxide dismutase (SOD) were detected to evaluate the oxidant stress in lung tissues. EDA showed a protective effect against oxidant stress. In conclusion, our findings demonstrated that EDA could suppress allergic airway inflammation by inhibiting oxidative stress and ERS, suggesting to serve as an adjunct medication for asthma in the future.}, } @article {pmid38215974, year = {2024}, author = {Eslami Ghayour, A and Nazari, S and Keramat, F and Shahbazi, F and Eslami-Ghayour, A}, title = {Evaluation of the efficacy of N-acetylcysteine and bromhexine compared with standard care in preventing hospitalization of outpatients with COVID-19: a double blind randomized clinical trial.}, journal = {Revista clinica espanola}, volume = {224}, number = {2}, pages = {86-95}, doi = {10.1016/j.rceng.2023.12.011}, pmid = {38215974}, issn = {2254-8874}, mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; Outpatients ; COVID-19 Vaccines ; *Bromhexine ; Iran ; Treatment Outcome ; Hospitalization ; }, abstract = {INTRODUCTION AND AIM: Since its emergence in December 2019, the coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 has become a global emergency, spreading rapidly worldwide. In response to the early referral of these patients to outpatient health centers, we decided to seek more effective treatments in the early stages of their referral. This study aims to prevent both the progression and deterioration of the physical conditions of COVID-19 patients, reduce the rate of referrals, and mitigate the risks of hospitalization and death.

MATERIAL AND METHODS: Conducted at Dibaj Therapeutic Center, Hamadan City, Iran, a double-blind randomized controlled trial encompassed 225 COVID-19 patients from April to September 2022. Ethical approval was obtained from Hamadan University of Medical Sciences (Approval No.: IR.UMSHA.REC.1400.957), with the protocol registered in the Iranian Registry of Clinical Trials (Registration No. : IRCT20220302054167N1). In this study, we included patients who tested positive for COVID-19- PCR and were symptomatic, excluding those who were pregnant or had received a COVID-19 vaccine. Patients with oxygen saturation above 92% were allocated to three groups: Group A received N-acetylcysteine, Group B received Bromhexine, and Group C received standard care. Follow-ups on oxygen levels, symptoms, and hospitalization needs were conducted on days 7 and 14, with hospitalized patients monitored for one month post-hospitalization.

RESULTS: The study found that both N-acetylcysteine and Bromhexine can effectively reduce hospitalization rates and mortality and shorten the duration of hospitalization. The third visit of patients who received N-acetylcysteine showed an increase of 1.33% in oxygen saturation compared to their first visit, and in patients who received Bromhexine, this increase was 1.19%. The mortality rate was 9.33% in the control group and zero in both groups of patients who received medication.

CONCLUSION: In conclusion, the results of this study indicate that NAC and bromhexine may be effective in the treatment of patients with positive COVID-19, with a lower hospitalization rate, shorter hospitalization, faster recovery time, and reduced mortality compared to the control group.}, } @article {pmid38215930, year = {2024}, author = {Katebi, SN and Torkaman-Boutorabi, A and Riahi, E and Haghparast, A}, title = {N-acetylcysteine attenuates accumbal core neuronal activity in response to morphine in the reinstatement of morphine CPP in morphine extinguished rats.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {131}, number = {}, pages = {110942}, doi = {10.1016/j.pnpbp.2024.110942}, pmid = {38215930}, issn = {1878-4216}, mesh = {Humans ; Rats ; Animals ; *Morphine/pharmacology ; *Acetylcysteine/pharmacology ; Rats, Wistar ; Extinction, Psychological/physiology ; Nucleus Accumbens ; Neurons ; }, abstract = {Numerous studies have suggested that N-acetylcysteine (NAC), has the potential to suppress drug craving in people with substance use disorder and reduce drug-seeking behaviors in animals. The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, with the nucleus accumbens core (NAcore) specifically implicated in compulsive drug seeking and relapse. In this study, we aimed to explore the impact of subchronic NAC administration during the extinction period and acute NAC administration on the electrical activity of NAcore neurons in response to a priming dose of morphine in rats subjected to extinction from morphine-induced place preference (CPP).We conducted single-unit recordings in anesthetized rats on the reinstatement day, following the establishment of morphine-induced conditioned place preference (7 mg/kg, s.c., 3 days), and subsequent drug-free extinction. In the subchronically NAC-treated groups, rats received daily injections of either NAC (50 mg/kg; i.p.) or saline during the extinction period. On the reinstatement day, we recorded the spontaneous activity of NAcore neurons for 15 min, administered a priming dose of morphine, and continued recording for an additional 45 min. While morphine excited most recorded neurons in saline-treated rats, it failed to alter firing rates in NAC-treated rats that had received NAC during the extinction period. For acutely NAC-treated animals, we recorded the baseline activity of NAcore neurons for 10 min before administering a single injection of either NAC (50 mg/kg; i.p.) or saline in rats with no treatment during the extinction. Following 30 min of recording and a priming dose of morphine (1 mg/kg, s.c.), the recording continued for an additional 30 min. The firing activity of NAcore neurons did not show significant changes after morphine or NAC injection. In conclusion, our findings emphasize that daily NAC administration during the extinction period significantly attenuates the morphine-induced increase in firing rates of NAcore neurons during the reinstatement of morphine CPP. However, acute NAC injection does not produce the same effect. These results suggest that modulating glutamate transmission through daily NAC during extinction may effectively inhibit the morphine place preference following the excitatory effects of morphine on NAcore neurons.}, } @article {pmid38213396, year = {2023}, author = {Fort, TD and Cain, ME}, title = {Inefficacy of N-acetylcysteine in mitigating cue-induced amphetamine-seeking.}, journal = {Addiction neuroscience}, volume = {8}, number = {}, pages = {}, pmid = {38213396}, issn = {2772-3925}, support = {P20 GM113109/GM/NIGMS NIH HHS/United States ; R15 DA035435/DA/NIDA NIH HHS/United States ; }, abstract = {Glutamatergic imbalances are characteristic of SUDs. Astrocytic and neuronal transporters help regulate glutamate homeostasis and disruptions in this homeostasis engender SUD. The cysteine-glutamate exchanger (xCT) is primarily localized on astrocytes and maintains glutamate concentrations. This process is disrupted by cocaine use, and the therapeutic N-acetylcysteine (NAC) lowers cue-induced relapse to cocaine by restoring xCT function. However, little research has shown how these effects extend to other psychostimulants, such as amphetamine (AMP). Here, we assessed xCT expression following relapse to AMP cues, and if NAC can attenuate relapse via changes to astrocyte and xCT expression. We administered NAC (100 mg/kg ip) daily during a 14-day abstinence period following AMP (0.1 mg/kg/infusion; 2 h sessions) self-administration. Relapse was tested following one (WD 1) or 14 days (WD 14) of withdrawal. The overall number of astrocytes was also quantified within the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb). NAC failed to lower cue-induced AMP craving via cue-induced relapse and reinstatement testing. Cue-induced craving did not increase from WD 1 to WD 14. AMP-exposed rats had greater astrocyte counts in the mPFC and ACb when compared AMP-naïve rats. Repeated injection with NAC decreased xCT expression within the mPFC and ACb. Overall, these results suggest that NAC may be an ineffective treatment option for lowering cue-induced relapse to AMP. Further, the results suggest that stimulating xCT via NAC may not be an effective therapeutic approach for decreasing cue-seeking for AMP.}, } @article {pmid38212360, year = {2024}, author = {Komakula, S and Bhatia, R and Sahib, A and Upadhyay, A and S, LJ and Garg, A and Y, VV and Pandit, AK and Vibha, D and Singh, MB and Tripathi, M and Srivastava, MVP}, title = {Safety and efficacy of N-acetylcysteine (NAC) as an adjunct to standard treatment in patients with acute ischemic stroke: a randomized controlled pilot trial (NACTLYS).}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {1103}, pmid = {38212360}, issn = {2045-2322}, mesh = {Humans ; Tissue Plasminogen Activator/adverse effects ; Acetylcysteine/adverse effects ; Pilot Projects ; *Ischemic Stroke/etiology ; Treatment Outcome ; Fibrinolytic Agents/adverse effects ; *Stroke ; Cerebral Hemorrhage/complications ; *Brain Ischemia/complications ; Thrombolytic Therapy/adverse effects ; }, abstract = {There is a pressing clinical need for thrombolytic agents that can effectively disaggregate arterial thrombi in acute ischemic stroke without significantly increasing the risk of bleeding. This pilot study aimed to investigate the safety and efficacy of N-acetylcysteine (NAC) as an adjunctive therapy to intravenous recombinant tissue plasminogen activator (rtPA or alteplase). A randomized, open-label, blinded assessor pilot study was conducted. Patients presenting with an acute ischemic stroke within 4.5 h from onset were randomized into two groups: intravenous NAC and rtPA or rtPA alone. Primary outcomes included intracerebral hemorrhage, symptomatic intracerebral hemorrhage, extracranial bleeding, and adverse reactions. Secondary outcomes comprised major neurological improvement assessed by (National Institute of Health Stroke Scale) NIHSS at 24 h, recanalization on first run of angiography in patients who underwent thrombectomy or on repeat vascular imaging at 24 h, modified Rankin scale, and three-month mortality. Forty patients were enrolled, with 21 receiving only rtPA and 19 receiving NAC with rtPA. Baseline characteristics were comparable among groups. No significant differences were observed in adverse events (p = 0.99), intracranial hemorrhage (p = 0.21), symptomatic intracerebral hemorrhage (p = 0.47), or extracranial bleeding (p = 0.21). Median NIHSS at 24 h was significantly lower in the intervention group (p = 0.03). Functional outcomes and three-month mortality were similar between groups (p = 0.85 and p = 0.99 respectively). The co-administration of N-acetylcysteine with alteplase did not significantly alter safety profiles, morbidity, or mortality at 3 months. While no substantial differences were noted, a slightly improved early neurological outcome was observed in the intervention arm. The study's findings were constrained by a small sample size, emphasizing the necessity for future large-scale trials to comprehensively evaluate the safety and efficacy of N-acetylcysteine as a thrombolytic agent in acute ischemic stroke.Trial Registration Clinical Trials Registry India-CTRI/2019/05/019305.}, } @article {pmid38212034, year = {2023}, author = {Ma, TX and Li, JT and Li, J and Zhang, Y and Liang, JQ}, title = {[Guiqi Yiyuan Ointment protects rat left lung from bystander effect of right lung injury induced by ~(12)C~(6+) beam].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {48}, number = {24}, pages = {6740-6748}, doi = {10.19540/j.cnki.cjcmm.20230914.702}, pmid = {38212034}, issn = {1001-5302}, mesh = {Rats ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; NF-kappa B/genetics/metabolism ; Inflammasomes/metabolism ; *Lung Injury/etiology/genetics ; Reactive Oxygen Species/metabolism ; Bystander Effect ; Ointments ; Rats, Wistar ; Lung/metabolism ; Caspase 1/metabolism ; RNA, Messenger ; Superoxide Dismutase ; }, abstract = {This study observed the effects of Guiqi Yiyuan Ointment(GQYY) on the left lung subjecting to bystander effect of right lung injury induced by ~(12)C~(6+) beam in rats and decipher the underlying mechanism from NOD-like receptor protein 3(NLRP3)/apoptosis-associated speck-like protein containing a CARD(ASC)/cysteinyl aspartate specific proteinase-1(caspase-1) pathway. Wistar rats were randomized into 7 groups: blank, model, inhibitor [200 mg·kg~(-1), N-acetylcysteine(NAC)], western drug [140 mg·kg~(-1) amifostine(AMI)], and high-, medium-, and low-dose(4.8, 2.4, and 1.2 g·kg~(-1), respectively) GQYY groups. The model of bystander effect damage was established by 4 Gy ~(12)C~(6+) beam irradiation of the right lung(with the other part shielded by a lead plate). The pathological changes in the lung tissue, the level of reactive oxygen species(ROS) in the lung tissue, and the levels of superoxide dismutase(SOD) and malondialdehyde(MDA) in the serum were observed and measured in each group. Furthermore, the mRNA and protein levels of NLRP3, ASC, caspase-1, and phosphorylated nuclear factor-κB p65(p-NF-κB p65)/nuclear factor-κB p65(NF-κB p65) were determined. Compared with the blank group, the model group showed thickened alveolar wall, narrowed alveolar cavity, and presence of massive red blood cells and inflammatory infiltration in the alveolar wall and alveolar cavity. In addition, the model group showed elevated ROS levels in both left and right lungs, elevated MDA level, lowered SOD level, and up-regulated mRNA and protein levels of NLRP3, ASC, caspase-1, and p-NF-κB p65/NF-κB p65. Compared with the model group, the drug administration in all the groups reduced inflammatory cell infiltration in the lung tissue. The inhibitor group and the western drug group showed enlarged alveolar cavity, thinned interstitium, and reduced inflammation. There was a small amount of alveolar wall rupture in the high-and medium-dose GQYY groups and reduced inflammatory cell infiltration in the low dose GQYY group. Compared with the model group, drug administration lowered level of ROS in the left and right lungs, lowered the MDA level, elevated the SOD level, and down-regulated the mRNA and protein levels of NLRP3, ASC, caspase-1, and p-NF-κB p65/NF-κB p65. GQYY can effectively reduce the damage caused by radiation and bystander effect, which may be associated with the ROS-mediated NLRP3 inflammasome activation.}, } @article {pmid38211826, year = {2024}, author = {Li, X and Kong, L and Pan, J and Liu, H and Wang, C and Xu, S and Liu, W and Sun, J}, title = {N-acetylcysteine protects against neurodevelopmental injuries induced by methylmercury exposure during pregnancy and lactation.}, journal = {Brain research}, volume = {1827}, number = {}, pages = {148761}, doi = {10.1016/j.brainres.2024.148761}, pmid = {38211826}, issn = {1872-6240}, mesh = {Humans ; Pregnancy ; Female ; Animals ; Mice ; *Acetylcysteine/pharmacology ; *Methylmercury Compounds/toxicity ; Lactation ; Antioxidants/pharmacology ; Brain ; }, abstract = {As an extremely dangerous environmental contaminant, methylmercury (MeHg) results in detrimental health effects in human brain nervous system, one of its main targets. However, as a developmental toxicant, the brain of offspring is vulnerable to MeHg during pregnancy and lactation exposure. Unfortunately, mechanisms of neurodevelopmental injuries induced by MeHg have not been fully elucidated. N-acetylcysteine (NAC) has been used for several decades as an antioxidant to antagonize oxidative stress. However, the molecular mechanisms of NAC alleviating MeHg-induced neurodevelopmental toxicity are not clear. Here, for evaluation of the dose-dependent effects of MeHg exposure on neurodevelopmental injuries of offspring, and the possible protective effects of NAC, the pregnant female mice were exposed to MeHg (4, 8, 12 mg/L, respectively) and NAC (50, 100, 150 mg/kg, respectively) from gestational day 1 (GD1) to postnatal day 21 (PND21). Our results indicated that administering MeHg caused behavioral impairment and neuronal injuries in the cerebral cortex of newborn mice. MeHg dose-dependently caused reactive oxygen species (ROS) overproduction and oxidative stress aggravation, together with expression of Nrf2, HO-1, Notch1, and p21 up-regulation, and CDK2 inhibition. NAC treatment dose-dependently antagonized MeHg-induced oxidative stress that may contribute to alleviating neurobehavioral and neurodevelopmental impairments. These results give insight into that NAC can protect against MeHg-induced neurodevelopmental toxicity by its antioxidation capacity.}, } @article {pmid38206362, year = {2024}, author = {Baumel-Alterzon, S and Katz, LS and Lambertini, L and Tse, I and Heidery, F and Garcia-Ocaña, A and Scott, DK}, title = {NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function.}, journal = {Diabetologia}, volume = {67}, number = {3}, pages = {547-560}, pmid = {38206362}, issn = {1432-0428}, support = {R01 DK114338/DK/NIDDK NIH HHS/United States ; UC4 DK104211/DK/NIDDK NIH HHS/United States ; UC4 DK108120/DK/NIDDK NIH HHS/United States ; U01 DK120456/DK/NIDDK NIH HHS/United States ; R01DK130300/DK/NIDDK NIH HHS/United States ; R01DK114338/DK/NIDDK NIH HHS/United States ; R01 DK130300/DK/NIDDK NIH HHS/United States ; P30 DK020541/DK/NIDDK NIH HHS/United States ; P30 DK020593/DK/NIDDK NIH HHS/United States ; K01 DK128387/DK/NIDDK NIH HHS/United States ; R24 DK106755/DK/NIDDK NIH HHS/United States ; DK128387-01A1/DK/NIDDK NIH HHS/United States ; }, mesh = {Male ; Humans ; Mice ; Animals ; Child ; Infant, Newborn ; Infant ; Blood Glucose/metabolism ; Antioxidants/metabolism ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2/genetics ; Animals, Newborn ; Organelle Biogenesis ; *Insulin-Secreting Cells/metabolism ; Glucose/metabolism ; Oxidation-Reduction ; DNA, Mitochondrial/metabolism ; Adenosine Triphosphate/metabolism ; *Insulins ; }, abstract = {AIMS/HYPOTHESIS: All forms of diabetes result from insufficient functional beta cell mass. Due to the relatively limited expression of several antioxidant enzymes, beta cells are highly vulnerable to pathological levels of reactive oxygen species (ROS), which can lead to the reduction of functional beta cell mass. During early postnatal ages, both human and rodent beta cells go through a burst of proliferation that quickly declines with age. The exact mechanisms that account for neonatal beta cell proliferation are understudied but mitochondrial release of moderated ROS levels has been suggested as one of the main drivers. We previously showed that, apart from its conventional role in protecting beta cells from oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is also essential for beta cell proliferation. We therefore hypothesised that NRF2, which is activated by ROS, plays an essential role in beta cell proliferation at early postnatal ages.

METHODS: Beta cell NRF2 levels and beta cell proliferation were measured in pancreatic sections from non-diabetic human cadaveric donors at different postnatal ages, childhood and adulthood. Pancreatic sections from 1-, 7-, 14- and 28-day-old beta cell-specific Nrf2 (also known as Nfe2l2)-knockout mice (βNrf2KO) or control (Nrf2[lox/lox]) mice were assessed for beta cell NRF2 levels, beta cell proliferation, beta cell oxidative stress, beta cell death, nuclear beta cell pancreatic duodenal homeobox protein 1 (PDX1) levels and beta cell mass. Seven-day-old βNrf2KO and Nrf2[lox/lox] mice were injected daily with N-acetylcysteine (NAC) or saline (154 mmol/l NaCl) to explore the potential contribution of oxidative stress to the phenotypes seen in βNrf2KO mice at early postnatal ages. RNA-seq was performed on 7-day-old βNrf2KO and Nrf2[lox/lox] mice to investigate the mechanisms by which NRF2 stimulates beta cell proliferation at early postnatal ages. Mitochondrial biogenesis and function were determined using dispersed islets from 7-day-old βNrf2KO and Nrf2[lox/lox] mice by measuring MitoTracker intensity, mtDNA/gDNA ratio and ATP/ADP ratio. To study the effect of neonatal beta cell-specific Nrf2 deletion on glucose homeostasis in adulthood, blood glucose, plasma insulin and insulin secretion were determined and a GTT was performed on 3-month-old βNrf2KO and Nrf2[lox/lox] mice fed on regular diet (RD) or high-fat diet (HFD).

RESULTS: The expression of the master antioxidant regulator NRF2 was increased at early postnatal ages in both human (1 day to 19 months old, 31%) and mouse (7 days old, 57%) beta cells, and gradually declined with age (8% in adult humans, 3.77% in adult mice). A significant correlation (R[2]=0.568; p=0.001) was found between beta cell proliferation and NRF2 levels in human beta cells. Seven-day-old βNrf2KO mice showed reduced beta cell proliferation (by 65%), beta cell nuclear PDX1 levels (by 23%) and beta cell mass (by 67%), and increased beta cell oxidative stress (threefold) and beta cell death compared with Nrf2[lox/lox] control mice. NAC injections increased beta cell proliferation in 7-day-old βNrf2KO mice (3.4-fold) compared with saline-injected βNrf2KO mice. Interestingly, RNA-seq of islets isolated from 7-day-old βNrf2KO mice revealed reduced expression of mitochondrial RNA genes and genes involved in the electron transport chain. Islets isolated from 7-day old βNrf2KO mice presented reduced MitoTracker intensity (by 47%), mtDNA/gDNA ratio (by 75%) and ATP/ADP ratio (by 68%) compared with islets from Nrf2[lox/lox] littermates. Lastly, HFD-fed 3-month-old βNrf2KO male mice displayed a significant reduction in beta cell mass (by 35%), a mild increase in non-fasting blood glucose (1.2-fold), decreased plasma insulin (by 14%), and reduced glucose tolerance (1.3-fold) compared with HFD-fed Nrf2[lox/lox] mice.

CONCLUSIONS/INTERPRETATION: Our study highlights NRF2 as an essential transcription factor for maintaining neonatal redox balance, mitochondrial biogenesis and function and beta cell growth, and for preserving functional beta cell mass in adulthood under metabolic stress.

DATA AVAILABILITY: Sequencing data are available in the NCBI Gene Expression Omnibus, accession number GSE242718 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242718).}, } @article {pmid38204261, year = {2024}, author = {ALRashdi, BM and Hussein, MM and Mohammed, RM and Abdelhamed, NW and Asaad, ME and Alruwaili, M and Alrashidi, SM and Habotta, OA and Abdel Moneim, AE and Ramadan, SS}, title = {Turmeric Extract-loaded Selenium Nanoparticles Counter Doxorubicin-induced Hepatotoxicity in Mice via Repressing Oxidative Stress, Inflammatory Cytokines, and Cell Apoptosis.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {24}, number = {6}, pages = {443-453}, pmid = {38204261}, issn = {1875-5992}, support = {DSR-2021-03-03112//Deanship of Scientific Research at Jouf University/ ; }, mesh = {Animals ; *Doxorubicin/pharmacology ; *Oxidative Stress/drug effects ; Mice ; *Selenium/chemistry/pharmacology ; *Apoptosis/drug effects ; *Plant Extracts/pharmacology/chemistry ; *Cytokines/metabolism ; *Nanoparticles/chemistry ; Male ; Curcuma/chemistry ; Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; Dose-Response Relationship, Drug ; Structure-Activity Relationship ; Antibiotics, Antineoplastic/pharmacology ; Cell Proliferation/drug effects ; }, abstract = {BACKGROUND: Doxorubicin (DOX) is an antitumor anthracycline used to treat a variety of malignancies; however, its clinical use is associated with noticeable hepatotoxicity. Therefore, the current study was designed to delineate if biosynthesized SeNPs with turmeric extract (Tur-SeNPs) could alleviate DOX-induced hepatic adverse effects.

METHODS: Mice were orally post-treated with Tur extract, Tur-SeNPs, or N-acetyl cysteine after the intraperitoneal injection of DOX.

RESULTS: Our findings have unveiled a remarkable liver attenuating effect in DOX-injected mice post-treated with Tur-SeNPs. High serum levels of ALT, AST, ALP, and total bilirubin induced by DOX were significantly decreased by Tur-SeNPs therapy. Furthermore, Tur-SeNPs counteracted DOX-caused hepatic oxidative stress, indicated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and mRNA expression levels of Nrf-2. Noteworthily, decreased hepatic IL-1β, TNF-α, and NF-κB p65 levels in addition to downregulated iNOS gene expression in Tur-SeNPs-treated mice have indicated their potent antiinflammatory impact. Post-treatment with Tur-SeNPs also mitigated the hepatic apoptosis evoked by DOX injection. A liver histological examination confirmed the biochemical and molecular findings.

CONCLUSIONS: In brief, the outcomes have demonstrated Tur loaded with nanoselenium to successfully mitigate the liver damage induced by DOX via blocking oxidative stress, and inflammatory and apoptotic signaling.}, } @article {pmid38203377, year = {2023}, author = {Govoni, S and Fantucci, P and Marchesi, N and Vertemara, J and Pascale, A and Allegri, M and Calvillo, L and Vanoli, E}, title = {N-Acetylcysteine Antagonizes NGF Activation of TrkA through Disulfide Bridge Interaction, an Effect Which May Contribute to Its Analgesic Activity.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203377}, issn = {1422-0067}, support = {GU Serie Generale n. 92 , April 19, 2014//MIUR (ministry of University and Research) GU Serie Generale n. 92 , April 19, 2014, funding Neuheart S.r.l. (516.456 €) for the project having the title "Sviluppo di farmaci agonisti ed antagonisti delle neurotrofine (Development of neurotrophin-receptor/ ; }, mesh = {Humans ; *Acetylcysteine/pharmacology ; Nerve Growth Factor/pharmacology ; *Neuroblastoma ; Analgesics/pharmacology ; Disulfides ; }, abstract = {N-acetylcysteine (NAC), a mucolytic agent and an antidote to acetaminophen intoxication, has been studied in experimental conditions and trials exploring its analgesic activity based on its antioxidant and anti-inflammatory properties. The purpose of this study is to investigate additional mechanisms, namely, the inhibition of nerve growth factor (NGF) and the activation of the Tropomyosin receptor kinase A (TrkA) receptor, which is responsible for nociception. In silico studies were conducted to evaluate dithiothreitol and NAC's interaction with TrkA. We also measured the autophosphorylation of TrkA in SH-SY5Y cells via ELISA to assess NAC's in vitro activity against NGF-induced TrkA activation. The in silico and in vitro tests show that NAC interferes with NGF-induced TrkA activation. In particular, NAC breaks the disulfide-bound Cys 300-345 of TrkA, perturbing the NGF-TrkA interaction and producing a rearrangement of the binding site, inducing a consequent loss of their molecular recognition and spatial reorganization, which are necessary for the induction of the autophosphorylation process. The latter was inhibited by 40% using 20 mM NAC. These findings suggest that NAC could have a role as a TrkA antagonist, an action that may contribute to the activity and use of NAC in various pain states (acute, chronic, nociplastic) sustained by NGF hyperactivity and/or accompanied by spinal cord sensitization.}, } @article {pmid38203359, year = {2023}, author = {Boguszewicz, Ł and Bieleń, A and Ciszek, M and Skorupa, A and Mrochem-Kwarciak, J and Składowski, K and Sokół, M}, title = {Metabolomic Insight into Implications of Induction Chemotherapy Followed by Concomitant Chemoradiotherapy in Locally Advanced Head and Neck Cancer.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203359}, issn = {1422-0067}, mesh = {Humans ; Squamous Cell Carcinoma of Head and Neck/therapy ; *Induction Chemotherapy ; Phosphorylcholine ; *Head and Neck Neoplasms/therapy ; Chemoradiotherapy/adverse effects ; Betaine ; Serine ; Tyrosine ; Lipids ; }, abstract = {The present study compares two groups of locally advanced patients with head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (cCHRT), specifically those for whom it is a first-line treatment and those who have previously received induction chemotherapy (iCHT). The crucial question is whether iCHT is a serious burden during subsequent treatment for LA-HNSCC and how iCHT affects the tolerance to cCHRT. Of the 107 LA-HNSCC patients, 54 received cisplatin-based iCHT prior to cCHRT. The patients were clinically monitored at weekly intervals from the day before until the completion of the cCHRT. The 843 blood samples were collected and divided into two aliquots: for laboratory blood tests and for nuclear magnetic resonance (NMR) spectroscopy (a Bruker 400 MHz spectrometer). The NMR metabolites and the clinical parameters from the laboratory blood tests were analyzed using orthogonal partial least squares analysis (OPLS) and the Mann-Whitney U test (MWU). After iCHT, the patients begin cCHRT with significantly (MWU p-value < 0.05) elevated blood serum lipids, betaine, glycine, phosphocholine, and reticulocyte count, as well as significantly lowered NMR inflammatory markers, serine, hematocrit, neutrophile, monocyte, red blood cells, hemoglobin, and CRP. During cCHRT, a significant increase in albumin and psychological distress was observed, as well as a significant decrease in platelet, N-acetyl-cysteine, tyrosine, and phenylalanine, in patients who received iCHT. Importantly, all clinical symptoms (except the decreased platelets) and most metabolic alterations (except for betaine, serine, tyrosine, glucose, and phosphocholine) resolve until the completion of cCHRT. In conclusion, iCHT results in hematological toxicity, altered lipids, and one-carbon metabolism, as well as downregulated inflammation, as observed at the beginning and during cCHRT. However, these complications are temporary, and most of them resolve at the end of the treatment. This suggests that iCHT prior to cCHRT does not pose a significant burden and should be considered as a safe treatment option for LA-HNSCC.}, } @article {pmid38199597, year = {2024}, author = {Yuan, Z and Yi, G and Ma, R and Wang, Z and Hu, J and Zhao, W and Hu, Y}, title = {Aldehyde oxidase 1 promotes gallbladder carcinogenesis through ROS-mediated activation of the Wnt/β-catenin pathway.}, journal = {Cellular signalling}, volume = {116}, number = {}, pages = {111042}, doi = {10.1016/j.cellsig.2024.111042}, pmid = {38199597}, issn = {1873-3913}, mesh = {Animals ; Humans ; Mice ; Aldehyde Oxidase ; beta Catenin ; Carcinogenesis ; *Gallbladder Neoplasms ; Reactive Oxygen Species ; Wnt Signaling Pathway ; }, abstract = {BACKGROUND: Aldehyde oxidase 1 (AOX1) is associated with various pathophysiological processes, including cancer. Specifically, AOX1 has been demonstrated to have a close relationship with the progression of certain cancers. However, the expression, function, and mechanisms of action of AOX1 in gallbladder cancer (GBC) remain unclear.

METHODS: Utilizing immunohistochemistry, the study quantified the prevalence of AOX1 within tissues of gallbladder carcinoma and those of the surrounding non-cancerous regions. In vitro assays using gallbladder carcinoma cell lines with modulated AOX1 expression levels were performed to assess the protein's role in cell proliferation, migration, and invasion. Furthermore, flow cytometry techniques were harnessed to determine the influence of AOX1 on the content of reactive oxygen species (ROS) in these cells. Additionally, the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt/β-catenin signaling pathway markersin cells with varied AOX1 expression, detected through Western blot analyses. An in vivo xenograft model involving athymic mice was implemented to explore the influence of AOX1 on gallbladder tumor growth, with Western blot analysis applied to measure EMT marker expression in the resulting tumours.

RESULTS: Elevated AOX1 protein levels have been observed in gallbladder carcinoma tissues, with such upregulation linked to a negative prognostic outlook for patients. In vitro analyses demonstrate that enhanced AOX1 expression facilitates gallbladder carcinoma cell proliferation, migration, and invasion, while AOX1 suppression yields an inhibitory effect on these cellular behaviors. Western blot results reveal an inverse relationship between AOX1 and E-cadherin levels, yet was positively correlation with N-cadherin, Vimentin, and Snail within both gallbladder cancer cells and in vivo xenograft tumours. Further mechanistic investigation indicates that AOX1 elevation augments reactive oxygen species (ROS) production and initiates the Wnt/β-catenin signaling pathway in these cells. The application of N-acetylcysteine (NAC) and/or KY1797K attenuates the proliferative, migratory, and invasive enhancements imparted by AOX1 overexpression and reinforces these effects when AOX1 is silenced-achieved through ROS mitigation and the obstruction of the Wnt/β-catenin pathway. In vivo studies corroborate these findings, showing AOX1 overexpression to amplify xenograft tumor growth and mesenchymal marker expression, whereas AOX1 interference did the opposite.

CONCLUSIONS: The study indicates that AOX1 functions as a carcinogenic factor in gallbladder carcinoma, enhancing cell proliferation, migration, invasion, and the EMT. These effects are driven by the activation of the Wnt/β-catenin pathway mediated by reactive oxygen species (ROS). Therefore,AOX1 presents potential as a valuable prognostic and diagnostic marker as well as a target for therapeutic intervention in the gallbladder cancer.}, } @article {pmid38194754, year = {2024}, author = {Yang, D and Yu, X and Li, X and Yu, B and Peng, H}, title = {Protective effects of l-cysteine and N-acetyl-l-cysteine on boar sperm quality during hypothermic liquid storage with bovine serum albumin as a protectant.}, journal = {Theriogenology}, volume = {216}, number = {}, pages = {185-195}, doi = {10.1016/j.theriogenology.2023.12.030}, pmid = {38194754}, issn = {1879-3231}, mesh = {Male ; Swine ; Animals ; *Semen ; Acetylcysteine/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Serum Albumin, Bovine/pharmacology/metabolism ; Antioxidants/pharmacology/metabolism ; AMP-Activated Protein Kinases/metabolism ; Sperm Motility ; Spermatozoa/physiology ; Semen Analysis/veterinary ; Glutathione/metabolism ; Adenosine Triphosphate/metabolism ; *Semen Preservation/veterinary/methods ; }, abstract = {Hypothermic liquid storage at 4-5 °C has emerged as a novel approach for preserving boar semen, offering innovative possibilities for semen preservation. However, this method also presents challenges, including cold shock and excessive reactive oxygen species (ROS) production. Therefore, reducing oxidative damage induced by low temperatures becomes essential while supplementing appropriate protectants. In this study, we investigated the efficacy of Bovine Serum Albumin (BSA) compared to Polyvinylpyrrolidone (PVP) and Skim Milk Powder (SMP) in maintaining boar sperm motility and progressive motility using computer-assisted sperm analysis (CASA). Among the tested concentrations, 4 g/L of BSA exhibited the best protective effect. Subsequently, we supplemented different concentrations of l-cysteine (LC) and N-acetyl-l-cysteine (NAC) as additives in the presence of BSA as a protectant. Our results demonstrated that 1 mmol/L of LC and 0.5 mmol/L of NAC exhibited superior protection of sperm quality compared to other concentrations. Furthermore, the 1 mmol/L LC and 0.5 mmol/L NAC groups showed significantly improved plasma membrane integrity and acrosome integrity compared to the control group. These groups also exhibited enhanced antioxidant capacity, evidenced by increased mitochondrial membrane potential (MMP), ATP production, total superoxide dismutase (T-SOD) activity, total antioxidant capacity (T-AOC), glutathione (GSH), glutathione peroxidase (GSH-PX), and GPX-4 levels. Additionally, they demonstrated decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as reduced oxidized glutathione (GSSG) and glutathione reductase (GR) levels. Furthermore, LC and NAC treatment enhanced AMP-activated protein kinase (AMPK) phosphorylation. However, inhibiting AMPK using compound C did not inhibit the protective effects of LC and NAC on low-temperature preserved boar sperm. These findings suggest that 4 g/L BSA can serve as an effective protectant for hypothermic liquid storage of boar semen. Additionally, LC and NAC supplementation reduces oxidative damage by enhancing antioxidant capacity rather than through AMPK-mediated ATP supplementation. These results contribute to advancing the application of LC and NAC in hypothermic liquid storage of boar semen.}, } @article {pmid38191622, year = {2024}, author = {Romero-Miguel, D and Casquero-Veiga, M and Lamanna-Rama, N and Torres-Sánchez, S and MacDowell, KS and García-Partida, JA and Santa-Marta, C and Berrocoso, E and Leza, JC and Desco, M and Soto-Montenegro, ML}, title = {N-acetylcysteine during critical neurodevelopmental periods prevents behavioral and neurochemical deficits in the Poly I:C rat model of schizophrenia.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {14}, pmid = {38191622}, issn = {2158-3188}, mesh = {Female ; Pregnancy ; Rats ; Animals ; Rats, Wistar ; *Acetylcysteine/pharmacology ; *Schizophrenia/drug therapy/prevention & control ; Poly I-C ; Inflammation ; }, abstract = {Schizophrenia is a chronic neurodevelopmental disorder with an inflammatory/prooxidant component. N-acetylcysteine (NAC) has been evaluated in schizophrenia as an adjuvant to antipsychotics, but its role as a preventive strategy has not been sufficiently explored. We aimed to evaluate the potential of NAC administration in two-time windows before the onset of symptoms in a schizophrenia-like maternal immune stimulation (MIS) rat model. Pregnant Wistar rats were injected with Poly I:C or Saline on gestational day (GD) 15. Three different preventive approaches were evaluated: 1) NAC treatment during periadolescence in the offspring (from postnatal day [PND] 35 to 49); 2) NAC treatment during pregnancy after MIS challenge until delivery (GD15-21); and 3) NAC treatment throughout all pregnancy (GD1-21). At postnatal day (PND) 70, prepulse inhibition (PPI) and anxiety levels were evaluated. In vivo magnetic resonance (MR) imaging was acquired on PND100 to assess structural changes in gray and white matter, and brain metabolite concentrations. Additionally, inflammation and oxidative stress (IOS) markers were measured ex vivo in selected brain regions. MIS offspring showed behavioral, neuroanatomical, and biochemical alterations. Interestingly, NAC treatment during periadolescence prevented PPI deficits and partially counteracted some biochemical imbalances. Moreover, NAC treatments during pregnancy not only replicated the beneficial outcomes reported by the treatment in periadolescence, but also prevented some neuroanatomical deficits, including reductions in hippocampal and corpus callosum volumes. This study suggests that early reduction of inflammation and prooxidation could help prevent the onset of schizophrenia-like symptoms, supporting the importance of anti-IOS compounds in ameliorating this disorder.}, } @article {pmid38190586, year = {2024}, author = {Lebrun, F and Levard, D and Lemarchand, E and Yetim, M and Furon, J and Potzeha, F and Marie, P and Lesept, F and Blanc, M and Haelewyn, B and Rubio, M and Letourneur, A and Violle, N and Orset, C and Vivien, D}, title = {Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages.}, journal = {Blood advances}, volume = {8}, number = {5}, pages = {1330-1344}, pmid = {38190586}, issn = {2473-9537}, support = {EP-D-14-002/EPA/EPA/United States ; }, mesh = {Mice ; Animals ; Humans ; Tissue Plasminogen Activator/pharmacology/therapeutic use ; Mice, Obese ; *Stroke/drug therapy/etiology ; Hemorrhage ; Inflammation/drug therapy ; *Ischemic Stroke/complications/drug therapy ; *Hyperglycemia/complications/drug therapy ; }, abstract = {The pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.}, } @article {pmid38188454, year = {2024}, author = {El-Sobky, H and El-Shanawany, SM and Ghanem, M and Atef, M}, title = {Role of N-acetylcysteine and vitamin B complex in improving outcomes of corrosive ingestion.}, journal = {Toxicology research}, volume = {13}, number = {1}, pages = {tfad125}, pmid = {38188454}, issn = {2045-452X}, abstract = {BACKGROUND: Corrosive ingestion remains a worldwide public health problem. To date, there are no specific medications with approved efficacy in reducing gastrointestinal injury progression following corrosive ingestion.

AIM: The current study assessed the efficacy of N-acetylcysteine (NAC) and vitamin B complex as adjuvant therapy in improving the outcome of patients with corrosive ingestion.

SUBJECTS AND METHODS: The study included 92 patients with acute corrosive ingestion admitted to Alexandria Poison Center. Patients were distributed into four equal-sized groups and managed as such; Group I received the standard treatment protocol. The other three groups received IV antioxidants in addition to the standard treatment; Group II received NAC, Group III received vitamin B complex, and Group IV received both NAC and vitamin B complex. To assess occurrence of delayed complications, barium swallow and meal were done 21 days after acute corrosive ingestion, and every patient was followed up for one year.

RESULTS: Start of oral intake was earliest among patients in Group II, and as a result, the need for parenteral nutrition decreased significantly with a subsequent decrease in duration of hospitalization. The highest percentage of patients showing normal findings of barium swallow and meal was among the two groups that received NAC (72.7% in Group II and 77.8% in Group IV). Group IV patients who received NAC and vitamin B complex had no esophageal strictures with improved outcomes.

CONCLUSION: NAC and vitamin B complex enhanced recovery in the acute stage, in addition to prevention of delayed complications, especially esophageal strictures.

HIGHLIGHTS: Acute corrosive ingestion is associated with high morbidity because of its catastrophic presentation and lifelong complications.This study was conducted on 92 patients admitted to Alexandria Poison Center (APC).IV NAC significantly decreased the time needed for starting oral intake after acute corrosive ingestion and consequently, the need for parenteral nutrition and duration of hospitalization.No patients suffered from esophageal strictures in the group which received both IV NAC and vitamin B complex.Both NAC and vitamin B complex improved the outcome of patients after ingestion of corrosives whether acids or alkalis.}, } @article {pmid38187538, year = {2023}, 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 = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38187538}, issn = {2692-8205}, support = {R01 AG062469/AG/NIA NIH HHS/United States ; }, 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 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 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 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 employed as tools. Our findings show elevated oxidative stress, 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 is the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than inflammation seen in wild type. The GSH surrogate and general antioxidant, ψ-GSH alleviated APAP toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against initial stages of APAP overdose.}, } @article {pmid38184979, year = {2024}, author = {Zhou, J and Zhang, Y and Zeng, L and Wang, X and Xiang, W and Su, P}, title = {Cadmium exposure induces pyroptosis of TM4 cells through oxidative stress damage and inflammasome activation.}, journal = {Ecotoxicology and environmental safety}, volume = {270}, number = {}, pages = {115930}, doi = {10.1016/j.ecoenv.2024.115930}, pmid = {38184979}, issn = {1090-2414}, mesh = {Male ; Humans ; *Inflammasomes/metabolism ; *Cadmium/toxicity ; Reactive Oxygen Species ; Pyroptosis ; Signal Transduction ; Oxidative Stress ; Acetylcysteine/pharmacology ; }, abstract = {Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11-7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.}, } @article {pmid38169912, year = {2023}, author = {Abdo, M and Kohaf, N and Hammad, MA and Ping, CC}, title = {The Role of Oral Ascorbic Acid Administration in Combination With IV N-acetylcysteine in Delaying Inflammatory Cascade in Sepsis: A Case Report.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e49868}, pmid = {38169912}, issn = {2168-8184}, abstract = {Sepsis is a life-threatening emergency that arises owing to a dysregulated host response to infection, leading to existence organ dysfunction. Vitamin C administration has led to a lower mortality rate in sepsis. N-acetylcysteine (NAC) treatment during sepsis improves hepatic function and enhances tissue oxygenation. The objective of this case report is to investigate the synergistic effect of the combination of vitamin C, thiamine, and NAC in delaying sepsis cascade and prolongation of survival time. In this case report, an oral dose of vitamin C 500 mg three times daily in combination with IV thiamine 100 mg three times daily, IV NAC, and hydrocortisone stress dose resulted in 12 days of survival of an immunocompromised patient with ventilator-associated pneumonia on single anti-pseudomonas beta-lactam antibiotic. The patient was a 60-year-old Malay female with previous bone marrow transplantation surgery and a medical history of ischemic stroke on phenytoin and valproate therapy. The patient was transferred to a medical ward in Penang General Hospital, Malaysia, due to community-acquired pneumonia. She was on ceftriaxone for five days, then sedated and ventilated in the ICU, with a shift to cefepime for three days, which was then changed to meropenem for nine days until the last day of life. Total anti-pseudomonas coverage was 12 days. The patient had multiple comorbidities from phenytoin-induced hepatic encephalopathy, acute kidney injury, and three sessions of hemodialysis. IV vitamin C was not available, so an oral dose was administered with potential efficacy in delaying the sepsis inflammatory cascade, leading to the use of a single (not double) anti-pseudomonas antibiotic for 12 days. Prolonged survival duration may be expected in the case of normal bone marrow patients with ventilator-associated pneumonia sepsis. In conclusion, Vitamin C, thiamine, and NAC combination resulted in delayed sepsis progression for 12 days and the survival of the immunocompromised patient on a single anti-pseudomonas beta-lactam antibiotic.}, } @article {pmid38169324, year = {2024}, author = {Bildik, G and Gray, JP and Mao, W and Yang, H and Ozyurt, R and Orellana, VR and De Wever, O and Carey, MS and Bast, RC and Lu, Z}, title = {DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.}, journal = {Autophagy}, volume = {20}, number = {3}, pages = {675-691}, pmid = {38169324}, issn = {1554-8635}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA083639/CA/NCI NIH HHS/United States ; P50 CA217685/CA/NCI NIH HHS/United States ; R01 CA266187/CA/NCI NIH HHS/United States ; }, mesh = {Female ; Humans ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Autophagy/physiology ; *Ovarian Neoplasms/drug therapy/genetics/metabolism ; *Pancreatic Neoplasms/drug therapy/genetics/pathology ; *Carcinoma, Pancreatic Ductal/pathology ; Chloroquine/pharmacology ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC.Abbreviations: AFR: autophagic flux reporter; ATG: autophagy related; CQ: chloroquine; DCFDA: 2'-7'-dichlorodihydrofluorescein diacetate; DIRAS3: DIRAS family GTPase 3; DOX: doxycycline; KRAS: KRAS proto-oncogene, LGSOC: low-grade serous ovarian cancer; MiT/TFE: microphthalmia family of transcription factors; NAC: N-acetylcysteine; PDAC: pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; TFEB: transcription factor EB.}, } @article {pmid38165196, year = {2023}, author = {Cole, JB and Oakland, CL and Lee, SC and Considine, KA and Rudis, MI and Swanson, AL and Olives, TD}, title = {Is Two Better Than Three? A Systematic Review of Two-bag Intravenous N-acetylcysteine Regimens for Acetaminophen Poisoning.}, journal = {The western journal of emergency medicine}, volume = {24}, number = {6}, pages = {1131-1145}, pmid = {38165196}, issn = {1936-9018}, mesh = {Child ; Humans ; *Acetaminophen/poisoning ; *Acetylcysteine/therapeutic use/adverse effects ; Analgesics, Non-Narcotic/therapeutic use ; Antidotes/therapeutic use ; *Drug Overdose/drug therapy ; *Drug-Related Side Effects and Adverse Reactions ; Infusions, Intravenous ; }, abstract = {INTRODUCTION: Acetaminophen poisoning is commonly treated by emergency physicians. First-line therapy is N-acetylcysteine (NAC), traditionally administered intravenously via a US Food and Drug Administration (FDA)-approved three-bag protocol in which each bag has a unique concentration and infusion duration. Recently, simplified, off-label two-bag NAC infusion protocols have become more common. The purpose of this review is to summarize the effectiveness and safety of two-bag NAC.

METHODS: We undertook a comprehensive search of PubMed, EMBASE, and MEDLINE from inception to December 13, 2022, for articles describing human acetaminophen poisonings treated with two-bag NAC, defined as any regimen involving two discrete infusions in two separate bags. Outcomes included effectiveness (measured by incidence of liver injury); incidence of non-allergic anaphylactoid reactions (NAAR); gastrointestinal, cutaneous, and systemic reactions; treatments for NAARs; incidence of NAC-related medication errors; and delays or interruptions in NAC administration.

RESULTS: Twelve articles met final inclusion, 10 of which compared two-bag NAC to the three-bag regimen. Nine articles evaluated the two-bag/20-hour regimen, a simplified version of the FDA-approved three-bag regimen in which the traditional first and second bags are combined into a single four-hour infusion. Nine articles assessed comparative effectiveness of two-bag NAC in terms of liver injury, most commonly assessed for by incidence of hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >1,000 international units per liter). No difference in liver injury was observed between two-bag and three-bag regimens. Of nine articles comparing incidence of NAARs, eight demonstrated statistically fewer NAARs with two-bag regimens, and one showed no difference. In seven articles evaluating treatment for NAARs (antihistamines, corticosteroids, epinephrine), all showed that patients received fewer medications for NAARs with two-bag NAC. Three articles evaluated NAC-related medication errors; two demonstrated no difference, while one study evaluating only children showed fewer errors with two-bag NAC. Two studies evaluated delays and/or interruptions in NAC infusions; both favored two-bag NAC.

CONCLUSION: For patients with acetaminophen poisoning, two-bag NAC regimens appear to have similar outcomes to the traditional three-bag regimen in terms of liver injury. Two-bag NAC regimens are associated with fewer adverse events and fewer treatments for those events than the three-bag regimen and fewer interruptions in antidotal therapy.}, } @article {pmid38164872, year = {2023}, author = {Sun, J and Zhang, X and Wang, L and Di Stefano, AFD and Zanin, V and Magrone, P and Yuan, Y}, title = {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 = {27}, number = {24}, pages = {12103-12111}, doi = {10.26355/eurrev_202312_34808}, pmid = {38164872}, issn = {2284-0729}, mesh = {Female ; Humans ; Male ; *Acetylcysteine/administration & dosage/pharmacokinetics ; Administration, Intravenous ; Administration, Oral ; Area Under Curve ; China ; Dose-Response Relationship, Drug ; Healthy Volunteers ; East Asian People ; }, abstract = {OBJECTIVE: The aim of the study was to determine the pharmacokinetics (PK) and safety of single and repeat doses of intravenous (IV) N-acetylcysteine (NAC) in Chinese subjects.

PATIENTS AND METHODS: A total of 24 healthy male and female Chinese subjects aged 19-40 years were enrolled in this open-label phase I study. All subjects received a single dose of NAC 600 mg IV on day 1 and, after a 3-day washout, received repeat doses of NAC 600 mg IV (twice daily on days 4 and 5 and once on day 6).

RESULTS: Following a single dose, plasma NAC concentrations peaked rapidly, starting to fall at the end of the 5-minute infusion in a multiphasic manner. Mean Cmax was 83.30 μg/mL (CV% 30.7%), median Tmax was 0.083 h (range 0.08-0.25 h), and mean AUC(0-12 h) was 81.87 h*μg/mL (CV 14.0%). Following repeat dosing, Cmax was approximately 20% higher than after a single dose, with similar Tmax. Total exposure AUC(0-12) was 13% higher at steady state than after single dosing. The accumulation ratio was approximately 1.13, indicating only a slight accumulation with multiple dosing. NAC was eliminated with T1/2 of approximately 8 hours. Around 15% of the total NAC dose was excreted in the urine in the 32 hours post-dose, keeping with extensive NAC metabolism and transformation. Renal clearance of NAC was 995.2 mL/h (CV 50.2%). IV NAC was well tolerated after both single and multiple dosing.

CONCLUSIONS: This is the first robust study evaluating the PK and safety of IV NAC 600 mg in Chinese subjects and provides important data if this agent is to be used IV as a mucolytic in this population.}, } @article {pmid38159349, year = {2024}, author = {Erkovich, AV and Korotkova, EI and Dorozhko, EV and Plotnikov, EV and Semin, VO and Chernova, AP and Barek, J and Solomonenko, AN and Aseeva, NV}, title = {A novel impedimetric sensor based on N-acetyl-L-cysteine for the determination of hydroxyl radicals in cell cultures in vitro.}, journal = {Talanta}, volume = {270}, number = {}, pages = {125600}, doi = {10.1016/j.talanta.2023.125600}, pmid = {38159349}, issn = {1873-3573}, mesh = {*Hydroxyl Radical ; Acetylcysteine ; Electrochemical Techniques/methods ; Gold/chemistry ; Electrodes ; Cell Culture Techniques ; Immunoglobulin E ; *Biosensing Techniques/methods ; Limit of Detection ; }, abstract = {We report a novel impedimetric sensor based on a graphite electrode impregnated with polyethylene and paraffin under vacuum (IGE) modified with electrochemically deposited gold and a self-assembled monolayer of N-acetyl-L-cysteine (NAC/Au/IGE) for selective and sensitive determination of extracellular hydroxyl radicals (OH[•]) generated by living cells. The application of a sulphur-containing molecule oxidized by OH[•] predicts the high selectivity of the sensor, and the utilization of the non-faradaic impedance spectroscopy for recording an analytical response makes it possible to achieve superior sensitivity with a detection limit of 0.01 nM and a linear dynamic range of 0.08-8 nM. Meanwhile, NAC/Au/IGE demonstrated a strong potential of detecting OH[•] generated by biological objects via successful determination of extracellular hydroxyl radicals generated by normal fibroblast cells and prostate carcinoma cells.}, } @article {pmid38157955, year = {2024}, author = {Asuku, AO and Ayinla, MT and Ajibare, AJ and Olajide, TS}, title = {Mercury chloride causes cognitive impairment, oxidative stress and neuroinflammation in male Wistar rats: The potential protective effect of 6-gingerol-rich fraction of Zingiber officinale via regulation of antioxidant defence system and reversal of pro-inflammatory markers increase.}, journal = {Brain research}, volume = {1826}, number = {}, pages = {148741}, doi = {10.1016/j.brainres.2023.148741}, pmid = {38157955}, issn = {1872-6240}, mesh = {Rats ; Male ; Animals ; Antioxidants/pharmacology/metabolism ; Rats, Wistar ; *Zingiber officinale ; Chlorides ; Neuroinflammatory Diseases ; Mercuric Chloride/toxicity ; Tumor Necrosis Factor-alpha/metabolism ; NF-kappa B/metabolism ; Interleukin-6 ; Acetylcholinesterase ; Oxidative Stress ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; Superoxide Dismutase/metabolism ; *Mercury/pharmacology ; *Cognitive Dysfunction ; *Catechols ; *Fatty Alcohols ; }, abstract = {This study investigated the effects of 6-gingerol-rich fraction of Zingiber officinale (6-GIRIFZO) on mercury chloride (HgCl2)-induced neurotoxicity in Wistar rats. Thirty -five male Wistar rats weighing between (150-200 g) were divided randomly into five groups (n = 7): group 1: control, received 0.5 mL of normal saline, group 2: received HgCl2 (5 mg/kg), group 3: received N-acetylcysteine (NAC) (50 mg/kg) as well as HgCl2 (5 mg/kg), group 4: received 6-GIRIFZO (100 mg/kg) and HgCl2 (5 mg/kg), group 5: had 6-GIRIFZO (200 mg/kg) and HgCl2 (5 mg/kg), consecutively for 14 days. On the day14, the rats were subjected to behavioural tests using a Morris water maze and novel object recognition tests. The rats were then euthanized to obtain brain samples for the determination of biochemical parameters (acetylcholinesterase (AchE), nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione (GSH), tumor necrosis factor- alpha (TNF-α), nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β) and interleukin-6 (IL-6)) using standard methods. The result revealed a significant increase in escape latency and a significant decrease in recognition ratio in the rats that were exposed to HgCl2 only. However, 6-GIRIFZO produced a significant reduction in the escape latency and (p < 0.05) increase in the recognition ratio. Similarly, HgCl2 exposure caused a significant (p < 0.05) decrease in the brain SOD, GPx, CAT, GSH with increased brain levels of MDA, NO, AchE, TNF-α, NF-κB, IL-1β and IL-6. Similarly to the standard drug, NAC, 6-GIRIFZO (100 and 200 mg/kg) significantly (p < 0.05) increased brain SOD, GPx, CAT, and GSH levels with decreased concentrations of MDA, NO, AchE, TNF-α, NF-κB, IL-1β and IL-6. Also, pre-treatment with 6-GIRIFZO prevented the HgCl2-induced morphological aberrations in the rats. This study concludes that 6-GIRIFZO prevents HgCl2-induced cognitive deficit via reduction of brain inflammation as well as oxidative stress in rats.}, } @article {pmid38157913, year = {2024}, author = {Wang, Y and Xing, C and Cai, B and Qiu, W and Zhai, J and Zeng, Y and Zhang, A and Shi, S and Zhang, Y and Yang, X and Fu, TM and Shen, H and Wang, C and Zhu, L and Ye, J}, title = {Impact of antioxidants on PM2.5 oxidative potential, radical level, and cytotoxicity.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {169555}, doi = {10.1016/j.scitotenv.2023.169555}, pmid = {38157913}, issn = {1879-1026}, mesh = {Cricetinae ; Animals ; *Antioxidants/metabolism ; beta Carotene ; *Air Pollutants/toxicity/analysis ; CHO Cells ; Vitamin A ; Cricetulus ; Particulate Matter/toxicity/analysis ; Vitamin E ; Glutathione ; Oxidative Stress ; *Hydroquinones ; }, abstract = {Antioxidants are typically seen as agents that mitigate environmental health risks due to their ability to scavenge free radicals. However, our research presents a paradox where these molecules, particularly those within lung fluid, act as prooxidants in the presence of airborne particulate matter (PM2.5), thus enhancing PM2.5 oxidative potential (OP). In our study, we examined a range of antioxidants found in the respiratory system (e.g., vitamin C, glutathione (GSH), and N-acetylcysteine (NAC)), in plasma (vitamin A, vitamin E, and β-carotene), and in food (tert-butylhydroquinone (TBHQ)). We aimed to explore antioxidants' prooxidant and antioxidant interactions with PM2.5 and the resulting OP and cytotoxicity. We employed OH generation assays and electron paramagnetic resonance assays to assess the pro-oxidative and anti-oxidative effects of antioxidants. Additionally, we assessed cytotoxicity interaction using a Chinese hamster ovary cell cytotoxicity assay. Our findings revealed that, in the presence of PM2.5, all antioxidants except vitamin E significantly increased the PM2.5 OP by generating more OH radicals (OH generation rate: 0.16-24.67 pmol·min[-1]·m[-3]). However, it's noteworthy that these generated OH radicals were at least partially neutralized by the antioxidants themselves. Among the pro-oxidative antioxidants, vitamin A, β-carotene, and TBHQ showed the least ability to quench these radicals, consistent with their observed impact in enhancing PM2.5 cytotoxicity (PM2.5 LC50 reduced to 91.2 %, 88.8 %, and 75.1 % of PM2.5's original level, respectively). Notably, vitamin A and TBHQ-enhanced PM2.5 OP were strongly associated with the presence of metals and organic compounds, particularly with copper (Cu) contributing significantly (35 %) to TBHQ's pro-oxidative effect. Our study underscores the potential health risks associated with the interaction between antioxidants and ambient pollutants.}, } @article {pmid38154185, year = {2024}, author = {Dong, B and Jiang, Y and Shi, B and Zhang, Z and Zhang, Z}, title = {Selenomethionine alleviates decabromodiphenyl ether-induced oxidative stress and ferroptosis via the NRF2/GPX4 pathway in the chicken brain.}, journal = {Journal of hazardous materials}, volume = {465}, number = {}, pages = {133307}, doi = {10.1016/j.jhazmat.2023.133307}, pmid = {38154185}, issn = {1873-3336}, mesh = {Chick Embryo ; Animals ; *Selenomethionine ; Chickens ; NF-E2-Related Factor 2 ; Antioxidants ; *Ferroptosis ; Oxidative Stress ; Brain ; *Halogenated Diphenyl Ethers ; }, abstract = {Decabromodiphenyl ether (BDE209) is a toxic environmental pollutant that can cause neurotoxicity, behavioral abnormalities, and cognitive impairment in animals. However, the specific mechanisms of BDE209-induced neurological injury and effective preventative and therapeutic interventions are lacking. Even though selenomethionine (Se-Met) has a significant detoxification effect and protects the nervous system, it remains unclear whether Se-Met can counteract the toxic effects of BDE209. For the in vivo test, we randomly divided 60 1-week-old hy-line white variety chicks into the Con, BDE209, Se-Met, and BDE209 +Se-Met groups. In vitro experiments were performed, exposing chick embryo brain neurons to BDE209, Se-Met, N-Acetylcysteine (NAC, a ROS inhibitor), and RSL3 (a GPX4 inhibitor). We demonstrated that BDE209 induced oxidative stress and ferroptosis in the chicken brain, which mainly manifested as mitochondrial atrophy, cristae breakage, increased Fe[2+] and MDA content, decreased antioxidant enzyme activity, and the inhibition of the NRF2/GPX4 signaling pathway in the brain neurons. However, Se-Met supplementation reversed these changes by activating the NRF2/GPX4 pathway, reducing mitochondrial damage, enhancing antioxidant enzyme activity, and alleviating ferroptosis. This study provides insight into the mechanism of BDE209-related neurotoxicity and suggests Se-Met as an effective preventative and control measure against BDE209 poisoning.}, } @article {pmid38150719, year = {2024}, author = {Liu, J and Yan, P and Liu, X and Long, Z and Bing, T and Zhang, N and Shangguan, D}, title = {Heptamethine Cyanine-Based Molecule Release Triggered by Mitochondrial ROS.}, journal = {ACS applied bio materials}, volume = {7}, number = {1}, pages = {362-368}, doi = {10.1021/acsabm.3c00955}, pmid = {38150719}, issn = {2576-6422}, mesh = {Reactive Oxygen Species ; *Hydrogen Peroxide ; *Mitochondria ; Fluorescent Dyes ; Acetylcysteine/pharmacology ; }, abstract = {Conditionally activated molecule release in live cells would provide spatiotemporal control for the study and intervention of biological processes, e.g., bioactive molecule monitoring and controlled drug release. Mitochondria are the main sites of reactive oxygen species (ROS) production in cells. Here, we report an ROS-triggered molecule release strategy in mitochondria. A molecule IRTO with dual targeting groups was designed by covalently linking IR-780 (a mitochondrial targeted heptamethine cyanine) and 4-aminobutyl-thiazole orange (NH2-TO, a nuclear dye). IRTO diffused into live cells and first accumulated in mitochondria. As the cyanine moiety reacted with mitochondrial ROS directly or with the help of mitochondrial cytochromes, NH2-TO was released, escaped from mitochondria, and finally located in the nucleus. This process could be visualized by fluorescent imaging, i.e., red fluorescence (from the cyanine moiety of IRTO) first located in mitochondria, and green fluorescence (from NH2-TO) appeared and gradually enhanced in the nucleus with the increase of incubation time. The addition of H2O2 or lipopolysaccharide (LPS, an ROS accelerator) could accelerate the release of NH2-TO, whereas N-acetyl-l-cysteine (NAC, an ROS inhibitor) and mitoquinone mesylate (MitoQ, a mitochondrial ROS scavenger) could obviously decrease the release of NH2-TO. These results suggest that IRTO could serve as a fluorescent probe for monitoring ROS in mitochondria and that IR-780 might be a promising endogenous ROS-triggered molecule release platform.}, } @article {pmid38145809, year = {2024}, author = {Shore, R and Behlen, J and McBee, D and Prayaga, K and Haugen, F and Craig, L and Shields, M and Mustapha, T and Harvey, N and Johnson, N}, title = {Lactational transfer of sulforaphane-N-acetylcysteine in vivo and in human breast milk.}, journal = {Toxicology and applied pharmacology}, volume = {482}, number = {}, pages = {116796}, pmid = {38145809}, issn = {1096-0333}, support = {P30 ES029067/ES/NIEHS NIH HHS/United States ; R01 ES028866/ES/NIEHS NIH HHS/United States ; T32 ES026568/ES/NIEHS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Child ; Infant, Newborn ; Humans ; Female ; *Acetylcysteine/pharmacology ; *Lactation ; Breast Feeding ; NF-E2-Related Factor 2/genetics/metabolism ; Milk, Human/metabolism ; Isothiocyanates/pharmacology ; *Sulfoxides ; }, abstract = {Sulforaphane (SFN) is a bioactive phytonutrient found in cruciferous vegetables. There is a lack of detailed information on the lactational transfer of SFN and SFN metabolites, and potential pharmacological effects on breastfeeding infants. We carried out two maternal supplementation studies in a mouse model, wherein lactating dams received either vehicle, 300 or 600 ppm SFN from postnatal day (PND) 1 to 5, or in a second experiment, vehicle or 600 ppm SFN from PND 1 to 14. The parent compound was only detectable in milk and plasma from dams receiving 600 ppm SFN for five days. The predominant metabolite SFN-N-acetylcysteine (SFN-NAC) was readily detected in milk from dams receiving 300 and 600 ppm SFN for five days or 600 ppm for 14 days. Maternal SFN-NAC plasma levels were elevated in both 600 ppm groups. Maternal hepatic and pulmonary expression of NRF2-related genes, Nqo1, Gsta2, Gstm1, and Gstp1, were significantly increased, generally following a dose-response; however, offspring induction varied. PND5 neonates in the 600-ppm group exhibited significantly elevated expression of Nqo1, Gsta2, and Gstp1 in liver, and Gstm1 and Gstp1 in lung. Findings support maternal dietary supplementation with SFN induces NRF2-related gene expression in neonates via lactational transfer of SFN-NAC. However, NQO1 enzyme activity was not significantly elevated, highlighting the need to optimize dosing strategy. Additionally, in a pilot investigation of lactating women consuming a typical diet, without any purified SFN supplementation, 7 out of 8 breast milk samples showed SFN-NAC above the limit of quantification (LOQ). Notably, the one sample below the LOQ was collected from the only participant who reported no consumption of cruciferous vegetables in the past 24 h. The parent compound was not detected in any of the human breast milk samples. Overall, these data indicate lactational transfer of SFN-NAC at dietary relevant levels. Future studies are needed to evaluate pharmacokinetics and pharmacodynamics of lactational transfer for potential preventive or therapeutic effects in breastfeeding children.}, } @article {pmid38142783, year = {2024}, author = {Singh, B and Patwardhan, RS and Pal, D and Maurya, DK and Singh, BG and Checker, R and Sharma, D and Sandur, SK}, title = {Repurposing of FDA approved kinase inhibitor bosutinib for mitigation of radiation induced damage via inhibition of JNK pathway.}, journal = {Toxicology and applied pharmacology}, volume = {482}, number = {}, pages = {116792}, doi = {10.1016/j.taap.2023.116792}, pmid = {38142783}, issn = {1096-0333}, mesh = {Animals ; Humans ; Mice ; *Aniline Compounds/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; DNA Damage ; *Drug Repositioning ; MAP Kinase Signaling System ; *Nitriles/pharmacology/therapeutic use ; *Quinolines/pharmacology/therapeutic use ; *Radiation Injuries/prevention & control ; *Radiation-Protective Agents/pharmacology/therapeutic use ; }, abstract = {Radiotherapy is a common modality for cancer treatment. However, it is often associated with normal tissue toxicity in 20-80% of the patients. Radioprotectors can improve the outcome of radiotherapy by selectively protecting normal cells against radiation toxicity. In the present study, compound libraries containing 54 kinase inhibitors and 80 FDA-approved drugs were screened for radioprotection of lymphocytes using high throughput cell analysis. A second-generation FDA-approved kinase inhibitor, bosutinib, was identified as a potential radioprotector for normal cells. The radioprotective efficacy of bosutinib was evinced from a reduction in radiation induced DNA damage, caspase-3 activation, DNA fragmentation and apoptosis. Oral administration of bosutinib protected mice against whole body irradiation (WBI) induced morbidity and mortality. Bosutinib also reduced radiation induced bone-marrow aplasia and hematopoietic damage in mice exposed to 4 Gy and 6 Gy dose of WBI. Mechanistic studies revealed that the radioprotective action of bosutinib involved interaction with cellular thiols and modulation of JNK pathway. The addition of glutathione and N-acetyl cysteine significantly reduced the radioprotective efficacy of bosutinib. Moreover, bosutinib did not protect cancer cells against radiation induced toxicity. On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.}, } @article {pmid38141851, year = {2024}, author = {Jayaram, L and King, PT and Hunt, J and Lim, M and Park, C and Hu, E and Dousha, L and Ha, P and Bartlett, JB and Southcott, AM and Muruganandan, S and Vogrin, S and Rees, MA and Dean, OM and Wong, CA}, title = {Evaluation of high dose N- Acetylcysteine on airway inflammation and quality of life outcomes in adults with bronchiectasis: A randomised placebo-controlled pilot study.}, journal = {Pulmonary pharmacology & therapeutics}, volume = {84}, number = {}, pages = {102283}, doi = {10.1016/j.pupt.2023.102283}, pmid = {38141851}, issn = {1522-9629}, mesh = {Adult ; Humans ; Male ; Aged ; *Acetylcysteine/adverse effects ; Quality of Life ; Pilot Projects ; *Bronchiectasis/drug therapy ; Inflammation/drug therapy ; Anti-Inflammatory Agents/adverse effects ; Double-Blind Method ; }, abstract = {BACKGROUND: High dose N acetylcysteine (NAC), a mucolytic, anti-inflammatory and antioxidant agent has been shown to significantly reduce exacerbations, and improve quality of life in placebo controlled, double blind randomised (RCT) studies in patients with COPD, and in an open, randomised study in bronchiectasis. In this pilot, randomised, double-blind, placebo-controlled study, we wished to investigate the feasibility of a larger clinical trial, and the anti-inflammatory and clinical benefits of high dose NAC in bronchiectasis.

AIMS: Primary outcome: to assess the efficacy of NAC 2400 mg/day at 6 weeks on sputum neutrophil elastase (NE), a surrogate marker for exacerbations. Secondary aims included assessing the efficacy of NAC on sputum MUC5B, IL-8, lung function, quality of life, and adverse effects.

METHODS: Participants were randomised to receive 2400 mg or placebo for 6 weeks. They underwent 3 visits: at baseline, week 3 and week 6 where clinical and sputum measurements were assessed.

RESULTS: The study was stopped early due to the COVID pandemic. In total 24/30 patients were recruited, of which 17 completed all aspects of the study. Given this, a per protocol analysis was undertaken: NAC (n = 9) vs placebo (n = 8): mean age 72 vs 62 years; male gender: 44% vs 50%; baseline median FEV11.56 L (mean 71.5 % predicted) vs 2.29L (mean 82.2% predicted). At 6 weeks, sputum NE fell by 47% in the NAC group relative to placebo (mean fold difference (95%CI: 0.53 (0.12,2.42); MUC5B increased by 48% with NAC compared with placebo. Lung function, FVC improved significantly with NAC compared with placebo at 6 weeks (mean fold difference (95%CI): 1.10 (1.00, 1.20), p = 0.045. Bronchiectasis Quality of life measures within the respiratory and social functioning domains demonstrated clinically meaningful improvements, with social functioning reaching statistical significance. Adverse effects were similar in both groups.

CONCLUSION: High dose NAC exhibits anti-inflammatory benefits, and improvements in aspects of quality of life and lung function measures. It is safe and well tolerated. Further larger placebo controlled RCT's are now warranted examining its role in reducing exacerbations.}, } @article {pmid38136214, year = {2023}, author = {Yang, Y and Liu, Z and Wu, J and Bao, S and Wang, Y and Li, J and Song, T and Sun, Y and Pi, J}, title = {Nrf2 Mitigates RANKL and M-CSF Induced Osteoclast Differentiation via ROS-Dependent Mechanisms.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38136214}, issn = {2076-3921}, support = {81830099 (J.P.), 82020108027 (J.P.), 82204090 (Z.L.)//National Natural Science Foundation of China/ ; 2018YFC1311600 (J.P.)//National Key R&D Program of China of the Ministry of Science and Technology of the People's Republic of China/ ; 2022JH2/101300028 (Y.R.)//The Liaoning Applied Basic Research Program/ ; 2022-BS-131, (Z.L.)//Liaoning Provincial Department of Science and Technology Doctoral Launch/ ; 2023JH2/101300024 (Y.S.)//The Liaoning Applied Basic Research Program/ ; }, abstract = {Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been shown to be a negative regulator of osteoclast differentiation, but the precise mechanisms have not yet been established. We examined the precise roles of Nrf2 in regulating antioxidants and reactive oxygen species (ROS) levels, especially the cytoplasmic and mitochondrial ROS during osteoclastogenesis in vitro. In the current study, we found that the absence of Nrf2 promotes osteoclast differentiation in bone-marrow-derived macrophages (BMMs) and RAW 264.7 cells. The receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) significantly lowered the levels of Nrf2 and its downstream antioxidant enzymes at mRNA and/or protein levels during osteoclast differentiation in the BMMs of mice and RAW 264.7 mouse leukemic monocytes. Compared to the wild-type cells, Nrf2-deficient cells exhibited heightened sensitivity to both transient RANKL-induced cytoplasmic ROS and prolonged RANKL and M-CSF-induced cytoplasmic and mitochondrial ROS accumulation. Furthermore, exogenous antioxidant agents, including N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and mitoquinone mesylate (MitoQ), exhibited substantial capability to suppress the elevation of ROS levels during osteoclast differentiation induced by Nrf2 deficiency, and they consequently inhibited osteoclast differentiation augmented by the lack of Nrf2. The activation of phosphorylated c-FOS resulting from elevated ROS promoted osteoclast differentiation. The inhibition of c-FOS blocked osteoclast differentiation, which was elevated by Nrf2-deficiency. Taken together, these data reveal that Nrf2 effectively decreased the accumulation of intracellular ROS and the phosphorylation of c-FOS during osteoclastic differentiation by regulating antioxidant enzymes and subsequently inhibited RANKL-induced osteoclast differentiation.}, } @article {pmid38136193, year = {2023}, author = {Cui, Y and Zhu, Q and Hao, H and Flaker, GC and Liu, Z}, title = {N-Acetylcysteine and Atherosclerosis: Promises and Challenges.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38136193}, issn = {2076-3921}, support = {R01 HL148196/HL/NHLBI NIH HHS/United States ; RF1 NS132279/NS/NINDS NIH HHS/United States ; }, abstract = {Atherosclerosis remains a leading cause of cardiovascular diseases. Although the mechanism for atherosclerosis is complex and has not been fully understood, inflammation and oxidative stress play a critical role in the development and progression of atherosclerosis. N-acetylcysteine (NAC) has been used as a mucolytic agent and an antidote for acetaminophen overdose with a well-established safety profile. NAC has antioxidant and anti-inflammatory effects through multiple mechanisms, including an increase in the intracellular glutathione level and an attenuation of the nuclear factor kappa-B mediated production of inflammatory cytokines like tumor necrosis factor-alpha and interleukins. Numerous animal studies have demonstrated that NAC significantly decreases the development and progression of atherosclerosis. However, the data on the outcomes of clinical studies in patients with atherosclerosis have been limited and inconsistent. The purpose of this review is to summarize the data on the effect of NAC on atherosclerosis from both pre-clinical and clinical studies and discuss the potential mechanisms of action of NAC on atherosclerosis, as well as challenges in the field.}, } @article {pmid38136155, year = {2023}, author = {Ovalle Rodríguez, P and Ramírez Ortega, D and Blanco Ayala, T and Roldán Roldán, G and Pérez de la Cruz, G and González Esquivel, DF and Gómez-Manzo, S and Sánchez Chapul, L and Salazar, A and Pineda, B and Pérez de la Cruz, V}, title = {Modulation of Kynurenic Acid Production by N-acetylcysteine Prevents Cognitive Impairment in Adulthood Induced by Lead Exposure during Lactation in Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38136155}, issn = {2076-3921}, support = {286885//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; }, abstract = {Lead (Pb[2+]) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb[2+]-induced cognitive impairment. The dams were divided into four groups: Control, Pb[2+], NAC, and Pb[2+]+NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb[2+]+NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb[2+] and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb[2+] group. As expected, Pb[2+] group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb[2+] were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.}, } @article {pmid38126172, year = {2024}, author = {Bresette, CA and Ashworth, KJ and Di Paola, J and Ku, DN}, title = {N-Acetyl Cysteine Prevents Arterial Thrombosis in a Dose-Dependent Manner In Vitro and in Mice.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {44}, number = {2}, pages = {e39-e53}, doi = {10.1161/ATVBAHA.123.319044}, pmid = {38126172}, issn = {1524-4636}, mesh = {Mice ; Humans ; Animals ; Platelet Aggregation Inhibitors/pharmacology ; Acetylcysteine/pharmacology ; *Thrombosis/chemically induced/prevention & control/drug therapy ; Platelet Aggregation ; Blood Platelets/metabolism ; *Thromboembolism ; Hemorrhage/metabolism ; von Willebrand Factor/metabolism ; }, abstract = {BACKGROUND: Platelet-rich thrombi occlude arteries causing fatal infarcts like heart attacks and strokes. Prevention of thrombi by current antiplatelet agents can cause major bleeding. Instead, we propose using N-acetyl cysteine (NAC) to act against the protein VWF (von Willebrand factor), and not platelets, to prevent arterial thrombi from forming.

METHODS: NAC was assessed for its ability to prevent arterial thrombosis by measuring platelet accumulation rate and occlusion time using a microfluidic model of arterial thrombosis with human blood. Acute clot formation, clot stability, and tail bleeding were measured in vivo with the murine modified Folts model. The effect of NAC in the murine model after 6 hours was also measured to determine any persistent effects of NAC after it has been cleared from the blood.

RESULTS: We demonstrate reduction of thrombi formation following treatment with NAC in vitro and in vivo. Human whole blood treated with 3 or 5 mmol/L NAC showed delayed thrombus formation 2.0× and 3.7× longer than control, respectively (P<0.001). Blood treated with 10 mmol/L NAC did not form an occlusive clot, and no macroscopic platelet aggregation was visible (P<0.001). In vivo, a 400-mg/kg dose of NAC prevented occlusive clots from forming in mice without significantly affecting tail bleeding times. A lower dose of NAC significantly reduced clot stability. Mice given multiple injections showed that NAC has a lasting and cumulative effect on clot stability, even after being cleared from the blood (P<0.001).

CONCLUSIONS: Both preclinical models demonstrate that NAC prevents thrombus formation in a dose-dependent manner without significantly affecting bleeding time. This work highlights a new pathway for preventing arterial thrombosis, different from antiplatelet agents, using an amino acid derivative as an antithrombotic therapeutic.}, } @article {pmid38118330, year = {2024}, author = {Fu, X and Song, L and Chen, L and Jin, S and Duan, Z and Zhang, B and Xing, Y and Wang, Y}, title = {Mechanistic insights into aniline-induced liver injury: Role of the mmu_circ_26984/Myh9/NLRP3 axis and modulation by N-acetylcysteine.}, journal = {Ecotoxicology and environmental safety}, volume = {270}, number = {}, pages = {115826}, doi = {10.1016/j.ecoenv.2023.115826}, pmid = {38118330}, issn = {1090-2414}, mesh = {Animals ; Mice ; *Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury, Chronic ; In Situ Hybridization, Fluorescence ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; RNA, Circular ; Aniline Compounds/toxicity ; Cytoskeletal Proteins ; Myosin Heavy Chains ; }, abstract = {Aniline is a widely used chemical. Chronic or high-dose exposure to aniline can lead to hepatocellular damage. Although the hepatic pathogenicity of aniline has been established in previous studies, studies involving pathogenic genes during aniline-induced liver injury are limited. Our study first discovered and identified the role and mechanism underlying a new circRNA mmu_circ_26984 in aniline-induced chemical liver injury. Further, we discuss the protective effect of N-acetylcysteine (NAC) in this pathway. After constructing in vitro and in vivo models of aniline treatment, we screened the circRNA with significant differences in expression in AML12 cells from control and aniline-treated groups by circRNA microarray analysis. Next, using RNA pulldown, liquid chromatography-mass spectrometry (LC-MS), and RNA immunoprecipitation, we analyzed the relationship between mmu_circ_26984 and myosin heavy chain 9 (Myh9). Subsequently, we determined the specific mechanism of action of mmu_circ_26984 and Myh9 in aniline-induced liver injury and the protective effect of NAC against aniline-induced liver injury process using Cell Counting Kit-8, Western blot, RNA extraction, a reverse transcription quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization, immunohistochemistry, and immunofluorescence. The expression of mmu_circ_26984 was significantly increased in liver tissues and AML12 cells of aniline-treated mice compared with the control group. This high expression of mmu_circ_26984 increased the expression of injury-related inflammatory factors, such as NLRP3, Caspase-1, IL-18, and IL-1β in vivo and ex vivo, which exacerbated the level of liver injury. The interaction of mmu_circ_26984 with Myh9 also affected the course of liver injury. Mmu_circ_26984 overexpression and reduced treatment affected the levels of Myh9 expression in AML12 cells, as well as downstream inflammatory factors associated with injury, such as NLRP3. In addition, NAC reduced the process of liver injury mediated by the mmu_circ_26984/Myh9/NLRP3 axis. In conclusion, mmu_circ_26984 is a potential molecular marker and therapeutic target in the process of aniline-induced liver injury that can mediate aniline-exposure-induced liver injury via modulation of the mmu_circ_26984/Myh9/NLRP3 axis, and NAC can effectively attenuate the effect of this liver injury.}, } @article {pmid38115863, year = {2023}, author = {Gugsa, E and Molla, TS and Bekele, T and Dejenie, TA}, title = {Hepatoprotective effect of hydromethanol extract of Otostegia integrifolia benth leaves in isoniazid and rifampicin induced Swiss albino mice.}, journal = {Metabolism open}, volume = {20}, number = {}, pages = {100255}, pmid = {38115863}, issn = {2589-9368}, abstract = {INTRODUCTION: Drug-induced liver injury is the most common cause of acute liver failure. Off-Target effect "hepatotoxicity "frequently detected during clinical examination of patients on anti-Tb medication particularly isoniazid (INH), and rifampin (RMP). However, there is no any treatment option against isoniazid and rifampicin induced hepatotoxicity. It is, therefore, necessary to search for effective affordable and safe drugs from medicinal plants for the prevention of liver toxicity caused by isoniazid and rifampicin. The aim the current study is to evaluate hepatoprotective effect of hydro methanol extract from Otostegia integrifolia leaves in isoniazid and rifampicin-induced hepatotoxicity in Swiss albino mice.

METHODS: O. integrifolia leaves powder was macerated in hydromethanol and thirty Swiss albino mice 29.0-40.6 g were grouped in to five groups. Group I were given 20 ml/kg distilled water, group II were given 100 mg INH and 150 mg RIF per kg body weight. Group III, group IV, and group V were given 200 mg extract, 400 mg extract, and 100 mg of N-acetyl cysteine respectively per kg 1hr before induction with 100 mg INH plus 150 mg RIF per kg. The treatments were followed for 14 days. On the 15th day, all mice were anaesthetized with diethyl ether; blood samples were collected for the assessment liver enzyme and function test.

RESULTS: Group II mice's serum ALT, AST and total bilirubin levels were significantly increased and serum total protein and albumin levels were significantly decreased as compared with group I mice. The groups of mice treated with O. integrifolia at a dose of 400 mg/kg and N-acetyl cysteine AST, ALT and total bilirubin level were significantly decreased; and total protein and albumin levels were significantly (P < 0.05) increased as compared with group II. The liver index of the group IV showed decreased (P < 0.05) as compared to the group II.

CONCLUSION: Evidence from our study revealed that the hydromethanol extract of O. integrifolia has a hepatoprotective effect against isoniazid and rifampicin-induced hepatotoxicity in Swiss Albino mice. This protective effect of O. integrifolia extract may be based on its metal ion reducing power, free radical scavenging activity, and anti-inflammatory activity and could be used as a potential therapeutic option.}, } @article {pmid38115663, year = {2023}, author = {Wang, L and Quan, C and Liu, S and Sun, Y and Liu, Y and Zhang, L}, title = {[KEAP1/PGAM5/AIFM1 mediated oxeiptosis pathway in TDCIPP-induced reduction of TM4 cell viability].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {52}, number = {6}, pages = {979-992}, doi = {10.19813/j.cnki.weishengyanjiu.2023.06.019}, pmid = {38115663}, issn = {1000-8020}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Cell Survival ; *NF-E2-Related Factor 2/metabolism ; *Phosphoprotein Phosphatases/metabolism/pharmacology ; }, abstract = {OBJECTIVE: To investigate the toxic effects and potential mechanisms of tri(1, 3-dichloro-2-propyl) phosphate(TDCIPP) exposure on the mouse testicular supporting cell line(TM4 cells).

METHODS: TM4 cells were treated with different concentrations of TDCIPP(0, 12.5, 25 and 50 μmol/L), or 50 μmol/L TDCIPP combined with antioxidant N-acetylcysteine(NAC) for 24 h. Cell viability was assessed using the CCK8 assay, intracellular ROS levels were detected using the DCFH-DA probe, and the protein levels of oxeiptosis-related proteins, such as KEAP1, PGAM5, AIFM1 and phosphorylated AIFM1(p-AIFM1), were detected using Western blot.

RESULTS: TDCIPP dose-dependently reduced TM4 cell viability(P<0.05). ROS levels in TM4 cells treated with 12.5, 25 and 50 μmol/L TDCIPP were 9.44±1.42, 17.25±1.81 and 18.38±2.66, respectively, significantly higher than the control group's 5.08±0.90(P<0.05). ROS levels in the 5 mmol/L NAC+50 μmol/L TDCIPP group were 14.70±0.50, significantly lower than the corresponding TDCIPP group's 26.44±0.73(P<0.05). The activity of TM4 cells in KEAP1siRNA+TDCIPP group and PGAM5siRNA+TDCIPP group were 77.00±1.73 and 76.67±1.53, respectively, significantly higher than TDCIPP group 68.67±1.53(P<0.05). The relative expression of KEAP1 protein in TM4 cells treated with 25 and 50 μmol/L TDCIPP were 0.77±0.04 and 0.82±0.02, respectively, significantly higher than the control group's 0.57±0.01(P<0.05). The relative expression of PGAM5 protein in TDCIPP-treated TM4 cells were 1.17±0.04, 1.38±0.03 and 1.41±0.03, respectively, significantly higher than the control group's 0.81±0.02(P<0.05). The relative expression of AIFM1 protein were 0.42±0.01, 0.63±0.01 and 0.68±0.02, respectively, significantly higher than the control group's 0.34±0.02(P<0.05). The relative expression of p-AIFM1 protein were 1.73±0.02, 1.52±0.02 and 0.73±0.01, respectively, significantly lower than the control group's 2.25±0.02(P<0.05). In the 5 mmol/L NAC+50 μmol/L TDCIPP group, the relative expression of KEAP1, PGAM5 and AIFM1 proteins in TM4 cells were 0.61±0.01, 0.58±0.01 and 0.48±0.03, respectively, significantly lower than the TDCIPP group's 0.86±0.12(P<0.05), 0.74±0.02(P<0.05) and 0.92±0.01(P<0.05). The relative expression of p-AIFM1 protein in the 5 mmol/L NAC+50 μmol/L TDCIPP group was 0.45±0.11, significantly higher than the TDCIPP group's 0.23±0.01(P<0.05).

CONCLUSION: The reduction of TM4 cell viability induced by TDCIPP may be related to ROS-mediated regulation of the KEAP1/PGAM5/AIFM1 pathway, leading to oxeiptosis.}, } @article {pmid38111943, year = {2023}, author = {Jing, RH and Hu, CH and Qi, TT and Ma, B}, title = {Role of reactive oxygen species in epithelial-mesenchymal transition and apoptosis of human lens epithelial cells.}, journal = {International journal of ophthalmology}, volume = {16}, number = {12}, pages = {1935-1941}, pmid = {38111943}, issn = {2222-3959}, abstract = {AIM: To investigate the role of reactive oxygen species (ROS) in epithelial-mesenchymal transition (EMT) and apoptosis of human lens epithelial cells (HLECs).

METHODS: Flow cytometry was used to assess ROS production after transforming growth factor β2 (TGF-β2) induction. Apoptosis of HLECs after H2O2 and TGF-β2 interference with or without ROS scavenger N-acetylcysteine (NAC) were assessed by flow cytometry. The corresponding protein expression levels of the EMT marker α-smooth muscle actin (α-SMA), the extracellular matrix (ECM), marker fibronectin (Fn), and apoptosis-associated proteins were detected by using Western blotting in the presence of an ROS scavenger (NAC). Wound-healing and Transwell assays were used to assess the migration capability of HLECs.

RESULTS: TGF-β2 stimulates ROS production within 8h in HLECs. Additionally, TGF-β2 induced HLECs cell apoptosis, EMT/ECM synthesis protein markers expression, and pro-apoptotic proteins production; nonetheless, NAC treatment prevented these responses. Similarly, TGF-β2 promoted HLECs cell migration, whereas NAC inhibited cell migration. We further determined that although ROS initiated apoptosis, it only induced the accumulation of the EMT marker α-SMA protein, but not COL-1 or Fn.

CONCLUSION: ROS contribute to TGF-β2-induced EMT/ECM synthesis and cell apoptosis of HLECs; however, ROS alone are not sufficient for EMT/ECM synthesis.}, } @article {pmid38111454, year = {2023}, author = {Hakobyan, N and Yadav, R and Pokhrel, A and Wasifuddin, M and John, MJ and Yadav, S and Boris, A}, title = {Miller-Fisher Syndrome Unveiled in the Presence of Cholangiocarcinoma.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e49016}, pmid = {38111454}, issn = {2168-8184}, abstract = {Miller-Fisher syndrome (MFS) is a rare variant of Guillain-Barré syndrome, characterized by ataxia, areflexia, ophthalmoplegia, and possible facial, swallowing and limb weakness alongside respiratory failure. Variations within MFS may include respiratory and limb weakness and Bickerstaff brainstem encephalitis (BBE), marked by altered consciousness, ataxia, ophthalmoparesis, and paradoxical hyperreflexia. MFS can emerge in both children and adults, often following bacterial or viral illness. While autoimmune-driven nerve damage occurs, most MFS patients recover within six months without specific treatment, with a low risk of lasting neurological deficits or relapses. Rarely fatal, MFS's co-occurrence with cholangiocarcinoma (CCA) presents unique management challenges. CCA, primarily affecting bile ducts, has a bleak prognosis; surgical resection offers limited cure potential due to late-stage detection and high recurrence rates. Advances in CCA's molecular understanding have led to novel diagnostic and therapeutic approaches, requiring a comprehensive interdisciplinary care approach for optimal MFS and CCA management outcomes. Herein, we present a 50-year-old male with a complex medical history who was admitted to the hospital due to abdominal discomfort, nausea, vomiting, and ascites. Imaging revealed pneumonia and secondary bacterial peritonitis. Later, he developed neurological symptoms, including weakness, gait abnormalities, and brainstem symptoms, leading to the diagnosis of MFS. Despite treatment efforts, his condition deteriorated, leading to acute liver failure and unexplained anasarca. N-acetyl cysteine was initiated for liver issues. Neurologically, he showed quadriparesis and areflexia. Intravenous immunoglobulin (IVIG) treatment improved his neurological symptoms but worsened gastrointestinal issues, including ileus and elevated CA19-9 levels, suggesting a potential carcinoma. A liver biopsy was performed. After IVIG treatment, he experienced widespread discomfort, emotional unresponsiveness, swallowing difficulties, and aspiration risk, ultimately leading to his demise.}, } @article {pmid38109166, year = {2023}, author = {Sangeet, S and Khan, A}, title = {An in-silico approach to identify bioactive phytochemicals from Houttuynia cordata Thunb. As potential inhibitors of human glutathione reductase.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/07391102.2023.2294181}, pmid = {38109166}, issn = {1538-0254}, abstract = {Cellular infections are central to the etiology of various diseases, notably cancer and malaria. Counteracting cellular oxidative stress via the inhibition of glutathione reductase (GR) has emerged as a promising therapeutic strategy. Houttuynia cordata, a medicinal plant known for its potent antioxidant properties, has been the focus of our investigation. In this study, we conducted comprehensive in silico analyses involving the phytochemical constituents of H. cordata to identify potential natural GR inhibitors. Our methodological approach encompassed multiple in silico techniques, including molecular docking, molecular dynamics simulations, MMPBSA analysis, and dynamic cross-correlation analysis. Out of 13 docked phytochemicals, Quercetin, Quercitrin, and Sesamin emerged as particularly noteworthy due to their exceptional binding affinities for GR. Notably, our investigation demonstrated that Quercetin and Sesamin exhibited promising outcomes compared to the well-established pharmaceutical agent N-acetylcysteine (NAC). Molecular dynamics analyses provided insights into the ability of these phytochemicals to induce structural compaction and stabilization of the GR protein, as evidenced by changes in radius of gyration and solvent-accessible surface area. Moreover, MMPBSA analysis highlighted the crucial roles of specific residues, namely Gly27, Gly28, Ser51, His52, and Val61, in mediating essential interactions with these phytochemicals. Furthermore, an assessment of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME-Tox) profiles underscored the favourable drug-like attributes of these phytochemicals. Thus, the current findings underscore the immense potential of Houttuynia cordata phytochemicals as potent antioxidants with the capacity to combat a spectrum of maladies, including malaria and cancer. This study not only unveils novel therapeutic avenues but also underscores the distinctive outcomes and paramount significance of harnessing H. cordata phytochemicals for their efficacious antioxidant properties.Communicated by Ramaswamy H. Sarma.}, } @article {pmid38107500, year = {2023}, author = {Tang, C and Wang, L and Chen, Z and Yang, J and Gao, H and Guan, C and Gu, Q and He, S and Yang, F and Chen, S and Ma, L and Zhang, Z and Zhao, Y and Tang, L and Xu, Y and Hu, Y and Luo, X}, title = {Efficacy and Safety of Hydrogen Therapy in Patients with Early-Stage Interstitial Lung Disease: A Single-Center, Randomized, Parallel-Group Controlled Trial.}, journal = {Therapeutics and clinical risk management}, volume = {19}, number = {}, pages = {1051-1061}, pmid = {38107500}, issn = {1176-6336}, abstract = {PURPOSE: Several in vivo experiments have shown that molecular hydrogen is a promising therapeutic agent for interstitial lung diseases (ILD). In this study, hydrogen therapy was investigated to determine whether it is superior to N-Acetylcysteine (NAC) for the treatment of patients with early-stage ILD.

PATIENTS AND METHODS: A prospective, single-center, randomized, controlled clinical trial was conducted in 87 patients with early-stage ILD. Hydrogen or NAC therapy was randomly assigned (1:1 ratio) to the eligible patients. The primary endpoint was the change in the high-resolution computed tomography (HRCT) and composite physiologic index (CPI) scores from baseline to week 48. Pulmonary function was evaluated as a secondary endpoint, and adverse events were recorded for safety analysis.

RESULTS: The rate of HRCT image improvement from the baseline in the HW group (63.6%) was higher than that in the NAC group (39.5%). A significant decrease in CPI and improvement in DLCO-sb were observed in the hydrogen group compared with those in the control group. Changes in other pulmonary function parameters, including FVC, FEV1, FEV1/FVC%, and TLC, were not significantly different between the two groups. Adverse events were reported in 7 (15.9%) patients in the HW group and 10 (23.3%) patients in the NAC group, but the difference was not significant (P=0.706).

CONCLUSION: Hydrogen therapy exhibits superior efficacy and acceptable safety compared with NAC therapy in patients with early-stage ILD.}, } @article {pmid38105264, year = {2023}, author = {Musillo, C and Creutzberg, KC and Collacchi, B and Ajmone-Cat, MA and De Simone, R and Lepre, M and Amrein, I and Riva, MA and Berry, A and Cirulli, F}, title = {Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity.}, journal = {Translational psychiatry}, volume = {13}, number = {1}, pages = {399}, pmid = {38105264}, issn = {2158-3188}, mesh = {Animals ; Female ; Male ; Mice ; Pregnancy ; Hippocampus/metabolism ; Hypothalamo-Hypophyseal System/metabolism ; *Obesity, Maternal/metabolism ; Pituitary-Adrenal System/metabolism ; *Prenatal Exposure Delayed Effects ; Stress, Psychological/metabolism ; }, abstract = {Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions.}, } @article {pmid38104651, year = {2024}, author = {Wen, T and Xie, J and Ma, L and Hao, Z and Zhang, W and Wu, T and Li, L}, title = {Vitamin D Receptor Activation Reduces Hepatic Inflammation via Enhancing Macrophage Autophagy in Cholestatic Mice.}, journal = {The American journal of pathology}, volume = {194}, number = {3}, pages = {369-383}, doi = {10.1016/j.ajpath.2023.11.016}, pmid = {38104651}, issn = {1525-2191}, mesh = {Animals ; Mice ; Acetylcysteine ; Autophagy/physiology ; *Cholestasis/metabolism ; *Inflammasomes/metabolism ; Inflammation/metabolism ; Interleukin-1beta/metabolism ; Macrophages/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Calcitriol/metabolism ; }, abstract = {Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1β to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1β during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1β generation. Mechanistically, the knockdown of VDR increased IL-1β generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1β production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1β, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1β, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.}, } @article {pmid38101763, year = {2024}, author = {Fu, C and Yang, C and Ni, C and Wang, L and Hou, J}, title = {Echinococcus granulosus cyst fluid inhibits the type I interferon response by promoting ROS in macrophages.}, journal = {Acta tropica}, volume = {250}, number = {}, pages = {107101}, doi = {10.1016/j.actatropica.2023.107101}, pmid = {38101763}, issn = {1873-6254}, mesh = {Animals ; *Interferon Type I ; *Echinococcus granulosus/metabolism ; Reactive Oxygen Species ; Cyst Fluid ; Macrophages/metabolism ; Nucleotidyltransferases/metabolism ; }, abstract = {In cystic echinococcosis (CE), Echinococcus granulosus cystic fluid (EgCF) could impede macrophage-mediated immunity. However, whether EgCF is implicated in the type I interferon response remains to be established. Here, we revealed that EgCF reduced 2'3'-cGAMP-induced IFN-β production in macrophages by inhibiting the cGAS-STING-IRF3 signaling. EgCF also increased the intracellular reactive oxygen species (ROS) levels. Administration of the ROS inhibitor N-acetylcysteine (NAC) restored the cGAS-STING-IRF3 signaling, which, in turn, upregulated IFN-β expression. The findings disclose that EgCF could increase macrophage ROS levels, thereby blocking cGAS-STING-IRF3 signaling and repressing the IFN-I response.}, } @article {pmid38092096, year = {2024}, author = {Zhu, R and Shang, GJ and Zhang, BY and Wang, HT and Li, L and Wei, XF and Li, DL and Yang, ZY and Qu, ZH and Quan, YN and Liu, SY and Wang, YT and Meng, ST and Wu, LF and Qin, GX}, title = {Unlocking the potential of N-acetylcysteine: Improving hepatopancreas inflammation, antioxidant capacity and health in common carp (Cyprinus carpio) via the MAPK/NF-κB/Nrf2 signalling pathway.}, journal = {Fish & shellfish immunology}, volume = {144}, number = {}, pages = {109294}, doi = {10.1016/j.fsi.2023.109294}, pmid = {38092096}, issn = {1095-9947}, mesh = {Animals ; *Antioxidants/metabolism ; NF-kappa B/metabolism ; Acetylcysteine/pharmacology ; *Carps/metabolism ; NF-E2-Related Factor 2/metabolism ; Hepatopancreas/metabolism ; Signal Transduction ; Diet/veterinary ; Inflammation/veterinary ; Glutathione ; Dietary Supplements ; }, abstract = {N-acetylcysteine (NAC) positively contributes to enhancing animal health, regulating inflammation and reducing stress by participating in the synthesis of cysteine, glutathione, and taurine in the body. The present study aims to investigate the effects of dietary different levels of NAC on the morphology, function and physiological state of hepatopancreas in juvenile common carp (Cyprinus carpio). 450 common carps were randomly divided into 5 groups: N1 (basal diet), N2 (1.5 g/kg NAC diet), N3 (3.0 g/kg NAC diet), N4 (4.5 g/kg NAC diet) and N5 (6.0 g/kg NAC diet), and fed for 8 weeks. The results indicated that dietary 3.0-6.0 g/kg NAC reduced hepatopancreas lipid vacuoles and nuclear translocation, and inhibited apoptosis in common carp. Simultaneously, the activities of hepatopancreas alanine aminotransferase and aspartate aminotransferase progressively increased with rising dietary NAC levels. Dietary NAC enhanced the non-specific immune function of common carp, and exerted anti-inflammatory effects by inhibiting the MAPK/NF-κB signaling pathway. Additionally, dietary 3.0-6.0 g/kg NAC significantly improved the antioxidant capacity of common carp, which was associated with enhanced glutathione metabolism, clearance of ROS and the activation of Nrf2 signaling pathway. In summary, NAC has the potential to alleviate inflammation, mitigate oxidative stress and inhibit apoptosis via the MAPK/NF-κB/Nrf2 signaling pathway, thereby improving hepatopancreas function and health of common carp. The current findings provide a theoretical basis for promoting the application of NAC in aquaculture and ecological cultivation of aquatic animals.}, } @article {pmid38091079, year = {2024}, author = {Mohamad, EA and Ali, AA and Sharaky, M and El-Gebaly, RH}, title = {Niosomes loading N-acetyl-L-cysteine for cancer treatment in vivo study.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {6}, pages = {4339-4353}, pmid = {38091079}, issn = {1432-1912}, mesh = {Animals ; *Acetylcysteine/pharmacology/administration & dosage ; Male ; *Mice, Inbred BALB C ; *Liposomes ; Mice ; Oxidative Stress/drug effects ; Antineoplastic Agents/administration & dosage/pharmacology ; Cell Line, Tumor ; Apoptosis/drug effects ; DNA Damage/drug effects ; Tumor Burden/drug effects ; Drug Carriers ; }, abstract = {Scientists are seeking to find an effective treatment for tumors that has no side effects. N-Acetyl-l-cysteine (NAC) is a thiol compound extracted from garlic. Current study explores the potential of NAC-loaded niosomes (NAC-NIO) for tumor treatment in mice. NAC-loaded niosomes' efficiency, morphology, UV absorption, size distribution, zeta potential, release, and FTIR analysis were evaluated. For vivo study, 25 male BALB/c mice were divided to five groups: gp1 negative control (receive saline), gp2 positive control (tumor group), gp3 treated with NAC, gp4 treated with NAC-NIO at the same time of tumor injection, and gp5 treated with NAC-NIO after tumor growth (day 14). The impact of NAC-NIO on the tumor treatment was evaluated by measuring tumor size progress, comet assay, oxidative stress parameters (GSH, nitric oxide, MDA), western blot analysis, and histopathological investigation of tissues. NAC-NIO showed 72 ± 3% encapsulation efficiency and zeta potential - 5.95 mV with spherical shape. It was found that oral administration of NAC-NIO in a dose of 50 mg/kg provided significant protection against tumor cells. Our formulation decreases DNA injury significantly (P < 0.05). It was noticed that NAC-NIO can increase oxidative stress levels in tumor tissue. On the other hand, the caspase 3 and caspase 9 gene expression were upregulated significantly (P < 0.001) in mice administrated NAC-NIO compared with all other groups. Histological studies confirmed the protective effect of NAC-NIO against tumor especially for treatment during tumor growth protocol. The results suggested that oral delivery of NAC-NIO formulation improved antioxidant effect.}, } @article {pmid38088332, year = {2024}, author = {Bahoush, G and Rahab, M and Ahmadvand, P}, title = {Can N-acetylcysteine reduce red blood cell transfusion burden in patients with transfusion-dependent β-thalassemia?.}, journal = {Pediatric hematology and oncology}, volume = {41}, number = {4}, pages = {251-259}, doi = {10.1080/08880018.2023.2292556}, pmid = {38088332}, issn = {1521-0669}, mesh = {Humans ; *beta-Thalassemia ; Erythrocyte Transfusion ; Acetylcysteine/therapeutic use ; Quality of Life ; *Iron Overload/drug therapy/etiology ; Hemoglobins/analysis ; }, abstract = {Patients with beta-thalassemia major require lifelong and frequent red blood cell transfusions for survival, impacting their quality of life and life expectancy. This treatment approach poses risks of organ damage, iron overload, and increased transfusion-transmitted diseases. N-acetylcysteine (NAC) has been studied for its potential antioxidant effects on hemoglobin stability, aiming to reduce the burden of red blood cell transfusions. To explore this possibility further, we conducted a quasi-experimental study involving 35 individuals with thalassemia major over six months All subjects were already receiving iron chelators and blood transfusions. They were given a daily oral dose of 10 mg/kg NAC for three months. After three months of treatment with NAC, the serum levels of ferritin and liver enzymes (SGOT and SGPT) did not show significant changes (p = 0.35, p = 0.352, and p = 0.686, respectively). However, the red blood cell transfusion burden was significantly reduced in all patients after NAC therapy (p = 0.029), with no corresponding decrease in serum hemoglobin levels (p = 0.931), indicating maintained hemoglobin concentration despite reduced transfusion volume. The study indicates that NAC can effectively decrease the burden of red blood cell transfusions without significant toxicity in these patients. This finding suggests the potential for NAC as a cost-effective and manageable treatment option for these patients. A larger clinical trial with more robust statistical methods could further confirm these results and pave the way for using NAC as a valuable therapeutic agent for managing beta-thalassemia major patients.}, } @article {pmid38088264, year = {2023}, author = {Kandhari, K and Kant, R and Mishra, N and Agarwal, C and Agarwal, R}, title = {Phenylarsine oxide induced corneal injury involves oxidative stress mediated unfolded protein response and ferroptotic cell death: Amelioration by NAC.}, journal = {Free radical biology & medicine}, volume = {209}, number = {Pt 2}, pages = {265-281}, pmid = {38088264}, issn = {1873-4596}, support = {U01 EY030405/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Rabbits ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Irritants ; *Arsenicals ; *Corneal Injuries/chemically induced ; Oxidative Stress ; Unfolded Protein Response ; Cell Death ; }, abstract = {Phenylarsine oxide (PAO), an analog of lewisite, is a highly toxic trivalent arsenical and a potential chemical warfare agent. PAO-induced toxicity has been studied in lung, liver, and skin tissues. Nevertheless, very few studies have been published to comprehend the impact of PAO-induced toxicity on ocular tissues, even though eyes are uniquely vulnerable to injury by vesicants. Notably, arsenical vesicants such as lewisite have been shown to cause edema of eyelids, inflammation, massive corneal necrosis, and blindness. Accordingly, human corneal epithelial cells were used to study the effects of PAO exposure. PAO (100 and 200 nM) induced significant oxidative stress in corneal epithelial cells. Simultaneous treatment with N-acetyl-l-cysteine (NAC), an FDA-approved antioxidant, reversed the PAO-induced toxicity in human corneal epithelial cells. Furthermore, oxidative stress induction by PAO was accompanied by unfolded protein response (UPR) signaling activation and ferroptotic cell death. Further, to validate the findings of our in vitro studies, we optimized injury biomarkers and developed an ex vivo rabbit corneal culture model of PAO exposure. Investigations using PAO in ex vivo rabbit corneas revealed similar results. PAO (5 or 10 μg) for 3, 5, and 10 min caused moderate to extensive corneal epithelial layer degradation and reduced the epithelial layer thickness in a concentration- and time-dependent manner. Similar to human corneal cells, injuries by PAO in ex vivo cultured rabbit corneas were also associated with elevated oxidative stress, UPR signaling, and ferroptosis induction. NAC mitigated PAO-induced corneal injuries in rabbit ex vivo cornea culture as well. The reversal of PAO toxicity upon NAC treatment observed in our studies could be attributed to its antioxidant properties. These findings suggest that PAO exposure can cause significant corneal injury and highlight the need for further mechanistic studies to better understand the pathobiology of different arsenical vesicants, including PAO and lewisite.}, } @article {pmid38086481, year = {2024}, author = {Wu, Q and Liu, C and Liu, D and Wang, Y and Qi, H and Liu, X and Zhang, Y and Chen, H and Zeng, Y and Li, J}, title = {Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {169260}, doi = {10.1016/j.scitotenv.2023.169260}, pmid = {38086481}, issn = {1879-1026}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Microplastics ; Polystyrenes/toxicity ; Endoplasmic Reticulum Chaperone BiP ; Endoribonucleases/pharmacology ; *Ferroptosis ; Protein Serine-Threonine Kinases ; Lung/metabolism ; Acetylcysteine/pharmacology ; Apoptosis ; Endoplasmic Reticulum Stress ; }, abstract = {It has been shown that exposure to nanoplastics (MNPs) through inhalation can induce pulmonary toxicity, but the toxicological mechanism of MNPs on the respiratory system remains unclear. Therefore, we explored the toxicological mechanism of exposure to polystyrene nanoplastics (PS-NPs) (0.05, 0.15, 0.2 mg/mL) on BEAS-2B cells. Results revealed that PS-NPs induce oxidative stress, increased apoptosis rate measured by flow cytometry, the key ferroptosis protein (GPX4 and FTH1) reduction, increased iron content, mitochondrial alterations, and increased malondialdehyde (MDA) level. Besides, consistent results were observed in mice exposed to PS-NPs (5 mg/kg/2d, 10 mg/kg/2d). Thus, we proved that PS-NPs induced cell death and lung damage through apoptosis and ferroptosis. In terms of mechanism, the elevation of the endoplasmic reticulum (ER) stress protein expression (IRE1α, PERK, XBP1S, and CHOP) revealed that PS-NPs induce lung damage by activating the two main ER stress pathways. Furthermore, the toxicological effects of PS-NPs observed in this study are attenuated by the ROS inhibitor N-acetylcysteine (NAC). Collectively, NPs-induced apoptosis and ferroptosis are attenuated by NAC via inhibiting the ROS-dependent ER stress in vitro and in vivo. This improves our understanding of the mechanism by which PS-NPs exposure leads to pulmonary injury and the potential protective effects of NAC.}, } @article {pmid38079440, year = {2023}, author = {Graham, RE and Elliott, RJR and Munro, AF and Carragher, NO}, title = {A cautionary note on the use of N-acetylcysteine as a reactive oxygen species antagonist to assess copper mediated cell death.}, journal = {PloS one}, volume = {18}, number = {12}, pages = {e0294297}, pmid = {38079440}, issn = {1932-6203}, mesh = {Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/chemistry ; *Copper/chemistry ; Disulfiram/pharmacology ; Cell Death ; Apoptosis ; Antioxidants/pharmacology ; Ionophores/pharmacology ; }, abstract = {A new form of cell death has recently been proposed involving copper-induced cell death, termed cuproptosis. This new form of cell death has been widely studied in relation to a novel class of copper ionophores, including elesclomol and disulfiram. However, the exact mechanism leading to cell death remains contentious. The oldest and most widely accepted biological mechanism is that the accumulated intracellular copper leads to excessive build-up of reactive oxygen species and that this is what ultimately leads to cell death. Most of this evidence is largely based on studies using N-acetylcysteine (NAC), an antioxidant, to relieve the oxidative stress and prevent cell death. However, here we have demonstrated using inductively coupled mass-spectrometry, that NAC pretreatment significantly reduces intracellular copper uptake triggered by the ionophores, elesclomol and disulfiram, suggesting that reduction in copper uptake, rather than the antioxidant activity of NAC, is responsible for the diminished cell death. We present further data showing that key mediators of reactive oxygen species are not upregulated in response to elesclomol treatment, and further that sensitivity of cancer cell lines to reactive oxygen species does not correlate with sensitivity to these copper ionophores. Our findings are in line with several recent studies proposing the mechanism of cuproptosis is instead via copper mediated aggregation of proteins, resulting in proteotoxic stress leading to cell death. Overall, it is vital to disseminate this key piece of information regarding NAC's activity on copper uptake since new research attributing the effect of NAC on copper ionophore activity to quenching of reactive oxygen species is being published regularly and our studies suggest their conclusions may be misleading.}, } @article {pmid38079000, year = {2023}, author = {AbdelRazek, M and Mohamed, O and Ashour, R and Alemam, M and El-Gelany, M and Abdel-Kader, MS}, title = {Effect of co-trimoxazole and N-acetylcysteine alone and in combination on bacterial adherence on ureteral stent surface.}, journal = {Urolithiasis}, volume = {52}, number = {1}, pages = {11}, pmid = {38079000}, issn = {2194-7236}, mesh = {Adult ; Child ; Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use ; Prospective Studies ; Escherichia coli ; *Ureter/surgery/microbiology ; Stents/adverse effects/microbiology ; Bacteria ; }, abstract = {To assess the effect of co-trimoxazole and N-acetylcysteine (NAC), alone and in combination, on bacterial adherence to biofilm formed on ureteral stent surfaces. This prospective randomized study was conducted on 636 patients who underwent double J ureteral stent insertion after variable urological procedures. Patients were randomized into four groups: A (n = 165), no antibiotics or mucolytics during stent indwelling; B (n = 153), oral NAC (200 mg/day for children aged < 12 years old and 600 mg/day for adults) during stent indwelling; C (n = 162), oral co-trimoxazole (2 mg TMP/kg/day) during stent indwelling; and D (n = 156), both oral NAC and co-trimoxazole during stent indwelling. Two weeks following double J stent (JJ stent) insertion, urinalysis was performed on all patients and urine culture was done for all the patients at the day of double J stent removal. The stent was removed 2 weeks postoperatively, and a stent segment sized 3-5 cm from the bladder segment of the stent was sent for culture. Positive stent cultures were found in 63.6% (105/165), 43.1% (66/153), 37% (60/162), and 19.2% (30/156) patients of groups A, B, C, and D, respectively. E. coli was the organism most commonly isolated from the stent culture in all groups. The combination of co-trimoxazole and NAC was more effective in reducing bacterial adherence on ureteral stent surfaces than either alone.}, } @article {pmid38076819, year = {2023}, author = {Zou, H and Boboltz, A and Cheema, Y and Song, D and Duncan, GA}, title = {Synthetic mucus barrier arrays as a nanoparticle formulation screening platform.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38076819}, issn = {2692-8205}, support = {R21 AI142050/AI/NIAID NIH HHS/United States ; }, 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 {pmid38072040, year = {2024}, author = {Xiao, Y and Huang, Z and Wang, Y and Wang, Y and Yu, L and Yang, J and Zou, H and Wan, W and Yang, X}, title = {Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway.}, journal = {European journal of pharmacology}, volume = {963}, number = {}, pages = {176227}, doi = {10.1016/j.ejphar.2023.176227}, pmid = {38072040}, issn = {1879-0712}, mesh = {Humans ; Collagen/metabolism ; Fibroblasts ; Fibrosis ; *NF-E2-Related Factor 2/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; *Scleroderma, Systemic/drug therapy/metabolism/pathology ; Skin ; Transforming Growth Factor beta/drug effects/metabolism ; Smad3 Protein/drug effects/metabolism ; }, abstract = {Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.}, } @article {pmid38071432, year = {2024}, author = {Şehirli, AÖ and Aksoy, U and Sibai, A and Orhan, K and Sayıner, S}, title = {Effects of N-acetyl-L-cysteine against apical periodontitis in rats with adriamycin-induced cardiomyopathy and nephropathy.}, journal = {International endodontic journal}, volume = {57}, number = {2}, pages = {195-207}, doi = {10.1111/iej.14010}, pmid = {38071432}, issn = {1365-2591}, mesh = {Rats ; Animals ; Rats, Wistar ; Acetylcysteine/pharmacology/therapeutic use ; Doxorubicin ; *Periapical Periodontitis/chemically induced/drug therapy ; *Cardiomyopathies/chemically induced/drug therapy ; Body Weight ; }, abstract = {AIM: This study aimed to investigate the potential protective effects of N-acetyl-L-cysteine (NAC) against apical periodontitis (AP) in rats with adriamycin (ADR)-induced kidney and heart diseases.

METHODOLOGY: Fourty-eight Wistar albino rats were divided into six groups: (1) Control group, (2) ADR group (1 mg/kg/day ip for 10 days), (3) AP Group (1st mandibular molar tooth), (4) AP + ADR Group, (5) AP + NAC group (150 mg/kg/day ip), and (6) AP + ADR + NAC group. After 3 weeks, the rats were decapitated and blood and tissue samples (heart, kidney, and jaw) were collected. Tissue samples were evaluated by biochemical (inflammatory cytokines and hemodynamic parameters) and radiological analyses. One-way anova with Tukey post hoc tests was used to compare data, considering p < .05 as statistically significant.

RESULTS: The serum levels of TNF-α, IL-1β, BUN, Creatinine, CK, and LDH were elevated in the test groups compared with the control group, and treatment with NAC reduced these levels (p < .05). Heart and kidney tissue analysis showed a higher heart-to-body weight ratio (HW/BW) and kidney-to-body weight ratio (KW/BW) in the test groups compared with the control group (p < .05). No significant differences in HW/BW and KW/BW were found between the control and AP + NAC groups. Volumetric apical bone resorption analysis showed an increase in periapical radiolucencies in AP-induced groups indicating apical periodontitis. NAC treatment reduced the total area and volume of resorption cavities (p < .05).

CONCLUSIONS: The results suggest that NAC's antioxidant and anti-inflammatory effects can reduce adriamycin-mediated heart and kidney damage and may have a positive effect on apical periodontitis in individuals with nephropathy and cardiomyopathy.}, } @article {pmid38071049, year = {2023}, author = {Lu, M and He, CL and Wu, ZT and Lyu, Y and Duan, XH and Wang, BX and Wang, SX and Wang, JH and Liang, R}, title = {[Effect of Baicalin on Pyroptosis of Diffuse Large B-Cell Lymphoma Cell Lines DB and Its Mechanism].}, journal = {Zhongguo shi yan xue ye xue za zhi}, volume = {31}, number = {6}, pages = {1706-1713}, doi = {10.19746/j.cnki.issn.1009-2137.2023.06.016}, pmid = {38071049}, issn = {1009-2137}, mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Reactive Oxygen Species/metabolism/pharmacology ; Pyroptosis ; Cell Line ; RNA, Messenger ; *Lymphoma, Large B-Cell, Diffuse ; }, abstract = {OBJECTIVE: To investigate the effect of Baicalin on the proliferation and pyroptosis of diffuse large B-cell lymphoma cell line DB and its mechanism.

METHODS: DB cells were treated with baicalin at different concentrations (0, 5, 10, 20, 40 μmol/L). Cell proliferation was detected by CCK-8 assay and half maximal inhibitory concentration (IC50) was calculated. The morphology of pyroptosis was observed under an inverted microscope, the integrity of the cell membrane was verified by LDH content release assay, and the expressions of pyroptosis-related mRNA and protein (NLRP3, GSDMD, GSDME, N-GSDMD, N-GSDME) were detected by real-time fluorescence quantitative PCR and Western blot. In order to further clarify the relationship between baicalin-induced pyroptosis and ROS production in DB cells, DB cells were divided into control group, baicalin group, NAC group and NAC combined with baicalin group. DB cells in the NAC group were pretreated with ROS inhibitor N-acetylcysteine (NAC) 2 mmol/L for 2 h. Baicalin was added to the combined treatment group after pretreatment, and the content of reactive oxygen species (ROS) in the cells was detected by DCFH-DA method after 48 hours of culture.

RESULTS: Baicalin inhibited the proliferation of DB cells in a dose-dependent manner (r=-0.99), and the IC50 was 20.56 μmol/L at 48 h. The morphological changes of pyroptosis in DB cells were observed under inverted microscope. Compared with the control group, the release of LDH in the baicalin group was significantly increased (P<0.01), indicating the loss of cell membrane integrity. Baicalin dose-dependently increased the expression levels of NLRP3, N-GSDMD, and N-GSDME mRNA and protein in the pyroptosis pathway (P<0.05). Compared with the control group, the level of ROS in the baicalin group was significantly increased (P<0.05), and the content of ROS in the NAC group was significantly decreased (P<0.05). Compared with the NAC group, the content of ROS in the NAC + baicalin group was increased. Baicalin significantly attenuated the inhibitory effect of NAC on ROS production (P<0.05). Similarly, Western blot results showed that compared with the control group, the expression levels of pyroptosis-related proteins was increased in the baicalin group (P<0.05). NAC inhibited the expression of NLRP3 and reduced the cleavage of N-GSDMD and N-GSDME (P<0.05). Compared with the NAC group, the NAC + baicalin group had significantly increased expression of pyroptosis-related proteins. These results indicate that baicalin can effectively induce pyroptosis in DB cells and reverse the inhibitory effect of NAC on ROS production.

CONCLUSION: Baicalin can inhibit the proliferation of DLBCL cell line DB, and its mechanism may be through regulating ROS production to affect the pyroptosis pathway.}, } @article {pmid38069498, year = {2024}, author = {Tiouririne, NA and Kalelioglu, T and Seneviratne, C and Wang, XQ}, title = {Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study.}, journal = {Alcohol and alcoholism (Oxford, Oxfordshire)}, volume = {59}, number = {2}, pages = {}, doi = {10.1093/alcalc/agad082}, pmid = {38069498}, issn = {1464-3502}, support = {//University of Virginia/ ; }, mesh = {Humans ; Alcohol Drinking ; *Alcoholism/drug therapy/psychology ; Cysteine ; Double-Blind Method ; Glutathione/metabolism ; Pilot Projects ; *Topiramate/adverse effects ; Treatment Outcome ; Drug Combinations ; }, abstract = {Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.}, } @article {pmid38068931, year = {2023}, author = {Pérez-Torres, I and Aisa-Álvarez, A and Casarez-Alvarado, S and Borrayo, G and Márquez-Velasco, R and Guarner-Lans, V and Manzano-Pech, L and Cruz-Soto, R and Gonzalez-Marcos, O and Fuentevilla-Álvarez, G and Gamboa, R and Saucedo-Orozco, H and Franco-Granillo, J and Soto, ME}, title = {Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38068931}, issn = {1422-0067}, mesh = {Humans ; Antioxidants/therapeutic use ; Interleukin-6 ; Cytokine Release Syndrome/drug therapy ; Interleukin-10 ; *Shock, Septic/drug therapy ; Reproducibility of Results ; Oxidative Stress ; Ascorbic Acid/therapeutic use ; Vitamin E/therapeutic use ; Acetylcysteine/therapeutic use ; *Melatonin/therapeutic use ; Adjuvants, Immunologic/therapeutic use ; }, abstract = {Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3[-] and NO2[-]), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.}, } @article {pmid38067442, year = {2023}, author = {Lee, BH and Song, E and Hong, J}, title = {Interaction of Thiol Antioxidants with α,β-Unsaturated Ketone Moiety: Its Implication for Stability and Bioactivity of Curcuminoids.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {23}, pages = {}, pmid = {38067442}, issn = {1420-3049}, support = {2021R1F1A1051466//National Research Foundation of Korea/ ; IHS GNU-2022-04//Institute of Health Sciences of Gyeongsang National University/ ; 2022//The research grant of the Gyeongsang National University/ ; }, mesh = {*Antioxidants/pharmacology ; Diarylheptanoids ; *Curcumin/pharmacology ; Sulfhydryl Compounds/pharmacology ; Glutathione/pharmacology ; Acetylcysteine/pharmacology ; }, abstract = {Many biological functions of curcumin have been reported. As certain bioactivities of curcumin are eliminated by antioxidants, reactive oxygen species generated by curcumin have been suggested as a relevant mechanism. In the present study, the effects of different types of antioxidants on the stability and bioactivities of curcumin were analyzed. High concentrations (>4 mM) of thiol antioxidants, including N-acetylcysteine (NAC), glutathione (GSH), and β-mercaptoethanol, accelerated the decomposition of curcumin and other curcuminoids; the submillimolar levels (<0.5 mM) of GSH and NAC rather improved their stability. Ascorbic acid or superoxide dismutase also stabilized curcumin, regardless of their concentration. The cellular levels and bioactivities of curcumin, including its cytotoxicity and the induction of heme oxygenase-1, were significantly reduced in the presence of 8 mM of GSH and NAC. The effects were enhanced in the presence of submillilmolar GSH and NAC, or non-thiol antioxidants. The present results indicate that antioxidants with a reduced thiol group could directly interact with the α,β-unsaturated carbonyl moiety of curcuminoids and modulate their stability and bioactivity.}, } @article {pmid38065397, year = {2024}, author = {Li, F and Zhu, X and Xu, X and Zhou, J and Lu, R and Wang, S and Xing, G and Ye, Y}, title = {Dibromoacetonitrile induced autophagy by mediating the PERK signalling pathway and ROS interaction in HT22 cell.}, journal = {Toxicology}, volume = {501}, number = {}, pages = {153698}, doi = {10.1016/j.tox.2023.153698}, pmid = {38065397}, issn = {1879-3185}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Protein Kinases/metabolism ; *Signal Transduction ; Endoplasmic Reticulum/metabolism ; Autophagy ; Endoplasmic Reticulum Stress ; Apoptosis ; Mammals/metabolism ; }, abstract = {Dibromoacetonitrile (DBAN) is a high-risk haloacetonitrile (HAN) generated as a byproduct of chloramine disinfection in drinking water. DBAN-induced neurotoxicity in mouse hippocampal neuronal cells (HT22) and mammals was observed to be related to reactive oxygen species (ROS). ROS, endoplasmic reticulum stress (ERS) and autophagy play crucial roles in regulating a variety of cellular processes. However, whether ERS and autophagy are associated with HAN-responsive apoptosis remains unclear. This study indicated that DBAN (10 μM, 24 h) activated the ERS protein kinase like endoplasmic reticulum kinase (PERK) signaling pathway. The ERS inhibitor 4-phenylbutyric acid (4-PBA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, indicating that activation of the ERS PERK pathway mediates DBAN induced cytotoxicity. Moreover, DBAN activated autophagy. The autophagy inhibitor 3-methyladenine(3-MA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, suggesting that autophagy activation mediates DBAN-induced cell toxicity. Notably, the results showed that 4-PBA inhibited DBAN-activated autophagy, demonstrating that ERS-PERK promotes DBAN-induced cellular autophagy. Pretreatment with antioxidant N-acetylcysteine (NAC) inhibited the increase in ROS production and the activation of ERS, and protected cells from toxicity. Furthermore, 4-PBA pretreatment reduced the increase in ROS production, indicating that the ROS and PERK promote each other and form a positive feedback loop. ROS also promoted DBAN-induced autophagy. In summary, our findings indicate that DBAN induced autophagy by mediating the PERK signalling pathway and ROS interaction, leading to HT22 cell damage. Accordingly, targeting these pathogenic mechanisms may provide a potential target and theoretical basis for preventing and improving HAN-induced neurotoxicity.}, } @article {pmid38062506, year = {2023}, author = {Kuo, SH and Hsu, WL and Wu, CY and Lai, YC and Chen, TC}, title = {Dolutegravir-induced growth and lifespan effects in Caenorhabditis elegans.}, journal = {BMC pharmacology & toxicology}, volume = {24}, number = {1}, pages = {74}, pmid = {38062506}, issn = {2050-6511}, support = {kmtth-104-019, kmtth-107-045, kmtth-109-001, kmtth-109-030, Kmtth-110-014//Kaohsiung Municipal Ta- Tung Hospital, Kaohsiung Medical University, Taiwan/ ; }, mesh = {Humans ; Animals ; *HIV Integrase Inhibitors/pharmacology/therapeutic use ; Caenorhabditis elegans ; Longevity ; *HIV Infections/drug therapy ; Reactive Oxygen Species ; *Drug-Related Side Effects and Adverse Reactions ; }, abstract = {BACKGROUND: Integrase strand transfer inhibitor (INSTIs)-based combination antiretroviral treatment in people living with HIV (PLWH) has been reportedly correlated with several adverse effects, such as weight gain, fetal defects or psychiatric disorders.

METHODS: To comprehensively understand the adverse effect of INSTIs, our study utilized Caenorhabditis Elegans (C. elegans) as a model to investigate how dolutegravir (DTG) affected its life cycle, growth, reproduction and lifespan.

RESULTS: Our results indicated that DTG enhanced body growth at the early stage of treatment, but no change was detected for long-term treatment. The treatment also influenced the reproductive system, decreased egg-hatching but had no effect on egg-laying. Besides, DTG resulted in lifespan reduction, which is dependent on increased levels of reactive oxidative species (ROS) accumulation. Treatment with N-acetyl-cysteine (NAC) in worms restrained intracellular ROS accumulation and improved DTG-induced lifespan reduction.

CONCLUSIONS: Our study demonstrates for the first time the effect of DTG treatment on life cycle. DTG-induced adverse effects are potentially associated with intracellular ROS accumulation. Quenching ROS accumulation might provide a novel strategy for dealing with the adverse effects of INSTIs.}, } @article {pmid38061079, year = {2024}, author = {Zhang, B and Huang, C and Xu, D and Huang, K and Li, Y and Jiao, L and Fu, B and Li, S and Li, Y}, title = {Patulin induces ROS-dependent cardiac cell toxicity by inducing DNA damage and activating endoplasmic reticulum stress apoptotic pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {269}, number = {}, pages = {115784}, doi = {10.1016/j.ecoenv.2023.115784}, pmid = {38061079}, issn = {1090-2414}, mesh = {Animals ; Humans ; *Patulin/toxicity/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; DNA Damage ; Apoptosis ; Endoplasmic Reticulum Stress ; }, abstract = {Patulin (PAT) is one of the mycotoxins commonly found in agricultural products and fruits, and has obvious toxic effects on animals and humans. PAT has been found to cause myocardial toxicity and oxidative damage, but the mechanism of myocardial toxicity remained to be elucidated. We investigated the toxic effects and potential mechanisms of PAT on human cardiomyocytes and explored the effects of reactive oxygen species (ROS) on them. The study showed that treatment with PAT for 24 h decreased cell viability and superoxide dismutase (SOD) activity, and increased ROS and lactate dehydrogenase (LDH) levels. Moreover, in addition to detecting increased γ-H2AX expression and observing nuclear damage, the comet assay also showed increased DNA tail distance in the PAT-treated group, followed by an increase in phosphorylation of the p53 protein and p21 protein expression, and a decrease in CDK1 and Cyclin B1 protein expression, and G2/M phase arrest. In addition, PAT induced endoplasmic reticulum stress (ERS) and induced apoptosis, as evidenced by Ca[2+] increase, ER enlargement and swelling, and upregulation of ERS-related genes and proteins expression, and increased expression of three apoptotic pathway proteins under ERS, including CHOP, JNK, and caspase-12. Meanwhile, N-acetylcysteine (NAC, a ROS scavenger) reversed the negative effects of PAT treatment on cells. These results clarify that excessive ROS production by PAT-treated AC16 cells not only causes DNA damage, leading to cell cycle arrest, but also causes ERS, which triggers apoptotic pathways to cause apoptosis.}, } @article {pmid38060590, year = {2023}, author = {Yoldaş, MA and Bekdaş, M and Danış, A and Çetinkaya, A and Düzcü, SE and Alışık, M and Kocabey, H and Türel, İ and Dinçel, GK}, title = {Protective and therapeutic effects of okra seed in acute nontraumatic brain injury.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/00207454.2023.2292948}, pmid = {38060590}, issn = {1563-5279}, abstract = {AIM: The purpose of this study was to examine the protective and therapeutic effects of okra (Abelmoschus esculentus [AE]) seed extract, with its known antioxidant, immunomodulatory, and anti-inflammatory properties, in an acetaminophen (paracetamol, N-acetyl- para-aminophenol)-induced model of hepatotoxicity and subsequent acute non-traumatic brain damage.

MATERIAL AND METHOD: Forty male Wistar rats were randomly divided into five equal groups, control, paracetamol (P), okra seed extract (AE), okra seed extract + paracetamol (P + AE), and okra seed extract + paracetamol + N-acetyl cysteine (NAC) (P + AE + N). AE was administered by oral gavage through a gastric tube at 600 mg/kg/day for seven days. On the eighth day of the procedure, a single 1 g/kg dose of paracetamol and 300 mg/kg NAC were injected via the intraperitoneal route 1.5 h after AE administration. Rat tissue specimens were subsequently subjected to biochemical and histopathological analyses. Levels of markers such as S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and matrix membrane metalloproteinase-9 (MMP-9) were investigated from rat serum specimens. Malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured to determine oxidant-antioxidant status.

RESULTS: S100B, NSE, MMP-9, MDA levels, and SOD enzyme activities were examined using biochemical methods. MDA levels were significantly lower in the P + AE group and MMP-9 levels in the AE, P + AE, and P + AE + N groups compared to the P group. Histopathological examination results supported the biochemical findings.

CONCLUSION: Okra seed extract exhibits a protective and therapeutic effect against non-traumatic brain damage resulting from acute paracetamol intoxication. We think that this benefit of AE derives from its antioxidant property.}, } @article {pmid38043497, year = {2024}, author = {Bai, W and Liu, D and Cheng, Q and Yang, X and Zhu, L and Qin, L and Fang, J}, title = {Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.}, journal = {Translational oncology}, volume = {40}, number = {}, pages = {101850}, pmid = {38043497}, issn = {1936-5233}, abstract = {PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce.

METHODS: A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo.

RESULTS: As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment.

CONCLUSION: Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.}, } @article {pmid38043329, year = {2024}, author = {Andrade, BF and Guimarães, AS and do Carmo, LR and Tanaka, MS and Fontes, PR and Ramos, ALS and Ramos, EM}, title = {S-nitrosothiols as nitrite alternatives: Effects on residual nitrite, lipid oxidation, volatile profile, and cured color of restructured cooked ham.}, journal = {Meat science}, volume = {209}, number = {}, pages = {109397}, doi = {10.1016/j.meatsci.2023.109397}, pmid = {38043329}, issn = {1873-4138}, mesh = {*Meat Products/analysis ; Sodium Nitrite ; *S-Nitrosothiols/chemistry ; Lipids ; Acetylcysteine/*analogs & derivatives ; }, abstract = {This study evaluated the use of the S-nitrosothiols, S-nitroso-N-acetylcysteine (NAC-SNO) and S-nitroso-N-acetylcysteine ethyl ester (NACET-SNO), at different concentrations (25-300 mg nitrite equivalent - NEq/kg) as sodium nitrite substitutes in restructured cooked hams. The pH value and instrumental cured color were not affected by the type or amount of curing agent used. Products with 25 and 50 mg/kg ingoing nitrite had lower thiobarbituric acid-reactive substance values than those with equimolar amounts of S-nitrosothiols. Products with >150 mg NEq/kg of S-nitrosothiols had residual nitrite similar to 50 mg/kg nitrite, and this resulted in the same volatile compound profile as nitrite added in equimolar amounts. A 300 mg NEq/kg of S-nitrosothiols was required to obtain a similar and minimally stable cured pink color perception as sliced samples with 50-150 mg/kg added nitrite. The results obtained reinforce the great potential of both alternative curing agents in the complete replacement of nitrite by equimolar amounts in restructured cooked products; however, differences in cured color stability should be considered.}, } @article {pmid38042493, year = {2024}, author = {Richartz, N and Pietka, W and Yadav, A and Bostad, M and Bhagwat, S and Naderi, S and Naderi, EH and Stokke, T and Ruud, E and Blomhoff, HK}, title = {N-acetyl cysteine turns EPAC activators into potent killers of acute lymphoblastic leukemia cells.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {1}, pages = {105509}, pmid = {38042493}, issn = {1083-351X}, mesh = {Animals ; Child ; Humans ; Mice ; *Acetylcysteine/pharmacology/therapeutic use ; *Cyclic AMP/analogs & derivatives/pharmacology/therapeutic use ; DNA/drug effects ; *Guanine Nucleotide Exchange Factors/agonists ; Mice, Inbred NOD ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Male ; Female ; Child, Preschool ; *Thionucleotides/pharmacology/therapeutic use ; DNA Damage ; Drug Therapy, Combination ; }, abstract = {Today, the majority of patients with pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL) survive their disease, but many of the survivors suffer from life-limiting late effects of the treatment. ALL develops in the bone marrow, where the cells are exposed to cAMP-generating prostaglandin E2. We have previously identified the cAMP signaling pathway as a putative target for improved efficacy of ALL treatment, based on the ability of cAMP signaling to reduce apoptosis induced by DNA damaging agents. In the present study, we have identified the antioxidant N-acetyl cysteine (NAC) as a powerful modifier of critical events downstream of the cell-permeable cAMP analog 8-(4-chlorophenylthio) adenosine-3', 5'- cyclic monophosphate (8-CPT). Accordingly, we found NAC to turn 8-CPT into a potent killer of ALL cells in vitro both in the presence and absence of DNA damaging treatment. Furthermore, we revealed that NAC in combination with 8-CPT is able to delay the progression of ALL in a xenograft model in NOD-scid IL2Rγ[null] mice. NAC was shown to rely on the ability of 8-CPT to activate the guanine-nucleotide exchange factor EPAC, and we demonstrated that the ALL cells are killed by apoptosis involving sustained elevated levels of calcium imposed by the combination of the two drugs. Taken together, we propose that 8-CPT in the presence of NAC might be utilized as a novel strategy for treating pediatric ALL patients, and that this powerful combination might be exploited to enhance the therapeutic index of current ALL targeting therapies.}, } @article {pmid38042273, year = {2023}, author = {Akakpo, JY and Ramachandran, A and Rumack, BH and Wallace, DP and Jaeschke, H}, title = {Lack of mitochondrial Cyp2E1 drives acetaminophen-induced ER stress-mediated apoptosis in mouse and human kidneys: Inhibition by 4-methylpyrazole but not N-acetylcysteine.}, journal = {Toxicology}, volume = {500}, number = {}, pages = {153692}, pmid = {38042273}, issn = {1879-3185}, support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; U54 DK126126/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; *Acetaminophen/toxicity ; Acetylcysteine/pharmacology/metabolism ; Fomepizole/pharmacology/therapeutic use ; Antidotes/pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; Mice, Inbred C57BL ; Liver ; Apoptosis ; Mitochondria/metabolism ; Kidney/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; }, abstract = {Acetaminophen (APAP) overdose causes liver injury and acute liver failure, as well as acute kidney injury, which is not prevented by the clinical antidote N-acetyl-L-cysteine (NAC). The absence of therapeutics targeting APAP-induced nephrotoxicity is due to gaps in understanding the mechanisms of renal injury. APAP metabolism through Cyp2E1 drives cell death in both the liver and kidney. We demonstrate that Cyp2E1 is localized to the proximal tubular cells in mouse and human kidneys. Virtually all the Cyp2E1 in kidney cells is in the endoplasmic reticulum (ER), not in mitochondria. By contrast, hepatic Cyp2E1 is in both the ER and mitochondria of hepatocytes. Consistent with this subcellular localization, a dose of 600 mg/kg APAP in fasted C57BL/6J mice induced the formation of APAP protein adducts predominantly in mitochondria of hepatocytes, but the ER of the proximal tubular cells of the kidney. We found that reactive metabolite formation triggered ER stress-mediated activation of caspase-12 and apoptotic cell death in the kidney. While co-treatment with 4-methylpyrazole (4MP; fomepizole) or the caspase inhibitor Ac-DEVD-CHO prevented APAP-induced cleavage of procaspase-12 and apoptosis in the kidney, treatment with NAC had no effect. These mechanisms are clinically relevant because 4MP but not NAC also significantly attenuated APAP-induced apoptotic cell death in primary human kidney cells. We conclude that reactive metabolite formation by Cyp2E1 in the ER results in sustained ER stress that causes activation of procaspase-12, triggering apoptosis of proximal tubular cells, and that 4MP but not NAC may be an effective antidote against APAP-induced kidney injury.}, } @article {pmid38034812, year = {2023}, author = {Wang, L and Xu, Y and Zhao, X and Zhu, X and He, X and Sun, A and Zhuang, G}, title = {Antagonistic effects of N-acetylcysteine on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast cells.}, journal = {Heliyon}, volume = {9}, number = {11}, pages = {e21847}, pmid = {38034812}, issn = {2405-8440}, abstract = {Lead (Pb) is a heavy metal that can have harmful effects on the environment, which has severe cytotoxicity in many animal tissues. N-acetylcysteine (NAC) has antioxidant activity, reducing lead-induced oxidative stress and apoptosis, but its role in chicken cells is unknown. The current study explored the antagonistic effect of NAC on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast (CEF). In this study, CEF was used as a model to measure the cytotoxic effects of lead nitrate at different concentrations, demonstrating a dose-dependent effect on CEF activity. Employing inverted microscopy, the investigation of morphological alterations in CEF cells was conducted. Fluorescence staining methodology enabled the assessment of reactive oxygen species (ROS) levels within CEF cells. Moreover, an enzyme-linked immunosorbent assay was utilized to detect the presence of oxidative damage indicators encompassing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) activity, malondialdehyde (MDA) content, and total antioxidant capacity (T-AOC) within CEF cells. Furthermore, the determination of the apoptosis rate of CEF cells was accomplished through the utilization of the Hoechst 33258 staining method in combination with the Annexin V-FITC dual staining method. By using RT-qPCR for detection, lead treatment increased expression of pro-apoptotic genes, caspase-3, and caspase-9, and reduced expression of anti-apoptotic genes, Bcl-2, and BI-1. Reduced antioxidant capacity was shown by increased ROS and MDA levels in CEF cells after lead treatment. The results showed that NAC inhibited the expression of caspase-3 and caspase-9 in lead-treated CEF cells, while NAC had a certain inhibitory effect on the relative expression of Bcl-2 and BI-1 mRNA in lead-induced CEF cells. NAC significantly reduced lead-induced oxidative damage and apoptosis. Overall, our results demonstrate a novel protective effect of NAC against lead-induced injury in chicken cells, providing a theoretical basis for future investigations of drugs that are effective in preventing lead poisoning in animals.}, } @article {pmid38031002, year = {2023}, author = {Zhang, XL and Cao, Y and Zheng, B}, title = {Efficacy of N-acetylcysteine plus pirfenidone in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.}, journal = {BMC pulmonary medicine}, volume = {23}, number = {1}, pages = {479}, pmid = {38031002}, issn = {1471-2466}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Pyridones/adverse effects ; Treatment Outcome ; *Idiopathic Pulmonary Fibrosis ; }, abstract = {BACKGROUND: Numerous studies have demonstrated the potential of pirfenidone to enhance the prognosis of patients afflicted with idiopathic pulmonary fibrosis (IPF). Although N-acetylcysteine (NAC) is utilized as an antioxidant in IPF treatment, the combination of NAC and pirfenidone has produced inconsistent outcomes in certain studies. To assess the clinical effectiveness and safety of NAC plus pirfenidone (designated as the treatment group) versus pirfenidone monotherapy (designated as the control group), we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS: RCTs of NAC plus pirfenidone were reviewed searching from databases and networks of unpublished and published studies in any language. Using pair-wise meta-analysis, changes in pulmonary function test (PFT) parameters and safety were evaluated.

RESULTS: Two independent reviewers selected and obtained data from 5 RCTs (n = 398), comprising 1 study from Japan, 1 from Europe, and 3 from China. NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of skin effects(RR 1.26 [95%CI 0.64 to 2.45]) and mortality(RR 0.35 [95%CI 0.07 to 1.68])(both moderate certainty). NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of at least one side effects(RR 1.00 [95%CI 0.84 to 1.19]; low certainty),severe side effects(RR 0.67 [95%CI 0.30 to 1.47]; low certainty) and gastrointestinal effects(RR 0.67 [95%CI 0.41 to 1.09]; low certainty) with possibly no effect in Δ%DLco(SMD -0.17 [95%CI -0.15 to 0.48]; low certainty). Meanwhile, the effect of NAS plus pirfenidone as compared to pirfenidone monotherapy on ΔFVC(SMD 0.18 [95%CI -0.68 to 1.05]), Δ%FVC(SMD -2.62 [95%CI -5.82 to 0.59]) and Δ6MWT(SMD -0.35 [95%CI -0.98 to 0.28]) is uncertain(extremely low certainty).

CONCLUSION: Moderate certainty evidence suggests that NAS plus pirfenidone, compared to pirfenidone monotherapy for IPF, does not reduce the incidence of skin effects and mortality.}, } @article {pmid38019375, year = {2024}, author = {Roy, A and Goenka, MK}, title = {Simethicone and N-acetyl cysteine in improving mucosal visibility: Towards a "clearer view" during endoscopy.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {43}, number = {5}, pages = {863-865}, pmid = {38019375}, issn = {0975-0711}, mesh = {Humans ; *Acetylcysteine ; *Simethicone/administration & dosage ; Endoscopy, Gastrointestinal/methods ; }, } @article {pmid38018602, year = {2023}, author = {Atefi, N and Goodarzi, A and Riahi, T and Khodabandehloo, N and Talebi Taher, M and Najar Nobari, N and Seirafianpour, F and Mahdi, Z and Baghestani, A and Valizadeh, R}, title = {Evaluation of the efficacy and safety of oral N-acetylcysteine in patients with COVID-19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial.}, journal = {Immunity, inflammation and disease}, volume = {11}, number = {11}, pages = {e1083}, pmid = {38018602}, issn = {2050-4527}, mesh = {Humans ; *Ritonavir/therapeutic use ; *COVID-19 ; Antiviral Agents/adverse effects ; Hydroxychloroquine/adverse effects ; Atazanavir Sulfate/adverse effects ; Acetylcysteine/therapeutic use ; C-Reactive Protein ; SARS-CoV-2 ; COVID-19 Drug Treatment ; Inflammation/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: The current absence of gold-standard or all-aspect favorable therapies for COVID-19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well-designed randomized controlled trial (RCT) sought to evaluate the efficacy and safety of N-acetylcysteine (NAC) as adjuvant therapy for 60 hospitalized Iranian patients with COVID-19.

METHODS: Two 30-person diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), were administered in the study.

RESULTS: At the end of the study, a further decrease in C-reactive protein was observed in the NAC group (P = 0.008), and no death occurred in the atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may reduce mortality. The atazanavir/ritonavir + HCQ and atazanavir/ritonavir + NAC groups exhibited the highest O2 saturation at the end of the study and a significant rise in O2 saturation following intervention commencement, including NAC (P > 0.05). Accordingly, oral or intravenous NAC, if indicated, may enhance O2 saturation, blunt the inflammation trend (by reducing C-reactive protein), and lower mortality in hospitalized patients with COVID-19.

CONCLUSION: The NAC could be more effective as prophylactic or adjuvant therapy in stable non-severe cases of COVID-19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation or could be effective for better controlling of COVID-19 or its therapy-related side effects.}, } @article {pmid38016189, year = {2023}, author = {Rosas-Gutiérrez, GDC and Fernández-Hernández, JP and Olea-González, AI}, title = {[Efficacy of intratympanic infiltration of N-acetyl cysteine in cisplatin ototoxicity].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {61}, number = {Suppl 2}, pages = {S318-S322}, pmid = {38016189}, issn = {2448-5667}, mesh = {Humans ; Middle Aged ; Cisplatin/adverse effects ; *Antineoplastic Agents/adverse effects ; Acetylcysteine/therapeutic use/pharmacology ; *Ototoxicity ; Prospective Studies ; }, abstract = {INTRODUCTION: Currently there is no approved preventive or therapeutic pharmacological treatment to treat ototoxicity caused by cisplatin. N-acetyl cysteine (NAC) is a safe and inexpensive antioxidant that has been studied as an otoprotective alternative.

OBJECTIVE: To describe the efficacy of intratympanic infiltration of NAC as prevention and treatment of ototoxicity induced in patients treated with cisplatin.

MATERIAL AND METHODS: Open, longitudinal, prospective, randomized clinical trial in cancer patients treated with cisplatin who met the inclusion criteria. Out of the sample of 22 patients, 11 underwent intratympanic NAC infiltration and 11 were taken as a control group. It was performed an audiometry at the beginning and one month after on all patients.

RESULTS: A sample of 22 patients with a mean age of 53 (±13) was collected. In our sample of 11 patients with infiltration in both ears, 1 ear showed improvement; on the other hand, in the control group that was not infiltrated, 4 showed an increase in hearing loss from mild to moderate in all 4 cases, 2 in the left ear and 2 in the right ear (Spearman's Rho = 0.93, p ≤ 0.001). Relative risk was of 1.22.

CONCLUSIONS: An association can be observed that intratympanic NAC could become an alternative for the prevention and treatment of cisplatin-induced ototoxicity.}, } @article {pmid38015959, year = {2023}, author = {Bosman, M and Krüger, DN and Favere, K and De Meyer, GRY and Franssen, C and Van Craenenbroeck, EM and Guns, PJ}, title = {Dexrazoxane does not mitigate early vascular toxicity induced by doxorubicin in mice.}, journal = {PloS one}, volume = {18}, number = {11}, pages = {e0294848}, pmid = {38015959}, issn = {1932-6203}, mesh = {Mice ; Animals ; Male ; *Dexrazoxane/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Cardiotoxicity/drug therapy/prevention & control/metabolism ; Acetylcholine/metabolism ; Doxorubicin/toxicity/metabolism ; Mice, Inbred C57BL ; Myocytes, Cardiac/metabolism ; Antibiotics, Antineoplastic/pharmacology ; }, abstract = {Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established in vivo and ex vivo model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg/kg) or DOX with DEXRA (40 mg/kg) to male C57BL6/J mice. In parallel, vascular reactivity was evaluated after ex vivo incubation (16h) of murine aortic segments with DOX (1 μM) or DOX with DEXRA (10 μM). In both in vivo and ex vivo experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the ex vivo setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-IIβ (TOP-IIβ), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 μM), a reactive oxygen species (ROS) scavenger, was evaluated ex vivo. NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-IIβ-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.}, } @article {pmid38013123, year = {2024}, author = {Alhajj, N and Yahya, MFZR and O'Reilly, NJ and Cathcart, H}, title = {Development and characterization of a spray-dried inhalable ternary combination for the treatment of Pseudomonas aeruginosa biofilm infection in cystic fibrosis.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {192}, number = {}, pages = {106654}, doi = {10.1016/j.ejps.2023.106654}, pmid = {38013123}, issn = {1879-0720}, mesh = {Humans ; Pseudomonas aeruginosa ; *Cystic Fibrosis/drug therapy ; Powders ; Particle Size ; Respiratory Aerosols and Droplets ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Administration, Inhalation ; Acetylcysteine ; Drug Combinations ; Biofilms ; Dry Powder Inhalers/methods ; *Pseudomonas Infections/drug therapy ; }, abstract = {Cystic fibrosis (CF) is an inherited lung disease characterised by the accumulation of thick layers of dried mucus in the lungs which serve as a nidus for chronic infection. Pseudomonas aeruginosa is the predominant cause of chronic lung infection in cystic fibrosis. The dense mucus coupled with biofilm formation hinder antibiotic penetration and prevent them from reaching their target. Mucoactive agents are recommended in the treatment of CF in combination with antibiotics. In spite of the extensive research in developing novel drug combinations for the treatment of lung infection in CF, to our knowledge, there is no study that combines antibiotic, antibiofilm and mucoactive agent in a single inhaled dry powder formulation. In the present study, we investigate the possibility of adding a mucoactive agent to our previously developed ciprofloxacinquercetin (antibiotic-antibiofilm) dry powder for inhalation. Three mucoactive agents, namely mannitol (MAN), N-acetyl-L-cysteine (NAC) and ambroxol hydrochloride (AMB), were investigated for this purpose. The ternary combinations were prepared via spray drying without the addition of excipients. All ternary combinations conserved or improved the antibacterial and biofilm inhibition activities of ciprofloxacin against P. aeruginosa (ATCC 10145). The addition of AMB resulted in an amorphous ternary combination (SD-CQA) with superior physical stability as indicated by DSC and nonambient XRPD. Furthermore, SD-CQA displayed better in vitro aerosolization performance (ED ∼ 71 %; FPF ∼ 49 %) compared to formulations containing MAN and NAC (ED ∼ 64 % and 44 %; FPF ∼ 44 % and 29 %, respectively). In conclusion, a ternary drug combination powder with suitable aerosolization, physical stability and antibacterial/antibiofilm properties was prepared by a single spray drying step.}, } @article {pmid38011683, year = {2024}, author = {Duan, F and Liu, C and Chang, C and Song, S and Zhai, H and Cheng, J and Yang, S}, title = {Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis.}, journal = {The American journal of drug and alcohol abuse}, volume = {50}, number = {2}, pages = {191-206}, doi = {10.1080/00952990.2023.2266117}, pmid = {38011683}, issn = {1097-9891}, mesh = {*Pentoxifylline/therapeutic use ; Humans ; *Hepatitis, Alcoholic/drug therapy/mortality ; *Granulocyte Colony-Stimulating Factor/therapeutic use ; *Network Meta-Analysis ; *Drug Therapy, Combination ; Randomized Controlled Trials as Topic ; }, abstract = {Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.}, } @article {pmid38004075, year = {2023}, author = {Aydin, H and Bulmus, O and Korkut, O and Altun, E and Ulusal, AE}, title = {An Evaluation of the Effectiveness of Melatonin and n-Acetylcysteine in Cerebral Ischemia-Reperfusion Injury in Adult Rats.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {11}, pages = {}, pmid = {38004075}, issn = {1648-9144}, support = {2020/111//Balıkesir University/ ; }, mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Melatonin/pharmacology/therapeutic use ; Rats, Wistar ; Antioxidants/pharmacology/therapeutic use ; *Reperfusion Injury/drug therapy ; }, abstract = {Background and Objectives: The purpose of this study was to apply histopathological and immunohistochemical methods to compare the protective efficacy of melatonin and N-acetylcysteine (NAC) application in rats with experimental brain ischemia/reperfusion (I/R) injury induced through occlusion of the middle cerebral artery (MCA), and to evaluate the protective effect of their combined use. Materials and Methods: Forty-one young adult male Wistar albino rats were divided into five groups-control (n = 8), I/R group (n = 8), melatonin (n = 8), NAC (n = 8), and melatonin + NAC (n = 9). Results: All scores differed between the groups, apart from vascular congestion (p < 0.05). At two-way comparisons, all histological scores were significantly higher in the I/R group than in the control group (p < 0.05). No change occurred in the vascular congestion scores with the administration of melatonin, although decreases were determined in all other scores. These decreases were statistically significant for cellular eosinophilic pyknotic degeneration, vacuolization, and edema (p < 0.05). All histopathological scores in the group administered NAC together with melatonin were significantly lower than in the I/R group (p < 0.05). Conclusions: The combined use of NAC and melatonin, the neuroprotective efficacy of which on histopathological parameters is shown in this study, now needs to be supported by further research.}, } @article {pmid38004033, year = {2023}, author = {Chiu, AH and Wang, CJ and Lin, YL and Wang, CL and Chiang, TI}, title = {N-Acetylcysteine Alleviates the Progression of Chronic Kidney Disease: A Three-Year Cohort Study.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {11}, pages = {}, pmid = {38004033}, issn = {1648-9144}, mesh = {Humans ; Cohort Studies ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Glomerular Filtration Rate ; Disease Progression ; Risk Factors ; *Renal Insufficiency, Chronic/complications/drug therapy/epidemiology ; *Kidney Failure, Chronic/epidemiology ; }, abstract = {Background and Objectives: The prevalence of chronic kidney disease (CKD) is approximately 10% of the population in many countries. CKD progresses to end-stage renal disease (ESRD), resulting in adverse outcomes, prolonged hospitalization, and increased healthcare costs. Therefore, reducing CKD progression to ESRD is recognized as an important health issue. Materials and Methods: Data from the study participants with stage 3 to stage 5 CKD (n = 7668) were collected from the National Health Insurance (NHI) program in Taiwan (1 November 2014 to 31 December 2020). CKD patients who had ingested or not ingested N-acetylcysteine (NAC) for three years were divided into the study group (NAC users; n = 165) and the control group (NAC non-users; n = 165) to explore whether NAC use could alleviate CKD progression and reduce the risks associated with hemodialysis in CKD patients. Results: The levels of serum creatinine (SCr) and estimated globular filtration rate (eGFR) were nearly unchanged and/or slightly changed in NAC users, but the SCr levels were slightly increased, and the eGFR levels were significantly decreased in NAC non-users at the six-month interval during the three years. A statistical difference was observed between the two groups for both levels from 12 months to 36 months. The incidence rate of hemodialysis was significantly lower in NAC users than in non-NAC users (4.8% vs. 12.7%, Wald test = 5.947, p = 0.015, OR = 34.9). These results indicated that NAC use may improve renal function of CKD patients by modulating SCr and eGFR and, in turn, reducing the risk of hemodialysis. Conclusions: We investigated whether NAC could be used to reduce CKD progression to ESRD. For the three-year retrospective study, the incidence rate of hemodialysis was significantly lower in NAC users than in non-NAC users via modulating SCr and eGRF levels. NAC use might be a useful clinical approach for reducing CKD progression to ESRD.}, } @article {pmid38001773, year = {2023}, author = {Banik, A and Eum, J and Hwang, BJ and Kee, Y}, title = {Differential Neuroprotective Effects of N-Acetylcysteine against Dithianon Toxicity in Glutamatergic, Dopaminergic, and GABAergic Neurons: Assessment Using Zebrafish.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001773}, issn = {2076-3921}, support = {NRF-2019M3C7A1031836//Ministry of Science and ICT/ ; NRF-2020R1I1A3063583//Ministry of Education/ ; }, abstract = {Despite the widespread agricultural use of dithianon as an antifungal agent, its neurotoxic implications for humans and wildlife have not been comprehensively explored. Using zebrafish embryonic development as our model, we found that dithianon treatment induced behavioral alterations in zebrafish larvae that appeared normal. Detailed quantitative analyses showed that dithianon at ≥0.0001 µgmL[-1] induced cytoplasmic and mitochondrial antioxidant responses sequentially, followed by the disruption of mitochondrial and cellular homeostasis. Additionally, dithianon at 0.01 and 0.1 µgmL[-1] downregulated the expressions of glutamatergic (slc17a6b), GABAergic (gad1b), and dopaminergic (th) neuronal markers. Contrarily, dithianon upregulated the expression of the oligodendrocyte marker (olig2) at concentrations of 0.001 and 0.01 µgmL[-1], concurrently suppressing the gene expression of the glucose transporter slc2a1a/glut1. Particularly, dithianon-induced increase in reactive oxygen species (ROS) production was reduced by both N-acetylcysteine (NAC) and betaine; however, only NAC prevented dithianon-induced mortality of zebrafish embryos. Moreover, NAC specifically prevented dithianon-induced alterations in glutamatergic and dopaminergic neurons while leaving GABAergic neurons unaffected, demonstrating that the major neurotransmission systems in the central nervous system differentially respond to the protective effects. Our findings contribute to a better understanding of the neurotoxic potential of dithianon and to developing preventive strategies.}, } @article {pmid38000947, year = {2024}, author = {Alvarez, R and Kurfis, J and Hendrickson, M and Sem, DS}, title = {Real-time thiol detection in iPSC-derived neuron cultures using SemKur-IM, a novel fluorescent dithio probe.}, journal = {SLAS discovery : advancing life sciences R & D}, volume = {29}, number = {3}, pages = {100127}, doi = {10.1016/j.slasd.2023.11.003}, pmid = {38000947}, issn = {2472-5560}, mesh = {*Induced Pluripotent Stem Cells/drug effects/metabolism/cytology ; *Neurons/drug effects/metabolism ; *Sulfhydryl Compounds/pharmacology/chemistry ; Humans ; *Fluorescent Dyes/chemistry ; Oxidative Stress/drug effects ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; Cells, Cultured ; Oxidation-Reduction/drug effects ; }, abstract = {Neurological disorders associated with inflammation and oxidative stress show reduced glutathione (GSH) levels in the human brain. Drug discovery efforts and pharmacological studies would benefit from tools (e.g. chemical probes) that detect changes to oxidative stress, from the perspective of physiologically-relevant reporters like cellular thiols, including GSH. To this end, we have developed a fluorescence visualization assay using iPSC-derived cortical glutamatergic neurons that were loaded with 25 μM of a novel thiol-detection fluorescent probe, SemKur-IM. This probe enables visualization of cellular thiol level changes in the neuronal somas and neurites, in response exposure to N-acetyl-cysteine (NAC). Cellular thiol redox state was observed to change, based on an increase in green fluorescence (485 nm excitation maximum; 525 nm emission maximum) due to changes in thiol levels, from 0 to 40 mM. Interestingly, prior to treatment with NAC, cells did not appear to have significant levels of reduced thiols. Our studies demonstrate the utility of SemKur-IM in the detection of thiol levels in live cells in response to chemical exposures, such as from drugs that return the cell to a healthier reduced state. An initial application to screening the effects of an Alzheimer's disease drug candidate, Posiphen, using fluorescence cell sorting is presented. Other potential applications include high throughput screening of central nervous system (CNS) drugs thought to work by affecting cellular redox state in neurons.}, } @article {pmid38000302, year = {2023}, author = {Liang, M and Deng, J and Gu, J and Yang, J and Ge, F and Huang, C and Wu, W}, title = {TMBPF-induced neurotoxicity and oxidative stress in zebrafish larvae: impacts on central nervous system development and dopamine neurons.}, journal = {Ecotoxicology and environmental safety}, volume = {268}, number = {}, pages = {115710}, doi = {10.1016/j.ecoenv.2023.115710}, pmid = {38000302}, issn = {1090-2414}, mesh = {Humans ; Animals ; *Zebrafish/metabolism ; *Dopaminergic Neurons/metabolism ; Larva ; Dopamine/metabolism ; Benzhydryl Compounds/metabolism ; Oxidative Stress ; Central Nervous System ; Acetylcysteine/pharmacology ; }, abstract = {Bisphenol A (BPA), a common bisphenol molecule, is well known in the environment as an endocrine disruptor. Furthermore, BPs (BPA, BPS, BPF, and BPAF) have been shown in recent years to be neurotoxic to zebrafish. Tetramethyl bisphenol F (TMBPF) has recently been introduced as a substitute for bisphenol A (BPA) in various industries, including plastics and food contact coatings. However, a growing number of studies have demonstrated that the toxicity of some BPA substitutes is similar to or even stronger than BPA, posing potential harm to human health and the environment. In this study, we used zebrafish larvae as a model to investigate the neurodevelopmental effects of TMBPF at different concentrations (0, 0.25, 0.5, 1, 2, 4 and 8 mg/L). Our results showed that exposure to TMBPF at concentrations higher than 4 mg/L for 72 h post-fertilization (hpf) resulted in zebrafish mortality, whereas exposure to 2 mg/L for 144 hpf caused deformities. Furthermore, TMBPF exposure inhibited the development of the central nervous system, motor nerves, and dopamine neurons in zebrafish. Real-time polymerase chain reaction (PCR) analysis revealed that TMBPF exposure significantly down-regulated the expression of oxidative stress-related genes (Cu/Zn-SOD, Mn-SOD, and CAT) and neurodevelopmental genes (mbp, gafp, and syn2a), while up-regulated the expression of dopamine-related genes (th1, th2, and dat). Notably, treatment with the antioxidant N-acetylcysteine (NAC) alleviated TMBPF-induced toxicity. NAC can regulate the expression of genes related to oxidative stress, neurodevelopment and dopamine development, and make the nerve development of zebrafish normal. Overall, our research suggested that TMBPF may disrupt the development of the early central nervous system and dopamine neurons, leading to abnormal motor behavior in zebrafish larvae. These results highlight the potential risks associated with the use of TMBPF in various industries and the importance to evaluate its potential risks to human health and the environment.}, } @article {pmid37996048, year = {2024}, author = {Cao, L and Shao, N and Du, J and Zhu, H and Gao, J and Li, Q and Sun, Y and Hu, J and Yin, G and Xu, G}, title = {Involvement of reactive oxygen species (ROS) in the hepatopancreatic cytotoxicity, oxidative stress, and apoptosis induced by microcystin-LR in Eriocheir sinensis.}, journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP}, volume = {276}, number = {}, pages = {109801}, doi = {10.1016/j.cbpc.2023.109801}, pmid = {37996048}, issn = {1532-0456}, mesh = {Animals ; Reactive Oxygen Species/metabolism ; *Brachyura/metabolism ; Oxidative Stress ; Microcystins/toxicity ; Apoptosis ; }, abstract = {There is limited knowledge about the toxicity of Microcystin-LR (MC-LR) in crustaceans, despite its high toxicity to aquatic organisms. This research aimed to explore the effects of MC-LR on cytotoxicity, oxidative stress, and apoptosis in the hepatopancreas of Eriocheir sinensis, as well as elucidate the involvement of reactive oxygen species (ROS) and potential mechanisms of toxicity. In vivo and in vitro exposures of crabs to MC-LR and N-acetylcysteine (NAC) were performed, followed by assessments of cell morphology, viability, tissue pathology, biochemical indicators, gene expression, and hepatopancreatic transcriptome. Results revealed that MC-LR facilitated the entry of the MC-LR transporter oatp3a into hepatopancreatic cells, leading to upregulated expression of phase I detoxification enzyme genes (cyp4c, cyp2e1, and cyp3) and downregulated the phase II enzyme genes (gst1, gpx, gsr2, gclc, and nqo1), resulting in increased ROS levels and cytotoxic effects. MC-LR exhibited cytotoxicity, reducing cell viability and inducing abnormal nuclear morphology with a 48 h-IC50 value of approximately 120 μm. MC-LR exposure caused biochemical changes indicative of oxidative stress damage and evident hepatopancreatic lesions. Additionally, MC-LR exposure regulated the levels of bax and bcl-2 expression, activating caspase 3 and 6 to induce cell apoptosis. Intervention with NAC attenuated MC-LR-induced ROS production and associated toxic effects. Transcriptome analysis revealed enrichment of differentially expressed genes in pathways related to cytochrome P450-mediated xenobiotic metabolism and the FoxO signaling pathway. These findings shed light on the potential mechanisms underlying MC-LR toxicity and provide valuable references for further research and conservation efforts regarding the health of aquatic animals.}, } @article {pmid37992493, year = {2024}, author = {Deng, YQ and Gao, M and Lu, D and Liu, QP and Zhang, RJ and Ye, J and Zhao, J and Feng, ZH and Li, QZ and Zhang, H}, title = {Compound-composed Chinese medicine of Huachansu triggers apoptosis of gastric cancer cells through increase of reactive oxygen species levels and suppression of proteasome activities.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {123}, number = {}, pages = {155169}, doi = {10.1016/j.phymed.2023.155169}, pmid = {37992493}, issn = {1618-095X}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Stomach Neoplasms/drug therapy/metabolism ; Proteasome Endopeptidase Complex ; Proto-Oncogene Proteins c-akt/metabolism ; Medicine, Chinese Traditional ; Phosphatidylinositol 3-Kinases/metabolism ; Proteomics ; Cell Line, Tumor ; Apoptosis ; *Amphibian Venoms ; }, abstract = {BACKGROUND: Huachansu (HCS), a known Chinese patent drug extracted from the Chinese toad skin, is frequently used for the treatment of various advanced cancers, especially gastric cancer, due to the good therapeutic effect. However, it is rather difficult to clarify the active substances and molecular mechanisms involved owing to the lack of appropriate research strategies. We recently proposed the concept and research ideas of compound-composed Chinese medicine formula.

PURPOSE: To discover compound-composed Chinese medicine from Huachansu and to explore its mechanism of action in inducing apoptosis of gastric cancer cells.

METHOD: Network pharmacology combined with serum pharmacochemistry was utilized to screen the predominant active constituents from HCS against gastric cancer. Then, the compound-composed Chinese medicine of HCS (CCMH) was prepared according to their relative contents in serum. The pharmacological effects and potential mechanisms for CCMH were investigated by assays for cell viability, cell cycle, apoptosis, mitochondrial membrane potential (MMP), proteomics, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, proteasome activity, and western blot.

RESULTS: CCMH was comprised of arenobufagin (11.14%), bufalin (18.67%), bufotalin (7.33%), cinobufagin (16.67%), cinobufotalin (16.74%), gamabufotalin (8.45%), resibufogenin (12.03%), and telocinobufagin (8.97%). CCMH evidently induced proliferation inhibition, cell cycle arrest, apoptosis, and MMP collapse in gastric cancer cells, possessing the better activities than HCS. Proteomic analysis showed that CCMH influenced ROS pathway, ubiquitin proteasome system, and PI3K/Akt and MAPK signaling pathways. CCMH markedly enhanced intracellular ROS levels in gastric cancer cells, which was reversed by NAC. Accordingly, NAC antagonized the apoptosis-inducing effect of CCMH. Significantly decreased proteasome 20S activity by CCMH was observed in gastric cancer cells. CCMH also regulated the expression of key proteins in PI3K/Akt and MAPK signaling pathways.

CONCLUSION: CCMH possesses more significant apoptotic induction effects on gastric cancer cells than HCS, which is achieved primarily through suppression of proteasome activities and increase of ROS levels, followed by regulating PI3K/Akt and MAPK signaling pathways. Network pharmacology combined with serum pharmacochemistry is an effective strategy for discovering compound-composed Chinese medicine from traditional Chinese medicine, which can help clarify the pharmacological substances and mechanisms of action for traditional Chinese medicine.}, } @article {pmid37987619, year = {2023}, author = {Marcano-Gómez, EC and de Souza, ABF and Machado-Junior, PA and Rodríguez-Herrera, AJ and Castro, TF and da Silva, SPG and Vieira, RG and Talvani, A and Nogueira, KOPC and de Oliveira, LAM and Bezerra, FS}, title = {N-acetylcysteine modulates redox imbalance and inflammation in macrophages and mice exposed to formaldehyde.}, journal = {Free radical research}, volume = {57}, number = {6-12}, pages = {444-459}, doi = {10.1080/10715762.2023.2284636}, pmid = {37987619}, issn = {1029-2470}, mesh = {Reactive Oxygen Species/metabolism ; Respiratory Hypersensitivity ; *Lung ; Macrophages/metabolism ; Formaldehyde/toxicity/metabolism/adverse effects ; Mice ; Animals ; Mice, Inbred C57BL ; Inflammation/chemically induced/drug therapy/metabolism ; Oxidation-Reduction ; *Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Oxidative Stress ; }, abstract = {This study aimed to evaluate the protective role of N-acetylcysteine (NAC) in cells and mice exposed to formaldehyde. For the in vitro study, J774A.1 macrophages cells were incubated for 8, 16 and 24 h with formaldehyde or NAC to assess cell viability and reactive oxygen species (ROS). In the in vivo study, C57BL/6 mice (n = 48) were divided into 6 groups: control (CG), vehicle (VG) that received saline by orogastric gavage, a group exposed to formaldehyde 1% (FG) and formaldehyde exposed groups that received NAC at doses of 100, 150 and 200 mg/Kg (FN100, FN150 and FN200) for a period of 5 days. In vitro, formaldehyde promoted a decrease in cell viability and increased ROS, while NAC reduced formaldehyde-induced ROS production. Animals exposed to formaldehyde presented higher leukocyte counts in the blood and in the bronchoalveolar lavage fluid, and promoted secretion of inflammatory markers IL-6, IL-15, and IL-10. The exposure to formaldehyde also promoted redox imbalance and oxidative damage characterized by increased activities of superoxide dismutase, catalase, decreased GSH/GSSG ratio, as well as it increased levels of protein carbonyls and lipid peroxidation. NAC administration after formaldehyde exposure attenuated oxidative stress markers, secretion of inflammatory mediators and lung inflammation. In conclusion, both in in vitro and in vivo models, NAC administration exerted protective effects, which modulated the inflammatory response and redox imbalance, thus preventing the development airway injury induced by formaldehyde exposure.}, } @article {pmid37984752, year = {2024}, author = {Zhang, WY and Zhao, CM and Wang, CS and Xie, X and Li, YQ and Chen, BB and Feng, L and Jiang, P}, title = {Methylglyoxal accumulation contributes to accelerated brain aging in spontaneously hypertensive rats.}, journal = {Free radical biology & medicine}, volume = {210}, number = {}, pages = {108-119}, doi = {10.1016/j.freeradbiomed.2023.11.012}, pmid = {37984752}, issn = {1873-4596}, mesh = {Rats ; Animals ; Rats, Inbred SHR ; *Pyruvaldehyde ; *Hypertension/metabolism ; Aging ; Acetylcysteine ; Brain/metabolism ; }, abstract = {While it is well-acknowledged that neurovascular dysfunction in hypertension is tightly associated with accelerated brain aging, we contend that the deleterious effects of hypertension may extend beyond affecting only the arteries. Methylglyoxal (MG) derived from glycolysis, is involved in the accumulation of advanced glycated end products (AGEs), which are the hallmarks of neurodegenerative disorders. Therefore, the present study aims to firstly investigate the role of MG metabolism in the hypertension-accelerated brain aging process. The results of our study indicate that the levels of MG increase with age in both the plasma and hippocampus of SHRs at 12, 16, and 30 weeks old. AGE methylglyoxal-hydro imidazoline-1 (MG-H1) is primarily localized in astrocytes, while its presence was not observed in neurons and microglia within the hypertensive hippocampus. Our observations also suggest that angiotensin II (Ang II) enhances glucose uptake and glycolysis while reducing the expression of Glo1 in cultured astrocytes. N-acetylcysteine (NAC) was found to counteract the increase in escape latency and inhibit the activation of the AGEs-RAGE axis in 30-week-old SHRs. NAC decreased Iba-1 immunofluorescence intensity, inhibited the levels of pro-inflammatory markers, and enhanced the abundance of anti-inflammatory markers in the hippocampus of SHRs. Moreover, NAC reduced the immunofluorescence signal of 4HNE and increased the content of GSH and SOD in SHRs. Finally, NAC was observed to inhibit apoptosis in the hippocampus of SHRs. Collectively, we firstly showed the enhanced accumulation of MG in the hypertensive brain, whereas the clearance of MG by NAC treatment mitigated the aging process and attenuated AGEs generation, neuroinflammation, and oxidative damage.}, } @article {pmid37982208, year = {2024}, author = {Allam, A and Ali, AA and Abdel Baky, NA and Balah, A}, title = {Omeprazole induces profibrotic gene expression in rat kidney: implication of TGF-β/Smad signaling pathway.}, journal = {Drug and chemical toxicology}, volume = {47}, number = {5}, pages = {748-755}, doi = {10.1080/01480545.2023.2282377}, pmid = {37982208}, issn = {1525-6014}, mesh = {Animals ; *Signal Transduction/drug effects ; *Omeprazole/pharmacology ; Male ; *Proton Pump Inhibitors/pharmacology ; *Kidney/drug effects/metabolism ; *Transforming Growth Factor beta/metabolism/genetics ; *Connective Tissue Growth Factor/genetics/metabolism ; Rats ; *Tissue Inhibitor of Metalloproteinase-1/metabolism/genetics ; Fibrosis ; Reactive Oxygen Species/metabolism ; Smad Proteins/metabolism/genetics ; Gene Expression Regulation/drug effects ; Rats, Wistar ; }, abstract = {Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications. However, PPI usage is linked to a higher risk of both acute and chronic renal damage by mechanisms not entirely known. The present study demonstrates that omeprazole (10 mg/kg body weight, i.p.) causes TGF-β/Smad signaling activation and subsequent expression of the profibrotic genes CTGF and TIMP-1 in rat kidney. Increased production of CTGF and TIMP-1 accompany activation of the TGF-β/Smad signaling cascade. However, simultaneous treatment of omeprazole and the TGF-β inhibitor, disitertide (P144) (1 mg/kg body weight i.p.) suppresses the TGF-β/Smad signaling pathway and subsequent production of CTGF and TIMP-1. Additionally, TGF-β level in rat kidney was highly reduced in animals treated with the ROS (reactive oxygen species) scavenger, N-acetyl cysteine (NAC) (100 mg/kg body weight i.p.) before omeprazole administration. Furthermore, the reduction in SOD activity brought by omeprazole was returned to the normal level in those animals. However, MDA level increased by omeprazole was highly reduced in the presence of NAC. Collectively, the current findings demonstrate that omeprazole has the ability to promote the expression of the profibrotic genes CTGF and TIMP-1 in a ROS and TGF-β dependent manner. The present study suggests the co-use of ROS scavenger to improve the therapeutic use of the PPI omeprazole.}, } @article {pmid37971568, year = {2023}, author = {Sırrı Akosman, M and Türkmen, R and Demirel, HH}, title = {The protective effect of N-acetylcysteine against MK-801-induced neurodegeneration in mice.}, journal = {Molecular biology reports}, volume = {50}, number = {12}, pages = {10287-10299}, pmid = {37971568}, issn = {1573-4978}, support = {17.Kariyer.45//Afyon Kocatepe Üniversitesi/ ; }, mesh = {Humans ; Mice ; Animals ; Male ; *Acetylcysteine/pharmacology ; *Dizocilpine Maleate/pharmacology ; Quality of Life ; Antioxidants/pharmacology ; Excitatory Amino Acid Antagonists ; Protective Agents ; }, abstract = {BACKGROUND: Neurological disorders result in not only a decline in the quality of life of patients but also a global economic burden. Therefore, protective medicine becomes more important for society. MK-801 is a chemical agent used to understand the etiology of behavioral disorders and brain degeneration in animal models. This study aims to determine whether N-acetylcysteine (NAC) is useful to treat brain degeneration caused by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist.

METHODS AND RESULTS: Four groups were formed by dividing 24 male BALB/c mice into groups of six. The control group was given a saline solution (10 ml/kg-i.p.). MK-801 (1 mg/kg-i.p.) was given alone to one group, and it was given with NAC (100 mg/kg-i.p.) to another group, while the last group was given only NAC (100 mg/kg-i.p.). The administration of drugs lasted for fourteen days. After the behavioral tests (open field and elevated plus-maze), all animals were euthanised, and brain tissues were collected for real-time PCR, TAS-TOS analysis, hematoxylin-eosin, Kluver-Barrera, and TUNEL staining. In the MK-801 group, besides nuclear shrinkage in neurons, glial cell infiltration, vacuolization in cortical neurons, white matter damage, and apoptosis were observed.

CONCLUSION: In the mice given NAC as a protective agent, it was observed that behavioral problems improved, antioxidant levels increased, and nuclear shrinkage, glial cell infiltration, vacuolization in neurons, and white matter degeneration were prevented. Moreover, MBP expression increased, and the number of TUNEL-positive cells significantly decreased. As a result, it was observed that NAC may have a protective effect against brain degeneration.}, } @article {pmid37969394, year = {2023}, author = {Wang, ZQ and Li, YQ and Wang, DY and Shen, YQ}, title = {Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity.}, journal = {Translational cancer research}, volume = {12}, number = {10}, pages = {2911-2922}, pmid = {37969394}, issn = {2219-6803}, abstract = {BACKGROUND: As a new form of cell death, ferroptosis has been shown to have inhibitory effects on a variety of tumor cells except oral squamous cell carcinoma (OSCC). There were few investigations on the effects and molecular mechanisms of piperlongumine (PL, a ferroptosis inducer) and CB-839 (a GLS1 inhibitor which promotes ferroptosis) on OSCC cells. This article assesses the anticancer effect and mechanism of PL as well as combined with CB-839.

METHODS: OSCC cells were treated with specified concentration of PL alone or with ferroptosis inhibitor Ferrostatin-1 (Fer-1) and antioxidant N-Acetylcysteine (NAC) to assess their effects on biological characteristics such as cell proliferation, cell death and intracellular ferroptosis related pathways. Also, cells were treated with PL combined with CB-839 to evaluate the synergistic effect of CB-839 on PL's anticancer effects.

RESULTS: The results showed that the proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner. PL can induce OSCC cells apoptosis. Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment. We found some protein changes significantly such as the expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased. In addition, the anti-proliferation effect of PL can be reversed by Fer-1 and NAC and the level of LPO and ROS was decreased accordingly. Importantly, we found that PL and CB-839 in combination could decrease the cell viability and the LPO level synergistically, accompanied by a large consumption of glutathione (GSH). These evidences prove that PL can induce ferroptosis of OSCC cells, which can be enhanced by CB-839.

CONCLUSIONS: Our study suggested that the nature product PL can induce the ferroptotic death of OSCC cells, which is further enhanced when combined with CB-839. The synergistic anticancer effect of these two may prove new strategy for OSCC treatment.}, } @article {pmid37965267, year = {2023}, author = {Manoharan, A and Farrell, J and Aldilla, VR and Whiteley, G and Kriel, E and Glasbey, T and Kumar, N and Moore, KH and Manos, J and Das, T}, title = {N-acetylcysteine prevents catheter occlusion and inflammation in catheter associated-urinary tract infections by suppressing urease activity.}, journal = {Frontiers in cellular and infection microbiology}, volume = {13}, number = {}, pages = {1216798}, pmid = {37965267}, issn = {2235-2988}, mesh = {Humans ; Urinary Catheterization ; Acetylcysteine/pharmacology ; Urease ; *Proteus Infections/drug therapy/prevention & control/microbiology ; Proteus mirabilis ; *Urinary Tract Infections/prevention & control/microbiology ; Catheters ; Inflammation/prevention & control ; Anti-Inflammatory Agents/pharmacology ; Biofilms ; }, abstract = {INTRODUCTION: Proteus mirabilis is a key pathobiont in catheter-associated urinary tract infections (CA-UTIs), which is well known to form crystalline biofilms that occlude catheters. Urease activity alkylates urine through the release of ammonia, consequentially resulting in higher levels of Mg[2+] and Ca[2+] and formation of crystals. In this study, we showed that N-acetyl cysteine (NAC), a thiol antioxidant, is a potent urease inhibitor that prevents crystalline biofilm formation.

METHODS: To quantify urease activity, Berthelot's method was done on bacterial extracts treated with NAC. We also used an in vitro catheterised glass bladder model to study the effect of NAC treatment on catheter occlusion and biofilm encrustation in P. mirabilis infections. Inductively-coupled plasma mass spectrometry (ICP-MS) was performed on catheter samples to decipher elemental profiles.

RESULTS: NAC inhibits urease activity of clinical P. mirabilis isolates at concentrations as low as 1 mM, independent of bacterial killing. The study also showed that NAC is bacteriostatic on P. mirabilis, and inhibited biofilm formation and catheter occlusion in an in vitro. A significant 4-8log10 reduction in viable bacteria was observed in catheters infected in this model. Additionally, biofilms in NAC treated catheters displayed a depletion of calcium, magnesium, or phosphates (>10 fold reduction), thus confirming the absence of any urease activity in the presence of NAC. Interestingly, we also showed that not only is NAC anti-inflammatory in bladder epithelial cells (BECs), but that it mutes its inflammatory response to urease and P. mirabilis infection by reducing the production of IL-6, IL-8 and IL-1b.

DISCUSSION: Using biochemical, microbiological and immunological techniques, this study displays the functionality of NAC in preventing catheter occlusion by inhibiting urease activity. The study also highlights NAC as a strong anti-inflammatory antibiofilm agent that can target both bacterial and host factors in the treatment of CA-UTIs.}, } @article {pmid37965065, year = {2023}, author = {Wei, H and Liu, R and Zhao, M and Ma, Y and He, Y and Sun, X}, title = {Ischemia‒Reperfusion accelerates neointimal hyperplasia via IL-1β-mediated pyroptosis after balloon injury in the rat carotid artery.}, journal = {Biochemistry and biophysics reports}, volume = {36}, number = {}, pages = {101567}, pmid = {37965065}, issn = {2405-5808}, abstract = {BACKGROUND: Ischemia‒reperfusion (IR) is a pathological process that causes secondary damage to blood vessels. However, whether IR can further worsen neointima formation after balloon injury and the detailed mechanism are unclear.

METHODS: An in vivo model of balloon injury to the rat carotid artery was established to study the effect of IR following balloon injury on neointima formation. Smooth muscle cells (SMCs) were isolated from rat aortas and exposed to hypoxia-reoxygenation to mimic the IR process in vitro. The in vitro cell model was used to investigate the mechanism of IR-mediated neointima formation after balloon injury, which was further confirmed in an in vivo rat model.

RESULTS: IR aggravated neointima formation in the rat carotid artery 2 weeks after balloon injury compared with that observed in the absence of balloon injury (P < 0.001). Compared with that of normal SMCs in the rat carotid artery, the expression of IL-1β, a key proinflammatory cytokine associated with pyroptosis, was increased more than 3-fold in the IR-induced neointima (P < 0.0001) and contributed to the proliferation and migration of rat primary aortic SMCs (P < 0.0001). This process was alleviated by the antioxidant acetylcysteine (NAC), suggesting its partial dependence on intracellular ROS. In the rat model of IR following balloon injury in the carotid artery, the carotid artery that was locally transfected with AAV carrying sh-IL-1β or sh-caspase-1, which alleviated neointima formation, as indicated by a reduction in intima-media thickness in the rat carotid artery (P < 0.0001).

CONCLUSION: Our results suggested that IR could promote IL-1β production in SMCs in the carotid artery after balloon injury and aggravate neointimal hyperplasia, which was alleviated by silencing caspase-1/IL-1β signaling in SMCs in the carotid artery. These results suggest that IL-1β may be an effective target to combat IR-related neointima formation.}, } @article {pmid37963954, year = {2023}, author = {Akkahadsee, P and Sawangjit, R and Phumart, P and Chaiyakunapruk, N and Sakloetsakun, D}, title = {Systematic review and network meta-analysis of efficacy and safety of interventions for preventing anti-tuberculosis drug induced liver injury.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19880}, pmid = {37963954}, issn = {2045-2322}, mesh = {Humans ; *Antitubercular Agents/adverse effects ; Network Meta-Analysis ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention & control ; }, abstract = {Anti-tuberculosis drug induced liver injury (Anti-TB DILI) is the most common adverse events (AEs) necessitating therapy interruption but there is no preventing regimen. This study aimed to examine the efficacy and safety of herbs/alternative medicines for preventing anti-TB DILI. Relevant articles were identified through a systematic search in 5 international databases from inception till March 2022. All randomized controlled trials (RCT) assessing the effects of herbal or alternative medicines against anti-TB DILI were included. The network meta-analysis (NMA) was used to synthesize the evidence for preventing hepatotoxicity using a random-effects model. A total of 3423 patients from 14 RCTs were included. The NMA indicated that supplementation of Turmeric plus Tinospora cordifolia (RR 0.07; 95% CI 0.02 to 0.28), and N-acetyl cysteine (NAC) (RR 0.09; 95% CI 0.01 to 0.75) significantly reduced the incidence of anti-TB DILI compared with placebo. In addition, poly herbal product significantly reduced alkaline phosphatase (ALP) (MD - 21.80; 95% CI - 33.80 to - 9.80) and total bilirubin (Tbil) compared with placebo (MD - 0.51; 95% CI - 0.76 to - 0.26). There was no statistically significant difference in the occurrence of AEs in any intervention. In conclusion, Turmeric plus Tinospora cordifolia, NAC and poly-herbal product may provide benefit for preventing anti-TB DILI in TB patients. However, these findings are based on a small number of studies. Additional studies are warranted to confirm the findings.}, } @article {pmid37960276, year = {2023}, author = {Diniz, MS and Magalhães, CC and Tocantins, C and Grilo, LF and Teixeira, J and Pereira, SP}, title = {Nurturing through Nutrition: Exploring the Role of Antioxidants in Maternal Diet during Pregnancy to Mitigate Developmental Programming of Chronic Diseases.}, journal = {Nutrients}, volume = {15}, number = {21}, pages = {}, pmid = {37960276}, issn = {2072-6643}, support = {SFRH/BPD/116061/2016; SFRH/BD/11934/2022; SFRH/BD/11924/2022; SFRH/BD/5539/2020//ERDF funds through the Operational Programme for Competitiveness/ ; HORIZON-HLTH-2022-STAYHLTH-101080329-2; PTDC/DTP-DES/1082/2014 (POCI-01-0145-FEDER-016657), CENTRO-01-0246-FEDER- 000010 (Multidisciplinary Institute of Ageing in Coimbra), strategic projects UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020//ERDF funds through the Operational Programme for Competitiveness-COMPETE 2020/ ; }, mesh = {Pregnancy ; Female ; Humans ; Antioxidants/pharmacology ; *Prenatal Exposure Delayed Effects/prevention & control/etiology ; Resveratrol/pharmacology ; *Diabetes, Gestational/prevention & control ; *Pregnancy Complications/prevention & control ; Diet ; *Obesity, Maternal/complications ; Fetal Growth Retardation/prevention & control ; Chronic Disease ; }, abstract = {Chronic diseases represent one of the major causes of death worldwide. It has been suggested that pregnancy-related conditions, such as gestational diabetes mellitus (GDM), maternal obesity (MO), and intra-uterine growth restriction (IUGR) induce an adverse intrauterine environment, increasing the offspring's predisposition to chronic diseases later in life. Research has suggested that mitochondrial function and oxidative stress may play a role in the developmental programming of chronic diseases. Having this in mind, in this review, we include evidence that mitochondrial dysfunction and oxidative stress are mechanisms by which GDM, MO, and IUGR program the offspring to chronic diseases. In this specific context, we explore the promising advantages of maternal antioxidant supplementation using compounds such as resveratrol, curcumin, N-acetylcysteine (NAC), and Mitoquinone (MitoQ) in addressing the metabolic dysfunction and oxidative stress associated with GDM, MO, and IUGR in fetoplacental and offspring metabolic health. This approach holds potential to mitigate developmental programming-related risk of chronic diseases, serving as a probable intervention for disease prevention.}, } @article {pmid37958311, year = {2023}, author = {Abdalbari, FH and Martinez-Jaramillo, E and Forgie, BN and Tran, E and Zorychta, E and Goyeneche, AA and Sabri, S and Telleria, CM}, title = {Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells.}, journal = {Cancers}, volume = {15}, number = {21}, pages = {}, pmid = {37958311}, issn = {2072-6694}, support = {2020//Ovarian Cancer Canada/ ; }, abstract = {High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.}, } @article {pmid37950627, year = {2023}, author = {Sultanli, S and Schneider, J and Burkart, SS and Binder, M and Kubatzky, KF}, title = {Cellular ROS tolerance determines the effect of plumbagin on osteoclast differentiation.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {37}, number = {12}, pages = {e23293}, doi = {10.1096/fj.202301415R}, pmid = {37950627}, issn = {1530-6860}, mesh = {*Osteoclasts/metabolism ; Reactive Oxygen Species/metabolism ; *Naphthoquinones/pharmacology ; Cell Differentiation ; RANK Ligand/pharmacology/metabolism ; }, abstract = {Plumbagin is used in traditional medicine because of its anti-inflammatory and anti-microbial properties. As a naphthoquinone, plumbagin triggers the production of reactive oxygen species (ROS). In vitro cancer studies showed that plumbagin triggers apoptosis in cancer cells through ROS production. As cancer-mediated chronic inflammation can affect bone density, it was hypothesized that plumbagin might directly inhibit the formation of bone-resorbing osteoclasts. We previously showed that the effect of plumbagin on osteoclastogenesis differed between bone marrow-derived macrophages and the macrophage cell line RAW 264.7. Although RAW 264.7 macrophages are able to initiate the gene program required for osteoclastogenesis, only primary macrophages successfully differentiate into osteoclasts. Here, we show that RAW 264.7 cells are more sensitive toward plumbagin-induced apoptosis. In the presence of plumbagin and the cytokine RANKL, which triggers ROS production to drive osteoclastogenesis, RAW 264.7 macrophages produce increased amounts of ROS and die. Addition of the ROS scavenger N-acetyl cysteine prevented cell death, linking the failure to differentiate to increased ROS levels. RAW 264.7 cells show reduced expression of genes protective against oxidative stress, while primary macrophages have a higher tolerance toward ROS. Our data suggest that it is indispensable to consider cell (line)-intrinsic properties when studying phytochemicals.}, } @article {pmid37949132, year = {2024}, author = {Ye, Y and Liu, B and Wang, Z and Liu, L and Zhang, Q and Zhang, Q and Jiang, W}, title = {Sodium p-perfluorous nonenoxybenzene sulfonate induces ROS-mediated necroptosis by directly targeting catalase in HepG2 cells.}, journal = {The Science of the total environment}, volume = {910}, number = {}, pages = {168446}, doi = {10.1016/j.scitotenv.2023.168446}, pmid = {37949132}, issn = {1879-1026}, mesh = {Humans ; Reactive Oxygen Species ; Catalase ; Hep G2 Cells ; Necroptosis ; Molecular Docking Simulation ; Necrosis/chemically induced ; *Alkanesulfonic Acids/toxicity ; Alkanesulfonates ; *Fluorocarbons/toxicity ; }, abstract = {Sodium p-perfluorous nonenoxybenzene sulfonate (OBS) has been widely used as a substitute for perfluorooctane sulfonic acid (PFOS) because of its high surface activity and low cost, but the knowledge of its biological effects is still limited. In this study, we compared the toxic effects of OBS and PFOS on human hepatoma cells (HepG2). OBS resulted in lower cell viability, higher ROS levels, and more severe necrosis than PFOS, indicating that OBS caused higher cytotoxicity than PFOS. In this process, OBS induced a burst of ROS and downregulation of catalase (CAT). OBS-induced oxidative stress was recovered after the CAT overexpression, but the CAT levels were not reversed after N-acetylcysteine (NAC) pretreatment. This indicates that the downregulated CAT is an upstream signal of the ROS burst. Moreover, drug affinity targeting assay, spectroscopic analysis and molecular docking were conducted, showing that OBS directly targeted CAT and therefore downregulated CAT. In addition, we found that OBS-induced necrosis is RIP1/RIP3-dependent programmed necroptosis. In summary, OBS directly targets CAT to reduce CAT levels and induces oxidative stress and necroptosis. Our findings are helpful to understand the toxicity of OBS and to evaluate the safety of OBS as a substitute for PFOS.}, } @article {pmid37945228, year = {2023}, author = {Wang, Y and Wang, A and Zhao, G and Liu, S and Li, K and Li, W and Peng, Y and Zheng, J}, title = {Glutathione conjugation and protein modification resulting from metabolic activation of pesticide metalaxyl in vitro and in vivo.}, journal = {Pesticide biochemistry and physiology}, volume = {196}, number = {}, pages = {105606}, doi = {10.1016/j.pestbp.2023.105606}, pmid = {37945228}, issn = {1095-9939}, mesh = {Rats ; Humans ; Mice ; Animals ; Activation, Metabolic ; *Pesticides/toxicity/metabolism ; Cysteine/metabolism/pharmacology ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; }, abstract = {Metalaxyl (MTL), a germicidal agent, is widely used in agriculture. Due to the biological amplification effect, MTL entering the ecological environment would result in a threat to human health through the food chain. MTL is reportedly accumulated in liver. The objectives of the study included investigating the metabolic activation of MTL in liver and defining the mechanisms participating in the hepatotoxicity of MTL. The corresponding glutathione (GSH), N-acetylcysteine (NAC) conjugate, and cysteine conjugates were observed in liver microsomes, prepared from liver tissues of mice, containing MTL and GSH, NAC or cysteine. These conjugates were also detected in urine and bile of rats receiving MTL. Apparently, MTL was biotransformed to a quinone imine intermediate dose-dependently attacking the thiols and cysteine residues of protein. The bioactivation of MTL required cytochrome P450 enzymes, and CYP3A dominated the bio-activation of MTL.}, } @article {pmid37944606, year = {2024}, author = {Sun, W and Xu, T and Lin, H and Yin, Y and Xu, S}, title = {BPA and low-Se exacerbate apoptosis and autophagy in the chicken bursa of Fabricius by regulating the ROS/AKT/FOXO1 pathway.}, journal = {The Science of the total environment}, volume = {908}, number = {}, pages = {168424}, doi = {10.1016/j.scitotenv.2023.168424}, pmid = {37944606}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Chickens/metabolism ; Reactive Oxygen Species/metabolism ; *Bursa of Fabricius/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Apoptosis ; Oxidative Stress ; Autophagy ; Forkhead Box Protein O1/metabolism/pharmacology ; }, abstract = {Bisphenol A (BPA) is a ubiquitous environmental pollutant that can have harmful effects on human and animal immune systems by inducing oxidative stress. Selenium (Se) deficiency damages immune organ tissues and exhibits synergistic effects on the toxicity of environmental pollutants. However, oxidative stress, cell apoptosis, and autophagy caused by the combination of BPA and low-Se, have not been studied in the bursa of Fabricius of the immune organ of poultry. Therefore, in this study, BPA and/or low-Se broiler models and chicken lymphoma cells (MDCC-MSB-1 cells) models were established to investigate the effects of BPA and/or low-Se on the bursa of Fabricius of poultry. The data showed that BPA and/or low-Se disrupted the normal structure of the bursa of Fabricius, BPA (60 μM) significantly reduced the activity of MDCC-MSB-1 cells and disrupted normal morphology (IC50 = 192.5 ± 1.026 μM). Compared with the Control group, apoptosis and autophagy were increased in the BPA or low-Se groups, and the generation of reactive oxygen species (ROS) was increased. This inhibited the AKT/FOXO1 pathway, leading to mitochondrial fusion/division imbalance (Mfn1, Mfn2, OPA1 were increased, DRP1 was decreased) and dysfunction (CI-NDUFB8, CII-SDHB, CIII-UQCRC2, CIV-MTCO1, CV-ATP5A1, ATP). Furthermore, combined exposure of BPA and low-Se aggravated the above-mentioned changes. Treatment with N-acetylcysteine (NAC) reduced ROS levels and activated the AKT/FOXO1 pathway to further alleviate BPA and low-Se-induced apoptosis and autophagy. Apoptosis induced by low-Se + BPA was exacerbated after 3-Methyladenine (3-MA, autophagy inhibitor) treatment. Together, these results indicated that BPA and low-Se aggravated apoptosis and autophagy of the bursa of Fabricius in chickens by regulating the ROS/AKT/FOXO1 pathway.}, } @article {pmid37942159, year = {2023}, author = {Zhang, H and Gong, J and Zhang, S and Luo, L and Luo, C and Bi, K and Wang, L and Kan, X and Tian, Z and Wang, X}, title = {N-acetylcysteine attenuates the incidence of phlebitis induced by carbomer/vinorelbine gel.}, journal = {Heliyon}, volume = {9}, number = {11}, pages = {e21235}, pmid = {37942159}, issn = {2405-8440}, abstract = {BACKGROUND: The high incidence and severe clinical manifestations of phlebitis pose a complex and urgent clinical challenge. The rapid and simple establishment of animal phlebitis models and the development of preventive strategies are crucial to resolving this problem.

METHODS: In this study, we established such models by mixing vinorelbine ditartrate (VNR) and carbomer to form a sustained-release gel carrier, and then injected it around the veins rather than inside the vessels. Furthermore, we analyzed the efficacy of the carbomer/VNR gel in inducing phlebitis by monitoring the morphology of the veins using HE staining, immunohistochemical and immunofluorescence staining, and western blotting. Reactive oxygen species (ROS) and lipid peroxidation levels were determined using flow cytometry. Finally, we evaluated the inhibitory effect of N-acetylcysteine (NAC) on VNR-induced phlebitis in rabbits and rats.

RESULTS: Our findings suggested that the carbomer/VNR gel rapidly and easily induced phlebitis due to by retention of the gel in situ, wrapping the veins, and the prolonged release of VNR. NAC alleviated the VNR-induced oxidative stress response and expression of inflammatory cytokines by attenuating mitochondrial damage in venous endothelial cells, thereby preventing the occurrence of phlebitis in rabbits and rats.

CONCLUSION: The in situ carbomer/VNR gel provides a rapid and simple method for establishing an animal model to study the pathogenesis of phlebitis. Furthermore, the observed therapeutic effect of NAC highlights its novel and efficacious role in preventing and treating phlebitis.}, } @article {pmid37937383, year = {2023}, author = {Fayed, MS and Brooks, J and Seaquist, ER and Kumar, A and Moheet, A and Eberly, L and Mishra, U and Coles, LD}, title = {Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.}, journal = {Clinical pharmacology in drug development}, volume = {12}, number = {12}, pages = {1234-1240}, doi = {10.1002/cpdd.1338}, pmid = {37937383}, issn = {2160-7648}, support = {2-SRA-2014-272-M-R/JDRF/Juvenile Diabetes Research Foundation/United States ; P30 DK020593/DK/NIDDK NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Acetylcysteine/pharmacokinetics ; Cross-Over Studies ; Glutathione/metabolism ; Healthy Volunteers ; *Hypoglycemia ; }, abstract = {Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.}, } @article {pmid37931470, year = {2023}, author = {Bauzá-Thorbrügge, M and Peris, E and Zamani, S and Micallef, P and Paul, A and Bartesaghi, S and Benrick, A and Wernstedt Asterholm, I}, title = {NRF2 is essential for adaptative browning of white adipocytes.}, journal = {Redox biology}, volume = {68}, number = {}, pages = {102951}, pmid = {37931470}, issn = {2213-2317}, mesh = {Animals ; Mice ; Acetylcysteine/pharmacology ; Adaptation, Physiological ; Adipocytes, Brown/metabolism ; *Adipocytes, White/metabolism ; Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Antioxidants/pharmacology/metabolism ; Lactates/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.}, } @article {pmid37926333, year = {2024}, author = {Aslanlar, DA and Vişneci, EF and Oz, M and Nurullahoglu Atalik, KE}, title = {N-acetylcysteine ameliorates chemotherapy-induced impaired anxiety and depression-like behaviors by regulating inflammation, oxidative and cholinergic status, and BDNF release.}, journal = {Behavioural brain research}, volume = {458}, number = {}, pages = {114740}, doi = {10.1016/j.bbr.2023.114740}, pmid = {37926333}, issn = {1872-7549}, mesh = {Rats ; Humans ; Male ; Animals ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology/therapeutic use ; Brain-Derived Neurotrophic Factor ; Rats, Wistar ; Depression/chemically induced/drug therapy ; Acetylcholinesterase ; Methotrexate ; Oxidative Stress ; Inflammation/chemically induced/drug therapy ; Anxiety/chemically induced/drug therapy ; *Antineoplastic Agents/pharmacology ; Cholinergic Agents/pharmacology ; }, abstract = {Mood disorders caused by chemotherapy have become more important as the survival of cancer patients increases, and new studies in this field will contribute to the prevention of this disorder. For this purpose, we used methotrexate, a chemotherapeutic agent frequently preferred in oncological cases. Mtx was administered as a single dose of 100 mg/kg intraperitoneally to male Wistar albino rats. Since oxidative stress plays an important role in chemotherapy-induced emotional impairment, n-acetylcysteine (NAC), a potent antioxidant, was administered at 500 mg/kg in two doses before Mtx administration. We evaluated anxiety and depression-like behaviors 24 h after Mtx administration, as well as some oxidative and inflammatory markers in blood serum and hippocampal tissue, acetylcholinesterase activity (AChE), and brain-derived neurotrophic factor (BDNF) release in hippocampal tissue. In rats, Mtx induced anxiety and depression-like behaviors as well as abnormalities in oxidative and inflammatory markers in blood serum and hippocampal tissue, increased AChE activity in hippocampal tissue, and decreased BDNF release. NAC treatment was found to ameliorate Mtx-induced anxiety and depression-like behaviors, increase antioxidant capacity, reduce oxidative stress and inflammatory response, and regulate AChE activity and BDNF release. In conclusion, the fact that NAC treatment of Mtx was effective is important for revising the treatment strategies for individuals suffering from this disorder, and this effect is thought to be related to the antioxidant and anti-inflammatory power of NAC.}, } @article {pmid37923393, year = {2024}, author = {Wang, H and Chang, Y and Liu, X and Liu, L and Hua, M and Li, A}, title = {Protective effects of baicalin on diethyl nitrosamine-induced liver cirrhosis by suppressing oxidative stress and inflammation.}, journal = {Chemical biology & drug design}, volume = {103}, number = {1}, pages = {e14386}, doi = {10.1111/cbdd.14386}, pmid = {37923393}, issn = {1747-0285}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Rats ; Animals ; Reactive Oxygen Species/metabolism ; *Liver Cirrhosis/chemically induced/drug therapy ; Liver ; Oxidative Stress ; Inflammation/chemically induced/drug therapy/metabolism ; *Nitrosamines/adverse effects/metabolism ; *Flavonoids ; }, abstract = {Baicalin (BA) is a natural product extract with anti-inflammatory, antioxidant, and hepatoprotective properties. Given that the exact underlying mechanisms responsible for the impact of BA on liver cirrhosis remain ambiguous, a detailed investigation is sorely needed. Accordingly, a rat liver cirrhosis model was established via the intraperitoneal injection of diethyl nitrosamine (DEN, 100 mg/kg). Following the modeling, these rats were given BA (100 mg/kg) or N-acetylcysteine (NAC, 150 mg/kg) alone or in combination. The pathological morphology of rat liver tissues in each group was observed by hematoxylin and eosin staining and Masson's trichrome staining. The expression of fibrosis-related proteins was evaluated by Western blot, and the levels of liver function-related biochemical indexes, oxidative stress-related indexes, and inflammatory factors in the serum by enzyme-linked immunosorbent assays (ELISA). The level of mitochondrial reactive oxygen species was measured by flow cytometry. The results depicted that in the rat model of DEN-induced liver cirrhosis, BA reduced the expression of fibrosis-related proteins (collagen type I alpha 1, α-smooth muscle actin, and transforming growth factor-β1), thereby alleviating the structural fibrosis of liver tissue. Furthermore, BA could diminish the level of mitochondrial reactive oxygen species, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1), while promoting albumin, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels. Notably, all these effects of BA above were strengthened following the combined treatment of BA and NAC. On the whole, BA suppresses liver fibrosis by inhibiting oxidative stress and inflammation, thereby exerting a hepatoprotective effect.}, } @article {pmid37923985, year = {2023}, author = {Huang, Z and Han, Y and Zhang, X and Sun, Y and Lin, Y and Feng, L and Zhou, T and Wang, Z}, title = {Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.}, journal = {BMC microbiology}, volume = {23}, number = {1}, pages = {321}, pmid = {37923985}, issn = {1471-2180}, mesh = {Animals ; Mice ; *Anti-Bacterial Agents/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Ceftazidime/pharmacology ; Azabicyclo Compounds/pharmacology ; Drug Combinations ; *Gammaproteobacteria/metabolism ; Microbial Sensitivity Tests ; beta-Lactamases/metabolism ; }, abstract = {BACKGROUND: Ceftazidime-avibactam (CZA) improves treatment outcomes for infections caused by carbapenem-resistant organisms, but has led to serious bacterial resistance. Acetylcysteine (NAC) is an approved medication that protects the respiratory tract through antioxidant and anti-inflammatory effects.

RESULTS: This study found that NAC combined with CZA effectively inhibits the growth of CZA-resistant clinical Enterobacterales strains. The CZA/NAC combination inhibits biofilm formation in vitro and decreases bacterial burden in a mouse thigh infection model. The combination is biocompatible and primarily increases cell membrane permeability to cause bacterial death.

CONCLUSIONS: These findings prove that the CZA/NAC combination has potential as a treatment for CZA-resistant Enterobacterales infections.}, } @article {pmid37923778, year = {2023}, author = {Clarke, G and Mao, J and Fan, Y and Hann, A and Gupta, A and Nutu, A and Buckel, E and Kayani, K and Murphy, N and Bangash, MN and Casey, AL and Wootton, I and Lawson, AJ and Dasari, BVM and Perera, MTPR and Mergental, H and Afford, SC}, title = {N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19022}, pmid = {37923778}, issn = {2045-2322}, support = {/WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Liver Transplantation/methods ; *Methemoglobinemia ; Acetylcysteine/pharmacology ; Organ Preservation/methods ; Methemoglobin ; Liver ; Perfusion/methods ; }, abstract = {Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N-acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87-102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90-184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration.}, } @article {pmid37921125, year = {2024}, author = {Zhao, J and Han, M and Tian, Y and Zhao, P and Liu, X and Dong, H and Feng, S and Li, J}, title = {N-acetylcysteine Attenuates Cigarette Smoke-induced Alveolar Epithelial Cell Apoptosis through Reactive Oxygen Species Depletion and Glutathione Replenish In vivo and In vitro.}, journal = {Current pharmaceutical biotechnology}, volume = {25}, number = {11}, pages = {1466-1477}, pmid = {37921125}, issn = {1873-4316}, support = {232102311215//Science and Technology Department of Henan Province/ ; }, mesh = {Animals ; *Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Mice ; *Glutathione/metabolism ; *Pulmonary Disease, Chronic Obstructive/drug therapy/metabolism/pathology ; *Alveolar Epithelial Cells/drug effects/metabolism ; Cell Line ; Smoke/adverse effects ; Male ; Endoplasmic Reticulum Stress/drug effects ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. N-acetylcysteine (NAC) is well known for its antioxidant properties, along with potential protective effects on COPD. However, the molecular mechanism of NAC against the apoptosis of alveolar epithelial cells (AECs) in COPD remains unclear.

OBJECTIVE: This study aimed to explore the anti-apoptosis effect of NAC in COPD mice and alveolar epithelial cells.

METHODS: In the present study, the mouse model of COPD was established by cigarette smoke (CS), and mouse alveolar epithelial (MLE-12) cells were treated with cigarette smoke extract (CSE). TdT-mediated dUTP nick-end labeling (TUNEL) assay, reverse transcription polymerase chain reaction (RT-PCR), and western blot were performed to evaluate the effects of NAC on apoptosis, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Meanwhile, Lbuthionine- sulfoximine (BSO), a glutathione (GSH) inhibitor, was used to uncover the mechanism of COPD treatment by NAC.

RESULTS: We found that NAC pretreatment could attenuate the protein levels of apoptosis, ER stress, and mitochondrial dysfunction-related genes caused by CS in vivo. Meanwhile, CSE could decrease MLE-12 cell viability, which was prevented by apoptosis inhibitor ZVAD-FMK but not necroptosis inhibitor necrostatin-1. Pretreatment of MLE-12 cells with NAC increased cellular GSH levels, inhibited cellular and mitochondrial reactive oxygen species (ROS) accumulation, and decreased protein level of apoptosis, ER stress, and mitochondrial dysfunction-related genes. Moreover, experiment results showed that BSO could completely reverse the beneficial effects of NAC.

CONCLUSION: Our study confirmed that NAC can attenuate CS-induced AEC apoptosis via alleviating ROS-mediated ER stress and mitochondrial dysfunction pathway, and the mechanism was found to be related to replenishing the cellular GSH content.}, } @article {pmid37918853, year = {2024}, author = {Bryan, A and Pingali, P and Faber, A and Landry, J and Akakpo, JY and Jaeschke, H and Li, H and Lee, WS and May, L and Patel, B and Neuwelt, A}, title = {High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {388}, number = {1}, pages = {209-217}, pmid = {37918853}, issn = {1521-0103}, support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; P30 CA016059/CA/NCI NIH HHS/United States ; IK2 BX004914/BX/BLRD VA/United States ; R21 AG073892/AG/NIA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; *Cytochrome P-450 CYP2E1/metabolism ; Fomepizole ; Mice, Inbred NOD ; Liver/metabolism ; Acetylcysteine/pharmacology ; }, abstract = {Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgamma[null] mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.}, } @article {pmid37918281, year = {2024}, author = {Li, Y and Yang, X and Bao, T and Sun, X and Li, X and Zhu, H and Zhang, B and Ma, T}, title = {Radix Astragali decoction improves liver regeneration by upregulating hepatic expression of aquaporin-9.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {122}, number = {}, pages = {155166}, doi = {10.1016/j.phymed.2023.155166}, pmid = {37918281}, issn = {1618-095X}, mesh = {Mice ; Animals ; Liver Regeneration ; Hydrogen Peroxide/metabolism ; Liver ; *Drugs, Chinese Herbal/chemistry ; *Astragalus Plant/chemistry ; *Aquaporins/genetics/metabolism/pharmacology ; }, abstract = {BACKGROUND: The therapeutic efficacy of liver injuries heavily relies on the liver's remarkable regenerative capacity, necessitating the maintenance of glycose/lipids homeostasis and oxidative eustasis during the recovery process. Astragali Radix, an herbal tonic widely used in China and many other countries, is believed to have many positive effects, including immune stimulation, nourishing, antioxidant, liver protection, diuresis, anti-diabetes, anti-cancer and expectorant. Astragali Radix is widely integrated into hepatoprotective formulas as it is believed to facilitate liver regeneration. Nevertheless, the precise molecular pharmacological mechanisms underlying this hepatoprotective effect remain elusive.

PURPOSE: To investigate the improving effects of Astragali Radix on liver regeneration and the underlying mechanisms.

METHODS: A mouse model of 70% partial hepatectomy (PHx) was employed to investigate the impact of Radix Astragali decoction (HQD) on liver regeneration. HQD was orally administered for 7 days before the PHx procedure and throughout the experiment. N-acetylcysteine (NAC) was used as a positive control for liver regeneration. Liver regeneration was assessed by evaluating the liver-to-body weight ratio (LW/BW) and the expression of representative cell proliferation marker proteins. Oxidative stress and glucose metabolism were analyzed using biochemical assays, Western blotting, dihydroethidium (DHE) fluorescence, and periodic acid-Schiff (PAS) staining methods. To understand the role of AQP9 as a potential molecular target of HQD in promoting liver regeneration, td-Tomato-tagged AQP9 transgenic mice (AQP9-RFP) were employed to determine the expression pattern of AQP9 protein. AQP9 knockout mice (AQP9[-/-]) were used to assess the specific targeting of AQP9 in the promotion of liver regeneration by HQD.

RESULTS: HQD significantly upregulated hepatic AQP9 expression, alleviated liver injury and promoted liver regeneration in wild-type (AQP9[+/+]) mice after 70% PHx. However, the beneficial impact of HQD on liver regeneration was absent in AQP9 gene knockout (AQP9[-/-]) mice. Moreover, HQD facilitated the uptake of glycerol by hepatocytes, enhanced gluconeogenesis, and concurrently reduced H2O2 content and oxidative stress levels in AQP9[+/+] but not AQP9[-/-] mouse livers. Additionally, main active substance of Radix Astragali, astragaloside IV (AS-IV) and cycloastragenol (CAG), demonstrated substantial upregulation of AQP9 expression and promoted liver regeneration in AQP9[+/+] but not AQP9[-/-] mice.

CONCLUSION: This study is the first to demonstrate that Radix Astragali and its main active constituents (AS-IV and CAG) improve liver regeneration by upregulating the expression of AQP9 in hepatocytes to increase gluconeogenesis and reduce oxidative stress. The study revealed novel molecular pharmacological mechanisms of Radix Astragali and provided a promising therapeutic target of liver diseases.}, } @article {pmid37913693, year = {2023}, author = {Yilmaz, H and Mercantepe, F and Tumkaya, L and Mercantepe, T and Yilmaz, A and Yilmaz Rakici, S}, title = {The potential antioxidant effect of N-acetylcysteine on X-ray ionizing radiation-induced pancreas islet cell toxicity.}, journal = {Biochemical and biophysical research communications}, volume = {685}, number = {}, pages = {149154}, doi = {10.1016/j.bbrc.2023.149154}, pmid = {37913693}, issn = {1090-2104}, mesh = {Humans ; Male ; Rats ; Animals ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; X-Rays ; Caspase 3/metabolism ; Glucagon ; Saline Solution/pharmacology ; Sodium Chloride/pharmacology ; Oxidative Stress ; Glutathione/metabolism ; Radiation, Ionizing ; *Radiation Injuries/drug therapy/prevention & control ; *Islets of Langerhans/metabolism ; *Insulins ; }, abstract = {PURPOSE: Previous research has highlighted the impact of X-ray irradiation-induced organ damage, on cancer patients after radiation therapy. The ionizing radiation-induced oxidative stress causes injury to the pancreatic islet cells of Langerhans. We used histopathological, immunohistochemical, and biochemical analyses to examine α- and β-cells in the islets of Langerhans in rats undergoing whole-body x-ray ionizing radiation, a group of which was treated with NAC.

MATERIAL AND METHODS: Twenty-four male rats were randomly divided into 3 groups, one control, and two experimental groups. Group I (Control) was administered only saline solution (0.09% NaCl) by oral gavage for 7 days. Group II (IR) was administrated whole body single dose 6 Gray ionizing radiation (IR) and saline solution (0.09% NaCl) by oral gavage for 7 days. Group III (IR + NAC) was administered 300 mg/kg NAC (N-acetylcysteine) by oral gavage for 7 days, 5 days before, and 2 days after 6 Gray IR application.

RESULTS: In the X-ray irradiation group, we observed diffuse necrotic endocrine cells in the islets of Langerhans. In addition, we found that Caspase-3, malondialdehyde (MDA) levels increased, and insulin, glucagon, and glutathione (GSH) levels decreased in the IR group compared to the control group. In contrast, we observed a decrease in Caspase-3, and MDA levels in necrotic endocrine cells, and an increase in insulin, glucagon, and GSH levels in the IR + NAC group compared to the IR group.

CONCLUSION: This study provides evidence for the beneficial effects of N-acetyl cysteine on islets of Langerhans cells with X-ray ionizing-radiation-induced damage in a rat model.}, } @article {pmid37913572, year = {2023}, author = {Feng, Q and Hu, K and Hu, H and Lu, Y and Zhang, H and Wang, G and Zhang, Q and Xu, Z and Gao, X and Jia, X and Zhu, H and Song, D and Yi, H and Peng, Y and Wu, X and Li, B and Zhu, W and Shi, J}, title = {Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells.}, journal = {International immunopharmacology}, volume = {125}, number = {Pt A}, pages = {111139}, doi = {10.1016/j.intimp.2023.111139}, pmid = {37913572}, issn = {1878-1705}, mesh = {Humans ; Apoptosis ; *Berberine/pharmacology ; Cell Line, Tumor ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/pathology ; MAP Kinase Signaling System ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {The most common neoplasm among adult lymphomas is diffuse large B-cell lymphoma (DLBCL), typically characterized by pain-free and progressive lymph node enlargement. Due to high heterogeneity of DLBCL, 30-40 % of patients are resistant to R-CHOP standard chemoimmunotherapy. DCZ0358 is a new compound designed and synthesized from berberine by our group and the molecular mechanism by which it inhibited DLBCL growth has attracted our widespread attention. In this study, we employed the CCK8 assay to reveal that DCZ0358 inhibited proliferation in a dependent manner of time and dosage of DLBCL cells. Moreover, flowcytometry and western blot results showed that DCZ0358 downregulated the expression of CDK4, CDK6 and CyclinD1 to block cell cycle progression in G0/G1 phase. Furthermore, DCZ0358 enhanced mitochondrial membrane potential depolarization, promoted mitochondrial permeability transport pore openness, increased cytoplastic Ca2+ levels and decreased intracellular adenosine triphosphate production, which led to mitochondrial dysfunction. In particular, DCZ0358 treatment triggered cell apoptosis and elevated intracellular reactive oxygen species (ROS) levels, which subsequently mediated JNK pathway activation. Further research indicated the pre-treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358. Most importantly, DCZ0358 exhibited synergistic anti-tumor effects when combined with etoposide, a common clinical anti-DLBCL drug, both in vitro and certainly in vivo. Above results demonstrated anti-tumor molecular mechanism of DCZ0358 in DLBCL cells and highlighted the ROS/JNK/DNA damage pathway as a potential target in therapies, which have implications for the development of more effective clinical treatments for DLBCL.}, } @article {pmid37908648, year = {2023}, author = {Li, H and Deng, X and Zhang, Z and Yang, Z and Huang, H and Ye, X and Zhong, L and Xu, G and Liu, R and Fang, Y}, title = {Nitric oxide/paclitaxel micelles enhance anti-liver cancer effects and paclitaxel sensitivity by inducing ferroptosis, endoplasmic reticulum stress and pyroptosis.}, journal = {RSC advances}, volume = {13}, number = {45}, pages = {31772-31784}, pmid = {37908648}, issn = {2046-2069}, abstract = {The objective of this study was to investigate the anticancer activities of biodegradable polymeric micelles composed of monomethoxy poly(ethylene glycol), polylactic acid, and nitric oxide (mPEG-PLA-NO) loaded with paclitaxel (PTX) as a nanomedicine delivery system. We aimed to compare the anticancer effects of these NO/PTX micelles with PTX alone and elucidate their mechanism of action. We evaluated the impact of NO/PTX and PTX on cell viability using Cell Counting Kit-8 (CCK8) assays conducted on the Bel-7402 liver cancer cell line. Additionally, we employed H22 xenografted mice to assess the in vivo tumor growth inhibitory activity of NO/PTX. To examine the cytotoxicity of NO/PTX, the intracellular levels of reactive oxygen species (ROS), and the expression of ferroptosis-related proteins, we conducted experiments in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) or the ROS inhibitor N-acetyl cysteine (NAC). Furthermore, we investigated the expression of endoplasmic reticulum stress (ERS) and apoptosis-associated proteins. Our results demonstrated that NO/PTX exhibited enhanced anticancer effects compared to PTX alone in both Bel-7402 cells and H22 xenografted mice. The addition of Fer-1 or NAC reduced the anticancer activity of NO/PTX, indicating the involvement of ferroptosis and ROS in its mechanism of action. Furthermore, NO/PTX modulated the expression of proteins related to ERS and apoptosis, indicating the activation of these cellular pathways. The anticancer effects of NO/PTX in liver cancer cells were mediated through the induction of ferroptosis, pyroptosis, ERS, and apoptosis-associated networks. Ferroptosis and pyroptosis were activated by treatment of NO/PTX at low concentration, whereas ERS was induced to trigger apoptosis at high concentration. The superior anti-tumor effect of NO/PTX may be attributed to the downregulation of a multidrug resistance transporter and the sensitization of cells to PTX chemotherapy. In summary, our study highlights the potential of mPEG-PLA-NO micelles loaded with PTX as a nanomedicine delivery system for liver cancer treatment. The observed enhancement in anticancer activity, combined with the modulation of key cellular pathways, provides valuable insights into the therapeutic potential of NO/PTX in overcoming resistance and improving treatment outcomes in liver cancer patients.}, } @article {pmid37902021, year = {2023}, author = {ALRashdi, BM and Mohamed, RA and Mohamed, AH and Samoul, FA and Mohamed, MI and Moussa, MM and Alrashidi, SM and Dawod, B and Habotta, OA and Abdel Moneim, AE and Ramadan, SS}, title = {Therapeutic activity of green synthesized selenium nanoparticles from turmeric against cisplatin-induced oxido-inflammatory stress and cell death in mice kidney.}, journal = {Bioscience reports}, volume = {43}, number = {11}, pages = {}, pmid = {37902021}, issn = {1573-4935}, mesh = {Mice ; Animals ; *Cisplatin/adverse effects ; *Selenium/pharmacology/metabolism ; Curcuma ; Kidney/pathology ; Apoptosis ; Oxidative Stress ; }, abstract = {Cisplatin (CDDP) is a commonly prescribed chemotherapeutic agent; however, its associated nephrotoxicity limits its clinical efficacy and sometimes requires discontinuation of its use. The existing study was designed to explore the reno-therapeutic efficacy of turmeric (Tur) alone or conjugated with selenium nanoparticles (Tur-SeNPs) against CDDP-mediated renal impairment in mice and the mechanisms underlying this effect. Mice were orally treated with Tur extract (200 mg/kg) or Tur-SeNPs (0.5 mg/kg) for 7 days after administration of a single dose of CDDP (5 mg/kg, i.p.). N-acetyl cysteine NAC (100 mg/kg) was used as a standard antioxidant compound. The results revealed that Tur-SeNPs counteracted CDDP-mediated serious renal effects in treated mice. Compared with the controls, Tur or Tur-SeNPs therapy remarkably decreased the kidney index along with the serum levels of urea, creatinine, Kim-1, and NGAL of the CDDP-injected mice. Furthermore, Tur-SeNPs ameliorated the renal oxidant status of CDDP group demonstrated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and gene expression levels of HO-1. Noteworthy, lessening of renal inflammation was exerted by Tur-SeNPs via lessening of IL-6 and TNF-α besides down-regulation of NF-κB gene expression in mouse kidneys. Tur-SeNPs treatment also restored the renal histological features attained by CDDP challenge and hindered renal apoptosis through decreasing the Bax levels and increasing Bcl-2 levels. Altogether, these outcomes suggest that the administration of Tur conjugated with SeNPs is effective neoadjuvant chemotherapy to guard against the renal adverse effects that are associated with CDDP therapy.}, } @article {pmid37899576, year = {2024}, author = {Sozer Karadagli, S and Gursoy, P}, title = {Liver toxicity with ribociclib in a patient with metastatic hormone receptor positive postmenopausal breast cancer.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {30}, number = {2}, pages = {404-407}, doi = {10.1177/10781552231208390}, pmid = {37899576}, issn = {1477-092X}, mesh = {Female ; Humans ; *Aminopyridines/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Breast Neoplasms/drug therapy/pathology ; Cysteine/therapeutic use ; *Drug-Related Side Effects and Adverse Reactions/drug therapy ; Liver ; Postmenopause ; *Purines/adverse effects ; Receptor, ErbB-2 ; }, abstract = {INTRODUCTION: In recent years, highly selective reversible CDK4/6 inhibitors have been combined with aromatase inhibitors for their efficacy and ease of application in the treatment of advanced stage of hormone-responsive breast cancers. Oral use of these drugs facilitates patient compliance. However, adverse drug reactions are reported due to these drugs, in the literature. Diverse adverse reactions such as skin reactions, liver toxicity, and vitiligo with ribociclib have been reported.

CASE REPORT: In this study, we present of liver toxicity due to the use of ribociclib in a case of advanced breast cancer with metastases. It is noteworthy that the patient did not have any other concomitant disease and did not take any other medication.

MANAGEMENT AND OUTCOME: After the 600 mg initial dose of ribociclib, neutropenia occurred at the beginning of the therapy, the dose was reduced to 400 mg, and liver enzymes started to rise in the second month of the therapy. In the fifth month of the intermittent treatment period, liver toxicity was grade 3.

DISCUSSION: Liver adverse reaction occurred due to ribociclib use in the patient who had no history of any other disease. The Naranjo algorithm score was evaluated as 9. Considering the excretion of ribociclib by sulfation, cysteine conjugation, and glucuronidation, which are phase II reactions, n-acetyl cysteine (NAC) treatment (600 mg/day) was started for the patient. NAC therapy is recommended to reduce elevated liver enzymes in the case. The patient's treatment has been continuing with palbociclib for 5 months. No increase in liver enzymes was observed.}, } @article {pmid37895148, year = {2023}, author = {Yang, YF and Singh, S}, title = {Pharmacogenomic Landscape of Ivermectin and Selective Antioxidants: Exploring Gene Interplay in the Context of Long COVID.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895148}, issn = {1422-0067}, mesh = {Humans ; *COVID-19/genetics ; Antioxidants/therapeutic use ; Post-Acute COVID-19 Syndrome ; Ivermectin/therapeutic use ; Pandemics ; Anthocyanins ; Pharmacogenetics ; *MicroRNAs/genetics ; }, abstract = {COVID-19 pandemic has caused widespread panic and fear among the global population. As such, repurposing drugs are being used as viable therapeutic options due to the limited effective treatments for Long COVID symptoms. Ivermectin is one of the emerging repurposed drugs that has been shown effective to have antiviral effects in clinical trials. In addition, antioxidant compounds are also gaining attention due to their capabilities of reducing inflammation and severity of symptoms. Due to the absence of knowledge in pharmacogenomics and modes of actions in the human body for these compounds, this study aims to provide a pharmacogenomic profile for the combination of ivermectin and six selected antioxidants (epigallocatechin gallate (EGCG), curcumin, sesamin, anthocyanins, quercetin, and N-acetylcysteine (NAC)) as potentially effective regimens for long COVID symptoms. Results showed that there were 12 interacting genes found among the ivermectin, 6 antioxidants, and COVID-19. For network pharmacology, the 12 common interacting genes/proteins had the highest associations with Pertussis pathway, AGE-RAGE signaling pathway in diabetic complications, and colorectal cancer in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Disease analyses also revealed that the top three relevant diseases with COVID-19 infections were diabetes mellitus, ischemia, reperfusion injury. We also identified 6 potential target microRNAs (miRNAs) of the 12 commonly curated genes used as molecular biomarkers for COVID-19 treatments. The established pharmacogenomic network, disease analyses, and identified miRNAs could facilitate developments of effective regimens for chronic sequelae of COVID-19 especially in this post-pandemic era. However, further studies and clinical trials are needed to substantiate the effectiveness and dosages for COVID-19 treatments.}, } @article {pmid37894999, year = {2023}, author = {Li, R and Kato, H and Fumimoto, C and Nakamura, Y and Yoshimura, K and Minagawa, E and Omatsu, K and Ogata, C and Taguchi, Y and Umeda, M}, title = {Essential Amino Acid Starvation-Induced Oxidative Stress Causes DNA Damage and Apoptosis in Murine Osteoblast-like Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37894999}, issn = {1422-0067}, support = {No. 23K19761//Japan Society for the Promotion of Science/ ; No. 21K09946//Japan Society for the Promotion of Science/ ; No. 22K09993//Japan Society for the Promotion of Science/ ; }, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Oxidative Stress ; *Apoptosis ; Acetylcysteine/pharmacology/metabolism ; DNA Damage ; Osteoblasts/metabolism ; Amino Acids, Essential/metabolism ; }, abstract = {Intracellular nutrient metabolism, particularly the metabolism of essential amino acids (EAAs), is crucial for cellular functions, including energy production and redox homeostasis. An EAA deficiency can lead to cellular dysfunction and oxidative stress. This study explores the mechanisms underlying cellular responses to EAA starvation, focusing on ROS-induced DNA damage and apoptosis. MC3T3-E1 cells were subjected to EAA starvation, and various assays were conducted to assess cell proliferation, survival, DNA damage, and apoptosis. The antioxidant N-acetylcysteine (NAC) was employed to block ROS formation and mitigate cellular damage. Gene expression and Western blot analyses were performed to elucidate molecular pathways. EAA starvation-induced ROS generation, DNA damage, and apoptosis in MC3T3-E1 cells. NAC administration effectively reduced DNA damage and apoptosis, highlighting the pivotal role of ROS in mediating these cellular responses during EAA deficiency. This study demonstrates that EAA starvation triggers ROS-mediated DNA damage and apoptosis, offering insights into the intricate interplay between nutrient deficiency, oxidative stress, and programmed cell death. NAC emerges as a potential therapeutic intervention to counteract these adverse effects.}, } @article {pmid37894565, year = {2023}, author = {Ntorkou, M and Tsanaktsidou, E and Chachlioutaki, K and Fatouros, DG and Markopoulou, CK}, title = {In Vitro Permeability Study of Homotaurine Using a High-Performance Liquid Chromatography with Fluorescence Detection Pre-Column Derivatization Method.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {20}, pages = {}, pmid = {37894565}, issn = {1420-3049}, mesh = {*Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid/methods ; *Memantine ; o-Phthalaldehyde/chemistry ; Indicators and Reagents ; Tiopronin ; Reproducibility of Results ; }, abstract = {Homotaurine (HOM) is considered a promising drug for the treatment of Alzheimer's and other neurodegenerative diseases. In the present work, a new high-performance liquid chromatography with fluorescence detection (HPLC-FLD) (λex. = 340 nm and λem. = 455 nm) method was developed and validated for the study of substance permeability in the central nervous system (CNS). Analysis was performed on a RP-C18 column with a binary gradient elution system consisting of methanol-potassium phosphate buffer solution (pH = 7.0, 0.02 M) as mobile phase. Samples of homotaurine and histidine (internal standard) were initially derivatized with ortho-phthalaldehyde (OPA) (0.01 M), N-acetylcysteine (0.01 M) and borate buffer (pH = 10.5; 0.05 M). To ensure the stability and efficiency of the reaction, the presence of different nucleophilic reagents, namely (a) 2-mercaptoethanol (2-ME), (b) N-acetylcysteine (NAC), (c) tiopronin (Thiola), (d) 3-mercaptopropionic acid (3-MPA) and (e) captopril, was investigated. The method was validated (R[2] = 0.9999, intra-day repeatability %RSD < 3.22%, inter-day precision %RSD = 1.83%, limits of detection 5.75 ng/mL and limits of quantification 17.43 ng/mL, recovery of five different concentrations 99.75-101.58%) and successfully applied to investigate the in vitro permeability of homotaurine using Franz diffusion cells. The apparent permeability (Papp) of HOM was compared with that of memantine, which is considered a potential therapeutic drug for various CNSs. Our study demonstrates that homotaurine exhibits superior permeability through the simulated blood-brain barrier compared to memantine, offering promising insights for enhanced drug delivery strategies targeting neurological conditions.}, } @article {pmid37891946, year = {2023}, author = {Tieu, S and Charchoglyan, A and Paulsen, L and Wagter-Lesperance, LC and Shandilya, UK and Bridle, BW and Mallard, BA and Karrow, NA}, title = {N-Acetylcysteine and Its Immunomodulatory Properties in Humans and Domesticated Animals.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891946}, issn = {2076-3921}, abstract = {N-acetylcysteine (NAC), an acetylated derivative of the amino acid L-cysteine, has been widely used as a mucolytic agent and antidote for acetaminophen overdose since the 1960s and the 1980s, respectively. NAC possesses antioxidant, cytoprotective, anti-inflammatory, antimicrobial, and mucolytic properties, making it a promising therapeutic agent for a wide range of diseases in both humans and domesticated animals. Oxidative stress and inflammation play a major role in the onset and progression of all these diseases. NAC's primary role is to replenish glutathione (GSH) stores, the master antioxidant in all tissues; however, it can also reduce levels of pro-inflammatory tumor necrosis factor-alpha (TNF-∝) and interleukins (IL-6 and IL-1β), inhibit the formation of microbial biofilms and destroy biofilms, and break down disulfide bonds between mucin molecules. Many experimental studies have been conducted on the use of NAC to address a wide range of pathological conditions; however, its effectiveness in clinical trials remains limited and studies often have conflicting results. The purpose of this review is to provide a concise overview of promising NAC usages for the treatment of different human and domestic animal disorders.}, } @article {pmid37886069, year = {2023}, author = {Pacios, O and Blasco, L and Ortiz Cartagena, C and Bleriot, I and Fernández-García, L and López, M and Barrio-Pujante, A and Cuenca, FF and Aracil, B and Oteo-Iglesias, J and Tomás, M}, title = {Molecular studies of phages-Klebsiella pneumoniae in mucoid environment: innovative use of mucolytic agents prior to the administration of lytic phages.}, journal = {Frontiers in microbiology}, volume = {14}, number = {}, pages = {1286046}, pmid = {37886069}, issn = {1664-302X}, abstract = {Mucins are important glycoproteins that form a protective layer throughout the gastrointestinal and respiratory tracts. There is scientific evidence of increase in phage-resistance in the presence of mucin for some bacterial pathogens. Manipulation in mucin composition may ultimately influence the effectiveness of phage therapy. In this work, two clinical strains of K. pneumoniae (K3574 and K3325), were exposed to the lytic bacteriophage vB_KpnS-VAC35 in the presence and absence of mucin on a long-term co-evolution assay, in an attempt to mimic in vitro the exposure to mucins that bacteria and their phages face in vivo. Enumerations of the bacterial and phage counts at regular time intervals were conducted, and extraction of the genomic DNA of co-evolved bacteria to the phage, the mucin and both was performed. We determined the frequency of phage-resistant mutants in the presence and absence of mucin and including a mucolytic agent (N-acetyl L-cysteine, NAC), and sequenced them using Nanopore. We phenotypically demonstrated that the presence of mucin induces the emergence of bacterial resistance against lytic phages, effectively decreased in the presence of NAC. In addition, the genomic analysis revealed some of the genes relevant to the development of phage resistance in long-term co-evolution, with a special focus on the mucoid environment. Genes involved in the metabolism of carbohydrates were mutated in the presence of mucin. In conclusion, the use of mucolytic agents prior to the administration of lytic phages could be an interesting therapeutic option when addressing K. pneumoniae infections in environments where mucin is overproduced.}, } @article {pmid37885115, year = {2024}, author = {Salehi, AM and Hasanzarrini, M and Salehi, H and Jenabi, E}, title = {Liraglutide and Liver Injury: Rare Case Report with Literature Review.}, journal = {Endocrine, metabolic & immune disorders drug targets}, volume = {24}, number = {6}, pages = {725-729}, pmid = {37885115}, issn = {2212-3873}, mesh = {Humans ; Female ; Adult ; *Liraglutide/adverse effects ; *Diabetes Mellitus, Type 2/diagnosis/drug therapy/chemically induced ; Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptide 1 ; Liver ; }, abstract = {BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus (T2DM). So far, few severe side effects have been reported for it.

CASE PRESENTATION: A 41-year-old woman was admitted to the Emergency Room with diffuse abdominal pain. The patient had a known case of T2DM, fatty liver disease, and hypertension and was treated with Metformin, Liraglutide, and Losartan. Her liver functional test (LFT) was consistent with hepatocellular injury; however, laboratory tests and abdominal ultrasound were used to rule out autoimmune hepatitis. Due to concerns for drug-induced liver injury (DILL), liraglutide was discontinued and N-acetyl cysteine was prescribed. On the fifth day of hospitalization, the patient's symptoms resolved and his LFT started to decrease on the sixth day after 2 months, the patient's liver enzyme levels returned to normal.

CONCLUSION: Liraglutide is one of the most important drugs in the treatment of T2DM.The most common side effects of this drug are constipation, nausea, vomiting, diarrhea, indigestion, and loss of appetite. In rare cases, symptoms of thyroid cancer, pancreatitis, and hypoglycemia have been reported, however, DILL is one of the extremely rare side effect of Liraglutide. It is important to increase the awareness of physicians about the liver injury of Liraglutide.}, } @article {pmid37884214, year = {2023}, author = {Kshirsagar, S and Dandekar, A and Srivastava, RK and Khan, J and Muzaffar, S and Athar, M and Banga, AK}, title = {Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury.}, journal = {International journal of pharmaceutics}, volume = {647}, number = {}, pages = {123547}, pmid = {37884214}, issn = {1873-3476}, support = {U01 AR078544/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Antidotes ; *Acetylcysteine ; Administration, Cutaneous ; Skin ; Drug Delivery Systems ; Needles ; }, abstract = {Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.}, } @article {pmid37877516, year = {2023}, author = {Li, S and Yang, N and Ma, Q and Li, S and Tong, S and Luo, J and Song, X and Yang, H}, title = {Tailoring Oxidation Responsiveness of Gold Nanoclusters via Ligand Engineering for Imaging Acute Kidney Injury.}, journal = {Analytical chemistry}, volume = {95}, number = {44}, pages = {16153-16159}, doi = {10.1021/acs.analchem.3c02698}, pmid = {37877516}, issn = {1520-6882}, mesh = {Animals ; Mice ; Gold/chemistry ; Ligands ; Diagnostic Imaging ; *Acute Kidney Injury ; *Metal Nanoparticles/chemistry ; }, abstract = {Gold nanoclusters (AuNCs) have shown great promise for in vivo imaging because of their definable structure, tunable photoluminescence (PL), and desired renal clearance. However, current understanding of the responsiveness of AuNCs to biological substances is still limited, which may hamper their biomedical applications. Herein, we explore the oxidation responsiveness of near-infrared II (NIR-II) luminescent AuNCs capped with two different ligands, which can be optimized for high-efficiency NIR-II PL imaging of mice acute kidney injury (AKI) featuring high-level peroxynitrite anions (ONOO[-]). We found that in the presence of ONOO[-], N-acetylcysteine-capped AuNCs (NAC-AuNCs) tended to be oxidized more easily than that capped with the macromolecular mercapto-β-cyclodextrin (CDS-AuNCs), resulting in the aggregation of NAC-AuNCs into large-sized assemblies, which was not observed in CDS-AuNCs. The oxidation-triggered morphology, composition, and NIR-II PL changes in NAC-AuNCs were then systematically studied. We finally demonstrated that NAC-AuNCs can be implemented for sensitive NIR-II PL imaging of mice AKI, facilitated by the synergetic in situ AuNC aggregation and decreased glomerular filtration rate (GFR) in the injured kidney, which outperforms the methods solely based on the decreased GFR effect. Therefore, this work highlights the critical significance of ligand engineering in AuNCs and may motivate future design of AuNCs for diverse bioimaging applications.}, } @article {pmid37877260, year = {2023}, author = {Wilson, SH and Sirianni, JM and Bridges, KH and Wolf, BJ and Valente, IE and Scofield, MD}, title = {The impact of intraoperative N-acetylcysteine on opioid consumption following spine surgery: a randomized pilot trial.}, journal = {Pain management}, volume = {13}, number = {10}, pages = {593-602}, pmid = {37877260}, issn = {1758-1877}, support = {R01 DA054154/DA/NIDA NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; UL1TR001450/TR/NCATS NIH HHS/United States ; UL1TR001450/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Acetylcysteine/therapeutic use ; *Analgesics, Opioid/therapeutic use ; Double-Blind Method ; Pain, Postoperative/drug therapy ; Pilot Projects ; Prospective Studies ; }, abstract = {Aim: N-acetylcysteine (NAC) decreases inflammation and could augment perioperative analgesia. Materials & methods: This prospective pilot trial examined postoperative opioid consumption at 12 h following intraoperative NAC. In phase I, 20 adults scheduled for posterior spine surgery were randomized to NAC (0, 50, 100 and 150 mg/kg) to determine the optimal dose. In phase II, 30 patients were randomized to placebo or NAC (150 mg/kg). Opioid consumption, pain ratings and time to opioid rescue were recorded. Results: Postoperative opioid consumption was reduced in the NAC group 19.3% at 12 h and 20% at 18 and 36 h. Opioid consumption was reduced 22-24% in the NAC group at all times after adjusting for intraoperative opioid administration. NAC subjects reported lower pain scores relative to placebo. Conclusion: Subjects randomized to NAC consumed less postoperative opioids and reported less pain versus placebo. Larger randomized controlled trials are needed to further evaluate NAC for analgesia. Clinical Trial Registration: NCT04562597 (ClinicalTrials.gov).}, } @article {pmid37870740, year = {2024}, author = {Agarwal, A and Jayashree, M and Angurana, SK and Sharma, R and Ghosh, A and Singh, MP and Nallasamy, K and Bansal, A}, title = {Clinical Profile, Intensive Care Needs and Predictors of Outcome Among Children Admitted with Non-COVID Severe Acute Respiratory Illness (SARI) During the Pandemic.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {4}, pages = {329-336}, pmid = {37870740}, issn = {0973-7693}, mesh = {Child ; Humans ; SARS-CoV-2 ; Pandemics ; Retrospective Studies ; *COVID-19 ; Critical Care ; *Respiratory Insufficiency ; }, abstract = {OBJECTIVES: To study the epidemiology of non-coronavirus disease-2019 (non-COVID-19) respiratory viral infections with respect to their clinical profile, intensive care needs and predictors of outcome once the non-pharmacological interventions (NPI) during the coronavirus disease-2019 (COVID-19) pandemic were relaxed.

METHODS: Retrospective analysis of children with Severe Acute Respiratory Illness (SARI) who were SARS-CoV-2 negative, admitted to the Pediatric Emergency/Intensive Care Unit (PICU) from July 2021 through October 2021 was conducted.

RESULTS: One hundred and thirty nine children with median age of 11 (4-28.5) mo were included. Besides respiratory symptoms in all, diarrhea was reported in 90 (64.7%) children. Nearly half (n = 66; 47%) presented in hypoxemic respiratory failure (SpO2 <88%). Fifty-two (37.4%) children had co-morbidities, commonest being congenital heart disease in 12 (23.1%). Baseline parameters revealed leukopenia (specifically lymphopenia) 39 (28%), elevated aspartate transaminase [Serum glutamic-oxaloacetic transaminase (SGOT)] in 108 (77.6%), elevated N-acetyl-cysteine-activated creatinine kinase (CK-NAC) 23 (79%) and lactate dehydrogenase (LDH) 15 (88%). Intensive care needs included mechanical ventilation 51 (36.6%), vasoactive support 34 (24.5%), and renal replacement therapy 10 (7.1%). Forty-two (30.2%) children developed multi-organ dysfunction syndrome (MODS). One hundred and three (74.1%) children were discharged, 31 (22.3%) died, and 5 (3.6%) left against medical advice. On multivariate regression analysis, elevated liver enzymes (>5 times normal), hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted mortality.

CONCLUSIONS: A surge in non-COVID SARI was observed once lockdown measures were relaxed. Nearly 1/3[rd] progressed to multi-organ failure and died. Elevated liver enzymes, hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted death.}, } @article {pmid37869073, year = {2023}, author = {Ye, R and Ma, S and Chen, Y and Shan, J and Tan, L and Su, L and Tong, Y and Zhao, Z and Chen, H and Fu, M and Guo, Z and Zuo, X and Yu, J and Zhong, W and Zeng, J and Liu, F and Chai, C and Guan, X and Wang, Z and Liu, T and Liang, J and Zhang, Y and Shi, H and Wen, Z and Xia, H and Zhang, R}, title = {Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.}, journal = {JHEP reports : innovation in hepatology}, volume = {5}, number = {11}, pages = {100908}, pmid = {37869073}, issn = {2589-5559}, abstract = {BACKGROUND & AIMS: Our previous study indicated that CD177[+] neutrophil activation has a vital role in the pathogenesis of biliary atresia (BA), which is partially ameliorated by N-acetylcysteine (NAC) treatment. Here, we evaluated the clinical efficacy of NAC treatment and profiled liver-resident immune cells via single cell RNA-sequencing (scRNA-seq) analysis to provide a comprehensive immune landscape of NAC-derived immune regulation.

METHODS: A pilot clinical study was conducted to evaluate the potential effects of intravenous NAC treatment on infants with BA, and a 3-month follow-up was carried out to assess treatment efficacy. scRNA-seq analysis of liver CD45[+] immune cells in the control (n = 4), BA (n = 6), and BA + NAC (n = 6) groups was performed and the effects on innate cells, including neutrophil and monocyte-macrophage subsets, and lymphoid cells were evaluated.

RESULTS: Intravenous NAC treatment demonstrated beneficial efficacy for infants with BA by improving bilirubin metabolism and bile acid flow. Two hepatic neutrophil subsets of innate cells were identified by scRNA-seq analysis. NAC treatment suppressed oxidative phosphorylation and reactive oxygen species production in immature neutrophils, which were transcriptionally and functionally similar to CD177[+] neutrophils. We also observed the suppression of hepatic monocyte-mediated inflammation, decreased levels of oxidative phosphorylation, and M1 polarisation in Kupffer-like macrophages by NAC. In lymphoid cells, enhancement of humoral immune responses and attenuation of cellular immune responses were observed after NAC treatment. Moreover, cell-cell interaction analysis showed that innate/adaptive proinflammatory responses were downregulated by NAC.

CONCLUSIONS: Our clinical and scRNA-seq data demonstrated that intravenous NAC treatment partially reversed liver immune dysfunction, alleviated the proinflammatory responses in BA by targeting innate cells, and exhibited beneficial clinical efficacy.

IMPACT AND IMPLICATIONS: BA is a serious liver disease that affects newborns and has no effective drug treatment. In this study, scRNA-seq showed that NAC treatment can partially reverse the immune dysfunction of neutrophil extracellular trap-releasing CD177+ neutrophils and Kupffer cells, and lower the inflammatory responses of other innate immune cells in BA. In consequence, intravenous NAC treatment improved the clinical outcomes of patients with BA in term of bilirubin metabolism.}, } @article {pmid37865270, year = {2023}, author = {Lefèvre, CR and Le Divenah, F and Collet, N and Pelletier, R and Robert, E and Ropert, M and Pawlowski, M and Gicquel, T and Bendavid, C}, title = {Avoiding falsely low creatinine concentrations measured in patients treated with N-acetylcysteine for acetaminophen intoxication using enzymo-amperometric method - An in vitro and in vivo study.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {551}, number = {}, pages = {117611}, doi = {10.1016/j.cca.2023.117611}, pmid = {37865270}, issn = {1873-3492}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Acetaminophen ; Creatinine ; Retrospective Studies ; Peroxidase ; Peroxidases ; }, abstract = {BACKGROUND: Circulating creatinine is a biomarker of paramount importance in clinical practice. In cases of acetaminophen (APAP) intoxication, the antidote, N-acetylcysteine (NAC), interferes with commonly used creatininase-peroxidase methods. This study aimed to assess whether creatininase-amperometric methods were affected in this context.

METHODS: This study includes in vitro interference tests, involving four creatinine assays using NAC-spiked plasma pools and an in vivo retrospective study comparing creatininase-peroxidase and creatininase-amperometric measurements in patients presenting with NAC-treated APAP poisoning.

RESULTS: Creatininase-peroxidase method was impacted by NAC interference in a clinically-significant manner at therapeutic NAC levels (basal value recovery of 80 % and 70 % for 500 and 1000 mg.L[-1] of NAC, respectively), surpassing the desirable Reference Change Value (RCV%). Enzymo-amperometric methods were not impacted. Among patients, a mean bias of -45.2 ± 28.0 % was observed for the peroxidase detection method compared to the amperometric in those who received NAC prior plasma sampling and -2.7 ± 5.4 % in those who did not.

CONCLUSIONS: Our findings indicate that enzymo-amperometric creatinine assays remain unaffected by NAC interference due to the absence of the peroxidase step in the analytical process. Therefore, these methods are suitable to prevent spurious hypocreatininemia in APAP intoxicated patients undergoing NAC therapy.}, } @article {pmid37864839, year = {2024}, author = {Chao, SP and Cheng, WL and Yi, W and Cai, HH and Deng, K and Cao, JL and Zeng, Z and Wang, H and Wu, X}, title = {N-Acetylcysteine Alleviates Phenylephrine-Induced Cardiomyocyte Dysfunction via Engaging PI3K/AKT Signaling Pathway.}, journal = {American journal of hypertension}, volume = {37}, number = {3}, pages = {230-238}, doi = {10.1093/ajh/hpad100}, pmid = {37864839}, issn = {1941-7225}, support = {HHYC2019003//yellow crane of excellence program/ ; ZNXKPY2021011//Zhongnan disciplinary platform/ ; }, mesh = {Rats ; Animals ; *Phosphatidylinositol 3-Kinase/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Myocytes, Cardiac/metabolism ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology ; Phenylephrine/pharmacology ; Signal Transduction ; Oxidative Stress ; Apoptosis ; }, abstract = {BACKGROUND: Increased reactive oxygen species (ROS) and oxidative stress response lead to cardiomyocyte hypertrophy and apoptosis, which play crucial roles in the pathogenesis of heart failure. The purpose of current research was to explore the role of antioxidant N-acetylcysteine (NAC) on cardiomyocyte dysfunction and the underlying molecular mechanisms.

METHODS AND RESULTS: Compared with control group without NAC treatment, NAC dramatically inhibited the cell size of primary cultured neonatal rat cardiomyocytes (NRCMs) tested by immunofluorescence staining and reduced the expression of representative markers associated with hypertrophic, fibrosis and apoptosis subjected to phenylephrine administration examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Moreover, enhanced ROS expression was attenuated, whereas activities of makers related to oxidative stress response examined by individual assay Kits, including total antioxidation capacity (T-AOC), glutathione peroxidase (GSH-Px), and primary antioxidant enzyme Superoxide dismutase (SOD) were induced by NAC treatment in NRCMs previously treated with phenylephrine. Mechanistically, we noticed that the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and AKT were increased by NAC stimulation. More importantly, we identified that the negative regulation of NAC in cardiomyocyte dysfunction was contributed by PI3K/AKT signaling pathway through further utilization of PI3K/AKT inhibitor (LY294002) or agonist (SC79).

CONCLUSIONS: Collected, NAC could attenuate cardiomyocyte dysfunction subjected to phenylephrine, partially by regulating the ROS-induced PI3K/AKT-dependent signaling pathway.}, } @article {pmid37860953, year = {2024}, author = {Dos Santos, AC and França, TCS and Venzon, L and Polli, V and Polleti, G and Trembulak, E and Pilati, SFM and da Silva, LM}, title = {Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {1}, pages = {e23560}, doi = {10.1002/jbt.23560}, pmid = {37860953}, issn = {1099-0461}, mesh = {Mice ; Animals ; Acetylcysteine/pharmacology ; *Silymarin/pharmacology ; Lipopolysaccharides/toxicity ; Interleukin-10 ; Ethanol/toxicity ; *Chemical and Drug Induced Liver Injury, Chronic/pathology ; Interleukin-6/pharmacology ; Liver/pathology ; Antioxidants/pharmacology ; Glutathione ; Transaminases/pharmacology ; }, abstract = {This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.}, } @article {pmid37859626, year = {2023}, author = {Wang, J and Zhang, C and Zhao, R and Wang, P and Jin, M and Xu, J}, title = {Antioxidant N-acetylcysteine removing ROS: an antifouling strategy inspired by mussels.}, journal = {Environmental science. Processes & impacts}, volume = {25}, number = {12}, pages = {1962-1973}, doi = {10.1039/d3em00191a}, pmid = {37859626}, issn = {2050-7895}, mesh = {Animals ; *Biofouling/prevention & control ; Antioxidants ; Acetylcysteine/pharmacology ; Reactive Oxygen Species ; Ecosystem ; *Bivalvia ; Dihydroxyphenylalanine ; }, abstract = {Marine biofouling is a thorny issue that causes serious economic losses and adverse ecological impacts on marine ecosystems. Effective and promising antifouling strategies such as surface hydration, flow shear force, and lubricant injection have been developed to address this challenge. However, for the complex marine environment, they still appear inadequate. Mussels are a common fouling organism with strong surface adhesion ability. However, when hypoxia and the oxidative cross-linking reaction of 3,4-dihydroxy phenyl-L-alanine (DOPA) in the structure of adhesion proteins are disrupted, their adhesion ability will be greatly reduced. Inspired by this, we developed an effective antifouling strategy based on reactive oxygen species (ROS) scavenging using N-acetylcysteine (NAC) and evaluated its performance. As a ROS scavenger interfered with the oxidative cross-linking reaction of DOPA in an aqueous solution, the adhesion of DOPA was also affected on the surface of NAC functionalized polyvinyl chloride (PVC) (PVC-NAC). In addition, the colonization level of mussels and the adhesion rate of marine bacteria and benthic diatoms on PVC-NAC were low. The antifouling strategy proposed in this paper was eco-friendly and broad-spectrum, and may provide a new idea for solving marine biofouling and reducing the environmental and economic impacts of fouling organisms.}, } @article {pmid37858742, year = {2023}, author = {Tüfekci, KK and Tatar, M and Terzi, F and Bakirhan, EG}, title = {An investigation of the endoplasmic reticulum stress in obesity exposure in the prenatal period.}, journal = {Journal of chemical neuroanatomy}, volume = {134}, number = {}, pages = {102348}, doi = {10.1016/j.jchemneu.2023.102348}, pmid = {37858742}, issn = {1873-6300}, mesh = {Humans ; Rats ; Female ; Animals ; Pregnancy ; Infant ; *Acetylcysteine ; *Endoplasmic Reticulum Stress ; Obesity ; Endoplasmic Reticulum Chaperone BiP ; Hippocampus/metabolism ; }, abstract = {OBJECTIVES: Exposure to maternal obesity has been shown to make offspring more prone to cognitive and metabolic disorders later in life. Although the underlying mechanisms are unclear, the role of endoplasmic reticulum (ER) stress in the fetal programming process is remarkable. ER stress can be activated by many chronic diseases, including obesity and diabetes. Therefore, our study aimed to investigate the role of ER stress caused by maternal diet-induced obesity in the offspring hippocampus. We also evaluated the protective effect of N-acetylcysteine (NAC) against ER stress.

METHODS: A rat obesity model was created by providing a high-fat (60 % kcal) diet. N-acetylcysteine (NAC) was administered at a dosage of 150 mg/kg via the intragastric route. The animals were mated at the age of 12 weeks. The same diet was maintained during pregnancy and lactation. The experiment was terminated on the postnatal 28th day, and the offspring's brain tissues were examined. Immunohistochemical staining for ER stress markers was performed on sections taken from tissues after routine histological procedures.

RESULTS: The results revealed increased GRP78, PERK, and eIF2α immunoreactivities in the hippocampal dentate gyrus (DG) and cornu ammonis 1 (CA1) regions in the obese group offspring, while the expression of those markers in those regions normalized with NAC supplementation (p < 0.01). Statistical analysis of XBP1 immunoreactivity H-scores revealed no difference between the study groups (p > 0.05).

DISCUSSION: These results suggest that exposure to obesity during the prenatal period may cause increased ER stress in hippocampal neurons, which have an important role in the regulation of learning, memory and behavior, and this may contribute to decreased cognitive performance. On the other hand, NAC stands out as an effective agent that can counteract hippocampal ER stress.}, } @article {pmid37858609, year = {2024}, author = {Roy, P and Kandel, R and Sawant, N and Singh, KP}, title = {Estrogen-induced reactive oxygen species, through epigenetic reprogramming, causes increased growth in breast cancer cells.}, journal = {Molecular and cellular endocrinology}, volume = {579}, number = {}, pages = {112092}, doi = {10.1016/j.mce.2023.112092}, pmid = {37858609}, issn = {1872-8057}, mesh = {Humans ; Female ; Reactive Oxygen Species/metabolism ; *Breast Neoplasms/genetics/metabolism ; Estrogens/pharmacology ; Estradiol/pharmacology ; Epigenesis, Genetic ; }, abstract = {Despite the progress made in cancer diagnosis and treatment, breast cancer remains the second leading cause of cancer-related death among the women. Exposure to elevated levels of endogenous estrogen or environmental estrogenic chemicals is an important risk factor for breast cancer. Estrogen metabolites and ROS generated during estrogen metabolism are known to play a critical role in estrogen carcinogenesis. However, the molecular mechanisms through which estrogen-induced ROS regulate gene expression is not clear. Epigenetic changes of DNA methylation and histone modifications are known to regulate genes expression. Therefore, the objective of this study was to evaluate whether estrogen-induced ROS, through aberrant expression of epigenetic regulatory genes and epigenetic reprogramming, causes growth of breast cancer cells. Estrogen responsive MCF-7 and T47D human breast cancer cells were exposed to natural estrogen 17 beta-estradiol (E2) and synthetic estrogen Diethylstilbestrol (DES) both alone and in combination with antioxidant N-acetyl cysteine. Effects of NAC-mediated scavenging of estrogen-induced ROS on cell growth, gene expression, and histone modifications were measured. The result of MTT and cell cycle analysis revealed significant abrogation of E2 and DES-induced growth by scavenging ROS through NAC. E2 and DES caused significant changes in expression of epigenetic regulatory genes for DNA methylation and histone modifications as well as changes in both gene activating and repressive marks in the Histone H3. NAC restored the expression of epigenetic regulatory genes and changes in histone marks. Novel findings of this study suggest that estrogen can induce growth of breast cancer cells through ROS-dependent regulation of epigenetic regulatory genes and epigenetic reprogramming of histone marks.}, } @article {pmid37853974, year = {2023}, author = {Nalbant, K and Erden, S}, title = {Possible effects of N-acetylcysteine in autism spectrum disorders: major clinical aspects, eating behaviors, and sleeping habits.}, journal = {The Turkish journal of pediatrics}, volume = {65}, number = {5}, pages = {832-844}, doi = {10.24953/turkjped.2022.573}, pmid = {37853974}, issn = {2791-6421}, mesh = {Child, Preschool ; Humans ; Child ; *Autism Spectrum Disorder/drug therapy ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Sleep ; Feeding Behavior ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is a promising agent for reducing irritability and hyperactivity and enhancing social responsiveness in children with autism spectrum disorders (ASD). This study aims to examine the effects of NAC on cardinal symptoms, eating, and sleeping habits in preschool children with autism.

METHODS: The medical records of ASD patients were investigated retrospectively. 37 children with ASD who regularly received oral NAC in two divided doses per day (400-600 mg/day) for 8 weeks were included as the study group. The control group consisted of 21 children with ASD who were recommended NAC but never used it. The initial and second assessment scores after 8 weeks of regular use of the NAC group and control group on the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Children Eating Behavior Questionnaire (CEBQ), and the Sleep Habits Questionnaire (CSHQ) were compared.

RESULTS: Our findings suggested that oral NAC alleviated the intensity of cardinal autistic symptoms in areas of social withdrawal, interpersonal relationships, body use, listening response, and verbal communication. Corresponding problem behaviors such as irritability, stereotypic behavior, and hyperactivity were reduced. It was determined that there was no difference between the two groups in terms of eating behaviors and sleeping habits.

CONCLUSIONS: According to the results, NAC alleviated the severity of cardinal symptoms and reduced problem behaviors in autism. Additional trials with more systematic planning, controlling for confounding effects, and long-term follow-up should be provided in future studies.}, } @article {pmid37852631, year = {2023}, author = {Fond, G and Mallet, J and Urbach, M and Benros, ME and Berk, M and Billeci, M and Boyer, L and Correll, CU and Fornaro, M and Kulkarni, J and Leboyer, M and Llorca, PM and Misdrahi, D and Rey, R and Schürhoff, F and Solmi, M and Sommer, IEC and Stahl, SM and Pignon, B and Berna, F}, title = {Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs.}, journal = {BMJ mental health}, volume = {26}, number = {1}, pages = {}, pmid = {37852631}, issn = {2755-9734}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Amino Acids/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Schizophrenia/drug therapy ; Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {QUESTION: This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia.

STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed.

FINDINGS: Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600 mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000 mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2 g/day) and minocycline (200-300 mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio.

CONCLUSIONS: The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.}, } @article {pmid37851785, year = {2023}, author = {Brasil, VP and Siqueira, RM and Campos, FG and Yoshitani, MM and Pereira, GP and Mendonça, RLDS and Kanno, DT and Pereira, JA and Martinez, CAR}, title = {Mucin levels in glands of the colonic mucosa of rats with diversion colitis subjected to enemas containing sucralfate and n-acetylcysteine alone or in combination.}, journal = {Acta cirurgica brasileira}, volume = {38}, number = {}, pages = {e384023}, pmid = {37851785}, issn = {1678-2674}, mesh = {Rats ; Animals ; *Sucralfate/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Rats, Wistar ; Colon ; *Colitis/drug therapy/prevention & control ; Mucins ; Sialomucins ; Intestinal Mucosa ; Enema/methods ; }, abstract = {PURPOSE: To evaluate the tissue content of neutral and acidic mucins, sulfomucins and sialomucins in colonic glands devoid of intestinal transit after enemas containing sucralfate and n-acetylcysteine alone or in combination.

METHODS: Sixty-four rats underwent intestinal transit bypass. A colonic segment was collected to compose the white group (without intervention). After derivation, the animals were divided into two groups according to whether enemas were performed daily for two or four weeks. Each group was subdivided into four subgroups according to the substance used: control group: saline 0.9%; sucralfate group (SCF): SCF 2 g/kg/day; n-acetylcysteine group (NAC): NAC 100 mg/kg/day; and SCF+NAC group: SCF 2 g/kg/day + NAC 100 mg/kg/day.Neutral and acidic mucins were stained by periodic acid-Schiff and alcian-blue techniques, respectively. The distinction between sulfomucins and sialomucin was made by the high alcian-blue iron diamine technique. The content of mucins in the colonic glands was measured by computerized morphometry. The inflammatory score was assessed using a validated scale. The results between the groups were compared by the Mann-Whitney's test, while the variation according to time by the Kruskal-Wallis' test (Dunn's post-test). A significance level of 5% was adopted.

RESULTS: There was reduction in the inflammatory score regardless of the application of isolated or associated substances. Intervention with SCF+NAC increased the content of all mucin subtypes regardless of intervention time.

CONCLUSIONS: The application of SCF+NAC reduced the inflammatory process of the colonic mucosa and increased the content of different types of mucins in the colonic glands of segments excluded from fecal transit.}, } @article {pmid37848768, year = {2024}, author = {Nabi, Z and Vamsi, M and Goud, R and Sayyed, M and Basha, J and Reddy, PM and Reddy, R and Reddy, P and Manchu, C and Darisetty, S and Gupta, R and Tandan, M and Rao, GV and Reddy, DN}, title = {Pre-medication with simethicone and N-acetyl cysteine for improving mucosal visibility during upper gastrointestinal endoscopy: A randomized controlled trial.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {43}, number = {5}, pages = {986-994}, pmid = {37848768}, issn = {0975-0711}, mesh = {Humans ; *Simethicone/administration & dosage ; Male ; Female ; *Acetylcysteine/administration & dosage ; Adult ; Double-Blind Method ; *Premedication/methods ; Middle Aged ; Endoscopy, Digestive System/methods ; Endoscopy, Gastrointestinal/methods ; }, abstract = {BACKGROUND AND AIM: Diagnostic performance of esophagogastroduodenoscopy (EGD) may be compromized due to adherent mucus and foam. In this study, we aimed at assessing the impact of premedication on mucosal visibility during endoscopy.

METHODS: This is a double-blinded (patient and investigator), randomized trial conducted at a tertiary care centre. Patients were randomized into four groups: A (water), B (simethicone [S]), C (N-acetyl cysteine [NAC]), D (S + NAC). Premedication solutions were administered 10-30 minutes before endoscopy and mucosal visibility graded from 1 (best) to 4 (worst) (1 best, 4 worst). Total mucosal visibility scores (TMVS) from six sites ranged from 6 (best) to 24 (worst) points. The primary outcome of study was comparison of TMVS between simethicone and combination (S + NAC) premedication groups. Secondary outcomes were adverse events and impact of endoscopy timing on TMVS.

RESULTS: Total 800 patients (39 years, 68.8% males) were randomized into four groups. Median TMVS were significantly lower in groups B (7 [6-8]) and D (8 [6-9]) as compared to A (11 [9-13]) and C (10 [8-12]). Proportion of cases with adequate gastric mucosal visibility (score < 7) was 26% in group A, 71% in group B, 36% in group C and 79% in group D. There was no difference in TMVS in groups A and C (p = 0.137). TMVS were significantly lower in late (> 20-30 minutes) vs. early (10-20 minutes) endoscopy sub-group (8 [7-11] vs, 9 ([7-11], p = 0.001). However, TMVS were similar between group B and group D in early endoscopy group (p = 0.451). There was no significant difference in the lesion detection rate among the different premedication drugs (p > 0.05).

CONCLUSIONS: Premedication with simethicone or combination (simethicone and NAC) significantly improves mucosal visibility during EGD. If early endoscopy is indicated, simethicone provides similar mucosal visibility and may be an effective alternative to combined premedication.

TRIAL REGISTRATION: NCT05951712.}, } @article {pmid37845590, year = {2024}, author = {Dai, Y and Sang, XB and Bai, WP}, title = {N-acetylcysteine and Hydroxychloroquine Ameliorate ADMA-Induced Fetal Growth Restriction in Mice via Regulating Oxidative Stress and Autophagy.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {31}, number = {3}, pages = {779-790}, pmid = {37845590}, issn = {1933-7205}, support = {2021-q03//Youth Fund of Beijing Shijitan Hospital/ ; }, mesh = {Humans ; Pregnancy ; Mice ; Female ; Animals ; *Placenta/metabolism ; *Acetylcysteine/pharmacology/therapeutic use/metabolism ; Fetal Growth Retardation/chemically induced/drug therapy/metabolism ; Hydroxychloroquine/pharmacology/therapeutic use/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Oxidative Stress ; TOR Serine-Threonine Kinases/metabolism ; Autophagy ; Arginine/*analogs & derivatives ; }, abstract = {Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR.}, } @article {pmid37841396, year = {2023}, author = {Liu, J and Su, H and Jin, X and Wang, L and Huang, J}, title = {The effects of N-acetylcysteine supplement on metabolic parameters in women with polycystic ovary syndrome: a systematic review and meta-analysis.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1209614}, pmid = {37841396}, issn = {2296-861X}, abstract = {OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common endocrine disease, often accompanied by metabolic disorders. Metformin, as an insulin sensitizer, is widely used to improve the metabolic function of PCOS, but may have gastrointestinal side effects. Emerging evidence suggests that N-acetylcysteine (NAC) improves metabolic parameters in PCOS and may be a potential alternative to metformin.

METHODS: We searched four online databases, PubMed, Embase, Web of Science, and Cochrane Library, from inception to April 1, 2023. The I[2] statistic and Cochrane's Q test were employed to determine heterogeneity between studies, with an I[2] value >50% or p < 0.1 considered significant. The data were expressed as standardized mean differences and corresponding 95% confidence intervals.

RESULTS: A total of 11 randomized controlled trials were included in the final analysis, including 869 women with PCOS. The results showed that NAC caused more changes in body mass index (SMD: -0.16, 95% CI: -0.40 to 0.08), body weight (SMD: -0.25, 95% CI: -0.50 to 0.00), fasting insulin (SMD: -0.24, 95% CI: -0.53 to 0.06), ratio of fasting blood glucose to fasting insulin (SMD: 0.38, 95% CI: -0.33 to 1.08), total cholesterol (SMD: -0.11, 95% CI: -0.39 to 0.17), triglycerides (SMD: -0.18, 95% CI: -0.63 to 0.28), and low-density lipoprotein (SMD: -0.09, 95% CI: -0.51 to 0.33) compared with metformin. Compared with metformin or placebo, NAC significantly reduced fasting blood-glucose levels (SMD: -0.23, 95% CI: -0.43 to -0.04; SMD: -0.54, 95% CI: -1.03 to -0.05, respectively). In addition, NAC significantly reduced total cholesterol (SMD: -0.74, 95% CI: -1.37 to -0.12), and this effect was observed when NAC was compared with placebo. However, NAC reduced HDL levels in women with PCOS compared with metformin (SMD: -0.14, 95% CI: -0.42 to 0.14).

CONCLUSION: This study suggests that NAC is effective in improving metabolic parameters in PCOS and may be a promising nutritional supplement for the treatment of PCOS.Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=415172, identifier CRD42022339171.}, } @article {pmid37839787, year = {2023}, author = {Zhu, S and Wu, H and Cui, H and Guo, H and Ouyang, Y and Ren, Z and Deng, Y and Geng, Y and Ouyang, P and Wu, A and Deng, J and Deng, H}, title = {Induction of mitophagy via ROS-dependent pathway protects copper-induced hypothalamic nerve cell injury.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {181}, number = {}, pages = {114097}, doi = {10.1016/j.fct.2023.114097}, pmid = {37839787}, issn = {1873-6351}, mesh = {Male ; Mice ; Animals ; *Mitophagy ; Copper/toxicity ; Reactive Oxygen Species/metabolism ; *Mitochondrial Diseases ; Neurons/metabolism ; }, abstract = {Copper (Cu) is one of the essential trace elements in the body, but excessive amounts of Cu harm multiple organs and tissues such as liver, kidneys, testis, ovaries, and brain. However, the mechanism of hypothalamic neurotoxicity induced by Cu is still unknown. This study examined the relationship between reactive oxygen species (ROS) and mitophagy in mouse hypothalamus treated with high Cu. The results demonstrated that high levels of copper sulfate (CuSO4) could cause histopathological and neuronal changes in the mouse hypothalamus, produce a large amount of ROS, induce mitophagy, and lead to an imbalance of mitochondrial fusion/fission. The main manifestations are an increase in the expression levels of LC3-II/LC3-I, p62, DRP1, and FIS1, and a decrease in the expression levels of MFN1 and MFN2. Cu can induce mitophagy also was confirmed by LC3 co-localization with TOMM20 (mitochondrial marker). Next, the effect of oxidative stress on CuSO4-induced mitophagy was demonstrated. The results showed that ROS inhibitor N-acetylcysteine (NAC) diminished CuSO4-induced mitophagy and reversed the disturbance of mitochondrial dynamics. Additionally, a study was carried out to evaluate the role of mitophagy in CuSO4-induced hypothalamic injury. The inhibition of mitophagy using mitophagy inhibitor (Mdivi-1) decreased cell viability and promoted CuSO4-inhibited mitochondrial fusion. The aforementioned results suggested that CuSO4 induced mitophagy via oxidative stress in N38 cells and mouse hypothalamus, and that the activation of mitophagy might generate protective mechanisms by alleviating Cu-induced mitochondrial dynamics disorder. This study provided a novel approach and theoretical basis for studying and preventing Cu neurotoxicity.}, } @article {pmid37836642, year = {2023}, author = {Samide, A and Dobriţescu, A and Tigae, C and Spînu, CI and Oprea, B}, title = {Experimental and Computational Study on Inhibitory Effect and Adsorption Properties of N-Acetylcysteine Amino Acid in Acid Environment.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836642}, issn = {1420-3049}, abstract = {Potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) were applied to study the inhibitory effect of N-acetylcysteine (NAC) on corrosion inhibition of carbon steel in hydrochloric acid solution. N-acetylcysteine influenced the iron dissolution to a greater extent than the hydrogen evolution reaction acting as a mixed inhibitor, predominantly anodic. The charge transfer resistance (Rct) gradually increased with the inhibitor concentration. From both methods, the inhibition efficiency (IE) reached a value of 89 ± 1% and NAC adsorption followed the Temkin isotherm. The value of adsorption Gibbs energy (ΔGadso), around -35 kJ mol[-1], indicated a spontaneous adsorption and mixed action mechanism, with NAC chemical adsorption prevailing over physical one. New data will be reported by the computational study, that was performed using the density functional theory (DFT) method in aqueous phase. Quantum chemical descriptors were determined by B3LYP theory level with 6-31G+(d) basis set. Metropolis Monte Carlo atomistic simulation was used to reveal the adsorption configuration and interactions between acetylcysteine molecules and the carbon steel surface. Theoretical results were consistent with the experimental data, showing that the inhibitor action mechanism consisted of mainly chemisorption of its molecules on the carbon steel surface accompanied by van der Waals forces and electrostatic interactions.}, } @article {pmid37836605, year = {2023}, author = {Doroudian, M and Thibault, ME and Gailer, J}, title = {N-Acetylcysteine Displaces Glutathionyl-Moieties from Hg[2+] and MeHg[+] to Form More Hydrophobic Complexes at Near-Physiological Conditions.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836605}, issn = {1420-3049}, mesh = {Animals ; Humans ; Acetylcysteine ; *Methylmercury Compounds/chemistry ; *Mercury/analysis ; Glutathione/analysis ; Sulfhydryl Compounds ; Mammals ; }, abstract = {The anthropogenic release of Hg is associated with an increased human exposure risk. Since Hg[2+] and MeHg[+] have a high affinity for thiols, their interaction with L-glutathione (GSH) within mammalian cells is fundamentally involved in their toxicological chemistry and excretion. To gain insight into the interaction of these mercurials with multiple small molecular weight thiols, we have investigated their competitive interactions with GSH and N-acetylcysteine (NAC) at near-physiological conditions, using a liquid chromatographic approach. This approach involved the injection of each mercurial onto a reversed-phase (RP)-HPLC column (37 °C) using a PBS buffer mobile phase containing 5.0 mM GSH to simulate cytosolic conditions with Hg being detected in the column effluent by an inductively coupled plasma atomic emission spectrometer (ICP-AES). When the 5.0 mM GSH mobile phase was amended with up to 10 mM NAC, gradually increasing retention times of both mercurials were observed. To explain this behavior, the experiment with 5.0 mM NAC and 5.0 mM GSH was replicated using 50 mM Tris buffer (pH 7.4), and the Hg-containing fractions were analyzed by electrospray ionization mass spectrometry. The results revealed the presence of Hg(GS)(NAC) and Hg(NAC)2 for Hg[2+] and MeHg(GS) and MeHg(NAC) for MeHg[+], which suggests that the coordination/displacement of GS-moieties from each mercurial by the more hydrophobic NAC can explain their retention behavior. Since the biotransformations of both mercurials were observed at near-physiological conditions, they are of toxicological relevance as they provide a biomolecular explanation for some results that were obtained when animals were administered with each mercurial and NAC.}, } @article {pmid37835464, year = {2023}, author = {Bryan, A and Pingali, P and Joslyn, M and Li, H and Bernas, T and Koblinski, J and Landry, J and Lee, WS and Patel, B and Neuwelt, A}, title = {High-Dose Acetaminophen with N-acetylcysteine Rescue Inhibits M2 Polarization of Tumor-Associated Macrophages.}, journal = {Cancers}, volume = {15}, number = {19}, pages = {}, pmid = {37835464}, issn = {2072-6694}, support = {IK2 BX004914/BX/BLRD VA/United States ; P30 CA016059/CA/NCI NIH HHS/United States ; }, abstract = {High-dose acetaminophen (AAP) with N-acetylcysteine (NAC) rescue is among the few treatments that has shown activity in phase I trials without achieving dose-limiting toxicity that has not progressed to evaluation in later line studies. While the anti-tumor effects of AAP/NAC appear not to be mediated by glutathione depletion and free radical injury, the mechanism of anti-tumor effects of AAP/NAC has not been definitively characterized. In vitro, the effects of AAP/NAC were evaluated on bone marrow derived macrophages. Effects of AAP on IL-4/STAT6 (M2) or IFN/LPS/STAT1 (M1) signaling and downstream gene and protein expression were studied. NAC reversed the AAP toxicity in the normal liver but did not reverse AAP cytotoxicity against tumor cells in vitro. AAP/NAC selectively inhibited IL-4-induced STAT6 phosphorylation but not IFN/LPS-induced STAT1 phosphorylation. Downstream, AAP/NAC inhibited IL-4 induction of M2-associated genes and proteins but did not inhibit the IFN/LPS induction of M1-associated genes and proteins. In vivo, AAP/NAC inhibited tumor growth in EF43.fgf4 and 4T1 triple-negative breast tumors. Flow cytometry of tumor-associated macrophages revealed that AAP/NAC selectively inhibited M2 polarization. The anti-tumor activity of high-dose AAP/NAC is lost in macrophage-depleted mouse syngeneic tumor models, suggesting a macrophage-dependent mechanism of action. In conclusion, our study is the first to show that high-dose AAP/NAC has profound effects on the tumor immune microenvironment that facilitates immune-mediated inhibition of tumor growth.}, } @article {pmid37834105, year = {2023}, author = {Gan, P and Li, P and Zhang, X and Li, H and Ma, S and Zong, D and He, C}, title = {Comparative Transcriptomic and Metabolomic Analyses of Differences in Trunk Spiral Grain in Pinus yunnanensis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834105}, issn = {1422-0067}, support = {YUWR-CYJS-2020-018//Yunnan Provincial "Ten-Thousand Program" for Leading Industry Innovation/ ; 202005AF150020//Applied Basic Research Programs of Yunnan Provincial Expert Workstation/ ; }, mesh = {*Transcriptome ; *Pinus/genetics ; Gene Expression Profiling ; Metabolomics ; Metabolome ; Edible Grain/genetics ; Deoxyuridine ; Gene Expression Regulation, Plant ; }, abstract = {Having a spiral grain is considered to be one of the most important wood properties influencing wood quality. Here, transcriptome profiles and metabolome data were analyzed in the straight grain and twist grain of Pinus yunnanensis. A total of 6644 differential expression genes were found between the straight type and the twist type. A total of 126 differentially accumulated metabolites were detected. There were 24 common differential pathways identified from the transcriptome and metabolome, and these pathways were mainly annotated in ABC transporters, arginine and proline metabolism, flavonoid biosynthesis, isoquinoline alkaloid biosynthesis, linoleic acid metabolism, phenylpropanoid, tryptophan metabolism, etc. A weighted gene coexpression network analysis showed that the lightblue4 module was significantly correlated with 2'-deoxyuridine and that transcription factors (basic leucine zipper (bZIP), homeodomain leucine zipper (HD-ZIP), basic helix-loop-helix (bHLH), p-coumarate 3-hydroxylase (C3H), and N-acetylcysteine (NAC)) play important roles in regulating 2'-deoxyuridine, which may be involved in the formation of spiral grains. Meanwhile, the signal transduction of hormones may be related to spiral grain, as previously reported. ARF7 and MKK4_5, as indoleacetic acid (IAA)- and ethylene (ET)-related receptors, may explain the contribution of plant hormones in spiral grain. This study provided useful information on spiral grain in P. yunnanensis by transcriptome and metabolome analyses and could lay the foundation for future molecular breeding.}, } @article {pmid37827291, year = {2023}, author = {Hu, TH and Wu, JC and Huang, ST and Chu, TH and Han, AJ and Shih, TW and Chang, YC and Yang, SM and Ko, CY and Lin, YW and Kung, ML and Tai, MH}, title = {HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {11}, pages = {105335}, pmid = {37827291}, issn = {1083-351X}, mesh = {Animals ; Mice ; *Carcinoma, Hepatocellular/genetics/pathology ; Reactive Oxygen Species ; Carcinogenesis/genetics ; }, abstract = {Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.}, } @article {pmid37823177, year = {2023}, author = {Haugsten Hansen, M and Sadredini, M and Hasic, A and Eriksen, M and Stokke, MK}, title = {Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1223496}, pmid = {37823177}, issn = {2297-055X}, abstract = {BACKGROUND: Arrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.

METHODS: MI was induced in 7 male and 7 female pigs (Norwegian landrace, 35-40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90 min, before observation for 1 h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70 min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60 min of ischemia, and 5 and 60 min of reperfusion. ECG and invasive blood pressure were monitored throughout.

RESULTS: The protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5 min of reperfusion compared to baseline, but not at 60 min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion.

CONCLUSION: Myocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias.}, } @article {pmid37820773, year = {2023}, author = {Gustafson, Å and Elfsmark, L and Karlsson, T and Jonasson, S}, title = {N-acetyl cysteine mitigates lung damage and inflammation after chlorine exposure in vivo and ex vivo.}, journal = {Toxicology and applied pharmacology}, volume = {479}, number = {}, pages = {116714}, doi = {10.1016/j.taap.2023.116714}, pmid = {37820773}, issn = {1096-0333}, mesh = {Mice ; Animals ; Swine ; *Acetylcysteine/pharmacology/therapeutic use ; Chlorine/toxicity ; *Lung Injury/chemically induced/drug therapy/prevention & control ; Antioxidants/pharmacology ; Lung ; Inflammation/chemically induced/drug therapy ; Inflammation Mediators ; }, abstract = {The objective of this study was to explore the effects of antioxidant treatments, specifically N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), in a mouse model of chlorine (Cl2)-induced lung injury. Additionally, the study aimed to investigate the utility of pig precision-cut lung slices (PCLS) as an ex vivo alternative for studying the short-term effects of Cl2 exposure and evaluating antioxidant treatments. The toxicological responses were analyzed in Cl2-exposed mice (inflammation, airway hyperresponsiveness (AHR)) and PCLS (viability, cytotoxicity, inflammatory mediators). Airways contractions were assessed using a small ventilator for mice and electric-field stimulation (EFS) for PCLS. Antioxidant treatments were administered to evaluate their effects. In Cl2-exposed mice, NAC treatment did not alleviate AHR, but it did reduce the number of neutrophils in bronchoalveolar lavage fluid and inflammatory mediators in lung tissue. In PCLS, exposure to Cl2 resulted in concentration-dependent toxicity, impairing the lung tissue's ability to respond to EFS-stimulation. NAC treatment increased viability, mitigated the toxic responses caused by Cl2 exposure, and maintained contractility comparable to unexposed controls. Interestingly, NACA did not provide any additional treatment effect beyond NAC in both models. In conclusion, the establishment of a pig model for Cl2-induced lung damage supports further investigation of NAC as a potential treatment. However, the lack of protective effects on AHR after NAC treatment in mice suggests that NAC alone may not be sufficient as a complete treatment for Cl2 injuries. Optimization of existing medications with a polypharmacy approach may be more successful in addressing the complex sequelae of Cl2-induced lung injury.}, } @article {pmid37817304, year = {2024}, author = {Ezhilarasan, D and Shree Harini, K and Karthick, M and Selvaraj, C}, title = {Ethyl gallate concurrent administration protects against acetaminophen-induced acute liver injury in mice: An in vivo and in silico approach.}, journal = {Chemical biology & drug design}, volume = {103}, number = {1}, pages = {e14369}, doi = {10.1111/cbdd.14369}, pmid = {37817304}, issn = {1747-0285}, mesh = {Mice ; Animals ; *Antioxidants/pharmacology/therapeutic use/metabolism ; Acetaminophen/toxicity ; Liver ; Gallic Acid/metabolism/pharmacology ; Anti-Inflammatory Agents/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Oxidative Stress ; }, abstract = {Acetaminophen (APAP) in high doses causes acute liver injury and acute liver failure. Ethyl gallate (EG) is a natural polyphenol, possessing antioxidant, anti-inflammatory, and anti-microbial properties. Therefore, in this study, we evaluated the protective role of EG against APAP-induced acute liver injury in mice. Acute liver injury was induced by a single dose of APAP (400 mg/kg., i.p.). In separate groups, EG (10 mg/kg), EG (20 mg/kg), and N-acetylcysteine (NAC; 1200 mg/kg., i.p.) were administered concurrently with APAP. The mice were sacrificed after 24 h of treatment. Liver marker enzymes of hepatotoxicity, antioxidant markers, inflammatory markers, and histopathological studies were done. APAP administration caused a significant elevation of marker enzymes of hepatotoxicity and lipid peroxidation. APAP administration also decreased enzymic and nonenzymic antioxidants. Acute APAP intoxication induced nuclear factor κ B, tumor necrosis factor-α, interleukin-1, p65, and p52 and downregulated IκB gene expressions. Our histopathological studies have confirmed the presence of centrilobular necrosis, 24 h after APAP intoxication. All the above abnormalities were significantly inhibited in groups of mice that were concurrently administered with APAP + EG and APAP + NAC. Our in silico analysis further confirms that hydroxyl groups of EG interact with the above inflammatory proteins at the 3,4,5-trihydroxybenzoic acid region. These effects of EG against APAP-induced acute liver injury could be attributed to its antioxidative, free radical scavenging, and anti-inflammatory potentials. Therefore, this study suggests that EG can be an efficient therapeutic approach to protect the liver from APAP intoxication.}, } @article {pmid37814098, year = {2023}, author = {Chitolina, R and Reis, CG and Stahlhofer-Buss, T and Linazzi, A and Benvenutti, R and Marcon, M and Herrmann, AP and Piato, A}, title = {Effects of N-acetylcysteine and acetyl-L-carnitine on acute PTZ-induced seizures in larval and adult zebrafish.}, journal = {Pharmacological reports : PR}, volume = {75}, number = {6}, pages = {1544-1555}, pmid = {37814098}, issn = {2299-5684}, mesh = {Animals ; Humans ; Adult ; *Zebrafish ; Acetylcysteine/therapeutic use ; Acetylcarnitine/adverse effects ; Larva ; Pentylenetetrazole/toxicity ; Seizures/chemically induced/drug therapy ; *Epilepsy/drug therapy ; Anticonvulsants/therapeutic use ; Disease Models, Animal ; }, abstract = {BACKGROUND: Epilepsy is a prevalent neurological disease, affecting approximately 1-2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to current pharmacological treatments. Consequently, exploring alternative therapeutic options for managing this condition is crucial. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of glutamatergic neurotransmission.

METHODS: This study aimed to assess the effects of varying concentrations (0.1, 1.0, and 10 mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances.

RESULTS: Our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and increased latencies to higher scores of epileptic seizures.

CONCLUSION: Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.}, } @article {pmid37812881, year = {2023}, author = {Zeng, Z and Li, T and Liu, X and Ma, Y and Luo, L and Wang, Z and Zhao, Z and Li, H and He, X and Zeng, H and Tao, Y and Chen, Y}, title = {DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell.}, journal = {Redox biology}, volume = {67}, number = {}, pages = {102916}, pmid = {37812881}, issn = {2213-2317}, mesh = {Animals ; Humans ; Mice ; *Cigarette Smoking/adverse effects ; *Dioxygenases/metabolism/pharmacology ; DNA/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Epithelial Cells/metabolism ; *Ferroptosis/genetics ; Inflammation/metabolism ; Lung/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Pulmonary Disease, Chronic Obstructive/chemically induced/genetics ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality currently. Long-term exposure of cigarette smoke (CS) inducing persistent inflammation, small airway remodeling and emphysematous lung are the distinguishing features of COPD. Ferroptosis, occurred in lung epithelial cells has recently been reported to be associated with COPD pathogenesis. DNA dioxygenase ten-eleven translocation 2 (TET2) is an important demethylase and its genetic mutation is associated with low forced expiratory volume in 1 s (FEV1) of lung function. However, its role in COPD remains elusive. Here, we found that TET2 regulates CS induced lipid peroxidation through demethylating glutathione peroxidase 4 (GPx4), thus alleviating airway epithelial cell ferroptosis in COPD. TET2 protein levels were mainly reduced in the airway epithelia of COPD patients, mouse models, and CS extract-treated bronchial epithelial cells. The deletion of TET2 triggered ferroptosis and further exaggerated CS-induced airway remodeling, inflammation, and emphysema in vivo. Moreover, we demonstrated that TET2 silencing intensified ferroptosis, while TET2 overexpression inhibited ferroptosis in airway epithelial cell treated with CSE. Mechanically, TET2 protected airway epithelial cells from CS-induced lipid peroxidation and ferroptosis through demethylating the promoter of glutathione peroxidase 4 (GPx4). Finally, co-administration of methylation inhibitor 5'-aza-2'-deoxycytidine (5-AZA) and the antioxidant N-acetyl-cysteine (NAC) have more protective effects on CS-induced COPD than either administration alone. Overall, our study reveals that TET2 is an essential modulator in the lipid peroxidation and ferroptosis of airway epithelial cell, and could act as a potential therapeutic target for CS-induced COPD.}, } @article {pmid37810545, year = {2023}, author = {Brown, C and Wang, J and Jiang, H and Elias, MF}, title = {Homocysteine Reduction for Stroke Prevention: Regarding the Recent AHA/ASA 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.}, journal = {Pharmacogenomics and personalized medicine}, volume = {16}, number = {}, pages = {895-900}, pmid = {37810545}, issn = {1178-7066}, abstract = {Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.}, } @article {pmid37804692, year = {2023}, author = {Guo, Y and Huang, C and Xu, C and Qiu, L and Yang, F}, title = {Dysfunction of ZNF554 promotes ROS-induced apoptosis and autophagy in Fetal Growth Restriction via the p62-Keap1-Nrf2 pathway.}, journal = {Placenta}, volume = {143}, number = {}, pages = {34-44}, doi = {10.1016/j.placenta.2023.09.009}, pmid = {37804692}, issn = {1532-3102}, mesh = {Female ; Humans ; Pregnancy ; Antioxidants/metabolism ; *Apoptosis/genetics ; Autophagy ; Cell Line, Tumor ; *Fetal Growth Retardation/genetics/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; *Placenta/metabolism ; Reactive Oxygen Species/metabolism ; Trophoblasts/metabolism ; *Kruppel-Like Transcription Factors/genetics/metabolism ; }, abstract = {Fetal growth restriction (FGR) is one of the most common complications of an abnormal pregnancy. Placental dysplasia has been established as a significant contributing factor to FGR. Zinc finger protein 554 (ZNF554) is a member of the Krüppel-associated box domain zinc finger protein subfamily, primarily expressed in the placenta and essential for maintaining normal pregnancy outcomes. However, its precise role in FGR remains uncertain. In this study, we confirmed that ZNF554 was low expressed in the placenta of the FGR pregnancy. To further elucidate the impact of ZNF554 on trophoblasts, we conducted experiments using siRNA and overexpression plasmids on HTR8/SVneo and JEG3 cells. Our findings revealed that silencing ZNF554 increased apoptosis and inhibited migration and invasion, while overexpression reduced apoptosis and promoted migration and invasion. Notably, ZNF554 knockdown decreased cellular antioxidant capacity and elevated the production of reactive oxygen species (ROS). Conversely, ZNF554 activated the nuclear factor E2-related factor 2 (NRF2) signaling pathway, exerting its antioxidant effects. Additionally, ZNF554 knockdown promoted cellular autophagy by suppressing P62 and enhancing LC3-II/LC3-I expression. Importantly, the antioxidant N-acetylcysteine (NAC) partially mitigated the impact of ZNF554 knockdown on mitochondrial ROS in trophoblast cells and subsequent effects on cellular autophagy and apoptosis. In conclusion, our results suggest that ZNF554 plays a pivotal role in modulating trophoblast cell invasion and may serve as a prognostic marker and potential therapeutic target for FGR.}, } @article {pmid37801672, year = {2024}, author = {Orhan, Ö and Talay, MN}, title = {Methemoglobinemia and acute ıntravascular hemolysis after naphthalene poisoning in a pediatric patient.}, journal = {Archivos argentinos de pediatria}, volume = {122}, number = {2}, pages = {e202310095}, doi = {10.5546/aap.2023-10095.eng}, pmid = {37801672}, issn = {1668-3501}, mesh = {Humans ; Male ; Child ; Infant ; Child, Preschool ; Hemolysis ; *Methemoglobinemia/chemically induced/diagnosis ; *Anemia, Hemolytic/diagnosis ; Ascorbic Acid ; Naphthalenes ; }, abstract = {Poisoning by naphthalene is uncommon in children. It is a type of poisoning brought on by ingesting, inhaling, or coming into touch with naphthalene-containing substances on the skin. Patients typically present with an initial onset of dark brown urine, watery diarrhea, and bile vomit. The signs include fever, tachycardia, hypotension, and low pulse oximetry readings even with oxygen support. Hemolytic anemia, methemoglobinemia, renal failure, and hyperbilirubinemia are all detected in blood tests. Erythrocyte transfusion, ascorbic acid, methylene blue, and N-acetylcysteine (NAC) therapies are provided to inpatients in addition to symptomatic treatment. We present a 23-month-old male patient who developed methemoglobinemia and acute ıntravascular hemolysis, who was followed up in the intensive care unit for five days due to naphthalene intoxication. Although naphthalene poisoning is very rare, it should be known that it has fatal consequences, and more care should be taken in its use and sale.}, } @article {pmid37798944, year = {2024}, author = {Vélez, EJ and Schnebert, S and Goguet, M and Balbuena-Pecino, S and Dias, K and Beauclair, L and Fontagné-Dicharry, S and Véron, V and Depincé, A and Beaumatin, F and Herpin, A and Seiliez, I}, title = {Chaperone-mediated autophagy protects against hyperglycemic stress.}, journal = {Autophagy}, volume = {20}, number = {4}, pages = {752-768}, pmid = {37798944}, issn = {1554-8635}, mesh = {Animals ; *Chaperone-Mediated Autophagy/drug effects/physiology/genetics ; *Lysosomes/metabolism/drug effects ; *Oncorhynchus mykiss/metabolism ; *Glucose/metabolism ; Hyperglycemia/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Lysosomal-Associated Membrane Protein 2/metabolism/genetics ; Autophagy/physiology/genetics/drug effects ; Molecular Chaperones/metabolism ; Humans ; }, abstract = {Chaperone-mediated autophagy (CMA) is a major pathway of lysosomal proteolysis critical for cellular homeostasis and metabolism, and whose defects have been associated with several human pathologies. While CMA has been well described in mammals, functional evidence has only recently been documented in fish, opening up new perspectives to tackle this function under a novel angle. Now we propose to explore CMA functions in the rainbow trout (RT, Oncorhynchus mykiss), a fish species recognized as a model organism of glucose intolerance and characterized by the presence of two paralogs of the CMA-limiting factor Lamp2A (lysosomal associated membrane protein 2A). To this end, we validated a fluorescent reporter (KFERQ-PA-mCherry1) previously used to track functional CMA in mammalian cells, in an RT hepatoma-derived cell line (RTH-149). We found that incubation of cells with high-glucose levels (HG, 25 mM) induced translocation of the CMA reporter to lysosomes and/or late endosomes in a KFERQ- and Lamp2A-dependent manner, as well as reduced its half-life compared to the control (5 mM), thus demonstrating increased CMA flux. Furthermore, we observed that activation of CMA upon HG exposure was mediated by generation of mitochondrial reactive oxygen species, and involving the antioxidant transcription factor Nfe2l2/Nrf2 (nfe2 like bZIP transcription factor 2). Finally, we demonstrated that CMA plays an important protective role against HG-induced stress, primarily mediated by one of the two RT Lamp2As. Together, our results provide unequivocal evidence for CMA activity existence in RT and highlight both the role and regulation of CMA during glucose-related metabolic disorders.Abbreviations: AREs: antioxidant response elements; CHC: α-cyano -4-hydroxycinnamic acid; Chr: chromosome; CMA: chaperone-mediated autophagy; CT: control; DMF: dimethyl fumarate; Emi: endosomal microautophagy; HG: high-glucose; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; KFERQ: lysine-phenylalanine-glutamate-arginine-glutamine; LAMP1: lysosomal associated membrane protein 1; LAMP2A: lysosomal associated membrane protein 2A; MCC: Manders' correlation coefficient; Manders' correlation coefficient Mo: morpholino oligonucleotide; NAC: N-acetyl cysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; PA-mCherry: photoactivable mCherry; PCC: Pearson's correlation coefficient; ROS: reactive oxygen species; RT: rainbow trout; siRNAs: small interfering RNAs; SOD: superoxide dismutase; Tsg101: tumor susceptibility 101; TTFA: 2-thenoyltrifluoroacetone; WGD: whole-genome duplication.}, } @article {pmid37797590, year = {2023}, author = {Palkovits, S and Schlatter, A and Ruiss, M and Georgiev, S and Zeilinger, J and Pilwachs, C and Findl, O}, title = {Occurrence of Corneal Staining after Cataract Surgery with and without Chitosan-N-Acetylcysteine Eye Drops.}, journal = {Ophthalmic research}, volume = {66}, number = {1}, pages = {1293-1299}, pmid = {37797590}, issn = {1423-0259}, mesh = {Humans ; Ophthalmic Solutions ; Acetylcysteine/therapeutic use/pharmacology ; *Chitosan ; *Cataract Extraction/adverse effects ; *Cataract ; *Dry Eye Syndromes ; }, abstract = {INTRODUCTION: The objective of this study was to evaluate the prevalence of ocular surface damage assessed by corneal staining scores right after cataract surgery and whether it can be prevented using chitosan-N-acetylcysteine (C-NAC) eye drops.

METHODS: We included patients scheduled for routine cataract surgery. Each patient was randomly assigned to one of three groups. Patients in group 1 underwent routine cataract surgery with no additional eye drops. In group 2, patients received C-NAC eye drops after cataract surgery, and in group 3, C-NAC was applied both before and after surgery. Both groups continued the treatment once daily for 4 days. Ocular surface alteration was assessed using the National Eye Institute (NEI) score, and the visual analog scale (VAS) was used to evaluate subjective complaints.

RESULTS: Thirty-six patients were included in the final analyses. One hour after cataract surgery, a statistically significant increase in corneal fluorescein staining was observed in all groups, which decreased again after 1 week. There was no significant difference between the groups 1 h after cataract surgery, though a tendency toward lower NEI scores was observed during this time point in group 3.

DISCUSSION: Cataract surgery induced ocular surface staining and subjective complaints after 1 h. However, the increase in VAS score was small and probably not clinically relevant. The application of perioperative C-NAC eye drops did reduce the rate of corneal staining after cataract surgery in a clinically relevant manner.}, } @article {pmid37797457, year = {2023}, author = {Liu, F and Li, Y and Zhu, J and Li, Y and Zhu, D and Luo, J and Kong, L}, title = {γ-Glutamyltranspeptidase-Activated Near-Infrared fluorescent probe for visualization of Drug-Induced liver injury.}, journal = {Bioorganic chemistry}, volume = {141}, number = {}, pages = {106899}, doi = {10.1016/j.bioorg.2023.106899}, pmid = {37797457}, issn = {1090-2120}, mesh = {Humans ; *Fluorescent Dyes ; Cell Line ; Hep G2 Cells ; *Chemical and Drug Induced Liver Injury/diagnosis ; gamma-Glutamyltransferase ; Glutathione ; }, abstract = {Drug-induced liver injury (DILI), induced by overdose or chronic administration of drugs, has become the leading cause of acute liver failure. Therefore, an accurate diagnostic method for DILI is critical to improve treatment efficiency. The production of γ-glutamyltranspeptidase (GGT) is closely related to the progression of drug-induced hepatotoxicity. KL-Glu exhibits a prominent GGT-activated NIR fluorescence (734 nm) with a large Stokes shift (137 nm) and good sensitivity/selectivity, making it favorable for real-time detection of endogenous GGT activity. Using this probe, we evaluated the GGT up-regulation under the acetaminophen-induced liver injury model. Moreover, KL-Glu was successfully used to assess liver injury induced by the natural active ingredient triptolide and the effective amelioration upon treatment with N-acetyl cysteine (NAC) or Glutathione (GSH) in cells and in vivo by fluorescent trapping the fluctuation of GGT for the first time. Therefore, the fluorescent probe KL-Glu can be used as a potential tool to explore the function of GGT in the progression of DILI and for the early diagnosis and prognostic evaluation of DILI.}, } @article {pmid37795573, year = {2023}, author = {Jung, IR and Ahima, RS and Kim, SF}, title = {Inositol polyphosphate multikinase modulates free fatty acids-induced insulin resistance in primary mouse hepatocytes.}, journal = {Journal of cellular biochemistry}, volume = {124}, number = {11}, pages = {1695-1704}, doi = {10.1002/jcb.30478}, pmid = {37795573}, issn = {1097-4644}, mesh = {Mice ; Animals ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Fatty Acids, Nonesterified/pharmacology ; *Insulin Resistance ; *Non-alcoholic Fatty Liver Disease ; Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism ; Insulin/pharmacology ; Hepatocytes/metabolism ; }, abstract = {Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of protein kinase B (Akt) phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-acetyl cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.}, } @article {pmid37794966, year = {2023}, author = {Sohouli, MH and Eslamian, G and Malekpour Alamdari, N and Abbasi, M and Fazeli Taherian, S and Behtaj, D and Zand, H}, title = {Effects of N-acetylcysteine on aging cell and obesity complications in obese adults: a randomized, double-blind clinical trial.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1237869}, pmid = {37794966}, issn = {2296-861X}, abstract = {BACKGROUND: We decided to conduct this study with the aim of investigating the effects of N-Acetylcysteine (NAC) on obesity complications and senescence of visceral adipose tissue in obese adults.

METHODS AND ANALYSIS: The present study was conducted as a randomized clinical trial (RCT) (Clinical trial registry number: IRCT20220727055563N1) on 40 obese adults candidates for bariatric surgery, who were randomly assigned to receive 600 mg of NAC (n = 20) or placebo as a control (n = 20) for 4 weeks. During bariatric surgery, visceral adipose tissue was used to examine gene expression and senescence cells using SA-β-gal.

RESULTS: Our findings showed that intervention with NAC significantly reduces SA-β-gal activity (as a marker of senescence) and expression of p16 and interleukin 6 (IL-6) genes in the visceral adipose tissue compared to placebo in obese adults for 4 weeks. In addition, our findings showed the potential and beneficial effect of NAC administration on reducing the levels of inflammatory factors including IL-6 and high-sensitivity C-reactive protein (hs-CRP), as well as the level of fasting blood sugar (FBS), homeostatic model assessment of insulin resistance (HOMA-IR), and insulin compared to placebo after adjusting for confounders. No significant effect was indicated on anthropometric factors and lipid profile.

CONCLUSION: Findings showed that NAC, in addition to having a potential beneficial effect on reducing some of the complications caused by obesity, seems to have synolytic/senomorphic potential as well.

CLINICAL TRIAL REGISTRATION: [https://clinicaltrials.gov/], identifier [IRCT20220727055563N1].}, } @article {pmid37790388, year = {2023}, author = {DeLouise, L and Piraino, L and Chen, CY and Mereness, J and Dunman, P and Benoit, D and Ovitt, C}, title = {Identifying novel radioprotective drugs via salivary gland tissue chip screening.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37790388}, issn = {2693-5015}, support = {F31 DE029658/DE/NIDCR NIH HHS/United States ; T32 ES007026/ES/NIEHS NIH HHS/United States ; UG3 DE027695/DE/NIDCR NIH HHS/United States ; }, abstract = {During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is FDA approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin were also tested to validate the ability of the assays to detect cell damage and radioprotection. All of the drugs except NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified exhibiting mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetic and pharmacodynamic data from the PubChem database. This led us to test Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited radioprotection equivalent to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with non-antioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.}, } @article {pmid37790125, year = {2023}, author = {Zhu, R and Zheng, R and Deng, B and Liu, P and Wang, Y}, title = {Association of N-acetylcysteine use with contrast-induced nephropathy: an umbrella review of meta-analyses of randomized clinical trials.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1235023}, pmid = {37790125}, issn = {2296-858X}, abstract = {BACKGROUND: The effectiveness of N-acetylcysteine (NAC) in treating contrast-induced nephropathy (CIN) has been the subject of conflicting meta-analyses, but the strength of the evidence for these correlations between NAC use and CIN has not been measured overall.

OBJECTIVE: To evaluate the data from randomized clinical studies (RCTs) that examined the relationships between NAC use and CIN in meta-analyses.

METHODS: Between the creation of the database and April 2023, searches were made in PubMed, Cochrane Library, EMBASE, and Web of Science. N-acetylcysteine, contrast-induced nephropathy, or contrast-induced renal disease were among the search keywords used, along with terms including systematic review and meta-analysis. The Assessment of Multiple Systematic Reviews, version 2, which assigned grades of extremely low, low, moderate, or high quality to each meta-analysis's scientific quality, was used to evaluate each meta-analysis. The confidence of the evidence in meta-analyses of RCTs was evaluated using the Grading of Recommendation, Assessment, Development and Evaluations method, with evidence being rated as very low, low, moderate, or high.

RESULTS: In total, 493 records were screened; of those, 46 full-text articles were assessed for eligibility, and 12 articles were selected for evidence synthesis as a result of the screening process. Based on the pooled data, which was graded as moderate-quality evidence, it can be concluded that NAC can decrease CIN (OR 0.72, 95% CI 0.65-0.79, p < 0.00001) and blood levels of serum creatinine (MD -0.09, 95% CI -0.17 to -0.01, p = 0.03). In spite of this, there were no associations between NAC and dialysis requirement or mortality in these studies.

CONCLUSION: The results of this umbrella review supported that the renal results were enhanced by NAC. The association was supported by moderate-quality evidence.

[https://clinicaltrials.gov/], identifier [CRD42022367811].}, } @article {pmid37782109, year = {2023}, author = {Pertiwi, H and Majdeddin, M and Degroote, J and Zhang, H and Michiels, J}, title = {N-acetyl-L-cysteine improves the performance of chronic cyclic heat-stressed finisher broilers but has no effect on tissue glutathione levels.}, journal = {British poultry science}, volume = {64}, number = {6}, pages = {751-762}, doi = {10.1080/00071668.2023.2264234}, pmid = {37782109}, issn = {1466-1799}, mesh = {Animals ; *Acetylcysteine ; Antioxidants/metabolism ; Chickens ; Cystine ; Glutathione ; Diet/veterinary ; *Amino Acids, Sulfur ; Heat-Shock Response ; Butyrates ; Dietary Supplements ; Animal Feed/analysis ; }, abstract = {1. It was hypothesised that dietary N-acetyl-L-cysteine (NAC) in feed, as a source of cysteine, could improve the performance of heat-stressed finisher broilers by fostering glutathione (GSH) synthesis. GSH is the most abundant intracellular antioxidant for which the sulphur amino acid cysteine is rate limiting for its synthesis.2. In the first experiment, four levels of NAC: 0, 500, 1000 and 2000 mg/kg were added to a diet with a suboptimal level of sulphur amino acids in the finisher phase. In the second experiment, NAC was compared to other sulphur amino acid sources at equal molar amounts of digestible sulphur amino acids. Birds were allocated to four groups: control, 2000 mg/kg NAC, 1479 mg/kg L-cystine, and 2168 mg/kg Ca-salt of 2-hydroxy-4-(methylthio)butanoic acid. A chronic cyclic heat stress model (temperature was increased to 34°C for 7 h daily) was initiated at 28 d of age.3. In the first experiment, growth performance and feed efficiency in the finisher phase were significantly improved by graded NAC. ADG was 88.9, 92.2, 93.7 and 97.7 g/d, and the feed-to-gain ratio was 2.18, 1.91, 1.85 and 1.81 for the 0, 500, 1000 and 2000 mg/kg NAC treatments, respectively. However, liver and heart GSH levels were not affected by NAC. On d 29, liver gene transcript of cystathionine-beta-synthase like was reduced by NAC, which suggested reduced trans-sulphuration activity. The second experiment showed that L-cystine and Ca-salt of 2-hydroxy-4-(methylthio) butanoic acid were more effective in improving performance than NAC.4. In conclusion, N-acetyl-L-cysteine improved dose-dependently growth and feed efficiency in heat-stressed finishing broilers. However, this was not associated with changes in tissue GSH levels, but more likely worked by sparing methionine and/or NAC's and cysteine's direct antioxidant properties.}, } @article {pmid37781647, year = {2023}, author = {Miyashita, L and Foley, G and Semple, S and Gibbons, JM and Pade, C and McKnight, Á and Grigg, J}, title = {Curbside particulate matter and susceptibility to SARS-CoV-2 infection.}, journal = {The journal of allergy and clinical immunology. Global}, volume = {2}, number = {4}, pages = {100141}, pmid = {37781647}, issn = {2772-8293}, abstract = {BACKGROUND: Biologic plausibility for the association between exposure to particulate matter (PM) less than 10 μm in aerodynamic diameter (PM10) and coronavirus disease 2019 (COVID-19) morbidity in epidemiologic studies has not been determined. The upregulation of angiotensin-converting enzyme 2 (ACE2), the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) entry receptor on host cells, by PM10 is a putative mechanism.

OBJECTIVE: We sought to assess the effect of PM10 on SARS-CoV-2 infection of cells in vitro.

METHODS: PM10 from the curbside of London's Marylebone Road and from exhaust emissions was collected by cyclone. A549 cells, human primary nasal epithelial cells (HPNEpCs), SARS-CoV-2-susceptible Vero-E6 and Calu3 cells were cultured with PM10. ACE2 expression (as determined by median fluorescent intensity) was assessed by flow cytometry, and ACE2 mRNA transcript level was assessed by PCR. The role of oxidative stress was determined by N-acetyl cysteine. The cytopathic effect of SARS-CoV-2 (percentage of infection enhancement) and expression of SARS-CoV-2 genes' open reading frame (ORF) 1ab, S protein, and N protein (focus-forming units/mL) were assessed in Vero-E6 cells. Data were analyzed by either the Mann-Whitney U test or Kruskal-Wallis test with the Dunn multiple comparisons test.

RESULTS: Curbside PM10 at concentrations of 10 μg/mL or more increased ACE2 expression in A549 cells (P = .0021). Both diesel PM10 and curbside PM10 in a concentration of 10 μg/mL increased ACE2 expression in HPNEpCs (P = .0022 and P = .0072, respectively). ACE2 expression simulated by curbside PM10 was attenuated by N-acetyl cysteine in HPNEpCs (P = .0464). Curbside PM10 increased ACE2 expression in Calu3 cells (P = .0256). In Vero-E6 cells, curbside PM10 increased ACE2 expression (P = .0079), ACE2 transcript level (P = .0079), SARS-CoV-2 cytopathic effect (P = .0002), and expression of the SARS-CoV-2 genes' ORF1ab, S protein, and N protein (P = .0079).

CONCLUSIONS: Curbside PM10 increases susceptibility to SARS-COV-2 infection in vitro.}, } @article {pmid37779397, year = {2023}, author = {Heidari, B and Seyedian, ZA and Mehrpooya, M and Ahmadimoghaddam, D and Mirjalili, M and Ghiasian, M}, title = {N-Acetyl Cysteine as an Add-on Therapy is Useful in Treating Acute Lumbar Radiculopathy Caused by Disc Herniation: Results of a Randomized, Controlled Clinical Trial.}, journal = {Reviews on recent clinical trials}, volume = {18}, number = {4}, pages = {288-299}, doi = {10.2174/0115748871250545230919055109}, pmid = {37779397}, issn = {1876-1038}, support = {No: 140004293667//Hamadan University of Medical Sciences/ ; }, mesh = {Humans ; *Intervertebral Disc Displacement/complications/diagnosis/drug therapy ; *Radiculopathy/drug therapy/etiology/diagnosis ; Cysteine/therapeutic use ; Lumbar Vertebrae ; Treatment Outcome ; Pain/complications/drug therapy ; Anti-Inflammatory Agents, Non-Steroidal ; }, abstract = {BACKGROUND: Available experimental and clinical evidence indicates that N-Acetyl cysteine (NAC) may have an analgesic role in specific pain conditions, particularly neuropathic pain. Thus, we hypothesized that NAC supplementation might be also helpful in decreasing pain and improving pain-related disability in patients with acute radiculopathy. We designed this study to investigate the potential use of NAC-adjunctive treatment to Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) in patients with acute radiculopathy secondary to lumbar intervertebral disc herniation.

METHODS: Sixty-two patients diagnosed with acute lumbar radiculopathy associated with disc herniation were randomly allocated to the NAC or the placebo groups. Besides naproxen at a dose of 500 mg twice a day, participants based on their allocation group started with NAC or matched placebo at a dose of 600 mg twice a day for eight weeks. The pain severity, measured by the Visual Analog Scale (VAS), and pain-related disability measured by the Oswestry Disability Index (ODI) were measured at baseline and weeks 2, 4, and 8 of treatment. Global improvement of symptoms rated by Patient and Clinical Global Impressions of Change (PGIC and CGIC) was also recorded at the end of week 8. All analyses were conducted on an Intentionto- Treat (ITT) analysis data set.

RESULTS: A comparison of the VAS and ODI scores at weeks 2 and 4 of the treatment between the two groups did not show a significant difference. In contrast, from week 4 to week 8, we noticed a significantly greater reduction in the mean VAS and ODI scores in the NAC group compared to the placebo group (p-value <0.001 for both variables). In parallel with these results, also, more NAC-treated than placebo-treated patients achieved treatment success defined as ''very much'' or ''much improved'' on CGIC and PGIC scales, and these differences reached a significant level (p-value = .011 and p-value = .043).

CONCLUSIONS: This study suggested that NAC might be a relevant candidate for adjunct therapy in managing acute lumbar radiculopathy. Additional clinical trials are needed to validate these findings.}, } @article {pmid37778984, year = {2023}, author = {Kaji, T and Kuroishi, T and Bando, K and Takahashi, M and Sugawara, S}, title = {N-acetyl cysteine inhibits IL-1α release from murine keratinocytes induced by 2-hydroxyethyl methacrylate.}, journal = {The Journal of toxicological sciences}, volume = {48}, number = {10}, pages = {557-569}, doi = {10.2131/jts.48.557}, pmid = {37778984}, issn = {1880-3989}, mesh = {Mice ; Animals ; *Acetylcysteine/pharmacology ; Reactive Oxygen Species/metabolism ; *Calpain ; Methacrylates/toxicity/chemistry ; Keratinocytes/metabolism ; Inflammation ; }, abstract = {The hydrophilic compound 2-hydroxyethyl methacrylate (HEMA) is a major component of dental bonding materials, and it enhances the binding of resin-composites to biomolecules. However, HEMA is a well-known contact sensitizer. We reported previously that intradermal injection of HEMA induces the production of IL-1 locally in the skin. Keratinocytes are the first barrier against chemical insults and constitutively express IL-1α. In this study, we analyzed whether HEMA induces the production of inflammatory cytokines from murine keratinocyte cell line Pam212 cells. We demonstrated that HEMA induced the release of 17-kDa mature IL-1α and caused cytotoxicity. The activity of calpain, an IL-1α processing enzyme, was significantly higher in HEMA-treated cells. The thiol-containing antioxidant N-acetyl cysteine (NAC) inhibited HEMA-induced IL-1α release but not cytotoxicity. NAC inhibited intracellular calpain activity and reactive oxygen species (ROS) production induced by HEMA. NAC post-treatment also inhibited IL-1α release and intracellular ROS production induced by HEMA. Furthermore, HEMA-induced in vivo inflammation also inhibited by NAC. NAC inhibited polymerization of HEMA through adduct formation via sulfide bonds between the thiol group of NAC and the reactive double bond of HEMA. HEMA-induced IL-1α release and cytotoxicity were also inhibited if HEMA and NAC were pre-incubated before adding to the cells. These results suggested that NAC inhibited IL-1α release through decreases in intracellular ROS and the adduct formation with HEMA. We concluded that HEMA induces IL-1α release from skin keratinocytes, and NAC may be a promising candidate as a therapeutic agent against inflammation induced by HEMA.}, } @article {pmid37777475, year = {2024}, author = {Khoury, ES and Patel, RV and O'Ferrall, C and Fowler, A and Sah, N and Sharma, A and Gupta, S and Scafidi, S and Kurtz, JS and Olmstead, SJ and Kudchadkar, SR and Kannan, RM and Blue, ME and Kannan, S}, title = {Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.}, journal = {Journal of neurochemistry}, volume = {168}, number = {5}, pages = {841-854}, pmid = {37777475}, issn = {1471-4159}, support = {F32 NS010085/NS/NINDS NIH HHS/United States ; P50 HD103538/HD/NICHD NIH HHS/United States ; R01 NS113140/NS/NINDS NIH HHS/United States ; R21NS10085/NS/NINDS NIH HHS/United States ; P50 HD103538/HD/NICHD NIH HHS/United States ; //Hartwell Foundation/ ; R01 NS113140/NS/NINDS NIH HHS/United States ; R21NS10085/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Rett Syndrome/genetics/drug therapy ; Female ; *Methyl-CpG-Binding Protein 2/genetics ; Mice ; *Neuroglia/drug effects/metabolism ; *Disease Models, Animal ; *Dendrimers ; Phenotype ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; Inflammation/drug therapy/metabolism ; Heterozygote ; Behavior, Animal/drug effects ; }, abstract = {Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.}, } @article {pmid37774561, year = {2023}, author = {Blum, K and Ashford, JW and Kateb, B and Sipple, D and Braverman, E and Dennen, CA and Baron, D and Badgaiyan, R and Elman, I and Cadet, JL and Thanos, PK and Hanna, C and Bowirrat, A and Modestino, EJ and Yamamoto, V and Gupta, A and McLaughlin, T and Makale, M and Gold, MS}, title = {Dopaminergic dysfunction: Role for genetic & epigenetic testing in the new psychiatry.}, journal = {Journal of the neurological sciences}, volume = {453}, number = {}, pages = {120809}, doi = {10.1016/j.jns.2023.120809}, pmid = {37774561}, issn = {1878-5883}, abstract = {Reward Deficiency Syndrome (RDS), particularly linked to addictive disorders, costs billions of dollars globally and has resulted in over one million deaths in the United States (US). Illicit substance use has been steadily rising and in 2021 approximately 21.9% (61.2 million) of individuals living in the US aged 12 or older had used illicit drugs in the past year. However, only 1.5% (4.1 million) of these individuals had received any substance use treatment. This increase in use and failure to adequately treat or provide treatment to these individuals resulted in 106,699 overdose deaths in 2021 and increased in 2022. This article presents an alternative non-pharmaceutical treatment approach tied to gene-guided therapy, the subject of many decades of research. The cornerstone of this paradigm shift is the brain reward circuitry, brain stem physiology, and neurotransmitter deficits due to the effects of genetic and epigenetic insults on the interrelated cascade of neurotransmission and the net release of dopamine at the Ventral Tegmental Area -Nucleus Accumbens (VTA-NAc) reward site. The Genetic Addiction Risk Severity (GARS) test and pro-dopamine regulator nutraceutical KB220 were combined to induce "dopamine homeostasis" across the brain reward circuitry. This article aims to encourage four future actionable items: 1) the neurophysiologically accurate designation of, for example, "Hyperdopameism /Hyperdopameism" to replace the blaming nomenclature like alcoholism; 2) encouraging continued research into the nature of dysfunctional brainstem neurotransmitters across the brain reward circuitry; 3) early identification of people at risk for all RDS behaviors as a brain check (cognitive testing); 4) induction of dopamine homeostasis using "precision behavioral management" along with the coupling of GARS and precision Kb220 variants; 5) utilization of promising potential treatments include neuromodulating modalities such as Transmagnetic stimulation (TMS) and Deep Brain Stimulation(DBS), which target different areas of the neural circuitry involved in addiction and even neuroimmune agents like N-acetyl-cysteine.}, } @article {pmid37773178, year = {2023}, author = {Koning, T and Cordova, F and Aguilar, G and Sarmiento, J and Mardones, GA and Boric, M and Varas-Godoy, M and Lladser, A and Duran, WN and Ehrenfeld, P and Sanchez, FA}, title = {S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.}, journal = {Biological research}, volume = {56}, number = {1}, pages = {51}, pmid = {37773178}, issn = {0717-6287}, support = {R01 GM122940/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/pathology ; Cell Adhesion ; Endothelial Cells ; Vascular Cell Adhesion Molecule-1/metabolism ; Nitric Oxide/metabolism ; Melanoma, Cutaneous Malignant ; }, abstract = {BACKGROUND: Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown.

RESULTS: We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases.

CONCLUSIONS: S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.}, } @article {pmid37771516, year = {2023}, author = {Meziu, E and Shehu, K and Koch, M and Schneider, M and Kraegeloh, A}, title = {Impact of mucus modulation by N-acetylcysteine on nanoparticle toxicity.}, journal = {International journal of pharmaceutics: X}, volume = {6}, number = {}, pages = {100212}, pmid = {37771516}, issn = {2590-1567}, abstract = {Human respiratory mucus is a biological hydrogel that forms a protective barrier for the underlying epithelium. Modulation of the mucus layer has been employed as a strategy to enhance transmucosal drug carrier transport. However, a drawback of this strategy is a potential reduction of the mucus barrier properties, in particular in situations with an increased exposure to particles. In this study, we investigated the impact of mucus modulation on its protective role. In vitro mucus was produced by Calu-3 cells, cultivated at the air-liquid interface for 21 days and used for further testing as formed on top of the cells. Analysis of confocal 3D imaging data revealed that after 21 days Calu-3 cells secrete a mucus layer with a thickness of 24 ± 6 μm. Mucus appeared to restrict penetration of 500 nm carboxyl-modified polystyrene particles to the upper 5-10 μm of the layer. Furthermore, a mucus modulation protocol using aerosolized N-acetylcysteine (NAC) was developed. This treatment enhanced the penetration of particles through the mucus down to deeper layers by means of the mucolytic action of NAC. These findings were supported by cytotoxicity data, indicating that intact mucus protects the underlying epithelium from particle-induced effects on membrane integrity. The impact of NAC treatment on the protective properties of mucus was probed by using 50 and 100 nm amine-modified and 50 nm carboxyl-modified polystyrene nanoparticles, respectively. Cytotoxicity was only induced by the amine-modified particles in combination with NAC treatment, implying a reduced protective function of modulated mucus. Overall, our data emphasize the importance of integrating an assessment of the protective function of mucus into the development of therapy approaches involving mucus modulation.}, } @article {pmid37769128, year = {2023}, author = {Chakraborty, S and Bhattacharya, I and Mitra, RK}, title = {Solvation Plays a Key Role in Antioxidant-Mediated Attenuation of Elevated Creatinine Level: An In Vitro Spectroscopic Investigation.}, journal = {The journal of physical chemistry. B}, volume = {127}, number = {40}, pages = {8576-8585}, doi = {10.1021/acs.jpcb.3c05334}, pmid = {37769128}, issn = {1520-5207}, mesh = {Humans ; *Antioxidants ; Creatinine/urine ; Ascorbic Acid ; *Kidney Diseases ; Spectroscopy, Fourier Transform Infrared ; Acetylcysteine ; }, abstract = {An elevated level of creatinine (CRN) is a mark of kidney ailment, and prolonged retention of such condition could lead to renal failure, associated with severe ischemia. Antioxidants are clinically known to excrete CRN from the body through urine, thereby reducing its level in blood. The molecular mechanism of such an exclusion process is still illusive. As the excretion channel is urine, solvation of the solute is expected to play a pivotal role. Here, we report a detailed time-domain and frequency-domain terahertz (THz) spectroscopic investigation to understand the solvation of CRN in the presence of two model antioxidants, mostly used to treat elevated CRN level: N-Acetyl-l-cysteine (NAC) and ascorbic acid (ASC). FTIR spectroscopy in the mid-infrared region and UV absorption spectroscopy measurements coupled with quantum chemical calculations [at the B3LYP/6-311G++(d,p) level] reveal that both NAC and ASC form HBonded complexes with CRN and rapidly undergo a barrier-less proton transfer process to form creatinium ions. THz measurements provide explicit evidence of the formation of highly solvated complexes compared with bare CRN, which eventually enables its excretion through urine. These observations could provide a foundation for designing more beneficial drugs to resolve kidney diseases..}, } @article {pmid37767143, year = {2023}, author = {Alizadeh, N and Yaryari, AM and Behnoush, AH and Raoufinejad, K and Behnoush, B}, title = {Late N-acetylcysteine for successful recovery of acetaminophen-related acute liver failure: A case report.}, journal = {Clinical case reports}, volume = {11}, number = {9}, pages = {e7946}, pmid = {37767143}, issn = {2050-0904}, abstract = {Acetaminophen toxicity is one of the leading causes of liver failure. Although N-acetylcysteine (NAC) is generally successful in preventing acetaminophen hepatotoxicity when given in a timely manner, if not prescribed in the early golden time, the only practical way to save the patient might be liver transplantation. The case presented was a 20-year-old female with an acetaminophen overdose (30 g), for which more than 24 h had passed since the ingestion. Despite the critical clinical condition, loss of consciousness (Glasgow Coma Score of 4) of the patient, and passing the golden time of antidote administration, the decision was made by the healthcare team to administer NAC. After transferring the patient to the intensive care unit, the three-bag NAC regimen was initiated and appropriate monitoring was performed. After this, the regimen of 3 g q8h was continued for the patient. The patient's condition began to improve slowly on the second day and then she was extubated on the fourth day. Finally, she was discharged on the tenth day. Although the golden period of antidote administration had passed outwardly, there was no need for a liver transplant and the patient recovered successfully with late NAC administration. Hence, clinicians can benefit from the use of NAC even in the late phases of acetaminophen liver toxicity.}, } @article {pmid37766400, year = {2023}, author = {Benizio, E and Moreira-Espinoza, MJ and Triquell, MF and Mezzano, L and Díaz-Luján, CM and Fretes, RE}, title = {Pro-inflammatory cytokines are modified during the multiplication of Trypanosoma cruzi within the placental chorionic villi and are associated with the level of infection via the signaling pathway NF-κB.}, journal = {American journal of reproductive immunology (New York, N.Y. : 1989)}, volume = {90}, number = {4}, pages = {e13777}, doi = {10.1111/aji.13777}, pmid = {37766400}, issn = {1600-0897}, mesh = {Pregnancy ; Female ; Humans ; NF-kappa B ; Chorionic Villi ; Placenta ; Interleukin-10 ; *Trypanosoma cruzi ; Cytokines ; Tumor Necrosis Factor-alpha ; Signal Transduction ; *Chagas Disease ; }, abstract = {PROBLEM: Congenital Trypanosoma cruzi (T. cruzi) infection has been associated with changes in the levels of TNF-α and IFN-γ during the pregnancy. Therefore, we propose to study the participation and dynamics of proinflammatory cytokines in the infection process of placental explants infected by T. cruzi in vitro.

METHOD OF STUDY: Chorionic villous explants (CVE) obtained of human term placentas (n = 8) from normal pregnancies were cultured with 10[5] trypomastigotes/mL of Tulahuen strain DTU VI for 0, 2, 4, 16, 24, 48 and 72 h. Explants were treated with sulfasalazine (SULF) (5 mM) and N-acetyl-cysteine (NAC) (15 mM), as inhibitors molecules of NF-κB pathway, or LPS (1 μg/mL) for 24 and 72 h p.i. Motile trypomastigotes were counted in culture supernatants. Immunohistochemistry and ELISA for TNF-α, IFN-γ, IL-1β, IL-4, and IL-10 were performed in CVE and culture supernatants respectively. The parasite load was measured by RT-qPCR.

RESULTS: T. cruzi invades the chorionic villi from 4 h p.i. increasing significantly its DNA at 48 and 72 h p.i. of culture (parasite multiplication phase). They were detected in stromal cells, which was related to elevation of TNF-α, IL-1β, IFN-γ, and IL-10. The inhibition of NF-κB activity in the explants decreased the production of the analyzed cytokines, showing elevated levels of T. cruzi DNA during the multiplication phase of the parasite.

CONCLUSIONS: Placental tissue modifies the secretion of pro-inflammatory cytokines during the phase of parasite multiplication, but not during the invasion phase, which in turns modifies the level of infection via the signaling pathway NF-κB.}, } @article {pmid37762548, year = {2023}, author = {Chen, JS and Chiu, SC and Huang, SY and Chang, SF and Liao, KF}, title = {Isolinderalactone Induces Apoptosis, Autophagy, Cell Cycle Arrest and MAPK Activation through ROS-Mediated Signaling in Colorectal Cancer Cell Lines.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762548}, issn = {1422-0067}, support = {TCMF-A 108-014//Buddhist Tzu Chi Medical Foundation/ ; TTCRD110-21//Buddhist Tzu Chi Medical Foundation/ ; TTCRD110-31//Buddhist Tzu Chi Medical Foundation/ ; TTCRD111-33//Buddhist Tzu Chi Medical Foundation/ ; }, mesh = {Humans ; Apoptosis ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; G2 Phase Cell Cycle Checkpoints ; Cell Cycle Checkpoints ; *Sesquiterpenes/pharmacology ; Autophagy ; *Colorectal Neoplasms/drug therapy ; Cell Proliferation ; }, abstract = {Colorectal cancer (CRC) is one of the most common malignancies worldwide. Isolinderalactone (ILL), a sesquiterpene isolated from the root extract of Lindera aggregata, has been reported to exhibit anti-proliferative and anti-metastatic activities in various cancer cell lines. However, the mechanisms associated with its antitumor effects on CRC cells remain unclear. ILL treatment significantly suppressed proliferation and induced cell cycle G2/M arrest in CRC cells by inhibiting the expression of cyclin B, p-cdc2, and p-cdc25c and up-regulating the expression of p21. In addition, ILL induced mitochondria-associated apoptosis through the up-regulation of cleaved -caspase-9 and -3 expression. ILL induced autophagy by increasing the levels of LC3B in CRC cells, which was partially rescued by treatment with an autophagy inhibitor (chloroquine). Furthermore, ILL increases the accumulation of reactive oxygen species (ROS) and activates the MAPK pathway. Application of the ROS scavenger, N-acetyl cysteine (NAC), effectively inhibited ILL toxicity and reversed ILL-induced apoptosis, cell cycle arrest, autophagy, and ERK activation. Taken together, these results suggest that ILL induces G2/M phase arrest, apoptosis, and autophagy and activates the MAPK pathway via ROS-mediated signaling in human CRC cells.}, } @article {pmid37761021, year = {2023}, author = {Ahmad, IM and Dafferner, AJ and Salloom, RJ and Abdalla, MY}, title = {Heme Oxygenase-1 Inhibition Modulates Autophagy and Augments Arsenic Trioxide Cytotoxicity in Pancreatic Cancer Cells.}, journal = {Biomedicines}, volume = {11}, number = {9}, pages = {}, pmid = {37761021}, issn = {2227-9059}, abstract = {Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that hypoxia and chemotherapy induced expression of Heme Oxygenase-1 (HO-1) in PDAC cells and tissues. Arsenic trioxide (ATO) is the first-line chemotherapeutic drug for acute promyelocytic leukemia (APL). ATO increases the generation of reactive oxidative species (ROS) and induces apoptosis in treated cells. The clinical use of ATO for solid tumors is limited due to severe systemic toxicity. In order to reduce cytotoxic side effects and resistance and improve efficacy, it has become increasingly common to use combination therapies to treat cancers. In this study, we used ATO-sensitive and less sensitive PDAC cell lines to test the effect of combining HO-1 inhibitors (SnPP and ZnPP) with ATO on HO-1 expression, cell survival, and other parameters. Our results show that ATO significantly induced the expression of HO-1 in different PDAC cells through the p38 MAPK signaling pathway. ROS production was confirmed using the oxygen-sensitive probes DCFH and DHE, N-acetyl cysteine (NAC), an ROS scavenger, and oxidized glutathione levels (GSSG). Both ATO and HO-1 inhibitors reduced PDAC cell survival. In combined treatment, inhibiting HO-1 significantly increased ATO cytotoxicity, disrupted the GSH cycle, and induced apoptosis as measured using flow cytometry. ATO and HO-1 inhibition modulated autophagy as shown by increased expression of autophagy markers ATG5, p62, and LC3B in PDAC cells. This increase was attenuated by NAC treatment, indicating that autophagy modulation was through an ROS-dependent mechanism. In conclusion, our work explored new strategies that could lead to the development of less toxic and more effective therapies against PDAC by combining increased cellular stress and targeting autophagy.}, } @article {pmid37760016, year = {2023}, author = {Mokra, D and Mokry, J and Barosova, R and Hanusrichterova, J}, title = {Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {9}, pages = {}, pmid = {37760016}, issn = {2076-3921}, support = {APVV-15_0075//Slovak Research and Development Agency/ ; APVV-18-0084//Slovak Research and Development Agency/ ; APVV-22-0342//Slovak Research and Development Agency/ ; VEGA 1/0131/22//VEGA/ ; VEGA 1/0093/22//VEGA/ ; }, abstract = {N-acetylcysteine (NAC) is widely used because of its mucolytic effects, taking part in the therapeutic protocols of cystic fibrosis. NAC is also administered as an antidote in acetaminophen (paracetamol) overdosing. Thanks to its wide antioxidative and anti-inflammatory effects, NAC may also be of benefit in other chronic inflammatory and fibrotizing respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, idiopathic lung fibrosis, or lung silicosis. In addition, NAC exerts low toxicity and rare adverse effects even in combination with other treatments, and it is cheap and easily accessible. This article brings a review of information on the mechanisms of inflammation and oxidative stress in selected chronic respiratory diseases and discusses the use of NAC in these disorders.}, } @article {pmid37746996, year = {2023}, author = {Abushanab, D and Gasim, M and Devi, D and Elbdairy, M and Elqasass, H and Ahmed, N and Vincent, M and Abdul Rouf, PV and Mohammed, HR and Hail, MA and Thomas, B and Elkassem, W and Hanssens, Y and Elgassim, M and Elmoheen, A and Azad, A and Mohammed, S and Salem, W}, title = {Patterns and outcomes of paracetamol poisoning management in Hamad Medical Corporation, Qatar: A retrospective cohort study.}, journal = {Medicine}, volume = {102}, number = {38}, pages = {e34872}, pmid = {37746996}, issn = {1536-5964}, mesh = {Young Adult ; Humans ; Adolescent ; Adult ; Qatar/epidemiology ; Acetaminophen ; Retrospective Studies ; *Drug-Related Side Effects and Adverse Reactions ; *Drug Overdose/therapy ; Acetylcysteine/therapeutic use ; }, abstract = {We aimed to investigate the characteristics and clinical outcomes of paracetamol poisoning and paracetamol overdose in Qatar. This retrospective cohort study included patients admitted to the emergency department (ED). We included patients who presented with excessive paracetamol ingestion, between December 2018 and September 2019. The primary outcomes were describing the characteristics and outcomes of paracetamol overdose (from a suicidal overdose or accidental overdose, dose ≤ 150 mg/kg, when serum levels of <60 mmol/L) or dose ingested (≤75 mg/kg) with staggered ingestion poisoning due to suicidal attempt or accidental attempt, defined as the dose ingested (>150 mg/kg), acute ingestion, nomogram level more than the treatment line, or dose ingested (>75 mg/kg) with staggered ingestion, and assessing the management of excessive paracetamol ingestion. Secondary outcomes included evaluation of the time difference between ingestion and time of administration, hospitalization, and adverse drug events. Significant differences were detected between patients who presented with paracetamol overdose and those who presented with paracetamol toxicity. A total of 69 patients were analyzed, of whom 43 received paracetamol overdose (mean age 27.5 ± 11.1 years) and 26 had paracetamol poisoning (mean age 25 ± 6.22 years). Paracetamol poisoning was identified in 26% of the patients with a 24.3% history of psychiatric illness, compared to 18.6% with paracetamol overdose. More patients presented with paracetamol toxicity in the time between ingestion and obtaining serum levels compared to the overdose group. A significantly longer length of hospitalization was observed in the toxicity group. A significantly higher number of patients in the toxicity group received N-acetylcysteine (NAC). More hypotension and rashes were observed among those who received NAC in the toxicity group. Patients presenting to the ED due to paracetamol toxicity are not uncommon, and most cases occur in young adults, and few in patients with a history of psychiatric illness, suggesting that preventive approaches are highly required.}, } @article {pmid37742933, year = {2023}, author = {Zhuang, J and Yuan, Q and Chen, C and Liu, G and Zhong, Z and Zhu, K and Guo, J}, title = {Nanosecond pulsed cold atmospheric plasma jet suppresses proliferation and migration of human glioblastoma cells via apoptosis promotion and EMT inhibition.}, journal = {Archives of biochemistry and biophysics}, volume = {747}, number = {}, pages = {109757}, doi = {10.1016/j.abb.2023.109757}, pmid = {37742933}, issn = {1096-0384}, mesh = {Humans ; *Glioblastoma/metabolism ; Epithelial-Mesenchymal Transition ; Reactive Oxygen Species ; Apoptosis ; Cell Proliferation ; Cell Line, Tumor ; Cell Movement ; *Brain Neoplasms/metabolism ; }, abstract = {Glioblastoma (GBM) is one of the most aggressive and challenging cancers to treat. Despite extensive research on dozens of cancer cells, including GBM, the effect of cold atmospheric plasma (CAP) on the invasive migration of GBM cells has received limited attention, and the underlying mechanisms remain poorly understood. This study aims to investigate the potential molecular mechanism of ns-CAPJ in inhibiting the invasive migration of human GBM cells. The findings indicate that ns-CAPJ significantly reduces GBM cell invasion and migration, and induces apoptosis in GBM cells. Further mechanistic studies demonstrate a direct correlation between the suppression of the epithelial-mesenchymal transition (EMT) signaling pathway and ns-CAPJ's inhibitory effect on GBM cell invasion and migration. Additionally, combined with the N-acetyl cysteine (NAC, a ROS inhibitor) assay, we found that the ROS stimulated by the ns-CAPJ plays an important role in suppressing the EMT process. This work is expected to provide new insight into understanding the molecular mechanisms of how ns-CAPJ inhibits the proliferation and migration of human GBM cells.}, } @article {pmid37742495, year = {2023}, author = {Zeng, Y and Yang, Q and Ouyang, Y and Lou, Y and Cui, H and Deng, H and Zhu, Y and Geng, Y and Ouyang, P and Chen, L and Zuo, Z and Fang, J and Guo, H}, title = {Nickel induces blood-testis barrier damage through ROS-mediated p38 MAPK pathways in mice.}, journal = {Redox biology}, volume = {67}, number = {}, pages = {102886}, pmid = {37742495}, issn = {2213-2317}, mesh = {Mice ; Male ; Animals ; *p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; *Blood-Testis Barrier/metabolism ; Reactive Oxygen Species/metabolism ; Nickel/toxicity/metabolism ; Testis/metabolism ; }, abstract = {Nickel (Ni) is an essential common environmental contaminant, it is hazardous to male reproduction, but the precise mechanisms are still unknown. Blood-testis barrier (BTB), an important testicular structure consisting of connections between sertoli cells, is the target of reproductive toxicity caused by many environmental toxins. In this study, ultrastructure observation and BTB integrity assay results indicated that NiCl2 induced BTB damage. Meanwhile, BTB-related proteins including the tight junction (TJ), adhesion junction (AJ) and the gap junction (GJ) protein expression in mouse testes as well as in sertoli cells (TM4) were significantly decreased after NiCl2 treatment. Next, the antioxidant N-acetylcysteine (NAC) was co-treated with NiCl2 to study the function of oxidative stress in NiCl2-mediated BTB deterioration. The results showed that NAC attenuated testicular histopathological damage, and the expression of BTB-related proteins were markedly reversed by NAC co-treatment in vitro and vivo. Otherwise, NiCl2 activated the p38 MAPK signaling pathway. And, NAC co-treatment could significantly inhibit p38 activation induced by NiCl2 in TM4 cells. Furthermore, in order to confirm the role of the p38 MAPK signaling pathway in NiCl2-induced BTB impairment, a p38 inhibitor (SB203580) was co-treated with NiCl2 in TM4 cells, and p38 MAPK signaling inhibition significantly restored BTB damage induced by NiCl2 in TM4 cells. These results suggest that NiCl2 treatment destroys the BTB, in which the oxidative stress-mediated p38 MAPK signaling pathway plays a vital role.}, } @article {pmid37741428, year = {2023}, author = {Araujo, AM and Cerqueira, SVS and Menezes-Filho, JER and Heimfarth, L and Matos, KKOG and Mota, KO and Conceição, MRL and Marques, LP and Roman-Campos, D and Santos-Neto, AGD and Albuquerque-Júnior, RLC and Santos, VCO and Vasconcelos, CML}, title = {Naringin improves post-ischemic myocardial injury by activation of KATP channels.}, journal = {European journal of pharmacology}, volume = {958}, number = {}, pages = {176069}, doi = {10.1016/j.ejphar.2023.176069}, pmid = {37741428}, issn = {1879-0712}, abstract = {Naringin (NRG) is a flavonoid with recognized cardioprotective effects. Then, it was investigated the cardioprotective mechanisms of NRG against ischemia-reperfusion (I/R) injury. The rats were pretreated for 7 days (v.o.) with NRG (25 mg/kg) or n-acetylcysteine (NAC, 100 mg/kg) and their isolated hearts were subjected to global ischemia (30 min) and reperfusion (60 min). Furthermore, isolated hearts were perfused with 5 μM NRG in the presence of 10 μM glibenclamide (GLI) and subjected to I/R protocol. In healthy ventricular cardiomyocyte, it was evaluated the acute effect of 5 μM NRG on the GLI sensitive current. The results showed that NRG pretreatment restored the cardiac function and electrocardiogram (ECG) alterations induced by I/R injury, decreasing arrhythmia scores and the occurrence of severe arrhythmias. Lactate dehydrogenase and infarct area were decreased while superoxide dismutase (SOD), catalase and citrate synthase activities increased. Expression of SOD CuZn and SOD Mn not was altered. NRG treatment decreased reactive oxygen species (ROS) generation and lipid peroxidation without alter sulfhydryl groups and protein carbonylation. Also, NRG (5 μM) increased the glibenclamide sensitive current in isolated cardiomyocytes. In isolated heart, the cardioprotection of NRG was significantly reduced by GLI. Furthermore, NRG promoted downregulation of Bax expression and Bax/Bcl-2. Histopathological analysis showed that NRG decreased cell edema, cardiomyocytes and nucleus diameter. Thus, NRG has a cardioprotective effect against cardiac I/R injury which is mediated by its antioxidant and antiapoptotic actions and KATP channels activation.}, } @article {pmid37741051, year = {2023}, author = {Fayyazi, F and Ebrahimi, V and Mamaghani, MM and Abgharmi, BA and Zarrini, G and Mosarrezaii, A and Charkhian, H and Gholinejad, Z}, title = {N-Acetyl cysteine amide and cerium oxide nanoparticles as a drug delivery for ischemic stroke treatment: Inflammation and oxidative stress crosstalk.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {80}, number = {}, pages = {127300}, doi = {10.1016/j.jtemb.2023.127300}, pmid = {37741051}, issn = {1878-3252}, mesh = {Humans ; Rats ; Animals ; Antioxidants/pharmacology/metabolism ; Chitinase-3-Like Protein 1/pharmacology ; *Ischemic Stroke ; Olive Oil/pharmacology ; Oxidative Stress ; *Cerium/pharmacology ; Inflammation/drug therapy/pathology ; *Nanoparticles ; Acetylcysteine/pharmacology ; Drug Delivery Systems ; Anti-Bacterial Agents/pharmacology ; Urea ; Amides/pharmacology ; }, abstract = {BACKGROUND: Inflammation and oxidative stress crosstalk is involved in the ischemic stroke(IS) pathogenesis and the new therapeutic options should be offered based on the targets that are critical in the golden hour of IS. YKL-40 and total antioxidant capacity(TAC), the inflammation and oxidative stress biomarkers, provide us with clues for proper intervention targets. N-acetyl cysteine amide (NACA), a lipophilic antioxidant, with a nanoparticle-based drug delivery system is permeable enough to penetrate blood-brain barrier (BBB) and was proposed as a new treatment option for IS. In this study, we evaluated the YKL-40 and TAC levels in the sera of IS patients to elucidate the best intervention target. A rat tissue model is used to assess the NACA efficiency. The microbiology tests performed to figure out the potential NACA and antibiotics interactions.

MATERIAL AND METHODS: The YKL-40 and TAC were measured in the serum of IS patients by ELISA and FRAP methods, respectively. The serum samples were obtained 12 h after the patient's admission and meantime other laboratory findings and NIHSS-based prognosis were recorded. In the animal study, the brain cortex, liver, kidney, adipose, and the heart of healthy rats were dissected and then incubated in DMEM cell culture media containing 50 micrograms/milliliter of nanoparticles; the nanoparticles were titanium dioxide nanoparticles (TiO2 NPs), copper oxide nanoparticles (CuO NPs) and cerium dioxide nanoparticles (CeO2 NPs). Olive oil and human serum albumin solution were exposed to the nanoparticles with and without NACA. TAC was measured in the supernatant culture media. With similar concentrations and settings, we evaluated the NACA, nanoparticle, and antibiotics interactions on pseudomonas aeruginosa.

RESULTS: There was a nonparametric correlation between YKL-40 levels and post stroke serum TAC levels. Nonsmokers had higher YKL-40 and TAC levels than smokers. A new calculated variable, urea*lymphocyte/age, predicts a poor prognosis with an acceptable AUC (0.708). Exposing to the nanoparticles, the liver, kidney, and brain had a significantly higher TAC than adipose and cardiac tissue. The NACA had an ameliorative effect against TiO2 NPs in the brain. This effectiveness of NACA was also observed against CuO NPs treatment. However, the CeO2 NPs exert a strong antioxidant property by reducing the TAC in the brain tissue but not the others. Albumin showed antioxidant properties by itself, but olive oil had an inert behavior. NACA had no interaction with the action of routine antibiotics.

CONCLUSION: Oxidative stress but not inflammation is the best point for intervention in IS patients because YKL-40 has not a relationship with NIHSS score. The CeO2 NPs and NACA combination are eligible option to develop antioxidant-based drug for the treatment of IS. As a complementary finding, the urea*lymphocyte/age is proposed as a NIHSS-based prognosis biomarker.}, } @article {pmid37739116, year = {2023}, author = {Mushtaq, I and Mushtaq, I and Akhlaq, A and Usman, S and Ishtiaq, A and Khan, M and Mustafa, G and Khan, MS and Urooj, I and Bibi, S and Liaqat, F and Akhtar, Z and Murtaza, I}, title = {Cardioprotective effect of tetra(aniline) containing terpolymers through miR-15a-5p and MFN-2 regulation against hypertrophic responses.}, journal = {Archives of biochemistry and biophysics}, volume = {747}, number = {}, pages = {109763}, doi = {10.1016/j.abb.2023.109763}, pmid = {37739116}, issn = {1096-0384}, abstract = {OBJECTIVE: Cardiac hypertrophy is a condition of abnormal cardiomyocyte enlargement accompanied by ventricular wall thickening. The study aims to investigate the role of miR-15a-5p in the regulation of mitofusin-2 (MFN-2) and to explore the cardioprotective effect of terpolymers ES-37 and L-37.

METHODS: In this study, the Sprague Dawley rats' cardiac hypertrophic model was established by administering 5 mg/kg Isoproterenol subcutaneously every other day for 14 days. As treatment rats received NAC (50 mg/kg), NAC treatment (50 mg/kg NAC + 5 mg/kg ISO), ES-37 (1 mg/kg) and ES-37 treatment (1 mg/kg ES-37+5 mg/kg ISO), L-37 (1 mg/kg) and L-37 treatment (1 mg/kg L-37+5 mg/kg ISO). subcutaneously every other day for 14 days. NAC, ES 37 and L-37 were given after 1 h of Isoproterenol administration in treatment groups. Cardiac hypertrophy was confirmed through morphological and histological analysis. For estimation of oxidative stress profiling, ROS and TBARS and antioxidative profiling superoxide dismutase (SOD), Catalase, and Glutathione (GSH) levels were checked. Triglyceride, cholesterol, alanine transaminase (ALT), and aspartate transaminase (AST) were performed to evaluate levels of lipid profiling and liver profiling. Molecular expression analysis was checked through real-time PCR, and western blotting both at the transcriptional and translational levels. Molecular docking studies were performed to study the interactions and modes of binding between the synthetic polymers with three proteins (Mitofusin-2, DRP-1 and PUMA). All the studies were carried out using the AutoDock Vina software and the protein-ligand complexes were visualized in Biovia Discovery Studio. Cardiac hypertrophy was confirmed by the relative changes in the cellular structure of the heart by histopathological examination and physiological changes by estimating organ weights. Biochemical profiling results depict elevated oxidative and lipid profiles signify myocardial damage. N-acetyl cysteine (NAC), ES-37, and L-37 overcome the cardiac hypertrophic responses through attenuating oxidative stress and enhancing the antioxidative signaling mechanism. miR-15a-5p was identified as hypertrophic microRNA directly regulating the expression of Mitofusin-2 (MFN-2). Significantly increased expression of miR-15a-5p, Dynamin related protein 1 (Drp1), and P53 upregulated modulator of apoptosis (PUMA), was observed in the disease group, whereas MFN-2 expression was observed downregulated. N-acetyl cysteine (NAC), ES-37, and L-37 showed increased expression of antiapoptotic maker MFN-2 and decreased expression of miR-15a-5p, Drp1, and PUMA in treatment groups suggesting their cardioprotective role in attenuation of cardiac hypertrophy. An analysis of the docking results shows that ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2.

CONCLUSION: The physiochemical properties of ES-37 and L-37 predicted it as a good drug-like molecule and its mechanism of action is predictably through inhibition of ROS. Molecular docking results shows that the polymer ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2. Thus, the study validates the role and targeting of miR-15a-5p and MFN-2 in cardiac hypertrophy as well as the therapeutic potential of NAC, ES-37, and L-37 in overcoming oxidative stress and myocardial damage.}, } @article {pmid37732506, year = {2023}, author = {Sharma, S and Sharma, V and Taneja, S and Alka Bhatia, and Anand, A and Patil, AN and Banerjee, D}, title = {Scopoletin a potential phytochemical therapy for antitubercular treatment drug induced liver injury (ATT-DILI) model in Wistar rats.}, journal = {Journal of complementary & integrative medicine}, volume = {20}, number = {4}, pages = {797-803}, pmid = {37732506}, issn = {1553-3840}, mesh = {Rats ; Animals ; Rats, Wistar ; *Scopoletin/pharmacology/therapeutic use/metabolism ; Plant Extracts/pharmacology/therapeutic use ; Antitubercular Agents/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy ; Liver ; Bilirubin/metabolism ; Alkaline Phosphatase/metabolism ; Carbon Tetrachloride/metabolism/pharmacology ; Alanine Transaminase/metabolism ; }, abstract = {OBJECTIVES: The hepatoprotective properties of scopoletin have been explored in carbon tetrachloride (CCl4) induced liver injury but not in drug-induced liver injury (DILI) scenarios. Only N-acetyl-cysteine (NAC) has proven efficacy in DILI treatment. Accordingly, we conducted a study to assess the hepatoprotective action of scopoletin in the anti-tubercular treatment (ATT)-DILI model in Wistar rats, if any.

METHODS: A total of 36 rats were evaluated, with six in each group. A 36-day ATT at 100 mg/kg dose for isoniazid, 300 mg/kg for rifampicin and 700 mg/kg for pyrazinamide were fed to induce hepatotoxicity in rats. Group I and II-VI received normal saline and ATT, respectively. Oral scopoletin (1,5 and 10 mg/kg) and NAC 150 mg/kg were administered in groups III, IV, V and VI, respectively, once daily for the last 15 days of the experiment. LFT monitoring was performed at baseline, days 21, 28, and 36. Rats were sacrificed for the histopathology examination.

RESULTS: Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin levels were significantly increased in group II (receiving ATT) compared to normal control on day 28 and day 36 (p<0.05). All three doses of scopoletin and NAC groups led to the resolution of AST, ALT, ALP, and bilirubin changes induced by ATT medications effect beginning by day 28 and persisting on day 36 (p<0.01). An insignificant effect was observed on albumin and total protein levels. The effect was confirmed with antioxidants and histopathology analysis.

CONCLUSIONS: The study confirms the hepatoprotective efficacy of scopoletin in a more robust commonly encountered liver injury etiology.}, } @article {pmid37730076, year = {2023}, author = {Zhou, X and Chen, Q and Chen, L and Liao, X and Wang, Z and Zhu, F}, title = {The effect of reactive oxygen species (ROS) in immunity and WSSV infection of Scylla paramamosain.}, journal = {Fish & shellfish immunology}, volume = {141}, number = {}, pages = {109075}, doi = {10.1016/j.fsi.2023.109075}, pmid = {37730076}, issn = {1095-9947}, mesh = {Animals ; Reactive Oxygen Species ; *Brachyura ; *White spot syndrome virus 1/physiology ; Arthropod Proteins ; Immunity, Innate/genetics ; *Virus Diseases ; Superoxide Dismutase ; Hemocytes ; }, abstract = {Reactive oxygen species (ROS) are typically regarded as being generated by the cellular respiratory chain or by cells under pathological damage, which play a crucial role as signaling molecules in promoting hemocytes circulation and normal cellular physiological functions. In this study, the antioxidant N-acetylcysteine (NAC) was used to reduce ROS in vivo and in vitro, which to analyze the effect of ROS on innate immunity and viral infection of mud crab. The total hemocyte count (THC), phenoloxidase (PO), superoxide dismutase (SOD) activity, immune-relative genes were analyzed, respectively. Moreover, the effect of ROS on WSSV infection was analyzed by THC and hemocytes apoptosis. The data showed that NAC could effectively remove and inhibit intracellular ROS. The THC of NAC group was reduced at 12 h and 24 h compared with that of control. And the inhibition of ROS by NAC could increase the SOD activity with control group, while increased the PO activity caused by early WSSV infection. And NAC could up-regulate the expression of MCM7, JAK, TLR and proPO significantly, while down-regulate the expression of Astakine, proPO, caspase and p53. Similarly, NAC could inhibit WSSV-induced apoptosis of S. paramamosain hemocytes. The data illustrated that ROS participates in the interaction between hemocytes and virus infection by regulating innate immunity. Especially, after NAC inhibited ROS, the expression of hemocytes proliferation gene Astakine was also inhibited, which may indicate that ROS is related to the process of hemocytes proliferation. The data will show a preliminary exploration on the regulatory role of ROS in crustacean immune system.}, } @article {pmid37726091, year = {2023}, author = {Sun, Z and Wu, K and Feng, C and Lei, XG}, title = {Selenium-dependent glutathione peroxidase 1 regulates transcription of elongase 3 in murine tissues.}, journal = {Free radical biology & medicine}, volume = {208}, number = {}, pages = {708-717}, doi = {10.1016/j.freeradbiomed.2023.09.010}, pmid = {37726091}, issn = {1873-4596}, mesh = {Humans ; Male ; Mice ; Animals ; Infant ; *Glutathione Peroxidase GPX1 ; *Selenium/metabolism ; Glutathione Peroxidase/genetics/metabolism ; Fatty Acid Elongases/genetics/metabolism ; Diquat/metabolism ; HEK293 Cells ; Mice, Knockout ; RNA, Messenger/metabolism ; Liver/metabolism ; }, abstract = {We have previously shown dysregulated lipid metabolism in tissues of glutathione peroxidase 1 (GPX1) overexpressing (OE) or deficient (KO) mice. This study explored underlying mechanisms of GPX1 in regulating tissue fatty acid (FA) biosynthesis. GPX1 OE, KO, and wild-type (WT) mice (n = 5, male, 3-6 months old) were fed a Se-adequate diet (0.3 mg/kg) and assayed for liver and adipose tissue FA profiles and mRNA levels of key enzymes of FA biosynthesis and redox-responsive transcriptional factors (TFs). These three genotypes of mice (n = 5) were injected intraperitoneally with diquat, ebselen, and N-acetylcysteine (NAC) at 10, 50, and 50 mg/kg of body weight, respectively, and killed at 0 and 12 h after the injections to detect mRNA levels of FA elongases and desaturases and the TFs in the liver and adipose tissue. A luciferase reporter assay with targeted deletions of mouse Elovl3 promoter was performed to determine transcriptional regulations of the gene by GPX1 mimic ebselen in HEK293T cells. Compared with WT, GPX1 OE and KO mice had 9-42% lower (p < 0.05) and 36-161% higher (p < 0.05) concentrations of C20:0, C22:0, and C24:0 in these two tissues, respectively, along with reciprocal increases and decreases (p < 0.05) of Elovl3 transcripts. Ebselen and NAC decreased (p < 0.05), whereas diquat decreased (p < 0.05), Elovl3 transcripts in the two tissues. Overexpression and knockout of GPX1 decreased (p < 0.05) and increased (p < 0.05) ELOVL3 levels in the two tissues, respectively. Three TFs (GABP, SP1, and DBP) were identified to bind the Elovl3 promoter (-1164/+33 base pairs). Deletion of DBP (-98/-86 base pairs) binding domain in the promoter attenuated (13%, p < 0.05) inhibition of ebselen on Elovl3 promoter activation. In summary, GPX1 overexpression down-regulated very long-chain FA biosynthesis via transcriptional inhibition of the Elovl3 promoter activation.}, } @article {pmid37716334, year = {2023}, author = {Chung, TW and Cheng, CL and Liu, YH and Huang, YC and Chen, WP and Panda, AK and Chen, WL}, title = {Dopamine-dependent functions of hyaluronic acid/dopamine/silk fibroin hydrogels that highly enhance N-acetyl-L-cysteine (NAC) delivered from nasal cavity to brain tissue through a near-infrared photothermal effect on the NAC-loaded hydrogels.}, journal = {Biomaterials advances}, volume = {154}, number = {}, pages = {213615}, doi = {10.1016/j.bioadv.2023.213615}, pmid = {37716334}, issn = {2772-9508}, mesh = {Rats ; Animals ; *Fibroins ; Acetylcysteine/pharmacology ; Hyaluronic Acid/pharmacology ; Dopamine/pharmacology ; Hydrogels/pharmacology ; Nasal Cavity ; Brain ; }, abstract = {Hyaluronic acid/silk fibroin (HA/SF or HS) hydrogels with remarkable mechanical characteristics have been reported as tissue engineering biomaterials. Herein, the addition of dopamine/polydopamine (DA/PDA) to HS hydrogels to develop multifunctional HA/PDA/SF (or HDS) hydrogels for the delivery of drugs such as N-acetyl-L-cysteine (NAC) from nasal to brain tissue is examined. Herein, DA-dependent functions of HDS hydrogels with highly adhesive forces, photothermal response (PTR) effects generated by near infrared (NIR) irradiation, and anti-oxidative effects were demonstrated. An in-vitro study shows that the HDS/NAC hydrogels could open tight junctions in the RPMI 2650 cell line, a model cell of the nasal mucosa, as demonstrated by the decreased values of transepithelial electrical resistance (TEER) and more discrete ZO-1 staining than those for the control group. This effect was markedly enhanced by NIR irradiation of the HDS/NAC-NIR hydrogels. Compared to the results obtained using NAC solution, an in-vivo imaging study (IVIS) in rats showed an approximately nine-fold increase in the quantity of NAC delivered from the nasal cavity to the brain tissue in the span of 2 h through the PTR effect generated by the NIR irradiation of the nasal tissue and administration of the HDS/NAC hydrogels. Herein, dopamine-dependent multifunctional HDS hydrogels were studied, and the nasal administration of HDS/NAC-NIR hydrogels with PTR effects generated by NIR irradiation was found to have significantly enhanced NAC delivery to brain tissues.}, } @article {pmid37715092, year = {2024}, author = {Peng, HX and Chai, F and Chen, KH and Huang, YX and Wei, GJ and Yuan, H and Pang, YF and Luo, SH and Wang, CF and Chen, WC}, title = {Reactive Oxygen Species-Mediated Mitophagy and Cell Apoptosis are Involved in the Toxicity of Aluminum Chloride Exposure in GC-2spd.}, journal = {Biological trace element research}, volume = {202}, number = {6}, pages = {2616-2629}, pmid = {37715092}, issn = {1559-0720}, support = {2020KY13017//Guangxi University Young and Middle-aged Teachers' Basic Ability Improvement Project/ ; GZZC2020248//Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine Self-financing Scientific Research Project/ ; Z20201416//Guangxi Zhuang Autonomous Region Health and Health Commission Self-financing Scientific Research Course/ ; 81960303//National Natural Science Foundation of China/ ; 2020GXNSFAA297257)//Guangxi Natural Science Foundation Project/ ; }, mesh = {*Aluminum Chloride/toxicity ; Animals ; *Apoptosis/drug effects ; Male ; *Reactive Oxygen Species/metabolism ; *Mitophagy/drug effects ; Mice ; Membrane Potential, Mitochondrial/drug effects ; Testis/drug effects/metabolism/pathology ; Cell Survival/drug effects ; Spermatocytes/drug effects/metabolism ; Cell Line ; Chlorides/toxicity ; Aluminum Compounds/toxicity ; }, abstract = {Aluminum chloride is an inorganic polymeric coagulant commonly found in daily life and various materials. Although male reproductive toxicity has been associated with AlCl3 exposure, the underlying mechanism remains unclear. This study aimed to examine the impact of AlCl3 exposure on mitophagy and mitochondrial apoptosis in testicular tissue and mouse spermatocytes. Reactive oxygen species (ROS) and ATP levels were measured in GC-2spd after AlCl3 exposure using a multifunctional enzyme labeler. The changes in mitochondrial membrane potential (MMP) and TUNEL were observed through confocal laser microscopy, and the expression of proteins associated with mitophagy and apoptosis was analyzed using Western blot. Our results demonstrated that AlCl3 exposure disrupted mitophagy and increased apoptosis-related protein expression in testicular tissues. In the in vitro experiments, AlCl3 exposure induced ROS production, suppressed cell viability and ATP production, and caused a decrease in MMP, leading to mitophagy and cell apoptosis in GC-2spd cells. Intervention with N-acetylcysteine (NAC) reduced ROS production and partially restored mitochondrial function, thereby reversing the resulting mitophagy and cell apoptosis. Our findings provide evidence that ROS-mediated mitophagy and cell apoptosis play a crucial role in the toxicity of AlCl3 exposure in GC-2spd. These results contribute to the understanding of male reproductive toxicity caused by AlCl3 exposure and offer a foundation for future research in this area.}, } @article {pmid37714033, year = {2023}, author = {Ma, R and Sun, T and Wang, X and Ren, K and Min, T and Xie, X and Wang, D and Li, K and Zhang, Y and Zhu, K and Mo, C and Dang, C and Yang, Y and Zhang, H}, title = {Chronic exposure to low-dose deltamethrin can lead to colon tissue injury through PRDX1 inactivation-induced mitochondrial oxidative stress injury and gut microbial dysbiosis.}, journal = {Ecotoxicology and environmental safety}, volume = {264}, number = {}, pages = {115475}, doi = {10.1016/j.ecoenv.2023.115475}, pmid = {37714033}, issn = {1090-2414}, mesh = {Humans ; Animals ; Mice ; Dysbiosis/chemically induced ; *Gastrointestinal Microbiome ; Colon ; Oxidative Stress ; Acetylcysteine ; Peroxiredoxins/genetics ; }, abstract = {OBJECTIVE: To date, it is unclear whether deltamethrin (DLM) intake causes damage to colon tissue. Hence, in this study, we aimed to clarify the effect of long-term exposure to low-dose DLM on colon tissues, and its potential mechanisms.

METHODS: Mice were treated with DLM (0.2 mg/kg/day) or DLM combined with N-acetyl-l-cysteine (NAC) (50 mg/kg/day) for 8 weeks. Human colon cancer cells (HCT-116) were treated with DLM (0, 25, 50, or 100 µM), NAC (2 mM), or overexpression plasmids targeting peroxiredoxin 1 (PRDX1) for 48 h. DLM was detected using a DLM rapid detection card. Colon injury was evaluated using haematoxylin and eosin staining and transmission electron microscopy. Apoptosis was determined using immunofluorescence staining (IF), western blotting (WB) and flow cytometry (FC) assays. MitoTracker, JC-1, and glutathione (GSH) detection were used to detect mitochondrial oxidative stress. Intestinal flora were identified by 16 S rDNA sequencing.

RESULTS: DLM accumulation was detected in the colon tissue and faeces of mice following long-term intragastric administration. Interestingly, our results showed that, even at a low dose, long-term intake of DLM resulted in severe weight loss and decreased the disease activity index scores and colon length. The results of IF, WB, and FC showed that DLM induced apoptosis in the colon tissue and cells. MitoTracker, JC-1, and GSH assays showed that DLM increased mitochondrial stress in colonic epithelial cells. Mechanistic studies have shown that increased mitochondrial stress and apoptosis are mediated by PRDX1 inhibition. Further experiments showed that PRDX1 overexpression significantly reduced DLM-induced oxidative stress injury and apoptosis. In addition, we observed that chronic exposure to DLM altered the composition of the intestinal flora in mice, including an increase in Odoribacter and Bacteroides and a decrease in Lactobacillus. The gut microbial richness decreased after DLM exposure in mice. Supplementation with NAC both in vivo and in vitro alleviated DLM-induced oxidative stress injury, colonic epithelial cell apoptosis, and gut microbial dysbiosis.

CONCLUSION: Chronic exposure to DLM, even at small doses, can cause damage to the colon tissue, which cannot be ignored. The production and use of pesticides such as DLM should be strictly regulated during agricultural production.}, } @article {pmid37712506, year = {2024}, author = {Zhang, Q and Liu, Z and Wang, T and Yu, M and Li, X}, title = {Efficacy and acceptability of adjunctive n-acetylcysteine for psychotic disorders: Systematic review and meta-analysis.}, journal = {Human psychopharmacology}, volume = {39}, number = {2}, pages = {e2880}, doi = {10.1002/hup.2880}, pmid = {37712506}, issn = {1099-1077}, mesh = {Humans ; Acetylcysteine/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Schizophrenia/drug therapy ; *Psychotic Disorders/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) augmentation of antipsychotic medication has been studied in psychotic disorders but the results are inconsistent. This meta-analysis aimed to evaluate the efficacy and acceptability of NAC as an augmentation strategy for psychotic disorders.

METHODS: PubMed, Web of Science, EMBASE, PsycINFO, Cochrane Library, and ClinicalTrials.gov were searched until the date of November 28, 2022. The inclusion criteria were randomized controlled trials (RCTs) comparing NAC and placebo in patients with psychotic disorders. The outcomes were the psychotic symptoms measured by the Positive and Negative Syndrome Scale (PANSS) and drop-out rates.

RESULTS: A total of 594 patients from eight trials were included. The results showed that no difference was found in score changes of PANSS total, positive, negative, or general psychopathology scale scores between the NAC group and placebo group in both time points (≤24 weeks and >24 weeks). There was also no statistical difference in drop-out rates between the two groups.

CONCLUSION: For the moment, it is not appropriate to recommend NAC as an augmentation of antipsychotic medication to treat psychotic disorders in routine clinical practice.}, } @article {pmid37711440, year = {2023}, author = {Yamamoto, T and Tanji, M and Mitsunaga, F and Nakamura, S}, title = {SARS-CoV-2 sublingual vaccine with RBD antigen and poly(I:C) adjuvant: Preclinical study in cynomolgus macaques.}, journal = {Biology methods & protocols}, volume = {8}, number = {1}, pages = {bpad017}, pmid = {37711440}, issn = {2396-8923}, abstract = {Mucosal vaccine for sublingual route was prepared with recombinant SARS-CoV-2 spike protein receptor binding domain (RBD) antigen and poly(I:C) adjuvant components. The efficacy of this sublingual vaccine was examined using Cynomolgus macaques. Nine of the macaque monkeys were divided into three groups of three animals: control [just 400 µg poly(I:C) per head], low dose [30 µg RBD and 400 µg poly(I:C) per head], and high dose [150 µg RBD and 400 µg poly(I:C) per head], respectively. N-acetylcysteine (NAC), a mild reducing agent losing mucin barrier, was used to enhance vaccine delivery to mucosal immune cells. RBD-specific IgA antibody secreted in pituita was detected in two of three monkeys of the high dose group and one of three animals of the low dose group. RBD-specific IgG and/or IgA antibodies in plasma were also detected in these monkeys. These indicated that the sublingual vaccine stimulated mucosal immune response to produce antigen-specific secretory IgA antibodies in pituita and/or saliva. This sublingual vaccine also affected systemic immune response to produce IgG (IgA) in plasma. Little RBD-specific IgE was detected in plasma, suggesting no allergic antigenicity of this sublingual vaccine. Thus, SARS-CoV-2 sublingual vaccine consisting of poly(I:C) adjuvant showed reasonable efficacy in a non-human primate model.}, } @article {pmid37710183, year = {2023}, author = {Du, YX and Zhao, YT and Sun, YX and Xu, AH}, title = {Acid sphingomyelinase mediates ferroptosis induced by high glucose via autophagic degradation of GPX4 in type 2 diabetic osteoporosis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {29}, number = {1}, pages = {125}, pmid = {37710183}, issn = {1528-3658}, mesh = {Animals ; Rats ; Autophagy ; Ceramides ; *Diabetes Mellitus, Type 2 ; *Ferroptosis ; Glucose ; *Osteoporosis/drug therapy/etiology ; Reactive Oxygen Species ; Sphingomyelin Phosphodiesterase/genetics ; X-Ray Microtomography ; }, abstract = {BACKGROUND: Ferroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), although the specific underlying mechanisms remain largely unknown. This study aimed to clarify the role and possible mechanism of acid sphingomyelinase (ASM)-mediated osteoblast ferroptosis in T2DOP.

METHODS: We treated hFob1.19 cells with normal glucose (NG) and different concentrations of high glucose (HG, 26.25 mM, 35 mM, or 43.75 mM) for 48 h. We then measured cell viability and osteogenic function, quantified ferroptosis and autophagy levels, and measured the levels of ASM and ceramide in the cells. To further investigate the specific mechanism, we examined these indicators by knocking down ASM expression, hydroxychloroquine (HCQ) treatment, or N-acetylcysteine (NAC) treatment. Moreover, a T2DOP rat model was induced and microcomputed tomography was used to observe the bone microstructure. We also evaluated the serum levels of iron metabolism-associated factors, ceramide and lipid peroxidation (LPO) and measured the expression of ASM, LC3 and GPX4 in bone tissues.

RESULTS: HG inhibited the viability and osteogenic function of osteoblasts by inducing ferroptosis in a concentration-dependent manner. Furthermore, the expression of ASM and ceramide and autophagy levels were increased by HG treatment, and these factors were required for the HG-induced reactive oxygen species (ROS) generation and LPO. Similarly, inhibiting intracellular ROS also reduced HG-induced ASM activation and autophagy. ASM-mediated activation of autophagy was crucial for HG-induced degradation of GPX4, and inhibiting ASM improved osteogenic function by decreasing HG-induced autophagy, GPX4 degradation, LPO and subsequent ferroptosis. We also found that inhibiting ASM could alleviated ferroptosis and autophagy and improved osteogenic function in a T2DOP rat model.

CONCLUSION: ASM-mediated autophagy activation induces osteoblast ferroptosis under HG conditions through the degradation of GPX4, providing a novel mechanistic insight into the treatment and prevention of T2DOP.}, } @article {pmid37705917, year = {2023}, author = {Granata, S and Bruschi, M and Verlato, A and Pontrelli, P and Gesualdo, L and Stallone, G and Zaza, G}, title = {Autophagy Activation in Peripheral Blood Mononuclear Cells of Peritoneal Dialysis Patients.}, journal = {Kidney international reports}, volume = {8}, number = {9}, pages = {1852-1863}, pmid = {37705917}, issn = {2468-0249}, abstract = {INTRODUCTION: The complete systemic deregulated biological network in patients on peritoneal dialysis (PD) is still only partially defined. High-throughput/omics techniques may offer the possibility to analyze the main biological fingerprints associated with this clinical condition.

METHODS: We applied an innovative bioinformatic analysis of gene expression microarray data (mainly based on support vector machine (SVM) learning) to compare the transcriptomic profile of peripheral blood mononuclear cells (PBMCs) of healthy subjects (HS), chronic kidney disease (CKD) patients, and patients on PD divided into a microarray group (5 HS, 9 CKD, and 10 PD) and a validation group (10 HS, 15 CKD, and 15 PD). Classical well-standardized biomolecular approaches (western blotting and flow cytometry) were used to validate the transcriptomic results.

RESULTS: Bioinformatics revealed a distinctive PBMC transcriptomic profiling for PD versus CKD and HS (n = 419 genes). Transcripts encoding for key elements of the autophagic pathway were significantly upregulated in PD, and the autophagy related 5 (ATG5) reached the top level of discrimination [-Log10 P-value = 11.3, variable importance in projection (VIP) score = 4.8, SVM rank:1]. Protein levels of ATG5 and microtubule associated protein 1 light chain 3 beta (LC3B), an important constituent of the autophagosome, validated microarray results. In addition, the incubation of PBMCs of HS with serum of patients on PD upregulated both proteins. Autophagy in PBMCs from patients on PD was attenuated by N-acetyl-cysteine or Resatorvid treatment.

CONCLUSIONS: Our data demonstrated, for the first time, that the autophagy pathway is activated in immune-cells of patients on PD, and this may represent a novel therapeutic target.}, } @article {pmid37705749, year = {2023}, author = {Wang, L and Huang, B and Zeng, Y and Yang, J and Li, Z and Ng, JPL and Xu, X and Su, L and Yun, X and Qu, L and Chen, R and Luo, W and Wang, Y and Chen, C and Yang, L and Qu, Y and Zhang, W and Chan, JTW and Wang, X and Law, BYK and Mok, SWF and Chung, SK and Wong, VKW}, title = {N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model.}, journal = {International journal of biological sciences}, volume = {19}, number = {13}, pages = {4082-4102}, pmid = {37705749}, issn = {1449-2288}, mesh = {Humans ; Animals ; Rats ; *Acetylcysteine/therapeutic use ; Leukocytes, Mononuclear ; Aldehydes ; *Arthritis, Rheumatoid/drug therapy ; }, abstract = {Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1β, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.}, } @article {pmid37705237, year = {2024}, author = {Sheng, Y and Zhang, C and Cai, D and Xu, G and Chen, S and Li, W and Dong, J and Shen, B and Tang, J and Xu, L}, title = {2,2',4,4'-Tetrabromodiphenyl ether and cadmium co-exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME-dependent pyroptosis in renal tubular epithelial cells.}, journal = {Environmental toxicology}, volume = {39}, number = {1}, pages = {289-298}, doi = {10.1002/tox.23957}, pmid = {37705237}, issn = {1522-7278}, support = {2023RC101//Medical Health Science and Technology Project of Zhejiang Provincial Health Commission/ ; 22206059//National Natural Science Foundation of China/ ; 2023R417A016//Zhejiang Provincial University Students Science and Technology Innovation Activity/ ; }, mesh = {*Receptors, Aryl Hydrocarbon/metabolism ; *Cadmium/toxicity ; Caspase 3/metabolism ; Reactive Oxygen Species/metabolism ; Pyroptosis ; Ether ; Epithelial Cells/metabolism ; }, abstract = {We have previously found that a mixture exposure of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand-receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 μM) or Cd (5 μM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.}, } @article {pmid37701655, year = {2023}, author = {Eslami, G and Ghorbani, A and Akbari, J and Farmoudeh, A and Faghih, F and Moghimi, M}, title = {Efficacy of Oral Mucoadhesive N-Acetylcysteine Tablets in Treatment of Recurrent Aphthous Stomatitis: A Randomized Double-Blind, Placebo-Controlled Clinical Trial.}, journal = {Frontiers in dentistry}, volume = {20}, number = {}, pages = {18}, pmid = {37701655}, issn = {2676-296X}, abstract = {Objectives: This study aimed to assess the efficacy of oral mucoadhesive N-acetylcysteine (NAC) tablets for treatment of recurrent aphthous stomatitis (RAS). Materials and Methods: Forty-nine patients with RAS were randomized to receive mucoadhesive NAC tablets (n=25) or placebo (n=24). Tablets were prescribed three times a day for 7 days in each group. Pain intensity was evaluated with visual analog scale (VAS) three times a day from day 1 to day 7. Also, patients were clinically examined on days 0 (before entering the study), 3, 5, and 7 using a metal caliper to measure the diameter of the lesions. The data were statistically analyzed and P<0.05 was considered statistically significant. Results: Regarding the VAS score, all participants in the treatment group showed complete recovery on day 7 (P<0.01). Also, the diameter of the lesions was significantly smaller in the treatment group than the placebo group at the end of the study (P<0.001). Conclusion: The results of this clinical trial showed for the first time that mucoadhesive NAC tablets can significantly decrease pain and the diameter of RAS lesions without any systemic complications.}, } @article {pmid37696227, year = {2023}, author = {Chan, CY and Conley, SF and Salameh, S and Sayegh, J and Wurzba, SDS and Grenier, K and Linn, DT and Partain, MP and Daniel, SJ}, title = {Otologic safety of intratympanic N-acetylcysteine in an animal model.}, journal = {International journal of pediatric otorhinolaryngology}, volume = {173}, number = {}, pages = {111702}, doi = {10.1016/j.ijporl.2023.111702}, pmid = {37696227}, issn = {1872-8464}, mesh = {Humans ; Animals ; Guinea Pigs ; *Acetylcysteine/pharmacology ; *Ototoxicity ; Models, Animal ; Ciprofloxacin ; Dexamethasone ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) is an anti-oxidant and mucolytic effective against bacterial biofilms, making it useful in the treatment of chronically discharging ears that are unresponsive to traditional treatment methods. The objective of this study was to evaluate the otologic safety of intratympanic NAC combined with Ciprodex® in an animal model.

METHODS: Baseline distortion product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR) measurements were performed for both ears on thirteen guinea pigs from the animal care research facilities of the McGill University Health Center. This was followed by intratympanic administration of control solution (Ciprofloxacin 0.3%/Dexamethasone 0.1%) to the left ear and experimental solution (1.25% NAC/Ciprofloxacin 0.3%/Dexamethasone 0.1%) to the right ear. Three additional intratympanic injections were performed over the next fourteen days. DPOAE and ABR measurements were repeated 3-4 weeks after the initial procedure. Outcome measures included differences in DPOAE and ABR thresholds after intervention, clinical evidence of vestibular dysfunction and histological evidence of ototoxicity.

RESULTS: There were no significant differences in the ABR thresholds and DPOAE results of the control and experimental ears at baseline and after intervention. There was neither clinical manifestation of vestibular dysfunction nor histological evidence of ototoxicity.

CONCLUSION: Our study suggests that intratympanic 1.25% NAC with ciprofloxacin and dexamethasone is safe in guinea pigs and support its potential use in the treatment of chronically discharging ears. Further studies in humans are required to analyze its efficacy relative to conventional treatments.

LEVEL OF EVIDENCE: Animal Research.}, } @article {pmid37692935, year = {2023}, author = {Zhang, J and Xu, X and Liang, Y and Wu, X and Qian, Z and Zhang, L and Wang, T}, title = {Particulate matter promotes the epithelial to mesenchymal transition in human lung epithelial cells via the ROS pathway.}, journal = {American journal of translational research}, volume = {15}, number = {8}, pages = {5159-5167}, pmid = {37692935}, issn = {1943-8141}, abstract = {OBJECTS: Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased rates of chronic cardiopulmonary diseases, including asthma and idiopathic pulmonary fibrosis (IPF). Several investigations have suggested that the epithelial-to-mesenchymal transition (EMT) may contribute to the complex pathobiology of environmental exposure-mediated pulmonary fibrosis. The present study was designed to characterize the mechanisms of PM-mediated EMT in human lung epithelial cells (HBECs).

METHODS AND RESULTS: PM induced significant dose (0-100 μg/ml) and time (0-72 h)-dependent increases in transforming growth factor β (TGFβ) and fibronectin (FN) protein levels in HBECs lysates. PM-activated TGFβ and FN protein production in HBECs was prevented by the antioxidant N-acetyl-cysteine (NAC, 5 mM). Furthermore, the NF-κB inhibitor BAY11-7082 (5 μM) abolished PM-induced FN production in HBECs. Biomarkers of EMT (ACTA2, SNAIL1 and SNAIL2) in PM-treated HBECs were significantly increased at the mRNA level compared to control cells.

CONCLUSIONS: These results demonstrate that PM increases protein levels of TGFβ and FN via reactive oxygen species (ROS)-dependent pathways. In addition, PM exposure induces EMT in human lung epithelial cells, supporting a novel mechanism for PM-induced pulmonary fibrosis.}, } @article {pmid37692924, year = {2023}, author = {Zhang, J and Wu, X and Liang, Y and Kelly, G and Burt, JM and Zhang, L and Wang, T}, title = {Particulate matter increases connexin 43 expression and exacerbates endothelial barrier disruption.}, journal = {American journal of translational research}, volume = {15}, number = {8}, pages = {5099-5109}, pmid = {37692924}, issn = {1943-8141}, abstract = {OBJECTIVES: Particulate Matter (PM) air pollution is known to exacerbate cardiopulmonary diseases. We previously demonstrated that PM mediates endothelial injury and barrier disruption by modulating the endothelial cytoskeleton and cell-cell junctions, but the effects of PM exposure on cell-cell communication and gap junction activity are still unknown.

METHODS: This study focused on the characterization of PM-regulated endothelial dysfunction through connexin 43 (Cx43), the most abundant gap junction protein expressed in lung endothelial cells (ECs), using cultured human lung endothelial cells and a well-characterized PM sample.

RESULTS: PM exposure induced a time-dependent increase of Cx43 in human lung ECs at both the mRNA and protein levels. N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, significantly suppressed PM-induced Cx43 expression. Cx43 proteins on the plasma membrane and ER/Golgi apparatus were elevated in response to a PM challenge. In addition, PM induced gap junction activity, which was indicated by green fluorescence dye transfer between two adjacent ECs. Moreover, GAP27, a selective Cx43 channel inhibitor, attenuated PM-induced human lung EC barrier disruption, which was reflected by rescued trans-endothelial electrical resistance (TER) with an electric cell-substrate impedance sensing system. Moreover, knocking down Cx43 alleviated PM-induced myosin light chain (MLC) phosphorylation.

CONCLUSIONS: These results strongly suggest that Cx43 plays a key role in PM-mediated endothelial barrier disruption and signal transduction. Cx43 may be a therapeutic target in PM-mediated cardiopulmonary disorders.}, } @article {pmid37685966, year = {2023}, author = {Muñoz-Sánchez, G and Godínez-Méndez, LA and Fafutis-Morris, M and Delgado-Rizo, V}, title = {Effect of Antioxidant Supplementation on NET Formation Induced by LPS In Vitro; the Roles of Vitamins E and C, Glutathione, and N-acetyl Cysteine.}, journal = {International journal of molecular sciences}, volume = {24}, number = {17}, pages = {}, pmid = {37685966}, issn = {1422-0067}, mesh = {Dietary Supplements ; Acetylcysteine/pharmacology ; Hyperaldosteronism ; Ascorbic Acid/pharmacology ; Glutathione Disulfide ; Horses ; Lipopolysaccharides/pharmacology ; Animals ; Glutathione ; Reactive Oxygen Species ; *Antioxidants/pharmacology ; Vitamins ; *Vitamin E/pharmacology ; }, abstract = {Neutrophil extracellular traps (NETs) require reactive oxygen species (ROS) to eliminate pathogens by inducing oxidative stress. However, this process can also cause tissue damage to the host. Neutrophils contain high concentrations of vitamin C (1.5 mM) compared to the bloodstream (0.1 mM), and this antioxidant can interact with vitamin E and glutathione (GSH) inside the cell to maintain the redox balance. Previous studies have investigated the effect of vitamins E or C and N-acetyl cysteine (NAC) on NET formation, but the interactions of these molecules in neutrophils remain unknown. In this study, we investigated the effect of antioxidants alone and two combinations on NET formation and oxidative stress. Neutrophils were pre-loaded with GSH + NAC or vitamin E + vitamin C + GSH + NAC (termed ALL), and LPS-induced NET formation was assessed using fluorometry and immunofluorescence. Antioxidant effects were evaluated by measuring the total antioxidant capacity (TAC), GSH/GSSG ratio, ROS production, nitrite + nitrate levels, and lipid peroxidation. Our results showed that even low doses of antioxidants are capable of decreasing NETs. Furthermore, the combinations augmented TAC and GSH/GSSG ratio and decreased ROS, nitrites + nitrates, and malondialdehyde (MDA) levels in supplemented neutrophils in vitro.}, } @article {pmid37684590, year = {2023}, author = {Liu, S and Guan, Y and Weng, Y and Liao, B and Tong, L and Hao, Z and Chen, J and Shi, J and Cheng, T}, title = {Genome-wide identification of the NAC gene family and its functional analysis in Liriodendron.}, journal = {BMC plant biology}, volume = {23}, number = {1}, pages = {415}, pmid = {37684590}, issn = {1471-2229}, support = {32101546//National Natural Science Foundation of China/ ; 32071784//National Natural Science Foundation of China/ ; 2021YFD2200103//National Key Research and Development Program of China during the 14th Five-year Plan Period/ ; PAPD//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; PAPD//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; }, mesh = {*Liriodendron ; Acetylcysteine ; Cell Nucleus ; Cytoplasm ; }, abstract = {As one of the largest plant specific transcription factor families, NAC family members play an important role in plant growth, development and stress resistance. To investigate the function of NAC transcription factors during abiotic stress, as well as during somatic embryogenesis, we identified and characterized the NAC gene family in Liriodendron chinense. We found that most LcNAC members contain more than three exons, with a relatively conserved gene and motif structure, especially at the N-terminus. Interspecies collinearity analysis revealed a closer relationship between the L. chinense NACs and the P. trichocarpa NACs. We analyzed the expression of LcNAC in different tissues and under three abiotic stresses. We found that 12 genes were highly expressed during the ES3 and ES4 stages of somatic embryos, suggesting that they are involved in the development of somatic embryos. 6 LcNAC genes are highly expressed in flower organs. The expression pattern analysis of LcNACs based on transcriptome data and RT-qPCR obtained from L. chinense leaves indicated differential expression responses to drought, cold, and heat stress. Genes in the NAM subfamily expressed differently during abiotic stress, and LcNAC6/18/41/65 might be the key genes in response to abiotic stress. LcNAC6/18/41/65 were cloned and transiently transformed into Liriodendron protoplasts, where LcNAC18/65 was localized in cytoplasm and nucleus, and LcNAC6/41 was localized only in nucleus. Overall, our findings suggest a role of the NAC gene family during environmental stresses in L. chinense. This research provides a basis for further study of NAC genes in Liriodendron chinense.}, } @article {pmid37683986, year = {2023}, author = {Lapenna, D}, title = {Glutathione and glutathione-dependent enzymes: From biochemistry to gerontology and successful aging.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102066}, doi = {10.1016/j.arr.2023.102066}, pmid = {37683986}, issn = {1872-9649}, mesh = {Humans ; Aged ; *Antioxidants/metabolism ; Hydrogen Peroxide ; Glutathione/metabolism ; Glutamate-Cysteine Ligase/genetics/metabolism ; Acetylcysteine ; Glycine ; *Geriatrics ; }, abstract = {The tripeptide glutathione (GSH), namely γ-L-glutamyl-L-cysteinyl-glycine, is an ubiquitous low-molecular weight thiol nucleophile and reductant of utmost importance, representing the central redox agent of most aerobic organisms. GSH has vital functions involving also antioxidant protection, detoxification, redox homeostasis, cell signaling, iron metabolism/homeostasis, DNA synthesis, gene expression, cysteine/protein metabolism, and cell proliferation/differentiation or death including apoptosis and ferroptosis. Various functions of GSH are exerted in concert with GSH-dependent enzymes. Indeed, although GSH has direct scavenging antioxidant effects, its antioxidant function is substantially accomplished by glutathione peroxidase-catalyzed reactions with reductive removal of H2O2, organic peroxides such as lipid hydroperoxides, and peroxynitrite; to this antioxidant activity also contribute peroxiredoxins, enzymes further involved in redox signaling and chaperone activity. Moreover, the detoxifying function of GSH is basically exerted in conjunction with glutathione transferases, which have also antioxidant properties. GSH is synthesized in the cytosol by the ATP-dependent enzymes glutamate cysteine ligase (GCL), which catalyzes ligation of cysteine and glutamate forming γ-glutamylcysteine (γ-GC), and glutathione synthase, which adds glycine to γ-GC resulting in GSH formation; GCL is rate-limiting for GSH synthesis, as is the precursor amino acid cysteine, which may be supplemented as N-acetylcysteine (NAC), a therapeutically available compound. After its cell export, GSH is degraded extracellularly by the membrane-anchored ectoenzyme γ-glutamyl transferase, a process occurring, as GSH synthesis and export, in the γ-glutamyl cycle. GSH degradation occurs also intracellularly by the cytoplasmic enzymatic ChaC family of γ-glutamyl cyclotransferase. Synthesis and degradation of GSH, together with its export, translocation to cell organelles, utilization for multiple essential functions, and regeneration from glutathione disulfide by glutathione reductase, are relevant to GSH homeostasis and metabolism. Notably, GSH levels decline during aging, an alteration generally related to impaired GSH biosynthesis and leading to cell dysfunction. However, there is evidence of enhanced GSH levels in elderly subjects with excellent physical and mental health status, suggesting that heightened GSH may be a marker and even a causative factor of increased healthspan and lifespan. Such aspects, and much more including GSH-boosting substances administrable to humans, are considered in this state-of-the-art review, which deals with GSH and GSH-dependent enzymes from biochemistry to gerontology, focusing attention also on lifespan/healthspan extension and successful aging; the significance of GSH levels in aging is considered also in relation to therapeutic possibilities and supplementation strategies, based on the use of various compounds including NAC-glycine, aimed at increasing GSH and related defenses to improve health status and counteract aging processes in humans.}, } @article {pmid37681263, year = {2023}, author = {Pepin, L and Matsler, N and Fontes, A and Heard, K and Flaherty, BF and Monte, AA}, title = {Fomepizole Therapy for Acetaminophen-Induced Liver Failure in an Infant.}, journal = {Pediatrics}, volume = {152}, number = {4}, pages = {}, doi = {10.1542/peds.2022-061033}, pmid = {37681263}, issn = {1098-4275}, abstract = {Acetaminophen overdose is common in the pediatric population. N-acetylcysteine (NAC) is effective at preventing liver injury in most patients when started shortly after the overdose. Delays to therapy increase risk of hepatotoxicity and liver failure that may necessitate organ transplant. Animal studies have demonstrated fomepizole may provide added benefit in acetaminophen overdose because of its ability to block the metabolic pathway that produces the toxic acetaminophen metabolite and downstream inhibition of oxidative stress pathways that lead to cell death. Several adult case reports describe use of fomepizole in patients at higher risk for poor outcomes despite NAC. We describe a case of a 7-month-old female who presented in acute liver failure with persistently elevated acetaminophen concentration secondary to repeated supratherapeutic doses of acetaminophen to manage fever. Fomepizole and NAC antidotes were used in the management of the patient. She fully recovered despite demonstrating multiple markers of poor outcome on initial presentation. Although randomized trials are lacking, this case suggests that fomepizole may safely provide additional benefit in pediatric patients at risk for severe acetaminophen toxicity.}, } @article {pmid37680754, year = {2023}, author = {Alqahtani, QH and Fadda, LM and Alhusaini, AM and Hasan, IH and Ali, HM}, title = {Involvement of Nrf2, JAK and COX pathways in acetaminophen-induced nephropathy: Role of some antioxidants.}, journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society}, volume = {31}, number = {10}, pages = {101752}, pmid = {37680754}, issn = {1319-0164}, abstract = {OBJECTIVES: Acetaminophen (APAP)-induced nephrotoxicity is detrimental consequence for which there has not been a standardized therapeutic regimen. Although, N-acetylcysteine (NAC) is a well-known antidote used in APAP-induced hepatotoxicity, its benefit in nephrotoxicity caused by APAP is almost lacking. This study aimed to compare the possible protective effect of thymoquinone (TQ), curcumin (CR), and α-lipoic acid (α-LA), either in solo or in combination regimens with that of NAC against APAP-induced renal injury.

DESIGN AND METHOD: Rats were divided into nine groups; control group, APAP intoxicated group (1000 mg/kg; orally), and the remaining seven groups received, in addition to APAP, oral doses of NAC, TQ, CR, α-LA, CR plus TQ, TQ plus α-LA, or CR plus α-LA. The first dose of the aforementioned antioxidants was given 24 h before APAP, and then the second dose was given 2 h after APAP, whereas the last dose was given 10 h after administration of APAP.

RESULTS: Treatment with APAP elevated kidney markers like serum uric acid, urea, and creatinine. In addition, it increased the serum level of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β) and thiobarbituric acid reactive species (TBARS). Also, the protein expression of renal janus kinase (JAK) and cyclooxygenase (COX)-2 were all upregulated by APAP. In contrast, the expression of Nrf2 and the renal levels of superoxide dismutase and glutathione were downregulated. Treatment with the indicated natural antioxidants resulted in amelioration of the aberrated parameters through exhibiting anti-inflammatory, antioxidant and free radical-scavenging effects with a variable degree.

CONCLUSION: The combined administration of CR and TQ exerted the most potent protection against APAP-induced nephrotoxicity through its anti-inflammatory and free radical-scavenging effects (antioxidant) which were comparable to that of NAC-treatment.}, } @article {pmid37670970, year = {2023}, author = {Zhang, Z and Luan, Q and Hao, W and Cui, Y and Li, Y and Li, X}, title = {NOX4-derived ROS Regulates Aerobic Glycolysis of Breast Cancer through YAP Pathway.}, journal = {Journal of Cancer}, volume = {14}, number = {13}, pages = {2562-2573}, pmid = {37670970}, issn = {1837-9664}, abstract = {Background: NOX4 is highly expressed in breast cancer and is closely associated with cell invasion and metastasis. The involvement of NOX4 in glycolysis in breast cancer remains unclear. The aim of this study was to investigate the role and mechanism of NOX4 in glycolysis in breast cancer. Methods: NOX4 expression in breast cancer cells was detected by qRT-PCR and western blotting. siRNAs and plasmids were used to silence or enhance the expression of NOX4. The mRNA and protein expression of HK2, GLUT1, PKM2, LDHA, and YAP was detected by qRT-PCR and western blotting, and the [18]F-FDG uptake rate was detected by γ-radiometer. Detection of reactive oxygen species (ROS) in cells was performed using a commercial ROS kit. After transfection, CCK8, EDU and Transwell experiments were conducted to detect cell proliferation and migration ability. MicroPET imaging was used to detect the effects of NOX4 on tumor metabolism. Immunohistochemistry was used to detect the expression of NOX4, glycolytic enzymes HK2, GLUT1, PKM2, LDHA, the proliferation index KI67, and the activation of YAP pathway molecule. Results: In this study, the expression of NOX4 in MDA-MB-231 and MDA-MB-453 was higher than in MCF10A. qRT-PCR and western blotting experiments showed that NOX4 downregulation decreased the expression of glycolytic enzymes HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Conversely, the overexpression of NOX4 enhanced the expression of HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Proliferation and migration experiments showed that after down-regulation of NOX4, cell proliferation and migration ability decreased, while NOX4 overexpression promoted cell proliferation and migration ability. Additionally, ROS content and YAP expression decreased after NOX4 down-regulation, while ROS content and YAP expression increased following NOX4 overexpression, which was reversed by N-acetyl cysteine (NAC), a ROS inhibitor. Furthermore, exposure to NAC and Peptide17, a YAP inhibitor, blocked the increase in glycolytic enzyme expression, and the enhancement of proliferation and migration caused by NOX4 overexpression. In addition, in animal experiments, the results of the MicroPET imaging showed that the glucose metabolism rate of the NOX4 inhibitor group was significantly lower than that of the control group. ROS levels in the NOX4 inhibitor group was lower than that in the control group. Immunohistochemistry showed that the expression of HK2, GLUT1, PKM2, LDHA, KI67, and YAP in the NOX4 knock-down group were decreased. Conclusions: NOX4 affects breast cancer glycolysis through ROS-induced activation of the YAP pathway, further promoting the proliferation and migration of breast cancer cells.}, } @article {pmid37670199, year = {2023}, author = {Kaya, S and Yalcın, T and Tektemur, A and Kuloğlu, T}, title = {N-Acetylcysteine may exert hepatoprotective effect by regulating Meteorin-Like levels in Adriamycin-induced liver injury.}, journal = {Cell stress & chaperones}, volume = {28}, number = {6}, pages = {849-859}, pmid = {37670199}, issn = {1466-1268}, support = {TF.21.11//Firat University Scientific Research Projects Management Unit/ ; }, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism/therapeutic use ; Doxorubicin/toxicity ; Caspase 3/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; Liver/metabolism ; Antioxidants/metabolism ; Oxidative Stress ; }, abstract = {Adriamycin (ADR) is an important chemotherapeutic drug, but it has serious side effects such as hepatotoxicity. This study aimed to evaluate whether N-acetylcysteine (NAC) has hepatoprotective effects against ADR-induced hepatotoxicity in rats. In addition, it was aimed to determine how Meteorin-Like (MtrnL), which has pleiotropic effects on immunology, inflammation, and metabolism, is affected by ADR and/or NAC applications in liver tissue. 28 rats were randomly assigned to one of four equal groups in the study: control (no treatment), NAC (150 mg/kg/day of NAC intraperitoneally (i.p), ADR (15 mg/kg only on the first day of the experiment), and ADR + NAC (ADR 15 mg/kg on the first day of the experiment + 150 mg/kg/day NAC i.p). After 15 days, liver enzyme levels in serum, oxidant/antioxidant parameters in liver tissue, histopathological changes, caspase 3 (Casp3) and heat shock protein 70 (HSP-70) immunoreactivities, and MtrnL levels were examined. Histopathological changes, liver enzyme levels, as well as HSP-70, and Casp3 immunoreactivities increased due to ADR application. Additionally, MtrnL levels in liver tissue were significantly increased as a result of ADR application. However, it was detected that the NAC application significantly regulated the ADR-induced changes. Furthermore, it was determined that NAC administration regulated the changes in ADR-induced oxidative stress parameters. We propose that NAC may exert a hepatoprotective effect by regulating ADR-induced altered oxidative stress parameters, MtrnL levels, Casp3, and HSP-70 immunoreactivities in the liver.}, } @article {pmid37666440, year = {2023}, author = {Wang, X and Zhou, P and Zhang, Z and Huang, Q and Chen, X and Ji, L and Cheng, X and Shi, Y and Yu, S and Tang, J and Sun, C and Zhao, X and Yu, J}, title = {A Drosophila model of gestational antimony exposure uncovers growth and developmental disorders caused by disrupting oxidative stress homeostasis.}, journal = {Free radical biology & medicine}, volume = {208}, number = {}, pages = {418-429}, doi = {10.1016/j.freeradbiomed.2023.09.002}, pmid = {37666440}, issn = {1873-4596}, mesh = {Animals ; *Antimony/toxicity ; *Drosophila/metabolism ; Developmental Disabilities ; Oxidative Stress ; Antioxidants/pharmacology/metabolism ; Glutathione/metabolism ; Acetylcysteine/pharmacology/metabolism ; }, abstract = {The toxic heavy metal antimony (Sb) is ubiquitous in our daily lives. Various models have shown that Sb induces neuronal and reproductive toxicity. However, little is known about the developmental toxicity of Sb exposure during gestation and the underlying mechanisms. To study its effects on growth and development, Drosophila stages from eggs to pupae were exposed to different Sb concentrations (0, 0.3, 0.6 and 1.2 mg/mL Sb); RNA sequencing was used to identify the underlying mechanism. The model revealed that prenatal Sb exposure significantly reduced larval body size and weight, the pupation and eclosion rates, and the number of flies at all stages. With 1.2 mg/mL Sb exposure in 3rd instar larvae, 484 genes were upregulated and 694 downregulated compared to controls. Biological analysis showed that the disrupted transcripts were related to the oxidative stress pathway, as verified by reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and glutathione (GSH) intervention experiments. Sb exposure induced oxidative stress imbalance could be rectified by chelation and antioxidant effects of NAC/GSH. The Drosophila Schneider 2 (S2) model further demonstrated that NAC and GSH greatly ameliorated cell death induced by Sb exposure. In conclusion, gestational Sb exposure disrupted oxidative stress homeostasis, thereby impairing growth and development.}, } @article {pmid37662796, year = {2023}, author = {Çavuş, UY and Yılmaz, A and Tascanov, MB and Ocak, M}, title = {Efficacy of combination of N-acetylcysteine and primrose in spinal cord injury; an experimental study.}, journal = {Heliyon}, volume = {9}, number = {9}, pages = {e19350}, pmid = {37662796}, issn = {2405-8440}, abstract = {INTRODUCTION: Spinal cord trauma represents a major cause of emergency department admissions, with high morbidity and mortality rates. It requires early and urgent treatment. This experimental study assessed the effectiveness of a combination of primrose and N-acetylcysteine (NAC) in managing spinal cord injury (SCI).

METHODS: We divided 46 adult male Wistar albino rats (6-8 months old, weighing 300-350 g) into five groups. Group 1 (n = 10) received only primrose; group 2 (n = 10) received only NAC; group 3 (n = 10) received a combination of NAC and primrose; group 4 (n = 10) received no intervention (first control group); group 5 (n = 10) underwent laminectomy only (second control group). Intergroup neurological and motor function were evaluated on days 1, 7, and 14. Oxidative biochemical markers, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), and malondialdehyde (MDA), were measured.

RESULTS: Significant differences were recorded in the GPX, SOD, and MDA values of groups 1, 2, 3, and 4 (p < 0.001, p = 0.005, and p = 0.097, respectively). Groupwise comparisons were conducted to identify the clinical significance of these markers. GPX and SOD levels were significantly higher in group 1 than in group 2; MDA levels were lower in group 1. GPX and SOD levels were significantly higher than in group 3 than in group 1; MDA levels were lower in group 3. Compared with group 5, group 1 demonstrated significantly higher GPX and SOD levels and lower MDA levels. Results in group 2 were similar to results in group 5. In group 3, GPX and SOD levels were significantly higher than in groups 2 and 5; MDA levels were significantly lower. Comparisons according to inclined plane angle level and motor function values revealed significant results on day 14, in favor of group 3 rats that had received the combined treatment.

CONCLUSION: The combined administration of NAC and primrose for traumatic SCI was more effective than either treatment alone in terms of improving biochemical and neurological functions. These findings suggest that the combination of NAC and primrose can serve as an effective treatment option for traumatic SCI.}, } @article {pmid37661403, year = {2023}, author = {Kadota, Y and Yamanokuchi, R and Ohnishi, N and Matsuoka, M and Kawakami, T and Sato, M and Suzuki, S}, title = {Metallothionein Gene Deficiency Facilitates the Differentiation of C2C12 Myoblasts into Slow-Twitch Myotubes.}, journal = {Biological & pharmaceutical bulletin}, volume = {46}, number = {9}, pages = {1240-1248}, doi = {10.1248/bpb.b23-00165}, pmid = {37661403}, issn = {1347-5215}, mesh = {Animals ; Mice ; *Muscle Fibers, Skeletal ; Cell Differentiation ; *Muscle, Skeletal ; Myoblasts ; Muscular Atrophy ; Acetylcysteine ; Antioxidants ; }, abstract = {Metallothionein (MT) 1 and 2 are ubiquitously expressed cysteine-rich, low molecular weight proteins. MT expression is upregulated in skeletal muscle during aging. MTs also play role in multiple types of skeletal muscle atrophy. Meanwhile, it has been reported that MT1 and MT2 gene deficiency increases myogenesis in MT knockout (MTKO) mice. However, little is known about the effect of MTs on muscle formation and atrophy. In this study, we investigated the effect of MT1 and MT2 gene knock-out using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (CRISPR-Cas9) system in an in vitro skeletal muscle differentiation model (C2C12 cell line). MT deficiency promoted myogenic differentiation and myotube formation in C2C12 cells. Muscle-specific transcription factors MyoD and myogenin were found to be upregulated at the late stage of myotube differentiation in MTKO cells. Furthermore, the fast-twitch myosin heavy chain (MyHC) protein expression was similar in MTKO and mock-transfected myotubes, but slow-MyHC expression was higher in MTKO cells than in mock cells. The MT gene deletion did not affect the number of fast MyHC-positive myotubes but increased the number of slow MyHC-positive myotubes. Treatment with the antioxidant N-acetylcysteine (NAC) inhibited the increase in the number of slow MyHC-positive myotubes as well as slow-MyHC expression in MTKO cells. In contrast, NAC treatment did not alter the number of fast MyHC-positive myotubes or the expression of fast-MyHC in MTKO cells. These results suggest that the antioxidant effects of MTs may be involved in slow-twitch myofiber formation in skeletal muscle.}, } @article {pmid37659111, year = {2023}, author = {Fraternale, A and Green, KA and Schiavano, GF and Bruschi, M and Retini, M and Magnani, M and Green, WR}, title = {Inhibition of myeloid-derived suppressor cell (MDSC) activity by redox-modulating agents restores T and B cell proliferative responses in murine AIDS.}, journal = {International immunopharmacology}, volume = {124}, number = {Pt A}, pages = {110882}, doi = {10.1016/j.intimp.2023.110882}, pmid = {37659111}, issn = {1878-1705}, abstract = {The mechanisms by which myeloid-derived suppressor cells (MDSCs) mediate inhibition prominently include the production of reactive nitrogen species, in particular those generated by inducible nitric oxide synthase (iNOS), and reactive oxygen species. LP-BM5 murine retroviral infection results in a profound immunodeficiency, known as murine AIDS, as well as in increased numbers and activity of monocytic-type MDSCs (M-MDSCs) that suppress both T and B cell responses. While M-MDSCs suppress T cells ex vivo in a fully iNOS/NO-dependent manner, M-MDSC suppression of B cell responses is only partially due to iNOS/NO. This study preliminarily explored the role of two redox-modulating compounds in inhibiting the M-MDSC suppressive activity in LP-BM5 infection. The tested molecules were: I-152 consisting in a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-cysteamine (SMEA) and C4-GSH that is the n-butanoyl glutathione (GSH) derivative. The results show that both molecules, tested in a concentration range between 3 and 20 mM, blocked the M-MDSC suppression of activated B and T cells ex vivo and restored their proliferative capacity in vivo. Ex vivo I-152 blockade of M-MDSC suppressiveness was more significant for T cell (about 70%) while M-MDSC blockade by C4-GSH was preferential for B cell responsiveness (about 60%), which was also confirmed by in vivo investigation. Beyond insights into redox-dependent suppressive effector mechanism(s) of M-MDSCs in LP-BM5 infection, these findings may ultimately be important to identify new immunotherapeutics against infectious diseases.}, } @article {pmid37654348, year = {2023}, author = {Veeraiyan, M and Kumar, YP and Chandhar, CY and Priyanka, Y and Jaiswal, M and Kemasaram, D}, title = {Evaluation of Smear Layer Removal and Micro Hardness Alteration of Radicular Dentin after Using Various Chelating Agents - An Atomic Force Microscopic Study.}, journal = {Journal of pharmacy & bioallied sciences}, volume = {15}, number = {Suppl 1}, pages = {S582-S587}, pmid = {37654348}, issn = {0976-4879}, abstract = {BACKGROUND AND AIMS: For endodontic therapy to be successful, the smear layer produced by the root canal instruments must be removed. The study's objective is to evaluate the effectiveness of radicular dentin microhardness modification and smear layer removal utilizing various chelating agents.

MATERIALS AND METHODS: Extracted human mandibular single-rooted premolar teeth were selected for the study. The specimens were sectioned to obtain a standard root length and, working length determination was done. Cleaning and shaping were done in all the samples till the size F3 (Protaper universal). Based on the chelating agents using samples were randomly divided into four groups, Group-I: Saline (negative control), Group-II: 17% EDTA (DeSmear, Ahmedabad, Gujarat) (positive control), Group-III: 0.2% Chitosan (Everest-Biotech, Bengaluru), Group-IV: 20% N-Acetyl cysteine (NAC) (Sisco Research Laboratories, Mumbai), Group-V: 5% Pentetic acid (New Alliance Fine chem Pvt Ltd, Mumbai). All the samples were prepared for smear layer removal and surface roughness evaluation using an atomic force microscope.

RESULTS: It was observed that significantly (P = 0.000) the mean roughness average was higher among group II EDTA (148 ± 8.5) followed by group III 0.2% Chitosan (92.5 ± 3.42), group IV 20% NAC (85.2 ± 2.17), and group V 5% Pentetic acid (73.3 ± 3.39) and least by group I Saline (59.3 ± 3.31). The highest smear layer removal was seen with group II (EDTA) followed by group III (0.2% Chitosan), group IV (20% NAC), and group V (Pentetic acid).

CONCLUSION: All the chelating agents removed smear layer in coronal third, middle third whereas none of them were able to entirely eliminate from the apical third. Chitosan with smear layer removal capacity equal to EDTA with limited roughness can be considered as a valid alternative as final irrigant.}, } @article {pmid37654090, year = {2024}, author = {Frediani, JK and Lal, AA and Kim, E and Leslie, SL and Boorman, DW and Singh, V}, title = {The role of diet and non-pharmacologic supplements in the treatment of chronic neuropathic pain: A systematic review.}, journal = {Pain practice : the official journal of World Institute of Pain}, volume = {24}, number = {1}, pages = {186-210}, doi = {10.1111/papr.13291}, pmid = {37654090}, issn = {1533-2500}, mesh = {Humans ; Adult ; Acetylcarnitine/therapeutic use ; Magnesium/therapeutic use ; *Thioctic Acid/therapeutic use ; *Carnosine/therapeutic use ; Glutamine/therapeutic use ; Cysteine/therapeutic use ; Prospective Studies ; Dietary Supplements ; Vitamins/therapeutic use ; *Neuralgia/drug therapy ; Vitamin E/therapeutic use ; Ascorbic Acid/therapeutic use ; Diet ; Antioxidants/therapeutic use ; Vitamin B 12 ; *Complex Regional Pain Syndromes ; Vitamin D/therapeutic use ; }, abstract = {BACKGROUND/IMPORTANCE: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases.

OBJECTIVE: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults.

EVIDENCE REVIEW: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non-pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence.

FINDINGS: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy-induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS-I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N-acetyl-cysteine (2), acetyl-l-carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha-lipoic acid (1), l-carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha-lipoic acid (5 studies), vitamin B12 (3), acetyl-l-carnitine (3), vitamin E (1), vitamin D (2), and a low-fat plant-based diet (1). Vitamin C was studied to treat CRPS-I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies.

CONCLUSIONS: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N-acetyl-cysteine, l-carnosine, crocin, and magnesium is warranted. Acetyl-l-carnitine was found to be likely ineffective or harmful. Alpha-lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha-lipoic acid, acetyl-l-carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS-I also seems promising. Further research is warranted to confirm these findings.}, } @article {pmid37652392, year = {2023}, author = {Xu, Y and Zhao, Z and Geng, Z and Zhou, H and Yang, C and Wang, Y and Kuerban, B and Xiao, Y and Luo, G}, title = {Enhancement of recombinant human interleukin-22 production by fusing with human serum albumin and supplementing N-acetylcysteine in Pichia Pastoris.}, journal = {Protein expression and purification}, volume = {212}, number = {}, pages = {106360}, doi = {10.1016/j.pep.2023.106360}, pmid = {37652392}, issn = {1096-0279}, mesh = {Saccharomycetales ; *Acetylcysteine/pharmacology ; Humans ; Interleukin-22 ; *Serum Albumin, Human/genetics ; Ascorbic Acid/pharmacology ; }, abstract = {Interleukin-22 (IL-22) plays an important role in the treatment of organ failure, which can induce anti-apoptotic and proliferative signaling pathways; Nevertheless, the practical utilization of IL-22 is hindered by the restricted efficacy of its production. Pichia pastoris presents a viable platform for both industrial and pharmaceutical applications. In this study, we successfully generated a fusion protein consisting of truncated human serum albumin and human IL-22 (HSA-hIL-22) using P. pastoris, and examined the impact of antioxidants on HSA-hIL-22 production. We have achieved the production of HSA-hIL-22 in the culture medium at a yield of approximately 2.25 mg/ml. Moreover, 0-40 mM ascorbic acid supplementation did not significantly affect HSA-hIL-22 production or the growth rate of the recombinant strain. However, 80 mM ascorbic acid treatment had a detrimental effect on the expression of HSA-hIL-22. In addition, 5-10 mM N-acetyl-l-cysteine (NAC) resulted in an increase of HSA-hIL-22 production, accompanied by a reduction in the growth rate of the recombinant strain. Conversely, 20-80 mM NAC supplementation inhibited the growth of the recombinant strains and reduced intact HSA-hIL-22 production. However, neither NAC nor ascorbic acid exhibited any effect on superoxide dismutase (SOD) and malondialdehyde (MDA) levels, except that NAC increased GSH content. Furthermore, our findings indicate that recombinant HSA-hIL-22, which demonstrated the ability to stimulate the proliferation of HepG2 cells, possesses bioactivity. In addition, NAC did not affect HSA-hIL-22 bioactivity. In conclusion, our study demonstrates that NAC supplementation can enhance the secretion of functional HSA-hIL-22 proteins produced in P. pastoris without compromising their activity.}, } @article {pmid37647428, year = {2023}, author = {Sun, X and Sun, Y and Cao, S and Liu, X}, title = {Effects of N-acetyl-L-cysteine polysulfides on periodontitis in a mouse model.}, journal = {Immunity, inflammation and disease}, volume = {11}, number = {8}, pages = {e959}, pmid = {37647428}, issn = {2050-4527}, mesh = {Animals ; Mice ; *Acetylcysteine/pharmacology ; Lipopolysaccharides/toxicity ; Toll-Like Receptor 4/genetics ; *Periodontitis/drug therapy ; Tumor Necrosis Factor-alpha ; Disease Models, Animal ; }, abstract = {BACKGROUND: Polysulfides are reported to be involved in various important biological processes. N-acetyl-l-cysteine polysulfide with 2 sulfane sulfur atoms (NAC-S2) regulates diverse toll-like receptor (TLR) signaling pathways. Here, we aimed to determine the role of NAC-S2 in periodontitis and explore the potential mechanism.

METHODS: A periodontitis mouse model was established by ligating the subgingival between the first and second molars in wild-type, TLR4[-/-] , and Myd88[-/-] mice.

RESULTS: NAC-S2 did not affect the proportion of macrophages (CD11b[+] F4/80[+]) or neutrophils (CD11b[+] GR-1[+]) in the bone marrow. Mechanically, lipopolysaccharides (LPS), Zymosan A, or poly I: C induced tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β expression in bone marrow-derived macrophages (BMDMs) could be inhibited by NAC-S2. On the other hand, NAC-S2 suppressed the phosphorylation levels of IκB-α, p65, and IκB kinase (IKK)-β induced by LPS in BMDMs, while LPS induced phosphorylation of ERK1/2, p38, and transforming growth factor β-activated kinase 1 (TAK1) could not be affected by NAC-S2. In wild-type periodontitis mice, NAC-S2 administration decreased the cemento-enamel-junction-alveolar bone crest (CEJ-ABC) distance and the relative mRNA expression of TNF, IL-6, and IL-1β, while such phenomena could not be observed in TLR4 deficiency or Myd88 deficiency mice.

CONCLUSIONS: All of these results indicate that NAC-S2 ameliorates TLR4/NF-κB pathway mediated inflammation in mouse periodontitis model.}, } @article {pmid37645523, year = {2023}, author = {Mi, K and Wu, S and Lv, C and Meng, Y and Yin, W and Li, H and Li, J and Yuan, H}, title = {Comparing the efficacy and safety of medications in adults with hypertrophic cardiomyopathy: a systematic review and network meta-analysis.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1190181}, pmid = {37645523}, issn = {2297-055X}, abstract = {BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. The purpose of this study was to evaluate the efficacy and safety of several medications and recommend better drug treatments for adults with HCM.

METHODS: A review of PubMed, Embase, the Cochrane Controlled Register of Trials (CENTRAL), ClinicalTrials.gov and CNKI databases was conducted for studies on the efficacy and safety of drugs for adults with HCM. A frequentist random effects model was used in this network analysis.

RESULTS: This network meta-analysis included 7 studies assessing seven medications, 6 studies evaluating monotherapy and 1 study evaluating combination therapy. Based on the network meta-analysis results, xiaoxinbi formula plus metoprolol (MD -56.50% [-72.43%, -40.57%]), metoprolol (MD -47.00% [-59.07%, -34.93%]) and mavacamten (MD -34.50% [-44.75%, -24.25%]) significantly reduced the resting left ventricular outflow tract gradient (LVOTG) in comparison with placebo. Resting LVOTG could also be reduced with N-acetylcysteine (NAC). The incidence of adverse drug reactions was not significantly different between the placebo group and the treatment group.

CONCLUSION: For adults with HCM, the top 4 treatments included xiaoxinbi formula plus metoprolol, metoprolol, mavacamten and NAC.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=374222], identifier [CRD42022374222].}, } @article {pmid37635852, year = {2023}, author = {Ng, WW and Tong, HF and Ng, WY and Yeung, JK and Young, JK and Woo, RK and Wong, MM}, title = {Pyroglutamic Acidosis - An Underrecognised Entity Associated with Acetaminophen Use.}, journal = {Romanian journal of anaesthesia and intensive care}, volume = {30}, number = {1}, pages = {26-30}, pmid = {37635852}, issn = {2392-7518}, abstract = {Pyroglutamic acidosis (PGA) is an underrecognized entity characterised by raised anion gap metabolic acidosis (RAGMA) and urinary hyper-excretion of pyroglutamic acid. It is frequently associated with chronic acetaminophen (APAP) ingestion. We report the case of a 73-year-old man with invasive pulmonary aspergillosis treated with voriconazole and APAP for analgesia with a cumulative dose of 160 g over 40 days. PGA was suspected as he developed severe RAGMA and common causes were excluded. Diagnosis was confirmed via urinary organic acid analysis which showed significant hyper-excretion of pyroglutamic acid. APAP was discontinued, and N-acetylcysteine (NAC) was administered. His RAGMA rapidly resolved following treatment.}, } @article {pmid37634582, year = {2023}, author = {Feng, C and Bai, H and Chang, X and Wu, Z and Dong, W and Ma, Q and Yang, J}, title = {Aflatoxin B1-induced early developmental hepatotoxicity in larvae zebrafish.}, journal = {Chemosphere}, volume = {340}, number = {}, pages = {139940}, doi = {10.1016/j.chemosphere.2023.139940}, pmid = {37634582}, issn = {1879-1298}, mesh = {Animals ; Aflatoxin B1/toxicity ; Zebrafish/genetics ; *Fatty Liver ; Acetylcysteine ; Larva/genetics ; *Chemical and Drug Induced Liver Injury ; }, abstract = {Aflatoxin B1 (AFB1) is a ubiquitous mycotoxin that causes oxidative damage in various organs. At present, the research studies on AFB1 are primarily focused on its effects on the terrestrial environment and animals. However, its toxicity mechanism in aquatic environments and aquatic animals has not been largely explored. Thus, in this study, zebrafish was used as a model to study the toxicity mechanism of AFB1 on the liver of developing larvae. The results showed that AFB1 exposure inhibited liver development and promoted fat accumulation in the liver. Transcriptome sequencing analysis showed that AFB1 affected liver redox metabolism and oxidoreductase activity. KEGG analysis showed that AFB1 inhibited the expression of gsto1, gpx4a, mgst3a, and idh1 in the glutathione metabolizing enzyme gene pathway, resulting in hepatic oxidative stress. At the same time, AFB1 also inhibited the expression of acox1, acsl1b, pparα, fabp2, and cpt1 genes in peroxidase and PPAR metabolic pathways, inducing hepatic steatosis and lipid droplet accumulation. Antioxidant N-Acetyl-l-cysteine (NAC) preconditioning up-regulated gsto1, gpx4a and idh1 genes, and improved the AFB1-induced lipid droplet accumulation in the liver. In summary, AFB1 induced hepatic oxidative stress and steatosis, resulting in abnormal liver fat metabolism and accumulation of cellular lipid droplets. NAC could be used as a potential preventative drug to improve AFB1-induced fat accumulation.}, } @article {pmid37632646, year = {2023}, author = {Chen, HY and Chen, RLC and Hsieh, BC and Cheng, TJ}, title = {Determination of o-phthalaldehyde for dose verification of the clinical disinfectant by fluorescent sequential injection analysis.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {39}, number = {12}, pages = {2007-2017}, pmid = {37632646}, issn = {1348-2246}, support = {MOST-105-2313-B-002-022//Ministry of Science and Technology of Taiwan/ ; MOST-107-2313-B-002-015//Ministry of Science and Technology of Taiwan/ ; }, mesh = {*o-Phthalaldehyde/analysis ; *Disinfectants ; Reproducibility of Results ; Glutaral ; Coloring Agents ; }, abstract = {A new automated, generic analytical approach for determining the clinical disinfectant o-phthalaldehyde (OPA) is reported in this study. The proposed sequential injection analysis (SIA) is based on the online reaction of the OPA with glycine/N-acetylcysteine (NAC) in a neutral medium (pH = 7.0) to form a highly fluorescent isoindole derivative. All critical flow and reaction variables were investigated, while validation was carried out in the linearity detection range (0.0075-0.02%). As a result, excellent linearity (R[2] > 0.99) and precision (1.5-2.4% for repeatability and 0.7-2.2% for reproducibility) were achieved for the reference OPA solutions. Furthermore, reasonable concentration verification of OPA disinfection (0.2-0.6%) in healthcare institutes can be achieved using the developed fluorescent SIA due to its good sensitivity (0.111 V/%) and precision (1.0-2.3% for intermediate precision) around the minimum effective concentration (MEC) of 0.3% for Cidex-OPA disinfectant.}, } @article {pmid37631065, year = {2023}, author = {Blagov, AV and Orekhova, VA and Sukhorukov, VN and Melnichenko, AA and Orekhov, AN}, title = {Potential Use of Antioxidant Compounds for the Treatment of Inflammatory Bowel Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, pmid = {37631065}, issn = {1424-8247}, support = {23-65-10014//Russian Science Foundation/ ; }, abstract = {Since inflammatory bowel diseases (IBDs) are chronic, the development of new effective therapeutics to combat them does not lose relevance. Oxidative stress is one of the main pathological processes that determines the progression of IBD. In this regard, antioxidant therapy seems to be a promising approach. The role of oxidative stress in the development and progression of IBD is considered in detail in this review. The main cause of oxidative stress in IBD is an inadequate response of leukocytes to dysbiosis and food components in the intestine. Passage of immune cells through the intestinal barrier leads to increased ROS concentration and the pathological consequences of exposure to oxidative stress based on the development of inflammation and impaired intestinal permeability. To combat oxidative stress in IBD, several promising natural (curcumin, resveratrol, quercetin, and melatonin) and artificial antioxidants (N-acetylcysteine (NAC) and artificial superoxide dismutase (aSOD)) that had been shown to be effective in a number of clinical trials have been proposed. Their mechanisms of action on pathological events in IBD and clinical manifestations from their impact have been determined. The prospects for the use of other antioxidants that have not yet been tested in the treatment of IBD, but have the properties of potential therapeutic candidates, have been also considered.}, } @article {pmid37628913, year = {2023}, author = {Alkandari, AF and Madhyastha, S and Rao, MS}, title = {N-Acetylcysteine Amide against Aβ-Induced Alzheimer's-like Pathology in Rats.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37628913}, issn = {1422-0067}, support = {YM07/19//Kuwait University/ ; }, mesh = {Male ; Rats ; Animals ; Acetylcysteine/pharmacology ; Rats, Wistar ; *Alzheimer Disease/chemically induced/drug therapy ; Synaptophysin ; *Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides ; Gliosis/chemically induced/drug therapy ; Glutathione ; }, abstract = {Oxidative stress with a depletion of glutathione is a key factor in the initiation and progression of Alzheimer's disease (AD). N-Acetylcysteine (NAC), a glutathione precursor, provides neuroprotective effects in AD animal models. Its amide form, N-Acetylcysteine amide (NACA), has an extended bioavailability compared to NAC. This study evaluates the neuroprotective effects of NACA against Aβ1-42 peptide-induced AD-like pathology in rats. Male Wistar rats (2.5 months old) were divided into five groups: Normal Control (NC), Sham (SH), Aβ, Aβ + NACA and NACA + Aβ + NACA (n = 8 in all groups). AD-like pathology was induced by the intracerebroventricular infusion of Aβ1-42 peptide into the lateral ventricle. NACA (75 mg/kg) was administered either as a restorative (i.e., injection of NACA for 7 consecutive days after inducing AD-like pathology (Aβ + N group)), or as prophylactic (for 7 days before and 7 days after inducing the pathology (N + Aβ + N group)). Learning and memory, neurogenesis, expression of AD pathology markers, antioxidant parameters, neuroprotection, astrogliosis and microgliosis were studied in the hippocampus and the prefrontal cortex. All data were analyzed with a one-way ANOVA test followed by Bonferroni's multiple comparison test. NACA treatment reversed the cognitive deficits and reduced oxidative stress in the hippocampus and prefrontal cortex. Western blot analysis for Tau, Synaptophysin and Aβ, as well as a histopathological evaluation through immunostaining for neurogenesis, the expression of neurofibrillary tangles, β-amyloid peptide, synaptophysin, neuronal morphology and gliosis, showed a neuroprotective effect of NACA. In conclusion, this study demonstrates the neuroprotective effects of NACA against β-amyloid induced AD-like pathology.}, } @article {pmid37628819, year = {2023}, author = {Heiserman, JP and Minhas, Z and Nikpayam, E and Cheon, DJ}, title = {Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37628819}, issn = {1422-0067}, support = {1/CX/CSRD VA/United States ; }, mesh = {Humans ; Female ; *Cisplatin/pharmacology ; HSP27 Heat-Shock Proteins/genetics ; Reactive Oxygen Species ; Neoplasm Recurrence, Local ; *Ovarian Neoplasms/drug therapy ; Cell Line ; Fatty Acids ; }, abstract = {Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin's cytotoxic effect.}, } @article {pmid37628771, year = {2023}, author = {Staskiewicz, A and Wong, E and Tucker, M and Farhin, R and Park, J and Saade, R and Alkhazali, T and Dang, T and Wang, X}, title = {Cytotoxic and Apoptotic Effects of Pinostilbene and Bortezomib Combination Treatment on Human Multiple Myeloma Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37628771}, issn = {1422-0067}, mesh = {Humans ; Bortezomib/pharmacology ; Caspase 3 ; *Multiple Myeloma/drug therapy ; Antioxidants ; *Antineoplastic Agents ; Resveratrol/pharmacology ; Tumor Microenvironment ; }, abstract = {Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow characterized by bone lesions, hypercalcemia, anemia, and renal failure. Bortezomib (BTZ), a common treatment for MM, is a proteasome inhibitor that induces apoptosis in MM cells. However, high doses of BTZ can be very toxic, signifying a need for a synergistic drug combination to improve treatment efficacy. Resveratrol (RES), a phenolic compound found in grapes, has been shown to inhibit MM cell growth. We sought to identify a synergistic combination of BTZ with a RES derivative and analyze the effects on reducing viability and inducing apoptosis in human MM cells. BTZ as well as RES and its derivatives pinostilbene (PIN) and piceatannol (PIC) decreased MM cell viability in a dose- and time-dependent manner and increased expression of cleaved proapoptotic proteins poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3 in a dose-dependent manner. The combination of 5 nM BTZ and 5 μM PIN was identified to have synergistic cytotoxic effects in MM RPMI 8226 cells. MM RPMI 8226 cells treated with this combination for 24 h showed increased cleaved PARP1 and caspase-3 expression and higher percentages of apoptotic cells versus cells treated with the individual compounds alone. The treatment also showed increased apoptosis induction in MM RPMI 8226 cells co-cultured with human bone marrow stromal HS-5 cells in a Transwell model used to mimic the bone marrow microenvironment. Expression of oxidative stress defense proteins (catalase, thioredoxin, and superoxide dismutase) in RPMI 8226 cells were reduced after 24 h treatment, and cytotoxic effects of the treatment were ameliorated by antioxidant N-acetylcysteine (NAC), suggesting the treatment impacts antioxidant levels in RPMI 8226 cells. Our results suggest that this combination of BTZ and PIN decreases MM cell viability synergistically by inducing apoptosis and oxidative stress in MM cells.}, } @article {pmid37627587, year = {2023}, author = {Cuevas-López, B and Romero-Ramirez, EI and García-Arroyo, FE and Tapia, E and León-Contreras, JC and Silva-Palacios, A and Roldán, FJ and Campos, ONM and Hernandez-Esquivel, L and Marín-Hernández, A and Gonzaga-Sánchez, JG and Hernández-Pando, R and Pedraza-Chaverri, J and Sánchez-Lozada, LG and Aparicio-Trejo, OE}, title = {NAC Pre-Administration Prevents Cardiac Mitochondrial Bioenergetics, Dynamics, Biogenesis, and Redox Alteration in Folic Acid-AKI-Induced Cardio-Renal Syndrome Type 3.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {8}, pages = {}, pmid = {37627587}, issn = {2076-3921}, support = {21-1252//Instituto Nacional de Cardiología/ ; }, abstract = {The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a central axis in CRS physiopathology. This study aimed to elucidate the molecular mechanisms associated with cardiac mitochondrial impairment and its role in CRS development in the folic acid-induced AKI (FA-AKI) model. Our results showed that 48 h after FA-AKI, the administration of N-acetyl-cysteine (NAC), a mitochondrial glutathione regulator, prevented the early increase in inflammatory and cell death markers and oxidative stress in the heart. This was associated with the ability of NAC to protect heart mitochondrial bioenergetics, principally oxidative phosphorylation (OXPHOS) and membrane potential, through complex I activity and the preservation of glutathione balance, thus preventing mitochondrial dynamics shifting to fission and the decreases in mitochondrial biogenesis and mass. Our data show, for the first time, that mitochondrial bioenergetics impairment plays a critical role in the mechanism that leads to heart damage. Furthermore, NAC heart mitochondrial preservation during an AKI event can be a valuable strategy to prevent CRS type 3 development.}, } @article {pmid37625774, year = {2023}, author = {Jhuo, JY and Tong, ZJ and Ku, PH and Cheng, HW and Wang, HT}, title = {Acrolein induces mitochondrial dysfunction and insulin resistance in muscle and adipose tissues in vitro and in vivo.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {336}, number = {}, pages = {122380}, doi = {10.1016/j.envpol.2023.122380}, pmid = {37625774}, issn = {1873-6424}, abstract = {Type 2 diabetes mellitus (DM) is a common chronic condition characterized by persistent hyperglycemia and is associated with insulin resistance (IR) in critical glucose-consuming tissues, including skeletal muscle and adipose tissue. Oxidative stress and mitochondrial dysfunction are known to play key roles in IR. Acrolein is a reactive aldehyde found in the diet and environment that is generated as a fatty acid product through the glucose autooxidation process under hyperglycemic conditions. Our previous studies have shown that acrolein impairs insulin sensitivity in normal and diabetic mice, and this effect can be reversed by scavenging acrolein. This study demonstrated that acrolein increased oxidative stress and inhibited mitochondrial respiration in differentiated C2C12 myotubes and differentiated 3T3-L1 adipocytes. As a result, insulin signaling pathways were inhibited, leading to reduced glucose uptake. Treatment with acrolein scavengers, N-acetylcysteine, or carnosine ameliorated mitochondrial dysfunction and inhibited insulin signaling. Additionally, an increase in acrolein expression correlated with mitochondrial dysfunction in the muscle and adipose tissues of diabetic mice. These findings suggest that acrolein-induced mitochondrial dysfunction contributes to IR, and scavenging acrolein is a potential therapeutic approach for treating IR.}, } @article {pmid37625683, year = {2023}, author = {Zhao, S and Li, Y and Li, G and Ye, J and Wang, R and Zhang, X and Li, F and Gao, C and Li, J and Jiang, J and Mi, Y}, title = {PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer.}, journal = {European journal of pharmacology}, volume = {957}, number = {}, pages = {176004}, doi = {10.1016/j.ejphar.2023.176004}, pmid = {37625683}, issn = {1879-0712}, mesh = {Humans ; Animals ; Mice ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Phosphatidylinositol 3-Kinases ; Reactive Oxygen Species ; *Lung Neoplasms/drug therapy ; TOR Serine-Threonine Kinases ; Polo-Like Kinase 1 ; }, abstract = {Small molecule drugs are of significant importance in the treatment of non-small cell lung cancer (NSCLC). Here, we explored biological effects of the PI3K/mTOR inhibitor VS-5584 on NSCLC. Our findings indicated that VS-5584 administration resulted in a dose-dependent inhibition of NSCLC cell proliferation, as well as the induction of apoptosis and cycle arrest. Additionally, we observed a significant increase in intracellular reactive oxygen species (ROS) levels following VS-5584 treatment. The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells. Treatment with VS-5584 led to an upregulation of genes associated with apoptosis and cell cycle, such as c-caspase 3 and P21. Conversely, a downregulation of cyclin-dependent kinase 1 (CDK1) expression was observed. Next, transcriptome analyses revealed that VS-5584 treatment altered the abundance of 1520 genes/transcripts in PC-9 cells, one of which was polo-like kinase 1 (PLK1). These differentially expressed genes were primarily enriched in biological processes such as cell cycle regulation and cell apoptosis, which are closely linked to the P53 and apoptosis pathways. Co-treatment with VS-5584 and PLK1 inhibitor NMS-P937 resulted in enhanced cancer cell death, exhibiting synergistic inhibitory activity. Notably, VS-5584 inhibited the growth of NSCLC in a patient-derived xenograft (PDX) mouse model without observable abnormalities in major organs. Overall, VS-5584 effectively suppressed the growth of NSCLC cells both in vitro and in vivo. VS-5584 combined with NMS-P937 exhibited a synergistic effect in inhibiting NSCLC cell growth. These findings suggest that VS-5584 has potential as a therapeutic strategy for treating NSCLC.}, } @article {pmid37621062, year = {2023}, author = {Chen, H and Zhou, H and Luo, C and Zong, K and Fu, Y and Li, W and Luo, C and Xue, G and Jiang, E and Duan, Y and Luo, T and Jiang, Y}, title = {Efficacy of treatment with N-acetylcysteine inhalation for AECOPD: A propensity-score-matched cohort study.}, journal = {The clinical respiratory journal}, volume = {17}, number = {10}, pages = {1038-1047}, pmid = {37621062}, issn = {1752-699X}, support = {2021-55//Social Undertakings and Livelihood Security Special Projects, the Science and Technology Bureau of Banan District, Chongqing/ ; }, mesh = {Humans ; *Acetylcysteine/adverse effects ; Cohort Studies ; Retrospective Studies ; Propensity Score ; *Pulmonary Disease, Chronic Obstructive ; Disease Progression ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, the value of NAC inhalation in the treatment of patients with AECOPD is still poorly understood. The study was conducted to evaluate the efficacy of NAC inhalation in AECOPD patients requiring hospitalization.

METHODS: In this single institutional, retrospective cohort study, all patients with AECOPD requiring hospitalization between January 2021 and January 2022 were included. Patients were divided into NAC group and Non-NAC group according to whether being treated with NAC inhalation and were matched using the propensity score. The primary outcome was a composite of progression to ventilation requirement, in-hospital mortality and readmission for AECOPD within 30 days. The effect on the mean hospitalized days, blood gas indexes and the incidence rate of adverse drug events were compared between the two groups.

RESULTS: Ninety-six patients in the NAC group were matched with 96 patients in the Non-NAC group. The differences in the primary composite end point (NAC group vs Non-NAC group, 5.2% vs 16.7%; P = 0.011) were significant. The median time to discharge was shorter in the NAC group (8.3 vs. 9.1 days, P = 0.030). The NAC group presented a larger increase in partial pressure of arterial oxygen (Pa O2) and a higher ratio of self-reported symptomatic improvement from admission to day 5. There was no definite difference between the two groups in the frequency of adverse event.

CONCLUSION: NAC inhalation is associated with an improved clinical outcome. A further study should be conducted to confirm the clinical usefulness of NAC inhalation in AECOPD patients.}, } @article {pmid37611476, year = {2023}, author = {Sun, S and Zhang, C and Zhang, Q and Li, C and Huang, D and Ding, R and Cao, J and Hao, J}, title = {Role of ROS-mediated PERK/ATF4 signaling activation in extracorporeal tube formation injury of human umbilical vein endothelial cells induced by cooking oil fume PM2.5 exposure.}, journal = {Ecotoxicology and environmental safety}, volume = {263}, number = {}, pages = {115332}, doi = {10.1016/j.ecoenv.2023.115332}, pmid = {37611476}, issn = {1090-2414}, mesh = {Humans ; Human Umbilical Vein Endothelial Cells ; Reactive Oxygen Species ; *Acetylcysteine/pharmacology ; *Cooking ; Gases ; Particulate Matter/toxicity ; Activating Transcription Factor 4/genetics ; }, abstract = {Cooking oil fume-derived PM2.5 (COF-PM2.5) is a major source of indoor air contamination in China, which has been demonstrated to be a hazard factor of cardiovascular and cerebrovascular diseases. This study aimed to investigate the role of ROS-mediated PERK/ATF4 signaling activation in COF-PM2.5-inhibited extracorporeal tube formation in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with 100 μg/mL COF-PM2.5 at different times, with or without 100 nM PERK activity inhibitor GSK2606414 (GSK) or 200 μM antioxidant N-acetylcysteine (NAC) pretreatment. Our results showed that COF-PM2.5 exposure can inhibit extracorporeal tube formation and down-regulate VEGFR2 expression in HUVECs. Furthermore, our data indicated that COF-PM2.5 exposure can activate the PERK/ATF4 signaling in HUVECs. Mechanistically, pretreatment with GSK interdicted PERK/ATF4 signaling, thereby reversing COF-PM2.5-downregulated VEGFR2 protein expression in HUVECs. Furthermore, NAC reversed VEGFR2 expression downregulated induced by COF-PM2.5 by inhibiting the upregulation of intracellular ROS levels and PERK/ATF4 signaling in HUVECs. As above, COF-PM2.5 exposure could induce ROS release from HUVECs, which in turn activate the endoplasmic reticulum PERK/ATF4 signaling and inhibit tube formation of HUVECs.}, } @article {pmid37609158, year = {2023}, author = {Gupta, K and Chen, D and Wells, RG}, title = {Microcystin-RR is a biliary toxin selective for neonatal cholangiocytes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37609158}, issn = {2692-8205}, support = {P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 DK119290/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Biliary atresia is a fibrosing cholangiopathy affecting neonates that is thought to be caused by a prenatal environmental insult to the bile duct. Biliatresone, a plant toxin with an α-methylene ketone group, was previously implicated in toxin-induced biliary atresia in Australian livestock, but is found in a limited location and is highly unlikely to be a significant human toxin. We hypothesized that other molecules with α-methylene ketone groups, some with the potential for significant human exposure, might also be biliary toxins.

APPROACH AND RESULTS: We focused on the family of microcystins, cyclic peptide toxins from blue-green algae that have an α-methylene ketone group and are found worldwide, particularly during harmful algal blooms. We found that microcystin-RR, but not 6 other microcystins, caused damage to cell spheroids made using cholangiocytes isolated from 2-3-day-old mice, but not from adult mice. We also found that microcystin-RR caused occlusion of extrahepatic bile duct explants from 2-day-old mice, but not 18-day-old mice. Microcystin-RR caused elevated reactive oxygen species in neonatal cholangiocytes, and treatment with N-acetyl cysteine partially prevented microcystin-RRinduced lumen closure, suggesting a role for redox homeostasis in its mechanism of action.

CONCLUSIONS: This study highlights the potential for environmental toxins to cause neonatal biliary disease and identifies microcystin-RR acting via increased redox stress as a possible neonatal bile duct toxin.}, } @article {pmid37607187, year = {2023}, author = {da Silva, RHS and de Moura, M and de Paula, L and Arantes, KC and da Silva, M and de Amorim, J and Miguel, MP and Martins, DB and de Melo E Silva, D and Melo, MM and Botelho, AFM}, title = {Effects of coenzyme Q10 and N-acetylcysteine on experimental poisoning by paracetamol in Wistar rats.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0290268}, pmid = {37607187}, issn = {1932-6203}, mesh = {Adult ; Humans ; Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Acetaminophen ; Rats, Wistar ; Saline Solution ; }, abstract = {Paracetamol (PAR) is a drug widely used in human and veterinary medicine as an analgesic and antipyretic, often involved in cases of intoxication. The most common clinical signs result from damage to red blood cells and hepatocytes, and this intoxication is considered a model for the induction of acute liver failure. In the present study, the hepatoprotective effects of coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC) against experimental paracetamol (PAR) poisoning were analysed. Thirty-five adult Wistar rats (Rattus novergicus albinus) were randomly assigned to five groups, and thirty-one of these survived the treatments. Negative control group (CON-) received 1mL of 0.9% NaCl orally (PO). Other groups received 1.2g/kg of PAR (PO). Positive control group (CON+) received only PAR. NAC group received 800 mg/kg intraperitoneally (IP) of NAC 1h after the administration of PAR and at 12 h received 1mL of 0.9% NaCl, IP. The fourth group (CoQ10) received 1h and 12 h after intoxication, CoQ10 (10mg/kg IP). And the fifth group (NAC+CoQ10) received NAC (800mg/kg, IP) and CoQ10 (10mg/kg, IP). After 12 hours, the rats were euthanized and necropsied to collect liver and kidney tissues for histopathological evaluation and electronic microscopy. A single dose of PAR caused severe acute hepatitis. NAC couldn't reverse the liver and kidney damages. The group that received CoQ10 and NAC had moderate liver damage, while the group that received only CoQ10 had lower values of liver enzymes and mild liver and kidney damage. Animals that received treatment with CoQ10 or NAC+CoQ10 presented normal hepatocyte mitochondria and nuclei. Although CoQ10 couldn't reverse PAR organ damage, results indicate promising hepatoprotection in Wistar rats.}, } @article {pmid37604367, year = {2023}, author = {Wang, X and Tian, X and Yan, H and Zhu, T and Ren, H and Zhou, Y and Zhao, D and Xu, D and Lian, X and Fang, L and Yu, Y and Liao, X and Liu, Y and Sun, J}, title = {Exposure to salinomycin dysregulates interplay between mitophagy and oxidative response to damage the porcine jejunal cells.}, journal = {The Science of the total environment}, volume = {900}, number = {}, pages = {166441}, doi = {10.1016/j.scitotenv.2023.166441}, pmid = {37604367}, issn = {1879-1026}, mesh = {Animals ; Swine ; *Mitophagy ; Kelch-Like ECH-Associated Protein 1 ; *Ecosystem ; Reactive Oxygen Species ; Chickens ; NF-E2-Related Factor 2 ; Antioxidants ; Oxidative Stress ; Protein Kinases ; }, abstract = {Salinomycin (SAL) has caused widespread pollution as a feed additive and growth promoter in livestock such as pigs, exerting a negative impact on public health. The toxicity mechanism of SAL has been widely studied in chickens, but the underlying mechanisms of SAL-induced toxicity to pigs and the ecosystem remain undefined. In this study, we explored the potential damage of SAL in IPEC-J2 cells to identify the effects of excessive SAL on the interplay between mitophagy and oxidative stress. The results showed that a concentration-dependent response was observed for SAL in altering cellular morphology and inducing cell death in IPEC-J2 cells, including the induction of cell cycle arrest and lactic dehydrogenase (LDH) release. Meanwhile, we found that excessive SAL led to oxidative damage by activating the Nrf2/Keap1/HO-1 pathway, accompanied by reactive oxygen species (ROS) elevation and the reduction of antioxidant enzyme activity. We also found that PINK1/Parkin-dependent mitophagy was activated by SAL exposure, particularly with mitochondrial membrane potential reduction. Interestingly, SAL-induced oxidative damages were prevented after the autophagy inhibitor 3-methyladenine (3-MA) treatment, and mitophagy was alleviated following ROS scavenger (N-acetylcysteine, NAC) treatment. Overall, our findings showed that SAL stimulated oxidative stress and mitophagy in IPEC-J2 cells resulting in cellular injury, and there was a strong connection between SAL-induced oxidative stress and mitophagy. Targeting ROS/PINK1/Parkin-dependent mitophagy and oxidative stress could be a novel protective mechanism in SAL-induced cell damage.}, } @article {pmid37598316, year = {2023}, author = {Etemadi, Y and Akakpo, JY and Ramachandran, A and Jaeschke, H}, title = {Nrf2 as a therapeutic target in acetaminophen hepatotoxicity: A case study with sulforaphane.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {12}, pages = {e23505}, pmid = {37598316}, issn = {1099-0461}, support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; NF-E2-Related Factor 2/metabolism ; Antidotes/pharmacology/therapeutic use/metabolism ; Mice, Inbred C57BL ; Liver/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention & control ; }, abstract = {Acetaminophen (APAP) overdose can cause severe liver injury and acute liver failure. The only clinically approved antidote, N-acetylcysteine (NAC), is highly effective but has a narrow therapeutic window. In the last 2 decades, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates acute phase proteins and antioxidant defense genes, has emerged as a putative new therapeutic target against APAP hepatotoxicity. However, virtually all studies that propose Nrf2 activation as mechanism of protection used prolonged pretreatment, which is not a clinically feasible approach to treat a drug overdose. Therefore, the objective of this study was to assess if therapeutic activation of Nrf2 is a viable approach to treat liver injury after APAP overdose. We used the water-soluble Nrf2 activator sulforaphane (SFN; 5 mg/kg) in a murine model of APAP hepatotoxicity (300 mg/kg). Our results indicate that short-term treatment (≤3 h) with SFN alone did not activate Nrf2 or its target genes. However, posttreatment with SFN after APAP partially protected at 6 h likely due to more rapid activation of the Nrf2-target gene heme oxygenase-1. A direct comparison of SFN with NAC given at 1 h after APAP showed a superior protection with NAC, which was maintained at 24 h unlike with SFN. Thus, Nrf2 activators have inherent problems like the need to create a cellular stress to activate Nrf2 and delayed adaptive responses which may hamper sustained protection against APAP hepatotoxicity. Thus, compared to the more direct acting antidote NAC, Nrf2 activators are less suitable for this indication.}, } @article {pmid37596428, year = {2023}, author = {Clark, RSB and Empey, PE and Kochanek, PM and Bell, MJ}, title = {N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {6}, pages = {1529-1537}, pmid = {37596428}, issn = {1878-7479}, support = {R01 NS069247/NS/NINDS NIH HHS/United States ; }, mesh = {Child ; Humans ; *Probenecid/therapeutic use/pharmacology ; Acetylcysteine/therapeutic use/pharmacology ; Pilot Projects ; *Brain Injuries, Traumatic/drug therapy ; Brain ; Blood-Brain Barrier ; }, abstract = {N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood-brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI-the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.}, } @article {pmid37595880, year = {2023}, author = {Yang, L and Mei, G and Yang, Y and Cui, J and Peng, S and Peng, Z and Cheng, Y}, title = {Hexachlorocyclohexane impairs human sperm motility by affecting lysine glutarylation and mitochondrial functions.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {179}, number = {}, pages = {113991}, doi = {10.1016/j.fct.2023.113991}, pmid = {37595880}, issn = {1873-6351}, mesh = {Humans ; Male ; Acetylcysteine ; *Hexachlorocyclohexane ; *Lysine ; Mitochondria ; Reactive Oxygen Species ; Semen ; Sperm Motility ; Glutarates/chemistry/pharmacology ; }, abstract = {Decreased sperm motility is a leading cause of male infertility and persistent organic pollutants are known to contribute significantly to the development of this disease. The effects of organochlorine pesticides such as hexachlorocyclohexane (HCH) on human sperm function and their mechanisms of action have received much attention, but are still not fully understood. Herein, we discovered that HCH has a concentration- and time-dependent inhibitory effect on human sperm motility in vitro. Moreover, HCH could reduce the levels of lysine glutarylation (Kglu) and glucose-6-phosphate dehydrogenase activity in sperm. Meanwhile, HCH could increase reactive oxygen species and thereby lead to mitochondrial depolarization and the down-regulation of adenosine triphosphate levels. In particular, we observed that sodium glutarate (Na-glu), the precursor of glutaryl-CoA, could alleviate the inhibitory effect of HCH on sperm Kglu levels, whereas the ROS scavenger N-acetyl-L-cysteine (NAC) had no effect. Intriguingly, both Na-glu and NAC were able to partially inhibit the HCH-induced increase in sperm ROS levels and impaired sperm motility. In conclusion, we propose that HCH inhibits sperm Kglu, leading to the disruption of mitochondrial energy metabolism, which in turn adversely affects sperm motility.}, } @article {pmid37595477, year = {2023}, author = {Zhu, X and Song, Y and Wang, X and Zhou, Y and Chai, Y and Yuan, R}, title = {Copper nanoclusters electrochemiluminescence with tunable near-infrared emission wavelength for ultrasensitive detection of matrix metalloproteinase-2.}, journal = {Biosensors & bioelectronics}, volume = {238}, number = {}, pages = {115580}, doi = {10.1016/j.bios.2023.115580}, pmid = {37595477}, issn = {1873-4235}, mesh = {Humans ; *Copper ; Matrix Metalloproteinase 2 ; *Biosensing Techniques ; Methionine ; Racemethionine ; Acetylcysteine ; }, abstract = {Herein, the methionine (Met)/N-acetyl-L-cysteine (NAC) templated copper nanoclusters (Met/NAC-Cu NCs) with tunable near-infrared region (NIR) electrochemiluminescence (ECL) emission wavelength was firstly synthesized as emitter for the ultrasensitive detection of matrix metalloproteinase-2 (MMP-2). Significantly, the NAC played the role of template and reductant of cupric to acquire Cu NCs, and the surface defect regulator Met was used to connect NAC through -S-S- bond, which could heighten the surface defect of Cu NCs to continuously regulate the maximum ECL emission by successively controlling the molar ratio of Met and NAC, leading to the ECL emission wavelength of Cu NCs ranged from 680 nm to 750 nm. In addition, a rapid target triggered catalyst hairpin assembly (CHA) recycling amplification strategy was constructed through orderly and equidistantly arranging hairpin to increase its local concentration, resulting in greatly accelerated signal amplification efficiency and reaction rate. As a proof of concept, based on Met/NAC-Cu NCs as NIR ECL emitter and effective signal amplification tactic, a super-sensitive ECL biosensor was fabricated to detect target MMP-2 with the detection limit (LOD) as low as 1.65 fg/mL and successfully utilized for detecting of MMP-2 that from Hela and MCF-7 cancer cells. This research provided a wonderful avenue for regulating the optical performance of metal nanoclusters-based ECL emitters, and the developed neoteric NIR ECL emitter with the merits of less photochemical damage and deeper tissue penetration exhibited great potential in ultrasensitive biosensing and high-definition ECL imaging.}, } @article {pmid37594415, year = {2023}, author = {Le-Vinh, B and Steinbring, C and Nguyen Le, NM and Matuszczak, B and Bernkop-Schnürch, A}, title = {S-Protected Thiolated Chitosan versus Thiolated Chitosan as Cell Adhesive Biomaterials for Tissue Engineering.}, journal = {ACS applied materials & interfaces}, volume = {15}, number = {34}, pages = {40304-40316}, pmid = {37594415}, issn = {1944-8252}, mesh = {*Chitosan ; Biocompatible Materials/pharmacology ; Tissue Engineering ; Acetylcysteine ; Carbodiimides ; Cryogels ; }, abstract = {Chitosan (Ch) and different Ch derivatives have been applied in tissue engineering (TE) because of their biocompatibility, favored mechanical properties, and cost-effectiveness. Most of them, however, lack cell adhesive properties that are crucial for TE. In this study, we aimed to design an S-protected thiolated Ch derivative exhibiting high cell adhesive properties serving as a scaffold for TE. 3-((2-Acetamido-3-methoxy-3-oxopropyl)dithio) propanoic acid was covalently attached to Ch via a carbodiimide-mediated reaction. Low-, medium-, and high-modified Chs (Ch-SS-1, Ch-SS-2, and Ch-SS-3) with 54, 107 and 140 μmol of ligand per gram of polymer, respectively, were tested. In parallel, three thiolated Chs, namely Ch-SH-1, Ch-SH-2, and Ch-SH-3, were prepared by conjugating N-acetyl cysteine to Ch at the same degree of modification to compare the effectiveness of disulfide versus thiol modification on cell adhesion. Ch-SS-1 showed better cell adhesion capability than Ch-SS-2 and Ch-SS-3. This can be explained by the more lipophilic surfaces of Ch-SS as a higher modification was made. Although Ch-SH-1, Ch-SH-2, and Ch-SH-3 were shown to be good substrates for cell adhesion, growth, and proliferation, Ch-SS polymers were superior to Ch-SH polymers in the formation of 3D cell cultures. Cryogels structured by Ch-SS-1 (SSg) resulted in homogeneous scaffolds with tunable pore size and mechanical properties by changing the mass ratio between Ch-SS-1 and heparin used as a cross-linker. SSg scaffolds possessing interconnected microporous structures showed good cell migration, adhesion, and proliferation. Therefore, Ch-SS can be used to construct tunable cryogel scaffolds that are suitable for 3D cell culture and TE.}, } @article {pmid37591474, year = {2023}, author = {Singh, S and Wairkar, S}, title = {Long-circulating thiolated chitosan nanoparticles of nintedanib with N-acetyl cysteine for treating idiopathic pulmonary fibrosis: In vitro assessment of cytotoxicity, antioxidant, and antifibrotic potential.}, journal = {International journal of pharmaceutics}, volume = {644}, number = {}, pages = {123322}, doi = {10.1016/j.ijpharm.2023.123322}, pmid = {37591474}, issn = {1873-3476}, mesh = {Chitosan/chemistry ; Acetylcysteine/chemistry ; Sulfhydryl Compounds/chemistry ; *Idiopathic Pulmonary Fibrosis/drug therapy ; Antioxidants/chemistry/pharmacology ; Cell Line ; Particle Size ; Humans ; Cell Survival/drug effects ; *Nanoparticles/chemistry ; }, abstract = {Nintedanib (NIN) is one of the FDA-approved tyrosine kinase inhibitor drugs used to treat idiopathic pulmonary fibrosis (IPF). This study aimed to formulate a long-circulating injection of Nintedanib to treat bedridden patients with IPF. Nintedanib was incorporated into chitosan nanoparticles (NIN-NP) via the ionic gelation method, and N-acetyl cysteine (NAC), a known antioxidant and mucolytic agent, was added to the NIN-NP (NAC-NIN-NP). The lyophilized formulation had a particle size of 174 nm, a polydispersity index of 0.511, and a zeta potential of 18.6 mV. The spherical nanoparticles were observed in transmission electron microscopy, whereas field emission scanning electron microscopy showed irregular clusters of NP. The thiolation of the chitosan in NAC-NIN-NP was confirmed by ATR-FTIR and NMR, which improved drug release profiles showing >90 % drug release that was 2.42-folds greater than NIN-NP lasting for five days. The DPPH assay showed that adding NAC increased the % inhibition of oxidation in blank-NP (from 54.59 % to 87.17 %) and NIN-NP (58.65 %-89.19 %). The MTT assay on A549 cells showed 67.57 % cell viability by NAC-NIN-NP with an IC50 value of 28 μg/mL. The NAC formulation reduced hydroxyproline content (56.77 μg/mL) compared to NIN-NP (69.48 μg/mL) in WI-38 cell lines. Meanwhile, the healthy cells count with NAC-NIN-NP was higher (5.104 × 10[3]) than with NIN-NP (4.878 × 10[3]). In Hoechst staining, no significant damage to DNA was observed by the drug or formulation. Therefore, NAC-NIN-NP could be a promising treatment option for IPF patients and can be studied further clinically.}, } @article {pmid37580920, year = {2023}, author = {Niloufar Darbandi, - and Samira Moghadasi, - and Hamid Reza Momeni, - and Matin Ramezani, -}, title = {Comparing the acute and chronic effects of metformin and antioxidant protective effects of N-acetyl cysteine on memory retrieval and oxidative stress in rats with Alzheimer's disease.}, journal = {Pakistan journal of pharmaceutical sciences}, volume = {36}, number = {3}, pages = {731-739}, pmid = {37580920}, issn = {1011-601X}, mesh = {Rats ; Animals ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; *Alzheimer Disease/chemically induced/drug therapy ; *Metformin/pharmacology ; Oxidative Stress ; Streptozocin/pharmacology ; Disease Models, Animal ; Maze Learning ; }, abstract = {It has been suggested that oxidative stress plays an important role in neural degeneration and Alzheimer's disease. Some studies have shown that metformin has some beneficial effects on the brain and reduces oxidative stress, while others reveal that metformin increases oxidative stress in diabetic patients. In this study acute and chronic effects of metformin and antioxidant protective effects of N-acetyl cysteine in Alzheimeric rats were investigated. Animals were divided into seven groups (n=8): Control, STZ, STZ + metformin (one, three and eleven weeks), STZ+ metformin (eleven weeks) +N-acetyl cysteine (eleven weeks) and N-acetyl cysteine (eleven weeks). ICV injections of saline (1μl/rat) or STZ (3mg/kg) and IP injections of Saline (1ml/kg), metformin (200mg/kg) and/or N-acetyl cysteine (100mg/kg) were done. Memory retrieval, CA1 neurons density and serums oxidative stress were investigated. STZ injections reduced memory retention, intact neurons and increased serum oxidative stress compared to the control (p<0/001). Metformin injection for one and three weeks (but not eleven weeks) improved the effects of STZ (p<0/001). Administration of N-acetylcysteine with metformin (eleven weeks) improved STZ bad effects (p<0/001). It seems that acute and chronic consumption of metformin have different effects on memory retrieval, CA1 neurons and serum oxidative stress factors in AD rats.}, } @article {pmid37579929, year = {2023}, author = {Kolomaznik, M and Hanusrichterova, J and Mikolka, P and Kosutova, P and Vatecha, M and Zila, I and Mokra, D and Calkovska, A}, title = {Efficiency of exogenous surfactant combined with intravenous N-acetylcysteine in two-hit rodent model of ARDS.}, journal = {Respiratory physiology & neurobiology}, volume = {316}, number = {}, pages = {104138}, doi = {10.1016/j.resp.2023.104138}, pmid = {37579929}, issn = {1878-1519}, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Lung Injury ; Antioxidants/pharmacology/therapeutic use ; Surface-Active Agents ; Rodentia ; *Hyperoxia ; Rats, Wistar ; Lung ; *Pulmonary Surfactants/pharmacology ; *Respiratory Distress Syndrome ; }, abstract = {Accumulation of reactive oxygen species during hyperoxia together with secondary bacteria-induced inflammation leads to lung damage in ventilated critically ill patients. Antioxidant N-acetylcysteine (NAC) in combination with surfactant may improve lung function. We compared the efficacy of NAC combined with surfactant in the double-hit model of lung injury. Bacterial lipopolysaccharide (LPS) instilled intratracheally and hyperoxia were used to induce lung injury in Wistar rats. Animals were mechanically ventilated and treated intravenously with NAC alone or in combination with intratracheal surfactant (poractant alfa; PSUR+NAC). Control received saline. Lung functions, inflammatory markers, oxidative damage, total white blood cell (WBC) count and lung oedema were evaluated during 4 hrs. Administration of NAC increased total antioxidant capacity (TAC) and decreased IL-6. This effect was potentiated by the combined administration of surfactant and NAC. In addition, PSUR+NAC reduced the levels of TNFα, IL-1ß, and TAC compared to NAC only and improved lung injury score. The combination of exogenous surfactant with NAC suppresses lung inflammation and oxidative stress in the experimental double-hit model of lung injury.}, } @article {pmid37577725, year = {2023}, author = {da Paz Martins, AS and de Andrade, KQ and de Araújo, ORP and da Conceição, GCM and da Silva Gomes, A and Goulart, MOF and Moura, FA}, title = {Extraintestinal Manifestations in Induced Colitis: Controversial Effects of N-Acetylcysteine on Colon, Liver, and Kidney.}, journal = {Oxidative medicine and cellular longevity}, volume = {2023}, number = {}, pages = {8811463}, pmid = {37577725}, issn = {1942-0994}, mesh = {Humans ; Male ; Mice ; Animals ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Interleukin-10/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Hydrogen Peroxide/pharmacology ; Glutathione Disulfide/metabolism ; *Colitis/chemically induced/complications/drug therapy ; Colon ; *Colitis, Ulcerative/chemically induced/drug therapy/pathology ; Antioxidants/pharmacology ; Inflammation/pathology ; Oxidative Stress ; Liver/metabolism ; Glutathione/metabolism ; Superoxide Dismutase/metabolism ; Dextran Sulfate/toxicity ; }, abstract = {Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD) characterized by continuous inflammation in the colonic mucosa. Extraintestinal manifestations (EIM) occur due to the disruption of the intestinal barrier and increased permeability caused by redox imbalance, dysbiosis, and inflammation originating from the intestine and contribute to morbidity and mortality. The aim of this study is to investigate the effects of oral N-acetylcysteine (NAC) on colonic, hepatic, and renal tissues in mice with colitis induced by dextran sulfate sodium (DSS). Male Swiss mice received NAC (150 mg/kg/day) in the drinking water for 30 days before and during (DSS 5% v/v; for 7 days) colitis induction. On the 38[th] day, colon, liver, and kidney were collected and adequately prepared for the analysis of oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione reduced (GSH), glutathione oxidized (GSSG), malondialdehyde (MDA), and hydrogen peroxide (H2O2)) and inflammatory biomarkers (myeloperoxidase (MPO) -, tumor necrosis factor alpha - (TNF-α, and interleukin-10 (IL-10)). In colon, NAC protected the histological architecture. However, NAC did not level up SOD, in contrast, it increased MDA and pro-inflammatory effect (increased of TNF-α and decreased of IL-10). In liver, colitis caused both oxidative (MDA, SOD, and GSH) and inflammatory damage (IL-10). NAC was able only to increase GSH and GSH/GSSG ratio. Kidney was not affected by colitis; however, NAC despite increasing CAT, GSH, and GSH/GSSG ratio promoted lipid peroxidation (increased MDA) and pro-inflammatory action (decreased IL-10). Despite some beneficial antioxidant effects of NAC, the negative outcomes concerning irreversible oxidative and inflammatory damage in the colon, liver, and kidney confirm the nonsafety of the prophylactic use of this antioxidant in models of induced colitis, suggesting that additional studies are needed, and its use in humans not yet recommended for the therapeutic routine of this disease.}, } @article {pmid37575813, year = {2023}, author = {Le, D and Hydro, BA and Jones, CL and Beauchamp, GA}, title = {Weight Loss or Liver Loss: A Case Report on Fulminant Hepatic Failure Secondary to Garcinia cambogia Supplementation.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e41778}, pmid = {37575813}, issn = {2168-8184}, abstract = {This case describes a 56-year-old man with a past medical history including sickle cell trait requiring blood transfusions, who presented to the emergency department (ED) with generalized weakness and fatigue following Garcinia cambogia supplementation. Initial laboratory abnormalities included: aspartate aminotransferase (AST) and alanine transaminase (ALT) 4,222 U/L and 4,664 U/L respectively, alkaline phosphatase 215 U/L, international normalized ratio (INR) 3.2, and his model for end-stage liver disease was 37. Creatinine, hemoglobin and hematocrit, and ferritin levels were all elevated. The differential diagnosis for his acute illness was broad ranging from hemochromatosis, anabolic steroid use, and portal venous thrombosis. The patient was started on N-acetylcysteine (NAC) and his liver function improved. He was discharged on hospital day 10 and instructed to discontinue his supplements and follow up for repeat blood work. This case explores the critical management of G. cambogia toxicity. The patient explored G. cambogia as an herbal supplementation resulting in weight loss, worsening generalized fatigue, and fulminant hepatic failure.}, } @article {pmid37575276, year = {2023}, author = {Tanomrat, R and Naktubtim, C and Aimvijarn, P and Suwannalert, P}, title = {N-acetylcysteine improves the inhibitory effect of Quercetin-rich onion extract on HT-29 and HCT-116 colorectal cancer migration and invasion through iNOS suppression.}, journal = {International journal of medical sciences}, volume = {20}, number = {9}, pages = {1123-1134}, pmid = {37575276}, issn = {1449-1907}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; *Colorectal Neoplasms/drug therapy/genetics/metabolism ; Glutathione/pharmacology ; Intercellular Adhesion Molecule-1 ; Matrix Metalloproteinase 2/genetics ; Onions ; Quercetin/pharmacology/therapeutic use ; }, abstract = {As colorectal cancer (CRC) usually presents at an advanced stage, it responds poorly to traditional surgery and chemoradiotherapy. Reactive oxygen species (ROSs) are a critical factor in cancer progression. Quercetin, a bioflavonoid derived from onion peel extract, provides great anti-oxidant and anti-cancer potential. Therefore, quercetin in combination with N-Acetylcysteine (NAC), a well-known anti-oxidant and adjuvant agent in cancer-chemotherapeutic drugs, was considered as a way of increasing treatment efficacy. Thus, this study aimed to evaluate the improvement effect of quercetin in combination with NAC in human CRC (HT-29 and HCT-116) cell progression, migration and invasion. Firstly, the effects of quercetin, NAC, and the combination of quercetin and NAC on cellular oxidants and glutathione levels were evaluated. Cell viability, anti-migrative activity and invasive activity were determined by MTT, wound healing, and Matrigel invasion tests, respectively. Then, the proteins involved in cell migration, invasion, and cellular oxidants were investigated. Moreover, the gene expression and overall survival were further validated by the GEPIA2 database. The results reveal that the combination was most effective in decreasing cellular oxidants and increasing glutathione levels, while there was a significant decrease in cancer cell migration and invasion involved in the suppression of iNOS, ICAM-1, and MMP-2 proteins. Furthermore, bioinformatic analysis verified that iNOS, ICAM-1, and MMP-2 were highly expressed in CRC tissue and also associated with a poor prognosis. This study demonstrated that Quercetin has higher efficacy when used in combination with NAC, representing a potential combination agent for anti-cancer drug development.}, } @article {pmid37573526, year = {2023}, author = {Rasaeifar, K and Zavareh, S and Hajighasem-Kashani, M and Nasiri, M}, title = {Effects of pulsed electromagnetic fields and N-acetylcysteine on transplantation of vitrified mouse ovarian tissue.}, journal = {Electromagnetic biology and medicine}, volume = {42}, number = {2}, pages = {67-80}, doi = {10.1080/15368378.2023.2246503}, pmid = {37573526}, issn = {1536-8386}, mesh = {Mice ; Female ; Animals ; *Acetylcysteine/pharmacology ; *Tumor Necrosis Factor-alpha/genetics ; Electromagnetic Fields ; Fibroblast Growth Factor 2 ; Interleukin-6 ; Vascular Endothelial Growth Factor A/genetics ; Antioxidants/pharmacology/metabolism ; }, abstract = {In this experimental study, adult female NMRI mice were randomly assigned to five groups: control ;(fresh ovarian transplantation, OT); sham ;(vitrified OT); NAC ;(vitrified OT treated with N-acetyl cysteine, NAC); EMF ;(vitrified OT treated with pulsed electromagnetic fields, PEMF); and NAC+EMF ;(vitrified OT combined with NAC and PEMF). We conducted histological assessments to evaluate follicle reservation and vascularization. Furthermore, we examined the relative expression of Fgf-2, Vegf, Tnf-α, Il-6, Il-1, and Cd31 genes on days 2 and 7 after OT. Additionally, we measured total antioxidant capacity (TAC), malondialdehyde (MDA) levels, as well as the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Our results demonstrated that NAC, PEMF, and NAC+PEMF treatments significantly increased the number of follicles. Moreover, we observed a more pronounced development of vascularization in the NAC, PEMF, and PEMF+NAC groups. The relative expression levels of Fgf-2, Vegf, Tnf-α, Il-1β, and Il-6 were significantly elevated in the NAC, PEMF, and NAC+PEMF groups. Notably, TAC levels decreased significantly in the NAC group compared to the control group. Additionally, the MDA level showed a significant decrease in the PEMF+NAC group when compared to the other groups. Overall, the combination of NAC and PEMF exhibited a synergistic effect in promoting angiogenesis and protecting against oxidative stress and inflammation during OT.}, } @article {pmid37572985, year = {2023}, author = {Kim, D and Oh, E and Kim, H and Baek, SM and Cho, J and Kim, EH and Choi, S and Bian, Y and Kim, W and Bae, ON}, title = {Mono-(2-ethylhexyl)-phthalate potentiates methylglyoxal-induced blood-brain barrier damage via mitochondria-derived oxidative stress and bioenergetic perturbation.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {179}, number = {}, pages = {113985}, doi = {10.1016/j.fct.2023.113985}, pmid = {37572985}, issn = {1873-6351}, mesh = {Rats ; Animals ; *Diethylhexyl Phthalate/toxicity ; Pyruvaldehyde ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; Oxidative Stress ; Energy Metabolism ; Mitochondria/metabolism ; }, abstract = {Phthalates in contaminated foods and personal care products are one of the most frequently exposed chemicals with a public health concern. Phthalate exposure is related to cardiovascular diseases, including diabetic vascular complications and cerebrovascular diseases, yet the mechanism is still unclear. The blood-brain barrier (BBB) integrity disruption is strongly associated with cardiovascular and neurological disease exacerbation. We investigated BBB damage by di-(2-ethylhexyl) phthalate (DEHP) or its metabolite mono-(2-ethylhexyl) phthalate (MEHP) using brain endothelial cells and rat models. BBB damage by the subthreshold level of MEHP, but not a DEHP, significantly increased by the presence of methylglyoxal (MG), a reactive dicarbonyl compound whose levels increase in the blood in hyperglycemic conditions in diabetic patients. Significant potentiation in apoptosis and autophagy activation, mitochondria-derived reactive oxygen species (ROS) production, and mitochondrial metabolic disturbance were observed in brain ECs by co-exposure to MG and MEHP. N-acetyl cysteine (NAC) restored autophagy activation as well as tight junction protein impairment induced by co-exposure to MG and MEHP. Intraperitoneal administration of MG and MEHP significantly altered mitochondrial membrane potential and tight junction integrity in rat brain endothelium. This study may provide novel insights into enhancing phthalate toxicity in susceptible populations, such as diabetic patients.}, } @article {pmid37569897, year = {2023}, author = {Khashab, R and Gutman-Sharabi, N and Shabtai, Z and Landau, R and Halperin, R and Fay-Karmon, T and Leibowitz, A and Sharabi, Y}, title = {Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569897}, issn = {1422-0067}, mesh = {Rats ; Animals ; *Parkinson Disease/drug therapy/etiology/metabolism ; Rotenone/pharmacology ; Dopamine/metabolism ; Selegiline ; Aldehyde Dehydrogenase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology ; Acetylcysteine/pharmacology ; }, abstract = {The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.}, } @article {pmid37569463, year = {2023}, author = {Pieri, BLDS and Rodrigues, MS and Farias, HR and Silveira, GB and Ribeiro, VSGDC and Silveira, PCL and De Souza, CT}, title = {Role of Oxidative Stress on Insulin Resistance in Diet-Induced Obesity Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569463}, issn = {1422-0067}, abstract = {Insulin resistance is the link between obesity and type 2 diabetes mellitus. The molecular mechanism by which obese individuals develop insulin resistance has not yet been fully elucidated; however, inconclusive and contradictory studies have shown that oxidative stress may be involved in the process. Thus, this study aimed to evaluate the effect of reactive species on the mechanism of insulin resistance in diet-induced obese mice. Obese insulin-resistant mice were treated with N-acetylcysteine (NAC; 50 mg/kg per day, for 15 days) by means of oral gavage. Twenty-four hours after the last NAC administration, the animals were euthanized and their tissues were extracted for biochemical and molecular analyses. NAC supplementation induced improved insulin resistance and fasting glycemia, without modifications in food intake, body weight, and adiposity. Obese mice showed increased dichlorofluorescein (DCF) oxidation, reduced catalase (CAT) activity, and reduced glutathione levels (GSH). However, treatment with NAC increased GSH and CAT activity and reduced DCF oxidation. The gastrocnemius muscle of obese mice showed an increase in nuclear factor kappa B (NFκB) and protein tyrosine phosphatase (PTP1B) levels, as well as c-Jun N-terminal kinase (JNK) phosphorylation compared to the control group; however, NAC treatment reversed these changes. Considering the molecules involved in insulin signaling, there was a reduction in insulin receptor substrate (IRS) and protein kinase B (Akt) phosphorylation. However, NAC administration increased IRS and Akt phosphorylation and IRS/PI3k (phosphoinositide 3-kinase) association. The results demonstrated that oxidative stress-associated obesity could be a mechanism involved in insulin resistance, at least in this animal model.}, } @article {pmid37569345, year = {2023}, author = {Kang, M and Kang, JH and Sim, IA and Seong, DY and Han, S and Jang, H and Lee, H and Kang, SW and Kim, SY}, title = {Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569345}, issn = {1422-0067}, support = {NRF- 2019M3A9G1104345//National Research Foundation of Korea/ ; }, mesh = {*Glucose/deficiency ; *Adenosine Triphosphate/metabolism ; Pentose Phosphate Pathway ; *Reactive Oxygen Species/metabolism ; NADP/metabolism ; Glutathione/metabolism ; Acetylcysteine/metabolism/pharmacology ; PC-3 Cells ; Humans ; *Neoplasms/metabolism/pathology ; Cell Death ; }, abstract = {In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We investigated the different response of glucose deprivation with two types of cancer cells including glucose insensitive cancer cells (GIC) which do not change ATP levels, and glucose sensitive cancer cells (GSC) which decrease ATP production in 24 h. Glucose deprivation-induced cell death in GSC by more than twofold after 12 h and by up to tenfold after 24 h accompanied by decreased ATP production to compare to the control (cultured in glucose). Glucose deprivation decreased the levels of metabolic intermediates of the pentose phosphate pathway (PPP) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in both GSC and GIC. However, glucose deprivation increased reactive oxygen species (ROS) only in GSC, suggesting that GIC have a higher tolerance for decreased NADPH than GSC. The twofold higher ratio of reduced/oxidized glutathione (GSH/GSSG) in GIS than in GSC correlates closely with the twofold lower ROS levels under glucose starvation conditions. Treatment with N-acetylcysteine (NAC) as a precursor to the biologic antioxidant glutathione restored ATP production by 70% and reversed cell death caused by glucose deprivation in GSC. The present findings suggest that glucose deprivation-induced cancer cell death is not caused by decreased ATP levels, but rather triggered by a failure of ROS regulation by the antioxidant system. Conclusion is clear that glucose deprivation-induced cell death is independent from ATP depletion-induced cell death.}, } @article {pmid37567958, year = {2023}, author = {Bhattacharya, R and Saini, S and Ghosh, S and Roy, P and Ali, N and Parvez, MK and Al-Dosari, MS and Mishra, AK and Singh, LR}, title = {Organosulfurs, S-allyl cysteine and N-acetyl cysteine sequester di-carbonyls and reduces carbonyl stress in HT22 cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {13071}, pmid = {37567958}, issn = {2045-2322}, mesh = {*Acetylcysteine/pharmacology ; *Cysteine/metabolism ; Glycation End Products, Advanced/metabolism ; Antioxidants/pharmacology ; Maillard Reaction ; }, abstract = {Diabetes, characterized by high blood glucose level, is a progressive metabolic disease that leads to serious health complications. One of the major pathological consequences associated with diabetes is the accumulation of highly reactive carbonyl compounds called advanced glycation end products (AGEs). Most of the AGEs are dicarbonyls and have the potential to covalently modify proteins especially at the lysine residues in a non-enzymatic fashion (a process termed as glycation) resulting in the functional impairment and/or toxic gain in function. Therefore, non-toxic small molecules that can inhibit glycation are of interest for the therapeutic intervention of diabetes. In the present communication, we have investigated the effect of organosulfurs (S-allyl cysteine, SAC and N-acetyl cysteine, NAC) that are major principal components of Allium sativa against the glycation of different proteins. We discovered that both SAC and NAC are potent anti-glycating agents. We also found that both SAC and NAC reduce ROS level and inhibit apoptosis caused by protein glycation.}, } @article {pmid37567916, year = {2023}, author = {Naushad, SM and Mandadapu, G and Ramaiah, MJ and Almajhdi, FN and Hussain, T}, title = {The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {13078}, pmid = {37567916}, issn = {2045-2322}, mesh = {Humans ; Male ; Adaptor Proteins, Signal Transducing/metabolism ; Adjuvants, Immunologic ; *COVID-19/genetics ; Myeloid Differentiation Factor 88/genetics/metabolism ; RNA, Viral ; SARS-CoV-2/genetics ; *Toll-Like Receptor 7/agonists/genetics ; COVID-19 Drug Treatment ; }, abstract = {We investigate the mechanism associated with the severity of COVID-19 in men with TLR7 mutation. Men with loss-of-function (LOF) mutations in TLR7 had severe COVID-19. LOF mutations in TLR7 increased the risk of critical COVID by 16.00-fold (95% confidence interval 2.40-106.73). The deleterious mutations affect the binding of SARS-CoV2 RNA (- 328.66 ± 26.03 vs. - 354.08 ± 27.70, p = 0.03) and MYD88 (β: 40.279, p = 0.003) to TLR7 resulting in the disruption of TLR7-MyD88-TIRAP complex. In certain hypofunctional variants and all neutral/benign variants, there is no disruption of TLR7-MyD88-TIRAP complex and four TLR7 agonists showed binding affinity comparable to that of wild protein. N-acetylcysteine (NAC) also showed a higher binding affinity for the LOF variants (p = 0.03). To conclude, TLR7 LOF mutations increase the risk of critical COVID-19 due to loss of viral RNA sensing ability and disrupted MyD88 signaling. Majority of hypofunctional and neutral variants of TLR7 are capable of carrying MyD88 signaling by binding to different TLR7 agonists and NAC.}, } @article {pmid37567457, year = {2023}, author = {Zheng, X and Su, F and Lei, M and Li, J and Zhang, C and Zhang, Y and Wei, M and Li, W and Chen, S and Liu, Y and Gao, Q and Hao, L}, title = {The novel peptide athycaltide-1 attenuates Ang II-induced pathological myocardial hypertrophy by reducing ROS and inhibiting the activation of CaMKII and ERK1/2.}, journal = {European journal of pharmacology}, volume = {957}, number = {}, pages = {175969}, doi = {10.1016/j.ejphar.2023.175969}, pmid = {37567457}, issn = {1879-0712}, mesh = {Animals ; Mice ; Angiotensin II/adverse effects/metabolism/toxicity ; Calcium Signaling ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cardiomegaly/chemically induced/drug therapy/metabolism ; Cells, Cultured ; *MAP Kinase Signaling System ; Myocytes, Cardiac ; Peptides/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Pathological myocardial hypertrophy initially develops as an adaptive response to cardiac stress, which can be induced by many diseases. It is accompanied by adverse cardiovascular events, including heart failure, arrhythmias, and death. The purpose of this research was to explore the molecular mechanism of a novel peptide Athycaltide-1 (ATH-1) in the treatment of Ang II-induced pathological myocardial hypertrophy. In this study, the mRNA of Control group, Ang II group, ATH-1 group and Losartan group mice were sequenced by high-throughput sequencing technology. The results showed that the differentially expressed genes (DEGs) were significantly enriched in cell response to oxidative stress, regulation of reactive oxygen species metabolism and calmodulin binding. Then, the oxidation level of mouse hearts and H9c2 cardiomyocytes in each group and the expression of key proteins of CaMKII/HDAC/MEF2C and ERK1/2 signaling pathways were detected to preliminarily verify the positive effect of ATH-1. At the same time, the effect of ATH-1 was further determined by adding reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC) and CaMKII inhibitor AIP in vitro. The results showed that ATH-1 could significantly reduce the level of oxidative stress in hypertrophic cardiomyocytes and inhibiting the activation of CaMKII and ERK1/2.}, } @article {pmid37562904, year = {2023}, author = {Sukumaran, D and Usharani, P and Paramjyothi, GK and Subbalaxmi, MVS and Sireesha, K and Abid Ali, M}, title = {A study to evaluate the hepatoprotective effect of N- acetylcysteine on anti tuberculosis drug induced hepatotoxicity and quality of life.}, journal = {The Indian journal of tuberculosis}, volume = {70}, number = {3}, pages = {303-310}, doi = {10.1016/j.ijtb.2022.05.012}, pmid = {37562904}, issn = {0019-5707}, mesh = {Humans ; Acetylcysteine/therapeutic use/pharmacology ; Quality of Life ; Prospective Studies ; *Tuberculosis/drug therapy ; *Chemical and Drug Induced Liver Injury/etiology/prevention & control ; Bilirubin ; Biomarkers ; }, abstract = {BACKGROUND: Drug induced liver injury (DILI) is a serious adverse effect caused by first-line anti-TB (ATT) drugs, limiting the TB-treatment. The tissue inflammation induced by free radical burst and poor dietary intake in TB induces oxidative stress, which was proposed as one of the mechanisms responsible for ATT induced DILI. N-acetylcysteine (NAC) exerts a hepato-protective effect by enhancing the cellular antioxidant defense mechanism. There are few studies evaluating the effect of NAC on ATT induced DILI in Indian-population.

METHODS: This is a prospective, randomized, double-blind, placebo-controlled, parallel-group study. Thirty-eight newly diagnosed TB patients on first-line ATT with normal liver function test (LFT) were recruited and randomized to receive either NAC 600 mg tablet or placebo twice daily for 4 weeks and followed-up for next 4 weeks. LFT [AST, ALT, ALP and Total bilirubin] was assessed at baseline, 2, 4 and 8 weeks. Oxidative-stress biomarkers [Malondialdehyde (MDA), Nitric Oxide (NO), Glutathione (GSH)] and quality of life (QOL) by SF-36 questionnaire were assessed at baseline, 4 and 8 weeks. Adverse Drug Reactions (ADRs) were monitored at every visit. Compliance was assessed by pill-count method.

RESULTS: Baseline characteristics were homogenous among both the groups. In the NAC group, there was significant reduction in ALT (p < 0.01), ALP (p < 0.01), total bilirubin (p < 0.001) at 4 weeks compared to baseline. AST, MDA and NO showed a reduction of 19%, 21.6% and 5.5% respectively from baseline and GSH at showed an increase of 2.6% from baseline at 4 weeks in the NAC group, however these were not statistically significant. These effects in LFT and oxidative biomarkers persisted even at the end of 8 weeks. Significant improvement from baseline in QOL was observed in both the groups (p < 0.05). Between group analysis showed, significant reduction in ALT (p < 0.05) and AST (p < 0.05) in NAC group at 4 weeks, whereas bilirubin, MDA, NO and GSH showed improvement at 4 weeks compared to placebo in NAC group, however it was not statistically significant. This improvement in the LFT and oxidative biomarkers continued even at the end of 8 weeks. Itching and rashes were the most common ADRs, with similar incidence in both the groups. Compliance to treatment was good in both the groups.

CONCLUSION: Significant improvement in liver function parameters is suggestive of hepatoprotective effect of NAC. This observed effect at 4 weeks was found to be persistent at 8 weeks, which signifies prolonged hepato-protective effect of NAC. Long duration studies with large sample size are required for further confirmation of hepato-protective action of NAC.}, } @article {pmid37562091, year = {2023}, author = {Geng, Y and Liu, P and Xie, Y and Liu, Y and Zhang, X and Hou, X and Zhang, L}, title = {Xanthatin suppresses pancreatic cancer cell growth via the ROS/RBL1 signaling pathway: In vitro and in vivo insights.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {119}, number = {}, pages = {155004}, doi = {10.1016/j.phymed.2023.155004}, pmid = {37562091}, issn = {1618-095X}, mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; Mice, Nude ; Cell Line, Tumor ; *Signal Transduction ; Cell Proliferation ; Apoptosis ; Cell Transformation, Neoplastic ; *Pancreatic Neoplasms/drug therapy ; }, abstract = {BACKGROUND: As a malignant digestive system tumor, pancreatic cancer has a high mortality rate. Xanthatin is a sesquiterpene lactone monomer compound purified from the traditional Chinese herb Xanthium strumarium L. It has been reported that Xanthatin exhibits inhibitory effects on various cancer cells in retinoblastoma, glioma, hepatoma, colon cancer, lung cancer, as well as breast cancer. However, in pancreatic cancer cells, only one report exists on the suppression of Prostaglandin E2 synthesis and the induction of caspase 3/7 activation in Xanthatin-treated MIA PaCa-2 cells, while systematic in vitro and in vivo investigations and related mechanisms have yet to be explored.

PURPOSE: This research aims to explore the in vitro and in vivo effects of Xanthatin on pancreatic cancer and its molecular mechanisms.

METHODS: The anticancer effects and mechanisms of Xanthatin on pancreatic cancer cells were assessed through employing cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, carboxyfluorescein diacetate succinimidyl ester (CFDA SE) cell proliferation assay, colony formation assay, wound healing assay, transwell assay, Annexin V-FITC/propidium iodide (PI) dual staining, Hoechst nuclear staining, Western blot analysis, phosphoproteomics, and reactive oxygen species (ROS) measurement. The in vivo anticancer effects of Xanthatin on pancreatic cancer cells were studied using a nude mouse model.

RESULTS: The present study showed that Xanthatin can prevent the proliferation and metastasis of pancreatic cancer cells and trigger the exposure of phosphatidylserine (PS), chromatin condensation, and caspase activation, thereby inducing apoptosis. Phosphoproteomic analysis indicated that Xanthatin inhibits the phosphorylation of the proliferation-associated protein RBL1, and oxidative stress can lead to RBL1 dephosphorylation. Further investigation revealed that Xanthatin significantly upregulates ROS levels in pancreatic cancer cells, and the antioxidant N-acetylcysteine (NAC) can reverse Xanthatin-induced cell proliferation inhibition and apoptosis. In addition, Xanthatin can suppress pancreatic cancer cell growth in a xenograft nude mouse model with low toxicity to the mice.

CONCLUSION: Xanthatin may inhibit the proliferation of pancreatic cancer cells and trigger apoptosis through the ROS/RBL1 signaling pathway.}, } @article {pmid37561633, year = {2023}, author = {Yao, H and Chen, X and Wang, T and Kashif, M and Qiao, X and Tüksammel, E and Larsson, LG and Okret, S and Sayin, VI and Qian, H and Bergo, MO}, title = {A MYC-controlled redox switch protects B lymphoma cells from EGR1-dependent apoptosis.}, journal = {Cell reports}, volume = {42}, number = {8}, pages = {112961}, doi = {10.1016/j.celrep.2023.112961}, pmid = {37561633}, issn = {2211-1247}, abstract = {Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma.}, } @article {pmid37559860, year = {2023}, author = {Mitchell, MC and Rogers, C}, title = {A Case of Cocaine-Induced Acute Liver Failure Reversed With N-Acetylcysteine.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e41579}, pmid = {37559860}, issn = {2168-8184}, abstract = {Acute liver failure (ALF) is a life-threatening injury that is most often caused by drug-induced injury, including acetaminophen overdose, in the United States. The hallmarks of ALF are hepatic encephalopathy and coagulopathy in a patient without an established history of liver disease. While acetaminophen overdose has an antidote, that is N-acetylcysteine (NAC), when given acutely, most other causes of hepatic failure require an urgent liver transplant. In this paper, we report a case of cocaine-induced acute liver failure that was reversed with the administration of NAC. Our case began when a middle-aged male presented to the emergency department complaining of nausea, vomiting, fatigue, and confusion for the past three days. His past medical history was pertinent for a history of opioid use disorder and his physical exam was remarkable for somnolence, asterixis, and periumbilical ecchymoses. His initial lab results showed markedly elevated liver function tests, prolonged coagulation studies, and a urine drug screen that was positive for cocaine. During the patient's interview, his vital signs became unstable. He was intubated for airway protection and transferred to a tertiary care facility for liver transplant evaluation with the diagnosis of cocaine-induced acute liver failure. There he received NAC, lactulose, rifaximin, and vasopressors. On day two of treatment, his clinical condition greatly improved, and he was extubated. He continued to receive NAC until day five when his liver function tests and coagulopathy improved enough to stop treatment. This case report highlights the clinical benefit of NAC in a case of cocaine-induced acute liver failure, improving the patient's survival and eliminating his need for a liver transplant.}, } @article {pmid37558010, year = {2023}, author = {Zhong, G and Guo, Y and Gong, X and Xu, M and Wang, Q and Wu, M and Zhang, X and Liang, Y and Zhao, W and Wang, H and Ye, J}, title = {Enhanced glycolysis by ATPIF1 gene inactivation increased the anti-bacterial activities of neutrophils through induction of ROS and lactic acid.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1869}, number = {8}, pages = {166820}, doi = {10.1016/j.bbadis.2023.166820}, pmid = {37558010}, issn = {1879-260X}, mesh = {Adenosine Triphosphate/metabolism ; Escherichia coli/metabolism ; Gene Silencing ; Glycolysis ; *Neutrophils/metabolism ; Nitric Oxide Synthase/metabolism ; *Peritonitis ; Reactive Oxygen Species/metabolism ; Animals ; Mice ; ATPase Inhibitory Protein ; }, abstract = {ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein that regulates the activity of FoF1-ATP synthase. Mice lacking ATPIF1 throughout their bodies (Atpif1[-/-]) exhibit a reduction in the number of neutrophils. However, it remains unclear whether the inactivation of ATPIF1 impairs the antibacterial function of mice, this study aimed to evaluate it using a mouse peritonitis model. Mice were intraperitoneally injected with E. coli to induce peritonitis, and after 24 h, the colonies of E. coli were counted in agarose plates containing mice peritoneal lavage fluids (PLF) or extract from the liver. Neutrophils were analyzed for glucose metabolism in glycolysis following LPS stimulation. Reactive oxygen species (ROS) and lactic acid (LA) levels in neutrophils were measured using flow cytometry and Seahorse analysis, respectively. N-Acetylcysteine (NAC) and 2-Deoxy-d-glucose (2-DG) were employed to assess the role of ROS and LA in neutrophil bactericidal activity. RNA-seq analysis was conducted in neutrophils to investigate potential mechanisms. In ATPIF1[-/-] neutrophils, bactericidal activity was enhanced, accompanied by increased levels of ROS and LA compared to wildtype neutrophils. The augmented bactericidal activity of ATPIF1[-/-] neutrophils was reversed by pretreatment with NAC or 2-DG. RNA-seq analysis revealed downregulation of multiple genes involved in glutathione metabolism, pyruvate oxidation, and heme synthesis, along with increased expression of inflammatory and apoptotic genes. This study suggests that the inactivation of the Atpif1 gene enhances glucose metabolism in neutrophils, resulting in increased bactericidal activity mediated by elevated levels of ROS and LA. Inhibiting ATPIF1 may be a potential approach to enhance antibacterial immunity.}, } @article {pmid37556466, year = {2023}, author = {Yu, H and Lv, M and Zhang, S and Zou, K and Qian, Y and Lv, S}, title = {Combination therapy with budesonide and acetylcysteine alleviates LPS-induced acute lung injury via the miR-381/NLRP3 molecular axis.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0289818}, pmid = {37556466}, issn = {1932-6203}, mesh = {Animals ; Rats ; *Acetylcysteine/therapeutic use ; *Acute Lung Injury/chemically induced/drug therapy/metabolism ; *Budesonide/therapeutic use ; Lipopolysaccharides/adverse effects ; Lung/pathology ; *MicroRNAs/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; *Pulmonary Edema/pathology ; Signal Transduction ; }, abstract = {BACKGROUND: Acute lung injury (ALI) usually has a high morbidity and mortality rate, but the current treatment is relatively scarce. Both budesonide (Bud) and N-acetylcysteine (NAC) exhibit protective effects in ALI, so we further investigated whether they have a synergistic effect on ALI when used together.

METHODS: Establishment of a rat model of ALI with Lipopolysaccharide (LPS). Bud and NAC were administered by nebulized inhalation alone or in combination. Subsequently, HE staining was performed to observe the pathological changes in lungs of rat. Evans blue staining was implemented to assess alveolar permeability, and the pulmonary edema was assessed by measuring the ratio of wet to dry weight of the lung. Moreover, a TUNEL kit was served to test apoptosis in lung tissues. Western blot and immunohistochemistry were analyzed for expression of scorch-related proteins and NLRP3 in lung tissue, respectively. ELISA was implemented to detect inflammatory factor levels in BALF. and RT-qPCR was utilized to assess the expression level of miR-381. After stable transfection of miR-381 inhibitor or OE-NLRP3 in BEAS-2B treated with LPS, Bud and NAC, miR-381 expression was assessed by RT-qPCR, scorch death-related protein expression was measured by western blot, cell proliferation/viability was assayed by CCK-8, apoptosis was measured by flow cytometry, and ELISA was implemented to assess inflammatory factor levels. Furthermore, the Dual-luciferase assay was used to verify the targeting relationship.

RESULTS: Bud and NAC treatment alone or in combination with nebulized inhalation attenuated the increased alveolar permeability, pulmonary edema, inflammatory response and scorching in LPS-induced ALI rats, and combined treatment with Bud and NAC was the most effective. In addition, combined treatment with Bud and NAC upregulated miR-381 expression and inhibited NLRP3 expression in cellular models and LPS-induced ALI rats. Transfection of the miR-381 inhibitor and OE-NLRP3 partially reversed the protective effects of Bud and NAC combination treatment on BEAS-2B cell proliferation inhibition, apoptosis, focal death and the inflammatory response.

CONCLUSION: Combined Bud and NAC nebulization therapy alleviates LPS-induced ALI by modulating the miR-381/NLRP3 molecular axis.}, } @article {pmid37555614, year = {2024}, author = {Stannard, LM and Doherty, A and Chapman, KE and Doak, SH and Jenkins, GJ}, title = {Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations.}, journal = {Mutagenesis}, volume = {39}, number = {1}, pages = {13-23}, pmid = {37555614}, issn = {1464-3804}, support = {NC/R001375/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {*Tumor Suppressor Protein p53/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Cadmium Chloride/toxicity/metabolism ; DNA Damage ; Cell Cycle ; Carcinogens/toxicity ; }, abstract = {Cadmium chloride (CdCl2) is a known genotoxic carcinogen, with a mechanism of action thought to partly involve the generation of reactive oxygen species (ROS). We applied here a multi-endpoint approach in vitro to explore the impact of CdCl2 on both the genome and on wider cell biology pathways relevant to cancer. Multi-endpoint approaches are believed to offer greater promise in terms of understanding the holistic effects of carcinogens in vitro. This richer understanding may help better classification of carcinogens as well as allowing detailed mechanisms of action to be identified. We found that CdCl2 caused DNA damage [micronuclei (MN)] in both TK6 and NH32 cells in a dose-dependent manner after 4 h exposure (plus 23 h recovery), with lowest observable effect levels (LOELs) for MN induction of 1 μM (TK6) and 1.6 μM (NH32). This DNA damage induction in TK6 cells was ROS dependent as pretreatment with the antioxidant N-Acetyl Cysteine (1 mM), abrogated this effect. However, 2',7'-dichlorofluorescin diacetate was not capable of detecting the ROS induced by CdCl2. The use of NH32 cells allowed an investigation of the role of p53 as they are a p53 null cell line derived from TK6. NH32 showed a 10-fold increase in MN in untreated cells and a similar dose-dependent effect after CdCl2 treatment. In TK6 cells, CdCl2 also caused activation of p53 (accumulation of total and phosphorylated p53), imposition of cell cycle checkpoints (G2/M) and intriguingly the production of smaller and more eccentric (elongated) cells. Overall, this multi-endpoint study suggests a carcinogenic mechanism of CdCl2 involving ROS generation, oxidative DNA damage and p53 activation, leading to cell cycle abnormalities and impacts of cell size and shape. This study shows how the integration of multiple cell biology endpoints studied in parallel in vitro can help mechanistic understanding of how carcinogens disrupt normal cell biology.}, } @article {pmid37554797, year = {2023}, author = {Zhou, Q and Zhou, Q and Xia, R and Zhang, P and Xie, Y and Yang, Z and Khan, A and Zhou, Z and Tan, W and Liu, L}, title = {Swertiamarin or heat-transformed products alleviated APAP-induced hepatotoxicity via modulation of apoptotic and Nrf-2/NF-κB pathways.}, journal = {Heliyon}, volume = {9}, number = {8}, pages = {e18746}, pmid = {37554797}, issn = {2405-8440}, abstract = {OBJECTIVE: Swertiamarin (STM) belongs to iridoid class of compounds, and the heat-transformed products (HTPS) are produced by STM in the process of drug processing. The purpose of this study was to explore the protective effect and mechanism of STM or HTPS on acetaminophen (APAP)-induced hepatotoxicity.

METHODS: Mice and L-O2 cells were given APAP to establish the hepatotoxicity model in vivo and in vitro. The effects of STM or HTPS on oxidative stress, inflammation, and apoptosis induced by APAP were evaluated, with N-acetylcysteine (NAC) as a positive control.

RESULTS: STM or HTPS reduced the APAP-induced apoptosis of L-O2 cells and significantly alleviated the liver injury index induced by APAP (p < 0.01, 0.005) Interestingly, HTPS had better protective effect against APAP-induced hepatotoxicity than STM (p < 0.05). In addition STM or HTPS improved the histological abnormalities; inhibited lipid peroxidation and reduced the level of inflammatory mediators. They also activated the defense system of nuclear factor erythroid 2 related factor 2 (Nrf-2) and inhibited nuclear factor-κ B (NF-κB).}, } @article {pmid37547958, year = {2023}, author = {Wang, X and Liu, B and Liu, Y and Wang, Y and Wang, Z and Song, Y and Xu, J and Xue, C}, title = {Antioxidants ameliorate oxidative stress in alcoholic liver injury by modulating lipid metabolism and phospholipid homeostasis.}, journal = {Lipids}, volume = {58}, number = {5}, pages = {229-240}, doi = {10.1002/lipd.12377}, pmid = {37547958}, issn = {1558-9307}, mesh = {Mice ; Animals ; *Antioxidants/pharmacology/metabolism ; Lipid Metabolism ; Mice, Inbred C57BL ; Liver/metabolism ; Oxidative Stress ; *Liver Diseases, Alcoholic/drug therapy/metabolism ; Ethanol/metabolism/pharmacology ; Ascorbic Acid/metabolism/pharmacology ; Triglycerides/metabolism ; Homeostasis ; Phospholipids/metabolism ; }, abstract = {Alcoholic liver disease (ALD) is a significant risk factor in the global disease burden. The antioxidants vitamin C (Vc) and N-acetyl cysteine (NAC) have shown hepatoprotective effects in preventing and treating ALD. However, the correlation between the improved effect of antioxidants and lipid metabolism is still unclear. In this study, AML12 cells and C57BL/6 mice stimulated with alcohol were used to investigate the protective effects and potential mechanisms of two antioxidants (Vc and NAC) on alcoholic liver injury. Results showed that Vc and NAC attenuated intracellular lipid accumulation and oxidative damage induced by excessive alcohol exposure in hepatic AML12 cells. The in vivo results indicated that antioxidants ameliorated alcohol-induced changes in histopathology, reducing the levels of alcohol metabolizing factors and aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (TC) contents, which demonstrated that antioxidants effectively mitigated liver injury in ALD mice. Further studies showed that antioxidants reversed the disruption of fatty acid (FA) synthesis and lipid transport induced by alcohol exposure, and restored phospholipid levels. Especially, Vc and NAC increased the endogenous antioxidant plasmenyl phosphatidylethanolamine (PlsEtn). Additionally, antioxidants ameliorated the alcohol-impaired mitochondrial function and inhibited excessive oxidative stress. In conclusion, antioxidants can regulate lipid metabolism and phospholipid homeostasis, which in turn inhibit oxidative stress and thereby exert protective effects against ALD.}, } @article {pmid37547194, year = {2023}, author = {Summerlin, JA and Wang, KM and McMahon, AJ and Lund, JA}, title = {Effect of a pharmacist-based toxicology consult service on appropriate use of intravenous N-acetylcysteine for acetaminophen toxicity: A retrospective cohort study.}, journal = {International journal of critical illness and injury science}, volume = {13}, number = {2}, pages = {54-59}, pmid = {37547194}, issn = {2229-5151}, abstract = {BACKGROUND: Incorporating clinical pharmacists on the medical team has been associated with fewer medication errors and increased error interception. Due to the logistical complexities of the intravenous (IV) N-acetylcysteine (NAC) regimen for acetaminophen toxicity, many opportunities for medication errors exist. A pharmacist-based toxicology consultation service was implemented at our institution, allowing pharmacists to formally aid in the management of toxicology patients throughout their hospital admission, including those with acetaminophen toxicity. The purpose of this study was to evaluate the effect of a house-wide pharmacist-based toxicology consult service on errors associated with IV NAC treatment for patients admitted with acetaminophen toxicity.

METHODS: A retrospective, pre-post cohort study was conducted on patients who received IV NAC for acetaminophen toxicity. The intervention evaluated was the implementation of a pharmacist-based toxicology consult service, known as the pharmacy toxicology team. The primary end point was the incidence of an error associated with IV NAC. An error was defined as the composite of inappropriate dose, administration rate, initiation, continuation, or discontinuation.

RESULTS: Eighty-four patients were included; 30 patients in the pregroup, and 54 patients in the postgroup. Fewer patients experienced an error in the postgroup compared to the pregroup (30% vs 63%, P = 0.003).

CONCLUSION: The implementation of this unique pharmacist-based toxicology consult service was associated with fewer patients experiencing an error related to IV NAC therapy for acetaminophen toxicity. Application of this data may aid in the justification for development of clinical pharmacist-based toxicology consult services at other institutions.}, } @article {pmid37545886, year = {2023}, author = {Pimentel, BNADS and De Annunzio, SR and Assis, M and Barbugli, PA and Longo, E and Vergani, CE}, title = {Biocompatibility and inflammatory response of silver tungstate, silver molybdate, and silver vanadate microcrystals.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {11}, number = {}, pages = {1215438}, pmid = {37545886}, issn = {2296-4185}, abstract = {Silver tungstate (α-Ag2WO4), silver molybdate (β-Ag2MoO4), and silver vanadate (α-AgVO3) microcrystals have shown interesting antimicrobial properties. However, their biocompatibility is not yet fully understood. Cytotoxicity and the inflammatory response of silver-containing microcrystals were analyzed in THP-1 and THP-1 differentiated as macrophage-like cells, with the alamarBlue™ assay, flow cytometry, confocal microscopy, and ELISA. The present investigation also evaluated redox signaling and the production of cytokines (TNFα, IL-1β, IL-6, and IL-8) and matrix metalloproteinases (MMP-8 and -9). The results showed that α-AgVO3 (3.9 μg/mL) did not affect cell viability (p > 0.05). α-Ag2WO4 (7.81 μg/mL), β-Ag2MoO4 (15.62 μg/mL), and α-AgVO3 (15.62 μg/mL) slightly decreased cell viability (p ≤ 0.003). All silver-containing microcrystals induced the production of O2 [-] and this effect was mitigated by Reactive Oxygen Species (ROS) scavenger and N-acetylcysteine (NAC). TNFα, IL-6 and IL-1β were not detected in THP-1 cells, while their production was either lower (p ≤ 0.0321) or similar to the control group (p ≥ 0.1048) for macrophage-like cells. The production of IL-8 by both cellular phenotypes was similar to the control group (p ≥ 0.3570). The release of MMP-8 was not detected in any condition in THP-1 cells. Although MMP-9 was released by THP-1 cells exposed to α-AgVO3 (3.9 μg/mL), no significant difference was found with control (p = 0.7). Regarding macrophage-like cells, the release of MMP-8 and -9 decreased in the presence of all microcrystals (p ≤ 0.010). Overall, the present work shows a promising biocompatibility profile of, α-Ag2WO4, β-Ag2MoO4, and α-AgVO3 microcrystals.}, } @article {pmid37545163, year = {2024}, author = {Nayak, J and P, SV and Sahoo, SK and Kumar, M and Vashistha, VK and Kumar, R}, title = {Computational insight of antioxidant and doxorubicin combination for effective cancer therapy.}, journal = {Journal of biomolecular structure & dynamics}, volume = {42}, number = {15}, pages = {7874-7882}, doi = {10.1080/07391102.2023.2242507}, pmid = {37545163}, issn = {1538-0254}, mesh = {*Molecular Docking Simulation ; *Doxorubicin/chemistry/pharmacology ; *Antioxidants/pharmacology/chemistry ; *Molecular Dynamics Simulation ; Humans ; Neoplasms/drug therapy ; DNA Topoisomerases, Type II/metabolism/chemistry ; Protein Binding ; Ligands ; Binding Sites ; Glutathione/metabolism/chemistry ; }, abstract = {Doxorubicin (DOX) is the most effective antineoplastic agent, destroys cancer cells by interrupting cellular function. However, the serious side effects on the heart limits its utility. To curb these unwanted side effects, nutritionist recommend antioxidants use along with DOX while chemotherapy. But it was not supported by various oncologists as it can alter the toxicity of DOX towards cancer cells. Therefore, here we explored the in silico pharmacokinetics and combination effect of DOX and antioxidants on topoisomerases-II (Top-II) and cyclophilin D (Cyp-D) therapeutic targets involved in cancer proliferation and post-myocardial infarction, respectively. The molecular docking study was conducted on target proteins and DOX including most prescribed antioxidants (melatonin, N-acetylcysteine (NAC), glutathione (GSH), β-carotene and vitamin C). GSH showed effective binding potential for Top-II and Cyp-D active sites, but other considered antioxidants possess low binding affinity. The highest docked conformations were subjected to molecular dynamics (MD) simulations to understand conformer stability of DOX and GSH with Cyp-D and Top-II for 100 ns. The results revealed that ligands pose at Top-II active sites where DOX showed strong binding affinity to DNA binding pocket and GSH to a buried site. The computational data summarised and proposed the GSH and DOX combination as antagonist effects on Top-II. Conversely, the binding compactness of GSH improved due to surface fit at the active pocket of Cyp-D and completely blocking DOX binding affinity, suppress adverse reactions of post-myocardial infarction.Communicated by Ramaswamy H. Sarma.}, } @article {pmid37544576, year = {2023}, author = {Su, AL and Lash, LH and Loch-Caruso, R}, title = {N-Acetyl-L-cysteine and aminooxyacetic acid differentially modulate toxicity of the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine in human placental villous trophoblast BeWo cells.}, journal = {Toxicology}, volume = {495}, number = {}, pages = {153611}, pmid = {37544576}, issn = {1879-3185}, support = {P42 ES017198/ES/NIEHS NIH HHS/United States ; T32 HD079342/HD/NICHD NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; T32 ES019851/ES/NIEHS NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Female ; Pregnancy ; *Acetylcysteine/pharmacology/metabolism ; Cysteine ; *Trichloroethylene/toxicity/metabolism ; Placenta/metabolism ; Aminooxyacetic Acid/metabolism/pharmacology ; Trophoblasts/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Hydrogen Peroxide/metabolism ; RNA, Messenger/metabolism ; }, abstract = {Trichloroethylene (TCE) is a known human carcinogen with toxicity attributed to its metabolism. S-(1,2-Dichlorovinyl)-L-cysteine (DCVC) is a metabolite of TCE formed downstream in TCE glutathione (GSH) conjugation and is upstream of several toxic metabolites. Despite knowledge that DCVC stimulates reactive oxygen species (ROS) generation and apoptosis in placental cells, the extent to which these outcomes are attributable to DCVC metabolism is unknown. The current study used N-acetyl-L-cysteine (NAC) at 5 mM and aminooxyacetic acid (AOAA) at 1 mM as pharmacological modifiers of DCVC metabolism to investigate DCVC toxicity at concentrations of 5-50 µM in the human placental trophoblast BeWo cell model capable of forskolin-stimulated syncytialization. Exposures of unsyncytialized BeWo cells, BeWo cells undergoing syncytialization, and syncytialized BeWo cells were studied. NAC pre/co-treatment with DCVC either failed to inhibit or exacerbated DCVC-induced H2O2 abundance, PRDX2 mRNA expression, and BCL2 mRNA expression. Although NAC increased mRNA expression of CYP3A4, which would be consistent with increased generation of the toxic metabolite N-acetyl-DCVC sulfoxide (NAcDCVCS), a CYP3A4 inhibitor ketoconazole did not significantly alter BeWo cell responses. Moreover, AOAA failed to inhibit cysteine conjugate β-lyase (CCBL), which bioactivates DCVC, and did not affect the percentage of nuclei condensed or fragmented, a measure of apoptosis, in all BeWo cell models. However, syncytialized cells had higher CCBL activity compared to unsyncytialized cells, suggesting that the former may be more sensitive to DCVC toxicity. Together, although neither NAC nor AOAA mitigated DCVC toxicity, differences in CCBL activity and potentially CYP3A4 expression dictated the differential toxicity derived from DCVC.}, } @article {pmid37540942, year = {2023}, author = {Kanaan, RA and Oliver, G and Dharan, A and Sendi, S and Maier, A and Mohebbi, M and Ng, C and Back, SE and Kalivas, P and Berk, M}, title = {A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD.}, journal = {Psychiatry research}, volume = {327}, number = {}, pages = {115398}, doi = {10.1016/j.psychres.2023.115398}, pmid = {37540942}, issn = {1872-7123}, mesh = {Adult ; Humans ; *Acetylcysteine/pharmacology/therapeutic use ; *Stress Disorders, Post-Traumatic/drug therapy ; Double-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUND: PTSD may involve oxidative stress, and N-acetylcysteine (NAC) may reduce the impact of oxidative stress in the brain. This study aims to investigate the efficacy of adjuvant NAC in people with treatment-resistant PTSD.

METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adults with PTSD unresponsive to first-line treatment. The intervention was either oral NAC 2.7 g/day or placebo for 12 weeks. The primary outcome was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks compared with baseline. Secondary outcomes included depression and substance craving. Follow-up measures were obtained at 16 and 64-weeks.

RESULTS: 133 patients were assessed, with 105 randomised; 81 participants completed the 12-week trial, 79 completed week-16 follow-up, and 21 completed week-64 follow-up. There were no significant differences between those taking NAC and those taking placebo in CAPS-5 scores at week 12, nor in secondary outcomes. Significant between-group differences were observed at week 64 in craving duration (Cohen's d = 1.61) and craving resistance (Cohen's d = 1.03), both in favour of NAC.

CONCLUSION: This was the first multicentre, double-blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. No benefit of NAC was observed in this group beyond that provided by placebo at end of the trial.

TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.}, } @article {pmid37540386, year = {2023}, author = {Zhang, J and Sun, J and Zhang, Y and Zhang, M and Liu, X and Yang, L and Yin, Y}, title = {Dehydrocostus lactone inhibits Candida albicans growth and biofilm formation.}, journal = {AMB Express}, volume = {13}, number = {1}, pages = {82}, pmid = {37540386}, issn = {2191-0855}, support = {2019SCZT053//the Special Fund for Medical Professionals of Jilin Province/ ; }, abstract = {Candida albicans infections are threatening public health but there are only several antifungal drugs available. This study was to assess the effects of dehydrocostus lactone (DL) on the Candida albicans growth and biofilms Microdilution assays revealed that DL inhibits a panel of standard Candida species, including C. albicans, as well as 9 C. albicans clinical isolates. The morphological transition of C. albicans in RPMI-1640 medium and the adhesion to polystyrene surfaces can also be decreased by DL treatment, as evidenced by microscopic, metabolic activity and colony forming unit (CFU) counting assays. The XTT assay and microscopy inspection demonstrated that DL can inhibit the biofilms of C. albicans. Confocal microscopy following propidium iodide (PI) staining and DCFH-DA staining after DL treatment revealed that DL can increase the membrane permeability and intracellular reactive oxygen species (ROS) production. N-acetyl-cysteine could mitigate the inhibitory effects of DL on growth, morphological transition and biofilm formation, further confirming that ROS production induced by DL contributes to its antifungal and antibiofilm effects. This study showed that DL demonstrated antifungal and antibiofilm activity against C. albicans. The antifungal mechanisms may involve membrane damage and ROS overproduction. This study shows the potential of DL to fight Candida infections.}, } @article {pmid37537647, year = {2023}, author = {Refsnes, M and Skuland, T and Jørgensen, R and Sæter-Grytting, V and Snilsberg, B and Øvrevik, J and Holme, JA and Låg, M}, title = {Role of different mechanisms in pro-inflammatory responses triggered by traffic-derived particulate matter in human bronchiolar epithelial cells.}, journal = {Particle and fibre toxicology}, volume = {20}, number = {1}, pages = {31}, pmid = {37537647}, issn = {1743-8977}, mesh = {Humans ; *Particulate Matter/toxicity ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Cyclooxygenase 2 ; Cytochrome P-450 CYP1A1/genetics ; Plasminogen Activator Inhibitor 2/metabolism/pharmacology ; Cytokines/metabolism ; Epithelial Cells ; Vehicle Emissions/toxicity ; *Air Pollutants/toxicity/metabolism ; }, abstract = {BACKGROUND: Traffic-derived particles are important contributors to the adverse health effects of ambient particulate matter (PM). In Nordic countries, mineral particles from road pavement and diesel exhaust particles (DEP) are important constituents of traffic-derived PM. In the present study we compared the pro-inflammatory responses of mineral particles and DEP to PM from two road tunnels, and examined the mechanisms involved.

METHODS: The pro-inflammatory potential of 100 µg/mL coarse (PM10-2.5), fine (PM2.5-0.18) and ultrafine PM (PM0.18) sampled in two road tunnels paved with different stone materials was assessed in human bronchial epithelial cells (HBEC3-KT), and compared to DEP and particles derived from the respective stone materials. Release of pro-inflammatory cytokines (CXCL8, IL-1α, IL-1β) was measured by ELISA, while the expression of genes related to inflammation (COX2, CXCL8, IL-1α, IL-1β, TNF-α), redox responses (HO-1) and metabolism (CYP1A1, CYP1B1, PAI-2) was determined by qPCR. The roles of the aryl hydrocarbon receptor (AhR) and reactive oxygen species (ROS) were examined by treatment with the AhR-inhibitor CH223191 and the anti-oxidant N-acetyl cysteine (NAC).

RESULTS: Road tunnel PM caused time-dependent increases in expression of CXCL8, COX2, IL-1α, IL-1β, TNF-α, COX2, PAI-2, CYP1A1, CYP1B1 and HO-1, with fine PM as more potent than coarse PM at early time-points. The stone particle samples and DEP induced lower cytokine release than all size-fractionated PM samples for one tunnel, and versus fine PM for the other tunnel. CH223191 partially reduced release and expression of IL-1α and CXCL8, and expression of COX2, for fine and coarse PM, depending on tunnel, response and time-point. Whereas expression of CYP1A1 was markedly reduced by CH223191, HO-1 expression was not affected. NAC reduced the release and expression of IL-1α and CXCL8, and COX2 expression, but augmented expression of CYP1A1 and HO-1.

CONCLUSIONS: The results indicate that the pro-inflammatory responses of road tunnel PM in HBEC3-KT cells are not attributed to the mineral particles or DEP alone. The pro-inflammatory responses seem to involve AhR-dependent mechanisms, suggesting a role for organic constituents. ROS-mediated mechanisms were also involved, probably through AhR-independent pathways. DEP may be a contributor to the AhR-dependent responses, although other sources may be of importance.}, } @article {pmid37537538, year = {2023}, author = {Duan, Y and Wu, W and Cui, J and Matsubara, JA and Kazlauskas, A and Ma, G and Li, X and Lei, H}, title = {Ligand-independent activation of platelet-derived growth factor receptor β promotes vitreous-induced contraction of retinal pigment epithelial cells.}, journal = {BMC ophthalmology}, volume = {23}, number = {1}, pages = {344}, pmid = {37537538}, issn = {1471-2415}, support = {G2022026027L//Introduction plan of high-level foreign experts/ ; 2021JJ41030//Natural Science Foundation of Hunan Province/ ; 82171085//National Natural Science Foundation of China/ ; 202103021224345//Natural Science Foundation of Shanxi province/ ; R01 EY031350/EY/NEI NIH HHS/United States ; 82070989//National Natural Science Foundation of China/ ; 2022-203//Research Project Supported by Shanxi Scholarship Council of China/ ; 19JCZDJC64000//Natural Science Foundation of Tianjin City/ ; 2022Jx22//Shanxi Bethune Hospital Education and Teaching Reform Foundation/ ; 2020004//Health Commission of Shanxi Province/ ; 2021RC005//Shanxi Bethune Hospital Foundation/ ; }, mesh = {Humans ; *Receptor, Platelet-Derived Growth Factor beta/genetics/metabolism ; Retinal Pigment Epithelium/pathology ; Proto-Oncogene Proteins c-akt ; Ligands ; Reactive Oxygen Species/metabolism ; *Vitreoretinopathy, Proliferative/genetics/metabolism ; Platelet-Derived Growth Factor/metabolism ; Epithelial Cells/metabolism ; Retinal Pigments/metabolism ; Cell Movement ; }, abstract = {BACKGROUND: Epiretinal membranes in patients with proliferative vitreoretinopathy (PVR) consist of extracellular matrix and a number of cell types including retinal pigment epithelial (RPE) cells and fibroblasts, whose contraction causes retinal detachment. In RPE cells depletion of platelet-derived growth factor (PDGF) receptor (PDGFR)β suppresses vitreous-induced Akt activation, whereas in fibroblasts Akt activation through indirect activation of PDGFRα by growth factors outside the PDGF family (non-PDGFs) plays an essential role in experimental PVR. Whether non-PDGFs in the vitreous, however, were also able to activate PDGFRβ in RPE cells remained elusive.

METHODS: The CRISPR/Cas9 technology was utilized to edit a genomic PDGFRB locus in RPE cells derived from an epiretinal membrane (RPEM) from a patient with PVR, and a retroviral vector was used to express a truncated PDGFRβ short of a PDGF-binding domain in the RPEM cells lacking PDGFRβ. Western blot was employed to analyze expression of PDGFRβ and α-smooth muscle actin, and signaling events (p-PDGFRβ and p-Akt). Cellular assays (proliferation, migration and contraction) were also applied in this study.

RESULTS: Expression of a truncated PDGFRβ lacking a PDGF-binding domain in the RPEM cells whose PDGFRB gene has been silent using the CRISPR/Cas9 technology restores vitreous-induced Akt activation as well as cell proliferation, epithelial-mesenchymal transition, migration and contraction. In addition, we show that scavenging reactive oxygen species (ROS) with N-acetyl-cysteine and inhibiting Src family kinases (SFKs) with their specific inhibitor SU6656 blunt the vitreous-induced activation of the truncated PDGFRβ and Akt as well as the cellular events related to the PVR pathogenesis. These discoveries suggest that in RPE cells PDGFRβ can be activated indirectly by non-PDGFs in the vitreous via an intracellular pathway of ROS/SFKs to facilitate the development of PVR, thereby providing novel opportunities for PVR therapeutics.

CONCLUSION: The data shown here will improve our understanding of the mechanism by which PDGFRβ can be activated by non-PDGFs in the vitreous via an intracellular route of ROS/SFKs and provide a conceptual foundation for preventing PVR by inhibiting PDGFRβ transactivation (ligand-independent activation).}, } @article {pmid37536438, year = {2023}, author = {Martis, RM and Grey, AC and Wu, H and Wall, GM and Donaldson, PJ and Lim, JC}, title = {N-Acetylcysteine amide (NACA) and diNACA inhibit H2O2-induced cataract formation ex vivo in pig and rat lenses.}, journal = {Experimental eye research}, volume = {234}, number = {}, pages = {109610}, doi = {10.1016/j.exer.2023.109610}, pmid = {37536438}, issn = {1096-0007}, support = {R21 EY033941/EY/NEI NIH HHS/United States ; }, mesh = {Rats ; Animals ; Swine ; Acetylcysteine/adverse effects ; Hydrogen Peroxide/pharmacology ; Cystine/adverse effects ; Chromatography, Liquid ; Rats, Wistar ; Tandem Mass Spectrometry ; *Lens, Crystalline/metabolism ; *Cataract/chemically induced ; Antioxidants ; Oxidative Stress ; Glutathione/metabolism ; Proteins ; Glutathione Disulfide ; }, abstract = {Oxidative stress plays a central role in cataract formation suggesting that antioxidants might slow cataract progression. The anticataract activity of N-acetylcysteine amide (NACA) and (2 R, 2 R')-3,3'-disulfanediyl bis(2-acetamidopropanamide) (diNACA) and/or N-acetylcysteine (NAC), were evaluated in porcine and rat lens models. Cataractogenesis via oxidation was induced with H2O2 and/or glucose oxidase (GO). Porcine lenses were incubated in 0.1 mM, 1 mM, or 10 mM NAC, NACA or diNACA for 24 h. Lenses were then transferred to media containing 0.75 mM H2O2 and 4.63U of GO in order to maintain a constant H2O2 level for an additional 8 h. At the end of incubation, lenses were imaged under darkfield microscopy. Separately, rat lenses were extracted from 3-week-old Wistar rats and incubated with either 10 mM NACA or 10 mM diNACA for 24 h prior to treatment with 0.2U GO to generate a steady source of ∼0.6 mM H2O2. Rat lenses were analyzed by LC-MS/MS to quantify changes in cysteine, cystine, glutathione (GSH) or oxidised glutathione (GSSG) levels in the lens epithelium, cortex or core. Pre-treatment with NACA or diNACA followed by oxidation with H2O2 and/or GO to stimulate cataract formation afforded rapid assessment in ex vivo porcine (32 h) and rat (48 h) lens models. Pre-treatment of isolated porcine lenses with 0.1 mM, 1 mM or 10 mM of either NAC, NACA or diNACA followed by H2O2/GO treatment resulted in reduced lens opacity relative to the lenses exposed to H2O2/GO, with NACA and diNACA reducing opacities to a greater extent than NAC. Rat lenses incubated with 10 mM NACA or 10 mM diNACA without exposure to H2O2 showed no signs of opacities. Pre-treatment of rat lenses with 10 mM NACA or 10 mM diNACA, followed by GO cataract induction resulted in reduced opacities compared to control (GO alone). LC-MS/MS analyses revealed that NACA, but not diNACA, increased cysteine, cystine and GSH levels in rat lens epithelium and cortex regions. Taken together, both NACA and diNACA inhibited cataract formation to a greater extent than NAC (all at 1-10 mM) in an ex vivo porcine lens model. Both NACA and diNACA (both at 10 mM) reduced cataract formation in rat lenses. Based on LC-MS/MS analyses, NACA-induced reduction in opacity observed in rat lenses was attributed to enhanced cysteine and GSH levels while the diNACA-induced reduction in opacity induced did not consistently increase cysteine, cystine and GSH levels and, therefore, appears to involve a different antioxidant mechanism. These screening studies warrant further testing of NACA and diNACA as anticataract agents.}, } @article {pmid37536084, year = {2023}, author = {Takeda, H and Murakami, S and Liu, Z and Sawa, T and Takahashi, M and Izumi, Y and Bamba, T and Sato, H and Akaike, T and Sekine, H and Motohashi, H}, title = {Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.}, journal = {Redox biology}, volume = {65}, number = {}, pages = {102834}, pmid = {37536084}, issn = {2213-2317}, mesh = {Mice ; Animals ; *Cystine ; Feedback ; *Lipopolysaccharides ; Macrophages/metabolism ; Acetylcysteine ; Sulfur/metabolism ; Amino Acid Transport System y+/genetics/metabolism ; }, abstract = {The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.}, } @article {pmid37534881, year = {2024}, author = {Ding, W and Fan, JH and Zhong, LR and Wang, NX and Liu, LH and Zhang, HB and Wang, L and Wang, MQ and He, BL and Wei, AY}, title = {N-acetylcysteine ameliorates erectile dysfunction in rats with hyperlipidemia by inhibiting oxidative stress and corpus cavernosum smooth muscle cells phenotypic modulation.}, journal = {Asian journal of andrology}, volume = {26}, number = {1}, pages = {99-106}, pmid = {37534881}, issn = {1745-7262}, mesh = {Male ; Animals ; *Hyperlipidemias/drug therapy/complications ; *Oxidative Stress/drug effects ; *Erectile Dysfunction/drug therapy/etiology ; *Acetylcysteine/pharmacology/therapeutic use ; *Rats, Sprague-Dawley ; Rats ; *Penis/drug effects/pathology ; *Myocytes, Smooth Muscle/drug effects ; Phenotype ; Penile Erection/drug effects ; }, abstract = {Hyperlipidemia is a major risk factor for erectile dysfunction (ED). Oxidative stress and phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs) are the key pathological factors of ED. N-acetylcysteine (NAC) can inhibit oxidative stress; however, whether NAC can alleviate pathological variations in the corpus cavernosum and promote erectile function recovery in hyperlipidemic rats remains unclear. A hyperlipidemia model was established using 27 eight-week-old male Sprague-Dawley (SD) rats fed a high-fat and high-cholesterol diet (hyperlipidemic rats, HR). In addition, 9 male SD rats were fed a normal diet to serve as controls (NC). HR rats were divided into three groups: HR, HR+normal saline (NS), and HR+NAC (n = 9 for each group; NS or NAC intraperitoneal injections were administered daily for 16 weeks). Subsequently, the lipid profiles, erectile function, oxidative stress, phenotypic modulation markers of CCSMCs, and tissue histology were analyzed. The experimental results revealed that erectile function was significantly impaired in the HR and HR + NS groups, but enhanced in the HR + NAC group. Abnormal lipid levels, over-activated oxidative stress, and multi-organ lesions observed in the HR and HR + NS groups were improved in the HR + NAC group. Moreover, the HR group showed significant phenotypic modulation of CCSMCs, which was also inhibited by NAC treatment. This report focuses on the therapeutic effect of NAC in restoring erectile function using a hyperlipidemic rat model by preventing CCSMC phenotypic modulation and attenuating oxidative stress.}, } @article {pmid37534078, year = {2023}, author = {Alam, MS and Hasan, MN and Maowa, Z and Khatun, F and Nazir, KHMNH and Alam, MZ}, title = {N-acetylcysteine reduces severity and mortality in COVID-19 patients: A systematic review and meta-analysis.}, journal = {Journal of advanced veterinary and animal research}, volume = {10}, number = {2}, pages = {157-168}, pmid = {37534078}, issn = {2311-7710}, abstract = {OBJECTIVES: Recent clinical studies suggest that oxidative stress is one of the key players in the pathogenesis of coronavirus disease 2019 (COVID-19), and N-acetylcysteine (NAC), a potent antioxidant, has been shown to improve clinical outcomes in COVID-19 patients. We conducted a systematic review and meta-analysis of the literature published on the therapeutic intervention of NAC on COVID-19 infection.

METHODS: We searched PubMed, Google Scholar, and Science Direct. We identified and screened eight studies with 20,503 participants, including 2,852 in the NAC-treated group and 17,651 in the placebo group, which reported the effect of NAC on COVID-19 infection. A meta-analysis was performed using forest plots under fixed effect estimates based on the standardized mean difference (SMD) and risk ratio (RR).

RESULTS: Pooled analysis showed that NAC was associated with lower mortality in patients with COVID-19 compared with the placebo group [RR, 0.65; (95% CI: 0.56 to 0.75); p < 0.0001]. Similarly, C-reactive protein (CRP) [SMD, -0.32; (95% CI: -56 to -0.09); p = 0.0070] and D-dimer [SMD, -0.35, (95% CI: -0.59 to -0.10; p = 0.0062] levels were significantly decreased, and the oxygenation marker, PaO2/FiO2 ratio, was increased in the NAC-treated group compared with the placebo group [SMD, 0.76; (95% CI: 0.48 to 1.03); p < 0.0001].

CONCLUSION: Although the number of included studies was minimal, this meta-analysis suggests that NAC may have a positive effect on COVID-19 outcomes, specifically, a significant decrease in CRP and D-dimer levels and a significant increase in oxygen saturation, which decreased mortality. We have also presented a comprehensive review of the role and mechanisms of NAC in patients with COVID-19.}, } @article {pmid37532734, year = {2023}, author = {Chen, W and Yin, Y and Zhang, Z}, title = {Effects of N-acetylcysteine on CG8005 gene-mediated proliferation and apoptosis of Drosophila S2 embryonic cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {12502}, pmid = {37532734}, issn = {2045-2322}, mesh = {Animals ; Male ; *Acetylcysteine/pharmacology ; *Antioxidants/pharmacology ; Apoptosis ; Cell Proliferation ; *Drosophila/embryology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Drosophila Proteins/genetics/physiology ; }, abstract = {To investigate the effect of the antioxidant N-acetylcysteine (NAC) on the proliferation and apoptosis in CG8005 gene-interfering Drosophila S2 embryonic cells by scavenging intracellular reactive oxygen species (ROS). The interfering efficiency of CG8005 gene in Drosophila S2 embryonic cells was verified by real-time quantitative PCR (qRT-PCR). Different concentrations of NAC and phosphate buffered saline (PBS) were used to affect the Drosophila S2 embryonic cells. The growth state of Drosophila S2 embryonic cells was observed by light microscope. Two probes dihydroethidium (DHE) and 2,7-dichlorodihydrofluorescein-acetoacetate (DCFH-DA) were used to observe the ROS production in each group after immunofluorescence staining. TUNEL staining and flow cytometry were used to investigate the apoptosis level of Drosophila S2 embryos, and CCK-8 (Cell Counting Kit-8) was used to detect the cell viability of Drosophila S2 embryos. The knockdown efficiency of siCG8005-2 fragment was high and stable, which was verified by interference efficiency (P < 0.05). There was no significant change in the growth of Drosophila S2 embryonic cells after the treatment of NAC as compared to PBS group. Moreover, knockdowning CG8005 gene resulted in an increase in ROS and apoptosis in Drosophila S2 embryonic cells (P < 0.05) and a decrease in proliferation activity (P < 0.05). In addition, the pretreatment of antioxidant NAC could inhibit ROS production in Drosophila S2 embryonic cells (P < 0.05), reduce cell apoptosis (P < 0.05), and improve cell survival (P < 0.05). The CG8005 gene in Drosophila S2 embryonic cells could regulate the proliferation and apoptosis of S2 embryonic cells by disrupting the redox homeostasis, and antioxidant NAC could inhibit cell apoptosis and promotes cell proliferation by scavenging ROS in Drosophila S2 embryonic cells, which is expected to provide novel insights for the pathogenesis of male infertility and spermatogenesis.}, } @article {pmid37531905, year = {2023}, author = {Zhai, BW and Zhao, H and Zhu, HL and Huang, H and Zhang, MY and Fu, YJ}, title = {Triterpene acids from Rosa roxburghii Tratt fruits exert anti-hepatocellular carcinoma activity via ROS/JNK signaling pathway-mediated cell cycle arrest and mitochondrial apoptosis.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {119}, number = {}, pages = {154960}, doi = {10.1016/j.phymed.2023.154960}, pmid = {37531905}, issn = {1618-095X}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; MAP Kinase Signaling System ; *Rosa ; Fruit ; *Carcinoma, Hepatocellular/pathology ; Cell Cycle Checkpoints ; Apoptosis ; Hep G2 Cells ; *Triterpenes/pharmacology ; *Liver Neoplasms/pathology ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Rosa roxburghii Tratt (RRT) is a famous healthy and medicinal edible fruit in southwest China and has been shown to have some hepatoprotective properties. However, whether the active components, such as the triterpene acids from Rosa roxburghii Tratt fruits (TAR), have anti-hepatocellular carcinoma (HCC) effects and the potential molecular mechanisms are still unclear.

PURPOSE: This study aimed to investigate the anti-HCC effects and potential action mechanisms of triterpene components in RRT fruits.

METHODS: The triterpene acids in TAR were analyzed by using UPLC-Q-Exactive Orbitrap/MS, and the main components were virtual screening for targets based on pharmacophore and then performed enrichment analysis. HepG2 cells were used for in vitro experiments, including MTT assay, wound healing assay, and flow cytometry to detect cell cycle, reactive oxygen species (ROS) level, caspase-3 activity, and mitochondrial membrane potential (MMP) changes. Moreover, the western blot was used to detect mitochondrial apoptosis and ROS/ c-Jun N-terminal kinase (JNK) signaling pathway-related proteins.

RESULTS: The main components in TAR are pentacyclic triterpene acids (mainly euscaphic acid and roxburic acid). TAR could inhibit cell viability, cell migration ability and suppress the proliferation of HepG2 cells through G2/M cell cycle arrest. On the other hand, TAR could induce HepG2 cells apoptosis, which was achieved by causing the accumulation of ROS and activation of the JNK signaling pathway, and our research showed that this apoptosis was mediated through the mitochondrial pathway. In addition, the free radical scavenger N-acetyl cysteine (NAC) could attenuate TAR-induced ROS accumulation and JNK signaling pathway activation, which ultimately reversed mitochondrial apoptosis.

CONCLUSION: TAR could activate the ROS/JNK signaling pathway, which could inhibit the proliferation through G2/M cell cycle arrest and promote apoptosis through the mitochondrial pathway in HCC cells. This supports the anti-tumor potential in RRT fruits.}, } @article {pmid37522842, year = {2023}, author = {Pan, X and Giustarini, D and Lang, F and Rossi, R and Wieder, T and Köberle, M and Ghashghaeinia, M}, title = {Desipramine induces eryptosis in human erythrocytes, an effect blunted by nitric oxide donor sodium nitroprusside and N-acetyl-L-cysteine but enhanced by Calcium depletion.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {22}, number = {17}, pages = {1827-1853}, pmid = {37522842}, issn = {1551-4005}, mesh = {Humans ; *Nitric Oxide Donors/pharmacology/metabolism ; Nitroprusside/pharmacology/metabolism ; *Eryptosis ; Calcium/metabolism ; Acetylcysteine/pharmacology ; Desipramine/pharmacology/metabolism ; Erythrocytes/metabolism ; Glutathione/metabolism/pharmacology ; Annexins/metabolism/pharmacology ; Phosphatidylserines/metabolism ; Cell Size ; Ceramides/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; }, abstract = {Background: Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER) and norepinephrine (NE) in the presynaptic membrane by directly blocking their respective transporters SERT and NET.Aims: To study the effect of desipramine on programmed erythrocyte death (eryptosis) and explore the underlying mechanisms.Methods: Phosphatidylserine (PS) exposure on the cell surface as marker of cell death was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry. Hemolysis was determined photometrically, and intracellular glutathione [GSH]i from high performance liquid chromatography.Results: Desipramine dose-dependently significantly enhanced the percentage of annexin-V-binding cells and didn´t impact glutathione (GSH) synthesis. Desipramine-induced eryptosis was significantly reversed by pre-treatment of erythrocytes with either nitric oxide (NO) donor sodium nitroprusside (SNP) or N-acetyl-L-cysteine (NAC). The highest inhibitory effect was obtained by using both inhibitors together. Calcium (Ca[2+]) depletion aggravated desipramine-induced eryptosis. Changing the order of treatment, i.e. desipramine first followed by inhibitors, could not influence the inhibitory effect of SNP or NAC.Conclusion: Antidepressants-caused intoxication can be treated by SNP and NAC, respectively. B) Patients with chronic hypocalcemia should not be treated with tricyclic anti-depressants or their dose should be noticeably reduced.}, } @article {pmid37522559, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Huerta-Yepez, S and Maharaj, D and Jewett, A}, title = {The Potential Role of Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis (ALS); A Longitudinal Case Study Comparing Patients with Genetically Identical Healthy Twin.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {27-39}, doi = {10.1615/CritRevImmunol.2023047233}, pmid = {37522559}, issn = {1040-8401}, abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neurons. The causes of ALS are heterogeneous, and are only partially understood to date. We studied percentage and function of immune cell subsets in particular natural killer (NK) and CD8+ T cells in an ALS patient and compared the results to those obtained from his genetically identical healthy twin in a longitudinal study. We found several basic mechanisms which were potentially involved in the disease induction and progression. Our findings demonstrate that ALS patient's peripheral blood contained higher NK and B cells and, lower T cell percentages compared with the healthy twin brother's peripheral blood. Significantly increased interferon-gamma secretion by anti-CD3/28 monoclonal antibody-treated peripheral blood mononuclear cells, and sorted CD8+ T cells were observed in the ALS patient, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism of ALS progression. Significant increase in NK cell function due to genetic mutations in ALS associated genes may partly be responsible for the increase expansion and function of CD8+ T cells with effector/memory phenotype, in addition to direct activation and expansion of antigen specific T cells by such mutations. Weekly N-acetyl cysteine infusion to block cell death in patient in addition to a number of other therapies listed in this paper were not effective, and even though the treatments might have extended the patient's life, it was not curative. Therefore, activated CD8+ T and NK cells are likely cells targeting motor neurons in the patient, and strategies should be designed to decrease the aggressive nature of these cells to achieve longer lasting therapeutic benefits.}, } @article {pmid37522557, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Huerta-Yepez, S and Maharaj, D and Malarkannan, S and Jewett, A}, title = {Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023047235}, pmid = {37522557}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Cytokines/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.}, } @article {pmid37522109, year = {2023}, author = {Girone, N and Benatti, B and Molteni, L and Cassina, N and Giacovelli, L and Arici, C and Dell'Osso, B}, title = {Partial Response to Antidepressant Treatment: The Role of Nutraceutical Compounds.}, journal = {Clinical neuropsychiatry}, volume = {20}, number = {3}, pages = {183-192}, pmid = {37522109}, issn = {2385-0787}, abstract = {OBJECTIVE: Depression represents one of the most severe psychiatric disorders, characterized by low mood episodes, as well as loss of interest. Major Depressive Episodes (MDE) treatment relies primarily on monoaminergic prescriptions. However, although the presence of many antidepressant medications, their efficacy is still partial. A promising intervention to improve antidepressant treatment may be the use of adjunctive nutraceuticals. Aim of the present study was to assess the efficacy of a N-Acetyl-cysteine, S-Adenosyl-L-Methionine and Folic acid's combination for the treatment of depressive symptoms in a sample of MDE patients.

METHOD: Fifty outpatients with a MDE diagnosis in the context of different psychiatric disorders such as Major Depression, Bipolar Disorder, Anxiety disorders, and Personality disorders were recruited. The sample was divided into different groups based on the nutraceutical administration: a) concurrently with an AD (starter group); b) add-on to an already prescribed treatment; c) single treatment.

RESULTS: A significant reduction of CGI-Severity and Improvement scores from baseline to the end of treatment was found. Moreover, the starter group showed a significantly greater CGI-Improvement score compared to the other groups. Ninety-four percent of patients did not show any side effects.

CONCLUSIONS: The present study showed promising results for the use of nutraceuticals in the add-on treatment of MDE. Those compounds may be considered a versatile, tolerable, and effective add-on treatment for the reduction of depressive symptoms impact and for improving the functioning of patients affected by MDE.}, } @article {pmid37521669, year = {2023}, author = {Shalaby, AS and Eid, HH and El-Shiekh, RA and Mohamed, OG and Tripathi, A and Al-Karmalawy, AA and Sleem, AA and Morsy, FA and Ibrahim, KM and Tadros, SH and Youssef, FS}, title = {Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity.}, journal = {ACS omega}, volume = {8}, number = {29}, pages = {26444-26457}, pmid = {37521669}, issn = {2470-1343}, abstract = {Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 μg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 μM Trolox eq/mL juice, 718.95-3749.47 μM Trolox eq/mL juice, and 2304.74-4390.32 μM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.}, } @article {pmid37520878, year = {2023}, author = {Afaghi, S and Moghimi, N and Malekpour Alamdari, N and Rahimi, FS and Irilouzadian, R and Esmaeili Tarki, F and Moghimi, M and Besharat, S and Salehi Omran, H and Karimi, A}, title = {N-acetylcysteine as adjuvant therapy for hospitalized Covid-19 patients: A single-center prospective cohort study.}, journal = {Caspian journal of internal medicine}, volume = {14}, number = {3}, pages = {543-552}, pmid = {37520878}, issn = {2008-6164}, abstract = {BACKGROUND: Whilst over two years have passed since the COVID-19 pandemic's emergence, the proper management of the disease remains challenging. N-acetylcysteine (NAC) as a potentially effective therapeutic option has been suggested by studies, while the exact clinical role of this agent is yet to be evaluated.

METHODS: This prospective case-control study was conducted in a major referral respiratory center in Tehran, Iran. We enrolled 217 patients treated with an intravenous daily dose of 1500 mg NAC as a case group; and 245 control patients who did not receive NAC. Two groups were matched based on other treatments, socio-demographics, medical history, and comorbidities.

RESULTS: After ten days of adjuvant therapy with NAC, patients in the NAC group and control group had median room-air SpO2 of 91% and 88%, respectively (P=0.02). Also, the SpO2 to FiO2 ratio had a median of 463 and 421 in the case and control groups, respectively (P=0.01). Furthermore, the case group's hospitalization period was three days shorter (P=0.002). Further, cough, dyspnea, and decreased appetite were reported to have a significantly lower incidence in the case group (P=0.03, 0.001, 0.008).

CONCLUSION: We showed that a daily intravenous dose of NAC in hospitalized COVID-19 patients could shorten the hospital stay and improve some clinical symptoms; however, it does not remarkably improve the risk of ICU admission and the 28 days in-hospital mortality rate.}, } @article {pmid37519003, year = {2023}, author = {Zhuo, Y and Chen, H and Liu, C and Zhang, Y and Fang, J and Li, M and Wang, Z and Jiang, Q and Yu, L and Pan, H and Wang, Q}, title = {Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.}, journal = {Current drug metabolism}, volume = {24}, number = {8}, pages = {611-620}, doi = {10.2174/1389200224666230727123006}, pmid = {37519003}, issn = {1875-5453}, abstract = {BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites.

OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST.

METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer.

RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor.

CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).}, } @article {pmid37517999, year = {2023}, author = {Cazzola, M and Page, CP and Wedzicha, JA and Celli, BR and Anzueto, A and Matera, MG}, title = {Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.}, journal = {Respiratory research}, volume = {24}, number = {1}, pages = {194}, pmid = {37517999}, issn = {1465-993X}, mesh = {Humans ; *Antioxidants/therapeutic use/pharmacology ; Sulfhydryl Compounds/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy/chemically induced ; Adrenal Cortex Hormones ; Oxidative Stress ; Acetylcysteine/therapeutic use ; Inflammation/drug therapy ; Expectorants/therapeutic use ; }, abstract = {BACKGROUND: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination.

MAIN BODY: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS.

CONCLUSIONS: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD.}, } @article {pmid37517847, year = {2023}, author = {}, title = {Retraction notice to "Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial".}, journal = {Fertility and sterility}, volume = {120}, number = {2}, pages = {395}, doi = {10.1016/j.fertnstert.2023.06.016}, pmid = {37517847}, issn = {1556-5653}, } @article {pmid37511170, year = {2023}, author = {Kubovcikova, M and Sobotova, R and Zavisova, V and Antal, I and Khmara, I and Lisnichuk, M and Bednarikova, Z and Jurikova, A and Strbak, O and Vojtova, J and Mikolka, P and Gombos, J and Lokajova, A and Gazova, Z and Koneracka, M}, title = {N-Acetylcysteine-Loaded Magnetic Nanoparticles for Magnetic Resonance Imaging.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511170}, issn = {1422-0067}, support = {ITMS 313011AVG3//Operational Programme Integrated Infrastructure co-funded by ERDF/ ; APVV-18-0284, APVV SK-TW-21-0004//the Slovak Research and Development Agency/ ; EGA 02/0176/21, VEGA 02/0164/22, VEGA 02/0049/23//Slovak Grant Agency/ ; IMTS: 313011BWX6//The application of spectroscopic methods for early, non-invasive real-time identification of selected diseases using gasses released from lungs and skin/ ; ITMS: 313011AVG3 "BIOVID"//he Operational Program Integrated Infrastructure funded by the ERDF ITMS2014+ 313011T553 "DIAGNAD"/ ; }, mesh = {*Magnetite Nanoparticles/chemistry ; Contrast Media/chemistry ; Acetylcysteine/pharmacology ; Magnetic Resonance Imaging/methods ; *Nanoparticles/chemistry ; Adsorption ; }, abstract = {Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by the rapid onset of lung inflammation Therefore, monitoring the spatial distribution of the drug directly administered to heterogeneously damaged lungs is desirable. In this work, we focus on optimizing the drug N-acetylcysteine (NAC) adsorption on poly-l-lysine-modified magnetic nanoparticles (PLLMNPs) to monitor the drug spatial distribution in the lungs using magnetic resonance imaging (MRI) techniques. The physicochemical characterizations of the samples were conducted in terms of morphology, particle size distributions, surface charge, and magnetic properties followed by the thermogravimetric quantification of NAC coating and cytotoxicity experiments. The sample with the theoretical NAC loading concentration of 0.25 mg/mL was selected as an optimum due to the hydrodynamic nanoparticle size of 154 nm, the surface charge of +32 mV, good stability, and no cytotoxicity. Finally, MRI relaxometry confirmed the suitability of the sample to study the spatial distribution of the drug in vivo using MRI protocols. We showed the prevailing transverse relaxation with high transverse relaxivity values and a high r2[(]*[)]/r1 ratio, causing visible hypointensity in the final MRI signal. Furthermore, NAC adsorption significantly affects the relaxation properties of PLLMNPs, which can help monitor drug release in vitro/in vivo.}, } @article {pmid37509878, year = {2023}, author = {Mao, B and Ren, B and Wu, J and Tang, X and Zhang, Q and Zhao, J and Zhang, L and Chen, W and Cui, S}, title = {The Protective Effect of Broccoli Seed Extract against Lipopolysaccharide-Induced Acute Liver Injury via Gut Microbiota Modulation and Sulforaphane Production in Mice.}, journal = {Foods (Basel, Switzerland)}, volume = {12}, number = {14}, pages = {}, pmid = {37509878}, issn = {2304-8158}, support = {2020B020226008//Key-Area Research and Development Program of Guangdong Province/ ; 31972086//National Natural Science Foundation of China/ ; }, abstract = {Broccoli seed extract (BSE) is rich in glucoraphanin (GRP), which may be transformed by intestinal microbes into sulforaphane (SFN), a compound with strong anti-inflammatory and antioxidant activities. Liver injury usually presents with inflammation and oxidative damage. Thus, dietary BSE supplementation may be an effective approach for alleviating liver injury. In this study, a mouse lipopolysaccharide (LPS)-induced acute liver injury model was used to evaluate the preventive effect of BSE and explore the relevant mechanisms. Compared with the LPS model group, the mice in the BSE group showed significantly lower activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) and higher levels of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Meanwhile, BSE significantly reduced the levels of pro-inflammatory cytokines (including IL-6 and TNF-α) in the liver and increased the level of anti-inflammatory factor (IL-10), indicating that BSE had a good preventive effect on acute liver injury. Additionally, after BSE intervention, the diversity of intestinal microbiota in the mice was higher than that in the LPS model group. The relative abundance of Akkermansia and Lactobacillus increased, while the relative abundance of Xylanophilum decreased. A correlation analysis revealed that the activities of SOD, GSH-Px, CAT and levels of IL-10 were positively correlated with the relative abundance of Lactobacillus. Furthermore, sulforaphane (SFN) and (Sulforaphane-N-Acetyl-Cysteine) SFN-NAC were detected in the urine of the mice after BSE intervention. Both q-PCR and an immunohistochemical analysis showed that BSE significantly regulated the expression level of the NF-κB (IκB-α, NF-κB) and Nrf2 (Nrf2, p-Nrf2 and HO-1) signaling pathways in the liver. In conclusion, BSE was shown to reduce LPS-induced acute liver injury through the conversion of glucoraphanin into sulforaphane and the regulation of the gut microbiota composition. These results suggest that BSE could be a promising ingredient in functional foods.}, } @article {pmid37508477, year = {2023}, author = {Siemsen, BM and Denton, AR and Parrila-Carrero, J and Hooker, KN and Carpenter, EA and Prescot, ME and Brock, AG and Westphal, AM and Leath, MN and McFaddin, JA and Jhou, TC and McGinty, JF and Scofield, MD}, title = {Heroin Self-Administration and Extinction Increase Prelimbic Cortical Astrocyte-Synapse Proximity and Alter Dendritic Spine Morphometrics That Are Reversed by N-Acetylcysteine.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508477}, issn = {2073-4409}, support = {F32 DA50427/NH/NIH HHS/United States ; T32 DA007288/NH/NIH HHS/United States ; DA046373/NH/NIH HHS/United States ; R01 DA054154/DA/NIDA NIH HHS/United States ; DA05154/NH/NIH HHS/United States ; DA037327/NH/NIH HHS/United States ; K01 DA053434/NH/NIH HHS/United States ; DA033680-11/NH/NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; P50 DA046373/DA/NIDA NIH HHS/United States ; DA044468/NH/NIH HHS/United States ; }, mesh = {Rats ; Animals ; Male ; Rats, Sprague-Dawley ; *Heroin/pharmacology ; *Acetylcysteine/pharmacology ; Astrocytes ; Synapses ; Glutamates ; Recurrence ; }, abstract = {Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astrocyte glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observe functional adaptations in the PrL cortical astrocyte following heroin self-administration (SA) and extinction as measured by the electrophysiologically evoked plasmalemmal glutamate transporter 1 (GLT-1)-dependent current. We likewise observed the increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astrocytic plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astrocytic complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased the apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased the co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, the accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Finally, we show that the NAC treatment and elimination of thrombospondin 2 (TSP-2) block cue-induced heroin relapse. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at the synapses. Additionally, these data demonstrate that NAC reverses PrL cortical heroin SA-and-extinction-induced adaptations in both astrocytes and corticostriatal neurons.}, } @article {pmid37507934, year = {2023}, author = {Eligini, S and Munno, M and Atlas, D and Banfi, C}, title = {N-acetylcysteine Amide AD4/NACA and Thioredoxin Mimetic Peptides Inhibit Platelet Aggregation and Protect against Oxidative Stress.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507934}, issn = {2076-3921}, support = {Ricerca Corrente//Italian Ministry of Health, Rome, Italy/ ; }, abstract = {In the present study, we tested the effect of small-molecular-weight redox molecules on collagen-induced platelet aggregation. We used N-acetylcysteine amide (AD4/NACA), the amide form of N-acetylcysteine (NAC), a thiol antioxidant with improved lipophilicity and bioavailability compared to NAC, and the thioredoxin-mimetic (TXM) peptides, TXM-CB3, TXM-CB13, and TXM-CB30. All compounds significantly inhibited platelet aggregation induced by collagen, with TXM-peptides and AD4 being more effective than NAC. The levels of TxB2 and 12-HETE, the main metabolites derived from the cyclooxygenase and lipoxygenase pathways following platelet activation, were significantly reduced in the presence of AD4, TXM peptides, or NAC, when tested at the highest concentration (0.6 mM). The effects of AD4, TXM-peptides, and NAC were also tested on the clotting time (CT) of whole blood. TXM-CB3 and TXM-CB30 showed the greatest increase in CT. Furthermore, two representative compounds, TXM-CB3 and NAC, showed an increase in the anti-oxidant free sulfhydryl groups of plasma detected via Ellman's method, suggesting a contribution of plasma factors to the antiaggregating effects. Our results suggest that these small-molecular-weight redox peptides might become useful for the prevention and/or treatment of oxidative stress conditions associated with platelet activation.}, } @article {pmid37507913, year = {2023}, author = {Martinez-Banaclocha, MA}, title = {Targeting the Cysteine Redox Proteome in Parkinson's Disease: The Role of Glutathione Precursors and Beyond.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507913}, issn = {2076-3921}, abstract = {Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson's disease.}, } @article {pmid37507904, year = {2023}, author = {Chamorro, B and Izquierdo-Bermejo, S and Martín-de-Saavedra, MD and López-Muñoz, F and Chioua, M and Marco-Contelles, J and Oset-Gasque, MJ}, title = {Neuroprotective and Antioxidant Properties of CholesteroNitrone ChN2 and QuinolylNitrone QN23 in an Experimental Model of Cerebral Ischemia: Involvement of Necrotic and Apoptotic Cell Death.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507904}, issn = {2076-3921}, support = {"MITOPI" and "NENTS"//Camilo José Cela University/ ; SAF2015-65586-R//Spanish Ministry of Economy and Competitiveness/ ; PID2021-122723OA100//Spanish Research Agency/ ; }, abstract = {Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments. In this regard, nitrones represent a very promising alternative due to their renowned antioxidant and anti-inflammatory effects. In this study, we aimed to further investigate the neuroprotective effects of two nitrones, cholesteronitrone 2 (ChN2) and quinolylnitrone 23 (QN23), which have previously shown great potential for the treatment of stroke. Using an experimental in vitro model of cerebral ischemia, we compared their anti-necrotic, anti-apoptotic, and antioxidant properties with those of three reference compounds. Both ChN2 and QN23 demonstrated significant neuroprotective effects (EC50 = 0.66 ± 0.23 μM and EC50 = 2.13 ± 0.47 μM, respectively) comparable to those of homo-bis-nitrone 6 (HBN6) and N-acetylcysteine (NAC) and superior to those of α-phenyl-N-tert-butylnitrone (PBN). While primarily derived from the nitrones' anti-necrotic capacities, their anti-apoptotic effects at high concentrations and antioxidant powers-especially in the case of QN23-also contribute to their neuroprotective effects.}, } @article {pmid37507857, year = {2023}, author = {Sahasrabudhe, SA and Terluk, MR and Kartha, RV}, title = {N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507857}, issn = {2076-3921}, abstract = {N-acetylcysteine (NAC), a precursor of cysteine and, thereby, glutathione (GSH), acts as an antioxidant through a variety of mechanisms, including oxidant scavenging, GSH replenishment, antioxidant signaling, etc. Owing to the variety of proposed targets, NAC has a long history of use as a prescription product and in wide-ranging applications that are off-label as an over-the-counter (OTC) product. Despite its discovery in the early 1960s and its development for various indications, systematic clinical pharmacology explorations of NAC pharmacokinetics (PK), pharmacodynamic targets, drug interactions, and dose-ranging are sorely limited. Although there are anecdotal instances of NAC benefits in a variety of diseases, a comprehensive review of the use of NAC in rare diseases does not exist. In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction along with the history of NAC usage, approved indications, mechanisms of action, safety, and PK characterization. Further, we introduce the research currently underway on other structural derivatives of NAC and acknowledge the continuum of efforts through pre-clinical and clinical research to facilitate further therapeutic development of NAC or its derivatives for rare diseases.}, } @article {pmid37503600, year = {2023}, author = {Onay, ZR and Ayhan, Y and Can Oksay, S and Mavi, D and Bilgin, G and Toksoz Yıldırım, A and Canbolat Ayhan, A and Girit, S}, title = {The First Definition of Pulmonary Component of Hypereosinophilic Syndrome: Bronchial Casts.}, journal = {Thoracic research and practice}, volume = {24}, number = {1}, pages = {49-52}, pmid = {37503600}, issn = {2979-9139}, abstract = {Hypereosinophilic syndrome is a heterogeneous disease characterized by eosinophilic tissue inflammation and eosinophilia. Pulmonary involvement could be seen in up to 55% among children with hypereosinophilic syndrome. A 3-year-old boy with chronic hypereosinophilia and respiratory complaints was diagnosed with idiopathic hypereosinophilic syndrome. Atelectasis was detected in the radiological evaluation, and bronchial casts with eosinophilic structures were removed by bronchoscopy. Steroid, inhaled hypertonic saline, inhaled bronchodilator, inhaled corticosteroid, and leukotriene receptor antagonist were used for 1 year in the management of hypereosinophilic syndrome, and related eosinophilic casts and repetitive bronchoscopies were administered for removal of the casts. The patient was successfully managed with an inhaled N-acetyl cysteine treatment. In children, the long-term prognosis of hypereosinophilic syndrome is uncertain. Comprehensive diagnostic tests are required for the early diagnosis and management of pediatric hypereosinophilic syndrome. In the presented case, the rare occurrence of pulmonary involvement of hypereosinophilic syndrome in a 3 year-old-boy with recurrent hypereosinophilic casts and its management were discussed.}, } @article {pmid37503369, year = {2023}, author = {Methods In Medicine, CAM}, title = {Retracted: N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells.}, journal = {Computational and mathematical methods in medicine}, volume = {2023}, number = {}, pages = {9819038}, pmid = {37503369}, issn = {1748-6718}, abstract = {[This retracts the article DOI: 10.1155/2021/7596343.].}, } @article {pmid37503292, year = {2023}, author = {Piraino, L and Chen, CY and Mereness, J and Dunman, PM and Ovitt, C and Benoit, D and DeLouise, L}, title = {Identifying novel radioprotective drugs via salivary gland tissue chip screening.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.07.12.548707}, pmid = {37503292}, issn = {2692-8205}, support = {F31 DE029658/DE/NIDCR NIH HHS/United States ; UG3 DE027695/DE/NIDCR NIH HHS/United States ; UH3 DE027695/DE/NIDCR NIH HHS/United States ; }, abstract = {During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC 50 values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.}, } @article {pmid37499713, year = {2023}, author = {He, D and Qian, L and Chen, X and He, B and Li, J}, title = {Durable cellulose paper by grafting thiol groups and controlling silver deposition for ultrahigh electromagnetic interference shielding.}, journal = {International journal of biological macromolecules}, volume = {248}, number = {}, pages = {125972}, doi = {10.1016/j.ijbiomac.2023.125972}, pmid = {37499713}, issn = {1879-0003}, mesh = {*Ammonia ; *Silver ; Acetylcysteine ; Cellulose ; Electric Conductivity ; Sulfhydryl Compounds ; }, abstract = {Electromagnetic interference (EMI) shielding paper with durability and high effectiveness is of significant importance to long-term service for preventing EMI pollution. Herein, we report a practical method for preparing cellulose paper/Ag composite with outstanding durable and ultrahigh EMI shielding performance by electroless silver plating. The silver deposition process, the surface morphology, the silver content and conductivity of the composite can be controlled by varying the amount of N-acetyl-L-cysteine (NAC) grafted onto the cellulose fibers and ammonia amount for silver-ammonia complex formation. Moreover, the grafted NAC with thiol groups on cellulose can enhance the adhesion between silver and cellulose paper, meanwhile, NAC as the reducing agent can result in a more complete flower-shaped silver structure and reducing the reflection of electromagnetic waves in silver layer. The composite exhibited excellent conductivity, EMI shielding effectiveness (SE) up to 106 dB and outstanding durability. After 10,000 bending times and 60 abrasion cycles respectively, the electrical resistance of the composite only increased from 0.030 Ω/sq. to 0.041 Ω/sq. and 0.050 Ω/sq., and the EMI SE decreased to 102 dB and 105 dB.}, } @article {pmid37495528, year = {2023}, author = {Korkmaz, Y and Gungor, H and Demirbas, A and Dik, B}, title = {Pomegranate peel extract, N-Acetylcysteine and their combination with Ornipural alleviate Cadmium-induced toxicity in rats.}, journal = {The Journal of veterinary medical science}, volume = {85}, number = {9}, pages = {990-997}, pmid = {37495528}, issn = {1347-7439}, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology ; Rats, Wistar ; Cadmium/toxicity ; *Pomegranate ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {Cadmium is a major environmental pollutant and a highly toxic metal. It was aimed to determine the effects of pomegranate peel extract (PPE), N-acetylcysteine (NAC) alone and along with Ornipural on cadmium-induced toxicity. Forty-six Wistar Albino male rats were divided into 6 groups and the groups were formed into healthy control, Cadmium group (5 mg/kg/day, oral), Cadmium + Pomegranate peel extract (500 mg/kg, oral), Cadmium + N-acetylcysteine (100 mg/kg, oral), Cadmium + Pomegranate peel extract (500 mg/kg, oral) + Ornipural (1 mL/kg, subcutaneous) and Cadmium + N-acetylcysteine (100 mg/kg, oral) + Ornipural (1 mL/kg, subcutaneous). Cadmium accumulated heavily in both liver and kidney tissue. The administration of N-acetylcysteine and pomegranate peel extract alone reduced cadmium levels in both tissues. N-acetylcysteine treatment prevented the increase in ALT and MDA levels by cadmium damage. N-acetylcysteine + Ornipural treatment inhibited the increase in liver 8-OHdG level in the liver. N-acetylcysteine and N-acetylcysteine + Ornipural treatments prevented the reduced serum MMP2 level. N-acetylcysteine and Pomegranate peel extract + Ornipural treatments significantly reduced the increased liver iNOS level in the liver. In conclusion, NAC therapy may be a successful treatment option for cadmium toxicity. However, further research is needed on the effects of PPE and Ornipural combinations for the treatment of cadmium toxicity. In future studies, various doses of these treatment options (with chelators) should be investigated for cadmium toxicity.}, } @article {pmid37495077, year = {2023}, author = {Ding, Q and Sun, B and Wang, M and Li, T and Li, H and Han, Q and Liao, J and Tang, Z}, title = {N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway.}, journal = {Life sciences}, volume = {329}, number = {}, pages = {121975}, doi = {10.1016/j.lfs.2023.121975}, pmid = {37495077}, issn = {1879-0631}, mesh = {Dogs ; Animals ; Antioxidants/metabolism ; Acetylcysteine/pharmacology/metabolism ; NF-E2-Related Factor 2/metabolism ; *Diabetes Mellitus, Type 1/complications/drug therapy/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; bcl-2-Associated X Protein/metabolism ; Signal Transduction ; Oxidative Stress ; Muscular Atrophy/drug therapy/prevention & control/metabolism ; Muscle, Skeletal/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis ; *Insulins/metabolism/pharmacology ; }, abstract = {AIMS: Type 1 diabetes mellitus (T1DM) has been linked to the occurrence of skeletal muscle atrophy. Insulin monotherapy may lead to excessive blood glucose fluctuations. N-acetylcysteine (NAC), a clinically employed antioxidant, possesses cytoprotective, anti-inflammatory, and antioxidant properties. The objective of our study was to evaluate the viability of NAC as a supplementary treatment for T1DM, specifically regarding its therapeutic and preventative impacts on skeletal muscle.

MAIN METHODS: Here, we used beagles as T1DM model for 120d to explore the mechanism of NRF2/HO-1-mediated skeletal muscle oxidative stress and apoptosis and the therapeutic effects of NAC. Oxidative stress and apoptosis related factors were analyzed by immunohistochemistry, immunofluorescence, western blotting, and RT-qPCR assay.

KEY FINDINGS: The findings indicated that the co-administration of NAC and insulin led to a reduction in creatine kinase levels, preventing weight loss and skeletal muscle atrophy. Improvement in the reduction of muscle fiber cross-sectional area. The expression of Atrogin-1, MuRF-1 and MyoD1 was downregulated, while Myh2 and MyoG were upregulated. In addition, CAT and GSH-Px levels were increased, MDA levels were decreased, and redox was maintained at a steady state. The decreased of key factors in the NRF2/HO-1 pathway, including NRF2, HO-1, NQO1, and SOD1, while KEAP1 increased. In addition, the apoptosis key factors Caspase-3, Bax, and Bak1 were found to be downregulated, while Bcl-2, Bcl-2/Bax, and CytC were upregulated.

SIGNIFICANCE: Our findings demonstrated that NAC and insulin mitigate oxidative stress and apoptosis in T1DM skeletal muscle and prevent skeletal muscle atrophy by activating the NRF2/HO-1 pathway.}, } @article {pmid37491222, year = {2023}, author = {Mahfouz Omer, SM and El-Sherbiny, RH and El-Desouky, SS}, title = {Effect of N-Acetylcysteine on initial Carious Enamel Lesions in primary teeth: an In-vitro study.}, journal = {BMC oral health}, volume = {23}, number = {1}, pages = {520}, pmid = {37491222}, issn = {1472-6831}, mesh = {Humans ; *Dental Caries/therapy ; Acetylcysteine/pharmacology/therapeutic use ; Dental Enamel ; Fluorides/pharmacology ; Tooth, Deciduous ; Tooth Remineralization/methods ; }, abstract = {BACKGROUND: Dental caries initiates with non-cavitated enamel lesions as the first stage. The cariogenic potential of N-Acetylcysteine (NAC) may be due to its usage frequency and form. This study aimed to evaluate the impact of exposure time of NAC on initial enamel caries-like lesions in primary teeth by assessing the morphological alteration using a scanning electron microscope (SEM) and mineral content using energy dispersive x-ray spectroscopy (EDX).

METHODS: Forty primary incisor teeth were randomly divided into 4 groups S, S1, S2, and S3 (10 specimens/group). Teeth crowns were cut from their roots and inserted into an acrylic mold with its buccal surface directed upward. Centrally isolated enamel window (2 × 2 mm) on the tooth was done. Ten specimens were selected to evaluate normal enamel while the remaining thirty specimens were immersed in demineralizing solution for 96 h to produce enamel caries-like lesions. PH cycling was performed by immersing each tooth sample in 20 mL of demineralizing solution for 3 h then, preserved for the remaining day hours in 10 ml of artificial saliva interspersed with treatments applications with 10 ml NAC for 10 min twice a day for one- or three-months different treatment modalities. Thermocycling was done for all specimens then they were subjected to SEM and EDX analysis. ANOVA and Bonferroni post hoc tests were utilized in data analysis.

RESULTS: In teeth treated by NAC for 3 months (group-S3), SEM images showed severe loss of enamel architecture with large NAC deposits detected. A meaningful difference was observed among different groups concerning calcium, phosphorus, fluoride, ca/P ratio, carbon, nitrogen, and oxygen contents (P < 0.05).

CONCLUSION: NAC had a detrimental impact on enamel caries-like lesions in human primary teeth.}, } @article {pmid37487871, year = {2023}, author = {Wang, L and Zhang, X and Xu, M and Zheng, G and Chen, J and Li, S and Cui, J and Zhang, S}, title = {Implication of ferroptosis in hepatic toxicity upon single or combined exposure to polystyrene microplastics and cadmium.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {334}, number = {}, pages = {122250}, doi = {10.1016/j.envpol.2023.122250}, pmid = {37487871}, issn = {1873-6424}, mesh = {Humans ; Microplastics/toxicity ; Polystyrenes/toxicity ; Cadmium/toxicity ; Plastics/toxicity ; Reactive Oxygen Species ; *Ferroptosis ; Antioxidants ; *Water Pollutants, Chemical/toxicity ; }, abstract = {Microplastics (MPs) are a newly emerging type of pollutants. To date, MPs have been found in the atmosphere, soil, water, and even in human samples, posing a non-negligible threat to humans. Furthermore, multiple heavy metals have been found to co-exist with MPs or be absorbed by MPs. This leads to a widespread concern about their combined toxicity, which is currently elusive. Herein, we investigated the single or combined toxic effects of polystyrene MPs (PS-MPs) and cadmium chloride (CdCl2) on the liver and hepatocytes. After co-incubation, cadmium (Cd) can be absorbed by PS-MPs, resulting in physiochemical alterations of PS-MPs. In vivo and in vitro experiments revealed that PS-MPs solely or together with CdCl2 induced ferroptosis in hepatocytes, a newly defined programmed cell death characterized by lipid oxidation and iron accumulation. PS-MPs exerted more ferroptotic effect on hepatocytes than CdCl2, and combined exposure to PS-MPs and CdCl2 enhanced their ferroptotic effect, mainly by stimulating reactive oxygen species (ROS) production and inhibiting antioxidant activity. Upon single or combined exposure to PS-MPs and CdCl2, the induction of ferroptosis in hepatocytes can be inhibited by N-acetyl-cysteine (NAC, an ROS scavenger), deferoxamine (DFO, an iron chelator), and particularly ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). Fer-1 efficiently rescued the cell viability of hepatocytes upon exposure to PS-MPs and CdCl2 through enhancing the antioxidant system via upregulating GPX4 and SLC7A11. These findings would contribute to an in-depth understanding of the single and combined toxicity of microplastics and cadmium.}, } @article {pmid37487865, year = {2023}, author = {Samandari-Bahraseman, MR and Khorsand, B and Zareei, S and Amanlou, M and Rostamabadi, H}, title = {Various concentrations of hesperetin induce different types of programmed cell death in human breast cancerous and normal cell lines in a ROS-dependent manner.}, journal = {Chemico-biological interactions}, volume = {382}, number = {}, pages = {110642}, doi = {10.1016/j.cbi.2023.110642}, pmid = {37487865}, issn = {1872-7786}, mesh = {Humans ; Female ; *Hesperidin/pharmacology ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Apoptosis ; Cell Line, Tumor ; Superoxide Dismutase/metabolism ; *Breast Neoplasms ; }, abstract = {The polyphenolic component of citrus fruits, hesperetin (Hst), is a metabolite of hesperidin. In this study, we examined the effect of varying doses and exposure times of hesperetin on MCF-7 and MDA-MB-231 cancer cells, as well as MCF-10A normal cells. By using MTT assay, real-time PCR, western blot, and flow cytometry, we determined the effects of Hst on cell viability, ROS levels, and markers of cell death. Furthermore, molecular docking was used to identify Hst targets that might be involved in ROS-dependent cell death. According to the results, different concentrations of Hst induced different modes of cell death at specific ROS levels. Paraptosis occurred in all cell lines at concentration ranges of IC35 to IC60, and apoptosis occurred at concentrations greater than IC65. In addition, MDA-MB-231 cells were subjected to senescence at sub-toxic doses when treated for a long period of time. When Hst levels were higher, N-acetylcysteine (NAC)'s effect on neutralizing ROS was more pronounced. According to the docking results, Hst may interact with several proteins involved in the regulation of ROS. As an example, the interaction of CCS (Copper chaperone for superoxide dismutase) with Hst might interfere with its chaperone function in folding SOD-1 (superoxide dismutase enzyme), contributing to an increase in cytoplasmic ROS levels. Finally, depending on the ROS level, Hst induces various modes of cell death.}, } @article {pmid37487439, year = {2023}, author = {Aki, T and Tanaka, H and Funakoshi, T and Unuma, K and Uemura, K}, title = {Excessive N-acetylcysteine exaggerates glutathione redox homeostasis and apoptosis during acetaminophen exposure in Huh-7 human hepatoma cells.}, journal = {Biochemical and biophysical research communications}, volume = {676}, number = {}, pages = {66-72}, doi = {10.1016/j.bbrc.2023.07.023}, pmid = {37487439}, issn = {1090-2104}, mesh = {Humans ; Acetylcysteine/metabolism ; Acetaminophen/toxicity ; *Carcinoma, Hepatocellular/pathology ; *Chemical and Drug Induced Liver Injury/pathology ; Glutathione/metabolism ; *Liver Neoplasms/pathology ; Apoptosis ; Oxidation-Reduction ; Homeostasis ; Liver/metabolism ; }, abstract = {Acetaminophen (APAP) hepatotoxicity is one of the biggest drawbacks of this relatively safe and widely used drug. In addition to its hepatotoxicity, APAP also cause comparable levels of toxicity on human hepatoma cells. Here we show activation of the intrinsic caspase-9/3 pathway of apoptosis followed by gasdermin E (GSDME) cleavage and subsequent ballooning in APAP (10 mM, 72 h)-treated Huh-7 human hepatocarcinoma cells. N-acetylcysteine (NAC), an antioxidant currently used as an antidote for APAP overdose, does not alleviate APAP toxicity in Huh-7 cells; NAC overdose (10 mM) rather aggravates APAP toxicity. NAC overdose not only aggravates cell death, but also decreases the cellular GSH/GSSG ratio, an indicator of redox homeostasis of glutathione. These results show for the first time that APAP-induced apoptosis in hepatoma cells is followed by secondary necrosis via the caspase-3/GSDME pathway. NAC overdose (10 mM) not only worsens the glutathione redox status, but also accelerates this pathway.}, } @article {pmid37480966, year = {2024}, author = {Ni, X and Yu, S and Jiang, X and Wu, F and Zhou, J and Mao, D and Wang, H and Tao, Y and Liu, Y and Jin, F}, title = {Celastrus orbiculatus Thunb. extract targeting DJ-1 inhibits non-small cell lung cancer invasion and metastasis through mitochondrial-induced ROS accumulation.}, journal = {Journal of ethnopharmacology}, volume = {318}, number = {Pt A}, pages = {116944}, doi = {10.1016/j.jep.2023.116944}, pmid = {37480966}, issn = {1872-7573}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; *Celastrus/chemistry ; Reactive Oxygen Species ; Plant Extracts/pharmacology/therapeutic use/chemistry ; Cell Line, Tumor ; *Lung Neoplasms/drug therapy ; Mitochondria ; }, abstract = {Celastrus orbiculatus Thunb. is an ancient traditional Chinese herb with a long history of medicinal use. The ethyl acetate extract of Celastrus orbiculatus Thunb. (COE) has been shown to have anti-tumor effects in various preclinical studies. However, the anti-invasive and metastatic efficacy of COE in non-small cell lung cancer (NSCLC) and the mechanism by which COE regulates cellular oxidation levels are yet to be elucidated.

AIM: To study the anti-dissemination effect of COE on NSCLC and to elucidate the molecular mechanism of COE in regulating cellular oxidation levels and its effect on lung cancer invasion and metastasis.

METHODS: CCK-8 assay was used to detect the toxic effects of COE on NSCLC. Transwell assay and high-content imaging was used to detect the Motility of NSCLC. Transmission electron microscopy and three-dimensional (3D) imaging of mitochondrial fluorescence were employed to detect the number and structure of mitochondria. JC-1 probe was used to detect the level of mitochondrial membrane potential. Firefly luciferase assay was used to detect the level of total intracellular ATP. MitoSox probe and DCFH-DA probe were applied to detect the level of reactive oxygen species (ROS) inside the mitochondria and the total intracellular ROS, respectively. Immunohistochemistry was used to detect protein expression in xenograft tumors.

RESULTS: COE inhibited motility and induced DJ-1 downregulation in NSCLC at low toxic concentrations, and the antiseptic effect of COE was reduced significantly after the overexpression of DJ-1. COE induced structural disruption of mitochondria in NSCLC and accumulation of superoxide compounds, decreased the volume of membrane potential depolarization, and impaired energy production, ultimately leading to a large accumulation of ROS at the cellular level. The antioxidant acetylcysteine (NAC) significantly reversed the antiseptic capacity of COE. In a xenograft tumor model, protein expression of DJ-1, E-cadherin, N-cadherin, and MMP-2 in COE group was significantly changed compared to the model group.

CONCLUSION: In the present study, COE inhibited NSCLC invasion and metastasis and was associated with the downregulation of DJ-1 and elevated ROS. COE-mediated downregulation of DJ-1 may be the primary cause of mitochondrial structural and functional dysfunction in NSCLC, eventually leading to ROS accumulation.}, } @article {pmid37477247, year = {2024}, author = {Debnath, U and Mitra, A and Dewaker, V and Prabhakar, YS and Tadala, R and Krishnan, K and Wagh, P and Velusamy, U and Baliyan, A and Kurpad, AV and Bhattacharyya, P and Mandal, AK}, title = {Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: an exploration of probable mechanism of action to combat COVID-19.}, journal = {Journal of biomolecular structure & dynamics}, volume = {42}, number = {10}, pages = {5042-5052}, doi = {10.1080/07391102.2023.2234031}, pmid = {37477247}, issn = {1538-0254}, mesh = {*Spike Glycoprotein, Coronavirus/chemistry/metabolism ; *Acetylcysteine/pharmacology/chemistry ; Humans ; *SARS-CoV-2/drug effects/metabolism ; *Angiotensin-Converting Enzyme 2/metabolism/chemistry ; *Protein Binding ; *COVID-19/virology ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; COVID-19 Drug Treatment ; Protein Conformation ; Binding Sites ; Antiviral Agents/pharmacology/chemistry ; }, abstract = {The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Based on in silico studies we hypothesized that perturbing the functionally active conformation of spike protein through the reduction of its solvent accessible disulfide bonds, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection by reducing the binding affinity towards ACE2 enzyme. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. Further, in silico analysis indicated that the presence of the selective covalent conjugation of NAC with Cys525 perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Interestingly, almost all SARS-CoV-2 variants conserved cystine residues in the spike protein. Our finding results possibly provides a molecular basis for identifying NAC and/or its analogues for targeting Cys-525 of the viral spike protein as fusion inhibitor and exploring in vivo pharmaco-preventive and its therapeutic potential activity for COVID-19 disease. However, in-vitro assay and animal model-based experiment are required to validate the probable mechanism of action.Communicated by Ramaswamy H. Sarma.}, } @article {pmid37476961, year = {2024}, author = {Gao, Y and Wu, F and He, W and Cai, Z and Pang, J and Zheng, Y}, title = {Reactive Oxygen Species-Related Disruptions to Cochlear Hair Cell and Stria Vascularis Consequently Leading to Radiation-Induced Sensorineural Hearing Loss.}, journal = {Antioxidants & redox signaling}, volume = {40}, number = {7-9}, pages = {470-491}, doi = {10.1089/ars.2022.0161}, pmid = {37476961}, issn = {1557-7716}, mesh = {Mice ; Animals ; *Stria Vascularis/pathology/physiology ; Reactive Oxygen Species ; Mice, Inbred C57BL ; *Hearing Loss, Sensorineural/chemically induced/pathology ; Hair Cells, Auditory, Outer/pathology/physiology ; Acetylcysteine/pharmacology ; }, abstract = {Aims: Radiation-induced sensorineural hearing loss (RISNHL) is one of the major side effects of radiotherapy for head and neck cancers. At present, no effective clinical treatment or prevention is available for RISNHL. This study thus aimed to investigate the cochlear pathology so that the underlying mechanisms of RISNHL may be elucidated, consequently paving the way for potential protective strategies to be developed. Results: Functional and morphological impairment in the stria vascularis (SV) was observed after irradiation (IR), as indicated by endocochlear potential (EP) reduction, hyperpermeability, and SV atrophy. The expression of zonulae occludins-1 was found to have decreased after IR. The loss of outer hair cells (OHCs) occurred later than SV damage. The disruption to the SV and OHCs could be attributed to reactive oxygen species (ROS)-related damage. In addition, EP shifts and the loss of OHCs were reduced when ROS was reduced by N-acetylcysteine (NAC) in C57BL/6 mice, attenuating auditory threshold shifts. Innovation: The damage to the SV was found to occur before OHC loss. ROS-related damage accounted for SV damage and OHC loss. The incidences of SV damage and OHC loss were decreased through ROS modulation by NAC, subsequently preventing RISNHL, suggesting the possible role of NAC as a possible protective agent against RISNHL. Conclusion: The findings from this study suggest oxidative stress-induced early SV injury and late OHC loss to be the key factors leading to RISNHL. NAC prevents IR-induced OHC loss, and attenuates auditory brainstem response and EP shifts by regulating the level of oxidative stress. Antioxid. Redox Signal. 40, 470-491.}, } @article {pmid37465907, year = {2023}, author = {Morley, KC and Peruch, S and Adams, C and Towers, E and Tremonti, C and Watt, J and Jamshidi, N and Haber, PS}, title = {N acetylcysteine in the treatment of alcohol use disorder: a randomized, double-blind, placebo-controlled trial.}, journal = {Alcohol and alcoholism (Oxford, Oxfordshire)}, volume = {58}, number = {5}, pages = {553-560}, doi = {10.1093/alcalc/agad044}, pmid = {37465907}, issn = {1464-3502}, support = {//MRFF Practitioner Fellowship/ ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Alcoholism/drug therapy ; Double-Blind Method ; Treatment Outcome ; Male ; Female ; Adult ; Middle Aged ; Aged ; }, abstract = {N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy.}, } @article {pmid37463651, year = {2023}, author = {Huang, M and Zou, M and Mao, S and Xu, W and Hong, Y and Wang, H and Gui, F and Yang, L and Lian, F and Chen, R}, title = {3,5,6-Trichloro-2-pyridinol confirms ototoxicity in mouse cochlear organotypic cultures and induces cytotoxicity in HEI-OC1 cells.}, journal = {Toxicology and applied pharmacology}, volume = {475}, number = {}, pages = {116612}, doi = {10.1016/j.taap.2023.116612}, pmid = {37463651}, issn = {1096-0333}, mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; *Ototoxicity ; Microphysiological Systems ; *Antineoplastic Agents/pharmacology ; Pyridines/pharmacology ; Apoptosis ; Cisplatin/pharmacology ; }, abstract = {The metabolite of organophosphate pesticide chlorpyrifos (CPF), 3,5,6-Trichloro-2-pyridinol (TCP), is persistent and mobile toxic substance in soil and water environments, exhibiting cytotoxic, genotoxic, and neurotoxic properties. However, little is known about its effects on the peripheral auditory system. Herein, we investigated the effects of TCP exposure on mouse postnatal day 3 (P3) cochlear culture and an auditory cell line HEI-OC1 to elucidate the underlying molecular mechanisms of ototoxicity. The damage of TCP to outer hair cells (OHC) and support cells (SC) was observed in a dose and time-dependent manner. OHC and SC were a significant loss from basal to apical turn of the cochlea under exposure over 800 μM TCP for 96 h. As TCP concentrations increased, cell viability was reduced whereas reactive oxygen species (ROS) generation, apoptotic cells, and the extent of DNA damage were increased, accordingly. TCP-induced phosphorylation of the p38 and JNK MAPK are the downstream effectors of ROS. The antioxidant agent, N-acetylcysteine (NAC), could reverse TCP-mediated intracellular ROS generation, inhibit the expressive level of cleaved-caspase 3 and block phosphorylation of p38/JNK. Overall, this is the first demonstration of TCP damaging to peripheral sensory HCs and SC in organotypic cultures from the postnatal cochlea. Data also showed that TCP exposure induced oxidase stress, cell apoptosis and DNA damage in the HEI-OC1 cells. These findings serve as an important reference for assessing the risk of TCP exposure.}, } @article {pmid37458841, year = {2023}, author = {Platt, I and Bisgin, A and Kilavuz, S}, title = {Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {11}, pages = {3827-3852}, pmid = {37458841}, issn = {1590-3478}, abstract = {BACKGROUND: Ethylmalonic encephalopathy (EE) is a rare intoxication-type metabolic disorder with multisystem involvement. It is caused by mutations in ETHE1, which encodes the ETHE1 enzyme in the mitochondrial matrix that plays a key role in hydrogen sulfide (H2S) detoxification acting as a sulphur dioxygenase.

RESULTS: This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases. The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively. A significant difference was found in EMA and C4 levels (p=0.003, p=0.0236) between classical and mild phenotypes. Urinary EMA, C4 and C5 levels were found to exhibit normal values in milder cases during attack-free periods. The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively. Fifty-two patients underwent cranial MRI. Basal ganglia signal alterations were detected in 42 cases. Of the 70 cases, eight had a mild phenotype and slow neurological progression with low levels of ethylmalonic acid (EMA) and C4 acylcarnitine. The current age of alive patients in the published articles with mild phenotype was significantly higher than the classical phenotype. (p=0.002). Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT).

CONCLUSION: Measuring EMA and C4 acylcarnitine during metabolic attacks is critical to diagnosing EE, allowing for early treatment initiation to prevent further encephalopathic crises. Experience with liver transplantation, diet and CRRT, is currently limited. An early multidisciplinary approach with combination therapies is vital to prevent irreversible neurological damage.}, } @article {pmid37458150, year = {2023}, author = {Gayatri Devi, R and Ezhilarasan, D}, title = {Concurrent administration of farnesol protects acetaminophen-induced acute hepatic necrosis in mice.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {11}, pages = {e23478}, doi = {10.1002/jbt.23478}, pmid = {37458150}, issn = {1099-0461}, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; Antioxidants/metabolism ; Farnesol/pharmacology/metabolism ; NF-kappa B/metabolism ; Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention & control/metabolism ; Liver/metabolism ; Glutathione/metabolism ; Necrosis ; Transaminases/metabolism/pharmacology ; Alanine Transaminase ; }, abstract = {Acetaminophen (APAP) is known to cause acute liver injury and acute liver failure in Western countries. This study investigates the protective role of farnesol (FAR) (C15 H26 O), a natural sesquiterpene alcohol in essential oils, against APAP-induced acute liver necrosis in mice. Mice were injected with a single dose of APAP (300 mg/kg) via an intraperitoneal route. Different groups of mice were concurrently treated with a single dose of FAR 25 mg/kg, FAR 50 mg/kg, and N-acetylcysteine. APAP administration caused a significant increase in transaminase activities and malondialdehyde (MDA) levels in the serum and liver tissue, respectively, with a concomitant decrease in intracellular antioxidants, including reduced glutathione (GSH) in the liver tissue. APAP intoxication upregulated proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, nuclear factor-κB (NF-κB), and IκB kinase β in the liver tissue. FAR and N-acetylcysteine (NAC) administrations concurrently with APAP prevented serum transaminase increase in serum and MDA levels in the liver tissue. A high dose of FAR and NAC treatments significantly inhibited GSH and other antioxidant depletion. FAR and NAC treatments also downregulated the expression of proinflammatory markers. FAR treatments protects against APAP-induced acute liver injury and offers antioxidant and anti-inflammatory effects by inhibiting the NF-κB pathway involved in the transcription of genes responsible for inflammatory cytokine synthesis.}, } @article {pmid37454274, year = {2023}, author = {Celebi, NK and Ozturk, SK and Palaoglu, I and Somay, A and Yaprak, G and Algul, E and Deveci, HS}, title = {Investigation of the efficacy of systemic N-Acetyl Cysteine therapy preventing nasal mucositis following radiotherapy.}, journal = {Rhinology}, volume = {61}, number = {5}, pages = {470-480}, doi = {10.4193/Rhin22.487}, pmid = {37454274}, issn = {0300-0729}, mesh = {Rats ; Animals ; Humans ; Female ; *Mucositis/etiology/prevention & control/pathology ; Quality of Life ; Rats, Sprague-Dawley ; Nasal Mucosa ; Acetylcysteine/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Radiotherapy (RT) is one of the main methods used in the treatment of head and neck cancers but may cause mucosal side effects in the tumor area and surrounding structures. These include nasal mucosal disorders and chronic rhinosinusitis due to disruption of the mucociliary system. This situation seriously affects the quality of life of the patients and there is no accepted effective method for its treatment yet. In our study, we aimed to examine the side effects of RT on the nasal mucosa and mucociliary system and to investigate histopathologically and immunohistochemically the effectiveness of N-acetyl cysteine (NAC) in preventing these side effects of RT.

METHODOLOGY: The study was carried out with 30 female Sprague Dawley rats devided in three groups. No intervention was made in the control group. On the second day of the experiment, 30 Gy radiotherapy was applied to the head area in the RT group. NAC was administered intraperitoneally at a dose of 1 g/kg/day for 14 days from the first day of the study to the RT+ NAC group. On the second day, 30 Gy of radiotherapy was applied to the head area 1 hour after the NAC application. On the 14th day, 1 hour after NAC was applied to the RT+NAC group, all animals were sacrificed. The nasal mucosa samples were stained with hematoxylin-eosin, and the intensity and extent of staining sentan in the nasopharyngeal tissue samples were evaluated by immunohistochemical staining using anti-SNTN antibody.

RESULTS: The loss of cilia in the nasal tissue was lower in the RT+NAC group than in the RT group. The intensity and extent of staining in the nasopharyngeal tissue of Sentan was higher in the RT+NAC group than in the RT group. Mucosal neutrophil and mononuclear inflammatory cell infiltration in the nasal tissue, vascular dilatation, hyperemia and hemorrhage, erosion and shedding of the mucosal epithelium, mucosal ulceration were found to be similar in the RT+NAC group and the control group. It was milder in the RT+NAC group than in the RT group, but not statistically significant.

CONCLUSIONS: Radiotherapy caused pathological changes in the nasal mucosa, caused loss of cilia and a decrease in the level of Sentan, the cilia apical protein. The results of our study showed that NAC treatment can reduce the side effects of RT on the nasal mucosa. It also showed that NAC was effective in preventing the loss of cilia, which is the building block of the mucociliary system, and improving the expression of Sentan.}, } @article {pmid37439802, year = {2023}, author = {Park, SY and Lee, KH}, title = {Comparison of Cytotoxicity and Genotoxicity in Three Types of Indirect Restorative Materials on Human Periodontal Stem Cells.}, journal = {Oral health & preventive dentistry}, volume = {21}, number = {}, pages = {243-250}, pmid = {37439802}, issn = {1757-9996}, mesh = {Humans ; Reactive Oxygen Species ; *Dental Materials ; *Glass Ionomer Cements/toxicity ; Stem Cells ; Materials Testing ; Composite Resins/toxicity ; }, abstract = {PURPOSE: This study aimed to compare the cell toxicity and biological characteristics of Ketac GIC (glass-ionomer cement), Nexus RMGIC (resin-modified glass-ionomer cement), and RelyX RC (resin cement) in human periodontal stem cells (PDSCs).

MATERIALS AND METHODS: To compare the effects of Ketac GIC, Nexus RMGIC, and RelyX RC on PDSCs, the cements were diluted from 1:2 to 1:8. PDSCs were then treated with the serially diluted cements with or without N-acetyl-cysteine (NAC), and cell survival was measured using water-soluble tetrazolium salt (WST-1) assay. Intracellular reactive oxygen species (ROS) was measured using 2',7'-dichlorofluorescin diacetate (DCFDA), and western blot analysis was performed to observe phosphorylation and activation of extracellular signal-regulated kinase (ERK) by Nexus RMGIC or RelyX RC.

RESULTS: Cell death and proliferation were dose-dependently reduced following Nexus RMGIC or RelyX RC treatment. In addition, Nexus RMGIC or RelyX RC showed an increase intracellular ROS generation compared to Ketac GIC. Pretreatment with NAC confirmed the suppression of cell toxicity and ROS generation induced by Nexus RMGIC or RelyX RC. Nexus RMGIC or RelyX RC activates ERK phosphorylation, not p38 phosphorylation, in PDSCs.

CONCLUSION: This study showed that the treatment with Nexus RMGIC or RelyX generates intracellular ROS and cell death through the ERK signaling pathway in PDSCs. In contrast, these effects were not observed with Ketac GIC, indicating that resin-based materials may have cytotoxic and genotoxic effects on PDSCs.}, } @article {pmid37439200, year = {2023}, author = {Kim, K and Cort, TA and Kunz, EM and Moerschel, J and Palzkill, VR and Dong, G and Moparthy, CN and Anderson, EM and Fazzone, B and O'Malley, KA and Robinson, ST and Berceli, SA and Ryan, TE and Scali, ST}, title = {N-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.}, journal = {American journal of physiology. Renal physiology}, volume = {325}, number = {3}, pages = {F271-F282}, pmid = {37439200}, issn = {1522-1466}, support = {P30 AG050911/AG/NIA NIH HHS/United States ; R01 HL148597/HL/NHLBI NIH HHS/United States ; }, mesh = {Male ; Female ; Animals ; Mice ; Acetylcysteine/pharmacology ; Renal Dialysis ; *Renal Insufficiency, Chronic/therapy/etiology ; *Kidney Failure, Chronic/therapy ; *Arteriovenous Shunt, Surgical/adverse effects ; *Arteriovenous Fistula ; Retrospective Studies ; }, abstract = {The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.}, } @article {pmid37435843, year = {2023}, author = {Su, M and Zhao, Y and Li, M and Jia, C and Liu, H and Zhang, Y and Li, W and Peng, Y and Zheng, J}, title = {Evidence for the Metabolic Activation of Deferasirox In Vitro and In Vivo.}, journal = {Chemical research in toxicology}, volume = {36}, number = {8}, pages = {1255-1266}, doi = {10.1021/acs.chemrestox.2c00416}, pmid = {37435843}, issn = {1520-5010}, mesh = {Rats ; Animals ; Activation, Metabolic ; Deferasirox/pharmacology/metabolism ; *Liver/metabolism ; *Hepatocytes/metabolism ; Microsomes, Liver/metabolism ; Acetylcysteine/metabolism ; Glutathione/metabolism ; }, abstract = {Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS in vitro and in vivo to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or N-acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.}, } @article {pmid37434745, year = {2023}, author = {Zhao, C and Yin, Y and Zhu, C and Zhu, M and Ji, T and Li, Z and Cai, J}, title = {Drug therapies for treatment of idiopathic pulmonary fibrosis: a systematic review, Bayesian network meta-analysis, and cost-effectiveness analysis.}, journal = {EClinicalMedicine}, volume = {61}, number = {}, pages = {102071}, pmid = {37434745}, issn = {2589-5370}, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis and a high economic burden for individuals and healthcare resources. Studies of the costs associated with the efficiency of IPF medications are scarce. We aimed to conduct a network meta-analysis (NMA) and cost-effectiveness analysis to identify the optimum pharmacological strategy among all currently available IPF regimens.

METHODS: We first performed a systematic review and network meta-analysis. We searched eight databases for eligible randomised controlled trials (RCTs) published, in any language, between January 1, 1992 and July 31, 2022, that investigated the efficacy or tolerability (or both) of drug therapies for the treatment of IPF. The search was updated on February 1, 2023. Eligible RCTs were enrolled, with no restriction on dose, duration, or length of follow-up, if they included at least one of: all-cause mortality, acute exacerbation rate, disease progression rate, serious adverse events, and any adverse events under investigation. A subsequent Bayesian NMA within random-effects models was performed, followed by a cost-effectiveness analysis using the data obtained from our NMA, by developing a Markov model from the US payer's perspective. Assumptions were checked by deterministic and probabilistic sensitivity approaches to identify sensitive factors. We prospectively registered the protocol (CRD42022340590) in PROSPERO.

FINDINGS: 51 publications comprising 12,551 participants with IPF were analysed for the NMA, and the findings indicated that pirfenidone and N-acetylcysteine (NAC) + pirfenidone were the most efficacious and tolerable. The pharmacoeconomic analysis showed that NAC + pirfenidone was associated with the highest potentiality of being cost-effective at willingness-to-pay (WTP) thresholds of US$150,000 and $200,000, on the basis of quality-adjusted life years (QALYs), disability-adjusted life years (DALYs) and mortality, with the probability ranging from 53% to 92%. NAC was the minimum cost agent. Compared with placebo, NAC + pirfenidone improved effectiveness by increasing QALYs by 7.02, and reducing DALYs by 7.10 and deaths by 8.40, whilst raising overall costs by $516,894.

INTERPRETATION: This NMA and cost-effectiveness analysis suggests that NAC + pirfenidone is the most cost-effective option for treatment of IPF at WTP thresholds of $150,000 and $200,000. However, given that clinical practice guidelines have not addressed the application of this therapy, large well-designed and multicentre trials are warranted to provide a better picture of IPF management.

FUNDING: None.}, } @article {pmid37429745, year = {2023}, author = {Emelogu, IK and Tran, CN and Greene, WR and Novak, JD}, title = {Successful treatment of distal intestinal obstruction syndrome with N-acetylcysteine and polyethylene glycol via colonoscopy.}, journal = {Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society}, volume = {22}, number = {6}, pages = {1123-1124}, doi = {10.1016/j.jcf.2023.06.014}, pmid = {37429745}, issn = {1873-5010}, mesh = {Humans ; Female ; Middle Aged ; Polyethylene Glycols ; Acetylcysteine ; *Cystic Fibrosis/diagnosis ; *Intestinal Obstruction/diagnosis/etiology/therapy ; Colonoscopy ; }, abstract = {We describe a case of a 46-year-old woman with cystic fibrosis who presented with several days of abdominal pain and distension. She was found to have a small bowel obstruction with inspissated stool in the distal ileum on CT imaging. Despite initial management with conservative measures, her symptoms worsened. She was taken for urgent colonoscopy with administration of 4% N-acetylcysteine (NAC) and polyethylene glycol (PEG) at the distal ileum with resultant dissolution of the fecalith. Over the following days, her symptoms improved, and she was discharged with outpatient follow-up.}, } @article {pmid37428372, year = {2023}, author = {Fraguas, S and Molina, MD and Cebrià, F}, title = {Colorimetric Whole-Mount In Situ Hybridization in Planarians.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2680}, number = {}, pages = {81-91}, pmid = {37428372}, issn = {1940-6029}, mesh = {Animals ; *Planarians/genetics ; In Situ Hybridization ; Colorimetry ; RNA, Messenger/genetics ; Digoxigenin ; }, abstract = {Whole-mount in situ hybridization (WISH) is an extremely useful technique for visualizing specific mRNA targets and solving many biological questions. In planarians, this method is really valuable, for example, for determining gene expression profiles during whole-body regeneration and analyzing the effects of silencing any gene to determine their functions. In this chapter, we present in detail the WISH protocol routinely used in our lab, using a digoxigenin-labelled RNA probe and developing with NBT-BCIP. This protocol is basically that already described in Currie et al. (EvoDevo 7:7, 2016), which put together several modifications developed from several laboratories in recent years that improved the original protocol developed in the laboratory of Kiyokazu Agata in 1997. Although this protocol, or slight modifications of it, is the most common protocol in the planarian field for NBT-BCIP WISH, our results show that key steps such as the use and time of NAC treatment to remove the mucus need to be taken into account depending on the nature of the gene analyzed, especially for the epidermal markers.}, } @article {pmid37427326, year = {2023}, author = {Mousavinezhad-Moghaddam, M and Behnam-Rassouli, M and Valizadeh, N and Mahdavi-Shahri, N and Rezaee, SA}, title = {Thiamine as a peripheral neuro-protective agent in comparison with N-acetyl cysteine in axotomized rats.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {8}, pages = {919-926}, pmid = {37427326}, issn = {2008-3866}, abstract = {OBJECTIVES: In this study, the impact of thiamine (Thi), N-acetyl cysteine (NAC), and dexamethasone (DEX) were investigated in axotomized rats, as a model for neural injury.

MATERIALS AND METHODS: Sixty-five axotomized rats were divided into two different experimental approaches, the first experiments included five study groups (n=5): intrathecal Thi (Thi.it), intraperitoneal (Thi), NAC, DEX, and control. Cell survival was assessed in L5DRG in the 4[th] week by histological assessment. In the second study, 40 animals were engaged to assess Bcl-2, Bax, IL-6, and TNF-α expression in L4-L5DRG in the 1[st] and 2[nd] weeks after sural nerve axotomy under treatment of these agents (n=10).

RESULTS: Ghost cells were observed in morphological assessment of L5DRG sections, and following stereological analysis, the volume and neuronal cell counts significantly were improved in the NAC and Thi.it groups in the 4[th] week (P<0.05). Although Bcl-2 expression did not show significant differences, Bax was reduced in the Thi group (P=0.01); and the Bcl-2/Bax ratio increased in the NAC group (1[st] week, P<0.01). Furthermore, the IL-6 and TNF-α expression decreased in the Thi and NAC groups, on the 1[st] week of treatment (P≤0.05 and P<0.01). However, in the 2[nd] week, the IL-6 expression in both Thi and NAC groups (P<0.01), and the TNF-α expression in the DEX group (P=0.05) were significantly decreased.

CONCLUSION: The findings may classify Thi in the category of peripheral neuroprotective agents, in combination with routine medications. Furthermore, it had strong cell survival effects as it could interfere with the destructive effects of TNF-α by increasing Bax.}, } @article {pmid37422055, year = {2023}, author = {Huang, J and Pang, X and Zhang, X and Qiu, W and Zhang, X and Wang, R and Xie, W and Bai, Y and Zhou, S and Liao, J and Xiong, Z and Tang, Z and Su, R}, title = {N-acetylcysteine combined with insulin attenuates myocardial injury in canines with type 1 diabetes mellitus by modulating TNF-α-mediated apoptotic pathways and affecting linear ubiquitination.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {262}, number = {}, pages = {1-11}, doi = {10.1016/j.trsl.2023.07.003}, pmid = {37422055}, issn = {1878-1810}, mesh = {Humans ; Animals ; Dogs ; *NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha ; Insulin/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; *Diabetes Mellitus, Type 1/complications/drug therapy ; Apoptosis ; Ubiquitination ; }, abstract = {The exact pathogenesis of type 1 diabetes mellitus (DM) is still unclear. Numerous organs, including the heart, will suffer damage and malfunction as a result of long-term hyperglycemia. Currently, insulin therapy alone is still not the best treatment for type 1 DM. In order to properly treat and manage patients with type 1 DM, it is vital to seek a combination that includes both insulin and additional medications. This study aims to explore the therapeutic effect and mechanism of N-acetylcysteine (NAC) combined with insulin on type 1 DM. By giving beagle canines injections of streptozotocin (STZ) and alloxan (ALX) (20 mg/kg each), a model of type 1 DM was created. The results showed that this combination could effectively control blood sugar level, improve heart function, avoid the damage of mitochondria and myocardial cells, and prevent the excessive apoptosis of myocardial cells. Importantly, the combination can activate nuclear factor kappa-B (NF-κB) by promoting linear ubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB-essential modulator (NEMO) and inhibitor of NF-κB (IκB) phosphorylation. The combination can increase the transcription and linear ubiquitination of Cellular FLICE (FADD-like IL-1β-converting enzyme) -inhibitory protein (c-FLIP), diminish the production of cleaved-caspase-8 p18 and cleaved-caspase-3 to reduce apoptosis. This study confirmed that NAC combined with insulin can promote the linear ubiquitination of RIPK1, NEMO and c-FLIP and regulate the apoptosis pathway mediated by TNF-α to attenuate the myocardial injury caused by type 1 DM. Meanwhile, the research served as a resource when choosing a clinical strategy for DM cardiac complications.}, } @article {pmid37419616, year = {2023}, author = {Medipally, A and Xiao, M and Satoskar, AA and Biederman, L and Dasgupta, A and Ivanov, I and Mikhalina, G and Rovin, B and Brodsky, SV}, title = {N-acetylcysteine ameliorates hematuria-associated tubulointerstitial injury in 5/6 nephrectomy mice.}, journal = {Physiological reports}, volume = {11}, number = {13}, pages = {e15767}, pmid = {37419616}, issn = {2051-817X}, support = {R01 DK117102/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Mice ; Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Warfarin/adverse effects ; Reactive Oxygen Species ; Tumor Necrosis Factor-alpha ; Mice, Inbred C57BL ; Kidney ; Nephrectomy ; Hematuria/etiology/chemically induced ; *Renal Insufficiency, Chronic/complications/drug therapy/chemically induced ; Fibrosis ; }, abstract = {Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.}, } @article {pmid37419232, year = {2023}, author = {Kwok, WT and Kwak, HA and Andreazza, AC}, title = {N-acetylcysteine modulates rotenone-induced mitochondrial Complex I dysfunction in THP-1 cells.}, journal = {Mitochondrion}, volume = {72}, number = {}, pages = {1-10}, doi = {10.1016/j.mito.2023.07.001}, pmid = {37419232}, issn = {1872-8278}, mesh = {Humans ; *Acetylcysteine/pharmacology/metabolism ; *Rotenone/toxicity ; THP-1 Cells ; Superoxides/metabolism ; Oxidative Stress ; Electron Transport Complex I/metabolism ; DNA, Mitochondrial/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial Complex I dysfunction and oxidative stress have been part of the pathophysiology of several diseases ranging from mitochondrial disease to chronic diseases such as diabetes, mood disorders and Parkinson's Disease. Nonetheless, to investigate the potential of mitochondria-targeted therapeutic strategies for these conditions, there is a need further our understanding on how cells respond and adapt in the presence of Complex I dysfunction. In this study, we used low doses of rotenone, a classical inhibitor of mitochondrial complex I, to mimic peripheral mitochondrial dysfunction in THP-1 cells, a human monocytic cell line, and explored the effects of N-acetylcysteine on preventing this rotenone-induced mitochondrial dysfunction. Our results show that in THP-1 cells, rotenone exposure led to increases in mitochondrial superoxide, levels of cell-free mitochondrial DNA, and protein levels of the NDUFS7 subunit. N-acetylcysteine (NAC) pre-treatment ameliorated the rotenone-induced increase of cell-free mitochondrial DNA and NDUFS7 protein levels, but not mitochondrial superoxide. Furthermore, rotenone exposure did not affect protein levels of the NDUFV1 subunit but induced NDUFV1 glutathionylation. In summary, NAC may help to mitigate the effects of rotenone on Complex I and preserve the normal function of mitochondria in THP-1 cells.}, } @article {pmid37415931, year = {2023}, author = {Kaya, ZB and Karakoc, E and McLean, PJ and Saka, E and Atilla, P}, title = {Post-inflammatory administration of N-acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease.}, journal = {FASEB bioAdvances}, volume = {5}, number = {7}, pages = {263-276}, pmid = {37415931}, issn = {2573-9832}, abstract = {Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha-synuclein (α-syn). Although the formation of α-syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll-like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α-syn and modulate its uptake by other cells. Lymphocyte-activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α-syn internalization; however, a recent study has disputed this role. Internalized α-syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, and IL-6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N-acetylcysteine (NAC), an anti-inflammatory and anti-carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti-inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild-type α-syn were treated with TNF-α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF-α-induced inflammation and apoptosis. SNCA gene transcription and α-syn protein expression were validated by q-PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q-PCR. TNF-α not only increased inflammation but also increased endogenous and overexpressed α-syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation-mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha-synuclein overexpression, via a TLR2-associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD.}, } @article {pmid37405379, year = {2023}, author = {Gamarra-Morales, Y and Herrera-Quintana, L and Molina-López, J and Vázquez-Lorente, H and Machado-Casas, JF and Castaño-Pérez, J and Pérez-Villares, JM and Planells, E}, title = {Response to Intravenous N-Acetylcysteine Supplementation in Critically Ill Patients with COVID-19.}, journal = {Nutrients}, volume = {15}, number = {9}, pages = {}, pmid = {37405379}, issn = {2072-6643}, support = {Project FIS PI10/1993//Instituto de Salud Carlos III/ ; REF. A-CTS-708-UGR20//Consejería de Educación/ ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *COVID-19 ; Critical Illness/therapy ; Glutathione ; Dietary Supplements ; }, abstract = {Administering N-acetylcysteine (NAC) could counteract the effect of free radicals, improving the clinical evolution of patients admitted to the Intensive Care Unit (ICU). This study aimed to investigate the clinical and biochemical effects of administering NAC to critically ill patients with COVID-19. A randomized controlled clinical trial was conducted on ICU patients (n = 140) with COVID-19 and divided into two groups: patients treated with NAC (NAC-treated group) and patients without NAC treatment (control group). NAC was administered as a continuous infusion with a loading dose and a maintenance dose during the study period (from admission until the third day of ICU stay). NAC-treated patients showed higher PaO2/FiO2 (p ≤ 0.014) after 3 days in ICU than their control group counterparts. Moreover, C-reactive protein (p ≤ 0.001), D-dimer (p ≤ 0.042), and lactate dehydrogenase (p ≤ 0.001) levels decreased on the third day in NAC-treated patients. Glutathione concentrations decreased in both NAC-treated (p ≤ 0.004) and control (p ≤ 0.047) groups after 3 days in ICU; whereas glutathione peroxidase did not change during the ICU stay. The administration of NAC manages to improve the clinical and analytical response of seriously ill patients with COVID-19 compared to the control group. NAC is able to stop the decrease in glutathione concentrations.}, } @article {pmid37401850, year = {2023}, author = {Xiao, P and Chen, X and Dong, Z and Fan, W and Chen, Y and Su, J and Wang, Q and Ma, L}, title = {BNIP3 overexpression may promote myeloma cell apoptosis by enhancing sensitivity to bortezomib via the p38 MAPK pathway.}, journal = {Hematology (Amsterdam, Netherlands)}, volume = {28}, number = {1}, pages = {2231739}, doi = {10.1080/16078454.2023.2231739}, pmid = {37401850}, issn = {1607-8454}, mesh = {Humans ; *p38 Mitogen-Activated Protein Kinases/metabolism/pharmacology ; Bortezomib/pharmacology ; Caspase 3/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism/pharmacology ; *Multiple Myeloma/drug therapy/genetics ; Apoptosis ; Proto-Oncogene Proteins c-bcl-2/metabolism/pharmacology ; Membrane Proteins/genetics/metabolism ; Proto-Oncogene Proteins/metabolism ; }, abstract = {BACKGROUND: BCL2-interacting protein 3 (BNIP3) expression varies among cancers, and its role in myeloma cells remains unknown. We investigated the role of BNIP3 overexpression in myeloma cells, and particularly its effects on apoptosis and mitochondria.

METHODS: A BNIP3-overexpressing plasmid was transfected into the MM.1S and RPMI8226 myeloma cell lines. Transfected cell apoptosis rate and mitochondrial function were determined via flow cytometry and western blotting. We verified the signaling pathway underlying myeloma cell sensitivity to bortezomib (BTZ).

RESULTS: Cell lines carrying the BNIP3-overexpressing plasmid exhibited higher rates of apoptosis and expression of Bax and Cleaved caspase 3 protein than the vector group, and less Bcl-2 protein expression than the control cells. Relative to the vector group, BNIP3-overexpressing strains contained more reactive oxygen species (ROS) and exhibited mitochondrial membrane potential (MMP) and dynamin-related protein 1 (Drp1) upregulation and mitofusin-1 (Mfn1) downregulation. BTZ supplementation increased BNIP3 expression. Relative to the BNIP3-OE group, the BNIP3-OE BTZ-treated group exhibited upregulated Bax and Cleaved caspase 3 protein expression, downregulated Bcl-2 protein expression, higher apoptosis rates, ROS levels, MMP, and Drp1 expression, and lower Mfn1 expression. BTZ treatment induced p38 MAPK (mitogen-activated protein kinase) signaling pathway activation in BNIP3-OE cells. Upon adding N-acetylcysteine (NAC) and the p38 MAPK inhibitor SB203580, the affected index levels returned to the baseline.

CONCLUSIONS: BNIP3 overexpression induced apoptosis in myeloma cells and increased myeloma cell sensitivity to BTZ. These effects may be mediated by the ROS/p38 MAPK signaling pathway.}, } @article {pmid37399733, year = {2023}, author = {Yi, SJ and Jang, YJ and Lee, S and Cho, SJ and Kang, K and Park, JI and Chae, HJ and Kim, HR and Kim, K}, title = {TMBIM6 deficiency leads to bone loss by accelerating osteoclastogenesis.}, journal = {Redox biology}, volume = {64}, number = {}, pages = {102804}, pmid = {37399733}, issn = {2213-2317}, mesh = {Animals ; Male ; Mice ; *Bone Resorption/genetics ; Cell Differentiation ; *Membrane Proteins/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; *Osteoclasts/cytology ; *Osteogenesis ; RANK Ligand/metabolism ; Signal Transduction ; Transcription Factor RelA/metabolism ; Oxidation-Reduction ; }, abstract = {TMBIM6 is an endoplasmic reticulum (ER) protein that modulates various physiological and pathological processes, including metabolism and cancer. However, its involvement in bone remodeling has not been investigated. In this study, we demonstrate that TMBIM6 serves as a crucial negative regulator of osteoclast differentiation, a process essential for bone remodeling. Our investigation of Tmbim6-knockout mice revealed an osteoporotic phenotype, and knockdown of Tmbim6 inhibited the formation of multinucleated tartrate-resistant acid phosphatase-positive cells, which are characteristic of osteoclasts. Transcriptome and immunoblot analyses uncovered that TMBIM6 exerts its inhibitory effect on osteoclastogenesis by scavenging reactive oxygen species and preventing p65 nuclear localization. Additionally, TMBIM6 depletion was found to promote p65 localization to osteoclast-related gene promoters. Notably, treatment with N-acetyl cysteine, an antioxidant, impeded the osteoclastogenesis induced by TMBIM6-depleted cells, supporting the role of TMBIM6 in redox regulation. Furthermore, we discovered that TMBIM6 controls redox regulation via NRF2 signaling pathways. Our findings establish TMBIM6 as a critical regulator of osteoclastogenesis and suggest its potential as a therapeutic target for the treatment of osteoporosis.}, } @article {pmid37397917, year = {2023}, author = {Sobh, ZK and Abd-Elhameed, A}, title = {The therapeutic benefit of antioxidants on the outcome of acute aluminum phosphide poisoning: a systemic review and meta-analysis.}, journal = {Toxicology research}, volume = {12}, number = {3}, pages = {345-354}, pmid = {37397917}, issn = {2045-452X}, abstract = {This systematic review and meta-analysis pool evidence available from clinical trials to verify the effect of antioxidants on the outcome of acute aluminum phosphide (AlP) poisoning. A systematic review complied with "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) Protocols. Meta-analysis was conducted on 10 studies that fulfill eligibility criteria. Four antioxidants were implemented: N-Acetyl cysteine (NAC), L-Carnitine, Vitamin E, and Co-enzyme Q10 (Co Q10). Risk of bias, publication bias, and heterogeneity were assessed to ensure the results' reliability. Antioxidants significantly decrease mortality of acute AlP poisoning around three folds (OR = 2.684, 95% CI: 1.764-4.083; P < .001) and decrease the need for intubation and mechanical ventilation by two folds (OR = 2.391, 95% CI 1.480-3.863; P < .001) compared with control. Subgroup analysis revealed that NAC significantly decreases mortality by nearly three folds (OR = 2.752, 95% CI: 1.580-4.792; P < .001), and vitamin E significantly decreases mortality by nearly six folds (OR = 5.667, 95% CI: 1.178-27.254; P = .03) compared with control. L-Carnitine showed a borderline significance (P = .050). Co Q10 decreased the mortality compared with the control; however, the difference was not statistically significant (P = .263). This meta-analysis provides solid evidence regarding the efficacy of antioxidants in improving the outcome of acute AlP poisoning with reference to NAC. Wide confidence interval and small relative weight affect reliability regarding vitamin E efficacy. Future clinical trials and meta-analyses are recommended. To our knowledge, no previous meta-analysis was conducted to investigate the efficacy of treatment modalities for acute AlP poisoning.}, } @article {pmid37393553, year = {2023}, author = {Ahmad, H and Crotts, MS and Jacobs, JC and Baer, RW and Cox, JL}, title = {Shikonin Causes Non-apoptotic Cell Death in B16F10 Melanoma.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {23}, number = {16}, pages = {1880-1887}, doi = {10.2174/1871520623666230701000338}, pmid = {37393553}, issn = {1875-5992}, mesh = {Humans ; Apoptosis ; Necrosis ; Reactive Oxygen Species/metabolism ; Cysteine/pharmacology ; Cell Line, Tumor ; *Naphthoquinones/pharmacology ; *Melanoma ; }, abstract = {BACKGROUND: Melanoma treatment is highly resistant to current chemotherapeutic agents. Due to its resistance towards apoptotic cell death, non-apoptotic cell death pathways are sought after.

OBJECTIVE: We investigated a Chinese herbal medicine, shikonin, and its effect on B16F10 melanoma cells in vitro.

METHODS: Cell growth of B16F10 melanoma cells treated with shikonin was analyzed using an MTT assay. Shikonin was combined with necrostatin, an inhibitor of necroptosis; caspase inhibitor; 3-methyladenine, an inhibitor of autophagy; or N-acetyl cysteine, an inhibitor of reactive oxygen species. Flow cytometry was used to assess types of cell death resulting from treatment with shikonin. Cell proliferation was also analyzed utilizing a BrdU labeling assay. Monodansylcadaverine staining was performed on live cells to gauge levels of autophagy. Western blot analysis was conducted to identify specific protein markers of necroptosis including CHOP, RIP1, and pRIP1. MitoTracker staining was utilized to identify differences in mitochondrial density in cells treated with shikonin.

RESULTS: Analysis of MTT assays revealed a large decrease in cellular growth with increasing shikonin concentrations. The MTT assays with necrostatin, 3-methyladenine, and N-acetyl cysteine involvement, suggested that necroptosis, autophagy, and reactive oxygen species are a part of shikonin's mechanism of action. Cellular proliferation with shikonin treatment was also decreased. Western blotting confirmed that shikonin-treated melanoma cells increase levels of stress-related proteins, e.g., CHOP, RIP, pRIP.

CONCLUSION: Our findings suggest that mainly necroptosis is induced by the shikonin treatment of B16F10 melanoma cells. Induction of ROS production and autophagy are also involved.}, } @article {pmid37393521, year = {2023}, author = {Chen, M and Hu, C and Yang, L and Guo, Q and Liang, Y and Wang, W}, title = {Saikosaponin-D induces the pyroptosis of lung cancer by increasing ROS and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {8}, pages = {e23444}, doi = {10.1002/jbt.23444}, pmid = {37393521}, issn = {1099-0461}, mesh = {Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology ; Tumor Microenvironment ; NF-kappa B/metabolism ; Phosphate-Binding Proteins/pharmacology ; Caspase 1/metabolism ; Bupleurum ; Humans ; Pore Forming Cytotoxic Proteins/metabolism/pharmacology ; Pyroptosis ; *Lung Neoplasms/drug therapy ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Inflammasomes/metabolism ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; }, abstract = {Saikosaponin-D (SSD), an active ingredient in Bupleurum chinense, exerts anticancer effects in various cancers by inhibiting cancer proliferation and inducing apoptosis. However, whether SSD can induce other forms of cell death is unknown. The current study aims to demonstrate that SSD can induce pyroptosis in non-small-cell lung cancer. In this study, HCC827 and A549 non-small-cell lung cancer cells were treated with different concentrations of SSD for 1.5 h. HE and TUNEL staining were used to verify cell damage caused by SSD. Immunofluorescence and western blotting were performed to verify the effect of SSD on the NF-κB/NLRP3/caspase-1/gasdermin D (GSDMD) pathway. Changes in inflammatory factors were detected by ELISAs. Finally, the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) was introduced to verify that SSD induces pyroptosis through the ROS/NF-κB pathway. The results of the HE and TUNEL staining showed that SSD resulted in balloon-like swelling of NSCLC cells accompanied by increased DNA damage. Immunofluorescence and western blot assays confirmed that SSD treatment activated the NLRP3/caspase-1/GSDMD pathway, stimulated an increase in ROS levels and activated NF-κB in lung cancer cells. The ROS scavenger N-acetylcysteine significantly attenuated SSD-induced NF-κB/NLRP3/caspase-1/GSDMD pathway activation and inhibited the release of the inflammatory cytokines IL-1β and IL-18. In conclusion, SSD induced lung cancer cell pyroptosis by inducing ROS accumulation and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway. These experiments lay the foundation for the application of SSD in the treatment of non-small-cell lung cancer and regulation of the lung cancer immune microenvironment.}, } @article {pmid37392235, year = {2024}, author = {Kouka, M and Bevern, N and Bitter, J and Guntinas-Lichius, O}, title = {N-Acetylcysteine combined with prednisolone treatment shows better hearing outcome than treatment with prednisolone alone for patients with idiopathic sudden sensorineural hearing loss: a retrospective observational study.}, journal = {European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery}, volume = {281}, number = {1}, pages = {107-116}, pmid = {37392235}, issn = {1434-4726}, mesh = {Humans ; Female ; Middle Aged ; Male ; Prednisolone/therapeutic use ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Glucocorticoids ; *Hearing Loss, Sudden/diagnosis/drug therapy ; *Hearing Loss, Sensorineural/diagnosis/drug therapy ; Audiometry, Pure-Tone ; Hearing ; Treatment Outcome ; }, abstract = {OBJECTIVES: Internationally, corticosteroids are still the mainstay treatment for patients with idiopathic sudden sensorineural hearing loss (ISSHL). This is a retrospective monocentric study investing the impact of adding N-acetylcysteine (NAC) to prednisolone treatment on patients with ISSHL at a tertiary university otorhinolaryngology department.

METHODS: 793 patients (median age 60 years; 50.9% women) with a new diagnosis of ISSHL from 2009 to 2015 were included in the study. 663 patients received NAC administration in addition to standard tapered prednisolone treatment. Univariate and multivariable analysis were performed to identify independent factors regarding negative prognosis of hearing recovery.

RESULTS: Mean initial ISSHL and hearing gain after treatment in 10-tone pure tone audiometry (PTA) were 54.8 ± 34.5 dB and 15.2 ± 21.2 dB, respectively. In univariate analysis, treatment with prednisolone and NAC was associated with a positive prognosis of hearing recovery in the Japan classification in 10-tone PTA. In multivariable analysis on Japan classification in 10-tone PTA including all significant factors from univariate analysis, negative prognosis of hearing recovery were age > median (odds ratio [OR] 1.648; 95% confidence interval [CI] 1.139-2.385; p = 0.008), diseased opposite ear (OR 3.049; CI 2.157-4.310; p < 0.001), pantonal ISSHL (OR 1.891; CI 1.309-2.732; p = 0.001) and prednisolone alone without NAC treatment (OR 1.862; CI 1.200-2.887; p = 0.005).

CONCLUSIONS: Prednisolone treatment combined with NAC resulted in better hearing outcomes in patients with ISSHL than treatment without NAC.}, } @article {pmid37387512, year = {2023}, author = {Sobh, ZK and Kholief, M and Sobh, EK and Balah, MIF}, title = {Exploring research gaps and trends in the management of acute phosphide poisoning: a systematic review.}, journal = {Critical reviews in toxicology}, volume = {53}, number = {3}, pages = {181-206}, doi = {10.1080/10408444.2023.2225539}, pmid = {37387512}, issn = {1547-6898}, mesh = {Animals ; *Pesticides/toxicity ; Evidence Gaps ; Antidotes ; Acetylcysteine/therapeutic use ; Aluminum Compounds/toxicity ; }, abstract = {Metal phosphides are highly toxic pesticides that result in high morbidities and mortalities worldwide. This systematic review included 350 studies that fulfilled the eligibility criteria. There were significant rising trends of studies on acute aluminum phosphide (AlP) and zinc phosphide (Zn3P2) poisoning (p-values = <.001), pointing to an increased number of phosphide-intoxicated patients. Acute AlP poisoning studies represented 81%, 89.3%, and 97.7% of all descriptive, analytical, and experimental interventional studies included in this review, respectively. High AlP poisoning mortality explains great research interest in AlP poisoning. Thus, after 2016, nearly half (49.7%) of studies on acute AlP poisoning were issued. Also, 78.82% of experimental interventional studies on AlP poisoning were published after 2016. The trends of in-vitro, animal, and clinical studies on AlP poisoning significantly increased with p-values equal to .021, <.001, and <.001, respectively. Seventy-nine treatment modalities for acute AlP poisoning were pooled from 124 studies; 39 management-related case reports, 12 in-vitro studies, 39 animal studies, and 34 clinical studies. All therapeutic modalities were summarized to formulate an integrated and comprehensive overview. For clinicians, therapeutic modalities significantly decreased mortality of acute AlP poisoning in clinical trials included extracorporeal membrane oxygenation (ECMO), N-acetyl cysteine (NAC), vitamin E, glucose-insulin-potassium (GIK) infusion, fresh packed RBCs infusion, and GIT decontamination using oils. However, meta-analyses are needed to provide solid evidence regarding their efficacies. To date, there is no effective antidote nor evidence-based standardized protocol for managing acute AlP poisoning. This article outlined the potential research gaps in phosphide poisoning that might promote and direct future medical research in this context.}, } @article {pmid37386885, year = {2023}, author = {Khalatbari Mohseni, G and Hosseini, SA and Majdinasab, N and Cheraghian, B}, title = {Effects of N-acetylcysteine on oxidative stress biomarkers, depression, and anxiety symptoms in patients with multiple sclerosis.}, journal = {Neuropsychopharmacology reports}, volume = {43}, number = {3}, pages = {382-390}, pmid = {37386885}, issn = {2574-173X}, mesh = {Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Anxiety/drug therapy/etiology ; Biomarkers ; Depression/drug therapy/etiology ; Glutathione/metabolism/pharmacology ; *Multiple Sclerosis/complications/drug therapy ; Oxidative Stress ; }, abstract = {AIM: N-acetylcysteine (NAC), a thiol-containing antioxidant and glutathione (GSH) precursor, attenuates oxidative stress, and possibly improves psychiatric disorders. This study aimed to evaluate the effects of oral NAC on oxidative stress, depression, and anxiety symptoms in patients with multiple sclerosis (MS).

METHODS: This clinical trial was conducted on 42 MS patients randomly assigned to intervention (n = 21) and control (n = 21) groups. The intervention group received 600 mg of NAC twice daily for 8 weeks, and the control group received a placebo with the same prescription form. An analysis of serum malondialdehyde (MDA), serum nitric oxide (NO), and erythrocyte GSH was carried out on both groups, along with a complete blood count. The Hospital Anxiety and Depression Scale (HADS) was used to assess symptoms of depression (HADS-D) and anxiety (HADS-A).

RESULTS: Compared to the control group, NAC consumption significantly decreased serum MDA concentrations (-0.33 [-5.85-2.50] vs. 2.75 [-0.25-5.22] μmol/L; p = 0.03) and HADS-A scores (-1.6 ± 2.67 vs. 0.33 ± 2.83; p = 0.02). No significant changes were observed in serum NO concentrations, erythrocyte GSH levels, and HADS-D scores (p > 0.05).

CONCLUSIONS: Based on the findings of the present study, NAC supplementation for 8 weeks decreased lipid peroxidation and improved anxiety symptoms in MS patients. The aforementioned results suggest that adjunctive therapy with NAC can be considered an effective strategy for MS management. Further randomized controlled studies are warranted.}, } @article {pmid37386836, year = {2023}, author = {Tan, KT and Shih, YH and Gong, JY and Zhang, X and Huang, CY and Su, JH and Sheu, JH and Lin, CC}, title = {Dihydroaustrasulfone alcohol induces apoptosis in nasopharyngeal cancer cells by inducing reactive oxygen species-dependent inactivation of the PI3K/AKT pathway.}, journal = {The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {27}, number = {4}, pages = {383-398}, pmid = {37386836}, issn = {1226-4512}, abstract = {Dihydroaustrasulfone alcohol (DA), the synthetic precursor of a natural compound (austrasulfone) isolated from the coral species Cladiella australis, has shown cytotoxic effects against cancer cells. However, it is unknown whether DA has antitumor effects on nasopharyngeal carcinoma (NPC). In this study, we determined the antitumor effects of DA and investigated its mechanism of action on human NPC cells. The MTT assay was used to determine the cytotoxic effect of DA. Subsequently, apoptosis and reactive oxygen species (ROS) analyses were performed by using flow cytometry. Apoptotic and PI3K/AKT pathway-related protein expression was determined using Western blotting. We found that DA significantly reduced the viability of NPC-39 cells and determined that apoptosis was involved in DA-induced cell death. The activity of caspase-9, caspase-8, caspase-3, and PARP induced by DA suggested caspase-mediated apoptosis in DA-treated NPC-39 cells. Apoptosis-associated proteins (DR4, DR5, FAS) in extrinsic pathways were also elevated by DA. The enhanced expression of proapoptotic Bax and decreased expression of antiapoptotic BCL-2 suggested that DA mediated mitochondrial apoptosis. DA reduced the expression of pPI3K and p-AKT in NPC-39 cells. DA also reduced apoptosis after introducing an active AKT cDNA, indicating that DA could block the PI3K/AKT pathway from being activated. DA increased intracellular ROS, but N-acetylcysteine (NAC), a ROS scavenger, reduced DA-induced cytotoxicity. NAC also reversed the chances in pPI3K/AKT expression and reduced DA-induced apoptosis. These findings suggest that ROS-mediates DA-induced apoptosis and PI3K/AKT signaling inactivation in human NPC cells.}, } @article {pmid37386230, year = {2023}, author = {Li, A and Cao, W}, title = {Downregulation of SODD mediates carnosol-induced reduction in cell proliferation in esophageal adenocarcinoma cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {10580}, pmid = {37386230}, issn = {2045-2322}, mesh = {Cell Proliferation ; Down-Regulation ; Esophageal Neoplasms ; Caspase 3 ; Humans ; *Adenocarcinoma/drug therapy ; NADPH Oxidases ; Reactive Oxygen Species ; *Hydrogen Peroxide ; }, abstract = {Esophageal adenocarcinoma carries a poor prognosis associated with a 5-year survival rate of 12.5-20%. Therefore, a new therapeutic modality is needed for this lethal tumor. Carnosol is a phenolic diterpene purified from the herbs such as rosemary and Mountain desert sage and has been shown to have anticancer activities in multiple cancers. In this study we examined the effect of carnosol on cell proliferation in esophageal adenocarcinoma cells. We found that carnosol dose-dependently decreased cell proliferation in FLO-1 esophageal adenocarcinoma cells and significantly increased caspase-3 protein, indicating that carnosol decreases cell proliferation and increases cell apoptosis in FLO-1 cells. Carnosol significantly increased H2O2 production and N-acetyl cysteine, a reactive oxygen species (ROS) scavenger, significantly inhibited carnosol-induced decrease in cell proliferation, indicating that ROS may mediate carnosol-induced decrease in cell proliferation. Carnosol-induced decrease in cell proliferation was partially reversed by NADPH oxidase inhibitor apocynin, suggesting that NADPH oxidases may be partially involved in carnosol's effect. In addition, carnosol significantly downregulated SODD protein and mRNA expression and knockdown of SODD significantly inhibited the carnosol-induced reduction in cell proliferation, suggesting that downregulation of SODD may contribute to carnosol-induced reduction in cell proliferation. We conclude that carnosol dose-dependently decreased cell proliferation and significantly increased caspase-3 protein. Carnosol's effect may be through the overproduction of ROS and the downregulation of SODD. Carnosol might be useful for the treatment of esophageal adenocarcinoma.}, } @article {pmid37385335, year = {2023}, author = {Wang, H and Zhang, Z and Sittirattanayeunyong, S and Hongpaisan, J}, title = {Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer's Disease Hippocampal CA1 Stratum Radiatum.}, journal = {Neuroscience}, volume = {526}, number = {}, pages = {204-222}, pmid = {37385335}, issn = {1873-7544}, support = {R01 AG058884/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Apolipoprotein E4/genetics/metabolism ; Apolipoproteins E ; CA1 Region, Hippocampal/pathology ; *Echinomycin/metabolism ; Hippocampus/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer's disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression. In AD + APOE4, an increase in strong oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), VEGF, and endothelial cell density were associated with increased diameter of arterioles and perivascular space dilation. In cultured human brain microvascular cells (HBMECs), treatment of ApoE4 protein plus amyloid-β (Aβ) oligomers increased superoxide production and the apoptotic marker cleaved caspase 3, sustained hypoxia inducible factor-1α (HIF-1α) stability that was associated with an increase in MnSOD, VEGF, and cell density. This cell over-proliferation was inhibited with the antioxidants N-acetyl cysteine and MnTMPyP, the HIF-1α inhibitor echinomycin, the VEGFR-2 receptor blocker SU1498, the protein kinase C (PKC) ε knock-down (KD) and the extracellular signal-regulated kinase 1/2 (ERK) inhibitor FR180204. The PKCε KD and echinomycin decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, while those in APOE4 carriers with AD are related with pathogenesis of cerebrovascular disease.}, } @article {pmid37377100, year = {2023}, author = {Zhang, YH and Wang, T and Li, YF and Deng, YN and He, XL and Wang, LJ}, title = {N-acetylcysteine improves autism-like behavior by recovering autophagic deficiency and decreasing Notch-1/Hes-1 pathway activity.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {248}, number = {11}, pages = {966-978}, pmid = {37377100}, issn = {1535-3699}, mesh = {Rats ; Humans ; Animals ; Female ; *Autistic Disorder/drug therapy ; Acetylcysteine/pharmacology ; Behavior, Animal ; *Neuroblastoma ; Valproic Acid/adverse effects ; Disease Models, Animal ; *Prenatal Exposure Delayed Effects/chemically induced ; }, abstract = {N-acetylcysteine (NAC) has been reported to improve social interaction behavior, irritability, self-injury, and anxiety-like behavior in autism. However, the molecular mechanism underlying the therapeutic roles of NAC in autism remains unknown. This study mainly aimed to investigate the therapeutic effect of NAC on valproic acid (VPA)-induced autism model and the underlying mechanisms. Our results showed that NAC ameliorated the deficits in sociability and the anxiety- and repetitive-like behaviors displayed by VPA-exposed rats. In addition, VPA exposure induced autophagic deficiency and enhanced Notch-1/Hes-1 pathway activity based on lowered Beclin-1 and LC3B levels, while increased expression of p62, Notch-1, and Hes-1 expression at the protein level. However, NAC recovered VPA-induced autophagic deficiency and reduced Notch-1/Hes-1 pathway activity in a VPA-exposed autism rat model and SH-SY5Y neural cells. The present results demonstrated that NAC improves autism-like behavioral abnormalities by inactivating Notch-1/Hes-1 signaling pathway and recovering autophagic deficiency. Taken together, this study helps to elucidate a novel molecular mechanism that underlies the therapeutic actions of NAC in autism and suggests its potential to ameliorate behavioral abnormalities in neurodevelopmental disorders.}, } @article {pmid37374326, year = {2023}, author = {Cervantes-Pérez, LA and Cervantes-Guevara, G and Cervantes-Pérez, E and Cervantes-Cardona, GA and Nápoles-Echauri, A and González-Ojeda, A and Fuentes-Orozco, C and Cervantes-Pérez, G and Reyes-Torres, CA and Hernández-Mora, FJ and Ron-Magaña, AL and Vázquez-Beltrán, JC and Hernández-Rivas, MI and Ramírez-Ochoa, S}, title = {Evaluation of the Effects of Atorvastatin and N-Acetyl Cysteine on Platelet Counts in Patients with Primary Immune Thrombocytopenia: An Exploratory Clinical Trial.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {6}, pages = {}, pmid = {37374326}, issn = {1648-9144}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Atorvastatin/pharmacology/therapeutic use ; Platelet Count ; *Purpura, Thrombocytopenic, Idiopathic/drug therapy ; *Thrombocytopenia/drug therapy ; Treatment Outcome ; }, abstract = {Objective: We aimed to evaluate the efficacy of the combination of atorvastatin and N-acetyl cysteine in increasing platelet counts in patients with immune thrombocytopenia who were resistant to steroid therapy or had a relapse after treatment. Material and Methods: The patients included in this study received oral treatment of atorvastatin at a dose of 40 mg daily and N-acetyl cysteine at a dose of 400 mg every 8 h. The desired treatment duration was 12 months, but we included patients who completed at least 1 month of treatment in the analysis. The platelet counts were measured prior to the administration of the study treatment and in the first, third, sixth, and twelfth months of treatment (if available). A p value < 0.05 was considered statistically significant. Results: We included 15 patients who met our inclusion criteria. For the total treatment duration, the global response was 60% (nine patients); eight patients (53.3%) had a complete response and one patient (6.7%) had a partial response. Six patients (40%) were considered as having undergone treatment failure. Of the responder group, five patients maintained a complete response after treatment (55.5%), three patients maintained a partial response (33.3%), and one patient (11.1%) lost their response to the treatment. All of the patients in the responder group had significant increases in their platelet counts after treatment (p < 0.05). Conclusion: This study provides evidence of a possible treatment option for patients with primary immune thrombocytopenia. However, further studies are needed.}, } @article {pmid37372022, year = {2023}, author = {Notaro, A and Lauricella, M and Di Liberto, D and Emanuele, S and Giuliano, M and Attanzio, A and Tesoriere, L and Carlisi, D and Allegra, M and De Blasio, A and Calvaruso, G and D'Anneo, A}, title = {A Deadly Liaison between Oxidative Injury and p53 Drives Methyl-Gallate-Induced Autophagy and Apoptosis in HCT116 Colon Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37372022}, issn = {2076-3921}, support = {FFR-D15 D'Anneo; FFR-D03-Lauricella//This work was partially sustained by Finalized Research Funding (FFR 2022), FFR-D15 D'Anneo and FFR-D03-Lauricella, Università degli Studi di Palermo, Palermo, Italy./ ; }, abstract = {Methyl gallate (MG), which is a gallotannin widely found in plants, is a polyphenol used in traditional Chinese phytotherapy to alleviate several cancer symptoms. Our studies provided evidence that MG is capable of reducing the viability of HCT116 colon cancer cells, while it was found to be ineffective on differentiated Caco-2 cells, which is a model of polarized colon cells. In the first phase of treatment, MG promoted both early ROS generation and endoplasmic reticulum (ER) stress, sustained by elevated PERK, Grp78 and CHOP expression levels, as well as an upregulation in intracellular calcium content. Such events were accompanied by an autophagic process (16-24 h), where prolonging the time (48 h) of MG exposure led to cellular homeostasis collapse and apoptotic cell death with DNA fragmentation and p53 and γH2Ax activation. Our data demonstrated that a crucial role in the MG-induced mechanism is played by p53. Its level, which increased precociously (4 h) in MG-treated cells, was tightly intertwined with oxidative injury. Indeed, the addition of N-acetylcysteine (NAC), which is a ROS scavenger, counteracted the p53 increase, as well as the MG effect on cell viability. Moreover, MG promoted p53 accumulation into the nucleus and its inhibition by pifithrin-α (PFT-α), which is a negative modulator of p53 transcriptional activity, enhanced autophagy, increased the LC3-II level and inhibited apoptotic cell death. These findings provide new clues to the potential action of MG as a possible anti-tumor phytomolecule for colon cancer treatment.}, } @article {pmid37371987, year = {2023}, author = {Caridade-Silva, R and Araújo, B and Martins-Macedo, J and Teixeira, FG}, title = {N-Acetylcysteine Treatment May Compensate Motor Impairments through Dopaminergic Transmission Modulation in a Striatal 6-Hydroxydopamine Parkinson's Disease Rat Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37371987}, issn = {2076-3921}, support = {POCI-01-0145-FEDER-029751//Fundação para a Ciência e Tecnologia/ ; MB-28-2019//Santa Casa da Misericórdia de Lisboa/ ; }, abstract = {Preventing degeneration and the loss of dopaminergic neurons (DAn) in the brain while mitigating motor symptoms remains a challenge in Parkinson's Disease (PD) treatment development. In light of this, developing or repositioning potential disease-modifying approaches is imperative to achieve meaningful translational gains in PD research. Under this concept, N-acetylcysteine (NAC) has revealed promising perspectives in preserving the dopaminergic system capability and modulating PD mechanisms. Although NAC has been shown to act as an antioxidant and (neuro)protector of the brain, it has yet to be acknowledged how this repurposed drug can improve motor symptomatology and provide disease-modifying properties in PD. Therefore, in the present work, we assessed the impact of NAC on motor and histological deficits in a striatal 6-hydroxydopamine (6-OHDA) rat model of PD. The results revealed that NAC enhanced DAn viability, as we found that it could restore dopamine transporter (DAT) levels compared to the untreated 6-OHDA group. Such findings were positively correlated with a significant amelioration in the motor outcomes of the 6-OHDA-treated animals, demonstrating that NAC may, somehow, be a modulator of PD degenerative mechanisms. Overall, we postulated a proof-of-concept milestone concerning the therapeutic application of NAC. Nevertheless, it is extremely important to understand the complexity of this drug and how its therapeutical properties interact with the cellular and molecular PD mechanisms.}, } @article {pmid37371878, year = {2023}, author = {Balázs, G and Balajthy, A and Seri, I and Hegyi, T and Ertl, T and Szabó, T and Röszer, T and Papp, Á and Balla, J and Gáll, T and Balla, G}, title = {Prevention of Chronic Morbidities in Extremely Premature Newborns with LISA-nCPAP Respiratory Therapy and Adjuvant Perinatal Strategies.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37371878}, issn = {2076-3921}, support = {11003//Eötvös Loránd Research Network/ ; OTKA-K 132828//Hungarian Government grants/ ; OTKA NKFI 142939//Hungarian Government grants/ ; TKP2021-EGA-18//Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund/ ; }, abstract = {Less invasive surfactant administration techniques, together with nasal continuous airway pressure (LISA-nCPAP) ventilation, an emerging noninvasive ventilation (NIV) technique in neonatology, are gaining more significance, even in extremely premature newborns (ELBW), under 27 weeks of gestational age. In this review, studies on LISA-nCPAP are compiled with an emphasis on short- and long-term morbidities associated with prematurity. Several perinatal preventative and therapeutic investigations are also discussed in order to start integrated therapies as numerous organ-saving techniques in addition to lung-protective ventilations. Two thirds of immature newborns can start their lives on NIV, and one third of them never need mechanical ventilation. With adjuvant intervention, these ratios are expected to be increased, resulting in better outcomes. Optimized cardiopulmonary transition, especially physiologic cord clamping, could have an additively beneficial effect on patient outcomes gained from NIV. Organ development and angiogenesis are strictly linked not only in the immature lung and retina, but also possibly in the kidney, and optimized interventions using angiogenic growth factors could lead to better morbidity-free survival. Corticosteroids, caffeine, insulin, thyroid hormones, antioxidants, N-acetylcysteine, and, moreover, the immunomodulatory components of mother's milk are also discussed as adjuvant treatments, since immature newborns deserve more complex neonatal interventions.}, } @article {pmid37371872, year = {2023}, author = {Petricca, S and Carnicelli, V and Luzi, C and Cinque, B and Celenza, G and Iorio, R}, title = {Oxidative Stress, Cytotoxic and Inflammatory Effects of Azoles Combinatorial Mixtures in Sertoli TM4 Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37371872}, issn = {2076-3921}, support = {07-RIA 2021 IORIO ROBERTO//intramural "DISCAB GRANT 2021 (code 07-RIA 2021 IORIO ROBERTO)"/ ; grant number CUP E11I18000300005//grant from MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca, Italy) to Roberto Iorio./ ; }, abstract = {Triazole and imidazole fungicides are an emerging class of contaminants with an increasing and ubiquitous presence in the environment. In mammals, their reproductive toxicity has been reported. Concerning male reproduction, a combinatorial activity of tebuconazole (TEB; triazole fungicide) and econazole (ECO; imidazole compound) in inducing mitochondrial impairment, energy depletion, cell cycle arrest, and the sequential activation of autophagy and apoptosis in Sertoli TM4 cells (SCs) has recently been demonstrated. Given the strict relationship between mitochondrial activity and reactive oxygen species (ROS), and the causative role of oxidative stress (OS) in male reproductive dysfunction, the individual and combined potential of TEB and ECO in inducing redox status alterations and OS was investigated. Furthermore, considering the impact of cyclooxygenase (COX)-2 and tumor necrosis factor-alpha (TNF-α) in modulating male fertility, protein expression levels were assessed. In the present study, we demonstrate that azoles-induced cytotoxicity is associated with a significant increase in ROS production, a drastic reduction in superoxide dismutase (SOD) and GSH-S-transferase activity levels, and a marked increase in the levels of oxidized (GSSG) glutathione. Exposure to azoles also induced COX-2 expression and increased TNF-α production. Furthermore, pre-treatment with N-acetylcysteine (NAC) mitigates ROS accumulation, attenuates COX-2 expression and TNF-α production, and rescues SCs from azole-induced apoptosis, suggesting a ROS-dependent molecular mechanism underlying the azole-induced cytotoxicity.}, } @article {pmid37371417, year = {2023}, author = {Du, Y and Chen, L and Qiao, H and Zhang, L and Yang, L and Zhang, P and Wang, J and Zhang, C and Jiang, W and Xu, R and Zhang, X}, title = {Hydrogen-Rich Saline-A Novel Neuroprotective Agent in a Mouse Model of Experimental Cerebral Ischemia via the ROS-NLRP3 Inflammasome Signaling Pathway In Vivo and In Vitro.}, journal = {Brain sciences}, volume = {13}, number = {6}, pages = {}, pmid = {37371417}, issn = {2076-3425}, support = {Grant number: 81974184//the National Natural Science Foundation of China/ ; grant number : 20211706//the Key Project of Medical Science Research of Hebei Province in 2021/ ; }, abstract = {BACKGROUND: Our previous research revealed that inflammation plays an important role in the pathophysiology of cerebral ischemia. The function of the NOD-like receptor protein 3 (NLRP3) inflammasome is to activate the inflammatory process. Recent findings suggest that reactive oxygen species (ROS) are essential secondary messengers that activate the NLRP3 inflammasome. Hydrogen-rich saline (HS) has attracted attention for its anti-inflammatory properties. However, the protective effect and possible mechanism of HSin brain ischemia have not been well elucidated.

METHODS: To test the therapeutic effect of HS, we established a mouse model of distal middle cerebral artery occlusion (dMCAO) and an in vitro model of BV2 cells induced by lipopolysaccharide (LPS). The ROS scavenger N-acetylcysteine (NAC) was used to investigate the underlying mechanisms of HS.

RESULTS: HS significantly improved neurological function, reduced infarct volume, and increased cerebral blood flow in a dMCAO mouse model. ROS, NLRP3, Caspase-1, and IL-1β expression increased after cerebral ischemia, and this was reversed by HS treatment. In BV2 cells, the application of NAC further demonstrated that HS could effectively inhibit the expression of the ROS-activated NLRP3 inflammasome.

CONCLUSIONS: HS, as a novel therapeutic option, could exert protect the brain by inhibiting the activation of the ROS-NLRP3 signaling pathway after cerebral ischemia.}, } @article {pmid37370701, year = {2023}, author = {Khalil, R and Green, RJ and Sivakumar, K and Varandani, P and Bharadwaj, S and Mohapatra, SS and Mohapatra, S}, title = {Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer.}, journal = {Cancers}, volume = {15}, number = {12}, pages = {}, pmid = {37370701}, issn = {2072-6694}, support = {I01 BX003413/BX/BLRD VA/United States ; IK6 BX004212/BX/BLRD VA/United States ; }, abstract = {Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)-a herbal compound-and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.}, } @article {pmid37368450, year = {2023}, author = {Choudhary, M and Pereira, J and Davidson, EB and Colee, J and Santra, S and Jones, JB and Paret, ML}, title = {Improved Persistence of Bacteriophage Formulation with Nano N-Acetylcysteine-Zinc Sulfide and Tomato Bacterial Spot Disease Control.}, journal = {Plant disease}, volume = {107}, number = {12}, pages = {3933-3942}, doi = {10.1094/PDIS-02-23-0255-RE}, pmid = {37368450}, issn = {0191-2917}, mesh = {*Bacteriophages ; Acetylcysteine/pharmacology ; *Solanum lycopersicum ; *Zinc Oxide ; Bacteria ; *Bacterial Infections ; }, abstract = {Bacteriophages are biocontrol agents used to manage bacterial diseases. They have long been used against plant pathogenic bacteria; however, several factors impede their use as a reliable disease management strategy. Short-lived persistence on plant surfaces under field conditions results mainly from rapid degradation by exposure to ultraviolet (UV) light. Currently, there are no effective commercial formulations that protect phages from UV. The phage ΦXp06-02-1, which lyses strains of the tomato bacterial spot pathogen Xanthomonas perforans, was mixed with different concentrations of the nanomaterial N-acetylcysteine surface-coated manganese-doped zinc sulfide (NAC-ZnS; 3.5 nm). In vitro, NAC-ZnS at 10,000 μg/ml formulated phage, when exposed to UV for 1 min, provided statistically equivalent plaque-forming unit (PFU) recovery as phages that were not exposed to UV. NAC-ZnS had no negative effect on the phage's ability to lyse bacterial cells under in vitro conditions. NAC-ZnS reduced phage degradation over time in comparison with the nontreated control, whereas N-acetylcysteine-zinc oxide (NAC-ZnO) had no effect. In fluorescent light, without UV exposure, NAC-ZnO-formulated phages were more infective than NAC-ZnS-formulated phages. The nanomaterial-phage mixture did not cause any phytotoxicity when applied to tomato plants. Following exposure to sunlight, the NAC-ZnS formulation improved phage persistence in the phyllosphere by 15 times compared with nonformulated phages. NAC-ZnO-formulated phage populations were undetectable within 32 h, whereas NAC-ZnS-formulated phage populations were detected at 10[3] PFU/g. At 4 h of sunlight exposure, NAC-ZnS-formulated phages at 1,000 μg/ml significantly reduced tomato bacterial spot disease severity by 16.4% compared with nonformulated phages. These results suggest that NAC-ZnS can be used to improve the efficacy of phages for bacterial diseases.}, } @article {pmid37368329, year = {2023}, author = {Fesharaki Zadeh, A and Arnsten, AFT and Wang, M}, title = {Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID.}, journal = {Neurology international}, volume = {15}, number = {2}, pages = {725-742}, pmid = {37368329}, issn = {2035-8385}, support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG061190/AG/NIA NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, abstract = {Sustained cognitive deficits are a common and debilitating feature of "long COVID", but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function. KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID.}, } @article {pmid37368165, year = {2023}, author = {Barrera-Chimal, J and Henley, N and Grant, MP and Cenatus, S and Geraldes, P and Pichette, V and Gerarduzzi, C}, title = {Tungsten toxicity on kidney tubular epithelial cells induces renal inflammation and M1-macrophage polarization.}, journal = {Cell biology and toxicology}, volume = {39}, number = {6}, pages = {3061-3075}, pmid = {37368165}, issn = {1573-6822}, mesh = {Male ; Mice ; Animals ; *Tungsten/toxicity ; Culture Media, Conditioned ; *Kidney ; Macrophages ; Epithelial Cells ; NF-kappa B ; Inflammation/chemically induced ; }, abstract = {Tungsten is widely used in medical, industrial, and military applications. The environmental exposure to tungsten has increased over the past several years, and few studies have addressed its potential toxicity. In this study, we evaluated the effects of chronic oral tungsten exposure (100 ppm) on renal inflammation in male mice. We found that 30- or 90-day tungsten exposure led to the accumulation of LAMP1-positive lysosomes in renal tubular epithelial cells. In addition, the kidneys of mice exposed to tungsten showed interstitial infiltration of leukocytes, myeloid cells, and macrophages together with increased levels of proinflammatory cytokines and p50/p65-NFkB subunits. In proximal tubule epithelial cells (HK-2) in vitro, tungsten induced a similar inflammatory status characterized by increased mRNA levels of CSF1, IL34, CXCL2, and CXCL10 and NFkB activation. Moreover, tungsten exposure reduced HK-2 cell viability and enhanced reactive oxygen species generation. Conditioned media from HK-2 cells treated with tungsten induced an M1-proinflammatory polarization of RAW macrophages as evidenced by increased levels of iNOS and interleukin-6 and decreased levels of the M2-antiinflammatory marker CD206. These effects were not observed when RAW cells were exposed to conditioned media from HK-2 cells treated with tungsten and supplemented with the antioxidant N-acetylcysteine (NAC). Similarly, direct tungsten exposure induced M1-proinflammatory polarization of RAW cells that was prevented by NAC co-treatment. Altogether, our data suggest that prolonged tungsten exposure leads to oxidative injury in the kidney ultimately leading to chronic renal inflammation characterized by a proinflammatory status in kidney tubular epithelial cells and immune cell infiltration.}, } @article {pmid37360438, year = {2023}, author = {Maria Francis, Y and Karunakaran, B and Ashfaq, F and Yahia Qattan, M and Ahmad, I and Alkhathami, AG and Idreesh Khan, M and Varadhan, M and Govindan, L and Ponnusamy Kasirajan, S}, title = {Mercuric Chloride Induced Nephrotoxicity: Ameliorative Effect of Carica papaya Leaves Confirmed by Histopathology, Immunohistochemistry, and Gene Expression Studies.}, journal = {ACS omega}, volume = {8}, number = {24}, pages = {21696-21708}, pmid = {37360438}, issn = {2470-1343}, abstract = {The present study analyzes the efficacy of the ethanolic extract of C. papaya leaves (ECP) against HgCl2-induced nephrotoxicity. The effects on the biochemical and percentage of body and organ weight against HgCl2-induced nephrotoxicity in female Wistar rats were studied. Wistar rats were divided into five groups with six animals in each group: control, HgCl2 (2.5 mg/kg b.w.), N-acetylcysteine (NAC 180 mg/kg) + HgCl2, ECP (300 mg/kg b.w.) + HgCl2, and ECP (600 mg/kg) + HgCl2 groups. After 28 days of study, animals were sacrificed on the 29th day to harvest the blood and kidneys for further analysis. The effect ECP was analyzed by immunohistochemistry (NGAL) and real-time PCR (KIM-1 and NGAL mRNA) in HgCl2-induced nephrotoxicity. The results revealed that the HgCl2 group showed prominent damage in the proximal tubules and glomerulus of nephrons and enormous expression of NGAL in immunohistochemistry and KIM-1 and NGAL in real-time PCR compared to the control group. The simultaneous pretreatment with NAC (180 mg/kg) and ECP (600 and 300 mg/kg) reduced renal damage and expression of NGAL in immunohistochemistry and KIM-1 and NGAL gene in real-time PCR. This study attests to the nephroprotective effect of ECP against HgCl2-induced toxicity.}, } @article {pmid37360166, year = {2023}, author = {Mazumdar, R and Eberhart, JK}, title = {Loss of Nicotinamide nucleotide transhydrogenase sensitizes embryos to ethanol-induced neural crest and neural apoptosis via generation of reactive oxygen species.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1154621}, pmid = {37360166}, issn = {1662-4548}, support = {T32 AA007471/AA/NIAAA NIH HHS/United States ; }, abstract = {Fetal alcohol spectrum disorders (FASD) are a continuum of birth defects caused by prenatal alcohol exposure. FASD are the most common environmentally induced birth defect and are highly variable. The genetics of an individual influence the severity of their FASD phenotype. However, the genes that sensitize an individual to ethanol-induced birth defects are largely unknown. The ethanol-sensitive mouse substrain, C57/B6J, carries several known mutations including one in Nicotinamide nucleotide transhydrogenase (Nnt). Nnt is a mitochondrial transhydrogenase thought to have an important role in detoxifying reactive oxygen species (ROS) and ROS has been implicated in ethanol teratogenesis. To directly test the role of Nnt in ethanol teratogenesis, we generated zebrafish nnt mutants via CRISPR/Cas9. Zebrafish embryos were dosed with varying concentrations of ethanol across different timepoints and assessed for craniofacial malformations. We utilized a ROS assay to determine if this could be a contributing factor of these malformations. We found that exposed and unexposed mutants had higher levels of ROS compared to their wildtype counterparts. When treated with ethanol, nnt mutants experienced elevated apoptosis in the brain and neural crest, a defect that was rescued by administration of the antioxidant, N-acetyl cysteine (NAC). NAC treatment also rescued most craniofacial malformations. Altogether this research demonstrates that ethanol-induced oxidative stress leads to craniofacial and neural defects due to apoptosis in nnt mutants. This research further supports the growing body of evidence implicating oxidative stress in ethanol teratogenesis. These findings suggest that antioxidants can be used as a potential therapeutic in the treatment of FASD.}, } @article {pmid37356397, year = {2023}, author = {Zhang, Q and Liu, W and Li, Q and Zeng, Y and Wu, M and Wu, T and Guo, S and Wang, L and Zhao, D and Yi, D and Hou, Y}, title = {Protective effects and mechanisms of N-acetylcysteine on indomethacin-induced intestinal injury in a porcine model.}, journal = {Ecotoxicology and environmental safety}, volume = {262}, number = {}, pages = {115173}, doi = {10.1016/j.ecoenv.2023.115173}, pmid = {37356397}, issn = {1090-2414}, abstract = {This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was "ubiquitin-like protein ligase binding" for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that "arginine biosynthesis" was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.}, } @article {pmid37351787, year = {2023}, author = {Kim, B and Lee, SM and Park, SJ and Lee, S and Kim, T}, title = {Role of Klotho and N-acetylcysteine in Oxidative Stress Associated with the Vitrification of Ovarian Tissue Cytoprotective Function of Klotho in Cryopreservation.}, journal = {Tissue engineering and regenerative medicine}, volume = {20}, number = {4}, pages = {637-646}, pmid = {37351787}, issn = {2212-5469}, support = {NRF-2016R1C1B3015250//National Research Foundation of Korea Grant/ ; }, mesh = {*Vitrification ; *Acetylcysteine/pharmacology/metabolism ; Reactive Oxygen Species/metabolism/pharmacology ; Cryopreservation/methods ; Oxidative Stress ; }, abstract = {BACKGROUND: Cryopreservation can cause mechanical and chemical stress, ultimately leading to the formation of reactive oxygen species (ROS) and oxidative stress. ROS inhibits the expression of antioxidant enzymes in cells, resulting in increased DNA fragmentation and apoptosis. In this paper, we used a vitrification method that has the advantage of producing less ice crystal formation, cost-effectiveness, and time efficiency during cryopreservation. The objective of this paper is to evaluate the degree of protection of ovarian tissue against oxidative stress when N-acetylcysteine (NAC) and Klotho proteins are treated in the vitrification process of ovarian tissue. METHODS: The control group and the cryopreservation groups were randomly assigned, and treated NAC, Klotho, or the combination (NAC + Klotho). The cell morphological change, DNA damage, senescence, and apoptosis of each group after the freeze-thaw process were compared using transmission electron microscopy, immunohistochemistry, and western blot analysis.

RESULTS: Both NAC and Klotho were found to be more effective at protecting against DNA damage than the control; however, DNA damage was greater in the NAC + Klotho group than in the group treated with NAC and Klotho, respectively. DNA damage and cellular senescence were also reduced during the vitrification process when cells were treated with NAC, Klotho, or the combination (NAC + Klotho). NAC increased apoptosis during cryopreservation, whereas Klotho inhibited apoptosis and NAC-induced apoptosis.

CONCLUSION: This study highlights Klotho's benefits in inhibiting DNA damage, cell senescence, and apoptosis, including NAC-induced apoptosis, despite its unclear role in vitrification.}, } @article {pmid37350963, year = {2023}, author = {Peng, N and Geng, Y and Ouyang, J and Liu, S and Yuan, F and Wan, Y and Chen, W and Yu, B and Tang, Y and Su, L and Liang, H and Wang, JH and Liu, J}, title = {Endothelial glycocalyx injury is involved in heatstroke-associated coagulopathy and protected by N-acetylcysteine.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1159195}, pmid = {37350963}, issn = {1664-3224}, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology ; Endothelial Cells ; Glycocalyx ; Reactive Oxygen Species ; Hydrogen Peroxide ; Retrospective Studies ; *Blood Coagulation Disorders/drug therapy/etiology ; *Heat Stroke/drug therapy ; *Sepsis/complications ; }, abstract = {INTRODUCTION: Damage to endothelial glycocalyx (EGCX) can lead to coagulation disorders in sepsis. Heat stroke (HS) resembles sepsis in many aspects; however, it is unclear whether EGCX injury is involved in its pathophysiology. The purpose of this study was to examine the relationship between the damage of EGCX and the development of coagulation disorders during HS.

METHODS: We retrospectively collected 159 HS patients and analyzed coagulation characteristics and prognosis of HS patients with or without disseminated intravascular coagulation (DIC). We also replicated a rat HS model and measured coagulation indexes, pulmonary capillary EGCX injury in HS rats. Finally, we evaluated the effect of the antioxidant N-acetylcysteine (NAC) on HS-initiated EGCX injury and coagulation disorders.

RESULTS: Clinical data showed that HS patients complicated with DIC had a higher risk of death than HS patients without DIC. In a rat HS model, we found that rats subjected to heat stress developed hypercoagulability and platelet activation at the core body temperature of 43°C, just before the onset of HS. At 24 h of HS, the rats showed a consumptive hypo-coagulation state. The pulmonary capillary EGCX started to shed at 0 h of HS and became more severe at 24 h of HS. Importantly, pretreatment with NAC substantially alleviated EGCX damage and reversed the hypo-coagulation state in HS rats. Mechanically, HS initiated reactive oxidative species (ROS) generation, while ROS could directly cause EGCX damage. Critically, NAC protected against EGCX injury by attenuating ROS production in heat-stressed or hydrogen peroxide (H2O2)-stimulated endothelial cells.

DISCUSSION: Our results indicate that the poor prognosis of HS patients correlates with severe coagulation disorders, coagulation abnormalities in HS rats are associated with the damage of EGCX, and NAC improves HS-induced coagulopathy, probably through its protection against EGCX injury by preventing ROS generation.}, } @article {pmid37349241, year = {2023}, author = {Iqbal, P and Karki, P and Abdelmottaleb, W and Al-Khazraji, Y and Mirza Fawad, A and Madani, K and Ahmed, F and Nawaz, S and Jamshaid, MB and Fernando, QM}, title = {Asymptomatic COVID-19 presenting with features of mixed pattern acute liver injury in a young healthy female, a case report.}, journal = {Journal of infection and public health}, volume = {16}, number = {9}, pages = {1481-1484}, pmid = {37349241}, issn = {1876-035X}, mesh = {Humans ; Female ; *COVID-19 ; Liver/diagnostic imaging ; Acetylcysteine ; }, abstract = {COVID-19 associated severe acute liver injury in a young healthy patient has not been reported much in the literature. And currently, there are no standard management guidelines. We want to report a case of acute liver injury of mixed pattern in a young healthy female with asymptomatic COVID-19 infection. She presented with abdominal pain, nausea, vomiting and yellowish discoloration of her skin. Further laboratory investigations revealed mixed pattern liver injury with highly raised liver enzymes. She was managed with N-acetyl cysteine protocol and monitoring of her liver enzymes. Other causes of acute liver injury were ruled out. She remained stable during her hospital stay and follow up. Our aim is to highlight the significance of acute liver injury in COVID 19 patients that may lead to fatal outcomes if not managed and monitored accordingly.}, } @article {pmid37348685, year = {2023}, author = {Cui, J and Xu, T and Lv, H and Guo, MY}, title = {Zinc deficiency causes oxidative stress, endoplasmic reticulum stress, apoptosis and inflammation in hepatocytes in grass carp.}, journal = {Fish & shellfish immunology}, volume = {139}, number = {}, pages = {108905}, doi = {10.1016/j.fsi.2023.108905}, pmid = {37348685}, issn = {1095-9947}, mesh = {Animals ; Diet ; *Carps ; Inflammation/chemically induced/veterinary ; Oxidative Stress ; Apoptosis ; Hepatocytes ; *Malnutrition ; Zinc/pharmacology ; Endoplasmic Reticulum Stress ; RNA, Messenger ; }, abstract = {A lack of the trace element zinc (Zn) in freshwater environments causes slow growth and malnutrition and affects the normal biological functions of organisms. In this study, a Zn deficiency model of grass carp hepatocytes was established with TPEN. Acetylcysteine (NAC) was used as an inhibitor. TPEN was added to L8824 cell culture medium, and LDH, AST, ALT, and AKP activities were enhanced in a Zn-deficient environment, leading to abnormal hepatopancreas function. Fluorescence microscopy showed an increase in ROS levels, and antioxidant enzyme activity assays revealed that SOD, CAT, GSH-PX, and T-AOC activities were decreased, indicating oxidative stress caused by Zn deficiency. The RT‒PCR results showed that the mRNA expression of GRP78, PERK, EIF2α, ATF4, and Chop was increased due to the addition of TPEN. Calcium kits showed increased Ca[2+] levels. The RT‒PCR results showed that the mRNA expression levels of Caspase-12, Caspase-9, Caspase-3, and PARP apoptotic were increased due to the addition of TPEN. RT‒PCR and ELISA showed that the expression levels of interleukin-1β (IL-1β), interleukin-8 (IL-8), tumour necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were increased. This led to the conclusion that Zn deficiency in the freshwater environment caused inflammation and apoptosis in hepatocytes in grass carp. For the first time, apoptosis caused by endoplasmic reticulum stress in grass carp hepatocytes due to Zn deficiency was studied in the context of Ca[2+]. The present study provided some insight into the adverse effects of Zn deficiency in freshwater environments on fish.}, } @article {pmid37333506, year = {2023}, author = {Chethan, GE and De, UK and Singh, MK and Chander, V and Raja, R and Paul, BR and Choudhary, OP and Thakur, N and Sarma, K and Prasad, H}, title = {Antioxidant supplementation during treatment of outpatient dogs with parvovirus enteritis ameliorates oxidative stress and attenuates intestinal injury: A randomized controlled trial.}, journal = {Veterinary and animal science}, volume = {21}, number = {}, pages = {100300}, pmid = {37333506}, issn = {2451-943X}, abstract = {A prospective randomized controlled clinical study was conducted to determine whether antioxidant supplementation as an adjunct therapy alters hemogram, oxidative stress, serum intestinal fatty acid binding protein-2 (IFABP-2) level, fecal viral load, clinical score (CS) and survivability in outpatient canine parvovirus enteritis (CPVE) dogs. The dogs with CPVE were randomized to one of the five treatment groups: supportive treatment (ST) alone, ST with N-acetylcysteine (ST+NAC), resveratrol (ST+RES), coenzyme Q10 (ST+CoQ10) or ascorbic acid (ST+AA). The primary outcome measures were reduction of CS and fecal HA titre, and enhancement of survivability. Secondary outcome measures were reduction of oxidative stress indices and IFABP-2 level from day 0 to day 7. The mean CS and HA titre were significantly (P < 0.05) decreased from day 0 to 7 in ST and all antioxidant groups. The supplementations of NAC, RES and AA along with ST markedly (P < 0.05) reduced the concentrations of malondialdehyde, nitric oxide and IFABP-2 on day 7 as compared to ST alone. Additionally, NAC and RES supplementations markedly (P < 0.05) improved the total leukocyte count and neutrophil count in CPVE-affected dogs. NAC and RES could serve as better antioxidants for the amelioration of oxidative stress in CPVE but, the antioxidants did not confer any additional benefits in reduction of CS, fecal HA tire, or survivability when compared with ST alone.}, } @article {pmid37332579, year = {2023}, author = {Csiki, DM and Ababneh, H and Tóth, A and Lente, G and Szöőr, Á and Tóth, A and Fillér, C and Juhász, T and Nagy, B and Balogh, E and Jeney, V}, title = {Hypoxia-inducible factor activation promotes osteogenic transition of valve interstitial cells and accelerates aortic valve calcification in a mice model of chronic kidney disease.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1168339}, pmid = {37332579}, issn = {2297-055X}, abstract = {INTRODUCTION: Valve calcification (VC) is a widespread complication in chronic kidney disease (CKD) patients. VC is an active process with the involvement of in situ osteogenic transition of valve interstitial cells (VICs). VC is accompanied by the activation of hypoxia inducible factor (HIF) pathway, but the role of HIF activation in the calcification process remains undiscovered.

METHODS AND RESULT: Using in vitro and in vivo approaches we addressed the role of HIF activation in osteogenic transition of VICs and CKD-associated VC. Elevation of osteogenic (Runx2, Sox9) and HIF activation markers (HIF-1α and HIF-2α) and VC occurred in adenine-induced CKD mice. High phosphate (Pi) induced upregulation of osteogenic (Runx2, alkaline-phosphatase, Sox9, osteocalcin) and hypoxia markers (HIF-1α, HIF-2α, Glut-1), and calcification in VICs. Down-regulation of HIF-1α and HIF-2α inhibited, whereas further activation of HIF pathway by hypoxic exposure (1% O2) or hypoxia mimetics [desferrioxamine, CoCl2, Daprodustat (DPD)] promoted Pi-induced calcification of VICs. Pi augmented the formation of reactive oxygen species (ROS) and decreased viability of VICs, whose effects were further exacerbated by hypoxia. N-acetyl cysteine inhibited Pi-induced ROS production, cell death and calcification under both normoxic and hypoxic conditions. DPD treatment corrected anemia but promoted aortic VC in the CKD mice model.

DISCUSSION: HIF activation plays a fundamental role in Pi-induced osteogenic transition of VICs and CKD-induced VC. The cellular mechanism involves stabilization of HIF-1α and HIF-2α, increased ROS production and cell death. Targeting the HIF pathways may thus be investigated as a therapeutic approach to attenuate aortic VC.}, } @article {pmid37325649, year = {2023}, author = {Chaumond, E and Peron, S and Daniel, N and Le Gouar, Y and Guédon, É and Williams, DL and Le Loir, Y and Jan, G and Berkova, N}, title = {Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1138539}, pmid = {37325649}, issn = {1664-3224}, mesh = {Female ; Humans ; Animals ; Cattle ; Reactive Oxygen Species ; *Immunity, Innate ; Staphylococcus aureus ; Trained Immunity ; Interleukin-8 ; Interleukin-6 ; *Staphylococcal Infections ; }, abstract = {INTRODUCTION: The mechanisms underlying innate immune memory (trained immunity) comprise epigenetic reprogramming of transcriptional pathways associated with alterations of intracellular metabolism. While the mechanisms of innate immune memory carried out by immune cells are well characterized, such processes in non-immune cells, are poorly understood. The opportunistic pathogen, Staphylococcus aureus, is responsible for a multitude of human diseases, including pneumonia, endocarditis and osteomyelitis, as well as animal infections, including chronic cattle mastitis that are extremely difficult to treat. An induction of innate immune memory may be considered as a therapeutic alternative to fight S. aureus infection.

METHODS: In the current work, we demonstrated the development of innate immune memory in non-immune cells during S. aureus infection employing a combination of techniques including Enzyme-linked immunosorbent assay (ELISA), microscopic analysis, and cytometry.

RESULTS: We observed that training of human osteoblast-like MG-63 cells and lung epithelial A549 cells with β-glucan increased IL-6 and IL-8 production upon a stimulation with S. aureus, concomitant with histones modifications. IL-6 and IL-8 production was positively correlated with an acetylation of histone 3 at lysine 27 (H3K27), thus suggesting epigenetic reprogramming in these cells. An addition of the ROS scavenger N-Acetylcysteine, NAC, prior to β-glucan pretreatment followed by an exposure to S. aureus, resulted in decreased IL-6 and IL-8 production, thereby supporting the involvement of ROS in the induction of innate immune memory. Exposure of cells to Lactococcus lactis resulted in increased IL-6 and IL-8 production by MG-63 and A549 cells upon a stimulation with S. aureus that was correlated with H3K27 acetylation, suggesting the ability of this beneficial bacterium to induce innate immune memory.

DISCUSSION: This work improves our understanding of innate immune memory in non-immune cells in the context of S. aureus infection. In addition to known inducers, probiotics may represent good candidates for the induction of innate immune memory. Our findings may help the development of alternative therapeutic approaches for the prevention of S. aureus infection.}, } @article {pmid37323955, year = {2022}, author = {Memudu, AE}, title = {The Efficacy of N-Acetyl-Cysteine (NAC) Supplementation in FST Model for Screening Antidepressants.}, journal = {Basic and clinical neuroscience}, volume = {13}, number = {6}, pages = {839-854}, pmid = {37323955}, issn = {2008-126X}, abstract = {INTRODUCTION: The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug.

METHODS: Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 μm thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC).

RESULTS: Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug.

CONCLUSION: NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.}, } @article {pmid37318485, year = {2023}, 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 = {Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.}, journal = {European review for medical and pharmacological sciences}, volume = {27}, number = {11}, pages = {5119-5127}, doi = {10.26355/eurrev_202306_32628}, pmid = {37318485}, issn = {2284-0729}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Expectorants/therapeutic use ; *Ambroxol/therapeutic use ; *Respiration Disorders ; Mucus ; Double-Blind Method ; }, abstract = {OBJECTIVE: Evidence for the mucolytic and expectorant efficacy of intravenous (IV) N-acetylcysteine (NAC) is limited. This study aimed to evaluate in a large, multicenter, randomized, controlled, subject, and rater-blinded study whether IV NAC is superior to placebo and non-inferior to ambroxol in improving sputum viscosity and expectoration difficulty.

PATIENTS AND METHODS: A total of 333 hospitalized subjects from 28 centers in China with respiratory disease (such as acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis, and bronchiectasis) and abnormal mucus secretion were randomly allocated in a 1:1:1 ratio to receive NAC 600 mg, ambroxol hydrochloride 30 mg, or placebo as an IV infusion twice daily for 7 days. Mucolytic and expectorant efficacy was assessed by ordinal categorical 4-point scales and analyzed by stratified and modified Mann-Whitney U statistics.

RESULTS: NAC showed consistent and statistically significant superiority to placebo and non-inferiority to ambroxol in change from baseline to day 7 in both sputum viscosity scores [mean (SD) difference 0.24 (0.763), p<0.001 vs. placebo] and expectoration difficulty score [mean (SD) difference 0.29 (0.783), p=0.002 vs. placebo]. Safety findings confirm the good tolerability profile of IV NAC reported from previous small studies, and no new safety concerns were identified.

CONCLUSIONS: This is the first large, robust study of the efficacy of IV NAC in respiratory diseases with abnormal mucus secretion. It provides new evidence for IV NAC administration in this indication in clinical situations where the IV route is preferred.}, } @article {pmid37312532, year = {2023}, author = {Gupta, M and Gupta, S and Sood, D and Gupta, A and Jesrani, G}, title = {Role of N-acetylcysteine in liver injury due to dengue fever.}, journal = {Tropical doctor}, volume = {53}, number = {4}, pages = {475-480}, doi = {10.1177/00494755231176317}, pmid = {37312532}, issn = {1758-1133}, mesh = {Humans ; Acetaminophen/toxicity ; *Acetylcysteine/therapeutic use ; *Dengue/complications/drug therapy ; *Liver Failure, Acute/drug therapy/etiology ; }, abstract = {Dengue fever (DF) is a common mosquito-borne viral infection which is endemic in Southeast Asia. Liver involvement may vary from asymptomatic elevation of liver enzymes to fulminant hepatitis. Although the valuable effects of N-acetylcysteine (NAC) in paracetamol toxicity and non-paracetamol liver failure have been extensively studied, its use in DF-associated hepatitis remains unclear. We made a literature search in an online format from libraries such as PubMed, Google Scholar, and EMBASE, and selected 33 articles including original research articles, case reports, and systemic analyses. The majority of the articles reviewed had a positive outcome but treatment strategies involved NAC together with supportive care. Hence, data on sole use of NAC from large randomised control trials remain unclear.}, } @article {pmid37311880, year = {2023}, author = {Li, J and Zhang, Y and Kong, D and Su, J and Wei, Y and Liu, X and Lu, S and Wang, J and Huang, F}, title = {Association between N-acetylcysteine treatment and in-hospital mortality in adult patients with acquired thrombotic thrombocytopenic purpura: a cohort study.}, journal = {Annals of hematology}, volume = {102}, number = {8}, pages = {2257-2265}, doi = {10.1007/s00277-023-05295-2}, pmid = {37311880}, issn = {1432-0584}, support = {GSWS2020006//Gusu Health Talents Programme/ ; SDFEYJC2105//Pre-Research Fund Project of the Second Affiliated Hospital of Soochow University/ ; }, mesh = {Humans ; Adult ; *Purpura, Thrombotic Thrombocytopenic/diagnosis ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Cohort Studies ; Hospital Mortality ; Plasma Exchange ; }, abstract = {Acquired thrombotic thrombocytopenic purpura (aTTP) is a fatal hematologic disease. Despite the currently high standards of care, some patients who develop refractory or recurrent disease still have a poor prognosis. Although N-acetylcysteine (NAC) is recommended for the treatment of aTTP, its use in aTTP treatment is still controversial. We aimed to evaluate the association of NAC with mortality in patients with aTTP. This was a retrospective cohort study of patients with aTTP with in-hospital mortality as the primary outcome and time to platelet recovery and neurological recovery as secondary outcomes. We used multifactorial COX regression analysis to check for an association of NAC with mortality. Moreover, we performed a sensitivity analysis check the stability of our results. Finally, 89 patients with aTTP were enrolled. After adjusting for potential confounders, we found NAC to be associated with 75% lower in-hospital mortality (HR = 0.25, 95% CI = 0.1-0.64). The results of sensitivity analyses performed remained stable as the risk of in-hospital mortality in patients reduced in patients with comorbid neurological symptoms (HR = 0.23, 95% CI = 0.06-0.89). However, NAC use did not affect the time to platelet recovery (HR = 1.19, 95% CI = 0.57-2.5) or neurological recovery (HR = 0.32, 95% CI = 0.08-1.25) in patients with aTTP. NAC treatment reduces in-hospital mortality in patients with aTTP but does not shorten the time to platelet recovery or neurological recovery.}, } @article {pmid37309335, year = {2023}, author = {Martini, N and Singla, P and Arbuckle, E and Goyal, G and Liu, Q and Santos-Zabala, ML and Zainah, H}, title = {SARS-CoV-2-Induced Autoimmune Hepatitis.}, journal = {Cureus}, volume = {15}, number = {5}, pages = {e38932}, pmid = {37309335}, issn = {2168-8184}, abstract = {Few case reports discuss the incidences of autoimmune hepatitis (AIH) in patients after SARS-CoV-2 infection. Here, we present a case of SARS-CoV-2-induced AIH in a male patient who came into the emergency department with complaints of weight loss, poor oral intake, nausea, dark-colored urine, clay-colored stools, and scleral icterus, which began two weeks after he tested positive for SARS-CoV-2 PCR. Liver biopsy and subsequent histology confirmed the diagnosis of AIH with the most probable etiology being SARS-CoV-2 infection. The patient was treated with N-acetylcysteine (NAC) and steroids with clinical improvement and eventual discharge home. Our goal is to provide a clinical presentation, treatment, and outcome in a patient with SARS-CoV-2-induced AIH.}, } @article {pmid37302535, year = {2023}, author = {Scaramboni, C and Arruda Moura Campos, ML and Junqueira Dorta, D and Palma de Oliveira, D and Batistuzzo de Medeiros, SR and de Oliveira Galvão, MF and Dreij, K}, title = {Reactive oxygen species-dependent transient induction of genotoxicity by retene in human liver HepG2 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {91}, number = {}, pages = {105628}, doi = {10.1016/j.tiv.2023.105628}, pmid = {37302535}, issn = {1879-3177}, mesh = {Humans ; Reactive Oxygen Species ; Hep G2 Cells ; *Particulate Matter ; *DNA Damage ; Oxidative Stress ; Liver ; }, abstract = {Retene is a polycyclic aromatic hydrocarbon (PAH) emitted mainly by biomass combustion, and despite its ubiquity in atmospheric particulate matter (PM), studies concerning its potential hazard to human health are still incipient. In this study, the cytotoxicity and genotoxicity of retene were investigated in human HepG2 liver cells. Our data showed that retene had minimal effect on cell viability, but induced DNA strand breaks, micronuclei formation, and reactive oxygen species (ROS) formation in a dose- and time-dependent manner. Stronger effects were observed at earlier time points than at longer, indicating transient genotoxicity. Retene activated phosphorylation of Checkpoint kinase 1 (Chk1), an indicator of replication stress and chromosomal instability, which was in accordance with increased formation of micronuclei. A protective effect of the antioxidant N-acetylcysteine (NAC) towards ROS generation and DNA damage signaling was observed, suggesting oxidative stress as a key mechanism of the observed genotoxic effects of retene in HepG2 cells. Altogether our results suggest that retene may contribute to the harmful effects caused by biomass burning PM and represent a potential hazard to human health.}, } @article {pmid37299425, year = {2023}, author = {Fernández-Lázaro, D and Domínguez-Ortega, C and Busto, N and Santamaría-Peláez, M and Roche, E and Gutiérez-Abejón, E and Mielgo-Ayuso, J}, title = {Influence of N-Acetylcysteine Supplementation on Physical Performance and Laboratory Biomarkers in Adult Males: A Systematic Review of Controlled Trials.}, journal = {Nutrients}, volume = {15}, number = {11}, pages = {}, pmid = {37299425}, issn = {2072-6643}, mesh = {Male ; Adult ; Humans ; *Acetylcysteine/pharmacology ; *Antioxidants ; Dietary Supplements ; Glutathione ; Physical Functional Performance ; Biomarkers ; Randomized Controlled Trials as Topic ; }, abstract = {N-acetylcysteine (NAC) is used as a sports supplement for its ability to modulate exercise-induced oxidative damage through its antioxidant actions and maintenance of glutathione homeostasis, positioning NAC as a strategy to improve physical performance. We aimed to evaluate the current evidence on the benefits of NAC supplementation on physical performance and laboratory biomarkers in adult men. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed studies indexed in the Web of Science, Scopus, and PubMed to assess the effects of NAC on physical performance, laboratory biomarkers, and adverse effects in adult men. Original articles published up to 30 April 2023 with a controlled trial design comparing NAC supplementation with a control group were included. The modified McMaster Critical Review Form for Quantitative Studies was used as an assessment tool and the Cochrane Risk of Bias was applied. Of the 777 records identified in the search, 16 studies met the inclusion and exclusion criteria. Overall, most of the trials reported beneficial effects of NAC supplementation and no serious adverse events were reported. Participants supplemented with NAC showed significant improvements in exercise performance, antioxidant capacity, and glutathione homeostasis. However, there was no clear evidence of beneficial effects of NAC supplementation on haematological markers, inflammatory response, and muscle behaviour. NAC supplementation appears to be safe and may regulate glutathione homeostasis, have antioxidant effects, and improve exercise performance. However, further studies are needed to clarify the relevance of its use.}, } @article {pmid37298254, year = {2023}, author = {Tyuryaeva, I and Lyublinskaya, O}, title = {Expected and Unexpected Effects of Pharmacological Antioxidants.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298254}, issn = {1422-0067}, support = {21-74-20178//Russian Science Foundation/ ; }, mesh = {*Antioxidants/pharmacology ; *Acetylcysteine/pharmacology ; Hydrogen Peroxide ; Ascorbic Acid/pharmacology ; Polyphenols/pharmacology ; }, abstract = {In this review, we have collected the existing data on the bioactivity of antioxidants (N-acetylcysteine, polyphenols, vitamin C) which are traditionally used in experimental biology and, in some cases, in the clinic. Presented data show that, despite the capacity of these substances to scavenge peroxides and free radicals in cell-free systems, their ability to exhibit these properties in vivo, upon pharmacological supplementation, has not been confirmed so far. Their cytoprotective activity is explained mainly by the ability not to suppress, but to activate multiple redox pathways, which causes biphasic hormetic responses and highly pleiotropic effects in cells. N-acetylcysteine, polyphenols, and vitamin C affect redox homeostasis by generating low-molecular-weight redox-active compounds (H2O2 or H2S), known for their ability to stimulate cellular endogenous antioxidant defense and promote cytoprotection at low concentrations but exert deleterious effects at high concentrations. Moreover, the activity of antioxidants strongly depends on the biological context and mode of their application. We show here that considering the biphasic and context-dependent response of cells on the pleiotropic action of antioxidants can help explain many of the conflicting results obtained in basic and applied research and build a more logical strategy for their use.}, } @article {pmid37297001, year = {2023}, author = {Becker, AL and Indra, AK}, title = {Oxidative Stress in Melanoma: Beneficial Antioxidant and Pro-Oxidant Therapeutic Strategies.}, journal = {Cancers}, volume = {15}, number = {11}, pages = {}, pmid = {37297001}, issn = {2072-6694}, support = {ME210206P1//United States Department of Defense/ ; }, abstract = {Cutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV melanoma remains at a meager 32%. Unfortunately, tumor resistance can impede the effectiveness of these treatments. Oxidative stress is a pivotal player in all stages of melanoma progression, with a somewhat paradoxical function that promotes tumor initiation but hinders vertical growth and metastasis in later disease. As melanoma progresses, it employs adaptive mechanisms to lessen oxidative stress in the tumor environment. Redox metabolic rewiring has been implicated in acquired resistance to BRAF/MEK inhibitors. A promising approach to enhance the response to therapy involves boosting intracellular ROS production using active biomolecules or targeting enzymes that regulate oxidative stress. The complex interplay between oxidative stress, redox homeostasis, and melanomagenesis can also be leveraged in a preventive context. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival.}, } @article {pmid37288204, year = {2023}, author = {Turk, A and Ulas, M and Karadag, A and Kocaman, N and Onalan, E and Kuloglu, T}, title = {The Effects of N-acetylcysteine on Transient Receptor Potential Melastatin 2 Channels Activation and Expression in Testicular Tissue of Diabetic Rats.}, journal = {Cureus}, volume = {15}, number = {5}, pages = {e38661}, pmid = {37288204}, issn = {2168-8184}, abstract = {INTRODUCTION: Diabetes mellitus (DM) is a common, chronic metabolic disease that has harmful effects on many diverse tissues, including the testis. One of the ways of tissue damage is the modification of transient receptor potential melastatin 2 (TRPM2) channels by increased reactive oxygen species (ROS). In our study for the first time, it was aimed to investigate TRPM2 channel activation in testicular tissues of diabetic rats induced by streptozotosin (STZ) and to examine the efficacy of N-acetylcysteine (NAC) treatment, which is an antioxidant.

METHODS: In our study, 28 Wistar albino male rats aged 8-10 weeks were used, and animals were divided into four groups: control group, NAC group, DM group, and DM + NAC group. The experimental phase was designed as eight weeks. The malondialdehyde (MDA) level, which is an indicator for lipid peroxidation due to oxidative stress, was measured by the spectrophotometric method. The Tunel assay was used to determine apoptosis on testicular tissue. TRPM2 immunoreactivity was determined by the avidin-biotin-peroxidase complex method, and quantitative polymerase chain reaction (QPCR) was used to determine TRPM2 expression levels.

RESULTS: It was seen that MDA levels were significantly increased in the DM group and decreased after NAC treatment. Similarly, it was observed that apoptosis levels, which increased significantly in diabetic rats, decreased to the levels of the control group after treatment. It was seen that TRPM2 activation and expression levels were significantly decreased in the DM group.

CONCLUSION:  The results of this study show that NAC regulates TRPM2 activation in the testicular tissue of patients with diabetes and has tissue-protective properties.}, } @article {pmid37285741, year = {2023}, author = {Luo, L and Pervaiz, S and Clement, MV}, title = {A superoxide-driven redox state promotes geroconversion and resistance to senolysis in replication-stress associated senescence.}, journal = {Redox biology}, volume = {64}, number = {}, pages = {102757}, pmid = {37285741}, issn = {2213-2317}, mesh = {*Superoxides/metabolism ; *Hydrogen Peroxide/metabolism ; Cellular Senescence ; Tumor Suppressor Protein p53/metabolism ; Oxidation-Reduction ; }, abstract = {Using S-phase synchronized RPE1-hTERT cells exposed to the DNA damaging agent, methyl methanesulfonate, we show the existence of a redox state associated with replication stress-induced senescence termed senescence-associated redox state (SA-redox state). SA-redox state is characterized by its reactivity with superoxide-sensing fluorescent probes such as dihydroethidine, lucigenin and mitosox and peroxynitrite or hydroxyl radical sensing probe hydroxyphenyl fluorescein (HPF) but not the hydrogen peroxide (H2O2) reactive fluorescent probe CM-H2DCFDA. Measurement of GSH and GSSH also reveals that SA-redox state mitigates the level of total GSH rather than oxidizes GSH to GSSG. Moreover, supporting the role of superoxide (O2[.-]) in the SA-redox state, we show that incubation of senescent RPE1-hTERT cells with the O2[.-] scavenger, Tiron, decreases the reactivity of SA-redox state with the oxidants' reactive probes lucigenin and HPF while the H2O2 antioxidant N-acetyl cysteine has no effect. SA-redox state does not participate in the loss of proliferative capacity, G2/M cell cycle arrest or the increase in SA-β-Gal activity. However, SA-redox state is associated with the activation of NF-κB, dictates the profile of the Senescence Associated Secretory Phenotype, increases TFEB protein level, promotes geroconversion evidenced by increased phosphorylation of S6K and S6 proteins, and influences senescent cells response to senolysis. Furthermore, we provide evidence for crosstalk between SA redox state, p53 and p21. While p53 mitigates the establishment of SA-redox state, p21 is critical for the sustained reinforcement of the SA-redox state involved in geroconversion and resistance to senolysis.}, } @article {pmid37279380, year = {2023}, author = {Liu, X and Hou, Y and Yang, M and Xin, X and Deng, Y and Fu, R and Xiang, X and Cao, N and Liu, X and Yu, W and Yang, B and Zhou, Y}, title = {N-Acetyl-l-cysteine-Derived Carbonized Polymer Dots with ROS Scavenging via Keap1-Nrf2 Pathway Regulate Alveolar Bone Homeostasis in Periodontitis.}, journal = {Advanced healthcare materials}, volume = {12}, number = {26}, pages = {e2300890}, doi = {10.1002/adhm.202300890}, pmid = {37279380}, issn = {2192-2659}, mesh = {Mice ; Humans ; Animals ; Reactive Oxygen Species/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Acetylcysteine/pharmacology/metabolism ; NF-E2-Related Factor 2/metabolism ; Osteogenesis ; Antioxidants/metabolism ; Oxidative Stress ; *Periodontitis/drug therapy/metabolism ; *Bone Resorption ; Homeostasis ; }, abstract = {Periodontitis is a type of chronic inflammatory oral disease characterized by the destruction of periodontal connective tissue and progressive alveolar bone resorption. As oxidative stress is the key cause of periodontitis in the early periodontal microenvironment, antioxidative therapy has been considered a viable treatment for periodontitis. However, more stable and effective reactive oxygen species (ROS)-scavenging nanomedicines are still highly needed due to the instability of traditional antioxidants. Herein, a new type of N-acetyl-l-cysteine (NAC)-derived red fluorescent carbonized polymer dots (CPDs) has been synthesized with excellent biocompatibility, which can serve as an extracellular antioxidant to scavenge ROS effectively. Moreover, NAC-CPDs can promote osteogenic differentiation in human periodontal ligament cells (hPDLCs) under H2 O2 stimulation. In addition, NAC-CPDs are capable of targeted accumulation in alveolar bone in vivo, reducing the level of alveolar bone resorption in periodontitis mice, as well as performing fluorescence imaging in vitro and in vivo. In terms of mechanism, NAC-CPDs may regulate redox homeostasis and promote bone formation in the periodontitis microenvironment by modulating the kelch-like ECH-associated protein l (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. This study provides a new strategy for the application of CPDs theranostic nanoplatform for periodontitis.}, } @article {pmid37278488, year = {2023}, author = {Colli, A and Fraquelli, M and Prati, D and Casazza, G}, title = {Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease.}, journal = {The Cochrane database of systematic reviews}, volume = {6}, number = {6}, pages = {CD013532}, pmid = {37278488}, issn = {1469-493X}, mesh = {Adult ; Humans ; *Esophageal and Gastric Varices/complications ; Quality of Life ; *Acute-On-Chronic Liver Failure/complications ; Gastrointestinal Hemorrhage ; Liver Cirrhosis/complications ; Stem Cells ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Intercellular Signaling Peptides and Proteins ; *Erythropoietin ; Growth Hormone ; }, abstract = {BACKGROUND: Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival.

OBJECTIVES: To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease.

SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type.

SELECTION CRITERIA: We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language.

DATA COLLECTION AND ANALYSIS: We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I[2] statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses.

MAIN RESULTS: We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, β-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I[2] = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I[2] = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I[2] = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence).

AUTHORS' CONCLUSIONS: G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.}, } @article {pmid37275759, year = {2023}, author = {Karimi, M and Ghasemzadeh Rahbardar, M and Razavi, BM and Hosseinzadeh, H}, title = {Amifostine inhibits acrylamide-induced hepatotoxicity by inhibiting oxidative stress and apoptosis.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {6}, pages = {662-668}, pmid = {37275759}, issn = {2008-3866}, abstract = {OBJECTIVES: Acrylamide (ACR) is a toxic chemical agent that can induce hepatotoxicity through different mechanisms including oxidative stress and apoptosis. Amifostine is an important hepatoprotective and anti-oxidant compound. In this research, the hepatoprotective effect of amifostine on ACR-induced hepatotoxicity in rats has been investigated.

MATERIALS AND METHODS: Male Wistar rats were randomly divided into 7 groups, including: 1. Control group, 2. ACR (50 mg/kg, 11 days, IP), 3-5. ACR+ amifostine (25, 50, 100 mg/kg, 11 days, IP), 6. ACR+ N-acetyl cysteine (NAC) (200 mg/kg, 11 days, IP), and 7. Amifostine (100 mg/kg, 11 days, IP). At the end of the injection period, animals' liver samples were collected to determine the content of glutathione (GSH), malondialdehyde (MDA), and apoptotic proteins (B-cell lymphoma 2 (Bcl2), Bcl-2-associated X protein (Bax), and cleaved caspase-3. Serum samples were also collected to measure alanine transaminase (ALT) and aspartate transaminase (AST) levels.

RESULTS: Administration of ACR increased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and decreased GSH content compared with the control group. The administration of amifostine with ACR decreased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and increased GSH content compared with the ACR group. Receiving NAC along with ACR reversed the alterations induced by ACR.

CONCLUSION: This study shows that pretreatment with amifostine can reduce ACR-induced toxicity in the liver tissue of rats. Since oxidative stress is one of the most important mechanisms in ACR toxicity, amifostine probably reduces the toxicity of ACR by increasing the anti-oxidant and anti-apoptotic capacity of the hepatic cells.}, } @article {pmid37271412, year = {2023}, author = {Herbst, ED and Pennington, DL and Borsari, B and Manuel, J and Yalch, M and Alcid, E and Martinez Rivas, M and Delacruz, J and Rossi, N and Garcia, B and Wong, N and Batki, SL}, title = {N-acetylcysteine for smoking cessation among dual users of tobacco and cannabis: Protocol and rationale for a randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {131}, number = {}, pages = {107250}, pmid = {37271412}, issn = {1559-2030}, support = {I21 HX003410/HX/HSRD VA/United States ; IK2 CX001510/CX/CSRD VA/United States ; R25 MH060482/MH/NIMH NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Smoking Cessation/methods ; *Cannabis ; Acetylcysteine/therapeutic use ; *Tobacco Use Disorder/therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Tobacco and cannabis co-use is a growing public health problem. The synergistic effects of cannabis and nicotine on neurobiological systems that mediate reward and shared environmental cues reinforcing use may make tobacco smoking cessation more difficult. N-acetylcysteine (NAC), an FDA-approved medication and over-the-counter supplement, has shown promise in animal studies and randomized controlled trials (RCTs) in reducing tobacco and cannabis craving and use. NAC's potential efficacy in treating addiction may be attributable to its central nervous system effects in reducing excessive glutamatergic activity, oxidative stress, and inflammation. To date, no RCT has examined NAC for smoking cessation among dual users of tobacco and cannabis.

METHOD: In a double-blind, placebo-controlled RCT, we will examine NAC for smoking cessation among dual users of tobacco and cannabis. Sixty adult cigarette-cannabis co-users are randomized to receive NAC 3600 mg per day or placebo over 8 weeks. Participants in both groups receive 8 weekly cognitive behavioral therapy sessions addressing smoking cessation and cannabis reduction. Outcomes are assessed at Weeks 0, 4, 8, and 12. Primary aims are to determine NAC's efficacy in decreasing cigarette craving, nicotine dependence, and use; and cannabis craving and use. Exploratory aims include examination of changes in neurocognition with NAC and their potential mediational effects on cigarette and cannabis use outcomes.

CONCLUSION: Results will inform smoking cessation treatment among dual users of tobacco and cannabis.

CLINICALTRIALS: gov Identifier: NCT04627922.}, } @article {pmid37271104, year = {2023}, author = {Fujiwara, N and Yamashita, S and Okamoto, M and Cooley, MA and Ozaki, K and Everett, ET and Suzuki, M}, title = {Perfluorooctanoic acid-induced cell death via the dual roles of ROS-MAPK/ERK signaling in ameloblast-lineage cells.}, journal = {Ecotoxicology and environmental safety}, volume = {260}, number = {}, pages = {115089}, pmid = {37271104}, issn = {1090-2414}, support = {K02 DE029531/DE/NIDCR NIH HHS/United States ; R01 DE027648/DE/NIDCR NIH HHS/United States ; }, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Ameloblasts/metabolism ; Cell Death ; Necrosis ; }, abstract = {Perfluorooctanoic acid (PFOA) is an artificial fluorinated organic compound that has generated increased public attention due to its potential health hazards. Unsafe levels of PFOA exposure can affect reproduction, growth and development. During tooth enamel development (amelogenesis), environmental factors including fluoride can cause enamel hypoplasia. However, the effects of PFOA on ameloblasts and tooth enamel formation remain largely unknown. In the present study we demonstrate several PFOA-mediated cell death pathways (necrosis/necroptosis, and apoptosis) and assess the roles of ROS-MAPK/ERK signaling in PFOA-mediated cell death in mouse ameloblast-lineage cells (ALC). ALC cells were treated with PFOA. Cell proliferation and viability were analyzed by MTT assays and colony formation assays, respectively. PFOA suppressed cell proliferation and viability in a dose dependent manner. PFOA induced both necrosis (PI-positive cells) and apoptosis (cleaved-caspase-3, γH2AX and TUNEL-positive cells). PFOA significantly increased ROS production and up-regulated phosphor-(p)-ERK. Addition of ROS inhibitor N-acetyl cysteine (NAC) suppressed p-ERK and decreased necrosis, and increased cell viability compared to PFOA alone, whereas NAC did not change apoptosis. This suggests that PFOA-mediated necrosis was induced by ROS-MAPK/ERK signaling, but apoptosis was not associated with ROS. Addition of MAPK/ERK inhibitor PD98059 suppressed necrosis and increased cell viability compared to PFOA alone. Intriguingly, PD98059 augmented PFOA-mediated apoptosis. This suggests that p-ERK promoted necrosis but suppressed apoptosis. Addition of the necroptosis inhibitor Necrostatin-1 restored cell viability compared to PFOA alone, while pan-caspase inhibitor Z-VAD did not mitigate PFOA-mediated cell death. These results suggest that 1) PFOA-mediated cell death was mainly caused by necrosis/necroptosis by ROS-MAPK/ERK signaling rather than apoptosis, 2) MAPK/ERK signaling plays the dual roles (promoting necrosis and suppressing apoptosis) under PFOA treatment. This is the initial report to indicate that PFOA could be considered as a possible causative factor for cryptogenic enamel malformation. Further studies are required to elucidate the mechanisms of PFOA-mediated adverse effects on amelogenesis.}, } @article {pmid37270170, year = {2023}, author = {Guo, Y and Zhou, A and Zhang, Y and Chen, Y and Chen, Y and Gao, Y and Miao, X}, title = {Serum response factor activates peroxidasin transcription to block senescence of hepatic stellate cells.}, journal = {Life sciences}, volume = {328}, number = {}, pages = {121824}, doi = {10.1016/j.lfs.2023.121824}, pmid = {37270170}, issn = {1879-0631}, mesh = {Mice ; Animals ; *Hepatic Stellate Cells/metabolism ; *Serum Response Factor/genetics/metabolism ; Liver Cirrhosis/pathology ; Liver/metabolism ; Extracellular Matrix Proteins/metabolism ; Mice, Knockout ; Peroxidasin ; }, abstract = {AIMS: Aberrant liver fibrosis is a hallmark event in end-stage liver diseases. Hepatic stellate cells (HSCs) are considered the major source of myofibroblasts in the liver that produce extracellular matrix proteins to promote liver fibrosis. HSCs undergo senescence in response to various stimuli, a process that can be exploited to dampen liver fibrosis. We investigated the role of serum response factor (SRF) in this process.

METHODS AND MATERIALS: Senescence was induced HSCs by serum withdrawal or progressive passage. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP).

RESULTS: SRF expression was down-regulated in HSCs entering into senescence. Coincidently, SRF depletion by RNAi accelerated HSC senescence. Of note, treatment of an anti-oxidant (N-acetylcysteine or NAC) blocked HSC senescence by SRF deficiency suggesting that SRF may antagonize HSC senescence by eliminating excessive reactive oxygen species (ROS). PCR-array based screening identified peroxidasin (PXDN) as a potential target for SRF in HSCs. PXDN expression was inversely correlated with HSC senescence whereas PXDN knockdown accelerated HSC senescence. Further analysis reveals that SRF directly bound to the PXDN promoter and activated PXDN transcription. Consistently, PXDN over-expression protected whereas PXDN depletion amplified HSC senescence. Finally, PXDN knockout mice displayed diminished liver fibrosis compared to wild type mice when subjected to bile duct ligation (BDL).

SIGNIFICANCE: Our data suggest that SRF, via its downstream target PXDN, plays a key role in regulating HSC senescence.}, } @article {pmid37266883, year = {2023}, author = {Guo, W and Jing, W}, title = {N-Acetyl-L-Cysteine Reduces Cervical Carcinogenesis by Promoting Apoptosis.}, journal = {Drugs in R&D}, volume = {23}, number = {2}, pages = {165-174}, pmid = {37266883}, issn = {1179-6901}, mesh = {Humans ; Female ; Animals ; Mice ; *Uterine Cervical Neoplasms/drug therapy/genetics/pathology ; Acetylcysteine/pharmacology/therapeutic use ; Cell Line, Tumor ; *Papillomavirus Infections/metabolism ; Apoptosis ; Carcinogenesis ; }, abstract = {BACKGROUND AND OBJECTIVE: Cervical cancer is the fourth leading cause of cancer death in women, and is one of the most common malignant tumors of the reproductive system. However, more effective treatment for cervical cancer is needed. In this study, we aim to investigate whether N-acetyl-L-cysteine (NAC) could inhibit the proliferation of human papillomavirus (HPV)-positive cells, and reduce cervical carcinogenesis.

METHODS: The cervical cancer cell lines SiHa, HeLa, HPV-negative cell line C33A, and the immortalized human cervical keratinocyte cells S12 were used. The protein expression was determined using Western blot assay. mRNA expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation was determined by Cell Counting Kit-8 assay. Cell apoptosis was evaluated using Annexin V-FITC apoptosis kits. The numbers of colonies were measured using colony-forming assay. Xenograft tumor necrosis and HPV16 E7 expression were determined using hematoxylin and eosin (H&E) staining and immunohistochemistry.

RESULTS: Our results showed that NAC treatment at the concentration of 1.5 mM significantly promoted cell apoptosis and reduced cell growth by inhibiting HPV16 E7 expression. NAC inhibited HPV16-oncoprotein-induced hypoxia-inducible factor (HIF)-1α protein expression and Akt activation in vitro. Additionally, NAC suppressed tumor growth, as evidenced by the smaller tumor size in the xenograft mouse model and decreased HPV16 E7 expression in tumor tissues.

CONCLUSION: Our findings demonstrate that NAC exhibits the potential to promote HPV-positive cell apoptosis, and suppress the proliferation of HPV-positive cells by inhibiting cell inhibitor of apoptosis protein 2 and HIF-1α.}, } @article {pmid37264973, year = {2023}, author = {Sun, J and Wang, Y and Du, Y and Zhang, W and Liu, Z and Bai, J and Cui, G and Du, Z}, title = {Involvement of the JNK/HO‑1/FTH1 signaling pathway in nanoplastic‑induced inflammation and ferroptosis of BV2 microglia cells.}, journal = {International journal of molecular medicine}, volume = {52}, number = {1}, pages = {}, pmid = {37264973}, issn = {1791-244X}, mesh = {Humans ; *Ferroptosis ; Microplastics/metabolism/pharmacology ; Microglia/metabolism ; MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Inflammation/metabolism ; Ferritins/metabolism/pharmacology ; Oxidoreductases/metabolism/pharmacology ; }, abstract = {Nanoplastics (NPs) are a newly discovered type of environmental pollutant. The potential for neurotoxicity caused by NPs and their mechanisms are unclear. The present study aimed to determine the molecular mechanism underlying neurotoxicity induced by NPs. Microglia (BV2) cells were used for in vitro studies, and it was found that NPs invaded cells, activated inflammasomes, induced the release of significant quantities of inflammatory factors by detection of inflammatory response‑associated proteins through Western blot and ELISA. By detection of FITC, SOD, GSH, cellular iron level, and ferroptosis‑related proteins, it was found that NPs compromised the anti‑oxidative mechanisms of cells, increased intracellular lipid peroxidation and Fe2+ concentration and triggered inflammatory reactions and ferroptosis. Pretreatment with reactive oxygen species (ROS) inhibitor N‑acetylcysteine (NAC) alleviated induction of inflammatory reactions and ferroptosis of cells. In addition, inhibiting expression of c‑Jun N‑terminal kinase (JNK) increased expression of heme oxygenase (HO‑1), resulting in decreased ferroptosis, indicating that the JNK/HO‑1 signaling pathway was involved in NP‑induced effects on ferroptosis in BV2 cells. In conclusion, NPs could induce inflammatory responses and ferroptosis in BV2 cells. JNK/HO‑1 mediated ferroptosis may serve an important role in the toxicity of microglia induced by NPs. This study provided novel evidence for the toxic effects of NPs and highlighted a theoretical mechanistic basis for safe prevention and treatment of plastic pollution‑induced neurotoxicity.}, } @article {pmid37263335, year = {2023}, author = {Zong, Q and Peng, X and Ding, Y and Wu, H and Lu, C and Ye, J and Sun, W and Zhang, J and Zhai, Y}, title = {Multifunctional hydrogel wound dressing with rapid on-demand degradation property based on aliphatic polycarbonate and chitosan.}, journal = {International journal of biological macromolecules}, volume = {244}, number = {}, pages = {125138}, doi = {10.1016/j.ijbiomac.2023.125138}, pmid = {37263335}, issn = {1879-0003}, mesh = {Humans ; *Chitosan ; Hydrogels/pharmacology ; Antioxidants/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bandages ; Carbonates ; }, abstract = {The multifunctional hydrogel dressings are effective strategy to treat chronic wounds of diabetes. In addition, the ability of selective degradation on demand to change dressings could provide better patient compliance. Here, an injectable, self-healing hydrogel with rapid degradability on-demand is designed to promote the healing of diabetes wounds. The block copolymer formed by aldehyde modified aliphatic cyclic carbonate monomer with polyethylene glycol (MBP) and chitosan (CS) were crosslinked through the Schiff base bond to obtain a hydrogel with excellent injectability and self-healing ability. Due to the presence of carbonate bonds in MBP, it showed the rapid on-demand degradation characteristics triggered by N-acetylcysteine (NAC). At the same time, gallic acid (GA) was loaded into the hydrogel, giving the hydrogel dressing antioxidant. In vivo and in vitro experiments showed that the hydrogel wound dressing possesses good natures, such as antibacterial, antioxidant, and friendly cell compatibility, which could promote wound healing. Overall, the multifunctional hydrogel wound dressings with rapid on-demand degradation characteristics are more practical for clinical applications.}, } @article {pmid37260659, year = {2023}, author = {Alaska, YA and Alghadeer, SM and Alrabiah, AA and Harb, A and Almadi, B}, title = {Assessment of N-acetylcysteine use for acetaminophen overdose in the emergency department of a community teaching hospital: A pilot study.}, journal = {Saudi journal of anaesthesia}, volume = {17}, number = {2}, pages = {168-173}, pmid = {37260659}, issn = {1658-354X}, abstract = {INTRODUCTION: N-acetylcysteine (NAC) is the first-line treatment for acetaminophen (APAP) overdose. However, using NAC inappropriately is associated with an increased risk of adverse effects as well as a substantial increase in hospitalization and healthcare costs. This study aims to assess NAC utilization for acute APAP overdose in the emergency department of a community teaching hospital in Saudi Arabia.

METHODS: A retrospective chart review in which the patients initiated on an NAC secondary to acute APAP overdose at KSUMC during the period of June 2015 till November 2018 were included and assessed based on developed validated evident-based protocol for administering NAC for acute APAP ingestion.

RESULTS: A total of 29 patients received NAC treatment for acute APAP overdose; 15 of which were adults, and 14 were pediatrics. Appropriate prescribing of NAC was observed in 14 (48.28%) patients, whereas NAC was inappropriately indicated for 15 (51.72%) patients; 9 of them were adults and 6 patients were pediatric. APAP-Ingestion <150 mg/kg (<200 mg/kg in children) was the most common reason for inappropriate use (n = 7, 46.67%) followed by administering NAC <4 hours post-APAP ingestion (n = 4, 26.67%).

CONCLUSION: Improper NAC administration appears to be a significant issue among patients with APAP overdose. The utilization of a protocol for the management of APAP overdose will reduce the unnecessary usage of NAC.}, } @article {pmid37259793, year = {2023}, author = {Li, G and Chen, Y and Wu, M and Chen, K and Zhang, D and Zhang, R and Yang, G and Huang, X}, title = {Di (2-ethyl) hexyl phthalate induces liver injury in chickens by regulating PTEN/PI3K/AKT signaling pathway via reactive oxygen species.}, journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP}, volume = {270}, number = {}, pages = {109639}, doi = {10.1016/j.cbpc.2023.109639}, pmid = {37259793}, issn = {1532-0456}, mesh = {Animals ; Female ; Male ; Apoptosis/physiology ; *Chickens/metabolism ; *Diethylhexyl Phthalate/toxicity ; Liver/metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; PTEN Phosphohydrolase/genetics/metabolism ; Reactive Oxygen Species/metabolism ; RNA, Messenger/metabolism ; Signal Transduction ; }, abstract = {Di (2-ethyl) hexyl phthalate (DEHP) is a common environmental endocrine disruptor that induces oxidative stress, posing a significant threat to human and animal health. Oxidative stress can activate the PTEN/PI3K/AKT pathway, which is closely related to cell apoptosis. However, it is unclear whether DEHP induces apoptosis of chicken liver cells by regulating the PTEN/PI3K/AKT pathway through oxidative stress. In this experiment, male laying hens were continuously exposed to 400 mg/kg, 800 mg/kg, and 1600 mg/kg DEHP for 14 d, 28 d, and 42 d. The results showed that liver injury was aggravated with the dose of DEHP gavage, and the ROS/MDA levels in L, M, and H DEHP exposure groups were significantly increased, while the T-AOC/T-SOD/GSH-PX levels were decreased. Meanwhile, DEHP exposure up-regulated the mRNA and protein expression levels of PTEN/Bax/Caspase-9/Caspase-3 and down-regulated the mRNA and protein expression levels of PI3K/AKT/BCL-2, indicating that DEHP may lead to hepatocyte apoptosis through ROS regulation of PTEN/PI3K/AKT axis. In order to further clarify the relationship between oxidative stress and liver injury, we treated chicken hepatocellular carcinoma cell line (LMH) with 2.5 mM N-acetylcysteine (NAC). NAC attenuated these phenomena. In summary, our study suggests that DEHP can induce apoptosis of chicken liver through ROS activation of the PTEN/PI3K/AKT axis.}, } @article {pmid37257582, year = {2023}, author = {Peng, H and Zhang, J and Zhang, Z and Turdi, S and Han, X and Liu, Q and Hu, H and Ye, H and Dong, M and Duan, Y and Yang, Y and Ashrafizadeh, M and Rabiee, N and Ren, J}, title = {Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced cardiac anomalies through reconciliation of autophagy and ferroptosis.}, journal = {Life sciences}, volume = {328}, number = {}, pages = {121821}, doi = {10.1016/j.lfs.2023.121821}, pmid = {37257582}, issn = {1879-0631}, mesh = {Mice ; Animals ; *Ferroptosis ; Lipopolysaccharides/pharmacology ; Caspase 3/metabolism ; Catalase/metabolism ; Antioxidants/pharmacology/metabolism ; Myocytes, Cardiac/metabolism ; *Heart Defects, Congenital/metabolism ; Autophagy ; }, abstract = {Lipopolysaccharide (LPS) from Gram-negative bacteria is a major contributor to cardiovascular failure, but the signaling mechanisms underlying its stress response are not fully understood. This study aimed to investigate the effect of the antioxidant enzyme catalase on LPS-induced cardiac abnormalities and the mechanisms involved, with particular focus on the interplay between autophagy, ferroptosis, and apoptosis. Cardiac-specific catalase (CAT) overexpression and wild-type (WT) mice were stimulated with LPS (6 mg/kg, intravenous injection), and cardiac morphology and function were evaluated. Oxidative stress, ferroptosis, apoptosis, and mitochondrial status were monitored, and survival curves were plotted based on the results of LPS stimulation. The results showed that, compared with WT mice, mice overexpressing catalase had a higher survival rate under LPS stimulation. Ultrasound echocardiography, cardiomyocyte characteristics, and Masson's trichrome staining showed that LPS inhibited cardiac function and caused cardiac fibrosis, while catalase alleviated these adverse effects. LPS increased apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), increased O2[·-] production, induced inflammation (TNF-α), autophagy, iron toxicity, and carbonyl damage, and significantly damaged mitochondria (mitochondrial membrane potential, mitochondrial proteins, and ultrastructure). These effects were significantly alleviated by catalase. Interestingly, the antioxidant N-acetylcysteine, autophagy inhibitor 3-methyladenine, and ferroptosis inhibitor lipostatin-1 all eliminated the LPS-induced contraction dysfunction and ferroptosis (using lipid peroxidation). Induction of ferroptosis could eliminate the cardioprotective effect of NAC. In conclusion, catalase rescues LPS-induced cardiac dysfunction by regulating oxidative stress, autophagy, ferroptosis, apoptosis, and mitochondrial damage in cardiomyocytes.}, } @article {pmid37256605, year = {2023}, author = {Wu, S and Shi, Y and Jiang, L and Bu, W and Zhang, K and Lin, W and Pan, C and Xu, Z and Du, J and Chen, H and Wang, H}, title = {N-Acetylcysteine-Derived Carbon Dots for Free Radical Scavenging in Intervertebral Disc Degeneration.}, journal = {Advanced healthcare materials}, volume = {12}, number = {24}, pages = {e2300533}, doi = {10.1002/adhm.202300533}, pmid = {37256605}, issn = {2192-2659}, mesh = {Humans ; *Intervertebral Disc Degeneration/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism ; Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Nucleus Pulposus/metabolism/pathology ; }, abstract = {Intervertebral disc degeneration (IVDD) is associated with oxidative stress induced reactive oxygen species (ROS) dynamic equilibrium disturbance. Nanozymes, as nanomaterials with enzyme-like activity, can regulate intro-cellular ROS levels. In this study, a new carbon dots nanozyme, N-acetylcysteine-derived carbon dots (NAC-CDs), is developed and proved to be an ideal antioxidant and anti-senescent agent in IVDD management. The results confirmed the NAC-CDs have satisfactory biocompatibility and strong superoxide dismutase (250 U mg[-1]), catalase, glutathioneperoxidase-like activity, and total antioxidant capacity. Then, the powerful free radical scavenging and antioxidant ability of NAC-CDs are demonstrated in vitro as observing the reduced ROS in H2 O2 induced senescent nucleus pulposus cells (NPCs), in which the elimination efficiency of toxic ROS is more than 90%. NAC-CDs also maintained mitochondrial homeostasis and suppressed cellular senescence, subsequently inhibited the expression of inflammatory factors in NPCs. In vivo, evaluations of imaging and tissue morphology assessments suggested that disc height index, magnetic resonance imaging grade and histological score are significantly improved from the degenerative models when NAC-CDs is applied. In conclusion, the study developed a novel carbon dots nanozyme, which efficiently rescues IVDD from ROS induced NPCs senescence and provides a potential strategy in management of IVDD in clinic.}, } @article {pmid37256235, year = {2023}, author = {Yang, K and Kim, HH and Shim, YR and Ryu, T and Kim, CW}, title = {Comprehensive transcriptomic analysis and meta-analysis identify therapeutic effects of N-acetylcysteine in nonalcoholic fatty liver disease.}, journal = {Frontiers in pharmacology}, volume = {14}, number = {}, pages = {1186582}, pmid = {37256235}, issn = {1663-9812}, abstract = {Introduction: The continuous rise in the prevalence of nonalcoholic fatty liver disease (NAFLD) is emerging as a global health issue. Although the protective effects of N-acetylcysteine (NAC), an antioxidant, against various diseases have been reported, it is still unclear whether NAC has therapeutic potential in NAFLD. Thus, the present meta-analysis aimed to investigate the efficacy of NAC on NAFLD in preclinical studies. Methods: By searching PubMed, Web of Science, and Cochrane Library, 13 studies were included. The methodological quality was assessed based on the SYstematic Review Centre for Laboratory animal Experimentation guideline, and heterogeneity was evaluated with I [2] and p values. Publication bias was assessed by Egger's test and sensitivity analysis was performed. Results: The results showed that NAC treatment significantly improved systemic and hepatic lipid metabolism (p < 0.01), inflammation-related liver injury (p < 0.01), glucose intolerance (p < 0.05), and hepatic steatosis (p < 0.01) by restoring hepatic glutathione (GSH) (p < 0.05) and GSH reductase (p < 0.05) levels compared to controls in NAFLD-induced animals. Consistently, in bulk, single-cell, and spatial transcriptomics data, the abovementioned target pathways of NAC were strongly associated with NAFLD development in mice and patients. Conclusion: Our study suggests that NAC has therapeutic potential for NAFLD and should be considered for future clinical trials.}, } @article {pmid37254915, year = {2023}, author = {Vishnevetskii, DV and Averkin, DV and Efimov, AA and Lizunova, AA and Shamova, OV and Vladimirova, EV and Sukhareva, MS and Mekhtiev, AR}, title = {L-Cysteine and N-acetyl-L-cysteine-mediated synthesis of nanosilver-based sols and hydrogels with antibacterial and antibiofilm properties.}, journal = {Journal of materials chemistry. B}, volume = {11}, number = {25}, pages = {5794-5804}, doi = {10.1039/d3tb00261f}, pmid = {37254915}, issn = {2050-7518}, mesh = {Humans ; *Acetylcysteine/pharmacology ; Hydrogels/pharmacology ; *Metal Nanoparticles/chemistry ; Silver/pharmacology/chemistry ; Microbial Sensitivity Tests ; Anti-Bacterial Agents/chemistry ; Bacteria ; Biofilms ; }, abstract = {The need of the synthesis of a new generation of medicines aimed at combating bacteria and biofilms that cause various infections is a great urgency. There has been a gradual decrease in the conventional techniques of treatment with the use of antibiotics. Consequently, much effort has focused on the search for new methods and approaches to obtain antibacterial drugs and determine their rational use such that microorganisms do not acquire resistance. Although silver nanoparticles (AgNPs) and silver nanoclusters (AgNCs) have exhibited certain levels of effectiveness against multidrug-resistant bacteria and biofilms, there are very few simple, cheap and easy-to-scale methods to obtain AgNPs and AgNCs with well-desired characteristics. In this study, we carried out the one-pot synthesis of sols and gels containing AgNPs and AgNCs using only L-cysteine (CYS) or N-acetyl-L-cysteine (NAC), as bioreducing/capping/gel-forming agents, and different silver salts - nitrate, nitrite and acetate. HRTEM, SAED, EDX mapping, AFM, SEM, EDX, ICP-MS and FTIR spectroscopy analysis confirmed the formation of spherical/elliptical CYS-AgNP and NAC-AgNC particles consisting of AgNPs or AgNCs "core" and CYS/Ag[+] or NAC/Ag[+] complexes "shell" with mean average diameters of 10 and 5 nm, respectively. UV-Vis spectroscopy fixed the localized surface plasmon resonance (LSPR) at 390-420 nm for the CYS-AgNPs systems and LSPR absence for the NAC-AgNCs ones. DLS and nanoparticle tracking analysis (NTA) data indicated that the mean average diameter of the particles is about 80 nm for the CYS-AgNPs systems and 20 nm for the NAC-AgNCs ones. The Zeta potential measurements showed that the particles possess positive and negative charge values for CYS-AgNPs and NAC-AgNCs systems, respectively. The prepared materials demonstrated the high antibacterial activity against the most common types of bacteria at the MIC range of 10-100 μM, wherein the effect of the NAC-AgNCs systems is 2 times stronger than that of the CYS-AgNPs ones. Both systems are non-toxic or have low-toxicity at 300 μM for normal human cells: erytrocytes, fibroblasts and macrophages. Sols and hydrogels in the concentration range of 20-40 μM showed the complete inhibition of the formation of biofilms from Acinetobacter baumannii and Pseudomonas aeruginosa, which belong to the ESKAPE pathogenes group and represent the most serious problem in practical medicine. NAC-AgNCs systems were the most active. The simple strategy of the preparation of AgNP/AgNC-based sols and gels, along with their pronounced antibacterial and antibiofilm activity, could open new perspectives for its applications in medicine.}, } @article {pmid37248505, year = {2023}, author = {Sun, D and Zhang, G and Xie, M and Wang, Y and Liang, X and Tu, M and Su, Z and Zeng, R}, title = {Softness enhanced macrophage-mediated therapy of inhaled apoptotic-cell-inspired nanosystems for acute lung injury.}, journal = {Journal of nanobiotechnology}, volume = {21}, number = {1}, pages = {172}, pmid = {37248505}, issn = {1477-3155}, support = {210715094530570//Science and Technology Planning Project of Shaoguan/ ; 2021KQNCX085//Foundation for Young Talents in Higher Education of Guangdong/ ; 31971270//National Natural Science Foundation of China/ ; 31370974//National Natural Science Foundation of China/ ; 2020B1515120078//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 202002020001//Science and Technology Program of Guangzhou/ ; }, mesh = {Mice ; Animals ; *Lung/metabolism ; *Acute Lung Injury/chemically induced/drug therapy ; Macrophages/metabolism ; Acetylcysteine/metabolism/pharmacology/therapeutic use ; }, abstract = {Engineered nanosystems offer a promising strategy for macrophage-targeted therapies for various diseases, and their physicochemical parameters including surface-active ligands, size and shape are widely investigated for improving their therapeutic efficacy. However, little is known about the synergistic effect of elasticity and surface-active ligands. Here, two kinds of anti-inflammatory N-acetylcysteine (NAC)-loaded macrophage-targeting apoptotic-cell-inspired phosphatidylserine (PS)-containing nano-liposomes (PSLipos) were constructed, which had similar size and morphology but different Young's modulus (E) (H, ~ 100 kPa > Emacrophage vs. L, ~ 2 kPa < Emacrophage). Interestingly, these PSLipos-NAC showed similar drug loading and encapsulation efficiency, and in vitro slow-release behavior of NAC, but modulus-dependent interactions with macrophages. Softer PSLipos-L-NAC could resist macrophage capture, but remarkably prolong their targeting effect period on macrophages via durable binding to macrophage surface, and subsequently more effectively suppress inflammatory response in macrophages and then hasten inflammatory lung epithelial cell wound healing. Especially, pulmonary administration of PSLipos-L-NAC could significantly reduce the inflammatory response of M1-like macrophages in lung tissue and promote lung injury repair in a bleomycin-induced acute lung injury (ALI) mouse model, providing a potential therapeutic approach for ALI. The results strongly suggest that softness may enhance ligand-directed macrophage-mediated therapeutic efficacy of nanosystems, which will shed new light on the design of engineered nanotherapeutics.}, } @article {pmid37247196, year = {2023}, author = {Ferretti, S and Curatola, A and Chiaretti, A and Graglia, B and Gatto, A and Capossela, L and Pansini, V}, title = {Early treatment with N-acetylcysteine reduces hepatotoxicity in acute acetaminophen poisoning.}, journal = {Acta bio-medica : Atenei Parmensis}, volume = {94}, number = {S1}, pages = {e2023033}, doi = {10.23750/abm.v94iS1.13714}, pmid = {37247196}, issn = {2531-6745}, mesh = {Adult ; Child ; Female ; Adolescent ; Humans ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention & control ; *Drug Overdose/drug therapy ; *COVID-19 ; *Digestive System Diseases ; }, abstract = {During the outbreak of COVID19 measures taken to contain the spread of the virus have influenced the mental well-being of adults and adolescents. Acetaminophen overdose is the major cause of drug intoxication among children and adolescents. We reported a case of a 15-year- old girl referred to our Emergency Department 3 hours after ingestion of 10 g of paracetamol for suicidal purposes. She promptly started the administration of intravenous N-acetylcysteine (NAC) and the patient was discharged after 5 days of hospitalization in good clinical condition and with neuropsychiatric follow-up. Our case shows that the timing of the intravenous NAC administration is considered the most important factor in the prevention of acetaminophen-induced hepatic failure, despite high serum levels after acetaminophen ingestion.}, } @article {pmid37245532, year = {2023}, author = {Yang, H and Li, X and Jin, H and Turkez, H and Ozturk, G and Doganay, HL and Zhang, C and Nielsen, J and Uhlén, M and Borén, J and Mardinoglu, A}, title = {Longitudinal metabolomics analysis reveals the acute effect of cysteine and NAC included in the combined metabolic activators.}, journal = {Free radical biology & medicine}, volume = {204}, number = {}, pages = {347-358}, doi = {10.1016/j.freeradbiomed.2023.05.013}, pmid = {37245532}, issn = {1873-4596}, mesh = {Humans ; *Acetylcysteine/metabolism ; *Cysteine ; NAD ; Glutathione/metabolism ; Metabolomics ; Niacinamide ; }, abstract = {Growing evidence suggests that the depletion of plasma NAD[+] and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD[+] precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl-l-cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators.}, } @article {pmid37242324, year = {2023}, author = {Gao, Y and Li, J and Guo, X and Guan, L and Wang, J and Huang, X and Wang, W and Yang, H}, title = {L-Tyrosine Limits Mycobacterial Survival in Tuberculous Granuloma.}, journal = {Pathogens (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37242324}, issn = {2076-0817}, support = {82270006//National Natural Science Foundation of China/ ; 82070007//National Natural Science Foundation of China/ ; 2021YFA1300902//National Key R&D Program of China/ ; }, abstract = {Caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), tuberculosis (TB) remains a massive global public health issue. A well-known and key TB trait is caseous necrotic granuloma, which allows mycobacteria to reactivate and disseminate, thus confounding TB eradication programs. Amino acid (AA) metabolism is key to regulating immune responses in Mtb infections; however, it is currently unclear if AAs can be used to treat tuberculous granulomas. Here, we screened 20 proteinogenic AAs using a Mycobacterium marinum-infected zebrafish granuloma model. Only L-tyrosine simultaneously reduced Mycobacterium marinum (M. marinum) levels in zebrafish larvae and adults and inhibited intracellular pathogen survival levels. Mechanistically, L-tyrosine significantly upregulated interferon-γ (IFN-γ) expression in M. marinum -infected zebrafish adults but not in larvae. Using N-acetylcysteine (NAC) to inhibit reactive oxygen species (ROS), L-tyrosine appeared to inhibit Mtb intracellular survival by promoting ROS production. Thus, L-tyrosine as a non-essential AA may reduce mycobacterial survival in both macrophages and tuberculous granulomas. Our research provides a platform for the clinical development of AAs for active or latent TB patients infected with drug-sensitive or drug-resistant Mtb.}, } @article {pmid37239911, year = {2023}, author = {Kenari, F and Molnár, S and Borges, ID and Napolitano, HB and Perjési, P}, title = {(E)-2-Benzylidenecyclanones: Part XVIII Study the Possible Link between Glutathione Reactivity and Cancer Cell Cytotoxic Effects of Some Cyclic Chalcone Analogs A Comparison of the Reactivity of the Open-Chain and the Seven-Membered Homologs.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, pmid = {37239911}, issn = {1422-0067}, support = {EFOP-3.6.1.-16-2016-00004//European Council/ ; }, mesh = {*Chalcone/pharmacology ; *Chalcones/pharmacology ; Glutathione/metabolism ; Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid ; *Antineoplastic Agents/pharmacology ; Sulfhydryl Compounds/chemistry ; *Neoplasms ; }, abstract = {Non-enzymatic thiol addition into the α,β-unsaturated carbonyl system is associated with several biological effects. In vivo, the reactions can form small-molecule thiol (e.g., glutathione) or protein thiol adducts. The reaction of two synthetic (4'-methyl- and 4'-methoxy substituted) cyclic chalcone analogs with reduced glutathione (GSH) and N-acetylcysteine (NAC) was studied by (high-pressure liquid chromatography-ultraviolet spectroscopy) HPLC-UV method. The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The structure of the formed adducts was confirmed by (high-pressure liquid chromatography-mass spectrometry) HPLC-MS. The incubations were performed under three different pH conditions (pH 3.2/3.7, 6.3/6.8, and 8.0/7.4). The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended on the substitution and the pH. The frontier molecular orbitals and the Fukui function were carried out to investigate the effects on open-chain and seven-membered cyclic analogs. Furthermore, machine learning protocols were used to provide more insights into physicochemical properties and to support the different thiol-reactivity. HPLC analysis indicated diastereoselectivity of the reactions. The observed reactivities do not directly relate to the different in vitro cancer cell cytotoxicity of the compounds.}, } @article {pmid37237960, year = {2023}, author = {Giustarini, D and Milzani, A and Dalle-Donne, I and Rossi, R}, title = {How to Increase Cellular Glutathione.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37237960}, issn = {2076-3921}, abstract = {Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly reduced, making cells more susceptible to oxidative damage. Therefore, there is a growing interest in determining the best method(s) to increase cellular glutathione for both disease prevention and treatment. This review summarizes the major strategies for successfully increasing cellular GSH stores. These include GSH itself, its derivatives, NRf-2 activators, cysteine prodrugs, foods, and special diets. The possible mechanisms by which these molecules can act as GSH boosters, their related pharmacokinetic issues, and their advantages and disadvantages are discussed.}, } @article {pmid37237933, year = {2023}, author = {Edemann-Callesen, H and Bernhardt, N and Hlusicka, EB and Hintz, F and Habelt, B and Winter, R and Neubert, I and Pelz, M and Filla, A and Soto-Montenegro, ML and Winter, C and Hadar, R}, title = {Supplement Treatment with NAC and Omega-3 Polyunsaturated Fatty Acids during Pregnancy Partially Prevents Schizophrenia-Related Outcomes in the Poly I:C Rat Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37237933}, issn = {2076-3921}, support = {DFG WI2140/4-1//Deutsche Forschungsgemeinschaft/ ; }, abstract = {BACKGROUND: Heightened levels of inflammation and oxidative stress are thought to be involved in the pathophysiology of schizophrenia. We aimed to assess whether intake of anti-inflammatory and anti-oxidant drugs during pregnancy prevents later schizophrenia-related outcomes in a neurodevelopmental rat model of this disorder.

METHODS: Pregnant Wistar rats were injected with polyriboinosinic-polyribocytidilic acid (Poly I:C) or saline and subsequently treated with either N-acetyl cysteine (NAC) or omega-3 polyunsaturated fatty acids (PUFAs) until delivery. Controls rats received no treatment. In the offspring, neuroinflammation and anti-oxidant enzyme activity were assessed on postnatal day (PND) 21, 33, 48, and 90. Behavioral testing was performed at PND 90, followed by post-mortem neurochemical assessment and ex vivo MRI.

RESULTS: The supplement treatment led to a quicker restoration of the wellbeing of dams. In the adolescent Poly I:C offspring, the supplement treatment prevented an increase in microglial activity and partially prevented a deregulation in the anti-oxidant defense system. In the adult Poly I:C offspring, supplement treatment partially prevented dopamine deficits, which was paralleled by some changes in behavior. Exposure to omega-3 PUFAs prevented the enlargement of lateral ventricles.

CONCLUSION: Intake of over-the-counter supplements may assist in especially targeting the inflammatory response related to schizophrenia pathophysiology, aiding in diminishing later disease severity in the offspring.}, } @article {pmid37237886, year = {2023}, author = {Kim, JE and Lee, DS and Kim, TH and Park, H and Kang, TC}, title = {Distinct Roles of CK2- and AKT-Mediated NF-κB Phosphorylations in Clasmatodendrosis (Autophagic Astroglial Death) within the Hippocampus of Chronic Epilepsy Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37237886}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; }, abstract = {The downregulation of glutathione peroxidase-1 (GPx1) plays a role in clasmatodendrosis (an autophagic astroglial death) in the hippocampus of chronic epilepsy rats. Furthermore, N-acetylcysteine (NAC, a GSH precursor) restores GPx1 expression in clasmatodendritic astrocytes and alleviates this autophagic astroglial death, independent of nuclear factor erythroid-2-related factor 2 (Nrf2) activity. However, the regulatory signal pathways of these phenomena have not been fully explored. In the present study, NAC attenuated clasmatodendrosis by alleviating GPx1 downregulation, casein kinase 2 (CK2)-mediated nuclear factor-κB (NF-κB) serine (S) 529 and AKT-mediated NF-κB S536 phosphorylations. 2-[4,5,6,7-Tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazole-1-yl]acetic acid (TMCB; a selective CK2 inhibitor) relieved clasmatodendritic degeneration and GPx1 downregulation concomitant with the decreased NF-κB S529 and AKT S473 phosphorylations. In contrast, AKT inhibition by 3-chloroacetyl-indole (3CAI) ameliorated clasmatodendrosis and NF-κB S536 phosphorylation, while it did not affect GPx1 downregulation and CK2 tyrosine (Y) 255 and NF-κB S529 phosphorylations. Therefore, these findings suggest that seizure-induced oxidative stress may diminish GPx1 expression by increasing CK2-mediated NF-κB S529 phosphorylation, which would subsequently enhance AKT-mediated NF-κB S536 phosphorylation leading to autophagic astroglial degeneration.}, } @article {pmid37235225, year = {2023}, author = {Li, X and Zhao, Z and Qu, Z and Li, X and Zhang, Z and Liang, X and Chen, J and Li, J}, title = {A Review of Traditional and Emerging Residual Chlorine Quenchers on Disinfection By-Products: Impact and Mechanisms.}, journal = {Toxics}, volume = {11}, number = {5}, pages = {}, pmid = {37235225}, issn = {2305-6304}, support = {BK20210737//the Natural Science Foundation of Jiangsu Province/ ; 2022M713301//China Postdoctoral Science Foundation/ ; 2021YXBKWKY026//the initial Scientific Research Fund of Soochow University, the Student's Extracurricular Scientific Research Fund of Medical College of Soochow University/ ; GWZX202204//the Suzhou Found for Prevention and Control Technology of critical illness and infectious diseases/ ; }, abstract = {Disinfection by-products (DBPs) are the most common organic contaminants in tap water and are of wide concern because of their highly developmental toxic, cytotoxic, and carcinogenic properties. Typically, to control the proliferation of pathogenic microorganisms, a certain concentration of residual chlorine is retained in the factory water, which reacts with the natural organic matter and the disinfection by-products that have been formed, thus affecting the determination of DBPs. Therefore, to obtain an accurate concentration, residual chlorine in tap water needs to be quenched prior to treatment. Currently, the most commonly used quenching agents are ascorbic acid, sodium thiosulfate, ammonium chloride, sodium sulfite, and sodium arsenite, but these quenching agents can cause varying degrees of DBPs degradation. Therefore, in recent years, researchers have attempted to find emerging chlorine quenchers. However, no studies have been conducted to systematically review the effects of traditional quenchers and new ones on DBPs, as well as their advantages, disadvantages, and scope of application. For inorganic DBPs (bromate, chlorate, and chlorite), sodium sulfite has been proven to be the ideal chlorine quencher. For organic DBPs, although ascorbic acid caused the degradation of some DBPs, it remains the ideal quenching agent for most known DBPs. Among the studied emerging chlorine quenchers, n-acetylcysteine (NAC), glutathione (GSH), and 1,3,5-trimethoxybenzene are promising for their application as the ideal chlorine quencher of organic DBPs. The dehalogenation of trichloronitromethane, trichloroacetonitrile, trichloroacetamide, and bromochlorophenol by sodium sulfite is caused by nucleophilic substitution reaction. This paper takes the understanding of DBPs and traditional and emerging chlorine quenchers as a starting point to comprehensively summarize their effects on different types of DBPs, and to provide assistance in understanding and selecting the most suitable residual chlorine quenchers during DBPs research.}, } @article {pmid37234375, year = {2023}, author = {Chennupati, R and Solga, I and Wischmann, P and Dahlmann, P and Celik, FG and Pacht, D and Şahin, A and Yogathasan, V and Hosen, MR and Gerdes, N and Kelm, M and Jung, C}, title = {Chronic anemia is associated with systemic endothelial dysfunction.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1099069}, pmid = {37234375}, issn = {2297-055X}, abstract = {BACKGROUND: In acute myocardial infarction and heart failure, anemia is associated with adverse clinical outcomes. Endothelial dysfunction (ED) is characterized by attenuated nitric oxide (NO)-mediated relaxation responses which is poorly studied in chronic anemia (CA). We hypothesized that CA is associated with ED due to increased oxidative stress in the endothelium.

METHODS: CA was induced by repeated blood withdrawal in male C57BL/6J mice. Flow-Mediated Dilation (FMD) responses were assessed in CA mice using ultrasound-guided femoral transient ischemia model. Tissue organ bath was used to assess vascular responsiveness of aortic rings from CA mice, and in aortic rings incubated with red blood cells (RBCs) from anemic patients. In the aortic rings from anemic mice, the role of arginases was assessed using either an arginase inhibitor (Nor-NOHA) or genetic ablation of arginase 1 in the endothelium. Inflammatory changes in plasma of CA mice were examined by ELISA. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), myeloperoxidase (MPO), 3-Nitrotyrosine levels, and 4-Hydroxynonenal (4-HNE) were assessed either by Western blotting or immunohistochemistry. The role of reactive oxygen species (ROS) in ED was assessed in the anemic mice either supplemented with N-Acetyl cysteine (NAC) or by in vitro pharmacological inhibition of MPO.

RESULTS: The FMD responses were diminished with a correlation to the duration of anemia. Aortic rings from CA mice showed reduced NO-dependent relaxation compared to non-anemic mice. RBCs from anemic patients attenuated NO-dependent relaxation responses in murine aortic rings compared to non-anemic controls. CA results in increased plasma VCAM-1, ICAM-1 levels, and an increased iNOS expression in aortic vascular smooth muscle cells. Arginases inhibition or arginase1 deletion did not improve ED in anemic mice. Increased expression of MPO and 4-HNE observed in endothelial cells of aortic sections from CA mice. NAC supplementation or inhibition of MPO improved relaxation responses in CA mice.

CONCLUSION: Chronic anemia is associated with progressive endothelial dysfunction evidenced by activation of the endothelium mediated by systemic inflammation, increased iNOS activity, and ROS production in the arterial wall. ROS scavenger (NAC) supplementation or MPO inhibition are potential therapeutic options to reverse the devastating endothelial dysfunction in chronic anemia.}, } @article {pmid37226070, year = {2023}, author = {Torres-Maure, M and Tapia-Ib Áñez, EX and Gamarra-L Ázaro, A and Bellido-Caparó, Á and García-Encinas, C}, title = {[Use of the Scottish and Newcastle Anti-Emetic Pretreatment (SNAP) scheme in recovery from massive overdose of acetaminophen poisoning with acute liver failure - Case report].}, journal = {Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru}, volume = {43}, number = {1}, pages = {53-56}, pmid = {37226070}, issn = {1609-722X}, mesh = {Female ; Humans ; Adolescent ; *Antiemetics/therapeutic use ; Acetaminophen ; Gastrointestinal Agents ; *Liver Failure, Acute/chemically induced/drug therapy ; Scotland ; }, abstract = {Acetaminophen is a drug widely used in the world and easily accessible due to its antipyretic, analgesics characteristics, among others (1); however, exposure to toxic doses causes organic damage and even death. We present the case of an 18-year-old female patient who ingested 40 grams of acetaminophen and developed severe liver dysfunction, being treated with N-acetylcysteine (NAC) antidotal therapy according to the simplified scheme: Scottish and Newcastle Anti-emetic Pretreatment Paracetamol Poisoning Study Regimen (SNAP), presenting improvement in the clinical course and decrease in liver profiles, coagulation disorder, INR and resolution of the condition.}, } @article {pmid37225709, year = {2023}, author = {Zhang, S and Liu, Q and Chang, M and Pan, Y and Yahaya, BH and Liu, Y and Lin, J}, title = {Chemotherapy impairs ovarian function through excessive ROS-induced ferroptosis.}, journal = {Cell death & disease}, volume = {14}, number = {5}, pages = {340}, pmid = {37225709}, issn = {2041-4889}, mesh = {Female ; Animals ; Reactive Oxygen Species ; *Ferroptosis ; Apoptosis ; Ovary ; *Antineoplastic Agents/toxicity ; }, abstract = {Chemotherapy was conventionally applied to kill cancer cells, but regrettably, they also induce damage to normal cells with high-proliferative capacity resulting in cardiotoxicity, nephrotoxicity, peripheral nerve toxicity, and ovarian toxicity. Of these, chemotherapy-induced ovarian damages mainly include but are not limited to decreased ovarian reserve, infertility, and ovarian atrophy. Therefore, exploring the underlying mechanism of chemotherapeutic drug-induced ovarian damage will pave the way to develop fertility-protective adjuvants for female patients during conventional cancer treatment. Herein, we firstly confirmed the abnormal gonadal hormone levels in patients who received chemotherapy and further found that conventional chemotherapeutic drugs (cyclophosphamide, CTX; paclitaxel, Tax; doxorubicin, Dox and cisplatin, Cis) treatment significantly decreased both the ovarian volume of mice and the number of primordial and antral follicles and accompanied with the ovarian fibrosis and reduced ovarian reserve in animal models. Subsequently, Tax, Dox, and Cis treatment can induce the apoptosis of ovarian granulosa cells (GCs), likely resulting from excessive reactive oxygen species (ROS) production-induced oxidative damage and impaired cellular anti-oxidative capacity. Thirdly, the following experiments demonstrated that Cis treatment could induce mitochondrial dysfunction through overproducing superoxide in GCs and trigger lipid peroxidation leading to ferroptosis, first reported in chemotherapy-induced ovarian damage. In addition, N-acetylcysteine (NAC) treatment could alleviate the Cis-induced toxicity in GCs by downregulating cellular ROS levels and enhancing the anti-oxidative capacity (promoting the expression of glutathione peroxidase, GPX4; nuclear factor erythroid 2-related factor 2, Nrf2 and heme oxygenase-1, HO-1). Our study confirmed the chemotherapy-induced chaotic hormonal state and ovarian damage in preclinical and clinical examination and indicated that chemotherapeutic drugs initiated ferroptosis in ovarian cells through excessive ROS-induced lipid peroxidation and mitochondrial dysfunction, leading to ovarian cell death. Consequently, developing fertility protectants from the chemotherapy-induced oxidative stress and ferroptosis perspective will ameliorate ovarian damage and further improve the life quality of cancer patients.}, } @article {pmid37224776, year = {2023}, author = {Li, J and Zhou, J and Zhao, N and Li, Z and Xu, X and Tang, J and Li, Z and Zhang, X and Wu, Y and Li, Q and Zhang, Q and Jiang, J}, title = {EM-2, a natural sesquiterpene lactone from Elephantopus mollis H.B.K., enhanced the sensitivity of breast cancer cells to epirubicin by blocking protective autophagy.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {116}, number = {}, pages = {154878}, doi = {10.1016/j.phymed.2023.154878}, pmid = {37224776}, issn = {1618-095X}, mesh = {Humans ; Female ; Epirubicin ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; *Breast Neoplasms/drug therapy/pathology ; Autophagy ; Apoptosis ; *Sesquiterpenes/pharmacology ; Cell Proliferation ; }, abstract = {BACKGROUND: EM-2, a natural sesquiterpene lactone isolated from Elephantopus mollis H.B.K., showed a good anti-breast cancer effect when combined with epirubicin (EPI). However, its synergistic sensitization mechanism remains unclear.

PURPOSE: This study aimed to determine the therapeutic effect and possible synergistic mechanism of EM-2 with EPI in vivo and in vitro and to provide an experimental basis for the treatment of human breast cancer.

METHODS: Cell proliferation was measured with MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) levels were examined through flow cytometry, and the expression levels of proteins related to apoptosis, autophagy, endoplasmic reticulum stress, and DNA damage were detected through Western blot analysis. Moreover, the caspase inhibitor Z-VAD-FMK, autophagy inhibitors bafilomycin A1 and chloroquine, ER stress inhibitor 4-phenylbutyric acid, and ROS scavenger N-acetyl cysteine were applied to verify signaling pathways. Breast cancer cell lines were used to evaluate the antitumor functions of EM-2 and EPI in vitro and in vivo.

RESULTS: We demonstrated that in MDA-MB-231 and SKBR3 cells, the IC50 of EPI combined with EM-2 (IC20) was 37.909 and 33.889 times lower than that of EPI alone, respectively. Further study verified that in EPI-resistant lines (MDA-MB-231/EPI), the IC50 of EPI combined with EM-2 (IC20) was 26.305 times lower than that of EPI alone. Mechanistically, EM-2 could reverse the protective effect of EPI against autophagy in SKBR3 and MDA-MB-231 cells. EM-2 and EPI could trigger ER stress. When EM-2 and EPI were used in combination, ER stress was continuously activated, and ER stress-mediated apoptosis was induced. Meanwhile, EM-2 combined with EPI promoted DNA damage then induced apoptosis. In vivo, the volume of breast cancer xenografts in the combination group was smaller than that in the control, EM-2, and EPI groups. Immunohistochemical experiments demonstrated that the combination of EM-2 and EPI could block autophagy and promote ER stress in vivo.

CONCLUSION: EM-2 enhances the sensitivity of MDA-MB-231, SKBR3, and EPI-resistant cells to EPI.}, } @article {pmid37224750, year = {2023}, author = {Gu, L and He, X and Zhang, Y and Li, S and Tang, J and Ma, R and Yang, X and Huang, H and Peng, Y and Xie, Y and Peng, Z and Meng, J and Hu, G and Tao, L and Liu, X and Yang, H}, title = {Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {164}, number = {}, pages = {114844}, doi = {10.1016/j.biopha.2023.114844}, pmid = {37224750}, issn = {1950-6007}, mesh = {Mice ; Animals ; *MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Acetaminophen/metabolism ; Lipopolysaccharides/pharmacology ; Anisomycin/metabolism/pharmacology ; Liver ; *Liver Failure, Acute/chemically induced/drug therapy/prevention & control ; Pyridones/pharmacology ; Necrosis/metabolism ; Mice, Inbred C57BL ; Hepatocytes ; }, abstract = {AIMS: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms.

METHODS: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies.

RESULTS: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing.

CONCLUSIONS: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.}, } @article {pmid37223155, year = {2023}, author = {Stashin, AR and Fikse, DJ and Orta, AM and Briggs, RP and Wheatley, SM and Koons, AL}, title = {You Dropped the Bomb on Me: A Case Series of Carbon Tetrachloride Toxicity.}, journal = {Cureus}, volume = {15}, number = {4}, pages = {e37879}, pmid = {37223155}, issn = {2168-8184}, abstract = {Carbon tetrachloride (CCl4) is a halogenated hydrocarbon that is a colorless, clear liquid with a sweetish, ether-like, nonirritant odor. It was previously used in dry cleaning agents, refrigerants, and fire extinguishers. CCl4 toxicity is rarely observed. Two patients with acute hepatitis following exposure to a CCl4-containing antique fire extinguisher are presented. A son (patient 1) and father (patient 2) were admitted to the hospital with acute, unexplained elevated transaminases. After extensive questioning, they reported recent exposure to a large amount of CCl4 when an antique firebomb shattered in their home. Both patients cleaned the debris without personal protective equipment and slept in the contaminated area. The patients presented to the emergency department (ED) at varying times between 24 and 72 hours after CCl4 exposure. Both patients received intravenous N-acetylcysteine (NAC); patient 1 also received oral cimetidine. Both recovered uneventfully without sequelae. Extensive workup for other causes of elevated transaminases was unremarkable. Serum analyses for CCl4 were also unremarkable due to the delay between exposure and hospital presentation. CCl4 is a potent hepatotoxin. CCl4 metabolism via cytochrome CYP2E1 produces its toxic metabolite, the trichloromethyl radical. This radical covalently binds to hepatocyte macromolecules and causes lipid peroxidation and oxidative damage with ensuing centrilobular necrosis. Treatment is not well established, but NAC is likely beneficial via glutathione repletion and antioxidant effects. Cimetidine blocks cytochrome P450 and, thus, metabolite formation. Cimetidine may also promote the stimulation of regenerative processes acting on DNA synthesis. CCl4 toxicity is rare and infrequently reported in current literature but should be maintained in the differential of acute hepatitis. Two patients presenting nearly identically - at two different ages but from the same household - offered a clue to this enigmatic diagnosis.}, } @article {pmid37217712, year = {2023}, author = {Fakhouri, H and Bakulić, MP and Zhang, I and Yuan, H and Bain, D and Rondepierre, F and Brevet, PF and Maršić, ŽS and Antoine, R and Bonačić-Koutecký, V and Maysinger, D}, title = {Ligand impact on reactive oxygen species generation of Au10 and Au25 nanoclusters upon one- and two-photon excitation.}, journal = {Communications chemistry}, volume = {6}, number = {1}, pages = {97}, pmid = {37217712}, issn = {2399-3669}, support = {RGPIN 2020-07011//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)/ ; }, abstract = {In photodynamic therapy (PDT), light-sensitive photosensitizers produce reactive oxygen species (ROS) after irradiation in the presence of oxygen. Atomically-precise thiolate-protected gold nanoclusters are molecule-like nanostructures with discrete energy levels presenting long lifetimes, surface biofunctionality, and strong near-infrared excitation ideal for ROS generation in PDT. We directly compare thiolate-gold macromolecular complexes (Au10) and atomically-precise gold nanoclusters (Au25), and investigate the influence of ligands on their photoexcitation. With the ability of atomically-precise nanochemistry, we produce Au10SG10, Au10AcCys10, Au25SG18, and Au25AcCys18 (SG: glutathione; AcCys: N-acetyl-cysteine) fully characterized by high-resolution mass spectrometry. Our theoretical investigation reveals key factors (energetics of excited states and structural influence of surface ligands) and their relative importance in singlet oxygen formation upon one- and two-photon excitation. Finally, we explore ROS generation by gold nanoclusters in living cells with one- and two-photon excitation. Our study presents in-depth analyses of events within gold nanoclusters when photo-excited both in the linear and nonlinear optical regimes, and possible biological consequences in cells.}, } @article {pmid37217588, year = {2023}, author = {Beloosesky, R and Gutzeit, O and Ginsberg, Y and Khatib, N and Ross, MG and Weiner, Z and Zmora, O}, title = {Intestine and brain TLR-4 modulation following N-acetyl-cysteine treatment in NEC rodent model.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {8241}, pmid = {37217588}, issn = {2045-2322}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology ; Animals, Newborn ; Brain/metabolism ; *Brain Injuries/metabolism ; Disease Models, Animal ; *Enterocolitis, Necrotizing/drug therapy/metabolism ; Glutathione/metabolism ; Ileum/metabolism ; Intestines ; Rats, Sprague-Dawley ; Rodentia/metabolism ; Toll-Like Receptor 4/metabolism ; }, abstract = {Necrotizing enterocolitis (NEC) brain injury is mediated through Toll-like receptor 4 (TLR4) on the intestinal epithelium and brain microglia. Our aim was to determine whether postnatal and/or prenatal NAC can modify NEC associated intestinal and brain TLR4 expression and brain glutathione levels in a rat model of NEC. Newborn Sprague-Dawley rats were randomized into three groups: Control (n = 33); NEC (n = 32)-hypoxia and formula feeding; and NEC-NAC (n = 34)-received NAC (300 mg/kg IP) in addition to NEC conditions. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg IV) for the last 3 days of pregnancy: NAC-NEC (n = 33) or NAC-NEC-NAC (n = 36) with additional postnatal NAC. Pups were sacrificed on the fifth day, and ileum and brains harvested for TLR-4 and glutathione protein levels. Brain and ileum TLR-4 protein levels were significantly increased in NEC offspring as compared to control (brain 2.5 ± 0.6 vs. 0.88 ± 0.12 U and ileum 0.24 ± 0.04 vs. 0.09 ± 0.01, p < 0.05). When NAC was administered only to dams (NAC-NEC) a significant decrease in TLR-4 levels was demonstrated in both offspring brain (1.53 ± 0.41 vs. 2.5 ± 0.6 U, p < 0.05) and ileum (0.12 ± 0.03 vs. 0.24 ± 0.04 U, p < 0.05) as compared to NEC. The same pattern was demonstrated when NAC was administered only or postnatally. The decrease in brain and ileum glutathione levels observed in NEC offspring was reversed with all NAC treatment groups. NAC reverses the increase in ileum and brain TLR-4 levels and the decrease in brain and ileum glutathione levels associated with NEC in a rat model, and thus may protect from NEC associated brain injury.}, } @article {pmid37216221, year = {2023}, author = {Aswani, SS and Mohan, MS and Aparna, NS and Boban, PT and Saja, K}, title = {Oxidized LDL-mediated upregulation of ADAMTS-4 in monocytes/macrophages involves ROS-NF-κB-SIRT-1 pathway.}, journal = {Physiology international}, volume = {110}, number = {2}, pages = {173-190}, doi = {10.1556/2060.2023.00170}, pmid = {37216221}, issn = {2498-602X}, mesh = {Humans ; *Atherosclerosis/metabolism ; Leukocytes, Mononuclear ; Macrophages/metabolism ; Monocytes/metabolism ; *NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Resveratrol/metabolism ; RNA, Messenger/metabolism ; Up-Regulation ; *ADAMTS4 Protein/metabolism ; }, abstract = {BACKGROUND AND AIMS: ADAMTS-4 is a protease enzyme involved in vascular remodeling and atherosclerosis. It was found to be upregulated in macrophages seen in atherosclerotic lesions. This study aimed to investigate the expression and regulation of ADAMTS-4 in oxidized LDL-induced human monocytes/macrophages system.

METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from human blood, and treated with oxidized LDL (50 μg mL-1) were used as the model system for the study. mRNA and protein expressions were studied by PCR, ELISA, and western blot analysis. ROS production and cell viability were determined by DCFDA staining and MTT assay, respectively.

RESULTS: In the presence of oxidized LDL, monocytes get differentiated into macrophages, which were confirmed by the increased expression of macrophage differentiation markers and pro-inflammatory cytokine TNF-α. Oxidized LDL increased the mRNA and protein expression of ADAMTS-4 in monocytes/macrophages. N- Acetyl cysteine, ROS scavenger, downregulate the protein expression of ADAMTS-4. The expression of ADAMTS-4 was decreased significantly in the presence of NF-κB inhibitors. SIRT-1 activity was significantly downregulated in the macrophages and was reversed in the presence of the SIRT-1 agonist, resveratrol. Acetylation of NF-κB and hence the expression of ADAMTS-4 were significantly downregulated in the presence of SIRT-1 activator, resveratrol.

CONCLUSIONS: Our study suggests that oxidized LDL significantly upregulated the expression of ADAMTS-4 in the monocytes/macrophages through ROS- NF-κB- SIRT-1 pathway.}, } @article {pmid37207578, year = {2023}, author = {Li, XL and Liu, YL and Liu, JY and Zhu, YY and Zhu, XX and Zhang, WW and Li, J and Zhao, Y and Zhao, LL and Zhang, C and Wang, H and Xu, DX and Gao, L}, title = {1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {259}, number = {}, pages = {115027}, doi = {10.1016/j.ecoenv.2023.115027}, pmid = {37207578}, issn = {1090-2414}, mesh = {Male ; Mice ; Animals ; *Testis/metabolism ; *Antioxidants/metabolism ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/physiology ; Testosterone/metabolism ; Oxidative Stress ; Acetylcysteine/pharmacology/metabolism ; }, abstract = {Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.}, } @article {pmid37206223, year = {2023}, author = {Porterfield, JE and Sharma, R and Jimenez, AS and Sah, N and McCracken, S and Zhang, L and An, HT and Lee, S and Kannan, S and Sharma, A and Kannan, RM}, title = {Galactosylated hydroxyl-polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning-induced liver failure.}, journal = {Bioengineering & translational medicine}, volume = {8}, number = {3}, pages = {e10486}, pmid = {37206223}, issn = {2380-6761}, support = {P30 EY001765/EY/NEI NIH HHS/United States ; R25 GM109441/GM/NIGMS NIH HHS/United States ; }, abstract = {Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose-conjugated hydroxyl polyamidoamine dendrimer (D4-Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)-induced liver failure. D4-Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non-Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4-Gal conjugated to N-acetyl cysteine (NAC) was tested in a mouse model of APAP-induced liver failure. A single intravenous dose of a conjugate of D4-Gal and NAC (Gal-d-NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4-Gal is effective in targeting and delivering therapies to hepatocytes and Gal-D-NAC has the potential to salvage and treat liver injury with a broader therapeutic window.}, } @article {pmid37205206, year = {2023}, author = {Ajitkumar, A and Mohan, G and Ghose, M and Yarrarapu, S and Afiniwala, S}, title = {Drug-Induced Liver Injury Secondary to Turmeric Use.}, journal = {European journal of case reports in internal medicine}, volume = {10}, number = {5}, pages = {003845}, pmid = {37205206}, issn = {2284-2594}, abstract = {UNLABELLED: Turmeric is a herbal medication and spice which has been used for thousands of years in traditional Eastern medicine for its flavour, colour, and purported anti-inflammatory, antioxidant, antineoplastic and antimicrobial properties. It has recently garnered interest and popularity worldwide for these reasons. While turmeric supplements are generally safe, some reports of toxicity are emerging. Compounds like piperine are added to turmeric to enhance its bioavailability, potentially contributing to its toxicity. Here, we describe a 55-year-old woman with progressive jaundice and elevated bilirubin and liver enzymes but no evidence of acute liver failure. She was treated with N-acetyl cysteine (NAC) for 24 hours and liver function tests (LFTs) were closely monitored. As a downtrend in LFTs was noted and the patient remained asymptomatic, she was discharged with close outpatient follow-up. LFTs eventually normalized 2 months after the initial presentation. Clinicians must keep this differential in mind when evaluating acute liver injury. With our case report, we question the utility of NAC in non-acetaminophen-related liver injury and encourage further studies.

LEARNING POINTS: Eliciting information on recent drug or supplement use should be part of comprehensive history-taking to evaluate acute liver injury.Turmeric supplements which may contain piperine to enhance bioavailability are a potential source of acute liver injury.The role of N-acetyl cysteine in managing non-acetaminophen-related liver injury is unclear and further studies are required.}, } @article {pmid37203858, year = {2023}, author = {Oliva, A and Pallecchi, L and Rossolini, GM and Travaglino, F and Zanatta, P}, title = {Rationale and evidence for the adjunctive use of N-acetylcysteine in multidrug-resistant infections.}, journal = {European review for medical and pharmacological sciences}, volume = {27}, number = {9}, pages = {4316-4325}, doi = {10.26355/eurrev_202305_32342}, pmid = {37203858}, issn = {2284-0729}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Drug Resistance, Multiple, Bacterial ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Expectorants/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; *Klebsiella Infections/drug therapy/microbiology ; Klebsiella pneumoniae ; Microbial Sensitivity Tests ; }, abstract = {Bacterial multidrug resistance has been a serious issue for healthcare systems in recent decades, responsible for many infections and deaths. Due to the increasing incidence of antimicrobial resistance and scarce treatment options, research is focused on finding possible therapeutic adjuvants able to increase the efficacy of antibiotics. The aim of this article is a review of available evidence on the use of N-acetylcysteine (NAC). MEDLINE/PubMed was searched for appropriate keywords. In vitro and in vivo preclinical studies, clinical studies, reviews, and meta-analyses were retrieved and selected based on relevance. A narrative review article was written, reporting published evidence and the expert opinion of the authors. Among possible adjunctive treatments, NAC has attracted the interest of researchers as a candidate for re-purposing. It is a widely used drug with a good tolerability profile, mainly used as a mucolytic agent, with antioxidant, anti-inflammatory properties and antibacterial activity. NAC acts on different mechanisms and stages of infections, resulting in inhibition of biofilm formation, disruption of preformed biofilms, and reduction of bacterial viability. NAC may be administered as an aerosol in many types of infections, including cystic fibrosis, bronchiectasis and infective flare of chronic obstructive pulmonary disease (COPD), and by the intravenous route in severe systemic infections (including septic shock) such as those caused by carbapenemase (KPC)-producing Klebsiella pneumoniae (Kp) and Carbapenem-Resistant Acinetobacter baumannii (CR-Ab). A rationale exists for using NAC as an adjunctive treatment in multidrug-resistant (MDR) infections, based on in vitro, in vivo and clinical evidence, and future research is needed to identify candidate patients and optimal schedules for specific clinical conditions.}, } @article {pmid37196773, year = {2023}, author = {Qiu, D and Song, S and Chen, N and Bian, Y and Yuan, C and Zhang, W and Duan, H and Shi, Y}, title = {NQO1 alleviates renal fibrosis by inhibiting the TLR4/NF-κB and TGF-β/Smad signaling pathways in diabetic nephropathy.}, journal = {Cellular signalling}, volume = {108}, number = {}, pages = {110712}, doi = {10.1016/j.cellsig.2023.110712}, pmid = {37196773}, issn = {1873-3913}, mesh = {Animals ; Humans ; Mice ; Cytokines ; *Diabetes Mellitus, Type 2 ; *Diabetic Nephropathies/metabolism ; Epithelial-Mesenchymal Transition ; Fibrosis ; Inflammation/metabolism ; *NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; Toll-Like Receptor 4/metabolism ; Transforming Growth Factor beta1/metabolism ; }, abstract = {OBJECTIVE: Diabetic nephropathy (DN) is one of the main complications of diabetes, and inflammation and fibrosis play an important role in its progression. NAD(P)H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and damage caused by toxic quinones. In the present study, we aimed to investigate the protective effects of NQO1 against diabetes-induced renal inflammation and fibrosis and the underlying mechanisms.

METHODS: In vivo, the kidneys of type 2 diabetes model db/db mice were infected with adeno-associated virus vectors to induce NQO1 overexpression. In vitro, human renal tubular epithelial (HK-2) cells transfected with NQO1 pcDNA3.1(+) were cultured under high-glucose (HG) conditions. Gene and protein expression was assessed by quantitative real-time PCR, Western blotting, immunofluorescence, and immunohistochemical staining. Mitochondrial reactive oxygen species (ROS) were detected with MitoSOX Red.

RESULT: Our study revealed that the expression of NQO1 was markedly downregulated and that Toll-like receptor (TLR)4 and TGF-β1 expression was upregulated in vivo and in vitro under diabetic conditions. Overexpression of NQO1 suppressed proinflammatory cytokine (IL-6, TNF-α, MCP-1) secretion, extracellular matrix (ECM) (collagen IV, fibronectin) accumulation and epithelial-mesenchymal transition (EMT) (α-SMA, E-cadherin) in the db/db mouse kidneys and HG-cultured HK-2 cells. Furthermore, NQO1 overexpression ameliorated HG-induced TLR4/NF-κB and TGF-β/Smad pathways activation. Mechanistic studies demonstrated that a TLR4 inhibitor (TAK-242) suppressed the TLR4/NF-κB signaling pathway, proinflammatory cytokine secretion, EMT and ECM-related protein expression in HG-exposed HK-2 cells. In addition, we found that the antioxidants N-acetylcysteine (NAC) and tempol increased the expression of NQO1 and decreased the expression of TLR4, TGF-β1, Nox1, and Nox4 and ROS production in HK-2 cells cultured under HG conditions.

CONCLUSIONS: These data suggest that NQO1 alleviates diabetes-induced renal inflammation and fibrosis by regulating the TLR4/NF-κB and TGF-β/Smad signaling pathways.}, } @article {pmid37193781, year = {2023}, author = {Kuo, CW and Su, PL and Huang, TH and Lin, CC and Chen, CW and Tsai, JS and Liao, XM and Chan, TY and Shieh, CC}, title = {Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {7894}, pmid = {37193781}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; *COVID-19 ; Reactive Oxygen Species ; Macrophages, Alveolar/metabolism ; SARS-CoV-2/metabolism ; Angiotensin-Converting Enzyme 2/genetics ; *Cigarette Smoking ; Peptidyl-Dipeptidase A/metabolism ; }, abstract = {Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb[-/-] mice; however, exogenous ROS increased the ACE2 in Cybb[-/-] AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.}, } @article {pmid37190230, year = {2023}, author = {Ajouaou, Y and Magnani, E and Madakashira, B and Jenkins, E and Sadler, KC}, title = {atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers.}, journal = {Cancers}, volume = {15}, number = {8}, pages = {}, pmid = {37190230}, issn = {2072-6694}, support = {AJF2018098//Al Jalila Foundation/ ; ADHPG-CGSB//Tamkeen under the NYU Abu Dhabi Research Institute Award/ ; RE188//REF/ ; To KCS//NYUAD Faculty Research Fund/ ; }, abstract = {The ataxia-telangiectasia mutated (atm) gene is activated in response to genotoxic stress and leads to activation of the tp53 tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in tp53-dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of atm on UHRF1-mediated phenotypes by generating zebrafish atm mutants. atm[-/-] adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or H2O2 exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, atm mutation and exposure to H2O2 further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of atm further enhances this, triggering elimination of these precancerous cells, leading to a small liver.}, } @article {pmid37183639, year = {2023}, author = {Zi, Y and Liao, K and Chen, H}, title = {[Cigarette Smoke Induces Gefitinib Resistance in NSCLC Cells via ROS/Sirt3/SOD2 Pathway].}, journal = {Zhongguo fei ai za zhi = Chinese journal of lung cancer}, volume = {26}, number = {4}, pages = {245-256}, pmid = {37183639}, issn = {1999-6187}, mesh = {Humans ; Gefitinib/pharmacology/therapeutic use ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism ; *Sirtuin 3/genetics/therapeutic use ; *Lung Neoplasms/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism/therapeutic use ; *Antineoplastic Agents/therapeutic use ; *Cigarette Smoking ; Sincalide/therapeutic use ; ErbB Receptors/metabolism ; Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations are the most common driver mutations in non-small cell lung cancer (NSCLC). To prolong the survival of the patients, EGFR tyrosine kinase inhibitors (TKIs) resistance in NSCLC is a major challenge that needs to be addressed urgently, and this study focuses on investigating the mechanism of cigarette smoke (CS) induced Gefitinib resistance in NSCLC.

METHODS: PC-9 and A549 cells were cultured in vitro and treated with 1 µmol/L Gefitinib for 4 h and 10% cigarette smoke extract (CSE) for 48 h. Western blot was used to detect Sirtuin 3 (Sirt3) and superoxide dismutase 2 (SOD2) protein expressions; DCFH-DA probe was used to detect intracellular reactive oxygen species (ROS); CCK-8 kit was used to detect cell activity, and EdU was used to detect cell proliferation ability. Sirt3 overexpression plasmid (OV-Sirt3) was transfected in PC-9 and A549 cells and treated with 1 µmol/L Gefitinib for 4 h and 10% CSE for 48 h after N-acetylcysteine (NAC) action. The expressions of Sirt3 and SOD2 were detected by Western blot; the ROS level in the cells was detected by DCFH-DA probe, and the cell activity was detected by CCK-8.

RESULTS: CSE induced an increase in the 50% inhibitory concentration (IC50) of both PC-9 and A549 cells to Gefitinib (P<0.01) and enhanced the proliferation of PC-9 and A549 cells, suggesting that CS induced Gefitinib resistance in NSCLC. ROS was involved in CSE-induced Gefitinib resistance (P<0.05). CSE induced low expressions of Sirt3 and SOD2 (P<0.01), and Sirt3/SOD2 was associated with poor prognosis in lung cancer patients (P<0.05). OV-Sirt3 in PC-9 and A549 cells reversed CSE-induced Gefitinib resistance (P<0.05) and significantly reduced ROS production. NAC reversed CSE-induced Gefitinib resistance in PC-9 and A549 cells (P<0.05).

CONCLUSIONS: The ROS/Sirt3/SOD2 pathway is involved in CS-induced Gefitinib resistance in NSCLC.}, } @article {pmid37176778, year = {2023}, author = {Mirea, L and Cobilinschi, C and Ungureanu, R and Cotae, AM and Darie, R and Tincu, R and Avram, O and Constantinescu, S and Minoiu, C and Baetu, A and Grintescu, IM}, title = {A Trend towards Diaphragmatic Muscle Waste after Invasive Mechanical Ventilation in Multiple Trauma Patients-What to Expect?.}, journal = {Journal of clinical medicine}, volume = {12}, number = {9}, pages = {}, pmid = {37176778}, issn = {2077-0383}, abstract = {Considering the prioritization of life-threatening injuries in trauma care, secondary dysfunctions such as ventilator-induced diaphragmatic dysfunction (VIDD) are often overlooked. VIDD is an entity induced by muscle inactivity during invasive mechanical ventilation, associated with a profound loss of diaphragm muscle mass. In order to assess the incidence of VIDD in polytrauma patients, we performed an observational, retrospective, longitudinal study that included 24 polytraumatized patients. All included patients were mechanically ventilated for at least 48 h and underwent two chest CT scans during their ICU stay. Diaphragmatic thickness was measured by two independent radiologists on coronal and axial images at the level of celiac plexus. The thickness of the diaphragm was significantly decreased on both the left and right sides (left side: -0.82 mm axial p = 0.034; -0.79 mm coronal p = 0.05; right side: -0.94 mm axial p = 0.016; -0.91 coronal p = 0.013). In addition, we obtained a positive correlation between the number of days of mechanical ventilation and the difference between the two measurements of the diaphragm thickness on both sides (r =0.5; p = 0.02). There was no statistically significant correlation between the body mass indexes on admission, the use of vitamin C or N-acetyl cysteine, and the differences in diaphragmatic thickness.}, } @article {pmid37175458, year = {2023}, author = {Lee, MY and Shiau, JP and Tang, JY and Hou, MF and Primus, PS and Kao, CL and Choo, YM and Chang, HW}, title = {Boesenbergia stenophylla-Derived Stenophyllol B Exerts Antiproliferative and Oxidative Stress Responses in Triple-Negative Breast Cancer Cells with Few Side Effects in Normal Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37175458}, issn = {1422-0067}, support = {MOST 111-2320-B-037-015-MY3; MOST 110-2314-B-037-074-MY3; MOST 109-2923-M-037-001-MY3; MOST 111-2113-M-037-014//Ministry of Science and Technology/ ; KMU-DK(A)112008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; GPF055B-2018 and ST004-2018//University of Malaya/ ; }, mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy ; DNA Damage ; Cell Proliferation ; Cell Line, Tumor ; Oxidative Stress ; Apoptosis ; Acetylcysteine/pharmacology ; }, abstract = {Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla, stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress (N-acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.}, } @article {pmid37174730, year = {2023}, author = {Aisa-Álvarez, A and Pérez-Torres, I and Guarner-Lans, V and Manzano-Pech, L and Cruz-Soto, R and Márquez-Velasco, R and Casarez-Alvarado, S and Franco-Granillo, J and Núñez-Martínez, ME and Soto, ME}, title = {Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System.}, journal = {Cells}, volume = {12}, number = {9}, pages = {}, pmid = {37174730}, issn = {2073-4409}, mesh = {Humans ; Antioxidants/therapeutic use ; *Shock, Septic/drug therapy ; Multiple Organ Failure/drug therapy ; Organ Dysfunction Scores ; *Selenium ; Vitamin E/therapeutic use ; Ascorbic Acid/therapeutic use ; *Melatonin ; Vitamins ; Intensive Care Units ; }, abstract = {BACKGROUND AND AIM: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems.

METHODS: Randomized clinical trial run between 2018 and 2022. One hundred and thirty-one patients with septic shock were included in five groups with 25, 27, 24, 26 and 29 patients each. Group 1 received vitamin C (Vit C), Group 2 vitamin E (Vit E), Group 3 n-acetylcysteine (NAC), Group 4 melatonin (MT) and group 5 no treatment. All antioxidants were administered orally or through a nasogastric tube for 5 days as an adjuvant to standard therapy.

RESULTS: All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NO3[-]/NO2[-] but increased Vit C levels. The SOFA score decreased with MT in 75%, Vit C 63% and NAC 50% vs. controls 33% (p = 0.0001, p = 0.03 and p = 0.001 respectively). MT diminished lipid peroxidation (LPO) (p = 0.01) and improved total antioxidant capacity (TAC) (p = 0.04). Vit E increased thiol levels (p = 0.02) and tended to decrease LPO (p = 0.06). Selenium levels were decreased in the control group (p = 0.04).

CONCLUSIONS: Antioxidants used as an adjuvant therapy in the standard treatment of septic shock decrease MOF and oxidative stress markers. They increase the TAC and thiols, and maintain selenium levels.}, } @article {pmid37171598, year = {2023}, author = {Español, I and Leal, JD and Blanquer, M and García-Candel, F and Heredia, A and Gómez-Espuch, J and González, C and Montserrat, J and Díaz-Carrasco, MS and Martínez, A and Moraleda, JM}, title = {N-Acetylcistein for thrombotic thrombocytopenic purpura: an observational case series study.}, journal = {Annals of hematology}, volume = {102}, number = {8}, pages = {2069-2075}, pmid = {37171598}, issn = {1432-0584}, mesh = {Humans ; *Purpura, Thrombotic Thrombocytopenic/diagnosis/drug therapy ; ADAMTS13 Protein ; Rituximab/therapeutic use ; Plasma Exchange ; Acetylcysteine/therapeutic use ; }, abstract = {Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. N-Acetylcysteine (NAC) rapidly degrades ultra-large von Willebrand factor multimers by disrupting the disulfide bonds. We report a series of twelve consecutive patients diagnosed with acquired TTP successfully treated with high-dose NAC (150 mg/kg/day) in combination with plasma exchange and steroids. Eight patients also received rituximab. Two patients presented refractory TTP. All patients achieved a quick clinical response in a median time of 5.5 days after starting NAC and are alive after a median follow-up of 29 months. The treatment was feasible and well tolerated. These data provide further evidence of the potential benefit and safety of adding NAC to the standard of care.}, } @article {pmid37168338, year = {2023}, author = {Lee, YP and Lin, CR and Chen, SS and Chen, RJ and Wu, YH and Chen, YH and Huang, BM}, title = {Combination treatment of cordycepin and radiation induces MA-10 mouse Leydig tumor cell death via ROS accumulation and DNA damage.}, journal = {American journal of cancer research}, volume = {13}, number = {4}, pages = {1329-1346}, pmid = {37168338}, issn = {2156-6976}, abstract = {Leydig cell tumor is the most frequent non-germ cell tumors of testis. The biggest challenge of using radiotherapy to treat testicular cancer is in effectively killing cancer cells and maintaining reproductive function after treatment. Our recently published article showed that cordycepin could enhance radiosensitivity to induce mouse Leydig tumor cell apoptosis by inducing cell cycle arrest, caspase pathway and endoplasmic reticulum (ER) stress. In the present study, the potency and mechanism of a previous combination treatment protocol on reactive oxygen species (ROS) induction and DNA damage were further investigated. Our results reveal that 25 μM cordycepin plus 4 Gy radiation leads to ROS accumulation accompanied by a decrease in heme oxygenase (HO)-1 protein expression in MA-10 mouse Leydig tumor cells. Subsequently, pronounced DNA damage with phosphorylated H2A histone family member X (γ-H2AX) increase and activation of DNA damage-related signaling pathways including double and single stranded break-induced ataxia telangiectasia mutated (ATM)/checkpoint kinase (Chk)2 and ataxia telangiectasia mutated and Rad3 related (ATR)/Chk1 signaling axes were identified. p53-dependent pathway was then initiated ultimately leading to cell death. Preincubated with free radical scavenger, N-acetylcysteine (NAC), down-regulated γ-H2AX expression in treated cells and partially reduced cell death, indicating that ROS overproduction is involved in combination treatment-induced DNA damage. Furthermore, the combination treatment effectively inhibited tumor growth as reflected in the reduction of tumor volume, size and weight, and high expression level of γ-H2AX in tumor tissue in vivo, suggesting that the combination treatment inhibited tumor growth via causing DNA damage in MA-10 cells. In summary, these results expound that the combination treatment of cordycepin and radiation induces MA-10 mouse Leydig tumor cell death through ROS accumulation and DNA damage. This finding can serve as a reference guideline for future clinical therapy of testicular cancer and provide potential targets for anti-cancer drug design.}, } @article {pmid37162825, year = {2023}, author = {Jung, IR and Ahima, RS and Kim, SF}, title = {IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37162825}, issn = {2692-8205}, support = {R01 DK135751/DK/NIDDK NIH HHS/United States ; }, abstract = {Insulin resistance is a critical mediator of the development of non-alcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of non-alcoholic fatty liver disease (NAFLD). Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of Akt phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-Acetyl Cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.}, } @article {pmid37155080, year = {2023}, author = {Wang, W and Zeng, J and Luo, P and Fang, J and Pei, Q and Yan, J and Zhu, C and Chen, W and Liu, Y and Huang, Z and Huang, Y and Wu, C and Pan, X}, title = {Engineered lipid liquid crystalline nanoparticles as an inhaled nanoplatform for mucus penetration enhancement.}, journal = {Drug delivery and translational research}, volume = {13}, number = {11}, pages = {2834-2846}, pmid = {37155080}, issn = {2190-3948}, mesh = {*Drug Carriers/chemistry ; *Nanoparticles/chemistry ; Mucus/metabolism ; Mucins ; Acetylcysteine ; Lipids/chemistry ; }, abstract = {Nanocarrier-assisted pulmonary drug delivery system has been widely employed for lung local disease treatment due to its enhanced drug lesion accumulation and reduced systematical side effects. However, the mucus barriers covered on the epithelia of trachea and bronchial tree construct a dense barrier for inhaled nanocarrier transport, which compromises the therapeutical effects. In this study, a lipid liquid crystalline nanoparticle NLP@Z with surface zwitterion material hexadecyl betaine (HB) modification and N-acetylcysteine (NAC) encapsulation was presented to exert the combination strategy of mucus-inert surface and mucus degradation. The HB modification endowed NLP@Z mucus-inert surface to inhibit the interaction between NLP@Z and mucins, and the encapsulated NAC could effectively degrade the mucins and further decrease the mucus viscosity. This combination strategy was proved to significantly promote the mucus penetration performance and enhance epithelial cell uptake. In addition, the proposed NLP@Z was equipped with desired nebulization property, which could be served as a potential pulmonary delivery nanoplatform. In summary, the proposed NLP@Z highlights the employment of the combination strategy for mucus penetration enhancement in pulmonary delivery, which may become a versatile platform for lung disease therapy.}, } @article {pmid37151623, year = {2023}, author = {Wu, X and Cao, Z and Ni, J and Zheng, X and Zhu, L and Xin Wang, and Lv, J and Zhou, S and Ding, Y and Wu, R}, title = {Compatibility and aerosol characteristics of beclomethasone mixed with N-acetylcysteine.}, journal = {Heliyon}, volume = {9}, number = {4}, pages = {e15357}, pmid = {37151623}, issn = {2405-8440}, abstract = {Mixing different kind inhalation medications for simultaneous inhalation is widely used in the treatment of chronic respiratory diseases, and it can minimize the administration time and improve patient adherence. To our knowledge, it is unclear whether beclomethasone (BDP, Clenil®) can bemixed with acetylcysteine (NAC, Fluimucil®), because the in vitro physico-chemical compatibility and aerosol characteristics of the mixture are unknown. In this study, we investigated physical compatibility, including the appearance, pH, osmotic pressure and chemical stability, as well as aerosol characteristics, including particle size corresponding to 10%/50%/90% of the cumulative percentage of total particle volume (X10/X50/X90), volume median droplet diameter (VMD), mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), fine particle dose (FPD) and geometric standard deviation (GSD), delivery rate, and total delivery of the above solutions. After mixing, there were no significant changes in visual appearance, pH, osmolality and drug content of the mixtures at room temperature for 12 h. The FDP of BDP in the mixture decreased by 16.49%, whereas the NAC increased by 10.85%. The delivery rates of BDP and NAC in the mixture decreased by 66.05% and 45.54%, and total delivery increased by 13.20% and 25.29%, respectively. However, the MMAD, FPF, particle size and GSD of the mixture were almost unchanged. We demonstrated that these admixtures are physico-chemically compatible but that coadministration of beclomethasone with acetylcysteine can markedly affect output and aerosol characteristics.}, } @article {pmid37151359, year = {2023}, author = {Elkhateeb, N and Hyde, S and Hogg, SL and Allsop, D and Shankar, A and Deegan, P and Tan, CY}, title = {Paracetamol toxicity in classic homocystinuria: Effect of N-acetylcysteine on total homocysteine.}, journal = {JIMD reports}, volume = {64}, number = {3}, pages = {238-245}, pmid = {37151359}, issn = {2192-8304}, abstract = {Classical homocystinuria (HCU) is caused by cystathionine β-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N-Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.}, } @article {pmid37147916, year = {2023}, author = {Hamedinasab, H and Rezayan, AH and Jaafari, MR and Mashreghi, M and Alvandi, H}, title = {The protective effect of N-acetylcysteine against liposome and chitosan-induced cytotoxicity.}, journal = {Journal of microencapsulation}, volume = {40}, number = {5}, pages = {357-365}, doi = {10.1080/02652048.2023.2209646}, pmid = {37147916}, issn = {1464-5246}, mesh = {Acetylcysteine/pharmacology ; Antioxidants ; *Chitosan/toxicity ; Drug Liberation ; Liposomes ; *Nanoparticles ; Particle Size ; }, abstract = {AIM: N-acetylcysteine (NAC) is an antioxidant used to moderate liposome and chitosan-induced cell cytotoxicity at their high concentrations.

METHODS: Liposome and chitosan were prepared and characterised. The cytotoxicity effect of liposome with NAC-loaded liposome (liposome-NAC) and chitosan solution with chitosan solution containing NAC (chitosan-NAC) on the A549 cell line was compared.

RESULTS: Particle size, zeta potential, and NAC drug release for liposome were 125.9 ± 8 nm, -34.7 ± 2.1 mV, and 51.1% ± 3%, respectively. Scanning electron microscope (SEM) and transmission electron microscope (TEM) indicated spherical shape of liposome. Encapsulation efficiency of liposome-NAC was 12% ± 0.98%. Particle size and zeta potential for chitosan solution were 361 ± 11.3 nm and 10.8 ± 1.52 mV. Stability storage study indicated good stability of chitosan and liposome. Cell viability of liposome-NAC and chitosan-NAC significantly was higher than liposome and chitosan at all four concentrations.

CONCLUSIONS: NAC has a protective effect against liposome and chitosan-induced cell toxicity.}, } @article {pmid37147040, year = {2023}, author = {Bhatara, VS and Daniel, J and Whitman, C and Vik, T and Bernstein, B and Simkin, DR}, title = {Complementary/Integrative Medicine Treatment and Prevention of Youth Psychosis.}, journal = {Child and adolescent psychiatric clinics of North America}, volume = {32}, number = {2}, pages = {273-296}, doi = {10.1016/j.chc.2022.08.009}, pmid = {37147040}, issn = {1558-0490}, mesh = {Adolescent ; Humans ; *Integrative Medicine ; *Psychotic Disorders/drug therapy/prevention & control ; *Antipsychotic Agents/therapeutic use ; *Fatty Acids, Omega-3/therapeutic use ; }, abstract = {The rationale for CIM treatments in youth psychoses is to optimize treatment by targeting symptoms not resolved by antipsychotics, such as negative symptoms (major drivers of disability). Adjunctive omega-3 fatty acids (ω-3 FA) or N-acetyl cystine (NAC usage for > 24-week) can potentially reduce negative symptoms and improve function. ω-3 FA or exercise may prevent progression to psychosis in youth (in prodromal stage). Weekly 90-minute moderate to vigorous physical activity or aerobic exercise can reduce positive and negative symptoms. Awaiting better research, CIM agents are also recommended because they are devoid of any serious side-effects.}, } @article {pmid37142668, year = {2023}, author = {Cheng, G and Hardy, M and Kalyanaraman, B}, title = {Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {7254}, pmid = {37142668}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Reactive Oxygen Species/pharmacology ; Mitochondria ; *Pancreatic Neoplasms/drug therapy ; }, abstract = {N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. NAC is not readily bioavailable and is used in high concentrations. The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. Here, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito10-NAC) that is functionally similar to NAC was synthesized and studied. Mito10-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito10-NAC is nearly 2000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito10-NAC also inhibited cancer cell proliferation. Mito10-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation. Results suggest that the antiproliferative effects of NAC and Mito10-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group-dependent redox modulatory effects.}, } @article {pmid37140849, year = {2023}, author = {Zhao, Y and Wang, L and Liu, M and Du, A and Qiu, M and Shu, H and Li, L and Kong, X and Sun, W}, title = {ROS inhibition increases KDM6A-mediated NOX2 transcription and promotes macrophages oxidative stress and M1 polarization.}, journal = {Cell stress & chaperones}, volume = {28}, number = {4}, pages = {375-384}, pmid = {37140849}, issn = {1466-1268}, mesh = {Reactive Oxygen Species/metabolism ; *Histones ; *Macrophages ; Oxidative Stress ; Interleukin-6/metabolism ; Histone Demethylases/pharmacology ; }, abstract = {Reactive oxygen species (ROS) play an essential role in macrophage polarization. However, the adverse effects of ROS reduction by influencing epigenetics are often ignored. In this study, lipopolysaccharide (LPS) was used to stimulate macrophages to increase the ROS in cells, and N-acetylcysteine (NAC) was used to reduce ROS. Inflammatory factors such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were used to evaluate the M1 polarization level of macrophages. Chip was used to detect the tri-methylation at lysine 27 of histone H3 (H3K27me3) level at the promoter site. It was found that the decrease of ROS in macrophages would also cause the increase of the H3K27me3 demethylase KDM6A and lead to the reduction of H3K27me3 in the NOX2 promoter, which would increase the transcription level of NOX2 and the production of ROS and ultimately promote the production of inflammatory factors. Knockout of KDM6A can reduce the transcription of NOX2 and the production of ROS of macrophages, thus preventing the M1 polarization of macrophages. The elimination of ROS in macrophages will affect macrophages by increasing KDM6A and making them produce more ROS, thus inducing oxidative stress. In comparison, direct inhibition of KDM6A can reduce ROS production and inhibit macrophage M1 polarization more effectively.}, } @article {pmid37139830, year = {2023}, author = {Maiti, S and Nazmeen, A and Banerjee, A}, title = {Significant impact of redox regulation of estrogen-metabolizing proteins on cellular stress responses.}, journal = {Cell biochemistry and function}, volume = {41}, number = {4}, pages = {461-477}, doi = {10.1002/cbf.3796}, pmid = {37139830}, issn = {1099-0844}, mesh = {Humans ; *Cysteine/metabolism ; *Estrogens ; Estradiol ; Oxidation-Reduction ; Mutagenesis, Site-Directed ; }, abstract = {The ultimate driving force, stress, promotes adaptability/evolution in proliferating organisms, transforming tumorigenic growth. Estradiol (E2) regulates both phenomena. In this study, bioinformatics-tools, site-directed-mutagenesis (human estrogen-sulfotransferase/hSULT1E1), HepG2 cells tested with N-acetyl-cysteine (NAC/thiol-inducer) or buthionine-sulfoxamine (BSO/thiol-depletory) were evaluated for hSULT1E1 (estradiol-sulphating/inactivating) functions. Reciprocal redox regulation of steroid sulfatase (STS, E2-desulfating/activating) results in the Cys-formylglycine transition by the formylglycine-forming enzyme (FGE). The enzyme sequences and structures were examined across the phylogeny. Motif/domain and the catalytic conserve sequences and protein-surface-topography (CASTp) were investigated. The E2 binding to SULT1E1 suggests that the conserved-catalytic-domain in this enzyme has critical Cysteine 83 at position. This is strongly supported by site-directed mutagenesis/HepG2-cell research. Molecular-docking and superimposition studies of E2 with the SULT1E1 of representative species and to STS reinforce this hypothesis. SULT1E1-STS are reciprocally activated in response to the cellular-redox-environment by the critical Cys of these two enzymes. The importance of E2 in organism/species proliferation and tissue tumorigenesis is highlighted.}, } @article {pmid37137784, year = {2023}, author = {Beyler, O and Demir, C}, title = {Use of n-acetylcysteine therapy in patients with relapsed refractory thrombotic thrombocytopenic purpura.}, journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis}, volume = {62}, number = {4}, pages = {103713}, doi = {10.1016/j.transci.2023.103713}, pmid = {37137784}, issn = {1473-0502}, mesh = {Humans ; *Purpura, Thrombotic Thrombocytopenic/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; von Willebrand Factor/therapeutic use ; Plasma Exchange ; *Anemia, Hemolytic ; *Thrombosis/drug therapy ; ADAMTS13 Protein/therapeutic use ; }, abstract = {There is limited data on the use of NAC in the literature. We would like to present the satisfactory results we obtained in our resistant and relapsed patients as a case series.Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by ADAMTS13 (a disintegrin with thrombospondin type 1 motif and metalloprotease activity, member13) deficiency. Von Willebrand factor (vWF) initiates platelet aggregation and thus thrombus formation. The multimers of vWF are cleaved by ADAMTS13. Because of the decreased activity of ADAMTS13, ultra-large multimers accumulate and end-organ damage occurs. TTP is characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and organ ischemia resulting from vascular occlusion caused by thrombi. Plasma exchange therapy (PEX) remains the mainstay of TTP therapy. Patients who do not respond to PEX and corticosteroids require additional treatments such as rituximab and caplacizumab. NAC reduces disulfide bonds in mucin polymers through its free sulfhydryl group. Thus, the size and viscosity of the mucins are reduced. VWF is structurally similar to mucin. Based on this similarity, Chen and colleagues showed that NAC can reduce the size and reactivity of ultralarge multimers of vWF, such as ADAMTS13. Currently, there is not much information to suggest that NAC has any clinical value in the treatment of TTP. In this case series of 4 refractory patients, we would like to present the responses we obtained with the addition of NAC therapy. NAC can be added to PEX and glucocorticoid therapy as supportive therapy, especially in unresponsive patients.}, } @article {pmid37134194, year = {2023}, author = {Orgel, E and Knight, KR and Chi, YY and Malvar, J and Rushing, T and Mena, V and Eisenberg, LS and Rassekh, SR and Ross, CJD and Scott, EN and Neely, M and Neuwelt, EA and Muldoon, LL and Freyer, DR}, title = {Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {29}, number = {13}, pages = {2410-2418}, pmid = {37134194}, issn = {1557-3265}, support = {K23 DC014291/DC/NIDCD NIH HHS/United States ; UL1 TR000130/TR/NCATS NIH HHS/United States ; UL1 TR001855/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Humans ; Child ; Cisplatin/adverse effects ; Acetylcysteine/therapeutic use/adverse effects ; *Hearing Loss/chemically induced/prevention & control ; *Neoplasms/drug therapy/chemically induced ; Administration, Intravenous ; }, abstract = {PURPOSE: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL.

PATIENTS AND METHODS: In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations.

RESULTS: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021-0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011-0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection.

CONCLUSIONS: NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.}, } @article {pmid37134105, year = {2023}, author = {Shim, JY and Chung, JO and Jung, D and Kang, PS and Park, SY and Kendi, AT and Lowe, VJ and Lee, S}, title = {Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells.}, journal = {PloS one}, volume = {18}, number = {5}, pages = {e0281496}, pmid = {37134105}, issn = {1932-6203}, mesh = {Humans ; Mitophagy ; Reactive Oxygen Species/metabolism ; Streptozocin/pharmacology ; *Insulin-Secreting Cells/metabolism ; Protein Kinases/metabolism ; *Diabetes Mellitus/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Tumor Suppressor Proteins/metabolism ; }, abstract = {Diabetes mellitus (DM) is one of the most researched metabolic diseases worldwide. It leads to extensive complications such as cardiovascular disease, nephropathy, retinopathy, and peripheral and central nervous system through an inability to produce or respond to insulin. Although oxidative stress-mediated mitophagy has been reported to play an important role in the pathogenesis of DM, specific studies are still lacking as well as remain highly controversial. Here, we found that Parkin-mediated mitophagy in pancreatic β cells under streptozotocin (STZ)-diabetic stress was induced by Polo-like kinase 3 (Plk3) and inhibited by the transcription factor Forkhead Box O3A (FOXO3A). STZ stress induces mitochondrial recruitment of Parkin through Plk3-mediated mitochondrial reactive oxygen species (ROS) generation, which causes pancreatic cell damage. Conversely, FOXO3A acts as negative feedback to prevent diabetic stress by inhibiting Plk3. Meanwhile, antioxidants including N-acetylcysteine (NAC) and natural COA water scientifically block these mitochondrial ROS and mitochondrial recruitment of Parkin by inhibiting Plk3. Through a 3D organoid ex vivo model, we confirmed that not only ROS inhibitors but also mitophagy inhibitory factors such as 3-MA or Parkin deletion can compensate for pancreatic cell growth and insulin secretion under STZ diabetic stress. These findings suggest that the Plk3-mtROS-PINK1-Parkin axis is a novel mitophagy process that inhibits pancreatic β-cell growth and insulin secretion and FOXO3A and antioxidants may provide new alternatives for effective diabetes treatment strategies in the future.}, } @article {pmid37132544, year = {2023}, author = {Wilson, MM and Danielian, PS and Salus, G and Ferretti, R and Whittaker, CA and Lees, JA}, title = {BMI1 is required for melanocyte stem cell maintenance and hair pigmentation.}, journal = {Pigment cell & melanoma research}, volume = {36}, number = {5}, pages = {399-406}, pmid = {37132544}, issn = {1755-148X}, support = {P30 CA014051/CA/NCI NIH HHS/United States ; P01 CA042063/CA/NCI NIH HHS/United States ; }, mesh = {Mice ; Animals ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; *Melanoma/metabolism ; Proto-Oncogene Proteins ; *Skin Neoplasms/metabolism ; Stem Cells/metabolism ; Polycomb Repressive Complex 1/genetics/metabolism ; Pigmentation ; Melanocytes/metabolism ; Hair/metabolism ; }, abstract = {The epigenetic repressor BMI1 plays an integral role in promoting the self-renewal and proliferation of many adult stem cell populations, and also tumor types, primarily through silencing the Cdkn2a locus, which encodes the tumor suppressors p16[Ink4a] and p19[Arf] . However, in cutaneous melanoma, BMI1 drives epithelial-mesenchymal transition programs, and thus metastasis, while having little impact on proliferation or primary tumor growth. This raised questions about the requirement and role for BMI1 in melanocyte stem cell (McSC) biology. Here, we demonstrate that murine melanocyte-specific Bmi1 deletion causes premature hair greying and gradual loss of melanocyte lineage cells. Depilation enhances this hair greying defect, accelerating depletion of McSCs in early hair cycles, suggesting that BMI1 acts to protect McSCs against stress. RNA-seq of McSCs, harvested before onset of detectable phenotypic defects, revealed that Bmi1 deletion derepresses p16[Ink4a] and p19[Arf] , as observed in many other stem cell contexts. Additionally, BMI1 loss downregulated the glutathione S-transferase enzymes, Gsta1 and Gsta2, which can suppress oxidative stress. Accordingly, treatment with the antioxidant N-acetyl cysteine (NAC) partially rescued melanocyte expansion. Together, our data establish a critical function for BMI1 in McSC maintenance that reflects a partial role for suppression of oxidative stress, and likely transcriptional repression of Cdkn2a.}, } @article {pmid37131727, year = {2023}, author = {Everton, E and Del Rio-Moreno, M and Villacorta-Martin, C and Singh Bawa, P and Lindstrom-Vautrin, J and Muramatsu, H and Rizvi, F and Smith, AR and Tam, Y and Pardi, N and Kineman, R and Waxman, DJ and Gouon-Evans, V}, title = {Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.04.17.537197}, pmid = {37131727}, issn = {2692-8205}, support = {I01 BX004448/BX/BLRD VA/United States ; R01 DK116878/DK/NIDDK NIH HHS/United States ; TL1 TR001410/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity.

APPROACH AND RESULTS: Our results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe nonintegrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice.

CONCLUSIONS: Our study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.}, } @article {pmid37123961, year = {2023}, author = {Mitra, JK and Hansda, U and Bandyopadhyay, D and Sarkar, S and Sahoo, J}, title = {The role of a combination of N-acetylcysteine and magnesium sulfate as adjuvants to standard therapy in acute organophosphate poisoning: A randomized controlled trial.}, journal = {Heliyon}, volume = {9}, number = {4}, pages = {e15376}, pmid = {37123961}, issn = {2405-8440}, abstract = {BACKGROUND: Mortality in acute organophosphate (OP) poisoning remains high despite current standard therapy with atropine and oximes. Due to dose-limiting side effects of atropine, novel therapies are targeting other putative mechanisms of injury, including oxidative damage, to reduce atropine dosage.

OBJECTIVES: N-acetylcysteine (NAC) and magnesium sulfate (MgSO4) have different mechanisms of actions and should act synergistically in OP poisoning. In this study, we wanted to evaluate whether this novel combination, used as an adjuvant to standard care, could improve clinical outcomes.

METHODS: The study was conducted in the Emergency Department and ICU of AIIMS Bhubaneswar (a tertiary care center and government teaching institute) between July 2019 and July 2021. Eighty-eight adult patients with history and clinical features of acute OP poisoning were randomly allocated (1:1) into two groups. The Study group received 600 mg NAC via nasogastric tube thrice daily for 3 days plus a single dose of 4 g Inj. MgSO4 IV on first day and the Control group received suitably matched placebo (double-blinding) - in addition to standard care in both the groups. The primary outcome measure was to compare the total dose of Inj. Atropine required (cumulative over the entire treatment duration) between the control group and the study group receiving NAC and MgSO4. The secondary outcome measures were lengths of ICU and hospital stays, need and duration of mechanical ventilation, the differences in BuChE activity, oxidative stress biomarkers - MDA and GSH levels, the incidences of adverse effects including delayed sequalae like intermediate syndrome and OPIDN, and comparison of mortality between the two groups.

RESULTS: Data from 43 patients in Control and 42 patients in Study group was finally analyzed. The baseline parameters were comparable. Total atropine requirements were lower in the Study group [175.33 ± 81.25 mg (150.01-200.65)] compared to the Control [210.63 ± 102.29 mg (179.15-242.11)] [Mean ± SD (95% CI)], but was not statistically significant. No significant differences in any of the other clinical or biochemical parameters were noted.

CONCLUSION: The N-acetylcysteine and MgSO4 combination as adjuvants failed to significantly reduce atropine requirements, ICU/hospital stay, mechanical ventilatory requirements, mortality and did not offer protection against oxidative damage.}, } @article {pmid37122089, year = {2023}, author = {Huang, S and Zhang, L and Luo, J and Wu, D and Ma, K and Chen, Y and Ma, S and Feng, L and Li, F and Liu, D and Deng, J and Tan, C}, title = {Cysteamine and N-Acetyl-cysteine Alleviate Placental Oxidative Stress and Barrier Function Damage Induced by Deoxynivalenol.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {18}, pages = {6846-6858}, doi = {10.1021/acs.jafc.3c00399}, pmid = {37122089}, issn = {1520-5118}, mesh = {Pregnancy ; Animals ; Female ; Swine ; *Placenta/metabolism ; *Cysteamine/metabolism/pharmacology ; Antioxidants/pharmacology/metabolism ; Acetylcysteine/pharmacology/metabolism ; Oxidative Stress ; }, abstract = {Sows are highly sensitive to deoxynivalenol (DON) and susceptible to reproductive toxicity caused by oxidative stress, but the potential mechanisms and effective interventions remain unclear. Here, we investigated the role of two antioxidants (cysteamine and N-acetyl-cysteine) in regulating the reproductive performance, redox status, and placental barrier function of sows and their potential mechanisms under DON exposure. Maternal dietary supply of antioxidants from day 85 of gestation to parturition reduced the incidence of stillbirths and low-birth-weight piglets under DON exposure. Moreover, the alleviation of DON-induced reproductive toxicity by dietary antioxidants was associated with the alleviation of placental oxidative stress, the enhancement of the placental barrier, and the vascular function of sows. Furthermore, in vivo and in vitro vascularized placental barrier modeling further demonstrated that antioxidants could reverse both DON transport across the placenta and DON-induced increase of placental barrier permeability. The molecular mechanism of antioxidant resistance to DON toxicity may be related to the signal transducer and activator of the transcription-3-occludin/zonula occludens-1 signaling pathway. Collectively, these results demonstrate the potential of antioxidants to protect the mother from DON-induced reproductive toxicity by alleviating placental oxidative stress and enhancing the placental barrier.}, } @article {pmid37119245, year = {2023}, author = {Wong, KK and Kua, KP and Ooi, KS and Cheah, FC}, title = {The effects of N-acetylcysteine on lung alveolar epithelial cells infected with respiratory syncytial virus.}, journal = {The Malaysian journal of pathology}, volume = {45}, number = {1}, pages = {43-50}, pmid = {37119245}, issn = {0126-8635}, mesh = {Child ; Infant ; Humans ; Child, Preschool ; Acetylcysteine/pharmacology/metabolism ; Alveolar Epithelial Cells/metabolism ; Epithelial Cells/metabolism ; *Respiratory Syncytial Virus, Human/metabolism ; Lung ; *Respiratory Syncytial Virus Infections/drug therapy/metabolism ; }, abstract = {INTRODUCTION: Respiratory syncytial virus (RSV) is one of the most common causes of acute lower respiratory infection in infants and young children. Mucolytic agents, such as acetylcysteine and carbocysteine have reported benefits in alleviating acute upper or lower respiratory infections. Among these, N-acetylcysteine (NAC) has cyto-protective effects when cells are infected with the RSV.

MATERIALS AND METHODS: Our study investigated primarily the dose-dependent effects of NAC on respiratory alveolar epithelial (A549) cells when co-cultured with RSV in vitro. Three different concentrations of NAC were used, 0.1 mM, 1 mM, and 10 mM. The cytotoxicity of RSV-infected cells was measured by lactate dehydrogenase and antiviral activity of NAC on cell cultures was evaluated by immunofluorescence.

RESULTS: Pre-treatment with the highest dose, 10 mM NAC, resulted in features of cell injury even without RSV infection. The proportion of cells infected by RSV and RSV-induced cell death decreased by more than 3-fold when cells were pre-treated with 1 mM NAC. Pre-treatment at the lowest dose, 0.1 mM, did not show any significant changes.

CONCLUSION: A moderate dose of NAC (1 mM) appeared protective of RSV infection to lung alveolar epithelial cells. However, a higher dose of NAC (10 mM) may be relatively toxic and injurious to these cells.}, } @article {pmid37119225, year = {2023}, author = {Russell, SE and Skvarc, DR and Mohebbi, M and Camfield, D and Byrne, LK and Turner, A and Ashton, MM and Berk, M and Dodd, S and Malhi, GS and Cotton, SM and Bush, AI and Dean, OM}, title = {The Impact of N-acetylcysteine on Major Depression: Qualitative Observation and Mixed Methods Analysis of Participant Change during a 12-week Randomised Controlled Trial.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {21}, number = {2}, pages = {320-331}, pmid = {37119225}, issn = {1738-1088}, abstract = {OBJECTIVE: N-acetylcysteine (NAC) is a novel therapeutic agent with multiple mechanisms of action in the central nervous system and a favourable side effect profile. Clinical evidence indicates that adjunctive NAC may reduce the severity of depressive symptoms in individuals with major depressive disorder (MDD).

METHODS: A 12-week randomised controlled trial of 2,000 mg/day adjunctive NAC for MDD found no significant improvement at the primary endpoint (week 12) but did see improvements at the post-discontinuation interview (week 16). Within the context of patient-centered treatment, mixed-methods qualitative analysis was also included to explore factors that may determine individual responses to adjunctive NAC treatment. These data were drawn, under blinded conditions, from clinician notes recorded in the case report form. Using the DSM-5 symptom profile for MDD as the initial framework, themes were developed and explored. Frequencies were compared between placebo and NAC groups.

RESULTS: Per protocol analysis of individual themes across the six interviews revealed group differences in favour of NAC for overall depressive affect, optimism, relationships and reduced functional impairment.

CONCLUSION: This study provides further evidence for the utility of the mixed methods approach complimenting the primary findings using traditional quantitative analyses, as well as being able to capture additional, often more subtle, evidence of individual symptom-level change that reflects improvement in functional abilities in response to NAC supplementation. The use of mixed methods to explore outcomes from psychiatric studies should be considered in future to work towards improved patient-centred care and both confirm quantitative findings and generate novel hypotheses.}, } @article {pmid37118950, year = {2023}, author = {Kim, KH and Park, MJ and Park, NC and Park, HJ}, title = {Effect of N-acetyl-L-cysteine on Testicular Tissue in Busulfan-Induced Dysfunction in the Male Reproductive System.}, journal = {The world journal of men's health}, volume = {41}, number = {4}, pages = {882-891}, pmid = {37118950}, issn = {2287-4208}, support = {20200007/PNUH/Pusan National University Hospital/Korea ; }, abstract = {PURPOSE: This study aimed to evaluate the protective effect of N-acetyl-L-cysteine (NAC) as an antioxidant on busulfan-induced testicular dysfunction in mice and elucidate its possible mechanism of action.

MATERIALS AND METHODS: Thirty-two C57BL/6 male mice were randomly divided into four groups (n=8/group) as follows: (1) control group (oral administration of saline [0.1 mL daily] for 35 days); (2) NAC group (oral administration of NAC [10 mg/kg daily] for 35 days); (3) busulfan group (double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg); and (4) busulfan+NAC group (after double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg, NAC administration [10 mg/kg daily] for 35 days). The testes were removed, weighed, and subjected to sperm parameter analysis and morphology assessment. Reproductive hormone, serum/testicular reactive oxygen species (ROS) level, oxidative stress and antioxidant markers were evaluated. The testicular expression of Nrf2 and HO-1 was examined using RT-qPCR.

RESULTS: Busulfan treatment significantly decreased testicular weight, sperm count, and serum testosterone levels. Atrophy and degeneration of germinal epithelium were observed in the busulfan group. NAC administration after busulfan treatment partially attenuated the deterioration of testis weight, sperm quality, serum hormones, histomorphometric changes, and oxidative and antioxidative status. NAC treatment resulted in a considerable improvement in Nrf2 and HO-1 mRNA expression levels.

CONCLUSIONS: This study provides compelling evidence that NAC as a potent antioxidant has significant protective effects against busulfan-induced male reproductive impairment possibly through modification of the Nrf2/HO-1 signaling pathway.}, } @article {pmid37116249, year = {2023}, author = {Bilister Egilmez, C and Azak Pazarlar, B and Erdogan, MA and Erbas, O}, title = {N-acetyl cysteine: A new look at its effect on PTZ-induced convulsions.}, journal = {Epilepsy research}, volume = {193}, number = {}, pages = {107144}, doi = {10.1016/j.eplepsyres.2023.107144}, pmid = {37116249}, issn = {1872-6844}, mesh = {Rats ; Animals ; Pentylenetetrazole/toxicity ; Rats, Sprague-Dawley ; *Myoclonus/drug therapy ; Acetylcysteine/adverse effects ; Electroencephalography ; *Epilepsy/drug therapy ; Seizures/chemically induced/drug therapy ; Superoxide Dismutase ; Anticonvulsants/adverse effects ; Disease Models, Animal ; }, abstract = {INTRODUCTION/AIM: Epilepsy is widely investigated as a common neurological disease requiring pharmacologically effective agents. N-acetyl cysteine (NAC), has become a remarkable molecule with its role in both antioxidant and glutaminergic modulation. There are many points and processes waiting to be revealed regarding the role of NAC in epilepsy.

MATERIALS AND METHODS: Pentylenetetrazole (PTZ) was administered to induce seizures in a total number of 48 Sprague-Dawley rats. 35 mg/kg PTZ dose as a sub-convulsive dose was administered to 24 animals to monitor EEG changes, while 70 mg/kg PTZ dose which was a convulsive dose was administered to 24 animals to determine seizure-related behavioral changes with the Racine's scale. 30 min before the seizure-induced procedure, NAC was administered at doses of 300 and 600 mg/kg as pretreatment to investigate anti-seizure and anti-oxidative effects. The spike percentage, the stage of convulsion, and the onset time of the first myoclonic jerk were evaluated to determine the anti-seizure effect. Furthermore, its effect on oxidative stress was determined by measuring both malondialdehyde (MDA) level and superoxide dismutase (SOD) enzyme activity.

RESULTS: There was a dose-dependent reduction in the seizure stage and prolonged onset time of the first myoclonic jerk in rats with NAC pretreatment. EEG recordings resulted in a dose-dependent decrease in spike percentages. Moreover, the same dose-dependent changes were observed in oxidative stress biomarkers, both 300 mg/kg NAC and 600 mg/kg decreased MDA levels and ameliorated SOD activity.

CONCLUSION: We can report that 300 mg/kg and 600 mg/kg doses of NAC are promising with their reducing effect on convulsions and have a beneficial effect by preventing oxidative stress. In addition, NAC has been also determined that this effect is dose-dependent. Detailed and comparative studies are needed on the convulsion-reducing effect of NAC in epilepsy.}, } @article {pmid37113636, year = {2023}, author = {Salajegheh, F and Shafieipour, S and Najminejad, Z and Pourzand, P and Nakhaie, M and Jahangiri, S and Sarmadian, R and Gilani, A and Rukerd, MRZ}, title = {HAV-induced acalculous cholecystitis: A case report and literature review.}, journal = {Clinical case reports}, volume = {11}, number = {4}, pages = {e7254}, pmid = {37113636}, issn = {2050-0904}, abstract = {Hepatitis A virus (HAV) has some life-threatening extrahepatic complications, such as acute acalculous cholecystitis (AAC). We present HAV-induced AAC in a young female, based on clinical, laboratory, and imaging findings, and conduct a literature review. The patient became irritable, which progressed to lethargy, as well as a significant decline in liver function, indicating acute liver failure (ALF). She was immediately managed in the intensive care unit with close airway and hemodynamic monitoring after being diagnosed with ALF (ICU). The patient's condition was improving, despite only close monitoring and supportive treatment with ursodeoxycholic acid (UDCA) and N-acetyl cysteine (NAC).}, } @article {pmid37111348, year = {2023}, author = {Soto, ME and Manzano-Pech, L and Palacios-Chavarría, A and Valdez-Vázquez, RR and Guarner-Lans, V and Pérez-Torres, I}, title = {N-Acetyl Cysteine Restores the Diminished Activity of the Antioxidant Enzymatic System Caused by SARS-CoV-2 Infection: Preliminary Findings.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {4}, pages = {}, pmid = {37111348}, issn = {1424-8247}, support = {312167//Consejo Nacional de Ciencia y Tecnología (CONACYT) México/ ; }, abstract = {SARS-CoV-2 infects type II pneumocytes and disrupts redox homeostasis by overproducing reactive oxygen species (ROS). N-acetyl cysteine (NAC) is a precursor of the synthesis of glutathione (GSH) and it restores the loss of redox homeostasis associated to viral infections. The aim of the study is to evaluate the effect of the treatment with NAC on the enzymatic antioxidant system in serum from patients infected by SARS-CoV-2. We evaluated the enzymatic activities of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), -S-transferase (GST), and reductase (GR) by spectrophotometry and the concentrations of the glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2[-]), and lipid peroxidation (LPO) in serum. The activity of the extracellular super oxide dismutase (ecSOD) was determined by native polyacrylamide gels, and 3-nitrotyrosine (3-NT) was measured by ELISA. A decrease in the activities of the ecSOD, TrxR, GPx, GST GR, (p = 0 ≤ 0.1), and the GSH, TAC, thiols, and NO2[-] (p ≤ 0.001) concentrations and an increase in LPO and 3-NT (p = 0.001) concentrations were found in COVID-19 patients vs. healthy subjects. The treatment with NAC as an adjuvant therapy may contribute to a reduction in the OS associated to the infection by SARS-CoV-2 through the generation of GSH. GSH promotes the metabolic pathways that depend on it, thus contributing to an increase in TAC and to restore redox homeostasis.}, } @article {pmid37109533, year = {2023}, author = {Amante, C and De Soricellis, C and Luccheo, G and Luccheo, L and Russo, P and Aquino, RP and Del Gaudio, P}, title = {Flogomicina: A Natural Antioxidant Mixture as an Alternative Strategy to Reduce Biofilm Formation.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {4}, pages = {}, pmid = {37109533}, issn = {2075-1729}, abstract = {The National Institute of Health has reported that approximately 80% of chronic infections are associated with biofilms, which are indicated as one of the main reasons for bacteria's resistance to antimicrobial agents. Several studies have revealed the role of N-acetylcysteine (NAC), in reducing biofilm formation induced by different microorganisms. A novel mixture made up of NAC and different natural ingredients (bromelain, ascorbic acid, Ribes nigrum, resveratrol, and pelargonium) has been developed in order to obtain a pool of antioxidants as an alternative strategy for biofilm reduction. The study has demonstrated that the mixture is able to significantly enhance NAC activity against different Gram-positive and Gram-negative bacteria. It has shown an increase in NAC permeation in vitro through an artificial fluid, moving from 2.5 to 8 μg/cm[2] after 30 min and from 4.4 to 21.6 μg/cm[2] after 180 min, and exhibiting a strongly fibrinolytic activity compared to the single components of the mixture. Moreover, this novel mixture has exhibited an antibiofilm activity against S aureus and the ability to reduce S. aureus growth by more than 20% in a time-killing assay, while on E. coli, and P. mirabilis, the growth was reduced by more than 80% compared to NAC. The flogomicina mixture has also been proven capable of reducing bacterial adhesion to abiotic surfaces of E.coli, by more than 11% concerning only the NAC. In combination with amoxicillin, it has been shown to significantly increase the drug's effectiveness after 14 days, offering a safe and natural way to reduce the daily dosage of antibiotics in prolonged therapies and consequently, reduce antibiotic resistance.}, } @article {pmid37108758, year = {2023}, author = {Zadrożniak, M and Szymański, M and Łuszczki, JJ}, title = {N-Acetyl-L-cysteine Affects Ototoxicity Evoked by Amikacin and Furosemide Either Alone or in Combination in a Mouse Model of Hearing Threshold Decrease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108758}, issn = {1422-0067}, support = {474/CU/CSP VA/United States ; }, mesh = {Mice ; Animals ; Amikacin/toxicity ; Furosemide/adverse effects ; Acetylcysteine/adverse effects ; *Ototoxicity ; *Hearing Loss/chemically induced/drug therapy/prevention & control ; Anti-Bacterial Agents/adverse effects ; Hearing ; Aminoglycosides ; *Deafness ; Auditory Threshold ; }, abstract = {Drug-induced ototoxicity resulting from therapy with aminoglycoside antibiotics and loop diuretics is one of the main well-known causes of hearing loss in patients. Unfortunately, no specific protection and prevention from hearing loss are recommended for these patients. This study aimed at evaluating the ototoxic effects produced by mixtures of amikacin (AMI, an aminoglycoside antibiotic) and furosemide (FUR, a loop diuretic) in the mouse model as the hearing threshold decreased by 20% and 50% using auditory brainstem responses (ABRs). Ototoxicity was produced by the combinations of a constant dose of AMI (500 mg/kg; i.p.) on FUR-induced hearing threshold decreases, and a fixed dose of FUR (30 mg/kg; i.p.) on AMI-induced hearing threshold decreases, which were determined in two sets of experiments. Additionally, the effects of N-acetyl-L-cysteine (NAC; 500 mg/kg; i.p.) on the hearing threshold decrease of 20% and 50% were determined by means of an isobolographic transformation of interactions to detect the otoprotective action of NAC in mice. The results indicate that the influence of a constant dose of AMI on FUR-induced hearing threshold decreases was more ototoxic in experimental mice than a fixed dose of FUR on AMI-induced ototoxicity. Moreover, NAC reversed the AMI-induced, but not FUR-induced, hearing threshold decreases in this mouse model of hearing loss. NAC could be considered an otoprotectant in the prevention of hearing loss in patients receiving AMI alone and in combination with FUR.}, } @article {pmid37108481, year = {2023}, author = {Brivio, P and Gallo, MT and Gruca, P and Lason, M and Litwa, E and Fumagalli, F and Papp, M and Calabrese, F}, title = {Chronic N-Acetyl-Cysteine Treatment Enhances the Expression of the Immediate Early Gene Nr4a1 in Response to an Acute Challenge in Male Rats: Comparison with the Antidepressant Venlafaxine.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108481}, issn = {1422-0067}, mesh = {Animals ; Male ; Rats ; *Acetylcysteine/pharmacology/therapeutic use ; Antidepressive Agents/therapeutic use ; *Genes, Immediate-Early ; Rats, Wistar ; Venlafaxine Hydrochloride/pharmacology/therapeutic use ; }, abstract = {Despite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1.}, } @article {pmid37108119, year = {2023}, author = {Chadwick, W and Maudsley, S and Hull, W and Havolli, E and Boshoff, E and Hill, MDW and Goetghebeur, PJD and Harrison, DC and Nizami, S and Bedford, DC and Coope, G and Real, K and Thiemermann, C and Maycox, P and Carlton, M and Cole, SL}, title = {The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108119}, issn = {1422-0067}, mesh = {Mice ; Humans ; Animals ; *Alzheimer Disease/genetics/pathology ; Amyloid beta-Peptides/genetics ; Memory ; *Cognition Disorders ; Animals, Genetically Modified ; Disease Models, Animal ; }, abstract = {Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.}, } @article {pmid37107344, year = {2023}, author = {Romero-Miguel, D and Casquero-Veiga, M and Fernández, J and Lamanna-Rama, N and Gómez-Rangel, V and Gálvez-Robleño, C and Santa-Marta, C and Villar, CJ and Lombó, F and Abalo, R and Desco, M and Soto-Montenegro, ML}, title = {Maternal Supplementation with N-Acetylcysteine Modulates the Microbiota-Gut-Brain Axis in Offspring of the Poly I:C Rat Model of Schizophrenia.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107344}, issn = {2076-3921}, support = {project number PI17/01766, and grant number BA21/00030//Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, co-financed by the European Regional Development Fund (ERDF), "A way to make Europe"/ ; project PID2021-128862OB-I00//MCIN /AEI /10.13039/501100011033 / FEDER, UE/ ; project number CB07/09/0031//CIBER de Salud Mental - Instituto de Salud Carlos III/ ; project numbers 2017/085, 2022/008917//Delegación del Gobierno para el Plan Nacional sobre Drogas/ ; 2016/01//Fundación Alicia Koplowitz/ ; grant, PEJD-2018-PRE/BMD-7899//Consejería de Educación e investigación, Comunidad de Madrid, co-funded by the European Social Fund "Investing in your future"/ ; "Programa Intramural de Impulso a la I+D+I 2019"//Instituto de investigación Sanitaria Gregorio Marañón/ ; PT20/00044//Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III/ ; x//The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505)/ ; Contrato Intramural Postdoctoral//FINBA/ ; SV-PA-21-AYUD/2021/51347//Ayudas para grupos de investigación de organismos del Principado de Asturias/ ; }, abstract = {The microbiota-gut-brain axis is a complex interconnected system altered in schizophrenia. The antioxidant N-acetylcysteine (NAC) has been proposed as an adjunctive therapy to antipsychotics in clinical trials, but its role in the microbiota-gut-brain axis has not been sufficiently explored. We aimed to describe the effect of NAC administration during pregnancy on the gut-brain axis in the offspring from the maternal immune stimulation (MIS) animal model of schizophrenia. Pregnant Wistar rats were treated with PolyI:C/Saline. Six groups of animals were studied according to the study factors: phenotype (Saline, MIS) and treatment (no NAC, NAC 7 days, NAC 21 days). Offspring were subjected to the novel object recognition test and were scanned using MRI. Caecum contents were used for metagenomics 16S rRNA sequencing. NAC treatment prevented hippocampal volume reduction and long-term memory deficits in MIS-offspring. In addition, MIS-animals showed lower bacterial richness, which was prevented by NAC. Moreover, NAC7/NAC21 treatments resulted in a reduction of proinflammatory taxons in MIS-animals and an increase in taxa known to produce anti-inflammatory metabolites. Early approaches, like this one, with anti-inflammatory/anti-oxidative compounds, especially in neurodevelopmental disorders with an inflammatory/oxidative basis, may be useful in modulating bacterial microbiota, hippocampal size, as well as hippocampal-based memory impairments.}, } @article {pmid37107324, year = {2023}, author = {Zhou, Z and Qi, J and Wu, Y and Li, C and Bao, W and Lin, X and Zhu, A}, title = {Nuciferine Effectively Protects Mice against Acetaminophen-Induced Liver Injury.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107324}, issn = {2076-3921}, support = {82104520//National Natural Science Foundation of China/ ; 82200663//National Natural Science Foundation of China/ ; 2021J05045//Natural Science Foundation of Fujian Province/ ; 2022J01199//Natural Science Foundation of Fujian Province/ ; }, abstract = {Acetaminophen (APAP) overdose still poses a major clinical challenge and is a leading cause of acute liver injury (ALI). N-acetylcysteine (NAC) is the only approved antidote to treat APAP toxicity while NAC therapy can trigger side effects including severe vomiting and even shock. Thus, new insights in developing novel therapeutic drugs may pave the way for better treatment of APAP poisoning. Previous research has reported that nuciferine (Nuci) possesses anti-inflammatory and antioxidant properties. Therefore, the objective of this study was proposed to investigate the hepatoprotective effects of Nuci and explore its underlying mechanisms. Mice were intraperitoneally (i.p.) administered with APAP (300 mg/kg) and subsequently injected with Nuci (25, 50, and 100 mg/kg, i.p.) at 30 min after APAP overdose. Then, all mice were sacrificed at 12 h after APAP challenge for further analysis. Nuci-treated mice did not show any side effects and our results revealed that treating Nuci significantly attenuated APAP-induced ALI, as confirmed by histopathological examinations, biochemical analysis, and diminished hepatic oxidative stress and inflammation. The in silico prediction and mRNA-sequencing analysis were performed to explore the underlying mechanisms of Nuci. GO and KEGG enrichment of the predicted target proteins of Nuci includes reactive oxygen species, drug metabolism of cytochrome P450 (CYP450) enzymes, and autophagy. Furthermore, the mRNA-sequencing analyses indicated that Nuci can regulate glutathione metabolic processes and anti-inflammatory responses. Consistently, we found that Nuci increased the hepatic glutathione restoration but decreased APAP protein adducts in damaged livers. Western blot analysis further confirmed that Nuci effectively promoted hepatic autophagy in APAP-treated mice. However, Nuci could not affect the expression levels of the main CYP450 enzymes (CYP1A2, CYP2E1, and CYP3A11). These results demonstrated that Nuci may be a potential therapeutic drug for APAP-induced ALI via amelioration of the inflammatory response and oxidative stress, regulation of APAP metabolism, and activation of autophagy.}, } @article {pmid37107239, year = {2023}, author = {Boonnate, P and Kariya, R and Okada, S}, title = {Shikonin Induces ROS-Dependent Apoptosis Via Mitochondria Depolarization and ER Stress in Adult T Cell Leukemia/Lymphoma.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107239}, issn = {2076-3921}, support = {22K08482//Grants-in-Aid for Science Research from the Ministry of Education, Science, Sports, and Culture of Japan/ ; }, abstract = {Adult T cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy that develops in some elderly human T-cell leukemia virus (HTVL-1) carriers. ATLL has a poor prognosis despite conventional and targeted therapies, and a new safe and efficient therapy is required. Here, we examined the anti-ATLL effect of Shikonin (SHK), a naphthoquinone derivative that has shown several anti-cancer activities. SHK induced apoptosis of ATLL cells accompanied by generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and induction of endoplasmic reticulum (ER) stress. Treatment with a ROS scavenger, N-acetylcysteine (NAC), blocked both loss of mitochondrial membrane potential and ER stress, and prevented apoptosis of ATLL cells, indicating that ROS is an upstream trigger of SHK-induced apoptosis of ATLL cells through disruption of the mitochondrial membrane potential and ER stress. In an ATLL xenografted mouse model, SHK treatment suppressed tumor growth without significant adverse effects. These results suggest that SHK could be a potent anti-reagent against ATLL.}, } @article {pmid37107211, year = {2023}, author = {Dimitriadis, F and Borgmann, H and Struck, JP and Salem, J and Kuru, TH}, title = {Antioxidant Supplementation on Male Fertility-A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107211}, issn = {2076-3921}, abstract = {UNLABELLED: Our aim was to review the current literature regarding the effect of antioxidant supplementation (AS) on male fertility parameters, as AS is commonly used to treat male infertility due to the availability and affordability of antioxidants in many parts of the world.

MATERIALS AND METHODS: PubMed, Medline, and Cochrane electronic bibliographies were searched using the modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate studies on the benefit of antioxidant therapy on infertile men. Results were analyzed regarding the following aspects: (a) ingredient and dose; (b) potential mechanism of action and rationale for use; and (c) effect on various reported outcomes.

RESULTS: Thus, 29 studies found a substantial positive effect of AS on outcomes of assisted reproductive therapy (ART), WHO semen parameters, and live-birth rate. Carnitines, Vitamin E and C, N-acetyl cysteine, coenzyme Q10, selenium, zinc, folic acid, and lycopene were beneficial ingredients. Nevertheless, some studies did not show a substantial change in one or more factors.

CONCLUSION: AS seems to have a positive effect on male fertility. Environmental factors may play an increasing role in fertility. Further studies are needed to determine the optimal AS combination and the influence of environmental factors.}, } @article {pmid37102780, year = {2023}, author = {Pillai, K and Mekkawy, AH and Akhter, J and Morris, DL}, title = {Effect of Nebulized BromAc on Rheology of Artificial Sputum: Relevance to Muco-Obstructive Respiratory Diseases.}, journal = {Advances in respiratory medicine}, volume = {91}, number = {2}, pages = {146-163}, pmid = {37102780}, issn = {2543-6031}, support = {N.A//Mucpahrm pty ltd/ ; }, mesh = {Humans ; Acetylcysteine/therapeutic use/pharmacology ; Sputum ; Bromelains/therapeutic use/pharmacology ; *COVID-19 ; Expectorants/therapeutic use/pharmacology ; *Respiration Disorders ; Rheology ; }, abstract = {Respiratory diseases such as cystic fibrosis, COPD, and COVID-19 are difficult to treat owing to viscous secretions in the airways that evade mucocilliary clearance. Earlier studies have shown success with BromAc as a mucolytic agent. Hence, we tested the formulation on two gelatinous airway representative sputa models, to determine whether similar efficacy exist. Sputum lodged in an endotracheal tube was treated to aerosol N-acetylcysteine, bromelain, or their combination (BromAc). After measuring the particle size of aerosolized BromAc, the apparent viscosity was measured using a capillary tube method, whilst the sputum flow was assessed using a 0.5 mL pipette. Further, the concentration of the agents in the sputa after treatment were quantified using chromogenic assays. The interaction index of the different formulations was also determined. Results indicated that the mean particle size of BromAc was suitable for aerosol delivery. Bromelain and N-acetylcysteine affected both the viscosities and pipette flow in the two sputa models. BromAc showed a greater rheological effect on both the sputa models compared to individual agents. Further, a correlation was found between the rheological effects and the concentration of agents in the sputa. The combination index using viscosity measurements showed synergy only with 250 µg/mL bromelain + 20 mg/mL NAC whilst flow speed showed synergy for both combinations of bromelain (125 and 250 µg/mL) with 20 mg/mL NAC. Hence, this study indicates that BromAc may be used as a successful mucolytic for clearing airway congestion caused by thick mucinous immobile secretions.}, } @article {pmid37100568, year = {2023}, author = {Balani, KA and Sahasrabudhe, TR and Mehta, K and Mirza, S}, title = {TB patients: Is sputum disinfection important?.}, journal = {The Indian journal of tuberculosis}, volume = {70}, number = {2}, pages = {142-146}, doi = {10.1016/j.ijtb.2022.03.027}, pmid = {37100568}, issn = {0019-5707}, mesh = {Humans ; *Mycobacterium tuberculosis ; Case-Control Studies ; Disinfection ; Sputum/microbiology ; *Tuberculosis, Pulmonary/drug therapy/prevention & control/microbiology ; *Disinfectants/pharmacology/therapeutic use ; Phenols/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Patients with pulmonary tuberculosis (TB) may produce large amount of infectious sputum which needs to be handled carefully both in health care and household settings. As mycobacteria may survive for long duration in sputum; proper collection, disinfection and disposal is necessary to avoid potential disease transmission. We aimed to assess the efficacy of bedside disinfectant treatment of sputum produced by TB patients using easily available disinfectants that can be used both in TB wards and household settings, to sterilize the infected sputum and compared it with sputum without disinfectant treatment.

METHODS: It was a prospective case control study. Sputum of total 95 patients with sputum smear positive pulmonary tuberculosis was collected in sputum containers with lids. Patients on anti-tubercular treatment for more than 2 weeks were excluded. Each patient was given 3 sterile sputum containers to expectorate, Container A containing 5% Phenol solution, Container B containing 4.8% Chloroxylenol and Container C without any disinfectant, acting as a control. Thick sputum was liquified with Mucolytic agent N-acetyl cysteine (NAC). Aliquots of the sputum were sent for culture in Lowenstein-Jensen medium on day 0 (to confirm alive mycobacteria) and on day 1 i.e., after 24 hours (to evaluate effective sterilization). Drug resistance testing was done on all grown mycobacteria.

RESULTS: If the samples on day 0 did not grow mycobacteria (indicating non-viable mycobacteria) or day 1 sample grew contaminants in any of the three containers, they were excluded from the analysis (15/95). In remaining 80 patients, bacilli were alive on day 0 and remained alive even after 24 hours (day 1) in control samples (without disinfectants). The sputum was effectively disinfected resulting in no growth after 24 hours (day 1) in 71/80 (88.75%) containing 5% Phenol and 72/80 (90%) with 4.8% Chloroxylenol. The efficacy of disinfection was 71/73 (97.2%) and 72/73 (98.6%) for drug sensitive mycobacteria respectively. The mycobacteria however remained alive with these disinfectants in all 7 samples of drug-resistant mycobacteria with an efficacy of 0%.

CONCLUSION: We recommend use of simple disinfectants like 5% Phenol or 4.8% Chloroxylenol for safe disposal of sputum of pulmonary tuberculosis patients. It is necessary as sputum collected without disinfection remained infectious after 24 hours. Resistance of all drug resistant mycobacteria to disinfectants was a novel chance finding. This needs further confirmatory studies.}, } @article {pmid37090713, year = {2023}, author = {Zhang, X and Xu, L and Ma, W and Shi, B and Liu, Q and Song, Y and Fang, C and Liu, P and Qiao, S and Cai, J and Zhang, Z}, title = {N-acetyl-L-cysteine alleviated the oxidative stress-induced inflammation and necroptosis caused by excessive NiCl2 in primary spleen lymphocytes.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1146645}, pmid = {37090713}, issn = {1664-3224}, mesh = {Mice ; Animals ; *Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Spleen/metabolism ; Necroptosis ; Hydrogen Peroxide/metabolism ; Oxidative Stress ; Inflammation/metabolism ; Lymphocytes/metabolism ; RNA, Messenger/metabolism ; }, abstract = {INTRODUCTION: Nickel (Ni) is widely used in industrial manufacturing and daily life due to its excellent physical and chemical properties. However, Ni has the potential to harm animals' immune system, and spleen is a typical immune organ. Therefore, it is crucial to understand the mechanism of NiCl2 damage to the spleen. The purpose of this study is to investigate the effects of different concentrations of NiCl2 exposure and intervening with strong antioxidants on spleen lymphocytes to better understand the damage mechanism of Ni on spleen lymphocytes.

METHODS: In this experiment, mice spleen lymphocytes were used as the research object. We first measured the degree of oxidative stress, inflammation, and necroptosis caused by different NiCl2 concentrations. Subsequently, we added the powerful antioxidant N-acetyl-L-cysteine (NAC) and used hydrogen peroxide (H2O2) as the positive control in subsequent experiments.

RESULTS: Our findings demonstrated that NiCl2 could cause spleen lymphocytes to produce a large number of reactive oxygen species (ROS), which reduced the mRNA level of antioxidant enzyme-related genes, the changes in GSH-PX, SOD, T-AOC, and MDA, the same to the mitochondrial membrane potential. ROS caused the body to produce an inflammatory response, which was manifested by tumor necrosis factor (TNF-α) in an immunofluorescence experiment, and the mRNA level of related inflammatory genes significantly increased. In the case of caspase 8 inhibition, TNF-α could cause the occurrence of necroptosis mediated by RIP1, RIP3, and MLKL. AO/EB revealed that spleen lymphocytes exposed to NiCl2 had significant necroptosis, and the mRNA and protein levels of RIP1, RIP3, and MLKL increased significantly. Moreover, the findings demonstrated that NAC acted as an antioxidant to reduce oxidative stress, inflammation, and necroptosis caused by NiCl2 exposure.

DISCUSSION: Our findings showed that NiCl2 could cause oxidative stress, inflammation, and necroptosis in mice spleen lymphocytes, which could be mitigated in part by NAC. The study provides a point of reference for understanding the toxicological effect of NiCl2. The study suggests that NAC may be useful in reducing the toxicological effect of NiCl2 on the immune system. The research may contribute to the development of effective measures to prevent and mitigate the toxicological effects of NiCl2 on the immune system.}, } @article {pmid37087805, year = {2023}, author = {Dong, H and Li, H and Fang, L and Zhang, A and Liu, X and Xue, F and Chen, Y and Liu, W and Chi, Y and Wang, W and Sun, T and Ju, M and Dai, X and Yang, R and Fu, R and Zhang, L}, title = {Increased reactive oxygen species lead to overactivation of platelets in essential thrombocythemia.}, journal = {Thrombosis research}, volume = {226}, number = {}, pages = {18-29}, doi = {10.1016/j.thromres.2023.04.001}, pmid = {37087805}, issn = {1879-2472}, mesh = {Mice ; Animals ; *Thrombocythemia, Essential/drug therapy/genetics ; Reactive Oxygen Species/metabolism ; Janus Kinases/metabolism/pharmacology ; Signal Transduction ; STAT Transcription Factors/metabolism/pharmacology ; Blood Platelets/metabolism ; *Thrombosis/metabolism ; Acetylcysteine/metabolism/pharmacology ; }, abstract = {INTRODUCTION: Platelet function, rather than platelet count, plays a crucial role in thrombosis in essential thrombocythemia (ET). However, little is known about the abnormal function of platelets in ET. Here, we investigated the functional characteristics of platelets in ET hemostasis to explore the causes of ET platelet dysfunction and new therapeutic strategies for ET.

MATERIALS AND METHODS: We analyzed platelet aggregation, activation, apoptosis, and reactive oxygen species (ROS) in ET patients and JAK2V617F-positive ET-like mice. The effects of ROS on platelet function and the underlying mechanism were investigated by inhibiting ROS using N-acetylcysteine (NAC).

RESULTS: Platelet aggregation, activation, apoptosis, ROS, and clot retraction were elevated in ET. No significant differences were observed between ET patients with JAK2V617F or CALR mutations. Increased ROS activated the JAK-STAT pathway, which may further influence platelet function. Inhibition of platelet ROS by NAC reduced platelet aggregation, activation, and apoptosis, and prolonged bleeding time. Furthermore, NAC treatment reduced platelet count in ET-like mice by inhibiting platelet production from megakaryocytes.

CONCLUSIONS: Elevated ROS in ET platelets resulted in enhanced platelet activation, function and increased risk of thrombosis. NAC offers a potential therapeutic strategy for reducing platelet count.}, } @article {pmid37084995, year = {2023}, author = {Li, Y and Guo, M and Niu, S and Shang, M and Chang, X and Sun, Z and Zhang, R and Shen, X and Xue, Y}, title = {ROS and DRP1 interactions accelerate the mitochondrial injury induced by polystyrene nanoplastics in human liver HepG2 cells.}, journal = {Chemico-biological interactions}, volume = {379}, number = {}, pages = {110502}, doi = {10.1016/j.cbi.2023.110502}, pmid = {37084995}, issn = {1872-7786}, mesh = {Humans ; *Microplastics/toxicity ; Reactive Oxygen Species/metabolism ; *Polystyrenes/toxicity ; Hep G2 Cells ; Plastics/metabolism/pharmacology ; Dynamins/metabolism ; Mitochondria ; Liver/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis ; }, abstract = {Microplastics have become a serious environmental pollutant and subsequently have harmful effects on human health. Thus, the impacts of microplastics on human cells need to be explored. In the present study, the cytotoxic effects at the subcellular-organelle levels to polystyrene nanoplastics (PS-NPs, diameter 21.5 ± 2.7 nm) were investigated in the human hepatocellular carcinoma (HepG2) cell line. The cell viability exposed to PS-NPs at the concentrations of 6.25, 12.5, 25 and 50 μg/mL for 24 h diminished in a concentration-dependent manner. The PS-NPs treatment induced mitochondrial injuries, including morphological changes, decreased adenosine triphosphate (ATP) production and the loss of mitochondrial membrane potentials (MMP). The PS-NPs treatment could further spark cell apoptosis by upregulating caspase 3, caspase 9, cytochrome c, and Bcl-2 associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) in HepG2 cells, which is related to the mitochondrial dysfunction. PS-NPs exposure stimulated the excessive cellular reactive oxygen species (ROS) production and also induced mitochondrial fission by upregulating dynamin-related protein 1 (DRP1) and P-DRP1, but downregulating optic atrophy protein 1 (OPA1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression levels. The above effects on mitochondria damage induced by PS-NPs were reversed by the pretreatment of N-acetylcysteine (NAC), mitochondrial division inhibitor 1 (Mdivi-1) and DRP1 siRNA. The results suggested that the interaction between ROS and DRP1-dependent mitochondrial division could promote mitochondrial lesions and mitochondria-related apoptosis caused by PS-NPs. These findings on molecular mechanisms provide a theoretical basis for preventing the hazards caused by microplastics to human health.}, } @article {pmid37080569, year = {2023}, author = {Addante, A and Raymond, W and Gitlin, I and Charbit, A and Orain, X and Scheffler, AW and Kuppe, A and Duerr, J and Daniltchenko, M and Drescher, M and Graeber, SY and Healy, AM and Oscarson, S and Fahy, JV and Mall, MA}, title = {A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases.}, journal = {The European respiratory journal}, volume = {61}, number = {5}, pages = {}, pmid = {37080569}, issn = {1399-3003}, support = {P01 HL128191/HL/NHLBI NIH HHS/United States ; R01 HL080414/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Humans ; Mice ; Animals ; Expectorants/therapeutic use ; Sulfhydryl Compounds/pharmacology/therapeutic use ; *Cystic Fibrosis ; Acetylcysteine/pharmacology/therapeutic use ; Sputum ; *Lung Diseases, Obstructive/drug therapy ; Inflammation/pathology ; Carbohydrates/pharmacology/therapeutic use ; Lung ; }, abstract = {BACKGROUND: Mucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (βENaC-Tg mice).

METHODS: We compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G') of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in βENaC-Tg mice to determine its mucolytic efficacy in vivo.

RESULTS: In CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G', was faster in decreasing sputum G' by 50% and caused mucolysis of a larger proportion of sputum samples within 15 min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1 day in adult βENaC-Tg mice decreased airway mucus content (16.8±3.2 versus 7.5±1.2 nL·mm[-2], p<0.01) and bronchoalveolar lavage cells (73 833±6930 versus 47 679±7736 cells·mL[-1], p<0.05). Twice-daily treatment with MUC-031 for 2 weeks also caused decreases in these outcomes in adult and neonatal βENaC-Tg mice and reduced mortality from 37% in vehicle-treated βENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05).

CONCLUSION: MUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in βENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.}, } @article {pmid37079050, year = {2023}, author = {Hannon Barroeta, P and O'Sullivan, MJ and Zisterer, DM}, title = {The role of the Nrf2/GSH antioxidant system in cisplatin resistance in malignant rhabdoid tumours.}, journal = {Journal of cancer research and clinical oncology}, volume = {149}, number = {11}, pages = {8379-8391}, pmid = {37079050}, issn = {1432-1335}, mesh = {Humans ; Child ; *Cisplatin/pharmacology ; Antioxidants/pharmacology ; *Rhabdoid Tumor/drug therapy ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; Glutathione/metabolism ; Buthionine Sulfoximine ; Apoptosis ; Cell Line, Tumor ; }, abstract = {PURPOSE: Malignant rhabdoid tumour (MRT) is a rare and aggressive childhood malignancy that occurs in the kidneys or central nervous system and is associated with very poor prognosis. Chemoresistance is a major issue in the treatment of this malignancy leading to an urgent need for a greater understanding of its underlying mechanisms in MRT and novel treatment strategies for MRT patients. The balance between oxidative stress mediated by reactive oxygen species (ROS) and the antioxidant system has become a subject of interest in cancer therapy research. Studies have implicated key players of the antioxidant system in chemotherapeutic including the well-known antioxidant glutathione (GSH) and the transcription factor nuclear erythroid-related factor-2 (Nrf2). METHODS: This study evaluated the role of these components in the response of MRT cells to treatment with the commonly used chemotherapeutic agent, cisplatin.

RESULTS: This study characterised the basal levels of GSH, ROS and Nrf2 in a panel of MRT cell lines and found a correlation between the expression profile of the antioxidant defence system and cisplatin sensitivity. Results showed that treatment with ROS scavenger N-acetylcysteine (NAC) protected cells from cisplatin-induced ROS and apoptosis. Interestingly, depleting GSH levels with the inhibitor buthionine sulphoximine (BSO) enhanced cisplatin-induced ROS and sensitised cells to cisplatin. Lastly, targeting Nrf2 with the small molecule inhibitor ML385 or by siRNA diminished GSH levels, enhanced ROS and sensitised resistant MRT cells to cisplatin.

CONCLUSIONS: These results suggest that targeting the Nrf2/GSH antioxidant system may present a novel therapeutic strategy to combat chemoresistance in rhabdoid tumours.}, } @article {pmid37075699, year = {2023}, author = {Yap, YS and Hu, J}, title = {Exploiting metabolic vulnerabilities in breast cancers with NF1 loss.}, journal = {Cell reports. Medicine}, volume = {4}, number = {4}, pages = {101010}, pmid = {37075699}, issn = {2666-3791}, mesh = {Humans ; Female ; Neurofibromin 1/genetics/metabolism ; *Breast Neoplasms/drug therapy ; Phosphatidylinositol 3-Kinases/metabolism ; *Biochemical Phenomena ; }, abstract = {Auf der Maur et al.[1] identify neurofibromin 1 (NF1) loss as a mechanism of resistance to PI3K inhibitor in breast cancer cells. NF1 loss leads to enhanced glycolysis, which may be targeted with the antioxidant N-acetyl cysteine (NAC).}, } @article {pmid37072676, year = {2023}, author = {Jensen, GS and Cruickshank, D and Hamilton, DE}, title = {Disruption of Established Bacterial and Fungal Biofilms by a Blend of Enzymes and Botanical Extracts.}, journal = {Journal of microbiology and biotechnology}, volume = {33}, number = {6}, pages = {715-723}, pmid = {37072676}, issn = {1738-8872}, mesh = {Humans ; Anti-Bacterial Agents/pharmacology/metabolism ; Staphylococcus aureus ; *Anti-Infective Agents/pharmacology ; *Staphylococcal Infections/microbiology ; Biofilms ; Pseudomonas aeruginosa ; Microbial Sensitivity Tests ; }, abstract = {Microbial biofilms are resilient, immune-evasive, often antibiotic-resistant health challenges, and increasingly the target for research into novel therapeutic strategies. We evaluated the effects of a nutraceutical enzyme and botanical blend (NEBB) on established biofilm. Five microbial strains with known implications in chronic human illnesses were tested: Candida albicans, Staphylococcus aureus, Staphylococcus simulans (coagulase-negative, penicillin-resistant), Borrelia burgdorferi, and Pseudomonas aeruginosa. The strains were allowed to form biofilm in vitro. Biofilm cultures were treated with NEBB containing enzymes targeted at lipids, proteins, and sugars, also containing the mucolytic compound N-acetyl cysteine, along with antimicrobial extracts from cranberry, berberine, rosemary, and peppermint. The post-treatment biofilm mass was evaluated by crystal-violet staining, and metabolic activity was measured using the MTT assay. Average biofilm mass and metabolic activity for NEBB-treated biofilms were compared to the average of untreated control cultures. Treatment of established biofilm with NEBB resulted in biofilm-disruption, involving significant reductions in biofilm mass and metabolic activity for Candida and both Staphylococcus species. For B. burgdorferi, we observed reduced biofilm mass, but the remaining residual biofilm showed a mild increase in metabolic activity, suggesting a shift from metabolically quiescent, treatment-resistant persister forms of B. burgdorferi to a more active form, potentially more recognizable by the host immune system. For P. aeruginosa, low doses of NEBB significantly reduced biofilm mass and metabolic activity while higher doses of NEBB increased biofilm mass and metabolic activity. The results suggest that targeted nutraceutical support may help disrupt biofilm communities, offering new facets for integrative combinational treatment strategies.}, } @article {pmid37072331, year = {2023}, author = {Khazaie, S and Jafari, M and Golamloo, M and Asgari, A and Heydari, J and Salehi, M and Salem, F}, title = {Cumulative Effects of Paraoxon and Leptin on Oxidative Damages in Rat Tissues: Prophylactic and Therapeutic Roles of N-Acetylcysteine.}, journal = {Biochemistry. Biokhimiia}, volume = {88}, number = {2}, pages = {165-178}, doi = {10.1134/S0006297923020013}, pmid = {37072331}, issn = {1608-3040}, mesh = {Rats ; Male ; Animals ; *Antioxidants/pharmacology/metabolism ; *Acetylcysteine/pharmacology ; Paraoxon/toxicity ; Rats, Wistar ; Leptin/pharmacology ; Oxidative Stress ; }, abstract = {Exposure to paraoxon (POX) and leptin (LP) could cause an imbalance between oxidants and antioxidants in an organism, which can be prevented by introduction of exogenous antioxidants such as N-acetylcysteine (NAC). The aim of this study was to evaluate synergic or additive effects of administration of exogenous LP plus POX on the antioxidant status, as well as the prophylactic and therapeutic roles of NAC in various rat tissues. Fifty-four male Wistar rats were divided into nine groups treated with different compounds: Control (no treatment), POX (0.7 mg/kg), NAC (160 mg/kg), LP (1 mg/kg), POX+LP, NAC-POX, POX-NAC, NAC-POX+LP, and POX+LP-NAC. In the last five groups, only the order of administered compounds differed. After 24 h, plasma and tissues were sampled and examined. The results showed that administration of POX plus LP significantly increased biochemical indices in plasma and antioxidant enzymes activities and decreased glutathione content in the liver, erythrocytes, brain, kidney, and heart. In addition, cholinesterase and paraoxonase 1 activities in the POX+LP-treated group were decreased and malondialdehyde level was increased in the liver, erythrocytes, and brain. However, administration of NAC rectified induced changes although not to the same extent. Our study suggests that POX or LP administration engage the oxidative stress system per se; however, their combination did not produce significantly greater effects. Moreover, both prophylactic and therapeutic treatments of rats with NAC supported the antioxidant defense against oxidative damage in tissues, most probably through both its free radical scavenging ability and maintaining intracellular GSH levels. It can therefore be suggested that NAC has particularly protective effects against POX or/and LP toxicity.}, } @article {pmid37072049, year = {2023}, author = {Hao, XS and Feng, PP and Zhang, YY and Wang, FZ and Wang, GL and Fei, HR}, title = {Scutebarbatine A induces ROS-mediated DNA damage and apoptosis in breast cancer cells by modulating MAPK and EGFR/Akt signaling pathway.}, journal = {Chemico-biological interactions}, volume = {378}, number = {}, pages = {110487}, doi = {10.1016/j.cbi.2023.110487}, pmid = {37072049}, issn = {1872-7786}, mesh = {Humans ; Female ; Reactive Oxygen Species/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Superoxides ; *Breast Neoplasms/drug therapy ; Signal Transduction ; *Antineoplastic Agents/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; Apoptosis ; DNA Damage ; ErbB Receptors/metabolism ; MAP Kinase Signaling System ; Cell Line, Tumor ; }, abstract = {Scutebarbatine A (SBT-A), a diterpenoid alkaloid, has exerted cytotoxicity on hepatocellular carcinoma cells in our previous works. Here, the antitumor activity of SBT-A in breast cancer cells and the underlying mechanism were explored. The anti-proliferative effect of SBT-A was measured by trypan blue staining, 5-ethynyl-2'-deoxyuridine (EdU) incorporation and colony formation assay. DNA double-strand breaks (DSBs) were evaluated by observing the nuclear focus formation of γ-H2AX. Cell cycle distribution was assessed by flow cytometry. Apoptosis was determined by a TUNEL assay. Intracellular reactive oxygen species (ROS) generation and superoxide production were measured with 2', 7'-dichlorofluorescein diacetate (DCFH-DA) and dihydroethidium (DHE) staining, respectively. The results indicated that SBT-A showed a dose-dependent cytotoxic effect against breast cancer cells while revealing less toxicity toward MCF-10A breast epithelial cells. Moreover, SBT-A remarkably induced DNA damage, cell cycle arrest and apoptosis in both MDA-MB-231 and MCF-7 cells. SBT-A treatment increased the levels of ROS and cytosolic superoxide production. Pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to block viability reduction, DNA damage, apoptosis and endoplasmic reticulum (ER) stress caused by SBT-A. By exposure to SBT-A, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) was upregulated, while the phosphorylation of extracellular signal-regulated kinase (ERK) was downregulated. In addition, SBT-A inhibited the EGFR signaling pathway by decreasing EGFR expression and phosphorylation of Akt and p70S6K. As mentioned above, SBT-A has a potent inhibitory effect on breast cancer cells through induction of DNA damage, apoptosis and ER stress via ROS generation and modulation of MAPK and EGFR/Akt signaling pathway.}, } @article {pmid37071164, year = {2023}, author = {Maestro, C and Leache, L and Gutiérrez-Valencia, M and Saiz, LC and Gómez, H and Bacaicoa, MC and Erviti, J}, title = {Efficacy and safety of N-acetylcysteine for preventing post-intravenous contrast acute kidney injury in patients with kidney impairment: a systematic review and meta-analysis.}, journal = {European radiology}, volume = {33}, number = {9}, pages = {6569-6581}, pmid = {37071164}, issn = {1432-1084}, mesh = {Humans ; *Acetylcysteine/administration & dosage/adverse effects ; *Acute Kidney Injury/etiology/prevention & control ; *Contrast Media/adverse effects ; Kidney/drug effects ; }, abstract = {OBJECTIVES: N-Acetylcysteine (NAC) may confer protection against post-contrast acute kidney injury (PC-AKI), although evidence is sparse and conflicting. The objective was to analyse the evidence on the efficacy and safety of NAC vs no administration of NAC in preventing PC-AKI in patients with pre-existing kidney impairment undergoing a non-interventional radiological examination requiring intravenous (IV) contrast media (CM) administration.

METHODS: We carried out a systematic review including randomised controlled trials (RCTs) published in MEDLINE, EMBASE, and Clinicaltrials.gov up to May 2022. The primary outcome was PC-AKI. Secondary outcomes included the requirement of renal replacement therapy, all-cause mortality, serious adverse events, and length of hospital stay. We conducted the meta-analyses using the Mantel-Haenszel method and following a random-effects model.

RESULTS: NAC was not associated with a significant reduction in PC-AKI (RR 0.47, 95%CI 0.20 to 1.11; 8 studies; 545 participants; I[2]: 56%; low certainty), all-cause mortality (RR 0.67, 95%CI 0.29 to 1.54; 2 studies; 129 participants; very low certainty), or length of hospital stay (mean difference 9.2 days, 95%CI - 20.08 to 38.48; 1 study; 42 participants; very low certainty). The impact on other outcomes could not be determined.

CONCLUSIONS: NAC may not reduce the risk of PC-AKI or all-cause mortality in people with kidney impairment who receive an IV CM prior to radiological imaging, although the certainty of the evidence is very low or low.

CLINICAL RELEVANCE STATEMENT: Our review concludes that prophylactic administration of N-acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging, which may support decision making in this common clinical scenario.

KEY POINTS: • N-Acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging. • All-cause mortality and length of hospital stay would not be decreased with the administration of N-Acetylcysteine in this setting.}, } @article {pmid37069635, year = {2023}, author = {Jia, D and Guo, S and Jia, Z and Gao, Z and You, K and Gong, J and Li, S}, title = {N-acetylcysteine in the Donor, Recipient, or Both Donor and Recipient in Liver Transplantation: A Systematic Review With Meta-analysis and Trial Sequential Analysis.}, journal = {Transplantation}, volume = {107}, number = {9}, pages = {1976-1990}, doi = {10.1097/TP.0000000000004597}, pmid = {37069635}, issn = {1534-6080}, mesh = {Humans ; Acetylcysteine/adverse effects ; *Liver Transplantation/adverse effects ; Graft Survival ; Transferases ; *Reperfusion Injury/etiology/prevention & control ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is a potentially effective drug for treating ischemia-reperfusion injury in transplanted livers, but its effect remains controversial.

METHODS: A systematic review and meta-analysis of relevant clinical trials published and registered in the Cochrane Library, MEDLINE, EMBASE, ClinicalTrial.gov , WHO ICTRP, etc, before March 20, 2022 were conducted and registered with PROSPERO (CRD42022315996). Data were pooled using a random effects model or a fixed effects model based on the amount of heterogeneity.

RESULTS: Thirteen studies with 1121 participants, 550 of whom received NAC, were included. Compared with the control, NAC significantly reduced the incidence of primary graft nonfunction (relative risk [RR], 0.27; 95% confidence interval [CI], 0.08-0.96), the incidence of postoperative complications (RR, 0.52; 95% CI, 0.41-0.67), the peak postoperative aspartate transferase level (mean difference [MD], -267.52; 95% CI, -345.35 to -189.68), and the peak alanine transferase level (MD, -293.29; 95% CI, -370.39 to -216.20). NAC also improved 2-y (RR, 1.18; 95% CI, 1.01-1.38) graft survival rate. However, NAC increased the intraoperative cryoprecipitate (MD, 0.94; 95% CI, 0.42-1.46) and red blood cell (MD, 0.67; 95% CI, 0.15-1.19) requirements. Moreover, NAC was administered in various modes in these studies, including to the donor, recipient, or both. Subgroup analysis and network meta-analysis showed that NAC administration to recipients could play a more significant role than the other 2 administration modes.

CONCLUSIONS: Our study supports the protective effect of NAC against LT-induced ischemia-reperfusion injury and shows better clinical outcomes of NAC administration to recipients.}, } @article {pmid37066621, year = {2023}, author = {Mazrad, ZAI and Leiske, MN and Tabor, RF and Nicolazzo, JA and Kempe, K}, title = {Comparison of the Anti-inflammatory Activity and Cellular Interaction of Brush Polymer-N-Acetyl Cysteine Conjugates in Human and Murine Microglial Cell Lines.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {5}, pages = {2686-2701}, doi = {10.1021/acs.molpharmaceut.3c00140}, pmid = {37066621}, issn = {1543-8392}, mesh = {Mice ; Humans ; Animals ; *Microglia/metabolism ; *Polymers/metabolism ; Lipopolysaccharides/pharmacology ; Neuroinflammatory Diseases ; Anti-Inflammatory Agents/pharmacology/metabolism ; Acetylcysteine/chemistry ; }, abstract = {Microglia-mediated neuroinflammation is commonly associated with neurodegeneration and has been implicated in several neurological disorders, such as Alzheimer's disease and Parkinson's disease. Therefore, it is crucial to develop a detailed understanding of the interaction of potential nanocarriers with microglial cells to efficiently deliver anti-inflammatory molecules. In this study, we applied brush polymers as a modular platform to systematically investigate their association with murine (BV-2) and human (HMC3) microglial cell lines in the presence and absence of the pro-inflammatory inducer lipopolysaccharide (LPS) using flow cytometry. Brush polymers of different sizes and shapes, ranging from ellipsoid to worm-like cylinders, were prepared through a combination of the two building blocks carboxylated N-acylated poly(aminoester)s (NPAEs)-based polymers and poly(2-ethyl-2-oxazoline)-NH2 (PEtOx-NH2) and characterized by [1]H NMR spectroscopy, size exclusion chromatography, and small-angle neutron scattering. Generally, ellipsoidal particles showed the highest cellular association. Moreover, while no significant differences in murine cell association were observed, the brush polymers revealed a significant accumulation in LPS-activated human microglia compared to resting cells, emphasizing their higher affinity to activated HMC3 cells. Brush polymers with the highest cell association were further modified with the anti-inflammatory agent N-acetyl cysteine (NAC) in a reversible manner. The brush polymer-NAC conjugates were found to significantly attenuate the production of interleukin 6 (p < 0.001) in LPS-activated HMC3 cells compared to LPS-activated BV-2 cells. Thus, the presented brush polymer-NAC conjugates showed a high anti-inflammatory activity in human microglia, suggesting their potential for disease-targeted therapy of microglial-mediated neuroinflammation in the future.}, } @article {pmid37065769, year = {2023}, author = {Gonzales-Moreno, C and Fernandez-Hubeid, LE and Holgado, A and Virgolini, MB}, title = {Low-dose N-acetyl cysteine prevents paraquat-induced mortality in Caenorhabditis elegans.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37065769}, issn = {2578-9430}, abstract = {Exposure to the herbicide paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium dichloride) affects the redox balance of the cell, an effect that can be restored by antioxidants, including N-acetyl cysteine (NAC). One hour of exposure to PQ (0 mM, 10 mM, 50 mM, or 100 mM) dose-dependently increased mortality in Caenorhabditis elegans after exposure (immediate toxicity), while this effect was more evident 24 hours thereafter (delayed toxicity). Importantly, pretreatment with NAC 0.5 mM for one hour partially prevented mortality in the immediate assay, while it had no effect in the delayed test, revealing the importance of long-term studies when evaluating toxicity.}, } @article {pmid37062330, year = {2023}, author = {Xue, J and Li, Z and Li, X and Hua, C and Shang, P and Zhao, J and Liu, K and Xie, F}, title = {Evaluation of cigarette smoke-induced oxidative stress and inflammation in BEAS-2B cells based on a lung microfluidic chip.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {176}, number = {}, pages = {113787}, doi = {10.1016/j.fct.2023.113787}, pmid = {37062330}, issn = {1873-6351}, mesh = {*Microfluidics ; *Cigarette Smoking ; Lung ; Oxidative Stress ; Inflammation/chemically induced/pathology ; Nicotiana ; }, abstract = {Oxidative stress and inflammation induced by cigarette smoking are associated with the pathology process of various chronic respiratory diseases, including asthma, emphysema, chronic obstructive pulmonary disease and cancer. Compared with conventional cell culture techniques, microfluidic chips can provide a continuous nutrient supply, mimic the in vivo physiological microenvironment of the cells, and conduct an integrated and flexible analysis of cell status and functions. Here, we designed and fabricated a bionic-lung chip, which was applied to perform cigarette smoke exposure of BEAS-2B cells cultured at the gas-liquid interface. The oxidative stress and inflammation in the cells exposed to cigarette smoke were investigated on chip. The results showed that cellular damage, oxidative stress and inflammatory response induced by cigarette smoke in the chip were dependent on smoke concentration and time after smoke exposure. N-Acetylcysteine (NAC) significantly inhibited these effects of cigarette smoke exposure on the cells at the gas-liquid interface within the chip.}, } @article {pmid39360158, year = {2024}, author = {Liu, L and Pang, W and Liu, J and Xu, S and Zhang, Z and Hao, R and Wan, J and Xie, W and Tao, X and Yang, P and Zhao, L and Zhai, Z and Wang, C}, title = {Inhibition of heterogeneous nuclear ribonucleoproteins A1 and oxidative stress reduces glycolysis via pyruvate kinase M2 in chronic thromboembolic pulmonary hypertension.}, journal = {Journal of translational internal medicine}, volume = {12}, number = {4}, pages = {437-451}, pmid = {39360158}, issn = {2450-131X}, abstract = {BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a lethal complication of pulmonary embolism involving pulmonary artery occlusion and microvascular disease. The glucose metabolism and reactive oxygen species (ROS) production may be perturbed in CTEPH, but the precise mechanisms are unclear. This study investigated glucose metabolism in CTEPH employing pulmonary endarterectomy (PEA)-derived pulmonary artery smooth muscle cells (PASMCs) and characterized the roles of pyruvate kinase M2 (PKM2) and its regulation by heterogeneous nuclear ribonucleoproteins A1 (hnRNPA1) and ROS in CTEPH.

METHODS: PEA tissues and blood samples of CTEPH patients were collected to study the levels of PKM2. Primary PASMCs were isolated from PEA tissues. We used small interfering RNAs to knock down PKM2 and hnRNPAI, and applied antioxidant N-acetylcysteine (NAC) and mito-TEMPO to reduce ROS production. The expression of glucometabolic genes, ROS production, glycolysis rate and proliferative and migratory activities were analyzed in PEA-derived PASMCs.

RESULTS: PKM2 levels in serum and PEA tissues of CTEPH patients were higher than that of the healthy controls. Compared to the control PASMCs, PEA-derived PASMCs showed increased PKM2 expression and ROS production. The rates of glycolysis, proliferation and migration were increased in PEA-PASMCs and could be mitigated by PKM2 downregulation through hnRNPA1 or ROS inhibition.

CONCLUSIONS: Increased glycolysis and PKM2 expression were found in PEA-PASMCs. Inhibition of hnRNPA1 or ROS corrected the aberrant glycolysis, cell proliferation and migration by downregulating PKM2. Regulation of the hnRNPA1/PKM2 axis represents a potential therapeutic target for the treatment of CTEPH.}, } @article {pmid39554835, year = {2023}, author = {Ferguson, M and Mebane, CM and Reddy, A}, title = {Prophylactic Effect of N-Acetylcysteine in an Adolescent With Trichotillomania After Acetaminophen Overdose.}, journal = {JAACAP open}, volume = {1}, number = {1}, pages = {74-75}, pmid = {39554835}, issn = {2949-7329}, abstract = {N-Acetylcysteine (NAC) is an essential drug for the treatment of acetaminophen overdose, with nearly 100% efficacy if delivered within 8 hours of ingestion. In addition to preventing hepatotoxicity following an overdose, there is some evidence that NAC may be effective in the treatment of trichotillomania, onychophagia, onychotillomania, and excoriation disorder. Here we report a 16-year-old female patient with an acetaminophen overdose who presented to the emergency department with normal liver function testing, despite ingesting approximately 100 tablets of acetaminophen 500 mg. The patient also had a history of trichotillomania and had been taking 600 mg twice daily of over-the-counter NAC for the week before the overdose. Therefore, the over-the-counter NAC treatment regimen may have serendipitously served as a prophylactic measure against hepatoxicity in her acetaminophen overdose.}, } @article {pmid39193224, year = {2023}, author = {Rodrigues, K and Hussain, R and Cooke, S and Zhang, G and Zhang, D and Yin, L and Tong, X}, title = {Fructose as a novel nutraceutical for acetaminophen (APAP)-induced hepatotoxicity.}, journal = {Metabolism and target organ damage}, volume = {3}, number = {4}, pages = {}, pmid = {39193224}, issn = {2769-6375}, support = {R25 HL108842/HL/NHLBI NIH HHS/United States ; R01 DK121170/DK/NIDDK NIH HHS/United States ; P30 DK089503/DK/NIDDK NIH HHS/United States ; P60 DK020572/DK/NIDDK NIH HHS/United States ; R01 DK099593/DK/NIDDK NIH HHS/United States ; }, abstract = {Acetaminophen (APAP) is the most widely used analgesic in the world. APAP overdose can cause severe hepatotoxicity and therefore is the most common cause of drug-induced liver injury. The only approved treatment for APAP overdose is N-acetyl-cysteine (NAC) supplementation. However, the narrow efficacy window of the drug severely limits its clinical use, prompting the search for other therapeutic options to counteract APAP toxicity. Recent research has pointed to fructose as a novel nutraceutical for APAP-induced liver injury. This review summarizes the current understanding of the molecular mechanisms underlying APAP-induced liver injury, introduces how fructose supplementation could prevent and treat APAP liver toxicity with a focus on the ChREBPα-FGF21 pathway, and proposes possible future directions of study.}, } @article {pmid38313355, year = {2023}, author = {Hatami, B and Abdi, S and Pourhoseingholi, MA and Eghlimi, H and Rabbani, AH and Masoumi, M and Hajimohammadebrahim-Ketabforoush, M}, title = {The effects of N-acetylcysteine on hepatic, hematologic, and renal parameters in cirrhotic patients: a randomized controlled trial.}, journal = {Gastroenterology and hepatology from bed to bench}, volume = {16}, number = {4}, pages = {432-440}, pmid = {38313355}, issn = {2008-2258}, abstract = {AIM: To evaluate the effects of N-acetylcysteine (NAC) supplementation in cirrhotic patients.

BACKGROUND: Chronic hepatic inflammation leads to fibrosis and cirrhosis through various mechanisms such as oxidative stress. NAC is one of the intracellular precursors of glutathione that can degrade most reactive oxygen species. Recently, the beneficial effects of NAC in animal and human studies on preventing liver injury progression and improving liver function have been examined. However, more studies on human subjects are still required.

METHODS: Well-known cirrhotic patients with a specific etiology and aged 18 to 70 years who referred to the gastrointestinal clinic of Ayatollah Taleghani Hospital from December 2018 to December 2019 were enrolled in the present randomized double-blind controlled trial. Patients in the intervention group received NAC tablets at a dose of 600 mg daily, and the control group received a placebo. Demographic data, medical characteristics, and Child-Pugh and MELD scores evaluated at baseline and after 6 months.

RESULTS: Totally, 60 patients completed the present study (30 patients in the intervention group, and 30 patients in the control group). Hematological and biochemical parameters were normal in both groups with no significant differences at baseline and 6 months after intervention values. Moreover, the renal function indicators including serum creatinine (Cr) and urea (BUN) decreased significantly after intervention. Hepatic parameters also decreased significantly 6 months after intervention. Decreases in the renal and hepatic parameters 6 months after baseline in the control group were not statistically significant.

CONCLUSION: The results of this study showed that NAC improved hepatic and renal function by decreasing serum urea and creatinine levels but had no significant effect on hematological and biochemical parameters. Furthermore, NAC significantly improved hepatic profiles by decreasing ALT, AST, and ALP in the liver enzymes between the intervention and control groups. Moreover, NAC caused a significant decrease in Child-Pugh and MELD scores.}, } @article {pmid38362235, year = {2022}, author = {Greenberg, NR and Farhadi, F and Kazer, B and Potenza, MN and Angarita, GA}, title = {The Potential of N-acetyl Cysteine in Behavioral Addictions and Related Compulsive and Impulsive Behaviors and Disorders: a Scoping Review.}, journal = {Current addiction reports}, volume = {9}, number = {4}, pages = {660-670}, pmid = {38362235}, issn = {2196-2952}, support = {R01 AT010508/AT/NCCIH NIH HHS/United States ; R01 DA052454/DA/NIDA NIH HHS/United States ; R01 DK121551/DK/NIDDK NIH HHS/United States ; R21 DA043055/DA/NIDA NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: Behavioral addictions (also termed disorders due to addictive behaviors) contain impulsive and compulsive features and have been shown to involve glutamate dysregulation. N-acetylcysteine (NAC), a well-tolerated cysteine pro-drug and antioxidant, may reduce addictive behaviors by restoring glutamate homeostasis. The current review details and discusses the use of NAC in behavioral addictions and related impulsive and compulsive behaviors, including gambling disorder, problematic use of the internet, problematic video gaming, compulsive sexual behavior, problematic shopping/buying, problematic stealing, repetitive self-injurious behavior, and binge eating disorder.

RECENT FINDINGS: Preliminary results have indicated the usefulness of NAC in gambling disorder, self-injurious behaviors, and compulsive sexual behaviors. Preclinical studies indicate that NAC is effective in improving binge eating behavior, but clinical trials are limited to a small open-label trial and case report. Studies are lacking on the efficacy of NAC in problematic use of the internet, problematic video gaming, problematic stealing, and problematic shopping/buying.

SUMMARY: NAC demonstrates potential for use in behavioral addictions and compulsive behaviors, particularly in gambling disorder and self-injury. However, more studies are needed to assess the effectiveness of NAC in other behavioral addictions and the mechanisms by which NAC improves these conditions.}, } @article {pmid38647894, year = {2022}, author = {Li, N and Zeng, Y and Chen, Y and Shen, Y and Wang, W}, title = {Induction of cellulase production by Sr[2+] in Trichoderma reesei via calcium signaling transduction.}, journal = {Bioresources and bioprocessing}, volume = {9}, number = {1}, pages = {96}, pmid = {38647894}, issn = {2197-4365}, support = {2021-02-08-00-12-F00758//Shanghai Agriculture Applied Technology Development Program, China/ ; 22ZR1417600//Natural Science Foundation of Shanghai/ ; 32000050//National Natural Science Foundation of China/ ; }, abstract = {Trichoderma reesei RUT-C30 is a well-known high-yielding cellulase-producing fungal strain that converts lignocellulose into cellulosic sugar for resource regeneration. Calcium is a ubiquitous secondary messenger that regulates growth and cellulase production in T. reesei. We serendipitously found that adding Sr[2+] to the medium significantly increased cellulase activity in the T. reesei RUT-C30 strain and upregulated the expression of cellulase-related genes. Further studies showed that Sr[2+] supplementation increased the cytosolic calcium concentration and activated the calcium-responsive signal transduction pathway of Ca[2+]-calcineurin-responsive zinc finger transcription factor 1 (CRZ1). Using the plasma membrane Ca[2+] channel blocker, LaCl3, we demonstrated that Sr[2+] induces cellulase production via the calcium signaling pathway. Supplementation with the corresponding concentrations of Sr[2+] also inhibited colony growth. Sr[2+] supplementation led to an increase in intracellular reactive oxygen species (ROS) and upregulated the transcriptional levels of intracellular superoxide dismutase (sod1) and catalase (cat1). We further demonstrated that ROS content was detrimental to cellulase production, which was alleviated by the ROS scavenger N-acetyl cysteine (NAC). This study demonstrated for the first time that Sr[2+] supplementation stimulates cellulase production and upregulates cellulase genes via the calcium signaling transduction pathway. Sr[2+] leads to an increase in intracellular ROS, which is detrimental to cellulase production and can be alleviated by the ROS scavenger NAC. Our results provide insights into the mechanistic study of cellulase synthesis and the discovery of novel inducers of cellulase.}, } @article {pmid37256553, year = {2022}, author = {Li, Y and Li, M and Ahmed, K and Yang, J and Song, L and Cui, ZG and Hiraku, Y}, title = {Mechanistic Study of Macranthoside B Effects on Apoptotic Cell Death in Human Cervical Adenocarcinoma Cells.}, journal = {Folia biologica}, volume = {68}, number = {5-6}, pages = {189-200}, doi = {10.14712/fb2022068050189}, pmid = {37256553}, issn = {0015-5500}, mesh = {Humans ; Caspase 3/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; HeLa Cells ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Apoptosis ; *Saponins/pharmacology ; *Adenocarcinoma ; Membrane Potential, Mitochondrial ; CCAAT-Enhancer-Binding Proteins/metabolism/pharmacology ; Ubiquitin-Protein Ligases/metabolism/pharmacology ; }, abstract = {Macranthoside B (MB) is a triterpenoid saponin extracted from Lonicera macranthoides, a traditional Chinese medicine. In the current study, we investigated the anticancer potential of MB in various cancer cells and elucidated its underlying mechanisms. MB exposure inhibited cell proliferation, induced mitochondrial membrane potential (MMP) loss, increased sub-G1 accumulation, and resulted in cleavage of caspase-3 and PARP, which are reflective of apoptosis. In HeLa cells, MB induced down-regulation of SOD2 and GPx1, phosphorylation of Akt and PDK1, and thus promoted ROS-mediated apoptosis. This was further supported by the protection of sub-G1 accumulation, MMP loss, cleavage of caspase-3 and PARP in the presence of N-acetylcysteine (NAC). Additionally, MB induced cell death via down-regulation of ubiquitin-like with PHD and ringfinger domains 1 (UHRF1) and Bcl-xL. Taken together, this study provides a new insight into the apoptosis- inducing potential of MB, and its molecular mechanisms are associated with an increase in oxidative stress and inhibition of the PDK1/Akt pathway.}, } @article {pmid37059385, year = {2023}, author = {Mao, Z and Li, H and Zhao, XL and Zeng, XH}, title = {Hydrogen sulfide protects Sertoli cells against toxicant Acrolein-induced cell injury.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {176}, number = {}, pages = {113784}, doi = {10.1016/j.fct.2023.113784}, pmid = {37059385}, issn = {1873-6351}, mesh = {Male ; Humans ; *Hydrogen Sulfide/pharmacology/metabolism ; Sertoli Cells/metabolism ; Acrolein/toxicity ; Sulfides/pharmacology ; Antioxidants/pharmacology ; }, abstract = {Acrolein (ACR), a highly toxic α,β-unsaturated aldehyde, is considered to be a common mediator behind the reproductive injury induced by various factors. However, the understanding of its reproductive toxicity and prevention in reproductive system is limited. Given that Sertoli cells provide the first-line defense against various toxicants and that dysfunction of Sertoli cell causes impaired spermatogenesis, we, therefore, examined ACR cytotoxicity in Sertoli cells and tested whether hydrogen sulfide (H2S), a gaseous mediator with potent antioxidative actions, could have a protective effect. Exposure of Sertoli cells to ACR led to cell injury, as indicated by reactive oxygen species (ROS) generation, protein oxidation, P38 activation and ultimately cell death that was prevented by antioxidant N-acetylcysteine (NAC). Further studies revealed that ACR cytotoxicity on Sertoli cells was significantly exacerbated by the inhibition of H2S-synthesizing enzyme cystathionine γ-lyase (CSE), while significantly suppressed by H2S donor Sodium hydrosulfide (NaHS). It was also attenuated by Tanshinone IIA (Tan IIA), an active ingredient of Danshen that stimulated H2S production in Sertoli cells. Apart from Sertoli cells, H2S also protected the cultured germ cells from ACR-initiated cell death. Collectively, our study characterized H2S as endogenous defensive mechanism against ACR in Sertoli cells and germ cells. This property of H2S could be used to prevent and treat ACR-related reproductive injury.}, } @article {pmid37058841, year = {2023}, author = {Wang, Y and Zhang, F and Liu, J and Yang, B and Yuan, Y and Zhou, Y and Bi, S}, title = {A fluorescence nanoprobe of N-Acetyl-L-Cysteine capped CdTe QDs for sensitive detection of nitrofurazone.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {297}, number = {}, pages = {122709}, doi = {10.1016/j.saa.2023.122709}, pmid = {37058841}, issn = {1873-3557}, mesh = {Animals ; Cattle ; *Quantum Dots/chemistry ; Acetylcysteine ; *Cadmium Compounds/chemistry ; Fluorescence ; Tellurium/chemistry ; Nitrofurazone ; Spectroscopy, Fourier Transform Infrared ; Spectrometry, Fluorescence/methods ; }, abstract = {A method was established for detecting the content of nitrofurazone (NFZ) by fluorescence quenching of N-Acetyl-L-Cysteine (NAC) coated cadmium telluride quantum dots (CdTe QDs). By means of transmission electron microscopy (TEM) and multispectral methods such as fluorescence and ultraviolet visible spectra (UV-vis), the synthesized CdTe QDs were characterized. The quantum yield (φ) of CdTe QDs was measured as 0.33 by reference method. The CdTe QDs had a better stability, the RSD of fluorescence intensity was 1.51% in three months. NFZ quenching the emission light of CdTe QDs was observed. The analyses of Stern-Volmer and time-resolved fluorescence suggested the quenching was static. The binding constants (Ka) between NFZ and CdTe QDs were 1.14 × 10[4] (293 K), 0.74 × 10[4] (303 K) and 0.51 × 10[4] (313 K) L mol[-1]. The hydrogen bond or van der Waals force was the dominated binding force between NFZ and CdTe QDs. The interaction was further characterized by UV-vis absorption as well as Fourier transform infrared spectra (FT-IR). Using fluorescence quenching effect, a quantitative determination of NFZ was carried out. The optimal experimental conditions were studied and determined as following: pH was 7 and contact time was 10 min. The effects of reagent addition sequence, temperature and the foreign substances including some metals (Mg[2+]; Zn[2+]; Ca[2+]; K[+]; Cu[2+]), glucose, bovine serum albumin (BSA) and furazolidone on the determination were studied. There was a high correlation between the concentration of NFZ (0.40 - 39.63 μg mL[-1]) and F0/F with the standard curve F0/F = 0.0262c + 0.9910 (r = 0.9994). The detection limit (LOD) reached 0.04 μg mL[-1] (3S0/S). The contents of NFZ in beef and bacteriostatic liquid were detected. The recovery of NFZ was 95.13% - 103.03% and RSD was 0.66% - 1.37% (n = 5).}, } @article {pmid37056637, year = {2023}, author = {Mokhtari, Z and Raeeszadeh, M and Akradi, L}, title = {Comparative Effect of the Active Substance of Thyme with N-Acetyl Cysteine on Hematological Parameters and Histopathological Changes of Bone Marrow and Liver in Rat Models of Acetaminophen Toxicity.}, journal = {Analytical cellular pathology (Amsterdam)}, volume = {2023}, number = {}, pages = {1714884}, pmid = {37056637}, issn = {2210-7185}, mesh = {Animals ; Rats ; Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Bone Marrow ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Liver ; Rats, Wistar ; *Thymus Plant ; }, abstract = {Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac + 100Ex, Ac + 200Ex, and Ac + 400Ex groups (acetaminophen + thyme extract at doses of 100, 200, 400 mg/kg); and Ac + NA group (acetaminophen + NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac + NA and Ac + 200Ex groups (P = 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac + 400Ex groups showed significant differences from those of the other test groups (P < 0.001). Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in Ac + 200Ex and Ac + NA groups showed a significant decrease compared to those of the other treatment groups (P = 0.043). Total antioxidant capacity (TAC) and glutathione peroxidase (GPx) had the lowest levels in Ac and Ac + 400Ex groups, while malondialdehyde (MDA) had the highest content. In this regard, the liver histopathological indices (necrosis, hyperemia, and hemorrhage) in the Ac + 200Ex and Ac + NA groups reached their lowest grades in the treatment groups. The mean number of erythroid and myeloid cells in the Ac group reached the lowest (17.40 ± 3.48). The microscopic appearance of the bone marrow cells was different from normocytosis in the control group to hypocytosis in the Ac and Ac + 400Ex groups. Thymol, as an effective ingredient in thyme extract at a dose of 200 mg/kg compared to NAC, had a unique effect on reducing bone marrow and liver cell-tissue changes due to the acetaminophen toxicity.}, } @article {pmid37055935, year = {2023}, author = {Xue, Q and Kang, R and Klionsky, DJ and Tang, D and Liu, J and Chen, X}, title = {Copper metabolism in cell death and autophagy.}, journal = {Autophagy}, volume = {19}, number = {8}, pages = {2175-2195}, pmid = {37055935}, issn = {1554-8635}, support = {R35 GM131919/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Autophagy/physiology ; Tumor Suppressor Protein p53 ; Apoptosis Inducing Factor ; Copper ; Ubiquinone ; Electron Transport Complex IV ; Autophagy-Related Protein-1 Homolog ; Proto-Oncogene Proteins p21(ras) ; Apoptosis/physiology ; Caspases ; Hypoxia-Inducible Factor 1 ; Superoxide Dismutase ; *Neoplasms ; Ions ; Proto-Oncogene Proteins c-bcl-2 ; }, abstract = {Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, copper ions can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays a dual role in regulating the survival or death fate of cells under various stress conditions. Pathologically, impaired copper metabolism due to environmental or genetic causes is implicated in a variety of human diseases, such as rare Wilson disease and common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents that can be used alone or in combination with other drugs or approaches to treat cancer. Here, we review the progress made in understanding copper metabolic processes and their impact on the regulation of cell death and autophagy. This knowledge may help in the design of future clinical tools to improve cancer diagnosis and treatment.Abbreviations: ACSL4, acyl-CoA synthetase long chain family member 4; AIFM1/AIF, apoptosis inducing factor mitochondria associated 1; AIFM2, apoptosis inducing factor mitochondria associated 2; ALDH, aldehyde dehydrogenase; ALOX, arachidonate lipoxygenase; AMPK, AMP-activated protein kinase; APAF1, apoptotic peptidase activating factor 1; ATF4, activating transcription factor 4; ATG, autophagy related; ATG13, autophagy related 13; ATG5, autophagy related 5; ATOX1, antioxidant 1 copper chaperone; ATP, adenosine triphosphate; ATP7A, ATPase copper transporting alpha; ATP7B, ATPase copper transporting beta; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCS, bathocuproinedisulfonic acid; BECN1, beclin 1; BID, BH3 interacting domain death agonist; BRCA1, BRCA1 DNA repair associated; BSO, buthionine sulphoximine; CASP1, caspase 1; CASP3, caspase 3; CASP4/CASP11, caspase 4; CASP5, caspase 5; CASP8, caspase 8; CASP9, caspase 9; CCS, copper chaperone for superoxide dismutase; CD274/PD-L1, CD274 molecule; CDH2, cadherin 2; CDKN1A/p21, cyclin dependent kinase inhibitor 1A; CDKN1B/p27, cyclin-dependent kinase inhibitor 1B; COMMD10, COMM domain containing 10; CoQ10, coenzyme Q 10; CoQ10H2, reduced coenzyme Q 10; COX11, cytochrome c oxidase copper chaperone COX11; COX17, cytochrome c oxidase copper chaperone COX17; CP, ceruloplasmin; CYCS, cytochrome c, somatic; DBH, dopamine beta-hydroxylase; DDIT3/CHOP, DNA damage inducible transcript 3; DLAT, dihydrolipoamide S-acetyltransferase; DTC, diethyldithiocarbamate; EIF2A, eukaryotic translation initiation factor 2A; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ER, endoplasmic reticulum; ESCRT-III, endosomal sorting complex required for transport-III; ETC, electron transport chain; FABP3, fatty acid binding protein 3; FABP7, fatty acid binding protein 7; FADD, Fas associated via death domain; FAS, Fas cell surface death receptor; FASL, Fas ligand; FDX1, ferredoxin 1; GNAQ/11, G protein subunit alpha q/11; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSH, glutathione; HDAC, histone deacetylase; HIF1, hypoxia inducible factor 1; HIF1A, hypoxia inducible factor 1 subunit alpha; HMGB1, high mobility group box 1; IL1B, interleukin 1 beta; IL17, interleukin 17; KRAS, KRAS proto-oncogene, GTPase; LOX, lysyl oxidase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAP1LC3, microtubule associated protein 1 light chain 3; MAP2K1, mitogen-activated protein kinase kinase 1; MAP2K2, mitogen-activated protein kinase kinase 2; MAPK, mitogen-activated protein kinases; MAPK14/p38, mitogen-activated protein kinase 14; MEMO1, mediator of cell motility 1; MT-CO1/COX1, mitochondrially encoded cytochrome c oxidase I; MT-CO2/COX2, mitochondrially encoded cytochrome c oxidase II; MTOR, mechanistic target of rapamycin kinase; MTs, metallothioneins; NAC, N-acetylcysteine; NFKB/NF-Κb, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NPLOC4/NPL4, NPL4 homolog ubiquitin recognition factor; PDE3B, phosphodiesterase 3B; PDK1, phosphoinositide dependent protein kinase 1; PHD, prolyl-4-hydroxylase domain; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PMAIP1/NOXA, phorbol-12-myristate-13-acetate-induced protein 1; POR, cytochrome P450 oxidoreductase; PUFA-PL, PUFA of phospholipids; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SCO1, synthesis of cytochrome C oxidase 1; SCO2, synthesis of cytochrome C oxidase 2; SLC7A11, solute carrier family 7 member 11; SLC11A2/DMT1, solute carrier family 11 member 2; SLC31A1/CTR1, solute carrier family 31 member 1; SLC47A1, solute carrier family 47 member 1; SOD1, superoxide dismutase; SP1, Sp1 transcription factor; SQSTM1/p62, sequestosome 1; STEAP4, STEAP4 metalloreductase; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TFEB, transcription factor EB; TM, tetrathiomolybdate; TP53/p53, tumor protein p53; TXNRD1, thioredoxin reductase 1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK1, Unc-51 like autophagy activating kinase 1; ULK1, unc-51 like autophagy activating kinase 1; ULK2, unc-51 like autophagy activating kinase 2; USP14, ubiquitin specific peptidase 14; VEGF, vascular endothelial gro wth factor; XIAP, X-linked inhibitor of apoptosis.}, } @article {pmid37054769, year = {2023}, author = {Vongsfak, J and Apaijai, N and Chunchai, T and Pintana, H and Arunsak, B and Maneechote, C and Singhanat, K and Wu, D and Liang, G and Chattipakorn, N and Chattipakorn, SC}, title = {Acute administration of myeloid differentiation factor 2 inhibitor and N-acetyl cysteine attenuate brain damage in rats with cardiac ischemia/reperfusion injury.}, journal = {Archives of biochemistry and biophysics}, volume = {740}, number = {}, pages = {109598}, doi = {10.1016/j.abb.2023.109598}, pmid = {37054769}, issn = {1096-0384}, mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Myocardial Reperfusion Injury/drug therapy/metabolism ; *Reperfusion Injury/drug therapy/pathology ; Brain/metabolism ; Oxidative Stress ; *Encephalitis/pathology ; Ischemia/pathology ; }, abstract = {Inflammation and oxidative stress are mechanisms which potentially underlie the brain damage that can occur after cardiac ischemic and reperfusion (I/R) injury. 2i-10 is a new anti-inflammatory agent, acting via direct inhibition of myeloid differentiation factor 2 (MD2). However, the effects of 2i-10 and the antioxidant N-acetylcysteine (NAC) on pathologic brain in cardiac I/R injury are unknown. We hypothesized that 2i-10 and NAC offer similar neuroprotection levels against dendritic spine reduction through attenuation of brain inflammation, loss of tight junction integrity, mitochondrial dysfunction, reactive gliosis, and suppression of AD protein expression in rats with cardiac I/R injury. Male rats were allocated to either sham or acute cardiac I/R group (30 min of cardiac ischemia and 120 min of reperfusion). Rats in cardiac I/R group were given one of following treatments intravenously at the onset of reperfusion: vehicle, 2i-10 (20 or 40 mg/kg), and NAC (75 or 150 mg/kg). The brain was then used to determine biochemical parameters. Cardiac I/R led to cardiac dysfunction with dendritic spine loss, loss of tight junction integrity, brain inflammation, and mitochondrial dysfunction. Treatment with 2i-10 (both doses) effectively reduced cardiac dysfunction, tau hyperphosphorylation, brain inflammation, mitochondrial dysfunction, dendritic spine loss, and improved tight junction integrity. Although both doses of NAC effectively reduced brain mitochondrial dysfunction, treatment using a high dose of NAC reduced cardiac dysfunction, brain inflammation, and dendritic spine loss. In conclusion, treatment with 2i-10 and a high dose of NAC at the onset of reperfusion alleviated brain inflammation and mitochondrial dysfunction, consequently reducing dendritic spine loss in rats with cardiac I/R injury.}, } @article {pmid37052190, year = {2023}, author = {Chin, HK and Lu, MC and Hsu, KC and El-Shazly, M and Tsai, TN and Lin, TY and Shih, SP and Lin, TE and Wen, ZH and Yang, YSH and Liu, YC}, title = {Exploration of anti-leukemic effect of soft coral-derived 13-acetoxysarcocrassolide: Induction of apoptosis via oxidative stress as a potent inhibitor of heat shock protein 90 and topoisomerase II.}, journal = {The Kaohsiung journal of medical sciences}, volume = {39}, number = {7}, pages = {718-731}, doi = {10.1002/kjm2.12678}, pmid = {37052190}, issn = {2410-8650}, support = {KAFGH_D_110031//Kaohsiung Armed Forces General Hospital/ ; KMUH DK(B)110001-3//Kaohsiung Medical University Hospital/ ; MOST 107-2320-B-259-004-MY3//Ministry of Science and Technology/ ; MOST 110-2314-B-037-083//Ministry of Science and Technology/ ; MOST 110-2320-B259-001-MY3//Ministry of Science and Technology/ ; 109T2560-5//National Dong Hwa University/ ; 110T2560-5//National Dong Hwa University/ ; NHRI-111A1-CACO-03222109//National Health Research Institutes/ ; }, mesh = {Humans ; Animals ; Mice ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Molecular Docking Simulation ; *Anthozoa/metabolism ; Oxidative Stress ; Apoptosis ; *Antineoplastic Agents/pharmacology/therapeutic use ; DNA Topoisomerases, Type II/metabolism ; Heat-Shock Proteins/metabolism/pharmacology ; }, abstract = {13-Acetoxysarcocrassolide (13-AC) is a marine cembranoid derived from the aquaculture soft coral of Lobophytum crassum. The cytotoxic effect of 13-AC against leukemia cells was previously reported but its mechanism of action is still unexplored. In the current study, we showed that 13-AC induced apoptosis of human acute lymphoblastic leukemia Molt4 cells, as evidenced by the cleavage of PARP and caspases, phosphatidylserine externalization, as well as the disruption of mitochondrial membrane potential. The use of N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, attenuated the cytotoxic effect induced by 13-AC. Molecular docking and thermal shift assay indicated that the cytotoxic mechanism of action of 13-AC involved the inhibition of heat shock protein 90 (Hsp 90) activity by eliciting the level of Hsp 70 and topoisomerase IIα in Molt4 cells. 13-AC also exhibited potent antitumor activity by reducing the tumor volume (48.3%) and weight (72.5%) in the in vivo Molt4 xenograft mice model. Our findings suggested that the marine cembranoid, 13-AC, acted as a dual inhibitor of Hsp 90 and topoisomerase IIα, exerting more potent apoptotic activity via the enhancement of ROS generation.}, } @article {pmid37051421, year = {2022}, author = {Sharma, S and Anand, A and Bhatia, A and Sharma, V and Singh, AK and Banerjee, D and Patil, AN}, title = {Pharmacological Evaluation of Scopoletin in the Carbon Tetrachloride-Induced Hepatotoxicity Model in Wistar Rats.}, journal = {Journal of pharmacy & bioallied sciences}, volume = {14}, number = {4}, pages = {201-206}, pmid = {37051421}, issn = {0976-4879}, abstract = {BACKGROUND: Several phyto-chemicals have been identified and suggested as potential therapeutic options for hepatotoxicity management.

OBJECTIVE: To assess the hepatoprotective effect of scopoletin, a pure phyto-chemical, in carbon tetrachloride (CCl4)-induced hepatotoxicity model in Wistar rats.

METHODS: Thirty-six rats in total, six in each group, were utilized in this study. Animals in group 1 received normal saline; those in group 2 received carbon tetrachloride in olive oil (0.5 ml/kg, i.p. in ratio 1:1); those in groups 3, 4, and 5 received oral scopoletin (1 mg/kg, 5 mg/kg, 10 mg/kg dose-wise groups); and those in group 6 received N-acetyl cysteine (NAC) 150 mg/kg. Blood sampling was performed on day -3, day 1, and day 7 of the CCl4 administration. Rats were sacrificed on day 7 of the experiment for histological examination and oxidative stress measurement of the liver.

RESULTS: The 5 mg/kg scopoletin group showed a maximum reduction in AST levels [727.33 ± 29.15 in medium dose (MD) group vs 1526.66 ± 60.72 in the experimental control (EC) group (P < 0.001) and ALT levels of 532.66 ± 24.23 in MD group vs 894.83 ± 52.47 in EC (P < 0.01)]. The dose-dependent action was not observed with scopoletin doses. The protective effect of scopoletin was confirmed by MDA and GSH levels (P < 0.05) coupled with histo-pathological findings. In the present study, a reversible model of CCl4-induced hepatotoxicity was observed to get normalized in a week's time.

CONCLUSION: The study confirms the hepatoprotective action of scopoletin in an acute model of hepatic injury with the putative anti-oxidant mechanism.}, } @article {pmid37049804, year = {2023}, author = {Xu, Y and Geng, Z and Yang, C and Zhou, H and Wang, Y and Kuerban, B and Luo, G}, title = {Effect of N-acetyl-l-cysteine on Cell Phenotype and Autophagy in Pichia pastoris Expressing Human Serum Albumin and Porcine Follicle-Stimulating Hormone Fusion Protein.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {7}, pages = {}, pmid = {37049804}, issn = {1420-3049}, support = {32102542//National Natural Science Foundation of China/ ; }, mesh = {Saccharomycetales ; Recombinant Proteins/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Autophagy ; Follicle Stimulating Hormone/metabolism ; Phenotype ; Swine ; Humans ; *Serum Albumin, Human/metabolism ; Recombinant Fusion Proteins/genetics ; Animals ; Pichia/genetics/metabolism ; }, abstract = {Pichia pastoris is widely used for the production of recombinant proteins, but the low secretion efficiency hinders its wide application in biopharmaceuticals. Our previous study had shown that N-acetyl-l-cysteine (NAC) promotes human serum albumin and porcine follicle-stimulating hormone fusion protein (HSA-pFSHβ) secretion by increasing intracellular GSH levels, but the downstream impact mechanism is not clear. In this study, we investigated the roles of autophagy as well as cell phenotype in NAC promoting HSA-pFSHβ secretion. Our results showed that NAC slowed down the cell growth rate, and its effects were unaffected by Congo Red and Calcofluor White. Moreover, NAC affected cell wall composition by increasing chitin content and decreasing β-1,3-glucan content. In addition, the expressions of vesicular pathway and autophagy-related genes were significantly decreased after NAC treatment. Further studies revealed that autophagy, especially the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy and pexophagy, was significantly increased with time, and NAC has a promoting effect on autophagy, especially at 48 h and 72 h of NAC treatment. However, the disruption of mitophagy receptor Atg32, but not pexophagy receptor Atg30, inhibited HSA-pFSHβ production, and neither of them inhibited the NAC-promoted effect of HSA-pFSHβ. In conclusion, vesicular transport, autophagy and cell wall are all involved in the NAC-promoted HSA-pFSHβ secretion and that disruption of the autophagy receptor alone does not inhibit the effect of NAC.}, } @article {pmid37048082, year = {2023}, author = {Seo, YN and Baik, JS and Lee, SM and Lee, JE and Ahn, HR and Lim, MS and Park, MT and Kim, SD}, title = {Ionizing Radiation Selectively Increases CXC Ligand 10 Level via the DNA-Damage-Induced p38 MAPK-STAT1 Pathway in Murine J774A.1 Macrophages.}, journal = {Cells}, volume = {12}, number = {7}, pages = {}, pmid = {37048082}, issn = {2073-4409}, mesh = {Animals ; Mice ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Endothelial Cells/metabolism ; Ligands ; Macrophages/metabolism ; Radiation, Ionizing ; DNA ; STAT1 Transcription Factor/metabolism ; }, abstract = {Ionizing radiation (IR) is an important means of tumor treatment in addition to surgery and drugs. Attempts have been made to improve the efficiency of radiotherapy by identifying the various biological effects of IR on cells. Components of the tumor microenvironment, such as macrophages, fibroblasts, and vascular endothelial cells, influence cancer treatment outcomes through communication with tumor cells. In this study, we found that IR selectively increased the production of CXC motif chemokine ligand 10 (CXCL10), which is emerging as an important biomarker for determining the prognosis of anticancer treatments, without changing the levels of CXCL9 and CXCL11 in murine J774A.1 macrophages. Pretreatment with KU55933, an ataxia telangiectasia mutated (ATM) kinase inhibitor, significantly inhibited IR-induced CXCL10 production. In contrast, pretreatment with N-acetyl-cysteine or glutathione, a reactive oxygen species scavenger, did not inhibit IR-induced CXCL10 production. Further, we attempted to identify the intracellular molecular target associated with the IR-induced increase in CXCL10 secretion by J774A.1 macrophages. IR phosphorylated p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1) in J774A.1 macrophages, and p38 MAPK and STAT1 were involved in CXCL10 via IR using pharmacological inhibitors (SB203580 and fludarabine, respectively) and the siRNA technique.}, } @article {pmid37044095, year = {2023}, author = {Auf der Maur, P and Trefny, MP and Baumann, Z and Vulin, M and Correia, AL and Diepenbruck, M and Kramer, N and Volkmann, K and Preca, BT and Ramos, P and Leroy, C and Eichlisberger, T and Buczak, K and Zilli, F and Okamoto, R and Rad, R and Jensen, MR and Fritsch, C and Zippelius, A and Stadler, MB and Bentires-Alj, M}, title = {N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer.}, journal = {Cell reports. Medicine}, volume = {4}, number = {4}, pages = {101002}, pmid = {37044095}, issn = {2666-3791}, mesh = {Humans ; Mice ; Animals ; Female ; *Breast Neoplasms/drug therapy/genetics/metabolism ; Phosphatidylinositol 3-Kinase ; Acetylcysteine/pharmacology ; Class I Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/genetics ; }, abstract = {A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CA[H1047R]-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CA[H1047R] breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.}, } @article {pmid37040789, year = {2023}, author = {Xing, S and Guo, Z and Lang, J and Zhou, M and Cao, J and He, H and Yu, L and Zhou, Y}, title = {N-Acetyl-l-cysteine ameliorates gestational diabetes mellitus by inhibiting oxidative stress.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {39}, number = {1}, pages = {2189969}, doi = {10.1080/09513590.2023.2189969}, pmid = {37040789}, issn = {1473-0766}, mesh = {Pregnancy ; Female ; Humans ; Mice ; Animals ; *Diabetes, Gestational ; Acetylcysteine ; Blood Glucose ; NF-E2-Related Factor 2 ; Oxidative Stress ; }, abstract = {Objective: Gestational diabetes mellitus (GDM) affects 7% of pregnant women worldwide. How to effectively treat GDM has always been a concern of people.Research methods: In this study, a diabetes model was established by drug-induced mice. Subsequently, the blood glucose levels and serum insulin changes of the mice after N-acetyl-l-cysteine (NAC) treatment were observed. At the same time, the effect of NAC on reproduction of GDM mice was recorded.Results of the study: Mice fed NAC showed significantly improved glucose tolerance and insulin sensitivity compared to Diabetic/Control. Total serum cholesterol, serum triglycerides, and serum low-density lipoprotein were significantly reduced, and atherosclerosis index was much lower than in control mice. In addition, Diabetic/Control mice had lower litter sizes and higher birth weights. NAC treatment significantly restored litter size and reduced birth weight in Diabetic/Control mice. It was found in WB assay that the NAC-fed group significantly increased nuclear Nrf2 and HO-1 expression levels.Conclusion: NAC can improve blood glucose tolerance in GDM mice; NAC effectively relieves the symptoms of hyperlipidemia caused by GDM; NAC enhances the expression of Nrf2/HO-1 in the liver, thereby restoring redox homeostasis. NAC can reduce gestational diabetes-related disease indicators by oral administration, and has a beneficial effect on the offspring of pregnant mice (reduces its diabetes disease indicators).}, } @article {pmid37033589, year = {2023}, author = {Sharieff, S and Idrees, A and Rafai, W and Bukhari, SUS}, title = {Use of Oral N-Acetylcysteine (NAC) in Non-Acetaminophen-Induced Acute Hepatic Failure.}, journal = {Cureus}, volume = {15}, number = {3}, pages = {e35852}, pmid = {37033589}, issn = {2168-8184}, abstract = {BACKGROUND: Acute liver failure (ALF) is a syndrome rather than a specific disease with several possible causes, and viral hepatitis is a major cause. The objective of the study was to assess the benefit of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF).

METHODS: A total of six patients with a diagnosis of acute liver failure (ALF) were included in the study. All six patients received oral NAC for 72 hrs. The parameters evaluated were demographic, clinical, biochemical, outcome, and length of ICU and hospital stay. The primary outcome was a reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate the safety of NAC and assess factors predicting mortality.

RESULTS: All patients improved and returned to normal or near-normal liver function with the use of NAC. No side effects were noted, and the use of NAC was associated with a shorter hospital stay.

CONCLUSION: In patients with non-acetaminophen-related acute liver failure, N-acetyl-L-cysteine (NAC) significantly improves overall survival and also decreases the length of hospital stay.}, } @article {pmid37027944, year = {2023}, author = {Wang, M and Xu, J and Zhao, Z and Gong, L and Su, Y and Fang, Z and Chen, P and Liu, Y and Zhang, L and Xu, F}, title = {Triphenyl phosphate induced apoptosis of mice testicular Leydig cells and TM3 cells through ROS-mediated mitochondrial fusion inhibition.}, journal = {Ecotoxicology and environmental safety}, volume = {256}, number = {}, pages = {114876}, doi = {10.1016/j.ecoenv.2023.114876}, pmid = {37027944}, issn = {1090-2414}, mesh = {Mice ; Animals ; Male ; *Leydig Cells/metabolism ; Reactive Oxygen Species/metabolism ; *Mitochondrial Dynamics ; Mice, Inbred C57BL ; Apoptosis ; Mitochondrial Proteins/metabolism ; Organophosphates/metabolism ; Testosterone/metabolism ; }, abstract = {Triphenyl phosphate (TPHP) is a widely used organophosphate flame retardant and has biological toxicity. Previous studies showed TPHP can restrain testosterone biosynthesis in Leydig cells, while the underlying mechanisms remain unclear. In this study, C57BL/6J male mice were exposed to 0, 5, 50, and 200 mg/kg B.W. of TPHP for 30 d by oral, as well as TM3 cells were treated with 0, 50, 100, and 200 μM of TPHP for 24 h. Results showed that TPHP induced testes damage, including spermatogenesis disorders and testosterone synthesis inhibition. Meanwhile, TPHP can cause apoptosis in testicular Leydig cells and TM3 cells, as evidenced by the increased apoptosis rate and decreased Bcl-2/Bax ratio. Moreover, TPHP disrupted mitochondrial ultrastructure of testicular Leydig cells and TM3 cells, reduced healthy mitochondria content and depressed mitochondrial membrane potential of TM3 cells, as well as inhibited mitochondrial fusion proteins mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (Opa1) expression, without effect on mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis1) in testicular tissue and/or TM3 cells. Then, the mitochondrial fusion promoter M1 was used to pre-treat TPHP-exposed TM3 cells to determine the roles of mitochondrial fusion inhibition in TPHP-induced Leydig cells apoptosis. The results showed M1 pretreatment alleviated the above changes and further mitigated TM3 cells apoptosis and testosterone levels decreased, indicating TPHP induced TM3 cells apoptosis by inhibited mitochondrial fusion. Intriguingly, the intervention experiment of N-acetylcysteine (NAC) showed that TPHP-induced mitochondrial fusion inhibition is ROS dependent, because inhibition of ROS overproduction alleviated mitochondrial fusion inhibition, and subsequently relieved TPHP-induced apoptosis in TM3 cells. In summary, above data revealed that apoptosis is a specific mechanism for TPHP-induced male reproductive toxicity, and that ROS-mediated mitochondrial fusion inhibition is responsible for Leydig cells apoptosis caused by TPHP.}, } @article {pmid37017249, year = {2023}, author = {Uehara, H and Itoigawa, Y and Morikawa, D and Koga, A and Tsurukami, H and Maruyama, Y and Ishijima, M}, title = {The Effect of Vitamin C and N-Acetylcysteine on Tendon-to-Bone Healing in a Rodent Model of Rotator Cuff Repair.}, journal = {The American journal of sports medicine}, volume = {51}, number = {6}, pages = {1596-1607}, doi = {10.1177/03635465231160772}, pmid = {37017249}, issn = {1552-3365}, mesh = {Rats ; Animals ; *Rotator Cuff/physiology ; Acetylcysteine/pharmacology/therapeutic use ; Matrix Metalloproteinase 13 ; Wound Healing/physiology ; Collagen/metabolism ; Rodentia/metabolism ; Rats, Sprague-Dawley ; Ascorbic Acid/pharmacology/therapeutic use ; Superoxide Dismutase-1/pharmacology ; Tendons/surgery ; *Rotator Cuff Injuries/drug therapy/surgery/pathology ; Biomechanical Phenomena ; }, abstract = {BACKGROUND: Oxidative stress inhibits tendon-to-bone healing after rotator cuff repair. Regulation of oxidative stress has the potential to accelerate this healing, but its mechanism remains unclear.

PURPOSE: To investigate the effects of reducing oxidative stress by applying antioxidants, such as N-acetylcysteine (NAC) and vitamin C (VC), on rotator cuff repair in a rat rotator cuff repair model.

STUDY DESIGN: Controlled laboratory study.

METHODS: A total of 48 Sprague Dawley rats underwent bilateral surgery to repair the infraspinatus tendon to its insertion site 1 week after detachment. Rats were assigned to either the NAC group, the VC group, or a control group. Histological evaluation was performed via hematoxylin-eosin or toluidine blue staining, and oxidative stress was assessed via dihydroethidium intensity and protein carbonyl concentration at 3 and 6 weeks. Superoxide dismutase 1 (SOD1), SOD2, SOD3, peroxiredoxin 5, collagen type I (COL1), COL3, matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 expression and SOD activity were determined at 3 and 6 weeks. Biomechanical tests were performed at 6 and 12 weeks.

RESULTS: Histological evaluation showed that the number of chondrocytes in the NAC group at 6 weeks and in the VC group at 3 and 6 weeks, the area of fibrocartilage at 6 weeks in the VC group, and collagen fibers at 6 weeks in the NAC and VC groups were significantly increased compared with those in the control group. Dihydroethidium intensity at 3 and 6 weeks and protein carbonyls at 6 weeks in the NAC and VC groups were significantly decreased. SOD1 expression and SOD activity at 3 weeks in the VC group and peroxiredoxin 5 expression at 6 weeks in the NAC group were significantly upregulated compared with that in the control group. COL3 expression was significantly upregulated at 6 weeks in the VC group, and MMP-13 expression was significantly decreased at 6 weeks in the NAC and VC groups. The biomechanical strength showed no significant difference.

CONCLUSION: Antioxidant treatment, via NAC or VC administration, reduced oxidative stress in the rotator cuff repair site and accelerated healing.

CLINICAL RELEVANCE: These findings provide essential indications to develop clinical strategies for improved healing after rotator cuff surgical repair in patients.}, } @article {pmid37016183, year = {2023}, author = {Yalçın, T and Kaya, S and Kuloğlu, T and Yiğin, A}, title = {N-Acetylcysteine May Regulate Altered Meteorin-Like Levels in Testicular Tissue due to Aluminum Exposure.}, journal = {Biological trace element research}, volume = {201}, number = {11}, pages = {5335-5345}, pmid = {37016183}, issn = {1559-0720}, mesh = {Rats ; Animals ; Male ; *Acetylcysteine/pharmacology ; *Aluminum/metabolism ; Testis ; Rats, Sprague-Dawley ; Antioxidants/pharmacology/metabolism ; Oxidative Stress ; Inflammation/metabolism ; }, abstract = {Aluminum (AL) is a heavy metal known to have toxic effects on the reproductive system. It is known that N-acetylcysteine (NAC), which has an antioxidant effect, is a useful chelator for heavy metals. This study aimed to determine whether NAC may reduce AL-induced oxidative stress, inflammation, and germ cell apoptosis in testicular tissues and its effects on meteorin-like (METRNL) levels, which are known to play a role in energy metabolism. In this experimental study, 28 Sprague-Dawley male rats were randomly divided into 4 groups (n = 7): control, AL (30 mg/kg/day AL), AL + NAC (30 mg/kg/day AL + 150 mg/kg/day NAC), and NAC (150 mg/kg/day NAC). All AL and NAC applications were performed intraperitoneally for 14 days. At the end of the experiment, the effects of AL and/or NAC applications on testicular tissue were examined histomorphometrically, histopathologically, immunohistochemically, and biochemically. It was determined that AL exposure caused histomorphometric and histopathological changes, oxidative stress, apoptosis of germ cells, and inflammation in testicular tissues. In addition, AL caused an increase in METRNL levels. It was determined that NAC treatment significantly reduced the negative effects of AL. NAC therapy may be a protective strategy in reproductive toxicity due to AL exposure.}, } @article {pmid37015815, year = {2023}, author = {Fleming, K and George, JL and Bazelak, SJ and Roeske, JA and Biggs, AD and Landry, CM and Lipchik, RJ and Truwit, JD}, title = {Optimizing Respiratory Therapy Resources by De-Implementing Low-Value Care.}, journal = {Respiratory care}, volume = {68}, number = {5}, pages = {559-564}, pmid = {37015815}, issn = {1943-3654}, mesh = {Humans ; *Low-Value Care ; Pandemics ; *COVID-19/therapy ; Respiratory Therapy ; Acetylcysteine ; }, abstract = {BACKGROUND: Our institution was experiencing a respiratory therapy staffing crisis during the COVID-19 pandemic, in part due to excessive workload. We identified an opportunity to reduce burden by limiting use of 3% hypertonic saline and/or N-acetylcysteine nebulizer therapies (3%HTS/NAC).

METHODS: Leveraging the science of de-implementation, we established a policy empowering respiratory therapists to discontinue 3%HTS/NAC not meeting the American Association for Respiratory Care (AARC) Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients. After a 3-month period of educating physicians and advanced practice practitioners the policy went to into effect. Outcomes measured included monthly number of treatments, orders, and full-time employees associated with administering nebulized 3%HTS/NAC.

RESULTS: Post policy activation, the monthly mean 3%HTS/NAC treatments were significantly reduced to 547.5 ± 284.3 from 3,565.2 ± 596.4 (P < .001) as were the associated monthly mean of full-time employees, 0.8 ± 0.41 from 5.1 ± 0.86 (P < .001). The monthly mean 3%HTS/NAC orders also fell to 93.8 ± 31.5 from 370.0 ± 46.9 (P < .001). Monthly mean non-3%HTS/NAC treatments remained stable; post policy was 3,089.4 ± 611.4 and baseline 3,279.6 ± 695.0 (P = 1.0).

CONCLUSIONS: Implementing a policy that empowers respiratory therapists to promote adherence to AARC Clinical Guidelines reduced low-value therapies, costs, and staffing needs.}, } @article {pmid37010946, year = {2023}, author = {Sumit, and Maravajjala, KS and Khanna, S and Kachwal, V and Swetha, KL and Manabala, S and Chowdhury, R and Roy, A and Laskar, IR}, title = {Rational Molecular Designing of Aggregation-Enhanced Emission (AEE) Active Red-Emitting Iridium(III) Complexes: Effect of Lipophilicity and Nanoparticle Encapsulation on Photodynamic Therapy Efficacy.}, journal = {ACS applied bio materials}, volume = {6}, number = {4}, pages = {1445-1459}, doi = {10.1021/acsabm.2c00998}, pmid = {37010946}, issn = {2576-6422}, mesh = {Humans ; Iridium/pharmacology ; Reactive Oxygen Species ; *Coordination Complexes/pharmacology ; *Photochemotherapy ; }, abstract = {Two "aggregation-enhanced emission" (AEE) active cyclometalated phosphorescent iridium(III) complexes, SM2 and SM4, were synthesized to evaluate the influence of lipophilicity on photodynamic therapy efficacy. Compared to SM2, SM4 had a higher logP due to the presence of naphthyl groups. As observed by confocal microscopy, this increased lipophilicity of SM4 significantly enhanced its cellular uptake in breast cancer cells. Both the molecules were found to be noncytotoxic under nonirradiating conditions. However, with light irradiation, SM4 exhibited significant cytotoxicity at a 500 nM dose, whereas SM2 remained noncytotoxic, signifying the influence of lipophilicity on cellular internalization and cytotoxicity. Mechanistically, light-irradiated SM4-treated cancer cells exhibited a significant increase in the intracellular reactive oxygen species (ROS) level. Neutralizing ROS with N-acetylcysteine (NAC) pretreatment partly abolished the cytotoxic ability, indicating ROS as one of the major effectors of cell cytotoxicity. Two nanoparticle (NP) formulations of SM4 were developed to improve the intracellular delivery: a PLGA-based NP and a Soluplus-based micelle. Interestingly, PLGA and Soluplus NP formulations exhibited a 10- and 22-fold increased emission intensity, respectively, compared to SM4. There was also an increase in the excited-state lifetime. Additionally, the Soluplus-based micelles encapsulating SM4 exhibited enhanced cellular uptake and increased cytotoxicity compared to the PLGA NPs encapsulating SM4. Altogether, the current study indicates the importance of rational molecular designing and the significance of a proper delivery vector for improving photodynamic therapy efficacy.}, } @article {pmid37005695, year = {2023}, author = {Mpagama, SG and Mvungi, HC and Mbelele, PM and Semvua, HH and Liyoyo, AA and de Guex, KP and Sloan, D and Kibiki, GS and Boeree, M and Phillips, PPJ and Heysell, SK}, title = {Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania.}, journal = {Pilot and feasibility studies}, volume = {9}, number = {1}, pages = {55}, pmid = {37005695}, issn = {2055-5784}, support = {D43 TW012247/TW/FIC NIH HHS/United States ; R34 AI112371/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications.

METHODS: This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900 mg daily, and an interventional arm of NAC 900 mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong'oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model.

DISCUSSION: Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials.

TRIAL REGISTRATION: PACTR202007736854169 Registered 03 July 2020.}, } @article {pmid37003188, year = {2023}, author = {Dong, Y and Han, F and Su, Y and Sun, B and Zhao, W and Pan, C}, title = {High uric acid aggravates apoptosis of lung epithelial cells induced by cigarette smoke extract through downregulating PRDX2 in chronic obstructive pulmonary disease.}, journal = {International immunopharmacology}, volume = {118}, number = {}, pages = {110056}, doi = {10.1016/j.intimp.2023.110056}, pmid = {37003188}, issn = {1878-1705}, mesh = {Humans ; Animals ; Mice ; Uric Acid/adverse effects ; Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Cigarette Smoking/adverse effects ; Lung ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Apoptosis ; Nicotiana ; Epithelial Cells ; RNA, Small Interfering/genetics ; Peroxiredoxins/genetics/adverse effects ; }, abstract = {Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens the elevation of reactive oxygen species (ROS) and thus leads to apoptosis. Hyperuricemia has been considered as a risk factor for COPD. However, the underlying mechanism for this aggravating effect remains unclear. The current study sought to examine the role of high uric acid (HUA) in COPD using cigarette smoke extract (CSE) exposed murine lung epithelial (MLE-12) cells. Our data showed that CSE induced the increase of ROS, mitochondrial dynamics disorder, and apoptosis, while HUA treatment aggravated the effects of CSE. Further studies suggested that HUA decreased the expression of antioxidant enzyme-peroxiredoxin-2 (PRDX2). Overexpression of PRDX2 inhibited excessive ROS generation, mitochondrial dynamics disorder, and apoptosis induced by HUA. Knockdown of PRDX2 by small interfering RNA (siRNA) promoted ROS generation, mitochondrial dynamics disorder, and apoptosis in MLE-12 cells treated with HUA. However, antioxidant N-acetylcysteine (NAC) reversed the effects of PRDX2-siRNA on MLE-12 cells. In conclusion, HUA aggravated CSE-induced cellular ROS levels and led to ROS-dependent mitochondrial dynamics disorder and apoptosis in MLE-12 cells through downregulating PRDX2.}, } @article {pmid36991205, year = {2023}, author = {Jin, X and Wu, P and Li, P and Xiong, C and Gui, M and Huang, W}, title = {Transcriptome analysis reveals insight into the protective effect of N-acetylcysteine against cadmium toxicity in Ganoderma lucidum (Polyporales: Polyporaceae).}, journal = {Environmental science and pollution research international}, volume = {30}, number = {20}, pages = {58436-58449}, pmid = {36991205}, issn = {1614-7499}, support = {2019ZG00906//Yunnan Agricultural University/ ; 2022ZZCX028-001//Sichuan Academy of Agricultural Sciences/ ; }, mesh = {Humans ; Animals ; *Reishi/genetics/metabolism ; Acetylcysteine/pharmacology ; Cadmium/metabolism ; *Polyporaceae/genetics/metabolism ; *Polyporales/genetics/metabolism ; Hydrogen Peroxide/metabolism ; Gene Expression Profiling ; *Ganoderma/metabolism ; }, abstract = {Ganoderma lucidum is widely cultivated and used as traditional medicine in China and other Asian countries. As a member of macrofungi, Ganoderma lucidum is also prone to bioaccumulation of cadmium and other heavy metals in a polluted environment, which affects the growth and production of Ganoderma lucidum, as well as human health. N-Acetyl-L-cysteine (NAC) is considered a general antioxidant and free radical scavenger that is involved in the regulation of various stress responses in plants and animals. However, whether NAC could regulate cadmium stress responses in macrofungi, particularly edible fungi, is still unknown. In this work, we found that the exogenous NAC could alleviate Cd-induced growth inhibition and reduce the cadmium accumulation in Ganoderma lucidum. The application of the NAC cloud also inhibit cadmium-induced H2O2 production in the mycelia. By using transcriptome analysis, 2920 and 1046 differentially expressed unigenes were identified in "Cd100 vs CK" and "NAC_Cd100 vs Cd100," respectively. These differential unigenes were classified into a set of functional categories and pathways, which indicated that various biological pathways may play critical roles in the protective effect of NAC against Cd‑induced toxicity in Ganoderma lucidum. Furthermore, it suggested that the ATP-binding cassette transporter, ZIP transporter, heat shock protein, glutathione transferases, and Cytochrome P450 genes contributed to the increased tolerance to cadmium stress after NAC application in Ganoderma lucidum. These results provide new insight into the physiological and molecular response of Ganoderma lucidum to cadmium stress and the protective role of NAC against cadmium toxicity.}, } @article {pmid36988041, year = {2023}, author = {Nesterowicz, M and Żendzian-Piotrowska, M and Ładny, JR and Zalewska, A and Maciejczyk, M}, title = {Biochemical and Biophysical in Vitro Studies and Systematic Literature Review on the Antioxidant and Antiglycation Activities of Trazodone.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {57}, number = {2}, pages = {82-104}, doi = {10.33594/000000617}, pmid = {36988041}, issn = {1421-9778}, support = {SUB/1/DN/22/002/3330//Medical University of Bialystok/Poland ; SUB/1/DN/20/001/3330//Medical University of Bialystok/Poland ; SUB/1/DN/21/001/3330//Medical University of Bialystok/Poland ; }, mesh = {*Antioxidants/metabolism ; *Trazodone/pharmacology ; Glycosylation ; Advanced Oxidation Protein Products/metabolism ; Molecular Docking Simulation ; Glycation End Products, Advanced/metabolism ; Serum Albumin, Bovine/chemistry/metabolism ; Glyoxal/chemistry ; Glucose ; }, abstract = {BACKGROUND/AIMS: Trazodone is a selective serotonin reuptake inhibitor; however, other mechanisms of the drug's anti-depressive properties have also been postulated. Hence, the aim of the study was to perform a systematic review and assess antiglycoxidative properties of trazodone in in vitro models.

METHODS: Trazodone's scavenging and chelating properties were measured with spectrophotometric method. The impact of the drug on carbonyl/oxidative stress was marked in the bovine serum albumin (BSA) model where sugars (glucose, fructose, galactose, ribose) and aldehydes (glyoxal and methylglyoxal) were used as glycation agents. Aminoguanidine and N-acetylcysteine (NAC) were applied as reference glycation/free radical inhibitors. Glycation biomarkers (kynurenine, N-formylkynurenine, dityrosine as well as advanced glycation end products contents) were assessed spectrofluorometrically. Concentrations of oxidation parameters (total thiols (TTs), protein carbonyls (PCs) and also advanced oxidation protein products (AOPPs) levels) were determined spectrophotometrically.

RESULTS: We demonstrated that trazodone poorly scavenged radicals (hydroxyl radical, nitric oxide, hydrogen peroxide and 2,2-diphenyl-1-picrylhydrazyl radical) and showed low ferrous ion chelating, unlike aminoguanidine and NAC. Sugars/aldehydes caused enhancement of glycation parameters, as well as a decrease of TTs and an increase of PCs and AOPPs levels compared to BSA incubated alone. Trazodone did not reduce oxidation parameters to the baseline (BSA) and significantly exacerbated glycation markers in comparison with both BSA and BSA+glycators. The content of glycation products was markedly lower in aminoguanidine and NAC than in trazodone. The molecular docking of trazodone to BSA revealed its very low affinity, which may indicate non-specific binding of trazodone, facilitating the attachment of glycation factors.

CONCLUSION: According to our findings, it may be concluded that trazodone poorly counteracts oxidation and intensifies glycation in vitro. A possible mechanism for antiglycoxidative effect of trazodone in vivo may be the enhancement of the body's adaptive response, as indicated by the results of our systematic review.}, } @article {pmid36986816, year = {2023}, author = {Eulálio, D and Pires Figueiredo, M and Taviot-Gueho, C and Leroux, F and Dos Reis Serra, CH and Faria, DLA and Constantino, VRL}, title = {Development of Dipeptide N-acetyl-L-cysteine Loaded Nanostructured Carriers Based on Inorganic Layered Hydroxides.}, journal = {Pharmaceutics}, volume = {15}, number = {3}, pages = {}, pmid = {36986816}, issn = {1999-4923}, support = {88887.352040/2019-00//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 149404/2018-2//National Council for Scientific and Technological Development/ ; 2016/13862-9//São Paulo Research Foundation/ ; 2012/13119-3//São Paulo Research Foundation/ ; 2016/21070-5//São Paulo Research Foundation/ ; INCT-INEO 2014/50869-6//São Paulo Research Foundation/ ; 314034/2021-8//National Council for Scientific and Technological Development/ ; PRC-Projets de recherché conjoints 1688 and SPRINT-São Paulo Researchers in International Collaboration 2016/50317-9//Research Academic Cooperation Agreement PRC-CNRS-FAPESP/ ; }, abstract = {N-acetyl-L-cysteine (NAC), a derivative of the L-cysteine amino acid, presents antioxidant and mucolytic properties of pharmaceutical interest. This work reports the preparation of organic-inorganic nanophases aiming for the development of drug delivery systems based on NAC intercalation into layered double hydroxides (LDH) of zinc-aluminum (Zn2Al-NAC) and magnesium-aluminum (Mg2Al-NAC) compositions. A detailed characterization of the synthesized hybrid materials was performed, including X-ray diffraction (XRD) and pair distribution function (PDF) analysis, infrared and Raman spectroscopies, solid-state [13]carbon and [27]aluminum nuclear magnetic resonance (NMR), simultaneous thermogravimetric and differential scanning calorimetry coupled to mass spectrometry (TG/DSC-MS), scanning electron microscopy (SEM), and elemental chemical analysis to assess both chemical composition and structure of the samples. The experimental conditions allowed to isolate Zn2Al-NAC nanomaterial with good crystallinity and a loading capacity of 27.3 (m/m)%. On the other hand, NAC intercalation was not successful into Mg2Al-LDH, being oxidized instead. In vitro drug delivery kinetic studies were performed using cylindrical tablets of Zn2Al-NAC in a simulated physiological solution (extracellular matrix) to investigate the release profile. After 96 h, the tablet was analyzed by micro-Raman spectroscopy. NAC was replaced by anions such as hydrogen phosphate by a slow diffusion-controlled ion exchange process. Zn2Al-NAC fulfil basic requirements to be employed as a drug delivery system with a defined microscopic structure, appreciable loading capacity, and allowing a controlled release of NAC.}, } @article {pmid36986437, year = {2023}, author = {Badr, AM and Al-Kharashi, LA and Attia, H and Alshehri, S and Alajami, HN and Ali, RA and Mahran, YF}, title = {TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {3}, pages = {}, pmid = {36986437}, issn = {1424-8247}, support = {NA//King Saud University/ ; }, abstract = {BACKGROUND: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA.

METHODS: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection.

RESULTS: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-κB and TNF-α) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1β) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes.

CONCLUSIONS: This study emphasizes that inhibition of TLR4/NLPR3/IL-1β/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.}, } @article {pmid36982552, year = {2023}, author = {Meliante, PG and Zoccali, F and Cascone, F and Di Stefano, V and Greco, A and de Vincentiis, M and Petrella, C and Fiore, M and Minni, A and Barbato, C}, title = {Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea.}, journal = {International journal of molecular sciences}, volume = {24}, number = {6}, pages = {}, pmid = {36982552}, issn = {1422-0067}, support = {Prot. N.0000625//BANCA D'ITALIA/ ; DSB.AD007.256//National Research Council/ ; }, mesh = {Humans ; *Pathology, Molecular ; Oxidative Stress ; *Sleep Apnea, Obstructive/pathology ; Antioxidants/therapeutic use/metabolism ; Biomarkers/metabolism ; Hypoxia/metabolism ; }, abstract = {Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. The derived oxidative stress (OS) leads to complications that do not only concern the sleep-wake rhythm but also systemic dysfunctions. The aim of this narrative literature review is to investigate molecular alterations, diagnostic markers, and potential medical therapies for OSAS. We analyzed the literature and synthesized the evidence collected. IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. We treated molecular alterations known to date as useful for understanding the pathogenetic mechanisms and for their potential application as diagnostic markers. The most promising pharmacological therapies are those based on N-acetylcysteine (NAC), Vitamin C, Leptin, Dronabinol, or Atomoxetine + Oxybutynin, but all require further experimentation. CPAP remains the approved therapy capable of reversing most of the known molecular alterations; future drugs may be useful in treating the remaining dysfunctions.}, } @article {pmid36981595, year = {2023}, author = {Anastasi, E and Scaramuzzino, S and Viscardi, MF and Viggiani, V and Piccioni, MG and Cacciamani, L and Merlino, L and Angeloni, A and Muzii, L and Porpora, MG}, title = {Efficacy of N-Acetylcysteine on Endometriosis-Related Pain, Size Reduction of Ovarian Endometriomas, and Fertility Outcomes.}, journal = {International journal of environmental research and public health}, volume = {20}, number = {6}, pages = {}, pmid = {36981595}, issn = {1660-4601}, mesh = {Pregnancy ; Female ; Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; *Endometriosis/complications/drug therapy ; Dysmenorrhea/complications ; Acetylcysteine/therapeutic use ; *Dyspareunia/complications ; Prospective Studies ; Cohort Studies ; Neoplasm Recurrence, Local ; Fertility ; }, abstract = {BACKGROUND: Endometriosis is a chronic, estrogen-dependent, inflammatory disease, whose pivotal symptoms are dysmenorrhea, dyspareunia, and chronic pelvic pain (CPP). Besides the usual medical treatments, recent evidence suggests there are potential benefits of oral N-acetylcysteine (NAC) on endometriotic lesions and pain. The primary objective of this prospective single-cohort study was to confirm the effectiveness of NAC in reducing endometriosis-related pain and the size of ovarian endometriomas. The secondary objective was to assess if NAC may play a role in improving fertility and reducing the Ca125 serum levels.

METHODS: Patients aged between 18-45 years old with a clinical/histological diagnosis of endometriosis and no current hormonal treatment or pregnancy were included in the study. All patients received quarterly oral NAC 600 mg, 3 tablets/day for 3 consecutive days of the week for 3 months. At baseline and after 3 months, dysmenorrhea, dyspareunia and CPP were assessed using the Visual Analog Scale score (VAS), while the size of the endometriomas was estimated through a transvaginal ultrasound. Analgesics (NSAIDs) intake, the serum levels of Ca125 and the desire for pregnancy were also investigated. Finally, the pregnancy rate of patients with reproductive desire was evaluated.

RESULTS: One hundred and twenty patients were recruited. The intensity of dysmenorrhea, dyspareunia and CPP significantly improved (p < 0.0001). The use of NSAIDs (p = 0.001), the size of the endometriomas (p < 0.0001) and the serum levels of Ca125 (p < 0.0001) significantly decreased. Among the 52 patients with reproductive desire, 39 successfully achieved pregnancy within 6 months of starting therapy (p = 0.001).

CONCLUSIONS: Oral NAC improves endometriosis-related pain and the size of endometriomas. Furthermore, it decreases Ca125 serum levels and may improve fertility in patients with endometriosis.}, } @article {pmid36978904, year = {2023}, author = {Kwak, AW and Kim, WK and Lee, SO and Yoon, G and Cho, SS and Kim, KT and Lee, MH and Choi, YH and Lee, JY and Park, JW and Shim, JH}, title = {Licochalcone B Induces ROS-Dependent Apoptosis in Oxaliplatin-Resistant Colorectal Cancer Cells via p38/JNK MAPK Signaling.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, pmid = {36978904}, issn = {2076-3921}, support = {2019R1A2C1005899//the Basic Science Research Program of the National Research Foundation Korea (NRF/ ; 2022R1A5A8033794//NRF grant funded by the Korean government (MSIT)/ ; }, abstract = {Licochalcone B (LCB) exhibits anticancer activity in oral cancer, lung cancer, and hepatocellular carcinoma cells. However, little is known about its antitumor mechanisms in human oxaliplatin-sensitive and -resistant colorectal cancer (CRC) cells. The purpose of the present study was to investigate the antitumor potential of LCB against human colorectal cancer in vitro and analyze its molecular mechanism of action. The viability of CRC cell lines was evaluated using the MTT assay. Flow cytometric analyses were performed to investigate the effects of LCB on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. The results demonstrated that LCB induced a reduction in cell viability, apoptosis, G2/M cell cycle arrest, ROS generation, MMP depolarization, activation of multi-caspase, and JNK/p38 MAPK. However, p38 (SB203580) and JNK (SP600125) inhibitors prevented the LCB-induced reduction in cell viability. The ROS scavenger N-acetylcysteine (NAC) inhibited LCB-induced reduction in cell viability, apoptosis, cell cycle arrest, ROS generation, MMP depolarization, and multi-caspase and JNK/p38 MAPK activities. Taken together, LCB has a potential therapeutic effect against CRC cells through the ROS-mediated JNK/p38 MAPK signaling pathway. Therefore, we expect LCB to have promising potential as an anticancer therapeutic and prophylactic agent.}, } @article {pmid36978427, year = {2023}, author = {Walter, H and Verspohl, J and Meißner, J and Oltmanns, H and Geks, AK and Busse, C}, title = {In Vitro Antimicrobial Activity of N-Acetylcysteine against Pathogens Most Commonly Associated with Infectious Keratitis in Dogs and Cats.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, pmid = {36978427}, issn = {2079-6382}, support = {60013053//CP Pharma/ ; }, abstract = {To determine the in vitro antimicrobial activity of N-acetylcysteine (NAC) against common pathogens associated with infectious keratitis in dogs and cats, clinical isolates of Staphylococcus (S.) pseudintermedius (n = 20), Streptococcus (St.) canis (n = 10) and Pseudomonas (P.) aeruginosa (n = 7) of canine and feline infectious ulcerative keratitis and a quality control strain (P. aeruginosa DSM 19880) were tested. The minimal inhibitory concentration (MIC) of NAC concentrations was determined using microdilution methodology. For S. pseudintermedius and P. aeruginosa, NAC concentrations in the range of 1.56 mg/mL (0.156%) to 100 mg/mL (10%), and for St. canis, concentrations ranging from 0.195 mg/mL (0.0195%) to 6.25 mg/mL (0.625%) were tested. For S. pseudintermedius, the MIC was 3.12 mg/mL (0.312%) for all tested isolates. For P. aeruginosa isolates and the quality control strain, the MIC ranged from 3.12 mg/mL (0.312%) to 6.25 mg/mL (0.625%). For St. canis, the MIC ranged from 1.56 mg/mL (0.156%) to 3.12 mg/mL (0.312%). NAC has an in vitro antimicrobial activity against three bacterial species commonly found in infectious keratitis in dogs and cats and therefore may be a promising alternative or adjuvant to topical antibiotics. The results warrant a clinical pilot study to assess the potential of NAC to reduce or replace the use of topical antibiotics in line with the One Health approach.}, } @article {pmid36976990, year = {2023}, author = {Wang, W and Guan, J and Feng, Y and Liu, S and Zhao, Y and Xu, Y and Xu, H and Fu, F}, title = {Polystyrene Microplastics Induced Ovarian Toxicity in Juvenile Rats Associated with Oxidative Stress and Activation of the PERK-eIF2α-ATF4-CHOP Signaling Pathway.}, journal = {Toxics}, volume = {11}, number = {3}, pages = {}, pmid = {36976990}, issn = {2305-6304}, support = {20194BCJ22004//Research Foundation from Academic and Technical Leaders of Major Disciplines in Jiangxi Province, China/ ; }, abstract = {Numerous reports confirm that microplastics exposure could induce reproductive toxicity in mammals. However, the effects of microplastics exposure during juveniles on ovarian apoptosis through oxidative and endoplasmic reticulum (ER) stresses remains unclear, which is the focus of our study. In the present study, female rats (4 weeks old) were exposed to polystyrene microplastics (PS-MPs, 1 μm) at different dosages (0, 0.5, and 2.0 mg/kg) for 28 days. Findings revealed that 2.0 mg/kg of PS-MPs distinctly increased the atretic follicle ratio in the ovary and dramatically reduced the serum levels of estrogen and progesterone. Additionally, the oxidative stress indicators declined, including the activity of superoxide dismutase and catalase, whereas the malondialdehyde content in the ovary was considerably enhanced in the 2.0 mg/kg PS-MPs group. Furthermore, the expressions of genes related to ER stress (PERK, eIF2α, ATF4, and CHOP) and apoptosis were remarkably elevated in the 2.0 mg/kg PS-MPs group compared with those in the control group. We found that PS-MPs induced oxidative stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats. Moreover, with the oxidative stress inhibitor N-acetyl-cysteine and eIF2α dephosphorylation blocker Salubrinal treatment, ovarian damage induced by PS-MPs was repaired and associated enzyme activities were improved. Overall, our results indicated that PS-MPs exposure induced ovarian injury associated with oxidative stress and activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats, providing new prospects for assessing the health risks of children exposed to microplastics.}, } @article {pmid36974638, year = {2023}, author = {Fayed, A and Hammad, AA and Abdulazim, DO and Hammad, H and Amin, M and Elhadidy, S and Salem, MM and ElAzim, IMA and Zsom, L and Csongradi, E and Soliman, KM and Sharaf El Din, UA}, title = {Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study.}, journal = {Renal failure}, volume = {45}, number = {1}, pages = {2194434}, pmid = {36974638}, issn = {1525-6049}, mesh = {Humans ; *Acute Kidney Injury/chemically induced/etiology/prevention & control ; *Allopurinol/administration & dosage/therapeutic use ; *Diabetic Nephropathies/classification/complications/diagnosis ; Kidney Failure, Chronic/complications/diagnosis ; *Linagliptin/administration & dosage/therapeutic use ; Prospective Studies ; Renal Insufficiency, Chronic/classification/complications/diagnosis ; *Contrast Media/adverse effects ; Chemoprevention/methods ; Drug Therapy, Combination ; Acetylcysteine/administration & dosage/therapeutic use ; *Protective Agents/administration & dosage/adverse effects/therapeutic use ; Saline Solution/administration & dosage/therapeutic use ; }, abstract = {BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD.

METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2[nd] received allopurinol, the 3[rd] group received linagliptin, and the 4[th] received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients.

RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis.

CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view.

NCT03470454.}, } @article {pmid36974603, year = {2023}, author = {Zhang, C and Zhou, T and Li, Y and Dai, W and Du, S}, title = {Activation of the CncC pathway is involved in the regulation of P450 genes responsible for clothianidin resistance in Bradysia odoriphaga.}, journal = {Pest management science}, volume = {79}, number = {9}, pages = {3071-3079}, doi = {10.1002/ps.7482}, pmid = {36974603}, issn = {1526-4998}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Reactive Oxygen Species ; Neonicotinoids/pharmacology/metabolism ; *Insecticides/pharmacology ; Nematocera/genetics ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Insecticide Resistance/genetics ; Larva/genetics/metabolism ; }, abstract = {BACKGROUND: Insect cytochrome P450 monooxygenases (P450s) play a key role in the detoxification metabolism of insecticides and their overexpression is often associated with insecticide resistance. Our previous research showed that the overexpression of four P450 genes is responsible for clothianidin resistance in B. odoriphaga. In this study, we characterized another P450 gene, CYP6FV21, associated with clothianidin resistance. However, the molecular basis for the overexpression of P450 genes in clothianidin-resistant strain remains obscure in B. odoriphaga.

RESULTS: In this study, the CYP6FV21 gene was significantly overexpressed in the clothianidin-resistant (CL-R) strain. Clothianidin exposure significantly increased the expression level of CYP6FV21. Knockdown of CYP6FV21 significantly increased the susceptibility of B. odoriphaga larvae to clothianidin. The transcription factor Cap 'n' Collar isoform-C (CncC) was highly expressed in the midgut of larvae in B. odoriphaga. The expression level of CncC was higher in the CL-R strain compared with the susceptible (SS) strain. Clothianidin exposure caused reactive oxygen species (ROS) accumulation and significantly increased the expression level of CncC. Knockdown of CncC caused a significant decrease in the expression of CYP3828A1 and CYP6FV21, and P450 enzyme activity, and led to a significant increase in mortality after exposure to lethal concentration at 30% (LC30) of clothianidin. After treatment with CncC agonist curcumin, the P450 activity and the expression levels of CYP3828A1 and CYP6FV21 significantly increased, and larval sensitivity to clothianidin decreased. The ROS scavenger N-acetylcysteine (NAC) treatment significantly inhibited the expression levels of CncC, CYP3828A1 and CYP6FV21 in response to clothianidin exposure and increased larval sensitivity to clothianidin.

CONCLUSION: Taken together, these results indicate that activation of the CncC pathway by the ROS burst plays a critical role in clothianidin resistance by regulating the expression of CYP3828A1 and CYP6FV21 genes in B. odoriphaga. This study provides more insight into the mechanisms underlying B. odoriphaga larval resistance to clothianidin. © 2023 Society of Chemical Industry.}, } @article {pmid36971326, year = {2023}, author = {Patwardhan, RS and Kundu, K and Purohit, V and Kumar, BK and Singh, B and Thoh, M and Undavia, K and Bhilwade, HN and Nayak, SK and Sharma, D and Sandur, SK}, title = {Malabaricone C, a constituent of spice Myristica malabarica, exhibits anti-inflammatory effects via modulation of cellular redox.}, journal = {Journal of biosciences}, volume = {48}, number = {2}, pages = {}, pmid = {36971326}, issn = {0973-7138}, mesh = {Mice ; Animals ; *Myristica/metabolism ; Spices ; Oxidation-Reduction ; NF-kappa B/genetics/metabolism ; Cytokines/genetics/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {The present study primarily focuses on the efficacy of Malabaricone C (Mal C) as an anti-inflammatory agent. Mal C inhibited mitogen-induced T-cell proliferation and cytokine secretion. Mal C significantly reduced cellular thiols in lymphocytes. N-acetyl cysteine (NAC) restored cellular thiol levels and abrogated Mal C-mediated inhibition of T-cell proliferation and cytokine secretion. Physical interaction between Mal C and NAC was evinced from HPLC and spectral analysis. Mal C treatment significantly inhibited concanavalin A-induced phosphorylation of ERK/JNK and DNA binding of NF-κB. Administration of Mal C to mice suppressed T-cell proliferation and effector functions ex vivo. Mal C treatment did not alter the homeostatic proliferation of T-cells in vivo but completely abrogated acute graft-versus-host disease (GvHD)-associated morbidity and mortality. Our studies indicate probable use of Mal C for prophylaxis and treatment of immunological disorders caused due to hyper-activation of T-cells.}, } @article {pmid36968922, year = {2023}, author = {Altaf, F and Qureshi, ZA and Kandhi, S and Khaja, M}, title = {Clinical Conundrum of Acute Hepatitis B With Concurrent Hepatitis E Infection Leading to Severe Acute Liver Injury.}, journal = {Cureus}, volume = {15}, number = {2}, pages = {e35216}, pmid = {36968922}, issn = {2168-8184}, abstract = {Acute liver injury in the setting of acute fulminant hepatitis caused by the hepatitis B virus (HBV) can occur both during primary infection and after chronic HBV reactivation. Guidelines recommend considering antiviral therapy in both cases. Antiviral therapy with a nucleoside analog may be beneficial in patients with acute liver failure from acute HBV infection, though not all studies have shown a benefit. This is a case of a 53-year-old woman with a past medical history of untreated hepatitis C with undetectable viral load and right breast cancer status post lumpectomy, who presented to the emergency department with complaints of yellowish skin and sclera discoloration with right upper quadrant pain for one week. She was a known intravenous drug abuser and binge alcohol user. Her labs were positive for hepatitis B, hepatitis E, and hepatitis C viruses. She also had elevated liver enzymes with hyperbilirubinemia showing severe acute liver injury. Computed tomography of the abdomen and pelvis with contrast was normal, and the abdominal ultrasound showed homogenous echotexture of the liver without a focal lesion. The patient was diagnosed with acute fulminant hepatitis B. After initial hemodynamic stabilization, N-acetylcysteine (NAC) and tenofovir were started, and transaminases were followed. Liver function tests showed a downtrend, and, in a few weeks, they came to baseline. Hepatitis B viral load became undetectable as well. Acute hepatitis B infection is seldom treated. The presented case depicts the use of tenofovir in the setting of severe acute liver injury due to hepatitis B. Starting antiviral therapy (especially tenofovir disoproxil fumarate) early in the disease course was shown to have very assuring results with complete resolution of symptoms and normalization of liver function tests. The treatment protocol for acute HBV deserves further investigation.}, } @article {pmid36965604, year = {2023}, author = {Camus, MF and Rodriguez, E and Kotiadis, V and Carter, H and Lane, N}, title = {Redox stress shortens lifespan through suppression of respiratory complex I in flies with mitonuclear incompatibilities.}, journal = {Experimental gerontology}, volume = {175}, number = {}, pages = {112158}, doi = {10.1016/j.exger.2023.112158}, pmid = {36965604}, issn = {1873-6815}, support = {BB/S003681/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Female ; *Longevity/genetics ; *Electron Transport Complex I ; Drosophila melanogaster/genetics ; Hydrogen Peroxide ; Oxidation-Reduction ; }, abstract = {Incompatibilities between mitochondrial and nuclear genes can perturb respiration, biosynthesis, signaling and gene expression. Here we investigate whether mild mitonuclear incompatibilities alter the physiological response to redox stress induced by N-acetyl cysteine (NAC). We studied three Drosophila melanogaster lines with mitochondrial genomes that were either coevolved (WT) or mildly mismatched (BAR, COX) to an isogenic nuclear background. Responses to NAC varied substantially with mitonuclear genotype, sex, tissue and dose. NAC caused infertility and high mortality in some groups, but not others. Using tissue-specific high-resolution fluorespirometry, we show that NAC did not alter H2O2 flux but suppressed complex I-linked respiration in female flies, while maintaining a reduced glutathione pool. The high mortality in BAR females was associated with severe (>50 %) suppression of complex I-linked respiration, rising H2O2 flux in the ovaries, and significant oxidation of the glutathione pool. Our results suggest that redox stress is attenuated by the suppression of complex-I linked respiration, to the point of death in some mitonuclear lines. We propose that suppression of complex I-linked respiration is a general mechanism to maintain redox homeostasis in tissues, which could offset oxidative stress in ageing, producing a metabolic phenotype linked with epigenetic changes and age-related decline.}, } @article {pmid36964576, year = {2023}, author = {Peng, C and Li, X and Ao, F and Li, T and Guo, J and Liu, J and Zhang, X and Gu, J and Mao, J and Zhou, B}, title = {Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1.}, journal = {Journal of translational medicine}, volume = {21}, number = {1}, pages = {218}, pmid = {36964576}, issn = {1479-5876}, mesh = {Humans ; Mitophagy ; *Carcinoma, Hepatocellular/pathology ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2/metabolism ; Up-Regulation ; Cell Survival ; Protein Kinases/metabolism ; *Liver Neoplasms/pathology ; Neoplasm Recurrence, Local/pathology ; Mitochondria/metabolism ; *Radiofrequency Ablation ; NADPH Oxidase 4/metabolism ; }, abstract = {BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains a major clinical problem. Cells that survive the sublethal heat stress that is induced by incomplete RFA are the main source of HCC relapse. Heat stress has long been reported to increase intracellular reactive oxygen species (ROS) generation. Although ROS can induce apoptosis, a pro-survival effect of ROS has also been demonstrated. However, the role of ROS in HCC cells exposed to sublethal heat stress remains unclear.

METHODS: HepG2 and HuH7 cells were used for this experiment. Insufficient RFA was performed in cells and in a xenograft model. ROS and antioxidant levels were measured. Apoptosis was analyed by Annexin-V/PI staining and flow cytometry. Protein expression was measured using western blotting. Colocalization of lysosomes and mitochondria was analyzed to assess mitophagy. Corresponding activators or inhibitors were applied to verify the function of specific objectives.

RESULTS: Here,we showed that sublethal heat stress induced a ROS burst, which caused acute oxidative stress. This ROS burst was generated by mitochondria, and it was initiated by upregulated NOX4 expression in the mitochondria. N-acetylcysteine (NAC) decreased HCC cell survival under sublethal heat stress conditions in vivo and in vitro. NOX4 triggers the production of mitochondrial ROS (mtROS), and NOX4 inhibitors or siNOX4 also decreased HCC cell survival under sublethal heat stress conditions in vitro. Increased mtROS trigger PINK1-dependent mitophagy to eliminate the mitochondria that are damaged by sublethal heat stress and to protect cells from apoptosis. Nrf2 expression was elevated in response to this ROS burst and mediated the ROS burst-induced increase in PINK1 expression after sublethal heat stress.

CONCLUSION: These data confirmed that the ROS burst that occurs after iRFA exerted a pro-survival effect. NOX4 increased the generation of ROS by mitochondria. This short-term ROS burst induced PINK1-dependent mitophagy to eliminate damaged mitochondria by increasing Nrf2 expression.}, } @article {pmid36963348, year = {2023}, author = {Zhao, K and Han, D and He, SR and Wu, LY and Liu, WY and Zhong, ZM}, title = {N-acetyl-L-cysteine attenuates oxidative stress-induced bone marrow endothelial cells apoptosis by inhibiting BAX/caspase 3 pathway.}, journal = {Biochemical and biophysical research communications}, volume = {656}, number = {}, pages = {115-121}, doi = {10.1016/j.bbrc.2023.03.045}, pmid = {36963348}, issn = {1090-2104}, mesh = {*Acetylcysteine/pharmacology/metabolism ; bcl-2-Associated X Protein/metabolism ; *Endothelial Cells/metabolism ; Caspase 3/metabolism ; Bone Marrow/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Apoptosis ; }, abstract = {Bone marrow endothelial cells (BMECs) play a crucial role in the maintenance of bone homeostasis. The decline in BMECs is associated with abnormal bone development and loss. At present, the mechanism of age-related oxidative stress enhancement in BMEC dysfunction remains unclear. Our experiment explored injury caused by oxidative stress enhancement in BMECs both in vivo and in vitro. The BMECs, indicators of oxidative stress, bone mass, and apoptosis-related proteins were analyzed in different age groups. We also evaluated the ability of N-Acetyl-L-cysteine (NAC) attenuate oxidative stress injury in BMECs. NAC treatment attenuated reactive oxygen species (ROS) overgeneration and apoptosis in BMECs in vitro and alleviated the loss of BMECs and bone mass in vivo. In conclusion, this study could improve our understanding of the mechanism of oxidative stress-induced BMECs injury and whether NAC has therapeutic potential in senile osteoporosis.}, } @article {pmid36961435, year = {2023}, author = {Li, Z and Wu, L and Huang, Z and Lv, B and Fu, Y and Zhou, L and Fu, X}, title = {CCCP Facilitates Aminoglycoside to Kill Late Stationary-Phase Escherichia coli by Elevating Hydroxyl Radical.}, journal = {ACS infectious diseases}, volume = {9}, number = {4}, pages = {801-814}, doi = {10.1021/acsinfecdis.2c00522}, pmid = {36961435}, issn = {2373-8227}, mesh = {Humans ; *Escherichia coli ; *Aminoglycosides/pharmacology/chemistry ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Hydroxyl Radical/pharmacology ; Anti-Bacterial Agents/pharmacology ; Tobramycin/pharmacology ; }, abstract = {Improving the efficacy of existing antibiotics is significant for combatting antibiotic resistance that poses a major threat to human health. Carbonyl cyanide m-chlorophenylhydrazine (CCCP), a well-known protonophore for dissipating proton motive force (PMF), has been widely used to block the PMF-dependent uptake of aminoglycoside antibiotics and thus suppress aminoglycoside lethality. Here, we report that CCCP and its functional analog FCCP, but not other types of protonophores, unprecedently potentiate aminoglycosides (e.g., tobramycin and gentamicin) by 3-4 orders of magnitude killing of Escherichia coli, Staphylococcus aureus, Shigella flexneri, and Vibrio alginolyticus cells in stationary phase but not these cells in exponential phase nor other 12 bacterial species we examined. Overall, the effect of CCCP on aminoglycoside lethality undergoes a gradual transition from suppression against E. coli exponential-phase cells to potentiation against late stationary-phase cells, with the cell growth status and culture medium being crucial. Consistently, disturbance of the PMF by changing transmembrane proton gradient (ΔpH) or electric potential (ΔΨ) also potentiates tobramycin. Nevertheless, CCCP neither increases the intracellular concentration of tobramycin nor decreases the MIC of the antibiotic, thus excluding that CCCP acts as an efflux pump inhibitor to potentiate aminoglycosides. Rather, we show that the combined treatment dramatically enhances the cellular level of hydroxyl radical under both aerobic and anaerobic culturing conditions, under which the antioxidant N-acetyl cysteine fully suppresses both hydroxyl radical accumulation and cell death. Together, these findings open a new avenue to develop certain protonophores as aminoglycoside adjuvants against pathogens in stationary phase and also illustrate an essential role of hydroxyl radical in aminoglycoside lethality regardless of aerobic respiration.}, } @article {pmid36950489, year = {2023}, author = {Thomas, L and Chandran, J and Goel, A and Jacob, E and Chacko, B and Subramani, K and Agarwal, I and Varughese, S and David, VG and Daniel, D and Mammen, J and Balakrishnan, V and Balasubramanian, KA and Lionel, AP and Adhikari, DD and Abhilash, KPP and Elias, E and Eapen, CE and Zachariah, U}, title = {Improving Transplant-free Survival With Low-volume Plasma Exchange to Treat Children With Rodenticide Induced Hepatotoxicity.}, journal = {Journal of clinical and experimental hepatology}, volume = {13}, number = {2}, pages = {252-258}, pmid = {36950489}, issn = {0973-6883}, abstract = {BACKGROUND: In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients.

OBJECTIVES: We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children.

METHODS: From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (≤18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival.

RESULTS: Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived.

CONCLUSIONS: PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.}, } @article {pmid36947366, year = {2023}, author = {Ezzat, GM and Nassar, AY and Bakr, MH and Mohamed, S and Nassar, GA and Kamel, AA}, title = {Acetylated Oligopeptide and N-acetyl cysteine Protected Against Oxidative Stress, Inflammation, Testicular-Blood Barrier Damage, and Testicular Cell Death in Iron-Overload Rat Model.}, journal = {Applied biochemistry and biotechnology}, volume = {195}, number = {8}, pages = {5053-5071}, pmid = {36947366}, issn = {1559-0291}, mesh = {Male ; Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism ; Testis ; NF-kappa B/metabolism ; Beclin-1/metabolism ; Claudin-1/metabolism ; Dextrans/metabolism ; Oxidative Stress ; Antioxidants/pharmacology ; *Iron Overload/drug therapy/metabolism/pathology ; Inflammation/drug therapy/metabolism ; Glutathione/metabolism ; Cell Death ; Testosterone/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Iron/metabolism ; }, abstract = {Multiple organs, including the testes, are damaged by iron overload. It has been shown that N-acetyl cysteine (NAC) influences oxidative stress in iron overload. The present study aimed to evaluate the roles of acetylated peptide (AOP) and NAC in the inhibition of iron-overload induced-testicular damage. At the beginning of the experiment, NAC (150 mg /kg) was given for a week to all 40 rats. Then, four groups were formed by dividing the animals (10 rats/group). Group I included healthy control rats. Group II (iron overload) was given intraperitoneal iron dextran (60 mg/kg/day) 5 days a week for 4 weeks. Group III (NAC) was given NAC orally at a dose of 150 mg/kg/day for 4 weeks in addition to iron dextran. Group IV (AOP) was given AOP orally at a dose of 150 mg/kg/day for 4 weeks besides iron dextran. When the experiment time was over, testosterone serum level, testicular B cell lymphoma-2 (BCL-2) and protein kinase B (PKB) protein levels, nuclear factor kappa-B (NF-κB), and Beclin1 mRNA expression levels, and malondialdehyde (MDA), and reduced glutathione (GSH) were determined by ELISA, quantitative reverse transcription-PCR, and chemical methods. Finally, histopathological examinations and immunohistochemical detection of claudin-1 and CD68 were performed. The iron overload group exhibited decreased testosterone, BCL-2, PKB, claudin-1, and GSH and increased MDA, NF-κB, Beclin1, and CD68, while both NAC and AOP treatments protected against the biochemical and histopathological disturbances occurring in the iron overload model. We concluded that NAC and AOP can protect against testes damage by iron overload via their antioxidant, anti-inflammatory, antiapoptotic, and ant-autophagic properties. The NAC and AOP may be used as preventative measures against iron overload-induced testicular damage.}, } @article {pmid36945164, year = {2023}, author = {Kemahli, E and Uyeturk, U and Cetinkaya, A and Erimsah, S and Uyeturk, U and Gucuk, A}, title = {Protective Effects of N-Acetyl Cysteine on Undescended Testis after Orchiopexy: A Rat-model Study.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {33}, number = {3}, pages = {319-324}, doi = {10.29271/jcpsp.2023.03.319}, pmid = {36945164}, issn = {1681-7168}, mesh = {Humans ; Pregnancy ; Female ; Male ; Rats ; Animals ; *Testis ; *Cryptorchidism/surgery ; Orchiopexy ; Acetylcysteine/pharmacology ; Flutamide ; Semen ; Antioxidants/pharmacology ; }, abstract = {UNLABELLED: ABSTRACT Objective: To assess the effectiveness of utilising N-acetyl cysteine (NAC) to treat tissue damage brought on by undescended testis (UT) in rats after orchiopexy.

STUDY DESIGN: Experimental study. Place and Duration of the Study: Bolu Abant İzzet Baysal University, Bolu, Turkey, from January 2018 to June 2020.

METHODOLOGY: The UT model was created by administering flutamide to pregnant rats. Four groups of animals were created as the control group (offsprings of pregnant rats without flutamide), group II (UT), group III (UT + orchiopexy), and group IV (UT + orchiopexy + NAC); each containing eight animals.

RESULTS: Group IV had a higher level of glutathione peroxidase than groups III and II (p=0.001 and p=0.002, respectively). Malondialdehyde was reduced in group IV compared with groups III and II (both p<0.001). There were differences in mean apoptotic cell counts (ACC) among the groups (p<0.001). ACC in group IV was lower than in group III (p<0.001). Sperm counts were higher in group IV than ın groups III and II, and in group III they were higher than group II (p<0.001 all) and similar between groups IV and control group (p=0.102).

CONCLUSION: Orchiopexy reduced UT-related testicular damage, additionally using NAC following orchiopexy may further reduce testicular damage through its antioxidant effects.

KEY WORDS: Undescended testis, Testis damage, Orchiopexy, N-acetyl cysteine, Antioxidant.}, } @article {pmid36941865, year = {2023}, author = {Sztolsztener, K and Bzdęga, W and Hodun, K and Chabowski, A}, title = {N-Acetylcysteine Decreases Myocardial Content of Inflammatory Mediators Preventing the Development of Inflammation State and Oxidative Stress in Rats Subjected to a High-Fat Diet.}, journal = {International journal of inflammation}, volume = {2023}, number = {}, pages = {5480199}, pmid = {36941865}, issn = {2090-8040}, abstract = {Arachidonic acid (AA) is a key precursor for proinflammatory and anti-inflammatory derivatives that regulate the inflammatory response. The modulation of AA metabolism is a target for searching a therapeutic agent with potent anti-inflammatory action in cardiovascular disorders. Therefore, our study aims to determine the potential preventive impact of N-acetylcysteine (NAC) supplementation on myocardial inflammation and the occurrence of oxidative stress in obesity induced by high-fat feeding. The experiment was conducted for eight weeks on male Wistar rats fed a standard chow or a high-fat diet (HFD) with intragastric NAC supplementation. The Gas-Liquid Chromatography (GLC) method was used to quantify the plasma and myocardial AA levels in the selected lipid fraction. The expression of proteins included in the inflammation pathway was measured by the Western blot technique. The concentrations of arachidonic acid derivatives, cytokines and chemokines, and oxidative stress parameters were determined by the ELISA, colorimetric, and multiplex immunoassay kits. We established that in the left ventricle tissue NAC reduced AA concentration, especially in the phospholipid fraction. NAC administration ameliorated the COX-2 and 5-LOX expression, leading to a decrease in the PGE2 and LTC4 contents, respectively, and augmented the 12/15-LOX expression, increasing the LXA4 content. In obese rats, NAC ameliorated NF-κB expression, inhibiting the secretion of proinflammatory cytokines. NAC also affected the antioxidant levels in HFD rats through an increase in GSH and CAT contents with a simultaneous decrease in the levels of 4-HNE and MDA. We concluded that NAC treatment weakens the NF-κB signaling pathway, limiting the development of myocardial low-grade inflammation, and increasing the antioxidant content that may protect against the development of oxidative stress in rats with obesity induced by an HFD.}, } @article {pmid36941180, year = {2023}, author = {Danışan, G and Taydaş, O and Özdemir, M and Ateş, ÖF and Küpeli, A and Öğüşlü, U and Erkin, A and Neşelioğlu, S and Eren, F}, title = {Dynamic thiol-disulphide homeostasis as a biomarker for predicting the development of contrast medium-associated acute kidney injury in the endovascular treatment of peripheral arterial disease: should intravenous N-acetylcysteine be given before the procedure?.}, journal = {Clinical radiology}, volume = {78}, number = {6}, pages = {466-472}, doi = {10.1016/j.crad.2023.02.016}, pmid = {36941180}, issn = {1365-229X}, mesh = {Adult ; Humans ; Acetylcysteine ; Biomarkers ; Disulfides ; Sulfhydryl Compounds ; Serum Albumin ; Contrast Media/adverse effects ; *Acute Kidney Injury/prevention & control ; Homeostasis ; *Peripheral Arterial Disease ; }, abstract = {AIM: To determine the predictive ability of serum thiol-disulphide levels for contrast medium-associated acute kidney injury (CA-AKI) after endovascular treatment (EVT) of peripheral arterial disease (PAD) and evaluate the efficacy of intravenous N-acetylcysteine (NAC) in preventing CA-AKI.

MATERIAL AND METHODS: This double-blind, randomised controlled study included 85 consecutive adult patients who underwent EVT for PAD. Patients were divided into NAC negative (NAC-) and positive (NAC+) groups. While the NAC- group received only 500 ml saline, the NAC + group received 500 ml saline plus intravenous 600 mg NAC before the procedure. Intra- and intergroup patient characteristics, procedural details, preoperative thiol-disulphide levels, and ischaemia-modified albumin (IMA) levels were recorded.

RESULTS: There was a significant difference between NAC- and NAC + groups regarding native thiol, total thiol, disulphide/native thiol ratio (D/NT), and disulphide/total thiol ratio (D/TT). There was also a significant difference between the NAC- (33.3%) and NAC+ (13%) groups in CA-AKI development. Logistic regression analysis showed that the D/TT (OR 2.463) and D/NT (OR 2.121) were the most influential parameters for CA-AKI development. In the receiver operating characteristic (ROC) curve analysis, the sensitivity of native thiol to detect the development of CA-AKI was 89.1%. The negative predictive values of native thiol and total thiol were 95.6% and 94.1%, respectively.

CONCLUSION: The serum thiol-disulphide level can be used as a biomarker to detect CA-AKI development and reveal patients with a low risk for CA-AKI development before EVT of PAD. Furthermore, thiol-disulphide levels allow for the indirect quantitative monitoring of NAC. Preprocedural intravenous NAC administration significantly inhibits CA-AKI development.}, } @article {pmid36933581, year = {2023}, author = {Ayed-Boussema, I and Rjiba-Touati, K and Hamdi, H and Chaabani, H and Abid-Essefi, S}, title = {Oxidative stress-mediated mitochondrial apoptosis induced by the acaricide, fenpyroximate, on cultured human colon cancer HCT 116 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {89}, number = {}, pages = {105587}, doi = {10.1016/j.tiv.2023.105587}, pmid = {36933581}, issn = {1879-3177}, mesh = {Humans ; HCT116 Cells ; *Acaricides/pharmacology ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; Oxidative Stress ; *Colonic Neoplasms ; Apoptosis ; RNA, Messenger/metabolism ; Membrane Potential, Mitochondrial ; }, abstract = {Fenpyroximate (FEN) is an acaricide that inhibits mitochondrial electron transport at the NADH-coenzyme Q oxidoreductase (complex I). The present study was designed to investigate the molecular mechanisms underling FEN toxicity on cultured human colon carcinoma cells (HCT116). Our data showed that FEN induced HCT116 cell mortality in a concentration dependent manner. FEN arrested cell cycle in G0/G1 phase and increased DNA damage as assessed by comet assay. Induction of apoptosis was confirmed in HCT116 cells exposed to FEN by AO-EB staining and Annexin V-FITC/PI double staining assay. Moreover, FEN induced a loss in mitochondrial membrane potential (MMP), increased p53 and Bax mRNA expression and decreased bcl2 mRNA level. An increase in caspase 9 and caspase 3 activities was also detected. All toghether, these data suggest that FEN induce apoptosis in HCT116 cells via mitochondrial pathway. To check the implication of oxidative stress in FEN-induced cell toxicity, we examined the oxidative stress statue in HCT116 cells exposed to FEN and we tested the effect of a powerful antioxidant, N-acetylcystein (NAC), on FEN-caused toxicity. It was observed that FEN enhanced ROS generation and MDA levels and disturbed SOD and CAT activities. Besides, cell treatment with NAC significantly protected cells from mortality, DNA damage, loss of MMP, and caspase 3 activity induced by FEN. To the best of our knowledge, this is the first study showing that FEN induced mitochondrial apoptosis via ROS generation and oxidative stress.}, } @article {pmid36927162, year = {2023}, author = {Huang, C and Kuo, S and Lin, L and Yang, Y}, title = {The efficacy of N-acetylcysteine in chronic obstructive pulmonary disease patients: a meta-analysis.}, journal = {Therapeutic advances in respiratory disease}, volume = {17}, number = {}, pages = {17534666231158563}, pmid = {36927162}, issn = {1753-4666}, mesh = {Humans ; *Acetylcysteine/adverse effects ; Disease Progression ; Vital Capacity ; *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) may reduce acute exacerbations of chronic obstructive pulmonary disease through an antioxidant effect. Due to the heterogeneity in studies, the currently available data do not confirm the efficacy of oral NAC therapy in chronic obstructive pulmonary disease patients. We hypothesize that chronic obstructive pulmonary disease patients receiving regular oral NAC therapy do not achieve improved clinical outcomes.

OBJECTIVES: The purpose of this meta-analysis was to determine the efficacy of long-term oral NAC therapy in chronic obstructive pulmonary disease patients.

DATA SOURCES AND METHODS: The literature search was performed using the PubMed, Web of Science, and Cochrane Library databases to identify all included clinical studies. Studies were eligible for inclusion only if they directly compared the outcomes of NAC versus placebo in adults with chronic obstructive pulmonary disease between 1 January 2000 and 30 May 2022. All studies were included if they reported one or more of the following outcomes: number of patients with no acute exacerbations, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), St George's Respiratory Questionnaire score, glutathione level, and adverse events.

RESULTS: Nine randomized controlled trials were included in the meta-analysis. There were 1061 patients in the NAC group and 1076 patients in the placebo group. The current meta-analysis provides evidence that the number of patients with no acute exacerbations (965 patients receiving NAC therapy, 979 control group patients), change in FEV1 (433 patients receiving NAC therapy, 447 control group patients), change in FVC (177 patients receiving NAC therapy, 180 control group patients), change in St George's Respiratory Questionnaire score (128 patients receiving NAC therapy, 131 control group patients), change in glutathione levels (38 patients receiving NAC therapy, 40 control group patients), and adverse events (832 patients receiving NAC therapy, 846 control group patients) were not significantly different between the two groups.

CONCLUSION: NAC did not reduce the risk of acute exacerbation or ameliorate the decline in lung volume in chronic obstructive pulmonary disease patients.}, } @article {pmid36923901, year = {2023}, author = {Lima, EMF and Almeida, FA and Sircili, MP and Bueris, V and Pinto, UM}, title = {N-acetylcysteine (NAC) attenuates quorum sensing regulated phenotypes in Pseudomonas aeruginosa PAO1.}, journal = {Heliyon}, volume = {9}, number = {3}, pages = {e14152}, pmid = {36923901}, issn = {2405-8440}, abstract = {The expression of many virulence genes in bacteria is regulated by quorum sensing (QS), and the inhibition of this mechanism has been intensely investigated. N-acetylcysteine (NAC) has good antibacterial activity and is able to interfere with biofilm-related respiratory infections, but little is known whether this compound has an effect on bacterial QS communication. This work aimed to evaluate the potential of NAC as a QS inhibitor (QSI) in Pseudomonas aeruginosa PAO1 through in silico and in vitro analyses, as well as in combination with the antibiotic tobramycin. Initially, a molecular docking analysis was performed between the QS regulatory proteins, LasR and RhlR, of P. aeruginosa with NAC, 3-oxo-C12-HSL, C4-HSL, and furanone C30. The NAC sub-inhibitory concentration was determined by growth curves. Then, we performed in vitro tests using the QS reporter strains P. aeruginosa lasB-gfp and rhlA-gfp, as well as the expression of QS-related phenotypes. Finally, the synergistic effect of NAC with the antibiotic tobramycin was calculated by fractional inhibitory concentrations index (FICi) and investigated against bacterial growth, pigment production, and biofilm formation. In the molecular docking study, NAC bound to LasR and RhlR proteins in a similar manner to the AHL cognate, suggesting that it may be able to bind to QS receptor proteins in vivo. In the biosensor assay, the GFP signal was turned down in the presence of NAC at 1000, 500, 250, and 125 μM for lasB-gfp and rhlA-gfp (p < 0.05), suggesting a QS inhibitory effect. Pyocyanin and rhamnolipids decreased (p < 0.05) up to 34 and 37%, respectively, in the presence of NAC at 125 μM. Swarming and swimming motilities were inhibited (p < 0.05) by NAC at 250 to 10000 μM. Additionally, 2500 and 10000 μM of NAC reduced biofilm formation. NAC-tobramycin combination showed synergistic effect with FICi of 0.8, and the best combination was 2500-1.07 μM, inhibiting biofilm formation up to 60%, besides reducing pyocyanin and pyoverdine production. Confocal microscopy images revealed a stronger, dense, and compact biofilm of P. aeruginosa PAO1 control, while the biofilm treated with NAC-tobramycin became thinner and more dispersed. Overall, NAC at low concentrations showed promising anti-QS properties against P. aeruginosa PAO1, adding to its already known effect as an antibacterial and antibiofilm agent.}, } @article {pmid36923240, year = {2023}, author = {Zhai, T and Zhang, J and Zhang, J and Liu, B and Zhou, Z and Liu, F and Wu, Y}, title = {Cathelicidin promotes liver repair after acetaminophen-induced liver injury in mice.}, journal = {JHEP reports : innovation in hepatology}, volume = {5}, number = {4}, pages = {100687}, pmid = {36923240}, issn = {2589-5559}, abstract = {BACKGROUND & AIMS: Acetaminophen (APAP)-induced acute liver injury (AILI) is a leading cause of acute liver failure (ALF). N-acetylcysteine (NAC) is only effective within 24 h after APAP intoxication, raising an urgent need for alternative approaches to treat this disease. This study aimed to test whether cathelicidin (Camp), which is a protective factor in chronic liver diseases, protects mice against APAP-induced liver injury and ALF.

METHODS: A clinically relevant AILI model and an APAP-induced ALF model were generated in mice. Genetic and pharmacological approaches were used to interfere with the levels of cathelicidin in vivo.

RESULTS: An increase in hepatic pro-CRAMP/CRAMP (the precursor and mature forms of mouse cathelicidin) was observed in APAP-intoxicated mice. Upregulated cathelicidin was derived from liver-infiltrating neutrophils. Compared with wild-type littermates, Camp knockout had no effect on hepatic injury but dampened hepatic repair in AILI and reduced survival in APAP-induced ALF. CRAMP administration reversed impaired liver recovery observed in APAP-challenged Camp knockout mice. Delayed CRAMP, CRAMP(1-39) (the extended form of CRAMP), or LL-37 (the mature form of human cathelicidin) treatment exhibited a therapeutic benefit for AILI. Co-treatment of cathelicidin and NAC in AILI displayed a stronger hepatoprotective effect than NAC alone. A similar additive effect of CRAMP(1-39)/LL-37 and NAC was observed in APAP-induced ALF. The pro-reparative role of cathelicidin in the APAP-damaged liver was attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced neutrophil phagocytosis of necrotic cell debris in an autocrine manner.

CONCLUSIONS: Cathelicidin reduces APAP-induced liver injury and ALF in mice by promoting liver recovery via facilitating inflammation resolution, suggesting a therapeutic potential for late-presenting patients with AILI with or without ALF.

IMPACT AND IMPLICATIONS: Acetaminophen-induced acute liver injury is a leading cause of acute liver failure. The efficacy of N-acetylcysteine, the only clinically approved drug against acetaminophen-induced acute liver injury, is significantly reduced for late-presenting patients. We found that cathelicidin exhibits a great therapeutic potential in mice with acetaminophen-induced liver injury or acute liver failure, which makes up for the limitation of N-acetylcysteine therapy by specifically promoting liver repair after acetaminophen intoxication. The pro-reparative role of cathelicidin, as a key effector molecule of neutrophils, in the APAP-injured liver is attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced phagocytic function of neutrophils in an autocrine manner.}, } @article {pmid36922946, year = {2023}, author = {El Khoury, R and Ramirez, SP and Loyola, CD and Joddar, B}, title = {Demonstration of doxorubicin's cardiotoxicity and screening using a 3D bioprinted spheroidal droplet-based system.}, journal = {RSC advances}, volume = {13}, number = {12}, pages = {8338-8351}, pmid = {36922946}, issn = {2046-2069}, support = {G12 MD007592/MD/NIMHD NIH HHS/United States ; SC1 HL154511/HL/NHLBI NIH HHS/United States ; }, abstract = {Doxorubicin (DOX) is a highly effective anthracycline chemotherapy agent effective in treating a broad range of life-threatening malignancies but it causes cardiotoxicity in many subjects. While the mechanism of its cardiotoxic effects remains elusive, DOX-related cardiotoxicity can lead to heart failure in patients. In this study, we investigated the effects of DOX-induced cardiotoxicity on human cardiomyocytes (CMs) using a three-dimensional (3D) bioprinted cardiac spheroidal droplet based-system in comparison with the traditional two-dimensional cell (2D) culture model. The effects of DOX were alleviated with the addition of N-acetylcysteine (NAC) and Tiron. Caspase-3 activity was quantified, and reactive oxygen species (ROS) production was measured using dihydroethidium (DHE) staining. Application of varying concentrations of DOX (0.4 μM-1 μM) to CMs revealed a dose-specific response, with 1 μM concentration imposing maximum cytotoxicity and 0.22 ± 0.11% of viable cells in 3D samples versus 1.02 ± 0.28% viable cells in 2D cultures, after 5 days of culture. Moreover, a flow cytometric analysis study was conducted to study CMs proliferation in the presence of DOX and antioxidants. Our data support the use of a 3D bioprinted cardiac spheroidal droplet as a robust and high-throughput screening model for drug toxicity. In the future, this 3D spheroidal droplet model can be adopted as a human-derived tissue-engineered equivalent to address challenges in other various aspects of biomedical pre-clinical research.}, } @article {pmid36917985, year = {2023}, author = {Duan, J and Matute, JD and Unger, LW and Hanley, T and Schnell, A and Lin, X and Krupka, N and Griebel, P and Lambden, C and Sit, B and Grootjans, J and Pyzik, M and Sommer, F and Kaiser, S and Falk-Paulsen, M and Grasberger, H and Kao, JY and Fuhrer, T and Li, H and Paik, D and Lee, Y and Refetoff, S and Glickman, JN and Paton, AW and Bry, L and Paton, JC and Sauer, U and Macpherson, AJ and Rosenstiel, P and Kuchroo, VK and Waldor, MK and Huh, JR and Kaser, A and Blumberg, RS}, title = {Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.}, journal = {Immunity}, volume = {56}, number = {5}, pages = {1115-1131.e9}, pmid = {36917985}, issn = {1097-4180}, support = {R37 DK044319/DK/NIDDK NIH HHS/United States ; R01 DK088199/DK/NIDDK NIH HHS/United States ; R01 DK051362/DK/NIDDK NIH HHS/United States ; R01 DK053056/DK/NIDDK NIH HHS/United States ; R01 AI169075/AI/NIAID NIH HHS/United States ; 106260/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; R01 DK117565/DK/NIDDK NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; 222497/Z/21/Z/WT_/Wellcome Trust/United Kingdom ; R01 DK044319/DK/NIDDK NIH HHS/United States ; R01 DK015070/DK/NIDDK NIH HHS/United States ; R01 AI042347/AI/NIAID NIH HHS/United States ; R37 DK015070/DK/NIDDK NIH HHS/United States ; R01 DK110559/DK/NIDDK NIH HHS/United States ; K12 HD000850/HD/NICHD NIH HHS/United States ; P30 DK034854/DK/NIDDK NIH HHS/United States ; R56 DK053056/DK/NIDDK NIH HHS/United States ; P30 DK020595/DK/NIDDK NIH HHS/United States ; }, mesh = {*Endoplasmic Reticulum Stress/drug effects ; *Intestinal Mucosa/drug effects/metabolism ; *Th17 Cells/cytology/metabolism ; Cell Differentiation ; Humans ; Animals ; Mice ; Mice, Transgenic ; Anti-Bacterial Agents/pharmacology ; }, abstract = {Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.}, } @article {pmid36916401, year = {2023}, author = {Lin, YP and Hseu, YC and Thiyagarajan, V and Vadivalagan, C and Pandey, S and Lin, KY and Hsu, YT and Liao, JW and Lee, CC and Yang, HL}, title = {The in vitro and in vivo anticancer activities of Antrodia salmonea through inhibition of metastasis and induction of ROS-mediated apoptotic and autophagic cell death in human glioblastoma cells.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {158}, number = {}, pages = {114178}, doi = {10.1016/j.biopha.2022.114178}, pmid = {36916401}, issn = {1950-6007}, mesh = {Polyporales ; Phosphatidylinositol 3-Kinases/metabolism ; Autophagy ; *Glioblastoma/drug therapy ; Apoptosis ; *Autophagic Cell Death ; Mice ; Animals ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Annexin A5 ; Humans ; Mice, Nude ; }, abstract = {BACKGROUND: Antrodia salmonea (AS) exhibits anticancer activities against various cancers.

OBJECTIVE: This study investigated the anticancer activities of AS on human glioblastoma (GBM8401 and U87MG) cells both in vitro and in vivo and explained the underlying molecular mechanism.

METHODS: MTT, colony formation, migration/invasion assay, immunoblotting, immunofluorescence, TUNEL, Annexin V/PI staining, AO staining, GFP-LC3 transfection, TEM, qPCR, siLC3, DCFH2-DA assay, and xenografted-nude mice were used to assess the potential of AS therapy.

RESULTS: AS treatment retarded growth and suppressed colony formation in glioblastoma cells. AS attenuates EMT by suppressing invasion and migration, increasing E-cadherin expression, decreasing Twist, Snail, and N-cadherin expression, and inhibiting Wnt/β-catenin pathways in GBM8401 and U87MG cells. Furthermore, AS induced apoptosis by activating caspase-3, cleaving PARP, and dysregulating Bax and Bcl-2 in both cell lines. TUNEL assay and Annexin V/PI staining indicated AS-mediated late apoptosis. Interestingly, AS induced autophagic cell death by LC3-II accumulation, AVO formation, autophagosome GFP-LC3 puncta, p62/SQSTM1 expression, and ATG4B inhibition in GBM8401 and U87MG cells. TEM data revealed that AS favored autophagosome and autolysosome formation. The autophagy inhibitors 3-MA/CQ and LC3 knockdown suppressed AS-induced apoptosis in glioblastoma cells, indicating that the inhibition of autophagy decreased AS-induced apoptosis. Notably, the antioxidant N-acetylcysteine (NAC) inhibited AS-mediated ROS production and AS-induced apoptotic and autophagic cell death. Furthermore, AS induced ROS-mediated inhibition of the PI3K/AKT/mTOR signaling pathway. AS reduced the tumor burden in GBM8401-xenografted nude mice and significantly modulated tumor xenografts by inducing anti-EMT, apoptosis, and autophagy. AS could be a potential antitumor agent in human glioblastoma treatment.}, } @article {pmid36916093, year = {2023}, author = {Zhou, Z and Zhang, H}, title = {CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress.}, journal = {Allergologia et immunopathologia}, volume = {51}, number = {2}, pages = {99-110}, pmid = {36916093}, issn = {1578-1267}, mesh = {Animals ; Humans ; Mice ; *Acute Kidney Injury/chemically induced ; Apoptosis ; Caspase 3/metabolism/pharmacology ; *Ferroptosis ; Lipopolysaccharides/adverse effects ; Oxidative Stress ; Poly(ADP-ribose) Polymerase Inhibitors/adverse effects ; *Sepsis/metabolism ; }, abstract = {BACKGROUND: Sepsis-induced acute kidney injury (AKI) is a singularly grievous and life-threatening syndrome. Its pathogenesis is closely related to inflammatory response, apoptosis, oxidative stress, and ferroptosis. Cation transport regulator-like protein 1 (CHAC1), as a proapoptic factor, may be involved in apoptosis, oxidative stress, and ferroptosis. This study aimed to explore the role of CHAC1 in the lipopolysaccharide (LPS)-induced the human renal proximal tubular epithelial (HK-2) cells.

METHODS: HK-2 cells were challenged with LPS to construct a model of sepsis-induced AKI in vitro. The role of CHAC1 in the LPS-induced HK-2 cells was explored using Western blot assay, cell counting kit-8 (CCK-8), flow cytometry, and colorimetric assays. Additionally, N-acetyl cysteine (NAC) was incubated with HK-2 cells to define deeply the relation between oxidative stress and apoptosis or ferroptosis.

RESULTS: The expression of CHAC1 was enhanced in the kidney tissues of mice with sepsis--induced multiple organ dysfunction syndrome (MODS), through the Gene Expression Omnibus database (GSE60088 microarray dataset), and in the LPS-induced HK-2 cells. The cell viability was significantly reduced by LPS treatment, which was at least partly restored by the transfection of siCHAC1#1 and siCHAC1#2 but not siNC. In addition, down-regulation of CHAC1 counteracted the LPS-induced reactive oxygen species level and malonaldehyde concentrations while restored the LPS-induced glutathione concentrations. Meanwhile, interference of CHAC1 neutralized LPS-induced apoptosis rate, and the relative level of cleaved poly(ADP-ribose) polymerase (PARP)/PARP, and cleaved caspase-3/caspase-3. In addition, silencing of CHAC1 recovered the LPS-induced enhanced protein level of glutathione peroxidase 4 (GPx4) whereas antagonized the LPS-induced relative protein level of ACSL4 and that of iron. Moreover, application of NAC inverted the effect of CHAC1 on apoptosis and ferroptosis in HK-2 cells.

CONCLUSION: CHAC1 exacerbated ferroptosis and apoptosis by enhancing oxidative stress in LPS-induced HK-2 cells.}, } @article {pmid36915477, year = {2023}, author = {Jin, S and Yoon, SJ and Jung, NY and Lee, WS and Jeong, J and Park, YJ and Kim, W and Oh, DB and Seo, J}, title = {Antioxidants prevent particulate matter-induced senescence of lung fibroblasts.}, journal = {Heliyon}, volume = {9}, number = {3}, pages = {e14179}, pmid = {36915477}, issn = {2405-8440}, abstract = {Particulate matter (PM) contributes to human diseases, particularly lung disease; however, the molecular mechanism of its action is yet to be determined. Herein, we found that prolonged PM exposure induced the cellular senescence of normal lung fibroblasts via a DNA damage-mediated response. This PM-induced senescence (PM-IS) was only observed in lung fibroblasts but not in A549 lung adenocarcinoma cells. Mechanistic analysis revealed that reactive oxygen species (ROS) activate the DNA damage response signaling axis, increasing p53 phosphorylation, ultimately leading to cellular senescence via an increase in p21 expression without affecting the p16-pRB pathway. A549 cells, instead, were resistant to PM-IS due to the PM-induced ROS production suppression. Water-soluble antioxidants, such as vitamin C and N-Acetyl Cysteine, were found to alleviate PM-IS by suppressing ROS production, implying that antioxidants are a promising therapeutic intervention for PM-mediated lung pathogenesis.}, } @article {pmid36914351, year = {2023}, author = {Song, WJ and Liu, PP and Meng, ZQ and Jie Ding, S and Xia Li, H}, title = {N-acetylcysteine promotes the proliferation of porcine adipose-derived stem cells during in vitro long-term expansion for cultured meat production.}, journal = {Food research international (Ottawa, Ont.)}, volume = {166}, number = {}, pages = {112606}, doi = {10.1016/j.foodres.2023.112606}, pmid = {36914351}, issn = {1873-7145}, mesh = {Animals ; Swine ; *Adipose Tissue/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Stem Cells/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Cell Proliferation ; }, abstract = {Cultured meat is an efficient, safe and sustainable meat production technology. Adipose-derived stem cell (ADSC) is a promising cell type for cultured meat. In vitro, obtaining numerous of ADSCs is a pivotal step for cultured meat. In this research, we demonstrated that the proliferation and adipogenic differentiation of ADSCs significantly decreased during serial passage. Then, senescence β-galactosidase (SA-β-gal) staining showed that the positive rate of P9 ADSCs was 7.74-fold than P3 ADSCs. Subsequently, RNA sequencing (RNA-seq) was performed for P3 and P9 ADSCs and found that PI3K-AKT pathway was up-regulated, but cell cycle and DNA repair pathway were down-regulated in P9 ADSCs. Then, N-Acetylcysteine (NAC) was added during long-term expansion and showed that NAC enhanced the ADSCs proliferation and maintained adipogenic differentiation. Finally, RNA-seq was performed for P9 ADSCs cultured with or without NAC and showed that NAC restored the cell cycle and DNA repair pathway in P9 ADSCs. These results highlighted that NAC was an excellent supplement for large-scale expansion of porcine ADSCs for cultured meat.}, } @article {pmid36913130, year = {2023}, author = {Arteaga-Henríquez, G and Gisbert, L and Ramos-Quiroga, JA}, title = {Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder: A Narrative Review of Randomized, Placebo-Controlled Trials.}, journal = {CNS drugs}, volume = {37}, number = {3}, pages = {215-229}, pmid = {36913130}, issn = {1179-1934}, mesh = {Humans ; Acetylcysteine/therapeutic use ; *Anti-Inflammatory Agents/therapeutic use ; *Autism Spectrum Disorder/drug therapy ; Celecoxib/therapeutic use ; *Fatty Acids, Omega-3/therapeutic use ; Minocycline/therapeutic use ; Prednisolone/therapeutic use ; Randomized Controlled Trials as Topic ; *Immunologic Factors/therapeutic use ; }, abstract = {Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD and immune/inflammatory processes, arising as a possible pathway for new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions on ASD symptoms is still limited. The aim of this narrative review was to summarize and discuss the latest evidence on the use of immunoregulatory and/or anti-inflammatory agents for the management of this condition. During the last 10 years, several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, N-acetylcysteine (NAC), sulforaphane (SFN), and/or omega-3 fatty acids have been performed. Overall, a beneficial effect of prednisolone, pregnenolone, celecoxib, and/or omega-3 fatty acids on several core symptoms, such as stereotyped behavior, was found. (Add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC, SFN, and/or omega-3 fatty acids was also associated with a significantly higher improvement in other symptoms, such as irritability, hyperactivity, and/or lethargy when compared with placebo. The mechanisms by which these agents exert their action and improve symptoms of ASD are not fully understood. Interestingly, studies have suggested that all these agents may suppress microglial/monocyte proinflammatory activation and also restore several immune cell imbalances (e.g., T regulatory/T helper-17 cell imbalances), decreasing the levels of proinflammatory cytokines, such as interleukin (IL)-6 and/or IL-17A, both in the blood and in the brain of individuals with ASD. Although encouraging, the performance of larger randomized placebo-controlled trials, including more homogeneous populations, dosages, and longer periods of follow-up, are urgently needed in order to confirm the findings and to provide stronger evidence.}, } @article {pmid36912486, year = {2023}, author = {Tashiro, M and Konishi, M and Watanabe, M and Yokoyama, U}, title = {Reduction of intracellular Mg[2+] caused by reactive oxygen species in rat ventricular myocytes.}, journal = {American journal of physiology. Cell physiology}, volume = {324}, number = {4}, pages = {C963-C969}, doi = {10.1152/ajpcell.00490.2022}, pmid = {36912486}, issn = {1522-1563}, mesh = {Rats ; Animals ; *Myocytes, Cardiac/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; *Hydrogen Peroxide/metabolism ; Biological Transport ; Ions/metabolism ; Calcium/metabolism ; }, abstract = {The concentration of intracellular free Mg[2+] ([Mg[2+]]i) should be maintained strictly for the regulation of cellular functions. Since reactive oxygen species (ROS) are liable to increase in various pathological conditions and induce cellular damage, we investigated whether ROS affect intracellular Mg[2+] homeostasis. We measured [Mg[2+]]i in ventricular myocytes from Wistar rats using the fluorescent indicator, mag-fura-2. The administration of hydrogen peroxide (H2O2) decreased [Mg[2+]]i in Ca[2+]-free Tyrode's solution. Intracellular free Mg[2+] was also reduced by endogenous ROS as generated by pyocyanin, which was inhibited by pretreatment with n-acetyl cysteine (NAC). The rate of change in [Mg[2+]]i by 500 μM H2O2 in 5 min (on average, -0.61 μM/s) was independent of extracellular Na[+], and intra- and extracellular Mg[2+] concentrations. When extracellular Ca[2+] was present, the rate of Mg[2+] decrease was significantly reduced, on average, by ∼60%. The half-maximal effective concentration of H2O2 on the Mg[2+] decrease was estimated to be between 400 and 425 μM. The Mg[2+] decrease by H2O2 in the absence of Na[+] was inhibited by 200 μM imipramine, a known inhibitor of Na[+]/Mg[2+] exchange. We perfused rat hearts with the Ca[2+]-free Tyrode's solution containing H2O2 (500 μM, 5 min) on the Langendorff apparatus,. H2O2 stimulation increased Mg[2+] concentration in the perfusate, suggesting the H2O2-induced decrease in [Mg[2+]]i was caused by Mg[2+] extrusion. Collectively, these results suggest the existence of a Na[+]-independent Mg[2+] efflux system activated by ROS in cardiomyocytes. The lower [Mg[2+]]i may in part be attributed to ROS-mediated cardiac dysfunction.}, } @article {pmid36907467, year = {2023}, author = {Wang, Y and Singh, A and Li, G and Yue, S and Hertel, K and Wang, ZJ}, title = {Opioid induces increased DNA damage in prefrontal cortex and nucleus accumbens.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {224}, number = {}, pages = {173535}, pmid = {36907467}, issn = {1873-5177}, support = {DP1 DA056804/DA/NIDA NIH HHS/United States ; K01 DA050908/DA/NIDA NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Analgesics, Opioid ; *Heroin/pharmacology ; Nucleus Accumbens ; Prefrontal Cortex ; Recurrence ; Self Administration ; }, abstract = {Opioid use disorder (OUD) is a chronic disease characterized by compulsive opioid taking and seeking, affecting millions of people worldwide. The high relapse rate is one of the biggest challenges in treating opioid addiction. However, the cellular and molecular mechanisms underlying relapse to opioid seeking are still unclear. Recent studies have shown that DNA damage and repair processes are implicated in a broad spectrum of neurodegenerative diseases as well as in substance use disorders. In the present study, we hypothesized that DNA damage is related to relapse to heroin seeking. To test our hypothesis, we aim to examine the overall DNA damage level in prefrontal cortex (PFC) and nucleus accumbens (NAc) after heroin exposure, as well as whether manipulating DNA damage levels can alter heroin seeking. First, we observed increased DNA damage in postmortem PFC and NAc tissues from OUD individuals compared to healthy controls. Next, we found significantly increased levels of DNA damage in the dorsomedial PFC (dmPFC) and NAc from mice that underwent heroin self-administration. Moreover, increased accumulation of DNA damage persisted after prolonged abstinence in mouse dmPFC, but not in NAc. This persistent DNA damage was ameliorated by the treatment of reactive oxygen species (ROS) scavenger N-acetylcysteine, along with attenuated heroin-seeking behavior. Furthermore, intra-PFC infusions of topotecan and etoposide during abstinence, which trigger DNA single-strand breaks and double-strand breaks respectively, potentiated heroin-seeking behavior. These findings provide direct evidence that OUD is associated with the accumulation of DNA damage in the brain (especially in the PFC), which may lead to opioid relapse.}, } @article {pmid36901935, year = {2023}, author = {Hsieh, MJ and Ho, HY and Lo, YS and Lin, CC and Chuang, YC and Abomughaid, MM and Hsieh, MC and Chen, MK}, title = {Semilicoisoflavone B Induces Apoptosis of Oral Cancer Cells by Inducing ROS Production and Downregulating MAPK and Ras/Raf/MEK Signaling.}, journal = {International journal of molecular sciences}, volume = {24}, number = {5}, pages = {}, pmid = {36901935}, issn = {1422-0067}, mesh = {Humans ; Apoptosis/drug effects ; *Carcinoma, Squamous Cell/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Mitogen-Activated Protein Kinase Kinases ; *Mouth Neoplasms/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; ras Proteins/drug effects/metabolism ; Proto-Oncogene Proteins c-raf/drug effects/metabolism ; }, abstract = {Oral squamous cell carcinoma (OSCC) is the sixth most common type of cancer worldwide. Despite advancement in treatment, advanced-stage OSCC is associated with poor prognosis and high mortality. The present study aimed to investigate the anticancer activities of semilicoisoflavone B (SFB), which is a natural phenolic compound isolated from Glycyrrhiza species. The results revealed that SFB reduces OSCC cell viability by targeting cell cycle and apoptosis. The compound caused cell cycle arrest at the G2/M phase and downregulated the expressions of cell cycle regulators including cyclin A and cyclin-dependent kinase (CDK) 2, 6, and 4. Moreover, SFB induced apoptosis by activating poly-ADP-ribose polymerase (PARP) and caspases 3, 8, and 9. It increased the expressions of pro-apoptotic proteins Bax and Bak, reduced the expressions of anti-apoptotic proteins Bcl-2 and Bcl-xL, and increased the expressions of the death receptor pathway protein Fas cell surface death receptor (FAS), Fas-associated death domain protein (FADD), and TNFR1-associated death domain protein (TRADD). SFB was found to mediate oral cancer cell apoptosis by increasing reactive oxygen species (ROS) production. The treatment of the cells with N-acetyl cysteine (NAC) caused a reduction in pro-apoptotic potential of SFB. Regarding upstream signaling, SFB reduced the phosphorylation of AKT, ERK1/2, p38, and JNK1/2 and suppressed the activation of Ras, Raf, and MEK. The human apoptosis array conducted in the study identified that SFB downregulated survivin expression to induce oral cancer cell apoptosis. Taken together, the study identifies SFB as a potent anticancer agent that might be used clinically to manage human OSCC.}, } @article {pmid36891481, year = {2023}, author = {Schechter, J and Brown, GW and Janda, M}, title = {A preliminary evaluation of N-acetylcysteine's effects on patient adherence to treatment for cocaine use disorder.}, journal = {The mental health clinician}, volume = {13}, number = {1}, pages = {4-10}, pmid = {36891481}, issn = {2168-9709}, abstract = {INTRODUCTION: Cocaine use disorder (CUD) is a disabling disease associated with high rates of relapse and intense cravings. Patients with CUD struggle to adhere to treatment, which contributes to relapse and frequent readmissions to residential rehab (RR) facilities. Preliminary studies suggest that N-acetylcysteine (NAC) attenuates cocaine-induced neuroplasticity and, therefore, may assist with cocaine abstinence and adherence to treatment.

METHODS: This retrospective cohort study obtained data from 20 RR facilities across Western New York. Eligible subjects were 18 or older, diagnosed with CUD, and were divided based on their exposure to 1200 mg NAC twice daily during RR. The primary outcome was treatment adherence measured by outpatient treatment attendance rates (OTA). Secondary outcomes included length of stay (LOS) in RR and craving severity on a 1 to 100 visual analog scale.

RESULTS: One hundred eighty-eight (N = 188) patients were included in this investigation: NAC, n = 90; control, n = 98. NAC did not significantly impact OTA (% appointments attended), NAC 68%; control 69%, (P = .89) or craving severity NAC 34 ± 26; control 30 ± 27, (P = .38). Subjects treated with NAC had a significantly longer average LOS in RR compared with controls, NAC 86 ± 30; control 78 ± 26, (P = .04).

DISCUSSION: In this study, NAC did not impact treatment adherence but was associated with a significantly longer LOS in RR for patients with CUD. Owing to limitations, these results may not be applicable to the general population. More rigorous studies examining NAC's impact on treatment adherence in CUD are warranted.}, } @article {pmid36880836, year = {2023}, author = {Tang, Y and Zhang, Z and Liu, S and Yao, Y and Pan, T and Qi, J and Kang, H and Liu, Y and Cai, C and Zhou, M and He, X and Hu, X and Ma, X and Wu, D and Han, Y}, title = {Conditioning therapy with N-acetyl-L-cysteine, decitabine and modified BUCY regimen for myeloid malignancies patients prior to allogeneic hematopoietic stem cell transplantation.}, journal = {American journal of hematology}, volume = {98}, number = {6}, pages = {881-889}, doi = {10.1002/ajh.26903}, pmid = {36880836}, issn = {1096-8652}, mesh = {Humans ; Decitabine ; Acetylcysteine/therapeutic use ; Busulfan ; Prospective Studies ; Reactive Oxygen Species ; *Myeloproliferative Disorders/complications ; *Hematopoietic Stem Cell Transplantation/methods ; Behavior Therapy ; *Neoplasms/complications ; Transplantation Conditioning/adverse effects ; *Leukemia, Myeloid, Acute/therapy ; *Graft vs Host Disease/etiology ; }, abstract = {Conditioning therapy is an essential procedure prior to hematopoietic stem cell transplant (HSCT), imposing a great impact on the outcomes of recipients. We performed a prospective randomized controlled trial to assess the outcome of HSCT recipients with myeloid malignancies after receiving the conditioning therapy consisting of modified BUCY (mBUCY), N-acetyl-L-cysteine (NAC), and decitabine. Enrolled patients were randomly allocated to either Arm A (decitabine, day -12 to -10; NAC, day -9 to +30; mBUCY, day -9 to -2), or Arm B (mBUCY regimen followed by stem cells infusion). Seventy-six patients in Arm A and 78 patients in Arm B were finally evaluated. The results showed platelet recovery accelerate in Arm A, with more patients achieving a platelet count of ≥50 × 10[9] /L than Arm B at day +30 and +60 (p = .004 and .043, respectively). The cumulative incidence of relapse is 11.8% (95% CI 0.06-0.22) in Arm A, and 24.4% (95% CI 0.16-0.35) in Arm B (p = .048). The estimated 3-year overall survival rate was 86.4% (±4.4%) and 79.9% (±4.7%) in 2 arms, respectively (p = .155). EFS at 3 years was 79.2% (±4.9%) in Arm A and 60.0% (±5.9%) in Arm B (p = .007). Intracellular reactive oxygen species (ROS) level was found to be reversely correlated with platelet recovery, and fewer patients in Arm A displayed excessive ROS within hematopoietic progenitor cells compared to Arm B. In conclusion, the addition of decitabine and NAC to mBUCY is a feasible and promising conditioning therapy for myeloid malignancies patients.}, } @article {pmid36880428, year = {2023}, author = {Shen, J and Kom, MC and Huang, H and Fu, G and Xie, Y and Gao, Y and Tang, Y and Yan, J and Jin, L}, title = {Role of NF-κB signaling pathway in hexavalent chromium-induced hepatotoxicity.}, journal = {Environmental toxicology}, volume = {38}, number = {6}, pages = {1361-1371}, doi = {10.1002/tox.23769}, pmid = {36880428}, issn = {1522-7278}, support = {SXAB202015//Open Fund of Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University/ ; 2018C37105//Zhejiang Province Science and Technology Project of China/ ; }, mesh = {Mice ; Humans ; Animals ; *NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; Chromium/toxicity ; Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury ; }, abstract = {Hexavalent chromium Cr (VI) is a primary human carcinogen with damaging toxic effects on multiple organs. Cr (VI) exposure can induce hepatotoxicity through oxidative stress, but its exact mechanism of action was still unclear. In our study, a model of acute Cr (VI) induced liver injury was established by exposing mice to different concentrations (0, 40, 80, and 160 mg/kg) of Cr (VI); RNA-seq was used to characterize changes in liver tissue transcriptome of C57BL/6 mice after exposing to 160 mg/kg Bw of Cr (VI). Changes in liver tissue structures, proteins, and genes were observed by hematoxylin and eosin (H&E), western blot, immunohistochemistry and RT-PCR. After Cr (VI) exposure, abnormal liver tissue structure, hepatocyte injury, and hepatic inflammatory response were observed in mice in a dose-dependent manner. RNA-seq transcriptome results indicated that oxidative stress, apoptosis, and inflammatory response pathways were increased after Cr (VI) exposure; KEGG pathway analysis found that activation of NF-κB signaling pathway was significantly upregulated. Consistent with the RNA-seq results, immunohistochemistry showed that Cr (VI) exposure resulted in infiltrating of Kupffer cells and neutrophils, increasing expression of inflammatory factors (TNF-α, IL-6, IL-1β), and activating of NF-κB signaling pathways (p-IKKα/β and p-p65). However, ROS inhibitor, N-acetyl-L-cysteine (NAC), could reduce infiltration of Kupffer cells and neutrophils and expression of inflammatory factors. Besides, NAC could inhibit NF-κB signaling pathway activation, and alleviate Cr (VI)-induced liver tissue damage. Our findings strongly suggested that inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)-associated liver fibrosis. Our findings revealed for the first time that Cr (VI) induced liver tissue damage through the inflammatory response mediated by the NF-κB signaling pathway, and inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)-associated hepatotoxicity.}, } @article {pmid36874025, year = {2023}, author = {Tan, J and Xiang, Y and Xiong, Y and Zhang, Y and Qiao, B and Zhang, H}, title = {Crebanine induces ROS-dependent apoptosis in human hepatocellular carcinoma cells via the AKT/FoxO3a signaling pathway.}, journal = {Frontiers in pharmacology}, volume = {14}, number = {}, pages = {1069093}, pmid = {36874025}, issn = {1663-9812}, abstract = {Background: Hepatocellular carcinoma (HCC), as an aggressive cancer with a high mortality rate, needs high-efficiency and low-toxicity drug therapy. Natural products have great potential as candidate lead compounds for the development of new HCC drugs. Crebanine is an isoquinoline alkaloid derived from Stephania with various potential pharmacological effects such as anti-cancer. However, the molecular mechanism underlying crebanine-induced liver cancer cells apoptosis has not been reported. Here, we investigated the effect of crebanine on HCC and identified a potential mechanism of action. Methods: In this paper, we intend to detect the toxic effects of crebanine on hepatocellular carcinoma HepG2 cells through a series of in vitro experiments, including detecting the effects of crebanine on the proliferation of HepG2 cells using the CCK8 method and plate cloning assay, observing the growth status and morphological changes of crebanine on HepG2 cells by inverted microscopy; and using the Transwell method to determine the the effect of crebanine on the migration and invasion ability of HepG2 cells; using Hoechst 33258 assay to stain cancer cells, thus observing the effect of crebanine on the morphology of HepG2 apoptotic cells, and detecting the apoptotic state and level of HepG2 cells by flow cytometry; using ROS kit and JC-1 assay kit to detect the changes of reactive oxygen species and mitochondrial membrane potential of HepG2 The immunofluorescence assay was taken to verify whether crebanine had an effect on the expression of p-FoxO3a in cancer cells; the Wetern blot assay was also used to examine the effect of crebanine on proteins related to the mitochondrial apoptotic pathway and its effect on the regulation of the relative protein expression of AKT/FoxO3a axis; after this, NAC and AKT inhibitor LY294002 were used to cells were pretreated with NAC and AKT inhibitor LY294002, respectively, in order to further validate the inhibitory effect of crebanine. Results: It was shown that crebanine effectively inhibited the growth and capacity of HepG2 cells migration and invasion in a dose-dependent manner. Furthermore, the effect of crebanine on the morphology of HepG2 cells was observed through microscopy. Meanwhile, crebanine induced apoptosis by causing reactive oxygen species (ROS) burst and mitochondrial membrane potential (MMP) disrupt. We found that crebanine could down-regulate Bcl-2 and up-regulate Bax, cleaved-PARP, cleaved-caspase-3 and cleaved-caspase-9, but these effects were overturned by ROS inhibitor N-acetylcysteine (NAC). Crebanine also down-regulated p-AKT and p-FoxO3a, and the PI3K inhibitor LY294002 significantly enhances this effect. We also found that the expression of AKT/FoxO3a signaling pathway was ROS-dependent. As shown by Western blots, NAC could partially attenuate the inhibitory effect of crebanine on AKT and FoxO3a phosphorylation. Conclusion: Based on our results, our results suggest that crebanine, as a compound with potential anticancer activity, has significant cytotoxic effects on hepatocellular carcinoma,and it likely induces apoptosis via ROS in the mitochondrial pathway and simultaneously affects the biological function of HCC via the ROS-AKT-FoxO3a signaling axis.}, } @article {pmid36873280, year = {2023}, author = {Maghsadi, Z and Azadmehr, A and Moghadamnia, AA and Feizi, F and Hamidi, N}, title = {N-Acetylcysteine attenuated pulmonary fibrosis induced by bleomycin via immunomodulation responses.}, journal = {Research in pharmaceutical sciences}, volume = {18}, number = {2}, pages = {177-184}, pmid = {36873280}, issn = {1735-5362}, abstract = {BACKGROUND AND PURPOSE: Pulmonary fibrosis (PF) is a chronic and life-threatening interstitial lung disease. N-acetyl cysteine (NAC) is an antioxidant pharmaceutically available to reduce endothelial dysfunction, inflammation, and fibrosis, however, the therapeutic effect of NAC on PF has not been clearly identified. This research aimed to investigate the possible therapeutic impact of NAC on PF induced by bleomycin in the rat model.

EXPERIMENTAL APPROACH: Rats received intraperitoneal injections of NAC at 150, 300, and 600 mg/kg for 28 days before bleomycin, while the positive and negative control groups were treated with bleomycin alone and normal saline, respectively. Then, rats' lung tissues were isolated and leukocyte infiltration and also collagen deposition were evaluated using hematoxylin and eosin and Mallory trichrome stainings, respectively. In addition, the levels of IL-17, and TGF-β cytokines in bronchoalveolar lavage fluid and hydroxyproline in homogenized lung tissues were assayed using the ELISA method.

FINDINGS/RESULTS: Histological findings indicated that NAC decreased leukocyte infiltration, collagen deposition, and fibrosis score in the bleomycin-induced PF tissue. Moreover, NAC significantly reduced TGF-β and hydroxyproline levels at 300-600 mg/kg, as well as IL-17 cytokine at 600 mg/kg.

CONCLUSION AND IMPLICATIONS: NAC showed a potential anti-fibrotic effect by reducing hydroxyproline and TGF-β as well as an anti-inflammatory effect by decreasing IL-17 cytokine. So, it may be administered as a prophylactic or therapeutic candidate agent to attenuate PF via immunomodulatory effects. Although, future studies are suggested.}, } @article {pmid36866174, year = {2023}, author = {Redwan, A and Kiriaev, L and Kueh, S and Morley, JW and Houweling, P and Perry, BD and Head, SI}, title = {Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle.}, journal = {Frontiers in physiology}, volume = {14}, number = {}, pages = {1109587}, pmid = {36866174}, issn = {1664-042X}, abstract = {Introduction: It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles. Methods: Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water. Post NAC treatment animals were euthanised and the EDL muscles dissected out and placed in an organ bath where the muscle was attached to a force transducer to measure contractile properties and susceptibility to force loss from eccentric contractions. After the contractile measurements had been made the EDL muscle was blotted and weighed. In order to assess the degree of pathological fiber branching mdx EDL muscles were treated with collagenase to release single fibers. For counting and morphological analysis single EDL mdx skeletal muscle fibers were viewed under high magnification on an inverted microscope. Results: During the six-week treatment phase NAC reduced body weight gain in three- to nine-week-old mdx and littermate control mice without effecting fluid intake. NAC treatment also significantly reduced the mdx EDL muscle mass and abnormal fiber branching and splitting. Discussion: We propose chronic NAC treatment reduces the inflammatory response and degenerative cycles in the mdx dystrophic EDL muscles resulting in a reduction in the number of complexed branched fibers reported to be responsible for the dystrophic EDL muscle hypertrophy.}, } @article {pmid36863618, year = {2023}, author = {Xue, Y and Zhang, D and Wei, Y and Guo, C and Song, B and Cui, Y and Zhang, C and Xu, D and Zhang, S and Fang, J}, title = {Polymeric nano-micelle of carbon monoxide donor SMA/CORM2 ameliorates acetaminophen-induced liver injury via suppressing HMGB1/TLR4 signaling pathway.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {184}, number = {}, pages = {106413}, doi = {10.1016/j.ejps.2023.106413}, pmid = {36863618}, issn = {1879-0720}, mesh = {Animals ; Mice ; Acetaminophen ; Anti-Inflammatory Agents/pharmacology ; Carbon Monoxide/metabolism/pharmacology ; *Chemical and Drug Induced Liver Injury/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; Disease Models, Animal ; *HMGB1 Protein/metabolism ; Liver/metabolism ; Mice, Inbred C57BL ; Micelles ; Signal Transduction ; Toll-Like Receptor 4/metabolism ; }, abstract = {Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of acute liver failure. Excessive generation of reactive oxygen species (ROS) and inflammatory responses are the major causes of necrosis and/or necroptosis of the liver cells. Currently, the treatment options for APAP-induced liver injury are very limited, N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose patients. It is of great necessity to develop new therapeutic strategies. In a previous study, we focused on the anti-oxidative, anti-inflammatory signal molecule carbon monoxide (CO), and developed a nano-micelle encapsulating CO donor, i.e., SMA/CORM2. Administration of SMA/CORM2 to the mice exposed to APAP significantly ameliorated the liver injury and inflammatory process, in which modulating macrophage reprogramming plays a critical role. Along this line, in this study, we investigated the potential effect of SMA/CORM2 on toll-like receptor 4 (TLR4) and high mobility group protein B1 (HMGB1) signaling pathways that are known to be closely involved in many inflammatory responses and necroptosis. In a mouse APAP-induced liver injury model, similar to the previous study, SMA/CORM2 at 10 mg/kg remarkably improved the condition of the liver after injury as evidenced by histological examination and liver function. During the process of liver injury triggered by APAP, TLR4 expression gradually increased over time, and it was significantly upregulated as early as 4 h after APAP exposure, whereas, an increase of HMGB1 was a late-stage event. Notably, SMA/CORM2 treatment suppressed significantly both TLR4 and HMGB1, consequently inhibiting the progression of inflammation and liver injury. Compared to CORM2 without SMA modification (native CORM2) of 1 mg/kg that is equivalent to 10 mg/kg of SMA/CORM2 (the amount of CORM2 in SMA/CORM2 is 10% [w/w]), SMA/CORM2 exhibited a much better therapeutic effect, indicating its superior therapeutic efficacy to native CORM2. These findings revealed that SMA/CORM2 protects against APAP-induced liver injury via mechanisms involving the suppression of TLR4 and HMGB1 signaling pathways. Taking together the results in this study and previous studies, SMA/CORM2 exhibits great therapeutic potential for APAP overdose-induced liver injury, we thus anticipate the clinical application of SMA/CORM2 for the treatment of APAP overdose, as well as other inflammatory diseases.}, } @article {pmid36860857, year = {2023}, author = {Lee, SH and Han, MS and Lee, TH and Lee, DB and Park, JH and Lee, SH and Kim, TH}, title = {Hydrogen peroxide attenuates rhinovirus-induced anti-viral interferon secretion in sinonasal epithelial cells.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1086381}, pmid = {36860857}, issn = {1664-3224}, mesh = {Humans ; Antiviral Agents/pharmacology ; Hydrogen Peroxide ; Rhinovirus ; *Nasal Polyps ; Toll-Like Receptor 3 ; Epithelial Cells ; Acetylcysteine/pharmacology ; *Interferon Type I ; Antioxidants ; }, abstract = {BACKGROUND: Altered innate defense mechanisms, including an imbalance between oxidants and antioxidants release, have been implicated in the pathogenesis of chronic rhinosinusitis (CRS). The aim of this study is to investigate whether oxidative stress may attenuate the secretion of anti-viral interferons in human sinonasal mucosa.

METHODS: The levels of H2O2 in nasal secretion were increased in patients with CRS with nasal polyps, compared with that of CRS patients without nasal polyps and control subjects. Normal sinonasal epithelial cells derived from healthy subjects were cultured under an air-liquid interface. The cultured cells were infected with rhinovirus 16 (RV 16) or treated with poly (I: C), TLR3 agonist, after being pretreated with an oxidative stressor, H2O2 or antioxidant, N-acetylcysteine (NAC). Thereafter, the expression levels of type I (IFN-β) and type III (IFN-λ1 and λ2) interferons and interferon-stimulated genes (ISGs) were evaluated with RT-qPCR, ELISA, and western blot.

RESULTS: The data showed that the production of type I (IFN-β) and type III (IFN-λ1 and λ2) interferons and ISGs was upregulated in cells infected with RV 16 or treated with poly (I: C). However, their up-regulated expression was attenuated in cells pretreated with H2O2, but not inhibited in cells pretreated with NAC. In line with these data, the up-regulated expression of TLR3, RIG-1, MDA5, and IRF3 was reduced in cells pretreated with H2O2, but not attenuated in cells treated with NAC. Furthermore, cells transfected with Nrf2 siRNA showed decreased secretion of anti-viral interferons whereas sulforaphane treatment enhanced the secretory capacity of antiviral interferons.

CONCLUSIONS: These results suggest that the production of RV16-induced antiviral interferons may be attenuated by oxidative stress.}, } @article {pmid36860082, year = {2023}, author = {Wei, M and Dhanasekaran, S and Ji, Q and Yang, Q and Zhang, H}, title = {Sustainable and efficient method utilizing N-acetyl-L-cysteine for complete and enhanced ochratoxin A clearance by antagonistic yeast.}, journal = {Journal of hazardous materials}, volume = {448}, number = {}, pages = {130975}, doi = {10.1016/j.jhazmat.2023.130975}, pmid = {36860082}, issn = {1873-3336}, mesh = {Humans ; *Saccharomyces cerevisiae ; Acetylcysteine ; *Mycotoxins ; Biodegradation, Environmental ; }, abstract = {With the increasing global climate change, ochratoxin A (OTA) pollution in food and environment has become a serious and potential risk element threatening food safety and human health. Biodegradation of mycotoxin is an eco-friendly and efficient control strategy. Still, research works are warranted to develop low-cost, efficient, and sustainable approaches to enhance the mycotoxin degradation efficiency of microorganisms. In this study, the activities of N-acetyl-L-cysteine (NAC) against OTA toxicity were evidenced, and its positive effects on the OTA degradation efficiency of antagonistic yeast, Cryptococcus podzolicus Y3 were verified. Co-culturing C. podzolicus Y3 with 10 mM NAC improved 100% and 92.6% OTA degradation rate into ochratoxin α (OTα) at 1 d and 2 d. The excellent promotion role of NAC on OTA degradation was observed even at low temperatures and alkaline conditions. C. podzolicus Y3 treated with OTA or OTA+NAC promoted reduced glutathione (GSH) accumulation. GSS and GSR genes were highly expressed after OTA and OTA+NAC treatment, contributing to GSH accumulation. In the early stages of NAC treatment, yeast viability and cell membrane were reduced, but the antioxidant property of NAC prevented lipid peroxidation. Our finding provides a sustainable and efficient new strategy to improve mycotoxin degradation by antagonistic yeasts, which could be applied to mycotoxin clearance.}, } @article {pmid36855363, year = {2023}, author = {Concessao, PL and Bairy, KL and Raghavendra, AP}, title = {Ameliorating effect of Mucuna pruriens seed extract on sodium arsenite-induced testicular toxicity and hepato-renal histopathology in rats.}, journal = {Veterinary world}, volume = {16}, number = {1}, pages = {82-93}, pmid = {36855363}, issn = {0972-8988}, abstract = {BACKGROUND AND AIM: A significant cause of arsenic poisoning is polluted groundwater. Arsenic poisoning results in the suppression of spermatogenesis and the liver and kidneys are vulnerable to the toxic effects as well. Mucuna pruriens has been identified to have fertility-enhancing and anti-lipid peroxidation properties. Based on these properties of M. pruriens, this study aimed to investigate the efficacy of M. pruriens seed extract in reducing sodium arsenite-induced testicular impairment and hepato-renal histopathology in rats.

MATERIALS AND METHODS: The study was divided into two groups; short-term (45 days) and long-term (90 days) treatment groups and each group was divided into nine subgroups. Subgroups 1 and 2 served as normal and N-acetyl cysteine (NAC) controls, respectively. Subgroups 3-9 received sodium arsenite in the drinking water (50 mg/L). Subgroup-4 received NAC (210 mg/kg body weight [BW]) orally once daily. Subgroups 5-7 received aqueous seed extract of M. pruriens (350, 530, and 700 mg/kg BW, respectively) orally once daily. Subgroups 8 and 9 received a combination of NAC and aqueous seed extract (350 and 530 mg/kg BW, respectively) orally once daily. Following the treatment, animals were sacrificed and sperm parameters and DNA damage were evaluated. Testis, liver, and kidneys were analyzed for histopathology.

RESULTS: Sodium arsenite-induced a significant reduction in sperm parameters and increase in the abnormal architecture of spermatozoa. Histology revealed tissue necrosis. The M. pruriens seed extract ameliorated the damaging effects of sodium arsenite with respect to tissue architecture and sperm parameters when coadministered.

CONCLUSION: Mucuna pruriens has beneficial effects against the deleterious effects of sodium arsenite on various tissues. Thus, M. pruriens (530 and 700 mg/kg BW) supplementation would reduce the adverse changes observed with sodium arsenite exposure.}, } @article {pmid36854537, year = {2023}, author = {Musa, MA and Kolawole, Q}, title = {7,8-Diacetoxy-3-(4-methylsulfonylphenyl)-4-phenylcoumarin Induces ROS-dependent Cell Death in the A549 Human Lung Cancer Cell Line.}, journal = {Anticancer research}, volume = {43}, number = {3}, pages = {1001-1007}, doi = {10.21873/anticanres.16244}, pmid = {36854537}, issn = {1791-7530}, mesh = {Male ; Humans ; Reactive Oxygen Species ; A549 Cells ; *Lung Neoplasms/drug therapy ; Cell Death ; Coumarins/pharmacology ; Cell Line ; }, abstract = {BACKGROUND/AIM: Coumarins comprise of a very large class of naturally occurring compounds with growing interest in their synthesis and possible applications in the treatment of various diseases. We herein report the in-vitro cytotoxic activity of 3,4-Diarylcoumarins (4a-i) in A549 (lung) and PC-3 (prostate) cancer cell lines.

MATERIALS AND METHODS: The cytotoxic activity was evaluated using crystal violet dye-binding. The most active compound effect on the cell-cycle phases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production and apoptosis were also evaluated.

RESULTS: Among the synthesized compounds that were evaluated, 7,8-Diacetoxy-3-(4-(methylsulfonyl)phenyl)-4-phenylcoumrin (4f) showed highest cytotoxicity (CC50=13.5%±0.15μM) in A549 cancer cell line. The mechanism of its cytotoxic action indicated significant cell arrest in G1/G0, S and G2 phases of the cell cycle, loss of mitochondrial membrane potential (MMP), increase in reactive oxygen species (ROS) production and induction of apoptotic cell death. The cell viability result of pretreated A549 cells with antioxidant N-acetylcysteine (NAC), followed by compound 4f treatment confirmed ROS-dependent cell death.

CONCLUSION: The presence of 3-4-methylsulfonyl and 7,8-diacetoxy groups on 3,4-Diarylcoumarin is critical in modulating higher cytotoxic activity and could serve as a valuable template for the development of novel synthetic compounds as potential anticancer agents for lung cancer treatment.}, } @article {pmid36852734, year = {2023}, author = {Akinlolu, A and Emojevwe, V and Uwejigho, R and Ilesanmi, J and Owolabi, R and Igandan, A}, title = {Neuro-protective potentials of N-acetylcysteine and zinc against di(2-ethylhexyl)-phthalate-induced neuro-histopathology and dys-regulations of Dopamine and Glutamate in rat brain.}, journal = {Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering}, volume = {58}, number = {1}, pages = {81-90}, doi = {10.1080/10934529.2023.2177449}, pmid = {36852734}, issn = {1532-4117}, mesh = {Animals ; Rats ; Rats, Wistar ; Male ; *Diethylhexyl Phthalate/toxicity ; Dopamine/genetics ; Glutamic Acid/genetics ; *Gene Expression Regulation/drug effects ; *Acetylcysteine/pharmacology ; *Zinc/pharmacology ; *Brain/drug effects ; }, abstract = {This study examined neuro-protective potentials of N-acetyl-cysteine (NAC) and Zinc on expression levels of Dopamine and Glutamate in the Cerebrum, Hypothalami and Pituitary Glands in Di(2-ethylhexyl)-phthalate (DEHP)-induced neurotoxicity in rats. Thirty-six adult male Wistar rats were randomly divided into 6 groups (n = 6). Group 1 was control. Groups 2-6 received oral administrations of 100 mg/kg NAC, 0.5 mg/kg Zinc, 750 mg/kg DEHP, DEHP + NAC doses and DEHP + Zinc doses respectively for 21 days. Brain histology (Heamatoxyline and Eosine technique), histochemical and enzyme-linked-immunosorbent assays of Dopamine and Glutamate in homogenates of Cerebrum, Hypothalami and Pituitary Glands were evaluated. Data were statistically analyzed using One-way-ANOVA with Tukey-post-hoc test at p ≤ 0.05. Histo-pathological evaluations of Cerebrum, Hypothalami and Pituitary Glands showed gross histo-alterations and neurodegenerative changes (Group 4), mild histo- and neuro-degenerative changes (Groups 5 and 6) and normal histology (Group 1). Histochemical analyses showed higher Dopamine levels in Hypothalami (Group 5) and Pituitary Glands (Groups 5 and 6), compared with Group 4. Furthermore, results showed lower Glutamate levels in Cerebrum, Hypothalami and Pituitary Glands of Groups 5 and 6, compared with Group 4. Overall, NAC and Zinc conferred neuro-protection and histo-protection against DEHP-induced neuro-toxicity, neuro-histopathology, decreased Dopamine levels and increased Glutamate levels.}, } @article {pmid36849104, year = {2023}, author = {Wang, H and Banerjee, N and Wang, G and Firoze Khan, M}, title = {Autophagy dysregulation in trichloroethene-mediated inflammation and autoimmune response.}, journal = {Toxicology}, volume = {487}, number = {}, pages = {153468}, pmid = {36849104}, issn = {1879-3185}, support = {P30 ES030285/ES/NIEHS NIH HHS/United States ; R01 ES016302/ES/NIEHS NIH HHS/United States ; R01 ES026887/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Autoimmune Diseases/chemically induced ; Autoimmunity ; Autophagy ; Inflammation/chemically induced ; Solvents/toxicity ; *Trichloroethylene/toxicity ; }, abstract = {Trichloroethene (TCE), an organic solvent extensively used for degreasing metals, can cause inflammatory autoimmune disorders [i.e., systemic lupus erythematosus (SLE) and autoimmune hepatitis] from both environmental and occupational exposure. Autophagy has emerged as a pivotal pathogenic factor in various autoimmune diseases. However, role of autophagy dysregulation in TCE-mediated autoimmunity is largely unknown. Here, we investigate whether autophagy dysregulation contributes to pathogenesis of TCE-mediated autoimmune responses. Using our established mouse model, we observed TCE-treated mice had elevated MDA-protein adducts, microtubule-associated protein light chain 3 conversion (LC3-II/LC3-I), beclin-1, phosphorylation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) phosphorylation in the livers of MRL+ /+ mice. Suppression of oxidative stress with antioxidant N-acetylcysteine (NAC) effectively blocked TCE-mediated induction of autophagy markers. On the other hand, pharmacological autophagy induction with rapamycin significantly reduced TCE-mediated hepatic inflammation (NLRP3, ASC, Caspase1 and IL1-β mRNA levels), systemic cytokines (IL-12 and IL-17) and autoimmune responses (ANA and anti-dsDNA levels). Taken together, these results suggest that autophagy plays a protective role against TCE-mediated hepatic inflammation and autoimmunity in MRL+ /+ mice. These novel findings on the regulation of autophagy could help in designing therapeutic strategies for chemical exposure-mediated autoimmune responses.}, } @article {pmid36842745, year = {2023}, author = {Liu, YX and Yang, JY and Sun, JL and Wang, AC and Wang, XY and Zhu, LB and Cao, HH and Huang, ZH and Liu, SH and Xu, JP}, title = {Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.}, journal = {International journal of biological macromolecules}, volume = {235}, number = {}, pages = {123834}, doi = {10.1016/j.ijbiomac.2023.123834}, pmid = {36842745}, issn = {1879-0003}, mesh = {Animals ; Phosphorylation ; *Nucleopolyhedroviruses/physiology ; Reactive Oxygen Species/metabolism ; Apoferritins/metabolism ; MAP Kinase Signaling System ; Cell Proliferation ; *Bombyx/metabolism ; Insect Proteins/metabolism ; }, abstract = {c-Jun N-terminal kinase (JNK) phosphorylation is widely observed during virus infection, modulating various aspects of the virus-host interaction. In our previous research, we have proved that B. mori ferritin heavy-chain homolog (BmFerHCH), an inhibitor of reactive oxygen species (ROS), facilitates B. mori nucleopolyhedrovirus (BmNPV) proliferation. However, one question remains: Which downstream signaling pathways does BmFerHCH regulate by inhibiting ROS? Here, we first determined that silencing BmFerHCH inhibits BmNPV proliferation, and this inhibition depends on ROS. Then, we substantiated that BmNPV infection activates the JNK signaling pathway. Interestingly, the JNK phosphorylation during BmNPV infection is activated by ROS. Further, we found that the enhanced nuclear translocation of phospho-JNK induced by BmNPV infection was dramatically reduced by pretreatment with the antioxidant N-acetylcysteine (NAC), whereas there was more detectable phospho-JNK in the cytoplasm. Next, we investigated how changes in BmFerHCH expression affect JNK phosphorylation. BmFerHCH overexpression suppressed the phosphorylation of JNK and nuclear translocation of phospho-JNK during BmNPV infection, whereas BmFerHCH knockdown facilitated phosphorylation of JNK and nuclear translocation of phospho-JNK. By measuring the viral load, we found the inhibitory effect of BmFerHCH knockdown on BmNPV infection depends on phosphorylated JNK. In addition, the JNK signaling pathway was involved in BmNPV-triggered apoptosis. Hence, we hypothesize that ROS-mediated JNK phosphorylation is involved in the regulation of BmFerHCH on BmNPV proliferation. These results elucidate the molecular mechanisms and signaling pathways of BmFerHCH-mediated response to BmNPV infection.}, } @article {pmid36840032, year = {2023}, author = {Kim, SH and Jung, DE and Song, JY and Jung, J and Jung, JK and Lee, H and Roh, E and Hong, JT and Han, SB and Kim, Y}, title = {Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice.}, journal = {Pharmaceutics}, volume = {15}, number = {2}, pages = {}, pmid = {36840032}, issn = {1999-4923}, abstract = {The kinase activity of inhibitory κB kinase β (IKKβ) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKβ activity on acetaminophen (APAP)-induced hepatotoxicity remains to be defined. Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKβ, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKβ activity. To understand the importance of IKKβ activity in sterile inflammation during hepatotoxicity, C57BL/6 mice were treated with CABA, IMD-0354, or sulfasalazine after APAP overdose. These small-molecule inhibitors of IKKβ activity protected the APAP-challenged mice from necrotic injury around the centrilobular zone in the liver, and rescued the mice from hepatic damage-associated lethality. From a molecular perspective, IKKβ inhibitors directly interrupted sterile inflammation in the Kupffer cells of APAP-challenged mice, such as damage-associated molecular pattern (DAMP)-induced activation of NF-κB activity via IKKβ, and NF-κB-regulated expression of cytokines and chemokines. However, CABA did not affect the upstream pathogenic events, including oxidative stress with glutathione depletion in hepatocytes after APAP overdose. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses.}, } @article {pmid36836353, year = {2023}, author = {Okamoto, M and Nakano, K and Takahashi-Nakaguchi, A and Sasamoto, K and Yamaguchi, M and Teixeira, MC and Chibana, H}, title = {In Candida glabrata, ERMES Component GEM1 Controls Mitochondrial Morphology, mtROS, and Drug Efflux Pump Expression, Resulting in Azole Susceptibility.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {9}, number = {2}, pages = {}, pmid = {36836353}, issn = {2309-608X}, abstract = {Mitochondrial dysfunction or morphological abnormalities in human pathogenic fungi are known to contribute to azole resistance; however, the underlying molecular mechanisms are unknown. In this study, we investigated the link between mitochondrial morphology and azole resistance in Candida glabrata, which is the second most common cause of human candidiasis worldwide. The ER-mitochondrial encounter structure (ERMES) complex is thought to play an important role in the mitochondrial dynamics necessary for mitochondria to maintain their function. Of the five components of the ERMES complex, deletion of GEM1 increased azole resistance. Gem1 is a GTPase that regulates the ERMES complex activity. Point mutations in GEM1 GTPase domains were sufficient to confer azole resistance. The cells lacking GEM1 displayed abnormalities in mitochondrial morphology, increased mtROS levels, and increased expression of azole drug efflux pumps encoded by CDR1 and CDR2. Interestingly, treatment with N-acetylcysteine (NAC), an antioxidant, reduced ROS production and the expression of CDR1 in Δgem1 cells. Altogether, the absence of Gem1 activity caused an increase in mitochondrial ROS concentration, leading to Pdr1-dependent upregulation of the drug efflux pump Cdr1, resulting in azole resistance.}, } @article {pmid36835209, year = {2023}, author = {Sakai, M and Yu, Z and Taniguchi, M and Picotin, R and Oyama, N and Stellwagen, D and Ono, C and Kikuchi, Y and Matsui, K and Nakanishi, M and Yoshii, H and Furuyashiki, T and Abe, T and Tomita, H}, title = {N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36835209}, issn = {1422-0067}, support = {20dm0107099h0005, JP19dm0107099, JP18ek0109183, JP22gm0910012, and JP22wm0425001//Ministry of Education, Culture, Sports, Science and Technology of Japan, the Strategic Research Program for Brain Sciences, and the Japan Agency for Medical Research and Development/ ; KAKENHI 21390329, 16K07210, 18H05429, 21H04812, and 19K16372//Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; No. 24116007//Grant-in-Aid for Scientific Research on Innovative Areas/ ; }, mesh = {Animals ; Humans ; Mice ; *Acetylcysteine/pharmacology ; *Inflammation/metabolism/pathology ; Lipopolysaccharides/pharmacology ; *Microglia/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; *Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.}, } @article {pmid36834536, year = {2023}, author = {Li, F and Liu, H and Wu, X and Song, Z and Tang, H and Gong, M and Liu, L and Li, F}, title = {Tetrathiomolybdate Decreases the Expression of Alkaline Phosphatase in Dermal Papilla Cells by Increasing Mitochondrial ROS Production.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36834536}, issn = {1422-0067}, support = {31972594//National Natural Science Foundation of China/ ; CARS-43-B-1//the earmarked fund for CARS/ ; ZR2021MC043//Natural Science Foundation of Shandong Province/ ; ZR2021QC108//Natural Science Foundation of Shandong Province/ ; SDAIT-21-16//Special Economic Animal Industry Technology System of Shandong Province/ ; 2021LZGC002//Agricultural Seed Improvement Project of Shandong Province/ ; }, mesh = {*Hair Follicle/metabolism ; *Dermis ; Cells, Cultured ; Alkaline Phosphatase/metabolism ; Reactive Oxygen Species/metabolism ; Proteomics ; Copper/metabolism ; Cell Proliferation ; }, abstract = {Dermal papilla cells (DPCs) play important roles in hair growth regulation. However, strategies to regrow hair are lacking. Here, global proteomic profiling identified the tetrathiomolybdate (TM)-mediated inactivation of copper (Cu) depletion-dependent mitochondrial cytochrome c oxidase (COX) as the primary metabolic defect in DPCs, leading to decreased Adenosine Triphosphate (ATP) production, mitochondrial membrane potential depolarization, increased total cellular reactive oxygen species (ROS) levels, and reduced expression of the key marker of hair growth in DPCs. By using several known mitochondrial inhibitors, we found that excessive ROS production was responsible for the impairment of DPC function. We therefore subsequently showed that two ROS scavengers, N-acetyl cysteine (NAC) and ascorbic acid (AA), partially prevented the TM- and ROS-mediated inhibition of alkaline phosphatase (ALP). Overall, these findings established a direct link between Cu and the key marker of DPCs, whereby copper depletion strongly impaired the key marker of hair growth in the DPCs by increasing excessive ROS production.}, } @article {pmid36831011, year = {2023}, author = {Li, H and Li, JJ and Lu, W and Yang, J and Xia, Y and Huang, P}, title = {Targeting Mitochondrial IDH2 Enhances Antitumor Activity of Cisplatin in Lung Cancer via ROS-Mediated Mechanism.}, journal = {Biomedicines}, volume = {11}, number = {2}, pages = {}, pmid = {36831011}, issn = {2227-9059}, support = {(No. 81902323, No. 81972595).//This work was supported in part by grants from the National Natural Science Foundation of China/ ; }, abstract = {Mitochondrial isocitrate dehydrogenase 2 (IDH2) is an important metabolic enzyme in the tricarboxylic acid cycle (TCA) cycle. Our previous study showed that high expression of wild-type IDH2 promotes the proliferation of lung cancer cells. This study aims to test the potential of targeting IDH2 as a therapeutic strategy to inhibit lung cancer in vitro and in vivo. First, we analyzed the available data from the databases gene expression omnibus (GEO) database to evaluate the clinical relevance of IDH2 expression in affecting lung cancer patient survival. We then generated a stable IDH2-knockdown lung cancer cell line using a lentivirus-based method for in vitro and in vivo study. Cell growth, apoptosis, cell viability, and colony formation assays were conducted to test the sensitivity of lung cancer cells with different IDH2 expression status to cisplatin or radiation treatment in vitro. For mechanistic study, Cellular oxygen consumption and extracellular acidification rates were measured using a Seahorse metabolic analyzer, and reactive oxygen species (ROS) generation was analyzed using flow cytometry. An animal study using a xenograft tumor model was performed to further evaluate the in vivo therapeutic effect on tumor growth. We found that high IDH2 expression was associated with poor survival in lung cancer patients undergoing chemotherapy. Inhibition of IDH2 significantly enhanced the anticancer activity of cisplatin and also increased the effect of radiation against lung cancer cells. IDH2 was upregulated in cisplatin-resistant lung cancer cells, which could be sensitized by targeted inhibition of IDH2. Mechanistic study showed that abrogation of IDH2 caused only minimal changes in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in lung cancer cells, but induced a significant increase in ROS, which rendered the cancer cells more sensitive to cisplatin. Pretreatment of lung cancer cells with the ROS scavenger N-acetyl-cysteine could partially rescue cells from the cytotoxic effect of cisplatin and IDH2 inhibition. Importantly, abrogation of IDH2 significantly increased the sensitivity of lung cancer cells to cisplatin in vivo.}, } @article {pmid36830070, year = {2023}, author = {Abu-Halaka, D and Shpaizer, A and Zeigerman, H and Kanner, J and Tirosh, O}, title = {DMF-Activated Nrf2 Ameliorates Palmitic Acid Toxicity While Potentiates Ferroptosis Mediated Cell Death: Protective Role of the NO-Donor S-Nitroso-N-Acetylcysteine.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {36830070}, issn = {2076-3921}, abstract = {Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that can develop into an aggressive form called nonalcoholic steatohepatitis (NASH), which ultimately progresses to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure. Currently, the deterioration of NAFLD is attributed to specific lipid toxicity which could be due to lipotoxicity and/or ferroptosis. In the current study, we evaluated the involvement of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf-2), which is a main activator of phase II metabolism in the two types of lipid-induced toxicity in hepatocytes, lipotoxicity by saturated fatty acids, and in ferroptosis, and the effect of NO donor treatment. AML12 cells were exposed to 600 μM palmitic acid to induce lipotoxicity or treated with 20 μM erastin or 5 μM RSL3 for ferroptosis. In SFA-lipotoxicity, pretreatment with the Nrf2 activator dimethyl fumarate (DMF) managed to ameliorate the cells and the oxidative stress level while aggravating ferroptosis due to emptying the thiol pool. On the other hand, the nitric oxide (NO)-donor, S-nitroso-N-acetylcysteine (NAC-SNO) proved to be effective in the prevention of hepatocytes ferroptosis.}, } @article {pmid36830062, year = {2023}, author = {Shakya, S and McGuffee, RM and Ford, DA}, title = {Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {36830062}, issn = {2076-3921}, support = {S10 OD025246/OD/NIH HHS/United States ; S10OD025246/NH/NIH HHS/United States ; R01 GM115553/GM/NIGMS NIH HHS/United States ; R01ES034383/NH/NIH HHS/United States ; R01 ES034383/ES/NIEHS NIH HHS/United States ; R01GM115553/NH/NIH HHS/United States ; }, abstract = {Hypochlorous acid is produced by leukocyte myeloperoxidase activity. 2-Chlorofatty aldehydes (2-ClFALDs) are formed when hypochlorous acid attacks the plasma membrane phospholipid plasmalogen molecular subclass and are thus produced following leukocyte activation as well as in the lungs of mice exposed to chlorine gas. The biological role of 2-ClFALD is largely unknown. Recently, we used an alkyne analog (2-ClHDyA) of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDA), to identify proteins covalently modified by 2-ClHDyA in endothelial cells and epithelial cells. Here, we demonstrate that 2-ClHDA reduces the metabolic activity of RAW 264.7 cells in a dose-dependent manner. 2-ClHDyA localizes to the mitochondria, endoplasmic reticulum and Golgi in RAW 264.7 cells and modifies many proteins. The thiol-containing precursor of glutathione, N-acetyl cysteine (NAC), was shown to produce an adduct with 2-ClHDA with the loss of Cl[-] (HDA-NAC). This adduct was characterized in both positive and negative ion modes using LC-MS/MS and electrospray ionization. NAC treatment of neutrophils reduced the 2-ClFALD levels in PMA-stimulated cells with subsequent increases in HDA-NAC. NAC treatments reduced the 2-ClHDA-elicited loss of metabolic activity in RAW 264.7 cells as well as 2-ClHDA protein modification. These studies demonstrate that 2-ClFALD toxic effects can be reduced by NAC, which reduces protein modification.}, } @article {pmid36828949, year = {2023}, author = {Dandekar, AA and Vora, D and Yeh, JS and Srivastava, RK and Athar, M and Banga, AK}, title = {Enhanced Transdermal Delivery of N-Acetylcysteine and 4-Phenylbutyric Acid for Potential Use as Antidotes to Lewisite.}, journal = {AAPS PharmSciTech}, volume = {24}, number = {3}, pages = {71}, pmid = {36828949}, issn = {1530-9932}, mesh = {*Skin Absorption ; Acetylcysteine/metabolism ; Antidotes ; Oleic Acid/metabolism ; Dimethyl Sulfoxide/metabolism ; Administration, Cutaneous ; Skin/metabolism ; *Arsenicals/metabolism ; Sodium Dodecyl Sulfate/metabolism ; }, abstract = {Lewisite is a highly toxic chemical warfare agent that leads to cutaneous and systemic damage. N-acetylcysteine (NAC) and 4-phenylbutryic acid (4-PBA) are two novel antidotes developed to treat toxicity caused by lewisite and similar arsenicals. Our in vivo studies demonstrated safety and effectiveness of these agents against skin injury caused by surrogate lewisite (Phenylarsine oxide) proving their potential for the treatment of lewisite injury. We further focused on exploring various enhancement strategies for an enhanced delivery of these agents via skin. NAC did not permeate passively from propylene glycol (PG). Iontophoresis as a physical enhancement technique and chemical enhancers were investigated for transdermal delivery of NAC. Application of cathodal and anodal iontophoresis with the current density of 0.2 mA/cm[2] for 4 h followed by passive diffusion till 24 h significantly enhanced the delivery of NAC with a total delivery of 65.16 ± 1.95 µg/cm[2] and 87.23 ± 7.02 µg/cm[2], respectively. Amongst chemical enhancers, screened oleic acid, oleyl alcohol, sodium lauryl ether sulfate, and dimethyl sulfoxide (DMSO) showed significantly enhanced delivery of NAC with DMSO showing highest delivery of 28,370.2 ± 2355.4 µg/cm[2] in 24 h. Furthermore, 4-PBA permeated passively from PG with total delivery of 1745.8 ± 443.5 µg/cm[2] in 24 h. Amongst the chemical enhancers screened for 4-PBA, oleic acid, oleyl alcohol, and isopropyl myristate showed significantly enhanced delivery with isopropyl myristate showing highest total delivery of 17,788.7 ± 790.2 µg/cm[2]. These studies demonstrate feasibility of delivering these antidotes via skin and will aid in selection of excipients for the development of topical/transdermal delivery systems of these agents.}, } @article {pmid36827603, year = {2023}, author = {Pitha, I and Kambhampati, S and Sharma, A and Sharma, R and McCrea, L and Mozzer, A and Kannan, RM}, title = {Targeted Microglial Attenuation through Dendrimer-Drug Conjugates Improves Glaucoma Neuroprotection.}, journal = {Biomacromolecules}, volume = {24}, number = {3}, pages = {1355-1365}, pmid = {36827603}, issn = {1526-4602}, support = {P30 EY001765/EY/NEI NIH HHS/United States ; U01 NS103882/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Microglia ; *Dendrimers ; Neuroprotection ; *Glaucoma ; Disease Models, Animal ; }, abstract = {Retinal microglial/macrophage activation and optic nerve (ON) microglial/macrophage activation are glaucoma biomarkers and potential therapeutic targets for this blinding disease. We report targeting of activated microglia by PAMAM dendrimers in a rat glaucoma model and neuroprotection by N-acetylcysteine-conjugated dendrimer (D-NAC) conjugates in a post-injury rescue experiment. Intravitreally delivered fluorescently labeled dendrimer (D-Cy5) conjugates targeted and were retained in Iba-1-positive cells (90% at 7 days and 55% after 28 days) in the retina following intraocular pressure (IOP) elevation, while systemically delivered D-Cy5 targeted ON cells. A single intravitreal D-NAC dose given 1 week after IOP elevation significantly reduced transcription of pro-inflammatory (IL-6, MCP-1, IL-1β) and A1 astrocyte (Serping1, Fkbp5, Amigo2) markers and increased survival of retinal ganglion cells (39 ± 12%) versus BSS- (20 ± 15%, p = 0.02) and free NAC-treated (26 ± 14%, p = 0.15) eyes. These results highlight the potential of dendrimer-targeted microglia and macrophages for early glaucoma detection and as a neuroprotective therapeutic target.}, } @article {pmid36827384, year = {2024}, author = {Ebrahimi, F and Zavareh, S and Nasiri, M}, title = {The Combination of Estradiol and N-Acetylcysteine Reduces Ischemia-Reperfusion Injuries of Mice Autografted Ovarian Tissue.}, journal = {Biopreservation and biobanking}, volume = {22}, number = {1}, pages = {29-37}, doi = {10.1089/bio.2022.0184}, pmid = {36827384}, issn = {1947-5543}, mesh = {Animals ; Mice ; *Estradiol/pharmacology ; Acetylcysteine/pharmacology ; Fibroblast Growth Factor 2 ; Interleukin-6 ; Vascular Endothelial Growth Factor A ; Antioxidants/pharmacology/therapeutic use ; *Reperfusion Injury/drug therapy ; Inflammation ; }, abstract = {Ischemia-reperfusion injuries are important issues after ovarian tissue transplantation (OTT). Our study examined the effects of N-acetylcysteine (NAC) and estradiol (E2) on mouse ovarian autografts. Mice (6-8 weeks) were divided into ovarian autograft as follows: Control: fresh OTT; Sham: cryopreserved/warmed OTT; NAC: cryopreserved/warmed OTT with NAC treatment; E2: cryopreserved/warmed OTT with E2 treatment; NAC+E2: cryopreserved/warmed OTT with the treatment of NAC and E2. In all groups, grafts were harvested on days 2, 7, and 28 after transplantation to evaluate histological parameters, inflammation relative to genes expression, and oxidative status. Histological analysis showed that NAC, E2, and a combination of NAC+E2 significantly increased the primordial, preantral, and antral follicular number. When NAC was used, it significantly reduced the expression of Tnf-α and Fgf-2, whereas it increased Il-1β, Il-6, and Vegf expression levels. The levels of Il-6, Fgf-2, and VEGF were dramatically increased in the E2-treated group. The combination of NAC and E2 significantly increased levels of Il-1β, Il-6, Fgf-2, and Vegf. NAC and E2 alone or in combination significantly increased total antioxidant capacity but did not affect the superoxide dismutase and glutathione peroxidase activities. In conclusion, after transplantation, NAC and E2 alone or in combination, could improve follicular development and angiogenesis as well as decline inflammation and ovarian oxidative damage.}, } @article {pmid36820266, year = {2023}, author = {Kielmann, J and Pucci, L and Xydis, A}, title = {Personalized Nutrition and Lifestyle Interventions in Systemic Lupus Erythematosus: A Case Report.}, journal = {Integrative medicine (Encinitas, Calif.)}, volume = {21}, number = {6}, pages = {22-27}, pmid = {36820266}, issn = {1546-993X}, abstract = {BACKGROUND: A 63-year-old male with a 4-year history of systemic lupus erythematosus (SLE) safely and successfully integrated personalized nutrition and lifestyle modifications to improve the symptomatic outcome of his illness.

CASE/INTERVENTION: The client presented to our nutritional practice with fatigue, acid reflux, joint pain, brain fog and skin rashes. During the nutritional intervention, he safely used a variety of nutritional interventions and supplementation, including dietary improvements, omega-3 fish oils, N-acetyl cysteine, prebiotics and intermittent fasting, along with stress reduction techniques. His symptoms decreased significantly, or disappeared, over 4 years of using these interventions.

CONCLUSION: This case demonstrates the safety and potential benefits of personalized nutrition, stress reduction techniques and targeted supplementation in helping to decrease symptoms of SLE. Our client's energy levels and overall performance improved, skin rashes and acid reflux resolved, joint pain and stiffness decreased and brain fog gradually lessened over the 4 years he was in our care.}, } @article {pmid36816622, year = {2023}, author = {Simasingha, N and Tanasoontrarat, W and Claimon, T and Sethasine, S}, title = {Efficacy of dexamethasone and N-acetylcysteine combination in preventing post-embolization syndrome after transarterial chemoembolization in hepatocellular carcinoma.}, journal = {World journal of gastroenterology}, volume = {29}, number = {5}, pages = {890-903}, pmid = {36816622}, issn = {2219-2840}, mesh = {Humans ; Acetylcysteine ; *Carcinoma, Hepatocellular/pathology ; *Chemoembolization, Therapeutic/adverse effects/methods ; Dexamethasone ; *Liver Neoplasms/pathology ; Nausea/etiology ; Treatment Outcome ; Vomiting/etiology ; Drug Combinations ; }, abstract = {BACKGROUND: Conventional transarterial chemoembolization (cTACE) is the current standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Post-embolization syndrome (PES) is complex clinical syndrome that presents as fever, abdominal pain, nausea, and vomiting. Either dexamethasone (DEXA) or N-acetylcysteine (NAC) is used to prevent PES; however, the synergistic effect of their combined therapy for preventing PES and liver decompensation has not been determined.

AIM: To evaluate the efficacy of DEXA and NAC combination in preventing PES and liver decompensation after cTACE.

METHODS: Patients with Barcelona Clinic Liver Cancer stage A or B HCC who were scheduled for TACE were prospectively enrolled. All patients were randomly stratified to receive NAC and DEXA or placebo. The dual therapy (NAC + DEXA) group received intravenous administration of 10 mg DEXA every 12 h, NAC 24 h prior to cTACE (150 mg/kg/h for 1 h followed by 12.5 mg/kg/h for 4 h), and a continuous infusion of 6.25 mg/h NAC plus 4 mg DEXA every 12 h for 48 h after cTACE. The placebo group received an infusion of 5% glucose solution until 48 h after procedure. PES was defined by South West Oncology Group toxicity code grading of more than 2 that was calculated using incidence of fever, nausea, vomiting, and pain.

RESULTS: One-hundred patients were enrolled with 50 patients in each group. Incidence of PES was significantly lower in the NAC + DEXA group compared with in the placebo group (6% vs 80%; P < 0.001). Multivariate analysis showed that the dual treatment is a protective strategic therapy against PES development [odds ratio (OR) = 0.04; 95% confidence interval (CI): 0.01-0.20; P < 0.001). Seven (14%) patients in the placebo group, but none in the NAC + DEXA group, developed post-TACE liver decompensation. A dynamic change in Albumin-Bilirubin score of more than 0.5 point was found to be a risk factor for post-TACE liver decompensation (OR = 42.77; 95%CI: 1.01-1810; P = 0.049).

CONCLUSION: Intravenous NAC + DEXA administration ameliorated the occurrence of PES event after cTACE in patients with intermediate-stage HCC.}, } @article {pmid36813253, year = {2023}, author = {Sasaki, S and Negishi, T and Tsuzuki, T and Yukawa, K}, title = {Methylmercury-induced reactive oxygen species-dependent and independent dysregulation of MAP kinase-related signaling pathway in cultured normal rat cerebellar astrocytes.}, journal = {Toxicology}, volume = {487}, number = {}, pages = {153463}, doi = {10.1016/j.tox.2023.153463}, pmid = {36813253}, issn = {1879-3185}, mesh = {Rats ; Animals ; Reactive Oxygen Species/metabolism ; *Antioxidants/pharmacology/metabolism ; MAP Kinase Signaling System ; *Methylmercury Compounds ; Astrocytes ; Oxidative Stress ; Glutathione/metabolism ; Acetylcysteine/pharmacology/metabolism ; Cells, Cultured ; }, abstract = {Methylmercury (MeHg), a global environmental pollutant, could seriously damage the central nervous system (CNS) and cause neurological disorders such as cerebellar symptoms. Although numerous studies have revealed detailed toxicity mechanisms of MeHg in neurons, toxicity in astrocytes is barely known. Here, we tried to shed light on the toxicity mechanisms of MeHg exposure in cultured normal rat cerebellar astrocytes (NRA), focusing on the involvement of reactive oxygen species (ROS) in MeHg toxicity by assessing the effects of major antioxidants Trolox, a free-radical scavenger, N-acetyl-L-cysteine (NAC), a potent thiol-containing antioxidant, and glutathione (GSH), an endogenous thiol-containing antioxidant. Exposure to MeHg at just approximately 2 µM for 96 h increased cell viability, which was accompanied by the increase in intracellular ROS level and at ≥ 5 µM induced significant cell death and lowered ROS level. Trolox and NAC suppressed 2 µM MeHg-induced increases in cell viability and ROS level corresponding to control, although GSH with 2 µM MeHg induced significant cell death and ROS increase. On the contrary, against 4 µM MeHg-induced cell loss and ROS decrease, NAC inhibited both cell loss and ROS decrease, Trolox inhibited cell loss and further enhanced ROS decrease, and GSH moderately inhibited cell loss and increased ROS level above the control level. MeHg-induced oxidative stress was suggested by increases in the protein expression levels of heme oxygenase-1 (HO-1), Hsp70, and Nrf2, except for the decrease in SOD-1 and no change in catalase. Furthermore, MeHg exposure dose-dependently induced increases in the phosphorylation of MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK) and phosphorylation and/or expression levels of transcription factors (CREB, c-Jun, and c-Fos) in NRA. NAC successfully suppressed 2 µM MeHg-induced alterations in all of the above-mentioned MeHg-responsive factors, whereas Trolox suppressed some MeHg-responsive factors but failed to suppress MeHg-induced increases in the protein expression levels of HO-1 and Hsp70 and increase in p38MAPK phosphorylation. Protein expression analyses in NRA exposed to 2 µM MeHg and GSH were excluded because of devastating cell death. These results suggested that MeHg could induce aberrant NRA activation, and ROS must be substantially involved in the toxicity mechanism of MeHg in NRA; however, other factors should be assumed.}, } @article {pmid36810107, year = {2023}, author = {Abbasifard, M and Khorramdelazad, H and Rostamian, A and Rezaian, M and Askari, PS and Sharifi, GTK and Parizi, MK and Sharifi, MTK and Najafizadeh, SR}, title = {Effects of N-acetylcysteine on systemic lupus erythematosus disease activity and its associated complications: a randomized double-blind clinical trial study.}, journal = {Trials}, volume = {24}, number = {1}, pages = {129}, pmid = {36810107}, issn = {1745-6215}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Severity of Illness Index ; *Lupus Erythematosus, Systemic/drug therapy ; Kidney ; Double-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUNDS: N-acetylcysteine (NAC) has broadly been used as an anti-oxidant agent in various types of diseases. This study aimed to assess the effect of NAC on the systemic lupus erythematosus (SLE) disease activity and outcome.

METHODS: In this randomized, double-blind clinical trial study, 80 SLE patients were recruited that were classified into two groups: 40 patients received NAC (1800 mg/day; 3 times per day with 8-h intervals) for 3 months and 40 patients as the control group received normal therapies. Laboratory measurements and disease activity based on the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index (SLEDAI) were determined before the initiation of treatment and after the study time period.

RESULTS: A statistically significant decrease in BILAG (P= 0.023) and SLEDAI (P= 0.034) scores after receiving NAC for a 3-month period was observed. BILAG (P= 0.021) and SLEDAI (P= 0.030) scores were significantly lower in NAC-receiving patients compared to the control group after 3 months. The disease activity in each organ based on BILAG score after treatment indicated a significant decrease in the NAC group compared to the baseline level in general (P=0.018), mucocutaneous (P=0.003), neurological (P=0.015), musculoskeletal (P=0.048), cardiorespiratory (P=0.047), renal (P=0.025), and vascular (P=0.048) complications. Analysis indicated a significant increase in CH50 level in the NAC group after treatment compared to the baseline level (P=0.049). No adverse event was reported by the study subjects.

CONCLUSIONS: It appears that the administration of 1800 mg/day NAC to SLE patients can decrease the SLE disease activity and its complications.}, } @article {pmid36809299, year = {2023}, author = {Chen, DW and Kang, T and Xu, XZ and Xia, WJ and Ye, X and Wu, YB and Xu, YR and Liu, J and Ren, H and Deng, J and Chen, YK and Ding, HQ and Aslam, M and Zelek, WM and Morgan, BP and Kapur, R and Santoso, S and Fu, YS}, title = {Mechanism and intervention of murine transfusion-related acute lung injury caused by anti-CD36 antibodies.}, journal = {JCI insight}, volume = {8}, number = {6}, pages = {}, pmid = {36809299}, issn = {2379-3708}, mesh = {Mice ; Humans ; Male ; Animals ; *Transfusion-Related Acute Lung Injury/pathology ; Blood Platelets/pathology ; Monocytes/pathology ; Complement System Proteins ; Complement Activation ; }, abstract = {Anti-CD36 Abs have been suggested to induce transfusion-related acute lung injury (TRALI) upon blood transfusion, particularly in Asian populations. However, little is known about the pathological mechanism of anti-CD36 Ab-mediated TRALI, and potential therapies have not yet been identified. Here, we developed a murine model of anti-CD36 Ab-mediated TRALI to address these questions. Administration of mouse mAb against CD36 (mAb GZ1) or human anti-CD36 IgG, but not GZ1 F(ab')2 fragments, induced severe TRALI in Cd36+/+ male mice. Predepletion of recipient monocytes or complement, but not neutrophils or platelets, prevented the development of murine TRALI. Moreover, plasma C5a levels after TRALI induction by anti-CD36 Abs increased more than 3-fold, implying a critical role of complement C5 activation in the mechanism of Fc-dependent anti-CD36-mediated TRALI. Administration of GZ1 F(ab')2, antioxidant (N-acetyl cysteine, NAC), or C5 blocker (mAb BB5.1) before TRALI induction completely protected mice from anti-CD36-mediated TRALI. Although no significant amelioration in TRALI was observed when mice were injected with GZ1 F(ab')2 after TRALI induction, significant improvement was achieved when mice were treated postinduction with NAC or anti-C5. Importantly, anti-C5 treatment completely rescued mice from TRALI, suggesting the potential role of existing anti-C5 drugs in the treatment of patients with TRALI caused by anti-CD36.}, } @article {pmid36808460, year = {2023}, author = {Dwivedi, SK and Arachchige, DL and Vohs, T and Tang, J and Usimaki, K and Olowolagba, AM and Fritz, DR and Luck, RL and Werner, T and Liu, H}, title = {Near-infrared rhodol dyes bearing salicylaldehyde moieties for ratiometric pH sensing in live cells during mitophagy and under hypoxia conditions.}, journal = {Journal of materials chemistry. B}, volume = {11}, number = {13}, pages = {2852-2861}, pmid = {36808460}, issn = {2050-7518}, support = {R15 GM114751/GM/NIGMS NIH HHS/United States ; R15 GM146206/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; HeLa Cells ; *Mitophagy ; *Hydrogen Peroxide ; Fluorescent Dyes ; Hypoxia ; Hydrogen-Ion Concentration ; }, abstract = {We describe a simple but efficient approach to make fluorescent probes A and B based on rhodol dyes incorporated with salicyaldehyde moiety for monitoring pH changes in mitochondria under oxidative stresses and hypoxia conditions, and for tracking mitophagy processes. Probes A and B possess pKa values (pKa ≈ 6.41 and 6.83 respectively) near physiological pH and exhibit decent mitochondria-targeted capabilities, low cytotoxicity, and useful ratiometric and reversible pH responses, which make the probes appropriate for monitoring pH fluctuations of mitochondria in living cells with built-in calibration feature for quantitative analysis. The probes have been effectively useful for the ratiometric determination of pH variations of mitochondria under the stimuli of carbonyl cyanide-4(trifluoromethoxy)phenylhydrazone (FCCP), hydrogen peroxide (H2O2), and N-acetyl cysteine (NAC), and during mitophagy triggered by cell nutrient deprivation, and under hypoxia conditions with cobalt chloride (CoCl2) treatment in living cells. In addition, probe A was efficient in visualizing pH changes in the larvae of fruit flies.}, } @article {pmid36807852, year = {2023}, author = {Wei, Y and Geng, W and Zhang, T and He, H and Zhai, J}, title = {N-acetylcysteine rescues meiotic arrest during spermatogenesis in mice exposed to BDE-209.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {17}, pages = {50952-50968}, pmid = {36807852}, issn = {1614-7499}, support = {NO. 82273598//the National Natural Science Foundation of China/ ; NO. 2108085MH305//the Nature Science Research Project of Anhui Province / ; }, mesh = {Mice ; Male ; Animals ; *Acetylcysteine/pharmacology ; *Meiosis ; Semen ; Spermatogenesis ; }, abstract = {Deca-bromodiphenyl ethers (BDE-209) has been widely used in electronic devices and textiles as additives to flame retardants. Growing evidence showed that BDE-209 exposure leads to poorer sperm quality and male reproductive dysfunction. However, the underlying mechanisms of BDE-209 exposure caused a decline in sperm quality remains unclear. This study aimed to evaluate the protective effects of N-acetylcysteine (NAC) on meiotic arrest in spermatocytes and decreased sperm quality in BDE-209-exposed mice. In the study, mice were treated with NAC (150 mg/kg BW) 2 h before administrated with BDE-209 (80 mg/kg BW) for 2 weeks. For the in vitro studies, spermatocyte cell line GC-2spd cells were pretreated with NAC (5 mM) 2 h before treated with BDE-209 (50 μM) for 24 h. We found that pretreatment with NAC attenuated the oxidative stress status induced by BDE-209 in vivo and in vitro. Moreover, pretreatment with NAC rescued the testicular histology impairment and decreased the testicular organ coefficient in BDE-209-exposed mice. In addition, NAC supplement partially promoted meiotic prophase and improved sperm quality in BDE-209-exposed mice. Furthermore, NAC pretreatment effectively improved DNA damage repair by recovering DMC1, RAD51, and MLH1. In conclusion, BDE-209 caused spermatogenesis dysfunction related to the meiotic arrest medicated by oxidative stress, decreasing sperm quality.}, } @article {pmid36806345, year = {2023}, author = {Zhang, X and Wang, S and Jin, Y and Wang, J and Wang, R and Yang, X and Zhang, S and Yan, T and Jia, Y}, title = {Wei-Tong-Xin ameliorated cisplatin-induced mitophagy and apoptosis in gastric antral mucosa by activating the Nrf2/HO-1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {308}, number = {}, pages = {116253}, doi = {10.1016/j.jep.2023.116253}, pmid = {36806345}, issn = {1872-7573}, mesh = {Mice ; Animals ; *NF-E2-Related Factor 2/metabolism ; *Cisplatin/pharmacology ; Heme Oxygenase-1/metabolism ; Mitophagy ; Pyloric Antrum/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Apoptosis ; Mucous Membrane ; }, abstract = {Wei-Tong-Xin (WTX) originated from the famous ancient Chinese formula "Wan Ying Yuan", recorded in the ancient Chinese medicine book "Zhong Zang Jing" by Hua Tuo. As "Jun" drugs, Dahuang and Muxiang have the effects of clearing heat and expelling fire, reducing food retention, regulating Qi and relieving pain. As "Chen" drug, Qianniuzi has the effect of assisting "Jun" drugs. Zhuyazao and Gancao, as "Zuo-Shi" drugs, can reduce toxicity and modulate the medicinal properties of other herbs.

AIM OF THE STUDY: The present study aimed to investigate the effect and mechanism of WTX on the oxidative stress of gastric antrum mucosa in mice with cisplatin (CIS)-induced dyspepsia.

MATERIALS: AND.

METHODS: A variety of experimental methods, including western blot, qRT-PCR, immunofluorescence and immunohistochemistry were performed in vivo and in vitro.

RESULTS: In vivo, WTX restored the number and function of interstitial cells of Cajal (ICCs), accompanied by the inhibition of lipid peroxidation. Moreover, WTX inhibited the activation of Parkin-dependent mitophagy and apoptosis. In vitro, WTX activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and inactivated mitophagy in GES-1 cells. To explore the role of Nrf2 in WTX's improvement of CIS-induced cell damage, Nrf2 inhibitor ML385 was used in cell experiments. We found that ML385 counteracted the regulation of WTX on mitophagy and apoptosis. Finally, N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, was applied in our experiments, and the results suggested that WTX suppressed the CIS-induced apoptosis via mitochondrial pathway.

CONCLUSIONS: The above results, for the first time, indicated that WTX inhibited mitophagy and apoptosis of gastric antral mucosal cells induced by CIS through the Nrf2/HO-1 signaling pathway.}, } @article {pmid36802832, year = {2023}, author = {Turk, T and Liu, C and Fujiwara, E and Straube, S and Hagtvedt, R and Dennett, L and Abba-Aji, A and Dytoc, M}, title = {Pharmacological Interventions for Primary Psychodermatologic Disorders: An Evidence Mapping and Appraisal of Randomized Controlled Trials.}, journal = {Journal of cutaneous medicine and surgery}, volume = {27}, number = {2}, pages = {140-149}, pmid = {36802832}, issn = {1615-7109}, mesh = {Humans ; Sertraline/therapeutic use ; Fluoxetine/therapeutic use ; Clomipramine/therapeutic use ; Olanzapine ; *Antipsychotic Agents/therapeutic use ; Desipramine ; Pimozide ; Randomized Controlled Trials as Topic ; Acetylcysteine/therapeutic use ; *Dermatitis/drug therapy ; }, abstract = {BACKGROUND: The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to identify, appraise, and summarize the currently available evidence about the safety and effectiveness of pharmacological management of PPDs through randomized controlled trials (RCTs).

METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRIMSA) statement and the Global Evidence Mapping Initiative guidance were followed. Medline, Embase, PsycInfo, Cochrane and Scopus were searched, and two reviewers independently completed article review, data extraction, and quality assessment.

RESULTS: Among 2618 unique studies, full texts of 83 were reviewed and 21 RCTs were included. Five PDDs were identified: trichotillomania (n = 12), pathologic skin picking (n = 5), nail biting (n = 2), delusional parasitosis (n = 1), and dermatitis from compulsive hand washing (n = 1). Seven different classes of medications were investigated: SSRIs (i.e., fluoxetine, sertraline, and citalopram), tricyclic antidepressants (i.e., clomipramine and desipramine), antipsychotics (i.e., olanzapine and pimozide), anticonvulsant (i.e., lamotrigine), N-acetylcysteine, inositol, and milk thistle. RCT-derived evidence supports the use of antidepressants in trichotillomania (sertraline and clomipramine), pathologic skin picking (fluoxetine), pathologic nail biting and dermatitis from compulsive hand washing (clomipramine or desipramine); antipsychotics in trichotillomania (olanzapine) and delusional parasitosis (pimozide); N-acetyl cysteine in trichotillomania and skin picking.

CONCLUSION: Few pharmacotherapies for primary psychodermatologic disorders are assessed through controlled trials in the literature. This review serves as a roadmap for researchers and clinicians to reach informed decisions with current evidence, and to build on it to establish guidelines in the future.}, } @article {pmid36799253, year = {2023}, author = {Xu, K and Ma, J and Lu, R and Shao, X and Zhao, Y and Cui, L and Qiu, Z and Tian, Y and Li, J}, title = {Effective-compound combination of Bufei Yishen formula III combined with ER suppress airway mucus hypersecretion in COPD rats: via EGFR/MAPK signaling.}, journal = {Bioscience reports}, volume = {43}, number = {11}, pages = {}, pmid = {36799253}, issn = {1573-4935}, mesh = {Animals ; Rats ; ErbB Receptors/metabolism ; *Interleukin-6/metabolism ; Lung/pathology ; Mucus/metabolism ; *Pulmonary Disease, Chronic Obstructive/pathology ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: The aim of this study was to explore the combined efficacy ofeffective-component compatibility of Bufei Yishen formula III (ECC-BYF III) and exercise rehabilitation (ER) in inhibiting airway mucus hypersecretion in a chronic obstructive pulmonary disease (COPD) rat model.

METHODS: A total of 48 SD rats were divided into control, model, acetylcysteine (NAC), ECC-BYF III, ER, and ECC-BYF III + ER groups (n=8). COPD rats were exposed to cigarette smoke and bacteria for 8 weeks and administered various treatments over the next eight weeks. Rats were euthanized at week 17 after pulmonary function testing. Pathological examination of lung tissues was performed. IL-6 and IL-10 levels were measured in bronchoalveolar lavage fluid (BALF) and protein levels of MUC5AC, MUC5B, AQP-5, EGFR, ERK, JNK, and p38 were measured in lung tissues.

RESULTS: Improved pulmonary function and pathological changes were observed in ECC-BYF III, ECC-BYF III + ER, and NAC groups. ECC-BYF III and ECC-BYF III + ER had greater mean alveolar number (MAN) compared with NAC. Lung inflammation and goblet cell generation were reduced and MUC5AC, MUC5B and AQP-5 expressions were lower in all treatment groups. ECC-BYF III has more significant effect on MUC5AC than ER and NAC. ECC-BYFIII + ER had a greater effect on suppressing IL-6 in BALF compared with other treatments. ECC-BYFIII, ER, and ECC-BYF III + ER reduced EGFR, ERK, JNK, and p38 phosphorylated protein levels. ECC-BYFIII+ER had a greater effect on p-JNK and p-p38 than ECC-BYFIII and NAC.

CONCLUSION: ECC-BYF III, ER, and ECC-BYF III + ER have efficacy in inhibiting airway mucus hypersecretion with improved pulmonary function and pathological changes. ECC-BYF III had a greater effect in improving MAN and MUC5AC in lung tissue. ECC-BYF III+ER had a greater effect in alleviating pulmonary pathology and inflammation. These effects may be mediated by inhibition of the EGFR/MAPK pathway.}, } @article {pmid36796651, year = {2023}, author = {Yoo, JY and Lee, YJ and Kim, YJ and Baik, TK and Lee, JH and Lee, MJ and Woo, RS}, title = {Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells.}, journal = {Neurotoxicology}, volume = {95}, number = {}, pages = {205-217}, doi = {10.1016/j.neuro.2023.02.006}, pmid = {36796651}, issn = {1872-9711}, mesh = {Humans ; *Acetylcysteine/pharmacology/metabolism ; Apoptosis ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/metabolism ; Cell Line, Tumor ; *Neuroblastoma/radiotherapy/metabolism ; Oxidative Stress ; Cell Survival ; }, abstract = {Recently, several studies have demonstrated that low-dose radiation (LDR) therapy has positively impacts on the treatment of Alzheimer's disease (AD). LDR suppresses the production of pro-neuroinflammation molecules and improves cognitive function in AD. However, it is unclear whether direct exposure to LDR causes beneficial effects and what mechanism is involved in neuronal cells. In this study, we first determined the effect of high-dose radiation (HDR) alone on C6 cells and SH-SY5Y cells. We found that SH-SY5Y cells were more vulnerable than C6 cells to HDR. Moreover, in neuronal SH-SY5Y cells exposed to single or multiple LDR, N-type cells showed decreased cell viability with increasing radiation exposure time and frequency, but S-type cells were unaffected. Multiple LDR increased proapoptotic molecules such as p53, Bax and cleaved caspase-3, and decreased anti-apoptotic molecule (Bcl2). Multiple LDR also generated free radicals in neuronal SH-SY5Y cells. We detected a change in the expression of the neuronal cysteine transporter EAAC1. Pretreatment with N-acetylcysteine (NAC) rescued the increased in EAAC1 expression and the generation of ROS in neuronal SH-SY5Y cells after multiple LDR. Furthermore, we verified whether the increased in EAAC1 expression induces cell defense or cell death promotion signaling. We showed that transient overexpression of EAAC1 reduced the multiple LDR-induced p53 overexpression in neuronal SH-SY5Y cells. Our results indicate that neuronal cells can be injured by increased production of ROS not only by HDR but also by multiple LDR, which suggests that combination treatment with anti-free radical agents such as NAC may be useful in multiple LDR therapy.}, } @article {pmid36795483, year = {2023}, author = {Bhardwaj, M and Lee, JJ and Versace, AM and Harper, SL and Goldman, AR and Crissey, MAS and Jain, V and Singh, MP and Vernon, M and Aplin, AE and Lee, S and Morita, M and Winkler, JD and Liu, Q and Speicher, DW and Amaravadi, RK}, title = {Lysosomal lipid peroxidation regulates tumor immunity.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {8}, pages = {}, pmid = {36795483}, issn = {1558-8238}, support = {R01 CA266404/CA/NCI NIH HHS/United States ; P50 CA174523/CA/NCI NIH HHS/United States ; R01 CA256945/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; S10 OD023586/OD/NIH HHS/United States ; R01 CA238237/CA/NCI NIH HHS/United States ; P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; P01 CA114046/CA/NCI NIH HHS/United States ; P50 CA261608/CA/NCI NIH HHS/United States ; }, mesh = {Mice ; Animals ; Lipid Peroxidation ; *Apoptosis ; Cell Death ; *Neoplasms/pathology ; Antioxidants/pharmacology ; Lysosomes/metabolism ; }, abstract = {Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.}, } @article {pmid36795166, year = {2023}, author = {Hammerschmidt, TG and Guerreiro, GB and Donida, B and Raabe, M and Kessler, RG and Ferro, MB and Moura, DJ and Giugliani, R and Vargas, CR}, title = {Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {396}, number = {7}, pages = {1563-1569}, pmid = {36795166}, issn = {1432-1912}, support = {2018-0648//Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA)./ ; 430443/2018-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Humans ; *Niemann-Pick Disease, Type C/drug therapy/genetics/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; DNA Damage ; }, abstract = {Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.}, } @article {pmid36791995, year = {2023}, author = {Mukherjee, S and Gupta, P and Ghosh, S and Choudhury, S and Das, A and Ahir, M and Adhikary, A and Chattopadhyay, S}, title = {Targeted tumor killing by pomegranate polyphenols: Pro-oxidant role of a classical antioxidant.}, journal = {The Journal of nutritional biochemistry}, volume = {115}, number = {}, pages = {109283}, doi = {10.1016/j.jnutbio.2023.109283}, pmid = {36791995}, issn = {1873-4847}, mesh = {Animals ; Mice ; Antioxidants/pharmacology/therapeutic use/chemistry ; Reactive Oxygen Species/metabolism ; *Pomegranate ; Fruit/chemistry ; Ascites ; Polyphenols/pharmacology/analysis ; Epithelial-Mesenchymal Transition ; Oxidative Stress ; NF-E2-Related Factor 2/metabolism ; *Carcinoma ; NF-kappa B/metabolism ; Apoptosis ; }, abstract = {One of the key biochemical features that distinguish a cancer cell from normal cells is its persistent pro-oxidative state that leads to intrinsic oxidative stress. Malignant cells have evolved sophisticated adaptation systems that involve high dependency on antioxidant functions and upregulation of pro-survival molecules to counteract the deleterious effects of reactive species and to maintain dynamic redox balance. This situation renders them vulnerable to further oxidative challenges by exogenous agents. In the present study, we advocated that pomegranate polyphenols act as pro-oxidants and trigger ROS-mediated apoptosis in cancer cells. With the help of both in vitro and in vivo models, we have established that pomegranate fruit extract (PFE) can cause a significant reduction in tumor proliferation while leaving normal tissues and cells unharmed. Administration of PFE (0.2% v/v) in Erhlich's ascites carcinoma-bearing mice for 3 weeks, inhibited the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element signaling cascade, increased intracellular reactive oxygen species content, altered glutathione cycle thereby activating reactive oxygen species-induced apoptotic pathway in Erhlich's ascites carcinoma cells. Moreover, PFE mitigated epithelial to mesenchymal transition and migration in triple negative breast cancer cells (MDA-MB 231 cells) by down-regulating nuclear factor kappa light-chain-enhancer of activated B cells. Pre-treatment of tumor cells with N-acetyl cysteine protected these cells from undergoing PFE-induced apoptosis while siRNA-mediated silencing of Nuclear factor (erythroid-derived 2)-like 2 and nuclear factor kappa light-chain-enhancer of activated B cells in tumor cells increased the cytotoxic potential and pro-oxidative activity of PFE, indicating a clear role of these transcription factors in orchestrating the anticancer/pro-oxidative properties of PFE. The seminal findings provided may be exploited to develop potential therapeutic targets for selective killing of malignant cells.}, } @article {pmid36791364, year = {2023}, author = {Hong, MK and Echanique, KA and Hoffman, LF and Kita, AE}, title = {Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model.}, journal = {Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology}, volume = {44}, number = {4}, pages = {373-381}, pmid = {36791364}, issn = {1537-4505}, support = {K08 DC019957/DC/NIDCD NIH HHS/United States ; }, mesh = {Rats ; Animals ; Cisplatin/toxicity ; *Antineoplastic Agents ; *Ototoxicity ; Acetylcysteine/pharmacology ; Gentamicins/toxicity ; Schwann Cells ; }, abstract = {HYPOTHESIS: The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear.

BACKGROUND: Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents.

METHODS: RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N -acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined.

RESULTS: The estimated 50% lethal concentration dose for gentamicin was 805.6 μM, which was 46-fold higher than that for cisplatin (17.5 μM). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% (p < 0.001) increase in cell viability when compared with cisplatin alone. However, this protective effect was not consistent across all trials. NAC was encapsulated into a PLGA microparticle and elution plateaued at 5 days.

CONCLUSION: When dosed at their respective therapeutic ranges, cisplatin is more likely than gentamicin to induce damage to the Schwann cell model. Although NAC demonstrates an uncertain role in protecting against cisplatin-induced Schwann cell cytotoxicity, this study establishes a method to screen for other otoprotective medications to encapsulate into a tunable microparticle for localized drug delivery.}, } @article {pmid36780980, year = {2023}, author = {Siddiqui, SI and Malik, C and Ghosh, S}, title = {Voltage dependent anion channel and its interaction with N-acetyl-L-Cysteine (NAC) under oxidative stress on planar lipid bilayer.}, journal = {Biochimie}, volume = {209}, number = {}, pages = {150-160}, doi = {10.1016/j.biochi.2023.02.005}, pmid = {36780980}, issn = {1638-6183}, mesh = {*Lipid Bilayers ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Hydrogen Peroxide/pharmacology/metabolism ; Voltage-Dependent Anion Channels/metabolism ; Oxidative Stress ; }, abstract = {Mitochondria are the major source of Hydrogen Peroxide (H2O2), a reactive oxygen species, in the cells. The reactive oxygen species generated by the mitochondria oxidize major proteins including Voltage Dependent Anion Channel (VDAC). We were interested to know how the effect of H2O2 is countered by antioxidants present around the mitochondria. N-Acetyl-l-Cysteine (NAC) is a naturally existing antioxidant in the cells. Keeping this in view, the modulatory effect of antioxidant NAC on H2O2 oxidized VDAC has been investigated through in vitro electrophysiological studies. First, the effect of H2O2 and NAC was studied on independently incorporated single-channel VDAC. It was observed that NAC suppresses VDAC conductance with a half-maximal inhibitory concentration (IC50) of ∼1.04 μM. In contrast, H2O2 enhances VDAC conductance. Later, oxidative stress was induced by H2O2 on VDAC increased conductance with half-maximal effective concentration (EC50) of ∼302 nM. An application of 1 μM NAC on H2O2 treated (300 nM) VDAC reversed the effect of oxidation. In the next step, NAC and H2O2 were added in reverse order. When oxidative stress was induced using H2O2, reduction in conductance by NAC was 4.5 ± 0.404 nS. The change in conductance is nearly 6.3%. However, if antioxidant NAC was incubated first followed by H2O2 treatment, the conductance of VDAC was 3.09 ± 0.27 nS. The change in conductance is near 33%. Both H2O2 and NAC also affected various conducting states of VDAC. In-silico studies indicated the binding of NAC at Lysine and Glutamic acid of VDAC. Hence, NAC was found to be effective in protection of VDAC against H2O2-induced oxidative stress due to its strong binding.}, } @article {pmid36779633, year = {2023}, author = {Fang, Z and Xu, Y and Liu, G and Shao, Q and Niu, X and Tai, W and Shen, T and Fan, M and Chen, M and Lei, L and Gao, W and Song, Y and Wang, Z and Du, X and Li, X}, title = {Narirutin activates TFEB (transcription factor EB) to protect against Acetaminophen-induced liver injury by targeting PPP3/calcineurin.}, journal = {Autophagy}, volume = {19}, number = {8}, pages = {2240-2256}, pmid = {36779633}, issn = {1554-8635}, mesh = {TOR Serine-Threonine Kinases/metabolism ; Autophagy/genetics ; *Calcineurin/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Cornea/abnormalities ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Liver/metabolism ; Eye Diseases, Hereditary ; Mice ; Glutathione/metabolism ; Corneal Diseases ; Acetaminophen ; Animals ; }, abstract = {Acetaminophen (APAP) overdose is the predominant cause of drug-induced liver injury worldwide. The macroautophagy/autophagy-lysosomal pathway (ALP) is involved in the APAP hepatotoxicity. TFEB (transcription factor EB) promotes the expression of genes related to autophagy and lysosomal biogenesis, thus, pharmacological activation of TFEB-mediated ALP may be an effective therapeutic approach for treating APAP-induced liver injury. We aimed to reveal the effects of narirutin (NR), the main bioactive constituents isolated from citrus peels, on APAP hepatotoxicity and to explore its underlying mechanism. Administration of NR enhanced activities of antioxidant enzymes, improved mitochondrial dysfunction and alleviated liver injury in APAP-treated mice, whereas NR did not affect APAP metabolism and MAPK/JNK activation. NR enhanced TFEB transcriptional activity and activated ALP in an MTOR complex 1 (MTORC1)-independent but PPP3/calcineurin-dependent manner. Moreover, knockout of Tfeb or knockdown of PPP3CB/CNA2 (protein phosphatase 3, catalytic subunit, beta isoform) in the liver abolished the beneficial effects of NR on APAP overdose. Mechanistically, NR bound to PPP3CB via PRO31, LYS61 and PRO347 residues and enhanced PPP3/calcineurin activity, thereby eliciting dephosphorylation of TFEB and promoting ALP, which alleviated APAP-induced oxidative stress and liver injury. Together, NR protects against APAP-induced liver injury by activating a PPP3/calcineurin-TFEB-ALP axis, indicating NR may be a potential agent for treating APAP overdose.Abbreviations: ALP: autophagy-lysosomal pathway; APAP: acetaminophen; APAP-AD: APAP-protein adducts; APAP-Cys: acetaminophen-cysteine adducts; CAT: catalase; CETSA: cellular thermal shift assay; CQ: chloroquine; CYP2E1: cytochrome P450, family 2, subfamily e, polypeptide 1; CYCS/Cyt c: cytochrome c, somatic; DARTS: drug affinity responsive target stability assay; ENGASE/NAG: endo-beta-N-acetylglucosaminidase; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; GSH: glutathione; GPX/GSH-Px: glutathione peroxidase; KD: dissociation constant; Leu: leupeptin; MCOLN1: mucolipin 1; MTORC1: MTOR complex 1; NAC: N-acetylcysteine; NAPQI: N-acetyl-p-benzoquinoneimine; NFAT: nuclear factor of activated T cells; NR: narirutin; OA: okadaic acid; RRAG: Ras related GTP binding; ROS: reactive oxygen species; PPP3CB/CNA2: protein phosphatase 3, catalytic subunit, beta isoform; PPP3R1/CNB1: protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type I); SOD: superoxide dismutase; SPR: surface plasmon resonance analysis; TFEB: transcription factor EB.}, } @article {pmid36779379, year = {2023}, author = {Zhang, Z and Shen, C and Zhou, F and Zhang, Y}, title = {Shikonin potentiates therapeutic efficacy of oxaliplatin through reactive oxygen species-mediated intrinsic apoptosis and endoplasmic reticulum stress in oxaliplatin-resistant colorectal cancer cells.}, journal = {Drug development research}, volume = {84}, number = {3}, pages = {542-555}, doi = {10.1002/ddr.22044}, pmid = {36779379}, issn = {1098-2299}, mesh = {Animals ; Mice ; Humans ; Oxaliplatin/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Apoptosis ; *Naphthoquinones/pharmacology/therapeutic use ; Cell Line, Tumor ; *Colorectal Neoplasms/drug therapy/metabolism ; Endoplasmic Reticulum Stress ; }, abstract = {Oxaliplatin (OXA) has been recognized as a third-generation platinum-based chemotherapeutic agent with stellar therapeutic efficacy in managing colorectal cancer (CRC). Nevertheless, resistance to OXA in CRC patients hinders its effectiveness. Shikonin (SHI), a natural naphthoquinone derived from Arnebia euchroma (Royle) Johnst., features a broad pharmacological profile and minimal toxicities. To assess the synergism of SHI and OXA towards OXA-resistant CRC cells (HCT116[R]), we employed in vitro and in vivo pharmacological assays. Our experiments provided evidence that SHI, either alone or in combination with OXA, considerably reduced cell proliferation, triggered apoptosis, and induced the generation of reactive oxygen species (ROS) in HCT116[R] cells. Furthermore, the combination of SHI and OXA dramatically curbed the extent of HCT116[R] -initiated xenograft growth in mouse models. Bioinformatics, western blot, and ROS assays highlighted that the mechanisms of SHI against OXA-resistant CRC cells may involve the induction of cellular responses to chemical stress, intrinsic apoptosis, as well as endoplasmic reticulum stress pathways mediated by ROS. Notably, the synergism of SHI+OXA was partially abrogated by an ROS inhibitor N-acetyl cysteine. Our findings imply the potential of SHI to boost the sensitivity of OXA to CRC, offering promising benefits for clinical strategies to combat OXA resistance.}, } @article {pmid36777598, year = {2023}, author = {Önem, AN and Sözgen Başkan, K and Apak, R}, title = {Voltammetric Measurement of Antioxidant Activity by Prevention of Cu(II)-Induced Oxidative Damage on DNA Bases Using a Modified Electrode.}, journal = {ACS omega}, volume = {8}, number = {5}, pages = {5103-5115}, pmid = {36777598}, issn = {2470-1343}, abstract = {The protective effect of antioxidants using electrochemical techniques can be evaluated by examining the oxidative changes in deoxyribonucleic acid (DNA) nucleobases. In this study, a gold nanoparticle (AuNP)-decorated and multiwalled carbon nanotube (MWCNT)-Nafion-modified glassy carbon electrode (GCE/AuNP/MWCNT-Nafion) was developed to evaluate the preventive ability of antioxidants on oxidative DNA damage. A modified working electrode was prepared and characterized by cyclic voltammetry, electrochemical impedance spectroscopy, and scanning electron microscopy. The developed electrochemical method relies on two phenomena: (i) reactive species (RS) produced by dissolved oxygen in the presence of copper(II) partially damage the DNA immobilized on the electrode surface and (ii) antioxidant compounds prevent this damage by scavenging the formed RS. Changes in guanine, adenine, and cytosine oxidation signals resulting from DNA damage were measured using differential pulse stripping voltammetry before/after the interaction of dsDNA with Cu(II) while antioxidants were absent or present. The DNA protective ability of antioxidants was assessed for a number of antioxidant compounds (i.e., ascorbic acid, gallic acid, epicatechin, catechin, epicatechin gallate, glutathione, chlorogenic acid, N-acetyl cysteine, rosmarinic acid, quercetin, and rutin). Quercetin was found to show the highest antioxidant effect, and its limit of detection was determined as 1 μM. The manufactured biosensor was put in an application for the determination of antioxidant activity of herbal teas.}, } @article {pmid36775116, year = {2023}, author = {Sharma, JR and Agraval, H and Yadav, UCS}, title = {Cigarette smoke induces epithelial-to-mesenchymal transition, stemness, and metastasis in lung adenocarcinoma cells via upregulated RUNX-2/galectin-3 pathway.}, journal = {Life sciences}, volume = {318}, number = {}, pages = {121480}, doi = {10.1016/j.lfs.2023.121480}, pmid = {36775116}, issn = {1879-0631}, mesh = {Humans ; Epithelial-Mesenchymal Transition ; Galectin 3 ; *Cigarette Smoking ; Reactive Oxygen Species ; *Adenocarcinoma of Lung ; *Lung Neoplasms/pathology ; Transcription Factors ; }, abstract = {AIMS: An elevated level of galectin-3, a carbohydrate-binding lectin implicated in tumorigenesis, metastasis, and epithelial-mesenchymal transition (EMT), has been found in cigarette smokers. However, the regulation of its expression and role in the pathogenesis of CS-induced EMT and lung cancer metastasis is unclear. Here, we have investigated the mechanism of CS-induced and galectin-3-mediated EMT in airway epithelial cells (AECs).

MAIN METHODS: A549 adenocarcinoma cells and primary small airway epithelial cells cultured on an air-liquid interface (ALI) were exposed to cigarette smoke extract (CSE), and MTT, trypan blue, migration, invasion, tumor spheroid and colony formation assays were performed to assess EMT phenotype. Immunoblotting was performed to assess EMT and stemness markers and other regulatory proteins.

KEY FINDINGS: CSE exposure affected cell survival and morphology, migration, invasion, and clonogenicity of AECs, which were concomitant with an increase in the expression of EMT markers, galectin-3, and runt-related transcription factor-2 (RUNX-2), an osteogenic transcription factor and upstream regulator of galectin-3. Chemical inhibition or silencing of RUNX-2 downregulated galectin-3 and modulated EMT marker expression, migration, invasion, and clonogenicity in CSE-exposed AECs. Recombinant human galectin-3 also induced EMT and stemness-associated changes in the AECs, and GB1107, a galectin-3 inhibitor, ameliorated these changes. Further, CSE-induced intracellular ROS enabled an increase in RUNX-2 and galectin-3 expression, which were reversed by n-acetyl-cysteine.

SIGNIFICANCE: These results provide a novel mechanistic insight into CSE-induced EMT via RUNX-2/galectin-3 axis mediated through ROS, which promoted EMT-associated changes, including invasion, migration, and stemness in AECs, which could be implicated in CS-induced lung cancer progression.}, } @article {pmid36774779, year = {2023}, author = {Kashif, M and Yao, H and Schmidt, S and Chen, X and Truong, M and Tüksammel, E and Liu, Y and Bergo, MO}, title = {ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis.}, journal = {Redox biology}, volume = {60}, number = {}, pages = {102619}, pmid = {36774779}, issn = {2213-2317}, mesh = {Animals ; Humans ; Mice ; Acetylcysteine ; *Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; *Melanoma/drug therapy/genetics/pathology ; Reactive Oxygen Species/metabolism ; Vitamins ; Vitamin A/pharmacology ; Melanoma, Cutaneous Malignant ; }, abstract = {Oxidative stress is a barrier of migration and metastasis for malignant melanoma cells. Consequently, reducing oxidative stress with the antioxidant N-acetylcysteine (NAC) stimulates melanoma cell migration in vitro and metastasis in vivo. However, it is not yet known whether the NAC effect is shared with other antioxidants. Here, we screened 104 redox-active compounds and identify 27 that increase migration of human malignant melanoma cells in two doses. Validation experiments in four cell lines and four drug doses resulted in a list of 18 compounds which were ranked based on their ability to increase migration and reduce ROS levels; vitamin C (VitC) ranked as number one, followed by the vitamin E analogue Trolox and several carotenoids and Vitamin A-related compounds. Four diet-relevant compounds from this list-VitC, β-carotene, retinyl palmitate, and canthaxanthin-were selected and found to accelerate metastasis in mice with BRAF[V600E]-driven malignant melanoma. Genomics analyses revealed that the transcription factor BACH1 is activated following antioxidant administration and knockout of Bach1 in mouse melanoma cells reduced lymph node and liver metastasis in xenograft mouse models. We conclude that a broad range of antioxidants accelerate melanoma migration and metastasis and that BACH1 is functionally linked to melanoma metastasis in vivo.}, } @article {pmid36773561, year = {2023}, author = {Chu, Y and Xu, Y and Yang, W and Chu, K and Li, S and Guo, L}, title = {N-acetylcysteine protects human periodontal ligament fibroblasts from pyroptosis and osteogenic differentiation dysfunction through the SIRT1/NF-κB/Caspase-1 signaling pathway.}, journal = {Archives of oral biology}, volume = {148}, number = {}, pages = {105642}, doi = {10.1016/j.archoralbio.2023.105642}, pmid = {36773561}, issn = {1879-1506}, mesh = {Humans ; *NF-kappa B/metabolism ; *Acetylcysteine/pharmacology ; Osteogenesis ; Caspase 1/metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Periodontal Ligament ; Lipopolysaccharides/pharmacology ; Sirtuin 1/metabolism/pharmacology ; Cells, Cultured ; Signal Transduction ; Cell Differentiation ; Fibroblasts ; Adenosine Triphosphate/metabolism ; }, abstract = {OBJECTIVE: This study was aimed to determine whether N-acetylcysteine (NAC) could inhibit lipopolysaccharides / adenosine triphosphate (ATP)-induced pyroptosis and alleviate the damage of osteogenic differentiation in human periodontal ligament fibroblasts (hPDLFs). Furthermore, this study detected whether NAC acted effectively by modulating the silent information regulator 2 homolog 1 (SIRT1)/ the nuclear factor-κB (NF-κB)/Caspase-1 signaling pathway in hPDLFs.

DESIGN: Cell Counting Kit-8 assay was employed to determine the appropriate concentration of NAC for the follow-up experiments. To explore the effect and the underlying mechanisms of NAC on pyroptosis and osteogenic differentiation in hPDLFs, intracellular reactive oxygen species levels were detected using 2',7'-Dichlorodihydrofluorescein Diacetate kits. Moreover, SIRT1 inhibitor, SIRT1 activator, NF-κB inhibitor and Caspase-1 inhibitor were applied, the incidence of pyroptosis was detected by flow cytometry, the osteogenic differentiation of hPDLFs was observed using alkaline phosphatase and alizarin red staining, Real-time quantitative polymerase chain reaction and Western Blot were used to detect the expression of relevant factors, the release of interleukin-1β, interleukin-18 and lactate dehydrogenase were detected by Enzyme-linked immunosorbent assay.

RESULTS: The results demonstrated that NAC protected hPDLFs from lipopolysaccharides/ATP-induced damage, alleviating pyroptosis and osteogenic differentiation dysfunction. Moreover, NAC abrogated the inhibition of SIRT1 activity by scavenging reactive oxygen species, thereby reduced pyroptosis and osteogenic differentiation dysfunction by inhibiting the NF-κB/Caspase-1signaling pathway.

CONCLUSION: NAC could inhibit pyroptosis and osteogenic differentiation dysfunction of hPDLFs by scavenging reactive oxygen species to regulate the SIRT1/NF-κB/Caspase-1 signaling axis.}, } @article {pmid36770846, year = {2023}, author = {Eom, JW and Lim, JW and Kim, H}, title = {Lutein Induces Reactive Oxygen Species-Mediated Apoptosis in Gastric Cancer AGS Cells via NADPH Oxidase Activation.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {3}, pages = {}, pmid = {36770846}, issn = {1420-3049}, support = {no number//BK21 FOUR project, Yonsei University, Republic of Korea./ ; }, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *NF-kappa B/metabolism ; *Stomach Neoplasms/drug therapy ; Lutein/pharmacology ; Antioxidants/pharmacology ; bcl-2-Associated X Protein ; Apoptosis ; Caspases ; NADPH Oxidases/metabolism ; }, abstract = {Disruption of apoptosis leads to cancer cell progression; thus, anticancer agents target apoptosis of cancer cells. Reactive oxygen species (ROS) induce apoptosis by activating caspases and caspase-dependent DNase, leading to DNA fragmentation. ROS increase the expression of apoptotic protein Bax, which is mediated by activation of nuclear factor-κB (NF--κB). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of endogenous ROS, and its activation is involved in apoptosis. Lutein, an oxygenated carotenoid and known antioxidant, is abundant in leafy dark green vegetables, such as spinach and kale, and in yellow-colored foods, such as corn and egg yolk. High amounts of lutein increase ROS levels and exhibit anticancer activity. However, its anticancer mechanism remains unclear. This study aimed to determine whether lutein activates NADPH oxidase to produce ROS and induce apoptosis in gastric cancer AGS cells. Lutein increased ROS levels and promoted the activation of NADPH oxidase by increasing the translocation of NADPH oxidase subunit p47 [phox] to the cell membrane. It increased NF-κB activation and apoptotic indices, such as Bax, caspase-3 cleavage, and DNA fragmentation, and decreased Bcl-2, cell viability, and colony formation in AGS cells. The specific NADPH oxidase inhibitor ML171, and the known antioxidant N-acetyl cysteine reversed lutein-induced cell death, DNA fragmentation, and NF-κB DNA-binding activity in AGS cells. These results suggest that lutein-induced ROS production is dependent on NADPH oxidase, which mediates NF-κB activation and apoptosis in gastric cancer AGS cells. Therefore, lutein supplementation may be beneficial for increasing ROS-mediated apoptosis in gastric cancer cells.}, } @article {pmid36769455, year = {2023}, author = {Ito, K and Kise, H and Suzuki, S and Nagai, S and Hachiya, K and Takeda, H and Kawabata, S and Ikeda, D and Takubo, K and Kaneko, S and Fujita, N}, title = {Potential Involvement of Oxidative Stress in Ligamentum Flavum Hypertrophy.}, journal = {Journal of clinical medicine}, volume = {12}, number = {3}, pages = {}, pmid = {36769455}, issn = {2077-0383}, support = {19K09634//JSPS/ ; }, abstract = {Oxidative stress (OS) results in many disorders, of which degenerative musculoskeletal conditions are no exception. However, the interaction between OS and ligamentum flavum (LF) hypertrophy in lumbar spinal canal stenosis is not clearly understood. The first research question was whether OS was involved in LF hypertrophy, and the second was whether the antioxidant N-acetylcysteine (NAC) was effective on LF hypertrophy. In total, 47 LF samples were collected from patients with lumbar spinal disorders. The cross-sectional area of LF was measured on axial magnetic resonance imaging. Immunohistochemistry of 8-OHdG and TNF-α were conducted on human LF samples. A positive association was found between 8-OHdG or TNF-α expression and cross-sectional area of LF. Flow cytometry analysis showed that H2O2, buthionine sulfoximine, and TNF-α treatment significantly increased intracellular reactive oxygen species in primary LF cells. NAC inhibited the induction of LF hypertrophy markers by OS or TNF in a real-time reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Western blotting analysis indicated that p38, Erk, and p65 phosphorylation were involved in intracellular OS signaling in LF cells. In conclusion, our results indicated that OS could be a therapeutic target for LF hypertrophy. Although this study included no in vivo studies to examine the longitudinal efficacy of NAC on LF hypertrophy, NAC may have potential as a therapeutic agent against lumbar spinal canal stenosis.}, } @article {pmid36764275, year = {2023}, author = {Zhou, Y and Zhang, Y and Wang, H and Zhang, X and Chen, Y and Chen, G}, title = {Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway.}, journal = {International immunopharmacology}, volume = {116}, number = {}, pages = {109725}, doi = {10.1016/j.intimp.2023.109725}, pmid = {36764275}, issn = {1878-1705}, mesh = {Animals ; Mice ; Caspase 1/metabolism ; *Cognitive Dysfunction/chemically induced/metabolism ; Hippocampus/metabolism ; *Inflammasomes/metabolism ; Microglia ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pyroptosis ; Reactive Oxygen Species/metabolism ; *Sevoflurane/adverse effects ; }, abstract = {BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication with its pathophysiological mechanisms not been fully elucidated. Pyroptosis is a novel type of pro-inflammatory cell death and considered to be associated with cognitive dysfunction. Therefore, our study aimed to examine the effect of pyroptosis on sevoflurane-induced cognitive impairment in aged mice as well as its underlying mechanism.

METHODS: A mice model of cognitive impairment was established by sevoflurane exposure and the levels of reactive oxygen species (ROS), N-GSDMD, cleaved caspase-1, ASC, IL-1β and IL-18, and NLRP3 in hippocampus was determined. To explore the underlying mechanism, a pyroptosis inhibitor, necrosulfonamide (NSA), and a ROS scavenger, N-acetylcysteine (NAC), were administrated before sevoflurane exposure both in vitro and in vivo. Neurobehavioral tests, western blot, transmission electron microscope (TEM) observation, and immunofluorescence staining were performed.

RESULTS: Sevoflurane induced hippocampal pyroptosis in the cognitive impairment model. NSA effectively inhibited the pyroptosis and improved cognitive function. Co-labeled immunofluorescence staining suggested sevoflurane induces microglial pyroptosis. Sevoflurane induced pyroptosis accompanied with ROS accumulation in a dose-independent manner in BV2 cells, and NAC effectively reduce the levels of ROS and pyroptosis through NLRP3 inflammasome pathway in both vitro and vivo. Furthermore, NAC could also alleviate sevoflurane-induced cognitive dysfunction.

CONCLUSIONS: Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway. Both pyroptosis inhibition and ROS scavenging might be potential approaches to ameliorate sevoflurane-induced neurocognitive dysfunction.}, } @article {pmid36762617, year = {2023}, author = {Zhai, L and Ruan, S and Wang, J and Guan, Q and Zha, L}, title = {NADPH oxidase 4 regulate the glycolytic metabolic reprogramming of microglial cells to promote M1 polarization.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {5}, pages = {e23318}, doi = {10.1002/jbt.23318}, pmid = {36762617}, issn = {1099-0461}, mesh = {Animals ; Mice ; *Glycolysis ; Lipopolysaccharides ; *Microglia/metabolism ; *NADPH Oxidase 4/genetics/metabolism ; *Neuroinflammatory Diseases ; Reactive Oxygen Species/metabolism ; }, abstract = {This work aimed to investigate the role and mechanism of NADPH oxidase 4 (NOX4) in the polarization of microglial cells. Microglial cells were transfected with the NOX4 overexpression plasmid (pGL3-NOX4), and later treated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) to induce its M1 polarization. Later, the F4/80 + CD86 + cell proportion was detected by flow cytometry (FCM), the inflammatory factor expression levels were analyzed through enzyme-linked immunosorbent assay (ELISA), while ionized calcium binding adapter molecule 1 (IBA-1) and PKM2 expression were measured by immunofluorescence (IF) staining. In addition, dichlorodihydrofluorescein diacetate probe was utilized to detect the reactive oxygen species (ROS) levels, glucose uptake, and glycolysis, as well as lactic acid level. The expression of glycolytic enzymes PKM2, HK2, and citrate (Si)-synthas (CS) was detected by Western-blot (WB) assay. Moreover, the polarization level of microglial cells was detected after ROS expression was suppressed by the ROS inhibitor N-acetylcysteine (NAC). In mouse experiments, LPS was applied in inducing central neuroinflammation in NOX4 knockdown mouse model (KO) and wild-type mice (WT). Thereafter, the inflammatory factor levels and lactic acid level in mouse tissues were detected; IBA-1 and CD86 expression in mice was measured by IF staining; and the expression of glycolytic enzymes PKM2, HK2, and CS in the central nervous system (CNS) was also detected. After NOX4 overexpression in microglial cells, the M1 polarization level was upregulated, the F4/80 + CD86 + cell proportion increased, and inflammatory factors were upregulated. At the same time, the expression of glycolytic enzymes PKM2, HK2, and CS was upregulated. NAC pretreatment suppressed the effects of NOX4, reduced the F4/80 + CD86 + cell proportion, and suppressed the expression of PKM2, HK2, and CS. In the mouse model, the expression levels of CD86 in KO group decreased, and the inflammatory factors were also downregulated. NOX4 promotes glycolysis of microglial cells via ROS, thus accelerating M1 polarization and inflammatory factor expression. In this regard, NOX4 is promising as a new target for the treatment of neuroinflammation.}, } @article {pmid36759944, year = {2022}, author = {Tan, R and Black, M and Home, J and Blackwell, J and Clark, I and Wylie, L and Vanhatalo, A and Jones, AM}, title = {Physiological and performance effects of dietary nitrate and N-acetylcysteine supplementation during prolonged heavy-intensity cycling.}, journal = {Journal of sports sciences}, volume = {40}, number = {23}, pages = {2585-2594}, doi = {10.1080/02640414.2023.2176052}, pmid = {36759944}, issn = {1466-447X}, mesh = {Humans ; Male ; *Exercise/physiology ; *Fruit and Vegetable Juices ; *Nitrates/blood ; *Acetylcysteine/administration & dosage ; Antioxidants/administration & dosage ; *Dietary Supplements ; Cross-Over Studies ; Reactive Oxygen Species ; Endurance Training ; Oxygen Consumption/physiology ; Nitrites/blood ; Adult ; *Plant Extracts/pharmacology ; Plant Roots ; }, abstract = {The purpose of this study was to investigate effects of concurrent and independent administration of dietary nitrate (NO3[-]), administered as NO3[-]-rich beetroot juice (BR; ~12.4 mmol of NO3[-]), and N-acetylcysteine (NAC; 70 mg·kg[-1]) on physiological responses during prolonged exercise and subsequent high-intensity exercise tolerance. Sixteen recreationally active males supplemented with NO3[-]-depleted beetroot juice (PL) or BR for 6 days and ingested an acute dose of NAC or maltodextrin (MAL) 1 h prior to performing 1 h of heavy-intensity cycling exercise immediately followed by a severe-intensity time-to-exhaustion (TTE) test in four conditions: 1) PL+MAL, 2) PL+NAC, 3) BR+MAL and 4) BR+NAC. Pre-exercise plasma [NO3[-]] and nitrite ([NO2[-]]) were elevated following BR+NAC and BR+MAL (both P < 0.01) compared with PL+NAC and PL+MAL; plasma [cysteine] was increased in PL+NAC and BR+NAC (both P < 0.01) compared to PL+MAL. Muscle excitability declined over time during the prolonged cycling bout in all conditions but was better preserved in PL+NAC compared to BR+NAC (P < 0.01) and PL+MAL (P < 0.05). There was no effect of supplementation on subsequent TTE . These findings indicate that co-ingestion of BR and NAC does not appreciably alter physiological responses during prolonged heavy-intensity cycling or enhance subsequent exercise tolerance.}, } @article {pmid36757588, year = {2023}, author = {Gupta, J and Rajamani, P}, title = {Size- and surface functionalization-driven molecular interaction of CdSe quantum dots with jack bean urease: multispectroscopic, thermodynamic, and AFM approach.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {16}, pages = {48300-48322}, pmid = {36757588}, issn = {1614-7499}, support = {UGC ref No.: 3798/ (NET-DEC 2018)//University Grants Commission/ ; }, mesh = {Humans ; *Quantum Dots/chemistry ; Urease/metabolism ; *Cadmium Compounds/chemistry ; *Selenium Compounds/chemistry ; Glutathione ; Acetylcysteine ; Thermodynamics ; *Cysts ; Tumor Microenvironment ; }, abstract = {Quantum dots (QDs) with distinctive optical properties have been extensively researched and developed for usage in solar cells, imaging, drug delivery, cellular targeting, etc. But the inevitable production of QDs can lead to their unavoidable release and increased environmental concentration. Depending on morphological and surface properties, QDs at the nano-bio interface considerably impact the activity and structure of bio-molecules. The present study investigates the interaction of metalloenzyme jack bean urease (JBU) and bi-sized CdSe QDs (2.43 nm and 3.63 nm), surface-functionalized to mercaptopropionic acid (MPA) (-COOH), L-cysteine (CYS), L-glutathione (GSH), N-acetyl L-cysteine (NAC) (-COOH, -NH2), and cysteamine hydrochloride (CYST) (-NH2) to assess any alterations in JBU's binding, microenvironment, structure, exciton lifetime, and activity. JBU catalyzes the hydrolysis of urea to produce ammonia and carbon dioxide; any changes in its properties could threaten the survival of several microbes and plants. Spectroscopy techniques such as UV-Vis, fluorescence, circular dichroism, synchronous, time-resolved fluorescence, atomic force microscopy, and JBU activity assay were studied. Results suggested highly spontaneous and energy-favored interactions, which involved static quenching and hydrophobic forces of varied magnitude, dependent on QDs properties. The size, surface modifications, and dosage of QDs significantly impacted the secondary structure and activity of JBUs. Even though the larger sizes of the relevant modifications demonstrated stronger binding, the smaller sizes had the greatest impact on α-helicity and activity. CYST-capped QDs with an average number of the binding site (n) = 1, reduced α-helicity by 16% and activity by 22-30% at 7 nM concentration. In contrast, MPA-capped QDs with n < 1 had the least effect on α-helical structure and activity. The smaller GSH-capped QDs increased the activity by 9%, via partially restoring JBU's α-helical content. The study thus thoroughly analyzed the impact of varied-size and surface-functionalized QDs on the structure and function of JBU, which can be exploited further for several biomedical applications.}, } @article {pmid36756299, year = {2023}, author = {Guo, M and Chen, Q and Huang, Y and Wu, Q and Zeng, Y and Tan, X and Teng, F and Ma, X and Pu, Y and Huang, W and Gu, J and Zhang, C and Long, Y and Xu, Y}, title = {High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease.}, journal = {Oxidative medicine and cellular longevity}, volume = {2023}, number = {}, pages = {2713864}, pmid = {36756299}, issn = {1942-0994}, mesh = {Rats ; Mice ; Animals ; *Diabetic Nephropathies ; Reactive Oxygen Species/metabolism ; Necroptosis ; *Diabetes Mellitus, Experimental/complications ; Kidney/metabolism ; Inflammation ; Glucose/toxicity ; }, abstract = {Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and is closely associated to programmed cell death. However, the complex mechanisms of necroptosis, an alternative cell death pathway, in DKD pathogenesis are yet to be elucidated. This study indicates that necroptosis is involved in DKD induced by high glucose (HG) both in vivo and in vitro. HG intervention led to the activation of RIPK1/RIPK3/MLKL signaling, resulting in renal tissue necroptosis and proinflammatory activation in streptozotocin/high-fat diet- (STZ/HFD-) induced diabetic mice and HG-induced normal rat kidney tubular cells (NRK-52E). We further found that in HG-induced NRK-52E cell, necroptosis might, at least partly, depend on the levels of reactive oxygen species (ROS). Meanwhile, ROS participated in necroptosis via a positive feedback loop involving the RIPK1/RIPK3 pathway. In addition, blocking RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS generation, could effectively protect the kidney against HG-induced damage, decrease the release of proinflammatory cytokines, and rescue renal function in STZ/HFD-induced diabetic mice. Inhibition of RIPK1 effectively decreased the activation of RIPK1-kinase-/NF-κB-dependent inflammation. Collectively, we demonstrated that high glucose induced DKD via renal tubular epithelium necroptosis, and Nec-1 or NAC treatment downregulated the RIPK1/RIPK3/MLKL pathway and finally reduced necroptosis, oxidative stress, and inflammation. Thus, RIPK1 may be a therapeutic target for DKD.}, } @article {pmid36756050, year = {2023}, author = {Yu, Q and Shen, C and Wang, X and Wang, Z and Liu, L and Zhang, J}, title = {Graphene Oxide/Gelatin Nanofibrous Scaffolds Loaded with N-Acetyl Cysteine for Promoting Wound Healing.}, journal = {International journal of nanomedicine}, volume = {18}, number = {}, pages = {563-578}, pmid = {36756050}, issn = {1178-2013}, mesh = {Mice ; Animals ; *Acetylcysteine/pharmacology ; Gelatin/pharmacology ; Wound Healing ; Cicatrix ; *Nanofibers/chemistry ; Tissue Scaffolds/chemistry ; }, abstract = {PURPOSE: We aimed to develop an antioxidant dressing material with pro-angiogenic potential that could promote wound healing. Gelatin (Gel) was selected to improve the biocompatibility of the scaffolds, while graphene oxide (GO) was added to enhance their mechanical property. The loaded N-Acetyl cysteine (NAC) was performing the effect of scavenging reactive oxygen species (ROS) at the wound site.

MATERIALS AND METHODS: The physicochemical and mechanical properties, NAC releases, and biocompatibility of the NAC-GO-Gel scaffolds were evaluated in vitro. The regeneration capability of the scaffolds was systemically investigated in vivo using the excisional wound-splinting model in mice.

RESULTS: The NAC-GO-Gel scaffold had a stronger mechanical property and sustainer NAC release ability than the single Gel scaffold, which resulted in a better capacity for cell proliferation and migration. Mice wound-splinting models revealed that the NAC-GO-Gel scaffold effectively accelerated wound healing, promoted re-epithelialization, enhanced neovascularization, and reduced scar formation.

CONCLUSION: The NAC-GO-Gel scaffold not only promotes wound healing but also reduces scar formation, showing a great potential application for the repair of skin defects.}, } @article {pmid36753335, year = {2023}, author = {Gong, B and Zhang, S and Wang, X and Ran, G and Zhang, X and Xi, J and Gao, Z and Lei, Y and Pan, J and Liu, Y and Luan, Y and Zhang, X and Peng, Y and Li, W and Zheng, J}, title = {Inflammation Intensifies Monocrotaline-Induced Liver Injury.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.2c07939}, pmid = {36753335}, issn = {1520-5118}, abstract = {Pyrrolizidine alkaloids (PAs) are the most common toxins of plant origin, and it is evident that PAs pollute soil, water, nearby plants, and derived foods. Cases of human poisoning due to ingestion of PA-contaminated foods have been reported in several countries. Monocrotaline (MCT) is a pyrrolizidine alkaloid from the plants of Crotalaria genus that causes hepatic and cardiopulmonary toxicities, and the exhibition of the toxicities requires the metabolic activation by CYP3A4 to form electrophilic dehydro-monocrotaline (DHM). The present study demonstrated that myeloperoxidase (MPO) also participated in the bioactivation of MCT. N-Chloromonocrotaline was detected in both HClO/MCT incubations and MPO/H2O2/MgCl2/MCT incubations. DHM-derived N-acetylcysteine (NAC) conjugates were detected in the above incubations fortified with NAC. Lipopolysaccharide-induced inflammation in mice resulted in an elevated level of hepatic MPO activity, increased metabolic activation of MCT, and intensified elevation of serum ALT and AST activity induced by MCT. MPO inhibitor 4-aminobenzoic acid hydrazide was found to reverse these alterations. Mpo-KO mice were resistant to the observed potentiating effect of inflammation on MCT-induced liver injury. In conclusion, inflammation intensified MCT-induced liver injury. MPO participated in the observed potentiating effect of inflammation on the hepatotoxicity induced by MCT.}, } @article {pmid36749578, year = {2023}, author = {Abedi, B and Tayefi-Nasrabadi, H and Kianifard, D and Basaki, M and Shahbazfar, AA and Piri, A and Dolatyarieslami, M}, title = {The effect of co-administration of artemisinin and N-acetyl cysteine on antioxidant status, spermatological parameters and histopathology of testis in adult male mice.}, journal = {Hormone molecular biology and clinical investigation}, volume = {44}, number = {2}, pages = {207-214}, pmid = {36749578}, issn = {1868-1891}, mesh = {Male ; Mice ; Animals ; *Antioxidants/pharmacology ; Acetylcysteine/pharmacology/metabolism ; Testis/metabolism ; Oxidative Stress ; Semen/metabolism ; Spermatozoa/metabolism ; Glutathione/metabolism ; *Artemisinins/adverse effects/metabolism ; }, abstract = {OBJECTIVES: This in vivo study aimed to evaluate the effect of various concentrations of artemisinin (Art) alone or together with N-acetyl cysteine (NAC) on spermatological indices, antioxidant status, and histopathological parameters of testicular tissue in adult male mice.

METHODS: Six groups of five healthy male mice (25-30 g) were randomly assigned to different experimental groups. These groups received DMSO and corn oil (0.1%) as an Art solvent (Control), 50 mg kg[-1] Art (Art-50), 250 mg kg[-1] Art (Art-250), 50 mg kg[-1] Art + 150 mg kg[-1] NAC (Art-50+NAC-150), 250 mg kg[-1] Art + 150 mg kg[-1] NAC (Art-250+NAC-150) and 150 mg kg[-1] NAC (NAC-150) for a period of 7 days. Testes and epididymis were prepared to evaluate the malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), spermatological indices, and histological parameters.

RESULTS: We showed that the high dose of Art (Art-250) significantly reduced the sperm count, motility, viability, and the activity of CAT and increased the levels of MDA compared to the control group. Also, the overdose of Art caused adverse changes in testicular tissue. Co-administration of NAC with Art (Art-250+NAC-150) corrected the adverse effects of Art.

CONCLUSIONS: The current study reports that a high dose of Art affects, spermatological parameters, antioxidant/stress oxidative status of the male reproductive system, and NAC is capable neutralize all adverse effects caused by Art.}, } @article {pmid36740148, year = {2023}, author = {Kandhari, K and Mishra, JPN and Agarwal, R and Singh, RP}, title = {Acacetin induces sustained ERK1/2 activation and RIP1-dependent necroptotic death in breast cancer cells.}, journal = {Toxicology and applied pharmacology}, volume = {462}, number = {}, pages = {116409}, doi = {10.1016/j.taap.2023.116409}, pmid = {36740148}, issn = {1096-0333}, mesh = {Female ; Humans ; Apoptosis ; *Breast Neoplasms/pathology ; Cell Line, Tumor ; MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/pharmacology ; }, abstract = {Acacetin (AC), a naturally occurring flavonoid has shown anticancer potential. Herein, we studied the mechanisms of cell death and growth inhibition by AC in breast carcinoma T-47D and MDA-MB-231 cells. AC (10-40 μM) significantly decreased the levels of G2/M phase cyclins and CDKs, simultaneously increasing the expression of CDK inhibitors including Cip1/p21. A concentration-dependent increase in cell death was noted in both breast cancer cell lines with no such considerable effects on MCF-10A non-tumorigenic breast cells. The cell death-inducing potential of AC was further confirmed using confocal microscopy and flow cytometry analysis. AC resulted in mitochondrial superoxide generation, DNA damage, and ROS generation. N-acetyl cysteine (NAC) pre-treatment inhibited ROS generation and partially reversed ERK1/2 activation as well as cell death by AC. Further, AC enhanced the expression of RIP1 and RIP3, which mediate necroptosis. RIP1-specific inhibitor Necrostatin-1 (NS-1) reversed the AC-induced DNA damage and cell death. Collectively, these findings, for the first time, suggested that AC exerts its antitumor potential through ROS induction and RIP1-dependent necroptosis in breast carcinoma cells.}, } @article {pmid36738354, year = {2023}, author = {Zhang, Y and Peng, X and Xue, M and Liu, J and Shang, G and Jiang, M and Chen, D and Liu, B and Wang, Y and Jia, X and Xu, J and Zhang, F and Hu, Y}, title = {SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway.}, journal = {Biogerontology}, volume = {24}, number = {5}, pages = {813-827}, pmid = {36738354}, issn = {1573-6768}, mesh = {Animals ; Humans ; *Spike Glycoprotein, Coronavirus/metabolism ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Tumor Suppressor Protein p53/metabolism ; Zebrafish ; *COVID-19 ; SARS-CoV-2/metabolism ; Cellular Senescence/physiology ; }, abstract = {SARS-Cov-2 infection, which has caused the COVID-19 global pandemic, triggers cellular senescence. In this study, we investigate the role of the SARS-COV-2 spike protein (S-protein) in regulating the senescence of RPE cells. The results showed that administration or overexpression of S-protein in ARPE-19 decreased cell proliferation with cell cycle arrest at the G1 phase. S-protein increased SA-β-Gal positive ARPE-19 cells with high expression of P53 and P21, senescence-associated inflammatory factors (e.g., IL-1β, IL-6, IL-8, ICAM, and VEGF), and ROS. Elimination of ROS by N-acetyl cysteine (NAC) or knocking down p21 by siRNA diminished S-protein-induced ARPE cell senescence. Both administrated and overexpressed S-protein colocalize with the ER and upregulate ER-stress-associated BIP, CHOP, ATF3, and ATF6 expression. S-protein induced P65 protein nuclear translocation. Inhibition of NF-κB by bay-11-7082 reduced S-protein-mediated expression of senescence-associated factors. Moreover, the intravitreal injection of S-protein upregulates senescence-associated inflammatory factors in the zebrafish retina. In conclusions, the S-protein of SARS-Cov-2 induces cellular senescence of ARPE-19 cells in vitro and the expression of senescence-associated cytokines in zebrafish retina in vivo likely by activating ER stress, ROS, and NF-κb. These results may uncover a potential association between SARS-cov-2 infection and development of AMD.}, } @article {pmid36736558, year = {2023}, author = {Hao, W and Zhao, C and Li, G and Wang, H and Li, T and Yan, P and Wei, S}, title = {Blue LED light induces cytotoxicity via ROS production and mitochondrial damage in bovine subcutaneous preadipocytes.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {322}, number = {}, pages = {121195}, doi = {10.1016/j.envpol.2023.121195}, pmid = {36736558}, issn = {1873-6424}, mesh = {Animals ; Cattle ; Reactive Oxygen Species/metabolism ; *Oxidative Stress ; *Apoptosis ; Light ; Antioxidants/metabolism ; Autophagy ; }, abstract = {The purpose of this study was to investigate the effect and mechanism of blue light irradiation on bovine subcutaneous preadipocytes. In this study, preadipocytes were divided into dark group (control) and blue light group. Results show that blue light exposure time-dependently reduced the viability of preadipocytes and induced mitochondrial damage, in accompaniment with the accumulation of intracellular reactive oxygen species (ROS). Meanwhile, blue light caused oxidative stress, as evidenced by the increased MDA level, the reduced T-AOC contents, as well as the decreased activities of antioxidant enzymes. Additionally, blue light treatment induced apoptosis and G2/M phase arrest via Bcl-2/Bax/cleaved caspase-3 pathway and P53/GADD45 pathway, respectively. Protein expressions of LC3-II/LC3-I and P62 were up-regulated under blue light exposure, indicating blue light initiated autophagy but impeded autophagic degradation. Moreover, blue light caused an increase in the secretion of pro-inflammatory factors (TNF-α, IL-1β, and IL-6). Pretreatment with N-acetylcysteine (NAC), a potent ROS scavenger, restored the loss of mitochondrial membrane potential (Δψ) and reduced excess ROS. Additionally, the above negative effects of blue light on cells were alleviated after NAC administration. In conclusion, this study demonstrates blue light induces cellular ROS overproduction and Δψ depolarization, resulting in the decrease of cell viability and the activation of apoptosis, autophagy, and inflammation, providing a reference for the application of blue light in the regulation of fat cells in the future.}, } @article {pmid36728396, year = {2023}, author = {Chen, CH and Hung, KF and Huang, CY and Leong, JL and Chu, YC and Chang, CY and Wang, ML and Chiou, SH and Cheng, YF}, title = {Is N -acetylcysteine effective in treating patients with coronavirus disease 2019? A meta-analysis.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {86}, number = {3}, pages = {274-281}, doi = {10.1097/JCMA.0000000000000869}, pmid = {36728396}, issn = {1728-7731}, mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; Length of Stay ; }, abstract = {BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has brought tremendous challenges to public health and medical systems around the world. The current strategy for drug repurposing has accumulated some evidence on the use of N -acetylcysteine (NAC) in treating patients with COVID-19. However, the evidence remains debated.

METHODS: We performed the systematic review and meta-analysis that complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five databases and reference lists were searched from inception to May 14, 2022. Studies evaluating the efficacy of NAC in treating patients with COVID-19 were regarded as eligible. The review was registered prospectively on PROSPERO (CRD42022332791).

RESULTS: Of 778 records identified from the preliminary search, four studies were enrolled in the final qualitative review and quantitative meta-analysis. A total of 355 patients were allocated into the NAC group and the control group. The evaluated outcomes included intubation rate, improvement, duration of intensive unit stay and hospital stay and mortality. The pooled results showed nonsignificant differences in intubation rate (OR, 0.55; 95% CI, 0.16-1.89; p = 0.34; I2 = 75%), improvement of oxygenation ([MD], 80.84; 95% CI, -38.16 to 199.84; p = 0.18; I2 = 98%), ICU stay (MD, -0.74; 95% CI, -3.19 to 1.71; p = 0.55; I2 = 95%), hospital stay (MD, -1.05; 95% CI, -3.02 to 0.92; p = 0.30; I2 = 90%), and mortality (OR, 0.58; 95% CI, 0.23-1.45; p = 0.24; I2 = 54%). Subsequent trial sequential analysis (TSA) showed conclusive nonsignificant results for mortality, while the TSA for the other outcomes suggested that a larger sample size is essential.

CONCLUSIONS: The current evidence reveals NAC is not beneficial for treating patients with COVID- 19 with regard to respiratory outcome, mortality, duration of ICU stay and hospital stay.}, } @article {pmid36723800, year = {2023}, author = {Liu, H and Alhassan, N and Yoon, KT and Almutlaq, L and Lee, SS}, title = {Oxidative stress triggers hyperdynamic circulation via central neural activation in portal hypertensive rats.}, journal = {Hepatology international}, volume = {17}, number = {3}, pages = {689-697}, pmid = {36723800}, issn = {1936-0541}, mesh = {Rats ; Animals ; *Peroxidase/metabolism/pharmacology ; Rats, Sprague-Dawley ; Hydrogen Peroxide/pharmacology ; *Hypertension, Portal ; Hemodynamics ; Portal Vein ; Oxidative Stress ; }, abstract = {BACKGROUND: Hyperdynamic circulation in portal hypertension (PHT) depends on central neural activation. However, the initiating mechanism that signals PHT to the central neural cardiovascular-regulatory centers remains unclear. We aimed to test the hypothesis that oxidative stress in the gut initiates the signal that activates central cardiovascular nuclei in portal hypertensive rats.

METHODS: Two groups of rats were used. One had portal hypertension produced by partial portal vein ligation, while controls underwent sham operation. Hemodynamics including portal pressure, cardiac output, mean arterial pressure (MAP) and peripheral vascular resistance were measured. Activation of central cardiovascular nuclei was determined by immunohistochemical Fos expression in the paraventricular nucleus (PVN) of the hypothalamus. Myeloperoxidase activity, an oxidative stress marker, was measured in the jejunum. Hydrogen peroxide, the antioxidant N-acetyl-cysteine (NAC) or saline controls were administered for 12-14 days by gavage or osmotic minipumps placed in the peritoneal cavity.

RESULTS: Compared with controls, PHT rats showed increased cardiac output (54.2 ± 9.5 vs 33.6 ± 2.4 ml/min/100 g BW, p < 0.01), decreased MAP (96.2 ± 6.4 mmHg vs 103.2 ± 7.8, p < 0.01) and systemic vascular resistance (1.84 ± 0.28 vs 3.14 ± 0.19 mmHg/min/ml/100 g BW, p < 0.01). PHT rats had increased jejunal myeloperoxidase and PVN Fos expression. NAC treatment eliminated the hyperdynamic circulation, decreased jejunal myeloperoxidase and PVN Fos expression in PHT rats, but had no effect on sham controls. H2O2 significantly increased PVN Fos expression and decreased MAP.

CONCLUSION: These results indicate that in PHT, mesenteric oxidative stress is the initial signal that activates chemoreceptors and triggers hyperdynamic circulation by central neural cardiovascular-regulatory centers.}, } @article {pmid36722116, year = {2023}, author = {Takeuchi, M and Nishisho, T and Toki, S and Kawaguchi, S and Tamaki, S and Oya, T and Uto, Y and Katagiri, T and Sairyo, K}, title = {Blue light induces apoptosis and autophagy by promoting ROS-mediated mitochondrial dysfunction in synovial sarcoma.}, journal = {Cancer medicine}, volume = {12}, number = {8}, pages = {9668-9683}, pmid = {36722116}, issn = {2045-7634}, mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Sarcoma, Synovial/therapy/pathology ; Apoptosis ; Autophagy ; Mitochondria ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Synovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS.

METHODS: Human SS cell lines were continuously irradiated with BL using light-emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs.

RESULTS: BL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N-acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3-methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model.

CONCLUSION: Taken together, our results revealed that BL induced apoptosis via the ROS-mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS.}, } @article {pmid36716335, year = {2023}, author = {Gaymon, DO and Barndt, R and Stires, H and Riggins, RB and Johnson, MD}, title = {ROS is a master regulator of in vitro matriptase activation.}, journal = {PloS one}, volume = {18}, number = {1}, pages = {e0267492}, pmid = {36716335}, issn = {1932-6203}, support = {R01 CA123223/CA/NCI NIH HHS/United States ; T32 CA009686/CA/NCI NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; }, mesh = {Reactive Oxygen Species/metabolism ; Lapatinib ; Etoposide ; *Phosphatidylinositol 3-Kinases ; *Mitogen-Activated Protein Kinase Kinases ; }, abstract = {Matriptase is a type II transmembrane serine protease that is widely expressed in normal epithelial cells and epithelial cancers. Studies have shown that regulation of matriptase expression and activation becomes deranged in several cancers and is associated with poor disease-free survival. Although the central mechanism of its activation has remained unknown, our lab has previously demonstrated that inflammatory conditions such as intracellular pH decrease strongly induces matriptase activation. In this investigation, we first demonstrate clear matriptase activation following Fulvestrant (ICI) and Tykerb (Lapatinib) treatment in HER2-amplified, estrogen receptor (ER)-positive BT474, MDA-MB-361 and ZR-75-30 or single ER-positive MCF7 cells, respectively. This activation modestly involved Phosphoinositide 3-kinase (PI3K) activation and occurred as quickly as six hours post treatment. We also demonstrate that matriptase activation is not a universal hallmark of stress, with Etoposide treated cells showing a larger degree of matriptase activation than Lapatinib and ICI-treated cells. While etoposide toxicity has been shown to be mediated through reactive oxygen species (ROS) and MAPK/ERK kinase (MEK) activity, MEK activity showed no correlation with matriptase activation. Novelly, we demonstrate that endogenous and exogenous matriptase activation are ROS-mediated in vitro and inhibited by N-acetylcysteine (NAC). Lastly, we demonstrate matriptase-directed NAC treatment results in apoptosis of several breast cancer cell lines either alone or in combination with clinically used therapeutics. These data demonstrate the contribution of ROS-mediated survival, its independence of kinase-mediated survival, and the plausibility of using matriptase activation to indicate the potential success of antioxidant therapy.}, } @article {pmid36713695, year = {2023}, author = {Mukherjee, S and Sawant, AV and Prassanawar, SS and Panda, D}, title = {Copper-Plumbagin Complex Produces Potent Anticancer Effects by Depolymerizing Microtubules and Inducing Reactive Oxygen Species and DNA Damage.}, journal = {ACS omega}, volume = {8}, number = {3}, pages = {3221-3235}, pmid = {36713695}, issn = {2470-1343}, abstract = {Here, we have synthesized a copper complex of plumbagin (Cu-PLN) and investigated its antiproliferative activities in different cancer cells. The crystal structure of Cu-PLN showed that the complex was square planar with a binding stoichiometry of 1:2 (Cu/Plumbagin). Cu-PLN inhibited the proliferation of human cervical carcinoma (HeLa), human breast cancer (MCF-7), and murine melanoma (B16F10) cells with half-maximal inhibitory concentrations (IC50) of 0.85 ± 0.05, 2.3 ± 0.1, and 1.1 ± 0.1 μM, respectively. Plumbagin inhibited the proliferation of HeLa, MCF-7, and B16F10 cells with IC50 of 7 ± 0.1, 8.2 ± 0.2, and 6.2 ± 0.4 μM, respectively, showing that Cu-PLN is a stronger antiproliferative agent than plumbagin. Interestingly, Cu-PLN showed much stronger toxicity against breast carcinoma and skin melanoma cells than noncancerous breast epithelial and skin fibroblast cells, indicating its specific cytotoxicity toward cancer cells. A short exposure of Cu-PLN triggered microtubule disassembly in cultured cancer cells, and the complex also inhibited the polymerization of purified tubulin much more strongly than plumbagin. Furthermore, Cu-PLN inhibited the binding of colchicine to tubulin. In addition to microtubule depolymerization, the antiproliferative mechanism of Cu-PLN involved induction of reactive oxygen species, reduction of the mitochondrial membrane potential, and DNA damage. Moreover, the cytotoxic effects of Cu-PLN reduced significantly in cells pre-treated with N-acetyl cysteine, suggesting that reactive oxygen species generation is crucial in Cu-PLN's mode of action. Thus, the complexation of plumbagin with copper yields a promising antitumor agent having a stronger antiproliferative activity than cisplatin, a widely used anticancer drug.}, } @article {pmid36713582, year = {2022}, author = {Brown, K and Jenkins, LMM and Crooks, DR and Surman, DR and Mazur, SJ and Xu, Y and Arimilli, BS and Yang, Y and Lane, AN and Fan, TW and Schrump, DS and Linehan, WM and Ripley, RT and Appella, E}, title = {Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {1094210}, pmid = {36713582}, issn = {2234-943X}, support = {P30 CA177558/CA/NCI NIH HHS/United States ; }, abstract = {TP53 is the most commonly mutated gene in cancer, and gain-of-function mutations have wide-ranging effects. Efforts to reactivate wild-type p53 function and inhibit mutant functions have been complicated by the variety of TP53 mutations. Identified from a screen, the NSC59984 compound has been shown to restore activity to mutant p53 in colorectal cancer cells. Here, we investigated its effects on esophageal adenocarcinoma cells with specific p53 hot-spot mutations. NSC59984 treatment of cells reactivated p53 transcriptional regulation, inducing mitochondrial intrinsic apoptosis. Analysis of its effects on cellular metabolism demonstrated increased utilization of the pentose phosphate pathway and inhibition of glycolysis at the fructose-1,6-bisphosphate to fructose 6-phosphate junction. Furthermore, treatment of cells with NSC59984 increased reactive oxygen species production and decreased glutathione levels; these effects were enhanced by the addition of buthionine sulfoximine and inhibited by N-acetyl cysteine. We found that the effects of NSC59984 were substantially greater in cells harboring the p53 R248W mutation. Overall, these findings demonstrate p53-dependent effects of NSC59984 on cellular metabolism, with increased activity in cells harboring the p53 R248W mutation. This research highlights the importance of defining the mutational status of a particular cancer to create a patient-centric strategy for the treatment of p53-driven cancers.}, } @article {pmid36708988, year = {2023}, author = {Ono, S and Ogura, J and Sugiura, H and Yamauchi, M and Tanaka, A and Sato, T and Maekawa, M and Yamaguchi, H and Mano, N}, title = {Glutathione depletion results in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells.}, journal = {Life sciences}, volume = {316}, number = {}, pages = {121442}, doi = {10.1016/j.lfs.2023.121442}, pmid = {36708988}, issn = {1879-0631}, mesh = {Humans ; Protein Disulfide-Isomerases/metabolism ; *Alzheimer Disease ; Endoribonucleases ; *Neuroblastoma/pathology ; Protein Serine-Threonine Kinases ; Glutathione ; Glutamates ; }, abstract = {AIMS: Protein disulfide isomerase (PDI) is an essential enzyme involved in oxidative protein folding. PDI is S-nitrosylated in the brains of Alzheimer's disease patients, and S-nitrosylated PDI is considered one of main causes of Alzheimer's disease. However, the mechanisms underlying PDI S-nitrosylation have not yet been elucidated. Because glutathione (GSH) depletion is a pathological feature of Alzheimer's disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI.

MAIN METHODS: SH-SY5Y cells, which is a human derived neuroblastoma cells, were used in this study. Glutamate and buthionine sulfoximine (BSO) were used as GSH depletors. S-nitrosylated PDI was detected by biotin-switch assay.

KEY FINDINGS: GSH depletion by glutamate, a cystine/glutamate antiporter xCT inhibitor, increased S-nitrosylated PDI at C343 in SH-SY5Y cells, and induced IRE1α phosphorylation. BSO, a γ-glutamylcysteine synthetase inhibitor, also increased S-nitrosylated PDI and phosphorylated IRE1α upon GSH depletion. Because S-nitrosylated PDI at C343 is stable in neuro cells, S-nitrosylated PDI by GSH depletion progresses to neurodegeneration by the induction of endoplasmic reticulum stress via phosphorylated IRE1α signaling from the early to late stage. Furthermore, treatment with neohesperidin, but not N-acetylcysteine (NAC), improved PDI S-nitrosylation level in GSH-depleted SH-SY5Y cells because nitrosylated compound of NAC induces PDI S-nitrosylation.

SIGNIFICANCE: The results of our study provide a new insight into the mechanisms of neurodegeneration, and may be useful for the development of drugs for Alzheimer's diseases.}, } @article {pmid36708663, year = {2023}, author = {Liu, X and Xi, H and Han, S and Zhang, H and Hu, J}, title = {Zearalenone induces oxidative stress and autophagy in goat Sertoli cells.}, journal = {Ecotoxicology and environmental safety}, volume = {252}, number = {}, pages = {114571}, doi = {10.1016/j.ecoenv.2023.114571}, pmid = {36708663}, issn = {1090-2414}, mesh = {Animals ; Male ; *Zearalenone/toxicity ; Sertoli Cells/metabolism ; Reactive Oxygen Species/metabolism ; Goats/metabolism ; Oxidative Stress ; Apoptosis ; Autophagy ; }, abstract = {Zearalenone (ZEA), one of the non-steroidal estrogen mycotoxin, can cause male reproductive damage and genotoxicity in mammals. Testicular oxidative injury is an important factor causing male sterility. Testicular Sertoli cells are essential for spermatogenesis and male fertility. At present, the mechanism of oxidative injury in dairy goat Sertoli cells after exposure to ZEA remains unclear. This study explored the effects of ZEA on oxidative stress and autophagy in dairy goat Sertoli cells. It was found that treatment of primary Sertoli cells with 25, 50 and 100 μmol/L ZEA for 24 h can promote ROS production, decrease cell viability, antioxidant enzyme activity and mitochondrial membrane potential, induce caspase-dependent cell apoptosis and autophagy activity. ZEA-induced autophagy was confirmed by LC3-I/LC3-II transformation. More importantly, N-acetylcysteine (NAC) pretreatment can remarkably inhibit ZEA-induced oxidative stress, apoptosis and autophagy in Sertoli cells by eliminating ROS. In conclusion, this study indicates that ZEA induces oxidative stress and autophagy in dairy goat Sertoli cells by promoting ROS production.}, } @article {pmid36708386, year = {2023}, author = {Fernández-Rodríguez, S and Cano-Cebrián, MJ and Esposito-Zapero, C and Pérez, S and Guerri, C and Zornoza, T and Polache, A}, title = {N-Acetylcysteine normalizes brain oxidative stress and neuroinflammation observed after protracted ethanol abstinence: a preclinical study in long-term ethanol-experienced male rats.}, journal = {Psychopharmacology}, volume = {240}, number = {4}, pages = {725-738}, pmid = {36708386}, issn = {1432-2072}, support = {GVA2016-096//Conselleria de Cultura, Educación y Ciencia, Generalitat Valenciana/ ; ACIF/2018/039//Conselleria de Cultura, Educación y Ciencia, Generalitat Valenciana/ ; UV-INV_AE18-785117//Universitat de València/ ; }, mesh = {Rats ; Male ; Animals ; *Ethanol ; Rats, Wistar ; *Acetylcysteine/pharmacology ; Alcohol Abstinence ; Neuroinflammatory Diseases ; Brain ; Chronic Disease ; Oxidative Stress ; Glutamates/metabolism ; Alcohol Drinking/drug therapy ; }, abstract = {RATIONALE: Using a preclinical model based on the Alcohol Deprivation Effect (ADE), we have reported that N-Acetylcysteine (NAC) can prevent the relapse-like drinking behaviour in long-term ethanol-experienced male rats.

OBJECTIVES: To investigate if chronic ethanol intake and protracted abstinence affect several glutamate transporters and whether NAC, administered during the withdrawal period, could restore the ethanol-induced brain potential dysfunctions. Furthermore, the antioxidant and anti-inflammatory effects of NAC during abstinence in rats under the ADE paradigm were also explored.

METHODS: The expression of GLT1, GLAST and xCT in nucleus accumbens (Nacc) and dorsal striatum (DS) of male Wistar was analysed after water and chronic ethanol intake. We used the model based on the ADE within another cohort of male Wistar rats. During the fourth abstinence period, rats were treated for 9 days with vehicle or NAC (60, 100 mg/kg; s.c.). The effects of NAC treatment on (i) glutamate transporters expression in the Nacc and DS, (ii) the oxidative status in the hippocampus (Hip) and amygdala (AMG) and (iii) some neuroinflammatory markers in prefrontal cortex (PFC) were tested.

RESULTS: NAC chronic administration during protracted abstinence restored oxidative stress markers (GSSG and GGSH/GSH) in the Hip. Furthermore, NAC was able to normalize some neuroinflammation markers in PFC without normalizing the observed downregulation of GLT1 and GLAST in Nacc.

CONCLUSIONS: NAC restores brain oxidative stress and neuroinflammation that we previously observed after protracted ethanol abstinence in long-term ethanol-experienced male rats. This NAC effect could be a plausible mechanism for its anti-relapse effect. Also, brain oxidative stress and neuroinflammation could represent and identify plausible targets for searching new anti-relapse pharmacotherapies.}, } @article {pmid36708242, year = {2022}, author = {yingBai, Y and meiCheng, Y and Wang, W and Yang, L and Yang, Y}, title = {In vivo and in vitro studies of Alloimperatorin induced autophagy in cervical cancer cells via reactive oxygen species pathway.}, journal = {Bioengineered}, volume = {13}, number = {6}, pages = {14299-14314}, pmid = {36708242}, issn = {2165-5987}, mesh = {Mice ; Animals ; Female ; Humans ; *Uterine Cervical Neoplasms/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Nude ; Autophagy ; Apoptosis ; Cell Line, Tumor ; }, abstract = {Alloimperatorin (Alloi) has been shown to have anti-proliferative effects in our previous studies. we aimed to investigate whether Alloimperatorin induces autophagy through the reactive oxygen species (ROS) pathway and anticancer activity in vivo. The anti-proliferative effect of Alloimperatorin was evaluated using a cell counting kit (CCK-8 kit). Apoptosis was detected using flow cytometry. Confocal microscopy, immunofluorescence, and mRFP-GFP-LC3 lentivirus transfection were used to verify autophagy. Electron microscopy detection of autophagosomes was induced by Alloimperatorin. Western blotting was used to detect autophagy proteins in HeLa and SiHa cells. A xenograft model was used to monitor the inhibitory effect of Alloimperatorin on tumor growth in nude mice. The results showed that Alloimperatorin induced ROS production and inhibited the proliferation of HeLa and SiHa cells. Furthermore, Alloimperatorin increased the apoptosis rate in HeLa and SiHa cells. Confocal microscopy fluorescence indicated that Alloimperatorin increased autophagy fluorescence of HeLa and SiHa cells. mRFP-GFP-LC3 lentivirus transfection and electron microscopy demonstrated that Alloimperatorin increased autophagy in HeLa and SiHa cells. Western blotting showed that Alloimperatorin induced the expression of autophagy proteins in HeLa and SiHa cells. However, N-acetylcysteine reversed the autophagy. These results demonstrate that Alloimperatorin can induce autophagy in HeLa and SiHa cells through the ROS pathway. In vivo xenograft experiments showed that Alloimperatorin could inhibit tumor growth in nude mice. Alloimperatorin is expected to be an effective new drug for cervical cancer treatment.Abbreviations: ROS, reactive oxygen species; Alloi, Alloimperatorin; CCK-8, Cell Counting Kit-8; NAC, N-acetyl-L-cysteine; DCFH-DA, 2,7-dichlorodihydrofluorescein diacetate; OD, optical density; PBS, phosphate buffer solution; BCA, bicinchoninic acid; DAPI, 4,6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.}, } @article {pmid36707135, year = {2023}, author = {Sahoo, DK and Chainy, GBN}, title = {Hormone-linked redox status and its modulation by antioxidants.}, journal = {Vitamins and hormones}, volume = {121}, number = {}, pages = {197-246}, doi = {10.1016/bs.vh.2022.10.007}, pmid = {36707135}, issn = {0083-6729}, mesh = {Humans ; Animals ; *Antioxidants/pharmacology/therapeutic use ; Reactive Oxygen Species/pharmacology ; Oxidative Stress/physiology ; Oxidation-Reduction ; *Melatonin/pharmacology ; }, abstract = {Hormones have been considered as key factors involved in the maintenance of the redox status of the body. We are making considerable progress in understanding interactions between the endocrine system, redox status, and oxidative stress with the dynamics of life, which encompasses fertilization, development, growth, aging, and various pathophysiological states. One of the reasons for changes in redox states of vertebrates leading to oxidative stress scenario is the disruption of the endocrine system. Comprehending the dynamics of hormonal status to redox state and oxidative stress in living systems is challenging. It is more difficult to come to a unifying conclusion when some hormones exhibit oxidant properties while others have antioxidant features. There is a very limited approach to correlate alteration in titers of hormones with redox status and oxidative stress with growth, development, aging, and pathophysiological stress. The situation is further complicated when considering various tissues and sexes in vertebrates. This chapter discusses the beneficial impacts of hormones with antioxidative properties, such as melatonin, glucagon, insulin, estrogens, and progesterone, which protect cells from oxidative damage and reduce pathophysiological effects. Additionally, we discuss the protective effects of antioxidants like vitamins A, E, and C, curcumin, tempol, N-acetyl cysteine, α-lipoic acid, date palm pollen extract, resveratrol, and flavonoids on oxidative stress triggered by hormones such as aldosterone, glucocorticoids, thyroid hormones, and catecholamines. Inflammation, pathophysiology, and the aging process can all be controlled by understanding how antioxidants and hormones operate together to maintain cellular redox status. Identifying the hormonal changes and the action of antioxidants may help in developing new therapeutic strategies for hormonal imbalance-related disorders.}, } @article {pmid36705628, year = {2023}, author = {Zhao, Y and Huang, H and Lv, N and Huang, C and Chen, H and Xing, H and Guo, C and Li, N and Zhao, D and Chen, X and Zhang, Y}, title = {Glutathione S-Transferases Mediate In Vitro and In Vivo Inactivation of Genipin: Implications for an Underlying Detoxification Mechanism.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {5}, pages = {2399-2410}, doi = {10.1021/acs.jafc.2c08175}, pmid = {36705628}, issn = {1520-5118}, mesh = {Rats ; Animals ; *Liver/metabolism ; Glutathione Transferase/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; Glutathione/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {Genipin (GP), the reactive metabolite of geniposide (GE), is responsible for GE-induced hepatotoxicity. As a potential detoxification pathway, the inactivation of GP by glutathione S-transferases (GSTs) has not yet been characterized. In this study, the thiol-GSH conjugates of GP, M532-1 and M532-2 were first identified and the catalytic activities of GSTs were investigated both in vitro and in vivo. GSTA1-1 and GSTA4-4 showed high activity in the formation of both thiol-GSH conjugates, whereas GSTA4-4 specifically catalyzed M532-2 formation in vitro. The active GST isoforms protect against alkylation of N-acetylcysteine (NAC), a classic model nucleophile. GST inhibition attenuated M532-1 formation in rat bile, confirming the in vivo catalytic role of GSTs. In conclusion, this study demonstrated the inactivation of GP by GSTs and implied that interindividual variability of GSTs may be a risk factor for susceptibility to GE-induced hepatotoxicity.}, } @article {pmid36703750, year = {2022}, author = {Huang, Z and Wang, H and Chun, C and Li, X and Xu, S and Zhao, Y}, title = {Self-assembled FGF21 nanoparticles alleviate drug-induced acute liver injury.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1084799}, pmid = {36703750}, issn = {1663-9812}, abstract = {Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases.}, } @article {pmid36700765, year = {2023}, author = {Jiang, X and Li, Y and Fu, D and You, T and Wu, S and Xin, J and Wen, J and Huang, Y and Hu, C}, title = {Caveolin-1 ameliorates acetaminophen-aggravated inflammatory damage and lipid deposition in non-alcoholic fatty liver disease via the ROS/TXNIP/NLRP3 pathway.}, journal = {International immunopharmacology}, volume = {114}, number = {}, pages = {109558}, doi = {10.1016/j.intimp.2022.109558}, pmid = {36700765}, issn = {1878-1705}, mesh = {Mice ; Animals ; *Non-alcoholic Fatty Liver Disease/drug therapy/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Acetaminophen ; Reactive Oxygen Species/metabolism ; Caveolin 1/metabolism ; Inflammasomes/metabolism ; Pyroptosis ; Thioredoxins/genetics/metabolism ; RNA, Small Interfering ; *Chemical and Drug Induced Liver Injury/drug therapy ; Lipids ; Carrier Proteins/genetics ; }, abstract = {The overuse of acetaminophen (APAP) may cause more severe hepatotoxicity in patients with non-alcoholic fatty liver disease (NAFLD). Caveolin-1 (CAV1), is an essential regulator of metabolic function, which can alleviate liver damage by scavenging reactive oxygen species (ROS). Evidence suggests that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated pyroptosis is involved in the development of NAFLD. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linking ROS to NLRP3 inflammasome. However, whether CAV1 alleviates APAP-aggravated hepatotoxicity in NAFLD via the ROS/TXNIP/NLRP3 pathway remains unclear. An in vivo fatty liver model was established by feeding mice a high-fat diet for 56 days. Additionally, using in vitro approach, AML-12 cells were incubated with free fatty acids for 48 h and APAP was added during the last 24 h. We found that the overuse of APAP in NAFLD not only induced oxidative stress, but also increased TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition. In addition to inhibiting ROS generation and lipid deposition, overexpression of CAV1 reduced the elevated levels of TXNIP expression and NLRP3-mediated pyroptosis. However, the effect of CAV1 on TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition was reversed by CAV1 small interfering RNA (siRNA) intervention. Finally, N-acetyl cysteine (NAC) treatment reduced CAV1 siRNA-mediated changes in TXNIP expression and NLRP3-mediated pyroptosis levels. These results demonstrate that the inhibitory effect of CAV1 on NLRP3-mediated pyroptosis may be mediated through the ROS/TXNIP axis. Moreover, the current study provides novel mechanistic insights into the protective effects of CAV1 on APAP-aggravated hepatotoxicity in NAFLD.}, } @article {pmid36700727, year = {2023}, author = {Grant, JE and Chamberlain, SR}, title = {Monoamine Oxidase Inhibitors for Trichotillomania: A Case Series.}, journal = {Journal of clinical psychopharmacology}, volume = {43}, number = {2}, pages = {149-151}, doi = {10.1097/JCP.0000000000001654}, pmid = {36700727}, issn = {1533-712X}, mesh = {United States ; Humans ; Monoamine Oxidase Inhibitors/therapeutic use ; *Trichotillomania/drug therapy ; Phenelzine ; *Obsessive-Compulsive Disorder/drug therapy ; Selective Serotonin Reuptake Inhibitors ; }, abstract = {PURPOSE/BACKGROUND: Despite several decades of research, there are no US Food and Drug Administration-approved medications for trichotillomania or medications generally approved in other geographical jurisdictions. Monoamine oxidase inhibitors show efficacy in the treatment of depression and some possible promise for obsessive compulsive disorder.

METHODS/PROCEDURES: We present new data from a case series collected in a specialty clinical practice over a 4-year period.

FINDINGS/RESULTS: In 5 treatment-resistant patients whose trichotillomania had not improved with at least 1 course of cognitive behavior therapy and trials of n -acetyl cysteine, an antipsychotic, and a serotonin selective reuptake inhibitor, 2 had marked clinical improvement (>40% improvement) on phenelzine, 1 improved on tranylcypromine, and 2 showed no improvement (<10%) on phenelzine. In 2 of the 3 patients who experienced improvement, there was co-occurring depression.

IMPLICATIONS/CONCLUSIONS: Monoamine oxidase inhibitors in trichotillomania may deserve large-scale randomized controlled trials, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.}, } @article {pmid36700278, year = {2023}, author = {Özdemir, M and Birinci, B and Haberal, B and Ok Atılgan, A and Demirkale, İ}, title = {In vivo study of the role of hyaluronic acid, N-acetyl cysteine, and deproteinized calf serum on injury-induced cartilage degeneration.}, journal = {Joint diseases and related surgery}, volume = {34}, number = {1}, pages = {158-165}, pmid = {36700278}, issn = {2687-4792}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; *Cartilage, Articular/injuries ; *Hyaluronic Acid/pharmacology/therapeutic use ; }, abstract = {OBJECTIVES: The aim of this study was to compare the effects of hyaluronic acid (HA), N-acetyl cysteine (NAC), and deproteinized calf serum on cartilage healing after the creation of traumatic cartilage injury in a rat model.

MATERIALS AND METHODS: A total of 48 rats, each weighing an average of 350 g, were randomly separated into four groups of 12. An osteochondral defect was created, 2-mm-wide and 3-mm deep in each rat. Injections were made to the knees of the rats as saline solution in Group 1, deproteinized calf serum in Group 2, NAC in Group 3, and HA in Group 4. At the end of 12 weeks, all rats were sacrificed and tissues were evaluated histologically.

RESULTS: The HA group had a better cell morphology, tissue morphology, surface architecture, and vascularity than the other groups (p<0.001). Matrix staining, chondrocyte clustering, and the assessment scores of the mid, deep, superficial zones, and overall were higher in the HA group than in the other groups (p<0.001). The NAC showed a better tissue morphology, cell morphology, and vascularity than the control group (p=0.003, p<0.001, and p<0.001, respectively).

CONCLUSION: Hyaluronic acid was the most effective agent in cartilage healing compared to NAC and deproteinized calf serum. In addition, the NAC was more effective compared to the control group.}, } @article {pmid36689858, year = {2023}, author = {Lin, CL and Yu, CI and Lee, TH and Chuang, JM and Han, KF and Lin, CS and Huang, WP and Chen, JY and Chen, CY and Lin, MY and Lee, CH}, title = {Plumbagin induces the apoptosis of drug-resistant oral cancer in vitro and in vivo through ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {111}, number = {}, pages = {154655}, doi = {10.1016/j.phymed.2023.154655}, pmid = {36689858}, issn = {1618-095X}, mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; *Zebrafish/metabolism ; Apoptosis ; Cell Line, Tumor ; Mitochondria ; *Mouth Neoplasms/drug therapy/metabolism ; Endoplasmic Reticulum Stress ; }, abstract = {BACKGROUND: Oral cancer is one of the leading causes of cancer-related deaths worldwide. Chemotherapy is widely used in the treatment of oral cancer, but its clinical efficacy is limited by drug resistance. Hence, novel compounds capable of overcoming drug-resistance are urgently needed.

PURPOSE: Plumbagin (PG), a natural compound isolated from Plumbago zeylanica L, has been used to treat various cancers. In this study, we investigated the anticancer effects of PG on drug-resistant oral cancer (CR-SAS) cells, as well as the underlying mechanism.

METHODS: MTT assays were used to evaluate the effect of PG on the viability of CR-SAS cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined using flow cytometry. Protein expression levels were detected by western blotting.

RESULTS: The results show that PG reduces the viability and causes the apoptosis of CR-SAS cells. PG is able to induce intracellular and mitochondrial ROS generation that leads to mitochondrial dysfunction. Furthermore, endoplasmic reticulum (ER) stress was triggered in PG-treated CR-SAS cells. The inhibition of ROS using N-acetylcysteine (NAC) abrogated the PG-induced ER stress and apoptosis, as well as the reduction in cell viability. Meanwhile, similar results were observed both in zebrafish and in murine models of drug-resistant oral cancer.

CONCLUSION: Our results indicate that PG induces the apoptosis of CR-SAS cells via the ROS-mediated ER stress pathway and mitochondrial dysfunction. It will be interesting to develop the natural compound PG for the treatment of drug-resistant oral cancer.}, } @article {pmid36687698, year = {2022}, author = {Wang, W and Guan, J and Feng, Y and Nie, L and Xu, Y and Xu, H and Fu, F}, title = {Polystyrene microplastics induced nephrotoxicity associated with oxidative stress, inflammation, and endoplasmic reticulum stress in juvenile rats.}, journal = {Frontiers in nutrition}, volume = {9}, number = {}, pages = {1059660}, pmid = {36687698}, issn = {2296-861X}, abstract = {INTRODUCTION: Unintended intake of microplastic particles has been demonstrated to exert adverse health effects, however, studies on relevant nephrotoxicity in juvenile mammals are lacking.

METHODS: Therefore, we investigated the potential nephrotoxicity of oral-exposed polystyrene microplastics (PSMPs) (1,000 nm, 2.0 mg/kg/d) for 28 days in juvenile rats. Levels of oxidative stress, inflammation, and endoplasmic reticulum (ER) stress in kidneys were analyzed.

RESULTS AND DISCUSSION: Results revealed that PSMPs noticeably decreased the growth rate of bodyweight, and organ index of the kidney, cardiac, and ovary. The intestinal injury caused by PSMPs exposure was also observed, which was distinctly alleviated with N-acetyl-cysteine (NAC) and Salubrinal (Sal) treatment compared with the single PSMPs group. PSMPs caused histological lesions of the kidney via disrupting the serum blood urea nitrogen (BUN), creatinine (CRE), and pro-inflammatory mediators IL-1β, IL-6, and TNF-α. Furthermore, PSMPs exposure induced ER stress and inflammation presumably potentially mediated by oxidative stress in kidneys of rats. Eventually, PSMPs also promoted renal cells apoptosis, manifested as an obvious increase in the number of positive cells for the dUTP nick end labeling of Terminal deoxynucleotidyl transferase, which also can be confirmed by the elevated expression of genes associated with apoptosis Bcl-2, Bax, Caspase-12, Caspase-9, Caspase-3, and IHC score of Caspase-12 in the PSMPs group. Supplementation of NAC and Sal not only ameliorated the PSMPs-induced oxidative stress and ER stress but also the inflammation and apoptosis in the kidney. Collectively, this study suggested that PSMPs caused nephrotoxicity in juvenile rats potentially through oxidative damage and ER stress, which call for greater efforts to be taken on regulating the PSMPs ingestion in children.}, } @article {pmid36686028, year = {2023}, author = {Dalai, MK and Singh, GK and Bairwa, Y and Chauhan, SS and Ingle, M}, title = {Premedication with simethicone and N-acetyl cysteine in esophagogastroduodenoscopy: Is it time to use it in practice?.}, journal = {Endoscopy international open}, volume = {11}, number = {1}, pages = {E81}, pmid = {36686028}, issn = {2364-3722}, } @article {pmid36678548, year = {2022}, author = {Song, F and Lin, J and Zhang, H and Guo, Y and Mao, Y and Liu, Z and Li, G and Wang, Y}, title = {Long-Term Sleep Deprivation-Induced Myocardial Remodeling and Mitochondrial Dysfunction in Mice Were Attenuated by Lipoic Acid and N-Acetylcysteine.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {1}, pages = {}, pmid = {36678548}, issn = {1424-8247}, support = {82270417;81970283;81870627//National Natural Science Foundation of China/ ; 2018YFA0107304//the National Key R&D Program of China/ ; 20720202013//Fundamental Research Funds for the Central Universities/ ; }, abstract = {The impact of long-term sleep deprivation on the heart and its underlying mechanisms are poorly understood. The present study aimed to investigate the impact of chronic sleep deprivation (CSD) on the heart and mitochondrial function and explore an effective drug for treating CSD-induced heart dysfunction. We used a modified method to induce CSD in mice; lipoic acid (LA) and N-acetylcysteine (NAC) were used to treat CSD mice. Echocardiography, hematoxylin-eosin (H&E) staining, Sirius red staining, and immunohistochemistry were used to determine heart function and cardiac fibrosis. The serum levels of brain natriuretic peptide (BNP), superoxide Dismutase (SOD), micro malondialdehyde (MDA), and glutathione (GSH) were measured to determine cardiovascular and oxidative stress-related damage. Transmission electron microscopy was used to investigate mitochondrial damage. RNA-seq and Western blotting were used to explore related pathways. We found that the left ventricular ejection fraction (LVEF) and fraction shortening (LVFS) values were significantly decreased and myocardial hypertrophy was induced, accompanied by damaged mitochondria, elevated reactive oxygen species (ROS), and reduced SOD levels. RNA-sequence analysis of the heart tissue showed that various differentially expressed genes in the metabolic pathway were enriched. Sirtuin 1 (Sirt1) and Glutathione S-transferase A3 (Gsta3) may be responsible for CSD-induced heart and mitochondrial dysfunction. Pharmacological inhibition of ROS by treating CSD mice with LA and NAC effectively reduced heart damage and mitochondrial dysfunction by regulating Sirt1 and Gsta3 expression. Our data contribute to understanding the pathways of CSD-induced heart dysfunction, and pharmacological targeting to ROS may represent a strategy to prevent CSD-induced heart damage.}, } @article {pmid36672522, year = {2022}, author = {Teschke, R}, title = {Treatment of Drug-Induced Liver Injury.}, journal = {Biomedicines}, volume = {11}, number = {1}, pages = {}, pmid = {36672522}, issn = {2227-9059}, abstract = {Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.}, } @article {pmid36672389, year = {2023}, author = {Schlörmann, W and Horlebein, C and Hübner, SM and Wittwer, E and Glei, M}, title = {Potential Role of ROS in Butyrate- and Dietary Fiber-Mediated Growth Inhibition and Modulation of Cell Cycle-, Apoptosis- and Antioxidant-Relevant Proteins in LT97 Colon Adenoma and HT29 Colon Carcinoma Cells.}, journal = {Cancers}, volume = {15}, number = {2}, pages = {}, pmid = {36672389}, issn = {2072-6694}, abstract = {The aim of the present study was to examine whether reactive oxygen species (ROS) contribute to chemopreventive effects of fermentation supernatants (FS) of different dietary fibers (Synergy1[®], oat-, barley-, yeast β-glucan, Curdlan) and butyrate as a fermentation metabolite. LT97 and HT29 cells were treated with butyrate and FS alone or with N-acetyl-cysteine (NAC) and their impact on ROS formation, cell growth, and protein expression (Cyclin D2, p21, PARP, Bid, GPx2) was investigated. Butyrate and FS significantly decreased cell growth. ROS levels were significantly increased, particularly in LT97 cells, while co-treatment with NAC decreased ROS formation and growth inhibitory effects in both cell lines. After treatment with butyrate and FS, Cyclin D2 expression was reduced in LT97 cells and p21 expression was increased in both cell lines. Levels of full-length PARP and Bid were decreased, while levels of cleaved PARP were enhanced. GPx2 expression was significantly reduced by fiber FS in HT29 cells. A notable effect of NAC on butyrate- and FS-modulated protein expression was observed exclusively for PARP and Bid in HT29 cells. From the present results, a contribution of ROS to growth inhibitory and apoptotic effects of butyrate and FS on LT97 and HT29 cells cannot be excluded.}, } @article {pmid36671018, year = {2023}, author = {Kim, JE and Park, H and Kang, TC}, title = {Peroxiredoxin 6 Regulates Glutathione Peroxidase 1-Medited Glutamine Synthase Preservation in the Hippocampus of Chronic Epilepsy Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36671018}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; }, abstract = {Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus.}, } @article {pmid36671002, year = {2023}, author = {Chhunchha, B and Kubo, E and Krueger, RR and Singh, DP}, title = {Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36671002}, issn = {2076-3921}, support = {R01 EY024589/EY/NEI NIH HHS/United States ; EY024589/EY/NEI NIH HHS/United States ; UNMC//UNMC/ ; }, abstract = {A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2's activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.}, } @article {pmid36670992, year = {2023}, author = {Mursaleen, L and Chan, SHY and Noble, B and Somavarapu, S and Zariwala, MG}, title = {Curcumin and N-Acetylcysteine Nanocarriers Alone or Combined with Deferoxamine Target the Mitochondria and Protect against Neurotoxicity and Oxidative Stress in a Co-Culture Model of Parkinson's Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36670992}, issn = {2076-3921}, abstract = {As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 (P68) and dequalinium (DQA) nanocarriers can improve the ability of curcumin, n-acetylcysteine (NAC) and/or deferoxamine (DFO), to access the brain, specifically target mitochondria and protect against rotenone by evaluating their effects in a combined Transwell® hCMEC/D3 BBB and SH-SY5Y based cellular Parkinson’s disease (PD) model. P68 + DQA nanoformulations enhanced the mean passage across the BBB model of curcumin, NAC and DFO by 49%, 28% and 49%, respectively (p < 0.01, n = 6). Live cell mitochondrial staining analysis showed consistent co-location of the nanocarriers within the mitochondria. P68 + DQA nanocarriers also increased the ability of curcumin and NAC, alone or combined with DFO, to protect against rotenone induced cytotoxicity and oxidative stress by up to 19% and 14% (p < 0.01, n = 6), as measured by the MTT and mitochondrial hydroxyl radical assays respectively. These results indicate that the P68 + DQA nanocarriers were successful at enhancing the protective effects of curcumin, NAC and/or DFO by increasing the brain penetrance and targeted delivery of the associated bioactives to the mitochondria in this model. This study thus emphasises the potential effectiveness of this nanocarrier strategy in fully utilising the therapeutic benefit of these antioxidants and lays the foundation for further studies in more advanced models of PD.}, } @article {pmid36670939, year = {2022}, author = {Campesi, I and Brunetti, A and Capobianco, G and Galistu, A and Montella, A and Ieri, F and Franconi, F}, title = {Sex Differences in X-ray-Induced Endothelial Damage: Effect of Taurine and N-Acetylcysteine.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36670939}, issn = {2076-3921}, abstract = {Ionizing radiation (IR) can induce some associated pathological conditions due to numerous cell damages. The influence of sex is scarcely known, and even less known is whether the effect of antioxidants is sex-dependent. Given the increased use of IR, we investigated whether male human umbilical vein endothelial cells (MHUVECs) and female human umbilical vein endothelial cells (FHUVECs) respond differently to IR exposure and whether the antioxidants 10 mM taurine (TAU) and 5 mM N-acetylcysteine (NAC) can prevent IR-induced damage in a sex-dependent way. In untreated cells, sex differences were observed only during autophagy, which was higher in FHUVECs. In non-irradiated cells, preincubation with TAU and NAC did not modify viability, lactate dehydrogenase (LDH) release, migration, or autophagy, whereas only NAC increased malondialdehyde (MDA) levels in FHUVECs. X-ray irradiation increased LDH release and reduced viability and migration in a sex-independent manner. TAU and NAC did not affect viability while reduced LDH release in irradiated cells: they have the same protective effect in FHUVECs, while, TAU was more protective than NAC in male cells.. Moreover, TAU and NAC significantly promoted the closure of wounds in both sexes in irradiated cells, but NAC was more effective at doing this in FHUVECs. In irradiated cells, TAU did not change autophagy, while NAC attenuated the differences between the sexes. Finally, NAC significantly decreased MDA in MHUVECs and increased MDA in FHUVECs. In conclusion, FHUVECs appear to be more susceptible to IR damage, and the effects of the two antioxidants present some sex differences, suggesting the need to study the influence of sex in radiation mitigators.}, } @article {pmid36670915, year = {2022}, author = {Lemminger, AK and Fiorenza, M and Eibye, K and Bangsbo, J and Hostrup, M}, title = {High-Intensity Exercise Training Alters the Effect of N-Acetylcysteine on Exercise-Related Muscle Ionic Shifts in Men.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36670915}, issn = {2076-3921}, abstract = {This study investigated whether high-intensity exercise training alters the effect of N-acetylcysteine (a precursor of antioxidant glutathione) on exercise-related muscle ionic shifts. We assigned 20 recreationally-active men to 6 weeks of high-intensity exercise training, comprising three weekly sessions of 4-10 × 20-s all-out bouts interspersed by 2 min recovery (SET, n = 10), or habitual lifestyle maintenance (n = 10). Before and after SET, we measured ionic shifts across the working muscle, using leg arteriovenous balance technique, during one-legged knee-extensor exercise to exhaustion with and without N-acetylcysteine infusion. Furthermore, we sampled vastus lateralis muscle biopsies for analyses of metabolites, mitochondrial respiratory function, and proteins regulating ion transport and antioxidant defense. SET lowered exercise-related H[+], K[+], lactate[-], and Na[+] shifts and enhanced exercise performance by ≈45%. While N-acetylcysteine did not affect exercise-related ionic shifts before SET, it lowered H[+], HCO3[-], and Na[+] shifts after SET. SET enhanced muscle mitochondrial respiratory capacity and augmented the abundance of Na[+]/K[+]-ATPase subunits (α1 and β1), ATP-sensitive K[+] channel subunit (Kir6.2), and monocarboxylate transporter-1, as well as superoxide dismutase-2 and glutathione peroxidase-1. Collectively, these findings demonstrate that high-intensity exercise training not only induces multiple adaptations that enhance the ability to counter exercise-related ionic shifts but also potentiates the effect of N-acetylcysteine on ionic shifts during exercise.}, } @article {pmid36670802, year = {2023}, author = {Zhang, Y and Tian, J and Wang, C and Wu, T and Yi, D and Wang, L and Zhao, D and Hou, Y}, title = {N-Acetylcysteine Administration Improves the Redox and Functional Gene Expression Levels in Spleen, Mesenteric Lymph Node and Gastrocnemius Muscle in Piglets Infected with Porcine Epidemic Diarrhea Virus.}, journal = {Animals : an open access journal from MDPI}, volume = {13}, number = {2}, pages = {}, pmid = {36670802}, issn = {2076-2615}, support = {32172763//National Natural Science Foundation of China/ ; 32072762//National Natural Science Foundation of China/ ; }, abstract = {Our previous study reported that N-acetylcysteine (NAC) administration improved the function of intestinal absorption in piglets infected with porcine epidemic diarrhea virus (PEDV). However, the effects of NAC administration on the functions of other tissues and organs in PEDV-infected piglets have not been reported. In this study, the effects of NAC on the liver, spleen, lung, lymph node, and gastrocnemius muscle in PEDV-infected piglets were investigated. Thirty-two 7-day-old piglets with similar body weights were randomly divided into one of four groups: Control group, NAC group, PEDV group, and PEDV+NAC group (eight replicates per group and one pig per replicate). The trial had a 2 × 2 factorial design consisting of oral administration of 0 or 25 mg/kg body weight NAC and oral administration of 0 or 1.0 × 10[4.5] TCID50 PEDV. The trial lasted 12 days. All piglets were fed a milk replacer. On days 5-9 of the trial, piglets in the NAC and PEDV + NAC groups were orally administered NAC once a day; piglets in the control and PEDV groups were orally administered the same volume of saline. On day 9 of trial, piglets in the PEDV and PEDV+NAC groups were orally administrated 1.0 × 10[4.5] TCID50 PEDV, and the piglets in the control and NAC groups were orally administrated the same volume of saline. On day 12 of trial, samples, including of the liver, spleen, lung, lymph node, and gastrocnemius muscle, were collected. PEDV infection significantly increased catalase activity but significantly decreased the mRNA levels of Keap1, Nrf2, HMOX2, IFN-α, MX1, IL-10, TNF-α, S100A12, MMP3, MMP13, TGF-β, and GJA1 in the spleens of piglets. NAC administration ameliorated abnormal changes in measured variables in the spleens of PEDV-infected piglets. In addition, NAC administration also enhanced the antioxidant capacity of the mesenteric lymph nodes and gastrocnemius muscles in PEDV-infected piglets. Collectively, these novel results revealed that NAC administration improved the redox and functional gene expression levels in the spleen, mesenteric lymph nodes, and gastrocnemius muscle in PEDV-infected piglets.}, } @article {pmid36670547, year = {2023}, author = {Luo, G and Huang, L and Zhang, Z}, title = {The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {248}, number = {5}, pages = {412-424}, pmid = {36670547}, issn = {1535-3699}, mesh = {Humans ; *Acetaminophen/adverse effects ; Oxidative Stress ; *Chemical and Drug Induced Liver Injury/drug therapy ; Acetylcysteine/therapeutic use ; }, abstract = {Acetaminophen (APAP), a widely used antipyretic and analgesic drug in clinics, is relatively safe at therapeutic doses; however, APAP overdose may lead to fatal acute liver injury. Currently, N-acetylcysteine (NAC) is clinically used as the main antidote for APAP poisoning, but its therapeutic effect remains limited owing to rapid disease progression and the general diagnosis of advanced poisoning. As is well known, APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), and the toxic mechanisms of AIH are complicated. Several cellular processes are involved in the pathogenesis of AIH, including liver metabolism, mitochondrial oxidative stress and dysfunction, sterile inflammation, endoplasmic reticulum stress, autophagy, and microcirculation dysfunction. Mitochondrial oxidative stress and dysfunction are the major cellular events associated with APAP-induced liver injury. Many biomolecules involved in these biological processes are potential therapeutic targets for AIH. Therefore, there is an urgent need to comprehensively clarify the molecular mechanisms underlying AIH and to explore novel therapeutic strategies. This review summarizes the various cellular events involved in AIH and discusses their potential therapeutic targets, with the aim of providing new ideas for the treatment of AIH.}, } @article {pmid36662362, year = {2023}, author = {Zhang, Q and Wang, M and Hu, X and Yan, A and Ho, PL and Li, H and Sun, H}, title = {Gold drugs as colistin adjuvants in the fight against MCR-1 producing bacteria.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {28}, number = {2}, pages = {225-234}, pmid = {36662362}, issn = {1432-1327}, support = {R7070-18//Research Grants Council, University Grants Committee/ ; 17308921//Research Grants Council, University Grants Committee/ ; F-HKU704/19//Research Grants Council, University Grants Committee/ ; 2122-7S04//Research Grants Council, University Grants Committee/ ; Norman//The University of Hong Kong/ ; Cecilia Yip Foundation//The University of Hong Kong/ ; CID-HKU-1-13//Health and Medical Research Fund/ ; 18171042//Health and Medical Research Fund/ ; }, mesh = {*Colistin/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacteria ; Gold/pharmacology ; Drug Resistance, Bacterial/genetics ; Plasmids ; *Escherichia coli Proteins/chemistry ; Microbial Sensitivity Tests ; }, abstract = {The emergence and rapid spread of the mobile colistin resistance gene mcr-1 among bacterial species and hosts significantly challenge the efficacy of "last-line" antibiotic colistin. Previously, we reported silver nitrate and auranofin serve as colistin adjuvants for combating mcr-1-positive bacteria. Herein, we uncovered more gold-based drugs and nanoparticles, and found that they exhibited varying degree of synergisms with colistin on killing mcr-1-positive bacteria. However, pre-activation of the drugs by either glutathione or N-acetyl cysteine, thus releasing and accumulating gold ions, is perquisite for their abilities to substitute zinc cofactor from MCR-1 enzyme. X-ray crystallography and biophysical studies further supported the proposed mechanism. This study not only provides basis for combining gold-based drugs and colistin for combating mcr-1-positive bacterial infections, but also undoubtedly opens a new horizon for metabolism details of gold-based drugs in overcoming antimicrobial resistance.}, } @article {pmid36652130, year = {2023}, author = {Xu, H and Shen, X and Li, X and Yang, X and Chen, C and Luo, D}, title = {The natural product dehydrocurvularin induces apoptosis of gastric cancer cells by activating PARP-1 and caspase-3.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {28}, number = {3-4}, pages = {525-538}, pmid = {36652130}, issn = {1573-675X}, mesh = {Humans ; Apoptosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; *Stomach Neoplasms/drug therapy/genetics ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Caspase 3/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Apoptosis Inducing Factor/genetics/metabolism ; *Antineoplastic Agents/pharmacology ; }, abstract = {The natural product dehydrocurvularin (DSE2) is a fungal-derived macrolide with potent anticancer activity, but the mechanism is still unclear. We found that DSE2 effectively inhibited the growth of gastric cancer cells and induced the apoptosis by activating Poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-3. Pharmacological inhibition and genetic knockdown with PARP-1 or caspase-3 suppressed DSE2-induced apoptosis. PARP-1 was previously reported to be cleaved into fragments during apoptosis. However, PARP-1 was barely cleaved in DSE2-induced apoptosis. DSE2 induced PARP-1 activation as indicated by rapid depletion of NAD[+] and the concomitant formation of poly(ADP-ribosylated) proteins (PARs). Interestingly, the PARP-1 inhibitor (Olaparib) attenuated the cytotoxicity of DSE2. Moreover, the combination of Olaparib and Z-DEVD-FMK (caspase-3 inhibitor) further reduced the cytotoxicity. It has been shown that PARP-1 activation triggers cytoplasm-nucleus translocation of apoptosis-inducing factor (AIF). Caspase-3 inhibitors inhibited PARP-1 activation and suppressed PARP-1-induced AIF nuclear translocation. These results indicated that DSE2-induced caspase-3 activation may occur before PARP-1 activation. The ROS inhibitor, N-acetyl-cysteine, significantly inhibited the activation of caspase-3 and PARP-1, indicating that ROS overproduction contributed to DSE2-induced apoptosis. Using an in vivo approach, we further found that DSE2 significantly inhibited gastric tumor growth and promoted translocation of AIF to the nucleus. In conclusion, DSE2 induces gastric cell apoptosis by activating caspase-3 and PARP-1, and shows potent antitumor activity against human gastric carcinoma in vitro and in vivo.}, } @article {pmid36651429, year = {2023}, author = {Costa, RIDD and Fischer, JMDS and Rasslan, R and Koike, MK and Utiyama, EM and Montero, EFS}, title = {Effects of N-acetylcysteine on the inflammatory response and bacterial translocation in a model of intestinal obstruction and ischemia in rats.}, journal = {Acta cirurgica brasileira}, volume = {37}, number = {12}, pages = {e371204}, pmid = {36651429}, issn = {1678-2674}, mesh = {Rats ; Animals ; Rats, Wistar ; Interleukin-10 ; Acetylcysteine/pharmacology/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Bacterial Translocation ; Saline Solution, Hypertonic/pharmacology ; Ischemia ; Inflammation/drug therapy ; *Intestinal Obstruction ; Resuscitation/methods ; *Shock, Hemorrhagic ; }, abstract = {PURPOSE: To evaluate effect of N-acetylcysteine (NAC) associated with Ringer lactate or hypertonic saline in inflammation and bacterial translocation on experimental intestinal obstruction (IO).

METHODS: Wistar rats was subjected to IO. Six or 24 hours after, rats were subjected to enterectomy and fluid resuscitation: IO, RL (subjected to the same procedures but with fluid resuscitation using Ringer's lactate solution); RLNAC (added NAC to Ringer's solution); and HSNAC (surgical procedure + fluid reposition with 7.5% hypertonic saline and NAC). After 24 h, tissues were collected to cytokines, bacterial translocation, and histological assessments.

RESULTS: In kidney, interleukin-1beta (IL-1beta) was lower in the groups with fluid resuscitation compared to IO group. The RLNAC showed lower levels compared to the RL. Interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and (IFN-gamma) were lower in the treatment groups than in IO. In lung, IL-1beta and IL-6 were lower in RLNAC compared to IO. IL-10 was lower in RL, RLNAC and HSNAC compared to IO. TNF-alpha was higher in HSNAC compared to both RL and RLNAC. Bacterial translocation was observed in all animals of IO group. In kidneys, inflammation and congestion degrees were lower in HSNAC compared to RL. In lungs, inflammation levels were higher in RLNAC compared with the sham group.

CONCLUSIONS: The data indicates that NAC associated with RL can promote a decrease in the inflammatory process in the kidneys and lungs in rats, following intestinal obstruction and ischemia in rats.}, } @article {pmid36647403, year = {2023}, author = {Wakil, A and Niazi, M and Meybodi, MA and Pyrsopoulos, NT}, title = {Emerging Pharmacotherapies in Alcohol-Associated Hepatitis.}, journal = {Journal of clinical and experimental hepatology}, volume = {13}, number = {1}, pages = {116-126}, pmid = {36647403}, issn = {0973-6883}, abstract = {UNLABELLED: The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis.

CONCLUSION: A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.}, } @article {pmid36647192, year = {2023}, author = {Chen, M and Qian, C and Jin, B and Hu, C and Zhang, L and Wang, M and Zhou, B and Zuo, W and Huang, L and Wang, Y}, title = {Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma.}, journal = {Cancer biology & therapy}, volume = {24}, number = {1}, pages = {2162807}, pmid = {36647192}, issn = {1555-8576}, mesh = {Humans ; Animals ; Mice ; *Curcumin/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Cell Line, Tumor ; Cell Death ; Apoptosis ; *Cholangiocarcinoma/drug therapy ; Cell Proliferation ; G2 Phase Cell Cycle Checkpoints ; Bile Ducts, Intrahepatic/metabolism/pathology ; *Bile Duct Neoplasms/drug therapy/pathology ; }, abstract = {Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.}, } @article {pmid36639145, year = {2023}, author = {Moosa, MS and Russomanno, G and Dorfman, JR and Gunter, H and Patel, C and Costello, E and Carr, D and Maartens, G and Pirmohamed, M and Goldring, C and Cohen, K}, title = {Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury.}, journal = {British journal of clinical pharmacology}, volume = {89}, number = {6}, pages = {1844-1851}, pmid = {36639145}, issn = {1365-2125}, support = {MR/L006758/1/MRC_/Medical Research Council/United Kingdom ; MR/M009114/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*MicroRNAs/blood ; *Acetylcysteine/administration & dosage ; *Chemical and Drug Induced Liver Injury/drug therapy ; Administration, Intravenous ; *Acetaminophen/adverse effects ; *Antibiotics, Antitubercular/adverse effects ; Alanine Transaminase/blood ; Humans ; Male ; Female ; Adult ; Placebos ; }, abstract = {AIM: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations.

METHODS: We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions.

RESULTS: We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively).

CONCLUSIONS: miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.}, } @article {pmid36638648, year = {2023}, author = {Silva, BR and Silva, JRV}, title = {Mechanisms of action of non-enzymatic antioxidants to control oxidative stress during in vitro follicle growth, oocyte maturation, and embryo development.}, journal = {Animal reproduction science}, volume = {249}, number = {}, pages = {107186}, doi = {10.1016/j.anireprosci.2022.107186}, pmid = {36638648}, issn = {1873-2232}, mesh = {Animals ; *Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Melatonin/pharmacology ; Resveratrol/pharmacology ; Lycopene/pharmacology ; Quercetin/pharmacology ; Cysteamine/metabolism/pharmacology ; Phycocyanin/metabolism/pharmacology ; In Vitro Oocyte Maturation Techniques/veterinary ; Oxidative Stress ; Oocytes/physiology ; Glutathione/pharmacology ; Acetylcysteine/pharmacology ; Carnitine/metabolism/pharmacology ; Ascorbic Acid/pharmacology ; Embryonic Development ; }, abstract = {In vitro follicle growth and oocyte maturation still has a series of limitations, since not all oocytes matured in vitro have the potential to develop in viable embryos. One of the factors associated with low oocyte quality is the generation of reactive oxygen species (ROS) during in vitro culture. Therefore, this review aims to discuss the role of non-enzymatic antioxidants in the control of oxidative stress during in vitro follicular growth, oocyte maturation and embryonic development. A wide variety of non-enzymatic antioxidants (melatonin, resveratrol, L-ascorbic acid, L-carnitine, N-acetyl-cysteine, cysteamine, quercetin, nobiletin, lycopene, acteoside, mogroside V, phycocyanin and laminarin) have been used to supplement culture media. Some of them, like N-acetyl-cysteine, cysteamine, nobiletin and quercetin act by increasing the levels of glutathione (GSH), while melatonin and resveratrol increase the expression of antioxidant enzymes and minimize oocyte oxidative stress. L-ascorbic acid reduces free radicals and reactive oxygen species. Lycopene positively regulates the expression of many antioxidant genes. Additionally, L-carnitine protects DNA against ROS-induced damage, while acteoside and laminarin reduces the expression of proapoptotic genes. Mogrosides increases mitochondrial function and reduces intracellular ROS levels, phycocyanin reduces lipid peroxidation, and lycopene neutralizes the adverse effects of ROS. Thus, it is very important to know their mechanisms of actions, because the combination of two or more antioxidants with different activities has great potential to improve in vitro culture systems.}, } @article {pmid36636887, year = {2023}, author = {Tanabe, P and Schlenk, D}, title = {Role of Aryl Hydrocarbon Receptor and Oxidative Stress in the Regioselective Toxicities of Hydroxychrysenes in Embryonic Japanese Medaka (Oryzias latipes).}, journal = {Environmental toxicology and chemistry}, volume = {42}, number = {3}, pages = {698-706}, doi = {10.1002/etc.5560}, pmid = {36636887}, issn = {1552-8618}, mesh = {Animals ; Cytochrome P-450 CYP1A1/metabolism ; *Oryzias/metabolism ; Oxidative Stress ; *Polycyclic Aromatic Hydrocarbons/toxicity ; Reactive Oxygen Species ; Receptors, Aryl Hydrocarbon/metabolism ; }, abstract = {Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are environmental contaminants that can be created through oxidation of parent PAHs. Previous studies have found that 2-hydroxychrysene (2-OHCHR) caused anemia in embryonic Japanese medaka whereas 6-hydroxychrysene (6-OHCHR) did not, an example of regioselective toxicity. Anemia was prevented by cytochrome P450 (CYP) inhibition, which reduced the formation of the potential oxidatively active metabolite, 1,2-catechol, from 2-OHCHR. 2-OHCHR has also been found to be a four-fold more potent aryl hydrocarbon receptor (AhR) agonist compared with 6-OHCHR. These findings led us to hypothesize that AhR activation and/or oxidative stress play an important role in 2-OHCHR toxicity. Although treatments with the AhR agonists polychlorinated biphenyl (PCB)126 and 2-methoxychrysene (2-MeOCHR) did not cause significant toxicity, pretreatments with the AhR antagonist, CH-223191, reduced anemia by 97.2 ± 0.84% and mortality by 96.6 ± 0.69%. Aryl hydrocarbon receptor inhibition by the antagonist was confirmed by significant reductions (91.0 ± 9.94%) in induced ethoxyresorufin-O-deethylase activity. Thiobarbituric acid reactive substances concentrations were 32.9 ± 3.56% higher (p < 0.05) in 2-OHCHR treatments at 100 hours postfertilization compared with controls. Staining 2-OHCHR-treated embryos with the reactive oxygen species (ROS) scavenger 2',7'-dichlorofluorescin diacetate revealed 32.6 ± 2.69% of 2-OHCHR-treated embryos exhibiting high concentrations of ROS in caudal tissues, which is a site for embryonic hematopoiesis in medaka. Pretreatment with antioxidants, N-acetylcysteine (NAC) or vitamin E (Vit E) significantly reduced 2-OHCHR-induced anemia (NAC: 80.7 ± 1.12% and Vit E: 99.1 ± 0.43%) and mortality (NAC: 67.1 ± 1.69% and Vit E: 98.9 ± 0.66%). These results indicate that AhR may mediate 2-OHCHR toxicity through canonical signaling by up-regulating CYP1, enhancing the formation of reactive metabolites of 2-OHCHR that generate ROS within caudal hematopoietic tissues, potentially disrupting hematopoiesis, leading to anemia and subsequent mortality. Environ Toxicol Chem 2023;42:698-706. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.}, } @article {pmid36634885, year = {2023}, author = {Tang, Y and Jin, L and Qi, W and Gao, Y and Xie, Y and Xie, X and Lv, J and Jiang, Z and Jiang, H and Fan, C and Yan, J}, title = {N-acetyl-L-cysteine attenuated the toxicity of ZIF-8 on EA.hy926 endothelial cells by wnt/β-catenin pathway.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {88}, number = {}, pages = {105553}, doi = {10.1016/j.tiv.2023.105553}, pmid = {36634885}, issn = {1879-3177}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *beta Catenin/metabolism ; *Endothelial Cells/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Wnt Signaling Pathway ; }, abstract = {As kinds of porous crystalline compounds, zeolitic imidazolate frameworks (ZIFs) have been developed quickly and attracted considerable attention for use in nano drug delivery systems, which raised concerns about cardiovascular disorders. At the present, the cytotoxic mechanism of ZIFs in cardiovascular disorders was still unclear. Our experiment explored the toxicity of ZIF-8, a typical kind of ZIFs, on human EA.hy926 vascular endothelial cells. The cell viability, ROS formation, apoptosis level, inflammatory response level, wound healing ability and atherosclerosis-related indicators of EA.hy926 endothelial cells were analyzed after ZIF-8 treatment. Meanwhile, we evaluated the ability of antioxidant N-Acetyl-L-cysteine (NAC) to attenuate the toxicity of ZIF-8 on EA.hy926 endothelial cells. As results, NAC attenuated ROS formation, cell apoptosis, LDH formation and endothelial dysfunction caused by ZIF-8. As the Wnt/β-catenin pathway was involved in endothelial cell dysfunction, we also studied the expression level of β-catenin and LEF1 in ZIF-8 and/or NAC treated EA.hy926 cells. As expected, ZIF-8 increased the protein expressions of β-catenin and LEF1in the IC50 group, which was significantly inhibited by co-treatment with NAC. Taken together, this study could help improve our understanding about the mechanism of ZIF-8-induced endothelial cells injury and NAC had therapeutic potential in preventing ZIF-8-associated endothelial dysfunction by wnt/β-catenin pathway.}, } @article {pmid36627753, year = {2023}, author = {Paraskevas, T and Kantanis, A and Karalis, I and Michailides, C and Karamouzos, V and Koniari, I and Pierrakos, C and Velissaris, D}, title = {N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis.}, journal = {Romanian journal of internal medicine = Revue roumaine de medecine interne}, volume = {61}, number = {1}, pages = {41-52}, doi = {10.2478/rjim-2023-0001}, pmid = {36627753}, issn = {2501-062X}, mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; Hospitalization ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is a mucolytic agents with anti-inflammatory properties that has been suggested as an adjunctive therapy in patients with COVID-19 pneumonia.

OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate available evidence on the possible beneficial effects of NAC on SARS-CoV-2 infection.

METHODS: In September 2022, we conducted a comprehensive search on Pubmed/Medline and Embase on randomized controlled trials (RCTs) and observational studies on NAC in patients with COVID-19 pneumonia. Study selection, data extraction and risk of bias assessment was performed by two independent authors. RCTs and observational studies were analyzed separately.

RESULTS: We included 3 RCTs and 5 non-randomized studies on the efficacy of NAC in patients with COVID-19, enrolling 315 and 20826 patients respectively. Regarding in-hospital mortality, the summary effect of all RCTs was OR: 0.85 (95% CI: 0.43 to 1.67, I[2]=0%) and for non-randomized studies OR: 1.02 (95% CI: 0.47 to 2.23, I[2]=91%). Need for ICU admission was only reported by 1 RCT (OR: 0.86, 95% CI:0.44-1.69, p=0.66), while all included RCTs reported need for invasive ventilation (OR:0.91, 95% CI:0.54 to 1.53, I[2]=0). Risk of bias was low for all included RCTs, but certainty of evidence was very low for all outcomes due to serious imprecision and indirectness.

CONCLUSION: The certainty of evidence in the included studies was very low, thus recommendations for clinical practice cannot be yet made. For all hard clinical outcomes point estimates in RCTs are close to the line of no effect, while observational studies have a high degree of heterogeneity with some of them suggesting favorable results in patients receiving NAC. More research is warranted to insure that NAC is both effective and safe in patients with COVID-19 pneumonia.}, } @article {pmid36626340, year = {2023}, author = {Safarinejad, MR and Safarinejad, S}, title = {Expression of Concern: Efficacy of Selenium and/or N-Acetyl-Cysteine for Improving Semen Parameters in Infertile Men: A Double-Blind, Placebo Controlled, Randomized Study.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000003113}, doi = {10.1097/JU.0000000000003113}, pmid = {36626340}, issn = {1527-3792}, } @article {pmid36619199, year = {2022}, author = {Ma, J and Liu, X and Wei, Y and Lu, R and Xu, K and Tian, Y and Li, J}, title = {Effective Component Compatibility of Bufei Yishen Formula III Which Regulates the Mucus Hypersecretion of COPD Rats via the miR-146a-5p/EGFR/MEK/ERK Pathway.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2022}, number = {}, pages = {9423435}, pmid = {36619199}, issn = {1741-427X}, abstract = {BACKGROUND: The effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) with 5 ingredients (ginsenoside Rh1, astragaloside, icariin, nobiletin, and paeonol) has been shown to protect against chronic obstructive pulmonary disease (COPD). The present study aimed to observe the effects of ECC-BYF III in a COPD rat model and dissect its potential mechanisms in regulating mucus hypersecretion via the miR-146a-5p/epidermal growth factor receptor (EGFR)/MEK/ERK pathway.

METHODS: COPD model rats were treated with normal saline, ECC-BYF III, or N-acetylcysteine (NAC). Pulmonary function, lung tissue histology with H & E and AB-PAS staining, expression levels of interleukin (IL)-4, IL-6, IL-1β, MUC5AC, MUC5B, and FOXA2 in lung tissues and the mRNA and proteins involved in the miR-146a-5p/EGFR/MEK/ERK pathway were evaluated.

RESULTS: The COPD rats showed a significant decrease in the pulmonary function and serious pathological damage to the lung tissue. ECC-BYF III and NAC significantly improved the ventilation function and small airway pathological damage in the COPD rats. The goblet cells and the expression levels of IL-1β, IL-6, MUC5AC, and MUC5B were increased in the COPD rats and were significantly decreased after ECC-BYF III or NAC intervention. The expression levels of IL-4 and FOXA2 in the COPD rats were markedly decreased and were improved in the ECC-BYF III and NAC groups. ECC-BYF III appeared to have a potent effect in restoring the reduced expression of miR-146a-5p. The increased phosphorylation levels of EGFR, MEK, and ERK1/2 and the protein expression levels of SPDEF in the lungs of COPD rats could be significantly reduced by ECC-BYF III.

CONCLUSIONS: ECC-BYF III has a significant effect in improving the airway mucus hypersecretion in COPD model rats, as well as a protective effect against limited pulmonary function and injured lung histopathology. The protective effect of ECC-BYF III in reducing airway mucus hypersecretion in COPD may involve the miR-146a-5p/EGFR/MEK/ERK pathway.}, } @article {pmid36615764, year = {2022}, author = {Alwadani, AH and Almasri, SA and Aloud, AA and Albadr, NA and Alshammari, GM and Yahya, MA}, title = {The Synergistic Protective Effect of γ-Oryzanol (OZ) and N-Acetylcysteine (NAC) against Experimentally Induced NAFLD in Rats Entails Hypoglycemic, Antioxidant, and PPARα Stimulatory Effects.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615764}, issn = {2072-6643}, support = {GSR//This research was funded by Deanship of scientific research in King Saud University through the initiative of DSR Graduate Students Research Support/ ; }, mesh = {Rats ; Male ; Animals ; *Non-alcoholic Fatty Liver Disease/drug therapy/etiology/prevention & control ; Antioxidants/metabolism ; Acetylcysteine/metabolism ; PPAR alpha/genetics/metabolism ; Hypoglycemic Agents/pharmacology ; Liver/metabolism ; Diet, High-Fat/adverse effects ; Glucose/metabolism ; }, abstract = {This study estimated that the combined effect of γ-Oryzanol and N-acetylcysteine (NAC) against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats also estimated some of their mechanisms of action. Adult male rats were divided into seven groups (n = 8 each) as control, control + NAC, control + γ-Oryzanol, HFD, HFD + NAC, HFD + γ-Oryzanol, and HFD + NAC + γ-Oryzanol. NAC was administered orally at a final concentration of 200 mg/kg, whereas γ-Oryzanol was added to diets at a concentration of 0.16. All treatments were conducted for 17 weeks and daily. Both NAC and γ-Oryzanol were able to reduce final body weights, fat weights, fasting glucose, fasting insulin, serum, and serum levels of liver function enzymes as well as the inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6), and leptin in HFD-fed rats. They also improved hepatic structure and glucose tolerance, increased adiponectin levels, and reduced serum and hepatic levels of triglycerides (TGs) and cholesterol (CHOL) in these rats. These effects were concomitant with a reduction in the hepatic levels of lipid peroxides (MDA) and serum levels of LDL-C, but also with an increment in the hepatic levels of superoxide dismutase (SOD) and glutathione (GSH). Interestingly, only treatment with γ-Oryzanol stimulated the mRNA levels of proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) in the liver and white adipose tissue (WAT) of rats. Of note, the combination therapy of both drugs resulted in maximum effects and restored almost normal liver structure and basal levels of all the above-mentioned metabolic parameters. In conclusion, a combination therapy of γ-Oryzanol and NAC is an effective therapy to treat NAFLD, which can act via several mechanisms on the liver and adipose tissue.}, } @article {pmid36611912, year = {2022}, author = {Tam, E and Sung, HK and Lam, NH and You, S and Cho, S and Ahmed, SM and Abdul-Sater, AA and Sweeney, G}, title = {Role of Mitochondrial Iron Overload in Mediating Cell Death in H9c2 Cells.}, journal = {Cells}, volume = {12}, number = {1}, pages = {}, pmid = {36611912}, issn = {2073-4409}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; Cell Death ; Mitochondria/metabolism ; Iron/metabolism ; *Iron Overload/metabolism ; }, abstract = {Iron overload (IO) is associated with cardiovascular diseases, including heart failure. Our study's aim was to examine the mechanism by which IO triggers cell death in H9c2 cells. IO caused accumulation of intracellular and mitochondrial iron as shown by the use of iron-binding fluorescent reporters, FerroOrange and MitoFerroFluor. Expression of cytosolic and mitochondrial isoforms of Ferritin was also induced by IO. IO-induced iron accumulation and cellular ROS was rapid and temporally linked. ROS accumulation was detected in the cytosol and mitochondrial compartments with CellROX, DCF-DA and MitoSOX fluorescent dyes and partly reversed by the general antioxidant N-acetyl cysteine or the mitochondrial antioxidant SkQ1. Antioxidants also reduced the downstream activation of apoptosis and lytic cell death quantified by Caspase 3 cleavage/activation, mitochondrial Cytochrome c release, Annexin V/Propidium iodide staining and LDH release of IO-treated cells. Finally, overexpression of MitoNEET, an outer mitochondrial membrane protein involved in the transfer of Fe-S clusters between mitochondrial and cytosol, was observed to lower iron and ROS accumulation in the mitochondria. These alterations were correlated with reduced IO-induced cell death by apoptosis in MitoNEET-overexpressing cells. In conclusion, IO mediates H9c2 cell death by causing mitochondrial iron accumulation and subsequent general and mitochondrial ROS upregulation.}, } @article {pmid36611209, year = {2023}, author = {Liu, Y and She, W and Li, Y and Wang, M and Liu, Y and Ning, B and Xu, T and Huang, T and Wei, Y}, title = {Aa-Z2 triggers ROS-induced apoptosis of osteosarcoma by targeting PDK-1.}, journal = {Journal of translational medicine}, volume = {21}, number = {1}, pages = {7}, pmid = {36611209}, issn = {1479-5876}, mesh = {Humans ; Apoptosis ; *Bone Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; *Osteosarcoma/drug therapy/pathology ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism ; }, abstract = {BACKGROUND: Osteosarcoma (OS) is the most frequent cancer derived from bone, and the prognosis of OS is poor. Metabolic alterations have been previously reported to contribute to the development of OS, and arsenic compounds have been suggested to exhibit strong anti-OS effects. However, few studies have described the therapeutic efficiency of arsenic compounds by targeting metabolism in OS.

METHODS: Here, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo.

RESULTS: Aa-Z2 induced OS cell apoptosis, G2/M phase arrest, and autophagy through the accumulation of reactive oxygen species (ROS). Elevated ROS functioned by promoting the mitochondrial-dependent caspase cascade and attenuating the PI3K/Akt/mTOR signalling pathway. N-acetylcysteine (NAC), a kind of ROS scavenger, could reverse the effects of Aa-Z2 treatment on 143B and HOS cells. Specifically, by targeting pyruvate dehydrogenase kinase 1 (PDK-1), Aa-Z2 induced changes in mitochondrial membrane potential and alterations in glucose metabolism to accumulate ROS. Overexpression of PDK-1 could partially desensitize OS cells to Aa-Z2 treatment. Importantly, Aa-Z2 suppressed tumour growth in our xenograft osteosarcoma model.

CONCLUSION: The study provides new insights into the mechanism of Aa-Z2-related metabolic alterations in OS inhibition, as well as pharmacologic evidence supporting the development of metabolism-targeting therapeutics.}, } @article {pmid36607576, year = {2023}, author = {Wang, W and Li, S and Wang, X and Wang, J and Zhang, Y}, title = {PbO nanoparticles increase the expression of ICAM-1 and VCAM-1 by increasing reactive oxygen species production in choroid plexus.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {14}, pages = {40162-40173}, pmid = {36607576}, issn = {1614-7499}, support = {ZD2020113//Science and Technology Project of Hebei Education Department/ ; H2020209250//Natural Science Foundation of Hebei Province/ ; 82073589//National Natural Science Foundation of China/ ; }, mesh = {*Vascular Cell Adhesion Molecule-1/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Reactive Oxygen Species/metabolism ; Choroid Plexus/metabolism ; Antioxidants/metabolism ; *Nanoparticles ; }, abstract = {PbO nanoparticles (nano-PbO) are widely used in the production of electrode materials, but exposure to them can cause brain damage. The first barrier preventing nano-PbO from entering the brain is the choroid plexus. However, the effect of nano-PbO on the choroid plexus remains unclear. Thus, the purpose of this study was to investigate the effect of nano-PbO exposure on lymphocyte cells infiltration, the adhesion protein of the choroid plexus as well as the role of reactive oxygen species (ROS) during the process. Results showed that nano-PbO exposure increased the percentage of lymphocyte cells in the brain and upregulated the expression of surface adhesion proteins, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in choroid plexus. Meanwhile, nano-PbO treatment also resulted in the increase of intercellular ROS production, and significantly decrease glutathione (GSH) content, glutathione peroxidase (GSH-PX) activity, and superoxide dismutase (SOD) activity in Z310 cells beside the increase of ICAM and VCAM-1 expression. Treatment with ROS inhibitor N-acetylcysteine (NAC) significantly downregulated the expression of ICAM-1 and VCAM-1expression. In conclusion, exposure to nano-PbO increases the expression of ICAM-1 and VCAM-1 through oxidative stress, which may contribute to peripheral lymphocyte cells infiltration into the brain.}, } @article {pmid36604630, year = {2023}, author = {Lu, K and Zhou, M and Wang, L and Wang, Y and Tang, H and He, G and Wang, H and Tang, C and He, J and Wang, W and Tang, K and Wang, Y and Deng, Z}, title = {N-Acetyl-L-cysteine facilitates tendon repair and promotes the tenogenic differentiation of tendon stem/progenitor cells by enhancing the integrin α5/β1/PI3K/AKT signaling.}, journal = {BMC molecular and cell biology}, volume = {24}, number = {1}, pages = {1}, pmid = {36604630}, issn = {2661-8850}, support = {CQYC2021059825//Chongqing talents funding/ ; CQYC2021059825//Chongqing talents funding/ ; CQYC2021059825//Chongqing talents funding/ ; 4174DH//National Key Research of China/ ; 4174DH//National Key Research of China/ ; 4174DH//National Key Research of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; cstc2021jcyj-msxmX0137//Chongqing Science & Technology Commission/ ; cstc2021jcyj-msxmX0137//Chongqing Science & Technology Commission/ ; cstc2021jcyj-msxmX0137//Chongqing Science & Technology Commission/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; }, mesh = {Rats ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism ; Integrin alpha5beta1/metabolism ; Acetylcysteine/pharmacology/metabolism ; Integrin alpha5/metabolism/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinase/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Tendons ; Cell Differentiation/genetics ; Stem Cells ; *Tendon Injuries/drug therapy/metabolism ; }, abstract = {BACKGROUND: Tendon injury is associated with oxidative stress, leading to reactive oxygen species (ROS) production and inflammation. N-acetyl-L-cysteine (NAC) is a potent antioxidant. However, how NAC affects the biological functions of tendon stem/progenitor cells (TSPCs) and tendon repair has not been clarified. METHOD: The impacts of NAC on the viability, ROS production, and differentiation of TSPCs were determined with the cell counting kit-8, fluorescence staining, Western blotting, and immunofluorescence. The effect of NAC on gene transcription in TSPCs was analyzed by transcriptomes and bioinformatics and validated by Western blotting. The potential therapeutic effect of NAC on tendon repair was tested in a rat model of Achilles tendon injury.

RESULTS: Compared with the untreated control, treatment with 500 µM NAC greatly promoted the proliferation of TSPCs and significantly mitigated hydrogen peroxide-induced ROS production and cytotoxicity in vitro. NAC treatment significantly increased the relative protein expression of collagen type 1 alpha 1 (COL1A1), tenascin C (TNC), scleraxis (SCX), and tenomodulin (TNMD) in TPSCs. Bioinformatics analyses revealed that NAC modulated transcriptomes, particularly in the integrin-related phosphoinositide 3-kinase (PI3K)/AKT signaling, and Western blotting revealed that NAC enhanced integrin α5β1 expression and PI3K/AKT activation in TSPCs. Finally, NAC treatment mitigated the tendon injury, but enhanced the protein expression of SCX, TNC, TNMD, and COLIA1 in the injured tissue regions of the rats.

CONCLUSION: NAC treatment promoted the survival and differentiation of TSPCs to facilitate tendon repair after tendon injury in rats. Thus, NAC may be valuable for the treatment of tendon injury.}, } @article {pmid36601378, year = {2022}, author = {Tamagawa, S and Sakai, D and Schol, J and Sako, K and Nakamura, Y and Matsushita, E and Warita, T and Hazuki, S and Nojiri, H and Sato, M and Ishijima, M and Watanabe, M}, title = {N-acetylcysteine attenuates oxidative stress-mediated cell viability loss induced by dimethyl sulfoxide in cryopreservation of human nucleus pulposus cells: A potential solution for mass production.}, journal = {JOR spine}, volume = {5}, number = {4}, pages = {e1223}, pmid = {36601378}, issn = {2572-1143}, abstract = {BACKGROUND: Cell therapy is considered a promising strategy for intervertebral disc (IVD) regeneration. However, cell products often require long-term cryopreservation, which compromises cell viability and potency, thus potentially hindering commercialization and off-the-shelf availability. Dimethyl sulfoxide (DMSO) is a commonly used cryoprotectant, however, DMSO is associated with cytotoxicity and cell viability loss. This study aimed to investigate the effects of DMSO on human nucleus pulposus cells (NPC) and the role of oxidative stress in DMSO-induced cytotoxicity. Furthermore, we examined the potential of antioxidant N-acetylcysteine (NAC) supplementation to mitigate the negative effects of DMSO.

METHODS: NPC were exposed to various concentrations of DMSO with or without a freezing cycle. Cell viability, cell apoptosis and necrosis rates, intracellular reactive oxygen species (ROS) levels, and gene expression of major antioxidant enzymes were evaluated. In addition, NAC was added to cryopreservation medium containing 10% DMSO and its effects on ROS levels and cell viability were assessed.

RESULTS: DMSO concentrations ≤1% for 24 h did not significantly affect the NPC viability, whereas exposure to 5 and 10% DMSO (most commonly used concentration) caused cell viability loss (loss of 57% and 68% respectively after 24 h) and cell death in a dose- and time-dependent manner. DMSO increased intracellular and mitochondrial ROS (1.9-fold and 3.6-fold respectively after 12 h exposure to 10% DMSO) and downregulated gene expression levels of antioxidant enzymes in a dose-dependent manner. Tempering ROS through NAC treatment significantly attenuated DMSO-induced oxidative stress and supported maintenance of cell viability.

CONCLUSIONS: This study demonstrated dose- and time-dependent cytotoxic effects of DMSO on human NPC. The addition of NAC to the cryopreservation medium ameliorated cell viability loss by reducing DMSO-induced oxidative stress in the freeze-thawing cycle. These findings may be useful for future clinical applications of whole cells and cellular products.}, } @article {pmid36597797, year = {2023}, author = {Shahveghar Asl, Z and Parastouei, K and Eskandari, E}, title = {The effects of N-acetylcysteine on ovulation and sex hormones profile in women with polycystic ovary syndrome: a systematic review and meta-analysis.}, journal = {The British journal of nutrition}, volume = {130}, number = {2}, pages = {202-210}, doi = {10.1017/S0007114522003270}, pmid = {36597797}, issn = {1475-2662}, mesh = {Humans ; Female ; *Polycystic Ovary Syndrome/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; Gonadal Steroid Hormones ; Follicle Stimulating Hormone ; Ovulation ; }, abstract = {Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases characterised by unusual levels of sex hormones and dysfunction of the ovaries. The infertility rate is high among patients with PCOS. Unusual hormonal status can lead to the inability of ovaries to release functional and mature follicles. Clinical trials on the effects of N-acetylcysteine (NAC) supplementation on ovulation and sex hormones profile in women with PCOS have been controversial. We performed a systematic review and meta-analysis to evaluate the potential effects of NAC supplementation on ovulation and sex hormones profile. PubMed, Scopus, Embase, Web of Science and Cochrane Central library international databases were searched till September 2021. Meta-analysis was performed using a random-effects approach in case of significant between-study heterogeneity. Eighteen studies, including 2185 participants, were included in the present meta-analysis. NAC significantly reduced total testosterone (TT) levels (standardised mean difference (SMD): −0·25 ng/ml; 95 % CI (−0·39, −0·10); ‘P < 0·001’, I[2] = 53·9 %, P = 0·034) and increased follicle-stimulating hormone (FSH) levels (SMD: 0·39 mg/ml; 95 % CI (0·07, 0·71); P = 0·01, I[2] = 70·9 %, P = 0·002). Oestrogen levels also increased after correcting publication bias. However, no significant effect was observed on the number of follicles, endometrial thickness, progesterone, serum luteinising hormone levels and sex hormone-binding globulin. The results indicated that NAC supplementation decreased TT levels and increased FSH levels. Overall, NAC supplementation might be effective in the improvement of reproductive system function in patients with PCOS.}, } @article {pmid36593372, year = {2023}, author = {Cepaityte, D and Leivaditis, K and Varouktsi, G and Roumeliotis, A and Roumeliotis, S and Liakopoulos, V}, title = {N-Acetylcysteine: more than preventing contrast-induced nephropathy in uremic patients-focus on the antioxidant and anti-inflammatory properties.}, journal = {International urology and nephrology}, volume = {55}, number = {6}, pages = {1481-1492}, pmid = {36593372}, issn = {1573-2584}, mesh = {Humans ; Antioxidants/therapeutic use/pharmacology ; Acetylcysteine/therapeutic use ; Reactive Oxygen Species ; *Kidney Failure, Chronic/therapy/drug therapy ; Oxidative Stress ; *Renal Insufficiency, Chronic/therapy/drug therapy ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Oxidative stress (OS) has been recognized as a pathophysiologic mechanism underlying the development and progression of chronic kidney disease (CKD). OS, which results from the disturbance of balance among pro-oxidants and antioxidants favoring the pro-oxidants, is present even in early CKD and increases progressively along with deterioration of kidney function to end-stage kidney disease (ESKD). In ESKD, OS is further exacerbated mainly due to dialysis procedures per se and predisposes to increased cardiovascular morbidity and mortality. Therefore, since OS plays a pivotal role in the pathogenesis and progression of atherosclerosis in uremic patients, several strategies aiming to ameliorate OS in these patients have been proposed. Among those, N-acetylcysteine (NAC), a thiol-containing antioxidant agent, has attracted special attention due to its pleiotropic functions and beneficial effect in various OS-related entities including paracetamol overdose and prevention of contrast-induced nephropathy. In this review, we present the currently available literature on the antioxidant and anti-inflammatory properties of NAC in CKD, including hemodialysis and peritoneal dialysis.}, } @article {pmid36592900, year = {2023}, author = {Wang, YH and Wang, YQ and Yu, XG and Lin, Y and Liu, JX and Wang, WY and Yan, CH}, title = {Chronic environmental inorganic arsenic exposure causes social behavioral changes in juvenile zebrafish (Danio rerio).}, journal = {The Science of the total environment}, volume = {867}, number = {}, pages = {161296}, doi = {10.1016/j.scitotenv.2022.161296}, pmid = {36592900}, issn = {1879-1026}, mesh = {Humans ; Animals ; Zebrafish/metabolism ; *Arsenic/toxicity/metabolism ; *Arsenicals/metabolism ; Oxidative Stress ; Zebrafish Proteins/metabolism ; *Water Pollutants, Chemical/metabolism ; }, abstract = {Arsenic (As) is a metalloid commonly found worldwide. Environmental As exposure may cause potential health hazards and behavioral changes in humans and animals. However, the effects of environmental As concentrations on social behavior, especially during the juvenile stage, are unclear. In this study, we observed behavioral changes in juvenile zebrafish after 28 days of exposure to inorganic As (NaAsO2 100 and 500 ppb) in water, especially anxiety and social deficits. Additionally, the level of oxidative stress in the zebrafish brain after As treatment increased, the content of dopamine (DA) decreased, and the transcription level of genes involved in DA metabolism with the activity of monoamine oxidase (MAO) increased. Oxidative stress is a recognized mechanism of nerve damage induced by As exposure. The zebrafish were exposed to N-acetylcysteine (NAC) to reduce As exposure-induced oxidative stress. The results showed improvements in social behavior, DA content, MAO activity, and gene transcription in zebrafish. In conclusion, environmental As exposure can induce behavioral abnormalities, such as anxiety and social deficits in zebrafish, which may be caused by As-induced oxidative stress altering gene transcription levels, causing an increase in MAO activity and a decrease in DA.}, } @article {pmid36591540, year = {2022}, author = {LoBianco, FV and Krager, KJ and Johnson, E and Godwin, CO and Allen, AR and Crooks, PA and Compadre, CM and Borrelli, MJ and Aykin-Burns, N}, title = {Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells.}, journal = {Frontiers in toxicology}, volume = {4}, number = {}, pages = {936149}, pmid = {36591540}, issn = {2673-3080}, support = {P20 GM109005/GM/NIGMS NIH HHS/United States ; R01 CA258673/CA/NCI NIH HHS/United States ; T32 GM106999/GM/NIGMS NIH HHS/United States ; }, abstract = {Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC's antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency in vitro. PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC in vitro, the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis.}, } @article {pmid36590525, year = {2022}, author = {Prylutskyy, Y and Nozdrenko, D and Gonchar, O and Prylutska, S and Bogutska, K and Franskevych, D and Hromovyk, B and Scharff, P and Ritter, U}, title = {C60 fullerene attenuates muscle force reduction in a rat during fatigue development.}, journal = {Heliyon}, volume = {8}, number = {12}, pages = {e12449}, pmid = {36590525}, issn = {2405-8440}, abstract = {C60 fullerene (C60) as a nanocarbon particle, compatible with biological structures, capable of penetrating through cell membranes and effectively scavenging free radicals, is widely used in biomedicine. A protective effect of C60 on the biomechanics of fast (m. gastrocnemius) and slow (m. soleus) muscle contraction in rats and the pro- and antioxidant balance of muscle tissue during the development of muscle fatigue was studied compared to the same effect of the known antioxidant N-acetylcysteine (NAC). C60 and NAC were administered intraperitoneally at doses of 1 and 150 mg kg[-1], respectively, daily for 5 days and 1 h before the start of the experiment. The following quantitative markers of muscle fatigue were used: the force of muscle contraction, the level of accumulation of secondary products of lipid peroxidation (TBARS) and the oxygen metabolite H2O2, the activity of first-line antioxidant defense enzymes (superoxide dismutase (SOD) and catalase (CAT)), and the condition of the glutathione system (reduced glutathione (GSH) content and the activity of the glutathione peroxidase (GPx) enzyme). The analysis of the muscle contraction force dynamics in rats against the background of induced muscle fatigue showed, that the effect of C60, 1 h after drug administration, was (15-17)% more effective on fast muscles than on slow muscles. A further slight increase in the effect of C60 was revealed after 2 h of drug injection, (7-9)% in the case of m. gastrocnemius and (5-6)% in the case of m. soleus. An increase in the effect of using C60 occurred within 4 days (the difference between 4 and 5 days did not exceed (3-5)%) and exceeded the effect of NAC by (32-34)%. The analysis of biochemical parameters in rat muscle tissues showed that long-term application of C60 contributed to their decrease by (10-30)% and (5-20)% in fast and slow muscles, respectively, on the 5th day of the experiment. At the same time, the protective effect of C60 was higher compared to NAC by (28-44)%. The obtained results indicate the prospect of using C60 as a potential protective nano agent to improve the efficiency of skeletal muscle function by modifying the reactive oxygen species-dependent mechanisms that play an important role in the processes of muscle fatigue development.}, } @article {pmid36589610, year = {2022}, author = {Heo, YR and Son, CN and Baek, WK and Kim, SH}, title = {Grape seed proanthocyanidin extract induces apoptotic and autophagic cell death in rheumatoid arthritis fibroblast-like synoviocytes.}, journal = {Archives of rheumatology}, volume = {37}, number = {3}, pages = {393-403}, pmid = {36589610}, issn = {2618-6500}, abstract = {OBJECTIVES: In this study, we aimed to evaluate the association between grape seed proanthocyanidin extract (GSPE) and rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs) and to investigate whether GSPE induces cell death in RA-FLSs.

MATERIALS AND METHODS: The FLSs were isolated from RA synovial tissues. Cell viability and cell cycle staging were analyzed using a hemocytometer and flow cytometry. Caspase 3 and poly (ADP-ribose) polymerase (PARP) proteins were analyzed using Western blotting with z-VAD-fmk. Protein LC3 and polyubiquitin-binding protein p62 that were degraded by autophagy were evaluated using Western blotting with 3-methyladenine and chloroquine. Reactive oxygen species (ROS) were also evaluated.

RESULTS: When RA-FLSs were treated with GSPE, cell viability decreased, the number of cells in sub-G1 and G2/M phases increased, and the expression of pro-PARP and pro-caspase 3 proteins decreased in a concentration-dependent manner. This result was offset, when the cells were co-treated with the pan-caspase inhibitor z-VAD-fmk. The reduced cell viability, increased expression of LC3-II protein, and reduced expression of p62 protein with GSPE treatment were offset, when RA-FLSs were co-treated with GSPE and autophagy inhibitors 3-methyladenine and chloroquine. The level of ROS in RA-FLSs treated with GSPE was significantly lower than treatment with N-acetyl-cysteine, a ROS inhibitor.

CONCLUSION: Our study results show that GSPE induces apoptotic and autophagic cell death and inhibites reactive oxygen species in RA-FLSs.}, } @article {pmid36587882, year = {2023}, author = {Behera, J and Pitchiah Kumar, M and Ireen Femela, A and Senguttuvan, G and Ramasamy, MS}, title = {miRNA-15/IL-10Rα axis promotes Kabasura Kudineer (Indian traditional Siddha formulation) induced immunomodulation by suppressing oxidative stress.}, journal = {Journal of ethnopharmacology}, volume = {305}, number = {}, pages = {116032}, doi = {10.1016/j.jep.2022.116032}, pmid = {36587882}, issn = {1872-7573}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; Antioxidants/pharmacology/metabolism ; Interleukin-6/metabolism ; Lipopolysaccharides/pharmacology ; Nitric Oxide/metabolism ; Inflammation ; Oxidative Stress ; Anti-Inflammatory Agents/pharmacology ; Glutathione/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Kabasura Kudineer (KK), the traditional Indian medicine of Siddha, effectively manages common respiratory symptoms such as flu, cold, and fever. However, there is no evidence of the immunomodulatory capacity of KK in the cultured Jurkat T-lymphocytes under the LPS insult studied.

AIM OF THE STUDY: Assess the effect of the traditional Indian medicine of Siddha, Kabasura Kudineer (KK) on immunomodulation by suppressing oxidative damage in cultured Jurkat T cells in vitro. The miRNA activity on anti-inflammatory gene receptors and cellular nitric oxide levels also was studied.

MATERIALS AND METHODS: Jurkat T cells were exposed to LPS treatment in the presence or absence of KK. Cell viability and nitric oxide (NO) were measured with MTT and Griess assay. Cellular antioxidant systems (glutathione and SOD) were determined using glutathione and SOD assay. Lipid peroxidation was measured using an MDA assay. MiRNA-15a-5p expression was performed using microRNA qPCR Assays. Both inflammatory and anti-inflammatory genes (IL-6, IL-1, IL-10, IL-13) were performed using a qPCR and ELISA assay.

RESULTS: The data showed that reduced cell proliferation and exaggerated NO production was observed in LPS treated condition compared to the control condition. Further, LPS treatment increased lipid peroxidation and reduced antioxidant enzyme activities (SOD and glutathione) in cultured Jurkat T cells. However, treatment with KK or N-acetyl cysteine (NAC; antioxidant) treatment mitigates the above effect. Mechanistically, LPS-induced oxidative stress upregulated miR- 15-5p expression and suppressed IL-10 Receptor alpha (IL-10Rα) by binding to its 3'-UTR region. The deregulated expression of IL-10Rα expression leads to increased IL-6 and IL-1β expression in LPS-induced Jurkat T cells; however, treatment with KK or NAC reversed the above effects.

CONCLUSION: Collectively, our study revealed the previously undefined mechanistic role of Kabasura Kudineer (KK) that alleviates the LPS-induced oxidative damage associated with inflammation by inhibiting the miRNA-15-5p/IL-10Rα axis.}, } @article {pmid36586713, year = {2023}, author = {Huang, D and Wang, Y and Xiao, J and Wang, Y and Zhu, X and Xu, B and Wang, M}, title = {Scavenging of reactive oxygen species effectively reduces Pseudomonas aeruginosa biofilms through disrupting policing.}, journal = {Environmental research}, volume = {220}, number = {}, pages = {115182}, doi = {10.1016/j.envres.2022.115182}, pmid = {36586713}, issn = {1096-0953}, mesh = {Reactive Oxygen Species/metabolism ; *Anti-Bacterial Agents/pharmacology ; *Pseudomonas aeruginosa/genetics ; Biofilms ; Drug Resistance, Microbial ; Acetylcysteine/pharmacology ; }, abstract = {Biofilm formation is likely to contribute greatly to antibiotic resistance in bacteria and therefore the efficient removal of bacterial biofilms needs addressing urgently. Here, we reported that the supplement of non-inhibitory concentration of N-acetyl-L-cysteine (NAC), a common reactive oxygen species (ROS) scavenger, can significantly reduce the biomass of mature Pseudomonas aeruginosa biofilms (corroborated by crystal violet assay and laser scanning confocal microscopy). 1 mM NAC increased the cheater (ΔlasR mutant) frequency to 89.4 ± 1.5% in the evolved PAO1 after the 15-day treatment. Scavenging of ROS by NAC induced the collapse of P. aeruginosa biofilms, but it did not alter quorum sensing-regulated genes expression (e.g., hcnC and cioAB) and hydrogen cyanide production. The replenishment of public good protease contributed to the recovery of biofilm biomass, indicating the role of disrupting policing in biofilm inhibition. Furthermore, 7 typical ROS scavengers (e.g., superoxide dismutase, catalase and peroxidase, etc.) also effectively inhibited mature P. aeruginosa biofilms. This study demonstrates that scavenging of ROS can promote the selective control of P. aeruginosa biofilms through policing disruption as a targeted biofilm control strategy in complex water environments.}, } @article {pmid36582212, year = {2022}, author = {Chen, X and Malaeb, SN and Pan, J and Wang, L and Scafidi, J}, title = {Editorial: Perinatal hypoxic-ischemic brain injury: Mechanisms, pathogenesis, and potential therapeutic strategies.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1086692}, pmid = {36582212}, issn = {1662-5102}, support = {P50 HD103538/HD/NICHD NIH HHS/United States ; R01 NS099461/NS/NINDS NIH HHS/United States ; R01 NS125653/NS/NINDS NIH HHS/United States ; }, } @article {pmid36577481, year = {2023}, author = {Mancini, L and Paolantoni, M and Schoubben, A and Ricci, M}, title = {Development of spray-dried N-acetylcysteine dry powder for inhalation.}, journal = {International journal of pharmaceutics}, volume = {631}, number = {}, pages = {122550}, doi = {10.1016/j.ijpharm.2022.122550}, pmid = {36577481}, issn = {1873-3476}, mesh = {*Acetylcysteine ; Powders/chemistry ; Leucine/chemistry ; Administration, Inhalation ; Aerosols/chemistry ; *Mannitol/chemistry ; Particle Size ; Dry Powder Inhalers ; }, abstract = {N-acetylcysteine (NAC) has both antioxidant and immunomodulatory activities and has been used as adjuvant therapy in several viral infections. Recently, NAC attracted attention for its possible role in reducing the affinity of the spike protein receptor binding domain to angiotensin-converting enzyme (ACE2) receptors. Since only NAC solutions are available for inhalation, the purpose of the work was to develop a NAC dry powder for inhalation using mannitol or leucine as excipient. The powder was successfully produced using co-spray-drying with leucine. ATR-FTIR analyses evidenced spectral variations ascribed to the formation of specific interactions between NAC and leucine. This effect on the NAC environment was not evident for NAC-mannitol powders, but mannitol was in a different polymorphic form compared to the supplied material. Both the feedstock concentration and the leucine content have an impact on the powder aerodynamic features. In particular, to maximize the respirable fraction, it is preferable to produce the powder starting from a 0.5 % w/v feedstock solution using 33 to 50 % w/w leucine content. The NAC-leucine powder was stable for ten months maintaining NAC content of 50 % (w/w) and about 200 μg of NAC was able to deposit on a transwell insert, useful for future in vitro studies.}, } @article {pmid36567856, year = {2022}, author = {Wei, B and Hao, Z and Zheng, H and Qin, Y and Zhao, F and Shi, L}, title = {Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5888636}, pmid = {36567856}, issn = {1942-0994}, mesh = {Humans ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxides/metabolism ; *Vascular Endothelial Growth Factor A/metabolism ; *Neovascularization, Pathologic/metabolism ; *Angiogenesis Inhibitors/pharmacology ; }, abstract = {Brevilin A (BA), a sesquiterpene lactone isolated from Centipeda minima herb, has been identified to exhibit potent anticancer activity. However, the potential pharmacological effect and mechanism of BA in regulating endothelial cell (EC) angiogenesis, a key event in tumor growth, is poorly understood. In this study, BA was shown to significantly prevent vascular endothelial growth factor (VEGF) induced EC angiogenic capacities in vitro, ex vivo, and in vivo. Subsequent functional assays revealed that BA dose dependently inhibited VEGF-stimulated survival, proliferation, migration, and triggered apoptosis activity in human umbilical vein endothelial cells (HUVECs), as well as suppressed the expression of antiapoptotic protein Bcl-2, increased the expression of proapoptotic protein caspase-3 and Bax, and suppressed PI3K/AKT pathway. Meanwhile, BA was also able to depolarize mitochondrial membranal permeability (MMP), accelerate mitochondrial superoxide accumulation, induce intracellular reactive oxygen species (ROS) production, and decreased intracellular glutathione (GSH) in HUVECs. Furthermore, both mitochondria-specific superoxide scavenger Mito-TEMPOL and broad-spectrum antioxidant N-acetyl-cysteine (NAC) dramatically abolished BA-induced mitochondrial dysfunction and mitochondrial ROS production, causing the reversion of PI3K/AKT pathway and repression of apoptosis, eventually correcting the impaired endothelial behavior in survival, growth, migration, and angiogenesis. Collectively, our data for the first time identified a new mechanism for antiangiogenic effect of BA in vascular EC, one that is based on the regulation of mitochondrial-dependent ROS overproduction.}, } @article {pmid36564154, year = {2023}, author = {Wilkinson, MGL and Moulding, D and McDonnell, TCR and Orford, M and Wincup, C and Ting, JYJ and Otto, GW and Restuadi, R and Kelberman, D and Papadopoulou, C and Castellano, S and Eaton, S and Deakin, CT and Rosser, EC and Wedderburn, LR}, title = {Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis.}, journal = {Annals of the rheumatic diseases}, volume = {82}, number = {5}, pages = {658-669}, pmid = {36564154}, issn = {1468-2060}, support = {18DS03/DH_/Department of Health/United Kingdom ; 085860/WT_/Wellcome Trust/United Kingdom ; 22936/DH_/Department of Health/United Kingdom ; MRF_MRF-057-0001-RG-ROSS-C0797/MRF/MRF/United Kingdom ; 21593/VAC_/Versus Arthritis/United Kingdom ; 14518/VAC_/Versus Arthritis/United Kingdom ; MRF_MRF-159-0006-ELP-MCDO-C0954/MRF/MRF/United Kingdom ; 21992/VAC_/Versus Arthritis/United Kingdom ; 20164/VAC_/Versus Arthritis/United Kingdom ; 21552/VAC_/Versus Arthritis/United Kingdom ; GOSH BRC 18IR33/DH_/Department of Health/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/N003322/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Child ; Humans ; *Dermatomyositis ; Leukocytes, Mononuclear/metabolism ; Monocytes/metabolism ; DNA, Mitochondrial ; *Interferon Type I/metabolism ; Nucleotidyltransferases ; }, abstract = {OBJECTIVES: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).

METHODS: RNA-sequencing was performed on CD4[+], CD8[+], CD14[+] and CD19[+] cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by [13]C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35.

RESULTS: Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC.

CONCLUSIONS: These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.}, } @article {pmid36563924, year = {2023}, author = {Yang, HL and Lin, YA and Pandey, S and Liao, JW and Way, TD and Yeh, YL and Chen, SJ and Hseu, YC}, title = {In vitro and in vivo anti-tumor activity of Antrodia salmonea against twist-overexpressing HNSCC cells: Induction of ROS-mediated autophagic and apoptotic cell death.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {172}, number = {}, pages = {113564}, doi = {10.1016/j.fct.2022.113564}, pmid = {36563924}, issn = {1873-6351}, mesh = {*Head and Neck Neoplasms/drug therapy ; *Apoptosis ; Reactive Oxygen Species/metabolism ; Polyporales ; Autophagy ; Mice ; Animals ; Cell Line, Tumor ; Mice, Nude ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; }, abstract = {Head and neck squamous cell carcinoma (HNSCC) is a relatively common malignancy, characterized by lethal morbidity. Herein, we attempted to investigate the autophagy/apoptosis activities of the submerged fermented broths of Antrodia salmonea (AS) in HNSCC Twist-overexpressing (OECM-1 and FaDu-Twist) cells. AS (0-150 μg/mL) effectively reduced cell viability, colony formation, and downregulated Twist expression in OECM-1 and FaDu-Twist cells compared to FaDu cells. AS- induced apoptosis was mainly associated with activation of caspase-3, PARP cleavage, increased expression of VDAC-1 and disproportionation of Bax/Bcl-2. Annexin V/PI staining suggested late apoptosis induction by AS treatment. AS exhibits enhanced autophagy process mediated via LC3-I/II accumulation, increased acidic vesicular organelles (AVOs) formation and p62/SQSTM1 expression feeding into the apoptotic program. However, pre-treatment with autophagy blockers 3-MA and CQ significantly diminished AS-induced cell death. Additionally, suppression of AS-induced ROS release by treatment with antioxidant N-acetylcysteine (NAC) resulted in reduction of apoptotic and autophagic cell death. In vivo studies strengthened the above observations and showed that AS effectively reduced the tumor volume and tumor weight in OECM-1-xenografted nude mice. This study discovered that Antrodia salmonea exhibits a novel anti-cancer mechanism which could be harnessed as a new potent drug for HNSCC treatment.}, } @article {pmid36563904, year = {2023}, author = {Mohammadi, E and Nikbakht, F and Vazifekhah, S and Babae, JF and Jogataei, MT}, title = {Evaluation the cognition-improvement effects of N-acetyl cysteine in experimental temporal lobe epilepsy in rat.}, journal = {Behavioural brain research}, volume = {440}, number = {}, pages = {114263}, doi = {10.1016/j.bbr.2022.114263}, pmid = {36563904}, issn = {1872-7549}, mesh = {Rats ; Animals ; *Epilepsy, Temporal Lobe/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism ; Maze Learning ; Hippocampus/metabolism ; Cognition ; *Epilepsy/metabolism ; Kainic Acid/pharmacology ; Memory Disorders/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Disease Models, Animal ; }, abstract = {Memory impairment is a critical issue in patients with temporal lobe epilepsy (TLE). Neuronal loss within the hippocampus and recurrent seizures may cause cognitive impairment in TLE. N -acetyl cysteine (NAC) is a sulfur-containing amino acid cysteine that is currently being investigated due to its protective effects on neurodegenerative disorders. NAC was orally administrated at a dose of 100 mg/kg for 8 days (7-day pretreatment and 1-day post-surgery). Neuronal viability, mTOR protein level, and spatial memory were detected in the kainite temporal epilepsy model via Nissl staining, western blot method, and Morris water maze task, respectively. Results showed that NAC delayed seizure activity and ameliorated memory deficit induced by Kainic acid. Histological analysis showed that NAC significantly increased the number of intact neurons in CA3 and hilar areas of the hippocampus following the induction of epilepsy. NAC also modulated the mTOR protein level 5 days after epilepsy compared to the KA-induced group. CONCLUSION: These results suggest that NAC improved memory impairment via anticonvulsant and neuroprotective activity and, in all probability, by lowering the level of mTOR.}, } @article {pmid36558992, year = {2022}, author = {Zhang, T and Xiu, YH and Xue, H and Li, YN and Cao, JL and Hou, WS and Liu, J and Cui, YH and Xu, T and Wang, Y and Jin, CH}, title = {A Mechanism of Isoorientin-Induced Apoptosis and Migration Inhibition in Gastric Cancer AGS Cells.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {12}, pages = {}, pmid = {36558992}, issn = {1424-8247}, support = {2020YFD1001400//National Key Research and Development Project of China/ ; 2019HTY078//Heilongjiang Touyan Innovation Team Program/ ; 2020GSP16//Central Government Supports Local College Reform and Development Fund Talent Training Projects/ ; }, abstract = {Isoorientin (ISO) is a flavonoid compound containing a luteolin structure, which can induce autophagy in some tumor cells. This study investigated the impact of ISO in gastric cancer AGS cells, and performed an experimental analysis on the main signaling pathways and transduction pathways it regulates. CCK-8 assay results showed that ISO reduced the survival rate of gastric cancer AGS cells, but the toxicity to normal cells was minimal. Hoechst 33342/PI double staining assay results showed that ISO induced apoptosis in gastric cancer AGS cells. Further analysis by flow cytometry and Western blot showed that ISO induced apoptosis via a mitochondria-dependent pathway. In addition, the level of reactive oxygen species (ROS) in gastric cancer AGS cells also increased with the extension of the ISO treatment time. However, cell apoptosis was inhibited by preconditioning cells with N-acetylcysteine (NAC). Moreover, ISO arrested the cell cycle at the G2/M phase by increasing intracellular ROS levels. Cell migration assay results showed that ISO inhibited cell migration by inhibiting the expression of p-AKT, p-GSK-3β, and β-catenin and was also related to the accumulation of ROS. These results suggest that ISO-induced cell apoptosis by ROS-mediated MAPK/STAT3/NF-κB signaling pathways inhibited cell migration by regulating the AKT/GSK-3β/β-catenin signaling pathway in gastric cancer AGS cells.}, } @article {pmid36557977, year = {2022}, author = {Huang, J and Wang, J and Song, G and Hu, C and Xu, Z and Chen, Z and Xu, C and Yang, D}, title = {Antiproliferative Evaluation of Novel 4-Imidazolidinone Derivatives as Anticancer Agent Which Triggers ROS-Dependent Apoptosis in Colorectal Cancer Cell.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {24}, pages = {}, pmid = {36557977}, issn = {1420-3049}, support = {cstc2020jcyj-msxmX0595//Natural Science Foundation of Chongqing/ ; KJQN201901331//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; KJZD-K202001302//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; P2021YX05//Scientific Research Foundation of the Chongqing University of Arts and Sciences/ ; KJQN202201330//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; }, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Apoptosis ; *Antineoplastic Agents/pharmacology/therapeutic use ; *Colorectal Neoplasms/drug therapy/metabolism ; }, abstract = {Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide, and more therapies are needed to treat CRC. To discover novel CRC chemotherapeutic molecules, we used a series of previously synthesized novel imidazolidin-4-one derivatives to study their anticancer role in several cancer cell lines. Among these compounds, compound 9r exhibited the best anticancer activity in CRC cell lines HCT116 and SW620. We further investigated the anticancer molecular mechanism of compound 9r. We found that compound 9r induced mitochondrial pathway apoptosis in HCT116 and SW620 cells by inducing reactive oxygen species (ROS) production. Moreover, the elevated ROS generation activated the c-Jun N-terminal kinase (JNK) pathway, which further accelerated apoptosis. N-acetylcysteine (NAC), an antioxidant reagent, suppressed compound 9r-induced ROS production, JNK pathway activation, and apoptosis. Collectively, this research synthesized a series of imidazolidin-4-one derivatives, evaluated their anticancer activity, and explored the molecular mechanism of compound 9r-induced apoptosis in CRC cells. The present results suggest that compound 9r has a potential therapeutic role in CRC. Hence, it deserves further exploration as a lead compound for CRC treatment.}, } @article {pmid36555816, year = {2022}, author = {Kesidou, E and Bitsina, C and Chatzisotiriou, A and Theotokis, P and Dandi, E and Tata, DA and Spandou, E}, title = {N-Acetylcysteine Administration Attenuates Sensorimotor Impairments Following Neonatal Hypoxic-Ischemic Brain Injury in Rats.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555816}, issn = {1422-0067}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Animals, Newborn ; Rats, Sprague-Dawley ; *Hypoxia-Ischemia, Brain/metabolism ; *Brain Injuries/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; Brain/metabolism ; }, abstract = {Hypoxic ischemic (HI) brain injury that occurs during neonatal period has been correlated with severe neuronal damage, behavioral deficits and infant mortality. Previous evidence indicates that N-acetylcysteine (NAC), a compound with antioxidant action, exerts a potential neuroprotective effect in various neurological disorders including injury induced by brain ischemia. The aim of the present study was to investigate the role of NAC as a potential therapeutic agent in a rat model of neonatal HI brain injury and explore its long-term behavioral effects. To this end, NAC (50 mg/kg/dose, i.p.) was administered prior to and instantly after HI, in order to evaluate hippocampal and cerebral cortex damage as well as long-term functional outcome. Immunohistochemistry was used to detect inducible nitric oxide synthase (iNOS) expression. The results revealed that NAC significantly alleviated sensorimotor deficits and this effect was maintained up to adulthood. These improvements in functional outcome were associated with a significant decrease in the severity of brain damage. Moreover, NAC decreased the short-term expression of iNOS, a finding implying that iNOS activity may be suppressed and that through this action NAC may exert its therapeutic action against neonatal HI brain injury.}, } @article {pmid36555541, year = {2022}, author = {Matsuura, T and Komatsu, K and Ogawa, T}, title = {N-Acetyl Cysteine-Mediated Improvements in Dental Restorative Material Biocompatibility.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555541}, issn = {1422-0067}, mesh = {Humans ; *Acetylcysteine/metabolism ; *Antioxidants/pharmacology ; Glutathione/metabolism ; Gingiva/metabolism ; Polymers ; Composite Resins/pharmacology ; Materials Testing ; Dental Materials/pharmacology ; }, abstract = {The fibroblast-rich gingival tissue is usually in contact with or adjacent to cytotoxic polymer-based dental restoration materials. The objective of this study was to determine whether the antioxidant amino acid, N-acetyl cysteine (NAC), reduces the toxicity of dental restorative materials. Human oral fibroblasts were cultured with bis-acrylic, flowable composite, bulk-fill composite, self-curing acrylic, and titanium alloy test specimens. Cellular behavior and function were analyzed on and around the materials. Impregnation of the bulk-fill composite and self-curing acrylic with NAC reduced their toxicity, improving the attachment, growth, and function of human oral fibroblasts on and around the materials. These mitigating effects were NAC dose dependent. However, NAC impregnation of the bis-acrylic and flowable composite was ineffective, with no cells attaching to nor around the materials. Although supplementing the culture medium with NAC also effectively improved fibroblast behaviors, direct impregnation of materials with NAC was more effective than supplementing the cultures. NAC-mediated improvements in fibroblast behavior were associated with reduced production of reactive oxygen species and oxidized glutathione together with increased glutathione reserves, indicating that NAC effectively directly scavenged ROS from materials and reinforced the cellular antioxidant defense system. These results establish a proof of concept of NAC-mediated improvements in biocompatibility in the selected dental restorative materials.}, } @article {pmid36553574, year = {2022}, author = {Ji, T and Chen, X and Zhang, Y and Fu, K and Zou, Y and Wang, W and Zhao, J}, title = {Effects of N-Acetylcysteine on the Proliferation, Hormone Secretion Level, and Gene Expression Profiles of Goat Ovarian Granulosa Cells.}, journal = {Genes}, volume = {13}, number = {12}, pages = {}, pmid = {36553574}, issn = {2073-4425}, mesh = {Female ; Animals ; Sheep ; *Transcriptome ; *Acetylcysteine/metabolism ; Goats/genetics ; Granulosa Cells/metabolism ; Cell Proliferation ; Hormones ; RNA, Messenger/metabolism ; }, abstract = {The purpose of this paper was to investigate the effects of N-acetylcysteine (NAC) on the proliferation, hormone secretion, and mRNA expression profiles of ovarian granulosa cells (GCs) in vitro. A total of 12 ovaries from 6 follicular-stage goats were collected for granulosa cell extraction. The optimum concentration of NAC addition was determined to be 200 μM via the Cell Counting Kit 8 (CCK-8) method. Next, GCs were cultured in a medium supplemented with 200 μM NAC (200 μM NAC group) and 0 μ M NAC (control group) for 48 h. The effects of 200 μM NAC on the proliferation of granulosa cells and hormones were studied by 5-ethynyl-2'-deoxyuridine (EdU) assay and enzyme-linked immunosorbent assay (ELISA). mRNA expression was analyzed by transcriptome sequencing. The results indicate that 200 μM NAC significantly increased cell viability and the proportion of cells in the S phase but promoted hormone secretion to a lesser degree. Overall, 122 differentially expressed genes (DEGs) were identified. A total of 51 upregulated and 71 downregulated genes were included. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that the most DEGs were enriched in terms of cell growth regulation, cell growth, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, the cAMP-signaling pathway, and the Wnt-signaling pathway. Seven genes related to granulosa cell proliferation were screened, IGFBP4, HTRA4, SST, SSTR1, WISP1, DAAM2, and RSPO2. The above results provide molecular theoretical support for NAC as a feed additive to improve follicle development and improve reproductive performance in ewes.}, } @article {pmid36550944, year = {2022}, author = {Lee, JH and Park, HJ and Kim, YA and Lee, DH and Noh, JK and Jung, JG and Yoon, HH and Lee, SK and Lee, S}, title = {Establishment of a Serum-Free Hepatocyte Cryopreservation Process for the Development of an "Off-the-Shelf" Bioartificial Liver System.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {9}, number = {12}, pages = {}, pmid = {36550944}, issn = {2306-5354}, support = {Technology Innovation Program (10078349)//the Ministry of Trade, Industry & Energy (MOTIE; Korea)/ ; SMO1220041//Future Medicine 2030 Project of the Samsung Medical center/ ; }, abstract = {To use hepatocytes immediately when necessary for hepatocyte transplantation and bioartificial liver (BAL) systems, a serum-free cryopreservation protocol ensuring the high survival of hepatocytes and maintenance of their functions should be developed. We established a serum-free protocol for the cryopreservation of primary hepatocytes, hepatocyte spheroids, and hepatocyte spheroid beads in liquid nitrogen. The serum-free cryopreservation solutions showed a significantly higher performance in maintaining enhanced viability and ammonia removal, urea secretion, and the albumin synthesis of hepatocyte spheroids and spheroid beads. The serum-free thawing medium, containing human serum albumin (HSA) and N-acetylcysteine (NAC), was compared with a fetal bovine serum-containing thawing medium for the development of a serum-free thawing medium. Our results show that hepatocyte spheroids and spheroid beads thawed using a serum-free thawing medium containing HSA and NAC exhibited increased hepatocyte viability, ammonia removal, urea secretion, and albumin synthesis compared to those thawed using the serum-containing medium. Finally, we evaluated the liver functions of the cryopreserved BAL system-applied serum-free cryopreservation process compared to the fresh BAL system. The ammonia removal efficiency of the cryopreserved hepatocyte spheroids BAL was lower than or similar to that of the fresh BAL system. Additionally, the urea concentrations in the media of all three BAL systems were not significantly different during BAL system operation. This cryopreserved spheroid-based BAL system using a serum-free process will be a good candidate for the treatment of patients.}, } @article {pmid36549672, year = {2023}, author = {Kim, NH and Lee, AY}, title = {Growth Factors Upregulated by Uric Acid Affect Guanine Deaminase-Induced Melanogenesis.}, journal = {Biomolecules & therapeutics}, volume = {31}, number = {1}, pages = {89-96}, pmid = {36549672}, issn = {1976-9148}, abstract = {Uric acid produced by guanine deaminase (GDA) is involved in photoaging and hyperpigmentation. Reactive oxygen species (ROS) generated by uric acid plays a role in photoaging. However, the mechanism by which uric acid stimulates melanogenesis in GDA-overexpressing keratinocytes is unclear. Keratinocyte-derived paracrine factors have been identified as important mechanisms of ultraviolet-induced melanogenesis. Therefore, the role of paracrine melanogenic growth factors in GDA-induced hypermelanosis mediated by uric acid was examined. The relationships between ROS and these growth factors were examined. Primary cultured normal keratinocytes overexpressed with wild type or mutant GDA and those treated with xanthine or uric acid in the presence or absence of allopurinol, H2O2, or N-acetylcysteine (NAC) were used in this study. Intracellular and extracellular bFGF and SCF levels were increased in keratinocytes by wild type, but not by loss-of-function mutants of GDA overexpression. Culture supernatants from GDA-overexpressing keratinocytes stimulated melanogenesis, which was restored by anti-bFGF and anti-SCF antibodies. Allopurinol treatment reduced the expression levels of bFGF and SCF in both GDA-overexpressing and normal keratinocytes exposed to exogenous xanthine; the exogenous uric acid increased their expression levels. H2O2-stimulated tyrosinase expression and melanogenesis were restored by NAC pretreatment. However, H2O2 or NAC did not upregulate or downregulate bFGF or SCF, respectively. Overall, uric acid could be involved in melanogenesis induced by GDA overexpression in keratinocytes via bFGF and SCF upregulation not via ROS generation.}, } @article {pmid36541703, year = {2023}, author = {Demers, ND and Riccio, V and Jo, DS and Bhandari, S and Law, KB and Liao, W and Kim, C and McQuibban, GA and Choe, SK and Cho, DH and Kim, PK}, title = {PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS.}, journal = {Autophagy}, volume = {19}, number = {6}, pages = {1781-1802}, pmid = {36541703}, issn = {1554-8635}, support = {PJT#156196//CIHR/Canada ; }, mesh = {Animals ; Humans ; Mice ; *Macroautophagy ; *Autophagy/physiology ; Reactive Oxygen Species/metabolism ; Leucine/metabolism ; Lysine/metabolism ; Actins/metabolism ; Zebrafish/metabolism ; Fibroblasts/metabolism ; Ubiquitin/metabolism ; Peroxisomes/metabolism ; Amino Acids/metabolism ; Oxygen/metabolism ; Sirolimus ; Membrane Proteins/metabolism ; }, abstract = {Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes are detected and removed from the cell is poorly understood. Recent studies suggest that the peroxisomal matrix protein import machinery may serve double duty as a quality control machinery, where they are directly involved in activating pexophagy. Here, we explored whether any matrix import factors are required to prevent pexophagy, such that their loss designates peroxisomes for degradation. Using gene editing and quantitative fluorescence microscopy on culture cells and a zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes. The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and an increase in peroxisome-dependent reactive oxygen species that coalesce to induce pexophagy. We also found that PEX13 protein level is downregulated to aid in the induction of pexophagy during amino acid starvation. Together, our study points to PEX13 as a novel pexophagy regulator that is modulated to maintain peroxisome homeostasis.Abbreviations: AAA ATPases: ATPases associated with diverse cellular activities; ABCD3: ATP binding cassette subfamily D member; 3ACOX1: acyl-CoA oxidase; 1ACTA1: actin alpha 1, skeletal muscle; ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; CAT: catalase; CQ: chloroquine; Dpf: days post fertilization: FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H2O2: hydrogen peroxide; HA - human influenza hemagglutinin; HBSS: Hanks' Balanced Salt Solution; HCQ; hydroxychloroquine; KANL: lysine alanine asparagine leucine; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYC: MYC proto-oncogene, bHLH transcription factor; MZ: maternal and zygotic; NAC: N-acetyl cysteine; NBR1 - NBR1 autophagy cargo receptor; PBD: peroxisome biogenesis disorder; PBS: phosphate-buffered saline; PEX: peroxisomal biogenesis factor; PTS1: peroxisome targeting sequence 1; RFP: red fluorescent protein; ROS: reactive oxygen speciess; iRNA: short interfering RNA; SKL: serine lysine leucine; SLC25A17/PMP34: solute carrier family 25 member 17; Ub: ubiquitin; USP30: ubiquitin specific peptidase 30.}, } @article {pmid36539667, year = {2023}, author = {Newman, SA and Short, JL and Nicolazzo, JA}, title = {Reduction in ABCG2 mRNA Expression in Human Immortalised Brain Microvascular Endothelial Cells by Ferric Ammonium Citrate is Mediated by Reactive Oxygen Species and Activation of ERK1/2 Signalling.}, journal = {Pharmaceutical research}, volume = {40}, number = {3}, pages = {651-660}, pmid = {36539667}, issn = {1573-904X}, mesh = {Humans ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/metabolism ; ATP-Binding Cassette Transporters/metabolism ; Brain/metabolism ; *Endothelial Cells/metabolism ; *MAP Kinase Signaling System ; Neoplasm Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; RNA, Messenger/genetics/metabolism ; }, abstract = {PURPOSE: The ATP-binding cassette (ABC) transport protein ABCG2 (also known as breast cancer resistance protein (BCRP)) is expressed at the luminal face of the blood-brain barrier (BBB), where it limits the brain uptake of a number of therapeutic drugs. We recently reported that the ABC efflux transporter P-glycoprotein (P-gp) was downregulated in human immortalised brain endothelial (hCMEC/D3) cells treated with ferric ammonium citrate (FAC). The aim of the present study, therefore, was to assess whether BCRP expression is also affected by FAC and identify any signalling mechanisms involved.

METHODS: ABCG2 mRNA was assessed by RT-qPCR. Protein levels of BCRP, phosphorylated extracellular-regulated kinases 1 and 2 (p-ERK1/2) and total ERK 1/2 were assessed by Western blot. Reactive oxygen species (ROS) levels were determined using 2',7'-dichlorofluorescin diacetate.

RESULTS: Treatment of hCMEC/D3 cells with FAC (250 µM, 72 h) significantly reduced ABCG2 mRNA levels (32.2 ± 3.7%) without a concomitant reduction in BCRP protein expression. ABCG2 mRNA levels were restored to control levels when co-treated with the antioxidant N-acetylcysteine (NAC), suggesting the effect of FAC was mediated by a ROS-sensitive pathway. We also found that FAC-treatment was associated with increased levels of p-ERK1/2, suggesting involvement of the ERK1/2 signalling pathway in the observed ABCG2 mRNA downregulation. The ERK1/2 signalling pathway inhibitor U0126 restored p-ERK1/2 levels and partially attenuated the FAC-induced reduction in ABCG2 mRNA.

CONCLUSIONS: This study suggests that FAC-induced downregulation of ABCG2 mRNA is driven by ROS and ERK1/2 signalling, mechanisms which may be exploited to modulate BCRP expression at the BBB.}, } @article {pmid36533744, year = {2022}, author = {Abdelrazik, E and Hassan, HM and Abdallah, Z and Magdy, A and Farrag, EA}, title = {Renoprotective effect of N-acetylcystein and vitamin E in bisphenol A-induced rat nephrotoxicity; Modulators of Nrf2/ NF-κB and ROS signaling pathway.}, journal = {Acta bio-medica : Atenei Parmensis}, volume = {93}, number = {6}, pages = {e2022301}, pmid = {36533744}, issn = {2531-6745}, mesh = {Animals ; Rats ; Male ; *NF-kappa B/metabolism/pharmacology/therapeutic use ; *NF-E2-Related Factor 2/metabolism/pharmacology/therapeutic use ; Reactive Oxygen Species/adverse effects/metabolism ; Vitamin E/adverse effects ; Oxidative Stress ; Signal Transduction ; Inflammation/drug therapy ; }, abstract = {Bisphenol A (BPA) is a chemical product that is widely used as a plastic precursor. It acts directly on the kidney mitochondria, causing renal dysfunction. N-acetylcysteine is effective in protecting the kidneys from chemical-induced damage. Vitamin E is an antioxidant that protects cells from the damaging effects of free radicals. The aim of this study is to further evaluate and compare NAC and vitamin E to oppose the nephrotoxicity caused by BPA.

RESEARCH DESIGN AND METHODS: Forty-two adult male rats were divided into 7 groups:  control, BPA, NAC, vitamin E, BPA plus NAC, BPA plus vitamin E, and combined BPA, NAC and vitamin E. BPA, NAC, vitamin E were given orally at doses of 50 mg/kg, 200 mg/kg, and 1000 mg/kg respectively, for 5 weeks.

RESULTS: NAC and vitamin E groups showed improved kidney function tests and alleviated BPA-induced oxidative stress; increased GSH and decreased MDA, NO and iNOS levels. NAC and vitamin E significantly attenuated inflammation; decreased NF-κB and increased IL-4, and Nrf2, in addition there was alleviation of renal histopathology. To some extent, vitamin E administration showed significant improvement. Moreover, combined NAC and vitamin E treatment showed more significance than either NAC or vitamin E separate groups.

CONCLUSIONS: This study determined the substantial protective effects of NAC and/or vitamin E in BPA-induced nephrotoxicity through modulation of Nrf2 with subsequent improvement of oxidative stress and inflammation. The alleviation was more significant in combined NAC and vitamin E treatment mainly through their synergistic effect on Nrf2.}, } @article {pmid36528076, year = {2023}, author = {Haugsten Hansen, M and Sadredini, M and Hasic, A and Anderson, ME and Sjaastad, I and Korseberg Stokke, M}, title = {CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor.}, journal = {Journal of molecular and cellular cardiology}, volume = {175}, number = {}, pages = {49-61}, doi = {10.1016/j.yjmcc.2022.12.002}, pmid = {36528076}, issn = {1095-8584}, support = {R35 HL140034/HL/NHLBI NIH HHS/United States ; }, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; *Methionine/metabolism ; Mice, Inbred C57BL ; Arrhythmias, Cardiac/metabolism ; Myocytes, Cardiac/metabolism ; Racemethionine/metabolism ; Reperfusion/adverse effects ; Phosphorylation ; }, abstract = {BACKGROUND: Available evidence suggest that Ca[2+]/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing.

METHODS: We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKIIδ by using hearts and cardiomyocytes from mice with CaMKIIδ resistant to oxidation of methionines 281 and 282 (MMVV).

RESULTS: Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca[2+] waves and Ca[2+] sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca[2+]-handling proteins in MMVV and WT hearts.

CONCLUSIONS: Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.}, } @article {pmid36526177, year = {2023}, author = {Shi, X and Xu, T and Cui, W and Qi, X and Xu, S}, title = {Combined negative effects of microplastics and plasticizer DEHP: The increased release of Nets delays wound healing in mice.}, journal = {The Science of the total environment}, volume = {862}, number = {}, pages = {160861}, doi = {10.1016/j.scitotenv.2022.160861}, pmid = {36526177}, issn = {1879-1026}, mesh = {Animals ; Mice ; *Diethylhexyl Phthalate/metabolism/toxicity ; Ecosystem ; *Extracellular Traps/metabolism ; Fibrosis ; Microplastics/metabolism ; *Plasticizers/toxicity/metabolism ; Plastics/metabolism ; *Wound Healing ; }, abstract = {Environmental harmful pollutants microplastics (MPs) and di (2-ethyl) hexyl phthalate (DEHP) are widely residual in the environment, which may cause lesion to multiple apparatus by inducing oxidative stress, threatening the health of human and animals. Neutrophil extracellular traps (Nets) are involved in skin wound healing. Most studies focused on the individual effects of different poisons on animals and ecosystems, but there are few studies on the accumulation and interaction of multiple poisons. The purpose of this study is to explore the effect of DEHP and MPs co-exposure on skin wound healing and the formation of Nets. For this purpose, we detected this hypothesis by replicating the DEHP and MPs-exposed skin wound model in mice, as well as the co-culture system of neutrophil and fibroblast. The results displayed that MPs and DEHP exposure delayed skin healing, which was more pronounced in the combined exposure group. In vitro and in vivo experiments confirmed that compared with the DEHP or MPs group, the DEHP+MPs group had more significant oxidative stress, increased Nets release and inflammatory factors, and inhibited the Wnt/β-catenin pathway and fibrosis-related factors. N-acetylcysteine (NAC) attenuated these phenomena. Through the co-culture system, we confirmed that the overproduction of Nets induced fibroblasts to exacerbate inflammatory responses and inhibit Wnt pathway and fibrosis. Overall, DEHP and MPs can produce synergistic toxic injury in mice skin wounds, and the excessive activation of ROS/Nets can aggravate inflammatory and inhibit fibrosis, resulting in delayed wound healing.}, } @article {pmid36525766, year = {2023}, author = {Xu, H and Du, Y and Wang, Q and Chen, L and Huang, J and Liu, Y and Zhou, C and Du, B}, title = {Comparative efficacy, acceptability, and tolerability of adjunctive anti-inflammatory agents on bipolar disorder: A systemic review and network meta-analysis.}, journal = {Asian journal of psychiatry}, volume = {80}, number = {}, pages = {103394}, doi = {10.1016/j.ajp.2022.103394}, pmid = {36525766}, issn = {1876-2026}, mesh = {Humans ; *Bipolar Disorder/drug therapy ; Network Meta-Analysis ; Anti-Inflammatory Agents/therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal ; Combined Modality Therapy ; }, abstract = {OBJECTIVES: We performed a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents to improve the treatment of bipolar disorder (BD) patients.

METHODS: Four databases (i.e., the Cochrane Library, Web of Science, PubMed, and Embase) were searched for randomized controlled trials (RCTs) published between 1995 and 2022 on the use of anti-inflammatory agents in the treatment of BD. A systematic review and NMA were conducted.

RESULTS: Adjunctive N-acetylcysteine (NAC) was superior to placebo for the treatment of BD according to the endpoint scale score (SMD -0.65, 95% confidence interval (CI): - 0.99 to - 0.31), response rate (odds ratio (OR) 3.42, 95% CI: 1.23-9.52), remission rate (OR 4.94, 95% CI: 1.03-41.38) and surface under the cumulative ranking curve (SUCRA) value of the endpoint scale score (0.84). Adjunctive nonsteroidal anti-inflammatory drugs (NSAIDs) were more favorable than placebo based on the remission rate (OR 3.93, 95% CI: 1.15-13.43) and were significantly more acceptable than other treatments (OR 0.60, 95% CI: 0.36-0.99). Adjunctive coenzyme Q10 (CoQ10) was superior to other agents in terms of the response rate (OR 18.85, 95% CI: 2.63-135.00), with a SUCRA value for the response rate of 0.90 and that for the remission rate of 0.71.

CONCLUSION: Adjunctive NAC is recommended for the treatment of BD. Adjunctive NSAIDs and CoQ10 are still seen as effective, but more high-quality clinical studies are needed to verify their efficacy. Other anti-inflammatory agents may not be recommended for clinical use at present. All anti-inflammatory agents demonstrated a good safety profile. We call for further research on the combined treatment of BD with different anti-inflammatory agents to be included in future trials.}, } @article {pmid36521547, year = {2023}, author = {Ma, F and Li, H and Huo, H and Han, Q and Liao, J and Zhang, H and Li, Y and Pan, J and Hu, L and Guo, J and Tang, Z}, title = {N-acetyl-L-cysteine alleviates FUNDC1-mediated mitophagy by regulating mitochondrial dynamics in type 1 diabetic nephropathy canine.}, journal = {Life sciences}, volume = {313}, number = {}, pages = {121278}, doi = {10.1016/j.lfs.2022.121278}, pmid = {36521547}, issn = {1879-0631}, mesh = {Animals ; Dogs ; Acetylcysteine/pharmacology ; *Diabetes Mellitus ; *Diabetic Nephropathies/pathology ; *Insulins/pharmacology ; Mitochondrial Dynamics ; Mitochondrial Proteins/metabolism ; Mitophagy ; }, abstract = {Diabetic nephropathy (DN) is a major complication of type 1 diabetes mellitus, and hyperglycemia and hypertension are the main risk factors for the development of DN. N-Acetyl-Cysteine (NAC) has a variety of effects, interfering with the production and scavenging of free radicals and regulating the metabolic activity of tissue cells. However, the efficacy of NAC on DN treatment is unclear. Thus, this study investigated the protective mechanism of NAC combined with insulin on renal injury in dogs with DN. The forty dogs were selected and divided into control group, DM group, INS group, INS + NAC group and NAC group to establish the model for a trial period of 4 months. The results revealed that INS + NAC was effective in reducing and stabilizing blood glucose levels. Biochemical results showed that INS + NAC treatment significantly regulated the stability of UREA, CREA and fructosamine indicators. Meanwhile, histopathology staining showed significant glomerular wrinkling and fibrosis in the DM group, which could be reversed after INS + NAC treatment. In addition, INS + NAC could restore mitochondria homeostasis by upregulating the levels of mitochondrial fission (MFN1, MFN2 and OPA1) and inhibiting of mitochondrial fusion (DRP1, FIS1 and MFF) related indicators. Further studies revealed that INS + NAC regulated the expression levels of renal BNIP3, NIX and FUNDC1 in the DM group, thereby alleviating mitophagy. Collectively, these results suggested that NAC combined with insulin protects DN by regulating the mitochondrial dynamics and FUNDC1-mediated mitophagy.}, } @article {pmid36518453, year = {2022}, author = {Henneh, IT and Ahlidja, W and Alake, J and Kwabil, A and Ahmed, MA and Kyei-Asante, B and Adinortey, MB and Ekor, M and Armah, FA}, title = {Ziziphus abyssinica root bark extract ameliorates paracetamol-induced liver toxicity in rats possibly via the attenuation of oxidative stress.}, journal = {Toxicology reports}, volume = {9}, number = {}, pages = {1929-1937}, pmid = {36518453}, issn = {2214-7500}, abstract = {Ziziphus abyssinica root bark is widely used in folk medicine to manage liver diseases, particularly, jaundice but its effect on paracetamol-induced liver toxicity (PILT) has not yet been validated. This study explored the ameliorative effect of ethanolic root bark extract of Ziziphus abyssinica (ZAE) against PILT in rats. The flavonoid and phenolic content of ZAE was evaluated using Folin-Ciocalteau and aluminium trichloride colorimetric methods, respectively. Antioxidant activity of ZAE was determined in vitro by evaluating its ferrous reducing antioxidant capacity (FRAC) as well as DPPH and nitic oxide (NO) radicals scavenging activities. Sprague-Dawley rats were assigned to six groups (n = 6) and administered with normal saline (10 mL/kg, p.o.), N-acetylcysteine (50 mg/kg, i.p.) and ZAE (30, 100, and 300 mg/kg, p.o.) respectively for seven days after which they received paracetamol (PCM, 3000 mg/kg, p.o.). Animals were sacrificed 48 h after paracetamol administration under light anaesthesia and assessed for liver toxicity and oxidative stress. Total flavonoid and phenolic contents of ZAE were 1313.425 µg/mL quercetin equivalence and 268.31 µg/mL gallic acid equivalence respectively. ZAE exhibited marked FRAC as well as DPPH and NO radical scavenging activities with IC50s of 80.41 ± 1.56, 67.56 ± 1.11 and 7.11 ± 1.48 μg/mL respectively. ZAE and N-acetylcysteine significantly (p < 0.05) reduced the paracetamol-mediated elevation of serum total bilirubin, proteins and activity of liver enzymes (AST, ALP, and ALT). Similarly, ZAE increased hepatic glutathione, total thiols and catalase activity of the paracetamol intoxicated rats. Morphological changes associated with the paracetamol hepatotoxicity were also ameliorated by ZAE. Overall, the hepatoprotective effect of ZAE may be related to its antioxidant property.}, } @article {pmid36517965, year = {2023}, author = {Wang, P and Ma, H and Hou, X and Song, L and Feng, M}, title = {N-acetyl-L-cysteine ameliorates gestational diabetes mellitus by inhibiting oxidative stress.}, journal = {Biotechnology and applied biochemistry}, volume = {70}, number = {3}, pages = {1128-1136}, doi = {10.1002/bab.2426}, pmid = {36517965}, issn = {1470-8744}, mesh = {Pregnancy ; Humans ; Female ; Mice ; Animals ; *Diabetes, Gestational/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism/therapeutic use ; Oxidative Stress ; Antioxidants/metabolism ; Inflammation ; }, abstract = {Gestational diabetes mellitus (GDM) is a common pregnant disorder that needs careful medical attention. N-acetyl-L-cysteine (NAC) is a well-recognized antioxidant to treat oxidative stress-induced diseases. Although its role in GDM has been reported, the mechanism remains largely unknown. Therefore, our current study further explored its protective role against GDM. An 8-week-old, db/+, female mice were injected with a single dose of 100 mg/kg streptozotocin (STZ) to induce diabetes. Pregnant mice were randomly treated with 1200 mg/kg NAC or water daily. On gestational day 19, oral glucose tolerance test was performed, and visceral fat tissue and blood samples were collected. After delivery, litter size and weight were recorded. NAC could effectively improve GDM-induced glucose intolerance, hyperlipidemia, activated inflammation, and oxidative stress in GDM mice. Moreover, NAC reduced the litter size and weight of GDM mice. NAC also activated the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in the liver of GDM mice. NAC effectively ameliorated GDM symptoms and the reproductive outcome of GDM mice through inhibiting oxidative stress, inflammation, and hyperlipidemia. Therefore, NAC might serve as a potential candidate drug against GDM.}, } @article {pmid36517743, year = {2022}, author = {Liu, F and Zhang, Y and Shi, Y and Xiong, K and Wang, F and Yang, J}, title = {Ceramide induces pyroptosis through TXNIP/NLRP3/GSDMD pathway in HUVECs.}, journal = {BMC molecular and cell biology}, volume = {23}, number = {1}, pages = {54}, pmid = {36517743}, issn = {2661-8850}, support = {81400058//Jin Yang/ ; }, mesh = {Humans ; *Pyroptosis/genetics ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Ceramides/pharmacology ; Caspase 1/genetics/metabolism/pharmacology ; Human Umbilical Vein Endothelial Cells ; RNA, Messenger/genetics ; Lactate Dehydrogenases/metabolism ; Carrier Proteins ; Phosphate-Binding Proteins/metabolism/pharmacology ; Pore Forming Cytotoxic Proteins/metabolism ; }, abstract = {BACKGROUND: Pyroptosis of endothelial cells is a new cause of endothelial dysfunction in multiple diseases. Ceramide acts as a potential bioactive mediator of inflammation and increases vascular endothelial permeability in many diseases, whether it can aggravate vascular endothelial injury by inducing cell pyroptosis remains unknown. This study was established to explore the effects of C8-ceramide (C8-Cer) on human umbilical vein vascular endothelial cells (HUVECs) and its possible underlying mechanism.

METHODS: HUVECs were exposed to various concentrations of C8-Cer for 12 h, 24 h, 48 h. The cell survival rate was measured using the cell counting kit-8 assay. Western blotting and Real-time polymerase chain reaction (RT-PCR) were used to detect the pyroptosis-releated protein and mRNA expressions, respectively. Caspase-1 activity assay was used to detect caspase-1 activity. Hoechst 33342/propidium iodide double staining and flow cytometry were adopted to measure positive staining of cells. Lactate dehydrogenase release assay and enzyme-linked immunosorbent assay were adopted to measure leakage of cellular contents. FITC method was used to detect the permeability of endothelial cells. ROS fluorescence intensity were detected by flow cytometry.

RESULTS: The viability of HUVECs decreased gradually with the increase in ceramide concentration and time. Ceramide upregulated the expression of thioredoxin interacting protein (TXNIP), NLRP3, GSDMD, GSDMD-NT, caspase-1 and Casp1 p20 at the protein and mRNA level in a dose-dependent manner. It also enhanced the PI uptake in HUVECs and upregulated caspase-1 activity. Moreover, it promoted the release of lactate dehydrogenase, interleukin-1β, and interleukin-18. Meanwhile, we found that ceramide led to increased vascular permeability. The inhibitor of NLRP3 inflammasome assembly, MCC950, was able to disrupt the aforementioned positive loop, thus alleviating vascular endothelial cell damage. Interestingly, inhibition of TXNIP either chemically using verapamil or genetically using small interfering RNA (siRNA) can effectively inhibit ceramide-induced pyroptosis and improved cell permeability. In addition, ceramide stimulated reactive oxygen species (ROS) generation. The pretreatment of antioxidant N-acetylcysteine (NAC), ROS scavenger, blocked the expression of pyroptosis markers induced by C8-cer in HUVECs.

CONCLUSION: The current study demonstrated that C8-Cer could aggravate vascular endothelial cell damage and increased cell permeability by inducing cell pyroptosis. The results documented that the ROS-dependent TXNIP/NLRP3/GSDMD signalling pathway plays an essential role in the ceramide-induced pyroptosis in HUVECs.}, } @article {pmid36514019, year = {2022}, author = {Podolanczuk, AJ and Kim, JS and Cooper, CB and Lasky, JA and Murray, S and Oldham, JM and Raghu, G and Flaherty, KR and Spino, C and Noth, I and Martinez, FJ and , }, title = {Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial.}, journal = {BMC pulmonary medicine}, volume = {22}, number = {1}, pages = {475}, pmid = {36514019}, issn = {1471-2466}, support = {U24 HL145265/HL/NHLBI NIH HHS/United States ; UH3 HL145266/HL/NHLBI NIH HHS/United States ; UH3HL145266/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Double-Blind Method ; Genotype ; *Idiopathic Pulmonary Fibrosis/drug therapy/genetics ; Treatment Outcome ; Vital Capacity ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Clinical Trials, Phase III as Topic ; }, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial.

METHODS: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC.

DISCUSSION: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.}, } @article {pmid36509450, year = {2023}, author = {Ramesh, R and Skog, S and Örkenby, L and Kugelberg, U and Nätt, D and Öst, A}, title = {Dietary Sugar Shifts Mitochondrial Metabolism and Small RNA Biogenesis in Sperm.}, journal = {Antioxidants & redox signaling}, volume = {38}, number = {16-18}, pages = {1167-1183}, pmid = {36509450}, issn = {1557-7716}, mesh = {Male ; Humans ; Animals ; Reactive Oxygen Species/metabolism ; Dietary Sugars/metabolism ; Hydrogen Peroxide/metabolism ; Proteomics ; Semen/metabolism ; Spermatozoa/metabolism ; Mitochondria/metabolism ; *MicroRNAs/genetics/metabolism ; Drosophila/metabolism ; *RNA, Small Untranslated/metabolism ; }, abstract = {Aims: Increasing concentrations of dietary sugar results in a linear accumulation of triglycerides in male Drosophila, while inducing a U-shaped obesity response in their offspring. Here, using a combination of proteomics and small RNA (sRNA) sequencing, we aimed at understanding the molecular underpinning in sperm for such plasticity. Results: Proteomic analysis of seminal vesicles revealed that increasing concentrations of dietary sugar resulted in a bell-shaped induction of proteins involved in metabolic/redox regulation. Using stains and in vivo redox reporter flies, this pattern could be explained by changes in sperm production of reactive oxygen species (ROS), more exactly mitochondria-derived H2O2. By quenching ROS with the antioxidant N-acetyl cysteine and performing sRNA-seq on sperm, we found that sperm miRNA is increased in response to ROS. Moreover, we found sperm mitosRNA to be increased in high-sugar diet conditions (independent of ROS). Reanalyzing our previously published data revealed a similar global upregulation of human sperm mitosRNA in response to a high-sugar diet, suggesting evolutionary conserved mechanisms. Innovation: This work highlights a fast response to dietary sugar in mitochondria-produced H2O2 in Drosophila sperm and identifies redox-sensitive miRNA downstream of this event. Conclusions: Our data support a model where changes in the sperm mitochondria in response to dietary sugar are the primary event, and changes in redox homoeostasis are secondary to mitochondrial ROS production. These data provide multiple candidates for paternal intergenerational metabolic responses as well as potential biomarkers for human male fertility. Antioxid. Redox Signal. 38, 1167-1183.}, } @article {pmid36506010, year = {2022}, author = {Magalhães, LS and Melo, EV and Damascena, NP and Albuquerque, ACB and Santos, CNO and Rebouças, MC and Bezerra, MO and Louzada da Silva, R and de Oliveira, FA and Santos, PL and da Silva, JS and Lipscomb, MW and da Silva, ÂM and de Jesus, AR and de Almeida, RP}, title = {Use of N-acetylcysteine as treatment adjuvant regulates immune response in visceral leishmaniasis: Pilot clinical trial and in vitro experiments.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {1045668}, pmid = {36506010}, issn = {2235-2988}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Adjuvants, Immunologic/therapeutic use ; Immunity ; Interleukin-10 ; *Leishmania infantum ; *Leishmaniasis, Visceral/drug therapy ; Leukocytes, Mononuclear ; }, abstract = {This investigation aimed to assess the effect of N-acetylcysteine (NAC) as an adjuvant treatment to alleviate visceral leishmaniasis (VL). The present work includes both blinded randomized clinical intervention and experimental in vitro studies. The clinical trial included 60 patients with VL randomly allocated into two groups: a test group (n = 30) treated with meglumine antimoniate plus NAC (SbV + NAC) and a control group (n = 30) treated with meglumine antimoniate only (SbV). The primary outcome was clinical cure (absence of fever, spleen and liver sizes reduction, and hematological improvement) in 180 days. The cure rate did not differ between the groups; both groups had similar results in all readout indices. The immunological parameters of the patients treated with SbV + NAC showed higher sCD40L in sera during treatment, and the levels of sCD40L were negatively correlated with Interleukin-10 (IL-10) serum levels. In addition, data estimation showed a negative correlation between the sCD40L levels and the spleen size in patients with VL. For the in vitro experiments, peripheral blood mononuclear cells (PBMCs) or PBMC-derived macrophages from healthy donors were exposed to soluble Leishmania antigen (SLA) or infected with stationary promastigotes of Leishmania infantum in the presence or absence of NAC. Results revealed that NAC treatment of SLA-stimulated PBMCs reduces the frequency of monocytes producing IL-10 and lowers the frequency of CD4+ and CD8+ T cells expressing (pro-)inflammatory cytokines. Together, these results suggest that NAC treatment may modulate the immune response in patients with VL, thus warranting additional investigations to support its case use as an adjuvant to antimony therapy for VL.}, } @article {pmid36502431, year = {2023}, author = {Tüfekci, KK and Bakirhan, EG and Terzi, F}, title = {A Maternal High-Fat Diet Causes Anxiety-Related Behaviors by Altering Neuropeptide Y1 Receptor and Hippocampal Volumes in Rat Offspring: the Potential Effect of N-Acetylcysteine.}, journal = {Molecular neurobiology}, volume = {60}, number = {3}, pages = {1499-1514}, pmid = {36502431}, issn = {1559-1182}, support = {KUBAP01/2021-03//Kastamonu Üniversitesi/ ; }, mesh = {Humans ; Rats ; Animals ; Male ; Female ; Pregnancy ; *Acetylcysteine/pharmacology/therapeutic use ; Diet, High-Fat/adverse effects ; *Obesity, Maternal/metabolism ; Hippocampus/metabolism ; Obesity/complications/drug therapy/metabolism ; Anxiety/complications ; }, abstract = {The children of obese mothers are known to have a high risk of obesity and metabolic disease and are prone to developing cognitive deficits, although the underlying mechanism is not yet fully understood. This study investigated the relationship between neuropeptide Y1 receptor (NPY1R) and anxiety-like behaviors in the hippocampi of male rat offspring exposed to maternal obesity and the potential neuroprotective effects of N-acetylcysteine (NAC). A maternal obesity model was created using a high-fat (60% k/cal) diet. NAC (150 mg/kg) was administered by intragastric gavage for 25 days in both the NAC and obesity + NAC (ObNAC) groups. All male rat offspring were subjected to behavioral testing on postnatal day 28, the end of the experiment. Stereological analysis was performed on hippocampal sections, while NPY1R expression was determined using immunohistochemical methods. Stereological data indicated significant decreases in the total volume of the hippocampus and CA1 and dentate gyrus (DG) regions in the obese (Ob) group (p < 0.01). Decreased NPY1R expression was observed in the Ob group hippocampus (p < 0.01). At behavioral assessments, the Ob group rats exhibited increased anxiety and less social interaction, although the ObNAC group rats exhibited stronger responses than the Ob group (p < 0.01). The study results show that NAC attenuated anxiety-like behaviors and NPY1R expression and also protected hippocampal volume against maternal obesity. The findings indicate that a decrease in NPY1R-positive neurons in the hippocampus of male rats due to maternal conditions may be associated with increased levels of anxiety and a lower hippocampal volume. Additionally, although there is no direct evidence, maintenance of NPY1R expression by NAC may be critical for regulating maternal obesity-induced anxiety-related behaviors and hippocampal structure.}, } @article {pmid36500398, year = {2022}, author = {Słowiński, D and Świerczyńska, M and Romański, J and Podsiadły, R}, title = {HPLC Study of Product Formed in the Reaction of NBD-Derived Fluorescent Probe with Hydrogen Sulfide, Cysteine, N-acetylcysteine, and Glutathione.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {23}, pages = {}, pmid = {36500398}, issn = {1420-3049}, support = {POWR.03.02.00-00-I029/16//National Center for Research and Development (Warsaw, Poland)/ ; }, mesh = {Humans ; *Cysteine ; Fluorescent Dyes ; *Hydrogen Sulfide ; Acetylcysteine ; Optical Imaging ; Glutathione ; Sulfhydryl Compounds ; Homocysteine ; HeLa Cells ; }, abstract = {Hydrogen sulfide (H2S) and its bioderivatives analogs, such as L-cysteine (L-Cys) and glutathione (GSH), are ubiquitous biological thiols in the physiological and pathological processes of living systems. Their aberrant concentration levels are associated with many diseases. Although several NBD-based fluorescence probes have been developed to detect biological thiols, the HPLC-detection of H2S, GSH, L-Cys, and N-acetylcysteine-specific products has not been described. Herein, a novel NBD-derived pro-coumarin probe has been synthesized and used to develop a new strategy for the triple mode detection of H2S and such thiols as GSH, L-Cys, and NAC. Hydrogen sulfide and those biothiols at physiological pH release fluorescent coumarin from the probe and cause a significant fluorescence enhancement at 473 nm. The appropriate NBD-derived product for H2S, L-Cys, GSH, and NAC has a different color and retention time that allows distinguishing these biological thiols meaning the probe has a great possibility in the biological application. Fluorescent imaging combined with colorimetric and HPLC detection of H2S/biothiol-specific product(s) brings a potential tool for confirming the presence of biological thiols and determining concentrations in various aqueous biological samples.}, } @article {pmid36499332, year = {2022}, author = {Feriotto, G and Tagliati, F and Brunello, A and Beninati, S and Tabolacci, C and Mischiati, C}, title = {A Central Contribution of TG2 Activity to the Antiproliferative and Pro-Apoptotic Effects of Caffeic Acid in K562 Cells of Human Chronic Myeloid Leukemia.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36499332}, issn = {1422-0067}, mesh = {Humans ; K562 Cells ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/metabolism ; Imatinib Mesylate/pharmacology/therapeutic use ; Caffeic Acids/pharmacology/therapeutic use ; Apoptosis ; Drug Resistance, Neoplasm ; }, abstract = {Caffeic acid (CA) has shown antitumor activity in numerous solid and blood cancers. We have recently reported that CA is active in reducing proliferation and triggering apoptosis in both Imatinib-sensitive and resistant Chronic Myeloid Leukemia (CML) cells. Tissue transglutaminase type 2 (TG2) enzyme is involved in cell proliferation and apoptosis of numerous types of cancer. However, its activity has different effects depending on the type of tumor. This work investigated the possible involvement of TG2 activation in the triggering of CA-dependent anticancer effects on the K562 cell line, which was studied as a model of CML. CA-dependent changes in TG2 activity were compared with the effects on cell proliferation and apoptosis. The use of N-acetylcysteine (NAC), an antioxidant molecule, suggested that the antiproliferative effect of CA was due to the increase in reactive oxygen species (ROS). The use of a TG2 inhibitor showed that TG2 activity was responsible for the increase in ROS generated by CA and reduced both caspase activation and triggering of CA-dependent apoptosis. The knocking-down of TGM2 transcripts confirmed the crucial involvement of TG2 activation in CML cell death. In conclusion, the data reported, in addition to ascertaining the important role of TG2 activation in the antiproliferative and pro-apoptotic mechanism of CA allowed us to hypothesize a possible therapeutic utility of the molecules capable of triggering the activation pathways of TG2 in the treatment of CML.}, } @article {pmid36498845, year = {2022}, author = {Milara, J and Martínez-Expósito, F and Montero, P and Roger, I and Bayarri, MA and Ribera, P and Oishi-Konari, MN and Alba-García, JR and Zapater, E and Cortijo, J}, title = {N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36498845}, issn = {1422-0067}, support = {PI20/01363//Instituto de Salud Carlos III/ ; PID2020-114871RB-I00//Instituto de Salud Carlos III/ ; CB06/06/0027//Centro de Investigación Biomédica en Red/ ; 2017/023/UV//Generalitat Valenciana/ ; }, mesh = {Humans ; *SARS-CoV-2/metabolism ; Inflammasomes/metabolism ; Acetylcysteine/pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *COVID-19 ; Cytokines ; Recombinant Proteins/pharmacology ; }, abstract = {Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.}, } @article {pmid36498831, year = {2022}, author = {Lee, JW and Cho, JY and Thuy, PX and Moon, EY}, title = {HeLa Cervical Cancer Cells Are Maintained by Nephronophthisis 3-Associated Primary Cilium Formation via ROS-Induced ERK and HIF-1α Activation under Serum-Deprived Normoxic Condition.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36498831}, issn = {1422-0067}, support = {Basic Research Program 2021R1A4A5033289//National Research Foundation of Korea/ ; }, mesh = {Female ; Humans ; Cell Hypoxia ; *Cilia/metabolism ; HeLa Cells ; Hydrogen Peroxide/metabolism ; *Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Kinesins/genetics/metabolism ; }, abstract = {The primary cilium (PC) is a microtubule-based antenna-like organelle projecting from the surface of the cell membrane. We previously reported that PC formation could be regulated by nephronophthisis 3 (NPHP3) expression followed by its interaction with thymosin β4. Here, we investigated whether cancer cell viability is regulated by NPHP3-mediated PC formation. The total and viable cell number were reduced by incubating cells under serum deprivation (SD) without fetal bovine serum (-FBS). PC frequency was increased by SD which enhanced NPHP3 expression and hypoxia inducible factor (HIF)-1α. The role of HIF-1α on NPHP3 expression and PC formation was confirmed by the binding of HIF-1α to the NPHP3 promoter and siRNA-based inhibition of HIF-1α (siHIF-1α), respectively. HIF-1α-stabilizing dimethyloxallyl glycine (DMOG) and hypoxic conditions increased NPHP3 expression and PC formation. In addition, as SD elevated the reactive oxygen species (ROS), PC frequency and NPHP3 expression were inhibited by a treatment with N-acetylcysteine (NAC), a ROS scavenger. PC formation was increased by H2O2 treatment, which was inhibited by siHIF-1α. The inhibition of ERK with P98059 decreased the frequency of PC formation and NPHP3 expression. Cell viability was reduced by a treatment with ciliobrevin A (CilioA) to inhibit PC formation, which was re-affirmed by using PC-deficient IFT88[-/-] cells. Taken together, the results imply that PC formation in cancer cells could be controlled by NPHP3 expression through ROS-induced HIF-1α and ERK activation under SD conditions. It suggests that cancer cell viability under SD conditions could be maintained by NPHP3 expression to regulate PC formation.}, } @article {pmid36497648, year = {2022}, author = {Gorbachev, V and Nikulchev, E and Kosenkov, AN and Sokolov, A and Zavalishin, I and Nikitin, I}, title = {Estimating the Mass of Food Components Necessary for the Utilization of Free Radical Particles in the Human Body.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {23}, pages = {}, pmid = {36497648}, issn = {1660-4601}, mesh = {Humans ; *Human Body ; Free Radicals ; *Diet ; Vitamins ; Ascorbic Acid ; }, abstract = {The article proposes an algorithm for an approximate assessment of the molar volume of free radicals generated in the human body per day. It takes into account the act of breathing, physical activity, food consumption, the influence of unfavorable environmental conditions, exposure to xenobiotics, as well as bad habits (alcohol and tobacco smoking). A calculation of the required set of the most commonly used food products for the disposal of free radicals was made. The calculation is a structure of four blocks with the possibility of adding optional data from human population genetic studies, environmental conditions, etc. In the proposed algorithm, the results of antiradical activity (ARA) of food products are used as input, including the results of predicting antiradical activity using artificial neural networks (ANN), which we published earlier. Based on the accepted values of one equivalent (in terms of the activity of 1 μmol of ascorbic acid), it was shown (for our data) that for the utilization of all free radicals produced in the human body per day, it will take an average of ≈260 to ≈540 g of food components in terms of dry mass (including proteins, fats, carbohydrates, etc.). At the same time, for the utilization of consumed xenobiotics, from 220 mg (in terms of vitamin C) to 260 mg (in terms of acetylcysteine -NAC) of additional plastic components or 11.5-13.0 g of essential amino acids will be required, which must be taken into account when calculating diets. This approach will be useful in the development of new functional foods, as well as in assessing the possible impact of diets on human health. Another applied point of this study is related to the possibility of using these data for better detailing and selection of food products for people working in conditions of increased radiation (in space conditions), in contact with harmful substances (chemical synthesis and production), for people practicing increased physical activity (bodybuilding and sports), and for the purposes of medical nutritional therapy.}, } @article {pmid36497051, year = {2022}, author = {Liu, B and Ding, C and Tang, W and Zhang, C and Gu, Y and Wang, Z and Yu, T and Li, Z}, title = {Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury.}, journal = {Cells}, volume = {11}, number = {23}, pages = {}, pmid = {36497051}, issn = {2073-4409}, support = {81974458, 82170607//National Natural Science Foundation of China/ ; 2021JJ30463, 2022JJ10037//Hunan Provincial Natural Science Foundation of China/ ; 2019RS1042, 2019TP1035//China Hunan Provincial Science/Technology Department/ ; 2022XKQ0205 and KF2022001//Hunan Normal University/ ; }, mesh = {Mice ; Animals ; Macrophage Activation ; Irinotecan/pharmacology ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Hepatocytes/metabolism ; *Fatty Liver/metabolism ; Acetylcysteine/pharmacology ; }, abstract = {Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice.}, } @article {pmid36495185, year = {2023}, author = {Panahi, Y and Ghanei, M and Rahimi, M and Samim, A and Vahedian-Azimi, A and Atkin, SL and Sahebkar, A}, title = {Evaluation the efficacy and safety of N-acetylcysteine inhalation spray in controlling the symptoms of patients with COVID-19: An open-label randomized controlled clinical trial.}, journal = {Journal of medical virology}, volume = {95}, number = {1}, pages = {e28393}, pmid = {36495185}, issn = {1096-9071}, mesh = {Humans ; *Acetylcysteine/administration & dosage/adverse effects ; *COVID-19/therapy ; Length of Stay ; SARS-CoV-2 ; Treatment Outcome ; Administration, Inhalation ; *Oral Sprays ; Nebulizers and Vaporizers ; }, abstract = {The aim of this study was to evaluate the effect and safety of N-acetylcysteine (NAC) inhalation spray in the treatment of patients with coronavirus disease 2019 (COVID-19). This randomized controlled clinical trial study was conducted on patients with COVID-19. Eligible patients (n = 250) were randomly allocated into the intervention group (routine treatment + NAC inhaler spray one puff per 12 h, for 7 days) or the control group who received routine treatment alone. Clinical features, hemodynamic, hematological, biochemical parameters and patient outcomes were assessed and compared before and after treatment. The mortality rate was significantly higher in the control group than in the intervention group (39.2% vs. 3.2%, p < 0.001). Significant differences were found between the two groups (intervention and control, respectively) for white blood cell count (6.2 vs. 7.8, p < 0.001), hemoglobin (12.3 vs. 13.3, p = 0.002), C-reactive protein (CRP: 6 vs. 11.5, p < 0.0001) and aspartate aminotransferase (AST: 32 vs. 25.5, p < 0.0001). No differences were seen for hospital length of stay (11.98 ± 3.61 vs. 11.81 ± 3.52, p = 0.814) or the requirement for intensive care unit (ICU) admission (7.2% vs. 11.2%, p = 0.274). NAC was beneficial in reducing the mortality rate in patients with COVID-19 and inflammatory parameters, and a reduction in the development of severe respiratory failure; however, it did not affect the length of hospital stay or the need for ICU admission. Data on the effectiveness of NAC for Severe Acute Respiratory Syndrome Coronavirus-2 is limited and further research is required.}, } @article {pmid36493885, year = {2023}, author = {Dong, W and Zhang, K and Gong, Z and Luo, T and Li, J and Wang, X and Zou, H and Song, R and Zhu, J and Ma, Y and Liu, G and Liu, Z}, title = {N-acetylcysteine delayed cadmium-induced chronic kidney injury by activating the sirtuin 1-P53 signaling pathway.}, journal = {Chemico-biological interactions}, volume = {369}, number = {}, pages = {110299}, doi = {10.1016/j.cbi.2022.110299}, pmid = {36493885}, issn = {1872-7786}, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Cadmium/toxicity ; Sirtuin 1/metabolism ; Tumor Suppressor Protein p53/metabolism ; Kidney/metabolism ; *Renal Insufficiency, Chronic/chemically induced/drug therapy ; Signal Transduction ; Fibrosis ; Cellular Senescence ; }, abstract = {With the development of modern industrial civilization, cadmium (Cd), a known nephrotoxic metal, has become a growing public safety issue due to its ability to induce various types of kidney disease. Maladaptive proximal tubule repair is a significant cause of Cd-induced chronic kidney disease (CKD), which is characterized by premature senescence and pro-fibrosis. Previously, we demonstrated that cadmium causes DNA damage and cycle arrest in renal tubular epithelial cells, which may be relevant to premature senescence regulated by sirtuin 1 (SIRT1). In this study, in vivo and in vitro studies were conducted to elucidate the role of SIRT1-mediated premature renal senescence in Cd-induced CKD. As oxidative stress is a significant cause of aging, we evaluated whether N-acetylcysteine (NAC) would inhibit Cd-induced premature aging and dysfunction in rat renal tubular epithelial cells. Cadmium induced premature renal senescence and fibrosis, and NAC inhibited premature renal senescence and fibrosis through the SIRT1-P53 pathway and delayed CKD progression. Overall, the results suggested that the SIRT1-P53 pathway mediates oxidative stress, premature renal senescence, and renal fibrosis during cadmium exposure, which may be a potential therapeutic target for Cd-induced CKD.}, } @article {pmid36481977, year = {2022}, author = {Ye, Z and Wang, Q and Dai, S and Ji, X and Cao, P and Xu, C and Bao, G}, title = {The Berberis vulgaris L. extract berberine exerts its anti-oxidant effects to ameliorate cholesterol overloading-induced cell apoptosis in the primary mice hepatocytes: an in vitro study.}, journal = {In vitro cellular & developmental biology. Animal}, volume = {58}, number = {10}, pages = {855-866}, pmid = {36481977}, issn = {1543-706X}, support = {202101AY070001-085//Basic Research Program of Yunnan Science and Technology Department/ ; 2018BS006//The Doctoral Research Fund of First Affiliated Hospital of Kunming Medical University/ ; }, mesh = {Animals ; Mice ; *Antioxidants/pharmacology/metabolism ; *Apoptosis/drug effects ; *Berberine/pharmacology/therapeutic use ; *Berberis/metabolism ; Cardiovascular Diseases/drug therapy ; Cholesterol/metabolism/pharmacology ; Hepatocytes/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Cholesterol overloading stress damages normal cellular functions in hepatocytes and induces metabolic disorders to facilitate the development of multiple diseases, including cardiovascular diseases, which seriously degrades the life quality of human beings. Recent data suggest that the Berberis vulgaris L. extract berberine is capable of regulating cholesterol homeostasis, which is deemed as potential therapeutic drug for the treatment of cholesterol overloading-associated diseases, but its detailed functions and molecular mechanisms are still largely unknown. In the present study, we evidenced that berberine suppressed cell apoptosis in high-cholesterol-diet mice liver and cholesterol-overloaded mice hepatocytes. Also, cholesterol overloading promoted reactive oxygen species (ROS) generation to trigger oxidative damages in hepatocytes, which were reversed by co-treating cells with both berberine and the ROS scavenger N-acetylcysteine (NAC). Moreover, the underlying mechanisms were uncovered, and we validated that berberine downregulated Keap1, and upregulated Nrf2 to activate the anti-oxidant Nrf2/HO-1 signaling pathway in cholesterol overloading-treated hepatocytes, and both Keap1 upregulation and Nrf2 downregulation abrogated the suppressing effects of berberine on cell apoptosis in the hepatocytes with cholesterol exposure. Taken together, we concluded that berberine activated the anti-oxidant Keap1/Nrf2/HO-1 pathway to eliminate cholesterol overloading-induced oxidative stress and apoptotic cell death in mice hepatocytes, and those evidences hinted that berberine might be used as putative therapeutic drug for the treatment of cholesterol overloading-associated cardiovascular diseases.}, } @article {pmid36471531, year = {2023}, author = {Guo, M and Zhang, W and Niu, S and Shang, M and Chang, X and Wu, T and Zhang, T and Tang, M and Xue, Y}, title = {Adaptive regulations of Nrf2 alleviates silver nanoparticles-induced oxidative stress-related liver cells injury.}, journal = {Chemico-biological interactions}, volume = {369}, number = {}, pages = {110287}, doi = {10.1016/j.cbi.2022.110287}, pmid = {36471531}, issn = {1872-7786}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Silver/toxicity ; NF-E2-Related Factor 2/metabolism ; *Metal Nanoparticles/toxicity ; Oxidative Stress ; Acetylcysteine/pharmacology ; Hep G2 Cells ; *Chemical and Drug Induced Liver Injury ; }, abstract = {Silver nanoparticles (AgNPs) are widely used in various fields such as industry, agriculture, and medical care because of their excellent broad-spectrum antibacterial activity. However, their extensive use has raised concerns about their health risks. Liver is one of the main target organs for the accumulation and action of AgNPs. Therefore, evaluating the toxic effects of AgNPs on liver cells and its mechanisms of action is crucial for the safe application of AgNPs. In the study, polyvinylpyrrolidone (PVP)-coated AgNPs were characterized. The human hepatoma cell line (HepG2) and the normal hepatic cell line (L02) were exposed to different concentrations of AgNPs (20-160 μg/mL) and pretreated with the addition of N-acetylcysteine (NAC) or by Nrf2 siRNA transfection. NAC was able to inhibit the concentration-dependent increase in the level of apoptosis induced by AgNPs in HepG2 cells and L02 cells. Interestingly, HepG2 cells were more sensitive to AgNPs than L02 cells, and this may be related to the different ROS generation and responses to AgNPs by cancer cells and normal cells. In addition, NAC also alleviated the imbalance of antioxidant system and cell cycle arrest, which may be related to AgNPs-induced DNA damage and autophagy. The knockdown of nuclear factor erythroid-derived factor 2-related factor (Nrf2) found that AgNPs-induced ROS and apoptosis levels were further upregulated, but the cell cycle arrest was alleviated. On the whole, Nrf2 exerts a protective role in AgNPs-induced hepatotoxicity. This study complements the hepatotoxicity mechanisms of AgNPs and provides data for a future exploration of AgNPs-related anti-hepatocellular carcinoma drugs.}, } @article {pmid36467056, year = {2022}, author = {Elsayed, S and Elsaid, KA}, title = {Protein phosphatase 2A regulates xanthine oxidase-derived ROS production in macrophages and influx of inflammatory monocytes in a murine gout model.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1033520}, pmid = {36467056}, issn = {1663-9812}, abstract = {Background: Gout is a common arthritis, due to deposition of monosodium urate (MSU) crystals which results in IL-1β secretion by tissue-resident macrophages. Xanthine oxidase (XO) catalyzes uric acid (UA) production and in the process, reactive oxygen species (ROS) are generated which contributes to NLRP3 inflammasome activation. Protein phosphatase 2A (PP2A) may be involved in regulating inflammatory pathways in macrophages. The objective of this study was to investigate whether PP2A regulates gout inflammation, mediated by XO activity modulation. We studied UA and ROS generations in MSU stimulated murine bone marrow derived macrophages (BMDMs) in response to fingolimod phosphate, a PP2A activator, and compared its anti-inflammatory efficacy to that of an XO inhibitor, febuxostat. Methods: BMDMs were stimulated with MSU, GM-CSF/IL-1β or nigericin ± fingolimod (2.5 μM) or febuxostat (200 μM) and UA levels, ROS, XO, and PP2A activities, Xdh (XO) expression and secreted IL-1β levels were determined. PP2A activity and IL-1β in MSU stimulated BMDMs ± N-acetylcysteine (NAC) (10 μM) ± okadaic acid (a PP2A inhibitor) were also determined. M1 polarization of BMDMs in response to MSU ± fingolimod treatment was assessed by a combination of iNOS expression and multiplex cytokine assay. The in vivo efficacy of fingolimod was assessed in a murine peritoneal model of acute gout where peritoneal lavages were studied for pro-inflammatory classical monocytes (CMs), anti-inflammatory nonclassical monocytes (NCMs) and neutrophils by flow cytometry and IL-1β by ELISA. Results: Fingolimod reduced intracellular and secreted UA levels (p < 0.05), Xdh expression (p < 0.001), XO activity (p < 0.001), ROS generation (p < 0.0001) and IL-1β secretion (p < 0.0001), whereas febuxostat enhanced PP2A activity (p < 0.05). NAC treatment enhanced PP2A activity and reduced XO activity and PP2A restoration mediated NAC's efficacy as co-treatment with okadaic acid increased IL-1β secretion (p < 0.05). Nigericin activated caspase-1 and reduced PP2A activity (p < 0.001) and fingolimod reduced caspase-1 activity in BMDMs (p < 0.001). Fingolimod reduced iNOS expression (p < 0.0001) and secretion of IL-6 and TNF-α (p < 0.05). Fingolimod reduced CMs (p < 0.0001), neutrophil (p < 0.001) and IL-1β (p < 0.05) lavage levels while increasing NCMs (p < 0.001). Conclusion: Macrophage PP2A is inactivated in acute gout by ROS and a PP2A activator exhibited a broad anti-inflammatory effect in acute gout in vitro and in vivo.}, } @article {pmid36467051, year = {2022}, author = {Liu, M and Hu, T and Gou, W and Chang, H and Li, Y and Li, Y and Zuo, D and Hou, W and Jiao, S}, title = {Exploring the pharmacological mechanisms of icaritin against nasopharyngeal carcinoma via network pharmacology and experimental validation.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {993022}, pmid = {36467051}, issn = {1663-9812}, abstract = {Background: Icaritin is a natural product with a wide range of anti-tumor effects. However, its anti-tumor mechanism has not been thoroughly studied. This study examined the inhibitory effect of icaritin on nasopharyngeal cancer and its underlying mechanism using network pharmacology along with in vivo and in vitro experiments. Methods: MTT and clone formation assays were used to detect the effects of icaritin on the viability and proliferation of nasopharyngeal carcinoma cells, followed by the construction of a HONE1 xenograft tumor model to evaluate the anti-tumor efficacy of icaritin in vivo. A public database was used to predict prospective targets, built a protein-protein interaction (PPI) network, and analyze gene enrichment and biological processes. Based on network pharmacological data, cell cycle-related proteins were identified using western blotting. Besides, cell cycle distribution, apoptosis, and intracellular reactive oxygen species (ROS) generation were identified using flow cytometry. In addition, SA-β-Gal staining was performed to detect cellular senescence, and western blotting was performed to detect the expression of P53, P21, and other proteins to verify key signaling pathways. Results: Icaritin effectively inhibited the viability and proliferation of nasopharyngeal carcinoma cell lines and showed good anti-tumor activity against HONE1 nasopharyngeal carcinoma cells in vivo. Key protein targets, including AKT1, HSP90AA1, CDK4, CCND1, and EGFR, were screened using PPI network topology analysis. GO and KEGG analysis revealed that the cell cycle, p53 signaling, and cell senescence pathways may be the main regulatory pathways. Flow cytometry and western blot experiments showed that icaritin caused S-phase arrest and promoted an increase in ROS. SA-β-Gal staining showed that icaritin significantly induced cellular senescence, and western blotting showed that the expression of senescence-related proteins p53 and P21 increased significantly. Moreover, inhibition of ROS levels by N-Acetylcysteine (NAC) enhanced cell viability, reversed cellular senescence and reduced cellular senescence-associated protein expression. Conclusion: The results of network pharmacological analysis and in vivo and in vitro experiments showed that icaritin effectively inhibited the growth of nasopharyngeal carcinoma cells, promoted ROS production, induced cellular senescence, and inhibited tumor cells, which are related to the regulation of P53/P21 signal pathway.}, } @article {pmid36464114, year = {2023}, author = {Abdallah, S and Jampy, A and Moison, D and Wieckowski, M and Messiaen, S and Martini, E and Campalans, A and Radicella, JP and Rouiller-Fabre, V and Livera, G and Guerquin, MJ}, title = {Foetal exposure to the bisphenols BADGE and BPAF impairs meiosis through DNA oxidation in mouse ovaries.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {317}, number = {}, pages = {120791}, doi = {10.1016/j.envpol.2022.120791}, pmid = {36464114}, issn = {1873-6424}, mesh = {Female ; Mice ; Animals ; *Meiosis ; *Ovary ; Benzhydryl Compounds/toxicity ; DNA ; Aneuploidy ; }, abstract = {Many endocrine disruptors have been proven to impair the meiotic process which is required for the production of healthy gametes. Bisphenol A is emblematic of such disruptors, as it impairs meiotic prophase I and causes oocyte aneuploidy following in utero exposure. However, the mechanisms underlying these deleterious effects remain poorly understood. Furthermore, the increasing use of BPA alternatives raises concerns for public health. Here, we investigated the effects of foetal exposure to two BPA alternatives, bisphenol A Diglycidyl Ether (BADGE) and bisphenol AF (BPAF), on oogenesis in mice. These compounds delay meiosis initiation, increase the number of MLH1 foci per cell and induce oocyte aneuploidy. We further demonstrate that these defects are accompanied by changes in gene expression in foetal premeiotic germ cells and aberrant mRNA splicing of meiotic genes. We observed an increase in DNA oxidation after exposure to BPA alternatives. Specific induction of oxidative DNA damage during foetal germ cell differentiation causes similar defects during oogenesis, as observed in 8-oxoguanine DNA Glycosylase (OGG1)-deficient mice or after in utero exposure to potassium bromate (KBrO3), an inducer of oxidative DNA damage. The supplementation of BPA alternatives with N-acetylcysteine (NAC) counteracts the effects of bisphenols on meiosis. Together, our results propose oxidative DNA lesion as an event that negatively impacts female meiosis with major consequences on oocyte quality. This could be a common mechanism of action for numerous environmental pro-oxidant pollutants, and its discovery, could lead to reconsider the adverse effect of bisphenol mixtures that are simultaneously present in our environment.}, } @article {pmid36459039, year = {2022}, author = {Santus, P and Danzo, F and Zuffi, A and Pini, S and Saad, M and Visconti, A and Radovanovic, D}, title = {Oxidative stress and viral Infections: rationale, experiences, and perspectives on N-acetylcysteine.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {22}, pages = {8582-8590}, doi = {10.26355/eurrev_202211_30395}, pmid = {36459039}, issn = {2284-0729}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress ; *Virus Diseases/drug therapy ; Inflammation ; }, abstract = {This article explores current evidence on the role of oxidative stress in viral infections, and on the use of antioxidant drugs as adjunctive treatment. MEDLINE/PubMed was searched for appropriate keywords, and preclinical and clinical studies with reviews were retrieved and examined by authors. Old and current evidence shows that GSH content reduction is the main mechanism of redox imbalance in viral-infected cells. Clinical studies found that GSH levels are depleted in patients with viral infections such as HIV and SARS-CoV. Viral infections activate inflammation through different pathways, and several of these mechanisms are related to oxidative stress. NAC is a precursor of GSH, and many of its intracellular effects are mediated by GSH replenishment, but it also activates some anti-inflammatory mechanisms. NAC has an excellent safety profile and better oral and topical bioavailability than GSH. These characteristics make NAC a suitable option as a repurposed drug. Adjunctive antioxidant treatment may improve the outcomes of antiviral therapies. Current evidence supports the rationale for this practice and some clinical experience showed encouraging results.}, } @article {pmid36458919, year = {2023}, author = {Amar, SK and Donohue, KB and Gust, KA}, title = {Cellular and molecular responses to ethyl-parathion in undifferentiated SH-SY5Y cells provide neurotoxicity pathway indicators for organophosphorus impacts.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {191}, number = {2}, pages = {285-295}, pmid = {36458919}, issn = {1096-0929}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Parathion/toxicity ; Cell Line, Tumor ; *Neuroblastoma/metabolism ; Apoptosis ; *Neurotoxicity Syndromes/etiology ; Cell Survival ; }, abstract = {High-fidelity nonanimal screening methods are needed that can rapidly and accurately characterize organophosphorus compound (OP)-induced neurotoxicity. Herein, the efficacy of human neuroblastoma cell line (SH-SY5Y) to provide molecular and cellular responses characteristic of the OP neurotoxicity pathway was investigated in response to the OP-model compound, ethyl-parathion. Undifferentiated SH-SY5Y cells were exposed to ethyl-parathion for 30 min at 0 (control), 0.5, 2.5, 5, 10, and 25 µg/ml. Dose-responsive reductions in cell viability were observed with significant reductions at ≥10 µg/ml. From these results, ethyl-parathion exposures of 0 (control), 5, and 10 µg/ml were selected to examine bioindicators underlying the OP neurotoxicity pathway including: reactive oxygen species (ROS), cell membrane peroxidation, mitochondrial membrane potential (MMP), and apoptosis. Ethyl-parathion elicited highly significant increases in ROS relative to controls (p < .01) at both exposure concentrations, confirmed using N-acetyl cysteine (NAC) as a ROS quencher which alleviated ROS increases. A response characteristic of increased ROS exposure, cell membrane-lipid peroxidation, significantly increased (p < .05) at the highest ethyl-parathion exposure (10 µg/ml). As a likely consequence of membrane-lipid peroxidation, ethyl-parathion-induced reductions in MMP were observed with significant effects at 10 µg/ml, reducing MMP by 58.2%. As a culmination of these cellular-damage indicators, apoptosis progression was investigated by phosphatidylserine translocation where ethyl-parathion-induced dose-responsive, highly significant (p < .01) increases at both 5 and 10 µg/ml. Overall, the mechanistic responses observed in undifferentiated SH-SY5Y cells corresponded with in vivo mammalian results demonstrating potential for this nonanimal model to provide accurate OP neurotoxicology screening.}, } @article {pmid36454053, year = {2022}, author = {Palsdottir, A and Snorradottir, AO and Hakonarson, H}, title = {[Did ketogenic diet in past centuries protect against the consequence of the cystatin L68Q mutation in carriers of HCCAA?].}, journal = {Laeknabladid}, volume = {108}, number = {12}, pages = {553-557}, doi = {10.17992/lbl.2022.12.721}, pmid = {36454053}, issn = {1670-4959}, mesh = {Humans ; *Cystatin C/genetics ; *Diet, Ketogenic ; Food ; Glutathione ; Mutation ; *Cerebral Amyloid Angiopathy, Familial/genetics ; }, abstract = {Hereditary cystatin C amyloid angiopathy (HCCAA) is a dominantly inherited disease caused by a mutation (L68Q) in the cystatin C gene, CST3. Mutant cystatin C protein accumulates as amyloid in arterioles in the brain leading to repeated brain hemorrhages and death of young carriers. Recently a possible treatment option was reported for HCCAA carriers involving an oral treatment with N-acetyl-cysteine in order to increase glutathione which was found to dissolve aggregates of mutant cystatin C. An earlier study described how the life span of carriers of the L68Q mutation shortened in the latter half of the 19th century. During the same decades a drastic change occured in the diet in Iceland. In the beginning of the century the diet was simple and low in carbohydrates, which mostly came from milk products. Import of grains and sugar was limited, but increased greatly according to import records. Due to lack of salt, food was preserved in acid whey, but gradually salt replaced whey as means of preserving food. This study aims to explore if changes in the diet of Icelanders during the same decades could possibly affect the amount of glutathione in people.}, } @article {pmid36453778, year = {2022}, author = {Erol, K and Y Sozmen, E and Küçük, Ü and Kucuk, L}, title = {Effect of pheniramine maleate on rat skeletal muscle ischemia-reperfusion injury.}, journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery : TJTES}, volume = {28}, number = {12}, pages = {1667-1673}, pmid = {36453778}, issn = {1307-7945}, mesh = {Male ; Animals ; Rats ; *Pheniramine ; Rats, Sprague-Dawley ; Poly(ADP-ribose) Polymerase Inhibitors ; Thiobarbituric Acid Reactive Substances ; *Reperfusion Injury/drug therapy ; Acetylcysteine ; Superoxide Dismutase ; Femoral Artery ; Muscle, Skeletal ; Nitric Oxide ; }, abstract = {BACKGROUND: Skeletal muscle ischemia-reperfusion injury (IRI) is a common clinical problem encountered after tourniquet ap-plication or replantation. This study investigated the effect of pheniramine maleate (Ph), which is frequently used in clinical practice to reduce IRI, and compared its efficacy in IRI with N-acetylcysteine (NAC), a molecule that has been shown to be effective in IRI.

METHODS: Twenty-eight male Sprague-Dawley rats were randomly divided into four groups (sham, ischemia-reperfusion [IR], IR+Ph, IR+NAC; n=7 rats per group). Ischemia was induced in the lower right extremities of rats for 3 h using a femoral artery clamp and an elastic tourniquet. Ph and NAC were administered intraperitoneally 15 min before ischemia was terminated. At 24 h after reperfusion, levels of thiobarbituric acid reactive substance (TBARS), catalase (CAT), myeloperoxidase (MPO), superoxide dismutase (SOD), polyadenosine diphosphate ribose polymerase (PARP), and neutrophil infiltration were evaluated. Inducible nitric oxide syn-thase (iNOS) density in muscle tissue was evaluated by immunohistochemical methods after 1 week.

RESULTS: SOD, MPO, PARP, CAT, and TBARS levels in muscle tissue were significantly lower in the sham group compared with the other groups (p<0.001). All parameters except TBARS were lower in the NAC and Ph groups than in the IR group (p<0.001). Neu-trophil infiltration in the muscle tissue samples from the IR group was significantly increased compared with the NAC and Ph groups (p<0.05). iNOS staining was not observed in the sham and NAC groups.

CONCLUSION: Ph is effective at reducing experimental rat skeletal muscle IRI.}, } @article {pmid36450250, year = {2022}, author = {Laoukili, J and van Schelven, S and Küçükköse, E and Verheem, A and Goey, K and Koopman, M and Borel Rinkes, I and Kranenburg, O}, title = {BRAF[V600E] in colorectal cancer reduces sensitivity to oxidative stress and promotes site-specific metastasis by stimulating glutathione synthesis.}, journal = {Cell reports}, volume = {41}, number = {9}, pages = {111728}, doi = {10.1016/j.celrep.2022.111728}, pmid = {36450250}, issn = {2211-1247}, mesh = {Humans ; Proto-Oncogene Proteins B-raf/genetics ; Oxidative Stress ; Glutamate-Cysteine Ligase/genetics ; Glutathione ; *Lung Neoplasms/genetics ; *Colorectal Neoplasms/genetics ; }, abstract = {The presence of BRAF[V600E] in colorectal cancer (CRC) is associated with a higher chance of distant metastasis. Oxidative stress in disseminated tumor cells limits metastatic capacity. To study the relationship between BRAF[V600E], sensitivity to oxidative stress, and metastatic capacity in CRC, we use patient-derived organoids (PDOs) and tissue samples. BRAF[V600E] tumors and PDOs express high levels of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Deletion of GCL in BRAF[V600E] PDOs strongly reduces their capacity to form distant liver and lung metastases but does not affect peritoneal metastasis outgrowth. Vice versa, the glutathione precursor N-acetyl-cysteine promotes organ-site-specific metastasis in the liver and the lungs but not in the peritoneum. BRAF[V600E] confers resistance to pharmacologically induced oxidative stress in vitro, which is partially overcome by treatment with the BRAF-inhibitor vemurafenib. We conclude that GCL-driven glutathione synthesis protects BRAF[V600E]-expressing tumors from oxidative stress during distant metastasis to the liver and the lungs.}, } @article {pmid36448959, year = {2023}, author = {Padoei, F and Mamsharifi, P and Hazegh, P and Boroumand, H and Ostadmohammady, F and Abbaszadeh-Mashkani, S and Banafshe, HR and Matini, AH and Ghaderi, A and Dehkohneh, SG}, title = {The therapeutic effect of N-acetylcysteine as an add-on to methadone maintenance therapy medication in outpatients with substance use disorders: A randomized, double-blind, placebo-controlled clinical trial.}, journal = {Brain and behavior}, volume = {13}, number = {1}, pages = {e2823}, pmid = {36448959}, issn = {2162-3279}, mesh = {Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; *Acetylcysteine/pharmacology/therapeutic use ; Outpatients ; Antioxidants ; Methadone/therapeutic use ; *Substance-Related Disorders ; Double-Blind Method ; }, abstract = {OBJECTIVE: Patients with substance use disorders (SUD) under methadone maintenance therapy (MMT) are susceptible to a number of complications (psychological and metabolic disorders). Evidence studies have shown the roles of the glutamatergic system in addiction. N-Acetylcysteine (NAC) enhances extracellular glutamate, and is effective in the treatment of neuropsychiatric disorders. We assessed oral NAC as an add-on to MMT medication for the treatment of SUD.

METHODS: In the current randomized, double-blind, placebo-controlled clinical trial, outpatients with SUD under MMT who were 18-60 years old received 2400 mg/day NAC (n = 30) or placebo (n = 30) for 12 weeks. Psychological status and metabolic biomarkers were assessed at baseline and the end of the trial.

RESULTS: Compared with the placebo group, NAC treatment resulted in a significant improvement in depression score (β -2.36; 95% CI, -3.97, -0.76; p = .005), and anxiety score (β -1.82; 95% CI, -3.19, -0.44; p = .01). Furthermore, NAC treatment resulted in a significant elevation in total antioxidant capacity levels (β 72.28 mmol/L; 95% CI, 11.36, 133.19; p = .02), total glutathione (GSH) levels (β 81.84 μmol/L; 95% CI, 15.40, 148.28; p = .01), and a significant reduction in high-sensitivity C-reactive protein levels (β -0.89 mg/L; 95% CI, -1.50, -0.28; p = .005), and homeostasis model of assessment-insulin resistance (β -0.33; 95% CI, -0.65, -0.009; p = .04), compared with the placebo group.

CONCLUSION: In the current study, improvement in depression and anxiety symptoms as well as some metabolic profiles with NAC treatment for 12 weeks in outpatients with SUD under MMT was detected.}, } @article {pmid36447062, year = {2023}, author = {Hammerschmidt, TG and Donida, B and Raabe, M and Faverzani, JL and de Fátima Lopes, F and Machado, AZ and Kessler, RG and Reinhardt, LS and Poletto, F and Moura, DJ and Vargas, CR}, title = {Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β-cyclodextrin nanoparticles.}, journal = {Metabolic brain disease}, volume = {38}, number = {2}, pages = {507-518}, pmid = {36447062}, issn = {1573-7365}, support = {430443/2018-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 2018-0648//Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA)/ ; }, mesh = {Animals ; *Niemann-Pick Disease, Type C/genetics ; Antioxidants/pharmacology/therapeutic use/metabolism ; *beta-Cyclodextrins/pharmacology/therapeutic use/metabolism ; Oxidation-Reduction ; Mitochondria/metabolism ; Cholesterol/metabolism ; }, abstract = {Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing β-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining β-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free β-CD. The results obtained are promising regarding the combined use of β-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease.}, } @article {pmid36445126, year = {2022}, author = {Llamosí, M and Sempere, J and Coronel, P and Gimeno, M and Yuste, J and Domenech, M}, title = {Combination of Cefditoren and N-acetyl-l-Cysteine Shows a Synergistic Effect against Multidrug-Resistant Streptococcus pneumoniae Biofilms.}, journal = {Microbiology spectrum}, volume = {10}, number = {6}, pages = {e0341522}, pmid = {36445126}, issn = {2165-0497}, mesh = {Humans ; Animals ; Mice ; Streptococcus pneumoniae ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology ; *COVID-19 ; SARS-CoV-2 ; Cephalosporins/pharmacology/therapeutic use ; Biofilms ; Anti-Bacterial Agents/pharmacology/therapeutic use ; *Respiratory Tract Infections/microbiology ; }, abstract = {Biofilm formation by Streptococcus pneumoniae is associated with colonization of the upper respiratory tract, including the carrier state, and with chronic respiratory infections in patients suffering from chronic obstructive pulmonary disease (COPD). The use of antibiotics alone to treat recalcitrant infections caused by biofilms is insufficient in many cases, requiring novel strategies based on a combination of antibiotics with other agents, including antibodies, enzybiotics, and antioxidants. In this work, we demonstrate that the third-generation oral cephalosporin cefditoren (CDN) and the antioxidant N-acetyl-l-cysteine (NAC) are synergistic against pneumococcal biofilms. Additionally, the combination of CDN and NAC resulted in the inhibition of bacterial growth (planktonic and biofilm cells) and destruction of the biofilm biomass. This marked antimicrobial effect was also observed in terms of viability in both inhibition (prevention) and disaggregation (treatment) assays. Moreover, the use of CDN and NAC reduced bacterial adhesion to human lung epithelial cells, confirming that this strategy of combining these two compounds is effective against resistant pneumococcal strains colonizing the lung epithelium. Finally, administration of CDN and NAC in mice suffering acute pneumococcal pneumonia caused by a multidrug-resistant strain was effective in clearing the bacteria from the respiratory tract in comparison to treatment with either compound alone. Overall, these results demonstrate that the combination of oral cephalosporins and antioxidants, such as CDN and NAC, respectively, is a promising strategy against respiratory biofilms caused by S. pneumoniae. IMPORTANCE Streptococcus pneumoniae is one of the deadliest bacterial pathogens, accounting for up to 2 million deaths annually prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccines have decreased the burden of diseases produced by S. pneumoniae, but the rise of antibiotic-resistant strains and nonvaccine serotypes is worrisome. Pneumococcal biofilms are associated with chronic respiratory infections, and treatment is challenging, making the search for new antibiofilm therapies a priority as biofilms become resistant to traditional antibiotics. In this work, we used the combination of an antibiotic (CDN) and an antioxidant (NAC) to treat the pneumococcal biofilms of relevant clinical isolates. We demonstrated a synergy between CDN and NAC that inhibited and treated pneumococcal biofilms, impaired pneumococcal adherence to the lung epithelium, and treated pneumonia in a mouse pneumonia model. We propose the widely used cephalosporin CDN and the repurposed drug NAC as a new antibiofilm therapy against S. pneumoniae biofilms, including those formed by antibiotic-resistant clinical isolates.}, } @article {pmid36435287, year = {2023}, author = {Zhang, Q and Deng, C and Peng, M and Li, C and Teng, Y and Guo, S and Wu, T and Yi, D and Hou, Y}, title = {Integration of transcriptomic and proteomic analyses reveals protective mechanisms of N-acetylcysteine in indomethacin-stimulated enterocytes.}, journal = {The Journal of nutritional biochemistry}, volume = {112}, number = {}, pages = {109231}, doi = {10.1016/j.jnutbio.2022.109231}, pmid = {36435287}, issn = {1873-4847}, mesh = {Humans ; Animals ; Swine ; *Acetylcysteine/pharmacology ; *Enterocytes/metabolism ; Transcriptome ; Indomethacin/pharmacology ; Proteomics ; Apoptosis ; }, abstract = {Intestinal health is critical for the growth and development of humans and animals. Our previous study has demonstrated that indomethacin (IDMT) could induce intestinal injury in piglets, and N-acetylcysteine (NAC) supplementation contributed to alleviating intestinal injury induced by various stimuli. In this study, we investigated the mechanism of IDMT-induced cell death in IPEC-1 cell lines and explored the role of NAC by using transcriptomic and proteomic analyses. Results showed that cell viability was substantially reduced with the increasing concentrations of IDMT, whereas NAC significantly increased the survival rate of IPEC-1 cells regardless of its addition method. Transcriptomics and proteomics data indicated that terms, such as cell cycle, energy metabolism, and cell proliferation, were significantly enriched by Gene ontology and pathway analyses. Flow cytometer analysis showed that IDMT induced cell cycle arrest at G0/G1 phase. The expression of cell cycle regulatory proteins (CDK1, CCNA2, and CDC45) was decreased by IDMT stimulation. Importantly, NAC treatment repaired IDMT-induced mitochondrial dysfunction by increasing ATP production, decreasing oxygen consumption rate in non-mitochondrial O2 consumption, and increasing the red/green fluorescence ratio. IDMT stimulation significantly increased caspase-3 expression, which was partially reversed by NAC treatment. These results suggest that IDMT-induced cell death may be attributable to disturbance of the cell cycle processes, mitochondria dysfunction and apoptosis, and NAC could confer a protective effect by restoring the mitochondrial function and inhibiting the apoptosis pathway. This study provides a theoretical basis for the pathogenesis of IDMT-induced intestinal injury and guides the clinic application of NAC.}, } @article {pmid36434296, year = {2022}, author = {Yilmaz, FN and Hacioglu, M and Aldogan, EH}, title = {Impact of N-Acetylcysteine and Antibiotics Against Single and Dual Species Biofilms of Pseudomonas aeruginosa and Achromobacter xylosoxidans.}, journal = {Current microbiology}, volume = {80}, number = {1}, pages = {5}, pmid = {36434296}, issn = {1432-0991}, mesh = {Animals ; Humans ; Pseudomonas aeruginosa ; *Achromobacter denitrificans ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Aztreonam/pharmacology ; *Cystic Fibrosis/microbiology ; Caenorhabditis elegans ; Biofilms ; Tobramycin/pharmacology ; Ciprofloxacin/pharmacology ; }, abstract = {Lungs of cystic fibrosis patients are often colonized or infected with organisms, such as Pseudomonas aeruginosa and other emerging pathogenic bacteria such as Achromobacter xylosoxidans. Further, it is well established that infections of the cystic fibrosis lung airways are caused by polymicrobial infections, although its composition and diversity may change throughout the patient's life. In the present study, we investigated the effects of N-acetylcysteine (NAC) and amikacin, aztreonam, ciprofloxacin, and tobramycin alone and in combination against single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans, in vitro and in the Caenorhabditis elegans infection model. Results showed that tobramycin and ciprofloxacin were the most effective antibiotics, while aztreonam was the least effective antibiotic against both single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans. However, NAC showed little effect on both single- and dual-species, even with a combination of antibiotics. Increased survival was observed in C. elegans when treated with NAC in combination with tobramycin or ciprofloxacin, compared to no treatment or NAC alone. Tobramycin and ciprofloxacin were found effective in biofilms, but more research is needed to better understand the effects of NAC and antibiotics against single- and dual-species biofilms.}, } @article {pmid36432632, year = {2022}, author = {Petkova, T and Yordanova, A and Milanova, A}, title = {Population Pharmacokinetics of Doxycycline, Administered Alone or with N-Acetylcysteine, in Chickens with Experimental Mycoplasma gallisepticum Infection.}, journal = {Pharmaceutics}, volume = {14}, number = {11}, pages = {}, pmid = {36432632}, issn = {1999-4923}, support = {N/A//TRAKIA UNIVERSITY, PhD program/ ; }, abstract = {Mycoplasmosis is a bacterial infection that significantly affects poultry production, and it is often controlled with antibiotics, including doxycycline. The conducted study aimed to determine population pharmacokinetic (PopPk) parameters of doxycycline in healthy (n = 12) and in Mycoplasma gallisepticum-challenged (n = 20) chickens after its oral administration via drinking water at the registered dose rate of 20 mg/kg b.w./24 h for five days, without or with co-administration of N-acetylcysteine (NAC, a dose of 100 mg/kg b.w./24 h) via the feed. Doxycycline concentrations in plasma were analyzed with the LC-MS/MS method. The values of tvV/F and tvke were 4.73 L × kg−1 and 0.154 h−1, respectively, and they showed low BSV. A high BSV of 93.17% was calculated for the value of tlag of 0.8 h, which reflects the inter-individual differences in the water consumption. PTA was computed after Monte Carlo simulation with the registered dose for doxycycline. The target of %fT > MIC ≥ 80% and 100% can be achieved in 90% of the broiler population, after a correction for protein binding, for bacteria with MIC ≤ 0.5 mg × L−1 and 0.25 mg × L−1, respectively. The applied PopPk model did not reveal significant effect of M. gallisepticum infection and co-administration of NAC on pharmacokinetic parameters of doxycycline.}, } @article {pmid36428416, year = {2022}, author = {Nascimento, DR and Azevedo, VAN and Barroso, PAA and Barrozo, LG and Silva, BR and Silva, AWB and Donato, MAM and Peixoto, CA and Silva, JRV}, title = {Effects of N-acetylcysteine on Growth, Viability, and Ultrastructure of In Vitro Cultured Bovine Secondary Follicles.}, journal = {Animals : an open access journal from MDPI}, volume = {12}, number = {22}, pages = {}, pmid = {36428416}, issn = {2076-2615}, support = {308737/2018-0//National Council for Scientific and Technological Development/ ; }, abstract = {This study aimed to investigate the effects of different concentrations of N-acetylcysteine (NAC) on the growth, antrum formation, viability, and ultrastructure of bovine secondary follicles cultured in vitro for 18 days. To this end, the follicles were cultured in TCM-199+ medium alone or supplemented with 1.0, 5.0, or 25.0 mM NAC. Follicular growth, antrum formation, viability (calcein-AM and ethidium homodimer-1) and ultrastructure were evaluated at the end of culture period. The results showed that 1.0 mM NAC increased the percentage of growing follicles and the fluorescence intensity for calcein-AM when compared to other treatments (p < 0.05). On the other hand, follicles cultured with 25.0 mM NAC had higher fluorescence intensity for ethidium homodimer-1, which is a sign of degeneration. Ultrastructural analysis showed that oocytes from follicles cultured in control medium alone or with 1 mM NAC had intact zonae pellucidae in close association with oolemmae, but the ooplasm showed mitochondria with a reduced number of cristae. On the other hand, oocytes from follicles cultured with 5 or 25 mM NAC had extremely vacuolated cytoplasm and no recognizable organelles. In conclusion, 1 mM NAC increases cytoplasmic calcein staining and the growth rate in bovine secondary follicles cultured in vitro, but the presence of 5 or 25 mM NAC causes damage in cellular membranes and organelles, as well as reducing the percentages of growing follicles.}, } @article {pmid36421484, year = {2022}, author = {Mapamba, DA and Sauli, E and Mrema, L and Lalashowi, J and Magombola, D and Buza, J and Olomi, W and Wallis, RS and Ntinginya, NE}, title = {Impact of N-Acetyl Cysteine (NAC) on Tuberculosis (TB) Patients-A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {11}, pages = {}, pmid = {36421484}, issn = {2076-3921}, support = {LMU-IMPH-TB Sequel-01//TB sequel project by the German Ministry of Education and Research/ ; }, abstract = {Sustained TB infection overproduces reactive oxygen species (ROS) as a host defense mechanism. Research shows ROS is destructive to lung tissue. Glutathione (GSH) neutralizes ROS, although it is consumed. NAC is a precursor of GSH synthesis, and administering an appropriate dose of NAC to patients with respiratory conditions may enhance lung recovery and replenish GSH. The present review searched for articles reporting on the effects of NAC in TB treatment from 1960 to 31 May 2022. The PICO search strategy was used in Google Scholar, PubMed, SciFinder, and Wiley online library databases. The COVIDENCE tool was used to delete inappropriate content. We eventually discovered five clinical trials, one case report, seven reviews, in vitro research, and four experimental animal studies from the twenty-four accepted articles. The use of NAC resulted in increased GSH levels, decreased treatment time, and was safe with minimal adverse events. However, the evidence is currently insufficient to estimate the overall effects of NAC, thus the study warrants more NAC clinical trials to demonstrate its effects in TB treatment.}, } @article {pmid36421407, year = {2022}, author = {Gençosman, S and Ceylanlı, D and Şehirli, AÖ and Teralı, K and Bölükbaşı, F and Çetinel, Ş and Sayıner, S}, title = {Investigation of the Possible Protective Effect of N-Acetylcysteine (NAC) against Irinotecan (CPT-11)-Induced Toxicity in Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {11}, pages = {}, pmid = {36421407}, issn = {2076-3921}, abstract = {Irinotecan (CPT-11) is a chemotherapeutic agent involved in the treatment regimens for several malignancies such as colorectal cancer. N-acetylcysteine (NAC) is a strong antioxidant and anti-inflammatory agent used in the treatment of several diseases related to oxidative stress and inflammation. This study aimed at investigating whether NAC provides protection against hepatorenal and gastrointestinal tissue damage induced by CPT-11. Thirty-two Wistar albino rats were divided into four groups as control, NAC, CPT-11, and CPT-11+NAC. Following the experimental period, blood, and tissue samples (liver, kidney, stomach, and small intestine) were collected, and biochemical indicators, together with pro-inflammatory cytokines (TNF-α and IL-1β), matrix metalloproteinases (MMPs), malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels were evaluated. Both the biochemical indicators and the pro-inflammatory cytokines, MMP, and MDA levels increased in animals treated with CPT-11, while SOD and GPx activities decreased. Histopathological evaluation revealed structural damage in all examined tissues. With NAC administration, significant improvements were observed, both biochemically and histologically. In conclusion, the results of the present study suggest that NAC treatment together with CPT-11 may have a beneficial effect on reducing CPT-11 toxicity in rats, by modulating inflammation and the oxidant-antioxidant balance. These results strongly promote further investigative studies.}, } @article {pmid36420805, year = {2022}, author = {Janković, SM}, title = {Acetaminophen toxicity and overdose: current understanding and future directions for NAC dosing regimens.}, journal = {Expert opinion on drug metabolism & toxicology}, volume = {18}, number = {11}, pages = {745-753}, doi = {10.1080/17425255.2022.2151893}, pmid = {36420805}, issn = {1744-7607}, mesh = {Humans ; Acetylcysteine ; Acetaminophen/therapeutic use ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury/drug therapy ; }, abstract = {INTRODUCTION: Although N-acetyl-cysteine (NAC) has long been used for the treatment of acetaminophen poisoning/overdose, the optimal NAC dosing regimen for varying patterns or severity of the poisoning/overdose is still unknown.

AREAS COVERED: Relevant literature was searched for in the MEDLINE (from 1964 until August 31[st], 2022), SCOPUS (from 2004 until August 31[st], 2022) and GOOGLE SCHOLAR (from 2004 until August 31[st], 2022) databases, without restriction in terms of publication date. The inclusion criteria were: original clinical studies reporting results, and studies investigating efficacy and safety of NAC dosing regimens in case(s) of overdose or poisoning with acetaminophen.

EXPERT OPINION: For a more effective treatment of acetaminophen poisoning in the future, it will be crucial to advance the technology of measuring acetaminophen, its metabolites and NAC in the serum, preferably with the point-of-care technique, so that in real time it can be continuously assessed whether it is necessary to administer NAC, and further to increase the dose of NAC and extend the duration of its administration, or not.}, } @article {pmid36418258, year = {2022}, author = {Zhang, YP and Zhang, Q and Deng, F and Chen, B and Zhang, JH and Hu, J}, title = {[Effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its mechanism].}, journal = {Zhonghua shao shang yu chuang mian xiu fu za zhi}, volume = {38}, number = {11}, pages = {1014-1022}, doi = {10.3760/cma.j.cn501225-20220630-00272}, pmid = {36418258}, issn = {2097-1109}, support = {82100889//Youth Science Foundation Project of National Natural Science Foundation of China/ ; CSTB2022BSXM-JCX0022//Chongqing Doctor "Through Train" Project/ ; XZ-2019-505-018//Science and Technology Ability Promotion Project of Army Medical University/ ; }, mesh = {Humans ; RNA, Small Interfering/genetics ; Cell Line ; *Epidermis ; *Glucose/pharmacology ; Epidermal Cells ; }, abstract = {Objective: To investigate the effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its possible molecular mechanism, so as to explore the mechanism of refractory diabetic foot wound healing. Methods: The method of experimental research was used. HaCaT cells in logarithmic growth phase was taken for experiment. The cells were collected and divided into normal control group (culture solution containing glucose with final molarity of 5.5 mmol/L) and high glucose (culture solution containing glucose with final molarity of 30.0 mmol/L) 24 h group, high glucose 48 h group, and high glucose 72 h group according to the random number table (the same grouping method below). The cells in normal control group were routinely cultured for 72 h, cells in high glucose 72 h group were cultured with high glucose for 72 h, cells in high glucose 48 h group were routinely cultured for 24 h then cultured with high glucose for 48 h, cells in high glucose 24 h group were routinely cultured for 48 h then cultured with high glucose for 24 h. Then the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal control group and high glucose group. After being correspondingly cultured for 48 h as before, the protein expression of P62 was detected by immunofluorescence method (indicated as green fluorescence). The cells were collected and divided into negative control small interfering RNA (siRNA) group, P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group, and transfected with the corresponding reagents. At post transfection hour (PTH) 72, the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group. After the corresponding treatment, the protein expression of P62 was detected by Western blotting at PTH 72 h, the cell migration rate was detected and calculated at 24 h after scratching by scratch test, with the number of samples being 9; and the range of cell movement was observed and the trajectory velocity was calculated within 3 h under the living cell workstation, with the number of samples being 76, 75, 80, and 79 in normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group, respectively. The cells were collected and divided into normal glucose+phosphate buffered solution (PBS) group, high glucose+PBS group, and high glucose+N-acetylcysteine (NAC) group. After the corresponding treatment, the protein expression of P62 at 48 h of culture was detected by Western blotting and immunofluorescence method, respectively. Except for scratch test and cell motility experiment, the number of samples was all 3 in the rest experiments. Data were statistically analyzed with one-way analysis of variance and least significant difference test. Results: Compared with the protein expression in normal control group, the protein expressions of P62 of cells in high glucose 24 h group, high glucose 48 h group, and high glucose 72 h group were significantly increased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose group was stronger than that in normal control group. At PTH 72, compared with the protein expression in negative control siRNA group, the protein expressions of P62 of cells in P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group were significantly decreased (P<0.01). At PTH 72, compared with the protein expression in normal glucose+negative control siRNA group, the protein expression of P62 of cells in normal glucose+P62-siRNA group was significantly decreased (P<0.01), while the protein expression of P62 of cells in high glucose+negative control siRNA group was significantly increased (P<0.01); compared with the protein expression in high glucose+negative control siRNA group, the protein expression of P62 of cells in high glucose+P62-siRNA group was significantly decreased (P<0.01). At 24 h after scratching, compared with (55±7)% in normal glucose+negative control siRNA group, the cell migration rate in normal glucose+P62-siRNA group was significantly increased ((72±14)%, P<0.01), while the cell migration rate in high glucose+negative control siRNA group was significantly decreased ((37±7)%, P<0.01); compared with that in high glucose+negative control siRNA group, the cell migration rate in high glucose+P62-siRNA group was significantly increased ((54±10)%, P<0.01). Within 3 h of observation, the cell movement range in high glucose+negative control siRNA group was smaller than that in normal glucose+negative control siRNA group, while the cell movement range in normal glucose+P62-siRNA group was larger than that in normal glucose+negative control siRNA group, and the cell movement range in high glucose+P62-siRNA group was larger than that in high glucose+negative control siRNA group. Compared with that in normal glucose+negative control siRNA group, the cell trajectory speed in normal glucose+P62-siRNA group was significantly increased (P<0.01), while the cell trajectory speed in high glucose+negative control siRNA group was significantly decreased (P<0.01); compared with that in high glucose+negative control siRNA group, the cell trajectory speed in high glucose+P62-siRNA group was significantly increased (P<0.01). At 48 h of culture, compared with that in normal glucose+PBS group, the protein expression of P62 of cells in high glucose+PBS group was significantly increased (P<0.01); compared with that in high glucose+PBS group, the protein expression of P62 of cells in high glucose+NAC group was significantly decreased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose+PBS group was stronger than that in normal glucose+PBS group, while the green fluorescence of P62 of cells in high glucose+NAC group was weaker than that in high glucose+PBS group. Conclusions: In HaCaT cells, high glucose microenvironment can promote the protein expression of P62; knockdown of P62 protein can promote the migration and increase the mobility of HaCaT cells; and the increase of reactive oxygen species in high glucose microenvironment may be the underlying mechanism for the increase of P62 expression.}, } @article {pmid36414340, year = {2022}, author = {Lee, M and McCarron, J and Balinski, A and Bower, R}, title = {Intravenous acetaminophen associated with acute liver failure.}, journal = {BMJ case reports}, volume = {15}, number = {11}, pages = {}, pmid = {36414340}, issn = {1757-790X}, mesh = {Female ; Humans ; Acetaminophen/adverse effects ; *Liver Failure, Acute/etiology ; Acetylcysteine/therapeutic use ; *Drug-Related Side Effects and Adverse Reactions ; *Brain Diseases/complications ; }, abstract = {A woman in her mid-60s, without known liver disease, was admitted to the hospital with a partial malignant colonic obstruction. Over a 6-day course, she received a total of 13 g of intravenous acetaminophen not exceeding 4 g over a 24-hour period. She developed encephalopathy and an international normalised ratio of 6.1 meeting criteria for acute liver failure (ALF). She was treated with intravenous N-acetyl cysteine and other causes of liver failure were excluded. The patient was discharged with subsequent resolution of encephalopathy and improvement of her liver chemistries. Though ALF is rare, in countries where acetaminophen is readily available, almost 50% of ALF cases are acetaminophen-induced hepatotoxicity and most have been documented as oral ingestion of acetaminophen. We present a rare case of intravenous acetaminophen-induced ALF.}, } @article {pmid36410267, year = {2022}, author = {Izquierdo-Alonso, JL and Pérez-Rial, S and Rivera, CG and Peces-Barba, G}, title = {N-acetylcysteine for prevention and treatment of COVID-19: Current state of evidence and future directions.}, journal = {Journal of infection and public health}, volume = {15}, number = {12}, pages = {1477-1483}, pmid = {36410267}, issn = {1876-035X}, mesh = {Humans ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; *Respiratory Distress Syndrome ; Immunotherapy ; *COVID-19 Drug Treatment ; }, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19) and can be associated with serious complications, including acute respiratory distress syndrome. This condition is accompanied by a massive release of cytokines, also denominated cytokine storm, development of systemic oxidative stress and a prothrombotic state. In this context, it has been proposed a role for acetylcysteine (NAC) in the management of patients with COVID-19. NAC is a molecule classically known for its mucolytic effect, but it also has direct and indirect antioxidant activity as a precursor of reduced glutathione. Other effects of NAC have also been described, such as modulating the immune and inflammatory response, counteracting the thrombotic state, and having an antiviral effect. The pharmacological activities of NAC and its effects on the mechanisms of disease progression make it a potential therapeutic agent for COVID-19. NAC is safe, tolerable, affordable, and easily available. Moreover, the antioxidant effects of the molecule may even prevent infection and play an important role as a complement to vaccination. Although the clinical efficacy and dosing regimens of NAC have been evaluated in the clinical setting with small series of patients, the results are promising. In this article, we review the pathogenesis of SARS-CoV-2 infection and the current knowledge of the mechanisms of action of NAC across disease stages. We also propose NAC posology strategies to manage COVID-19 patients in different clinical scenarios.}, } @article {pmid36409196, year = {2023}, author = {Lopez-Mejia, IC and Pijuan, J and Navaridas, R and Santacana, M and Gatius, S and Velasco, A and Castellà, G and Panosa, A and Cabiscol, E and Pinyol, M and Coll, L and Bonifaci, N and Peña, LP and Vidal, A and Villanueva, A and Gari, E and Llobet-Navàs, D and Fajas, L and Matias-Guiu, X and Yeramian, A}, title = {Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.}, journal = {Molecular oncology}, volume = {17}, number = {1}, pages = {98-118}, pmid = {36409196}, issn = {1878-0261}, mesh = {Humans ; *Antioxidants/metabolism ; Cell Line, Tumor ; Cell Movement ; *Cystadenocarcinoma, Serous/drug therapy/pathology ; *Focal Adhesion Kinase 1/metabolism ; Oxidative Stress ; Phosphorylation ; Reactive Oxygen Species ; Tyrosine/metabolism ; Animals ; }, abstract = {Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide-based tyrosine-kinase-activity profiling approach to quantify the changes in tyrosine kinase activation between USC and EEC. Among the tyrosine kinases highly activated in USC, we identified focal adhesion kinase (FAK). We conducted mechanistic studies using cellular models. In a USC cell line, targeting FAK either by inhibitors PF-573228 and defactinib (VS-6063) or by gene silencing limits 3D cell growth and reduces cell migration. Moreover, results from our studies suggest that oxidative stress is increased in USC tumors compared to EEC ones. Reactive oxygen species (ROS) induce tyrosine phosphorylation of FAK and a concomitant tyrosine phosphorylation of paxillin, a mediator of FAK signal transduction. Mechanistically, by tracking hundreds of individual cells per condition, we show that ROS increased cell distance and migration velocity, highlighting the role of ROS-FAK-PAX signaling in cell migration. Both defactinib and ROS scavenger N-acetylcysteine (NAC) revert this effect, pointing toward ROS as potential culprits for the increase in USC cell motility. A proof of concept of the role of FAK in controlling cell growth was obtained in in vivo experiments using cancer-tissue-originated spheroids (CTOS) and a patient-derived orthotopic xenograft model (orthoxenograft/PDOX). Defactinib reduces cell proliferation and protein oxidation, supporting a pro-tumoral antioxidant role of FAK, whereas antioxidant NAC reverts FAK inhibitor effects. Overall, our data points to ROS-mediated FAK activation in USC as being responsible for the poor prognosis of this tumor type and emphasize the potential of FAK inhibition for USC treatment.}, } @article {pmid36407165, year = {2022}, author = {Santosa, Y and Harca, AD and Yuwono, A and Hermanto, A and Oliver, MS and Sukmadja, E and Soewardi, R}, title = {Is It Safe to Do Percutaneous Coronary Intervention in Moderate to Severe Chronic Kidney Disease Patients? A Prospective Cohort Study.}, journal = {Cureus}, volume = {14}, number = {10}, pages = {e30312}, pmid = {36407165}, issn = {2168-8184}, abstract = {INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a common and potentially serious complication of percutaneous coronary intervention (PCI) procedures, as it induces acute kidney injury (AKI), especially in previously diagnosed chronic kidney disease (CKD) patients, particularly in those who also have diabetes. Adequate hydration and using a minimal volume of contrast media are the recommended measures to decrease CI-AKI in CKD patients. A combination of sodium bicarbonate and N-acetylcysteine (NAC) may be a superior strategy for preventing CI-AKI. This study is aimed to evaluate the safety of PCI in moderate to severe CKD patients.

METHOD: This was a prospective, single-center study, from 2019 to 2021. We included all chronic kidney disease who undergo PCI procedures. The kidney level was measured on admission and 24 hours after the PCI procedure. The patients received 75 meq/500 mL of sodium bicarbonate one to six hours before procedures, oral acetylcysteine 600 mg bid for three days, and rehydration with 1000 ml of normal saline infusion for eight hours in patients without congestive heart failure. SPSS Version 23.0 (IBM SPSS Statistics for Windows, Version 23.0., IBM Corp., Armonk, NY) was used to input and process the data.

RESULTS: This study included 118 subjects, with baseline characteristics of age 58.77 ± 9.08 years, 80.5% male, 47.5% diabetic, 50% hypertension, and 59.5% congestive heart failure. From the coronary angiogram, we found most of our subjects (57.6%) had three-vessel disease, 28.8% had two-vessel disease, and 15.6% had one-vessel disease. About 67.8% of subjects used <50 ml of low molecular contrast. The baseline creatinine level was 2.46 ± 1.04 mg/dL and the estimated glomerular filtration rate (eGFR) was 30 ± 12.65 mL/min. There were 19 (16.1%) patients with stage 3A CKD, 45 (38.1%) stage 3B, 41 (34.7%) stage 4, and 41 (34.7%) stage 5. The kidney function test after 24 hours of contrast admission showed a creatinine level of 2.37 ± 1.20 mg/dL (P<0.05) and the eGFR of 34.74 ± 16.10 mL/min. There was no significant difference in creatinine levels between stage 3A and stage 5 CKD. There was a significant reduction in creatinine in stage 3B CKD, from 1.917 ± 0.22 to 1.71 ± 0.37 mg/dL (P = 0.001); and stage 4 CKD, from 2.77 ± 0.55 to 2.72 ± 0.94 mg/dL (P = 0.013).

DISCUSSION: CKD is a risk factor for developing CI-AKI after PCI, which is a marker of poor long-term outcomes. The development of CI-AKI is a strong predictor of post-PCI bleeding, which aggravates hemodynamic instability. The combination of NAC and NaHCO3 exerts a better antioxidative effect, which reduces the harmful short-term and long-term consequences of contrast media. Previous studies revealed the use of low-to-zero contrast media was safer in CKD patients who had undergone PCI. By applying these measures, our study showed a good outcome of PCI with no worsening renal function in CKD patients.

CONCLUSION: With good prophylaxis measures, such as using minimal volume contrast media, adequate rehydration, and the combination of sodium bicarbonate and acetylcysteine, it is safe to do PCI in moderate to severe CKD patients.}, } @article {pmid36406192, year = {2022}, author = {Min, WL and Wang, BF and Liang, BB and Zhang, L and Pan, JY and Huang, Y and Zhao, Y and Lin, S and Zhao, YH and Zhang, SQ and Ma, QY}, title = {A ROS/Akt/NF-κB Signaling Cascade Mediates Epidermal Growth Factor-Induced Epithelial-Mesenchymal Transition and Invasion in Human Breast Cancer Cells.}, journal = {World journal of oncology}, volume = {13}, number = {5}, pages = {289-298}, pmid = {36406192}, issn = {1920-454X}, abstract = {BACKGROUND: As one of the most widely used anti-diabetic drugs for type II diabetes, metformin has been shown to exhibit anti-cancer activity in recent years. Epidermal growth factor (EGF) and its receptor, EGFR, play important roles in cancer metastasis in various tumors, including breast cancer. Epithelial-mesenchymal transition (EMT) is a critical process for cancer invasion and metastasis. In this study, we use EGF as a metastatic inducer to investigate the effect of metformin on cancer cell migration, invasion and EMT.

METHODS: Human breast cancer MCF-7 cells were exposed to EGF with or without metformin or N-acetyl cysteine (NAC). The effects of metformin on breast cancer cell proliferation were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The production of reactive oxygen species (ROS) was tested using 2,7-dichlorodihydrofluorecein diacetate (DCFH-DA). The migratory and invasive abilities of tumor cells were analyzed using wound healing assay and transwell invasion assay, respectively. The expressions of E-cadherin, N-cadherin and Snail were tested using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting at mRNA and protein levels. The activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) were measured by western blotting.

RESULTS: Our results showed that metformin inhibited breast cancer cell proliferation in a dose-dependent manner with or without EGF. EGF-induced alterations in cell morphology that are characteristic of EMT were reversed by metformin. Metformin also inhibited the EGF-modulated expression of E-cadherin, N-cadherin and Snail and further suppressed cell invasion and migration. In addition, metformin suppressed EGF-induced phosphorylation of Akt and NF-κB. ROS is involved in EGF-induced cancer invasion and activation of phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB pathway.

CONCLUSION: Taken together, these data indicate that metformin suppresses EGF-induced breast cancer cell migration, invasion and EMT through the inhibition of the PI3K/Akt/NF-κB pathway. These results provide a novel mechanism to explain the role of metformin as a potent anti-metastatic agent in breast cancer cells.}, } @article {pmid36403891, year = {2023}, author = {Wei, Y and Ni, L and Pan, J and Li, X and Deng, Y and Xu, B and Yang, T and Sun, J and Liu, W}, title = {Methylmercury promotes oxidative stress and autophagy in rat cerebral cortex: Involvement of PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways and attenuation by N-acetyl-L-cysteine.}, journal = {Neurotoxicology and teratology}, volume = {95}, number = {}, pages = {107137}, doi = {10.1016/j.ntt.2022.107137}, pmid = {36403891}, issn = {1872-9738}, mesh = {Animals ; Rats ; *Acetylcysteine/pharmacology ; AMP-Activated Protein Kinases/metabolism/pharmacology ; Autophagy ; Cerebral Cortex ; *Methylmercury Compounds/toxicity ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases ; }, abstract = {Methylmercury (MeHg) is a potent neurotoxicant that could induce oxidative stress and autophagy. However, the underlying mechanisms through which MeHg affects the central nervous system have not been fully elucidated, and little has been known of the interaction between oxidative stress and autophagy. Therefore, rats were administrated with different MeHg concentrations to evaluate the neurotoxic effects and autophagy in cerebral cortex. Moreover, we have investigated the neuroprotective role of N-acetyl-L-cysteine (NAC) against MeHg-induced neurotoxicity in order to estimate the regulation effects of oxidative stress on autophagy. A total of 64 rats, 40 of which were randomly divided into control and MeHg-treated (4, 8 and 12 μ mol/kg) groups. The remaining 24 rats were divided into control, NAC control (1 mmol/kg), 12 μ mol/kg MeHg, and NAC pretreatment. Administration of 12 μ mol/kg MeHg significantly increased behavioral and pathological abnormalities, and autophagy levels. In addition, the oxidative stress levels increased, together with abnormal expression of autophagy-related molecules. Pretreatment with NAC significantly prevented MeHg-induced oxidative stress and PI3K/AKT/mTOR or AMPK/TSC2/mTOR-mediated autophagy. In conclusion, the present study suggested that oxidative stress can regulate autophagy through PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways. This study provides a theoretical basis for the study and treatment of MeHg-induced neurotoxicity.}, } @article {pmid36402045, year = {2023}, author = {Cao, X and Guo, L and Zhou, C and Huang, C and Li, G and Zhuang, Y and Yang, F and Liu, P and Hu, G and Gao, X and Guo, X}, title = {Effects of N-acetyl-l-cysteine on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets.}, journal = {Poultry science}, volume = {102}, number = {1}, pages = {102274}, pmid = {36402045}, issn = {1525-3171}, mesh = {Animals ; Female ; *Acetylcysteine/pharmacology/metabolism ; *Chickens/physiology ; Ovary/metabolism ; Oxidative Stress ; Antioxidants/metabolism ; Inflammation/veterinary/metabolism ; Heat-Shock Response ; Cytokines/metabolism ; }, abstract = {The aims of this study were to investigate the effects of supplemental N-acetyl-l-cysteine (NAC) on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets. A total of 120, 12-wk-old, Hy-Line Brown hens were randomly separated into 4 groups with 6 replicates of 5 birds in each group for 21 d. The 4 treatments were as follows: the CON group and CN group were supplemented with basal diet or basal diet with 1 g/kg NAC, respectively; and the HS group and HSN group were heat-stressed groups supplemented with basal diet or basal diet with 1 g/kg NAC, respectively. The results indicated that the ovaries suffered pathological damage due to chronic heat stress and that NAC effectively ameliorated these changes. Compared with the HS group, antioxidant enzyme activities (including SOD, GSH-Px, CAT, and T-AOC) were enhanced, while the MDA contents and the expression levels of HSP70 were decreased in the HSN group. In addition, NAC upregulated the expression levels of HO-1, SOD2, and GST by upregulating the activity of Nrf2 at different time points to mitigate oxidative stress caused by heat exposure. Simultaneously, NAC attenuated chronic heat stress-induced NF-κB pathway activation and decreased the expression levels of the proinflammatory cytokines IL-8, IL-18, TNF-α, IKK-α, and IFN-γ. Cumulatively, our results indicated that NAC could ameliorate chronic heat stress-induced ovarian damage by upregulating the antioxidative capacity and reducing the secretion of proinflammatory cytokines.}, } @article {pmid36400163, year = {2023}, author = {Suresh, V and Behera, P and Parida, D and Mohapatra, AP and Das, SK and Kumari, S and Avula, K and Mohapatra, A and Syed, GH and Senapati, S}, title = {Therapeutic role of N-acetyl cysteine (NAC) for the treatment and/or management of SARS-CoV-2-induced lung damage in hamster model.}, journal = {European journal of pharmacology}, volume = {938}, number = {}, pages = {175392}, pmid = {36400163}, issn = {1879-0712}, mesh = {Animals ; Cricetinae ; *SARS-CoV-2 ; Acetylcysteine/pharmacology/therapeutic use ; *COVID-19 ; Interleukin-6 ; Reactive Oxygen Species ; Lung ; }, abstract = {Oxidative stress by reactive oxygen species (ROS) has been hypothesized to be the major mediator of SARS-CoV-2-induced pathogenesis. During infection, the redox homeostasis of cells is altered as a consequence of virus-induced cellular stress and inflammation. In such scenario, high levels of ROS bring about the production of pro-inflammatory molecules like IL-6, IL-1β, etc. that are believed to be the mediators of severe COVID-19 pathology. Based on the known antioxidant, anti-inflammatory, mucolytic and antiviral properties of NAC, it has been hypothesized that NAC will have beneficial effects in COVID-19 patients. In the current study efforts have been made to evaluate the protective effect of NAC in combination with remdesivir against SARS-CoV-2 induced lung damage in the hamster model. The SARS-CoV-2 infected animals were administered with high (500 mg/kg/day) and low (150 mg/kg/day) doses of NAC intraperitoneally with and without remdesivir. Lung viral load, pathology score and expression of inflammatory molecules were checked by using standard techniques. The findings of this study show that high doses of NAC alone can significantly suppress the SARS-CoV-2 mediated severe lung damage (2 fold), but on the contrary, it fails to restrict viral load. Moreover, high doses of NAC with and without remdesivir significantly suppressed the expression of pro-inflammatory genes including IL-6 (4.16 fold), IL-1β (1.96 fold), and TNF-α (5.55 fold) in lung tissues. Together, results of this study may guide future preclinical and clinical attempts to evaluate the efficacy of different doses and routes of NAC administration with or without other drugs against SARS-CoV-2 infection.}, } @article {pmid36399957, year = {2022}, author = {Yin, YL and Chen, Y and Ren, F and Wang, L and Zhu, ML and Lu, JX and Wang, QQ and Lu, CB and Liu, C and Bai, YP and Wang, SX and Wang, JZ and Li, P}, title = {Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.}, journal = {Redox biology}, volume = {58}, number = {}, pages = {102540}, pmid = {36399957}, issn = {2213-2317}, mesh = {Animals ; Humans ; Mice ; *Cognitive Dysfunction/etiology/metabolism ; Cysteine/metabolism ; Endothelial Cells/metabolism ; GTP Cyclohydrolase ; *Hyperhomocysteinemia/chemically induced/metabolism ; Nitric Oxide/metabolism ; Nitrosative Stress ; }, abstract = {BACKGROUND: s: Hyperhomocysteinemia (HHcy) is one of risk factors for vascular cognitive impairment (VCI). GTP cyclohydrolase 1 (GCH1) deficiency is critical to oxidative stress in vascular dysfunction. The aim of this study was designed to examine whether HHcy induces VCI through GCH1 S-nitrosylation, a redox-related post-translational modification of cysteine.

METHODS: The VCI model was induced by feeding mice homocysteine thiolactone (HTL) for 16 consecutive weeks. The cognitive functions were evaluated by step-down avoidance test, passive avoidance step-through task test, and Morris water maze (MWM) test. Protein S-nitrosylation was assayed using a biotin-switch method.

RESULTS: In cell-free system, nitric oxide (NO) donor induced GCH1 protein S-nitrosylation and decreased GCH1 activity. In endothelial cells, HTL increased GCH1 S-nitrosylation, reduced tetrahydrobiopterin, and induced oxidative stress, which were attenuated by N-acetyl-cysteine, L-N6-1-Iminoethyl-lysine, mutant of GCH1 cysteine 141 to alanine (MT-GCH1) or gene deletion of inducible NO synthase (iNOS). Further, HTL incubation or iNOS overexpression promoted endothelial cellular senescence, but abolished by exogenous expression of MT-GCH1 or pharmacological approaches including N-acetyl-cysteine, L-sepiapterin, and tempol. In wildtype mice, long-term administration of HTL induced GCH1 S-nitrosylation and vascular stiffness, decreased cerebral blood flow, and damaged the cognitive functions. However, these abnormalities induced by HTL administration were rescued by enforced expression of MT-GCH1 or gene knockout of iNOS. In human subjects, GCH1 S-nitrosylation was increased and cognitive functions were impaired in patients with HHcy.

CONCLUSION: The iNOS-mediated nitrosative stress induced by HTL drives GCH1 S-nitrosylation to induce cerebral vascular stiffness and cognitive impairments.}, } @article {pmid36396003, year = {2023}, author = {Elkin, ER and Su, AL and Dou, JF and Colacino, JA and Bridges, D and Padmanabhan, V and Harris, SM and Boldenow, E and Loch-Caruso, R and Bakulski, KM}, title = {Sexually concordant and dimorphic transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue.}, journal = {Toxicology}, volume = {483}, number = {}, pages = {153371}, pmid = {36396003}, issn = {1879-3185}, support = {P30 AG053760/AG/NIA NIH HHS/United States ; P42 ES017198/ES/NIEHS NIH HHS/United States ; T32 DK071212/DK/NIDDK NIH HHS/United States ; R01 ES025574/ES/NIEHS NIH HHS/United States ; R01 DK107535/DK/NIDDK NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; R01 ES025531/ES/NIEHS NIH HHS/United States ; T32 HD079342/HD/NICHD NIH HHS/United States ; R01 ES028802/ES/NIEHS NIH HHS/United States ; R01 AG055406/AG/NIA NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; R01 AG067592/AG/NIA NIH HHS/United States ; }, mesh = {Female ; Male ; Rats ; Pregnancy ; Animals ; *Trichloroethylene/toxicity/metabolism ; Acetylcysteine/pharmacology ; Rats, Wistar ; Antioxidants/pharmacology ; Placenta/metabolism ; }, abstract = {Numerous Superfund sites are contaminated with the volatile organic chemical trichloroethylene (TCE). In women, exposure to TCE in pregnancy is associated with reduced birth weight. Our previous study reported that TCE exposure in pregnant rats decreased fetal weight and elevated oxidative stress biomarkers in placentae, suggesting placental injury as a potential mechanism of TCE-induced adverse birth outcomes. In this study, we investigated if co-exposure with the antioxidant N-acetylcysteine (NAC) attenuates TCE exposure effects on RNA expression. Timed-pregnant Wistar rats were exposed orally to 480 mg TCE/kg/day on gestation days 6-16. Exposure of 200 mg NAC/kg/day alone or as a pre/co-exposure with TCE occurred on gestation days 5-16 to stimulate antioxidant genes prior to TCE exposure. Tissue was collected on gestation day 16. In male and female placentae, we evaluated TCE- and/or NAC-induced changes to gene expression and pathway enrichment analyses using false discovery rate (FDR) and fold-change criteria. In female placentae, exposure to TCE caused significant differential expression 129 genes while the TCE+NAC altered 125 genes, compared with controls (FDR< 0.05 + fold-change >1). In contrast, in male placentae TCE exposure differentially expressed 9 genes and TCE+NAC differentially expressed 35 genes, compared with controls (FDR< 0.05 + fold-change >1). NAC alone did not significantly alter gene expression in either sex. Differentially expressed genes observed with TCE exposure were enriched in mitochondrial biogenesis and oxidative phosphorylation pathways in females whereas immune system pathways and endoplasmic reticulum stress pathways were differentially expressed in both sexes (FDR<0.05). TCE treatment was differentially enriched for genes regulated by the transcription factors ATF6 (both sexes) and ATF4 (males only), indicating a cellular condition triggered by misfolded proteins during endoplasmic reticulum stress. This study demonstrates novel genes and pathways involved in TCE-induced placental injury and showed antioxidant co-treatment largely did not attenuate TCE exposure effects.}, } @article {pmid36394765, year = {2022}, author = {Alomar, FA}, title = {Methylglyoxal in COVID-19-induced hyperglycemia and new-onset diabetes.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {21}, pages = {8152-8171}, doi = {10.26355/eurrev_202211_30169}, pmid = {36394765}, issn = {2284-0729}, mesh = {Humans ; Pyruvaldehyde ; *COVID-19 ; Magnesium Oxide ; SARS-CoV-2 ; *Hyperglycemia ; *Diabetes Mellitus/drug therapy ; Insulin ; }, abstract = {Elevation in blood glucose is common in COVID-19 patients. There is also a high incidence of new-onset diabetes mellitus (DM) in COVID-19 patients following hospitalization. To date, the underlying cause(s) for the hyperglycemia and new-onset DM post-COVID-19 remain poorly understood. In this narrative review, we suggest that upregulation of the cytotoxic and diffusible glycolytic byproduct methylglyoxal (MGO) arising from increased glycolysis in infected pancreatic islets, macrophages, and peripheral cells/tissues is impairing insulin production, secretion, and signaling. This hypothesis is based on our recent discovery that MGO levels were elevated in the plasma of hospitalized COVID-19 patients without and with DM and even higher in COVID-19 patients that succumb to the disease. In pancreatic islets infected with SARS-CoV-2, elevated MGO will disrupt mitochondrial function, perturb Ca2+ homeostasis, and activate the receptors for advanced glycation end-product (RAGE) and nuclear factor kappa B (NF-kB) resulting in impaired insulin production and secretion. In macrophages, excess MG production can diffuse into the vasculature disrupting endothelial function and triggering micro/macro hemorrhage, ischemia, and tissue fibrosis. In skeletal muscle and liver cells, MGO disruption of insulin signaling can blunt glucose absorption. Metformin and N-acetyl cysteine have recently been shown to decrease morbidity and mortality in COVID-19 patients. Here we propose that these agents may be exerting their beneficial effects by chemically reacting with and lowering MGO levels. Knowledge gained from this review should provide novel mechanistic insights for hyperglycemia in COVID-19 patients and strategies to blunt the development of new-onset of DM in post-COVID patients.}, } @article {pmid36384314, year = {2023}, author = {Parli, GM and Gales, MA and Gales, BJ}, title = {"N-Acetylcysteine for Obsessive-Compulsive and Related Disorders in Children and Adolescents: A Review".}, journal = {The Annals of pharmacotherapy}, volume = {57}, number = {7}, pages = {847-854}, doi = {10.1177/10600280221138092}, pmid = {36384314}, issn = {1542-6270}, mesh = {Humans ; Adolescent ; Child ; Child, Preschool ; Young Adult ; Adult ; Acetylcysteine/therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Obsessive-Compulsive Disorder/drug therapy/diagnosis/psychology ; *Cognitive Behavioral Therapy ; *Drug-Related Side Effects and Adverse Reactions ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To evaluate clinical data using oral n-acetylcysteine (NAC) in obsessive-compulsive and related disorders (OCDRD) treatment.

DATA SOURCES: PubMed, Ovid MEDLINE (1946-July 2022), and the Cochrane Library database were searched using the terms NAC, children, adolescent, obsessive-compulsive disorder (OCD), trichotillomania (TTM), excoriation, hoarding disorder, and body dysmorphic disorder. Bibliographies were reviewed for relevant trials and case studies.

English language, clinical trials, or case studies analyzing NAC use in patients aged 3 to 21 years old with OCDRD as determined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.

DATA SYNTHESIS: Three randomized double-blind placebo-controlled trials of NAC in children and adolescents studied 121 patients with OCDRD. Trials assessed symptom severity from baseline to 10 to 12 weeks of NAC therapy. Two OCD trials identified statistically significant improvements, with only 1 trial demonstrating a clear clinically relevant difference from placebo. One trial in TTM found no difference between the NAC and placebo. Adverse effects were mild and included nausea, blurred vision, fatigue, tremor, and sweats. N-acetylcysteine titrated to 2400 or 2700 mg/day in divided doses was the most studied regimen.

Many OCDRD patients fail to completely respond to first-line treatment with cognitive behavioral therapy (CBT) and/or selective serotonin reuptake inhibitors (SSRIs) leaving practitioners with few additional treatment options. Preliminary efficacy and safety data are presented in this review.

CONCLUSIONS: Limited evidence suggests children and adolescents with OCD refractory to SSRIs or CBT may benefit from NAC augmentation.}, } @article {pmid36383882, year = {2022}, author = {Alavinejad, P and Tran, NN and Eslami, O and Shaarawy, OE and Hormati, A and Seiedian, SS and Parsi, A and Ahmed, MH and Behl, NS and Abravesh, AA and Tran, QT and Vignesh, S and Salman, S and Sakr, N and Ara, TF and Hajiani, E and Hashemi, SJ and Patai, ÁV and Butt, AS and Lee, SH}, title = {ORAL N-ACETYL CYSTEINE VERSUS RECTAL INDOMETHACIN FOR PREVENTION OF POST ERCP PANCREATITIS: A MULTICENTER MULTINATIONAL RANDOMIZED CONTROLLED TRIAL.}, journal = {Arquivos de gastroenterologia}, volume = {59}, number = {4}, pages = {508-512}, doi = {10.1590/S0004-2803.202204000-90}, pmid = {36383882}, issn = {1678-4219}, abstract = {BACKGROUND: This multicenter multinational RCT designed to compare the efficacy of suppository indomethacin and NAC for prevention of PEP.

METHODS: During a 6-month period, all of the ERCP cases in seven referral centers were randomly assigned to receive either 1200 mg oral NAC, indomethacin suppository 100 mg, 1200 mg oral NAC plus indomethacin suppository 100 mg or placebo 2 hours before ERCP. The primary outcomes were the rate and severity of any PEP.

RESULTS: A total of 432 patients included (41.4% male). They were originally citizens of 6 countries (60.87% Caucasian). They were randomly allocated to receive either NAC (group A, 84 cases), rectal indomethacin (group B, 138 cases), NAC + rectal indomethacin (group C, 115 cases) or placebo (group D, 95 cases). The rate of PEP in groups A, B and C in comparison with placebo were 10.7%, 17.4%, 7.8% vs 20% (P=0.08, 0.614 & 0.01 respectively). The NNT for NAC, indomethacin and NAC + indomethacin was 11, 38 and 8 respectively.

CONCLUSION: Oral NAC is more effective than rectal indomethacin when compared to placebo for prevention of PEP and the combination of NAC and Indomethacin had the lowest incidence of PEP and may have synergistic effect in preventing of PEP (IRCT20201222049798N1; 29/12/2020).}, } @article {pmid36382021, year = {2022}, author = {Soleymani, M and Masoudkabir, F and Shabani, M and Vasheghani-Farahani, A and Behnoush, AH and Khalaji, A}, title = {Updates on Pharmacologic Management of Microvascular Angina.}, journal = {Cardiovascular therapeutics}, volume = {2022}, number = {}, pages = {6080258}, pmid = {36382021}, issn = {1755-5922}, mesh = {Humans ; Female ; *Microvascular Angina/diagnosis/drug therapy ; *Coronary Artery Disease ; Coronary Angiography ; Angiotensin Receptor Antagonists/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; }, abstract = {Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n-acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously.}, } @article {pmid36374790, year = {2022}, author = {Flores, A and Moyano, P and Sola, E and García, JM and García, J and Anadon, MJ and Frejo, MT and Naval, MV and Fernadez, MC and Pino, JD}, title = {Single and repeated bisphenol A treatment induces ROS, Aβ and hyperphosphorylated-tau accumulation, and insulin pathways disruption, through HDAC2 and PTP1B overexpression, leading to SN56 cholinergic apoptotic cell death.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {170}, number = {}, pages = {113500}, doi = {10.1016/j.fct.2022.113500}, pmid = {36374790}, issn = {1873-6351}, mesh = {*tau Proteins/metabolism ; Reactive Oxygen Species/metabolism ; Histone Deacetylase 2/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Amyloid beta-Peptides/metabolism ; Cholinergic Neurons/metabolism ; Apoptosis ; Cholinergic Agents/metabolism ; *Insulins/metabolism ; }, abstract = {Bisphenol-A (BPA), a polymer component extensively used, produces memory and learning alterations after acute and long-term exposure. However, the mechanisms are not well known. Cortex and hippocampus neuronal networks control cognitive functions, which are innervated by basal forebrain cholinergic neurons (BFCN), and their neurodegeneration induces cognitive dysfunctions. Wild type or protein tyrosine phosphatase 1B (PTP1B), histone deacetylase 2 (HDAC2), tau or β amyloid precursor protein (βAPP) silenced SN56 cells treated with BPA (0.001 μM-100 μM) with or without N-acetylcysteine (NAC; 1 mM), following 1 and 14 days, were used, as a model of BFCN to determine the insulin pathway dysfunction, oxidative stress (OS) generation and amyloid-β (Aβ) and tau proteins accumulation involvement in the BCFN cell death induction, as a possible mechanism that could produce the cognitive disorders reported. BPA-induced BFCN cell death, after 24 h and 14 days of treatment, through insulin pathway dysfunction, OS generation, mediated by NRF2 pathway downregulation, and Aβ and tau proteins accumulation, which were in turn induced by HDAC2 and PTP1B overexpression. This is relevant information to explain the BFCN neurodegeneration mechanisms that could trigger the neurodegeneration in the rest of the regions innerved by them, leading to cognitive disorders.}, } @article {pmid36374720, year = {2023}, author = {Hsu, SS and Lin, YS and Chio, LM and Liang, WZ}, title = {Evaluation of the mycotoxin patulin on cytotoxicity and oxidative stress in human glioblastoma cells and investigation of protective effect of the antioxidant N-acetylcysteine (NAC).}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {221}, number = {}, pages = {106957}, doi = {10.1016/j.toxicon.2022.106957}, pmid = {36374720}, issn = {1879-3150}, mesh = {Humans ; *Patulin/toxicity ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology/metabolism ; *Glioblastoma/drug therapy/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Mycotoxins are secondary metabolites produced by various kinds of fungi that can induce disease in humans. The fungal species Penicillium expansum produces patulin (C7H6O4), a polyketide lactone mycotoxin found in fruits. Patulin is classified as noncarcinogen; however, recently, it has been associated with harmful effects on the central nervous system. Patulin's toxic action has been established in various brain models; however, its effect on human glioblastoma remains elusive. This study explores whether patulin induces cytotoxicity through oxidative stress in DBTRG-05MG human glioblastoma cells. This study also evaluates whether the antioxidant N-acetylcysteine (NAC) protects against patulin-induced cytotoxicity. In DBTRG-05MG cells, patulin concentration (10-60 μM) dependently induced cytotoxicity. Concerning oxidative stress, patulin (10 and 20 μM) increased the production of intracellular reactive oxygen species (ROS) but depleted reduced glutathione (GSH) contents and regulated the expressions of antioxidant-related proteins (Nrf2 and HO-1). Furthermore, patulin induced cytotoxicity via modulation of apoptosis-related protein expressions (Bax, cleaved caspase-9, and cleaved caspase-3). These cytotoxic responses were partially reversed via pretreatment with NAC (10 μM). In summary, these data help us understand the toxicology of patulin in human glioblastoma and evaluate whether NAC could clinically reduce patulin-affected brain damage.}, } @article {pmid36364008, year = {2022}, author = {Zhang, Y and Tang, Y and Tang, X and Wang, Y and Zhang, Z and Yang, H}, title = {Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {21}, pages = {}, pmid = {36364008}, issn = {1420-3049}, support = {2020J01176, 2021J02028 and 2022J01172//Fujian Natural Science Foundation/ ; 2021G02023 and 2022G023//Key Projects of Scientific and Technological Innovation in Fujian Province/ ; 2020L3008//Special Funds of the Central Government Guilding Local Science and Technology Development/ ; I202003009 and I202102008//Innovation and Entrepreneurship Project of Fujian Normal University/ ; }, mesh = {Male ; Humans ; Reactive Oxygen Species/metabolism ; Paclitaxel/pharmacology ; Caspase 3/genetics/pharmacology ; Apoptosis ; *Prostatic Neoplasms/drug therapy/genetics/pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/pharmacology ; *Antineoplastic Agents/pharmacology ; }, abstract = {Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1α works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1α mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1α through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1α signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa.}, } @article {pmid36362692, year = {2022}, author = {Mylonas, KS and Sarantis, P and Kapelouzou, A and Karamouzis, MV and Kapetanakis, EI and Kontzoglou, K and Iliopoulos, DC and Nikiteas, N and Schizas, D}, title = {Mechanosensitive Stem-Cell Genes and Klotho in Atherosclerotic Aortas: Regulating Spatially Deranged Expression Patterns Using Colchicine Regimens.}, journal = {Journal of clinical medicine}, volume = {11}, number = {21}, pages = {}, pmid = {36362692}, issn = {2077-0383}, support = {N/A//Hellenic Atherosclerosis Society/ ; N/A//Hellenic Surgical Society/ ; }, abstract = {AIMS: Inflammatory dysregulation of mechanosensitive developmental genes may be central to atherogenesis. In the present seven-week model, we utilized colchicine regimens to curtail aortic atherogenesis in New Zealand White rabbits. We also explored the effect of colchicine regimens on atheroprotective (Klotho, HOXA5, NOTCH1, and OCT4) and proatherogenic (HIF1a, SOX2, BMP4, and NANOG) genes.

METHODS: The control (n = 6) and group A (n = 6) received standard and cholesterol-enriched chow, respectively. Groups B (n = 8) and C (n = 8) were fed hypercholesterolemic diet and were treated with colchicine plus fenofibrate or N-acetylcysteine (NAC), respectively.

RESULTS: Group A developed significantly greater thoracic and abdominal aortic atherosclerosis compared to groups B (p < 0.001) and C (p < 0.001). Combining colchicine with NAC resulted in stronger atheroprotection both in the thoracic and the abdominal aorta. In group A thoracic aortas, Klotho was downregulated compared to controls (95% CI: 1.82-15.76). Both colchicine regimens upregulated Klotho back to baseline levels (p < 0.001). Colchicine/fenofibrate also significantly upregulated thoracic NOTCH1 compared to controls (95% CI: -8.09 to -0.48). Colchicine/NAC significantly reduced thoracic NANOG expression compared to hyperlipidemic diet alone (95% CI: 0.37-8.29). In the abdominal aorta, hypercholesterolemic diet resulted in significant downregulation of HOXA5 (95% CI: 0.03-2.74) which was reversed with colchicine/NAC back to baseline (95% CI: -1.19 to 1.51). Colchicine/fenofibrate downregulated HIF1a compared to baseline (95% CI: 0.83-6.44). No significant differences were noted in terms of BMP4, SOX2, and OCT4.

CONCLUSIONS: Overall, the aortic expression pattern of mechanosensitive genes seems to be spatially influenced by a hyperlipidemic diet and can be modified using colchicine-based therapy.}, } @article {pmid36359827, year = {2022}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Chovatiya, N and Huerta-Yepez, S and Ni, W and Mackay, S and Zhou, J and Maharaj, D and Malarkannan, S and Jewett, A}, title = {The Potential Role of Cytotoxic Immune Effectors in Induction, Progression and Pathogenesis of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359827}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/metabolism/pathology ; *CD8-Positive T-Lymphocytes/metabolism ; Cytokines/metabolism ; Granzymes/metabolism ; Leukocytes, Mononuclear/metabolism ; *T-Lymphocytes, Cytotoxic/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients' peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients' NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients' CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients' CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.}, } @article {pmid36359406, year = {2022}, author = {Aiyer, A and Das, T and Whiteley, GS and Glasbey, T and Kriel, FH and Farrell, J and Manos, J}, title = {The Efficacy of an N-Acetylcysteine-Antibiotic Combination Therapy on Achromobacter xylosoxidans in a Cystic Fibrosis Sputum/Lung Cell Model.}, journal = {Biomedicines}, volume = {10}, number = {11}, pages = {}, pmid = {36359406}, issn = {2227-9059}, support = {IMCRC/WLY/08052019.1 and CT20584//This research was funded by COMMERCIAL DEVELOPMENT & INDUSTRY PARTNERSHIP, grant number CT20584-University of Sydney and Whiteley Corporation and DEPARTMENT OF IN-DUSTRY, INNOVATION AND SCIENCE (Innovative Manufacturing CRC Ltd.) and WHITELEY CORPORATION/ ; }, abstract = {Cystic fibrosis (CF) is a disorder causing dysfunctional ion transport resulting in the accumulation of viscous mucus. This environment fosters a chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans, a gram-negative aerobic bacillus, has been increasingly associated with antibiotic resistance and chronic colonisation in CF. In this study, we aimed to create a reproducible model of CF infection using an artificial sputum medium (ASMDM-1) with bronchial (BEAS-2B) and macrophage (THP-1) cells to test A. xylosoxidans infection and treatment toxicity. This study was conducted in three distinct stages. First, the tolerance of BEAS-2B cell lines and two A. xylosoxidans strains against ASMDM-1 was optimised. Secondly, the cytotoxicity of combined therapy (CT) comprising N-acetylcysteine (NAC) and the antibiotics colistin or ciprofloxacin was tested on cells alone in the sputum model in both BEAS-2B and THP-1 cells. Third, the efficacy of CT was assessed in the context of a bacterial infection within the live cell/sputum model. We found that a model using 20% ASMDM-1 in both cell populations tolerated a colistin-NAC-based CT and could significantly reduce bacterial loads in vitro (~2 log10 CFU/mL compared to untreated controls). This pilot study provides the foundation to study other bacterial opportunists that infect the CF lung to observe infection and CT kinetics. This model also acts as a springboard for more complex co-culture models.}, } @article {pmid36357979, year = {2023}, author = {Li, ZQ and Zhang, C and Fan, S and Wang, LL and Jiang, Y and Li, HJ}, title = {Evidence for exposure biomarkers in dictamnine-induced liver injury resulting from metabolic activation in vitro and in mice.}, journal = {Journal of applied toxicology : JAT}, volume = {43}, number = {5}, pages = {662-679}, doi = {10.1002/jat.4414}, pmid = {36357979}, issn = {1099-1263}, mesh = {Mice ; Animals ; Activation, Metabolic ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Microsomes, Liver/metabolism ; Acetylcysteine ; Glutathione/metabolism ; }, abstract = {Dictamnine (DTN), a furoquinoline alkaloid isolated from Dictamni Cortex, is responsible for the liver injury caused by Dictamni Cortex and the preparations. Discovering new biomarkers with high specificity and sensitivity for diagnosis and tracing the source of DTN-induced liver injury is urgently needed. Considering that metabolic activation of DTN has been suggested as a primary trigger initiating hepatotoxicity, the present study aimed to investigate the bio-activation process of DTN in vitro and in mice and to explore whether the adducts could be developed as exposure biomarkers. When trapping with N-acetyl-cysteine (NAC) and glutathione (GSH) in mouse liver microsomes and CYP3A4 overexpressed L02 cells, two isomers of DTN-NAC adducts were detected in both systems and one DTN-GSH adduct was found in mouse liver microsomes. As expected, one DTN-NAC adduct was also found in plasma and bile of mice with liver injury after DTN exposure. Moreover, mouse liver microsomes were used to simulate the conjugation of serum albumin with metabolically activated DTN. The sole modified peptide [25] DAHKSEVAHR[34] was found, and the oxidative metabolites of DTN might bind to the side chain amino of albumin at Arg34. The above findings not only provided confirmative evidence that DTN was metabolically activated to induce liver injury but also suggested that the adducts had the potential to be developed as exposure biomarkers of DTN-induced liver injury.}, } @article {pmid36354958, year = {2022}, author = {Kandel, R and Singh, KP}, title = {Higher Concentrations of Folic Acid Cause Oxidative Stress, Acute Cytotoxicity, and Long-Term Fibrogenic Changes in Kidney Epithelial Cells.}, journal = {Chemical research in toxicology}, volume = {35}, number = {11}, pages = {2168-2179}, pmid = {36354958}, issn = {1520-5010}, support = {R15 DK121362/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Animals ; Mice ; *Folic Acid/pharmacology ; *Antioxidants ; Reactive Oxygen Species ; Oxidative Stress ; Kidney ; Acetylcysteine ; Epithelial Cells ; Fibrosis ; }, abstract = {Kidney fibrosis is a common step during chronic kidney disease (CKD), and its incidence has been increasing worldwide. Aberrant recovery after repeated acute kidney injury leads to fibrosis. The mechanism of fibrogenic changes in the kidney is not fully understood. Folic acid-induced kidney fibrosis in mice is an established in vivo model to study kidney fibrosis, but the mechanism is poorly understood. Moreover, the effect of higher concentrations of folic acid on kidney epithelial cells in vitro has not yet been studied. Oxidative stress is a common property of nephrotoxicants. Therefore, this study evaluated the role of folic acid-induced oxidative stress in fibrogenic changes by using the in vitro renal proximal tubular epithelial cell culture model. To obtain comprehensive and robust data, three different cell lines derived from human and mouse kidney epithelium were treated with higher concentrations of folic acid for both acute and long-term durations, and the effects were determined at the cellular and molecular levels. The result of cell viability by the MTT assay and the measurement of reactive oxygen species (ROS) levels by the DCF assay revealed that folic acid caused cytotoxicity and increased levels of ROS in acute exposure. The cotreatment with antioxidant N-acetyl cysteine (NAC) protected the cytotoxic effect, suggesting the role of folic acid-induced oxidative stress in cytotoxicity. In contrast, the long-term exposure to folic acid caused increased growth, DNA damage, and changes in the expression of marker genes for EMT, fibrosis, oxidative stress, and oxidative DNA damage. Some of these changes, particularly the acute effects, were abrogated by cotreatment with antioxidant NAC. In summary, the novel findings of this study suggest that higher concentrations of folic acid-induced oxidative stress act as the driver of cytotoxicity as an acute effect and of fibrotic changes as a long-term effect in kidney epithelial cells.}, } @article {pmid36352994, year = {2022}, author = {Parvizrad, R and Marghamlki, EG and Nikfar, S and Dermani, SK}, title = {Effects of melatonin and N-acetylcysteine on aluminum phosphide poisoning in rats.}, journal = {Journal of family medicine and primary care}, volume = {11}, number = {8}, pages = {4500-4504}, pmid = {36352994}, issn = {2249-4863}, abstract = {INTRODUCTION: Aluminum phosphide (ALP) poisoning is one of the deadliest types of poisoning in the world. The antioxidant properties of melatonin and N-acetylcysteine and their effects on reducing cell death have been identified. The aim of this study was to evaluate the effects of N-acetylcysteine and melatonin in the treatment of aluminum phosphide poisoning in rats.

MATERIALS AND METHODS: Fifty male Wistar rats weighing 200-250 g were tested in five groups of ten. The first group was the control group; the second group received (10 mg/kg) of ALP, the third group received (10 mg/kg) of ALP and (10 mg/kg) of melatonin, the fourth group received (10 mg/kg) of ALP and (10 mg/kg) of N-acetylcysteine, and the last group received (10 mg/kg) of ALP and (10 mg/kg) of melatonin and N-acetylcysteine. The plasma of samples was isolated, and the activity of antioxidant enzymes (glutathione S-transferase (GST), Superoxide dismutase (SOD), and catalase (CAT)) was analyzed.

RESULTS: The concentrations of CAT, GST, Glutathione, GSH were decreased in plasma, liver, and kidneys of mice treated with aluminum phosphide; also, the concentrations of aspartate aminotransferase (AST), ALT, and AlK were increased (P < 0.05), while the activity of SOD did not change significantly (P > 0.05). Treatment with N-acetylcysteine and melatonin led to an increase in the activity of CAT, GST, and GSH in plasma, liver, and kidney. After the administration of N-acetylcysteine and melatonin to mice, the levels of all enzymes were close to normal, and the mice survived for 12-15 hours after administration.

DISCUSSION: The administration of N-acetylcysteine (NAC) and melatonin at a dose of 10 mg/kg improves hepatic manifestations and prevents liver necrosis; also, they are considered potential therapeutic agents in the treatment of this poisoning.}, } @article {pmid36345724, year = {2022}, author = {Zalachoras, I and Ramos-Fernández, E and Hollis, F and Trovo, L and Rodrigues, J and Strasser, A and Zanoletti, O and Steiner, P and Preitner, N and Xin, L and Astori, S and Sandi, C}, title = {Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort.}, journal = {eLife}, volume = {11}, number = {}, pages = {}, pmid = {36345724}, issn = {2050-084X}, mesh = {Humans ; Male ; Rats ; Animals ; *Nucleus Accumbens/physiology ; *Motivation ; Antioxidants/metabolism ; Reward ; Glutathione/metabolism ; }, abstract = {Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes, and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy at ultra-high field in both male humans and rodent populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly, steady performance over time in effort-related tasks. Causality was established in in vivo experiments in rats that, first, showed that downregulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine increased accumbal GSH levels in rats and led to improved performance, potentially mediated by a cell-type-specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and an individual's capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.}, } @article {pmid36344940, year = {2022}, author = {Liao, Y and Wu, Y and Zi, K and Shen, Y and Wang, T and Qin, J and Chen, L and Chen, M and Liu, L and Li, W and Zhou, H and Xiong, S and Wen, F and Chen, J}, title = {The effect of N-acetylcysteine in patients with non-cystic fibrosis bronchiectasis (NINCFB): study protocol for a multicentre, double-blind, randomised, placebo-controlled trial.}, journal = {BMC pulmonary medicine}, volume = {22}, number = {1}, pages = {401}, pmid = {36344940}, issn = {1471-2466}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Quality of Life ; Prospective Studies ; RNA, Ribosomal, 16S ; Anti-Bacterial Agents ; *Bronchiectasis/complications ; Double-Blind Method ; *Cystic Fibrosis/complications ; Fibrosis ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC), which is specifically involved in airway mucus clearance and antioxidation, is recommended by the treatment guideline for non-cystic fibrosis bronchiectasis (NCFB). However, there is little clinical evidence of its long-term efficacy concerning quality of life (QoL) and exacerbation in patients with NCFB. In addition, the influences of NAC on airway bacterial colonization, chronic inflammation and oxidative stress in NCFB are also unclear.

METHODS: NINCFB is a prospective, multicentre, double-blind, randomised, placebo-controlled trial that will recruit 119 patients with NCFB and randomly divide them into an NAC group (n = 79) and a control group (n = 40). Participants in the NAC group will receive 600 mg oral NAC twice daily for 52 weeks, while patients in the control group will receive 600 mg placebo twice daily for 52 weeks. The information at baseline will be collected once participants are enrolled. The primary endpoints are the changes in St George's Respiratory Questionnaire scores and the number of exacerbations in 52 weeks. The secondary endpoints are the 16S rRNA of sputum and the levels of inflammatory factors and oxidative stressors in sputum and serum. Other data related to radiography, lung function tests, number of oral and/or intravenous antibiotic therapies and adverse events (AEs) will also be analysed. Further subgroup analysis distinguished by the severity of disease, severity of lung function, airway bacterial colonization and exacerbation frequency will be performed.

DISCUSSION: The objective of this study is to determine the long-term efficacy of NAC on QoL and exacerbation of NCFB and to explore the effectiveness of NAC for antibiosis, anti-inflammation and antioxidation in NCFB. The study results will provide high-quality clinical proof for the revision and optimization of treatment guidelines and for expert consensus on NCFB treatment.

TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Register at April 11, 2020 (chictr.org.cn , ChiCTR2000031817).}, } @article {pmid36341071, year = {2022}, author = {Akibekov, OS and Syzdykova, AS and Lider, LA and Zhumalin, AK and Baibolin, ZK and Zhagipar, FS and Akanova, ZZ and Ibzhanova, AA and Gajimuradova, AM}, title = {Hematological, biochemical, and serological parameters of experimentally infected rabbits with Trichinella nativa and Trichinella spiralis for early identification of trichinellosis.}, journal = {Veterinary world}, volume = {15}, number = {9}, pages = {2285-2292}, pmid = {36341071}, issn = {0972-8988}, abstract = {BACKGROUND AND AIM: Trichinellosis remains a dangerous disease for humans and animals, which can lead to a lethal outcome. The study of specific body reactions in response to invasion by different types of Trichinella can help in the early diagnosis of the disease. This study aimed to investigate the hematological, biochemical, and serological characteristics of rabbits experimentally infected with trichinellosis, as well as the possibility of using changes in these parameters at various disease stages for early hematological, biochemical, and serological diagnosis of trichinellosis.

MATERIALS AND METHODS: Three groups of rabbits were orally infected with Trichinella nativa and Trichinella spiralis derived from encysted T. spirtalis larvae in pork muscle samples. The first and second groups were infected with T. nativa and T. spiralis, respectively, while the third group served as control by receiving a physiological solution. An ADVIA 2120i automatic hematology analyzer with a blood smear staining module was used to determine the hematological parameters of rabbits. Antigens were used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies in the sera of infected rabbits that were supernatants containing excretory-secretory antigens (ES-Ag) and somatic antigen (S-Ag).

RESULTS: The detection of biochemical responses to the invasion of T. nativa and T. spiralis isolates was detected and hematological parameters were featured in two cases. Trichinella nativa increased the number of erythrocytes, neutrophils, eosinophils, monocytes, basophils, and thrombocytes on day 7 in rabbits. Creatine kinase (CK) is regarded as the most important indicator for the early detection of parasite invasion. Blood biochemistry showed no active response to T. spiralis infection. However, counts of erythrocytes, neutrophils, lymphocytes, and CK rose significantly. In both color indicators, the number of thrombocytes decreased. Enzyme-linked immunosorbent assay with ES-Ag and S-Ag of these isolates demonstrated the ability to detect antibodies as early as 7 days after infection, with a significant increase in the marker up to 70 days.

CONCLUSION: On the 7[th] day after infection, blood tests of infected animals revealed CK-N-acetyl-cysteine (18.2%) and neutrophils (43%) when infected with T. nativa and neutrophils (26.7%) and lymphocytes (20%) when infected with T. spiralis. These indicators may serve as specific parameters for the early detection of Trichinella spp. invasion.}, } @article {pmid36338342, year = {2022}, author = {Hsu, YC and Chuang, HC and Tsai, KL and Tu, TY and Shyong, YJ and Kuo, CH and Liu, YF and Shih, SS and Lin, CL}, title = {Administration of N-Acetylcysteine to Regress the Fibrogenic and Proinflammatory Effects of Oxidative Stress in Hypertrophic Ligamentum Flavum Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {1380353}, pmid = {36338342}, issn = {1942-0994}, mesh = {Humans ; *Ligamentum Flavum/metabolism ; Acetylcysteine/pharmacology/metabolism ; Vimentin/metabolism ; Hydrogen Peroxide/metabolism ; Hypertrophy/drug therapy/metabolism ; Transforming Growth Factor beta/metabolism ; Collagen Type I/metabolism ; Oxidative Stress ; }, abstract = {Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal stenosis (LSS). In hypertrophic ligamentum flavum (LF) cells, oxidative stress activates intracellular signaling and induces the expression of inflammatory and fibrotic markers. This study explored whether healthy and hypertrophic LF cells respond differently to oxidative stress, via examining the levels of phosphorylated p38 (p-p38), inducible nitric oxide synthase (iNOS), and α-smooth muscle actin (α-SMA). Furthermore, the efficacy of N-acetylcysteine (NAC), an antioxidant, in reversing the fibrogenic and proinflammatory effects of oxidative stress in hypertrophic LF cells was investigated by assessing the expression levels of p-p38, p-p65, iNOS, TGF-β, α-SMA, vimentin, and collagen I under H2O2 treatment with or without NAC. Under oxidative stress, p-p38 increased significantly in both hypertrophic and healthy LF cells, and iNOS was elevated in only the hypertrophic LF cells. This revealed that oxidative stress negatively affected both hypertrophic and healthy LF cells, with the hypertrophic LF cells exhibiting more active inflammation than did the healthy cells. After H2O2 treatment, p-p38, p-p65, iNOS, TGF-β, vimentin, and collagen I increased significantly, and NAC administration reversed the effects of oxidative stress. These results can form the basis of a novel therapeutic treatment for LFH using antioxidants.}, } @article {pmid36337710, year = {2022}, author = {Liu, LF and Hu, Y and Liu, YN and Shi, DW and Liu, C and Da, X and Zhu, SH and Zhu, QY and Zhang, JQ and Xu, GH}, title = {Reactive oxygen species contribute to delirium-like behavior by activating CypA/MMP9 signaling and inducing blood-brain barrier impairment in aged mice following anesthesia and surgery.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1021129}, pmid = {36337710}, issn = {1663-4365}, abstract = {Postoperative delirium (POD) is common in the elderly and is associated with poor clinical outcomes. Reactive oxygen species (ROS) and blood-brain barrier (BBB) damage have been implicated in the development of POD, but the association between these two factors and the potential mechanism is not clear. Cyclophilin A (CypA) is a specifically chemotactic leukocyte factor that can be secreted in response to ROS, which activates matrix metalloproteinase 9 (MMP9) and mediates BBB breakdown. We, therefore, hypothesized that ROS may contribute to anesthesia/surgery-induced BBB damage and delirium-like behavior via the CypA/MMP9 pathway. To test these hypotheses, 16-month-old mice were subjected to laparotomy under 3% sevoflurane anesthesia (anesthesia/surgery) for 3 h. ROS scavenger (N-acetyl-cysteine) and CypA inhibitor (Cyclosporin A) were used 0.5 h before anesthesia/surgery. A battery of behavior tests (buried food test, open field test, and Y maze test) was employed to evaluate behavioral changes at 24 h before and after surgery in the mice. Levels of tight junction proteins, CypA, MMP9, postsynaptic density protein (PSD)-95, and synaptophysin in the prefrontal cortex were assessed by western blotting. The amounts of ROS and IgG in the cortex of mice were observed by fluorescent staining. The concentration of S100β in the serum was detected by ELISA. ROS scavenger prevented the reduction in TJ proteins and restored the permeability of BBB as well as reduced the levels of CypA/MMP9, and further alleviated delirium-like behavior induced by anesthesia/surgery. Furthermore, the CypA inhibitor abolished the increased levels of CypA/MMP, which reversed BBB damage and ameliorated delirium-like behavior caused by ROS accumulation. Our findings demonstrated that ROS may participate in regulating BBB permeability in aged mice with POD via the CypA/MMP9 pathway, suggesting that CypA may be a potential molecular target for preventing POD.}, } @article {pmid36332383, year = {2023}, author = {Chilvery, S and Yelne, A and Khurana, A and Saifi, MA and Bansod, S and Anchi, P and Godugu, C}, title = {Acetaminophen induced hepatotoxicity: An overview of the promising protective effects of natural products and herbal formulations.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {108}, number = {}, pages = {154510}, doi = {10.1016/j.phymed.2022.154510}, pmid = {36332383}, issn = {1618-095X}, mesh = {Mice ; Animals ; Acetaminophen/adverse effects ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention & control/metabolism ; *Biological Products/pharmacology ; Mice, Inbred C57BL ; Liver ; Plant Extracts/pharmacology/metabolism ; }, abstract = {BACKGROUND: The liver plays an important role in regulating the metabolic processes and is the most frequently targeted organ by toxic chemicals. Acetaminophen (APAP) is a well-known anti-allergic, anti-pyretic, non-steroidal anti-inflammatory drug (NSAID), which upon overdose leads to hepatotoxicity, the major adverse event of this over-the-counter drug.

PURPOSE: APAP overdose induced acute liver injury is the second most common cause that often requires liver transplantation worldwide, for which N-acetyl cysteine is the only synthetic drug clinically approved as an antidote. So, it was felt that there is a need for the novel therapeutic approach for the treatment of liver diseases with less adverse effects. This review provides detailed analysis of the different plant extracts; phytochemicals and herbal formulations for the amelioration of APAP-induced liver injury.

METHOD: The data was collected using different online resources including PubMed, ScienceDirect, Google Scholar, Springer, and Web of Science using keywords given below.

RESULTS: Over the past decades various reports have revealed that plant-based approaches may be a better treatment choice for the APAP-induced hepatotoxicity in pre-clinical experimental conditions. Moreover, herbal compounds provide several advantages over the synthetic drugs with fewer side effects, easy availability and less cost for the treatment of life-threatening diseases.

CONCLUSION: The current review summarizes the hepatoprotective effects and therapeutic mechanisms of various plant extracts, active phytoconstituents and herbal formulations with potential application against APAP induced hepatotoxicity as the numbers of hepatoprotective natural products are more without clinical relativity. Further, pre-clinical pharmacological research will contribute to the designing of natural products as medicines with encouraging prospects for clinical application.}, } @article {pmid36322347, year = {2023}, author = {Albeltagy, RS and Dawood, SM and Mumtaz, F and Abdel Moneim, AE and El-Habit, OH}, title = {Antioxidant capacity of N-acetylcysteine against the molecular and cytotoxic implications of cadmium chloride leading to hepatotoxicity and vital progression.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {9}, pages = {23237-23247}, pmid = {36322347}, issn = {1614-7499}, mesh = {Male ; Rats ; Acetylcysteine/pharmacology ; *Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; bcl-2-Associated X Protein ; Cadmium/pharmacology ; Cadmium Chloride/pharmacology ; *Chemical and Drug Induced Liver Injury ; Glutathione/pharmacology ; Oxidative Stress ; Proto-Oncogene Proteins c-bcl-2 ; Animals ; }, abstract = {Many studies have reported that cadmium (Cd) can induce liver cell injury; however, the toxicity mechanisms of Cd on the liver have not been fully explained. Thirty-two male albino rats were divided into four groups: the control group, the N-acetylcysteine (NAC) group orally as effervescent instant sachets with a concentration of 200 mg dissolved in distilled water and dosage was 200 mg/kg body weight freshly prepared, the cadmium chloride (CdCl2) group (treated with 3 mg/kg orally), and the N-acetylcysteine (NAC) + cadmium chloride group (treated with 200 mg/kg orally post to CdCl2) for 60 days. The NAC alone did not make notable changes in most of the parameters. The CdCl2 alone, compared to control, induced significant alterations in oxidative stress markers (increment in lipid peroxidation (LPO) and nitric oxide (NO)) and antioxidant defense system (decrement in superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)), which resulted in a downregulation of pro-apoptotic Bcl2-associated X protein (Bax) and caspase-3 and upregulation of anti-apoptotic B-cell leukemia/lymphoma 2 (Bcl2) protein as well as the survival fate of hepatic cells. Post-administration of NAC to CdCl2 resulted in a reduction in oxidative stress markers, shifting of cells from the G2/M phase to the G0/G1 inhibiting signal-regulated kinase activation, and impairment of the anti-apoptotic signaling pathway when compared to the CdCl2 group alone. Accordingly, the Bcl2/Bax ratio was reduced to 1.17-fold change, as an adaptive process to hepatic tissue injury. These findings demonstrated that NAC would attenuate the possibility of oxidative stress and cytotoxicity of hepatic tissue induced by CdCl2.}, } @article {pmid36321532, year = {2022}, author = {Zhang, Q and Li, P and Li, H and Yi, D and Guo, S and Wang, L and Zhao, D and Wang, C and Wu, T and Hou, Y}, title = {Multifaceted Effects and Mechanisms of N-Acetylcysteine on Intestinal Injury in a Porcine Epidemic Diarrhea Virus-Infected Porcine Model.}, journal = {Molecular nutrition & food research}, volume = {66}, number = {24}, pages = {e2200369}, doi = {10.1002/mnfr.202200369}, pmid = {36321532}, issn = {1613-4133}, mesh = {Animals ; Acetylcysteine/pharmacology ; *Coronavirus Infections/drug therapy/veterinary ; Interferons ; *Porcine epidemic diarrhea virus/genetics ; Proteomics ; Swine ; *Swine Diseases/drug therapy ; }, abstract = {SCOPE: This study investigates the potential effects of N-acetylcysteine (NAC) on intestinal injury in a porcine epidemic diarrhea virus (PEDV)-infected porcine model.

METHODS AND RESULTS: Thirty-two piglets are randomly assigned to one of four groups: the control, PEDV, NAC, and NAC+PEDV. Piglets in the NAC+PEDV group are orally administrated with NAC (100 mg (kg·BW)[-1]  day[-1]) for 4 consecutive days after 2 days of PEDV infection. The results show that NAC administration decreases the diarrhea rate and improves intestinal morphology. The concentration of diamine oxidase and intestinal fatty-acid binding protein, as well as IL-1β, IL-8, and TNF-α in the plasma, is decreased by NAC. Intriguingly, NAC administration significantly increases the viral load in the jejunum and ileum and down-regulates the expression of interferon-related genes. Microarray and proteomic analyses show that the differentially expressed genes/proteins between NAC+PEDV and PEDV groups are highly enriched in substance transport. Furthermore, aquaporin 8/10 expression is significantly increased by NAC upon PEDV infection.

CONCLUSION: NAC administration alleviates PEDV-induced intestinal injury by inhibiting inflammatory responses and improving substance transport, but promotes viral replication by inhibiting interferon signaling. These results suggest NAC exhibits multifaceted effects upon PEDV infection, and thus caution is required when using NAC as a dietary supplement to prevent viral infection.}, } @article {pmid36321244, year = {2022}, author = {Jannatifar, R and Asa, E and Sahraei, SS and Verdi, A and Piroozmanesh, H}, title = {N-acetyl-l-cysteine and alpha lipoic acid are protective supplement on human sperm parameters in cryopreservation of asthenoteratozoospermia patients.}, journal = {Andrologia}, volume = {54}, number = {11}, pages = {e14612}, doi = {10.1111/and.14612}, pmid = {36321244}, issn = {1439-0272}, support = {//Academic Center for Education, Culture and Research/ ; }, mesh = {Humans ; Male ; *Thioctic Acid/pharmacology/therapeutic use ; Sperm Motility ; *Semen Preservation/methods ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use/metabolism ; *Asthenozoospermia/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; Cryopreservation/methods ; Spermatozoa/metabolism ; }, abstract = {The aim of this study is to evaluate the beneficial effects of N-acetyl-cysteine (NAC), alpha lipoic acid (ALA) and combination of NAC + ALA supplement in freezing medium on Sperm structural and functional in asthenoteratozoospermia patients. Thirty freshly ejaculated semen samples were cryopreserved with sperm freezing medium (SFM) as control group and three group that SFM supplemented with NAC, ALA and their combination NAC+ ALA. The sperm samples were analysed according to WHO. Mitochondrial membrane potential (MMP), acrosome reaction (AR), antioxidant enzymes and DNA fragmentation were assessed using by Rhodamine123, PSA- FITC ELISA and TUNEL staining respectively. Expression level of NRF2 was assessed by real-time PCR assay. NAC and ALA alone significantly improved sperm motility, viability and DNA fragmentation (p < 0.05). MMP increased in NAC and ALA separately (p < 0.05). While did not affect the amount of sperm morphology and AR (p > 0.05). Antioxidant enzymes significantly difference in NAC and ALA groups (p < 0.05). In addition, NAC and ALA groups showed a significantly higher expression of NRF2 gene compared with other groups (p < 0.05). Our results revealed that the ALA and NAC supplements had a protective effect in cryopreservation process on the structural and functional characteristics of sperm.}, } @article {pmid36315628, year = {2023}, author = {Zhang, M and Ma, B and Yang, S and Wang, J and Chen, J}, title = {Bisphenol A (BPA) induces apoptosis of mouse Leydig cells via oxidative stress.}, journal = {Environmental toxicology}, volume = {38}, number = {2}, pages = {312-321}, doi = {10.1002/tox.23690}, pmid = {36315628}, issn = {1522-7278}, support = {81660255//National Natural Science Foundation of China/ ; 82060278//National Natural Science Foundation of China/ ; 82171591//National Natural Science Foundation of China/ ; //Major Discipline Academic and Technical Leaders Training Program of Jiangxi Province/ ; 20212ACB206036//Natural Science Foundation of Jiangxi Province/ ; 20204BCJ22031//Natural Science Foundation of Jiangxi Province/ ; }, mesh = {Animals ; Male ; Mice ; Acetylcysteine ; *Apoptosis ; Benzhydryl Compounds/toxicity/metabolism ; *Leydig Cells/metabolism ; *Oxidative Stress ; RNA, Messenger/metabolism ; *Semen/metabolism ; Testis/metabolism ; *Phenols/metabolism/toxicity ; }, abstract = {As one of the most frequently produced synthetic compounds worldwide, bisphenol A (BPA) has been widely used in many kinds of products such as appliances, housewares, and beverage cans. BPA has been shown to cause damage to male reproductive system; however, the potential mechanism remains to be investigated. In the present study, BPA exposure decreased the testis and epididymis coefficient, caused a disintegration of germinal epithelium, decreased the density and motility of sperm in the epididymis tissue, and increased the number of abnormal sperm morphology, which indicated that BPA exposure could cause damage to testis. BPA was also shown to induce apoptosis and oxidative stress in the testis tissue. The serum testosterone concentration was decreased in the BPA-treated group, suggesting that BPA could lead to Leydig cell damage. Subsequently, mouse TM3 cell, a kind of mouse Leydig cell line, was utilized to investigate the potential mechanism. Herein, we showed that BPA exposure could inhibit cell viability and induce apoptosis of TM3 cells. Furthermore, oxidative stress in the cells could also be induced by BPA, while the inhibition of oxidative stress by N-acetyl-L-cysteine (NAC), an oxidative stress scavenger, could reverse the inhibition of cell viability and induction of apoptosis by BPA exposure, indicating that oxidative stress was involved in BPA-induced apoptosis of TM3 cells. Finally, RNA-sequencing and real-time PCR were utilized to screen and validate the potential oxidative stress-related genes involving in BPA-induced apoptosis. We found that BPA exposure increased the mRNA levels of oxidative stress-related genes such as Lonp1, Klf4, Rack1, Egln1, Txn2, Msrb1, Atox1, Mtr, and Atp2a2, as well as decreased the mRNA level of Dhfr gene; while NAC could rescue the expression of these genes. Taken together, oxidative stress was involved in BPA-induced apoptosis of mouse Leydig cells.}, } @article {pmid36314307, year = {2022}, author = {Oğuz Cumaoğlu, M and Cumaoğlu, B and Tekin, Y and Günay, N}, title = {Therapeutic effect of 6-shogaol on acetaminophen-induced hepatotoxicity in mice: an experimental study.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {20}, pages = {7371-7378}, doi = {10.26355/eurrev_202210_30006}, pmid = {36314307}, issn = {2284-0729}, mesh = {Mice ; Animals ; Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy ; Nitrites/pharmacology ; Nitrates/pharmacology ; Aspartate Aminotransferases ; Alanine Transaminase ; Acetylcysteine/pharmacology ; Liver ; Glutathione ; *Liver Diseases ; }, abstract = {OBJECTIVE: Acetaminophen (APAP) is one of the most commonly used analgesics and antipyretics. It causes serious liver damage when taken in large quantities by adults or children. Also, 6-shogaol is an active compound obtained from ginger with anti-inflammatory and antioxidant properties. This study aimed at examining the therapeutic effect of 6-shogaol in APAP-induced hepatotoxicity.

MATERIALS AND METHODS: The mice were separated into five groups. After the mice were sacrificed, the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in the blood, glutathione (GSH) level in the liver tissue homogenate, and levels of induced nitrite oxide synthetase (INOS) and total nitrite/nitrate were measured by spectrophotometric methods.

RESULTS: APAP administration significantly increased the serum levels of ALT, AST, and ALP, INOS activity in liver tissue, and total nitrite/nitrate levels compared with control and significantly decreased GSH levels. After APAP toxicity, 6-shogaol and N-acetylcysteine (NAC) administration significantly decreased the levels of ALT, AST, INOS, and total nitrite/nitrate levels and significantly increased GSH levels compared with control. Also, 6-shogaol was found to be better than NAC in increasing the GSH level.

CONCLUSIONS: The study showed that 6-shogaol might have an early therapeutic effect on APAP-induced liver damage.}, } @article {pmid36313085, year = {2022}, author = {Finnegan, E and Daly, E and Pearce, AJ and Ryan, L}, title = {Nutritional interventions to support acute mTBI recovery.}, journal = {Frontiers in nutrition}, volume = {9}, number = {}, pages = {977728}, pmid = {36313085}, issn = {2296-861X}, abstract = {UNLABELLED: When mild traumatic brain injury (mTBI) occurs following an impact on the head or body, the brain is disrupted leading to a series of metabolic events that may alter the brain's ability to function and repair itself. These changes may place increased nutritional demands on the body. Little is known on whether nutritional interventions are safe for patients to implement post mTBI and whether they may improve recovery outcomes. To address this knowledge gap, we conducted a systematic review to determine what nutritional interventions have been prescribed to humans diagnosed with mTBI during its acute period (<14 days) to support, facilitate, and result in measured recovery outcomes.

METHODS: Databases CINAHL, PubMed, SPORTDiscus, Web of Science, and the Cochrane Library were searched from inception until January 6, 2021; 4,848 studies were identified. After removing duplicates and applying the inclusion and exclusion criteria, this systematic review included 11 full papers.

RESULTS: Patients that consumed enough food to meet calorie and macronutrient (protein) needs specific to their injury severity and sex within 96 h post mTBI had a reduced length of stay in hospital. In addition, patients receiving nutrients and non-nutrient support within 24-96 h post mTBI had positive recovery outcomes. These interventions included omega-3 fatty acids (DHA and EPA), vitamin D, mineral magnesium oxide, amino acid derivative N-acetyl cysteine, hyperosmolar sodium lactate, and nootropic cerebrolysin demonstrated positive recovery outcomes, such as symptom resolution, improved cognitive function, and replenished nutrient deficiencies (vitamin D) for patients post mTBI.

CONCLUSION: Our findings suggest that nutrition plays a positive role during acute mTBI recovery. Following mTBI, patient needs are unique, and this review presents the potential for certain nutritional therapies to support the brain in recovery, specifically omega-3 fatty acids. However, due to the heterogenicity nature of the studies available at present, it is not possible to make definitive recommendations.

The systematic review conducted following the PRISMA guidelines protocol was registered (CRD42021226819), on Prospero.}, } @article {pmid36312742, year = {2022}, author = {Nasr, S and Perl, A}, title = {Principles behind SLE treatment with N-acetylcysteine.}, journal = {Immunometabolism (Cobham, Surrey)}, volume = {4}, number = {4}, pages = {e00010}, pmid = {36312742}, issn = {2633-0407}, abstract = {Systemic lupus erythematous (SLE) is a multisystem chronic autoimmune disease in which disrupted molecular pathways lead to multiple clinical manifestations. Currently approved treatments include hydroxychloroquine, some immunosuppressive medications, and some biologics. They all come with a range of side effects. N-acetylcysteine (NAC) is an antioxidant that has shown potential benefits in SLE patients without having major side effects. The following review highlights the molecular mechanisms behind the therapeutic effect of NAC in SLE patients. A higher-than normal mitochondrial transmembrane potential or mitochondrial hyperpolarization (MHP) was found in lymphocytes from SLE patients. MHP is attributed the blocked electron transport, and it is associated with the depletion of ATP and glutathione and the accumulation of oxidative stress-generating mitochondria due to diminished mitophagy. Comprehensive metabolome analyses identified the accumulation of kynurenine as the most predictive metabolic biomarker of lupus over matched healthy subjects. Cysteine is the rate-limiting constituent in the production of reduced glutathione, and it can be replaced by its precursor NAC. Kynurenine accumulation has been reversed by treatment with NAC but not placebo in the setting of a double-blind placebo-controlled clinical trial of 3-month duration. Mitochondrial oxidative stress and its responsiveness to NAC have been linked to systemic inflammation, gut microbiome changes, and organ damage in lupus-prone mice. Given the unique safety of NAC and chronicity of SLE, the clinical trial of longer duration is being pursued.}, } @article {pmid36312610, year = {2022}, author = {Kumar, S and Bhagat, P and Pandey, S and Pandey, R}, title = {The Role of Antioxidant Agent (N-Acetylcysteine) in Oleic Acid-Induced Acute Lung Injury in a Rat Model.}, journal = {Cureus}, volume = {14}, number = {9}, pages = {e29478}, pmid = {36312610}, issn = {2168-8184}, abstract = {Context Reactive oxygen species (ROS) produced by inflammatory cells play a major role in mediating lung injury in sepsis or hyperoxic lung injury. Aims N-Acetylcysteine (NAC), an antioxidant, was examined in this research to see whether it helps prevent acute lung injury (ALI). Materials and methods Experiments were performed on Charles-Foster strain healthy male adult albino rats. All the animals were randomly divided into one control and two experimental groups. In control/group I, saline was administered, and cardiorespiratory parameters were recorded. Oleic acid (OA) was administered in group II to produce ALI. In group III, OA was administered to NAC-pretreated rats, and cardiorespiratory parameters were recorded to observe the effect of NAC on ALI. This study used analysis of variance (ANOVA) with two factors and a post hoc test (multiple comparisons - least significant difference (LSD) test) for statical analysis. For determining survival time, the Mantel-Cox test and Kaplan-Meier survival curves were used. A P value < 0.05 was considered significant. Results Respiratory arrest, pulmonary edema, and reduced partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio were all indications of OA-induced ALI in rats. The animals in the NAC + OA group had better respiratory and cardiac statistics than those in the OA alone group, and their survival duration was extended. However, NAC pretreatment could not protect the animals against the development of pulmonary edema. Conclusions These observations indicate that NAC (an antioxidant agent) protected rats against ALI in the initial phase and prolonged the survival time but failed to prevent the development of pulmonary edema.}, } @article {pmid36308430, year = {2023}, author = {Khalid, F and Phan, T and Qiang, M and Maity, P and Lasser, T and Wiese, S and Penzo, M and Alupei, M and Orioli, D and Scharffetter-Kochanek, K and Iben, S}, title = {TFIIH mutations can impact on translational fidelity of the ribosome.}, journal = {Human molecular genetics}, volume = {32}, number = {7}, pages = {1102-1113}, pmid = {36308430}, issn = {1460-2083}, mesh = {Humans ; Transcription Factor TFIIH/genetics/metabolism ; DNA Repair/genetics ; *Xeroderma Pigmentosum/genetics/pathology ; Mutation ; *Trichothiodystrophy Syndromes/genetics/pathology ; Ribosomes/genetics/metabolism ; }, abstract = {TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.}, } @article {pmid36306926, year = {2022}, author = {Wang, JX and Wang, XL and Xu, ZQ and Zhang, Y and Xue, D and Zhu, R and Chen, Q and Li, YH and Zhu, GQ and Tan, X}, title = {Chemerin-9 in paraventricular nucleus increases sympathetic outflow and blood pressure via glutamate receptor-mediated ROS generation.}, journal = {European journal of pharmacology}, volume = {936}, number = {}, pages = {175343}, doi = {10.1016/j.ejphar.2022.175343}, pmid = {36306926}, issn = {1879-0712}, mesh = {Animals ; Male ; Rats ; Blood Pressure ; Dizocilpine Maleate/pharmacology ; NADPH Oxidases/metabolism ; *Paraventricular Hypothalamic Nucleus ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Receptors, Chemokine ; Receptors, Glutamate ; *Superoxides ; Sympathetic Nervous System ; Verapamil/pharmacology ; }, abstract = {Chemerin is an adipokine involved in regulating energy homeostasis and reproductive function. Excessive sympathetic activity contributes to hypertension, chronic heart failure and chronic renal disease. Hypothalamic paraventricular nucleus (PVN) is crucial in regulating sympathetic activity and blood pressure. The present study is designed to investigate the roles of chemerin in the PVN in regulating sympathetic activity and blood pressure and underlying mechanisms. Microinjections were performed in the bilateral PVN in male adult rats under anesthesia. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded. The PVN microinjection of chemerin-9, an active fragment of chemerin, increased RSNA and MAP, which were abolished by chemokine-like receptor 1 (CMKLR1) antagonist α-NETA, a superoxide scavenger tempol, antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and apocynin. Immunofluorescence analyses showed that N-methyl-D-aspartate (NMDA) receptors existed in most of cells of the PVN, and some of them co-existed with chemerin. The effects of chemerin-9 on RSNA and MAP were prevented by glutamate-binding site antagonist L-phenylalanine, NMDA receptor antagonist MK-801, and calcium channel blocker verapamil or nifedipine, but only attenuated by non-NMDA receptor antagonist CNQX. Moreover, chemerin-9 increased NADPH oxidase activity and superoxide production, which were prevented by α-NETA, MK-801, or verapamil. These results indicate that chemerin-9 in the PVN increases sympathetic activity and blood pressure via CMKLR1-dependent calcium influx, and glutamate receptor-mediated NADPH oxidase activation and subsequent superoxide production.}, } @article {pmid36305293, year = {2022}, author = {Shakya, R and Park, GH and Joo, SH and Shim, JH and Choi, JS}, title = {Hydroxyzine Induces Cell Death in Triple-Negative Breast Cancer Cells via Mitochondrial Superoxide and Modulation of Jak2/STAT3 Signaling.}, journal = {Biomolecules & therapeutics}, volume = {30}, number = {6}, pages = {585-592}, pmid = {36305293}, issn = {1976-9148}, abstract = {Treatment of triple-negative breast cancer (TNBC) has been limited due to the lack of molecular targets. In this study, we evaluated the cytotoxicity of hydroxyzine, a histamine H1 receptor antagonist in human triple-negative breast cancer BT-20 and HCC-70 cells. Hydroxyzine inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay showed that hydroxyzine induced apoptosis. The hydroxyzine-induced apoptosis was accompanied down-regulation of cyclins and CDKs, as well as the generation of reactive oxygen species (ROS) without cell cycle arrest. The effect of hydroxyzine on the induction of ROS and apoptosis on TNBC cells was prevented by pre-treatment with ROS scavengers, N-acetyl cysteine or Mito-TEMPO, a mitochondria-targeted antioxidant, indicating that an increase in the generation of ROS mediated the apoptosis induced by hydroxyzine. Western blot analysis showed that hydroxyzine-induced apoptosis was through down-regulation of the phosphorylation of JAK2 and STAT3 by hydroxyzine treatment. In addition, hydroxyzine induced the phosphorylation of JNK and p38 MAPK. Our results indicate that hydroxyzine induced apoptosis via mitochondrial superoxide generation and the suppression of JAK2/STAT3 signaling.}, } @article {pmid36302499, year = {2022}, author = {Su, Y and Yin, X and Huang, X and Guo, Q and Ma, M and Guo, L}, title = {Astragaloside IV ameliorates sepsis-induced myocardial dysfunction by regulating NOX4/JNK/BAX pathway.}, journal = {Life sciences}, volume = {310}, number = {}, pages = {121123}, doi = {10.1016/j.lfs.2022.121123}, pmid = {36302499}, issn = {1879-0631}, mesh = {Animals ; Rats ; Apoptosis ; bcl-2-Associated X Protein ; Caspase 3 ; Lipopolysaccharides ; Myocytes, Cardiac/metabolism ; NADPH Oxidase 4 ; Rats, Sprague-Dawley ; *Sepsis/complications/drug therapy/metabolism ; *Saponins/therapeutic use ; *Triterpenes/therapeutic use ; }, abstract = {AIMS: Sepsis can induce multiple organ dysfunction, and sepsis-induced myocardial dysfunction (SIMD) is relatively common. The current dilemma might ascribe partly to SIMD's lack of unified molecular mechanisms. Our study aims to assess the function of Astragaloside IV (ASI) in cecal ligation and puncture (CLP)-induced cardiac dysfunction and explore its underlying mechanisms.

MAIN METHODS: In vivo, ASI (30 mg/kg/day), NADPH oxidase 4 (NOX4) inhibitor 4-hydroxy-3-methoxyacetophenone (APO, 30 mg/kg/day), reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC, 150 mg/kg/day) and c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125, 15 mg/kg/day) were severally administered to Sprague Dawley rats following the CLP surgery. The cardiac function, cardiac enzyme markers, proinflammatory cytokine, and cell apoptosis-associated proteins were detected. In vitro, cardiomyocyte H9C2 cells were treated with lipopolysaccharide (LPS, 40 μg/ml) after the presence of ASI (100 μmol/ml), SP600125 (10 μmol/ml), APO (10 μmol/ml). A series of experiments verified the relationship among NOX4, JNK, and BAX.

KEY FINDINGS: The results indicated that CLP-induced sepsis increased the secretion of creatine kinase isoenzymes (CKMB), brain natriuretic peptide (BNP), cardiac troponin T (c-TnI), interleukin-1β (IL-1β) and interleukin-18 (IL-18), as well as the protein expression of NOX4 and Caspase-3 in vivo. LPS increased the protein level of NOX4 and Caspase-3, upregulated the rate of p-JNK/JNK, and downregulated the rate of Bcl2/BAX in vitro. ASI can reverse these changes in vivo and has a synergistic effect with APO and SP600125 in vitro.

SIGNIFICANCE: This study suggested that ASI may ameliorate SIMD, through regulating NOX4/JNK/BAX signaling pathway, which may be a feasible therapeutic strategy.}, } @article {pmid36300938, year = {2022}, author = {Deng, Z and Sun, R and Han, X and Zhang, Y and Zhou, Y and Shan, Y and Xu, J and Li, X and He, F and Fang, W}, title = {Porcine Circovirus 2 Activates the PERK-Reactive Oxygen Species Axis To Induce p53 Phosphorylation with Subsequent Cell Cycle Arrest at S Phase in Favor of Its Replication.}, journal = {Journal of virology}, volume = {96}, number = {22}, pages = {e0127422}, pmid = {36300938}, issn = {1098-5514}, mesh = {Animals ; Acetylcysteine/pharmacology ; *Cell Cycle Checkpoints ; *Circoviridae Infections/veterinary/virology ; *Circovirus/physiology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; S Phase ; Swine ; *Swine Diseases/virology ; Tumor Suppressor Protein p53/genetics/metabolism ; Virus Replication/genetics ; Endoplasmic Reticulum Stress ; eIF-2 Kinase/metabolism ; }, abstract = {Porcine circovirus type 2 (PCV2), the causative agent of porcine circovirus-associated diseases (PCVAD), is known to induce oxidative stress, activate p53 with induction of cell cycle arrest, and trigger the PERK (protein kinase R-like endoplasmic reticulum kinase) branch of the endoplasmic reticulum (ER) stress pathway. All these cellular responses could enhance PCV2 replication. However, it remains unknown whether PERK activation by PCV2 is involved in p53 signaling with subsequent changes of cell cycle. Here, we demonstrate that PCV2 infection induced cell cycle arrest at S phase to favor its replication via the PERK-reactive oxygen species (ROS)-p53 nexus. PCV2 infection promoted phosphorylation of p53 (p-p53) at Ser15 in porcine alveolar macrophages. Inhibition of PERK by RNA silencing downregulated total p53 (t-p53) and p-p53. Treatment with the MDM2 inhibitor nutlin-3 led to partial recovery of t-p53 in perk-silenced and PCV2-infected cells. perk silencing markedly downregulated ROS production. Scavenging of ROS with N-acetylcysteine (NAC) of PCV2-infected cells downregulated t-p53 and p-p53. Increased accumulation of p-p53 in the nuclei during PCV2 infection could be downregulated by silencing of perk or NAC treatment. Further studies showed that perk silencing or NAC treatment alleviated S phase accumulation and downregulated cyclins E1 and A2 in PCV2-infected cells. These findings indicate that the PCV2-activated PERK-ROS axis promotes p-p53 and contributes to cell cycle accumulation at S phase when more cellular enzymes are available to favor viral DNA synthesis. Overall, our study provides a novel insight into the mechanism how PCV2 manipulates the host PERK-ROS-p53 signaling nexus to benefit its own replication via cell cycle arrest. IMPORTANCE Coinfections or noninfectious triggers have long been considered to potentiate PCV2 infection, leading to manifestation of PCVAD. The triggering mechanisms remain largely unknown. Recent studies have revealed that PERK-mediated ER stress, oxidative stress, and cell cycle arrest during PCV2 infection are conducive to viral replication. However, how PCV2 employs such host cell responses requires further research. Here, we provide a novel mechanism of PCV2-induced ER stress and enhanced viral replication: the PCV2-activated PERK-ROS-p53 nexus increases S phase cell population, a cell cycle period of DNA synthesis favorable for PCV2 replication. The fact that PCV2 deploys the simple ROS molecules to activate p53 to benefit its replication provides novel insights into the triggering factors, that is, certain stimuli or management measures that induce ER stress with subsequent generation of ROS would exacerbate PCVAD. Use of antioxidants is justified on farms where PCVAD is severe.}, } @article {pmid36299882, year = {2022}, author = {Mesmar, J and Abdallah, R and Hamade, K and Baydoun, S and Al-Thani, N and Shaito, A and Maresca, M and Badran, A and Baydoun, E}, title = {Ethanolic extract of Origanum syriacum L. leaves exhibits potent anti-breast cancer potential and robust antioxidant properties.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {994025}, pmid = {36299882}, issn = {1663-9812}, abstract = {UNLABELLED: Background: Breast cancer (BC) is the second most common cancer overall. In women, BC is the most prevalent cancer and the leading cause of cancer-related mortality. Triple-negative BC (TNBC) is the most aggressive BC, being resistant to hormonal and targeted therapies.

HYPOTHESIS/PURPOSE: The medicinal plant Origanum syriacum L. is a shrubby plant rich in bioactive compounds and widely used in traditional medicine to treat various diseases. However, its therapeutic potential against BC remains poorly investigated. In the present study, we screened the phytochemical content of an ethanolic extract of O. syriacum (OSEE) and investigated its anticancer effects and possible underlying mechanisms of action against the aggressive and highly metastatic human TNBC cell line MDA-MB-231.

METHODS: MTT, trans-well migration, and scratch assays were used to assess cell viability, invasion, or migration, respectively. Antioxidant potential was evaluated in vitro using the DPPH radical-scavenging assay and levels of reactive oxygen species (ROS) were assessed in cells in culture using DHE staining. Aggregation assays were used to determine cell-cell adhesion. Flow cytometry was used to analyze cell cycle progression. Protein levels of markers of apoptosis (BCL-2, pro-Caspase3, p53), proliferation (p21, Ki67), cell migration, invasion, or adhesion (FAK, E-cadherin), angiogenesis (iNOS), and cell signaling (STAT3, p38) were determined by immunoblotting. A chorioallantoic Membrane (CAM) assay evaluated in ovo angiogenesis.

RESULTS: We demonstrated that OSEE had potent radical scavenging activity in vitro and induced the generation of ROS in MDA-MB-231 cells, especially at higher OSEE concentrations. Non-cytotoxic concentrations of OSEE attenuated cell proliferation and induced G0/G1 cell cycle arrest, which was associated with phosphorylation of p38 MAPK, an increase in the levels of tumor suppressor protein p21, and a decrease of proliferation marker protein Ki67. Additionally, only higher concentrations of OSEE were able to attenuate inhibition of proliferation induced by the ROS scavenger N-acetyl cysteine (NAC), indicating that the anti-proliferative effects of OSEE could be ROS-dependent. OSEE stimulated apoptosis and its effector Caspase-3 in MDA-MB-231 cells, in correlation with activation of the STAT3/p53 pathway. Furthermore, the extract reduced the migration and invasive properties of MDA-MB-231 cells through the deactivation of focal adhesion kinase (FAK). OSEE also reduced the production of inducible nitric oxide synthase (iNOS) and inhibited in ovo angiogenesis.

CONCLUSION: Our findings reveal that OSEE is a rich source of phytochemicals and has robust anti-breast cancer properties that significantly attenuate the malignant phenotype of MD-MB-231 cells, suggesting that O. syriacum may not only act as a rich source of potential TNBC therapeutics but may also provide new avenues for the design of novel TNBC drugs.}, } @article {pmid36296600, year = {2022}, author = {Kwon, JH and Lee, NG and Kang, AR and Ahn, IH and Choi, IY and Song, JY and Hwang, SG and Um, HD and Choi, JR and Kim, J and Park, JK}, title = {JNC-1043, a Novel Podophyllotoxin Derivative, Exerts Anticancer Drug and Radiosensitizer Effects in Colorectal Cancer Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {20}, pages = {}, pmid = {36296600}, issn = {1420-3049}, support = {505382022//Ministry of Science ICT and Future Planning/ ; 505312022//Ministry of Science ICT and Future Planning/ ; 2021R1F1A1055981//National Research Foundation of Korea/ ; NRF-2020M2D9A2094153//National Research Foundation of Korea/ ; }, mesh = {Humans ; Podophyllotoxin/pharmacology ; Reactive Oxygen Species/metabolism ; Annexin A5 ; Acetylcysteine/pharmacology ; Propidium/pharmacology ; *Radiation-Sensitizing Agents/pharmacology ; Apoptosis ; *Antineoplastic Agents/pharmacology ; Cell Proliferation ; *Colorectal Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; }, abstract = {The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo [3',4':6,7] naphtho [2,3-d] [1,3]dioxol-6-one (JNC-1043), which is a novel chemical derivative of β-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells. Firstly, we used MTT assays to assess whether JNC-1043 could inhibit the cell proliferation of HCT116 and DLD-1 cells. The IC50 values of these cell lines were calculated as 114.5 and 157 nM, respectively, at 72 h of treatment. Using doses approximating the IC50 values, we tested whether JNC-1043 had a radiosensitizing effect in the CRC cell lines. Clonogenic assays revealed that the dose-enhancement ratios (DER) of HCT116 and DLD-1 cells were 1.53 and 1.25, respectively. Cell-counting assays showed that the combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50~60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20~30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30~40% compared to that induced by JNC-1043 or IR alone. DCFDA- and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by the combination of JNC-1043 and IR. Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.}, } @article {pmid36293450, year = {2022}, author = {Wang, XL and Wang, JX and Chen, JL and Hao, WY and Xu, WZ and Xu, ZQ and Jiang, YT and Luo, PQ and Chen, Q and Li, YH and Zhu, GQ and Li, XZ}, title = {Asprosin in the Paraventricular Nucleus Induces Sympathetic Activation and Pressor Responses via cAMP-Dependent ROS Production.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293450}, issn = {1422-0067}, support = {31871148 & 32071106//National Natural Science Foundation of China/ ; }, mesh = {Male ; Rats ; Animals ; *Paraventricular Hypothalamic Nucleus/metabolism ; Reactive Oxygen Species/metabolism ; *Superoxides/metabolism ; Adenylyl Cyclases/metabolism ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; Rats, Sprague-Dawley ; Sympathetic Nervous System ; Blood Pressure ; NADPH Oxidases/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Adipokines/metabolism ; RNA, Messenger/metabolism ; }, abstract = {Asprosin is a newly discovered adipokine that is involved in regulating metabolism. Sympathetic overactivity contributes to the pathogenesis of several cardiovascular diseases. The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in the regulation of sympathetic outflow and blood pressure. This study was designed to determine the roles and underlying mechanisms of asprosin in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male adult SD rats under anesthesia. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded, and PVN microinjections were performed bilaterally. Asprosin mRNA and protein expressions were high in the PVN. The high asprosin expression in the PVN was involved in both the parvocellular and magnocellular regions according to immunohistochemical analysis. Microinjection of asprosin into the PVN produced dose-related increases in RSNA, MAP, and HR, which were abolished by superoxide scavenger tempol, antioxidant N-acetylcysteine (NAC), and NADPH oxidase inhibitor apocynin. The asprosin promoted superoxide production and increased NADPH oxidase activity in the PVN. Furthermore, it increased the cAMP level, adenylyl cyclase (AC) activity, and protein kinase A (PKA) activity in the PVN. The roles of asprosin in increasing RSNA, MAP, and HR were prevented by pretreatment with AC inhibitor SQ22536 or PKA inhibitor H89 in the PVN. Microinjection of cAMP analog db-cAMP into the PVN played similar roles with asprosin in increasing the RSNA, MAP, and HR, but failed to further augment the effects of asprosin. Pretreatment with PVN microinjection of SQ22536 or H89 abolished the roles of asprosin in increasing superoxide production and NADPH oxidase activity in the PVN. These results indicated that asprosin in the PVN increased the sympathetic outflow, blood pressure, and heart rate via cAMP-PKA signaling-mediated NADPH oxidase activation and the subsequent superoxide production.}, } @article {pmid36291336, year = {2022}, author = {Dogaru, IA and Puiu, MG and Manea, M and Dionisie, V}, title = {Current Perspectives on Pharmacological and Non-Pharmacological Interventions for the Inflammatory Mechanism of Unipolar Depression.}, journal = {Brain sciences}, volume = {12}, number = {10}, pages = {}, pmid = {36291336}, issn = {2076-3425}, abstract = {Since depression remains a major public health issue there is a constant need for new and more efficient therapeutic strategies based on the mechanisms involved in the aetiology of depression. Thus, the pathogenic link between depression and inflammation is considered to play a potential key role in the development of such therapies. This review summarizes the results of various pharmacological (non-steroidal anti-inflammatory drugs, aspirin, cyclooxygenase inhibitors, cytokine inhibitors, corticosteroids, statins, minocycline, N-acetyl cysteine, omega-3 fatty acids and probiotics) and non-pharmacological interventions (electroconvulsive therapy, physical exercise and psychological therapy) and outlines their efficacy and discusses potential challenges. Both conventional and non-conventional anti-inflammatory drugs showed promising results according to the specific group of patients. The pre-existing pro-inflammatory status was, in most cases, a predictor for clinical efficacy and, in some cases, a correlation between clinical improvement and changes in various biomarkers was found. Some of the non-pharmacological interventions (physical exercise and electroconvulsive therapy) have also showed beneficial effects for depressive patients with elevated inflammatory markers. Treatments with anti-inflammatory action may improve clinical outcomes in depression, at least for some categories of patients, thus opening the way for a future personalised approach to patients with unipolar depression regarding the inflammation-related mechanism.}, } @article {pmid36291178, year = {2022}, author = {La Maestra, S and Garibaldi, S and Balansky, R and D'Agostini, F and Micale, RT and De Flora, S}, title = {Inhibition of the Cell Uptake of Delta and Omicron SARS-CoV-2 Pseudoviruses by N-Acetylcysteine Irrespective of the Oxidoreductive Environment.}, journal = {Cells}, volume = {11}, number = {20}, pages = {}, pmid = {36291178}, issn = {2073-4409}, mesh = {Humans ; *Angiotensin-Converting Enzyme 2 ; SARS-CoV-2 ; Acetylcysteine/pharmacology ; Hydrogen Peroxide/pharmacology ; Reactive Oxygen Species ; Antioxidants/pharmacology ; HEK293 Cells ; Peptidyl-Dipeptidase A/metabolism ; Ascorbic Acid/pharmacology ; Oxidants/pharmacology ; Sulfhydryl Compounds/pharmacology ; *COVID-19 Drug Treatment ; }, abstract = {The binding of SARS-CoV-2 spikes to the cell receptor angiotensin-converting enzyme 2 (ACE2) is a crucial target both in the prevention and in the therapy of COVID-19. We explored the involvement of oxidoreductive mechanisms by investigating the effects of oxidants and antioxidants on virus uptake by ACE2-expressing cells of human origin (ACE2-HEK293). The cell uptake of pseudoviruses carrying the envelope of either Delta or Omicron variants of SARS-CoV-2 was evaluated by means of a cytofluorimetric approach. The thiol N-acetyl-L-cysteine (NAC) inhibited the uptake of both variants in a reproducible and dose-dependent fashion. Ascorbic acid showed modest effects. In contrast, neither hydrogen peroxide (H2O2) nor a system-generating reactive oxygen species (ROS), which play an important role in the intracellular alterations produced by SARS-CoV-2, were able to affect the ability of either Delta or Omicron SARS-CoV-2 pseudoviruses to be internalized into ACE2-expressing cells. In addition, neither H2O2 nor the ROS generating system interfered with the ability of NAC to inhibit that mechanism. Moreover, based on previous studies, a preventive pharmacological approach with NAC would have the advantage of decreasing the risk of developing COVID-19, irrespective of its variants, and at the same time other respiratory viral infections and associated comorbidities.}, } @article {pmid36290795, year = {2022}, author = {Chen, YN and Chan, CK and Yen, CY and Shiau, JP and Chang, MY and Wang, CC and Jeng, JH and Tang, JY and Chang, HW}, title = {Antioral Cancer Effects by the Nitrated [6,6,6]Tricycles Compound (SK1) In Vitro.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290795}, issn = {2076-3921}, support = {MOST 111-2320-B-037-015-MY3; MOST 110-2314-B-037-074-MY3//Ministry of Science and Technology/ ; KMU-DK(A)111008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {A novel nitrated [6,6,6]tricycles-derived compound containing nitro, methoxy, and ispropyloxy groups, namely SK1, was developed in our previous report. However, the anticancer effects of SK1 were not assessed. Moreover, SK1 contains two nitro groups (NO2) and one nitrogen-oxygen (N-O) bond exhibiting the potential for oxidative stress generation, but this was not examined. The present study aimed to evaluate the antiproliferation effects and oxidative stress and its associated responses between oral cancer and normal cells. Based on the MTS assay, SK1 demonstrated more antiproliferation ability in oral cancer cells than normal cells, reversed by N-acetylcysteine. This suggests that SK1 causes antiproliferation effects preferentially in an oxidative stress-dependent manner. The oxidative stress-associated responses were further validated, showing higher ROS/MitoSOX burst, MMP, and GSH depletion in oral cancer cells than in normal cells. Meanwhile, SK1 caused oxidative stress-causing apoptosis, such as caspases 3/8/9, and DNA damages, such as γH2AX and 8-OHdG, to a greater extent in oral cancer cells than in normal cells. Siilar to cell viability, these oxidative stress responses were partially diminished by NAC, indicating that SK1 promoted oxidative stress-dependent responses. In conclusion, SK1 exerts oxidative stress, apoptosis, and DNA damage to a greater extent to oral cancer cells than in normal cells.}, } @article {pmid36290682, year = {2022}, author = {Georgiou-Siafis, SK and Samiotaki, MK and Demopoulos, VJ and Panayotou, G and Tsiftsoglou, AS}, title = {Glutathione-Hemin/Hematin Adduct Formation to Disintegrate Cytotoxic Oxidant Hemin/Hematin in Human K562 Cells and Red Blood Cells' Hemolysates: Impact of Glutathione on the Hemolytic Disorders and Homeostasis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290682}, issn = {2076-3921}, abstract = {Hemin, an oxidized form of heme, acts as potent oxidant to regulate glutathione (GSH) content in pro-erythroid K562 nucleated cells, via activation of the KEAP1/NRF2 defensive signaling pathway. Moreover, GSH, as an essential metabolite, is involved in the regulation of cell-redox homeostasis and proposed to scavenge cytotoxic free heme, which is released from hemoglobin of damaged red blood cells (RBCs) during different hemolytic disorders. In the present study, we aimed to uncover the molecular mechanism by which GSH inhibits hemin-induced cytotoxicity (HIC) by affecting hemin's structural integrity in K562 cells and in RBC hemolysates. GSH, along with other thiols (cysteine, thioglycolic acid, and mercaptoethanol) altered the spectrum of hemin, while each of them co-added with hemin in cultures of K562 cells prevented HIC and growth arrest and markedly reduced the intracellular level of hemin. In addition, GSH endogenous levels served as a barrier to HIC in K562 cells, as shown by the depletion in GSH. LC-MS/MS analysis of the in vitro reaction between hemin and GSH revealed at least five different isomers of GSH-hemin adducts, as well as hydroxy derivatives as reaction products, which are characterized by unique mass spectra (MS). The latter allowed the detection of adducts in human RBC hemolysates. Based on these findings, we proposed a molecular mechanism via which GSH prevents HIC and structurally disintegrates heme. An analogous reaction was observed in RBC hemolysates via direct inter-reaction between hematin (ferric and hydroxide heme) released from hemoglobin and GSH. Overall, GSH-hematin adducts could be considered as novel entities of the human metabolome of RBCs in hemolytic disorders.}, } @article {pmid36290612, year = {2022}, author = {Jin, W and Kam, MK and Lee, SW and Park, YH and Lee, HJ and Lee, DS}, title = {Peroxiredoxin 2 Ameliorates AβO-Mediated Autophagy by Inhibiting ROS via the ROS-NRF2-p62 Pathway in N2a-APP Swedish Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290612}, issn = {2076-3921}, support = {2020R1A2B5B01002563//Republic of Korea government/ ; 20009707//the Ministry of Trade, Industry & Energy (MOTIE, Korea)/ ; 2021R1I1A1A01042201//the Ministry of Education/ ; }, abstract = {In Alzheimer's disease, reactive oxygen species (ROS) are generated by the deposition of amyloid-beta oligomers (AβOs), which represent one of the important causes of neuronal cell death. Additionally, AβOs are known to induce autophagy via ROS induction. Previous studies have shown that autophagy upregulation aggravates neuronal cell death. In this study, the effects of peroxiredoxin 2 (Prx2), a member of the peroxidase family of antioxidant enzymes, on regulating AβO-mediated autophagy were investigated. Prx2 decreased AβO-mediated oxidative stress and autophagy in N2a-APPswe cells. Further, we examined the relationship between the neuronal protective effect of Prx2 and a decrease in autophagy. Similar to the effects of N-acetyl cysteine, Prx2 decreased AβO-induced ROS and inhibited p62 protein expression levels by downregulating the activation of NRF2 and its translocation to the nucleus. In addition, treatment with 3-methyladenine, an autophagy inhibitor, ameliorates neuronal cell death. Overall, these results demonstrate that the Prx2-induced decrease in autophagy was associated with the inhibition of ROS via the ROS-NRF2-p62 pathway in N2a-APPswe cells. Therefore, our results revealed that Prx2 is a potential therapeutic target in anti-Alzheimer therapy.}, } @article {pmid36290607, year = {2022}, author = {Kim, JE and Lee, DS and Kang, TC}, title = {Sp1-Mediated Prdx6 Upregulation Leads to Clasmatodendrosis by Increasing Its aiPLA2 Activity in the CA1 Astrocytes in Chronic Epilepsy Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290607}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; }, abstract = {Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood. Peroxiredoxin-6 (Prdx6), the "non-selenium glutathione peroxidase (NSGPx)", is the only member of the 1-cysteine peroxiredoxin family. Unlike the other Prdx family, Prdx6 has multiple functions as glutathione peroxidase (GPx) and acidic calcium-independent phospholipase (aiPLA2). The present study shows that Prdx6 was upregulated in CA1 astrocytes in chronic epilepsy rats. 2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and N-acetylcysteine (NAC, a precursor of glutathione) ameliorated clasmatodendrosis accompanied by reduced Prdx6 level in CA1 astrocytes. Specificity protein 1 (Sp1) expression was upregulated in CA1 astrocyte, which was inhibited by mithramycin A (MMA). MMA alleviated clasmatodendrosis and Prdx6 upregulation. Sp1 expression was also downregulated by CDDO-Me and NAC. Furthermore, 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) attenuated clasmatodendrosis without affecting Prdx6 expression. All chemicals shortened spontaneous seizure duration but not seizure frequency and behavioral seizure severity in chronic epilepsy rats. Therefore, our findings suggest that Sp1 activation may upregulate Prdx6, whose aiPLA2 activity would dominate over GPx activity in CA1 astrocytes and may lead to prolonged seizure activity due to autophagic astroglial degeneration.}, } @article {pmid36290593, year = {2022}, author = {Rambaud, V and Marzo, A and Chaumette, B}, title = {Oxidative Stress and Emergence of Psychosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290593}, issn = {2076-3921}, abstract = {Treatment and prevention strategies for schizophrenia require knowledge about the mechanisms involved in the psychotic transition. Increasing evidence suggests a redox imbalance in schizophrenia patients. This narrative review presents an overview of the scientific literature regarding blood oxidative stress markers' evolution in the early stages of psychosis and chronic patients. Studies investigating peripheral levels of oxidative stress in schizophrenia patients, first episode of psychosis or UHR individuals were considered. A total of 76 peer-reviewed articles published from 1991 to 2022 on PubMed and EMBASE were included. Schizophrenia patients present with increased levels of oxidative damage to lipids in the blood, and decreased levels of non-enzymatic antioxidants. Genetic studies provide evidence for altered antioxidant functions in patients. Antioxidant blood levels are decreased before psychosis onset and blood levels of oxidative stress correlate with symptoms severity in patients. Finally, adjunct treatment of antipsychotics with the antioxidant N-acetyl cysteine appears to be effective in schizophrenia patients. Further studies are required to assess its efficacy as a prevention strategy. Redox imbalance might contribute to the pathophysiology of emerging psychosis and could serve as a therapeutic target for preventive or adjunctive therapies, as well as biomarkers of disease progression.}, } @article {pmid36289489, year = {2022}, author = {Li, Y and Yu, H and Lv, M and Li, Q and Zou, K and Lv, S}, title = {Combination therapy with budesonide and N-acetylcysteine ameliorates LPS-induced ALI by attenuating neutrophil recruitment through the miR-196b-5p/Socs3 molecular axis.}, journal = {BMC pulmonary medicine}, volume = {22}, number = {1}, pages = {388}, pmid = {36289489}, issn = {1471-2466}, mesh = {Rats ; Animals ; Lipopolysaccharides ; Acetylcysteine ; Neutrophil Infiltration ; Budesonide/pharmacology ; Eosine Yellowish-(YS)/adverse effects ; Hematoxylin ; *Acute Lung Injury/chemically induced/drug therapy/metabolism ; *MicroRNAs/genetics/metabolism ; RNA, Messenger ; Suppressor of Cytokine Signaling 3 Protein/genetics/metabolism ; }, abstract = {BACKGROUND: Neutrophil infiltration accelerates the inflammatory response and is highly correlated to the development of acute lung injury (ALI). Budesonide (BUD) and N-acetylcysteine (NAC) both inhibit the inflammatory response to alleviate ALI, so we further investigated whether their combination is better for ALI.

METHODS: In this study, we investigated the effect and mechanism of Combined BUD and NAC therapy on LPS-induced ALI. Rat ALI model and neutrophil abnormal activation model were established by lipopolysaccharide (LPS). BUD and NAC were treated alone or in combination, or cells were transfected with miR-196b-5p mimic or si-Socs3 to evaluate the efficacy and mechanism of BUD and NAC alone or in combination. Histopathological observation of lungs was performed by Hematoxylin Eosin (HE) staining. The quantity of neutrophils and inflammatory factors level in bronchoalveolar lavage fluid (BALF) were determined by Richter-Gimza complex stain and Enzyme-Linked Immunosorbnent Assay (ELISA), respectively. ReverseTranscription-PolymeraseChainReaction (RT-qPCR) was utilized to assess miR-196b-5p and inflammatory factor mRNA levels. The expression level of Socs3 was detected by immunohistochemistry or Western Blot.

RESULTS: BUD and NAC combined treatment had a better effect on neutrophil recruitment and inflammatory response in LPS-induced ALI than did BUD and NAC alone. Transfection of the miR-196b-5p mimic reversed the effect of combined BUD and NAC. In conclusion, the combination of BUD and NAC is a better treatment for ALI.

CONCLUSIONS: Combination therapy with BUD and NAC ameliorates LPS-induced ALI by attenuating neutrophil recruitment through the miR-196b-5p/Socs3 molecular axis.}, } @article {pmid36285551, year = {2022}, author = {Jalalian, R and Maleki, M and Ghafari, R and Habibi, V and Heydari, S and Iranian, M}, title = {Comparing the efficacy of N-acetylcysteine plus carvedilol versus carvedilol in the prevention of atrial fibrillation following coronary artery bypass graft surgery.}, journal = {Journal of cardiac surgery}, volume = {37}, number = {12}, pages = {4698-4704}, doi = {10.1111/jocs.17062}, pmid = {36285551}, issn = {1540-8191}, mesh = {Humans ; Carvedilol/therapeutic use ; *Atrial Fibrillation/epidemiology/etiology/prevention & control ; Acetylcysteine/therapeutic use ; Coronary Artery Bypass/adverse effects ; Adrenergic beta-Antagonists/therapeutic use ; Postoperative Complications/epidemiology/prevention & control ; }, abstract = {BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia following open-heart surgery. Agents with antioxidant properties may reduce postoperative complications like postoperative AF (POAF) in patients undergoing open-heart surgery. This study was conducted to assess the effect of N-acetylcysteine (NAC) in prevention of AF following coronary artery bypass graft (CABG) surgery.

METHODS: Three hundred patients who underwent CABG surgery were entered in the study. Patients with contraindications for beta-blockers and patients were simultaneously replacing or repairing the valve with open-heart surgery were excluded. The patients were randomly divided into two groups (n = 150) and they were received NAC plus carvedilol or carvedilol. The patients were monitored for 5 days after surgery and the incidence of AF during hospitalization was recorded.

RESULTS: AF was detected in 14 patients in the NAC with Carvedilol group (9.33%) and 23 patients in Carvedilol group (15.33%). There was no significant difference in the incidence of POAF between the two groups (p value = 0.112). The result of multivariable regression model represented that although the incidence of POAF was lower in NAC plus carvedilol group, it wasn't statistically significant (p value = 0.10).

CONCLUSIONS: NAC was not associated with a decreased incidence of AF following CABG surgery.}, } @article {pmid36280140, year = {2023}, author = {Zheng, Z and Xie, J and Ma, L and Hao, Z and Zhang, W and Li, L}, title = {Vitamin D Receptor Activation Targets ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Hepatocytes in Cholestasic Mice.}, journal = {Cellular and molecular gastroenterology and hepatology}, volume = {15}, number = {4}, pages = {887-901}, pmid = {36280140}, issn = {2352-345X}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Receptors, Calcitriol/metabolism ; Hepatocytes/metabolism ; Apoptosis ; Extracellular Signal-Regulated MAP Kinases/metabolism ; *Cholestasis/pathology ; Autophagy/genetics ; Mitogen-Activated Protein Kinase Kinases/metabolism ; RNA, Small Interfering/metabolism ; }, abstract = {BACKGROUND & AIMS: Observational epidemiologic studies have associated vitamin D deficiency with cholestasis. We reported previously that activation of the vitamin D/vitamin D receptor (VDR) axis in cholangiocytes mitigates cholestatic liver injury by remodeling the damaged bile duct. However, the function of VDR in hepatocytes during cholestasis remains unclear.

METHODS: Paricalcitol (VDR agonist, 200 ng/kg) was injected intraperitoneally into bile duct-ligated mice every other day for 5 days. Primary hepatocytes and HepG2 hepatoma cells were transfected with Vdr short hairpin RNA, control short hairpin RNA, Vdr plasmid, control vector, Atg5 small interfering RNA (siRNA), and control siRNA. Liver histology, cell proliferation, and autophagy were evaluated.

RESULTS: Treatment with the VDR agonist paricalcitol improved liver injury in bile duct-ligated mice by up-regulating VDR expression in hepatocytes, which in turn reduced hepatocyte apoptosis by inhibiting reactive oxygen species (ROS) generation via suppressing the Ras-related C3 botulinum toxin substrate 1/reduced nicotinamide adenine dinucleotide phosphate oxidase 1 pathway. Mechanistically, upon exposure to an ROS-inducing compound, Vdr siRNA contributed to apoptosis, whereas the Vdr overexpression caused resistance to apoptosis. Interestingly, up-regulated VDR expression also increased the generation of autophagosomes and macroautophagic/autophagic flux, which was the underlying mechanism for reduced apoptosis following VDR activation. Autophagy depletion impaired the positive effects of VDR overexpression, whereas autophagy induction was synergystic with VDR overexpression. Importantly, up-regulation of VDR promoted autophagy activation by suppressing the activation of the extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (p38MAPK) pathway. Thus, a p38MAPK inhibitor abrogated the Vdr siRNA-induced decrease in autophagy and the Vdr siRNA-induced increase in apoptosis. In contrast, a Mitogen-activated protein kinase kinase (MEK)/ERK activator prevented the enhancement of autophagy and decreased apoptosis following Vdr overexpression. Moreover, the ROS inhibitor N-acetylcystein (NAC) blocked Vdr siRNA-enhanced activation of the ERK/p38MAPK pathway.

CONCLUSIONS: VDR activation mitigated liver cholestatic injury by reducing autophagy-dependent hepatocyte apoptosis and suppressing the activation of the ROS-dependent ERK/p38MAPK pathway. Thus, VDR activation may be a potential target for the treatment of cholestatic liver disease.}, } @article {pmid36275479, year = {2022}, author = {Xu, Y and Zhao, Y and Liu, S and Lv, S and Chen, L and Wang, W and Feng, Y and Fu, F and Xu, H}, title = {Zinc Oxide Particles Can Cause Ovarian Toxicity by Oxidative Stress in Female Mice Model.}, journal = {International journal of nanomedicine}, volume = {17}, number = {}, pages = {4947-4960}, pmid = {36275479}, issn = {1178-2013}, mesh = {Female ; Mice ; Animals ; *Zinc Oxide/pharmacology ; NF-E2-Related Factor 2/metabolism ; Ovary ; Kelch-Like ECH-Associated Protein 1/metabolism ; Antioxidants/pharmacology ; Eosine Yellowish-(YS)/metabolism/pharmacology ; Hematoxylin/metabolism/pharmacology ; Progesterone ; Oxidative Stress ; *Nanoparticles ; Malondialdehyde/metabolism ; Acetylcysteine/pharmacology ; Superoxide Dismutase/metabolism ; Estradiol/pharmacology ; }, abstract = {INTRODUCTION: Zinc oxide nanoparticles (ZnO NPs) participate in all aspects of our lives, but with their wide application, more and more disadvantages are exposed. The goal of this study was to investigate the toxicity of ZnO NPs in female mice ovaries and explore its potential mechanism.

METHODS: In this study, adult female mice were orally exposed to 0, 100, 200, and 400 mg/kg ZnO NPs for 7 days. We explored the underlying mechanisms via the intraperitoneal injection of N-acetyl-cysteine (NAC), an inhibitor of oxidative stress, and salubrinal (Sal), an inhibitor of endoplasmic reticulum (ER) stress.

RESULTS: The results indicated that serum estradiol and progesterone levels declined greatly with increasing ZnO NPs dosage. Hematoxylin and eosin (HE) staining revealed increased atretic follicles and exfoliated follicular granulosa cells. Moreover, at the transcriptional level, antioxidant-related genes such as Keap1 and Nrf2, and ER stress-related genes PERK, eIF2α, and ATF4 were markedly upregulated. In addition, the expression of Caspase12, Caspase9, and Caspase3, which are genes related to apoptosis, was also upregulated in all ZnO NPs treatment groups. Serum malondialdehyde (MDA) content was remarkably up-regulated, whereas superoxide dismutase (SOD) activity was down-regulated. The 400 mg/kg ZnO NPs treatment group suffered the most substantial harm. However, ovarian damage was repaired when NAC and Sal were added to this group.

CONCLUSION: ZnO NPs had toxic effects on the ovary of female mice, which were due to oxidative stress, ER stress, and the eventual activation of apoptosis.}, } @article {pmid36273750, year = {2022}, author = {Gregory, EA and Binagia, EM}, title = {Anaphylaxis due to First-Time Intravenous Infusion of N-Acetylcysteine in a Dog.}, journal = {Topics in companion animal medicine}, volume = {51}, number = {}, pages = {100734}, doi = {10.1016/j.tcam.2022.100734}, pmid = {36273750}, issn = {1946-9837}, mesh = {Humans ; Female ; Dogs ; Animals ; Acetylcysteine/therapeutic use ; *Anaphylaxis/chemically induced/drug therapy/veterinary ; Infusions, Intravenous/veterinary ; Diphenhydramine/therapeutic use ; Epinephrine ; *Dog Diseases/chemically induced/drug therapy ; }, abstract = {A 4-year-old female spayed Pomeranian was referred to the emergency service for intermittent trouble breathing and an enlarged liver found on ultrasound. A severe mixed hepatopathy was found on bloodwork, and ultrasound-guided liver aspirates showed marked hepatocellular vacuolar changes and rare neutrophils. An intravenous (IV) loading dose of n-acetylcysteine (NAC) was given for the first time in this patient, and immediately after the infusion the patient collapsed, became hypotensive, hypothermic, tachycardic, and developed gallbladder wall edema. Treatment for anaphylaxis was immediately initiated with IV fluids, an epinephrine bolus and then continuous rate infusion, diphenhydramine, and famotidine. Clinical signs resolved within an hour of treatment with no recurrence. The hepatic enzymopathy improved, and the patient was ultimately diagnosed with a steroid hepatopathy based on laparoscopic liver biopsies. Anaphylaxis caused by first-time administration of IV NAC in a dog has not previously been reported, though it is known to occur in humans. Based on this report, it would be clinically wise to give careful consideration before prescribing NAC in cases where it is not a specific antidote or if other options are available, and to closely monitor the patient during and immediately after administration.}, } @article {pmid36273620, year = {2022}, author = {Tang, D and Zheng, S and Liu, C and Zuo, N and Yan, R and Wu, C and Ma, J and Wang, C and Chen, B and Liu, S and He, Y}, title = {Kinesin spindle protein inhibitor exacerbates cisplatin-induced hair cell damage.}, journal = {Archives of biochemistry and biophysics}, volume = {731}, number = {}, pages = {109432}, doi = {10.1016/j.abb.2022.109432}, pmid = {36273620}, issn = {1096-0384}, mesh = {Mice ; Animals ; Cisplatin/toxicity ; Kinesins ; *Ototoxicity ; Superoxides ; *Antineoplastic Agents/toxicity ; Reactive Oxygen Species/metabolism ; Cell Survival ; Apoptosis ; }, abstract = {There is emerging evidence indicating that Kinesin family, plays vital roles in influencing the growth of axons, interference with the progression of tumor. However, the function of Kinesin member in the auditory organs remains unknown. SB743921, a kinesin spindle protein (KSP) inhibitor, was applied in mouse organ of Corti and House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line to examine the role of KSP in auditory system with and without cisplatin damage. Cell Counting Kit-8 (CCK-8) and Lactase dehydrogenase (LDH) release assay were conducted to evaluate cell activity and toxicity. Pretreatment with SB743921 increased the sensitivity of HEI-OC1 cells to cisplatin ototoxicity through promoting cell apoptosis and deteriorating superoxide generation mediated damage from cisplatin. SB743921 also enhanced cisplatin induced hair cell damage in explants of mouse cochleae in vitro. Furthermore, the combined N-acetylcysteine (NAC) treatment with cisplatin or with cisplatin and SB743921 both completely rescued the reduced number of hair cells impaired by cisplatin, confirming the strengthening function of superoxide accumulation by SB743921 after cisplatin treatment. Inhibition of kinesin spindle protein enhanced the susceptibility of hair cells to cisplatin induced damage in mouse cochlear explants and HEI-OC1 cells, indicating that kinesin spindle protein might be an unprecedented target to weaken the ototoxicity of platinum medicaments.}, } @article {pmid36270032, year = {2022}, author = {Mohammadi, E and Nikbakht, F and Barati, M and Roghani, M and Vazifekhah, S and Khanizadeh, AM and Heidari, Z}, title = {Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR.}, journal = {Neuropeptides}, volume = {96}, number = {}, pages = {102294}, doi = {10.1016/j.npep.2022.102294}, pmid = {36270032}, issn = {1532-2785}, mesh = {Animals ; Rats ; *Acetylcysteine/metabolism ; *Epilepsy, Temporal Lobe/drug therapy/chemically induced ; Hippocampus ; Mitochondrial Dynamics ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Understanding the underlying molecular mechanisms involved in epilepsy is critical for the development of more effective therapies. It is believed that mTOR (Mechanistic Target of Rapamycin kinases) activity and the mitochondrial dynamic balance change during epilepsy. mTOR affects mitochondrial fission by stimulating the translation of mitochondrial fission process 1 (MTFP1). In This study, the protective role of N-acetylcysteine was studied in temporal lobe epilepsy (TLE) through the regulation of mTOR and mitochondrial dynamic proteins. Rats received N-acetylcysteine (oral administration) seven days before induction of epilepsy, followed by one day after epilepsy. TLE was induced by microinjection of kainite into the left lateral ventricle. The total mTOR and Drp1 levels in the hippocampus were evaluated by western blotting. MFN1 was assessed using immunohistochemistry, and the expression of Fis.1 and MTFP1 (fission-related proteins) and OPA (fusion-related protein) were detected by real-time PCR. The mitochondrial membrane potential was measured by Rhodamin 123. The results showed that 72 h after induction of epilepsy, the mTOR protein level increased, and the balance of the mitochondrial dynamic was disturbed; however, oral administration of NAC decreased the mTOR protein level and improved the mitochondrial dynamic. These findings indicate that NAC plays a neuroprotective role in temporal lobe epilepsy, probably through decreasing the mTOR protein level, which can improve the imbalance in the mitochondrial dynamic.}, } @article {pmid36267623, year = {2022}, author = {Li, X and Wang, Z and Wang, H and Xu, H and Sheng, Y and Lian, F}, title = {Role of N-acetylcysteine treatment in women with advanced age undergoing IVF/ICSI cycles: A prospective study.}, journal = {Frontiers in medicine}, volume = {9}, number = {}, pages = {917146}, pmid = {36267623}, issn = {2296-858X}, abstract = {OBJECTIVE: The main objective of this study was to explore the efficacy of a new antioxidant N-acetylcysteine (NAC) supplementation in reproductive outcomes of advanced age women undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET), and the effect on the expression of L-glutathione (GSH) in follicular fluid (FF) and mitochondrial DNA (mtDNA) copy number of granulosa cells.

METHODS: The present prospective randomized controlled study was conducted in 200 patients with advanced age women undergoing GnRH antagonist protocol. The treatment group (group A) consisted of 100 women who received N-acetylcysteine treatment from the menstrual phase of the previous cycle for about 45 days using the GnRH antagonist protocol. The control group (group B) consisted of 100 women who received the same protocol without N-acetylcysteine. Total gonadotrophin dosage the number of oocyte received, high-quality blastocysts, and pregnancy outcomes were compared between two groups. Pregnancy outcomes included biochemical pregnancy rate, clinical pregnancy rate, embryo implantation rate, ectopic pregnancy rate, multiple pregnancy rate, and ongoing pregnancy rate. Follicular fluid (FF) was collected after oocytes were gathered. The GSH content in the FF was tested with enzyme linked immunosorbent assay (ELISA). The mtDNA copy number of the granulosa cells was measured using real-time PCR techniques.

RESULTS: Total doses of Gn in the NAC treatment group were less than those in the control group (2385.50 ± 879.19 vs. 2527.63 ± 1170.33, P = 0.047). Compared with the control, the number of high-quality blastocysts in NAC treatment increased significantly (1.82 ± 2.12 vs. 1.43 ± 1.58, p = 0.014). Clinical pregnancy rates did not differ in both groups (all P > 0.05). At the same time, the GSH content in the FF differed significantly between the two groups (1.88 ± 1.23 vs. 1.07 ± 0.70, p = 0.001). There was no significant difference in the mtDNA copy number between the two groups (P = 0.157).

CONCLUSION: A combination of NAC and Gn treatment is capable of improving the ovarian response to superovulation drugs in assisted reproductive technologies (ARTs) and also in aged populations. The addition of NAC during IVF can improve the quality of blastocysts in advanced age female subjects. However, more clinical trials are required to be designed to confirm this conclusion in future.

ETHICS AND DISSEMINATION: The experiment solicited approval from the Institutional ethics committee of the Affiliated Reproductive Hospital of Shandong University. All the participants provided written informed consent. This survey was conducted as per the Declaration of Helsinki and relevant amendments.

TRIAL REGISTRATION NUMBER: www.chictr.org.cn, identifier ChiCTR2100048297.}, } @article {pmid36263951, year = {2023}, author = {Bian, J and Liang, H and Zhang, M}, title = {Comparison of Clinical Effectiveness Between Ambroxol and N-Acetylcysteine in Surgical Patients: A Retrospective Cohort Study.}, journal = {Journal of clinical pharmacology}, volume = {63}, number = {2}, pages = {172-179}, doi = {10.1002/jcph.2157}, pmid = {36263951}, issn = {1552-4604}, mesh = {Humans ; Adolescent ; Adult ; *Acetylcysteine/therapeutic use ; *Ambroxol/therapeutic use ; Retrospective Studies ; Lung ; Expectorants/therapeutic use ; Postoperative Complications/prevention & control/drug therapy/epidemiology ; Treatment Outcome ; }, abstract = {Postoperative pulmonary complications (PPCs) are a major cause of postoperative morbidity, mortality, and longer hospital stays. Expectorants are widely used during the perioperative period to reduce PPCs. This study aimed to compare the clinical effectiveness between ambroxol (AMB) and N-acetylcysteine (NAC) in patients undergoing surgery. A multicenter, retrospective cohort study was conducted using deidentified medical records from hospital information system. Between July 1, 2015, and November 30, 2017, patients aged ≥18 years, who received intravenous AMB or nebulized NAC as the only expectorant therapy for >3 days during their hospitalization for thoracic, abdominal, and neurosurgery, were included in this study. The clinical outcomes were evaluated, and propensity score matching was used to adjust significant differences between 2 groups. A total of 4025 cases in the AMB group and 2062 in NAC group after propensity score matching were identified. The incidence of PPCs (13.9% vs 11.6%; P = .013), postoperative sputum suction (17.2% vs 8.0%; P < .001), intensive care unit admission after surgery (25.1% vs 22.5%; P = .024), and postoperative mechanical ventilation (22.3% versus 17.5%; P < .001) in the AMB group were all significantly higher than those in the NAC group. This study suggested that patients treated with NAC during the perioperative period had a significantly lower risk of PPCs. However, further prospective study is needed to ensure the replicability of our findings.}, } @article {pmid36258210, year = {2022}, author = {Zhan, Y and Zhang, Z and Liu, Y and Fang, Y and Xie, Y and Zheng, Y and Li, G and Liang, L and Ding, Y}, title = {NUPR1 contributes to radiation resistance by maintaining ROS homeostasis via AhR/CYP signal axis in hepatocellular carcinoma.}, journal = {BMC medicine}, volume = {20}, number = {1}, pages = {365}, pmid = {36258210}, issn = {1741-7015}, mesh = {Humans ; *Carcinoma, Hepatocellular/metabolism ; Receptors, Aryl Hydrocarbon/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Liver Neoplasms/metabolism ; Nuclear Proteins/metabolism ; Acetylcysteine ; Signal Transduction ; Homeostasis ; Cytochrome P-450 Enzyme System/metabolism ; Cell Line, Tumor ; Apoptosis ; }, abstract = {BACKGROUND: Radiotherapy (RT) is one of the major therapeutic approaches to hepatocellular carcinoma (HCC). Ionizing radiation (IR) inducing the generation of reactive oxygen species (ROS) leads to a promising antitumor effect. However, the dysregulation of the redox system often causes radioresistance and impairs the efficacy of RT. Increasing evidence indicates that nuclear protein 1 (NUPR1) plays a critical role in redox reactions. In this study, we aim to explore the role of NUPR1 in maintaining ROS homeostasis and radioresistance in HCC.

METHODS: The radioresistant role of NUPR1 was determined by colony formation assay, comet assay in vitro, and xenograft tumor models in vivo. Probes for ROS, apoptosis assay, and lipid peroxidation assay were used to investigate the functional effect of NUPR1 on ROS homeostasis and oxidative stress. RNA sequencing and co-immunoprecipitation assay were performed to clarify the mechanism of NUPR1 inhibiting the AhR/CYP signal axis. Finally, we analyzed clinical specimens to assess the predictive value of NUPR1 and AhR in the radiotherapeutic efficacy of HCC.

RESULTS: We demonstrated that NUPR1 was upregulated in HCC tissues and verified that NUPR1 increased the radioresistance of HCC in vitro and in vivo. NUPR1 alleviated the generation of ROS and suppressed oxidative stress, including apoptosis and lipid peroxidation by downregulating cytochrome P450 (CYP) upon IR. ROS scavenger N-acetyl-L-cysteine (NAC) and CYP inhibitor alizarin restored the viability of NUPR1-knockdown cells during IR. Mechanistically, the interaction between NUPR1 and aryl hydrocarbon receptor (AhR) promoted the degradation and decreased nuclear translation of AhR via the autophagy-lysosome pathway, followed by being incapable of CYP's transcription. Furthermore, genetically and pharmacologically activating AhR abrogated the radioresistant role of NUPR1. Clinical data suggested that NUPR1 and AhR could serve as novel biomarkers for predicting the radiation response of HCC.

CONCLUSIONS: Our findings revealed the role of NUPR1 in regulating ROS homeostasis and oxidative stress via the AhR/CYP signal axis upon IR. Strategies targeting the NUPR1/AhR/CYP pathway may have important clinical applications for improving the radiotherapeutic efficacy of HCC.}, } @article {pmid36255562, year = {2023}, author = {Pan, J and Zhao, J and Feng, L and Xu, X and He, Z and Liang, W}, title = {Inhibition of USP14 Suppresses ROS-dependent Ferroptosis and Alleviates Renal Ischemia/Reperfusion Injury.}, journal = {Cell biochemistry and biophysics}, volume = {81}, number = {1}, pages = {87-96}, pmid = {36255562}, issn = {1559-0283}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Ferroptosis ; Kidney/metabolism ; *Reperfusion Injury/drug therapy/metabolism ; Ischemia ; *Acute Kidney Injury/drug therapy ; Ubiquitin Thiolesterase ; }, abstract = {The ubiquitin-specific protease 14 (USP14) is a deubiquitinating enzyme, its inhibitor was reported could alleviate the ischemia/reperfusion (I/R)-stimulated cerebral neuronal damage. However, its specific role in I/R-induced acute kidney injury (AKI) remains unclear. We established hypoxia/reoxygenation (H/R)-induced HK-2 cell injury model in vitro and I/R-induced kidney injury mice model in vivo. The expression or activity of USP14 was inhibited by siRNA or IU1, a small molecule inhibitor of USP14. ROS were scavenged by N-acetyl-cysteine (NAC). Biochemical index analysis and hematoxylin & eosin (H&E) staining were performed to evaluate renal injury. The results indicated that USP14 was upregulated in H/R-induced HK-2 cells and kidney tissues of I/R mice. Inhibition of USP14 suppressed the cell death, inflammatory, oxidative stress and reactive oxygen species (ROS)-dependent ferroptosis of H/R-induced HK-2 cells. What's more, IU1 and NAC effectively alleviated renal injury of I/R mice. In summary, this study suggested that inhibition of USP14 protected renal from I/R injury.}, } @article {pmid36250047, year = {2022}, author = {Singh, A and Zhao, X and Drlica, K}, title = {Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {938032}, pmid = {36250047}, issn = {2235-2988}, mesh = {Animals ; Anti-Bacterial Agents/pharmacology ; Antitubercular Agents/pharmacology/therapeutic use ; Cysteine ; DNA Gyrase/genetics ; *Disinfectants ; *Extensively Drug-Resistant Tuberculosis/drug therapy ; Fluoroquinolones/pharmacology ; Mice ; Microbial Sensitivity Tests ; Moxifloxacin ; *Mycobacterium tuberculosis/genetics/metabolism ; NAD ; Reactive Oxygen Species ; *Tuberculosis, Multidrug-Resistant/drug therapy ; }, abstract = {With tuberculosis, the emergence of fluoroquinolone resistance erodes the ability of treatment to interrupt the progression of MDR-TB to XDR-TB. One way to reduce the emergence of resistance is to identify heteroresistant infections in which subpopulations of resistant mutants are likely to expand and make the infections fully resistant: treatment modification can be instituted to suppress mutant enrichment. Rapid DNA-based detection methods exploit the finding that fluoroquinolone-resistant substitutions occur largely in a few codons of DNA gyrase. A second approach for restricting the emergence of resistance involves understanding fluoroquinolone lethality through studies of antimicrobial tolerance, a condition in which bacteria fail to be killed even though their growth is blocked by lethal agents. Studies with Escherichia coli guide work with Mycobacterium tuberculosis. Lethal action, which is mechanistically distinct from blocking growth, is associated with a surge in respiration and reactive oxygen species (ROS). Mutations in carbohydrate metabolism that attenuate ROS accumulation create pan-tolerance to antimicrobials, disinfectants, and environmental stressors. These observations indicate the existence of a general death pathway with respect to stressors. M. tuberculosis displays a variation on the death pathway idea, as stress-induced ROS is generated by NADH-mediated reductive stress rather than by respiration. A third approach, which emerges from lethality studies, uses a small molecule, N-acetyl cysteine, to artificially increase respiration and additional ROS accumulation. That enhances moxifloxacin lethality with M. tuberculosis in culture, during infection of cultured macrophages, and with infection of mice. Addition of ROS stimulators to fluoroquinolone treatment of tuberculosis constitutes a new direction for suppressing the transition of MDR-TB to XDR-TB.}, } @article {pmid36249602, year = {2022}, author = {Alsugoor, MH}, title = {Availability of Antidotes for Management of Acute Toxicity Cases at Emergency Departments in Qassim Hospitals: A Retrospective Study.}, journal = {Cureus}, volume = {14}, number = {9}, pages = {e28992}, pmid = {36249602}, issn = {2168-8184}, abstract = {BACKGROUND: Drug overdose is a medico-social issue worldwide that may occur intentionally or unintentionally. It is one of the most common reasons for emergency department visits, and it is also a frequent cause of morbidity and mortality globally. This study aims to determine the occurrence of acute toxicity cases and their management outcomes at the emergency departments in Qassim Province hospitals in Saudi Arabia. In addition, the study aims to investigate the antidote availabilities at those medical centers.

METHODS: A retrospective hospital record-based study of acute toxicity cases admitted to the emergency department in hospitals in Qassim during the period from January 1, 2020, to December 31, 2020, was conducted. Data were collected based on hospital resources such as gastrointestinal decontamination, stabilization, elimination enhancement resources, and antidotes from Qassim hospitals, and the availability of antidotes as well as the clinical data of the patients with the management outcome.

RESULTS: A total of 264 patients with acute toxicity were admitted to the emergency departments of 14 hospitals in Qassim Province in 2020. Of the 264 cases, 179 (68%) were males, and 85 (32%) cases were females. Ninety-five percent of the cases were admitted to public hospitals, whereas 5% were admitted to private hospitals. The largest group by age of admitted cases were aged 11-20 years (19.3%). This study showed that 99% received appropriate treatment for their cause of toxicity, whereas 1% did not. The most common causes of toxicity in Qassim were found to be food poisoning (20.5%), followed by intentional suicide attempts with warfarin/enoxaparin/aspirin overdoses (15.9%) and acetaminophen (paracetamol) overdosage seen in 15.5% of admitted cases. Flagyl, in addition to fluids, was used in the management of 16.7% of cases, N-acetyl cysteine was used for 16.3%, and vitamins K and B6 were used for 14.0% of cases. Activated charcoal, atropine, calcium chloride, calcium gluconate, flumazenil, insulin, magnesium, sodium bicarbonate, and vitamin K were available at all the studied hospitals. However, all the hospitals lacked both ethylenediaminetetraacetic acid (EDTA) and a cyanide kit. Methylene blue and leucovorin were available in only one of the studied hospitals.}, } @article {pmid36247436, year = {2022}, author = {Chen, JJ and Lee, TH and Kuo, G and Huang, YT and Chen, PR and Chen, SW and Yang, HY and Hsu, HH and Hsiao, CC and Yang, CH and Lee, CC and Chen, YC and Chang, CH}, title = {Strategies for post-cardiac surgery acute kidney injury prevention: A network meta-analysis of randomized controlled trials.}, journal = {Frontiers in cardiovascular medicine}, volume = {9}, number = {}, pages = {960581}, pmid = {36247436}, issn = {2297-055X}, abstract = {OBJECTS: Cardiac surgery is associated with acute kidney injury (AKI). However, the effects of various pharmacological and non-pharmacological strategies for AKI prevention have not been thoroughly investigated, and their effectiveness in preventing AKI-related adverse outcomes has not been systematically evaluated.

METHODS: Studies from PubMed, Embase, and Medline and registered trials from published through December 2021 that evaluated strategies for preventing post-cardiac surgery AKI were identified. The effectiveness of these strategies was assessed through a network meta-analysis (NMA). The secondary outcomes were prevention of dialysis-requiring AKI, mortality, intensive care unit (ICU) length of stay (LOS), and hospital LOS. The interventions were ranked using the P-score method. Confidence in the results of the NMA was assessed using the Confidence in NMA (CINeMA) framework.

RESULTS: A total of 161 trials (involving 46,619 participants) and 53 strategies were identified. Eight pharmacological strategies {natriuretic peptides [odds ratio (OR): 0.30, 95% confidence interval (CI): 0.19-0.47], nitroprusside [OR: 0.29, 95% CI: 0.12-0.68], fenoldopam [OR: 0.36, 95% CI: 0.17-0.76], tolvaptan [OR: 0.35, 95% CI: 0.14-0.90], N-acetyl cysteine with carvedilol [OR: 0.37, 95% CI: 0.16-0.85], dexmedetomidine [OR: 0.49, 95% CI: 0.32-0.76;], levosimendan [OR: 0.56, 95% CI: 0.37-0.84], and erythropoietin [OR: 0.62, 95% CI: 0.41-0.94]} and one non-pharmacological intervention (remote ischemic preconditioning, OR: 0.76, 95% CI: 0.63-0.92) were associated with a lower incidence of post-cardiac surgery AKI with moderate to low confidence. Among these nine strategies, five (fenoldopam, erythropoietin, natriuretic peptides, levosimendan, and remote ischemic preconditioning) were associated with a shorter ICU LOS, and two (natriuretic peptides [OR: 0.30, 95% CI: 0.15-0.60] and levosimendan [OR: 0.68, 95% CI: 0.49-0.95]) were associated with a lower incidence of dialysis-requiring AKI. Natriuretic peptides were also associated with a lower risk of mortality (OR: 0.50, 95% CI: 0.29-0.86). The results of a sensitivity analysis support the robustness and effectiveness of natriuretic peptides and dexmedetomidine.

CONCLUSION: Nine potentially effective strategies were identified. Natriuretic peptide therapy was the most effective pharmacological strategy, and remote ischemic preconditioning was the only effective non-pharmacological strategy. Preventive strategies might also help prevent AKI-related adverse outcomes. Additional studies are required to explore the optimal dosages and protocols for potentially effective AKI prevention strategies.}, } @article {pmid36244131, year = {2022}, author = {Koda, Y and Nagasaki, Y}, title = {Design of cysteine-based self-assembling polymer drugs for anticancer chemotherapy.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {220}, number = {}, pages = {112909}, doi = {10.1016/j.colsurfb.2022.112909}, pmid = {36244131}, issn = {1873-4367}, mesh = {Humans ; Mice ; Animals ; *Micelles ; *Polymers/chemistry ; Cysteine/chemistry ; Polyethylene Glycols/chemistry ; Drug Carriers/chemistry ; }, abstract = {Reactive oxygen species (ROS) play essential roles in the body, such as the production of energy in oxidative phosphorylation and signal transduction for homeostasis. Redox balance in biological systems gradually collapses due to various environmental factors, including aging and disease, and induces oxidative stress in the body. None of the natural or synthetic antioxidants have been approved clinically, owing to their adverse effects. Herein, we developed L-cysteine (Cys)-based polymer micelles as new self-assembling antioxidants to reduce the adverse effects of conventional antioxidants. Poly(ethylene glycol)-block-poly(L-cysteine) (PEG-block-PCys) was synthesized via anionic ring-opening polymerization. Because the free SH groups in the side chains of the PCys segment were protected by disulfide bonds, the obtained block copolymers were amphiphilic and formed polymer micelles (Nano[Cys]s) of tens of nanometers in size in aqueous media. The stability of Nano[Cys]s in the presence of bovine serum albumin (BSA) was increased by increasing the molecular weight (MW) of the PCys segments, which was analyzed using dynamic light scattering (DLS). The size and coagulation tendency of Nano[Cys]s were also analyzed using DLS measurements by changing the pH and NaCl concentration. Nano[Cys]s were confirmed to be less toxic both in vitro and in vivo than N-acetylcysteine (NAC) because of their size and biocompatible PEG surface layer. Intraperitoneal (i.p.) administration of Nano[Cys]s to the tumor xenograft mouse model successfully suppressed tumor growth. Interestingly, this effect depended on the MW of the PCys segments.}, } @article {pmid36243239, year = {2022}, author = {Chen, Y and Xi, Y and Li, M and Wu, Y and Yan, W and Dai, J and Wu, M and Ding, W and Zhang, J and Zhang, F and Zhou, S and Wang, S}, title = {Maternal exposure to PM2.5 decreases ovarian reserve in neonatal offspring mice through activating PI3K/AKT/FoxO3a pathway and ROS-dependent NF-κB pathway.}, journal = {Toxicology}, volume = {481}, number = {}, pages = {153352}, doi = {10.1016/j.tox.2022.153352}, pmid = {36243239}, issn = {1879-3185}, mesh = {Humans ; Female ; Mice ; Animals ; *Ovarian Reserve/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species ; NF-KappaB Inhibitor alpha/metabolism ; Follicular Atresia ; Maternal Exposure/adverse effects ; Signal Transduction ; Mice, Inbred C57BL ; Particulate Matter/toxicity ; }, abstract = {There is evidence of an association between exposure to ambient fine particulate matter (PM2.5) and female ovarian dysfunction in adults. However, it is not fully clear whether maternal exposure to PM2.5 negatively affects the ovarian function in offspring. The size of primordial follicle pool, definitely assembled during fetal life, determines ovarian reserve and ovarian function. In this study, female C57BL/6 mice were exposed to either ambient PM2.5 (mean daily concentration 49 µg/m[3]) or filtered air through a whole-body exposure system for 4 weeks before mating, and remained exposed until postpartum. We found that maternal exposure to PM2.5 reduces the initial size of primordial follicle pool and impairs its development in offspring mice. The number of primordial follicles and total follicles was decreased in PM2.5-exposed offspring mice on postnatal day 3 (PND3) and postnatal day 7 (PND7). Maternal PM2.5 exposure promoted the activation of primordial follicles and upregulated the level of p-AKT in offspring mice, accelerating the depletion of primordial follicle pool. While LY294002, a specific inhibitor of PI3K, reversed the overactivation of primordial follicles induced by PM2.5. Besides, maternal PM2.5 exposure induced follicular atresia and granulosa cell apoptosis, increased the accumulation of lipid peroxidation products 4-HNE, and elevated the expression of oxidative stress-related genes and p-p65, p-IκBα in offspring mice. While N-acetylcysteine (NAC) pretreatment abolished the increases of apoptosis, reactive oxygen species (ROS), p-p65 and p-IκBα levels in ovarian granulosa COV434 cells induced by PM2.5 exposure. These findings reveal that maternal exposure to PM2.5 decreases the initial size of primordial follicle pool, and impairs ovarian follicular development in offspring mice. Our data suggest that this involves the activation of the PI3K/AKT/FoxO3a pathway and the ROS-dependent NF-κB pathway. Our study implicates a link between maternal PM2.5 exposure and ovarian reserve in offspring, and improves our understanding of the effects of PM2.5 on reproductive health.}, } @article {pmid36242913, year = {2022}, author = {Kalyanaraman, B}, title = {NAC, NAC, Knockin' on Heaven's door: Interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells.}, journal = {Redox biology}, volume = {57}, number = {}, pages = {102497}, pmid = {36242913}, issn = {2213-2317}, abstract = {N-acetylcysteine (NAC) has been used as a direct scavenger of reactive oxygen species (hydrogen peroxide, in particular) and an antioxidant in cancer biology and immuno-oncology. NAC is the antioxidant drug most frequently employed in studies using tumor cells, immune cells, and preclinical mouse xenografts. Most studies use redox-active fluorescent probes such as dichlorodihydrofluorescein, hydroethidine, mitochondria-targeted hydroethidine, and proprietary kit-based probes (i.e., CellROX Green and CellROX Red) for intracellular detection of superoxide or hydrogen peroxide. Inhibition of fluorescence by NAC was used as a key experimental observation to support the formation of reactive oxygen species and redox mechanisms proposed for ferroptosis, tumor metastasis, and redox signaling in the tumor microenvironment. Reactive oxygen species such as superoxide and hydrogen peroxide stimulate or abrogate tumor cells and immune cells depending on multiple factors. Understanding the mechanism of antioxidants is crucial for interpretation of the results. Because neither NAC nor the fluorescent probes indicated above react directly with hydrogen peroxide, it is critically important to reinterpret the results to advance our understanding of the mechanism of action of NAC and shed additional mechanistic insight on redox-regulated signaling in tumor biology. To this end, this review is focused on how NAC could affect multiple pathways in cancer cells, including iron signaling, ferroptosis, and the glutathione-dependent antioxidant and redox signaling mechanism, and how NAC could inhibit oxidation of the fluorescent probes through multiple mechanisms.}, } @article {pmid36235607, year = {2022}, author = {Wang, N and Hao, Y and Fu, L}, title = {Trimethylamine-N-Oxide Promotes Osteoclast Differentiation and Bone Loss via Activating ROS-Dependent NF-κB Signaling Pathway.}, journal = {Nutrients}, volume = {14}, number = {19}, pages = {}, pmid = {36235607}, issn = {2072-6643}, support = {82172456//National Natural Science Foundation of China/ ; 20210407//Seeds Fund of Engineering Research Center of Digital Medicine of the Ministry of Education/ ; 2017ZZ01023//Shanghai Clinical Medical Center/ ; shslczdzk06701//Shanghai Municipal Key Clinical Specialty/ ; }, mesh = {Acetylcysteine/metabolism ; Actins/metabolism ; Animals ; *Bone Resorption/metabolism ; Cattle ; Cell Differentiation ; Methylamines ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; NFATC Transcription Factors/genetics/metabolism ; Nitriles ; Osteoclasts/metabolism ; Osteogenesis ; *Osteoporosis/metabolism ; Oxides/metabolism ; Proto-Oncogene Proteins c-fos/genetics/metabolism ; RANK Ligand/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Sulfones ; TNF Receptor-Associated Factor 6/metabolism ; }, abstract = {Trimethylamine-N-oxide (TMAO), an important gut microbiota (GM)-derived metabolite, has been shown to be abnormally increased in osteoporosis. However, the role and underlying mechanism of TMAO in regulating bone loss during osteoporosis have not been fully investigated. In the current study, we found that 100-400 μM TMAO dose-dependently enhanced TRAP-positive osteoclasts, F-actin ring formation, and resorption area on bovine bone slices and up-regulated osteoclast-related gene expression (Calcr, Traf6, Dcstamp, Acp5, C-Fos, and NFATc1). Western blotting validated that TMAO not only activated NF-κB signaling pathway but also stimulated c-Fos and NFATc1 protein expression in a dose-dependent manner. Furthermore, BAY 11-7082, an NF-κB inhibitor, pretreatment markedly suppressed TRAP-positive osteoclast formation and osteoclast-related genes under TMAO treatment. BAY 11-7082 also inhibited p-p65/p65, c-Fos, and NFATc1 protein expression promoted by TMAO. Moreover, TMAO significantly increased ROS production, which was inhibited by N-acetylcysteine (NAC), an ROS antagonist. In addition, we proved that NAC pretreatment could inhibit TMAO-promoted NF-κB activation. NAC also suppressed TRAP-positive osteoclast formation, osteoclast-related gene expression, and protein expression of c-Fos and NFATc1 under TMAO treatment. In vivo studies showed significantly decreased bone mass and increased TRAP-positive osteoclasts in TMAO-treated C57BL/6 mice. Moreover, western-blotting and immunohistochemical staining showed that TMAO administration markedly stimulated NF-κB p65 expression. Additionally, TMAO administration significantly promoted the gene and protein expression of C-Fos and NFATc1. In conclusion, TMAO could promote osteoclast differentiation and induce bone loss in mice by activating the ROS-dependent NF-κB signaling pathway.}, } @article {pmid36232686, year = {2022}, author = {Yao, Q and Zou, X and Liu, S and Wu, H and Shen, Q and Kang, J}, title = {Oxidative Stress as a Contributor to Insulin Resistance in the Skeletal Muscles of Mice with Polycystic Ovary Syndrome.}, journal = {International journal of molecular sciences}, volume = {23}, number = {19}, pages = {}, pmid = {36232686}, issn = {1422-0067}, support = {82171634//National Natural Science Foundation of China/ ; 31971068//National Natural Science Foundation of China/ ; 81670733//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Biomarkers/metabolism ; Dehydroepiandrosterone ; Female ; Humans ; *Insulin Resistance ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/metabolism ; NADP/metabolism ; Oxidative Stress ; Oxidoreductases/metabolism ; *Polycystic Ovary Syndrome/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Androgen/metabolism ; Testosterone/metabolism ; }, abstract = {Polycystic ovarian syndrome (PCOS) is a reproductive, endocrine, and metabolic disorder. Circulating markers of oxidative stress are abnormal in women with PCOS. There is a close relationship between oxidative stress and insulin resistance (IR). However, little information is available about oxidative stress in the skeletal muscles of those affected by PCOS. In this study, PCOS was induced in prepubertal C57BL/6J mice by injection with dehydroepiandrosterone. Oxidative stress biomarkers were then measured in both serum and skeletal muscles. The underlying mechanisms were investigated in C2C12 myotubes treated with testosterone (T). We discovered increased oxidative biomarkers, increased ROS production, and damaged insulin sensitivity in the skeletal muscles of mice with PCOS. High levels of T caused mitochondrial dysfunction and increased ROS levels through the androgen receptor (AR)-nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) signaling pathway in C2C12 cells. Treatment of C2C12 cells with an antioxidant N-acetylcysteine (NAC) decreased T-induced ROS production, improved mitochondrial function, and reversed IR. Administration of NAC to mice with PCOS improved insulin sensitivity in the skeletal muscles of the animals. Hyperandrogenism caused mitochondrial dysfunction and redox imbalance in the skeletal muscles of mice with PCOS. We discovered that oxidative stress contributed to skeletal muscle IR in PCOS. Reducing ROS levels may improve the insulin sensitivity of skeletal muscles in patients with PCOS.}, } @article {pmid36230633, year = {2022}, author = {Kim, W and Park, A and Jang, HH and Kim, SE and Park, KS}, title = {Breast Tumor Cell-Stimulated Bone Marrow-Derived Mesenchymal Stem Cells Promote the Sprouting Capacity of Endothelial Cells by Promoting VEGF Expression, Mediated in Part through HIF-1α Increase.}, journal = {Cancers}, volume = {14}, number = {19}, pages = {}, pmid = {36230633}, issn = {2072-6694}, support = {NRF-2022R1F1A1072927//National Research Foundation of Korea/ ; NRF-2017M3A9E4065331//National Research Foundation of Korea/ ; 1415179737, 20018551//Ministry of Trade, Industry and Energy/ ; }, abstract = {Breast tumor cells recruit bone marrow-derived mesenchymal stem cells (BM-MSCs) and alter their cellular characteristics to establish a tumor microenvironment. BM-MSCs enhance tumor angiogenesis through various mechanisms. We investigated the mechanisms by which BM-MSCs promote angiogenesis in response to breast tumor. Conditioned media from MDA-MB-231 (MDA CM) and MCF7 (MCF7 CM) breast tumor cells were used to mimic breast tumor conditions. An in vitro spheroid sprouting assay using human umbilical vein endothelial cells (HUVECs) was conducted to assess the angiogenesis-stimulating potential of BM-MSCs in response to breast tumors. The ROS inhibitor N-acetylcysteine (NAC) and JAK inhibitor ruxolitinib attenuated increased HIF-1α in BM-MSCs in response to MDA CM and MCF7 CM. HIF-1α knockdown or HIF-1β only partially downregulated VEGF expression and, therefore, the sprouting capacity of HUVECs in response to conditioned media from BM-MSCs treated with MDA CM or MCF7 CM. Inactivation of the VEGF receptor using sorafenib completely inhibited the HUVECs' sprouting. Our results suggest that increased HIF-1α expression under normoxia in BM-MSCs in response to breast tumor cells is mediated by ROS and JAK/Stat3, and that both HIF-1α-dependent and -independent mechanisms increase VEGF expression in BM-MSCs to promote the angiogenic sprouting capacity of endothelial cells in a VEGF-dependent manner.}, } @article {pmid36225391, year = {2022}, author = {Bühner, LM and Kapanaiah, SKT and Kätzel, D}, title = {Chronic N-acetylcysteine treatment improves anhedonia and cognition in a mouse model of the schizophrenia prodrome.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {1002223}, pmid = {36225391}, issn = {1662-5153}, abstract = {Schizophrenia is a severe psychiatric disorder whose neurodevelopmental pathogenesis includes a prodromal phase before its diagnostically decisive-namely psychotic-symptoms are present. This prodrome is characterized by cognitive and affective deficits, and it may constitute a critical time period for an early therapeutic intervention to improve or even prevent further disease development. N-acetylcysteine (NAC) is an easily repurposable compound that has recently shown promise in improving non-psychotic symptoms in patients with established schizophrenia. Its therapeutic mechanism may involve the amelioration of circuit abnormalities like a hyper-glutamatergic state and oxidative stress in cortex which have been proposed to drive the pathogenesis of this disease. However, it is currently unknown to what extent NAC can actually improve prodromal aberrations. To investigate this preclinically, we deployed the cyclin-D2 knockout mouse model (CD2-KO) that shares physiological and behavioral abnormalities with the schizophrenia prodrome, including a hyperactive CA1 region, and cognitive and affective deficits. Applying NAC chronically in drinking water (0.9 g/l) during development (∼P22-P70), we found that excessive novelty-induced hyperlocomotion was neither ameliorated during (∼P68) nor after (∼P75) treatment; similarly, T-maze working memory (tested after treatment; ∼P84) was unaffected. However, once chronic NAC treatment was resumed (at approximately P134) in those mice that had received it before, working memory, cognitive flexibility (tested under NAC), and anhedonia (sucrose-preference, tested 1 day after NAC-treatment stopped) were improved in CD2-KO mice. This suggests that chronic NAC treatment may be a therapeutic strategy to improve some cognitive and affective dysfunctions in the schizophrenia prodrome.}, } @article {pmid36222315, year = {2023}, author = {Garcia-Serrano, AM and Vieira, JPP and Fleischhart, V and Duarte, JMN}, title = {Taurine and N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice.}, journal = {Nutritional neuroscience}, volume = {26}, number = {11}, pages = {1090-1102}, doi = {10.1080/1028415X.2022.2131062}, pmid = {36222315}, issn = {1476-8305}, mesh = {Mice ; Animals ; Female ; *Acetylcysteine/therapeutic use/pharmacology ; *Diet, High-Fat/adverse effects ; Creatine/metabolism ; Phosphocreatine/metabolism ; Obesity/metabolism ; Memory Disorders/etiology/prevention & control ; Hippocampus/metabolism ; Lactates/metabolism ; Mice, Inbred C57BL ; }, abstract = {Background: Obesity constitutes a risk factor for cognitive impairment. In rodent models, long-term exposure to obesogenic diets leads to hippocampal taurine accumulation. Since taurine has putative cyto-protective effects, hippocampal taurine accumulation in obese and diabetic models might constitute a counteracting response to metabolic stress. Objective: We tested the hypothesis that treatment with taurine or with N-acetylcysteine (NAC), which provides cysteine for the synthesis of taurine and glutathione, prevent high-fat diet (HFD)-associated hippocampal alterations and memory impairment. Methods: Female mice were fed either a regular diet or HFD. Some mice had access to 3%(w/v) taurine or 3%(w/v) NAC in the drinking water. After 2 months, magnetic resonance spectroscopy (MRS) was used to measure metabolite profiles. Memory was assessed in novel object and novel location recognition tests. Results: HFD feeding caused memory impairment in both tests, and reduced concentration of lactate, phosphocreatine-to-creatine ratio, and the neuronal marker N-acetylaspartate in the hippocampus. Taurine and NAC prevented HFD-induced memory impairment and N-acetylaspartate reduction. NAC, but not taurine, prevented the reduction of lactate and phosphocreatine-to-creatine ratio. MRS revealed NAC/taurine-induced increase of hippocampal glutamate and GABA levels. Conclusion: NAC and taurine can prevent memory impairment, while only NAC prevents alterations of metabolite concentrations in HFD-exposed female mice.}, } @article {pmid36219247, year = {2022}, author = {Becchi, S and Hood, J and Kendig, MD and Mohammadkhani, A and Shipman, ML and Balleine, BW and Borgland, SL and Corbit, LH}, title = {Food for thought: diet-induced impairments to decision-making and amelioration by N-acetylcysteine in male rats.}, journal = {Psychopharmacology}, volume = {239}, number = {11}, pages = {3495-3506}, pmid = {36219247}, issn = {1432-2072}, support = {401526/CAPMC/CIHR/Canada ; 147473/CAPMC/CIHR/Canada ; 950-232211//Canada Research Chairs/ ; 401526/CAPMC/CIHR/Canada ; 147473/CAPMC/CIHR/Canada ; }, mesh = {Rats ; Male ; Animals ; *Acetylcysteine/pharmacology ; *Corpus Striatum ; Learning ; Glutamic Acid ; Diet ; }, abstract = {RATIONALE: Attempts to lose weight often fail despite knowledge of the health risks associated with obesity and determined efforts. We previously showed that rodents fed an obesogenic diet displayed premature habitual behavioural control and weakened flexible decision-making based on the current value of outcomes produced by their behaviour. Thus, habitual control may contribute to failed attempts to modify eating behaviours.

OBJECTIVES: To examine the effects of an obesogenic diet on behavioural control and glutamate transmission in dorsal striatum regions and to assess the ability of N-acetylcysteine (NAC) to reverse deficits.

METHODS: Here, we examined diet-induced changes to decision-making and used in vitro electrophysiology to investigate the effects of diet on glutamate transmission within the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas that control goal-directed and habitual behaviours, respectively. We administered NAC in order to normalize glutamate release and tested whether this would restore goal-directed performance following an obesogenic diet.

RESULTS: We found that an obesogenic diet reduced sensitivity to outcome devaluation and increased glutamate release in the DMS, but not DLS. Administration of NAC restored goal-directed control and normalized mEPSCs in the DMS. Finally, NAC administered directly to the DMS was sufficient to reinstate sensitivity to outcome devaluation following an obesogenic diet.

CONCLUSIONS: These data indicate that obesogenic diets alter neural activity in the basal ganglia circuit responsible for goal-directed learning and control which leads to premature habitual control. While the effects of diet are numerous and widespread, normalization of glutamatergic activity in this circuit is sufficient for restoring goal-directed behaviour.}, } @article {pmid36217638, year = {2022}, author = {Calefi, PHS and de Azevedo Queiroz, I and Alcalde, M and Oliveira, S and Vivan, RR and Weckwerth, PH and Kato, AS and Duarte, MAH}, title = {Comparison of the Physicochemical Properties, Antimicrobial Action, and Cytotoxicity of Ambroxol Hydrochloride, N-acetylcysteine, and Calcium Hydroxide Pastes.}, journal = {European endodontic journal}, volume = {7}, number = {3}, pages = {217-222}, pmid = {36217638}, issn = {2548-0839}, mesh = {Acetylcysteine/pharmacology ; *Ambroxol/pharmacology ; *Anti-Infective Agents/pharmacology ; Calcium Hydroxide/toxicity ; Chemical Phenomena ; Enterococcus faecalis ; Water ; }, abstract = {OBJECTIVE: To evaluate the solubility, pH, antimicrobial action, and cytotoxicity of ambroxol hydrochloride (AMB), N-acetylcysteine (NAC), and calcium hydroxide (CH) pastes for use as intracanal medications.

METHODS: Solubility was determined by micro-CT, based on the paste volume remaining after immersion in water for 7 days. pH was measured by immersing acrylic tubes containing the pastes in ultrapure water and then measuring pH after 3 hours, 3 days, and 7 days. Antimicrobial action against Enterococcus faecalis was assessed based on the percentage of living cells, using the live/dead staining method under confocal microscopy. Cytotoxicity was assessed based on the cell viability of L929 fibroblast-like cells after 6, 24, and 48 hours. Cytotoxicity data were compared using the ANOVA and Tukey tests, and the antimicrobial data were compared using the Kruskal-Wallis and Dunn tests. The significance level used was 5% (α=0.05).

RESULTS: The solubility values for all the study groups were significantly different (P<0.05), where the highest values were for NAC, followed by AMB, and then CH. Likewise, the pH levels were all significantly different (P<0.05), where NAC and AMB levels were acidic, and CH levels were alkaline. The antimicrobial action of AMB was significantly higher than that of CH (P<0.05), and that of NAC was also higher than that of CH, albeit not significantly. AMB and NAC were more cytotoxic than CH, and higher dilutions of CH promoted higher cell viability levels than lower dilutions of the same paste (P<0.05).

CONCLUSION: The NAC and AMB pastes were more soluble and cytotoxic than the CH paste and had acidic pH levels. The AMB paste displayed the highest antimicrobial action against Enterococcus faecalis biofilm.}, } @article {pmid36216166, year = {2022}, author = {Brites, G and Basso, J and Miranda, M and Miguel Neves, B and Vitorino, C and Cruz, MT}, title = {Development of a new hydrogel for the prevention of allergic contact dermatitis.}, journal = {International journal of pharmaceutics}, volume = {628}, number = {}, pages = {122265}, doi = {10.1016/j.ijpharm.2022.122265}, pmid = {36216166}, issn = {1873-3476}, mesh = {Humans ; *Hydrogels ; *Dermatitis, Allergic Contact/prevention & control ; Allergens ; Skin ; }, abstract = {Allergic contact dermatitis (ACD) is the most prevalent occupational disease and the most common form of immunotoxicity in humans. Preventing exposure to the triggering allergens is the mainstay of treatment. However, avoidance is not always possible in an occupational setting. From a pathophysiological point of view, a variety of events are involved in the development of ACD, including the formation of immunogenic complexes following the stable association of the allergen with skin proteins, which is thought to be the molecular initiating event responsible for the development of ACD. Previously, the team identified molecules that exhibited higher antiallergic potential due to their capacity to block the interaction between allergens and skin proteins. These assumptions were the starting point for the design of this work aiming to develop and characterize a new hydrogel containing the active ingredients lysine and N-acetyl cysteine under the premises of quality- and safety- by design. Two factorial plannings were established envisioning the optimization of the hydrogel in terms of mechanical and rheological properties. In vitro release and permeation studies supported its skin surface barrier effect. In addition, the selected hydrogel proved to be safe without causing human skin irritation or skin sensitization.}, } @article {pmid36211962, year = {2022}, author = {Ma, C and Wu, X and Zhang, X and Liu, X and Deng, G}, title = {Heme oxygenase-1 modulates ferroptosis by fine-tuning levels of intracellular iron and reactive oxygen species of macrophages in response to Bacillus Calmette-Guerin infection.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {1004148}, pmid = {36211962}, issn = {2235-2988}, support = {P30 DK054759/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antioxidants ; BCG Vaccine ; Cysteine ; Cytokines ; *Ferroptosis ; Heme Oxygenase-1 ; Iron/metabolism ; Macrophages ; Membrane Proteins ; Mice ; *Mycobacterium bovis ; Phospholipid Hydroperoxide Glutathione Peroxidase ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; *Tuberculosis/pathology ; *Tuberculosis, Pulmonary/pathology ; }, abstract = {Macrophages are the host cells and the frontline defense against Mycobacterium tuberculosis (Mtb) infection, and the form of death of infected macrophages plays a pivotal role in the outcome of Mtb infections. Ferroptosis, a programmed necrotic cell death induced by overwhelming lipid peroxidation, was confirmed as one of the mechanisms of Mtb spread following infection and the pathogenesis of tuberculosis (TB). However, the mechanism underlying the macrophage ferroptosis induced by Mtb infection has not yet been fully understood. In the present study, transcriptome analysis revealed the upregulation of heme oxygenase-1 (HMOX1) and pro-ferroptosis cytokines, but downregulation of glutathione peroxidase 4 (GPX4) and other key anti-lipid peroxidation factors in the peripheral blood of both patients with extra-pulmonary tuberculosis (EPTB) and pulmonary tuberculosis (PTB). This finding was further corroborated in mice and RAW264.7 murine macrophage-like cells infected with Bacillus Calmette-Guerin (BCG). A mechanistic study further demonstrated that heme oxygenase-1 protein (HO-1) regulated the production of reactive oxygen species (ROS) and iron metabolism, and ferroptosis in BCG-infected murine macrophages. The knockdown of Hmox1 by siRNA resulted in a significant increase of intracellular ROS, Fe[2+], and iron autophagy-mediated factor Ncoa4, along with the reduction of antioxidant factors Gpx4 and Fsp1 in macrophages infected with BCG. The siRNA-mediated knockdown of Hmox1 also reduced cell survival rate and increased the release of intracellular bacteria in BCG-infected macrophages. By contrast, scavenging ROS by N-acetyl cysteine led to the reduction of intracellular ROS, Fe[2+], and Hmox1 concentrations, and subsequently inhibited ferroptosis and the release of intracellular BCG in RAW264.7 cells infected with BCG. These findings suggest that HO-1 is an essential regulator of Mtb-induced ferroptosis, which regulates ROS production and iron accretion to alter macrophage death against Mtb infections.}, } @article {pmid36201094, year = {2022}, author = {Ahmed, HM and Shehata, HH and El-Saeed, GSM and Gabal, HHA and El-Daly, SM}, title = {Ameliorative effect of Lactobacillus rhamnosus GG on acetaminophen-induced hepatotoxicity via PKC/Nrf2/PGC-1α pathway.}, journal = {Journal, genetic engineering & biotechnology}, volume = {20}, number = {1}, pages = {142}, pmid = {36201094}, issn = {2090-5920}, abstract = {BACKGROUND: Acetaminophen (APAP) overdose is a common cause of hepatotoxicity. Antioxidants like N-acetyl cysteine are recommended as a therapeutic option; nevertheless, it has limitations. The search for efficient alternatives is ongoing. Probiotics are live microorganisms that maintain a healthy gut microecology. Lactobacillus rhamnosus GG (LGG) is one of the widely used probiotics. Our study aimed to assess the protective and therapeutic effects of probiotic LGG on APAP-induced hepatotoxicity and evaluate the molecular pathways behind this effect.

METHODS: Wistar Albino male rats were randomly distributed into the following experimental groups: group 1, non-treated rats (vehicle); group 2, rats received oral gavage of suspension of probiotic LGG (5 × 10[10] CFU GG/0.5 ml in PBS) daily for 2 weeks (probiotic control); group 3, rats received APAP dose of 2 g/kg body weight (positive control); group 4, rats received oral gavage of suspension of probiotic LGG for 2 weeks followed by a single dose of APAP injection (prophylactic); and group 5, rats received a single dose of APAP and then 24 h later treated with oral gavage of probiotic LGG daily for 2 weeks (treatment).

RESULTS: Our study revealed that administration of probiotic LGG (either as prophylactic or treatment) exhibited a remarkable reduction in APAP-induced liver injury as resembled by the decrease in liver enzymes (ALT and AST) and the histopathological features of liver sections. Moreover, the significant reduction in the oxidative marker malondialdehyde, along with the enhancement in glutathione reductase, and the significant reduction in inflammatory markers (nitric oxide and tumor necrosis factor-α) were all indicators of the efficiency of LGG in ameliorating the alterations accompanied with APAP-induced hepatotoxicity. Our findings also demonstrate that LGG administration boosted the expression of Nrf2 and PGC-1 while decreasing the expression of protein kinase C (PKC). As a result, the nuclear abundance of Nrf2 is increased, and the expression of various antioxidants is eventually upregulated.

CONCLUSION: Our study shows that probiotic LGG supplementation exerts a prophylactic and therapeutic effect against APAP-induced hepatotoxicity through modulating the expression of PKC and the Nrf2/PGC-1α signaling pathway and eventually suppressing oxidative damage from APAP overdose.}, } @article {pmid36199646, year = {2022}, author = {Singh, A and Singh, G and Singh, S and Kazi, SE and Gill, M}, title = {N-acetylcysteine in the Treatment of Internet Gaming Disorder.}, journal = {Cureus}, volume = {14}, number = {9}, pages = {e28662}, pmid = {36199646}, issn = {2168-8184}, abstract = {Internet gaming disorder (IGD) is the persistent and recurrent use of the internet to engage in video gaming through a single or multiplayer interface that can lead to significant impairment or distress. With technological advancements in the last decade via portable handheld devices, along with their global availability, video games have found a new medium in which they can provide instantaneous access for casual and enthusiastic users alike. Unfortunately, this exponentially increases the possibility of addiction. IGD shares a similar pathophysiological etiology to addiction as drugs or gambling. However, it can be challenging to manage IGD due to the ease of video game access and limited understanding of the newly recognized disorder. This study aims to fill in the knowledge gap concerning the limited research on internet gaming addiction, its consequential effects on human cognitive-behavioral functioning, and pharmacotherapy management as observed in our patient, who developed IGD, starting initially as a casual recreational hobby among peers. This case also highlights the lack of social awareness and seriousness attributed to this disorder. It focuses on using N-acetylcysteine in the management as well as other psychological and psychotropic drugs.}, } @article {pmid36192693, year = {2022}, author = {Zhang, S and Bei, Y and Huang, Y and Huang, Y and Hou, L and Zheng, XL and Xu, Y and Wu, S and Dai, X}, title = {Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {28}, number = {1}, pages = {121}, pmid = {36192693}, issn = {1528-3658}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Cyclooxygenase 2/metabolism/pharmacology ; Disease Models, Animal ; *Ferroptosis ; Hyperplasia/metabolism ; Iron/metabolism/pharmacology ; Mice ; Muscle, Smooth, Vascular/metabolism ; Myocytes, Smooth Muscle/metabolism ; *Neointima ; Osteopontin/metabolism/pharmacology ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Smooth Muscle Myosins/metabolism ; }, abstract = {BACKGROUND: Stent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear.

METHODS: The mouse common right carotid arteries were ligated for 16 or 30 days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments.

RESULTS: Ferroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-L-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs.

CONCLUSIONS: Ferroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.}, } @article {pmid36191663, year = {2023}, author = {Guan, F and Zhang, S and Fan, L and Sun, Y and Ma, Y and Cao, C and Zhang, Y and He, M and Du, H}, title = {Kunling Wan improves oocyte quality by regulating the PKC/Keap1/Nrf2 pathway to inhibit oxidative damage caused by repeated controlled ovarian hyperstimulation.}, journal = {Journal of ethnopharmacology}, volume = {301}, number = {}, pages = {115777}, doi = {10.1016/j.jep.2022.115777}, pmid = {36191663}, issn = {1872-7573}, mesh = {Animals ; Female ; Mice ; Pregnancy ; Antioxidants/pharmacology/metabolism ; *Hydrogen Peroxide/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; Oocytes/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Kunling Wan (KW) is a traditional Chinese medicine that is principally used for kidney deficiency, qi stagnation, and blood stasis, which are basic syndromes of infertility in China. KW can improve ovarian follicular development, ovarian function, and endometrial receptivity, which lead to improving pregnancy outcomes. Repeated controlled ovarian hyperstimulation (COH) reduces oocyte quality and results in a lower pregnancy rate. Whether KW has the potential to improve oocyte quality reduced by repeated COH has yet to be determined.

AIMS OF THE STUDY: The aim of this study wwas to evaluate the effect of KW on oocyte quality after damage due to repeated COH, and to investigate the mechanism(s) underlying the antioxidative protection of oocytes by mitochondria.

MATERIALS AND METHODS: Female Kunming mice were randomly divided into four groups: normal group, model (repeated COH) group, KW group, and N-acetylcysteine (NAC) group. We observed the morphology and quality of mitochondria, level of reactive oxygen species (ROS), and antioxidant enzymes activity of each group. Oocytes were treated with H2O2 and KW-containing serum, and we determined the antioxidant effects of KW on H2O2-treated oocytes and the mechanism involved in the regulation of Nrf2 in reducing oxidative damage.

RESULTS: Our results revealed that repeated COH caused oxidative damage and impaired oocyte mitochondrial function and structure, resulting in poor oocyte quality. KW pretreatment reduced oxidative damage by inhibiting ROS production and improving mitochondrial structure and function, thereby enhancing overall oocyte quality. In response to H2O2, KW activated the PKC/Keap1/Nrf2-signaling pathway and promoted the translocation of Nrf2 from the cytoplasm to the nucleus, which activated the expression of SOD and GSH-Px, and removed the excess ROS that caused the initial mitochondrial damage.

CONCLUSIONS: KW improved oocyte quality perturbed by repeated COH via reducing oxidative effects and improving mitochondrial function. The mechanism may be related to regulation of the PKC/Keap1/Nrf2 pathway in removing excess ROS.}, } @article {pmid36191509, year = {2023}, author = {Vivoli, A and Ghislain, J and Filali-Mouhim, A and Angeles, ZE and Castell, AL and Sladek, R and Poitout, V}, title = {Single-Cell RNA Sequencing Reveals a Role for Reactive Oxygen Species and Peroxiredoxins in Fatty Acid-Induced Rat β-Cell Proliferation.}, journal = {Diabetes}, volume = {72}, number = {1}, pages = {45-58}, pmid = {36191509}, issn = {1939-327X}, support = {R01 DK058096/DK/NIDDK NIH HHS/United States ; MOP 77686//CIHR/Canada ; }, mesh = {Rats ; Animals ; Fatty Acids/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Oleic Acid/pharmacology ; *Diabetes Mellitus, Type 2/metabolism ; Insulin/metabolism ; *Insulin-Secreting Cells/metabolism ; Cell Proliferation ; Palmitates/metabolism ; Glucose/metabolism ; Sequence Analysis, RNA ; *Islets of Langerhans/metabolism ; }, abstract = {The functional mass of insulin-secreting pancreatic β-cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing β-cells. Type 2 diabetes appears when these compensatory mechanisms fail. Nutrients including glucose and fatty acids are important contributors to the β-cell compensatory response, but their underlying mechanisms of action remain poorly understood. We investigated the transcriptional mechanisms of β-cell proliferation in response to fatty acids. Isolated rat islets were exposed to 16.7 mmol/L glucose with or without 0.5 mmol/L oleate (C18:1) or palmitate (C16:0) for 48 h. The islet transcriptome was assessed by single-cell RNA sequencing. β-Cell proliferation was measured by flow cytometry. Unsupervised clustering of pooled β-cells identified different subclusters, including proliferating β-cells. β-Cell proliferation increased in response to oleate but not palmitate. Both fatty acids enhanced the expression of genes involved in energy metabolism and mitochondrial activity. Comparison of proliferating versus nonproliferating β-cells and pseudotime ordering suggested the involvement of reactive oxygen species (ROS) and peroxiredoxin signaling. Accordingly, N-acetyl cysteine and the peroxiredoxin inhibitor conoidin A both blocked oleate-induced β-cell proliferation. Our study reveals a key role for ROS signaling through peroxiredoxin activation in oleate-induced β-cell proliferation.}, } @article {pmid36184612, year = {2023}, author = {Shim, SM and Choi, HR and Kwon, SC and Kim, HY and Sung, KW and Jung, EJ and Mun, SR and Bae, TH and Kim, DH and Son, YS and Jung, CH and Lee, J and Lee, MJ and Park, JW and Kwon, YT}, title = {The Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10.}, journal = {Autophagy}, volume = {19}, number = {6}, pages = {1642-1661}, pmid = {36184612}, issn = {1554-8635}, mesh = {Animals ; Mice ; Sequestosome-1 Protein/metabolism ; *Macroautophagy ; *Autophagy/physiology ; Reactive Oxygen Species/metabolism ; Cysteamine ; Cysteine ; Ubiquitin/metabolism ; Arginine/metabolism ; Transferases/metabolism ; }, abstract = {In the N-degron pathway, N-recognins recognize cognate substrates for degradation via the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). We have recently shown that the autophagy receptor SQSTM1/p62 (sequestosome 1) is an N-recognin that binds the N-terminal arginine (Nt-Arg) as an N-degron to modulate autophagic proteolysis. Here, we show that the N-degron pathway mediates pexophagy, in which damaged peroxisomal fragments are degraded by autophagy under normal and oxidative stress conditions. This degradative process initiates when the Nt-Cys of ACAD10 (acyl-CoA dehydrogenase family, member 10), a receptor in pexophagy, is oxidized into Cys sulfinic (Cys[O2]) or sulfonic acid (Cys[O3]) by ADO (2-aminoethanethiol (cysteamine) dioxygenase). Under oxidative stress, the Nt-Cys of ACAD10 is chemically oxidized by reactive oxygen species (ROS). The oxidized Nt-Cys2 is arginylated by ATE1-encoded R-transferases, generating the RC[OX] N-degron. RC[OX]-ACAD10 marks the site of pexophagy via the interaction with PEX5 and binds the ZZ domain of SQSTM1/p62, recruiting LC3[+]-autophagic membranes. In mice, knockout of either Ate1 responsible for Nt-arginylation or Sqstm1/p62 leads to increased levels of peroxisomes. In the cells from patients with peroxisome biogenesis disorders (PBDs), characterized by peroxisomal loss due to uncontrolled pexophagy, inhibition of either ATE1 or SQSTM1/p62 was sufficient to recover the level of peroxisomes. Our results demonstrate that the Cys-N-degron pathway generates an N-degron that regulates the removal of damaged peroxisomal membranes along with their contents. We suggest that tannic acid, a commercially available drug on the market, has a potential to treat PBDs through its activity to inhibit ATE1 R-transferases.Abbreviations: ACAA1, acetyl-Coenzyme A acyltransferase 1; ACAD, acyl-Coenzyme A dehydrogenase; ADO, 2-aminoethanethiol (cysteamine) dioxygenase; ATE1, arginyltransferase 1; CDO1, cysteine dioxygenase type 1; ER, endoplasmic reticulum; LIR, LC3-interacting region; MOXD1, monooxygenase, DBH-like 1; NAC, N-acetyl-cysteine; Nt-Arg, N-terminal arginine; Nt-Cys, N-terminal cysteine; PB1, Phox and Bem1p; PBD, peroxisome biogenesis disorder; PCO, plant cysteine oxidase; PDI, protein disulfide isomerase; PTS, peroxisomal targeting signal; R-COX, Nt-Arg-CysOX; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNP, sodium nitroprusside; UBA, ubiquitin-associated; UPS, ubiquitinproteasome system.}, } @article {pmid36182795, year = {2022}, author = {Xu, L and He, D and Wu, Y and Shen, L and Wang, Y and Xu, Y}, title = {Tanshinone IIA inhibits cardiomyocyte apoptosis and rescues cardiac function during doxorubicin-induced cardiotoxicity by activating the DAXX/MEK/ERK1/2 pathway.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {107}, number = {}, pages = {154471}, doi = {10.1016/j.phymed.2022.154471}, pmid = {36182795}, issn = {1618-095X}, mesh = {Animals ; Mice ; *Abietanes/pharmacology ; Acetylcysteine/pharmacology ; Apoptosis ; *Cardiotoxicity/drug therapy ; Caspase 3 ; Caspase 8 ; Co-Repressor Proteins ; Doxorubicin/adverse effects ; *MAP Kinase Signaling System ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase Kinases ; Molecular Chaperones/pharmacology ; Myocytes, Cardiac ; RNA ; }, abstract = {BACKGROUND: Heart failure (HF) is a common cardiovascular syndrome. Tanshinone IIA (Tan IIA) is a pharmacologically active monomer that exerts a significant cardioprotective effect in the clinic; however, the specific mechanisms are not fully understood.

PURPOSE: We mainly investigated the protective effects of Tan IIA on doxorubicin (DOX)-induced HF.

METHODS: In an in vitro study, H9C2 and HL-1 cells were cultured and treated with DOX and Tan IIA for 24 h, we investigated the mechanism underlying Tan IIA-mediated protection. In an in vivo study, a model of DOX-induced HF was established in C57BL/6 mice that were divided into the six groups randomly: a control group, a DOX group, DOX groups treated with Tan IIA (DOX+Tan IIA) at dosages of 2.5, 5 and 10 mg/kg/day and DOX groups treated with N-acetylcysteine (NAC) at dosages of 200 mg/kg/day.

RESULT: The results demonstrated that Tan IIA significantly increased cell viability and protected against DOX-induced apoptosis. RNA-sequencing showed that the genes expression associated with the apoptotic signaling pathway was altered by Tan IIA. Among the differentially expressed genes, death-domain associated protein (DAXX), which plays an critical role in apoptotic signaling, exhibited increased expression under Tan IIA treatment. In addition, RNA interference was used to silence the expression of DAXX, which abolished Tan IIA-mediated protection against DOX-induced apoptosis; this effect was associated with extracellular signal-regulated protein kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) expression. In the in vivo study, the echocardiography results revealed that heart function was rescued by Tan IIA, and the histomorphology results showed that Tan IIA prevented myocardial structural alteration and myofibril disruption. Furthermore, Tan IIA induced the expressions of DAXX, p-ERK1/2 and p-MEK. Tan IIA also inhibited apoptosis by suppressing the expression of cleaved caspase-8, p-P38 and cleaved caspase-3.

CONCLUSION: Our results provide novel interpretations into the important role of DAXX in DOX-induced cardiotoxicity and show that Tan IIA may be a novel agent strategy for HF treatment via activating the DAXX/MEK/ERK1/2 pathway.}, } @article {pmid36182028, year = {2022}, author = {Schoeps, VA and Graves, JS and Stern, WA and Zhang, L and Nourbakhsh, B and Mowry, EM and Henry, RG and Waubant, E}, title = {N-Acetyl Cysteine as a Neuroprotective Agent in Progressive Multiple Sclerosis (NACPMS) trial: Study protocol for a randomized, double-blind, placebo-controlled add-on phase 2 trial.}, journal = {Contemporary clinical trials}, volume = {122}, number = {}, pages = {106941}, doi = {10.1016/j.cct.2022.106941}, pmid = {36182028}, issn = {1559-2030}, mesh = {Humans ; *Neuroprotective Agents/adverse effects ; *Multiple Sclerosis ; Acetylcysteine/adverse effects ; Disease Progression ; *Multiple Sclerosis, Chronic Progressive/diagnostic imaging/drug therapy ; Double-Blind Method ; Treatment Outcome ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase II as Topic ; }, abstract = {INTRODUCTION: Patients with progressive multiple sclerosis (PMS) experience relentless disability worsening. Current approved therapies have very modest effects on disability progression and purely focus on immunomodulation. While some inflammatory processes exist in non-active PMS, other biological processes such as neuronal injury from oxidative stress are likely more critical. N-acetyl cysteine (NAC) directly scavenges free radicals and restores neuronal glutathione, a major endogenous antioxidant. Our group has recently evaluated the safety of high dose NAC in a pilot trial in PMS with no tolerability concerns. We aim now to assess the safety, tolerability, and effect of NAC on progression of several MRI, clinical and biological markers in PMS patients.

METHODS: The NACPMS trial is a multi-site, randomized, double-blind, parallel-group, placebo-controlled add-on phase 2 trial. Ninety-eight PMS patients with EDSS 3.0-7.0 and aged 40-70 years will be randomized to NAC 1200 mg TID or matching placebo (1:1) as an add-on to the standard of care stratified by site and disease type during a 15-month intervention period. It is hypothesized that a reduction in oxidative stress injury will lessen brain atrophy estimated by MRI. The primary outcome analysis will compare the percent change over 12 months (Month 15 vs Month 3) between treatment and control arms using multivariable linear regression adjusted by age, sex, and disease duration.

ETHICS: This study was approved by the Institutional Review Board at the University of California, San Francisco (IRB21-34143), and an Investigational New Drug approval was obtained from the FDA (IND127184).

TRIAL REGISTRATION: NCT05122559.}, } @article {pmid36170201, year = {2022}, author = {Andrade, C}, title = {Antipsychotic Augmentation With N-Acetylcysteine for Patients With Schizophrenia.}, journal = {The Journal of clinical psychiatry}, volume = {83}, number = {5}, pages = {}, doi = {10.4088/JCP.22f14664}, pmid = {36170201}, issn = {1555-2101}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Clozapine/therapeutic use ; Humans ; *Schizophrenia/drug therapy ; }, abstract = {N-acetylcysteine (NAC) augmentation of antipsychotic medication is one of very many antipsychotic augmentation strategies that have been studied in schizophrenia. A recent systematic review and meta-analysis of 6 randomized controlled trials (RCTs) found that NAC (median dose, 2,000 mg/d) improved several clinical outcomes at different time points with medium to large effect sizes; however, many of the significant findings in this meta-analysis are suspect because they appeared to be influenced by 2 short-term (8-week) RCTs with outlying characteristics. Important findings not influenced by the 2 outlying RCTs were significant attenuation by NAC of negative symptom (3 RCTs) and total psychopathology (2 RCTs) ratings at ≥ 24 weeks and improvement in working memory but not processing speed (3 RCTs). Of these findings, reduction in psychopathology ratings, though statistically significant, appeared too small to be clinically meaningful. Finally, a newly published, moderately large RCT of NAC (2,000 mg/d) in schizophrenia patients refractory to clozapine found that 1 year of treatment with NAC did not outperform placebo for any clinical, cognitive, or quality of life outcome. The take-home message is that it is premature to recommend the use of NAC to treat schizophrenia for any target domain in routine clinical practice and that there does not appear to be a role for NAC for any indication in clozapine-refractory schizophrenia. However, it may be worth studying whether NAC, dosed at 2,000 mg/d or higher for 6 months or longer, improves functional outcomes in schizophrenia.}, } @article {pmid36169181, year = {2022}, author = {Wang, T and Liu, J and Huang, X and Zhang, C and Shangguan, M and Chen, J and Wu, S and Chen, M and Yang, Z and Zhao, S}, title = {Gomisin A enhances the antitumor effect of paclitaxel by suppressing oxidative stress in ovarian cancer.}, journal = {Oncology reports}, volume = {48}, number = {5}, pages = {}, pmid = {36169181}, issn = {1791-2431}, mesh = {Animals ; Carcinoma, Ovarian Epithelial ; Cell Line, Tumor ; Cell Proliferation ; Complex Mixtures/pharmacology ; Cyclin B1/metabolism ; Cyclin-Dependent Kinase 4/metabolism ; Cyclooctanes ; Cysteine/pharmacology ; Dioxoles ; Eosine Yellowish-(YS)/pharmacology/therapeutic use ; Female ; Humans ; Lignans ; Mice ; *Ovarian Neoplasms/pathology ; Oxidative Stress ; *Paclitaxel/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Gomisin A (GA) is an effective component of Schisandra. The crude extracts of Schisandra chinensis and its active ingredients have been shown to inhibit multidrug resistance in tumour cells. Reactive oxygen species (ROS) have different roles in cancer and may contribute to therapy resistance. The human ovarian cancer (OC) cell lines SKOV3 and A2780, and a mouse model of OC, were used in the present study. MTT assay, colony formation assay, flow cytometry, western blot analysis, and haematoxylin and eosin (H&E) staining were performed to determine the antitumor effect of GA and paclitaxel (PTX) in vitro and in vivo. The ROS inhibitor N‑acetyl cysteine (NAC) was used to assess the mechanism underlying the chemosensitizing effects of GA. Notably, the proliferation of OC cells was inhibited by PTX, which could be enhanced by the ROS inhibitor NAC or GA. Treatment with NAC + PTX or GA + PTX enhanced the cell cycle arrest, but not apoptosis, induced by PTX. Moreover, the molecular mechanism underlying this effect may be that GA decreases the levels of ROS in ovarian cancer cells and inhibits cell cycle progression by downregulating the expression of the cell cycle proteins cyclin‑dependent kinase 4 and cyclin B1. In conclusion, the combination of PTX and the ROS inhibitor GA may be a novel strategy in OC chemotherapy.}, } @article {pmid36159904, year = {2022}, author = {Bai, X and Wang, M and Niu, X and Yu, H and Yue, JX and Sun, Y}, title = {Effect of N-acetyl-cysteine treatment on sensorineural hearing loss: a meta-analysis.}, journal = {World journal of otorhinolaryngology - head and neck surgery}, volume = {8}, number = {3}, pages = {205-212}, pmid = {36159904}, issn = {2589-1081}, abstract = {N-acetyl-cysteine (NAC) is an efficacious treatment for sensorineural hearing loss in animal models, such as noise-induced hearing loss (NIHL), however previous research into the effect of NAC on patients with hearing loss produced contradictory results. In this study, we investigated the effect of NAC treatment on sensorineural hearing loss. PubMed, Web of Science and Embase databases were searched in their entirety using the key words: hearing loss, NAC, N-acetylcysteine, and sensorineural hearing loss. Studies which included assessment of hearing loss with pure-tone threshold (PTA) data were selected. Eligible studies regarding the effects of NAC treatment on patients with hearing loss were collected by two independent reviewers. A total of 1197 individuals were included from seven published studies. Two studies reported data for a sudden idiopathic sensorineural hearing loss (SISNHL) group. Three studies reported data for a NIHL group. Other studies reported data for drug-induced hearing loss. The meta-analysis demonstrated that the overall effect of NAC treatment on sensorineural hearing loss was invalid. However, NAC treatment was linked with improved patient outcomes of hearing tests in cases of sudden hearing loss, but did not prevent hearing loss induced by noise or ototoxicity. However, there is a need for better-designed studies with larger samples to further prove the correlation between the effect of NAC and hearing loss.}, } @article {pmid36159825, year = {2022}, author = {Yin, X and Zhuang, X and Luo, W and Liao, M and Huang, L and Cui, Q and Huang, J and Yan, C and Jiang, Z and Liu, Y and Wang, W}, title = {Andrographolide promote the growth and immunity of Litopenaeus vannamei, and protects shrimps against Vibrio alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {990297}, pmid = {36159825}, issn = {1664-3224}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anisomycin ; Anti-Bacterial Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis ; Diterpenes ; Immunity, Innate ; Inflammation ; Interleukin-1beta/metabolism ; *Penaeidae ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Suppressor Protein p53/genetics ; *Vibrio alginolyticus ; bcl-2-Associated X Protein ; }, abstract = {Vibrio alginolyticus (V. alginolyticus) is one of the major pathogens causing mass mortality of shrimps worldwide, affecting energy metabolism, immune response and development of shrimps. In the context of the prohibition of antibiotics, it is necessary to develop a drug that can protect shrimp from V. alginolyticus. Andrographolide (hereinafter called Andr), a traditional drug used in Chinese medicine, which possesses diverse biological effects including anti-bacteria, antioxidant, immune regulation. In this study, we investigated the effect of Andr on growth, immunity, and resistance to V. alginolyticus infection of Litopenaeus vannamei (L. vannamei) and elucidate the underlying molecular mechanisms. Four diets were formulated by adding Andr at the dosage of 0 g/kg (Control), 0.5 g/kg, 1 g/kg, and 2 g/kg in the basal diet, respectively. Each diet was randomly fed to one group with three replicates of shrimps in a 4-week feeding trial. The results showed that dietary Andr improved the growth performance and non-specific immune function of shrimps. L. vannamei fed with Andr diets showed lower mortality after being challenged by V. alginolyticus. After 6 h of V. alginolyticus infection, reactive oxygen species (ROS) production, tissue injury, apoptosis, expression of inflammatory factors (IL-1 β and TNFα) and apoptosis-related genes (Bax, caspase3 and p53) were increased in hemocytes and hepatopancreas, while feeding diet with 0.5 g/kg Andr could inhibit the increase. Considering that JNK are important mediators of apoptosis, we examined the influence of Andr on JNK activity during V. alginolyticus infection. We found that Andr inhibited JNK activation induced by V. alginolyticus infection on L. vannamei. The ROS scavenger N-acetyl-l-cysteine (NAC) suppressed V. alginolyticus-induced inflammation and apoptosis, suggesting that ROS play an important role in V. alginolyticus-induced inflammation and apoptosis. Treated cells with JNK specific activator anisomycin, the inflammation and apoptosis inhibited by Andr were counteracted. Collectively, Andr promote the growth and immunity of L. vannamei, and protects shrimps against V. alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway. These results improve the understanding of the pathogenesis of V. alginolyticus infection and provide clues to the development of effective drugs against V. alginolyticus.}, } @article {pmid36158364, year = {2022}, author = {Gautam, A and Singh, H}, title = {Dengue Fever With Fulminant Liver Failure and Fatal Pulmonary Alveolar Hemorrhage: A Case Report.}, journal = {Cureus}, volume = {14}, number = {8}, pages = {e28302}, pmid = {36158364}, issn = {2168-8184}, abstract = {Dengue infection may rarely present with end-organ dysfunction. A 22-year-old male patient presented with a serologically confirmed dengue infection, with clinical manifestations and laboratory pictures suggestive of fulminant hepatitis. The in-hospital disease course was complicated with encephalopathy, recurrent hypoglycemic episodes, coagulopathy, pulmonary alveolar hemorrhage, hypotension, and kidney injury. He was managed with intravenous fresh frozen plasma, platelet concentrate, crystalloids and N-acetyl cysteine (NAC) along with other recommended supportive measures for dengue and fulminant hepatic failure. The patient did not show any improvement in liver function despite therapy and succumbed to his illness on day 6 of hospitalization. In view of the large burden of disease in developing nations and atypical manifestations of dengue infection, research into effective treatment strategies is warranted.}, } @article {pmid36157143, year = {2022}, author = {Ballester, MP and Sittner, R and Jalan, R}, title = {Alcohol and Acute-on-Chronic Liver Failure.}, journal = {Journal of clinical and experimental hepatology}, volume = {12}, number = {5}, pages = {1360-1370}, pmid = {36157143}, issn = {0973-6883}, abstract = {Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high short-term mortality. Alcohol is one of the leading causes of ACLF and the most frequently reported aetiology of underlying chronic liver disease. Among patients with alcoholic hepatitis (AH), ACLF is a frequent and severe complication. It is characterised by both immune dysfunction associated to an increased risk of infection and high-grade systemic inflammation that ultimately induce organ failure. Diagnosis and severity of ACLF determine AH prognosis, and therefore, ACLF prognostic scores should be used in severe AH with organ failure. Corticosteroids remain the first-line treatment for severe AH but they seem insufficient when ACLF is associated. Novel therapeutic targets to contain the excessive inflammatory response and reduce infection have been identified and are under investigation. With liver transplantation remaining one of the most effective therapies for severe AH and ACLF, adequate organ allocation represents a growing challenge. Hence, a clear understanding of the pathophysiology, clinical implications and management strategies of ACLF in AH is essential for hepatologists, which is narrated briefly in this review.}, } @article {pmid36156107, year = {2022}, author = {Tras, B and Eser Faki, H and Ozdemir Kutahya, Z and Bahcivan, E and Dik, B and Uney, K}, title = {The effects of dexamethasone and minocycline alone and combined with N-acetylcysteine and vitamin E on serum matrix metalloproteinase-9 and coenzyme Q10 levels in aflatoxin B1 administered rats.}, journal = {Polish journal of veterinary sciences}, volume = {25}, number = {3}, pages = {419-427}, doi = {10.24425/pjvs.2022.142026}, pmid = {36156107}, issn = {2300-2557}, mesh = {*Acetylcysteine/pharmacology ; *Aflatoxin B1/toxicity ; Animals ; Dexamethasone/pharmacology ; Male ; Matrix Metalloproteinase 9/genetics ; Minocycline/pharmacology ; Rats ; Rats, Wistar ; Reducing Agents ; Ubiquinone/analogs & derivatives ; Vitamin E/pharmacology ; }, abstract = {This study aimed to determine the effects of dexamethasone and minocycline alone and combined treatment with N-acetylcysteine (NAC) and vitamin E on serum coenzyme Q10 (CoQ10) and matrix metalloproteinase-9 (MMP-9) levels in rats administered aflatoxin B1 (AFB1). The study was carried out on 66 male Wistar rats. Following the intraperitoneal (IP) administration of AFB1 at dose of 2 mg/kg, minocycline (45 and 90 mg/kg, IP) and dexamethasone (5 and 20 mg/kg, IP) were administered alone and combined with NAC (200 mg/kg, IP) and vitamin E (600 mg/kg, IP). CoQ10 and MMP-9 levels were analyzed using the HPLC-UV method and a commercial kit by ELISA, respectively. AFB1 increased MMP-9 level and decreased CoQ10 level compared to the control group. After dexamethasone and minocycline administration, there is no increase in CoQ10 level, which is caused by AFB1. However, dexamethasone and minocycline combined with NAC+vitamin E caused significant increases in CoQ10 levels. Dexamethasone and minocycline alone and combined with NAC+vitamin E decreased MMP-9 levels compared to the single AFB1 treated group. The use of MMPs inhibitors and oxidative stress-reducing agents is anticipated to be beneficial in the poisoning with AFB1.}, } @article {pmid36155419, year = {2022}, author = {Harchegani, AB and Rostami, S and Mohsenifar, Z and Dafchahi, AB and Moghadam, FM and Jaafarzadeh, M and Saraabestan, SS and Ranji, N}, title = {Anti-apoptotic properties of N-Acetyl cysteine and its effects on of Liver X receptor and Sirtuin 1 expression in the liver of rats exposed to Lead.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {74}, number = {}, pages = {127070}, doi = {10.1016/j.jtemb.2022.127070}, pmid = {36155419}, issn = {1878-3252}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Caspase 3/genetics/metabolism ; Lead/metabolism ; Lipids ; Liver/metabolism ; Liver X Receptors/genetics/metabolism ; Rats ; *Sirtuin 1/genetics/metabolism/pharmacology ; bcl-2-Associated X Protein/metabolism/pharmacology ; }, abstract = {BACKGROUND: This study aimed to evaluate the expression of Liver X receptor (Lxr), Sirtuin 1 (Sirt1), apoptotic-related genes, and the protective role of N-acetylcysteine (NAC) in the liver of rats treated with Lead (Pb).

METHODS: Rats were randomly divided into 5 groups, including G1 (control), G2 (single dose of Pb), G3 (continuous dose of Pb), G4 (single dose of Pb + NAC), and G5 (continuous dose of Pb + NAC). Lipid profiles and liver specific enzymes were assessed. Expression of Lxr, Sirt1, Bax and Caspase-3 genes was considered using RT-PCR.

RESULTS: Exposure to Pb caused a significant accumulation of Pb in the blood and liver tissue, increase in serum AST, ALT and ALP enzymes, as well as lipid profiles. Chronic exposure to Pb caused a significant decrease in Lxr (3.15-fold; p < 0.001) and Sirt1 (2.78-fold; p = 0.009), but significant increase in expression of Bax (4.49-fold; p < 0.001) and Caspase-3 (4.10-fold; p < 0.001) genes when compared to the control. Combined therapy with Pb + NAC in rats caused a significant decrease in AST, ALT and ALP values (28.93%, 20.80% and 28.86%, respectively) in the blood as compared to rats treated with Pb alone. Co-treated with Pb + NAC significantly increased the expression of Lxr (1.72-fold; p = 0.043) and Sirt1 (2.45-fold; p = 0.008), but decreased the expression of Bax (1.96-fold; p = 0.03) and Caspase 3 (2.22-fold; p = 0.029) genes when compared to rats treated with Pb alone.

CONCLUSION: Chronic exposure to Pb is strongly associated with accumulation of Pb in the blood and liver, hepatic cells apoptosis, down-expression of Lxr and Sirt1 genes and consequently liver injury and abnormal lipid profiles. NAC reversed the Pb-induced toxicity on the liver tissue.}, } @article {pmid36155047, year = {2023}, author = {Wu, Y and Yao, Y and Bai, H and Shimizu, K and Li, R and Zhang, C}, title = {Investigation of pulmonary toxicity evaluation on mice exposed to polystyrene nanoplastics: The potential protective role of the antioxidant N-acetylcysteine.}, journal = {The Science of the total environment}, volume = {855}, number = {}, pages = {158851}, doi = {10.1016/j.scitotenv.2022.158851}, pmid = {36155047}, issn = {1879-1026}, mesh = {Humans ; Animals ; Mice ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Acetylcysteine/pharmacology ; Antioxidants ; Polystyrenes/toxicity ; Microplastics ; }, abstract = {Accumulating evidences show that the hazardous substance atmospheric nanoplastics increase the respiratory risk of individuals, but the inside toxicity mechanisms to lung tissue remain unclear. This study aims at investigating the potential mechanisms of inhaled cationic polystyrene nanoplastics (amine-polystyrene nanoplastics, APS-NPs)-induced pulmonary toxicity on mice. In vivo, the mice intratracheal administrated with APS-NPs suspension (5 mg/kg) were found inflammatory infiltrates in lung tissues through histopathology analysis. Furthermore, transcriptome analysis demonstrated that 1821 differentially expressed mRNA between APS group and control group were dominantly associated with 288 known KEGG pathways, indicating that APS-NPs might cause early inflammatory responses in lung tissue by activating the NLRP3/capase-1/IL-1β signaling pathway. Moreover, in vitro results also showed that NLRP3 inflammasome could be activated to induce pyroptosis in MLE-12 cells after exposure to APS-NPs. And, MH-S cells after exposure to APS-NPs exhibited increased Irg1 proteins, leading to the increasing generation of ROS and inflammatory factors (e.g., tnf-α, il-6, il-1β). In conclusion, these results revealed that Irg1/NF-κB/NLRP3/Caspase-1 signaling pathway was activated significantly after exposing to APS-NPs, leading to pulmonary toxicity on mice. Intriguingly, prior administration of the clinical antioxidant N-acetylcysteine (NAC) could serve as a possible candidate for the prevention and treatment of pulmonary toxicity induced by APS-NPs. The study contributes to a better understanding of the potential risks of environmental nanoplastics to humans and its improvement measure.}, } @article {pmid36154299, year = {2022}, author = {Zhao, Y and Li, F and Li, S and Ji, J and Qiao, W and Fang, J}, title = {Aluminum chloride induces G0/G1 phase arrest via regulating the reactive oxygen species-depended non-canonical STAT1 pathway in hFOB1.19 cells.}, journal = {Human & experimental toxicology}, volume = {41}, number = {}, pages = {9603271221129846}, doi = {10.1177/09603271221129846}, pmid = {36154299}, issn = {1477-0903}, mesh = {Aluminum Chloride/toxicity ; *Cysteine/pharmacology ; G1 Phase ; Phosphorylation ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; STAT1 Transcription Factor/metabolism ; Serine/metabolism/pharmacology ; *Signal Transduction ; }, abstract = {Treatment with aluminum chloride (AlCl3) suppresses the growth of osteoblastic cells; however, the molecular mechanisms underlying the impact of AlCl3 on cell growth have not been fully characterized. In this study, we observed that exposure of hFOB1.19 cells to AlCl3 arrested cells at G0/G1 phase by inducing p21 expression. Further studies indicated that AlCl3 upregulated the phosphorylation level of signal transducer and activator of transcription 1 (STAT1) at serine 727 site (Ser727). By chromatin immunoprecipitation and electrophoretic mobility shift assay, we found that AlCl3 promoted STAT1/DNA binding activity to p21 promoter, thus resulting in the upregulation of p21. Moreover, siRNA-mediated knockdown of STAT1 attenuated p21 level induced by AlCl3. Notably, using hFOB1.19 cells stably expressing dominant-negative STAT1 (Ser727Ala), we demonstrated that phosphorylation of STAT1 at Ser727 site is required for p21-mediated cycle arrest induced by AlCl3. Mechanism investigation indicated that AlCl3 stimulated the phosphorylation of JNK, and administration of JNK inhibitor SP600125 prevented AlCl3-induced G0/G1 arrest through suppressing the phosphorylation of STAT1. Notably, pretreatment with N-acetyl-cysteine, a reactive oxygen species scavenger, conferred a significantly inhibitory effect on AlCl3-mediated activation of JNK/STAT1 signaling pathway. Taken together, our findings provide the molecular mechanism for G0/G1 arrest induced by AlCl3 in osteoblastic cells.}, } @article {pmid36148786, year = {2022}, author = {Barrozo, LG and Silva, BR and Paulino, LRFM and Barbalho, EC and Nascimento, DR and Costa, FC and Batista, ALPS and Lopes, EPF and Rodrigues, APR and Silva, JRV}, title = {N-Acetyl cysteine reduces the levels of reactive oxygen species and improves in vitro maturation of oocytes from medium-sized bovine antral follicles.}, journal = {Zygote (Cambridge, England)}, volume = {30}, number = {6}, pages = {882-890}, doi = {10.1017/S0967199422000429}, pmid = {36148786}, issn = {1469-8730}, mesh = {Cattle ; Animals ; *In Vitro Oocyte Maturation Techniques/methods ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Oocytes ; Meiosis ; Superoxide Dismutase/metabolism ; Glutathione Peroxidase/metabolism ; RNA, Messenger/genetics/metabolism ; }, abstract = {This study aims to evaluate the effects of N-acetylcysteine (NAC) on bovine oocyte maturation, mitochondrial activity and transzonal projections (TZP), as well as on the levels of reactive oxygen species (ROS) and messenger RNA (mRNA) for catalase (CAT) superoxide dismutase (SOD), periredoxin-6 (Prdx6), glutathione peroxidase (GPx), growth and differentiation factor-9 (GDF9), histone H1Foo, cyclin B1 (CCNB1) and c-Mos. Bovine cumulus-oocyte complexes (COC) of medium-sized antral follicles (3.0-6.0 mm) were prematured in TCM-199 for 8 h at 38.5°C in 5% CO2. After prematuration in the presence of forskolin and C-type natriuretic peptide, COCs were matured in TCM-199 alone or with 0.1, 0.5 or 2.5 mM NAC. Then, oocytes were classified according to the stage of chromatin. Furthermore, mitochondrial activity and intracellular levels of ROS and TZP were also evaluated. The levels of mRNAs for CAT, SOD, Prdx6, GPx, GDF9, H1Foo, CCNB1 and c-Mos were evaluated using real-time polymerase chain reaction (RT-PCR). The results showed that NAC significantly increased the percentages of oocytes with resumption of meiosis when compared with those oocytes matured in control medium. Oocytes had homogeneous mitochondrial distribution, and those cultured with 0.1 and 0.5 mM NAC had lower levels of ROS when compared with the control. In addition, 0.5 mM NAC reduced TZP and the levels of mRNA for CCNB1. In contrast, NAC did not influence the expression of CAT, GPx, Prdx6, SOD, GDF9, H1Foo, and c-Mos. In conclusion, 0.5 mM NAC reduced the levels of ROS, TZP and mRNA for CCNB1, and improved in vitro resumption of meiosis in oocytes from medium-sized bovine antral follicles.}, } @article {pmid36148515, year = {2023}, author = {Hegde, G and Sharma, P and Lekhadia, U and Gopani, S and Kandoi, N}, title = {Entrapped Malecot catheter removal: Our experience.}, journal = {Tropical doctor}, volume = {53}, number = {1}, pages = {146-147}, doi = {10.1177/00494755221125082}, pmid = {36148515}, issn = {1758-1133}, mesh = {Humans ; *Drainage ; Device Removal ; Catheters ; *Liver Abscess ; }, abstract = {Some surgeons use a Malecot catheter for drainage of intra-abdominal or mediastinal collections. These tubes are usually removed after 2-3 weeks. If left later, they may become entrapped due to the ingrowing of tissue, and fibrosis within the flower-like tip of the Malecot's catheter. Its removal then needs careful manipulation to prevent organ damage. We present our experience in ensuring the safe removal of such entrapped Malecot's catheters in liver abscess patients.}, } @article {pmid36148239, year = {2022}, author = {Liggett, JR and Kang, J and Ranjit, S and Rodriguez, O and Loh, K and Patil, D and Cui, Y and Duttargi, A and Nguyen, S and He, B and Lee, Y and Oza, K and Frank, BS and Kwon, D and Li, HH and Kallakury, B and Libby, A and Levi, M and Robson, SC and Fishbein, TM and Cui, W and Albanese, C and Khan, K and Kroemer, A}, title = {Oral N-acetylcysteine decreases IFN-γ production and ameliorates ischemia-reperfusion injury in steatotic livers.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {898799}, pmid = {36148239}, issn = {1664-3224}, support = {R21 AI130800/AI/NIAID NIH HHS/United States ; T32 DK120521/DK/NIDDK NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; S10 OD025153/OD/NIH HHS/United States ; R01 DK127830/DK/NIDDK NIH HHS/United States ; R01 DK116567/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cytokines ; *Fatty Liver/drug therapy ; Interferon-gamma ; Ligands ; Mice ; Mice, Inbred C57BL ; Peroxisome Proliferator-Activated Receptors ; Phospholipids ; *Reperfusion Injury/etiology ; Triglycerides ; }, abstract = {Type 1 Natural Killer T-cells (NKT1 cells) play a critical role in mediating hepatic ischemia-reperfusion injury (IRI). Although hepatic steatosis is a major risk factor for preservation type injury, how NKT cells impact this is understudied. Given NKT1 cell activation by phospholipid ligands recognized presented by CD1d, we hypothesized that NKT1 cells are key modulators of hepatic IRI because of the increased frequency of activating ligands in the setting of hepatic steatosis. We first demonstrate that IRI is exacerbated by a high-fat diet (HFD) in experimental murine models of warm partial ischemia. This is evident in the evaluation of ALT levels and Phasor-Fluorescence Lifetime (Phasor-FLIM) Imaging for glycolytic stress. Polychromatic flow cytometry identified pronounced increases in CD45+CD3+NK1.1+NKT1 cells in HFD fed mice when compared to mice fed a normal diet (ND). This observation is further extended to IRI, measuring ex vivo cytokine expression in the HFD and ND. Much higher interferon-gamma (IFN-γ) expression is noted in the HFD mice after IRI. We further tested our hypothesis by performing a lipidomic analysis of hepatic tissue and compared this to Phasor-FLIM imaging using "long lifetime species", a byproduct of lipid oxidation. There are higher levels of triacylglycerols and phospholipids in HFD mice. Since N-acetylcysteine (NAC) is able to limit hepatic steatosis, we tested how oral NAC supplementation in HFD mice impacted IRI. Interestingly, oral NAC supplementation in HFD mice results in improved hepatic enhancement using contrast-enhanced magnetic resonance imaging (MRI) compared to HFD control mice and normalization of glycolysis demonstrated by Phasor-FLIM imaging. This correlated with improved biochemical serum levels and a decrease in IFN-γ expression at a tissue level and from CD45+CD3+CD1d+ cells. Lipidomic evaluation of tissue in the HFD+NAC mice demonstrated a drastic decrease in triacylglycerol, suggesting downregulation of the PPAR-γ pathway.}, } @article {pmid36145638, year = {2022}, author = {Pontremoli, C and Boffito, M and Laurano, R and Iviglia, G and Torre, E and Cassinelli, C and Morra, M and Ciardelli, G and Vitale-Brovarone, C and Fiorilli, S}, title = {Mesoporous Bioactive Glasses Incorporated into an Injectable Thermosensitive Hydrogel for Sustained Co-Release of Sr[2+] Ions and N-Acetylcysteine.}, journal = {Pharmaceutics}, volume = {14}, number = {9}, pages = {}, pmid = {36145638}, issn = {1999-4923}, support = {685872//H2020-NMP-PILOTS-2015/ ; }, abstract = {An injectable delivery platform for promoting delayed bone healing has been developed by combining a thermosensitive polyurethane-based hydrogel with strontium-substituted mesoporous bioactive glasses (MBG_Sr) for the long-term and localized co-delivery of pro-osteogenic Sr[2+] ions and an osteogenesis-enhancing molecule, N-Acetylcysteine (NAC). The incorporation of MBG_Sr microparticles, with a final concentration of 20 mg/mL, did not alter the overall properties of the thermosensitive hydrogel, in terms of sol-to-gel transition at a physiological-like temperature, gelation time, injectability and stability in aqueous environment at 37 °C. In particular, the hydrogel formulations (15% w/v polymer concentration) showed fast gelation in physiological conditions (1 mL underwent complete sol-to-gel transition within 3-5 min at 37 °C) and injectability in a wide range of temperatures (5-37 °C) through different needles (inner diameter in the range 0.4-1.6 mm). In addition, the MBG_Sr embedded into the hydrogel retained their full biocompatibility, and the released concentration of Sr[2+] ions were effective in promoting the overexpression of pro-osteogenic genes from SAOS2 osteoblast-like cells. Finally, when incorporated into the hydrogel, the MBG_Sr loaded with NAC maintained their release properties, showing a sustained ion/drug co-delivery along 7 days, at variance with the MBG particles as such, showing a strong burst release in the first hours of soaking.}, } @article {pmid36145547, year = {2022}, author = {Coelho, AM and Queiroz, IF and Perucci, LO and Souza, MO and Lima, WG and Talvani, A and Costa, DC}, title = {Piperine as Therapeutic Agent in Paracetamol-Induced Hepatotoxicity in Mice.}, journal = {Pharmaceutics}, volume = {14}, number = {9}, pages = {}, pmid = {36145547}, issn = {1999-4923}, support = {00//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 00//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 00//Universidade Federal de Ouro Preto/ ; }, abstract = {High doses of paracetamol (APAP) can cause irreversible liver damage. Piperine (P) inhibits cytochrome P450, which is involved in the metabolism of various xenobiotics, including paracetamol. We evaluated the hepatoprotective effects of piperine with or without N-acetylcysteine (NAC) in APAP-induced hepatotoxicity. The mice were treated with two doses of piperine (P20 or P40) and/or NAC at 2 h after administration of APAP. The NAC+P20 and NAC+P40 groups showed a reduced area of necrosis, MMP-9 activity, and Casp-1 expression. Furthermore, the NAC+P20 group was the only treatment that reduced alanine aminotransferase (ALT) and increased the levels of sulfhydryl groups (-SH). In the NAC+P40 group, NLRP-3 expression was reduced. Aspartate aminotransferase (AST), thiobarbituric acid-reactive substances (TBARS), and IL-1β expression decreased in the NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The liver necrosis area, TNF levels, carbonylated protein, and IL-18 expression decreased in the P40, NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The cytokine IL-6 was reduced in all treatments. Piperine can be used in combination with NAC to treat APAP-induced hepatotoxicity.}, } @article {pmid36144576, year = {2022}, author = {Shi, Z and Zhao, Y and Liu, S and Wang, Y and Yu, Q}, title = {Size-Dependent Impact of Magnetic Nanoparticles on Growth and Sporulation of Aspergillus niger.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {18}, pages = {}, pmid = {36144576}, issn = {1420-3049}, support = {3217010793//National Natural Science Foundation of China/ ; TSBICIP-KJGG-006//Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project/ ; 2021BEG02002//Natural Foundation of Ningxia Hui Nationality Autonomous Region/ ; }, mesh = {Acetylcysteine ; Aspergillus niger ; Chitin ; DNA ; Iron ; *Magnetite Nanoparticles ; Reactive Oxygen Species ; }, abstract = {Magnetic nanoparticles (MNPs) are becoming important DNA nanocarriers for genetic engineering of industrial fungi. However, the biological effect of MNPs on industrial fungi remains unknown. In this study, we prepared three kinds of magnetic nanoparticles with different sizes (i.e., 10 nm, 20 nm, and 200 nm) to investigate their impact on the growth and sporulation of the important industrial fungus Aspergillus niger. Transmission electron microscopy, X-ray diffraction analysis and Zeta potential analysis revealed that the three kinds of MNPs, including MNP10, MNP20 and MNP200, had uniform size distribution, regular Fe3O4 X-ray diffraction (XRD) patterns and similar Zeta potentials. Interestingly, although the three kinds of MNPs did not obviously inhibit growth of the fungus, the MNP20 at 500 mg/L strongly attenuated sporulation, leading to a remarkable decrease in spore numbers on culturing plates. Further investigation showed that MNP20 at the high concentration led to drastic chitin accumulation in the cell wall, indicating cell wall disruption of the MNP20-treated fungal cells. Moreover, the MNPs did not cause unusual iron dissolution and reactive oxygen species (ROS) accumulation, and the addition of ferrous ion, ferric ion or the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) had no impact on the sporulation of the fungus, suggesting that both iron dissolution and ROS accumulation did not contribute to attenuated sporulation by MNP20. This study revealed the size-dependent effect of MNPs on fungal sporulation, which was associated with MNP-induced cell wall disruption.}, } @article {pmid36140239, year = {2022}, author = {Chen, J and Hwang, DW and Chen, YW and Chen, TC and Yadav, NN and Stait-Gardner, T and Price, WS and Zheng, G}, title = {MRI Detection of Hepatic N-Acetylcysteine Uptake in Mice.}, journal = {Biomedicines}, volume = {10}, number = {9}, pages = {}, pmid = {36140239}, issn = {2227-9059}, support = {G2015031594478959//Sigma Xi/ ; MOST 110-2113-M-001-031//MInistry of Science and Technology of the Republic of China (Taiwan)/ ; }, abstract = {This proof-of-concept study looked at the feasibility of using a thiol-water proton exchange (i.e., CEST) MRI contrast to detect in vivo hepatic N-acetylcysteine (NAC) uptake. The feasibility of detecting NAC-induced glutathione (GSH) biosynthesis using CEST MRI was also investigated. The detectability of the GSH amide and NAC thiol CEST effect at B0 = 7 T was determined in phantom experiments and simulations. C57BL/6 mice were injected intravenously (IV) with 50 g L[-1] NAC in PBS (pH 7) during MRI acquisition. The dynamic magnetisation transfer ratio (MTR) and partial Z-spectral data were generated from the acquisition of measurements of the upfield NAC thiol and downfield GSH amide CEST effects in the liver. The [1]H-NMR spectroscopy on aqueous mouse liver extracts, post-NAC-injection, was performed to verify hepatic NAC uptake. The dynamic MTR and partial Z-spectral data revealed a significant attenuation of the mouse liver MR signal when a saturation pulse was applied at -2.7 ppm (i.e., NAC thiol proton resonance) after the IV injection of the NAC solution. The [1]H-NMR data revealed the presence of hepatic NAC, which coincided strongly with the increased upfield MTR in the dynamic CEST data, providing strong evidence that hepatic NAC uptake was detected. However, this MTR enhancement was attributed to a combination of NAC thiol CEST and some other upfield MT-generating mechanism(s) to be identified in future studies. The detection of hepatic GSH via its amide CEST MRI contrast was inconclusive based on the current results.}, } @article {pmid36139851, year = {2022}, author = {Hsu, YY and Chuang, YT and Yen, CY and Cheng, MY and Chen, CY and Cheng, YB and Chang, HW}, title = {Methanol Extract of Clavularia inflata Exerts Apoptosis and DNA Damage to Oral Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {36139851}, issn = {2076-3921}, support = {MOST 111-2320-B-037-015-MY3; MOST-108-2320-B-110-009-MY3//Ministry of Science and Technology/ ; KMU-DK(A)111008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Antiproliferation effects of Clavularia-derived natural products against cancer cells have been reported on, but most studies have focused on identifying bioactive compounds, lacking a detailed investigation of the molecular mechanism. Crude extracts generally exhibit multiple targeting potentials for anticancer effects, but they have rarely been assessed for methanol extracts of Clavularia inflata (MECI). This investigation aims to evaluate the antiproliferation of MECI and to examine several potential mechanisms between oral cancer and normal cells. A 24 h MTS assay demonstrated that MECI decreased cell viability in several oral cancer cell lines more than in normal cells. N-acetylcysteine (NAC), an oxidative stress inhibitor, recovered these antiproliferation effects. Higher oxidative stress was stimulated by MECI in oral cancer cells than in normal cells, as proven by examining reactive oxygen species and mitochondrial superoxide. This preferential induction of oxidative stress was partly explained by downregulating more cellular antioxidants, such as glutathione, in oral cancer cells than in normal cells. Consequently, the MECI-generated high oxidative stress in oral cancer cells was preferred to trigger more subG1 population, apoptosis expression (annexin V and caspase activation), and DNA damage, reverted by NAC. In conclusion, MECI is a potent marine natural product showing preferential antiproliferation against oral cancer cells.}, } @article {pmid36139832, year = {2022}, author = {Altomare, AA and Brioschi, M and Eligini, S and Bonomi, A and Zoanni, B and Iezzi, A and Jemos, C and Porro, B and D'Alessandra, Y and Guarino, A and Omodeo Salè, E and Aldini, G and Agostoni, P and Banfi, C}, title = {N-Acetylcysteine Regenerates In Vivo Mercaptoalbumin.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {36139832}, issn = {2076-3921}, support = {Ricerca Corrente 2021, 2764191//Ministero della Salute/ ; }, abstract = {Human serum albumin (HSA) represents the most abundant plasma protein, with relevant antioxidant activity due to the presence of the sulfhydryl group on cysteine at position 34 (Cys34), the latter being one of the major target sites for redox-dependent modifications leading to the formation of mixed disulfide linkages with low molecular weight thiols. Thiolated forms of HSA (Thio-HSA) may be useful as markers of an unbalanced redox state and as a potential therapeutic target. Indeed, we have previously reported that albumin Cys34 can be regenerated in vitro by N-Acetylcysteine (NAC) through a thiol-disulfide breaking mechanism, with a full recovery of the HSA antioxidant and antiplatelet activities. With this case study, we aimed to assess the ability of NAC to regenerate native mercaptoalbumin (HSA-SH) and the plasma antioxidant capacity in subjects with redox unbalance, after oral and intravenous administration. A placebo-controlled crossover study, single-blinded, was performed on six hypertensive subjects, randomized into two groups, on a one-to-one basis with NAC (600 mg/die) or a placebo, orally and intravenously administered. Albumin isoforms, HSA-SH, Thio-HSA, and glutathione levels were evaluated by means of mass spectrometry. The plasma antioxidant activity was assessed by a fluorimetric assay. NAC, orally administered, significantly decreased the Thio-HSA levels in comparison with the pre-treatment conditions (T0), reaching the maximal effect after 60 min (-24.7 ± 8%). The Thio-HSA reduction was accompanied by a concomitant increase in the native HSA-SH levels (+6.4 ± 2%). After intravenous administration of NAC, a significant decrease of the Thio-HSA with respect to the pre-treatment conditions (T0) was observed, with a maximal effect after 30 min (-68.9 ± 10.6%) and remaining significant even after 6 h. Conversely, no effect on the albumin isoforms was detected with either the orally or the intravenously administered placebo treatments. Furthermore, the total antioxidant activity of the plasma significantly increased after NAC infusion with respect to the placebo (p = 0.0089). Interestingly, we did not observe any difference in terms of total glutathione corrected for hemoglobin, ruling out any effect of NAC on the intracellular glutathione and supporting its role as a disulfide-breaking agent. This case study confirms the in vitro experiments and demonstrates for the first time that NAC is able to regenerate mercaptoalbumin in vivo, allowing us to hypothesize that the recovery of Cys34 content can modulate in vivo oxidative stress and, hopefully, have an effect in oxidative-based diseases.}, } @article {pmid36139457, year = {2022}, author = {Ouyang, J and Xiao, Y and Ren, Q and Huang, J and Zhou, Q and Zhang, S and Li, L and Shi, W and Chen, Z and Wu, L}, title = {7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells.}, journal = {Cells}, volume = {11}, number = {18}, pages = {}, pmid = {36139457}, issn = {2073-4409}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Core Binding Factor Alpha 1 Subunit ; Ketocholesterols/pharmacology ; *Osteogenesis ; *Oxysterols/pharmacology ; Superoxide Dismutase ; }, abstract = {7-Ketocholesterol (7KC) is one of the oxysterols produced by the auto-oxidation of cholesterol during the dysregulation of cholesterol metabolism which has been implicated in the pathological development of osteoporosis (OP). Oxiapoptophagy involving oxidative stress, autophagy, and apoptosis can be induced by 7KC. However, whether 7KC produces negative effects on MC3T3-E1 cells by stimulating oxiapoptophagy is still unclear. In the current study, 7KC was found to significantly decrease the cell viability of MC3T3-E1 cells in a concentration-dependent manner. In addition, 7KC decreased ALP staining and mineralization and down-regulated the protein expression of OPN and RUNX2, inhibiting osteogenic differentiation. 7KC significantly stimulated oxidation and induced autophagy and apoptosis in the cultured MC3T3-E1 cells. Pretreatment with the anti-oxidant acetylcysteine (NAC) could effectively decrease NOX4 and MDA production, enhance SOD activity, ameliorate the expression of autophagy-related factors, decrease apoptotic protein expression, and increase ALP, OPN, and RUNX2 expression, compromising 7KC-induced oxiapoptophagy and osteogenic differentiation inhibition in MC3T3-E1 cells. In summary, 7KC may induce oxiapoptophagy and inhibit osteogenic differentiation in the pathological development of OP.}, } @article {pmid36139298, year = {2022}, author = {Yang, P and Chen, X and Tian, X and Zhou, Z and Zhang, Y and Tang, W and Fu, K and Zhao, J and Ruan, Y}, title = {A Proteomic Study of the Effect of N-acetylcysteine on the Regulation of Early Pregnancy in Goats.}, journal = {Animals : an open access journal from MDPI}, volume = {12}, number = {18}, pages = {}, pmid = {36139298}, issn = {2076-2615}, support = {2021YFD1200403//National Key Research & Development plan/ ; 32060753//National Natural Science Foundation of China/ ; Qian Kehe foundation-ZK [2021] General 151//Science and Technology Project of Guizhou Province/ ; Qian Kehe platform talents [2022]021-1//Guizhou high level Innovative Talents Project/ ; }, abstract = {Dietary supplementation with N-acetyl-L-cysteine (NAC) may support early pregnancy regulation and fertility in female animals. The purpose of this study was to investigate the effect of supplementation with 0.07% NAC on the expression of the uterine keratin gene and protein in Qianbei-pockmarked goats during early pregnancy using tandem mass spectrometry (TMT) relative quantitative proteomics. The results showed that there were significant differences in uterine keratin expression between the experimental group (NAC group) and the control group on day 35 of gestation. A total of 6271 proteins were identified, 6258 of which were quantified by mass spectrometry. There were 125 differentially expressed proteins (DEPs), including 47 upregulated and 78 downregulated proteins, in the NAC group. Bioinformatic analysis showed that these DEPs were mainly involved in the transport and biosynthesis of organic matter and were related to the binding of transition metal ions, DNA and proteins and the catalytic activity of enzymes. They were enriched in the Jak-STAT signalling pathway, RNA monitoring pathway, amino acid biosynthesis, steroid biosynthesis and other pathways that may affect the early pregnancy status of does through different pathways and thus influence early embryonic development. Immunohistochemistry, real-time quantitative PCR and Western blotting were used to verify the expression and localization of glial fibrillary acidic protein (GFAP) and pelota mRNA surveillance and ribosomal rescue factor (PELO) in uterine horn tissue. The results showed that both PELO and GFAP were localized to endometrial and stromal cells, consistent with the mass spectrometry data at the transcriptional and translational levels. Moreover, NAC supplementation increased the levels of the reproductive hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol (E2), progesterone (P4), superoxide dismutase (SOD), glutamate peroxidase (GSH-Px) and nitric oxide (NO) in the serum of does. These findings provide new insight into the mechanism by which NAC regulates early pregnancy and embryonic development in goats.}, } @article {pmid36139290, year = {2022}, author = {Fu, K and Chen, X and Guo, W and Zhou, Z and Zhang, Y and Ji, T and Yang, P and Tian, X and Wang, W and Zou, Y}, title = {Effects of N Acetylcysteine on the Expression of Genes Associated with Reproductive Performance in the Goat Uterus during Early Gestation.}, journal = {Animals : an open access journal from MDPI}, volume = {12}, number = {18}, pages = {}, pmid = {36139290}, issn = {2076-2615}, support = {2021YFD1200403//the National Key Research and Development plan of China/ ; 32060753//the National Natural Science Foundation of China/ ; Qian Kehe foundation-ZK [2021] General 151//the Science and Technology Project of Guizhou Province/ ; Qian Kehe Platform Talents [2022]021-1//the Guizhou High Level Innovative Talents Project/ ; Qian Jiaohe YJSKYJJ [2021]011//the Guizhou Provincial Education Department Postgraduate Research Fund/ ; }, abstract = {N acetylcysteine (NAC) affects antioxidation and reactive oxygen species scavenging in the body and thereby promotes embryonic development and implantation and inhibits inflammation. The mechanism through which NAC regulates reproductive performance in the uteri of goats during early gestation remains unclear. In this study, the treatment group was fed 0.07% NAC for the first 35 days of gestation, whereas the control group received no NAC supplementation. The regulatory genes and key pathways associated with goat reproductive performance under NAC supplementation were identified by RNA-seq. RT-qPCR was used to verify the sequencing results and subsequently construct tissue expression profiles of the relevant genes. RNA-seq identified 19,796 genes coexpressed in the control and treatment groups and 1318 differentially expressed genes (DEGs), including 787 and 531 DEGs enriched in the treatment and control groups, respectively. A GO analysis revealed that the identified genes mapped to pathways such as cell activation, cytokine production, cell mitotic processes, and angiogenesis, and a KEGG enrichment analysis showed that the DEGs were enriched in pathways associated with reproductive regulation, immune regulation, resistance to oxidative stress, and cell adhesion. The RT-qPCR analysis showed that BDNF and CSF-1 were most highly expressed in the uterus, that WIF1 and ESR2 showed low expression in the uterus, and that CTSS, PTX3, and TGFβ-3 were most highly expressed in the oviduct, which indicated that these genes may be directly or indirectly involved in the modulation of reproduction in early-gestation goats. These findings provide fundamental data for the NAC-mediated modulation of the reproductive performance of goats during early gestation.}, } @article {pmid36139036, year = {2022}, author = {Bao, M and Hua, X and Mo, H and Sun, Z and Xu, B and Chen, X and Xu, M and Xu, X and Song, J}, title = {N-Acetylcysteine, an ROS Inhibitor, Alleviates the Pathophysiology of Hyperthyroidism-Induced Cardiomyopathy via the ROS/Ca[2+] Pathway.}, journal = {Biomolecules}, volume = {12}, number = {9}, pages = {}, pmid = {36139036}, issn = {2218-273X}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Calpain/pharmacology ; *Cardiomyopathies/drug therapy/etiology ; Caspase 3 ; Fibrosis ; Humans ; *Hyperthyroidism/complications/drug therapy ; NF-kappa B/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species/metabolism ; }, abstract = {Hyperthyroidism is common and can induce cardiomyopathy, but there is no effective therapeutic strategy. The purpose of this study was to investigate the molecular mechanism of hyperthyroidism-induced cardiomyopathy (HTC) and the effect of N-acetylcysteine (NAC), an ROS inhibitor, on the pathophysiology of HTC in vivo and in vitro. Compared with those in the control groups in vivo and in vitro, TT3 and TT4 were significantly increased, the structure of myocardial cells was enlarged and disordered, and interstitial fibrosis and the apoptosis of myocardial cells were markedly increased in the L-Thy group. The ROS and inflammatory response were increased in the hyperthyroidism group. In the NAC group, the contents of TT3 and TT4 were decreased, the myocardial cell structure was slightly disturbed, fibrosis and apoptosis were significantly reduced, and the ROS level and inflammatory response were significantly reduced. Interestingly, L-Thy decreased the viability of fibroblasts and H9c2 cells, suggesting that L-Thy-induced fibrosis was not caused by the proliferation of fibroblasts. The molecular mechanism of HTC could be explained by the fact that L-Thy could cause cardiac hypertrophy, inflammation, and fibrosis by regulating the Ca[2+]/calpain/Rcan1-dependent signalling pathway, the Ca[2+]/Rcan1/NF-κB/p65-dependent signalling pathway, and the Ca[2+]/ROS/Bcl-2/caspase-3-dependent signalling pathway. In conclusion, NAC can alleviate the pathophysiology of hyperthyroidism-induced cardiomyopathy, probably by regulating the ROS/Ca[2+]-dependent pathway.}, } @article {pmid36138415, year = {2022}, author = {Abdulrab, S and Mostafa, N and Al-Maweri, SA and Abada, H and Halboub, E and Alhadainy, HA}, title = {Correction: Antibacterial and anti-inflammatory efficacy of N-acetyl cysteine in endodontic treatment: a scoping review.}, journal = {BMC oral health}, volume = {22}, number = {1}, pages = {419}, doi = {10.1186/s12903-022-02458-x}, pmid = {36138415}, issn = {1472-6831}, } @article {pmid36130098, year = {2023}, author = {Hameed, MQ and Hodgson, N and Lee, HHC and Pascual-Leone, A and MacMullin, PC and Jannati, A and Dhamne, SC and Hensch, TK and Rotenberg, A}, title = {N-acetylcysteine treatment mitigates loss of cortical parvalbumin-positive interneuron and perineuronal net integrity resulting from persistent oxidative stress in a rat TBI model.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {33}, number = {7}, pages = {4070-4084}, pmid = {36130098}, issn = {1460-2199}, support = {P50 HD105351/HD/NICHD NIH HHS/United States ; R01 NS088583/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism ; Parvalbumins/metabolism ; *Brain Injuries, Traumatic/metabolism ; Oxidative Stress/physiology ; Interneurons/metabolism ; }, abstract = {Traumatic brain injury (TBI) increases cerebral reactive oxygen species production, which leads to continuing secondary neuronal injury after the initial insult. Cortical parvalbumin-positive interneurons (PVIs; neurons responsible for maintaining cortical inhibitory tone) are particularly vulnerable to oxidative stress and are thus disproportionately affected by TBI. Systemic N-acetylcysteine (NAC) treatment may restore cerebral glutathione equilibrium, thus preventing post-traumatic cortical PVI loss. We therefore tested whether weeks-long post-traumatic NAC treatment mitigates cortical oxidative stress, and whether such treatment preserves PVI counts and related markers of PVI integrity and prevents pathologic electroencephalographic (EEG) changes, 3 and 6 weeks after fluid percussion injury in rats. We find that moderate TBI results in persistent oxidative stress for at least 6 weeks after injury and leads to the loss of PVIs and the perineuronal net (PNN) that surrounds them as well as of per-cell parvalbumin expression. Prolonged post-TBI NAC treatment normalizes the cortical redox state, mitigates PVI and PNN loss, and - in surviving PVIs - increases per-cell parvalbumin expression. NAC treatment also preserves normal spectral EEG measures after TBI. We cautiously conclude that weeks-long NAC treatment after TBI may be a practical and well-tolerated treatment strategy to preserve cortical inhibitory tone post-TBI.}, } @article {pmid36129244, year = {2022}, author = {Tan, JL and Stam, J and van den Berg, AP and van Rheenen, PF and Dekkers, BGJ and Touw, DJ}, title = {Amanitin intoxication: effects of therapies on clinical outcomes - a review of 40 years of reported cases.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {11}, pages = {1251-1265}, doi = {10.1080/15563650.2022.2098139}, pmid = {36129244}, issn = {1556-9519}, mesh = {Humans ; *Amanitins ; *Mushroom Poisoning/drug therapy/complications ; Amanita ; Alanine Transaminase ; Acetylcysteine/therapeutic use ; Silybin/therapeutic use ; Penicillin G/therapeutic use ; }, abstract = {BACKGROUND AND AIMS: Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified.

METHODS: We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity.

RESULTS: We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14-13.04]) and 89% (OR 5.24 [2.87-9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality.

CONCLUSION: Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes.}, } @article {pmid36121248, year = {2022}, author = {Su, Y and Yin, X and Huang, X and Guo, Q and Ma, M and Guo, L}, title = {The BCL2/BAX/ROS pathway is involved in the inhibitory effect of astragaloside IV on pyroptosis in human umbilical vein endothelial cells.}, journal = {Pharmaceutical biology}, volume = {60}, number = {1}, pages = {1812-1818}, pmid = {36121248}, issn = {1744-5116}, mesh = {Acetylcysteine/pharmacology ; Caspase 1/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Lipopolysaccharides/pharmacology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; *Pyroptosis ; Reactive Oxygen Species/metabolism ; Saponins ; Triterpenes ; bcl-2-Associated X Protein ; }, abstract = {CONTEXT: Astragaloside IV (AS-IV) is extracted from Astragalus membranaceus (Fisch.) Bunge (Fabaceae). However, its effects on endothelial cell injury remain unclear.

OBJECTIVE: To investigate the mechanisms underlying the effects of AS-IV on lipopolysaccharide (LPS)-induced endothelial injury in vitro.

MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were pre-treated with AS-IV (100 µmol/mL), 4-hydroxy-3-methoxyacetophenone (APO, 10 µmol/mL), N-acetylcysteine (NAC, 50 µmol/mL) and Ac-YVAD-cmk (AC, 5 µmol/mL) for 2 h before 1 μg/mL LPS 24 h exposure. Untreated cells cultured without any exposure were used as controls. Cell viability, reactive oxygen species (ROS) and pyroptosis assays were performed. The pyroptosis related proteins were detected by western blot.

RESULTS: The rate in late pyroptosis (Q2-2) of AS-IV (13.65 ± 0.74%), APO (13.69 ± 0.67%) and NAC (15.87 ± 0.46%) groups was lower than the LPS group (21.89 ± 0.66%, p < 0.05), while the rate in early pyroptosis (Q2-4) of AS-IV group (12.00 ± 0.26%) was lower than other groups (p < 0.05). The expression of NOX4, GSDMD, NLRP3, ASC and caspase-1 decreased after AS-IV, NAC or AC intervention (p < 0.05). The ROS production in AS-IV (4664 ± 153.20), APO (4094 ± 78.37), NAC (5103 ± 131.10) and AC (3994 ± 102.50) groups was lower than the LPS (5986 ± 127.30) group, while the mitochondrial BCL2/BAX protein expression ratio increased in AS-IV, APO and NAC groups (p < 0.05).

DISCUSSION AND CONCLUSIONS: AS-IV suppressed pyroptosis in LPS-activated HUVECs by inducing ROS/NLRP3-mediated inhibition of the inflammatory response, providing a scientific basis for clinical applications of AS-IV.}, } @article {pmid36116068, year = {2022}, author = {Anraku, T}, title = {Anoxia/reoxygenation enhances spontaneous contractile activity via TRPA1 channel and COX2 activation in isolated rat whole bladder.}, journal = {Neurourology and urodynamics}, volume = {41}, number = {8}, pages = {1692-1702}, doi = {10.1002/nau.25045}, pmid = {36116068}, issn = {1520-6777}, mesh = {Rats ; Animals ; TRPA1 Cation Channel ; *Urinary Bladder ; Cyclooxygenase 2 ; *Urinary Bladder Diseases ; Hypoxia/complications ; Ischemia ; }, abstract = {PURPOSE: Bladder ischemia/reperfusion is an important etiologic factor for overactive bladder disease. The occurrence of this disease is closely associated with enhanced spontaneous contractile activity of the bladder. However, the relationship between bladder ischemia/reperfusion and altered spontaneous bladder contractions (SBC) remains poorly studied. Therefore, the present study investigated whether ischemia/reperfusion affects SBC ex vivo.

METHODS: SBC was measured using isolated whole bladder preparations from rats. The preparations were exposed to anoxia (95% N2) for 0.5-6 h, followed by reoxygenation (95% O2) in Krebs medium.

RESULTS: Anoxia followed by reoxygenation significantly enhanced the amplitude of SBC without affecting its frequency in an anoxic duration-dependent manner. The 5 h anoxia/reoxygenation-induced enhancement of SBC amplitude was completely suppressed by an antioxidant combination of L(+)-ascorbate/D, L-α-tocopherol, or N-acetyl cysteine. Additionally, the enhanced SBC amplitude was inhibited in a concentration-dependent manner by the nonselective TRP antagonist ruthenium red, or selective TRPA1 antagonists HC-030031 or AP-18. A similar inhibitory effect was obtained after repeated treatment with the TRPA1 agonist allyl isothiocyanate, as it induced acute desensitization of TRPA1 channels. Further, the enhanced SBC amplitude was significantly diminished by the nonselective cyclooxygenase (COX) inhibitor indomethacin or selective COX2 inhibitor NS-398, but not by the selective COX1 inhibitor SC-560 and 5-lipoxygenase inhibitor MK-886.

CONCLUSIONS: The study findings reveal that the spontaneous contractile activity of the bladder is significantly enhanced in response to anoxia/reoxygenation, and that oxidative stress and activation of TRPA1 and COX2 (the resulting production of prostaglandins) are involved in the enhanced SBC activity.}, } @article {pmid36115584, year = {2022}, author = {Hussain, Y and Singh, J and Raza, W and Meena, A and Rajak, S and Sinha, RA and Luqman, S}, title = {Purpurin ameliorates alcohol-induced hepatotoxicity by reducing ROS generation and promoting Nrf2 expression.}, journal = {Life sciences}, volume = {309}, number = {}, pages = {120964}, doi = {10.1016/j.lfs.2022.120964}, pmid = {36115584}, issn = {1879-0631}, mesh = {Animals ; Mice ; Alanine Transaminase/metabolism ; *Anthraquinones/pharmacology ; Antioxidants/pharmacology ; Aspartate Aminotransferases/metabolism ; Buthionine Sulfoximine/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention & control ; Cysteine/pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; *Ethanol/toxicity ; Glutathione/metabolism ; Ligands ; *NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {INTRODUCTION AND AIM: Purpurin, a naturally occurring anthraquinone isolated from the roots of Rubia cordifolia, exhibits anti-cancer, anti-genotoxic, anti-microbial, neuromodulatory and photodynamic activity. However, purpurin's in vivo and in vitro antioxidant mechanism remains unexplored. The present study explores the anti-oxidative mechanism of purpurin under the influence of alcohol using in vivo and in vitro test systems.

METHODS: Mice hepatocytes and alcohol-induced liver toxicity model were used to evaluate the effect of purpurin. The non-enzymatic and enzymatic oxidative stress markers were estimated by the colorimetric method. The reactive oxygen species (ROS) were quantified in mitochondria and cells using flow cytometer. Real-time PCR and western blotting were used to quantify cytochrome 450 subtype 2E1 (CYP2E1) and Nrf2 expression in the liver tissue of mice. In silico studies were performed through receptor-ligand binding interaction.

KEY FINDINGS: Purpurin effectively reduced total cellular and mitochondrial ROS in primary hepatocytes and WRL-68 cells. It prevented alcohol-induced ROS-dependent biochemical and cellular insults observed by analysing the serum glutamic pyruvic transaminase (SGPT), glutamic-oxaloacetic transaminase (SGOT) levels and CYP2E1 expression in liver tissue of alcohol-administered mice. Moreover, it also restored the activity of antioxidant enzymes. Its antioxidant effect was established by glutathione and ROS-dependent mechanisms using buthionine sulfoximine and N-acetyl cysteine. Along with alcohol, purpurin up-regulated Nrf2 expression in hepatocytes.

SIGNIFICANCE: This work confirmed the ameliorative effect of purpurin for alcohol-induced hepatotoxicity by drabbing free radicals and curbing oxidative stress via activation of antioxidant signalling pathways.}, } @article {pmid36115150, year = {2022}, author = {He, YM and Shen, XL and Guo, YN and Liang, SS and Ding, KN and Lu, MH and Tang, LP}, title = {Yinhuang oral liquid protects acetaminophen-induced acute liver injury by regulating the activation of autophagy and Nrf2 signaling.}, journal = {Ecotoxicology and environmental safety}, volume = {244}, number = {}, pages = {114073}, doi = {10.1016/j.ecoenv.2022.114073}, pmid = {36115150}, issn = {1090-2414}, mesh = {Acetaminophen/metabolism/toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antioxidants/metabolism ; Aspartate Aminotransferases/metabolism ; Autophagy ; Autophagy-Related Protein-1 Homolog/metabolism ; Beclin-1/metabolism ; *Chemical and Drug Induced Liver Injury/etiology/metabolism/prevention & control ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Liver ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress ; RNA, Messenger/metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; TOR Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {This study aimed to investigate the protective effect and potential mechanism of Yinhuang oral liquid (YOL) against acetaminophen (APAP) induced liver injury in mice. C57BL/6 mice were randomly divided into control group, model group (300 mg/kg APAP), NAC group and YOL group. Mice were treated intragastrical with YOL (8 g/kg) and N-Acetylcysteine (NAC, 300 mg/kg) 6 h before and 6 h after the APAP (300 mg/kg) intraperitoneal injection. 12 h after APAP exposure, blood and liver samples were collected for subsequent testing. The results showed that APAP decreased liver index, induced liver pathological injury with hepatocytes swelling, necrosis and apoptosis and inflammatory cell infiltration. APAP exposure significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels to 35 and 6 multiples than their original levels. YOL alleviated liver pathological damage, decreased the serum levels of ALT and AST in APAP exposure mice, and it worked better than NAC. Moreover, APAP promoted oxidative stress by increasing lipid peroxidation (MDA) and decreasing anti-oxidant enzyme activities of SOD and GSH, inhibited the mRNA levels of Nrf2, HO-1, Gclc and Gclm, and decreased the protein levels of Nrf2, HO-1 and Keap1, compared to control group. Furthermore, APAP exposure significantly down-regulated the mRNA and protein levels of autophagy related genes (Beclin-1, LC3-II, LC3-I, Atg4B, Atg5, Atg16L1 and Atg7). However, the gene levels of mTOR and p-mTOR increased, and p-ULK1 protein level decreased in liver of APAP treated mice. Additionally, YOL alleviated the oxidative injury by up-regulating Nrf2 pathway. The gene and protein levels of autophagy-related genes Beclin-1, LC3-II, LC3-I, Atg4B, Atg5, Atg16L1 and Atg7 reached the basal levels after YOL treatment. In conclusion, YOL had a protective and therapeutic role in APAP-induced liver injury in mice by activating Nrf2 signaling pathway and autophagy.}, } @article {pmid36115081, year = {2022}, author = {Rana, AK and Sharma, S and Upadhyay, D and Chamoli, P and Prasad, S}, title = {Antibiogram guided optimized medical treatment in chronic otitis media: A useful interventional strategy before surgery?.}, journal = {American journal of otolaryngology}, volume = {43}, number = {6}, pages = {103628}, doi = {10.1016/j.amjoto.2022.103628}, pmid = {36115081}, issn = {1532-818X}, mesh = {Humans ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Cysteine/therapeutic use ; *Otitis Media/drug therapy/surgery ; *Otitis Media, Suppurative/drug therapy/surgery ; Tympanoplasty ; Ciprofloxacin/therapeutic use ; Microbial Sensitivity Tests ; Chronic Disease ; Treatment Outcome ; Mastoid/surgery ; }, abstract = {BACKGROUND: Chronic otitis media is a middle ear cleft disease presenting with tympanic membrane perforation and discharge. Wet ear after tympanoplasty and discharging mastoid cavity are problematic in clinical practice.

MATERIAL AND METHODS: 1050 patients of age 10 to 50 years presenting with active ear discharge and clinically diagnosed with unilateral chronic suppurative otitis media were included in the study. The patients were equally divided into two equal groups, Group ET, and AT. All patients were prescribed topical ciprofloxacin, oral levocetirizine 5 mg and n-acetyl cysteine 600 mg BD for one week. Swabs of ear discharge were collected in ET groups for antibiogram. Both groups were evaluated on next visit and treatment changed in AT groups and result observed in next visit. Surgical outcome was evaluated at end of 2 yrs.

RESULT: A total of 1158 organisms were isolated in culture out of which, 69.94 % were aerobes, 13.47 % anaerobes and 16.58 % were fungi. On the second visit in group AT, treatment of 85.14 % patients was changed in accordance with culture sensitivity report. In patients with mucosal disease, only 46.87 % patients of group ET had a favorable outcome in comparison to 90.28 % patients of group AT while in patients with squamosal disease, 17.56 % patients of group ET and 28.99 % patients in group AT had a dry ear. Surgeries in AT group were found to have statistically significant higher success rate as compared to ET group.}, } @article {pmid36113554, year = {2022}, author = {Matsumoto, T and Kudo, M and Osada, T and Taguchi, K and Kobayashi, T}, title = {Methylglyoxal impairs ATP- and UTP-induced relaxation in the rat carotid arteries.}, journal = {European journal of pharmacology}, volume = {933}, number = {}, pages = {175259}, doi = {10.1016/j.ejphar.2022.175259}, pmid = {36113554}, issn = {1879-0712}, mesh = {*Acetylcholine/pharmacology ; Acetylcysteine ; Adenosine ; Adenosine Triphosphate/pharmacology ; Animals ; Antioxidants/pharmacology ; Arachidonic Acid ; Arginine ; Carotid Arteries ; Cyclooxygenase Inhibitors ; Indomethacin/pharmacology ; Magnesium Oxide ; Nitric Oxide ; Polyphosphates ; Prostaglandin-Endoperoxide Synthases ; Prostaglandins ; *Pyruvaldehyde/pharmacology ; Rats ; Receptors, Purinergic P2Y ; Sodium ; Uridine ; Uridine Triphosphate/pharmacology ; Vasoconstrictor Agents ; }, abstract = {Although methylglyoxal (MGO), a highly reactive dicarbonyl compound, influences the functioning of the vasculature, modulating its effects on vascular reactivity to various substances remains unclear, especially purinoceptor ligands. Therefore, we sought to investigate the direct effects of MGO on relaxation induced by adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) in isolated rat carotid arteries. When carotid arteries were exposed to MGO (420 μM for 1 h), relaxation induced by acetylcholine or sodium nitroprusside was not affected by MGO. However, ATP- and UTP-induced relaxation was impaired by MGO compared with the control. In both ATP- and UTP-induced relaxation, endothelial denudation, incubation with the nitric oxide (NO) synthase inhibitor N[G]-nitro-L-arginine or the selective P2Y purinoceptor 2 (P2Y2) receptor antagonist AR-C118925XX reduced relaxation in both the control and MGO groups, while the differences between the control and MGO groups were eliminated. The cyclooxygenase (COX) inhibitor indomethacin inhibited the differences in ATP/UTP-mediated relaxations between the control and MGO groups. Moreover, N-acetyl-L-cysteine (NAC), an antioxidant, could augment carotid arterial relaxation induced by ATP/UTP in the presence of MGO. MGO increased arachidonic acid-induced contraction, which was suppressed by NAC. Following both ATP/UTP stimulation, MGO increased the release of prostanoids. These results suggest that MGO impaired ATP- and UTP-induced relaxation in carotid arteries, which was caused by suppressed P2Y2 receptor-mediated signaling and reductions in endothelial NO. Moreover, MGO partially contributed to COX-derived vasoconstrictor prostanoids through increased oxidative stress.}, } @article {pmid36108767, year = {2022}, author = {Li, X and Wu, H and Huo, H and Ma, F and Zhao, M and Han, Q and Hu, L and Li, Y and Zhang, H and Pan, J and Tang, Z and Guo, J}, title = {N-acetylcysteine combined with insulin alleviates the oxidative damage of cerebrum via regulating redox homeostasis in type 1 diabetic mellitus canine.}, journal = {Life sciences}, volume = {308}, number = {}, pages = {120958}, doi = {10.1016/j.lfs.2022.120958}, pmid = {36108767}, issn = {1879-0631}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/pharmacology ; Blood Glucose ; Catalase/metabolism ; *Cerebrum/metabolism ; Claudin-1/metabolism ; *Diabetes Mellitus, Type 1/complications/drug therapy ; Dogs ; Glutathione Disulfide/metabolism/pharmacology ; Homeostasis ; Hydrogen Peroxide/pharmacology ; Insulin/metabolism ; Lipids/pharmacology ; Occludin/metabolism ; Oxidation-Reduction ; Oxidative Stress ; RNA, Messenger/metabolism ; }, abstract = {Neurodegenerative diseases are one of the major complications of type 1 diabetes mellitus (T1DM). The effect of insulin monotherapy on controlling blood glucose and neurodegeneration associated with diabetes is unsatisfactory. It is revealed that oxidative stress is a key element in T1DM. Therefore, N-acetylcysteine (NAC) was used together with insulin to investigate the therapeutic effect on neuronal damage in T1DM in this study. A total of 40 beagles were randomly divided into 5 groups (control group, DM group, insulin monotherapy group, NAC combined with insulin group, and NAC monotherapy group) to explore the effects of NAC on alleviating the oxidative damage in cerebrum. Our results showed that the contents of H2O2, 8-OHdg and MDA were apparently increased in DM group, while DNA and lipid oxidative damage was alleviated by the treatment of NAC and insulin. Histopathology revealed the sparse of neurofibrils and vacuolar degeneration in DM group. Additionally, compared with the control group, the mRNA expression levels of HO-1, nqo1, GCLC and GSTM1 were significantly decreased in DM group, while the opposite trend could be shown under NAC combined with insulin treatment. Meanwhile, the tight junction proteins of ZO-1, occludin and Claudin-1 were up-regulated with the treatment of NAC combined with insulin. Additionally, NAC further alleviated oxidative damage by enhancing the activity of GSH, Trx and TrxR and reducing the activity of catalase, GSSG and Grx to maintain redox homeostasis. These results demonstrated that NAC combined with insulin exerted protective effects against T1DM-induced cerebral injury via maintaining cerebral redox homeostasis.}, } @article {pmid36100129, year = {2022}, author = {Chen, S and Sun, P and Li, Y and Shen, W and Wang, C and Zhao, P and Cui, H and Xue, JY and Du, GQ}, title = {Melatonin activates the Mst1-Nrf2 signaling to alleviate cardiac hypertrophy in pulmonary arterial hypertension.}, journal = {European journal of pharmacology}, volume = {933}, number = {}, pages = {175262}, doi = {10.1016/j.ejphar.2022.175262}, pmid = {36100129}, issn = {1879-0712}, mesh = {Animals ; Antioxidants/pharmacology/therapeutic use ; Arginine Vasopressin ; Cysteine/therapeutic use ; Disease Models, Animal ; Familial Primary Pulmonary Hypertension ; Hepatocyte Growth Factor/metabolism ; *Hypertension, Pulmonary/chemically induced/complications/drug therapy ; Hypertrophy, Right Ventricular ; Malondialdehyde ; *Melatonin/pharmacology/therapeutic use ; Monocrotaline ; NF-E2-Related Factor 2 ; Proto-Oncogene Proteins/metabolism ; *Pulmonary Arterial Hypertension/drug therapy ; RNA, Small Interfering/therapeutic use ; Rats ; Ventricular Remodeling ; }, abstract = {Among pulmonary arterial hypertension (PAH) patients, right ventricular (RV) functioning has been considered a major determining factor for cardiac capacity and survival. However, despite the recognition of the clinical importance for preserving RV functioning, no effective treatments are currently available for RV failure. This study aims to suggest one such possible treatment, through investigating the cardio-protective capabilities of the anti-oxidant, melatonin (Mel), for treating adverse RV remodeling in PAH, along with its underlying mechanisms. Arginine vasopressin induced neonatal rat cardiomyocyte hypertrophy in vitro; in vivo, PAH was induced in rats through intraperitoneal monocrotaline (MCT) injections, and Mel was administered intraperitoneally 24 h prior to MCT. Mel reduced rat cardiomyocyte hypertrophy and mitochondrial oxidative stress in vitro by activating the Mst1-Nrf2 pathway, which were all reversed upon siRNA knockdown of Mst1. Likewise, in vivo, Mel pre-treatment significantly ameliorated MCT-induced deterioration in cardiac function, RV hypertrophy, fibrosis and dilation. These beneficial effects were also associated with Mst1-Nrf2 pathway up regulation and its associated reduction in oxidative stress, as evidenced by the decrease in RV malondialdehyde content. Notably, results from Mel treatment were similar, or even superior, to those obtained from N-acetyl cysteine (NAC), which has already been-confirmed as an anti-oxidative treatment for PAH. By contrast, co-treatment with the Mst1 inhibitor XMU-MP-1 reversed all of those Mel-associated beneficial effects. Our findings thus identified Mel as a potent cardio-protective agent against the onset of maladaptive RV remodeling, through enhancement of the anti-oxidative response via Mst1-Nrf2 pathway activation.}, } @article {pmid36096839, year = {2022}, author = {Abdulrab, S and Mostafa, N and Al-Maweri, SA and Abada, H and Halboub, E and Alhadainy, HA}, title = {Antibacterial and anti-inflammatory efficacy of N-acetyl cysteine in endodontic treatment: a scoping review.}, journal = {BMC oral health}, volume = {22}, number = {1}, pages = {398}, pmid = {36096839}, issn = {1472-6831}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Calcium Hydroxide/pharmacology/therapeutic use ; Chlorhexidine ; Humans ; }, abstract = {BACKGROUND: This scoping review systematically summarized the available evidence about the efficacy of N-acetyl cysteine (NAC) as an intracanal antibacterial and/or anti-inflammatory.

METHODS: PubMed, Scopus, Web of Science, and Google scholar search engines/databases were searched up to February 2022 to retrieve relevant studies. The studies were evaluated for eligibility criteria, and identifying relevant studies.

RESULTS: Out of 193 studies, 15 fulfilled the inclusion criteria and were processed for data extraction. Thirteen in vitro studies assessed antibacterial/antibiofilm efficacy of NAC, and reported good and promising efficacy: NAC was found as efficacious as the comparators (chlorhexidine, sodium hypochlorite, calcium hydroxide), or even showed higher efficacy. Regarding the anti-inflammatory efficacy of NAC, one in vitro study found it equivalent to, while one clinical trial revealed it more efficacious than calcium hydroxide.

CONCLUSIONS: There is accumulating evidence on the anti-microbial and anti-inflammatory efficacy of NAC in context of endodontics. However, further clinical trials with robust methodology and objective and reliable clinical, biological and microbial outcomes are warranted to translate its use for clinical practice on humans.}, } @article {pmid36094079, year = {2022}, author = {Cai, X and Hua, S and Deng, J and Du, Z and Zhang, D and Liu, Z and Khan, NU and Zhou, M and Chen, Z}, title = {Astaxanthin Activated the Nrf2/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury.}, journal = {ACS applied materials & interfaces}, volume = {14}, number = {38}, pages = {42887-42903}, doi = {10.1021/acsami.2c10506}, pmid = {36094079}, issn = {1944-8252}, mesh = {Acetaminophen/metabolism ; Acetylcysteine ; Autophagy ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/prevention & control ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; *Ferroptosis ; Heme Oxygenase-1/metabolism ; *Hereditary Sensory and Motor Neuropathy/drug therapy/metabolism/pathology ; Humans ; Liver/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Silicon Dioxide/pharmacology ; Xanthophylls ; }, abstract = {Acetaminophen (APAP)-induced liver injury (AILI) is a common liver disease in clinical practice. Only one clinically approved drug, N-acetylcysteine (NAC), for the treatment of AILI is available in clinics, but novel treatment strategies are still needed due to the complicated pathological changes of AILI and the side effects of NAC. Here, we found that astaxanthin (ASX) can prevent AILI through the Nrf2/HO-1 pathway. After treatment with ASX, there was a positive activation of the Nrf2/HO-1 pathway in AILI models both in vivo and in vitro accompanied by enhanced autophagy and reduced ferroptosis. In APAP-challenged L02 liver cells, ASX reduced autophagy and enhanced apoptosis of the cells. Furthermore, we developed ASX-loaded hollow mesoporous silica nanoparticles (HMSN@ASX) to improve the aqueous solubility of ASX and targeted delivery of ASX to the liver and then significantly improve the therapeutic effects. Taken together, we found that ASX can protect against AILI by activating the Nrf2/HO-1 pathway, which mainly affects oxidative stress, autophagy, and ferroptosis processes, and the HMSN@ASX nanosystem can target the liver to enhance the treatment efficiency of AILI.}, } @article {pmid36093092, year = {2022}, author = {Schuurman, M and Wallace, M and Sahi, G and Barillaro, M and Zhang, S and Rahman, M and Sawyez, C and Borradaile, N and Wang, R}, title = {N-acetyl-L-cysteine treatment reduces beta-cell oxidative stress and pancreatic stellate cell activity in a high fat diet-induced diabetic mouse model.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {938680}, pmid = {36093092}, issn = {1664-2392}, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; *Diabetes Mellitus, Experimental/complications/drug therapy ; *Diabetes Mellitus, Type 2/metabolism ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/complications/etiology ; Oxidative Stress ; Pancreatic Stellate Cells/metabolism ; }, abstract = {Obesity plays a major role in type II diabetes (T2DM) progression because it applies metabolic and oxidative stress resulting in dysfunctional beta-cells and activation of intra-islet pancreatic stellate cells (PaSCs) which cause islet fibrosis. Administration of antioxidant N-acetyl-L-cysteine (NAC) in vivo improves metabolic outcomes in diet-induced obese diabetic mice, and in vitro inhibits PaSCs activation. However, the effects of NAC on diabetic islets in vivo are unknown. This study examined if dosage and length of NAC treatment in HFD-induced diabetic mice effect metabolic outcomes associated with maintaining healthy beta-cells and quiescent PaSCs, in vivo. Male C57BL/6N mice were fed normal chow (ND) or high-fat (HFD) diet up to 30 weeks. NAC was administered in drinking water to HFD mice in preventative treatment (HFD[pNAC]) for 23 weeks or intervention treatment for 10 (HFD[iNAC]) or 18 (HFD[iNAC+)] weeks, respectively. HFD[pNAC] and HFD[iNAC+], but not HFD[iNAC], mice showed significantly improved glucose tolerance and insulin sensitivity. Hyperinsulinemia led by beta-cell overcompensation in HFD mice was significantly rescued in NAC treated mice. A reduction of beta-cell nuclear Pdx-1 localization in HFD mice was significantly improved in NAC treated islets along with significantly reduced beta-cell oxidative stress. HFD-induced intra-islet PaSCs activation, labeled by αSMA, was significantly diminished in NAC treated mice along with lesser intra-islet collagen deposition. This study determined that efficiency of NAC treatment is beneficial at maintaining healthy beta-cells and quiescent intra-islet PaSCs in HFD-induced obese T2DM mouse model. These findings highlight an adjuvant therapeutic potential in NAC for controlling T2DM progression in humans.}, } @article {pmid36090543, year = {2022}, author = {Chen, M and Ke, J and Ma, S and Chai, H and Zhang, L and Zhang, L}, title = {Application of Melatonin with N-Acetylcysteine Exceeds Traditional Treatment for Acetaminophen-Induced Hepatotoxicity.}, journal = {Emergency medicine international}, volume = {2022}, number = {}, pages = {2791743}, pmid = {36090543}, issn = {2090-2840}, abstract = {Acetaminophen (APAP) overdose is one of the leading causes of acute liver damage. Given N-acetylcysteine (NAC) and melatonin (MLT) both have an attenuated value for APAP-induced liver toxification, where an optimized integrated treatment has not been well deciphered. Here, by giving a single dose of APAP (500 mg/kg) to wild-type male mice, combined with a single dose of 500 mg/kg NAC or 100 mg/kg MLT separately as the therapeutic method, this study aimed to investigate the effects of NAC and melatonin (MLT) alone or combined on acetaminophen (APAP)-induced liver injury. In this study, NAC and MLT both partially have an alleviated function in APAP-challenged liver injury. However, MLT's add-on role strengthens the hepatoprotective effect of NAC on APAP-induced liver damage and resolute the inflammatory infiltration. Meanwhile, the combination of two reagents attenuates the decreased glutathione (GSH) and activation of the p38/JNK pathway. The combination of MLT and NAC can further ameliorate APAP-induced liver injury, which provides a novel strategy for drug-induced liver injury (DILI).}, } @article {pmid36086867, year = {2023}, author = {Wu, J and Wang, D and Zhou, J and Li, J and Xie, R and Li, Y and Huang, J and Liu, B and Qiu, J}, title = {Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells.}, journal = {Phytotherapy research : PTR}, volume = {37}, number = {1}, pages = {310-328}, doi = {10.1002/ptr.7614}, pmid = {36086867}, issn = {1099-1573}, support = {2019A1515010386//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Male ; Humans ; *MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Apoptosis ; Endoplasmic Reticulum Stress ; Autophagy ; Cell Line, Tumor ; Acetylcysteine/metabolism/pharmacology ; *Prostatic Neoplasms/drug therapy ; }, abstract = {Prostate cancer (PCa) is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC) with limited therapies. Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti-tumor capacity in various cancers. Our results showed that GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells. In addition, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA. Moreover, the activation of JNK pathway and the induction of apoptosis and autophagy triggered by GNA were attenuated by JNK inhibitor SP600125. We also found that GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. Meanwhile, suppressing ER stress with 4-phenylbutyric acid (4-PBA) markedly blocked the activation of JNK pathway induced by GNA. Further research indicated that ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA. Furthermore, NAC and 4-PBA significantly reversed GNA-triggered apoptosis and autophagy. Finally, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo. In conclusion, the present study revealed that GNA induced apoptosis and autophagy through ROS-mediated ER stress via JNK signaling pathway in PCa cells. Thus, GNA might be a promising therapeutic drug against PCa.}, } @article {pmid36077566, year = {2022}, author = {Yi, Y and Gao, K and Zhang, L and Lin, P and Wang, A and Jin, Y}, title = {Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway.}, journal = {International journal of molecular sciences}, volume = {23}, number = {17}, pages = {}, pmid = {36077566}, issn = {1422-0067}, support = {31772817//National Natural Science Foundation of China/ ; 2018BBF33001//Key R&D Program of Ningxia Hui Autonomous Region/ ; }, mesh = {Animals ; Calcium/metabolism ; Calcium, Dietary ; Goats/metabolism ; *Necroptosis ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Stromal Cells/metabolism ; *Zearalenone/toxicity ; }, abstract = {Zearalenone (ZEA) is a fungal mycotoxin known to exert strong reproductive toxicity in animals. As a newly identified type of programmed cell death, necroptosis is regulated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like pseudokinase (MLKL). However, the role and mechanism of necroptosis in ZEA toxicity remain unclear. In this study, we confirmed the involvement of necroptosis in ZEA-induced cell death in goat endometrial stromal cells (gESCs). The release of lactate dehydrogenase (LDH) and the production of PI-positive cells markedly increased. At the same time, the expression of RIPK1 and RIPK3 mRNAs and P-RIPK3 and P-MLKL proteins were significantly upregulated in ZEA-treated gESCs. Importantly, the MLKL inhibitor necrosulfonamide (NSA) dramatically attenuated gESCs necroptosis and powerfully blocked ZEA-induced reactive oxygen species (ROS) generation and mitochondrial dysfunction. The reactive oxygen species (ROS) scavengers and N-acetylcysteine (NAC) inhibited ZEA-induced cell death. In addition, the inhibition of MLKL alleviated the intracellular Ca[2+] overload caused by ZEA. The calcium chelator BAPTA-AM markedly suppressed ROS production and mitochondrial damage, thus inhibiting ZEA-induced necroptosis. Therefore, our results revealed the mechanism by which ZEA triggers gESCs necroptosis, which may provide a new therapeutic strategy for ZEA poisoning.}, } @article {pmid36077493, year = {2022}, author = {Morgan, C and Sáez-Briones, P and Barra, R and Reyes, A and Zepeda-Morales, K and Constandil, L and Ríos, M and Ramírez, P and Burgos, H and Hernández, A}, title = {Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity.}, journal = {International journal of molecular sciences}, volume = {23}, number = {17}, pages = {}, pmid = {36077493}, issn = {1422-0067}, support = {021943HK//Dirección de Investigación Científica y Tecnológica (DICYT) of the University of Santiago de Chile/ ; 1181622//FONDECYT/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Diet, High-Fat/adverse effects ; Humans ; Male ; Mice ; *Nucleus Accumbens ; Obesity/drug therapy/etiology/prevention & control ; Prefrontal Cortex ; Weight Gain ; }, abstract = {A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.}, } @article {pmid36076297, year = {2022}, author = {Wang, L and Mao, B and Fan, K and Sun, R and Zhang, J and Liang, H and Liu, Y}, title = {ROS attenuates TET2-dependent ZO-1 epigenetic expression in cerebral vascular endothelial cells.}, journal = {Fluids and barriers of the CNS}, volume = {19}, number = {1}, pages = {73}, pmid = {36076297}, issn = {2045-8118}, support = {2018YFC2000202//the National Key R&D Program of China/ ; }, mesh = {Animals ; Blood-Brain Barrier/metabolism ; DNA-Binding Proteins/metabolism ; *Dioxygenases/metabolism ; *Endothelial Cells/metabolism ; Epigenesis, Genetic ; Humans ; Hydrogen Peroxide/metabolism ; Mice ; Mice, Knockout ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Tight Junction Proteins/metabolism ; Tight Junctions/metabolism ; Zonula Occludens-1 Protein/metabolism ; }, abstract = {AIMS: To investigate whether DNA active demethylase TET regulates the expression of tight junction proteins in endothelial cells of the blood-brain barrier (BBB).

METHODS: Correlations between TET2 activity (indicated by its catalytic product 5hmC) and the expression of BBB tight junction proteins were examined in Tet2 knockout mice and post-mortem human brain tissues. In cultured endothelial cells, the impact of changes of TET activity on the expression of tight junction protein, ZO-1, was studied. BBB permeability assays were performed in Tet2 knockout mice.

RESULTS: It was found that the level of 5hmC decreased in brain microvascular endothelial cells of aging mice. In Tet2 knockout mice, the level of 5hmC in endothelial cells was weaker and significantly correlated with the reduced expression of tight junction protein ZO-1. In cultured endothelial cells, H2O2 significantly decreased the expression of 5hmC and ZO-1. Tet2 knock-down using siRNA significantly downregulated the expression of ZO-1 in endothelial cells. hMeChip-PCR showed that H2O2 decreased the level of 5hmC in the ZO-1 promoter region, which was rescued by N-acetyl cysteine (NAC). Consistently, Tet2 knock-down using siRNA significantly downregulated the level of 5hmC in the ZO-1 promoter region. It was also found that the level of 5hmC decreased in endothelial cells of aging human brains compared with that of adult brains, and the level of ZO-1 was positively correlated with that of 5hmC in microvascular endothelial cells.

CONCLUSIONS: These findings suggest that TET activity is essential in regulating ZO-1 expression of BBB. It might be a potential target for neuroprotection during aging and in diverse neurological conditions.}, } @article {pmid36076278, year = {2022}, author = {Meng, Z and Liu, J and Feng, Z and Guo, S and Wang, M and Wang, Z and Li, Z and Li, H and Sui, L}, title = {N-acetylcysteine regulates dental follicle stem cell osteogenesis and alveolar bone repair via ROS scavenging.}, journal = {Stem cell research & therapy}, volume = {13}, number = {1}, pages = {466}, pmid = {36076278}, issn = {1757-6512}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Cell Differentiation/physiology ; Cells, Cultured ; Dental Sac/metabolism ; Humans ; *Osteogenesis/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; RNA/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Stem Cells/metabolism ; }, abstract = {BACKGROUND: Dental follicle stem cells (DFSCs) show mesenchymal stem cell properties with the potential for alveolar bone regeneration. Stem cell properties can be impaired by reactive oxygen species (ROS), prompting us to examine the importance of scavenging ROS for stem cell-based tissue regeneration. This study aimed to investigate the effect and mechanism of N-acetylcysteine (NAC), a promising antioxidant, on the properties of DFSCs and DFSC-based alveolar bone regeneration.

METHODS: DFSCs were cultured in media supplemented with different concentrations of NAC (0-10 mM). Cytologic experiments, RNA-sequencing and antioxidant assays were performed in vitro in human DFSCs (hDFSCs). Rat maxillary first molar extraction models were constructed, histological and radiological examinations were performed at day 7 post-surgery to investigate alveolar bone regeneration in tooth extraction sockets after local transplantation of NAC, rat DFSCs (rDFSCs) or NAC-treated rDFSCs.

RESULTS: 5 mM NAC-treated hDFSCs exhibited better proliferation, less senescent rate, higher stem cell-specific marker and immune-related factor expression with the strongest osteogenic differentiation; other concentrations were also beneficial for maintaining stem cell properties. RNA-sequencing identified 803 differentially expressed genes between hDFSCs with and without 5 mM NAC. "Developmental process (GO:0032502)" was prominent, bioinformatic analysis of 394 involved genes revealed functional and pathway enrichment of ossification and PI3K/AKT pathway, respectively. Furthermore, after NAC treatment, the reduction of ROS levels (ROS, superoxide, hydrogen peroxide), the induction of antioxidant levels (glutathione, catalase, superoxide dismutase), the upregulation of PI3K/AKT signaling (PI3K-p110, PI3K-p85, AKT, phosphorylated-PI3K-p85, phosphorylated-AKT) and the rebound of ROS level upon PI3K/AKT inhibition were showed. Local transplantation of NAC, rDFSCs or NAC-treated rDFSCs was safe and promoted oral socket bone formation after tooth extraction, with application of NAC-treated rDFSCs possessing the best effect.

CONCLUSIONS: The proper concentration of NAC enhances DFSC properties, especially osteogenesis, via PI3K/AKT/ROS signaling, and offers clinical potential for stem cell-based alveolar bone regeneration.}, } @article {pmid36075319, year = {2022}, author = {Fan, C and Tian, Y and Zhang, Y and Teng, J and Zhao, X}, title = {Ceramide induces macrophage migration inhibitory factor -mediated parthanatos in mouse neurons by increasing ROS levels.}, journal = {Neuroscience letters}, volume = {788}, number = {}, pages = {136862}, doi = {10.1016/j.neulet.2022.136862}, pmid = {36075319}, issn = {1872-7972}, mesh = {Animals ; Apoptosis Inducing Factor/metabolism ; Ceramides/metabolism/pharmacology ; *Macrophage Migration-Inhibitory Factors/metabolism ; Mice ; Neurons/metabolism ; *Parthanatos ; Poly(ADP-ribose) Polymerase Inhibitors ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Ceramides, the key component of sphingolipid metabolism and second messengers, have been associated with neurodegenerative diseases progression and pathology, and can induce neuronal apoptosis and necrosis, but the effect of ceramide on parthanatos has not been fully elucidated. In this study, we investigated the ceramide-mediated parthanatos pathway and the role of macrophage inhibitory factor (MIF) in parthanatos. We found that ceramide significantly diminished the viability and induced the death of primary cortical neurons. These effects were not prevented by treatment with the pan-caspase inhibitor Z-VAD-FMK treatment; in contrast, treatment with the poly (ADP ribosyl) polymerase-1 (PARP-1) inhibitor ABT-888 prevented these ceramide-mediated effects. Specifically, ceramide induced PARP-1 overactivation, increased PAR polymer levels, facilitated apoptosis-inducing factor (AIF) and MIF nuclear translocation and induced DNA damage. Knockdown of MIF with an adenovirus carrying a MIF short hairpin RNA (shRNA) inhibited ceramide-induced DNA damage and neuronal death, but nuclear translocation of AIF was unaffected. Furthermore, ceramide increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) significantly inhibited PAR production and neuronal death. These findings suggested that ceramide induced neuronal parthanatos by increasing ROS levels and that MIF might be downstream of AIF in the ceramide-mediated parthanatos pathway. In conclusion, our results suggest that knocking down MIF expression may be a potential therapeutic strategy for nervous system diseases.}, } @article {pmid36068741, year = {2022}, author = {Liu, N and Li, G and Guan, Y and Wang, R and Ma, Z and Zhao, L and Yao, S}, title = {N-acetylcysteine alleviates pulmonary alveolar proteinosis induced by indium-tin oxide nanoparticles in male rats: involvement of the NF-κB signaling pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {241}, number = {}, pages = {113812}, doi = {10.1016/j.ecoenv.2022.113812}, pmid = {36068741}, issn = {1090-2414}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/metabolism ; Indium/toxicity ; Lung ; *Lung Injury/chemically induced/drug therapy/metabolism ; Male ; NF-kappa B/metabolism ; *Nanoparticles/toxicity ; *Pulmonary Alveolar Proteinosis/chemically induced/metabolism/pathology ; *Pulmonary Fibrosis/chemically induced/drug therapy/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Tin Compounds ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Indium-tin oxide (ITO) was previously found to have a toxic effect on lung tissues, and oxidative stress and the inflammatory response are two important mechanisms of ITO‑induced lung injury. N-acetylcysteine (NAC) has been found to exhibit antioxidant and anti‑inflammatory properties. The current study aimed to evaluate the possible protective effects of NAC against ITO nanoparticle (Nano-ITO)-induced pulmonary alveolar proteinosis (PAP) in adult male Sprague-Dawley rats, especially via modulation of nuclear factor-kappa B (NF-κB) signaling. For this purpose, 50 rats were randomly allocated into five groups (10 rats each) as follows: (1) control group; (2) saline group; (3) NAC (200 mg/kg) group; (4) PAP model group receiving a repeated intratracheal dose of Nano-ITO (6 mg/kg); and (5) PAP model+NF-κB inhibitor (NAC) group pre-treated intraperitoneally with NAC (200 mg/kg) twice per week before the administration of an intratracheal dose of Nano-ITO (6 mg/kg). Rats were then euthanized under anesthesia, and their lungs were removed for histopathological and biochemical investigations. A 6 mg/kg dose of Nano-ITO markedly altered the levels of some oxidative stress biomarkers. The histological examination of Nano-ITO-exposed rats demonstrated diffused alveolar damage that involved PAP, cholesterol crystals, alveolar fibrosis, pulmonary fibrosis, and alveolar emphysema. The immunohistochemical results of Nano-ITO-exposed rats revealed strongly positive NF-κB p65 and inhibitory kappa B kinase (IKK)-β and weakly positive inhibitor of kappa-B subunit alpha (IκB-α) staining reactivity in the nuclei of cells lining the epithelium of the bronchioles and alveoli. Moreover, Nano-ITO activated the NF-κB pathway. However, pre-treatment with NAC significantly attenuated Nano-ITO-evoked alterations in the previously mentioned parameters, highlighting their antioxidant, anti-inflammatory, and anti-apoptotic potential. The results indicated that the degree of pulmonary fibrosis and proteinosis in the NAC‑treated group was improved compared with that in the Nano-ITO-induced PAP model group. The level of malondialdehyde was also decreased overall in the NAC-treated group compared with that in the Nano-ITO-induced model group, indicating that the pulmonary fibrosis degree and oxidation levels were decreased. The present study also demonstrated that NAC increased the activity of antioxidant enzyme superoxide dismutase and total antioxidant capacity, indicating that it could alleviate oxidative stress in the lung tissue of Nano-ITO‑exposed rats. In addition, NAC reduced the production of pro‑inflammatory cytokines interleukin (IL)‑1β, IL‑6, and tumor necrosis factor (TNF)‑α, and increased the levels of anti‑inflammatory factor IL‑10. The current study demonstrated that NAC can effectively attenuate Nano-ITO‑induced lung injury by reducing oxidative damage and the inflammatory response.}, } @article {pmid36067963, year = {2022}, author = {Jiang, Y and Geng, N and Wang, M and Wu, W and Feng, N and Zhang, X}, title = {5-HMF affects cardiovascular development in zebrafish larvae via reactive oxygen species and Wnt signaling pathways.}, journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP}, volume = {262}, number = {}, pages = {109452}, doi = {10.1016/j.cbpc.2022.109452}, pmid = {36067963}, issn = {1532-0456}, mesh = {Acetylcysteine/metabolism/pharmacology ; Aldehydes/metabolism/pharmacology ; Animals ; Antioxidants/metabolism ; Embryo, Nonmammalian ; Humans ; Larva/metabolism ; Reactive Oxygen Species/metabolism ; *Wnt Signaling Pathway ; *Zebrafish/metabolism ; }, abstract = {5-Hydroxymethylfurfural (5-HMF) is a small molecule aldehyde compound produced by the Maillard reaction. As 5-HMF exists in a variety of foods and drugs and is easily ingested by humans, it has attracted extensive toxicological attention in recent years. Relevant research showed that 5-HMF has cytotoxicity, genotoxicity, and tumor effects. However, the cardiovascular effects of 5-HMF are unknown. To investigate the cardiovascular effects of 5-HMF in zebrafish, wild-type and transgenic embryos were treated with 10, 25, and 50 μg/mL of 5-HMF, followed by toxicological evaluation, histological observation, fluorescence observation, cell apoptosis staining, and gene quantitative analysis. High 5-HMF concentrations led to a significant increase in the heart rate and pericardial edema ratio, larger venous sinus-arterial bulb distance, more apoptosis of cardiac cells, cardiac linearization, defects in angiogenesis and cardiovascular development, and apoptosis-related gene expression disorders in zebrafish larvae. The abnormal phenotype caused by 5-HMF can be rescued by antioxidant N-acetyl-L-cysteine (NAC) and Wnt signaling pathway activator BML-284. It is inferred that high 5-HMF concentrations increased the level of reactive oxygen species, inhibited the transduction of the Wnt signaling pathway, and resulted in abnormal cardiovascular development in zebrafish larvae. This study provides a reference for understanding the mechanism of 5-HMF effects on cardiac development.}, } @article {pmid36066601, year = {2022}, author = {Güven, D and Özbek, İ}, title = {Characteristics, Treatment, and Prognosis of Elemental Mercury Intoxication in Children: A Single-Center Retrospective Study.}, journal = {Pediatric emergency care}, volume = {38}, number = {10}, pages = {481-488}, doi = {10.1097/PEC.0000000000002834}, pmid = {36066601}, issn = {1535-1815}, mesh = {Acetylcysteine ; Child ; Humans ; *Mercury ; *Mercury Poisoning/diagnosis/drug therapy ; Penicillamine/therapeutic use ; Prognosis ; Retrospective Studies ; Succimer/therapeutic use ; Sulfonic Acids ; }, abstract = {OBJECTIVES: Mercury exposure is common and can be toxic, especially in children. Children are often drawn to elemental mercury because of its density, color, and proclivity to form beads.

METHODS: We present data on 49 children with mercury intoxication (MI) and 60 children with mercury exposure from Turkey.

RESULTS: The most common source of mercury was broken thermometer in schools. Inhaling mercury vapor was the most common route of exposure. The median exposure time was 6 (6-16) hours in the MI group, and the time to 1st symptoms was 10 (0-24) hours. In the MI group, the median blood mercury level was 21 μg/L (13-32.3), the median spot urine mercury level was 40 μg/L (7.66-78), and the median 24-hour urine mercury level was 25.8 μg/L (11-64). The most common symptoms in patients with MI were malaise, muscle pain, muscle cramps, abdominal pain, nausea, headache, and decreased appetite. The patients were treated with n-acetyl cysteine, 2,3-dimercaptopropane sulfonic acid, D-penicillamine, and meso 2,3-dimercaptosuccinic acid. A positive correlation was found between exposure time and urinary mercury level in the MI group (r = 0.793, P < 0.001). A positive moderate correlation was found between exposure time and blood level in the mercury exposure group (r = 0.535, P < 0.00). The neurological and systemic examinations of patients were all normal at the 1st follow-up visit 1 month after discharge.

CONCLUSIONS: Diagnosis, removal of the exposure source, and use of chelation therapy can result in complete resolution of the signs and symptoms of MI.}, } @article {pmid36063970, year = {2023}, author = {Fredriksson, I and Jayaram-Lindström, N and Kalivas, PW and Melas, PA and Steensland, P}, title = {N-acetylcysteine improves impulse control and attenuates relapse-like alcohol intake in long-term drinking rats.}, journal = {Behavioural brain research}, volume = {436}, number = {}, pages = {114089}, doi = {10.1016/j.bbr.2022.114089}, pmid = {36063970}, issn = {1872-7549}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Alcohol Drinking/drug therapy ; *Alcoholism/drug therapy ; Animals ; Cystine ; Ethanol/pharmacology ; Glutamates/therapeutic use ; Male ; *Prodrugs/therapeutic use ; Rats ; Rats, Wistar ; Recurrence ; Self Administration ; }, abstract = {Increasing evidence suggests that individuals with alcohol use disorder (AUD) present with a disrupted glutamatergic system that underlies core components of addictive disorders, including drug relapse and low impulse control. N-acetylcysteine (NAC) is a cystine prodrug that has been found to promote glutamate homeostasis and drug abstinence. However, no studies to date have evaluated NAC's effect on impulsivity in substance use disorders. Here we determined whether NAC would decrease alcohol-intake behaviors, in addition to improving impulse control, in long-term alcohol drinking male Wistar-Han rats. Before the start of the experiments, all rats were exposed to long-term intermittent access to 20% ethanol for at least seven weeks. Next, in different groups of rats, the effect of NAC (60 and/or 90 mg/kg) was evaluated on (i) voluntary alcohol drinking using a two-bottle free choice paradigm, (ii) the motivation to self-administer alcohol under a progressive ratio schedule of reinforcement, and (iii) relapse-like drinking using the alcohol deprivation effect model. Finally, (iv) NAC's effect on impulse control was evaluated using the five-choice serial reaction time task. Results showed that NAC administration at 90 mg/kg significantly reduced relapse-like drinking and improved impulse control. In contrast, NAC had no effect on levels of alcohol drinking or motivation to drink alcohol. In conclusion, our findings continue to support the use of NAC as an adjuvant treatment for the maintenance of abstinence in AUD. Moreover, we provide evidence for NAC's efficacy in improving impulse control following drinking, which warrants further investigation in substance use settings.}, } @article {pmid36061354, year = {2022}, author = {Han, L and Hao, Y and Wu, X and Hu, D}, title = {PSMB5 Alleviates Ulcerative Colitis by Inhibiting ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis.}, journal = {Disease markers}, volume = {2022}, number = {}, pages = {2329904}, pmid = {36061354}, issn = {1875-8630}, mesh = {Animals ; Body Weight ; Caspase 1/metabolism/pharmacology ; *Colitis, Ulcerative/chemically induced/drug therapy ; *Inflammasomes/metabolism/pharmacology ; Interleukin-18/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase ; }, abstract = {Ulcerative colitis (UC) is a chronic inflammatory disease. Intestinal mucosal injury is a significant factor in UC. Pyroptosis is a kind of programmed cell death induced by inflammatory caspases. Proteasome 20S subunit beta 5 (PSMB5) promotes cell viability. The purpose of this study was to determine the impact of PSMB5 on intestinal mucosal injury and to elucidate the underlying processes in dextran sulfate sodium- (DSS-) induced UC mice. Kunming (KM) mice received 3% DSS for 5 days to induce UC. We collected clinical symptoms, body weight, colon length, and histological changes. MDA (malondialdehyde) and SOD (superoxide dismutase) levels were determined using an ELISA assay. RT-PCR was used to assess the expression of IL-1β and IL-18. PSMB5 demonstrated a significant effect against UC by increasing body weight and colon length and decreasing DAI (disease activity index), colon macroscopic damage index (CMDI), histological injury scores, and reactive oxygen species (ROS), MDA, and SOD levels, thereby alleviating histopathological changes and inhibiting oxidative stress. HIEC-6 cells were exposed to lipopolysaccharide (LPS) condition with or without PSMB5, along with caspase-1 inhibitor (Z-VAD-FMK), NLRP3 inhibitor (MCC950), and ROS scavenger N-acetylcysteine (NAC). The viability of the cells, the release of lactate dehydrogenase (LDH), and intracellular ROS generation were determined using assay kits. Western blot analysis was used to determine the levels of NLRP3, ASC, cleaved caspase-1 (p20), pro-IL-1β, IL-1β, pro-IL-18, and IL-18. PSMB5 overexpression enhanced the inflammatory damage in LPS-treated HIEC-6 cells by activating the NLRP3 inflammasome and mediating pyroptosis, as demonstrated by increased LDH release and lower cell viability, as well as increased expression of NLRP3, ASC, cleaved caspase-1 (p20), IL-1, and IL-18. Meanwhile, NAC protected HIEC-6 cells from LPS-induced damage by reversing the activation of the NLRP3 inflammasome-mediated pyroptosis. In conclusion, PSMB5 may lower HIEC-6 cell susceptibility to LPS and ameliorate UC-induced HIEC-6 cell damage by decreasing ROS generation and hence inhibiting NLRP3-mediated pyroptosis.}, } @article {pmid36058431, year = {2022}, author = {Ma, W and Wang, X and Sun, H and Xu, B and Song, R and Tian, Y and Zhao, L and Xu, Y and Zhao, Y and Yang, F and Chen, H and Gong, R and Yu, Y and Li, X and Li, S and Zhang, W and Zhang, T and Ne, J and Cai, B}, title = {Oxidant stress-sensitive circRNA Mdc1 controls cardiomyocyte chromosome stability and cell cycle re-entry during heart regeneration.}, journal = {Pharmacological research}, volume = {184}, number = {}, pages = {106422}, doi = {10.1016/j.phrs.2022.106422}, pmid = {36058431}, issn = {1096-1186}, mesh = {Animals ; Animals, Newborn ; Cell Cycle ; Cell Cycle Proteins/genetics ; Cell Proliferation ; Chromosomal Instability ; Cysteine/metabolism ; Heart/physiology ; Mice ; *Myocardial Infarction/metabolism ; *Myocytes, Cardiac/metabolism ; Oxidants/metabolism ; RNA, Circular/genetics ; Regeneration/physiology ; }, abstract = {Targeting cardiomyocyte plasticity has emerged as a new strategy for promoting heart repair after myocardial infarction. However, the precise mechanistic network underlying heart regeneration is not completely understood. As noncoding RNAs, circular RNAs (circRNAs) play essential roles in regulating cardiac physiology and pathology. The present study aimed to investigate the potential roles of circMdc1 in cardiac repair after injury and elucidate its underlying mechanisms. Here, we identified that circMdc1 levels were upregulated in postnatal mouse hearts but downregulated in the regenerative myocardium. The expression of circMdc1 in cardiomyocytes is sensitive to oxidative stress, which was attenuated by N-acetyl-cysteine. Enforced circMdc1 expression inhibited cardiomyocyte proliferation, while circMdc1 silencing led to cardiomyocyte cell cycle re-entry. In vivo, the cardiac-specific adeno-associated virus-mediated knockdown of circMdc1 promoted cardiac regeneration and heart repair accompanied by improved heart function. Conversely, circMdc1 overexpression blunted the regenerative capacity of neonatal hearts after apex resection. Moreover, circMdc1 was able to block the translation of its host gene Mdc1 specifically by binding to PABP, affecting DNA damage and the chromosome stability of cardiomyocytes. Furthermore, overexpression of Mdc1 caused damaged mouse hearts to regenerate and repair after myocardial infarction in vivo. Oxidative stress-sensitive circMdc1 plays an important role in cardiac regeneration and heart repair after injury by regulating DNA damage and chromosome stability in cardiomyocytes by blocking the translation of the host gene Mdc1.}, } @article {pmid36058351, year = {2022}, author = {Wang, Y and Cui, J and Zheng, G and Zhao, M and Hao, Z and Lian, H and Li, Y and Wu, W and Zhang, X and Wang, J}, title = {Ochratoxin A induces cytotoxicity through ROS-mediated endoplasmic reticulum stress pathway in human gastric epithelium cells.}, journal = {Toxicology}, volume = {479}, number = {}, pages = {153309}, doi = {10.1016/j.tox.2022.153309}, pmid = {36058351}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Beclin-1 ; *Endoplasmic Reticulum Stress ; Epithelium ; Humans ; *Ochratoxins/toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium species that greatly threatens human health. We previously showed that OTA induced cycle arrest, apoptosis and autophagy in human gastric epithelium cells (GES-1). However, the mechanism underlying these effects is still unclear. Here, we showed that OTA exposure increased the expression of endoplasmic reticulum (ER) stress indicators (GRP78, PERK, ATF6, eIF2α, and CHOP), suggesting the activation of the unfolded protein response pathway. 4-phenylbutyric acid (4-PBA), an ER stress-specific inhibitor, attenuated OTA-induced loss of cell viability and apoptosis in GES-1 cells. It also attenuated the G2 phase arrest and autophagy induced by OTA, as evidenced by upregulated G2 phase-related proteins (Cdc2, Cdc25C, and cyclinB1) and downregulated autophagy markers (LC3B and Beclin-1). Moreover, OTA was found to increase ROS generation, and the inhibition of ROS formation by N-acetylcysteine (NAC), an ROS inhibitor, attenuated OTA-induced ER stress and subsequent apoptosis, cell cycle arrest, and autophagy. Collectively, these results suggest that the ROS-mediated ER stress pathway contributes to the OTA toxin-induced cytotoxicity in GES-1 cells. This study offers new insights into the molecular mechanisms underlying OTA toxicity in gastric cells.}, } @article {pmid36047304, year = {2022}, author = {Jia, Y and Zhang, J and Zhao, Y and Dong, R and Wang, H and Jiang, X}, title = {Gold nanoparticles bearing a clinically used non-antibiotic drug for combating multi-drug resistant bacteria.}, journal = {Chemical communications (Cambridge, England)}, volume = {58}, number = {75}, pages = {10544-10547}, doi = {10.1039/d2cc03460c}, pmid = {36047304}, issn = {1364-548X}, mesh = {Acetylcysteine ; Anti-Bacterial Agents/pharmacology ; Bacteria ; *Gold/pharmacology ; *Metal Nanoparticles ; Microbial Sensitivity Tests ; }, abstract = {We introduce N-acetyl-L-cysteine (NAC), a clinically used non-antibiotic drug, to the synthesis of antibacterial gold nanoparticles (Au_NAC). Au_NAC shows excellent antibacterial activities against multi-drug resistant (MDR) Gram-negative bacteria and possesses wound healing capabilities. We provide a new direction for antibiotic design and novel uses of known drugs.}, } @article {pmid36047270, year = {2022}, author = {Lin, R and Pian, Y and Zhang, C and Zhou, L and Ren, X}, title = {[N-acetylcysteine alleviates cadmium-induced testicular interstitial cell apoptosis by activating protein kinase B pathway].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {51}, number = {4}, pages = {632-637}, doi = {10.19813/j.cnki.weishengyanjiu.2022.04.022}, pmid = {36047270}, issn = {1000-8020}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Apoptosis ; *Cadmium/toxicity ; Leydig Cells/metabolism ; Male ; Mice ; Oxidative Stress ; Proto-Oncogene Proteins c-akt/metabolism/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {OBJECTIVE: To investigate the regulation mechanism of N-acetylcysteine(NAC) on cadmium-induced apoptosis of mouse testicular interstitial cells based on protein kinase B pathway(AKT pathway).

METHODS: Mouse testicular mesenchymal cells(TM3) were divided into fourgroups according to different treatment, control group, cadmium group(Cd, 5, 10, 20, 30, 40 and 50 μmol/L), NAC group(NAC, 500 μmol/L) and NAC+Cd group(500 μmol/L NAC+20 μmol/L Cd). Cells of NAC+Cd group were pretreated with NAC for 30 min, and then combined with cadmium for 24 h. Cell viability was determined by CCK8. Hoechst staining was used to determine cell morphology. Cell apoptosis rate was analyzed by flow cytometry. Malondialdehyde(MDA) and glutathione(GSH) were measured simultaneously. Western blot was used to detect the expression levels of AKT protein, B-cell lymphoma-2(Bcl-2) and Bcl-2 associated X protein(Bax).

RESULTS: Cadmium inhibited the proliferation of TM3 cells in a dose-effect relationship. Cell morphology observation showed that with the increase of cadmium concentration, the cells shrank, became round and even fell off, and appeared dense nuclear staining. The MDA level in Cd group was(1.56±0.11) μmol/mg prot, which was significantly higher than that in control group(P<0.01). Compared to the control group, the level of GSH was significantly decreased to(1.28±0.25) μmol/mg prot(P<0.01). NAC pretreatment could reduce the MDA content and increase the GSH level, and the difference was statistically significant compared with the Cd group(P<0.01). Western blot result showed that NAC pretreatment significantly increased levels of phosphorylated AKT and Bcl-2, the levels were 0.65±0.05 and 0.45±0.03, respectively(P<0.01). The Bax/Bcl-2 ratio was 1.54±0.15, which was significantly lower than that of the Cd group(P<0.01).

CONCLUSION: NAC can inhibit cadmium-mediated TM3 cell damage and apoptosis, which may be related to the improvement of oxidative stress state, activation of TM3 AKT pathway and reduction of Bax/Bcl-2 ratio.}, } @article {pmid36046596, year = {2022}, author = {Chi, L and Shan, Y and Cui, Z}, title = {N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression.}, journal = {Analytical cellular pathology (Amsterdam)}, volume = {2022}, number = {}, pages = {4846336}, pmid = {36046596}, issn = {2210-7185}, mesh = {Acetylcysteine/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Antiviral Agents/metabolism/pharmacology ; Cell Line ; Epithelial Cells/metabolism ; ErbB Receptors/metabolism ; Glutathione Disulfide/metabolism/pharmacology ; HSP70 Heat-Shock Proteins ; Humans ; Oxidative Stress ; Reactive Oxygen Species/metabolism/pharmacology ; *Respiratory Syncytial Virus Infections/drug therapy/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Objective. Respiratory syncytial virus (RSV) infection is an important cause of hospitalization of children worldwide, leading to significant morbidity and mortality. RSV infection leads to increasing inflammatory and apoptosis events in the airway epithelium through mechanisms involving ROS generation. The antioxidant N-acetyl-L-cysteine (NAC) has been shown to inhibit influenza virus replication and to reduce the secretion of inflammatory and apoptotic mediators during virus infection. The study aims to investigate the effects of NAC on human bronchial epithelial cells BEAS-2B and HSPA6 expression during RSV infection. Methods. CCK-8 assays were performed to evaluate cell survival. The production of proinflammatory factors, TNF-α, IL-6, IL-1β, IL-18, and MUC5AC was examined by quantitative real-time PCR and ELISA. Oxidative stress was determined by reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)/glutathione disulfide (GSSG) ratio. Immunoblotting analysis of epidermal growth factor receptor (EGFR) and its phosphorylation was performed. The antiviral effect of NAC was assessed by determining viral titers using plaque assay. Results. RSV infection reduced cell survival, promoted the release of proinflammatory factors, increased the ROS production and MDA concentration, and diminished the SOD activity and GSH/GSSG ratio, all which were attenuated by NAC treatment. Accordingly, NAC treatment inhibited the activation of EGFR and MUC5AC in BEAS-2B cells with RSV infection. Furthermore, NAC administration resulted in a marked decrease in RSV-induced HSPA6 expression in BEAS-2B cells. Concomitantly, EPB treatment led to an evident inhibition of RSV fusion gene and viral replication in RSV-infected BEAS-2B cells. Conclusion. This work supports the use of NAC to exert antimucin synthesis, anti-inflammatory, antioxidant, and antiviral effects on airway epithelium during RSV infection.}, } @article {pmid36041358, year = {2022}, author = {Zhu, Q and Xiao, Y and Jiang, M and Liu, X and Cui, Y and Hao, H and Flaker, GC and Liu, Q and Zhou, S and Liu, Z}, title = {N-acetylcysteine attenuates atherosclerosis progression in aging LDL receptor deficient mice with preserved M2 macrophages and increased CD146.}, journal = {Atherosclerosis}, volume = {357}, number = {}, pages = {41-50}, doi = {10.1016/j.atherosclerosis.2022.08.008}, pmid = {36041358}, issn = {1879-1484}, support = {R01 HL124122/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aging ; Animals ; *Atherosclerosis/drug therapy/genetics/prevention & control ; CD146 Antigen ; Diet, High-Fat ; *Hyperlipidemias/complications/drug therapy/genetics ; Inflammation/pathology ; Macrophages/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Reactive Oxygen Species ; Receptors, LDL/genetics ; }, abstract = {BACKGROUND AND AIMS: Inflammation and reactive oxygen species (ROS) are important to the pathogenesis of atherosclerosis. The effect of antioxidants on atherosclerosis is inconsistent, and sometimes controversial. We aimed to test the hypothesis that attenuation of atherosclerosis by N-acetylcysteine (NAC) depends on NAC treatment timing and duration.

METHODS: Male LDL receptor deficient (LDLR[-/-]) mice were fed a normal diet (ND) and divided into controls (on ND for 24 months), models 1-2 (at age of 9 months, starting NAC treatment for 3 or 6 months), and model 3 (at age of 18 months, starting NAC treatment for 6 months). To determine if hyperlipidemia compromises NAC treatment outcome, mice were fed a high fat diet (HFD) starting at age of 6 weeks and treated with NAC starting at 9 months of age for 6 months.

RESULTS: NAC treatment for 6 months, not for 3 months, significantly attenuated atherosclerosis progression, but did not reverse atherosclerotic lesions, in aging LDLR[-/-] mice on ND. NAC had no effect on atherosclerotic lesions in mice on HFD. NAC treatment significantly decreased aortic ROS production, and the levels of inflammatory cytokines in serum and aorta of aging LDLR[-/-] mice with increased CD146 level. Bone marrow transplantation study with GFP-positive bone marrow cells showed that NAC treatment preserved M2 population and M2 polarization in the aorta of LDLR[-/-] mice.

CONCLUSIONS: Early and adequate NAC treatment could effectively attenuate inflammation and atherosclerosis progression with preserved M2 population and increased CD146 level in aging LDLR[-/-] mice without extreme hyperlipidemia.}, } @article {pmid36039439, year = {2022}, author = {Ii, H and Taniguchi, K and Yoshiya, T and Nohara, Y and Kageyama, S and Kawauchi, A and Nakata, S}, title = {The γ-Glutamylcyclotransferase Inhibitor Pro-GA Induces an Antiproliferative Effect Through the Generation of Mitochondrial Reactive Oxygen Species.}, journal = {Anticancer research}, volume = {42}, number = {9}, pages = {4311-4317}, doi = {10.21873/anticanres.15931}, pmid = {36039439}, issn = {1791-7530}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Breast Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; MCF-7 Cells ; Mice ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; *gamma-Glutamylcyclotransferase ; }, abstract = {BACKGROUND/AIM: γ-Glutamylcyclotransferase (GGCT) is up-regulated in a broad range of cancers, including breast cancer, and GGCT inhibition has been shown to be a promising strategy for therapy. Herein, we evaluated the efficacy and mechanism of action of pro-GA, a GGCT enzymatic inhibitor, in MCF7 breast cancer cells.

MATERIALS AND METHODS: Proliferation was evaluated by WST-8 and trypan blue dye exclusion assays. Western blot analysis was conducted to examine the expression of cyclin-dependent kinase inhibitors (CDKI), including p21, p27, and p16. Induction of senescence was assessed by senescence-associated β-galactosidase staining. Generation of mitochondrial superoxide reactive oxygen species (ROS) was assessed using flow cytometry. The effect of N-acetylcysteine (NAC) on pro-GA dependent inhibition of proliferation, ROS generation, and senescence was also studied. The efficacy of systemic administration of pro-GA was evaluated in a MCF7 xenograft mouse model.

RESULTS: Treatment with pro-GA inhibited proliferation of MCF7 cells, increased CDKI expression and mitochondrial ROS, and induced cellular senescence. We found that cotreatment with NAC restored proliferation in pro-GA treated cells. NAC similarly suppressed CDKI expression, mitochondrial ROS generation, and senescence induced by pro-GA. Furthermore, the systemic administration of pro-GA in an MCF7 xenograft model had significant antitumor effects without toxicity.

CONCLUSION: Pro-GA may be a promising therapeutic agent for the treatment of breast cancer.}, } @article {pmid36034775, year = {2022}, author = {Licata, A and Minissale, MG and Stankevičiūtė, S and Sanabria-Cabrera, J and Lucena, MI and Andrade, RJ and Almasio, PL}, title = {N-Acetylcysteine for Preventing Acetaminophen-Induced Liver Injury: A Comprehensive Review.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {828565}, pmid = {36034775}, issn = {1663-9812}, abstract = {Aims: N-Acetylcysteine (NAC) is used as an antidote in acetaminophen (APAP) overdose to prevent and mitigate drug-induced liver injury (DILI). Our objective was to systematically review evidence of the use of NAC as a therapeutic option for APAP overdose and APAP-related DILI in order to define the optimal treatment schedule and timing to start treatment. Methods: Bibliographic databases (PubMed, Web of Science, Embase, and MEDLINE) were searched for retrospective and prospective cohort studies, case series, and clinical trials. The prespecified primary outcomes were DILI-related mortality, hepatotoxicity, and adverse events (AEs). Results: In total, 34 studies of NAC usage in APAP-related DILI cases with 19,580 patients were identified, of which 2,376 patients developed hepatotoxicities. The mortality rate across different studies ranged from 0 to 52%. Large variability of NAC regimens was found, i.e., intravenous (I.V.) (100-150 mg/kg) and oral (70-140 mg/kg), and length of treatment varied-12, 24, or 48 h for I.V. regimen and 72 h for oral administration. The timing of initiation of NAC treatment showed different results in terms of occurrence of hepatotoxicity and mortality; if started within 8 h and no more than 24 h from APAP overdose, either intravenously or orally, NAC administration was efficacious in terms of mortality. The most frequent AEs reported were anaphylactic reactions, followed by cutaneous AEs for the IV route and intestinal AEs for the oral one. Conclusion: NAC improves hepatotoxicity and reduces mortality. Timing of treatment, ranging from 8 to 24 h from APAP overdose, regardless of the regimen or route of administration, is important to prevent or minimize liver damage, particularly in children and in elderly and obese patients.}, } @article {pmid36033949, year = {2022}, author = {Le, JW and Sun, M and Zhu, JH and Fan, H}, title = {Protective effect of N-acetylcysteine on acute lung injury in septic rats by inhibiting inflammation, oxidation, and apoptosis.}, journal = {Iranian journal of basic medical sciences}, volume = {25}, number = {7}, pages = {859-864}, pmid = {36033949}, issn = {2008-3866}, abstract = {OBJECTIVES: Acute lung injury (ALI) is a common comorbidity in patients with sepsis, and finding drugs that can effectively reduce its mortality is a hot spot in current research. The purpose of this study is to explore the protective mechanism of N-acetylcysteine (NAC) on ALI in septic rats.

MATERIALS AND METHODS: We used NAC to intervene in septic rats to evaluate the plasma inflammatory factors and lung tissue pathological damage. Biochemical methods were used to determine the levels of oxidases in lung tissue, the expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) proteins, and observed lung tissue cell apoptosis.

RESULTS: NAC pretreatment decreased the mortality of septic rats, improved lung tissue pathological damage, reduced the levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-8, and malondialdehyde, and increased activity of superoxide dismutase, glutathione peroxidase, and catalase. Moreover, NAC pretreatment significantly decreased iNOS protein expression and increased eNOS protein expression in lung tissue. Meanwhile, NAC significantly decreased the number of apoptosis and the levels of Bax and Caspase-3 mRNA and increased the level of Bcl-2 mRNA in the lung tissue of septic rats.

CONCLUSION: NAC protects ALI in septic rats by inhibiting inflammation, oxidative stress, and apoptosis.}, } @article {pmid36032833, year = {2022}, author = {İskender Emekli, Z and Şentürk, F and Bahadir, O}, title = {Protective Effects of Curcumin and N-Acetyl Cysteine Against Noise-Induced Sensorineural Hearing Loss: An Experimental Study.}, journal = {Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India}, volume = {74}, number = {Suppl 1}, pages = {467-471}, pmid = {36032833}, issn = {2231-3796}, abstract = {We investigated the effectiveness of N-acetyl cysteine (NAC) and curcumin, which have known antioxidant and anti-inflammatory effects, in reducing acoustic trauma. We randomly divided 40 adult male rats into four groups: a control group (group 1), a curcumin group (group 2), a NAC group (group 3), and an ethyl alcohol group (group 4). The rats were exposed to 110 dB sound at a frequency of 4 kHz for 2 h to simulate acoustic trauma. Group 1, group 2, group 3, and group 4 received 1 ml saline, 200 mg/kg curcumin, 350 mg/kg NAC, or 1 ml ethyl alcohol, respectively, intraperitoneally 30 min before and 24 and 48 h after acoustic trauma. Distortion product otoacoustic emissions (DPOAEs) were recorded before and after the acoustic trauma, and 72 h after drug administration. In group 2, signal-to-noise ratio (SNR) values in frequencies of 1000 Hz, 1500 Hz, and 4000 Hz decreased in the second measurements when compared to the first, and showed improvements in the third measurements in comparison to the second ones. In group 3, SNR values decreased in the second measurements, but only the values at 6000 Hz were found to be statistically significant (p = 0.007). The values in the third measurements were statistically significant when compared to the second ones. There was a statistically significant difference in the third measurements in both groups 2 and 3, possibly due to curcumin and NAC treatment. This study showed that curcumin and NAC may be effective against noise-induced hearing loss.}, } @article {pmid36029289, year = {2022}, author = {Zhang, F and Wang, F and Li, W and Liang, L and Sang, X}, title = {The toxicity mechanism of glabridin in prostate cancer cells is involved in reactive oxygen species-dependent PI3K/Akt pathway: Integrated utilization of bioinformatic analysis and in vitro test validation.}, journal = {Environmental toxicology}, volume = {37}, number = {12}, pages = {2937-2946}, doi = {10.1002/tox.23649}, pmid = {36029289}, issn = {1522-7278}, mesh = {Male ; Humans ; Reactive Oxygen Species/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Caspase 3/metabolism ; Computational Biology ; Prospective Studies ; Apoptosis ; Cell Proliferation ; *Prostatic Neoplasms ; Acetylcysteine/pharmacology ; In Vitro Techniques ; }, abstract = {Glabridin is a prenylated isoflavonoid with considerable anticancer property. Reactive oxygen species (ROS) have evolved as regulators of many cellular signaling pathways in prostate cancer (PC). However, the role of ROS signaling in the anticancer activity of glabridin has not been investigated. Here, we attempted to evaluate the effect of glabridin on PC and the involvement of ROS signaling. Intracellular ROS and mitochondrial ROS (mitoROS) production in PC cell lines, DU-145 and LNCaP, were measured by H2DCFDA and MitoSOX Red staining, respectively. MTT assay was used to analyze the cellular viability. EdU staining assay was conducted to analyze the cell proliferation. To analyze apoptotic rate, TUNEL assay was performed. Caspase-3 activity was detected to reflect cell apoptosis. Western blot was carried out to detect the expression levels of Akt and p-Akt. We found that intracellular ROS and mitoROS levels were dose-dependently upregulated after glabridin treatment in both DU-145 and LNCaP cells, which was reversed by the treatment of ROS inhibitor, N-acetyl-L-cysteine (NAC). Glabridin inhibited the cell viability and reduced the number of EdU-positive DU-145 and LNCaP cells, which were respectively proved by MTT assay and EdU staining assay. Glabridin promoted cell death with increased apoptotic rate and caspase-3 activity in DU-145 and LNCaP cells. The effects of glabridin on cell proliferation and apoptosis were reversed by NAC. Moreover, glabridin suppressed the ratio of p-Akt/Akt, while NAC mitigated the decreased p-Akt/Akt ratio. In addition, the effects of glabridin on cell proliferation and apoptosis were also attenuated by Akt activator, SC79. Collectively, our results demonstrated that glabridin suppressed proliferation and induced apoptosis in PC cells via regulating ROS-mediated PI3K/Akt pathway. These findings suggested that glabridin might hold a promising prospective as a therapeutic agent against PC.}, } @article {pmid36028602, year = {2022}, author = {Liu, Q and Wang, Y and Tan, D and Liu, Y and Zhang, P and Ma, L and Liang, M and Chen, Y}, title = {The Prevention and Reversal of a Phenytoin-Resistant Model by N-acetylcysteine Therapy Involves the Nrf2/P-Glycoprotein Pathway at the Blood-Brain Barrier.}, journal = {Journal of molecular neuroscience : MN}, volume = {72}, number = {10}, pages = {2125-2135}, pmid = {36028602}, issn = {1559-1166}, support = {82071458//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; *Phenytoin/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Nimodipine/pharmacology ; Anticonvulsants/pharmacology/therapeutic use ; NF-E2-Related Factor 2/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics/metabolism ; Brain/metabolism ; *Drug Resistant Epilepsy/metabolism ; }, abstract = {The transporter hypothesis is one of the most popular hypotheses of drug-resistant epilepsy (DRE). P-glycoprotein (P-gp), a channel protein at the blood-brain barrier (BBB), plays an important role in the transport of some anti-seizure drugs from brain tissue into vessels, which reduces drug concentrations and diminishes the effects of drug treatment. We performed this study to test whether P-gp is overexpressed in DRE and identify ways to prevent and reverse DRE. In this study, we established a phenytoin (PHT)-resistant mouse model and revealed that P-gp was overexpressed at the BBB in PHT-resistant mice. The P-gp inhibitor nimodipine decreased the resistance of phenytoin. Antioxidative preventive treatment with N-acetylcysteine (NAC) prevented the mice from entering a PHT-resistant state, and NAC therapy tended to reverse PHT resistance into sensitivity. We were also able to induce PHT resistance by activating the Nrf2/P-gp pathway, which indicates that oxidative stress plays an important role in drug resistance. Taken together, these findings suggest that antioxidative therapy may be a promising strategy for overcoming DRE.}, } @article {pmid36028178, year = {2022}, author = {Zhang, Y and Yang, S and Qiu, Z and Huang, L and Huang, L and Liang, Y and Liu, X and Wang, M and Zhou, B}, title = {Pyrogallol enhances therapeutic effect of human umbilical cord mesenchymal stem cells against LPS-mediated inflammation and lung injury via activation of Nrf2/HO-1 signaling.}, journal = {Free radical biology & medicine}, volume = {191}, number = {}, pages = {66-81}, doi = {10.1016/j.freeradbiomed.2022.08.030}, pmid = {36028178}, issn = {1873-4596}, mesh = {Acetylcysteine/metabolism ; *Acute Lung Injury/drug therapy/therapy ; Animals ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Inflammation/drug therapy/therapy ; Inflammation Mediators/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Lipopolysaccharides ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology ; NF-E2-Related Factor 2/genetics/metabolism ; NF-kappa B/metabolism ; *Pyrogallol/pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 4/genetics/metabolism ; Umbilical Cord/cytology ; }, abstract = {The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced acute lung injury (ALI). hUCMSCs with pyrogallol treatment increased expression of HO-1 at both mRNA and protein levels, accompanied by Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2 protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by pyrogallol was reversed by pretreatment with N-acetylcysteine (NAC) and a P38 kinase inhibitor (SB203580). Whereas, NAC pretreatment abrogated pyrogallol-mediated activation of P38 kinase, indicating that pyrogallol-derived ROS led to P38 kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P-P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with pyrogallol-primed hUCMSCs transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-κB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based therapy for treating LPS-associated ALI.}, } @article {pmid36016767, year = {2022}, author = {Kashi, EA and Salmani, AA and Shafagh, S and Mousavi, GA and Mousavi, N and Heydari, M and Hajian, A}, title = {Effects of oral N-acetyl cysteine on pain and plasma biochemical parameters in fibrocystic breast disorder: A randomized controlled trial.}, journal = {Surgery open science}, volume = {10}, number = {}, pages = {69-73}, pmid = {36016767}, issn = {2589-8450}, abstract = {BACKGROUND: Fibrocystic change is the most common benign lesion in breasts of a woman in her reproductive age. It is an outcome of estrogen excess due to sex hormone imbalance. Cyclical pain as the most common symptom worsens life quality, compels patient to seek health care support continuously, and imposes large amounts of expense to both patient and health system. Current study aims to evaluate effects of N-acetyl cysteine on decreasing pain and changes in plasma biochemistry.

METHOD: A total of 64 eligible women participated in this double-blinded randomized controlled trial. They were between 18 and 40 years. Participants were randomly allocated into oral N-acetyl cysteine and placebo receivers. Intervention and follow-up lasted for, respectively, a 12-week drugs-on and 12-month drugs-off period. Visual analog scaling was applied to measure severity of pain. Peripheral venous plasma was extracted and compared for inflammatory parameters including high-sensitivity C-reactive protein, total antioxidant capacity, malondialdehyde, total plasma glutathione, lipid profile, and fasting blood sugar.

RESULTS: Oral N-acetyl cysteine significantly decreased feeling of cyclical mastalgia (P < .01) after 12 weeks of consumption. In addition to lowering of plasma level of high-sensitivity C-reactive protein (P = .008), total plasma glutathione significantly increased (P = .02) among N-acetyl cysteine receivers. No change in lipid profile and insulin sensitivity was seen.

CONCLUSION: N-Acetyl cysteine could mitigate cyclical mastalgia. Inflammation as a considered reason for cyclical mastalgia also was halted by N-acetyl cysteine consumption.}, } @article {pmid36014444, year = {2022}, author = {Cui, XY and Park, SH and Park, WH}, title = {Anti-Cancer Effects of Auranofin in Human Lung Cancer Cells by Increasing Intracellular ROS Levels and Depleting GSH Levels.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {16}, pages = {}, pmid = {36014444}, issn = {1420-3049}, support = {2019R1I1A2A01041209//The Basic Science Research Program through the National Research Foundation of Korea (NRF)/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis ; *Auranofin/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Glutathione/metabolism ; Humans ; *Lung Neoplasms/drug therapy/metabolism ; Membrane Potential, Mitochondrial ; Reactive Oxygen Species/metabolism ; }, abstract = {Auranofin, as a thioredoxin reductase (TrxR) inhibitor, has promising anti-cancer activity in several cancer types. However, little is known about the inhibitory effect of auranofin on lung cancer cell growth. We, therefore, investigated the antigrowth effects of auranofin in various lung cancer cells with respect to cell death, reactive oxygen species (ROS), and glutathione (GSH) levels. Treatment with 0~5 µM auranofin decreased cell proliferation and induced cell death in Calu-6, A549, SK-LU-1, NCI-H460, and NCI-H1299 lung cancer cells at 24 h. In addition, 0~5 µM auranofin increased ROS levels, including O2[•-], and depleted GSH levels in these cells. N-acetyl cysteine (NAC) prevented growth inhibition and mitochondrial membrane potential (MMP, ∆Ψm) loss in 3 and 5 µM auranofin-treated Calu-6 and A549 cells at 24 h, respectively, and decreased ROS levels and GSH depletion in these cells. In contrast, L-buthionine sulfoximine (BSO) enhanced cell death, MMP (∆Ψm) loss, ROS levels, and GSH depletion in auranofin-treated Calu-6 and A549 cells. Treatment with 3 and 5 µM auranofin induced caspase-3 activation and poly (ADP ribose) polymerase (PARP) cleavage in Calu-6 and A549 cells, respectively. Both were prevented by NAC, but enhanced by BSO. Moreover, TrxR activity was reduced in auranofin-treated Calu-6 and A549 cells. That activity was decreased by BSO, but increased by NAC. In conclusion, these findings demonstrate that auranofin-induced cell death is closely related to oxidative stress resulted from increased ROS levels and GSH depletion in lung cancer cells.}, } @article {pmid36012934, year = {2022}, author = {Wang, J and Wang, Y and Ling, X and Zhang, Z and Deng, Y and Tian, P}, title = {Comparison of Sputum Treated with Power Ultrasound and Routine NALC-NaOH Methods for Mycobacterial Culture: A Prospective Study.}, journal = {Journal of clinical medicine}, volume = {11}, number = {16}, pages = {}, pmid = {36012934}, issn = {2077-0383}, support = {2021SFGC0504//Department of Science and Technology of Shandong Province/ ; 2019WS532.//Health Science and Technology Development Plan of Shandong Province/ ; }, abstract = {Mycobacterial culture remains the gold standard for the diagnosis of active tuberculosis. However, an appropriate digestion and decontamination method is essential for the effective recovery of tubercle bacilli in culture. The study was designed to compare the efficacy of sputum treated with power ultrasound (PU) and routine NALC-NaOH methods for mycobacterial culture from clinically suspected cases of pulmonary tuberculosis. To evaluate the PU and routine NALC-NaOH methods, sputum specimens (n = 597) were studied (culturing on MGIT 960), and the performances were compared. Of the 597 samples, 89 (14.91%) sputum samples treated with the NaOH-NALC method were mycobacterial culture positive, including Mycobacterium tuberculosis (M.TB; n = 77, 12.90%) and nontuberculous mycobacteria (NTM; n = 12, 2.01%). One hundred and ten (18.43%) sputum samples treated with the PU method were culture positive, including M.TB (n = 87, 14.57%) and NTM (n = 23, 3.85%). The PU method detected 10 additional cases of M.TB and 11 additional cases of NTM when compared to the NALC-NaOH method. Statistical analysis showed that a significant difference was found in the culture-positive ratio of M.TB and NTM between the two method groups (p < 0.05). Compared with that of the NALC-NaOH method (8.04%), sputum treated with PU method (4.86%) had a significantly lower contamination rate (p < 0.05). In conclusion, our data indicate that, compared with the NALC-NaOH method, the PU method is a rapid and effective approach for mycobacterial culture when detecting active TB. However, its accurate mechanism has not been well addressed, and further investigation is still required.}, } @article {pmid36012679, year = {2022}, author = {Lai, CC and Baskaran, R and Tsao, CY and Tuan, LH and Siow, PF and Palani, M and Lee, LJ and Liu, CM and Hwu, HG and Lee, LJ}, title = {Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012679}, issn = {1422-0067}, support = {105-2628-B-002-004-MY3//Ministry of Science and Technology of the Republic of China/ ; 108-2320-B-002-066-MY3//Ministry of Science and Technology of the Republic of China/ ; }, mesh = {Acetylcysteine/pharmacology ; *Amphetamine/pharmacology ; Animals ; Disease Models, Animal ; Dopamine/metabolism ; Female ; Glycogen Synthase Kinase 3 ; Humans ; Mice ; Nerve Tissue Proteins ; Pregnancy ; Receptors, Dopamine ; *Schizophrenia/drug therapy/genetics/prevention & control ; }, abstract = {Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders.}, } @article {pmid36012632, year = {2022}, author = {Luo, Q and Jia, L and Huang, C and Qi, Q and Jahangir, A and Xia, Y and Liu, W and Shi, R and Tang, L and Chen, Z}, title = {Polyphyllin I Promotes Autophagic Cell Death and Apoptosis of Colon Cancer Cells via the ROS-Inhibited AKT/mTOR Pathway.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012632}, issn = {1422-0067}, support = {2020YFH0148//Sichuan international science and technology innovation cooperation project/ ; }, mesh = {Apoptosis ; *Autophagic Cell Death ; Autophagy ; Cell Line, Tumor ; *Colonic Neoplasms/drug therapy ; Diosgenin/analogs & derivatives ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Colon cancer is a common malignant tumor of the digestive tract, and it is considered among the biggest killers. Scientific and reasonable treatments can effectively improve the survival rate of patients if performed in the early stages. Polyphyllin I (PPI), a pennogenyl saponin isolated from Paris polyphylla var. yunnanensis, has exhibited strong anti-cancer activities in previous studies. Here, we report that PPI exhibits a cytotoxic effect on colon cancer cells. PPI suppressed cell viability and induced autophagic cell death in SW480 cells after 12 and 24 h, with the IC50 values 4.9 ± 0.1 μmol/L and 3.5 ± 0.2 μmol/L, respectively. Furthermore, we found PPI induced time-concentration-dependent autophagy and apoptosis in SW480 cells. In addition, down-regulated AKT/mTOR activity was found in PPI-treated SW480 cells. Increased levels of ROS might link to autophagy and apoptosis because reducing the level of ROS by antioxidant N-acetylcysteine (NAC) treatment mitigated PPI-induced autophagy and apoptosis. Although we did not know the molecular mechanism of how PPI induced ROS production, this is the first study to show that PPI induces ROS production and down-regulates the AKT/mTOR pathway, which subsequently promotes the autophagic cell death and apoptosis of colon cancer cells. This present study reports PPI as a potential therapeutic agent for colon cancer and reveals its underlying mechanisms of action.}, } @article {pmid36012403, year = {2022}, author = {Chen, GS and Chen, SY and Liu, ST and Hsieh, CC and Lee, SP and Huang, SM}, title = {Stabilization of the c-Myc Protein via the Modulation of Threonine 58 and Serine 62 Phosphorylation by the Disulfiram/Copper Complex in Oral Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012403}, issn = {1422-0067}, support = {MND-MAB-111-094 to S-M Huang//Ministry of National Defense-Medical Affairs Bureau, Taiwan/ ; A1111035 to S-M Huang//Teh-Tzer Study Group for Human Medical Research Foundation, Taiwan/ ; TSGH-E-111200 to S-P Lee//Tri-Service General Hospital, Taiwan/ ; }, mesh = {*Carcinoma, Squamous Cell/drug therapy ; Cell Line, Tumor ; Copper/metabolism/pharmacology ; Disulfiram/pharmacology ; Humans ; *Mouth Neoplasms/drug therapy ; Phosphorylation ; Proto-Oncogene Proteins c-myc/metabolism ; Reactive Oxygen Species/metabolism ; Serine/metabolism ; Threonine/metabolism ; }, abstract = {MYC has a short half-life that is tightly regulated through phosphorylation and proteasomal degradation. Many studies have claimed that treatment with disulfiram (DSF) with or without copper ions can cause cancer cell death in a reactive oxygen species (ROS)-dependent manner in cancer cells. Our previous study showed that the levels of c-Myc protein and the phosphorylation of threonine 58 (T58) and serine 62 (S62) increased in DSF-Cu-complex-treated oral epidermoid carcinoma Meng-1 (OECM-1) cells. These abovementioned patterns were suppressed by pretreatment with an ROS scavenger, N-acetyl cysteine. The overexpression of c-Myc failed to induce hypoxia-inducible factor 1α protein expression, which was stabilized by the DSF-Cu complex. In this study, we further examined the regulatory mechanism behind the induction of the c-Myc of the DSF-Cu complex in an OECM-1 cell compared with a Smulow-Glickman (SG) human normal gingival epithelial cell. Our data showed that the downregulation of c-Myc truncated nick and p62 and the induction of the ratio of H3P/H3 and p-ERK/ERK might not be involved in the increase in the amount of c-Myc via the DSF/copper complexes in OECM-1 cells. Combined with the inhibitors for various signaling pathways and cycloheximde treatment, the increase in the amount of c-Myc with the DSF/copper complexes might be mediated through the increase in the stabilities of c-Myc (T58) and c-Myc (S62) proteins in OECM-1 cells. In SG cells, only the c-Myc (T58) protein was stabilized by the DSF-Cu (I and II) complexes. Hence, our findings could provide novel regulatory insights into the phosphorylation-dependent stability of c-Myc in DSF/copper-complex-treated oral squamous cell carcinoma.}, } @article {pmid36010550, year = {2022}, author = {Huang, Z and Gan, S and Zhuang, X and Chen, Y and Lu, L and Wang, Y and Qi, X and Feng, Q and Huang, Q and Du, B and Zhang, R and Liu, Z}, title = {Artesunate Inhibits the Cell Growth in Colorectal Cancer by Promoting ROS-Dependent Cell Senescence and Autophagy.}, journal = {Cells}, volume = {11}, number = {16}, pages = {}, pmid = {36010550}, issn = {2073-4409}, mesh = {Animals ; Apoptosis ; Artesunate/pharmacology ; Autophagy ; Cell Line, Tumor ; Cell Proliferation ; Cellular Senescence ; *Colorectal Neoplasms/drug therapy/metabolism ; *Endoribonucleases ; Mice ; Protein Serine-Threonine Kinases ; Reactive Oxygen Species/metabolism ; }, abstract = {Although artesunate has been reported to be a promising candidate for colorectal cancer (CRC) treatment, the underlying mechanisms and molecular targets of artesunate are yet to be explored. Here, we report that artesunate acts as a senescence and autophagy inducer to exert its inhibitory effect on CRC in a reactive oxygen species (ROS)-dependent manner. In SW480 and HCT116 cells, artesunate treatment led to mitochondrial dysfunction, drastically promoted mitochondrial ROS generation, and consequently inhibited cell proliferation by causing cell cycle arrest at G0/G1 phase as well as subsequent p16- and p21-mediated cell senescence. Senescent cells underwent endoplasmic reticulum stress (ERS), and the unfolded protein response (UPR) was activated via IRE1α signaling, with upregulated BIP, IRE1α, phosphorylated IRE1α (p-IRE1α), CHOP, and DR5. Further experiments revealed that autophagy was induced by artesunate treatment due to oxidative stress and ER stress. In contrast, N-Acetylcysteine (NAC, an ROS scavenger) and 3-Methyladenine (3-MA, an autophagy inhibitor) restored cell viability and attenuated autophagy in artesunate-treated cells. Furthermore, cellular free Ca[2+] levels were increased and could be repressed by NAC, 3-MA, and GSK2350168 (an IRE1α inhibitor). In vivo, artesunate administration reduced the growth of CT26 cell-derived tumors in BALB/c mice. Ki67 and cyclin D1 expression was downregulated in tumor tissue, while p16, p21, p-IRE1α, and LC3B expression was upregulated. Taken together, artesunate induces senescence and autophagy to inhibit cell proliferation in colorectal cancer by promoting excessive ROS generation.}, } @article {pmid36009471, year = {2022}, author = {Petrillo, T and Semprini, E and Tomatis, V and Arnesano, M and Ambrosetti, F and Battipaglia, C and Sponzilli, A and Ricciardiello, F and Genazzani, AR and Genazzani, AD}, title = {Putative Complementary Compounds to Counteract Insulin-Resistance in PCOS Patients.}, journal = {Biomedicines}, volume = {10}, number = {8}, pages = {}, pmid = {36009471}, issn = {2227-9059}, abstract = {Polycystic ovary syndrome (PCOS) is the most frequent endocrine-metabolic disorder among women at reproductive age. The diagnosis is based on the presence of at least two out of three criteria of the Rotterdam criteria (2003). In the last decades, the dysmetabolic aspect of insulin resistance and compensatory hyperinsulinemia have been taken into account as the additional key features in the etiopathology of PCOS, and they have been widely studied. Since PCOS is a complex and multifactorial syndrome with different clinical manifestations, it is difficult to find the gold standard treatment. Therefore, a great variety of integrative treatments have been reported to counteract insulin resistance. PCOS patients need a tailored therapeutic strategy, according to the patient's BMI, the presence or absence of familiar predisposition to diabetes, and the patient's desire to achieve pregnancy or not. The present review analyzes and discloses the main clinical insight of such complementary substances.}, } @article {pmid36009344, year = {2022}, author = {Lad, A and Hunyadi, J and Connolly, J and Breidenbach, JD and Khalaf, FK and Dube, P and Zhang, S and Kleinhenz, AL and Baliu-Rodriguez, D and Isailovic, D and Hinds, TD and Gatto-Weis, C and Stanoszek, LM and Blomquist, TM and Malhotra, D and Haller, ST and Kennedy, DJ}, title = {Antioxidant Therapy Significantly Attenuates Hepatotoxicity following Low Dose Exposure to Microcystin-LR in a Murine Model of Diet-Induced Non-Alcoholic Fatty Liver Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {36009344}, issn = {2076-3921}, support = {P30 ES020957/ES/NIEHS NIH HHS/United States ; P30 ES020957/NH/NIH HHS/United States ; F31 HL160178/HL/NHLBI NIH HHS/United States ; }, abstract = {We have previously shown in a murine model of Non-alcoholic Fatty Liver Disease (NAFLD) that chronic, low-dose exposure to the Harmful Algal Bloom cyanotoxin microcystin-LR (MC-LR), resulted in significant hepatotoxicity including micro-vesicular lipid accumulation, impaired toxin metabolism as well as dysregulation of the key signaling pathways involved in inflammation, immune response and oxidative stress. On this background we hypothesized that augmentation of hepatic drug metabolism pathways with targeted antioxidant therapies would improve MC-LR metabolism and reduce hepatic injury in NAFLD mice exposed to MC-LR. We chose N-acetylcysteine (NAC, 40 mM), a known antioxidant that augments the glutathione detoxification pathway and a novel peptide (pNaKtide, 25 mg/kg) which is targeted to interrupting a specific Src-kinase mediated pro-oxidant amplification mechanism. Histological analysis showed significant increase in hepatic inflammation in NAFLD mice exposed to MC-LR which was attenuated on treatment with both NAC and pNaKtide (both p ≤ 0.05). Oxidative stress, as measured by 8-OHDG levels in urine and protein carbonylation in liver sections, was also significantly downregulated upon treatment with both antioxidants after MC-LR exposure. Genetic analysis of key drug transporters including Abcb1a, Phase I enzyme-Cyp3a11 and Phase II metabolic enzymes-Pkm (Pyruvate kinase, muscle), Pklr (Pyruvate kinase, liver, and red blood cell) and Gad1 (Glutamic acid decarboxylase) was significantly altered by MC-LR exposure as compared to the non-exposed control group (all p ≤ 0.05). These changes were significantly attenuated with both pNaKtide and NAC treatment. These results suggest that MC-LR metabolism and detoxification is significantly impaired in the setting of NAFLD, and that these pathways can potentially be reversed with targeted antioxidant treatment.}, } @article {pmid36009205, year = {2022}, author = {Mlejnek, P}, title = {Direct Interaction between N-Acetylcysteine and Cytotoxic Electrophile-An Overlooked In Vitro Mechanism of Protection.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {36009205}, issn = {2076-3921}, support = {IGA_LF_2022_034//Palacký University, Olomouc/ ; }, abstract = {In laboratory experiments, many electrophilic cytotoxic agents induce cell death accompanied by reactive oxygen species (ROS) production and/or by glutathione (GSH) depletion. Not surprisingly, millimolar concentrations of N-acetylcysteine (NAC), which is used as a universal ROS scavenger and precursor of GSH biosynthesis, inhibit ROS production, restore GSH levels, and prevent cell death. The protective effect of NAC is generally used as corroborative evidence that cell death induced by a studied cytotoxic agent is mediated by an oxidative stress-related mechanism. However, any simple interpretation of the results of the protective effects of NAC may be misleading because it is unable to interact with superoxide (O2•[-]), the most important biologically relevant ROS, and is a very weak scavenger of H2O2. In addition, NAC is used in concentrations that are unnecessarily high to stimulate GSH synthesis. Unfortunately, the possibility that NAC as a nucleophile can directly interact with cytotoxic electrophiles to form non-cytotoxic NAC-electrophile adduct is rarely considered, although it is a well-known protective mechanism that is much more common than expected. Overall, apropos the possible mechanism of the cytoprotective effect of NAC in vitro, it is appropriate to investigate whether there is a direct interaction between NAC and the cytotoxic electrophile to form a non-cytotoxic NAC-electrophilic adduct(s).}, } @article {pmid36009056, year = {2022}, author = {Ashar, Y and Teng, Q and Wurpel, JND and Chen, ZS and Reznik, SE}, title = {Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function.}, journal = {Biomolecules}, volume = {12}, number = {8}, pages = {}, pmid = {36009056}, issn = {2218-273X}, support = {R16 GM145586/GM/NIGMS NIH HHS/United States ; 1R16GM145586/NH/NIH HHS/United States ; }, mesh = {Cell Movement/physiology ; Female ; Folic Acid/metabolism ; Humans ; Multidrug Resistance-Associated Proteins ; Palmitic Acid/metabolism/pharmacology ; *Placenta/metabolism ; Pregnancy ; *Trophoblasts/metabolism ; Vascular Remodeling ; }, abstract = {Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs' role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetylcysteine (NAC) prevented the palmitic acid-mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an ABCC1 knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in utero environment.}, } @article {pmid36006894, year = {2022}, author = {Miller, R and Kim, Y and Park, CG and Torres, C and Kim, B and Lee, J and Flaherty, D and Han, HS and Kim, YJ and Kong, H}, title = {Extending the Bioavailability of Hydrophilic Antioxidants for Metal Ion Detoxification via Crystallization with Polysaccharide Dopamine.}, journal = {ACS applied materials & interfaces}, volume = {14}, number = {35}, pages = {39759-39774}, doi = {10.1021/acsami.2c08889}, pmid = {36006894}, issn = {1944-8252}, mesh = {Acetylcysteine ; Adenosine Triphosphate/metabolism ; *Antioxidants/metabolism/pharmacology ; Biological Availability ; Crystallization ; Dihydroxyphenylalanine ; *Dopamine/pharmacology ; Humans ; Ions ; Oxidative Stress ; Polysaccharides/pharmacology ; Reactive Oxygen Species/metabolism ; Silver/toxicity ; }, abstract = {Although metal ions, such as silver and gold, have been shown to have strong antimicrobial properties, their potential to have toxic effects on human and environmental health has gained interest with an improved understanding of their mechanisms to promote oxidative stress. Redox control is a major focus of many drug delivery systems and often incorporates an antioxidant as the active pharmaceutical ingredient (API) to neutralize overproduced reactive oxygen species (ROS). Nevertheless, there are still limitations with bioavailability and extended redox control with regard to antioxidant drug delivery. Herein, this study develops a colloidal antioxidant crystal system that dissolves sustainably through polymer stabilization using sodium hyaluronate conjugated with dopamine (HA-dopa). We explore the role of dopamine incorporation into crystal-stabilizing polymers and quantify the balance between drug-polymer interactions and competing polymer-polymer interactions. We propose that this type of analysis is useful in the engineering of and provides insight into the release behavior of polymer-crystal complexes. In developing our crystal complex, N-acetylcysteine (NAC) was used as the model antioxidant to protect against silver ion toxicity. We found that our optimized HA-dopa-stabilized NAC crystals prolong the release time of NAC 5-fold compared to a polymer-free NAC crystal. Therefore, following sublethal exposure to AgNO3, the extended lifetime of NAC was able to maintain normal intracellular ROS levels, modulate metabolic function, mitigate fluctuations in ATP levels and ATP synthase activity, and preserve contraction frequency in engineered cardiac muscle tissue. Furthermore, the protective effects of the HA-dopa-stabilized NAC crystals were extended to a Daphnia magna model where silver-ion-induced change to both cell-level biochemistry and organ function was alleviated. As such, we propose that the packaging of hydrophilic antioxidants as colloidal crystals drastically extends the lifetime of the API, better maintains ROS homeostasis post metal ion exposure, and therefore preserves both intracellular biochemistry and tissue functionality.}, } @article {pmid36006112, year = {2022}, author = {Branco, V and Coppo, L and Aschner, M and Carvalho, C}, title = {N-Acetylcysteine or Sodium Selenite Prevent the p38-Mediated Production of Proinflammatory Cytokines by Microglia during Exposure to Mercury (II).}, journal = {Toxics}, volume = {10}, number = {8}, pages = {}, pmid = {36006112}, issn = {2305-6304}, support = {UID/DTP/04138/2019//Fundação para a Ciência e Tecnologia/ ; R01 ES007331/ES/NIEHS NIH HHS/United States ; PTDC/MED-FAR/31136/2017//Fundação para a Ciência e Tecnologia/ ; DL57/2016/CP1376/CT002//Fundação para a Ciência e Tecnologia/ ; (NIEHS) R01ES07331/ES/NIEHS NIH HHS/United States ; }, abstract = {Mercury (Hg) is known for its neurotoxicity and is reported to activate microglia cells at low exposure levels. Since mercury decreases the activity of the glutathione and thioredoxin systems, we hypothesize that Hg would, in turn, disrupt microglia homeostasis by interfering with redox regulation of signaling pathways. Thus, in this work, we analyzed the effect of exposure to Hg[2+] on nuclear translocation and activation of NF-kB (p50) and p38 and pro-inflammatory gene transcription (IL-1ß; iNOS, TNF-alpha) considering the interaction of Hg with the glutathione system and thioredoxin systems in microglial cells. N9 (mouse) microglia cells were exposed to different concentrations of Hg[2+] and the 24 h EC50 for a reduction in viability was 42.1 ± 3.7 μM. Subsequent experiments showed that at sub-cytotoxic levels of Hg[2+], there was a general increase in ROS (≈40%) accompanied by a significant depletion (60-90%) of glutathione (GSH) and thioredoxin reductase (TrxR) activity. Upon 6 h of exposure to Hg[2+], p38 (but not p50) accumulated in the nucleus (50% higher than in control), which was accompanied by an increase in its phosphorylation. Transcript levels of both IL1-ß and iNOS were increased over two-fold relative to the control. Furthermore, pre-exposure of cells to the p38 inhibitor SB 239063 hindered the activation of cytokine transcription by Hg[2+]. These results show that disruption of redox systems by Hg[2+] prompts the activation of p38 leading to transcription of pro-inflammatory genes in microglia cells. Treatment of N9 cells with NAC or sodium selenite-which caused an increase in basal GSH and TrxR levels, respectively, prevented the activation of p38 and the transcription of pro-inflammatory cytokines. This result demonstrates the importance of an adequate nutritional status to minimize the toxicity resulting from Hg exposure in human populations at risk.}, } @article {pmid36002994, year = {2022}, author = {Gandhi, VV and Bihani, SC and Phadnis, PP and Kunwar, A}, title = {Diselenide-derivative of 3-pyridinol targets redox enzymes leading to cell cycle deregulation and apoptosis in A549 cells.}, journal = {Biological chemistry}, volume = {403}, number = {10}, pages = {891-905}, doi = {10.1515/hsz-2022-0123}, pmid = {36002994}, issn = {1437-4315}, mesh = {A549 Cells ; *Apoptosis ; Cell Cycle ; *Glutathione/metabolism ; Glutathione Transferase/metabolism/pharmacology ; Humans ; Molecular Docking Simulation ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {The aim of present study was to understand the mechanism of action of 2,2'-diselenobis(3-pyridinol) or DISPOL in human lung cancer (A549) cells. A549 cells were treated with 10 µM (∼IC50) of DISPOL for varying time points to corelate the intracellular redox changes with its cytotoxic effect. The results indicated that DISPOL treatment led to a time dependant decrease in the basal level of reactive oxygen species (ROS). Additionally, DISPOL treatment elevated the ratio of reduced (GSH) and oxidised (GSSG) glutathione by upregulating gamma-glutamylcysteine ligase (γ-GCL) involved in GSH biosynthesis and inhibiting the activities of redox enzymes responsible for GSH utilization and recycling, such as glutathione-S-transferase (GST) and glutathione reductase (GR). Molecular docking analysis suggests putative interactions of DISPOL with GST and GR which could account for its inhibitory effect on these enzymes. Further, DISPOL induced reductive environment preceded G1 arrest and apoptosis as evidenced by decreased expression of cell cycle genes (Cyclin D1 and Cyclin E1) and elevation of p21 and apoptotic markers (cleaved caspase 3 and cleaved PARP). The combinatorial experiments involving DISPOL and redox modulatory agents such as N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) indeed confirmed the role of reductive stress in DISPOL-induced cell death. Finally, Lipinski's rule suggests attributes of drug likeness in DISPOL. Taken together, DISPOL exhibits a novel mechanism of reductive stress-mediated cell death in A549 cells that warrants future exploration as anticancer agent.}, } @article {pmid35995981, year = {2022}, author = {Zhou, L and Wang, B and Xie, H and Du, C and Tang, J and Tang, W}, title = {Intrauterine exposure to oxidative stress induces caspase-1-dependent enteric nerve cell pyroptosis.}, journal = {Pediatric surgery international}, volume = {38}, number = {11}, pages = {1555-1567}, pmid = {35995981}, issn = {1437-9813}, support = {81801496, 81900460, 81700449//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Caspase 1/metabolism ; Caspase 3/metabolism ; Cathepsin D/metabolism ; Galactose ; Hydrogen Peroxide ; *Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Neurons ; Oxidative Stress ; Propidium ; *Pyroptosis/physiology ; RNA, Small Interfering/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: This study determined whether oxidative stress causes the developmental abnormalities of the enteric nervous system during the embryonic period.

METHODS: Using the test results of tissue specimens of children with Hirschsprung disease (HSCR), we established a pregnant rat model of oxidative stress and a cellular oxidative stress model to conduct related molecular, cellular, and histopathological experiments for exploration and validation.

RESULTS: The results of the quantitative real-time polymerase chain reaction assay indicated overexpression of pyroptosis markers (NLRP3, ASC, and caspase-1) in HSCR lesions and newborn pups in the oxidative stress group (treated with D-galactose). The expression of cathepsin D was significantly decreased in intestinal tissues of newborn pups in the oxidative stress group compared to the control group. Reactive oxygen species scavengers (N-acetyl-cysteine, NAC), the caspase-1 inhibitor (VX-765), and the NLRP3 siRNA could reverse the release of LDH, decrease the number of propidium iodide stained cells, and reduce the percentage of TUNEL/caspase-3 double-positive cells in the H2O2-treated group.

CONCLUSION: Oxidative stress can induce the death of enteric nerve cells by activating caspase-1-dependent pyroptosis through NLRP3 inflammasomes, which may contribute to abnormal enteric nervous system development.}, } @article {pmid35994611, year = {2022}, author = {Zhao, Y and Sun, C and Su, M and Shi, J and Hu, Z and Peng, Y and Zheng, J}, title = {Evidence for Metabolic Activation of Omeprazole In Vitro and In Vivo.}, journal = {Chemical research in toxicology}, volume = {35}, number = {9}, pages = {1493-1502}, doi = {10.1021/acs.chemrestox.2c00111}, pmid = {35994611}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; Benzoquinones/metabolism ; *Cytochrome P-450 CYP3A/metabolism ; Glutathione/metabolism ; Humans ; Imines/metabolism ; Ketoconazole/metabolism ; Microsomes, Liver/metabolism ; *Omeprazole/metabolism/pharmacology ; Proton Pump Inhibitors/metabolism ; Rats ; }, abstract = {Omeprazole (OPZ) is a proton pump inhibitor commonly used for the treatment of gastric acid hypersecretion. Studies have revealed that use of OPZ can induce hepatotoxicity, but the mechanisms by which it induces liver injury are unclear. This study aimed to identify reactive metabolites of OPZ, determine the pathways of the metabolic activation, and define the correlation of the bioactivation with OPZ cytotoxicity. Quinone imine-derived glutathione (GSH), N-acetylcysteine (NAC), and cysteine (Cys) conjugates were detected in OPZ-fortified rat and human liver microsomal incubations captured with GSH, NAC, or Cys. The same GSH conjugates were detected in bile of rats and cultured liver primary cells after exposure to OPZ. Similarly, the same NAC conjugates were detected in urine of OPZ-treated rats. The resulting quinone imine was found to react with Cys residues of hepatic protein. CYP3A4 dominated the metabolic activation of OPZ. Exposure to OPZ resulted in decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole attenuated the susceptibility of hepatocytes to the cytotoxicity of OPZ.}, } @article {pmid35992575, year = {2022}, author = {du Preez, HN and Aldous, C and Kruger, HG and Johnson, L}, title = {N-Acetylcysteine and Other Sulfur-Donors as a Preventative and Adjunct Therapy for COVID-19.}, journal = {Advances in pharmacological and pharmaceutical sciences}, volume = {2022}, number = {}, pages = {4555490}, pmid = {35992575}, issn = {2633-4690}, abstract = {The airway epithelial glycocalyx plays an important role in preventing severe acute respiratory syndrome coronavirus 2 entry into the epithelial cells, while the endothelial glycocalyx contributes to vascular permeability and tone, as well as modulating immune, inflammatory, and coagulation responses. With ample evidence in the scientific literature that coronavirus disease 2019 (COVID-19) is related to epithelial and endothelial dysfunction, preserving the glycocalyx should be the main focus of any COVID-19 treatment protocol. The most studied functional unit of the glycocalyx is the glycosaminoglycan heparan sulfate, where the degree and position of the sulfate groups determine the biological activity. N-acetylcysteine (NAC) and other sulfur donors contribute to the inorganic sulfate pool, the rate-limiting molecule in sulfation. NAC is not only a precursor to glutathione but also converts to hydrogen sulfide, inorganic sulfate, taurine, Coenzyme A, and albumin. By optimising inorganic sulfate availability, and therefore sulfation, it is proposed that COVID-19 can be prevented or at least most of the symptoms attenuated. A comprehensive COVID-19 treatment protocol is needed to preserve the glycocalyx in both the prevention and treatment of COVID-19. The use of NAC at a dosage of 600 mg bid for the prevention of COVID-19 is proposed, but a higher dosage of NAC (1200 mg bid) should be administered upon the first onset of symptoms. In the severe to critically ill, it is advised that IV NAC should be administered immediately upon hospital admission, and in the late stage of the disease, IV sodium thiosulfate should be considered. Doxycycline as a protease inhibitor will prevent shedding and further degradation of the glycocalyx.}, } @article {pmid35989889, year = {2021}, author = {Hyppolite, JJ and Hilzenrat, N}, title = {Palbociclib-induced severe hepatitis: A case study and literature review.}, journal = {Canadian liver journal}, volume = {4}, number = {4}, pages = {433-437}, pmid = {35989889}, issn = {2561-4444}, abstract = {Palbociclib is a selective and reversible CDK4/6 inhibitor approved for patients presenting with HR+ HER2- locally advanced or metastatic breast cancer. Its adverse effect (AE) is mainly reported on the occurrence of leukopenia and fatigue. Even though palbociclib has an extensive hepatic metabolism, there are rare reports about significant liver toxicity. We present the case of a 61-year-old female with metastatic breast cancer treated with palbociclib and an aromatase inhibitor (letrozole). The patient developed a rare AE of severe acute drug-induced hepatitis but improved dramatically after stopping the palbociclib and receiving treatment with N-acetylcysteine (NAC). The treatment with NAC may be a proof of concept for the mechanism of palbociclib liver injury.}, } @article {pmid35987016, year = {2022}, author = {Kwak, AW and Park, JW and Lee, SO and Lee, JY and Seo, JH and Yoon, G and Lee, MH and Choi, JS and Shim, JH}, title = {Isolinderalactone sensitizes oxaliplatin-resistance colorectal cancer cells through JNK/p38 MAPK signaling pathways.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {105}, number = {}, pages = {154383}, doi = {10.1016/j.phymed.2022.154383}, pmid = {35987016}, issn = {1618-095X}, mesh = {Apoptosis ; Caspases ; Cell Line, Tumor ; *Colorectal Neoplasms ; Humans ; JNK Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System ; Oxaliplatin ; Reactive Oxygen Species ; *Sesquiterpenes ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {BACKGROUND: Isolinderalactone (ILL), a sesquiterpene lactone compound, can be extracted from the root of Lindera aggregate. Physiological activities of ILL, including anti-inflammatory and anti-proliferative effects, have been investigated in multiple diseases. Nevertheless, little is known regarding its anti-cancer activities and the mechanism of action of ILL in targeting human CRC cells.

PURPOSE: To determine ILL-mediated anti-proliferative effects on oxaliplatin (Ox)-sensitive and resistant colorectal cancer (CRC) cells and underlying mechanisms involved in its effects focusing on signal transduction.

METHODS: Inhibitory effect of ILL on CRC cells was evaluated by analyzing mitochondrial membrane potential (MMP) dysfunction and multi-caspase activity. Apoptosis-regulating proteins and JNK/p38 signaling molecules were monitored by Western blotting. ROS-dependent physiological modifications by ILL were confirmed by pretreatment with N-acetylcysteine (NAC). Moreover, the involvement of JNK/p38 signaling in ROS-mediated apoptosis was verified by treatment with SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor).

RESULTS: ILL decreased cell viability and colony formation in both CRC Ox-sensitive (HCT116 and HT29) and Ox-resistant (OxR) (HCT116-OxR and HT29-OxR) cells. ILL induced G2/M phase cell cycle arrest, ROS generation, phosphorylated (p)JNK/p38 MAPK activation, mitochondrial membrane potential (MMP) depolarization, and multi-caspase activation, which eventually triggered apoptotic cell death of CRC cells. In addition, combined treatment with ILL and SP600125, SB203580, or pan-caspase inhibitor (Z-VAD-FMK) prevented decreases in cell viability seen after treatment with ILL alone. Pretreatment with NAC attenuated ILL-mediated apoptosis, ROS production, and p-JNK/p38 expression.

CONCLUSION: Taken together, our results suggest that ILL can exert its anticancer effect in CRC Ox-sensitive and OxR cells by inducing ROS-mediated apoptosis through JNK/p38 MAPK signaling pathways. This is the first study demonstrating that ILL has a potential to improve drug efficacy against resistance mechanisms, providing a new insight into therapeutic strategies targeting drug-resistant CRC.}, } @article {pmid35986432, year = {2022}, author = {Wang, K and Chen, YS and Chien, HW and Chiou, HL and Yang, SF and Hsieh, YH}, title = {Melatonin inhibits NaIO3-induced ARPE-19 cell apoptosis via suppression of HIF-1α/BNIP3-LC3B/mitophagy signaling.}, journal = {Cell & bioscience}, volume = {12}, number = {1}, pages = {133}, pmid = {35986432}, issn = {2045-3701}, support = {110-2320-B-040-005-MY3//Ministry of Science and Technology, Taiwan/ ; }, abstract = {BACKGROUND: Age-related macular degeneration (AMD) leads to gradual central vision loss and eventual irreversible blindness. Melatonin, an endogenous hormone, exhibits anti-inflammatory and antitumor effects; however, the role it plays in AMD remains unclear. Herein, we investigated the anti-AMD molecular mechanism of melatonin after sodium iodate (NaIO3) treatment of ARPE-19 cells in vitro and in animal models with the goal of improving the therapeutic effect.

RESULTS: The in vitro results showed that melatonin protected against NaIO3-induced cell viability decline, mitochondrial dysfunction and apoptosis in ARPE-19 cells, and melatonin also alleviated NaIO3-induced reactive oxygen species (ROS) production, mitochondrial dysfunction and mitophagy activation. Melatonin reduced NaIO3-induced mitophagy activation through HIF-1α-targeted BNIP3/LC3B transcription, whereas ROS inhibition realized with N-acetylcysteine (NAC, a ROS inhibitor) combined with melatonin reduced the effect of NaIO3 on mitophagy. An animal model of AMD was established to confirm the in vitro data. Mouse tail vein injection of NaIO3 and melatonin was associated with enhanced repair of retinal layers within 7 days, as observed by optical coherence tomography (OCT) and hematoxylin and eosin (H&E) staining. A reduction in BNIP3 and HIF-1α levels, as determined by immunohistochemistry (IHC) assay, was also observed.

CONCLUSIONS: These results indicate that melatonin attenuated NaIO3-induced mitophagy of ARPE-19 cells via reduction in ROS-mediated HIF-1α targeted BNIP3/LC3B signaling in vitro and in vivo. Melatonin may be a potential therapeutic drug in the treatment of AMD.}, } @article {pmid35982963, year = {2022}, author = {Nazir, LA and Shahid, NH and Amit, K and Umar, SA and Rajni, S and Bharate, S and Sangwan, PL and Tasduq, SA}, title = {Synthesis and anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid against B16F10 cells via induction of endoplasmic reticulum stress-mediated autophagy through ERK/AKT signaling pathway.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {890299}, pmid = {35982963}, issn = {2234-943X}, abstract = {Melanoma is an aggressive form of cancer with poor prognosis and survival rates and limited therapeutic options. Here, we report the anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid (NPC-402), a derivative of glycyrrhtinic acid, from a reputed medicinal plant Glycyrrhiza glabra against B16F10 cells. We studied the cytotoxic effect of NPC-402 on melanoma cells and investigated the role of mitogen-activated protein (MAP) kinase, AKT axis, and endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated autophagy as the involved signaling cascade by studying specific marker proteins. In this study, 4-phenylbutyric acid (4PBA, a chemical chaperone) and small interference RNA (siRNA) knockdown of C/EBP Homologous Protein (CHOP)/growth arrest- and DNA damage-inducible gene 153(GAD153) blocked NPC-402-mediated autophagy induction, thus confirming the role of ER stress and autophagy in melanoma cell death. NPC-402 induced oxidative stress and apoptosis in melanoma cells, which were effectively mitigated by treatment with N-acetylcysteine (NAC). In vivo studies showed that intraperitoneal (i.p.) injection of NPC-402 at 10 mg/kg (5 days in 1 week) significantly retarded angiogenesis in the Matrigel plug assay and reduced the tumor size and tumor weight without causing any significant toxic manifestation in C57BL/6J mice. We conclude that NPC-402 has a high potential to be developed as a chemotherapeutic drug against melanoma.}, } @article {pmid35981484, year = {2022}, author = {Feng, Y and Yuan, H and Wang, W and Xu, Y and Zhang, J and Xu, H and Fu, F}, title = {Co-exposure to polystyrene microplastics and lead aggravated ovarian toxicity in female mice via the PERK/eIF2α signaling pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {243}, number = {}, pages = {113966}, doi = {10.1016/j.ecoenv.2022.113966}, pmid = {35981484}, issn = {1090-2414}, mesh = {Animals ; Eukaryotic Initiation Factor-2/metabolism ; Female ; Lead/toxicity ; Mammals/metabolism ; Mice ; Mice, Inbred C57BL ; *Microplastics ; Ovary/metabolism ; Plastics ; *Polystyrenes/metabolism/toxicity ; Signal Transduction ; }, abstract = {Generally, individual microplastics (MPs) or lead (Pb) exposure could initiate ovarian toxicity. However, their combined effects on the ovary and its mechanism in mammals remained unclear. Female C57BL/6 mice were used in this study to investigate the combined ovarian toxicity of polystyrene MPs (PS-MPs, 0.1 mg/d/mouse) and Pb (1 g/L) for 28 days. Results showed that co-exposure to PS-MPs and Pb increased the accumulation of Pb in ovaries, the histopathological damage in ovaries and uterus, the serum malondialdehyde levels and decreased serum superoxide dismutase and sex hormone levels significantly when compared with single PS-MPs and Pb exposure. These observations indicated that co-exposure exerted more severe toxicity to mouse ovaries and uterus. Furthermore, co-exposure to PS-MPs and Pb caused endoplasmic reticulum (ER) stress by activating the PERK/eIF2α signaling pathway in the ovary, which resulted in apoptosis. However, the oxidative and ovarian damage were alleviated, and the mRNA levels of genes related to the PERK/eIF2α signaling pathway were down-regulated to levels of the control mice in the PS-MPs and Pb co-exposed mice administered with ER stress inhibitor (Salubrinal, Sal) or the antioxidant (N-acetyl-cysteine, NAC). In conclusion, our findings suggested that the combination of PS-MPs and Pb aggravated ovarian toxicity in mice by inducing oxidative stress and activating the PERK/eIF2α signaling pathway, thereby providing a basis for future studies into the combined toxic mechanism of PS-MPs and Pb in mammals.}, } @article {pmid35975988, year = {2022}, author = {Shee, S and Singh, S and Tripathi, A and Thakur, C and Kumar T, A and Das, M and Yadav, V and Kohli, S and Rajmani, RS and Chandra, N and Chakrapani, H and Drlica, K and Singh, A}, title = {Moxifloxacin-Mediated Killing of Mycobacterium tuberculosis Involves Respiratory Downshift, Reductive Stress, and Accumulation of Reactive Oxygen Species.}, journal = {Antimicrobial agents and chemotherapy}, volume = {66}, number = {9}, pages = {e0059222}, pmid = {35975988}, issn = {1098-6596}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {2,2'-Dipyridyl/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase ; Cysteine ; Iron ; Iron Chelating Agents/pharmacology ; Mice ; Moxifloxacin/pharmacology ; *Mycobacterium tuberculosis ; NAD ; Reactive Oxygen Species/metabolism ; Sulfur/pharmacology ; Thiourea ; *Tuberculosis/microbiology ; }, abstract = {Moxifloxacin is central to treatment of multidrug-resistant tuberculosis. Effects of moxifloxacin on the Mycobacterium tuberculosis redox state were explored to identify strategies for increasing lethality and reducing the prevalence of extensively resistant tuberculosis. A noninvasive redox biosensor and a reactive oxygen species (ROS)-sensitive dye revealed that moxifloxacin induces oxidative stress correlated with M. tuberculosis death. Moxifloxacin lethality was mitigated by supplementing bacterial cultures with an ROS scavenger (thiourea), an iron chelator (bipyridyl), and, after drug removal, an antioxidant enzyme (catalase). Lethality was also reduced by hypoxia and nutrient starvation. Moxifloxacin increased the expression of genes involved in the oxidative stress response, iron-sulfur cluster biogenesis, and DNA repair. Surprisingly, and in contrast with Escherichia coli studies, moxifloxacin decreased expression of genes involved in respiration, suppressed oxygen consumption, increased the NADH/NAD[+] ratio, and increased the labile iron pool in M. tuberculosis. Lowering the NADH/NAD[+] ratio in M. tuberculosis revealed that NADH-reductive stress facilitates an iron-mediated ROS surge and moxifloxacin lethality. Treatment with N-acetyl cysteine (NAC) accelerated respiration and ROS production, increased moxifloxacin lethality, and lowered the mutant prevention concentration. Moxifloxacin induced redox stress in M. tuberculosis inside macrophages, and cotreatment with NAC potentiated the antimycobacterial efficacy of moxifloxacin during nutrient starvation, inside macrophages, and in mice, where NAC restricted the emergence of resistance. Thus, NADH-reductive stress contributes to moxifloxacin-mediated killing of M. tuberculosis, and the respiration stimulator (NAC) enhances lethality and suppresses the emergence of drug resistance.}, } @article {pmid35975308, year = {2023}, author = {Kumar, P and Liu, C and Suliburk, J and Hsu, JW and Muthupillai, R and Jahoor, F and Minard, CG and Taffet, GE and Sekhar, RV}, title = {Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {78}, number = {1}, pages = {75-89}, pmid = {35975308}, issn = {1758-535X}, support = {R01 AG041782/AG/NIA NIH HHS/United States ; R01AG041782/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; Aged ; *Acetylcysteine/pharmacology/metabolism ; Glycine/metabolism ; Health Promotion ; Oxidative Stress ; Aging/physiology ; Glutathione ; Dietary Supplements ; *Insulin Resistance/physiology ; Inflammation/drug therapy/metabolism ; Mitochondria/metabolism ; }, abstract = {BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure.

RESULTS: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects.

CONCLUSION: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.}, } @article {pmid35972898, year = {2023}, author = {Panwar, A and Vaidyanathan, S and Udupa, ST and Munoli, RN and Praharaj, SK}, title = {Anticraving Effect of N-Acetyl Cysteine in a Patient With Pregabalin and Alcohol Dependence.}, journal = {American journal of therapeutics}, volume = {30}, number = {6}, pages = {e597-e598}, doi = {10.1097/MJT.0000000000001544}, pmid = {35972898}, issn = {1536-3686}, mesh = {Humans ; *Alcoholism/complications/drug therapy ; Pregabalin/therapeutic use ; Acetylcysteine/therapeutic use ; }, } @article {pmid35968645, year = {2022}, author = {Rjiba-Touati, K and Ayed-Boussema, I and Hamdi, H and Azzebi, A and Abid, S}, title = {Bromuconazole fungicide induces cell cycle arrest and apoptotic cell death in cultured human colon carcinoma cells (HCT116) via oxidative stress process.}, journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals}, volume = {27}, number = {7}, pages = {659-670}, doi = {10.1080/1354750X.2022.2098378}, pmid = {35968645}, issn = {1366-5804}, mesh = {Humans ; *Fungicides, Industrial/toxicity ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; Acetylcysteine/metabolism ; Fluorescein-5-isothiocyanate/metabolism/pharmacology ; Cell Line, Tumor ; Cell Cycle Checkpoints ; Apoptosis ; Triazoles/toxicity ; Oxidative Stress ; Biomarkers/metabolism ; Colon/metabolism ; *Carcinoma/metabolism ; DNA ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND: Bromuconazole, a fungicide belonging to the triazole family, is a plant protection product used to control, repel or destroy fungi that may develop on crops. We investigated the pro-apoptotic effect of bromuconazole and the role of oxidative stress in the death mechanism induced by this fungicide in this study.

METHODS: The human colon HCT116 cell line was treated with Bromuconazole (IC50/4, IC50/2, and IC50) for 24 h. Cells were collected and analysed for biomarkers of apoptotic cell death and oxidative stress as well as for the assessment of genotoxic damage.

RESULTS: Our study showed that bromuconazole caused a concentration-dependent increase in cell mortality with an IC50 of 180 µM. Bromuconazole induced cell cycle arrest in the G0/G1 phase and DNA synthesis inhibition. The Comet assay showed that bromuconazole caused DNA damage in a concentration-dependent manner. Bromuconazole-induced apoptosis was observed by, Annexin-V/FITC-PI and BET/AO staining, by mitochondrial membrane depolarisation, and by increased caspase-3 activity. In addition, bromuconazole induced a significant increase in ROS and lipid peroxidation levels and a disruption in SOD and CAT activities. N-acetylcysteine (NAC) strongly prevents cytotoxic and genotoxic damage caused by bromuconazole.

CONCLUSION: Bromuconazole toxicity was through the oxidative stress process, which causes DNA damage and mitochondrial dysfunction, leading to cell cycle arrest and apoptotic death of HCT116 cells.}, } @article {pmid35965824, year = {2022}, author = {Zhou, Z and Dun, L and Xu, H and Yu, P and Chen, C and Si, T and An, H and Lu, J and Wei, B and Guo, D and Yang, Q and Zheng, N and Yi, P}, title = {The neuroprotective effect of YaoYi-moxibustion on ischemic stroke by attenuating NK-κB expression in rats.}, journal = {Annals of translational medicine}, volume = {10}, number = {14}, pages = {791}, pmid = {35965824}, issn = {2305-5839}, abstract = {BACKGROUND: Traditional Chinese medicine (TCM) has become a crucial direction for ischemic stroke treatment. This study sought to explore the underlying roles of YaoYi-moxibustion (YY-moxi) in ischemic stroke.

METHODS: A total of 75 Sprague-Dawley rats were randomly divided into the following 5 groups: (I) the sham-operated group; (II) the middle cerebral artery occlusion model (MCAO) group; (III) the YY-moxi group; (IV) the antioxidant (N-acetylcysteine, NAC) group; and (V) the NAC + YY-moxi group. After the model had been established, the NAC group received intracerebroventricular injections of NAC, the YY-moxi group received YY-moxi, and the NAC + YY-moxi group received a combination of these 2 interventions. The neurological deficit score was confirmed, and the cerebral infarction was examined by triphenyl tetrazolium chloride (TTC) staining. In the ischemia site of stroke, terminal deoxynucleotidyl transferase-mediated Dutp nick end labeling staining was applied to examine the apoptotic cells. Additionally, the apoptosis-associated genes and protein expressions in the ischemic brains were investigated by the reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), immunohistochemistry, and western blot analysis.

RESULTS: YY-moxi alone and YY-moxi combined with NAC significantly reduced the neurological scores and cerebral infarction area of the MCAO rats. Additionally, YY-moxi alone and the combined application of YY-moxi and NAC improved the pathological status of ischemic brain tissues. Further, we found that YY-moxi alone and YY-moxi in combination with NAC could enhanced the antioxidation ability and reduced the inflammatory response of the MCAO model rats. We also proved that YY-moxi alone and YY-moxi combined with NAC significantly suppressed apoptosis-related proteins in the MCAO model rats.

CONCLUSIONS: These findings indicate that YY-moxi exerts a protective effect on cerebral ischemic injury by reducing apoptosis. The study suggests that the mechanism may be related to its downregulating the expression of nuclear factor kappa B (NK-κB).}, } @article {pmid35965681, year = {2022}, author = {Yuan, S and Pan, Y and Xu, T and Zhang, L and Chen, X and Wang, F and Liu, Q and Jia, L}, title = {Daurisoline Inhibits ESCC by Inducing G1 Cell Cycle Arrest and Activating ER Stress to Trigger Noxa-Dependent Intrinsic and CHOP-DR5-Dependent Extrinsic Apoptosis via p-eIF2α-ATF4 Axis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5382263}, pmid = {35965681}, issn = {1942-0994}, mesh = {Activating Transcription Factor 4/metabolism ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins ; Benzylisoquinolines ; Cell Line, Tumor ; *Esophageal Neoplasms ; *Esophageal Squamous Cell Carcinoma/drug therapy/metabolism ; Eukaryotic Initiation Factor-2/metabolism ; G1 Phase Cell Cycle Checkpoints ; Humans ; Mice ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Esophageal squamous cell carcinoma (ESCC), one of the most malignant human cancers in clinic, requires novel treatment. Daurisoline (DAS) is a component of traditional Chinese herb, which exhibits anti-cancer effects by autophagy inhibition and metastasis suppression. However, the effect and mechanism of DAS on ESCC remain unclear. Here, we found that DAS inhibited cell proliferation and colony formation in both human ESCC cell lines EC1 and ECA109. Mechanistically, DAS induced p21-/p27-dependent G1 phase cell cycle arrest and apoptosis in a dose-dependent manner. The induction of apoptosis by DAS was largely dependent on the activation of the transcription factor ATF4 and its downstream NOXA-dependent intrinsic and CHOP-DR5-dependent extrinsic apoptotic pathway. ATF4 activation induced by DAS was due to the generation of excessive reactive oxygen species (ROS) and the subsequent activation of endoplasmic reticulum (ER) stress through the p-eIF2α-ATF4 signal pathway, which can be largely abrogated by N-acetylcysteine (NAC), a scavenger of ROS. Moreover, DAS treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model by up-regulating key proteins related to cell cycle arrest and apoptotic pathway. Taken together, these findings identified DAS as a novel candidate for the treatment of ESCC.}, } @article {pmid35963952, year = {2022}, author = {Tandra, HV and Rupakumar, T and Vijayasekharan, K and V R, P and C S, G and T, PK}, title = {A stitch in time saves nine: timely use of N-acetyl cysteine (NAC) for chemotherapy-induced veno-occlusive disease (VOD)-is it a cost-effective alternative?.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {30}, number = {11}, pages = {8611-8614}, pmid = {35963952}, issn = {1433-7339}, mesh = {Child ; Humans ; Polydeoxyribonucleotides/pharmacology ; *Hepatic Veno-Occlusive Disease/therapy/drug therapy ; Cost-Benefit Analysis ; Acetylcysteine/therapeutic use ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Vascular Diseases/drug therapy/etiology ; *Antineoplastic Agents/adverse effects ; }, abstract = {Chemotherapy-induced veno-occlusive disease (VOD) is a rare liver dysfunction seen among pediatric cancer patients which could lead to severe morbidity and mortality. Defibrotide is the commonly used antidote in the management of both stem cell transplant and chemotherapy-associated VOD along with liver supportive measures. Defibrotide is costly and generally not accessible to majority of patients treated at resource poor settings. In this report, we describe the successful management of chemotherapy-induced VOD with timely administration of N-acetyl cysteine.}, } @article {pmid35956786, year = {2022}, author = {Thalappil, MA and Butturini, E and Carcereri de Prati, A and Bettin, I and Antonini, L and Sapienza, FU and Garzoli, S and Ragno, R and Mariotto, S}, title = {Pinus mugo Essential Oil Impairs STAT3 Activation through Oxidative Stress and Induces Apoptosis in Prostate Cancer Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {15}, pages = {}, pmid = {35956786}, issn = {1420-3049}, support = {RM11916B8876093E, RM120172B8EB30C5, RM12117A89F5B8BB//Sapienza University of Rome/ ; }, mesh = {*Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Glutathione/metabolism ; Humans ; Male ; *Oils, Volatile/pharmacology/therapeutic use ; Oxidative Stress ; *Pinus/metabolism ; *Plant Oils/pharmacology/therapeutic use ; *Prostatic Neoplasms/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *STAT3 Transcription Factor/genetics/metabolism ; }, abstract = {Essential oils (EOs) and their components have been reported to possess anticancer properties and to increase the sensitivity of cancer cells to chemotherapy. The aim of this work was to select EOs able to downregulate STAT3 signaling using Western blot and RT-PCR analyses. The molecular mechanism of anti-STAT3 activity was evaluated through spectrophotometric and fluorometric analyses, and the biological effect of STAT3 inhibition was analyzed by flow cytometry and wound healing assay. Herein, Pinus mugo EO (PMEO) is identified as an inhibitor of constitutive STAT3 phosphorylation in human prostate cancer cells, DU145. The down-modulation of the STAT3 signaling cascade decreased the expression of anti-proliferative as well as anti-apoptotic genes and proteins, leading to the inhibition of cell migration and apoptotic cell death. PMEO treatment induced a rapid drop in glutathione (GSH) levels and an increase in reactive oxygen species (ROS) concentration, resulting in mild oxidative stress. Pretreatment of cells with N-acetyl-cysteine (NAC), a cell-permeable ROS scavenger, reverted the inhibitory action of PMEO on STAT3 phosphorylation. Moreover, combination therapy revealed that PMEO treatment displayed synergism with cisplatin in inducing the cytotoxic effect. Overall, our data highlight the importance of STAT3 signaling in PMEO cytotoxic activity, as well as the possibility of developing adjuvant therapy or sensitizing cancer cells to conventional chemotherapy.}, } @article {pmid35956498, year = {2022}, author = {Picchi, V and Calzone, A and Gobbi, S and Paccani, S and Lo Scalzo, R and Marti, A and Faoro, F}, title = {Oxidative Stress Mitigation by Chitosan Nanoparticles in Durum Wheat Also Affects Phytochemicals and Technological Quality of Bran and Semolina.}, journal = {Plants (Basel, Switzerland)}, volume = {11}, number = {15}, pages = {}, pmid = {35956498}, issn = {2223-7747}, support = {ID052- Project NA-NOTOX//Ministry of Agricultural, Food and Forestry Policies/ ; }, abstract = {In our previous work, durum wheat cv. Fabulis was grown over two consecutive seasons (2016-2017 and 2017-2018) in an experimental field in the north of Italy. With the aim of mitigating oxidative stress, plants were subjected to four treatments (deionized water, CHT 0.05 mg/mL, CHT-NPs, and CHT-NPs-NAC) three times during the experiment. Chitosan nanoparticles (CHT-NPs) reduced symptom severity on wheat leaves and positively influenced the final grain yield. The present work aimed at investigating whether CHT treatments and particularly N-acetyl cysteine (NAC)-loaded or -unloaded CHT-NPs, while triggering plant defense mechanisms, might also vary the nutritional and technological quality of grains. For this purpose, the grains harvested from the previous experiment were analyzed for their content in phytochemicals and for their technological properties. The results showed that CHT increased the polyphenol and tocopherol content and the reducing capacity of bran and semolina, even if the positive effect of the nano-formulation remained still unclear and slightly varied between the two years of cultivation. The positive effect against oxidative stress induced by the chitosan treatments was more evident in the preservation of both the starch pasting properties and gluten aggregation capacity, indicating that the overall technological quality of semolina was maintained. Our data confirm the role of chitosan as an elicitor of the antioxidant defense system in wheat also at the grain level.}, } @article {pmid35955744, year = {2022}, author = {Sinha, BK and Tokar, EJ and Bortner, CD}, title = {Molecular Mechanisms of Cytotoxicity of NCX4040, the Non-Steroidal Anti-Inflammatory NO-Donor, in Human Ovarian Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {15}, pages = {}, pmid = {35955744}, issn = {1422-0067}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; *Antineoplastic Agents/pharmacology ; Aspirin/analogs & derivatives ; Carcinoma, Ovarian Epithelial ; Doxorubicin/pharmacology ; Female ; Humans ; Nitro Compounds ; *Ovarian Neoplasms/pathology ; Peroxynitrous Acid ; Reactive Nitrogen Species ; Reactive Oxygen Species ; }, abstract = {NCX4040, the non-steroidal anti-inflammatory-NO donor, is cytotoxic to several human tumors, including ovarian tumor cells. We have found that NCX4040 is also cytotoxic against both OVCAR-8 and its adriamycin resistant (NCI/ADR-RES) tumor cell lines. Here, we have examined mechanism(s) for the cytotoxicity of NCX4040 in OVCAR-8 and NCI/ADR-RES cell lines. We found that NCX4040 induced significant apoptosis in both cell lines. Furthermore, NCX4040 treatment caused significant depletion of cellular glutathione, causing oxidative stress due to the formation of reactive oxygen/nitrogen species (ROS/RNS). Significantly more ROS/RNS were detected in OVCAR-8 cells than in NCI/ADR-RES cells which may have resulted from increased activities of SOD, glutathione peroxidase and transferases expressed in NCI/ADR-RES cells. NCX4040 treatment resulted in the formation of double-strand DNA breaks in both cells; however, more of these DNA breaks were detected in OVCAR-8 cells. RT-PCR studies indicated that NCX4040-induced DNA damage was not repaired as efficiently in NCI/ADR-RES cells as in OVCAR-8 cells which may lead to a differential cell death. Pretreatment of OVCAR-8 cells with N-acetylcysteine (NAC) significantly decreased cytotoxicity of NCX4040 in OVCAR-8 cells; however, NAC had no effects on NCX4040 cytotoxicity in NCI/ADR-RES cells. In contrast, FeTPPS, a peroxynitrite scavenger, completely blocked NCX4040-induced cell death in both cells, suggesting that NCX4040-induced cell death could be mediated by peroxynitrite formed from NCX4040 following cellular metabolism.}, } @article {pmid35952519, year = {2022}, author = {Blum, AW and Grant, JE}, title = {N-acetylcysteine in the treatment of compulsive sexual behavior disorder: A case series.}, journal = {Journal of psychiatric research}, volume = {154}, number = {}, pages = {203-206}, doi = {10.1016/j.jpsychires.2022.07.066}, pmid = {35952519}, issn = {1879-1379}, mesh = {*Acetylcysteine/therapeutic use ; Compulsive Behavior/drug therapy ; Glutamic Acid ; Humans ; Male ; Sexual Behavior ; *Sexual Dysfunctions, Psychological ; }, abstract = {Although compulsive sexual behavior disorder (CSBD) is a relatively common disorder with an estimated prevalence of at least 3%, clinicians currently have limited evidence and no FDA-approved drugs to guide their treatment of this condition. N-acetylcysteine (NAC), an amino acid that seems to restore extracellular levels of glutamate in the nucleus accumbens, has previously demonstrated efficacy in treating multiple psychiatric disorders, including substance use disorders and putative behavioral addictions. However, no study has assessed the use of NAC (or any other glutamatergic agent, for that matter) in the treatment of CSBD. Here, we present data from a case series of 8 male patients with CSBD treated with NAC in routine clinical practice in a specialty outpatient clinic. Of these 8 patients, all of whom had previously been treated for CSBD with medications, therapy, or both, 5 had marked clinical improvement (>35% improvement on a modified version of Yale-Brown Obsessive Compulsive Scale) on NAC, and 3 showed minimal or no improvement (<15%). These findings suggest that NAC may be a potentially promising, well-tolerated treatment option for patients with CSBD, including those who have failed more traditional therapies.}, } @article {pmid35948106, year = {2022}, author = {Zhang, M and Chen, J and Jiang, Y and Chen, T}, title = {Fine particulate matter induces heart defects via AHR/ROS-mediated endoplasmic reticulum stress.}, journal = {Chemosphere}, volume = {307}, number = {Pt 2}, pages = {135962}, doi = {10.1016/j.chemosphere.2022.135962}, pmid = {35948106}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Butylamines ; Cardiotoxicity ; Endoplasmic Reticulum Stress ; *Heart Defects, Congenital ; *Hydrocarbons, Aromatic/metabolism ; Particulate Matter/pharmacology ; Pharmaceutical Preparations/metabolism ; Reactive Oxygen Species/metabolism ; Zebrafish/metabolism ; }, abstract = {Accumulating body of evidence indicates that exposure to fine particulate matter (PM2.5) is closely associated with congenital heart disease in the offspring, but the underlying molecular mechanisms remain to be elucidated. We previously reported that extractable organic matter (EOM) from PM2.5 induces reactive oxygen species (ROS) overproduction by activating aromatic hydrocarbon receptor (AHR), leading to heart defects in zebrafish embryos. We hypothesized that endoplasmic reticulum (ER) stress might be elicited by the excessive ROS production and thereby contribute to the cardiac developmental toxicity of PM2.5. In this study, we examined the effects of EOM on endoplasmic reticulum (ER) stress, apoptosis, and Wnt signal pathway in zebrafish embryos, and explored their roles in EOM-induced heart defects. Our results showed that 4-Phenylbutyric acid (4-PBA), a pharmaceutical inhibitor of ER stress, significantly attenuated the EOM-elevated heart malformation rates. Moreover, EOM upregulated the expression levels of ER stress marker genes including CHOP and PDI in the heart of zebrafish embryos, which were counteracted by genetic or pharmaceutical inhibition of AHR activity. The ROS scavenger N-Acetyl-l-cysteine (NAC) also abolished the EOM-induced ER stress. We further demonstrated that both 4-PBA and CHOP genetic knockdown rescued the PM2.5-induced ROS overproduction, apoptosis and suppression of Wnt signaling. In conclusion, our results indicate that PM2.5 induces AHR/ROS-mediated ER stress, which leads to apoptosis and Wnt signaling inhibition, ultimately resulting in heart defects.}, } @article {pmid35946140, year = {2023}, author = {do Amaral, GCLS and Hassan, MA and Sloniak, MC and Pannuti, CM and Romito, GA and Villar, CC}, title = {Effects of antimicrobial mouthwashes on the human oral microbiome: Systematic review of controlled clinical trials.}, journal = {International journal of dental hygiene}, volume = {21}, number = {1}, pages = {128-140}, doi = {10.1111/idh.12617}, pmid = {35946140}, issn = {1601-5037}, mesh = {Adult ; Humans ; *Anti-Infective Agents/pharmacology/therapeutic use ; *Anti-Infective Agents, Local/therapeutic use ; Chlorhexidine/therapeutic use ; *Dental Plaque/drug therapy ; *Microbiota ; Mouthwashes/therapeutic use ; Phylogeny ; Controlled Clinical Trials as Topic ; }, abstract = {OBJECTIVES: This review aimed to assess the impact of mouthwashes on the composition of the human oral microbiome.

METHOD: An electronic search algorithm was adapted to MEDLINE-PubMed, Scopus, Embase and ISI Web of Science, and reference lists of relevant sources were manually searched. Inclusion criteria were controlled clinical trials published in English whose population were adult individuals who rinse with antimicrobial mouthwashes and that analysed changes in the oral microbiome by metataxonomy, metagenomics or phylogenetic microarray. Identified studies were screened and assessed following the PRISMA guidelines, and results were compiled into qualitative synthesis of the evidence.

RESULTS: Five controlled clinical studies were included. These studies found associations between the daily use of mouthwashes and changes in the oral microbiome, but the nature of the effect varied according to the mouthwash. Chlorhexidine (CHX) rinses lowered microbial diversity. While 7-day use of CHX led to increases in the abundance of Neisseria, Streptococcus and Granulicatella and a decrease in the abundance of Actinomyces, its prolonged use led to widespread reductions in several genera and species. Cetylpyridinium chloride-containing mouthwashes specifically lowered the abundance of gingivitis-associated genera. In contrast, N-acetyl cysteine-based mouthwashes did not promote changes in the oral microbiome.

CONCLUSIONS: Despite substantial heterogeneity, we found evidence to support the hypothesis that CHX and CPC mouthwashes promote changes in oral microbial structure and/or reductions in community diversity that favour the resolution of dysbiosis. However, future large population-based studies of adequate duration are needed to fully understand the extent to which antimicrobial mouthwashes modulate the microbiome.}, } @article {pmid35945549, year = {2022}, author = {Liu, X and Jiang, M and Pang, C and Wang, J and Hu, L}, title = {Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.}, journal = {BMC cancer}, volume = {22}, number = {1}, pages = {870}, pmid = {35945549}, issn = {1471-2407}, mesh = {Animals ; Apoptosis ; *Carcinoma, Renal Cell/drug therapy ; Cell Line, Tumor ; Cell Proliferation ; Humans ; *Kidney Neoplasms/drug therapy ; Mice ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Sodium Selenite/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study.

METHODS: ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo.

RESULTS: Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo.

CONCLUSION: These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-κB signaling in renal cancer cells.}, } @article {pmid35940529, year = {2022}, author = {Pan, T and Qi, J and Tang, Y and Yao, Y and Chen, J and Wang, H and Yang, J and Xu, X and Shi, Q and Liu, Y and He, X and Chen, F and Ma, X and Hu, X and Wu, X and Wu, D and Han, Y}, title = {N-Acetylcysteine as Prophylactic Therapy for Transplantation-Associated Thrombotic Microangiopathy: A Randomized, Placebo-Controlled Trial.}, journal = {Transplantation and cellular therapy}, volume = {28}, number = {11}, pages = {764.e1-764.e7}, doi = {10.1016/j.jtct.2022.07.029}, pmid = {35940529}, issn = {2666-6367}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Prospective Studies ; Retrospective Studies ; *Thrombotic Microangiopathies/drug therapy ; *Hematopoietic Stem Cell Transplantation/adverse effects ; }, abstract = {Transplantation-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication for patients undergoing hematopoietic stem cell transplantation (HSCT). N-acetylcysteine (NAC) has recently been considered as a potential treatment for patients with thrombotic thrombocytopenic purpura. To assess the value of NAC for the prevention of TA-TMA, we conducted a prospective study at the First Affiliated Hospital of Soochow University. This open-label, randomized placebo-controlled trial included 160 patients who were scheduled for allogeneic HSCT. Participants were assigned at random 1:1 to either oral NAC (50 mg/kg/day from 9 days before HSCT to 30 days after HSCT) or placebo treatment. The primary outcome was the incidence of TA-TMA. Overall survival (OS) and event-free survival (EFS) were assessed in the NAC and placebo control groups. The incidence of TA-TMA was 9.1% (95% confidence interval [CI], 2% to 16.2%) in the NAC group, compared with 23% (95% CI, 13.2% to 32.8%) in the control group, with a rate ratio of .34 (95% CI, .123 to .911; P = .039). The median time to the onset of TA-TMA was 60 days (interquartile range [IQR], 42 to 129 days) in the NAC group and 36 days (IQR, 30.5 to 51 days) in the control group (P = .063). The 2-year OS rate was 75.4% (95% CI, 28.65% to 73.53%) in the NAC group and 63.0% (95% CI, 50.8% to 73.5%) in the control group, with a hazard ratio (HR) of .622 (95% CI, .334-1.155; P = .132). The EFS rate was 25.8% in the NAC patients and 8.1% in controls (HR, .254; 95% CI, .094 to .692; P = .024). The median time of EFS was 60 days in the NAC group and 38 days in controls. Our findings suggest that NAC may be a potential treatment to reduce the incidence of TA-TMA.}, } @article {pmid35938960, year = {2022}, author = {Park, C and Cha, HJ and Lee, H and Jeong, JW and Han, M and Song, KS and Kim, GY and Chang, YC and Leem, SH and Hyun, JW and Kim, HS and Hong, SH and Choi, YH}, title = {Induction of apoptosis through inactivation of ROS-dependent PI3K/Akt signaling pathway by platycodin D in human bladder urothelial carcinoma cells.}, journal = {General physiology and biophysics}, volume = {41}, number = {4}, pages = {263-274}, doi = {10.4149/gpb_2022013}, pmid = {35938960}, issn = {0231-5882}, mesh = {Apoptosis ; *Carcinoma, Transitional Cell ; Humans ; Phosphatidylinositol 3-Kinase/metabolism/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; *Saponins/pharmacology ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; *Triterpenes/pharmacology ; Urinary Bladder/metabolism ; *Urinary Bladder Neoplasms/drug therapy/metabolism/pathology ; }, abstract = {Platycodin D (PD) is a triterpenoid saponin, a major bioactive constituent of the roots of Platycodon grandiflorum, which is well known for possessing various pharmacological properties. However, the anti-cancer mechanism of PD in bladder cancer cells remains poorly understood. In the current study, we investigated the effect of PD on the growth of human bladder urothelial carcinoma cells. PD treatment significantly reduced the cell survival of bladder cancer cells associated with induction of apoptosis and DNA damage. PD inhibited the expression of inhibitor of apoptosis family members, activated caspases, and induced cleavage of poly (ADP-ribose) polymerase. PD also increased the release of cytochrome c into the cytoplasm by disrupting the mitochondrial membrane potential while upregulating the expression ratio of Bax to Bcl-2. The PD-mediated anti-proliferative effect was significantly inhibited by pre-treatment with a pancaspase inhibitor, but not by an inhibitor of necroptosis. Moreover, PD suppressed the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and the apoptosis-inducing effect of PD was further enhanced by a PI3K inhibitor. In addition, PD increased the accumulation of reactive oxygen species (ROS), whereas N-acetyl cysteine (NAC), an ROS inhibitor, significantly attenuated the growth inhibition and inactivation of the PI3K/Akt/mTOR signaling caused by PD. Furthermore, NAC significantly suppressed apoptosis, DNA damage, and decreased cell viability induced by PD treatment. Collectively, our findings indicated that PD blocked the growth of bladder urothelial carcinoma cells by inducing ROS-mediated inactivation of the PI3K/Akt/mTOR signaling.}, } @article {pmid35938289, year = {2022}, author = {Kelley, RC and Lapierre, SS and Muscato, DR and Hahn, D and Christou, DD and Ferreira, LF}, title = {Cardiac and respiratory muscle responses to dietary N-acetylcysteine in rats consuming a high-saturated fat, high-sucrose diet.}, journal = {Experimental physiology}, volume = {107}, number = {11}, pages = {1312-1325}, pmid = {35938289}, issn = {1469-445X}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; R01 HL130318/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Male ; Rats ; *Acetylcysteine/therapeutic use ; Antioxidants/therapeutic use ; Diet, High-Fat ; Fatty Acids ; Obesity ; Rats, Wistar ; Respiratory Muscles ; *Sucrose ; }, abstract = {NEW FINDINGS: What is the central question of this study? This study addresses whether a high-fat, high-sucrose diet causes cardiac and diaphragm muscle abnormalities in male rats and whether supplementation with the antioxidant N-acetylcysteine reverses diet-induced dysfunction. What is the main finding and its importance? N-Acetylcysteine attenuated the effects of high-fat, high-sucrose diet on markers of cardiac hypertrophy and diastolic dysfunction, but neither high-fat, high-sucrose diet nor N-acetylcysteine affected the diaphragm. These results support the use of N-acetylcysteine to attenuate cardiovascular dysfunction induced by a 'Western' diet.

ABSTRACT: Individuals with overweight or obesity display respiratory and cardiovascular dysfunction, and oxidative stress is a causative factor in the general aetiology of obesity and of skeletal and cardiac muscle pathology. Thus, this preclinical study aimed to define diaphragmatic and cardiac morphological and functional alterations in response to an obesogenic diet in rats and the therapeutic potential of an antioxidant supplement, N-acetylcysteine (NAC). Young male Wistar rats consumed ad libitum a 'lean' or high-saturated fat, high-sucrose (HFHS) diet for ∼22 weeks and were randomized to control or NAC (2 mg/ml in the drinking water) for the last 8 weeks of the dietary intervention. We then evaluated diaphragmatic and cardiac morphology and function. Neither HFHS diet nor NAC supplementation affected diaphragm-specific force, peak power or morphology. Right ventricular weight normalized to estimated body surface area, left ventricular fractional shortening and posterior wall maximal shortening velocity were higher in HFHS compared with lean control animals and not restored by NAC. In HFHS rats, the elevated deceleration rate of early transmitral diastolic velocity was prevented by NAC. Our data showed that the HFHS diet did not compromise diaphragmatic muscle morphology or in vitro function, suggesting other possible contributors to breathing abnormalities in obesity (e.g., abnormalities of neuromuscular transmission). However, the HFHS diet resulted in cardiac functional and morphological changes suggestive of hypercontractility and diastolic dysfunction. Supplementation with NAC did not affect diaphragm morphology or function but attenuated some of the cardiac abnormalities in the rats receiving the HFHS diet.}, } @article {pmid35924425, year = {2022}, author = {Ruan, S and Zha, L}, title = {Moronic acid improves intestinal inflammation in mice with chronic colitis by inhibiting intestinal macrophage polarization.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {11}, pages = {e23188}, doi = {10.1002/jbt.23188}, pmid = {35924425}, issn = {1099-0461}, support = {82000495//National Natural Science Foundation of China/ ; 2022AD30019//Science and Technology Project of Jiaxing/ ; }, mesh = {Mice ; Animals ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species ; *Colitis/chemically induced/drug therapy/metabolism ; Cytokines/metabolism ; Macrophages/metabolism ; Lipopolysaccharides/toxicity ; *Inflammatory Bowel Diseases ; Inflammation/drug therapy ; }, abstract = {This study focuses on exploring the role and mechanism of moronic acid (MOA), a small triterpenoid molecule, against inflammatory bowel disease (IBD). Intestinal macrophages were cultured in vitro, and their M1 polarization was induced by lipopolysaccharide (LPS) and interferon gamma (IFN-γ). After intervention with MOA, the proportion of M1 macrophages was detected, and the levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) were examined by ELISA. IFA staining was performed to determine the P50 and CD86 expressions, while DCFH-DA was used to determine the reactive oxygen species (ROS) level, as well as the p-P50 and NLRP3 protein levels. Additionally, we also used N-acetylcysteine, a ROS inhibitor, to further explore the association between MOA and ROS-NF-κB signaling. In murine experimentation, colitis was induced in mice with DSS. After MOA intervention, we assessed the mucosal barrier damage, tissue ROS, as well as protein and inflammatory cytokine levels. MOA could inhibit the M1 polarization of intestinal macrophages, suppress the expressions of inflammatory cytokines, and reduce the level of ROS-NF-κB-NLRP3 signaling. After inhibiting ROS through NAC treatment, the effect of MOA was evidently weakened. Clearly, MOA exerted its activity via ROS. In the murine model, MOA could lower the CD86 level in the intestinal tissues, inhibit the M1 polarization of macrophages, and reduce the tissue levels of inflammatory cytokines. This study finds that MOA can regulate ROS-NF-κB-NLRP3 signaling by inhibiting ROS, thereby suppressing the M1 polarization of intestinal macrophages, which plays a protective role in IBD.}, } @article {pmid35921555, year = {2023}, author = {Datta, S and Cano, M and Satyanarayana, G and Liu, T and Wang, L and Wang, J and Cheng, J and Itoh, K and Sharma, A and Bhutto, I and Kannan, R and Qian, J and Sinha, D and Handa, JT}, title = {Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.}, journal = {Autophagy}, volume = {19}, number = {3}, pages = {966-983}, pmid = {35921555}, issn = {1554-8635}, support = {R01 EY031594/EY/NEI NIH HHS/United States ; P30 EY006360/EY/NEI NIH HHS/United States ; K99 EY029010/EY/NEI NIH HHS/United States ; P30 EY001765/EY/NEI NIH HHS/United States ; R01 EY027691/EY/NEI NIH HHS/United States ; R00 EY029010/EY/NEI NIH HHS/United States ; R01 EY033765/EY/NEI NIH HHS/United States ; P30 EY008098/EY/NEI NIH HHS/United States ; }, mesh = {Humans ; Aged ; Mitophagy/genetics ; Autophagy ; Thioredoxin Reductase 1 ; Antioxidants ; Acetylcysteine ; *Dendrimers ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Retinal Pigment Epithelium ; *Macular Degeneration ; Phosphatidylinositol 3-Kinase ; Basic-Leucine Zipper Transcription Factors ; Amines ; Retinal Pigments ; Serine ; }, abstract = {Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial (RPE) cell heterogeneity is a well-recognized but understudied pathogenic factor. Due to the daily phagocytosis of photoreceptor outer segments, unique photo-oxidative stress, and high metabolism for maintaining vision, the RPE has robust macroautophagy/autophagy, and mitochondrial and antioxidant networks. However, the autophagy subtype, mitophagy, in the RPE and AMD is understudied. Here, we found decreased PINK1 (PTEN induced kinase 1) in perifoveal RPE of early AMD eyes. PINK1-deficient RPE have impaired mitophagy and mitochondrial function that triggers death-resistant epithelial-mesenchymal transition (EMT). This reprogramming is mediated by novel retrograde mitochondrial-nuclear signaling (RMNS) through superoxide, NFE2L2 (NFE2 like bZIP transcription factor 2), TXNRD1 (thioredoxin reductase 1), and phosphoinositide 3-kinase (PI3K)-AKT (AKT serine/threonine kinase) that induced canonical transcription factors ZEB1 (zinc finger E-box binding homeobox 1) and SNAI1 (Snail family transcriptional repressor 1) and an EMT transcriptome. NFE2L2 deficiency disrupted RMNS that paradoxically normalized morphology but decreased function and viability. Thus, RPE heterogeneity is defined by the interaction of two cytoprotective pathways that is triggered by mitophagy function. By neutralizing the consequences of impaired mitophagy, an antioxidant dendrimer tropic for the RPE and mitochondria, EMT (a recognized AMD alteration) was abrogated to offer potential therapy for early AMD, a stage without treatment.Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; AMD: age-related macular degeneration; CCCP: cyanide m-chlorophenyl hydrazone; CDH1: cadherin 1; DAVID: Database for Annotation, Visualization and Integrated Discovery; DHE: dihydroethidium; D-NAC: N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSEA: Gene Set Enrichment Analysis; HSPD1: heat shock protein family D (Hsp60) member 1; IVT: intravitreal; KD: knockdown; LMNA, lamin A/C; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NAC: N-acetyl-l-cysteine; NQO1: NAD(P)H quinone dehydrogenase 1; NFE2L2: NFE2 like bZIP transcription factor 2; O2[-]: superoxide anion; OCR: oxygen consumption rate; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; RMNS: retrograde mitochondrial-nuclear signaling; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SNAI1: snail family transcriptional repressor 1; TJP1: tight junction protein 1; TPP-D-NAC: triphenyl phosphinium and N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; Trig: trigonelline; TXNRD1: thioredoxin reductase 1; VIM: vimentin; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.}, } @article {pmid35917249, year = {2022}, author = {Gilli, M and Hollaert, TG and Setbon, HM and des Rieux, A and Leprince, JG}, title = {Quality of Cure in Depth of Commercially Available Bulk-fill Composites: A Layer-by-layer Mechanical and Biological Evaluation.}, journal = {Operative dentistry}, volume = {47}, number = {4}, pages = {437-448}, doi = {10.2341/21-084-L}, pmid = {35917249}, issn = {1559-2863}, mesh = {*Composite Resins/chemistry/therapeutic use ; Culture Media, Conditioned ; *Dental Materials/chemistry ; Humans ; Materials Testing ; Polymerization ; Viscosity ; }, abstract = {Despite their popularity, the use of bulk-fill composites remains controversial, both in terms of their properties and their in-depth development. The objectives of the present work were (1) to provide a more comprehensive evaluation of the quality of cure in depth of commercially available bulk-fill composites by combining various key mechanical and biological characterization methods, (2) to evaluate the inter-material differences when optimally cured, and (3) to evaluate the efficiency of an antioxidant-N-acetyl-cysteine (NAC)-to restrain the adverse effects of the leached components on cell viability. Nine bulk-fill composites (including flowable and high-viscosity materials) were investigated and compared to two conventional resin-based composites, one flowable and one high-viscosity restorative material. The materials were injected or packed into Teflon molds of various configurations, up to 6 mm material thickness. They were then light-cured from the top for 20 seconds with Bluephase G2 (Ivoclar Vivadent, irradiance = 1050 mW/cm2). The following physico-mechanical properties were measured for the upper (0-2 mm), intermediate (2-4 mm), and lower (4-6 mm) layers: degree of conversion using Raman Spectrometry (DC, in %), microhardness using a Vickers micro-indenter before (VHN dry) and after 24 hours of storage in ethanol (VHN EtOH), and flexural strength (in MPa) and flexural modulus (in GPa) using a three-point bend test. Each composite layer and an uncured layer were also stored for one week in a standard cell growth medium to generate conditioned media. Human dental pulp cells were then cultured for 24 hours with the latter and cell viability was measured using an MTS assay. A similar experiment was repeated with conditioned media produced in contact with uncured composites, with and without the addition of 4 mM NAC. The data were subjected to a Shapiro-Wilk test, then one-way ANOVA or Kruskal-Wallis test, followed either by Tukey's test (inter-material comparison) or by Dunnett's or Dunn's test (comparison between layers relative to the upper one). The level of statistical significance was set at 0.05. Some materials (EverX, X-traF, VenusBF, X-traB) did not show any significant differences (p>0.05) for any of the properties considered between the intermediate layers compared to the upper one (considered as reference). Others displayed significant differences, at least for some properties, highlighting the value of combining various key mechanical and biological characterization methods when investigating the quality of cure in depth. Significant inter-material differences (p<0.05) were observed when comparing the properties of their upper layer, considered as "optimally" polymerized. Hence, one needs to consider the absolute property values, not only their relative evolution concerning layer thickness. Finally, the use of NAC appeared as beneficial to reduce the risk of harmful effects to dental pulp cells, especially in case of excessive thickness use, and may therefore be of potential interest as an additive to composites in the future.}, } @article {pmid35911996, year = {2022}, author = {Li, Y and Yu, H and Zhou, X and Jin, L and Li, W and Li, GL and Shen, X}, title = {Multiple Sevoflurane Exposures During the Neonatal Period Cause Hearing Impairment and Loss of Hair Cell Ribbon Synapses in Adult Mice.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {945277}, pmid = {35911996}, issn = {1662-4548}, abstract = {OBJECTIVES: This study aims to investigate the effects of multiple sevoflurane exposures in neonatal mice on hearing function in the later life and explores the underlying mechanisms and protective strategies.

MATERIALS AND METHODS: Neonatal Kunming mice were exposed to sevoflurane for 3 days. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) tests, immunofluorescence, patch-clamp recording, and quantitative real-time PCR were performed to observe hearing function, hair cells, ribbon synapses, nerve fibers, spiral ganglion neurons, and oxidative stress.

RESULTS: Compared to control group, multiple sevoflurane exposures during the neonatal time significantly elevated ABR thresholds at 8 kHz (35.42 ± 1.57 vs. 41.76 ± 1.97 dB, P = 0.0256), 16 kHz (23.33 ± 1.28 vs. 33.53 ± 2.523 dB, P = 0.0012), 24 kHz (30.00 ± 2.04 vs. 46.76 ± 3.93 dB, P = 0.0024), and 32 kHz (41.25 ± 2.31 vs. 54.41 ± 2.94 dB, P = 0.0028) on P30, caused ribbon synapse loss on P15 (13.10 ± 0.43 vs. 10.78 ± 0.52, P = 0.0039) and P30 (11.24 ± 0.56 vs. 8.50 ± 0.84, P = 0.0141), and degenerated spiral ganglion neuron (SGN) nerve fibers on P30 (110.40 ± 16.23 vs. 55.04 ± 8.13, P = 0.0073). In addition, the V half of calcium current become more negative (-21.99 ± 0.70 vs. -27.17 ± 0.60 mV, P < 0.0001), exocytosis was reduced (105.40 ± 19.97 vs. 59.79 ± 10.60 fF, P < 0.0001), and Lpo was upregulated (P = 0.0219) in sevoflurane group than those in control group. N-acetylcysteine (NAC) reversed hearing impairment induced by sevoflurane.

CONCLUSION: The findings suggest that multiple sevoflurane exposures during neonatal time may cause hearing impairment in adult mice. The study also demonstrated that elevated oxidative stress led to ribbon synapses impairment and SGN nerve fibers degeneration, and the interventions of antioxidants alleviated the sevoflurane-induced hearing impairment.}, } @article {pmid35910843, year = {2022}, author = {Li, J and Jia, B and Cheng, Y and Song, Y and Li, Q and Luo, C}, title = {Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {3999083}, pmid = {35910843}, issn = {1942-0994}, mesh = {*Ferroptosis ; Humans ; Lipid Peroxidation ; *Nervous System Diseases ; Oxidative Stress/physiology ; Reactive Oxygen Species ; }, abstract = {With the acceleration of population aging, nervous system diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), anxiety, depression, stroke, and traumatic brain injury (TBI) have become a huge burden on families and society. The mechanism of neurological disorders is complex, which also lacks effective treatment, so relevant research is required to solve these problems urgently. Given that oxidative stress-induced lipid peroxidation eventually leads to ferroptosis, both oxidative stress and ferroptosis are important mechanisms causing neurological disorders, targeting mediators of oxidative stress and ferroptosis have become a hot research direction at present. Our review provides a current view of the mechanisms underlying ferroptosis and oxidative stress participate in neurological disorders, the potential application of molecular mediators targeting ferroptosis and oxidative stress in neurological disorders. The target of molecular mediators or agents of oxidative stress and ferroptosis associated with neurological disorders, such as reactive oxygen species (ROS), nuclear factor erythroid 2-related factor-antioxidant response element (Nrf2-ARE), n-acetylcysteine (NAC), Fe[2+], NADPH, and its oxidases NOX, has been described in this article. Given that oxidative stress-induced ferroptosis plays a pivotal role in neurological disorders, further research on the mechanisms of ferroptosis caused by oxidative stress will help provide new targets for the treatment of neurological disorders.}, } @article {pmid35909484, year = {2022}, author = {Baponwa, O and Amang, AP and Mezui, C and Koubala, BB and Siwe, GT and Vandi, VL and Tan, PV}, title = {Antioxidant Mechanism of Renal and Hepatic Failure Prevention Related to Paracetamol Overdose by the Aqueous Extract of Amblygonocarpus andongensis Stem Bark.}, journal = {BioMed research international}, volume = {2022}, number = {}, pages = {1846558}, pmid = {35909484}, issn = {2314-6141}, mesh = {Acetaminophen/pharmacology ; Animals ; *Antioxidants/metabolism ; Kidney/pathology ; Liver/pathology ; *Liver Failure/metabolism ; Oxidative Stress ; Plant Bark/metabolism ; Plant Extracts/therapeutic use ; Rats ; Water/metabolism ; }, abstract = {Paracetamol is a commonly used analgesic/antipyretic whose long-term intake or overdose is associated with renal and hepatic injuries. The aim of this study was to determine the hepatonephroprotective mechanisms of the aqueous extract of Amblygonocarpus andongensis stem bark (AEAASB) on renal and hepatic failure resulting from paracetamol overdose. Forty-five rats were divided into nine groups (n = 5); these were treated once daily for 8 days with 5 ml/kg distilled water (normal, negative, and satellite controls); 0.9% normal saline and 140 mg/kg N-acetyl-cysteine (positive controls); 125, 250, and 500 mg/kg AEAASB (test groups); and 500 mg/kg AEAASB (satellite test). On day 8 after different treatments, hepatonephrotoxicity was induced in all the groups except the normal group by oral administration of a single dose of paracetamol (1000 mg/kg). Urinary, hematological, serum, and oxidative stress parameters and in vitro antioxidant activity of AEAASB were evaluated. Histological sections of the liver and kidney were performed. AEAASB significantly decreased urea, creatinine, transaminases, alkaline phosphatase, and bilirubin (p < 0.001) at 500 mg/kg compared to the negative control. Significant decreases in hepatic (p < 0.01) and renal (p < 0.001) malondialdehyde levels were associated with increases in superoxide dismutase, catalase, and reduced glutathione levels in 500 mg/kg AEAASB compared with the negative control. Histological analysis showed that AEAASB prevented paracetamol-induced renal and liver tissue damage. Furthermore, AEAASB revealed a very strong antioxidant activity (inhibitory concentration 50 = 180 μg/ml, antioxidant activity index = 5.55) with an ability to scavenge 63.03% 2,2-diphenyl-2-picrylhy-drazyl radical and reduced ferric iron by 52.68 mgEqVitC/100 g DM. The hepatonephroprotective effect of AEAASB might result from its ability to improve the antioxidant status through the stimulation of antioxidant factors and the scavenging of free radicals. This property could be ascribed to the presence of some classes of bioactive compounds such as phenolic compounds in great amounts.}, } @article {pmid35909335, year = {2022}, author = {Wang, X and Zhang, W and Ge, P and Yu, M and Meng, H}, title = {Parthanatos participates in glutamate-mediated HT22 cell injury and hippocampal neuronal death in kainic acid-induced status epilepticus rats.}, journal = {CNS neuroscience & therapeutics}, volume = {28}, number = {12}, pages = {2032-2043}, pmid = {35909335}, issn = {1755-5949}, mesh = {Rats ; Animals ; *Parthanatos ; Kainic Acid ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Glutamic Acid ; Poly (ADP-Ribose) Polymerase-1/metabolism/pharmacology ; Cell Death ; Hippocampus/metabolism ; *Status Epilepticus ; Acetylcysteine/pharmacology ; }, abstract = {AIMS: Epileptic seizures or status epilepticus (SE) can cause hippocampal neuronal death, which has detrimental effects. Parthanatos, a new form of programmed cell death, is characterized by hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1), excessive synthesis of poly ADP-ribose polymer, mitochondrial depolarization, and nuclear translocation of apoptosis-inducing factor, observed in various neurodegenerative disorders but rarely reported in epilepsy. We aimed to investigate whether parthanatos participates in the mechanism of seizure-induced hippocampal neuronal death.

METHODS: Glutamate-mediated excitotoxicity cell model was used to study the mechanism of seizure-induced cell injury. Injection of kainic acid into the amygdala was used to establish the epileptic rat model. Corresponding biochemical tests were carried out on hippocampal tissues and HT22 cells following indicated treatments.

RESULTS: In vitro, glutamate time-dependently induced HT22 cell death, accompanied by parthanatos-related biochemical events. Pretreatment with PJ34 (PARP-1 inhibitor) or small interfering RNA-mediated PARP-1 knockdown effectively protected HT22 cells against glutamate-induced toxic effects and attenuated parthanatos-related biochemical events. Application of the antioxidant N-acetylcysteine (NAC) rescued HT22 cell death and reversed parthanatos-related biochemical events. In vivo, PJ34 and NAC afforded protection against SE-induced hippocampal neuronal damage and inhibited parthanatos-related biochemical events.

CONCLUSION: Parthanatos participates in glutamate-induced HT22 cell injury and hippocampal neuronal damage in rats following epileptic seizures. ROS might be the initiating factor during parthanatos.}, } @article {pmid35904459, year = {2022}, author = {Roydhouse, J and Tomko, RL and Gray, KM and Gutman, R}, title = {Assessment of patient perception of treatment assignment and patient-reported outcomes in a cannabis use disorder trial.}, journal = {The American journal of drug and alcohol abuse}, volume = {48}, number = {6}, pages = {651-661}, doi = {10.1080/00952990.2022.2097918}, pmid = {35904459}, issn = {1097-9891}, mesh = {Female ; Humans ; *Marijuana Abuse/drug therapy ; Patient Reported Outcome Measures ; Perception ; }, abstract = {Background: Blinding is a cornerstone of trial methodology. Prior work indicates participant-perceived assignment may be associated with trial outcomes. Less is known about how perception changes over time and if this is associated with outcomes.Objectives: To evaluate if participants change their perception of assignment over time in a blinded trial, and if perception is associated with different types of patient-reported outcomes (PROs).Methods: This was a secondary analysis of data from the Achieving Cannabis Cessation-Evaluating N-Acetylcysteine Treatment (ACCENT) trial, which evaluated the efficacy of N-acetylcysteine (NAC) relative to placebo for treating cannabis use disorder. Participants (N = 234; 164 men, 70 women) were asked at weeks 5 and 9 what treatment (placebo or NAC) they believed they were receiving. We included PROs proximal (cannabis-associated problems, craving) and distal (anxiety) to the intervention. Analysis was by multiple linear regression and mixed models.Results: Approximately 20% of participants in both arms changed their perception over time. Relative to participants who consistently perceived assignment to placebo, participants who consistently perceived assignment to NAC did not always have comparatively better average scores (coefficient -3.3 [95% CI: -7.0, 0.5]). In some analyses, participants who switched to guessing NAC from placebo had comparatively better average scores (coefficient -3.0 [95% CI: -9.3, 3.4]), but this was inconsistent across outcomes or strata defined by actual assignment or guess accuracy.Conclusion: The study suggests that the proportion of individuals who switch their perception over time is modest. However, this group may influence the estimates of intervention effects on some PROs.}, } @article {pmid35902628, year = {2022}, author = {Czekus, C and Steullet, P and Orero López, A and Bozic, I and Rusterholz, T and Bandarabadi, M and Do, KQ and Gutierrez Herrera, C}, title = {Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm[-/-] mice.}, journal = {Molecular psychiatry}, volume = {27}, number = {11}, pages = {4394-4406}, pmid = {35902628}, issn = {1476-5578}, support = {320030_179565 / 1//Swiss Re | Swiss Re Foundation (SwissRe Foundation)/ ; 18.1.2018/25.1.2024//Universität Bern (University of Bern)/ ; }, mesh = {Mice ; Humans ; Animals ; *Glutamate-Cysteine Ligase ; *Sleep/physiology ; Thalamus ; Thalamic Nuclei ; Oxidative Stress ; Cerebral Cortex ; }, abstract = {Schizophrenia is associated with alterations of sensory integration, cognitive processing and both sleep architecture and sleep oscillations in mouse models and human subjects, possibly through changes in thalamocortical dynamics. Oxidative stress (OxS) damage, including inflammation and the impairment of fast-spiking gamma-aminobutyric acid neurons have been hypothesized as a potential mechanism responsible for the onset and development of schizophrenia. Yet, the link between OxS and perturbation of thalamocortical dynamics and sleep remains unclear. Here, we sought to investigate the effects of OxS on sleep regulation by characterizing the dynamics of thalamocortical networks across sleep-wake states in a mouse model with a genetic deletion of the modifier subunit of glutamate-cysteine ligase (Gclm knockout, KO) using high-density electrophysiology in freely-moving mice. We found that Gcml KO mice exhibited a fragmented sleep architecture and impaired sleep homeostasis responses as revealed by the increased NREM sleep latencies, decreased slow-wave activities and spindle rate after sleep deprivation. These changes were associated with altered bursting activity and firing dynamics of neurons from the thalamic reticularis nucleus, anterior cingulate and anterodorsal thalamus. Administration of N-acetylcysteine (NAC), a clinically relevant antioxidant, rescued the sleep fragmentation and spindle rate through a renormalization of local neuronal dynamics in Gclm KO mice. Collectively, these findings provide novel evidence for a link between OxS and the deficits of frontal TC network dynamics as a possible mechanism underlying sleep abnormalities and impaired homeostatic responses observed in schizophrenia.}, } @article {pmid35901044, year = {2022}, author = {Li, YX and Hsiao, CH and Chang, YF}, title = {N-acetyl cysteine prevents arecoline-inhibited C2C12 myoblast differentiation through ERK1/2 phosphorylation.}, journal = {PloS one}, volume = {17}, number = {7}, pages = {e0272231}, pmid = {35901044}, issn = {1932-6203}, mesh = {Acetylcysteine/metabolism/pharmacology ; *Arecoline/pharmacology ; Cell Differentiation ; *MAP Kinase Signaling System ; Muscle Development ; Myoblasts/metabolism ; Phosphorylation ; Reactive Oxygen Species/metabolism ; }, abstract = {Arecoline is known to induce reactive oxygen species (ROS). Our previous studies showed that arecoline inhibited myogenic differentiation and acetylcholine receptor cluster formation of C2C12 myoblasts. N-acetyl-cysteine (NAC) is a known ROS scavenger. We hypothesize that NAC scavenges the excess ROS caused by arecoline. In this article we examined the effect of NAC on the inhibited myoblast differentiation by arecoline and related mechanisms. We found that NAC less than 2 mM is non-cytotoxic to C2C12 by viability analysis. We further demonstrated that NAC attenuated the decreased number of myotubes and nuclei in each myotube compared to arecoline treatment by H & E staining. We also showed that NAC prevented the decreased expression level of the myogenic markers, myogenin and MYH caused by arecoline, using immunocytochemistry and western blotting. Finally, we found that NAC restored the decreased expression level of p-ERK1/2 by arecoline. In conclusion, our results indicate that NAC attenuates the damage of the arecoline-inhibited C2C12 myoblast differentiation by the activation/phosphorylation of ERK. This is the first report to demonstrate that NAC has beneficial effects on skeletal muscle myogenesis through ERK1/2 upon arecoline treatment. Since defects of skeletal muscle associates with several diseases, NAC can be a potent drug candidate in diseases related to defects in skeletal muscle myogenesis.}, } @article {pmid35898618, year = {2022}, author = {Ren, C and Hu, C and Wu, Y and Li, T and Zou, A and Yu, D and Shen, T and Cai, W and Yu, J}, title = {Nicotinamide Mononucleotide Ameliorates Cellular Senescence and Inflammation Caused by Sodium Iodate in RPE.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5961123}, pmid = {35898618}, issn = {1942-0994}, mesh = {Cellular Senescence ; Humans ; Inflammation/metabolism ; Iodates ; *Macular Degeneration/metabolism ; NAD/metabolism ; Nicotinamide Mononucleotide/metabolism/pharmacology ; Oxidative Stress ; *Retinal Pigment Epithelium/metabolism ; }, abstract = {Senescent cells have been demonstrated to have lower cellular NAD[+] levels and are involved in the development of various age-related diseases, including age-related macular degeneration (AMD). Sodium iodate (NaIO3) has been primarily used as an oxidant to establish a model of dry AMD. Results of previous studies have showed that NaIO3 induced retinal tissue senescence in vivo. However, the role of NaIO3 and the mechanism by which it induces retinal pigment epithelium (RPE) senescence remains unknown. In this study, RPE cell senescence was confirmed to be potentially induced by NaIO3. The results showed that the number of senescence-associated-β-galactosidase (SA-β-gal-)-positive cells and the protein levels of p16 and p21 increased after NaIO3 treatment. Additionally, the senescent RPE cells underwent oxidative stress and NAD[+] depletion. Furthermore, significant DNA damage and mitochondrial dysfunction were also detected in senescent RPE cells. The antioxidant N-acetylcysteine (NAC) could alleviate cellular senescence only by a minimal degree, whereas supplementation with nicotinamide mononucleotide (NMN) strongly ameliorated RPE senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. Moreover, both the expression of senescence markers of RPE and subretinal inflammatory cell infiltration were decreased by NMN treatment in vivo. Our results indicate that RPE senescence induced by NaIO3 acquired several key features of AMD. More importantly, NMN may potentially be used to treat RPE senescence and senescence-associated pre-AMD changes by restoring the NAD[+] levels in cells and tissues.}, } @article {pmid35897820, year = {2022}, author = {Wu, MF and Huang, YH and Chiu, LY and Cherng, SH and Sheu, GT and Yang, TY}, title = {Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation.}, journal = {International journal of molecular sciences}, volume = {23}, number = {15}, pages = {}, pmid = {35897820}, issn = {1422-0067}, support = {CSH-2018-C-024//Chung Shan Medical University Hospital/ ; TCVGH-1103202C//Taichung Veterans General Hospital/ ; }, mesh = {Apoptosis ; *Curcumin/pharmacology ; Eukaryotic Initiation Factor-2/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Lung Neoplasms/drug therapy ; MAP Kinase Signaling System ; Phosphorylation ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells.}, } @article {pmid35893741, year = {2022}, author = {Yang, CW and Chien, TM and Yen, CH and Wu, WJ and Sheu, JH and Chang, HW}, title = {Antibladder Cancer Effects of Excavatolide C by Inducing Oxidative Stress, Apoptosis, and DNA Damage In Vitro.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {8}, pages = {}, pmid = {35893741}, issn = {1424-8247}, support = {MOST 108-2314-B-037-021-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 111-P20//National Sun Yat-sen University-KMU Joint Research Project/ ; KMU-DK(A)111008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Excavatolide C (EXCC) is a bioactive compound derived from the gorgonian octocoral Briareum excavatum, and its anticancer effects are rarely addressed, particularly for bladder cancer. This investigation aimed to explore the potential impacts of EXCC on inhibiting the proliferation of three kinds of bladder cancer cells (5637, BFTC905, and T24). EXCC inhibits bladder cancer cell proliferation based on 48 h ATP assay. This antiproliferation function is validated to be oxidative stress dependent. Cellular and mitochondrial oxidative stresses were upregulated by EXCC, accompanied by depleting glutathione and mitochondrial membrane potential. These antiproliferation and oxidative stress events were suppressed by N-acetylcysteine (NAC), indicating that EXCC has an oxidative stress-regulating function for antiproliferation of bladder cancer cells. Oxidative stress-related responses such as apoptosis, caspase activation, and DNA damage were upregulated by EXCC and reverted by NAC. Taken together, the antiproliferation function of EXCC provides a potential treatment against bladder cancer cells via oxidative stress modulation.}, } @article {pmid35893129, year = {2022}, author = {Sun, T and Zhang, Q and Li, M and Tang, S and Dai, C}, title = {T-2 Toxin Induces Apoptotic Cell Death and Protective Autophagy in Mouse Microglia BV2 Cells.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {8}, number = {8}, pages = {}, pmid = {35893129}, issn = {2309-608X}, support = {31972740//National Natural Science Foundation of China/ ; }, abstract = {T-2 toxin exposure could cause neurotoxicity; however, the precise molecular mechanisms remain unclear. In the present study, we investigated T-2 toxin-induced cytotoxicity and underlying molecular mechanisms using a mouse microglia BV2 cell line. The results show that T-2 toxin treatment-induced cytotoxicity of BV2 cells was dose- and time-dependent. Compared to the control, T-2 toxin treatment at 1.25-5 ng/mL significantly increased reactive oxygen species (ROS) production and triggered oxidative stress. T-2 toxin treatment also caused mitochondrial dysfunction in BV2 cells, which was evidenced by decreased mitochondrial transmembrane potential, upregulated expression of Bax protein, and decreased expression of Bcl-2 protein. Meanwhile, T-2 toxin treatment upregulated the expression of cleaved-caspase-3, cleaved-PARP-1 proteins, and downregulated the expression of HO-1 and nuclear Nrf2 proteins, finally inducing cell apoptosis in BV2 cells. N-acetylcysteine (NAC) supplementation significantly attenuated T-2 toxin-induced cytotoxicity. Moreover, T-2 toxin treatment activated autophagy and upregulated autophagy flux, and the inhibition of autophagy significantly promoted T-2 toxin-induced cell apoptosis. Taken together, our results reveal that T-2 toxin-induced cytotoxicity in BV2 cells involves the production of ROS, the activation of the mitochondrial apoptotic pathway, and the inhibition of the Nrf2/HO-1 pathway. Our study offers new insight into the underlying molecular mechanisms in T-2 toxin-mediated neurotoxicity.}, } @article {pmid35892873, year = {2022}, author = {Obrador, E and Salvador-Palmer, R and López-Blanch, R and Oriol-Caballo, M and Moreno-Murciano, P and Estrela, JM}, title = {N-Acetylcysteine Promotes Metastatic Spread of Melanoma in Mice.}, journal = {Cancers}, volume = {14}, number = {15}, pages = {}, pmid = {35892873}, issn = {2072-6694}, support = {SBT-001//Scientia BioTech S.L./ ; }, abstract = {N-acetylcysteine (NAC) is a direct Cys donor and a promoter of glutathione (GSH) synthesis. GSH regulates melanoma growth and NAC has been suggested to increase melanoma metastases in mice. We found that high therapeutic doses of NAC do not increase the growth of melanoma xenografts, but can cause metastatic spread and distant metastases. Nevertheless, this is not due to an antioxidant effect since NAC, in fact, increases the generation of reactive oxygen species in the growing metastatic melanoma. Trolox, an antioxidant vitamin E derivative, administered in vivo, decreased metastatic growth. Metastatic cells isolated from NAC-treated mice showed an increase in the nuclear translocation of Nrf2, as compared to controls. Nrf2, a master regulator of the antioxidant response, controls the expression of different antioxidant enzymes and of the γ-glutamylcysteine ligase (the rate-limiting step in GSH synthesis). Cystine uptake through the xCT cystine-glutamate antiporter (generating intracellular Cys) and the γ-glutamylcysteine ligase activity are key to control metastatic growth. This is associated to an increase in the utilization of L-Gln by the metastatic cells, another metastases promoter. Our results demonstrate the potential of NAC as an inducer of melanoma metastases spread, and suggest that caution should be taken when administering GSH promoters to cancer patients.}, } @article {pmid35889482, year = {2022}, author = {Malkawi, A and Alrabadi, N and Haddad, R and Malkawi, A and Khaled, K and Ovenseri, AC}, title = {Development of Self-Emulsifying Drug Delivery Systems (SEDDSs) Displaying Enhanced Permeation of the Intestinal Mucus Following Sustained Release of Prototype Thiol-Based Mucolytic Agent Load.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {14}, pages = {}, pmid = {35889482}, issn = {1420-3049}, support = {I.u-27-2441//Isra University/ ; }, mesh = {Caco-2 Cells ; Delayed-Action Preparations ; Drug Delivery Systems ; *Emulsifying Agents ; Emulsions ; *Expectorants ; Humans ; Mucus ; Permeability ; Sulfhydryl Compounds ; }, abstract = {In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from −17.31 mV to −7.72 mV. On Caco-2 cells, SEDDSs at 1−3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100−NAC and RS 100−NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting.}, } @article {pmid35884757, year = {2022}, author = {Tang, Q and Li, T and Chen, K and Deng, X and Zhang, Q and Tang, H and Shi, Z and Zhu, T and Zhu, J}, title = {PS-NPs Induced Neurotoxic Effects in SHSY-5Y Cells via Autophagy Activation and Mitochondrial Dysfunction.}, journal = {Brain sciences}, volume = {12}, number = {7}, pages = {}, pmid = {35884757}, issn = {2076-3425}, abstract = {Polystyrene nanoparticles (PS-NPs) are organic pollutants that are widely detected in the environment and organisms, posing potential threats to both ecosystems and human health. PS-NPs have been proven to penetrate the blood-brain barrier and increase the incidence of neurodegenerative diseases. However, information relating to the pathogenic molecular mechanism is still unclear. This study investigated the neurotoxicity and regulatory mechanisms of PS-NPs in human neuroblastoma SHSY-5Y cells. The results show that PS-NPs caused obvious mitochondrial damages, as evidenced by inhibited cell proliferation, increased lactate dehydrogenase release, stimulated oxidative stress responses, elevated Ca[2+] level and apoptosis, and reduced mitochondrial membrane potential and adenosine triphosphate levels. The increased release of cytochrome c and the overexpression of apoptosis-related proteins apoptotic protease activating factor-1 (Apaf-1), cysteinyl aspartate specific proteinase-3 (caspase-3), and caspase-9 indicate the activation of the mitochondrial apoptosis pathway. In addition, the upregulation of autophagy markers light chain 3-II (LC3-II), Beclin-1, and autophagy-related protein (Atg) 5/12/16L suggests that PS-NPs could promote autophagy in SHSY-5Y cells. The RNA interference of Beclin-1 confirms the regulatory role of autophagy in PS-NP-induced neurotoxicity. The administration of antioxidant N-acetylcysteine (NAC) significantly attenuated the cytotoxicity and autophagy activation induced by PS-NP exposure. Generally, PS-NPs could induce neurotoxicity in SHSY-5Y cells via autophagy activation and mitochondria dysfunction, which was modulated by mitochondrial oxidative stress. Mitochondrial damages caused by oxidative stress could potentially be involved in the pathological mechanisms for PS-NP-induced neurodegenerative diseases.}, } @article {pmid35883905, year = {2022}, author = {Zhu, J and Gillissen, B and Dang Tran, DL and May, S and Ulrich, C and Stockfleth, E and Eberle, J}, title = {Inhibition of Cell Proliferation and Cell Viability by Sinecatechins in Cutaneous SCC Cells Is Related to an Imbalance of ROS and Loss of Mitochondrial Membrane Potential.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {35883905}, issn = {2076-3921}, support = {S0251/10015/2020//Deutsches Stiftungszentrum GmbH/ ; }, abstract = {The term sinecatechins designates an extract containing a high percentage of catechins obtained from green tea, which is commercially registered as Veregen or Polyphenon E (PE) and may be considered for treatment of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK). As shown here, treatment of four cSCC cell lines with 200 µg/mL of PE resulted in strong, dose-dependent decrease in cell proliferation (20-30%) as well as strongly decreased cell viability (4-21% of controls, 48 h). Effects correlated with loss of mitochondrial membrane potential, whereas early apoptosis was less pronounced. At the protein level, some activation of caspase-3 and enhanced expression of the CDK inhibitor p21 were found. Loss of MMP and induced cell death were, however, largely independent of caspases and of the proapoptotic Bcl-2 proteins Bax and Bak, suggesting that sinecatechins induce also non-apoptotic, alternative cell death pathways, in addition to apoptosis. Reactive oxygen species (ROS) were downregulated in response to PE at 4 h, followed by an increase at 24 h. The contributory role of initially reduced ROS was supported by the antioxidant N-acetyl cysteine, which in combination with PE further enhanced the negative effects on cell viability. Thus, sinecatechins inhibited cell proliferation and viability of cSCC cells, which could suggest the use of PE for AK treatment. The mechanisms appear as linked to an imbalance of ROS levels.}, } @article {pmid35883857, year = {2022}, author = {Galli, F and Marcantonini, G and Giustarini, D and Albertini, MC and Migni, A and Zatini, L and Gioiello, A and Rossi, R and Bartolini, D}, title = {How Aging and Oxidative Stress Influence the Cytopathic and Inflammatory Effects of SARS-CoV-2 Infection: The Role of Cellular Glutathione and Cysteine Metabolism.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {35883857}, issn = {2076-3921}, support = {19837 (2020.0522)//Fondazione Cassa di Risparmio di Perugia/ ; 10435 (2019.0320)//Fondazione Cassa di Risparmio di Perugia/ ; 20420 (2021.0339).//Fondazione Cassa di Risparmio di Perugia/ ; }, abstract = {SARS-CoV-2 infection can cause a severe respiratory distress syndrome with inflammatory and thrombotic complications, the severity of which increases with patients' age and presence of comorbidity. The reasons for an age-dependent increase in the risk of severe COVID-19 could be many. These include defects in the homeostatic processes that control the cellular redox and its pivotal role in sustaining the immuno-inflammatory response to the host and the protection against oxidative stress and tissue degeneration. Pathogens may take advantage of such age-dependent abnormalities. Alterations of the thiol redox balance in the lung tissue and lining fluids may influence the risk of infection, and the host capability to respond to pathogens and to avoid severe complications. SARS-CoV-2, likewise other viruses, such as HIV, influenza, and HSV, benefits in its replication cycle of pro-oxidant conditions that the same viral infection seems to induce in the host cell with mechanisms that remain poorly understood. We recently demonstrated that the pro-oxidant effects of SARS-CoV-2 infection are associated with changes in the cellular metabolism and transmembrane fluxes of Cys and GSH. These appear to be the consequence of an increased use of Cys in viral protein synthesis and to ER stress pathway activation that interfere with transcription factors, as Nrf2 and NFkB, important to coordinate the metabolism of GSH with other aspects of the stress response and with the pro-inflammatory effects of this virus in the host cell. This narrative review article describes these cellular and molecular aspects of SARS-CoV-2 infection, and the role that antivirals and cytoprotective agents such as N-acetyl cysteine may have to limit the cytopathic effects of this virus and to recover tissue homeostasis after infection.}, } @article {pmid35883843, year = {2022}, author = {Yu, TJ and Shiau, JP and Tang, JY and Yen, CH and Hou, MF and Cheng, YB and Shu, CW and Chang, HW}, title = {Physapruin A Induces Reactive Oxygen Species to Trigger Cytoprotective Autophagy of Breast Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {35883843}, issn = {2076-3921}, support = {MOST 108-2320-B-037-015-MY3, MOST 110-2314-B-037-074-MY3, and MOST 108-2320-B-110-008-MY3//Ministry of Science and Technology/ ; NSYSUKMU 111-P20 and NSYSUKMU 111-P11//National Sun Yat-sen University-KMU Joint Research Project/ ; 111-05//NSYSU-KCGMH Joint Research Project/ ; KMUH110-0M39//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Physalis peruviana-derived physapruin A (PHA) is a potent compound that selectively generates reactive oxygen species (ROS) and induces cancer cell death. Autophagy, a cellular self-clearance pathway, can be induced by ROS and plays a dual role in cancer cell death. However, the role of autophagy in PHA-treated cancer cells is not understood. Our study initially showed that autophagy inhibitors such as bafilomycin A1 enhanced the cytotoxic effects of PHA in breast cancer cell lines, including MCF7 and MDA-MB-231. PHA treatment decreased the p62 protein level and increased LC3-II flux. PHA increased the fluorescence intensity of DAPGreen and DALGreen, which are used to reflect the formation of autophagosome/autolysosome and autolysosome, respectively. ROS scavenger N-acetylcysteine (NAC) decreased PHA-elevated autophagy activity, implying that PHA-induced ROS may be required for autophagy induction in breast cancer cells. Moreover, the autophagy inhibitor increased ROS levels and enhanced PHA-elevated ROS levels, while NAC scavenges the produced ROS resulting from PHA and autophagy inhibitor. In addition, the autophagy inhibitor elevated the PHA-induced proportion of annexin V/7-aminoactinmycin D and cleavage of caspase-3/8/9 and poly (ADP-ribose) polymerase. In contrast, NAC and apoptosis inhibitor Z-VAD-FMK blocked the proportion of annexin V/7-aminoactinmycin D and the activation of caspases. Taken together, PHA induced ROS to promote autophagy, which might play an antioxidant and anti-apoptotic role in breast cancer cells.}, } @article {pmid35882152, year = {2022}, author = {Chen, C and Wang, J and Liang, Z and Li, M and Fu, D and Zhang, L and Yang, X and Guo, Y and Ge, D and Liu, Y and Sun, B}, title = {Monosodium urate crystals with controlled shape and aspect ratio for elucidating the pathological progress of acute gout.}, journal = {Biomaterials advances}, volume = {139}, number = {}, pages = {213005}, doi = {10.1016/j.bioadv.2022.213005}, pmid = {35882152}, issn = {2772-9508}, mesh = {*Arthritis, Gouty/chemically induced ; *Gout/drug therapy ; Humans ; Inflammasomes/adverse effects ; Macrophages/metabolism ; Uric Acid/adverse effects ; }, abstract = {Gout is a self-limiting inflammatory arthritis mediated by the precipitation of monosodium urate (MSU) crystals that further activate the NLRP3 inflammasome and initiate a cascade of inflammatory events. However, the key physicochemical properties of MSU crystals that determine the acute phase of gout have not been fully identified. In this study, a library of engineered MSU crystals with well-controlled size and shape is designed to explore their proinflammatory potentials in mediating the pathological progress of gout. It is demonstrated that medium-sized long aspect ratio MSU crystals induce more prominent IL-1β production in vitro due to enhanced cellular uptake and the production of mitochondrial reactive oxygen species (mtROS). The characteristics of MSU crystals are also correlated with their inflammatory potentials in both acute peritonitis and arthritis models. Furthermore, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is demonstrated to inhibit MSU-induced oxidative burst by removing plasma membrane cholesterol. As a result, it attenuates the inflammatory responses both in vitro and in vivo. Additionally, antioxidant N-acetylcysteine (NAC) is shown to alleviate acute gouty symptom by suppressing oxidative stress. This study identifies the key physicochemical properties of MSU crystals that mediate the pathogenesis of gout, which sheds light on novel design strategies for the intervention of gout.}, } @article {pmid35878501, year = {2022}, author = {Tang, M and Yang, Z and Liu, J and Zhang, X and Guan, L and Liu, X and Zeng, M}, title = {Combined intervention with N-acetylcysteine and desipramine alleviated silicosis development by regulating the Nrf2/HO-1 and ASMase/ceramide signaling pathways.}, journal = {Ecotoxicology and environmental safety}, volume = {242}, number = {}, pages = {113914}, doi = {10.1016/j.ecoenv.2022.113914}, pmid = {35878501}, issn = {1090-2414}, mesh = {*Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism ; Ceramides/metabolism ; *Desipramine/metabolism/therapeutic use ; Disease Models, Animal ; Drug Therapy, Combination ; Dust ; Fibrosis ; Heme Oxygenase (Decyclizing) ; Lung ; Matrix Metalloproteinase 1/metabolism/toxicity ; NF-E2-Related Factor 2 ; *Pulmonary Fibrosis/chemically induced/drug therapy/metabolism ; Rats ; Rats, Wistar ; Signal Transduction ; Silicon Dioxide/toxicity ; *Silicosis/metabolism ; Sphingomyelin Phosphodiesterase/metabolism/toxicity ; Tissue Inhibitor of Metalloproteinase-1 ; }, abstract = {Silicosis is a systemic disease characterized by diffuse fibrosis of the lung tissue caused by long-term inhalation of large amounts of free silica (SiO2) dust. The pathogenesis of silicosis has not been fully elucidated, and there is a lack of effective treatment methods. N-acetylcysteine (NAC) can potentially treat pulmonary fibrosis by exerting antioxidant effects. Desipramine (DMI) can influence pulmonary fibrosis development by inhibiting acid sphingomyelinase (ASMase) activity and regulating ceramide concentrations. Both can interfere with pulmonary fibrosis through different mechanisms, but the intervention effects of NAC combined with DMI on silicosis fibrosis have not been reported. Therefore, this study established a rat silicosis model using a single tracheal drip of SiO2 dust suspension in Wistar rats to investigate the effect of NAC combined with DMI on SiO2 dust-induced silicosis and its related molecular mechanisms. The histopathological examination of the SiO2 dust-induced silicosis rats suggested that NAC and DMI alone or in combination could decrease the severity of pulmonary fibrosis in rats. The combined intervention had a better effect on reducing fibrosis than the individual interventions. NAC and DMI, alone or in combination, decreased the levels of markers related to pulmonary fibrosis in rats (smooth muscle α-actin (α-SMA), collagen (Col) I, Col III, hydroxyproline (HYP), inflammatory factors (transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α)), and lipid peroxidase malondialdehyde (MDA)). The nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme-oxygenase-1 (HO-1) and ASMase/ceramide pathways were inhibited to some extent by increasing the superoxide dismutase (SOD) levels of antioxidant enzymes and 8-iso-prostaglandin F2α (8-iso-PGF2α) levels of lipid peroxides. The combined intervention and NAC alone inhibited the SiO2 dust-induced elevation of matrix metalloproteinase 1 (MMP-1) and tissue inhibitor matrix metalloproteinase 1 (TIMP-1), but the effect was not significant in the DMI-treated group. Combining DMI and NAC inhibited Col I deposition and reduced HO-1, TIMP-1, and ASMase levels in lung tissues compared to individual treatments. In summary, the SiO2 dust could induce oxidative stress and inflammation in rats, resulting in an imbalance in extracellular matrix (ECM) synthesis/catabolism and ASMase/ceramide signaling pathway activation, leading to silicosis development.The combined intervention of DMI and NAC may synergistically regulate the Nrf2/HO-1 pathway, maintain the anabolic balance of the ECM, inhibit ASMase/ceramide signaling pathway activation by suppressing the inflammatory response and effectively delay silicosis fibrosis progression.}, } @article {pmid35871676, year = {2022}, author = {San-Martín-Martínez, D and Serrano-Lemus, D and Cornejo, V and Gajardo, AIJ and Rodrigo, R}, title = {Pharmacological Basis for Abrogating Myocardial Reperfusion Injury Through a Multi-Target Combined Antioxidant Therapy.}, journal = {Clinical pharmacokinetics}, volume = {61}, number = {9}, pages = {1203-1218}, pmid = {35871676}, issn = {1179-1926}, mesh = {Antioxidants/pharmacology/therapeutic use ; Humans ; *Myocardial Infarction/drug therapy ; *Myocardial Reperfusion Injury/drug therapy/prevention & control ; }, abstract = {The main goal of the treatment for acute myocardial infarction is to achieve reperfusion of the affected myocardial tissue, with percutaneous coronary angioplasty being the gold standard procedure. However, this strategy has been associated with additional heart damage termed "lethal reperfusion injury," which is responsible for up to half of the final infarct size. Among the possible underlying mechanisms that are likely to explain this damage, studies suggest that oxidative stress plays a key role. Although this has not been translated into clinical benefits in most studies, recent preclinical studies reported promising results and a possible synergy with the combined use of vitamin C (VC), N-acetylcysteine (NAC), and deferoxamine (DFO). However, to implement a combined therapy with these drugs for patients requires further studies to understand their pharmacokinetic properties. Available data of the clinical trials have not been validated by looking into the pharmacokinetics in their design. Therefore, this article presents an update and comparison of the evidence for the efficacy of these administration schemes for each drug in cardioprotection, their pharmacokinetic properties and mechanisms of action for their use against "lethal reperfusion injury." To achieve a cardioprotective effect using a new pharmacological strategy before the onset of reperfusion, it is helpful to consider the pharmacokinetics of each drug. In this regard, to design a fast and short pharmacologic therapeutic strategy, theoretically VC and DFO concentrations could be modeled by a one-compartment model whereas NAC could be modeled by a three-compartment model with an initial short half-life.}, } @article {pmid35870339, year = {2022}, author = {He, X and Jarrell, ZR and Liang, Y and Ryan Smith, M and Orr, ML and Marts, L and Go, YM and Jones, DP}, title = {Vanadium pentoxide induced oxidative stress and cellular senescence in human lung fibroblasts.}, journal = {Redox biology}, volume = {55}, number = {}, pages = {102409}, pmid = {35870339}, issn = {2213-2317}, support = {RC2 DK118619/DK/NIDDK NIH HHS/United States ; T32 ES012870/ES/NIEHS NIH HHS/United States ; R01 ES031980/ES/NIEHS NIH HHS/United States ; F32 ES033908/ES/NIEHS NIH HHS/United States ; R01 ES032189/ES/NIEHS NIH HHS/United States ; P30 ES019776/ES/NIEHS NIH HHS/United States ; R21 ES031824/ES/NIEHS NIH HHS/United States ; }, abstract = {Both environmental exposure to vanadium pentoxide (V2O5, V[+5] for its ionic counterparts) and fibroblast senescence are associated with pulmonary fibrosis, but whether V[+5] causes fibroblast senescence remains unknown. We found in a dose-response study that 2-40 μM V[+5] caused human lung fibroblasts (HLF) senescence with increased senescence-associated β-galactosidase activity and p16 expression, while cell death occurred at higher concentration (LC50, 82 μM V[+5]). Notably, measures of reactive oxygen species (ROS) production with fluorescence probes showed no association of ROS with V[+5]-dependent senescence. Preloading catalase (polyethylene-conjugated), a H2O2 scavenger, did not alleviate the cellular senescence induced by V[+5]. Analyses of the cellular glutathione (GSH) system showed that V[+5] oxidized GSH, increased GSH biosynthesis, stimulated cellular GSH efflux and increased protein S-glutathionylation, and addition of N-acetyl cysteine inhibited V[+5]-elevated p16 expression, suggesting that thiol oxidation mediates V[+5]-caused senescence. Moreover, strong correlations between GSSG/GSH redox potential (Eh), protein S-glutathionylation, and cellular senescence (R[2] > 0.99, p < 0.05) were present in V[+5]-treated cells. Studies with cell-free and enzyme-free solutions showed that V[+5] directly oxidized GSH with formation of V[+4] and GSSG in the absence of O2. Analyses of V[+5] and V[+4] in HLF and culture media showed that V[+5] was reduced to V[+4] in cells and that a stable V[+4]/V[+5] ratio was rapidly achieved in extracellular media, indicating ongoing release of V[+4] and reoxidation to V[+5]. Together, the results show that V[+5]-dependent fibroblast senescence is associated with a cellular/extracellular redox cycling mechanism involving the GSH system and occurring under conditions that do not cause cell death. These results establish a mechanism by which environmental vanadium from food, dietary supplements or drinking water, can cause or contribute to lung fibrosis in the absence of high-level occupational exposures and cytotoxic cell death.}, } @article {pmid35861217, year = {2022}, author = {Aksoy, N and Vatansever, C and Zengin Ersoy, G and Adakli Aksoy, B and Fışgın, T}, title = {The effect of biofilm inhibitor N-acetylcysteine on the minimum inhibitory concentration of antibiotics used in Gram-negative bacteria in the biofilm developed on catheters.}, journal = {The International journal of artificial organs}, volume = {45}, number = {10}, pages = {865-870}, doi = {10.1177/03913988221112969}, pmid = {35861217}, issn = {1724-6040}, mesh = {Acetylcysteine/pharmacology ; Amikacin ; *Anti-Bacterial Agents/pharmacology ; Biofilms ; Catheters ; Cefepime/pharmacology ; Ceftazidime/pharmacology ; Child ; *Colistin/pharmacology ; Escherichia coli ; Gram-Negative Bacteria ; Humans ; Meropenem/pharmacology ; Microbial Sensitivity Tests ; Pseudomonas aeruginosa ; }, abstract = {The study determined the effect of N-acetylcysteine (NAC) on the susceptibility of various antibiotics used to treat Gram-negative catheter-related infection in isolates obtained from pediatric patients admitted to the hematology and oncology department of Medical Park Bahçelievler hospital in Istanbul, Turkey. Biofilms were created in vitro utilizing clinical isolates of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas putida, and Proteus mirabilis. 24 h old biofilms were developed on 96-well plate with strains and the minimum biofilm inhibitory concentration (MBIC) of six antibiotics were measured before and after the addition of 75 mg/ml N-acetylcysteine with microplate reader at 450 nm after crystal violet assay. The addition of NAC reduce the MBIC of cefepime, ceftazidime, colistin, meropenem from (16, 16, 8, 4 μg/ml) to (8, 4, 4, 2 μg/ml) respectively in E. coli (isolate 1). In P. aeruginosa (isolate 4), the MBIC of amikacin, ceftazidime, meropenem (64, 32, and 32 μg/ml) reduced to (8, 1, and 0.5 μg/ml) respectively. MBIC of cefepime, colistin, meropenem (32, 16,and 16 μg/ml) reduced to (2, 2,and 0.5 μg/ml) respectively in P. putida (isolate 5). In P. mirabilis (isolate 6), MBIC of amikacin, cefepime, ceftazidime, colisitin and meropenem (64, 128, 32, 4, and 32 μg/ml) reduced to (8, 8, 1, 1, 4 μg/ml). NAC in combination therapy can practically reduce the MBIC of antibiotics used to treat Gram negative bacteria that develop biofilm in medical catheters. As a result, these combinations can be considered as an essential alternative for increasing the antibiotic susceptibility of pathogenic microorganisms and thus increasing treatment success rates.}, } @article {pmid35858325, year = {2022}, author = {Fernandez, AM and Martinez-Rachadell, L and Navarrete, M and Pose-Utrilla, J and Davila, JC and Pignatelli, J and Diaz-Pacheco, S and Guerra-Cantera, S and Viedma-Moreno, E and Palenzuela, R and Ruiz de Martin Esteban, S and Mostany, R and Garcia-Caceres, C and Tschöp, M and Iglesias, T and de Ceballos, ML and Gutierrez, A and Torres Aleman, I}, title = {Insulin regulates neurovascular coupling through astrocytes.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {29}, pages = {e2204527119}, pmid = {35858325}, issn = {1091-6490}, mesh = {Animals ; *Astrocytes/metabolism ; *Brain/blood supply ; Glial Fibrillary Acidic Protein/genetics ; Glucose/metabolism ; *Insulin/metabolism ; Mice ; Mice, Knockout ; *Neovascularization, Physiologic ; *Neurovascular Coupling ; Reactive Oxygen Species/metabolism ; Receptor, Insulin/genetics ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.}, } @article {pmid35857752, year = {2022}, author = {Neill, E and Rossell, SL and Yolland, C and Meyer, D and Galletly, C and Harris, A and Siskind, D and Berk, M and Bozaoglu, K and Dark, F and Dean, OM and Francis, PS and Liu, D and Phillipou, A and Sarris, J and Castle, DJ}, title = {N-Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms.}, journal = {Schizophrenia bulletin}, volume = {48}, number = {6}, pages = {1263-1272}, pmid = {35857752}, issn = {1745-1701}, mesh = {Humans ; *Clozapine/adverse effects ; *Schizophrenia/drug therapy/chemically induced ; Acetylcysteine/pharmacology ; Quality of Life/psychology ; Treatment Outcome ; Australia ; *Antipsychotic Agents/adverse effects ; Double-Blind Method ; }, abstract = {BACKGROUND AND HYPOTHESIS: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC).

STUDY DESIGN: A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks.

STUDY RESULTS: NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26).

CONCLUSIONS: NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with "Australian and New Zealand Clinical Trials" on the 30 May, 2016 (Registration Number: ACTRN12615001273572).}, } @article {pmid35856379, year = {2022}, author = {Micheletto, C and Izquierdo, JL and Avdeev, SN and Rada Escobar, RA and Pacheco Gallego, MC}, title = {N-acetylcysteine as a therapeutic approach to post-COVID-19 pulmonary fibrosis adjunctive treatment.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {13}, pages = {4872-4880}, doi = {10.26355/eurrev_202207_29212}, pmid = {35856379}, issn = {2284-0729}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Anti-Inflammatory Agents ; Antioxidants/pharmacology ; Glutathione ; Humans ; *Pulmonary Fibrosis/chemically induced/drug therapy ; Quality of Life ; *COVID-19 Drug Treatment ; }, abstract = {OBJECTIVE: Growing interest is directed to the outcomes of COVID-19 in survivors, both in the convalescent period and in the long-term, which are responsible for morbidity and quality of life deterioration. This article aims to describe the mechanisms supporting the possible use of NAC as an adjuvant treatment for post-COVID-19 pulmonary fibrosis.

MATERIALS AND METHODS: A search was performed in PubMed/MEDLINE.

RESULTS: Interstitial changes have been observed in the CT scan of COVID-19 pneumonia. In patients with respiratory outcomes in the post-COVID-19 stage, glutathione (GSH) deficiency was found and interpreted as a reaction to the inflammatory cascade caused by the viral infection, while the pathophysiological process of pulmonary fibrosis involves numerous cytokines, such as TGF-β, TNF-α, IL-1, PDGF and VEGF. NAC has a good tolerability profile, is easily administered orally and inexpensively, and has antioxidant and anti-inflammatory effects that may target the pathophysiologic mechanisms involved in pulmonary fibrosis. It may revert GSH deficiency, exerts direct and indirect antioxidant activity, anti-inflammatory activity and improves immune T-cell response.

CONCLUSIONS: The mechanism of action of NAC suggests a role in the treatment of pulmonary fibrosis induced by COVID-19.}, } @article {pmid35856373, year = {2022}, author = {Buha, I and Mirić, M and Agić, A and Simić, M and Stjepanović, M and Milenković, B and Nagorni-Obradović, L and Škodrić-Trifunović, V and Ilić, B and Popević, S and Dimic-Janjic, S and Ilić, A}, title = {A randomized, double-blind, placebo-controlled study evaluating the efficacy of propolis and N-acetylcysteine in exacerbations of chronic obstructive pulmonary disease.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {13}, pages = {4809-4815}, doi = {10.26355/eurrev_202207_29206}, pmid = {35856373}, issn = {2284-0729}, mesh = {Acetylcysteine/adverse effects ; Disease Progression ; Double-Blind Method ; Humans ; *Propolis/therapeutic use ; *Pulmonary Disease, Chronic Obstructive ; }, abstract = {OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) accelerate the progressive impairment of lung function and general health. Together with maintenance therapy for chronic obstructive pulmonary disease (COPD), N-acetylcysteine (NAC) and natural propolis have demonstrated pharmacological properties that address crucial pathophysiological processes underlying COPD and may prevent AECOPDs. This study aims at responding to dose-dependent efficacy and safety concerns regarding a propolis-NAC combination for the reduction of COPD exacerbation rates.

PATIENTS AND METHODS: This was a single-center, randomized, double-blind, phase IV trial with three treatment arms: Placebo and two active substance groups, one (AS-600) received 600 mg of NAC + 80 mg of propolis while the other (AS-1,200) received 1,200 mg of NAC + 160 mg of propolis. Following an AECOPD, frequent-exacerbation phenotype patients (n=46) were assigned a once-daily three-month therapy with the study drug and one year follow-up. The primary endpoint was the COPD exacerbation incidence rate during the follow-up period as a measure of dose-dependent efficacy of NAC-propolis combination compared to placebo.

RESULTS: There was a statistically significant difference in the AECOPD incidence rate: 52.6% in patients that received placebo, 15.4% that received AS-600 and only 7.1% that received AS-1,200 (Fisher's exact test, p = 0.013). Compared to placebo, AECOPD frequency was significantly lower only in AS-1,200 (p=0.009). Compared to placebo, the relative risk for exacerbation was 0.29 in AS-600 and 0.13 in AS-1,200. No adverse events related to the treatment were reported.

CONCLUSIONS: Oral combination of natural propolis with NAC confirmed formulation efficiency with a favorable safety profile. Our results need to be confirmed by larger clinical trials.}, } @article {pmid35851521, year = {2022}, author = {Wu, L and Zeng, W and Ishigaki, Y and Zhang, J and Bai, H and Harimoto, T and Suzuki, T and Ye, D}, title = {A Ratiometric Photoacoustic Probe with a Reversible Response to Hydrogen Sulfide and Hydroxyl Radicals for Dynamic Imaging of Liver Inflammation.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {61}, number = {37}, pages = {e202209248}, doi = {10.1002/anie.202209248}, pmid = {35851521}, issn = {1521-3773}, mesh = {Animals ; Fluorescent Dyes ; *Hydrogen Sulfide ; Hydroxyl Radical ; Liver/diagnostic imaging ; Mice ; Oxidation-Reduction ; *Photoacoustic Techniques/methods ; Spectrum Analysis ; }, abstract = {Reversible imaging probes that allow for the dynamic visualization of the redox cycle between hydroxyl radical (⋅OH) and hydrogen sulfide (H2 S) are vital to probe the redox imbalance-involved pathological process in vivo. Herein, we report a reversible ratiometric photoacoustic (PA) imaging nanoprobe (1-PAIN) for the real-time imaging of ⋅OH/H2 S redox cycle in vivo. 1-PAIN displays a low PA ratio between 690 and 825 nm (PA690 /PA825), which significantly increases by ≈5-fold upon oxidation by ⋅OH, and is switched back to the initially low PA690 /PA825 value upon reduction by H2 S. 1-PAIN could dynamically report on the hepatic ⋅OH production in mice during the lipopolysaccharide (LPS)-induced liver inflammation process, and visualize hepatic H2 S generation during the N-acetyl cysteine (NAC)-induced anti-inflammation process. 1-PAIN can act as a useful tool to probe the redox state in living biology, beneficial for the study of redox imbalance-related diseases.}, } @article {pmid35850245, year = {2022}, author = {Huo, H and Wu, H and Ma, F and Li, X and Liao, J and Hu, L and Han, Q and Li, Y and Pan, J and Zhang, H and Tang, Z and Guo, J}, title = {N-acetyl-L-cysteine ameliorates hepatocyte pyroptosis of dog type 1 diabetes mellitus via suppression of NLRP3/NF-κB pathway.}, journal = {Life sciences}, volume = {306}, number = {}, pages = {120802}, doi = {10.1016/j.lfs.2022.120802}, pmid = {35850245}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Diabetes Mellitus, Type 1/drug therapy ; Dogs ; Hepatocytes/metabolism ; Insulin/pharmacology ; *NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pyroptosis ; Rats ; Rats, Sprague-Dawley ; Streptozocin/pharmacology ; }, abstract = {Type 1 diabetes mellitus (T1DM) is a chronic and represented by insulin-causing pancreatic β-cell disruption and hyperglycemia. N-Acetyl-Cysteine (NAC) is regarded as facilitating endothelial cell function and angiogenesis and may have treatment effect in the case of diabetes. However, the impact of NAC on T1DM are unknown. Here we reported that inflammatory pathogenesis of canine type 1 diabetes liver disease and the therapeutic effect of NAC combined with insulin. For this purpose, the model was established by intravenous injection of streptozotocin (20 mg/kg). Forty adult dogs were used and divided into 5 groups: control group, DM group, insulin treatment group, NAC combined with insulin therapy, and NAC group, while study lasted for 16 weeks. Results showed that the level of liver function enzyme activity were apparently increased in DM group, while the NAC with insulin treatment remarkable decreased liver function enzyme levels. Histopathology revealed that obvious changes in liver structure of all DM group, as evidenced by hepatocyte disorder and cellular swelling. Liver structure was evaluated by Periodic Acid Schiff (PAS) and Masson staining, the tissues appeared glycogen deposition and collagen deposition, indicating that DM aggravated liver injury. Compared with control group, the protein and mRNA expression of NLRP3, Caspase-1, ASC, and GSDMD were significantly induced in the DM group, while INS and NAC combined with INS treatment reversed the above changes. The levels of NF-κB P65, p-NF-κB, and IFN γ were availably enhanced in the DM group, which decreased through insulin and NAC combined with insulin treatment. This study demonstrated that NAC combined with INS exerted protective effects against STZ-induced liver injury by inhibiting the NLRP3/NF-κB pathway. The findings indicated that NAC combined with INS may serve as a potential candidate therapy for the treatment of T1DM.}, } @article {pmid35849165, year = {2022}, author = {Abbas, AA and Hamdy, A and Ahmed, AE}, title = {Compromised blood-bile barrier after acetaminophen overdose.}, journal = {Archives of toxicology}, volume = {96}, number = {10}, pages = {2825-2827}, pmid = {35849165}, issn = {1432-0738}, mesh = {Acetaminophen ; Acetylcysteine/pharmacology ; Bile ; Bile Acids and Salts ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose ; Humans ; Liver ; }, abstract = {N-acetylcysteine (NAC) is the only approved drug for the treatment of acetaminophen (APAP) intoxication. A limitation of NAC is the short therapeutic time-window as it is only effective within approximately eight hours after APAP ingestion, which is critical since patients seek medical attention often after the onset of symptoms approximately 24 h after overdose. Recently, a so far unknown mechanism was identified by which APAP causes an increase of intracellular bile acid concentrations in hepatocytes to concentrations that exceed cytotoxic thresholds. APAP compromises the tight junctions of bile canaliculi that leads to the leakage of highly concentrated bile acids into the sinusoids. From the sinusoidal blood, a high fraction of the released bile acids is transported back into hepatocytes by basolateral uptake carriers and secreted into bile canaliculi. Repeated leakage from the canaliculi followed by hepatocellular reuptake and canalicular secretion causes an increase of intracellular bile acid concentrations and finally hepatocyte death. Importantly, inhibition of bile acid uptake carriers reduced intracellular bile acid concentrations and strongly ameliorated APAP hepatotoxicity, a finding that could result in a new therapeutic option for APAP-intoxicated patients.}, } @article {pmid35843301, year = {2022}, author = {Rhana, P and Barros, GM and Santos, VCO and Costa, AD and Santos, DMD and Fernandes-Braga, W and Durço, AO and Santos, MRV and Roman-Campos, D and Vasconcelos, CML and Cruz, JS and Souza, DS}, title = {S-limonene protects the heart in an experimental model of myocardial infarction induced by isoproterenol: Possible involvement of mitochondrial reactive oxygen species.}, journal = {European journal of pharmacology}, volume = {930}, number = {}, pages = {175134}, doi = {10.1016/j.ejphar.2022.175134}, pmid = {35843301}, issn = {1879-0712}, mesh = {Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; *Heart Injuries/metabolism ; Isoproterenol/toxicity ; Limonene/metabolism/pharmacology/therapeutic use ; Models, Theoretical ; *Myocardial Infarction/chemically induced/drug therapy/prevention & control ; Myocardium/metabolism ; Myocytes, Cardiac/metabolism ; Oxidative Stress ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Myocardial infarction (MI) is associated with high mortality rates, despite the fact that there are therapies available. Importantly, excessive oxidative stress may contribute to ischemia/reperfusion injury leading to death related to MI. In this scenario, naturally occurring antioxidant compounds are an important source of possible therapeutic intervention. Thus, this study sought to elucidate the mechanisms of cardioprotection of s-limonene in an isoproterenol-induced MI animal model.

METHODS: Wistar rats were treated with 1 mg/kg s-limonene (SL) or 100 mg/kg N-acetylcysteine (NAC, positive control) once, 30 min after isoproterenol-induced MI (applied in two doses with a 24 h interval). The protective effects of SL in the heart were examined via the serum level of creatine kinase myocardial band (CK-MB), electrocardiographic profile, infarct size and histological parameters. Using isolated cardiomyocytes, we also assessed calcium transient amplitude, cytosolic and mitochondrial oxidative stress and the expression of proteins related to oxidative stress.

RESULTS: SL at a concentration of 1 mg/kg attenuated isoproterenol-induced MI injury, by preventing ST-segment elevation and QTc prolongation in the ECG. SL reduced the infarct size and collagen content in cardiac tissue. At the cellular level, SL prevented increased Ca[2+], associated with attenuation of cytosolic and mitochondrial oxidative stress. These changes resulted in a reduction of the oxidized form of Ca[2+] Calmodulin-Dependent Kinase II (CaMKII) and restored superoxide dismutase and glutathione peroxidase activity.

CONCLUSION: Our data show that s-limonene promotes cardioprotection against MI injury, probably through inhibition of increased Ca[2+] and attenuation of oxidative stress via CaMKII.}, } @article {pmid35842931, year = {2022}, author = {Emojevwe, V and Nwangwa, EK and Naiho, AO and Oyovwi, MO and Igiehon, O and Ogunwole, E and Makinde-Taylor, MS and Ayotomide, OA and Akinola, AO and Edesiri, PT and Oghenetega, BO and Ovuakporaye, SI}, title = {Therapeutic efficacy of N-acetylcysteine and zinc sulphate against di-(2-ethylhexyl) phthalate-induced testicular oxido-nitrergic stress in male Wistar rat.}, journal = {Andrologia}, volume = {54}, number = {9}, pages = {e14508}, doi = {10.1111/and.14508}, pmid = {35842931}, issn = {1439-0272}, mesh = {Animals ; Male ; Rats ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; *Diethylhexyl Phthalate/toxicity ; Phthalic Acids ; Rats, Wistar ; *Testis ; Zinc Sulfate/pharmacology ; }, abstract = {The therapeutic efficacy of N-acetylcysteine (NAC) and zinc sulphate on di-(2-ethylhexyl) phthalate (DEHP)-induced testicular oxido-nitrergic stress in rats was investigated in 36 male Wistar rats (170 ± 10 g) randomly assigned into one of six groups (n = 6). Group 1 (control) received 2.5 ml/kg of distilled water for 42 days, while group 2 (vehicle) received 2.5 ml/kg of corn oil for 42 days. Groups 3,4,5, and 6 were administered DEHP (750 mg/kg/day) for 21 days, after which groups 4, 5, and 6 received zinc sulphate (0.5 mg/kg/day), NAC (100 mg/kg/day), and zinc sulphate (0.5 mg/kg/day) + NAC (100 mg/kg/day) for an additional 21 days respectively. After the experimental period, the animals were euthanized by light thiopental sodium, and their testes were carefully dissected out for histological and biochemical assays. The result shows a significant alteration in testicular levels of malondialdehyde, nitric oxide, antioxidant enzymes, total antioxidant capacity, sulphydryl levels, dehydrogenases and testicular architecture following the administration of DEHP. These effects were reversed by coadministration of NAC and zinc sulphate in the study. We therefore concluded that the combined effects of NAC and ZnSO4 effectively improved testicular antioxidant status and reduced testicular nitregic stress, thus improving testicular architecture and functions.}, } @article {pmid35839558, year = {2022}, author = {Yang, YS and Maddock, RJ and Zhang, H and Lee, J and Hellemann, G and Marder, SR and Green, MF}, title = {N-Acetylcysteine effects on glutathione and glutamate in schizophrenia: A preliminary MRS study.}, journal = {Psychiatry research. Neuroimaging}, volume = {325}, number = {}, pages = {111515}, doi = {10.1016/j.pscychresns.2022.111515}, pmid = {35839558}, issn = {1872-7506}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Glutamic Acid ; Glutathione ; Humans ; *Psychotic Disorders/diagnostic imaging/drug therapy ; *Schizophrenia/diagnostic imaging/drug therapy ; }, abstract = {N-acetylcysteine (NAC) is a commonly used antioxidant that may have beneficial effects for schizophrenia. In this double-blind, randomized, placebo-controlled preliminary study, 40 patients with schizophrenia or schizoaffective disorder were randomized to receive 2400 mg NAC daily or placebo over eight weeks to examine the effects of NAC on prefrontal magnetic resonance spectroscopy levels of glutathione and glutamate. Secondary outcomes included negative symptoms, cognition, and plasma glutathione levels. We found that NAC treatment was associated with increased glutathione (statistically significant) and decreased glutamate (trend-level) compared with placebo in medial prefrontal cortex but not dorsolateral prefrontal cortex. We also observed a baseline association between medial prefrontal cortex levels of glutathione and plasma reduced / oxidized glutathione ratios. No treatment effects on symptoms or cognition were observed. Taken together, these findings indicate that treatment with N-acetylcysteine may increase medial prefrontal cortical levels of glutathione after eight weeks of treatment. These changes in cortical levels of glutathione may serve as an early biomarker of later clinical change and may underlie the cognitive and symptomatic improvements reported in longer-term treatment studies.}, } @article {pmid35834022, year = {2022}, author = {Temel, A and Erac, B}, title = {Investigating Biofilm Formation and Antibiofilm Activity Using Real Time Cell Analysis Method in Carbapenem Resistant Acinetobacter baumannii Strains.}, journal = {Current microbiology}, volume = {79}, number = {9}, pages = {256}, pmid = {35834022}, issn = {1432-0991}, mesh = {*Acinetobacter Infections/microbiology ; *Acinetobacter baumannii ; Anti-Bacterial Agents/pharmacology ; Biofilms ; Carbapenems/pharmacology ; Humans ; Microbial Sensitivity Tests ; }, abstract = {Acinetobacter baumannii is a significant nosocomial pathogen, with its biofilm forming capacity playing an important role in its pathogenicity. The fast and reliable detection of the biofilm formation and measurement of antibiofilm activity of various molecules are critical for combating A. baumannii infections. In this study, we aimed to detect biofilm formation by real time cell analyses (RTCA) method in clinical A. baumannii isolates and to investigate antibiofilm activities of tigecycline (TGC), N-acetylcysteine (NAC), and acetylsalicylic acid (ASA). The effect of the tested drugs on expressions of biofilm-related genes bap and csuE in clinical A. baumannii strains was also analyzed by real time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Biofilm forming capacities for strong and weak biofilm producer A. baumannii strains were detected within 10 h by RTCA method (P < 0.05). We also observed that sub-minimum inhibitory concentrations of NAC + TGC and ASA + TGC combinations could significantly reduce biofilm formation and expression of biofilm-related genes in A. baumanii strains. No statistically significant activity of the tested drugs was detected against mature biofilms of the bacterial strains with the RTCA method. These results suggest that reproducible results on biofilm production capacity of A. baumannii strains and antibiofilm activities of various compounds can be obtained in a short time using RTCA method. Therefore, RTCA method seems to be a beneficial technique for biofilm detection and can help in combating A. baumannii infections by giving health providers the opportunity of implementing antibiofilm treatment strategies in a timely manner.}, } @article {pmid35832486, year = {2022}, author = {Li, S and Luo, G and Zeng, R and Lin, L and Zou, X and Yan, Y and Ma, H and Xia, J and Zhao, Y and Zhou, X}, title = {Endoplasmic Reticulum Stress Contributes to Ventilator-Induced Diaphragm Atrophy and Weakness in Rats.}, journal = {Frontiers in physiology}, volume = {13}, number = {}, pages = {897559}, pmid = {35832486}, issn = {1664-042X}, abstract = {Background: Accumulating evidence indicates that endoplasmic reticulum (ER) stress plays a critical role in the regulation of skeletal muscle mass. In recent years, much attention has been given to ventilator-induced diaphragm dysfunction (VIDD) because it strongly impacts the outcomes of critically ill patients. Current evidence suggests that the enhancement of oxidative stress is essential for the development of VIDD, but there are no data on the effects of ER stress on this pathological process. Methods: VIDD was induced by volume-controlled mechanical ventilation (MV) for 12 h; Spontaneous breathing (SB, for 12 h) rats were used as controls. The ER stress inhibitor 4-phenylbutyrate (4-PBA), the antioxidant N-acetylcysteine (NAC), and the ER stress inducer tunicamycin (TUN) were given before the onset of MV or SB. Diaphragm function, oxidative stress, and ER stress in the diaphragms were measured at the end of the experiments. Results: ER stress was markedly increased in diaphragms relative to that in SB after 12 h of MV (all p < 0.001). Inhibition of ER stress by 4-PBA downregulated the expression levels of proteolysis-related genes in skeletal muscle, including Atrogin-1 and MuRF-1, reduced myofiber atrophy, and improved diaphragm force-generating capacity in rats subjected to MV (all p < 0.01). In addition, mitochondrial reactive oxygen species (ROS) production and protein level of 4-HNE (4-hydroxynonenal) were decreased upon 4-PBA treatment in rats during MV (all p < 0.01). Interestingly, the 4-PBA treatment also markedly increased the expression of peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) (p < 0.01), a master regulator for mitochondrial function and a strong antioxidant. However, the antioxidant NAC failed to reduce ER stress in the diaphragm during MV (p > 0.05). Finally, ER stress inducer TUN largely compromised diaphragm dysfunction in the absence of oxidative stress (all p < 0.01). Conclusion: ER stress is induced by MV and the inhibition of ER stress alleviates oxidative stress in the diaphragm during MV. In addition, ER stress is responsible for diaphragm dysfunction in the absence of oxidative stress. Therefore, the inhibition of ER stress may be another promising therapeutic approach for the treatment of VIDD.}, } @article {pmid35829920, year = {2022}, author = {Tsikas, D and Mikuteit, M}, title = {N-Acetyl-L-cysteine in human rheumatoid arthritis and its effects on nitric oxide (NO) and malondialdehyde (MDA): analytical and clinical considerations.}, journal = {Amino acids}, volume = {54}, number = {9}, pages = {1251-1260}, pmid = {35829920}, issn = {1438-2199}, mesh = {*Acetylcysteine/pharmacology ; *Arthritis, Rheumatoid/drug therapy ; Biomarkers ; Humans ; Malondialdehyde ; Nitric Oxide/metabolism ; Oxidative Stress ; }, abstract = {N-Acetyl-L-cysteine (NAC) is an endogenous cysteine metabolite. The drug is widely used in chronic obstructive pulmonary disease (COPD) and as antidote in acetaminophen (paracetamol) intoxication. Currently, the utility of NAC is investigated in rheumatoid arthritis (RA), which is generally considered associated with inflammation and oxidative stress. Besides clinical laboratory parameters, the effects of NAC are evaluated by measuring in plasma or serum nitrite, nitrate or their sum (NOx) as measures of nitric oxide (NO) synthesis. Malondialdehyde (MDA) and relatives such as 4-hydroxy-nonenal and 15(S)-8-iso-prostaglandin F2α serve as measures of oxidative stress, notably lipid peroxidation. In this work, we review recent clinico-pharmacological studies on NAC in rheumatoid arthritis. We discuss analytical, pre-analytical and clinical issues and their potential impact on the studies outcome. Major issues include analytical inaccuracy due to interfering endogenous substances and artefactual formation of MDA and relatives during storage in long-term studies. Differences in the placebo and NAC groups at baseline with respect to these biomarkers are also a serious concern. Modern applied sciences are based on data generated using commercially available instrumental physico-chemical and immunological technologies and assays. The publication process of scientific work rarely undergoes rigorous peer review of the analytical approaches used in the study in terms of accuracy/trueness. There is pressing need of considering previously reported reference concentration ranges and intervals as well as specific critical issues such as artefactual formation of particular biomarkers during sample storage. The latter especially applies to surrogate biomarkers of oxidative stress, notably MDA and relatives. Reported data on NO, MDA and clinical parameters, including C-reactive protein, interleukins and tumour necrosis factor α, are contradictory in the literature. Furthermore, reported studies do not allow any valid conclusion about utility of NAC in RA. Administration of NAC patients with rheumatoid arthritis is not recommended in current European and American guidelines.}, } @article {pmid35821597, year = {2023}, author = {Zhou, S and Rao, Z and Xia, Y and Wang, Q and Liu, Z and Wang, P and Cheng, F and Zhou, H}, title = {CCAAT/Enhancer-binding Protein Homologous Protein Promotes ROS-mediated Liver Ischemia and Reperfusion Injury by Inhibiting Mitophagy in Hepatocytes.}, journal = {Transplantation}, volume = {107}, number = {1}, pages = {129-139}, pmid = {35821597}, issn = {1534-6080}, mesh = {Animals ; Mice ; Apoptosis ; Beclin-1/metabolism ; Hepatocytes/metabolism ; Hypoxia/metabolism ; Ischemia ; Liver/metabolism ; *Liver Diseases/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; *Reperfusion Injury/prevention & control/metabolism ; *Transcription Factor CHOP/genetics/metabolism ; }, abstract = {BACKGROUND: Liver ischemia and reperfusion (IR) injury represent a major risk factor in both partial hepatectomy and liver transplantation. CCAAT/enhancer-binding protein homologous protein (CHOP) is a key regulator of cell death, its precise molecular basis in regulating hepatocyte death during liver IR has not been delineated.

METHODS: Hepatocellular CHOP deficient mice were generated by bone marrow chimera models using global CHOP knockout mice. Liver partial warm ischemia model and hypoxia/reoxygenation model of primary hepatocytes were applied. Liver injury and mitophagy-related signaling pathways were investigated. IR-stressed patient liver tissues and serum samples were analyzed as well.

RESULTS: Mice with hepatocellular CHOP deficiency exhibited alleviated cell death, decreased reactive oxygen species (ROS) expression, and enhanced mitophagy in hepatocytes after IR, confirmed by in vitro studies of hepatocytes after hypoxia/reoxygenation. Mitochondria ROS scavenge by Mito TEMPO effectively attenuated hepatocyte death and liver IR injury of wild-type mice, whereas no significant effects were observed in hepatocellular CHOP -deficient mice. CHOP depletion upregulated dynamin-related protein 1 and Beclin-1 activation in the mitochondria of hepatocytes leading to enhanced mitophagy. Following IR, increased CHOP expression and impaired mitophagy activation were observed in the livers of patients undergoing hepatectomy. N-acetyl cysteine pretreatment significantly improved the liver function of patients after surgery.

CONCLUSIONS: IR-induced CHOP activation exacerbates ROS-mediated hepatocyte death by inhibiting dynamin-related protein 1-Beclin-1-dependent mitophagy.}, } @article {pmid35818509, year = {2022}, author = {Trabattoni, D and Brambilla, M and Canzano, P and Becchetti, A and Teruzzi, G and Porro, B and Fiorelli, S and Muratori, M and Tedesco, CC and Veglia, F and Montorsi, P and Bartorelli, AL and Tremoli, E and Camera, M}, title = {Migraine in Patients Undergoing PFO Closure: Characterization of a Platelet-Associated Pathophysiological Mechanism: The LEARNER Study.}, journal = {JACC. Basic to translational science}, volume = {7}, number = {6}, pages = {525-540}, pmid = {35818509}, issn = {2452-302X}, abstract = {The association between migraine and patent foramen ovale (PFO) has been documented. We aimed to investigate platelet activation, prothrombotic phenotype, and oxidative stress status of migraineurs with PFO on 100 mg/day aspirin, before and 6 months after PFO closure. Data show that, before PFO closure, expression of the classical platelet activation markers is comparable in patients and aspirin-treated healthy subjects. Conversely, MHA-PFO patients display an increased prothrombotic phenotype (higher tissue factor[pos] platelets and microvesicles and thrombin-generation potential), sustained by an altered oxidative stress status. This phenotype, which is more controlled by P2Y12-blockade than by aspirin, reverted after PFO closure together with a complete migraine remission. (pLatelEts And MigRaine iN patEnt foRamen Ovale [LEARNER]; NCT03521193).}, } @article {pmid35814787, year = {2022}, author = {Zhao, J and Li, M and Tan, C}, title = {Efficacy of N-acetylcysteine in Preventing Acute Kidney Injury and Major Adverse Cardiac Events After Cardiac Surgery: A Meta-Analysis and Trial Sequential Analysis.}, journal = {Frontiers in medicine}, volume = {9}, number = {}, pages = {795839}, pmid = {35814787}, issn = {2296-858X}, abstract = {BACKGROUND: The effect of N-acetylcysteine (NAC), an antioxidant, on preventing acute kidney injury (AKI) and major adverse cardiac events (MACE) remains controversial. Therefore, we conducted this meta-analysis and trial sequential analysis to evaluate its efficacy on cardiac surgery-related adverse events.

METHODS: PubMed, Embase, and Cochrane Library were searched for relevant studies from inception to June 2021. We selected randomized controlled trials comparing NAC with controls in patients undergoing cardiac surgery.

RESULTS: Twenty-five studies including 2,444 patients met the inclusion criteria. The pooled results showed that there was no significant difference in the incidence of AKI between the NAC and control groups [relative risk (RR) = 0.91, 95% confidence interval (CI) = 0.77, 1.08, P = 0.28], but the trial sequential analysis (TSA) could not confirm this result. No difference was observed in the need for renal replacement therapy (RRT), all-cause mortality, MACE, length of stay in the intensive care unit (ICU), and length of stay in the hospital. Results of subgroup analysis results showed that intravenous infusion instead of oral NAC could significantly reduce the incidence of AKI and arrhythmia (RR = 0.84, 95% CI = 0.71, 0.99, P = 0.03, I [2] = 3% and RR = 0.74, 95% CI = 0.61, 0.91, P = 0.004, I [2] = 48%, respectively).

CONCLUSION: Intravenous administration of NAC can reduce the incidence of AKI and arrhythmia in patients after cardiac surgery, but cannot reduce all-cause mortality, AMI, cardiac insufficiency, and the number of patients using RRT. Oral NAC has no significant effect on the outcomes of patients after cardiac surgery.}, } @article {pmid35814364, year = {2022}, author = {Domingo-Vidal, M and Whitaker-Menezes, D and Mollaee, M and Lin, Z and Tuluc, M and Philp, N and Johnson, JM and Zhan, T and Curry, J and Martinez-Outschoorn, U}, title = {Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {906494}, pmid = {35814364}, issn = {2234-943X}, support = {R37 CA234239/CA/NCI NIH HHS/United States ; }, abstract = {The most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor stroma of ADT cancers and exert pro-tumorigenic functions. Metabolically, glycolytic CAFs support the energy needs of oxidative (OXPHOS) carcinoma cells. Upregulation of the monocarboxylate transporter 4 (MCT4) and downregulation of isocitrate dehydrogenase 3α (IDH3α) are markers of glycolysis in CAFs, and upregulation of the monocarboxylate transporter 1 (MCT1) and the translocase of the outer mitochondrial membrane 20 (TOMM20) are markers of OXPHOS in carcinoma cells. It is unknown if glycolytic metabolism in CAFs is a driver of ADT cancer aggressiveness. In this study, co-cultures in vitro and co-injections in mice of ADT carcinoma cells with fibroblasts were used as experimental models to study the effects of fibroblasts on metabolic compartmentalization, oxidative stress, carcinoma cell proliferation and apoptosis, and overall tumor growth. Glycolytic metabolism in fibroblasts was modulated using the HIF-1α inhibitor BAY 87-2243, the antioxidant N-acetyl cysteine, and genetic depletion of MCT4. We found that ADT human tumors express markers of metabolic compartmentalization and that co-culture models of ADT cancers recapitulate human metabolic compartmentalization, have high levels of oxidative stress, and promote carcinoma cell proliferation and survival. In these models, BAY 87-2243 rescues IDH3α expression and NAC reduces MCT4 expression in fibroblasts, and these treatments decrease ADT carcinoma cell proliferation and increase cell death. Genetic depletion of fibroblast MCT4 decreases proliferation and survival of ADT carcinoma cells in co-culture. Moreover, co-injection of ADT carcinoma cells with fibroblasts lacking MCT4 reduces tumor growth and decreases the expression of markers of metabolic compartmentalization in tumors. In conclusion, metabolic compartmentalization with high expression of MCT4 in CAFs drives aggressiveness in ADT cancers.}, } @article {pmid35810264, year = {2022}, author = {Feng, H and Xi, F}, title = {Miltirone Attenuates Reactive Oxygen Species-Dependent Neuronal Apoptosis in MPP[+]-Induced Cell Model of Parkinson's Disease Through Regulating the PI3K/Akt Pathway.}, journal = {Neurochemical research}, volume = {47}, number = {10}, pages = {3137-3149}, pmid = {35810264}, issn = {1573-6903}, mesh = {1-Methyl-4-phenylpyridinium/toxicity ; Apoptosis ; Caspase 3/metabolism ; Cell Line, Tumor ; Humans ; *Neuroblastoma ; *Parkinson Disease/metabolism ; *Phenanthrenes/pharmacology ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Miltirone is a phenanthrene-quinone derived from Salvia miltiorrhiza Bunge with anti-inflammatory and anti-oxidant effects. Our study aimed to explore the protective effect of miltirone on 1-methyl-4-phenylpyridinium (MPP[+])-induced cell model of Parkinson's disease (PD). PharmMapper database was employed to predict the targets of miltirone. PD-related genes were identified using GeneCards database. The overlapping genes between miltirone and PD were screened out using Venn diagram. KEGG analysis was performed using DAVID and KOBAS databases. Cell viability, reactive oxygen species (ROS) generation, apoptosis, and caspase-3 activity were detected by CCK-8 assay, a ROS assay kit, TUNEL, and caspase-3 activity assay, respectively. Effect of miltirone on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway was explored by western blot analysis. A total of 214 targets of miltirone and 372 targets related to PD were attained, including 29 overlapping targets. KEGG analysis demonstrated that the 29 overlapping targets were both significantly enriched in the PI3K/Akt pathway. MPP[+] stimulation reduced the cell viability in SH-SY5Y cells and neuronal primary cultures derived from human brain. Miltirone or N-acetylcysteine (NAC) attenuated MPP[+]-induced reduction in cell viability, ROS production, SOD activity reduction, apoptosis, and increase of caspase-3 activity. Additionally, miltirone recuperated MPP[+]-induced inactivation of the PI3K/Akt pathway. Moreover, treatment with LY294002, an inhibitor of the PI3K/Akt pathway, reversed the inhibitory effect of miltirone on MPP[+]-induced ROS generation and apoptosis in SH-SY5Y cells and neuronal primary cultures. In conclusion, miltirone attenuated ROS-dependent apoptosis in MPP[+]-induced cellular model of PD through activating the PI3K/Akt pathway.}, } @article {pmid35806270, year = {2022}, author = {Ward, RJ and Dexter, DT and Crichton, RR}, title = {Iron, Neuroinflammation and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {23}, number = {13}, pages = {}, pmid = {35806270}, issn = {1422-0067}, mesh = {Humans ; Inflammation/metabolism ; *Iron/metabolism ; Iron-Regulatory Proteins/metabolism ; Microglia/metabolism ; *Neuroinflammatory Diseases ; }, abstract = {Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation.}, } @article {pmid35802043, year = {2022}, author = {Behera, J and Ison, J and Voor, MJ and Tyagi, N}, title = {Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage-Dependent miR-150-FNDC5/Pyroptosis Axis.}, journal = {Diabetes}, volume = {71}, number = {12}, pages = {2777-2792}, pmid = {35802043}, issn = {1939-327X}, support = {R01 AR067667/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Female ; Mice ; *Diabetes Mellitus, Experimental/genetics/metabolism ; *Diabetes Mellitus, Type 2/complications/genetics/metabolism ; *Fibronectins/metabolism ; *Glucose Intolerance/metabolism ; Mice, Inbred C57BL ; Muscle, Skeletal/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Osteoporosis/genetics/prevention & control ; Oxidative Stress ; Pyroptosis ; X-Ray Microtomography ; MicroRNAs/genetics ; }, abstract = {Recent evidence suggests that physical exercise (EX) promotes skeletal development. However, the impact of EX on the progression of bone loss and deterioration of mechanical strength in mice with type 2 diabetic mellitus (T2DM) remains unexplored. In the current study, we investigated the effect of EX on bone mass and mechanical quality using a diabetic mouse model. The T2DM mouse model was established with a high-fat diet with two streptozotocin injections (50 mg/kg/body wt) in C57BL/6 female mice. The diabetic mice underwent treadmill exercises (5 days/week at 7-11 m/min for 60 min/day) for 8 weeks. The data showed that diabetes upregulated miR-150 expression through oxidative stress and suppressed FNDC5/Irisin by binding to its 3'-untranslated region. The decreased level of irisin further triggers the pyroptosis response in diabetic bone tissue. EX or N-acetyl cysteine or anti-miRNA-150 transfection in T2DM mice restored FNDC5/Irisin expression and bone formation. Furthermore, EX or recombinant irisin administration prevented T2DM-Induced hyperglycemia and improved glucose intolerance in diabetic mice. Furthermore, osteoblastic knockdown of Nlrp3 silencing (si-Nlrp3) or pyroptosis inhibitor (Ac-YVADCMK [AYC]) treatment restores bone mineralization in diabetic mice. Micro-computed tomography scans and mechanical testing revealed that trabecular bone microarchitecture and bone mechanical properties were improved after EX in diabetic mice. Irisin, either induced by skeleton or daily EX or directly administered, prevents bone loss by mitigating inflammasome-associated pyroptosis signaling in diabetic mice. This study demonstrates that EX-induced skeletal irisin ameliorates diabetes-associated glucose intolerance and bone loss and possibly provides a mechanism of its effects on metabolic osteoporosis.}, } @article {pmid35799894, year = {2022}, author = {Zhu, D and Fan, T and Chen, Y and Huo, X and Li, Y and Liu, D and Cai, Y and Cheung, CW and Tang, J and Cui, J and Xia, Z}, title = {CXCR4/CX43 Regulate Diabetic Neuropathic Pain via Intercellular Interactions between Activated Neurons and Dysfunctional Astrocytes during Late Phase of Diabetes in Rats and the Effects of Antioxidant N-Acetyl-L-Cysteine.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8547563}, pmid = {35799894}, issn = {1942-0994}, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism ; Astrocytes/metabolism ; *Connexin 43/metabolism ; *Diabetes Mellitus, Experimental/metabolism ; *Diabetic Neuropathies/drug therapy/metabolism ; Hyperalgesia/drug therapy/metabolism ; *Neuralgia/drug therapy/metabolism ; Neurons/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Receptors, CXCR4/metabolism ; Receptors, Chemokine/metabolism ; Spinal Cord/metabolism ; }, abstract = {Growing evidence suggests that the interactions between astrocytes and neurons exert important functions in the central sensitization of the spinal cord dorsal horn in rodents with diabetes and neuropathic pain (DNP). However, it still remains unclear how signal transmission occurs in the spinal cord dorsal horn between astrocytes and neurons, especially in subjects with DNP. Chemokine CXC receptor 4 (CXCR4) plays critical roles in DNP, and connexin 43 (CX43), which is also primarily expressed by astrocytes, contributes to the development of neuropathy. We thus postulated that astrocytic and neuronal CXCR4 induces and produces inflammatory factors under persistent peripheral noxious stimulation in DNP, while intercellular CX43 can transmit inflammatory stimulation signals. The results showed that streptozotocin-induced type 1 diabetic rats developed heat hyperalgesia and mechanical allodynia. Diabetes led to persistent neuropathic pain. Diabetic rats developed peripheral sensitization at the early phase (2 weeks) and central sensitization at the late phase (5 weeks) after diabetes induction. Both CXCR4 and CX43, which are localized and coexpressed in neurons and astrocytes, were enhanced significantly in the dorsal horn of spinal cord in rats undergoing DNP during late phase of diabetes, and the CXCR4 antagonist AMD3100 reduced the expression of CX43. The nociceptive behavior was reversed, respectively, by AMD3100 at the early phase and by the antioxidant N-acetyl-L-cysteine (NAC) at the late phase. Furthermore, rats with DNP demonstrated downregulation of glial fibrillary acidic protein (GFAP) as well as upregulation of c-fos in the spinal cord dorsal horn at the late phase compared to the controls, and upregulation of GFAP and downregulation of c-fos were observed upon treatment with NAC. Given that GFAP and c-fos are, respectively, makers of astrocyte and neuronal activation, our findings suggest that CXCR4 as an inflammatory stimulation protein and CX43 as an intercellular signal transmission protein both may induce neurons excitability and astrocytes dysfunction in developing DNP.}, } @article {pmid35795313, year = {2022}, author = {Zhang, L and Xiong, Y and Du, L}, title = {Efficacy and Safety of N-Acetylcysteine for Chronic Obstructive Pulmonary Disease and Chronic Bronchitis.}, journal = {BioMed research international}, volume = {2022}, number = {}, pages = {9133777}, pmid = {35795313}, issn = {2314-6141}, mesh = {Acetylcysteine/adverse effects ; *Bronchitis, Chronic/chemically induced/drug therapy ; Double-Blind Method ; Humans ; *Pulmonary Disease, Chronic Obstructive ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis are associated with poor clinical outcomes. N-acetylcysteine (NAC) is a widely used therapeutic option for such patients; however, the clinical efficacy of NAC has not been conclusively determined. We hypothesized that high-dose oral NAC can improve the clinical outcomes for patients with concurrent chronic bronchitis and COPD. Objective and Methods. This was a randomized, double-blind, placebo-controlled trial evaluating the efficacy of high-dose NAC for COPD patients with concurrent chronic bronchitis. Study participants were randomized into two groups and administered with NAC (900 mg) twice daily or matching placebo for 3 months. Then, respiratory health status was evaluated using the St. George's Respiratory Questionnaire (SGQR), which was set as the primary end point.

RESULTS: A total of 143 COPD patients with chronic bronchitis were screened, and as a result, only 100 patients were enrolled in this study (50 participants were randomized to receive placebo, and others were randomized to receive NAC). After treatment, differences in SGQR scores between the placebo and NAC groups were not significant. Moreover, differences in secondary end points between the two groups after treatment were insignificant. Discussion. High-dose NAC has no marked clinical benefits for COPD patients with concurrent chronic bronchitis.}, } @article {pmid35791005, year = {2022}, author = {Kuruoglu, T and Altun, G and Kuruoglu, E and Turan, DB and Önger, ME}, title = {Actions of N-acetylcysteine, daptomycin, vancomycin, and linezolid on methicillin-resistant Staphylococcus aureus biofilms in the ventriculoperitoneal shunt infections: an experimental study.}, journal = {Chinese neurosurgical journal}, volume = {8}, number = {1}, pages = {15}, pmid = {35791005}, issn = {2057-4967}, abstract = {BACKGROUND: Shunt systems are used to provide cerebrospinal fluid drainage in the treatment of hydrocephalus. Recently, antibiotic-impregnated shunt systems are used to prevent colonization in the ventriculoperitoneal catheters. Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative microorganism of shunt infections. The aim of the study is to investigate effects of several substances on MRSA biofilms in the ventriculoperitoneal catheters.

METHODS: The present study consists of mainly eight groups (each has two subgroups as antibiotic-impregnated and nonantibiotic-impregnated catheters). In addition, each group contains six molds using MRSA strains. In this study, daptomycin (DAPT) (2 mg/ml), vancomycin (VAN) (10 mg/ml), linezolid (LIN) (2 mg/ml), N-acetylcysteine (NAC) (6 mg/ml), and various combinations of these substances were used to evaluate the treatment against MRSA using scanning electron microscope (SEM) images and microbiological enumeration.

RESULTS: The colony count in the antibiotic-impregnated samples significantly decreased compared to nonantibiotic-impregnated samples in the MRSA, MRSA + DAPT, and MRSA + LIN groups (p < 0.01), respectively. Conversely, the colony count in antibiotic-impregnated samples significantly increased compared to nonantibiotic-impregnated samples in NAC + DAPT and NAC + VAN groups (p < 0.01), respectively.

CONCLUSIONS: The results showed that the use of antibiotic-impregnated catheters has a significant impact on the prevention of infection whereas the combination of NAC and DAPT showed better antibiofilm and antibacterial effects than other combinations on the prevention and treatment of nonantibiotic-impregnated catheter infections.}, } @article {pmid35788981, year = {2022}, author = {Panda, M and Biswal, BK}, title = {Evodiamine inhibits stemness and metastasis by altering the SOX9-β-catenin axis in non-small-cell lung cancer.}, journal = {Journal of cellular biochemistry}, volume = {123}, number = {9}, pages = {1454-1466}, doi = {10.1002/jcb.30304}, pmid = {35788981}, issn = {1097-4644}, support = {1201//Department of Science and Technology, Odisha, India/ ; ECR/2016/000792//Science and Engineering Research Board/ ; }, mesh = {*Alkaloids/pharmacology ; Apoptosis ; Cadherins ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cysteine ; Humans ; *Lung Neoplasms/drug therapy ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Quinazolines ; Reactive Oxygen Species ; SOX9 Transcription Factor ; Vimentin ; beta Catenin/metabolism ; }, abstract = {Evodiamine (EVO), a natural dietary alkaloid extracted from the roots of the Evodia rutaecarpa, has shown anticancer activities. Here, we have investigated EVO's role in inhibiting cell proliferation and migration in A549 and NCI-H522 lung cancer cells. EVO decreased the cell viability in A549 and NCI-H522 cells in a dose- and time-dependent manner. It also induced apoptosis by downregulating the expression of antiapoptotic Bcl-2 and upregulating the expression of cleaved caspase-3 and PARP. In addition, the treatment of EVO elevated the level of reactive oxygen species (ROS) generation inside the cells to induce the cell death pathways. In contrast, the pretreatment of ROS scavenger, N-acetyl cysteine, reverses the effect of EVO and attenuates cell death. Moreover, excess ROS generation in response to EVO resulted in the depletion of mitochondrial membrane potential. Furthermore, it induced DNA damage and arrested the cell cycle at the G2/M phase in A549 and NCI-H522 cells. Our study also investigated that EVO significantly suppressed tumorigenicity by inhibiting colony formation and tumorsphere formation. However, the treatment of EVO downregulated the cancer stem cell markers CD44 and CD133 in non-small-cell lung cancer. The inhibitory effect of EVO on cell invasion was mediated by altering the expression of E-cadherin, ZO-1, N-cadherin, and Vimentin. Additionally, we have revealed that EVO treatment showed downregulation of SOX9, an upstream component of β-catenin. Lastly, we have demonstrated that EVO targets the SOX9-β-catenin axis by reducing SOX9 and β-catenin expression. These findings suggested that EVO could be a promising agent for treating human lung cancer.}, } @article {pmid35788669, year = {2022}, author = {Magner, K and Ilin, JV and Clark, EG and Kong, JWY and Davis, A and Hiremath, S}, title = {Meta-analytic Techniques to Assess the Association Between N-acetylcysteine and Acute Kidney Injury After Contrast Administration: A Systematic Review and Meta-analysis.}, journal = {JAMA network open}, volume = {5}, number = {7}, pages = {e2220671}, pmid = {35788669}, issn = {2574-3805}, mesh = {*Acetylcysteine/adverse effects/therapeutic use ; *Acute Kidney Injury/chemically induced/prevention & control ; Humans ; Publication Bias ; Renal Dialysis ; Renal Replacement Therapy ; }, abstract = {IMPORTANCE: The most suitable analytic method to systematically analyze numerous trials with contradictory results is unclear. Multiple trials assessing the use of N-acetylcysteine (NAC) for prevention of contrast-induced acute kidney injury (CI-AKI) have had contradictory results with recent trials confirming a lack of benefit.

OBJECTIVE: To systematically review the literature on NAC for the prevention of CI-AKI, and to explore the heterogeneity, publication bias, and small-study effect to determine the most suitable analytic method in a setting where the literature is contradictory.

DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials databases were used to find randomized clinical trials (RCTs) comparing NAC with any other prophylactic agent or placebo in adults.

STUDY SELECTION: The search included studies published in English from database inception to January 2020. Two independent reviewers screened the studies, extracted data, and performed the risk of bias assessment.

DATA EXTRACTION AND SYNTHESIS: A meta-analysis was conducted about the effect of NAC on CI-AKI, the need for dialysis, and mortality. Fixed and random effects analyses were also performed. Funnel plots and the trim and fill method were used for assessment of publication bias. Metaregression was performed to explore the heterogeneity and subgroup analysis to examine the association between NAC and CI-AKI when studies were categorized according to sample size and number of events.

RESULTS: A total of 101 trials were included in this meta-analysis. The median sample size was 112 (range, 20 to 4993). Twenty-nine trials had a sample size of 200 or more, and only 3 trials had a sample size of 500 or more. Forty-five trials reported the need for kidney replacement therapy, and 41 trials reported mortality as an outcome. NAC seemed to show a benefit, with a pooled OR of 0.72 (95% CI, 0.63-0.82) using random effects model and a pooled OR of 0.82 (95% CI 0.76-0.90) using a fixed effects model. However, there was significant heterogeneity (I2 = 37.6; P < .001) and significant publication bias, which was reduced only when restricting to large RCTs (N ≥ 500). The clinical outcomes (ie, the need for kidney replacement therapy and mortality) revealed little heterogeneity and no publication bias, and each provided a robust neutral summary result.

CONCLUSIONS AND RELEVANCE: In this meta-analysis, NAC was associated with a benefit in the prevention of CI-AKI. However, because of substantial publication bias and other biases, standard meta-analytic techniques resulted in significant heterogeneity and a spurious, or factitious, association, even when using a random effects model. When the analysis was restricted to RCTs with a large sample size to account for publication bias or restricted to trials with clinical outcomes, this issue was reduced and resulted in more robust and neutral effect sizes.}, } @article {pmid35783478, year = {2022}, author = {Licks, F and Minuzzo Hartmann, R and Schemitt, E and Raskopf Colares, J and Marques, C and Fillmann, H and Possa Marroni, N}, title = {Synergistic antioxidant and anti-inflammatory action of N-acetylcysteine in portal hypertensive gastropathy in rats.}, journal = {Hepatology forum}, volume = {3}, number = {2}, pages = {51-56}, pmid = {35783478}, issn = {2757-7392}, abstract = {BACKGROUND AND AIM: Portal hypertension (PH) is a syndrome associated with cirrhosis and characterized by a progressive increase in portal pressure, with consequent compensatory vascular dilation. Gastric vascular changes associated with oxidative and nitrosative stress characterize the clinical presentation of portal hypertensive gastropathy (PHG). In addition, the inflammatory process is considered an aggravating factor for severity by contributing to gastric tissue injury. The aim of this study was to investigate the synergistic anti-inflammatory and antioxidant action of N-acetylcysteine (NAC) in the stomach of rats with PH.

MATERIALS AND METHODS: Eighteen Wistar male rats were used in this experimental protocol and were divided into three groups with six in each group: sham-operated (SO), partial portal vein ligation (PPVL), and PPVL + NAC. Treatment with NAC at a dose of 10 mg/kg (i.p.) was initiated on day 8 after surgery and continued for 7 days. We evaluated the expression of iNOS, NQO-1, HSP-90, and SOD by Western blot, as well as nuclear factor-kappa B (NF-κB) and tumor necrosis factor (TNF)-α staining by immunohistochemistry, in the rat stomach.

RESULTS: The PPVL group exhibited increased expression of HSP-90, iNOS, SOD, and NQO-1 when compared with controls. NAC reduced the expression of all studied proteins. Similarly, NF-κB and TNF-α staining was increased in PPVL animals versus controls and reduced in PPVL + NAC versus PPVL animals, respectively.

CONCLUSION: These results suggest the effectiveness of NAC as a dual anti-inflammatory and antioxidant in animals with experimental PHG induced by partial ligation of the portal vein.}, } @article {pmid35779304, year = {2022}, author = {Motallebzadeh, E and Suliman Maashi, M and Mahmoud, MZ and Aliasgharzedeh, A and Vakili, Z and Talaei, SA and Mohseni, M}, title = {Radioprotective effects of N-acetylcysteine on rats' brainstem following megavoltage X-irradiations.}, journal = {Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine}, volume = {187}, number = {}, pages = {110348}, doi = {10.1016/j.apradiso.2022.110348}, pmid = {35779304}, issn = {1872-9800}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Antioxidants/metabolism ; *Brain Stem/metabolism/radiation effects ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; *Radiation-Protective Agents/pharmacology ; Rats ; Superoxide Dismutase/metabolism ; X-Rays/adverse effects ; }, abstract = {PURPOSE: This study aimed to determine the radioprotective effect of N-acetylcysteine (NAC) on the radiation-induced oxidative stress (OS) in the rats' brainstem.

MATERIALS AND METHODS: Eighty rats in four identical groups, including vehicle control (VC), irradiation alone (RAD), irradiation with 1 g/kg of NAC treatment (RAN), and NAC treatment without radiation (NAC) were used. Whole-brain irradiation was performed with a single dose of 25 Gy. The rats received the treatments via intraperitoneal (IP) injection 1 h before the irradiation process. Nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), and glutathione peroxidase (GPx) were measured in the rats' brainstem and compared between the groups. Furthermore, the pathological study was performed to assess tissue damage after 24 h, 72 h, and 5 days of irradiation.

RESULTS: The levels of NO and MDA in the brainstem tissue for the RAD group were 60.37 ± 3.35 μmol/L and 45.10 ± 2.48 μM, respectively, which were higher than those of VC group (NO: 30.41 ± 1.83 μmol/L; MDA: 31.02 ± 1.71 μM). The level of SOD, CAT, TAC, and GPx declined in the RAD compared to the VC group. Pre-treatment with NAC decreased the level of NO and MDA and also enhanced the antioxidant activities. The greatest pathological changes in the rats' brainstems were seen in RAD animals compared to the VC group at 24 h, 72 h, and 5 days. Furthermore, the pathological changes were not observed in the NAC group in all the assessed times.

CONCLUSION: Based on the results, NAC can decrease the irradiation-induced oxidative stress and pathology damages in the rats' brainstem. It can be concluded that NAC can be an appropriate radioprotection candidate for the human brainstem.}, } @article {pmid35777681, year = {2022}, author = {Zhang, T and Shen, Y and Zhu, R and Shan, W and Li, Y and Yan, M and Zhang, Y}, title = {Benzo[a]pyrene exposure promotes RIP1-mediated necroptotic death of osteocytes and the JNK/IL-18 pathway activation via generation of reactive oxygen species.}, journal = {Toxicology}, volume = {476}, number = {}, pages = {153244}, doi = {10.1016/j.tox.2022.153244}, pmid = {35777681}, issn = {1879-3185}, mesh = {Animals ; *Benzo(a)pyrene/toxicity ; Cell Death ; *Interleukin-18 ; MAP Kinase Kinase 4/metabolism ; Mice ; Osteocytes/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) of environmental pollutants, readily produced during the processing of petroleum and fatty foods. BaP exposure can cause skeletal deformities. However, whether BaP affects osteocytes, making up over 95% of all the bone cells, remains unknown. This study aimed to investigate the effect of BaP on osteocytes in vivo and in vitro, as well as explore the underlying mechanisms. The in vivo data showed that BaP (50 mg/kg) exposure for 12 weeks could cause bone destruction, and increase osteocytes death in mouse cortical femur. Our in vitro results revealed that BaP (25-100 μmol/L) exposure inhibited cell viability of MLO-Y4 cells, and resulted in cell death in a dose-dependent manner. Furthermore, BaP exposure significantly triggered necroptosis of MLO-Y4 cells, as indicated by increased propidium iodide (PI)-positive cells and up-regulation of necroptosis-related protein expressions of receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). This necrotic effect was reversed by the RIP1 inhibitor necrostatin-1 (Nec-1). Simultaneously, BaP activated the downstream c-Jun N-terminal kinase (JNK)/ interleukin (IL)-18 signaling pathway, which was suppressed after the JNK inhibitor SP600125 or Nec-1 treatment. In addition, BaP exposure promoted the production of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), and elevated malondialdehyde (MDA) levels; while BaP decreased superoxide dismutase (SOD) activity and antioxidant enzymes including nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels, leading to oxidative damage. The ROS scavenger N-acetylcysteine (NAC) inhibited this necroptotic death and the JNK/IL-18 pathway activation. Collectively, BaP exposure may cause RIP1-mediated necroptotic death of osteocytes and activate the JNK/IL-18 pathway via ROS generation.}, } @article {pmid35777452, year = {2022}, author = {Martínez-González, JJ and Ríos-Morales, SL and Guevara-Flores, A and Ramos-Godinez, MDP and López-Saavedra, A and Rendón, JL and Del Arenal Mena, IP}, title = {Evaluating the effect of curcumin on the metacestode of Taenia crassiceps.}, journal = {Experimental parasitology}, volume = {239}, number = {}, pages = {108319}, doi = {10.1016/j.exppara.2022.108319}, pmid = {35777452}, issn = {1090-2449}, mesh = {Animals ; *Anthelmintics/pharmacology ; *Curcumin/pharmacology ; *Cysticercosis/drug therapy ; Cysticercus ; Mice ; Mice, Inbred BALB C ; Oxidative Stress ; *Taenia ; }, abstract = {Curcumin, a curcuminoid present in the rhizome of the plant Curcuma longa has multiple pharmacological effects including anticarcinogenic and anti-inflammatory properties. This work evaluates the anthelmintic effect of the curcumin molecule (98% pure) on Taenia crassiceps cysticerci viability in vitro. Cysticerci incubated in the presence of increasing concentrations of curcumin showed a dose-dependent mortality correlated with a significant increase in the production of reactive oxygen species and a partial inhibition of thioredoxin-glutathione reductase, the only disulfide reductase present in these parasites. At 500 μM curcumin, a 100% of cysticerci lethality was obtained after 2 h of treatment. These results suggest the curcumin-induced oxidative stress could be in the origin of the anthelminthic effect of curcumin. Mice with cysticerci were injected intraperitoneally with 20, 40, or 60 mM curcumin daily for 30 days. A decrease in the burden of cysticerci (46%) was observed with a 60 mM dose of curcumin, supporting this compound as a potential anthelmintic drug.}, } @article {pmid35777063, year = {2022}, author = {Chen, SL and Ho, CY and Chin, SC}, title = {Effects of oral N-acetylcysteine combined with oral prednisolone on idiopathic sudden sensorineural hearing loss.}, journal = {Medicine}, volume = {101}, number = {26}, pages = {e29792}, pmid = {35777063}, issn = {1536-5964}, mesh = {Acetylcysteine/therapeutic use ; Glucocorticoids/therapeutic use ; *Hearing Loss, Sensorineural/diagnosis/drug therapy ; *Hearing Loss, Sudden/diagnosis/drug therapy ; Humans ; Prednisolone/therapeutic use ; Retrospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is an acute condition that presents with sudden hearing loss, for which steroids remain the main treatment. N-acetylcysteine (NAC), as a precursor of glutathione, can reduce the production of reactive oxygen species to protect hair cells in the inner ear from damage. However, data regarding the therapeutic outcomes of oral steroid combined with oral NAC for ISSNHL are still limited. This study was performed to investigate this issue.

METHODS: Between June 2016 and October 2021, 219 patients (219 ears) diagnosed with ISSNHL and treated with oral prednisolone were enrolled in this retrospective study. Oral NAC was prescribed to 94 of these patients (NAC group) but not to the remaining 125 patients (non-NAC group). The clinical and audiological findings were assessed.

RESULTS: The NAC group showed a mean hearing level gain of 29.5 ± 21.8 dB, speech reception threshold (SRT) gain of 26.2 ± 34.4 dB, and speech discrimination score (SDS) gain of 25.5 ± 30.4%. Although the NAC group had better mean hearing level, SRT, and SDS gains than the non-NAC group, the differences were not statistically significant (all P > .05). The only significant difference between the NAC and non-NAC groups was the posttreatment pure tone audiometry (PTA) thresholds at 8 kHz, which were 54.2 ± 24.4 and 60.9 ± 34.1 dB, respectively (P = .046).

CONCLUSIONS: This study demonstrated the effect of oral steroid combined with oral NAC for ISSNHL. Both the NAC and non-NAC groups showed obvious improvement in all PTA thresholds, as well as mean hearing level, SRT, and SDS gains. The NAC group showed significantly better PTA performance at a high frequency (8 kHz) than the non-NAC group. Therefore, for oral treatment of ISSNHL, we advocate concurrent use of oral prednisolone and oral NAC.}, } @article {pmid35775164, year = {2022}, author = {Tu, C and Lai, S and Huang, Z and Cai, G and Zhao, K and Gao, J and Wu, Z and Zhong, Z}, title = {Accumulation of advanced oxidation protein products contributes to age-related impairment of gap junction intercellular communication in osteocytes of male mice.}, journal = {Bone & joint research}, volume = {11}, number = {7}, pages = {413-425}, pmid = {35775164}, issn = {2046-3758}, abstract = {AIMS: Gap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes' GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes' GJIC in aged male mice and its mechanism.

METHODS: Changes in AOPP levels, expression of connexin43 (Cx43), osteocyte network, and bone mass were detected in 18-month-old and three-month-old male mice. Cx43 expression, GJIC function, mitochondria membrane potential, reactive oxygen species (ROS) levels, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation were detected in murine osteocyte-like cells (MLOY4 cells) treated with AOPPs. The Cx43 expression, osteocyte network, bone mass, and mechanical properties were detected in three-month-old mice treated with AOPPs for 12 weeks.

RESULTS: The AOPP levels were increased in aged mice and correlated with degeneration of osteocyte network, loss of bone mass, and decreased Cx43 expression. AOPP intervention induced NADPH oxidase activation and mitochondrial dysfunction, triggered ROS generation, reduced Cx43 expression, and ultimately impaired osteocytes' GJIC, which were ameliorated by NADPH oxidase inhibitor apocynin, mitochondria-targeted superoxide dismutase mimetic (mito-TEMPO), and ROS scavenger N-acetyl cysteine. Chronic AOPP loading accelerated the degradation of osteocyte networks and decreased Cx43 expression, resulting in deterioration of bone mass and mechanical properties in vivo.

CONCLUSION: Our study suggests that AOPP accumulation contributes to age-related impairment of GJIC in osteocytes of male mice, which may be part of the pathogenic mechanism responsible for bone loss during ageing. Cite this article: Bone Joint Res 2022;11(7):413-425.}, } @article {pmid35770045, year = {2022}, author = {Xin, Q and Ji, Q and Zhang, Y and Ma, W and Tian, B and Liu, Y and Chen, Y and Wang, F and Zhang, R and Wang, X and Yuan, J}, title = {Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {1112987}, pmid = {35770045}, issn = {1942-0994}, mesh = {*Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis ; *Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Proliferation ; Cisplatin/pharmacology/therapeutic use ; Drug Resistance, Neoplasm ; Humans ; *Lung Neoplasms/pathology ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.}, } @article {pmid35769842, year = {2021}, author = {Mosayebi, S and Soltani, R and Shafiee, F and Assarzadeh, S and Hakamifard, A}, title = {Evaluation of the Effectiveness of N-Acetylcysteine in the Prevention of Colistin-Induced Nephrotoxicity: A Randomized Controlled Clinical Trial.}, journal = {Journal of research in pharmacy practice}, volume = {10}, number = {4}, pages = {159-165}, pmid = {35769842}, issn = {2319-9644}, abstract = {OBJECTIVE: The present study aimed to evaluate the effectiveness of N-Acetylcysteine (NAC), as an antioxidant, in preventing nephrotoxicity in patients receiving colistin.

METHODS: In a randomized controlled clinical trial, eligible participants receiving colistin were divided into two groups including drug (n = 43) and control (n = 39). In the drug group, 1200 mg of NAC was administered daily for 10 days concurrently with colistin. Patients in the control group received only colistin. The serum creatinine level (SCr), blood urea nitrogen (BUN), and creatinine clearance (CrCl) at baseline and every other day, and the number of cases with acute kidney injury (AKI) during the study were recorded. Before starting treatment and on day 5, the level of urinary neutrophil gelatinase-associated lipocalin (NGAL) was determined. Finally, the values were compared between the groups.

FINDINGS: There was a significant increase in SCr and BUN and a significant reduction in CrCl in both groups, but there was not any significant difference between the two groups at any time. Changes in the urine NGAL levels were not significantly different between the two groups. Even though the number of cases with AKI in the drug group (8 cases, 18.6%) was less than the control group (11 cases, 28.2%), the difference was not statistically significant (P = 0.303).

CONCLUSION: Simultaneous administration of NAC with a dose of 1200 mg daily does not have any effect in the prevention of colistin-induced nephrotoxicity.}, } @article {pmid35769058, year = {2022}, author = {Song, K and Yang, GM and Han, J and Gil, M and Dayem, AA and Kim, K and Lim, KM and Kang, GH and Kim, S and Jang, SB and Vellingiri, B and Cho, SG}, title = {Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4'-Dihydroxyflavone, U0126, and N-Acetyl Cysteine.}, journal = {International journal of stem cells}, volume = {15}, number = {3}, pages = {334-345}, pmid = {35769058}, issn = {2005-3606}, abstract = {BACKGROUND AND OBJECTIVES: Flavonoids form the largest group of plant phenols and have various biological and pharmacological activities. In this study, we investigated the effect of a flavonoid, 3, 4'-dihydroxyflavone (3, 4'-DHF) on osteogenic differentiation of equine adipose-derived stromal cells (eADSCs).

METHODS AND RESULTS: Treatment of 3, 4'-DHF led to increased osteogenic differentiation of eADSCs by increasing phosphorylation of ERK and modulating Reactive Oxygen Species (ROS) generation. Although PD98059, an ERK inhibitor, suppressed osteogenic differentiation, another ERK inhibitor, U0126, apparently increased osteogenic differentiation of the 3, 4'-DHF-treated eADSCs, which may indicate that the effect of U0126 on bone morphogenetic protein signaling is involved in the regulation of 3, 4'-DHF in osteogenic differentiation of eADSCs. We revealed that 3, 4'-DHF could induce osteogenic differentiation of eADSCs by suppressing ROS generation and co-treatment of 3, 4'-DHF, U0126, and/or N-acetyl cysteine (NAC) resulted in the additive enhancement of osteogenic differentiation of eADSCs.

CONCLUSIONS: Our results showed that co-treatment of 3, 4'-DHF, U0126, and/or NAC cumulatively regulated osteogenesis in eADSCs, suggesting that 3, 4'-DHF, a flavonoid, can provide a novel approach to the treatment of osteoporosis and can provide potential therapeutic applications in therapeutics and regenerative medicine for human and companion animals.}, } @article {pmid35765435, year = {2022}, author = {Madarshahian, S and Enayati, M and Vinyes Parés, G and Ufheil, G and Abbaspourrad, A}, title = {Solid phase wax coating of N-acetylcysteine (NAC) to decrease its solubility profile as a ready to mix supplement.}, journal = {RSC advances}, volume = {12}, number = {27}, pages = {17550-17558}, pmid = {35765435}, issn = {2046-2069}, abstract = {N-Acetylcysteine (NAC) has health benefits attributed to its antioxidant properties and disulfide bond cleavage ability. Unfortunately, solutions of NAC are acidic with an undesirable taste and an unpleasant aftertaste. A method for slowing NAC release in water was developed using a solid phase wax coating. A coating of natural waxes, using food grade corn oil as the solvent and surfactants to facilitate the wax coating on the particles was used to decrease the solubility of NAC powder, crystals, and granules in water. A high NAC loading, between 55 and 91% for NAC granules and NAC crystals, was achieved as measured using LC-MS. The NAC wax-coated particles were fully characterized, and microscopy and SEM images revealed the shape, morphology, and size of the particles. Conductometry was used to study NAC release profile in water from wax-coated particles and the results indicate that solid phase wax coatings slowed the release of NAC into water.}, } @article {pmid35761113, year = {2023}, author = {Abedini Bajgiran, F and Khazaei Koohpar, Z and Salehzadeh, A}, title = {Effects of N-Acetylcysteine Supplementation on Oxidative Stress and Expression of Apoptosis-Related Genes in Testicular Tissue of Rats Exposed to Lead.}, journal = {Biological trace element research}, volume = {201}, number = {5}, pages = {2407-2415}, pmid = {35761113}, issn = {1559-0720}, mesh = {Rats ; Male ; Animals ; *Antioxidants/pharmacology/metabolism ; *Acetylcysteine/pharmacology ; Lead/metabolism ; Semen/metabolism ; Testis ; Oxidative Stress ; Spermatozoa ; 8-Hydroxy-2'-Deoxyguanosine/metabolism/pharmacology ; Apoptosis ; Dietary Supplements ; }, abstract = {BACKGROUND: Lead occupational exposure is now a main concern in the modern world. Lead is a non-biodegradable element with multi-devastating effects on different organs. Acute or chronic exposure to lead is reported to be one of the most important causes of infertility both in males and females basically by inducing oxidative stress and apoptosis.

OBJECTIVES: The current study scrutinized the mitigating effects of N-acetylcysteine (NAC) on lead toxicity, oxidative stress, and apoptotic/anti-apoptotic genes in the testis tissues of male rats.

METHODS: Rats were randomly divided into a control group (G1) and four study groups treated with single and continuous doses of lead with and without NAC administration. Malondialdehyde (MDA), total antioxidant capacity (TAC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were analyzed as oxidative stress biomarkers and the expression of apoptosis-related genes was studied using RT-PCR.

RESULTS: Continuous exposure to lead caused a significant decrease in sperm count, motility, viability, and morphology (P < 0.001). Number of germinal cells, Leydig cells, spermatocytes, and the diameter of seminiferous tubule were significantly decreased (P < 0.001) in G3 group. Continuous exposure to lead significantly decreased TAC content, but increased the levels of MDA and 8-OHdG (P < 0.001). Administration of continuous dose of lead dramatically increased expression of Bax, Caspase-3, Caspase-8, Cytochrome-C, MMP2, and MMP9 genes in testicular tissue. NAC treatments not only improved morphological changes and sperm quality, but also enhanced antioxidant balance and modulated apoptosis process in testicular tissue of rats.

CONCLUSION: Lead exposure strongly motivated testicular cells towards apoptosis, caused an oxidant/antioxidant imbalance, and decreased sperm quality along with morphological changes in testis cells. NAC treatments was associated with protective effects on testicular tissue mainly by rebalancing of the antioxidants capacity, as well as downregulation of apoptosis-related genes.}, } @article {pmid35756790, year = {2022}, author = {Xi, X and Li, ZX and Zhao, Y and Liu, H and Chen, S and Liu, DX}, title = {N-acetylcysteine promotes cyclic mechanical stress-induced osteogenic differentiation of periodontal ligament stem cells by down-regulating Nrf2 expression.}, journal = {Journal of dental sciences}, volume = {17}, number = {2}, pages = {750-762}, pmid = {35756790}, issn = {2213-8862}, abstract = {BACKGROUND/PURPOSE: Mechanical stress plays a vital role in osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Cyclic mechanical stress may up-regulate reactive oxygen species (ROS) level. N-acetylcysteine (NAC) possesses powerful antioxidant capacity. However, it is undefined the impact of NAC on osteogenic differentiation stimulated by cyclic mechanical stress in PDLSCs. The aim of our research was to study the effect of NAC on PDLSCs during osteogenic differentiation under cyclic mechanical stress.

MATERIALS AND METHODS: The expression levels of osteogenesis markers were used to examine the osteogenic differentiation of PDLSCs. ROS production were measured by flow cytometry. The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) were analyzed. We also examined the changes of alveolar bone and periodontal ligament (PDL) tissues in orthodontic rats by micro-computed tomography (micro-CT) system and immunohistochemistry (IHC) staining. The nuclear factor erythroid-2-related factor-2 (Nrf2) expression was examined.

RESULTS: NAC could enhance the osteogenic differentiation and up-regulate the GSH level as well as the ratio of GSH/GSSG, while down-regulate ROS generation and Nrf2 expression induced by cyclic mechanical stress in PDLSCs. NAC had beneficial effects on the microstructure of alveolar bone and enhanced the expression levels of osteogenesis markers, such as alkaline phosphatase (ALP) and collagen type 1 (COL1) in PDL in orthodontic rats at the tension side.

CONCLUSION: NAC could improve the osteogenic differentiation stimulated by cyclic mechanical stress in PDLSCs and in orthodontic rats, suggesting a potential therapeutic approach for alveolar bone remodeling in orthodontics.}, } @article {pmid35755270, year = {2022}, author = {Mendivil-Perez, M and Jimenez-Del-Rio, M and Velez-Pardo, C}, title = {Polycationic peptide R[7]-G-Aβ25-35 selectively induces cell death in leukemia Jurkat T cells through speedy mitochondrial depolarization, and CASPASE-3 -independent mechanism.}, journal = {Biochemistry and biophysics reports}, volume = {31}, number = {}, pages = {101300}, pmid = {35755270}, issn = {2405-5808}, abstract = {BACKGROUND: Acute lymphoblastic leukemia (ALL) is still incurable hematologic neoplasia in an important percentage of patients. Therefore, new therapeutic approaches need to be developed.

METHODS: To evaluate the cellular effect of cell-penetrating peptides (C-PP) on leukemia cells, Jurkat cells -a model of ALL were exposed to increasing concentration (50-500 μM) Aβ25-35, R[7]-G-Aβ25-35 and Aβ25-35-G-R[7] peptide for 24 h. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry (FC), and fluorescent microscopy (FM) analysis were used to assess metabolic viability, cell cycle and proliferation, mitochondria functionality, oxidative stress, and cell death markers.

RESULTS: We report for the first time that the R[7]-G-Aβ25-35, but not Aβ25-35 peptide, induced selective cell death in Jurkat cells more efficiently than the Aβ25-35-G-R[7] peptide. Indeed, R[7]-G-Aβ25-35 (200 μM) altered the metabolic activity (-25%), arrested the cell cycle in the G2/M-phase (15%), and induced a significant reduction of cellular proliferation (i.e., -74% reduction of Ki-67 nuclei reactivity). Moreover, R[7]-G-Aβ25-35 induced the dissipation of mitochondrial membrane potential (ΔΨm, 51%) and produced an important amount of reactive oxygen species (ROS, 75% at 8 h) in Jurkat cells. The exposure of cells to antioxidant/cytoprotectant N-acetylcysteine (NAC) did not prevent R[7]-G-Aβ25-35 from a loss of ΔΨm in Jurkat cells. The peptide was also unable to activate the executer CASPASE-3, thereby preserving the integrity of the cellular DNA corroborated by the fact that the caspase-3 inhibitor NSCI was unable to protect cells from R[7]-G-Aβ25-35 -induced cell damage. Further analysis showed that the R[7]-G-Aβ25-35 peptide is specifically localized at the outer mitochondria membrane (OMM) according to colocalization with the protein translocase TOMM20. Additionally, the cytotoxic effect of the poly-R[7] peptide resembles the toxic action of the uncoupler FCCP, mitocan oligomycin, and rotenone in Jurkat cells. Importantly, the R[7]-G-Aβ25-35 peptide was innocuous to menstrual mesenchymal stromal cells (MenSC) -normal non-leukemia proliferative cells.

CONCLUSION: Our findings demonstrated that the cationic Aβ peptide possesses specific anti-leukemia activity against Jurkat cells through oxidative stress (OS)- and CASPASE-3-independent mechanism but fast mitochondria depolarization.}, } @article {pmid35753672, year = {2022}, author = {Ben Othmène, Y and Monceaux, K and Belhadef, A and Karoui, A and Ben Salem, I and Boussabbeh, M and Abid-Essefi, S and Lemaire, C}, title = {Triazole fungicide tebuconazole induces apoptosis through ROS-mediated endoplasmic reticulum stress pathway.}, journal = {Environmental toxicology and pharmacology}, volume = {94}, number = {}, pages = {103919}, doi = {10.1016/j.etap.2022.103919}, pmid = {35753672}, issn = {1872-7077}, mesh = {Animals ; Apoptosis ; *Endoplasmic Reticulum Stress ; *Fungicides, Industrial/toxicity ; Mammals/metabolism ; Reactive Oxygen Species/metabolism ; Triazoles/toxicity ; }, abstract = {Tebuconazole (TEB) is a common triazole fungicide that has been widely applied in the treatment of fungal diseases. It is reported that TEB could exert harmful effects on mammals' health. However, the molecular mechanism involved in TEB toxicity remain undefined. Our study aimed to investigate the mechanisms of TEB-induced toxicity in intestinal cells. We found that TEB stimulates apoptosis through the mitochondrial pathway. Additionally, TEB triggers endoplasmic reticulum (ER) stress as demonstrated by the activation of the three arms of unfolded protein response (UPR). The incubation with the chemical chaperone 4-phenylbutyrate (4-PBA) alleviated ER stress and reduced TEB-induced apoptosis, suggesting that ER stress plays an important role in mediating TEB-induced toxicity. Furthermore, inhibition of ROS by N-acetylcysteine (NAC) inhibited TEB-induced ER stress and apoptosis. Taken together, these findings suggest that TEB exerts its toxic effects in HCT116 cells by inducing apoptosis through ROS-mediated ER stress and mitochondrial apoptotic pathway.}, } @article {pmid35753275, year = {2022}, author = {Zhang, Y and Hu, B and Qian, X and Xu, G and Jin, X and Chen, D and Tang, J and Xu, L}, title = {Transcriptomics-based analysis of co-exposure of cadmium (Cd) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) indicates mitochondrial dysfunction induces NLRP3 inflammasome and inflammatory cell death in renal tubular epithelial cells.}, journal = {Ecotoxicology and environmental safety}, volume = {241}, number = {}, pages = {113790}, doi = {10.1016/j.ecoenv.2022.113790}, pmid = {35753275}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cadmium/toxicity ; Caspase 1/metabolism ; Epithelial Cells ; Ether/metabolism/pharmacology ; *Halogenated Diphenyl Ethers/metabolism/toxicity ; Humans ; *Inflammasomes/genetics/metabolism ; Mitochondria/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Transcriptome ; }, abstract = {Environmental pollution often releases multiple contaminants resulting in as yet largely uncharacterized additive toxicities. Cadmium (Cd) is a widespread pollutant that induces nephrotoxicity in animal models and humans. However, the combined effect of Cd in causing nephrotoxicity with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a typical congener of polybrominated diphenyl ethers (PBDEs), has not been evaluated and mechanisms are not completely clear. Here, we applied transcriptome sequencing analysis to investigate the combined toxicity of Cd and BDE-47 in the renal tubular epithelial cell lines HKCs. Cd or BDE-47 exposure decreased cell viability in a dose-dependent manner, and exhibited cell swelling and rounding similar to necrosis, which was exacerbated by co-exposure. Transcriptomic analysis revealed 2191, 1331 and 3787 differentially-expressed genes following treatment with Cd, BDE-47 and co-exposure, respectively. Interestingly, functional annotation and enrichment analyses showed involvement of pathways for oxidative stress, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and inflammatory cell death for all three treatments. Examination of indices of mitochondrial function and oxidative stress in HKC cells showed that the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and intracellular calcium ion concentration [Ca[2+]]i were elevated, while superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) were decreased. The ratio of apoptotic and necrotic cells and intracellular lactate dehydrogenase (LDH) release were increased by Cd or BDE-47 exposure, and was aggravated by co-exposure, and was attenuated by ROS scavenger N-Acetyl-L-cysteine (NAC). NLRP3 inflammasome and pyroptosis pathway-related genes of NLRP3, adaptor molecule apoptosis-associated speck-like protein (ASC), caspase-1, interleukin-18 (IL-18) and IL-1β were elevated, while gasdermin D (GSDMD) was down-regulated, and protein levels of NLRP3, cleaved caspase-1 and cleaved GSDMD were increased, most of which were relieved by NAC. Our data demonstrate that exposure to Cd and BDE-47 induces mitochondrial dysfunction and triggers NLRP3 inflammasome and GSDMD-dependent pyroptosis leading to nephrotoxicity, and co-exposure exacerbates this effect, which could be attenuated by inhibiting ROS. This study provides a further mechanistic understanding of kidney damage, and co-exposure impact is worthy of concern and should be considered to improve the accuracy of environmental health assessment.}, } @article {pmid35749991, year = {2022}, author = {Yang, D and Zhu, J and Zhou, X and Pan, D and Nan, S and Yin, R and Lei, Q and Ma, N and Zhu, H and Chen, J and Han, L and Ding, M and Ding, Y}, title = {Polystyrene micro- and nano-particle coexposure injures fetal thalamus by inducing ROS-mediated cell apoptosis.}, journal = {Environment international}, volume = {166}, number = {}, pages = {107362}, doi = {10.1016/j.envint.2022.107362}, pmid = {35749991}, issn = {1873-6750}, mesh = {Pregnancy ; Female ; Humans ; Animals ; Mice ; Polystyrenes/toxicity/metabolism ; Plastics/metabolism ; Reactive Oxygen Species/metabolism ; Tissue Distribution ; Fetus/metabolism ; Apoptosis ; gamma-Aminobutyric Acid/metabolism ; *Nanoparticles/toxicity ; *Water Pollutants, Chemical/toxicity ; }, abstract = {The adverse effects of plastic on adult animal and human health have been receiving increasing attention. However, its potential toxicity to fetuses has not been fully elucidated. Herein, biodistribution of polystyrene (PS) particles was determined after the maternal mice were orally given PS micro- and/or nano-particles with and without surface modifications during gestational days 1 to 17. The results showed that PS microplastics (MPs) and nanoparticles (NPs) mainly emerged in the alimentary tract, brain, uterus, and placenta in maternal mice, and only the latter infiltrated into the fetal thalamus. PS NPs and carboxyl-modified NPs induced differentially expressed genes mainly enriched in oxidative phosphorylation and GABAergic synapse. Maternal administration of PS particles during gestation led to anxiety-like behavior of the progenies and their γ-aminobutyric acid (GABA) reduction in the prefrontal cortex and amygdala at Week 8. N-Acetylcysteine (NAC), an antioxidant, alleviated PS particles-induced oxidative injury in the fetal brain and rescued the anxiety-like behavior of the progenies. Additionally, PS nanoparticles caused excessive ROS and apoptosis in neuronal cell lines, which were prevented by glutathione supplementation. These results suggested that PS particles produced a negative effect on fetuses by inducing oxidative injury and suppressing GABA synthesis in their brain. The findings contribute to estimating the risk for PS particles to human and animal health.}, } @article {pmid35749822, year = {2022}, author = {Tráj, P and Herrmann, EM and Sebők, C and Vörösházi, J and Mackei, M and Gálfi, P and Kemény, Á and Neogrády, Z and Mátis, G}, title = {Protective effects of chicoric acid on polyinosinic-polycytidylic acid exposed chicken hepatic cell culture mimicking viral damage and inflammation.}, journal = {Veterinary immunology and immunopathology}, volume = {250}, number = {}, pages = {110427}, doi = {10.1016/j.vetimm.2022.110427}, pmid = {35749822}, issn = {1873-2534}, mesh = {Animals ; Caffeic Acids ; Cell Culture Techniques/veterinary ; *Chickens/metabolism ; Cytokines/genetics ; Hepatocytes/metabolism ; Inflammation/veterinary ; *Poly I-C/pharmacology ; Succinates ; }, abstract = {Virus induced damage triggered by excessive inflammation and free radical production is a major threat in the poultry industry, leading to low productivity even in vaccinated flocks. The purpose of the study was to induce inflammation with the viral double-stranded RNA analog polyinosinic-polycytidylic acid (poly I:C) on chicken primary hepatocyte - non-parenchymal cell co-cultures to investigate the immunomodulatory and cell protectant effects of chicoric acid (CA) in comparison to N-acetylcysteine (NAC). Poly I:C significantly elevated the activity of the cell damage marker, lactate dehydrogenase (LDH) and the concentration of inflammatory cytokines (IL-6, IL-8, IFN-α, IFN-γ and M-CSF) in the culture medium and decreased cellular metabolic activity. CA significantly reduced the elevated LDH and cytokine levels in a dose-dependent manner, moreover, the higher (100 µg/mL) concentration of CA even elevated the level of metabolic activity. In contrast, 10 µg/mL NAC treatment decreased the level of each inflammatory cytokine but did not rectify cell damage or metabolic depression. The results indicate, that CA, present in common plants of the Asteraceae family, proves to be a beneficial hepatoprotective, and along with NAC, an immunomodulatory supplement in vitro under a stimulus mimicking viral infection.}, } @article {pmid35739993, year = {2022}, author = {Zhu, Q and Liu, X and Zhu, Q and Liu, Z and Yang, C and Wu, H and Zhang, L and Xia, X and Wang, M and Hao, H and Cui, Y and Zhang, G and Hill, MA and Flaker, GC and Zhou, S and Liu, Z}, title = {N-Acetylcysteine Enhances the Recovery of Ischemic Limb in Type-2 Diabetic Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {6}, pages = {}, pmid = {35739993}, issn = {2076-3921}, support = {NIH HL124122/NH/NIH HHS/United States ; }, abstract = {Critical limb ischemia (CLI) is a severe complication of diabetes mellitus that occurs without effective therapy. Excessive reactive oxygen species (ROS) production and oxidative stress play critical roles in the development of diabetic cardiovascular complications. N-acetylcysteine (NAC) reduces ischemia-induced ROS production. The present study aimed to investigate the effect of NAC on the recovery of ischemic limb in an experimental model of type-2 diabetes. TALLYHO/JngJ diabetic and SWR/J non-diabetic mice were used for developing a CLI model. For NAC treatment, mice received NAC (1 mg/mL) in their drinking water for 24 h before initiating CLI, and continuously for the duration of the experiment. Blood flow, mechanical function, histology, expression of antioxidant enzymes including superoxide dismutase (SOD)-1, SOD-3, glutathione peroxidase (Gpx)-1, catalase, and phosphorylated insulin receptor substrate (IRS)-1, Akt, and eNOS in ischemic limb were evaluated in vivo or ex vivo. Body weight, blood glucose, plasma advanced glycation end-products (AGEs), plasma insulin, insulin resistance index, and plasma TNF-a were also evaluated during the experiment. NAC treatment effectively attenuated ROS production with preserved expressions of SOD-1, Gpx-1, catalase, phosphorylated Akt, and eNOS, and enhanced the recovery of blood flow and function of the diabetic ischemic limb. NAC treatment also significantly decreased the levels of phosphorylated IRS-1 (Ser307) expression and plasma TNF-α in diabetic mice without significant changes in blood glucose and AGEs levels. In conclusion, NAC treatment enhanced the recovery of blood flow and mechanical function in ischemic limbs in T2D mice in association with improved tissue redox/inflammatory status and insulin resistance.}, } @article {pmid35739949, year = {2022}, author = {Iciek, M and Bilska-Wilkosz, A and Kozdrowicki, M and Górny, M}, title = {Reactive Sulfur Compounds in the Fight against COVID-19.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {6}, pages = {}, pmid = {35739949}, issn = {2076-3921}, abstract = {The SARS-CoV-2 coronavirus pandemic outbreak in 2019 resulted in the need to search for an effective and safe strategy for treating infected patients, relieving symptoms, and preventing severe disease. SARS-CoV-2 is an RNA virus that can cause acute respiratory failure and thrombosis, as well as impair circulatory system function. Permanent damage to the heart muscle or other cardiovascular disorders may occur during or after the infection. The severe course of the disease is associated with the release of large amounts of pro-inflammatory cytokines. Due to their documented anti-inflammatory, antioxidant, and antiviral effects, reactive sulfur compounds, including hydrogen sulfide (H2S), lipoic acid (LA), N-acetylcysteine (NAC), glutathione (GSH), and some other lesser-known sulfur compounds, have attracted the interest of scientists for the treatment and prevention of the adverse effects of diseases caused by SARS-CoV-2. This article reviews current knowledge about various endogenous or exogenous reactive sulfur compounds and discusses the possibility, or in some cases the results, of their use in the treatment or prophylaxis of COVID-19.}, } @article {pmid35739442, year = {2022}, author = {Chen, J and Yao, Y and Wang, Y and Wang, X and Peng, X and Li, T and Liu, Y and Du, J}, title = {Autophagy triggered by the ROS/ERK signaling pathway protects mouse embryonic palatal cells from apoptosis induced by nicotine.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {54}, pages = {81909-81922}, pmid = {35739442}, issn = {1614-7499}, support = {81570940//the National Natural Science Foundation of China/ ; 81873706//the National Natural Science Foundation of China/ ; 82170912//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; Nicotine/pharmacology ; MAP Kinase Signaling System ; Acetylcysteine/pharmacology ; *Cleft Lip ; *Electronic Nicotine Delivery Systems ; Osteogenesis ; Teratogens ; *Cleft Palate/chemically induced ; Autophagy ; Apoptosis ; Signal Transduction ; Microtubule-Associated Proteins/metabolism ; Chloroquine/pharmacology ; }, abstract = {Maternal cigarette smoking during pregnancy is a known high-risk factor for having a child with a cleft lip and/or palate (CLP), a common congenital malformation. Nicotine is the major teratogen component of cigarettes and e-cigarettes, and nicotine plays an important role in the development of CLP. However, the mechanism underlying nicotine's effect on CLP remains unclear. Here, we aimed to determine the role and molecular mechanisms of nicotine-induced autophagy, an important process involved in regulating the cellular stress response in mouse embryonic palatal cells (MEPCs). First, we found that nicotine promoted MEPCs proliferation and inhibited their apoptosis from 0 to 12 h. After 12 h, the proliferation was inhibited, and apoptosis was promoted. The migration of MEPCs was also inhibited by nicotine. Simultaneously, long-term nicotine stimulation inhibited the osteogenic differentiation of MEPCs. We then found that nicotine significantly increased autophagy flux in MEPCs at 12 h by increasing the expression of microtubule-associated protein light chain 3 (LC3) and reducing P62 expression levels. After nicotine exposure, intracellular reactive oxygen species (ROS) and extracellular signal-regulated kinase-1/2 (ERK1/2) expression significantly increased, and the expression of ERK1/2 was reversed by the ROS scavenging agent N-acetylcysteine (NAC). Moreover, the autophagy induced by nicotine was reversed by SCH772984, a specific inhibitor of ERK1/2, and the autophagy inhibitor chloroquine (CQ). These results suggest that in the early stage of nicotine exposure, MEPCs may trigger autophagy through the ROS/ERK1/2 signaling pathway to avoid cell damage caused by nicotine.}, } @article {pmid35738838, year = {2022}, author = {Ok, SH and Ahn, SH and Lee, SH and Kim, HJ and Sim, G and Park, JK and Sohn, JT}, title = {Lipid emulsion attenuates propranolol-induced early apoptosis in rat cardiomyoblasts.}, journal = {Human & experimental toxicology}, volume = {41}, number = {}, pages = {9603271221110852}, doi = {10.1177/09603271221110852}, pmid = {35738838}, issn = {1477-0903}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Caspase 3 ; Emulsions/pharmacology ; Lipids/pharmacology ; *Propranolol/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: Propranolol is used to treat several cardiovascular diseases; however, toxic doses of propranolol cause severe myocardial depression and cardiac arrest. The aim of this study was to examine the effects of lipid emulsion (LE) on cardiotoxicity induced by toxic doses of propranolol in H9C2 rat cardiomyoblast cell line and to elucidate the underlying mechanism.

METHODS: The experimental groups comprised control, propranolol alone, esmolol alone, or LE followed by propranolol or esmolol treatment, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine (NAC) followed by propranolol treatment. The effects of propranolol, esmolol, NAC, and LE, alone or in combination, on cell viability, apoptosis, and ROS production were examined. Additionally, we investigated the effect of LE on propranolol concentration.

RESULTS: LE and NAC reversed the inhibition of cell viability induced by propranolol (p < .001). However, LE had no effect on the inhibition of cell viability caused by esmolol. The LE inhibited propranolol-induced expressions of cleaved caspase-3 (p < .001), caspase-9 (p < .001), and Bax (p < .01), but not caspase-8. NAC inhibited the propranolol-induced expression of cleaved caspase-3. LE inhibited propranolol-induced early apoptosis, but had no effect on late apoptosis. Additionally, LE inhibited the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells generated by propranolol. It attenuated propranolol-induced ROS production. However, it had no effect on propranolol concentration.

CONCLUSION: LE inhibits early apoptosis caused by a toxic dose of propranolol by suppressing the intrinsic apoptotic pathway, via direct inhibition of ROS production.}, } @article {pmid35735984, year = {2022}, author = {Valzano, F and Boncompagni, SR and Micieli, M and Di Maggio, T and Di Pilato, V and Colombini, L and Santoro, F and Pozzi, G and Rossolini, GM and Pallecchi, L}, title = {Activity of N-Acetylcysteine Alone and in Combination with Colistin against Pseudomonas aeruginosa Biofilms and Transcriptomic Response to N-Acetylcysteine Exposure.}, journal = {Microbiology spectrum}, volume = {10}, number = {4}, pages = {e0100622}, pmid = {35735984}, issn = {2165-0497}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Biofilms ; Colistin/pharmacology/therapeutic use ; *Cystic Fibrosis ; Disease Progression ; Humans ; Microbial Sensitivity Tests ; *Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa/genetics ; Transcriptome ; }, abstract = {Chronic colonization by Pseudomonas aeruginosa is critical in cystic fibrosis (CF) and other chronic lung diseases, contributing to disease progression. Biofilm growth and a propensity to evolve multidrug resistance phenotypes drastically limit the available therapeutic options. In this perspective, there has been growing interest in evaluating combination therapies, especially for drugs that can be administered by nebulization, which allows high drug concentrations to be reached at the site of infections while limiting systemic toxicity. Here, we investigated the potential antibiofilm activity of N-acetylcysteine (NAC) alone and in combination with colistin against a panel of P. aeruginosa strains (most of which are from CF patients) and the transcriptomic response of a P. aeruginosa CF strain to NAC exposure. NAC alone (8,000 mg/L) showed a limited and strain-dependent antibiofilm activity. Nonetheless, a relevant antibiofilm synergism of NAC-colistin combinations (NAC at 8,000 mg/L plus colistin at 2 to 32 mg/L) was observed with all strains. Synergism was also confirmed with the artificial sputum medium model. RNA sequencing of NAC-exposed planktonic cultures revealed that NAC (8,000 mg/L) mainly induced (i) a Zn[2+] starvation response (known to induce attenuation of P. aeruginosa virulence), (ii) downregulation of genes of the denitrification apparatus, and (iii) downregulation of flagellar biosynthesis pathway. NAC-mediated inhibition of P. aeruginosa denitrification pathway and flagellum-mediated motility were confirmed experimentally. These findings suggested that NAC-colistin combinations might contribute to the management of biofilm-associated P. aeruginosa lung infections. NAC might also have a role in reducing P. aeruginosa virulence, which could be relevant in the very early stages of lung colonization. IMPORTANCE Pseudomonas aeruginosa biofilm-related chronic lung colonization contributes to cystic fibrosis (CF) disease progression. Colistin is often a last-resort antibiotic for the treatment of such P. aeruginosa infections, and it has been increasingly used in CF, especially by nebulization. N-acetylcysteine (NAC) is a mucolytic agent with antioxidant activity, commonly administered with antibiotics for the treatment of lower respiratory tract infections. Here, we show that NAC potentiated colistin activity against in vitro biofilms models of P. aeruginosa strains, with both drugs tested at the high concentrations achievable after nebulization. In addition, we report the first transcriptomic data on the P. aeruginosa response to NAC exposure.}, } @article {pmid35730047, year = {2022}, author = {Sengupta, P and Dutta, S}, title = {N-acetyl cysteine as a potential regulator of SARS-CoV-2-induced male reproductive disruptions.}, journal = {Middle East Fertility Society journal}, volume = {27}, number = {1}, pages = {14}, pmid = {35730047}, issn = {1110-5690}, abstract = {BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has shown its persistent pandemic strength. This viral infectivity, kinetics, and the mechanisms of its actions in human body are still not completely understood. In addition, the infectivity and COVID-19 severity reportedly differ with patient's gender with men being more susceptible to the disease. Thus, different studies have also suggested the adverse impact of COVID-19 on male reproductive functions, mainly emphasizing on high expressions of angiotensin-converting enzyme 2 (ACE2) in the testes that allows the viral entry into the cells.

MAIN BODY: The N-acetylcysteine (NAC), a potent therapeutic agent of COVID-19, may be effective in reducing the impairing impacts of this disease on male reproductive functions. NAC acts as mucolytic agent by reducing sulfide bonds in the cross-linked glycoprotein matrix in mucus owing to its free sulfhydryl group. Since NAC also breaks the viral disulfide bonds required for the host cell invasion, it may help to prevent direct SARS-CoV-2 invasion into the testicular cells as well. NAC also acts as a potent anti-inflammatory and antioxidant, directly scavenging reactive oxygen species (ROS) and regulating the redox state by maintaining the thiol pool being a precursor of cysteine (an essential substrate for glutathione synthesis). Since it is suggested that male reproductive impairment in COVID-19 patient may be caused by secondary immune responses owing to systemic inflammation and OS, the anti-inflammatory and antioxidant properties of NAC explained above may attribute in protecting the male reproduction functions from these COVID-19-mediated damages.

CONCLUSION: This article explains the mechanisms how NAC treatment for COVID-19 may prevent the infection-mediated disruptions in male reproduction.}, } @article {pmid35725091, year = {2022}, author = {Ding, S and Wu, M and Xiao, R and Fang, C and Wang, Q and Xu, B and Chu, W}, title = {Evaluation of N-acetylcysteine and glutathione as quenching agents for the analysis of halogenated disinfection by-products.}, journal = {Journal of environmental sciences (China)}, volume = {117}, number = {}, pages = {71-79}, doi = {10.1016/j.jes.2022.01.033}, pmid = {35725091}, issn = {1001-0742}, mesh = {Acetylcysteine/analysis ; *Disinfectants/analysis ; Disinfection/methods ; *Drinking Water/analysis ; Glutathione ; Halogenation ; *Water Pollutants, Chemical/analysis ; *Water Purification/methods ; }, abstract = {Disinfection by-products (DBPs), formed from the reactions of disinfectants with natural organic matter and halides in drinking water, were considered to be cytotoxic and genotoxic, and might trigger various cancers. The relatively low concentration of DBPs in finished water (low µg/L or even ng/L levels) and the interference from water matrix inhibited in situ determination of DBPs. Moreover, the further formation and degradation of DBPs by disinfectants during the holding time (several hours to several days) from sample collection to analysis could adversely affect the determination of DBPs. To obtain accurate, precise and reliable data of DBP occurrence and formation, robust and reliable sample preservation is indispensable. However, the commonly used quenching agents (e.g., sodium sulfite, sodium thiosulfate, and ascorbic acid) for sample preservation can decompose reactive DBPs by reductive dehalogenation. This study evaluated the performance of N-acetylcysteine (NAC) and glutathione (GSH) as quenching agents for the analysis of halogenated DBPs by investigating the stoichiometry of the disinfectant-quenching agent reaction, the formation of DBPs during chlor(am)ination of NAC or GSH, and the effects of NAC or GSH on the stability of 18 individual DBPs and total organic halogen (TOX). Based on the results of this study, NAC and GSH were considered to be ideal quenching agents for the analysis of most DBPs and TOX, except halonitromethanes.}, } @article {pmid35724513, year = {2022}, author = {Getsy, PM and Baby, SM and May, WJ and Lewis, THJ and Bates, JN and Hsieh, YH and Gaston, B and Lewis, SJ}, title = {L-NAC reverses of the adverse effects of fentanyl infusion on ventilation and blood-gas chemistry.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {153}, number = {}, pages = {113277}, pmid = {35724513}, issn = {1950-6007}, support = {P01 HL101871/HL/NHLBI NIH HHS/United States ; R61 HL154136/HL/NHLBI NIH HHS/United States ; U01 DA051373/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs & derivatives/pharmacology ; *Analgesics, Opioid/adverse effects ; Animals ; *Fentanyl/adverse effects ; Humans ; Lysine/analogs & derivatives ; Male ; Pain/chemically induced/drug therapy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {There is an urgent need for development of drugs that are able to reverse the adverse effects of opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes the effects of bolus injections of N-acetyl-L-cysteine (L-NAC, 500 μmol/kg, IV) on ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) and analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion of fentanyl (1 μg/kg/min, IV). Fentanyl infusion elicited pronounced disturbances in (1) ventilatory parameters (e.g., decreases in frequency of breathing, tidal volume and minute ventilation), (2) ABG chemistry (decreases in pH, pO2, sO2 with increases in pCO2), (3) A-a gradient (increases that were consistent with reduced alveolar gas exchange), and (4) sedation and analgesia. Bolus injections of L-NAC given 60 and 90 min after start of fentanyl infusion elicited rapid and sustained reversal of the deleterious effects of fentanyl infusion on ventilatory parameters and ABG chemistry, whereas they did not affect the sedative or analgesic effects of fentanyl. Systemic L-NAC is approved for human use, and thus our findings raise the possibility that this biologically active thiol may be an effective compound to combat opioid-induced respiratory depression in human subjects.}, } @article {pmid35723848, year = {2022}, author = {Mamashli, M and Nasseri, S and Mohammadi, Y and Ayati, S and Zarban, A}, title = {Anti-inflammatory effects of N-Acetylcysteine and Elaeagnus angustifolia extract on acute lung injury induced by λ-carrageenan in rat.}, journal = {Inflammopharmacology}, volume = {30}, number = {5}, pages = {1759-1768}, pmid = {35723848}, issn = {1568-5608}, mesh = {Acetylcysteine/pharmacology ; *Acute Lung Injury/chemically induced/drug therapy/pathology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Carrageenan/pharmacology ; Cytokines ; *Elaeagnaceae/chemistry ; Free Radical Scavengers/pharmacology ; Interleukin-6 ; Lung ; Plant Extracts/pharmacology ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {N-Acetylcysteine (NAC) is a chemical compound with anti-inflammatory and antioxidant activity and acts as a free radical scavenger. Elaeagnus angustifolia (EA) is a plant native to the western part of Iran, with antioxidant and anti-inflammatory properties. The present study been taken evaluated the protective effect afforded by EA and NAC extracts on carrageenan-induced acute lung injury in Wistar rats. In this study, 42 rats were randomly assigned into seven groups. NAC and EA extracts were orally administered once/day for 21 continuous days. Pulmonary damage was induced by intratracheal injection of 100 μl of 2% λ-Carrageenan on day 21. Twenty-four hours post-surgery, the rats were euthanized and the samples were collected. Pretreatment with NAC and EA extracts reduced the total and differential cell accumulation as well as IL-6, and TNF-α cytokines. Antioxidant indicators demonstrate that in the groups receiving NAC and EA extract, MDA decreased while thiol and antioxidant capacity elevated. Treatment with NAC and EA significantly reduced Carrageenan-induced pathological pulmonary tissue injury. NAC and EA extract has protective effects on acute carrageenan-induced lung injury.}, } @article {pmid35723751, year = {2023}, author = {Martinho, FC and Corazza, BJM and Khoury, RD and Orozco, EIF and Toia, CC and Machado, FP and Valera, MC}, title = {Impact of N-acetylcysteine (NAC) and calcium hydroxide intracanal medications in primary endodontic infection: a randomized clinical trial.}, journal = {Clinical oral investigations}, volume = {27}, number = {2}, pages = {817-826}, pmid = {35723751}, issn = {1436-3771}, mesh = {Humans ; *Chlorhexidine/pharmacology/therapeutic use ; Calcium Hydroxide/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Dental Pulp Cavity/microbiology ; Root Canal Irrigants/pharmacology/therapeutic use ; Bacteria ; *Periapical Periodontitis/drug therapy/microbiology ; Saline Solution ; DNA ; Root Canal Preparation ; }, abstract = {OBJECTIVES: This RCT investigated the impact of N-acetylcysteine (NAC) and calcium hydroxide [Ca(OH)2] intracanal medications (ICMs) in primary endodontic infection with apical periodontitis (PEIAP).

MATERIALS AND METHODS: Thirty-six teeth with PEIAP were randomly divided into groups according to the ICM: NAC, Ca(OH)2 + saline solution (SSL), and Ca(OH)2 + 2% chlorhexidine-gel (2% CHX-gel) (all, n = 12). Root canal samples (RCSs) were collected before (s1) and after instrumentation (s2) and after 14 days of ICM (s3). Chemomechanical preparation (CMP) was performed with a Reciproc file and 2.5% NaOCl. Checkerboard DNA-DNA hybridization was used to assess 40 target bacteria species.

RESULTS: At s1, bacterial DNA was detected in 100% of RCSs (36/36). All 40 bacterial species were found in PEIAP. The mean number of species per RCS was 17.92 ± 13.18. The most frequent bacteria were S. mitis (65%), E. nodatum (63%), E. faecalis (63%), F. nucl sp vicentii (58%), T. forsythia (58%), and F. periodonticum (56%). CMP reduced the mean number of species per RCS to 6.8 ± 2.36 (p < 0.05). At s3, the intragroup analysis revealed a broader antimicrobial activity for Ca (OH)2 + 2% CHX-gel and NAC than Ca(OH)2 + SSL (p < 0.05). NAC eliminated 8/12 bacteria species resistant to both Ca (OH)2 ICMs, including P. micra, P. nigrescens, T. denticola, A. israelii, P. endodontalis, P. acnes, C. ochracea, and E. corrodens.

CONCLUSIONS: Ca (OH)2 + 2% chlorhexidine gel (2% CHX gel) showed a greater bacterial elimination over the number of bacterial species; however, NAC eliminated 8/12 bacteria species resistant to both Ca (OH)2 ICMs (RBR-3xbnnn).

CLINICAL RELEVANCE: The use of intracanal medication with a broad antimicrobial activity can optimize root canal disinfection. Ca(OH)2 + 2% CHX gel and NAC showed a broader antimicrobial activity than Ca(OH)2 + SSL against endodontic pathogens in primary root canal infection.

TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (REBEC), No. RBR-3xbnnn.}, } @article {pmid35716031, year = {2022}, author = {Cui, Y and Li, B and Du, J and Huo, S and Song, M and Shao, B and Wang, B and Li, Y}, title = {Dibutyl phthalate causes MC3T3-E1 cell damage by increasing ROS to promote the PINK1/Parkin-mediated mitophagy.}, journal = {Environmental toxicology}, volume = {37}, number = {10}, pages = {2341-2353}, doi = {10.1002/tox.23600}, pmid = {35716031}, issn = {1522-7278}, support = {//Jilin Scientific and Technological Development Program/ ; }, mesh = {Acetylcysteine/pharmacology ; *Dibutyl Phthalate/toxicity ; *Mitophagy/genetics ; Protein Kinases/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; }, abstract = {Dibutyl phthalate (DBP) is a plasticizer widely used in daily production, which causes serious environmental pollution, and damage to brain, liver, kidney, and lung by producing excessive reactive oxygen species (ROS) after entering the body. DBP can also cause skeletal dysplasia, but it is unclear whether ROS is involved. In addition, overproduction of ROS can activate mitophagy, which is an important mechanism for regulating mitochondrial quality and cell homeostasis. In order to investigate whether DBP can damage MC3T3-E1 cells (osteoblast cell line) and whether ROS and mitophagy are involved, DBP toxicity experiment, Parkin gene silencing experiment, and N-acetylcysteine (NAC) intervention experiment were performed on MC3T3-E1 cells in turn. First, we found that DBP caused MC3T3-E1 cell viability decline and osteogenic dysfunction, accompanied by the overproduction of ROS and the activation of mitophagy. Then, we found that silencing Parkin expression alleviated DBP-induced apoptosis and osteogenic dysfunction of MC3T3-E1 cells. In addition, NAC treatment inhibited the PINK1/Parkin-mediated mitophagy and alleviated the apoptosis and osteogenic dysfunction of MC3T3-E1 cells caused by DBP. Our research results showed that DBP could cause MC3T3-E1 cell damage by increasing ROS to promote the PINK1/Parkin-mediated mitophagy.}, } @article {pmid35715620, year = {2022}, author = {Mizugaki, A and Kato, H and Takeda, T and Inoue, Y and Hasumura, M and Hasegawa, T and Murakami, H}, title = {Cystine reduces mitochondrial dysfunction in C2C12 myotubes under moderate oxidative stress induced by H2O2.}, journal = {Amino acids}, volume = {54}, number = {8}, pages = {1203-1213}, pmid = {35715620}, issn = {1438-2199}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Apoptosis ; *Cystine/pharmacology ; Glutathione/metabolism ; *Hydrogen Peroxide/metabolism/pharmacology ; Mitochondria/metabolism ; Muscle Fibers, Skeletal/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Moderate oxidative stress induces temporal impairment in mitochondrial ATP production. As glutathione (GSH) content is reduced to eliminate oxidative stress by oxidation-reduction reaction, intracellular GSH content is crucial for maintaining mitochondrial function under oxidative stress. GSH precursors such as N-acetyl cysteine (NAC) and cysteine are known to suppress oxidative stress based on the supply of cysteine residues being rate-limiting for GSH synthesis. However, it remains unclear whether cystine (Cys2) can suppress mitochondrial dysfunction under oxidative stress conditions. Therefore, we examined whether Cys2 could attenuate mitochondrial dysfunction under moderate oxidative stress without scavenging reactive oxygen species (ROS) in the medium. C2C12 myotubes were incubated for 120 min in a Cys2-supplemented medium and subsequently exposed to hydrogen peroxide (H2O2). Heme oxygenase-1 (HO-1) gene expression, intracellular cysteine and GSH content, intracellular ATP level, and maximal mitochondrial respiration were assessed. Cys2 treatment significantly increased GSH content in a dose-dependent manner under oxidative stress. Cys2 treatment significantly decreased HO-1 expression induced by H2O2 exposure. In addition, maximal mitochondrial respiration rate was decreased by H2O2 exposure, but improved by Cys2 treatment. In conclusion, Cys2 treatment mitigates oxidative stress-induced mitochondrial dysfunction by maintaining GSH content under moderate oxidative stress without scavenging ROS in the medium.}, } @article {pmid35714510, year = {2022}, author = {Yue, Q and Zhang, W and Lin, S and Zheng, T and Hou, Y and Zhang, Y and Li, Z and Wang, K and Yue, L and Abay, B and Li, M and Fan, L}, title = {Ejiao ameliorates lipopolysaccharide-induced pulmonary inflammation via inhibition of NFκB regulating NLRP3 inflammasome and mitochondrial ROS.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {152}, number = {}, pages = {113275}, doi = {10.1016/j.biopha.2022.113275}, pmid = {35714510}, issn = {1950-6007}, mesh = {*Acute Lung Injury/chemically induced/drug therapy/metabolism ; Animals ; Caspase 1/metabolism ; Gelatin ; Inflammasomes/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pneumonia/chemically induced/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {There is no effective treatment for acute lung injury (ALI) at present. Some studies have reported the anti-inflammatory effect of Ejiao, but no study has addressed the underlying action mechanism. In this study, the CCK8 assay displayed Ejiao had a protective effect against LPS-elicited inflammatory lung epithelial Beas 2B cells (LILEB 2B cells). Beas 2B cells treated with LPS and Ejiao were challenged with NFκB inhibitor Bay11-7082 and ROS scavenger N-acetyl cysteine (NAC) alone and in combination. The results of qRT-PCR, Western blotting and fluorescence labeling experiments using Bay11-7082 and NAC demonstrated Ejiao could significantly decrease the expression of p-p65 and p-IκBα in NFκB signaling pathway and its downstream NLRP3, ASC, Caspase-1 and IL-1β related to pyroptosis of LILEB 2B cells. Moreover, Ejiao reduced the production of mitochondrial ROS and reversed the change of mitochondrial membrane potential of LILEB 2B cells. Then, HE staining demonstrated Ejiao had a protective effect against the LPS-elicited ALI mouse model (LAMM). Ejiao also dramatically decreased the cell amount and the overall protein concentration of bronchoalveolar lavage fluid in LAMM. Immunohistochemical staining showed Ejiao remarkably reduced the expression of p-p65 and p-IκBα in NFκB signaling pathway and its downstream NLRP3, ASC, Caspase-1 and IL-1β. The ELISA of IL-1β revealed Ejiao could dose-dependably decrease the concentration of IL-1β in lung tissues, serum and BALF of LAMM. Finally, fluorescence labeling demonstrated Ejiao significantly reduced the mitochondrial ROS generation in the lung tissue of LAMM. This finding may afford a novel strategy for the precaution and therapy of ALI.}, } @article {pmid35711363, year = {2022}, author = {Wang, Q and Park, KH and Geng, B and Chen, P and Yang, C and Jiang, Q and Yi, F and Tan, T and Zhou, X and Bian, Z and Ma, J and Zhu, H}, title = {MG53 Inhibits Necroptosis Through Ubiquitination-Dependent RIPK1 Degradation for Cardiac Protection Following Ischemia/Reperfusion Injury.}, journal = {Frontiers in cardiovascular medicine}, volume = {9}, number = {}, pages = {868632}, pmid = {35711363}, issn = {2297-055X}, abstract = {RATIONALE: While reactive oxygen species (ROS) has been recognized as one of the main causes of cardiac injury following myocardial infarction, the clinical application of antioxidants has shown limited effects on protecting hearts against ischemia-reperfusion (I/R) injury. Thus, the precise role of ROS following cardiac injury remains to be fully elucidated.

OBJECTIVE: We investigated the role of mitsugumin 53 (MG53) in regulating necroptosis following I/R injury to the hearts and the involvement of ROS in MG53-mediated cardioprotection.

METHODS AND RESULTS: Antioxidants were used to test the role of ROS in MG53-mediated cardioprotection in the mouse model of I/R injury and induced human pluripotent stem cells (hiPSCs)-derived cardiomyocytes subjected to hypoxia or re-oxygenation (H/R) injury. Western blotting and co-immunoprecipitation were used to identify potential cell death pathways that MG53 was involved in. CRISPR/Cas 9-mediated genome editing and mutagenesis assays were performed to further identify specific interaction amino acids between MG53 and its ubiquitin E3 ligase substrate. We found that MG53 could protect myocardial injury via inhibiting the necroptosis pathway. Upon injury, the generation of ROS in the infarct zone of the hearts promoted interaction between MG53 and receptor-interacting protein kinase 1 (RIPK1). As an E3 ubiquitin ligase, MG53 added multiple ubiquitin chains to RIPK1 at the sites of K316, K604, and K627 for proteasome-mediated RIPK1 degradation and inhibited necroptosis. The application of N-acetyl cysteine (NAC) disrupted the interaction between MG53 and RIPK1 and abolished MG53-mediated cardioprotective effects.

CONCLUSIONS: Taken together, this study provided a molecular mechanism of a potential beneficial role of ROS following acute myocardial infarction. Thus, fine-tuning ROS levels might be critical for cardioprotection.}, } @article {pmid35710106, year = {2022}, author = {Yang, W and Guo, R and Pi, A and Ding, Q and Hao, L and Song, Q and Chen, L and Dou, X and Na, L and Li, S}, title = {Long non-coding RNA-EN_181 potentially contributes to the protective effects of N-acetylcysteine against non-alcoholic fatty liver disease in mice.}, journal = {The British journal of nutrition}, volume = {}, number = {}, pages = {1-15}, doi = {10.1017/S0007114522001829}, pmid = {35710106}, issn = {1475-2662}, abstract = {N-acetylcysteine (NAC) possesses a strong capability to ameliorate high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mice, but the underlying mechanism is still unknown. Our study aimed to clarify the involvement of long non-coding RNA (lncRNA) in the beneficial effects of NAC on HFD-induced NAFLD. C57BL/6J mice were fed a normal-fat diet (10 % fat), a HFD (45 % fat) or a HFD plus NAC (2 g/l). After 14-week of intervention, NAC rescued the deleterious alterations induced by HFD, including the changes in body and liver weights, hepatic TAG, plasma alanine aminotransferase, plasma aspartate transaminase and liver histomorphology (haematoxylin and eosin and Oil red O staining). Through whole-transcriptome sequencing, 52 167 (50 758 known and 1409 novel) hepatic lncRNA were detected. Our cross-comparison data revealed the expression of 175 lncRNA was changed by HFD but reversed by NAC. Five of those lncRNA, lncRNA-NONMMUT148902·1 (NO_902·1), lncRNA-XR_001781798·1 (XR_798·1), lncRNA-NONMMUT141720·1 (NO_720·1), lncRNA-XR_869907·1 (XR_907·1), and lncRNA-ENSMUST00000132181 (EN_181), were selected based on an absolute log2 fold change value of greater than 4, P-value < 0·01 and P-adjusted value < 0·01. Further qRT-PCR analysis showed the levels of lncRNA-NO_902·1, lncRNA-XR_798·1, and lncRNA-EN_181 were decreased by HFD but restored by NAC, consistent with the RNA sequencing. Finally, we constructed a ceRNA network containing lncRNA-EN_181, 3 miRNA, and 13 mRNA, which was associated with the NAC-ameliorated NAFLD. Overall, lncRNA-EN_181 might be a potential target in NAC-ameliorated NAFLD. This finding enhanced our understanding of the biological mechanisms underlying the beneficial role of NAC.}, } @article {pmid35706905, year = {2022}, author = {Chung, H and Lee, SW and Hyun, M and Kim, SY and Cho, HG and Lee, ES and Kang, JS and Chung, CH and Lee, EY}, title = {Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {800574}, pmid = {35706905}, issn = {2296-634X}, abstract = {Podocyte loss is well known to play a critical role in the early progression of diabetic nephropathy. A growing number of studies are paying attention to necroptosis, a programmed form of cell necrosis as a mechanism of podocyte loss. Although necroptosis is a recently established concept, the significance of receptor interacting serine/threonine kinase 3 (RIPK3), a gene that encodes for the homonymous enzyme RIPK3 responsible for the progression of necroptosis, is well studied. Curcumin, a natural hydrophobic polyphenol compound responsible for the yellow color of Curcuma longa, has drawn attention due to its antioxidant and anti-inflammatory effects on cells prone to necroptosis. Nonetheless, effects of curcumin on high glucose-induced podocyte necroptosis have not been reported yet. Therefore, this study investigated RIPK3 expression in high glucose-treated podocytes to identify the involvement of necroptosis via the RIPK3 pathway and the effects of curcumin treatment on RIPK3-dependent podocytopathy in a hyperglycemic environment. The study discovered that increased reactive oxygen species (ROS) in renal podocytes induced by high glucose was improved after curcumin treatment. Curcumin treatment also significantly restored the upregulated levels of VEGF, TGF-β, and CCL2 mRNAs and the downregulated level of nephrin mRNA in cultured podocytes exposed to a high glucose environment. High glucose-induced changes in protein expression of TGF-β, nephrin, and CCL2 were considerably reverted to their original levels after curcumin treatment. Increased expression of RIPK3 in high glucose-stimulated podocytes was alleviated by curcumin treatment as well as N-acetyl cysteine (NAC, an antioxidant) or GSK'872 (a RIPK3 inhibitor). Consistent with this, the increased necroptosis-associated molecules, such as RIPK3, pRIPK3, and pMLKL, were also restored by curcumin in high glucose-treated mesangial cells. DCF-DA assay confirmed that such a result was attributed to the reduction of RIPK3 through the antioxidant effect of curcumin. Further observations of DCF-DA-sensitive intracellular ROS in NAC-treated and GSK'872-treated podocyte groups showed a reciprocal regulatory relationship between ROS and RIPK3. The treatment of curcumin and GSK'872 in podocytes incubated with high glucose protected from excessive intracellular superoxide anion production. Taken together, these results indicate that curcumin treatment can protect against high glucose-induced podocyte injuries by suppressing the abnormal expression of ROS and RIPK3. Thus, curcumin might be a potential therapeutic agent for diabetic nephropathy as an inhibitor of RIPK3.}, } @article {pmid35704698, year = {2022}, author = {Chaudhari, S and Yazdizadeh Shotorbani, P and Tao, Y and Kasetti, R and Zode, G and Mathis, KW and Ma, R}, title = {Neogenin pathway positively regulates fibronectin production by glomerular mesangial cells.}, journal = {American journal of physiology. Cell physiology}, volume = {323}, number = {1}, pages = {C226-C235}, pmid = {35704698}, issn = {1522-1563}, support = {R01 DK115424/DK/NIDDK NIH HHS/United States ; R01 EY026177/EY/NEI NIH HHS/United States ; R01 EY028616/EY/NEI NIH HHS/United States ; R01 HL153703/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; *Diabetes Mellitus, Experimental/metabolism ; *Diabetic Nephropathies/genetics/metabolism ; Extracellular Matrix Proteins/genetics/metabolism ; Fibronectins/metabolism ; Glucose/metabolism ; *Membrane Proteins/genetics ; Mesangial Cells/metabolism ; Mice ; Transcription Factors/metabolism ; }, abstract = {Neogenin, a transmembrane receptor, was recently found in kidney cells and immune cells. However, the function of neogenin signaling in kidney is not clear. Mesangial cells (MCs) are a major source of extracellular matrix (ECM) proteins in glomerulus. In many kidney diseases, MCs are impaired and manifest myofibroblast phenotype. Overproduction of ECM by the injured MCs promotes renal injury and accelerates the progression of kidney diseases. The present study aimed to determine if neogenin receptor was expressed in MCs and if the receptor signaling regulated ECM protein production by MCs. We showed that neogenin was expressed in the glomerular MCs. Deletion of neogenin using CRISPR/Cas9 lentivirus system significantly reduced the abundance of fibronectin, an ECM protein. Netrin-1, a ligand for neogenin, also significantly decreased fibronectin production by MCs and decreased neogenin protein expression in MCs. Furthermore, treatment of human MCs with high glucose (HG, 25 mM) significantly increased the protein abundance of neogenin as early as 8 h. Consistently, neogenin expression in glomerulus significantly increased in the eNOS[-/-]db/db diabetic mice starting as early as the age of 8 wk and this increase sustained at least to the age of 24 wk. We further found that the HG-induced increase in neogenin abundance was blunted by antioxidant PEG-catalase and N-acetyl cysteine. Taken together, our results suggest a new mechanism of regulation of fibronectin production by MCs. This previously unrecognized neogenin-fibronectin pathway may contribute to glomerular injury responses during the course of diabetic nephropathy.}, } @article {pmid35703373, year = {2022}, author = {Ahmadi Kahjoogh, H and Yazdanian, N and Behrangi, E and Roohaninasab, M and Hejazi, P and Goodarzi, A}, title = {Efficacy, safety, tolerability, and satisfaction of N-acetylcysteine and pentoxifylline in lichen planopilaris patients under treatment with topical clobetasol: A triple arm blinded randomized controlled trial.}, journal = {Dermatologic therapy}, volume = {35}, number = {8}, pages = {e15639}, doi = {10.1111/dth.15639}, pmid = {35703373}, issn = {1529-8019}, mesh = {Acetylcysteine/adverse effects ; Administration, Topical ; Adult ; Clobetasol/therapeutic use ; Female ; Humans ; *Lichen Planus/drug therapy ; Male ; Middle Aged ; Patient Satisfaction ; *Pentoxifylline/adverse effects ; Personal Satisfaction ; Treatment Outcome ; }, abstract = {Lichen planoplaris (LPP) is one of the most common causes of inflammatory cicatricial alopecias. There is no definitive cure for the disease and most of the available therapeutic options can potentially lead to serious complications following their use for extended durations. In this study, we aimed to evaluate the efficacy, safety and tolerability of N-acetylcysteine (NAC) and pentoxyfillin (PTX), as adjunctive therapies, in the management of LPP. In a randomized, assessor- and analyst-blinded controlled trial, patients with proven LPP were randomly assigned to three groups of 10. Group I (the control group) received clobetasol 0.05%lotion; Group II, a combination of clobetasol 0.05% lotion and oral PTX; Group III, a combination of clobetasol lotion 0.05% and oral NAC. Lichen planopilaris activity index (LPPAI), the possible side effects, tolerability and patients satisfaction were assessed before and two and four months after the initiation of the treatments. Thirty patients, 96.7% women, with a mean age of 46.8 ± 13.3 years old, were included in the study. Four months into the treatments, the overall LPPAI and the severity and/or frequency of most of its determinants significantly decreased in all groups. In a comparison among the groups, patients who received either of the combination therapies showed more decline in their LPPAI than those receiving only clobetasol. The decline was more noticeable and statistically significant only in the NAC group. Three patients in the PTX group developed complications that were not statistically significant when compared with the other groups. There were no substantial differences in the tolerability of the treatments among the study arms. The use of oral NAC and PTX added to the therapeutic efficacy of topical clobetasol in the treatment of LPP, suggesting that they might be beneficial and safe adjuvant therapies and add to the efficacy of topical treatment without any noticeable impact on the adverse effects experienced by patients.}, } @article {pmid35699521, year = {2022}, author = {Biegański, P and Kovalski, E and Israel, N and Dmitrieva, E and Trzybiński, D and Woźniak, K and Vrček, V and Godel, M and Riganti, C and Kopecka, J and Lang, H and Kowalski, K}, title = {Electronic Coupling in 1,2,3-Triazole Bridged Ferrocenes and Its Impact on Reactive Oxygen Species Generation and Deleterious Activity in Cancer Cells.}, journal = {Inorganic chemistry}, volume = {61}, number = {25}, pages = {9650-9666}, pmid = {35699521}, issn = {1520-510X}, mesh = {*Antineoplastic Agents/chemistry ; *Carcinoma, Non-Small-Cell Lung ; Electronics ; Humans ; *Lung Neoplasms ; Metallocenes ; Reactive Oxygen Species/metabolism ; Triazoles/chemistry ; }, abstract = {Mixed-valence (MV) binuclear ferrocenyl compounds have long been studied as models for testing theories of electron transfer and in attempts to design molecular-scale electronic devices (e.g., molecular wires). In contrary to that, far less attention has been paid to MV binuclear ferrocenes as anticancer agents. Herein, we discuss the synthesis of six 1,2,3-triazole ferrocenyl compounds for combined (spectro)electrochemical, electron paramagnetic resonance (EPR), computational, and anticancer activity studies. Our synthetic approach was based on the copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction and enabled us to obtain in one step compounds bearing either one, two, or three ferrocenyl entities linked to the common 1,2,3-triazole core. Thus, two series of complexes were obtained, which pertain to derivatives of 3'-azido-3'-deoxythymidine (AZT) and 3-azidopropionylferrocene, respectively. Based on the experimental and theoretical data, the two mono-oxidized species corresponding to binuclear AZT and trinuclear 3-azidopropionylferrocene complexes have been categorized as class II mixed-valence according to the classification proposed by Robin and Day. Of importance is the observation that these two compounds are more active against human A549 and H1975 non-small-cell lung cancer cells than their congeners, which do not show MV characteristics. Moreover, the anticancer activity of MV species competes or surpasses, dependent on the cell line, the activity of reference anticancer drugs such as cisplatin, tamoxifen, and 5-fluorouracil. The most active from the entire series of compounds was the binuclear thymidine derivative with the lowest IC50 value of 5 ± 2 μM against lung H1975 cancer cells. The major mechanism of antiproliferative activity for the investigated MV compounds is based on reactive oxygen species generation in cancer cells. This hypothesis was substantiated by EPR spin-trapping experiments and the observation of decreased anticancer activity in the presence of N-acetyl cysteine (NAC) free-radical scavenger.}, } @article {pmid35698331, year = {2022}, author = {Sheng, Y and Sun, X and Han, J and Hong, W and Feng, J and Xie, S and Li, Y and Yan, F and Li, K and Tian, B}, title = {N-acetylcysteine functionalized chitosan oligosaccharide-palmitic acid conjugate enhances ophthalmic delivery of flurbiprofen and its mechanisms.}, journal = {Carbohydrate polymers}, volume = {291}, number = {}, pages = {119552}, doi = {10.1016/j.carbpol.2022.119552}, pmid = {35698331}, issn = {1879-1344}, mesh = {Acetylcysteine/chemistry/pharmacology ; Animals ; Chickens ; *Chitosan/chemistry ; Cornea/metabolism ; Female ; *Flurbiprofen/pharmacokinetics ; Oligosaccharides/metabolism/pharmacology ; Palmitic Acid ; Particle Size ; Rabbits ; }, abstract = {An N-acetylcysteine functionalized chitosan oligosaccharide-palmitic acid conjugate (NAC-COS-PA) with bioadhesive and permeation promoting properties was synthesized to enhance transocular drug delivery. Flurbiprofen (FB) loaded self-assembled NAC-COS-PA nanomicelles (NAC-COS-PA-FB) were prepared and the drug loading was 7.35 ± 0.32%. Human immortalized corneal epithelial (HCE-T) cell cytotoxicity and hen's egg test-chorioallantoic membrane assays confirmed that the conjugate had good biocompatibility. The transportation efficiency of coumarin-6 (C6) loaded nanomicelles in the HCE-T cell monolayer was approximately 1.97 times higher than that of free C6. Decreased intracellular Ca[2+] concentration and cell membrane potential, increased cell membrane fluidity, and reversible changes in the F-actin cytoskeleton are presumed to be responsible for the enhanced drug permeation. NAC-COS-PA exhibited strong binding capacity with mucin and rabbit eyeball. In vivo pharmacokinetics indicated that the area under the curve (AUC0-6 h) and the maximum concentration (Cmax) of NAC-COS-PA-FB were approximately 1.92 and 2.44 times that of the FB solution, respectively. NAC-COS-PA-FB demonstrated the best in vivo anti-inflammatory efficacy compared to unfunctionalized nanomicelles (COS-PA-FB) and FB solution. Consequently, NAC-COS-PA appears to be a promising bioadhesive carrier for ophthalmic delivery.}, } @article {pmid35695627, year = {2022}, author = {Amid, R and Alamdari, MI and Kadkhodazadeh, M}, title = {Effect of Enamel Matrix Derivative and N-Acetyl Cysteine on Proliferation and Osteogenic Activity of Dental Pulp Stem Cells.}, journal = {Journal of long-term effects of medical implants}, volume = {32}, number = {2}, pages = {51-59}, doi = {10.1615/JLongTermEffMedImplants.2022040074}, pmid = {35695627}, issn = {1940-4379}, mesh = {*Acetylcysteine/pharmacology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Dental Pulp ; Humans ; *Osteogenesis ; Stem Cells ; }, abstract = {Successful bone regeneration often requires induction by signaling molecules. Enamel matrix derivative (EMD) is said to enhance initial phases of healing. N-acetyl cysteine (NAC) is a molecule assumed to enhance osteogenesis and induce osteoblastic differentiation. This study sought to compare effects of EMD and NAC on proliferation, mineralization, and enzymatic activity of dental pulp mesenchymal stem cells (DPSCs). DPSCs were cultured on mineralized bone allograft (MBA) powder. After 24 hours, EMD in concentrations of 10, 50, and 100 μg/mL and NAC in 5 mM concentration were added. Methyl thiazolyl tetrazolium (MTT) assay was used for cell proliferation assessment at 1, 2, and 3 days. Osteoblastic differentiation of DPSCs was evaluated at 30 days, by alizarin red staining and assessment of alkaline phosphatase (ALP) activity. Both EMD and NAC caused time-dependent reduction of cell proliferation compared with the negative control. Maximum proliferation of DPSCs was observed in the 10 μg/mL EMD group at all time points, whereas NAC caused higher ALP activity and mineralization of DPSCs compared with EMD. In vitro application of NAC, as a signaling molecule, may effectively enhance bone regeneration by the induction of mineralization and enzymatic activity, despite the resultant reduction in cell proliferation rate.}, } @article {pmid35691282, year = {2022}, author = {Shahreki, E and Kaykhaei, MA and Mosallanezhad, Z and Adineh, Z and Mokhtari, AM and Mohammadi, M and Hosseini, R and Bazi, A}, title = {Effects of Selenium and/or N-Acetyl-Cysteine Supplementation on Nonthyroidal Illness Syndrome in Hemodialysis Patients: A Factorial Randomized Controlled Trial.}, journal = {Pharmacology}, volume = {107}, number = {9-10}, pages = {480-485}, doi = {10.1159/000525094}, pmid = {35691282}, issn = {1423-0313}, mesh = {Acetylcysteine/therapeutic use ; Dietary Supplements ; Humans ; Renal Dialysis/adverse effects ; *Selenium/pharmacology ; Thyrotropin ; }, abstract = {INTRODUCTION: Nonthyroidal illness syndrome (NTIS) is common in hemodialysis patients (HPs). However, limited clinical trials have been conducted in this field. Therefore, the aim of this study was to investigate the effect of Se and/or N-acetyl-cysteine (NAC) on NTIS parameters in HPs.

METHODS: In this factorial randomized controlled trial, 68 HPs were divided into four groups: group A received placebo of Se and NAC, group B received 600 μg per day of NAC and placebo of Se, group C received 200 μg of Se per day and placebo of NAC and group D received 200 μg of selenium and 600 μg of NAC per day for 12 weeks. Blood samples were taken at baseline and after 12 weeks to assess free tri-iodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), and reverse T3 (rT3) concentrations.

RESULTS: Our finding demonstrated that rT3 levels were decreased in B, C, and D groups and increased nearly to baseline levels in the A group after 12 weeks, with a marked difference between the groups (p < 0.001) based on ANOVA. Although there were no significant differences in FT3 (p = 0.39), FT4 (p = 0.76), and TSH (p = 0.71) between the groups at the end of the trial.

CONCLUSION: This trial showed that Se and/or NAC exert beneficial effects on rT3 levels in HPs. However, long-term clinical trials with a larger sample size using more appropriate biomarkers are recommended to evaluate the efficacy and safety of Se and/or NAC in HPs.}, } @article {pmid35690339, year = {2022}, author = {Marni, R and Kundrapu, DB and Chakraborti, A and Malla, R}, title = {Insight into drug sensitizing effect of diallyl disulfide and diallyl trisulfide from Allium sativum L. on paclitaxel-resistant triple-negative breast cancer cells.}, journal = {Journal of ethnopharmacology}, volume = {296}, number = {}, pages = {115452}, doi = {10.1016/j.jep.2022.115452}, pmid = {35690339}, issn = {1872-7573}, mesh = {Allyl Compounds ; Antioxidants/pharmacology ; Apoptosis ; Cell Line, Tumor ; Disulfides ; *Garlic/chemistry ; Humans ; Paclitaxel/pharmacology ; Reactive Oxygen Species ; Sulfides/pharmacology ; *Triple Negative Breast Neoplasms/drug therapy ; }, abstract = {Ayurvedic practitioners and herbal healers in India and China have extensively used garlic (Allium sativum L.) to treat cancers. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are major volatile organosulfur phytochemical constituents found in garlic.

AIM OF THE STUDY: To find new insight into the drug sensitizing effect of DADS and DATS on paclitaxel (PTX)-resistant triple-negative breast cancer cells (TNBC/PR).

MATERIALS AND METHODS: This study estimates the non-toxic concentration of DADS and DATS against normal healthy breast epithelial cell line (MCF-12A) by using a trypan blue viability assay. Also, it evaluates the effect of DADS and DATS on the sensitization of established stable TNBC/PR cell clones (MDA-MB 231 PR and MDA-MB 468 PR) by MTT, BrdU incorporation, intracellular ROS, cell cycle, and apoptosis assays.

RESULTS: The results show that DADS and DATS are non-cytotoxicity against MCF-12A cells. Nevertheless, DADS and DATS have shown significantly high cytotoxicity against MDA-MB 231 PR and MDA-MB 468 PR cells. They also inhibited PTX-resistant cell proliferation by blocking the cell cycle. Further, they induced apoptosis by activation of caspase 3 and 9. N-acetyl cysteine pre-treatment inhibited DADS and DATS-induced intracellular ROS release. In silico study shows that DADS and DATS interact with a large extracellular loop (LEL) of CD151 with a binding energy of -4.0 kcal/mol and transmembrane domain (TM) with a binding affinity of 11.7 and 13.6 kcal/mol, respectively. They also inhibited the surface expression of CD151 in TNBC/PR cells.

CONCLUSION: This study implies that DADS and DATS could be considered for sensitizing drug-resistant breast cancers.}, } @article {pmid35689653, year = {2022}, author = {Yang, X and Yang, P and Zhang, J and Yang, Y and Xiong, M and Shi, F and Li, N and Jin, Y}, title = {Silica nanoparticle exposure inhibits surfactant protein A and B in A549 cells through ROS-mediated JNK/c-Jun signaling pathway.}, journal = {Environmental toxicology}, volume = {37}, number = {9}, pages = {2291-2301}, doi = {10.1002/tox.23596}, pmid = {35689653}, issn = {1522-7278}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Apoptosis ; Genes, jun/genetics ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Lung/metabolism ; *Nanoparticles/toxicity ; *Pulmonary Surfactant-Associated Protein A/metabolism ; *Pulmonary Surfactant-Associated Protein B/metabolism ; Pulmonary Surfactants/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Silicon Dioxide/toxicity ; }, abstract = {Exposure to silica nanoparticles (SiNPs) is related to the dysregulation of pulmonary surfactant that maintains lung stability and function. Nevertheless, there are limited studies concerning the interaction and influence between SiNPs and pulmonary surfactant, and the damage and mechanism are still unclear. Herein, we used A549 cells to develop an in vitro model, with which we investigated the effect of SiNPs exposure on the expression of pulmonary surfactant and the potential regulatory mechanism. The results showed that SiNPs were of cytotoxicity in regarding of reduced cell viability and promoted the production of excessive reactive oxygen species (ROS). Additionally, the JNK/c-Jun signaling pathway was activated, and the expression of surfactant protein A (SP-A) and surfactant protein B (SP-B) was decreased. After the cells being treated with N-acetyl-L-cysteine (NAC), we found that the ROS content was effectively downregulated, and the expression of proteins related to JNK and c-Jun signaling pathways was suppressed. In contrast, the expression of SP-A and SP-B was enhanced. Furthermore, we treated the cells with JNK inhibitor and c-Jun-siRNA and found that the expression of protein related to JNK and c-Jun signaling pathways, as well as SP-A and SP-B, changed in line with that of NAC treatment. These findings suggest that SiNPs exposure can upregulate ROS and activate the JNK/c-Jun signaling pathway in A549 cells, thereby inhibiting the expression of SP-A and SP-B proteins.}, } @article {pmid35684427, year = {2022}, author = {Papavasileiou, K and Tsiasioti, A and Tzanavaras, PD and Zacharis, CK}, title = {HPLC Determination of Colistin in Human Urine Using Alkaline Mobile Phase Combined with Post-Column Derivatization: Validation Using Accuracy Profiles.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {11}, pages = {}, pmid = {35684427}, issn = {1420-3049}, mesh = {Acetylcysteine ; Chromatography, High Pressure Liquid/methods ; *Colistin/urine ; Humans ; o-Phthalaldehyde ; }, abstract = {In this study, the development, validation, and application of a new liquid chromatography post-column derivatization method for the determination of Colistin in human urine samples is demonstrated. Separation of Colistin was performed using a core-shell C18 analytical column in an alkaline medium in order (i) to be compatible with the o-phthalaldehyde-based post-column derivatization reaction and (ii) to obtain better retention of the analyte. The Colistin derivative was detected spectrofluorometrically (λext/λem = 340/460 nm) after post-column derivatization with o-phthalaldehyde and N-acetyl cysteine. The post-column derivatization parameters were optimized using the Box-Behnken experimental design, and the method was validated using the total error concept. The β-expectation tolerance intervals did not exceed the acceptance criteria of ±15%, meaning that 95% of future results would be included in the defined bias limits. The limit of detection of the method was adequate corresponding to 100 nmol·L[-1]. The mean analytical bias (expressed as relative error) in the spiking levels was suitable, being in the range of -2.8 to +2.5% for both compounds with the percentage relative standard deviation lower than 3.4% in all cases. The proposed analytical method was satisfactorily applied to the analysis of the drug in human urine samples.}, } @article {pmid35682881, year = {2022}, author = {Valent, I and Bednárová, L and Schreiber, I and Bujdák, J and Valachová, K and Šoltés, L}, title = {Reaction of N-Acetylcysteine with Cu[2+]: Appearance of Intermediates with High Free Radical Scavenging Activity: Implications for Anti-/Pro-Oxidant Properties of Thiols.}, journal = {International journal of molecular sciences}, volume = {23}, number = {11}, pages = {}, pmid = {35682881}, issn = {1422-0067}, support = {VEGA 2/0019/19//Scientific Grant Agency of the Ministry of Education of Slovak Republic and of Slovak Academy of Sciences/ ; CA17120//European Cooperation in Science and Technology/ ; }, mesh = {*Acetylcysteine ; Antioxidants ; Copper/chemistry ; Disulfides ; Oxidation-Reduction ; Oxygen/chemistry ; Reactive Oxygen Species ; *Sulfhydryl Compounds ; }, abstract = {We studied the kinetics of the reaction of N-acetyl-l-cysteine (NAC or RSH) with cupric ions at an equimolar ratio of the reactants in aqueous acid solution (pH 1.4−2) using UV/Vis absorption and circular dichroism (CD) spectroscopies. Cu2+ showed a strong catalytic effect on the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical (ABTSr) consumption and autoxidation of NAC. Difference spectra revealed the formation of intermediates with absorption maxima at 233 and 302 nm (ε302/Cu > 8 × 103 M−1 cm−1) and two positive Cotton effects centered at 284 and 302 nm. These intermediates accumulate during the first, O2-independent, phase of the NAC autoxidation. The autocatalytic production of another chiral intermediate, characterized by two positive Cotton effects at 280 and 333 nm and an intense negative one at 305 nm, was observed in the second reaction phase. The intermediates are rapidly oxidized by added ABTSr; otherwise, they are stable for hours in the reaction solution, undergoing a slow pH- and O2-dependent photosensitive decay. The kinetic and spectral data are consistent with proposed structures of the intermediates as disulfide-bridged dicopper(I) complexes of types cis-/trans-CuI2(RS)2(RSSR) and CuI2(RSSR)2. The electronic transitions observed in the UV/Vis and CD spectra are tentatively attributed to Cu(I) → disulfide charge transfer with an interaction of the transition dipole moments (exciton coupling). The catalytic activity of the intermediates as potential O2 activators via Cu(II) peroxo-complexes is discussed. A mechanism for autocatalytic oxidation of Cu(I)−thiolates promoted by a growing electronically coupled −[CuI2(RSSR)]n− polymer is suggested. The obtained results are in line with other reported observations regarding copper-catalyzed autoxidation of thiols and provide new insight into these complicated, not yet fully understood systems. The proposed hypotheses point to the importance of the Cu(I)−disulfide interaction, which may have a profound impact on biological systems.}, } @article {pmid35681955, year = {2022}, author = {Lee, DK and Lipner, SR}, title = {The Potential of N-Acetylcysteine for Treatment of Trichotillomania, Excoriation Disorder, Onychophagia, and Onychotillomania: An Updated Literature Review.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {11}, pages = {}, pmid = {35681955}, issn = {1660-4601}, mesh = {Acetylcysteine/therapeutic use ; Compulsive Behavior ; Humans ; Nail Biting/therapy ; Retrospective Studies ; *Trichotillomania/drug therapy/psychology ; }, abstract = {BACKGROUND: Trichotillomania (TTM), excoriation disorder, onychophagia, and onychotillomania are categorized as body focused repetitive behavior (BFRB) disorders, causing damage to the skin, hair, and/or nails with clinically significant psychosocial consequences. Currently, there are no standardized treatments for these compulsive, self-induced disorders. Studies on treatment of these disorders using psychotropic drugs (i.e., selective serotonin reuptake inhibitors, tricyclic antidepressants, anticonvulsants) have shown variable efficacy. Recently, there is a growing interest in N-acetylcysteine (NAC) for treating BFRBs. NAC is a glutamate modulator that has shown promise in successfully reducing the compulsive behaviors in BFRB disorders. This article provides an updated review of the literature on the use of NAC in TTM, excoriation disorder, onychophagia, and onychotillomania.

METHODS: Relevant articles were searched in the PubMed/MEDLINE database.

RESULTS: Twenty-four clinical trials, retrospective cohort studies, and case reports assessing the efficacy of NAC in TTM, excoriation disorder, and onychophagia were included. No studies for onychotillomania were found in our search.

CONCLUSIONS: Although NAC has proven successful for treatment of BFRB disorders, data is derived from few clinical trials and case reports assessing small numbers of patients. Larger studies with longer durations are needed to fully establish the efficacy of NAC in these disorders.}, } @article {pmid35677385, year = {2022}, author = {Wu, Y and Pi, D and Chen, Y and Zuo, Q and Zhou, S and Ouyang, M}, title = {Ginsenoside Rh4 Inhibits Colorectal Cancer Cell Proliferation by Inducing Ferroptosis via Autophagy Activation.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2022}, number = {}, pages = {6177553}, pmid = {35677385}, issn = {1741-427X}, abstract = {Colorectal cancer (CRC) is a severe threat to human health. Ginsenosides such as ginsenoside Rh4 have been widely studied in the antitumor field. Here, we investigated the antiproliferative activity and mechanism of Rh4 against CRC in vivo and in vitro. The CRC xenograft model showed that Rh4 inhibited xenograft tumor growth with few side effects (p < 0.05). As determined by MTT colorimetric assays, Western blotting, and immunohistochemical analysis, Rh4 effectively inhibited CRC cell proliferation through autophagy and ferroptosis (p < 0.05). Rh4 significantly upregulated autophagy and ferroptosis marker expression in CRC cells and xenograft tumor tissues in the present study (p < 0.05). Interestingly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed Rh4-induced ferroptosis (p < 0.05). Moreover, the autophagy inhibitor 3-methyladenine (3-MA) also reversed Rh4-induced ferroptosis (p < 0.05). These results indicate that Rh4-induced ferroptosis is regulated via the autophagy pathway. In addition, Rh4 increased reactive oxygen species (ROS) accumulation, leading to the activation of the ROS/p53 signaling pathway (p < 0.05). Transcriptome sequencing also confirmed this (p < 0.05). Moreover, the ROS scavenger N-acetyl-cysteine (NAC) reversed the inhibitory effect of Rh4 on CRC cells (p < 0.05). Therefore, this study proves that Rh4 inhibits cancer cell proliferation by activating the ROS/p53 signaling pathway and activating autophagy to induce ferroptosis, which provides necessary scientific evidence of the great anticancer potential of Rh4.}, } @article {pmid35674828, year = {2022}, author = {Quinn, KM and Roberts, L and Cox, AJ and Borg, DN and Pennell, EN and McKeating, DR and Fisher, JJ and Perkins, AV and Minahan, C}, title = {Blood oxidative stress biomarkers in women: influence of oral contraception, exercise, and N-acetylcysteine.}, journal = {European journal of applied physiology}, volume = {122}, number = {8}, pages = {1949-1964}, pmid = {35674828}, issn = {1439-6327}, support = {112//Sport Performance Innovation and Knowledge Excellence unit, Queensland Academy of Sport/ ; }, mesh = {*Acetylcysteine/pharmacology ; Biomarkers ; Contraception ; Contraceptives, Oral/pharmacology ; Cross-Over Studies ; Double-Blind Method ; Female ; Humans ; Malondialdehyde ; *Oxidative Stress ; }, abstract = {PURPOSE: To compare physiological responses to submaximal cycling and sprint cycling performance in women using oral contraceptives (WomenOC) and naturally cycling women (WomenNC) and to determine whether N-acetylcysteine (NAC) supplementation mediates these responses.

METHODS: Twenty recreationally trained women completed five exercise trials (i.e., an incremental cycling test, a familiarisation trial, a baseline performance trial and two double-blind crossover intervention trials). During the intervention trials participants supplemented with NAC or a placebo 1 h before exercise. Cardiopulmonary parameters and blood biochemistry were assessed during 40 min of fixed-intensity cycling at 105% of gas-exchange threshold and after 1-km cycling time-trial.

RESULTS: WomenOC had higher ventilation (β [95% CI] = 0.07 L·min[-1] [0.01, 0.14]), malondialdehydes (β = 12.00 mmol·L[-1] [6.82, 17.17]) and C-reactive protein (1.53 mg·L[-1] [0.76, 2.30]), whereas glutathione peroxidase was lower (β =  22.62 mU·mL[-1] [- 41.32, - 3.91]) compared to WomenNC during fixed-intensity cycling. Plasma thiols were higher at all timepoints after NAC ingestion compared to placebo, irrespective of group (all p < 0.001; d = 1.45 to 2.34). For WomenNC but not WomenOC, the exercise-induced increase in malondialdehyde observed in the placebo trial was blunted after NAC ingestion, with lower values at 40 min (p = 0.018; d = 0.73). NAC did not affect cycling time-trial performance.

CONCLUSIONS: Blood biomarkers relating to oxidative stress and inflammation are elevated in WomenOC during exercise. There may be an increased strain on the endogenous antioxidant system during exercise, since NAC supplementation in WomenOC did not dampen the exercise-induced increase in malondialdehyde. Future investigations should explore the impact of elevated oxidative stress on exercise adaptations or recovery from exercise in WomenOC.}, } @article {pmid35666067, year = {2022}, author = {Yang, C and Zhang, X and Ge, X and He, C and Liu, S and Yang, S and Huang, C}, title = {N-Acetylcysteine protects against cobalt chloride-induced endothelial dysfunction by enhancing glucose-6-phosphate dehydrogenase activity.}, journal = {FEBS open bio}, volume = {12}, number = {8}, pages = {1475-1488}, pmid = {35666067}, issn = {2211-5463}, mesh = {*Acetylcysteine/pharmacology ; Cobalt ; Glucosephosphate Dehydrogenase/pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; Hypoxia ; *Vascular Diseases ; }, abstract = {Hypoxia-induced endothelial dysfunction is known to be involved in the pathogenesis of several vascular diseases. However, it remains unclear whether the pentose phosphate pathway (PPP) is involved in regulating the response of endothelial cells to hypoxia. Here, we established an in vitro model by treating EA.hy926 (a hybrid human umbilical vein cell line) with cobalt chloride (CoCl2 ; a chemical mimic that stabilizes HIF-1α, thereby leading to the development of hypoxia), and used this to investigate the involvement of PPP by examining expression of its key enzyme, glucose-6-phosphate dehydrogenase (G6PD). We report that CoCl2 induces the accumulation of HIF-1α, leading to endothelial cell dysfunction characterized by reduced cell viability, proliferation, tube formation, and activation of cytokine production, accompanied with a significant decrease in G6PD expression and activity. The addition of 6-aminonicotinamide (6-AN) to inhibit PPP directly causes endothelial dysfunction. Additionally, N-Acetylcysteine (NAC), a precursor of glutathione, was further evaluated for its protective effects; NAC displayed a protective effect against CoCl2 -induced cell damage by enhancing G6PD activity, and this was abrogated by 6-AN. The effects of CoCl2 and the involvement of G6PD in endothelial dysfunction have been confirmed in primary human aortic endothelial cells. In summary, G6PD was identified as a novel target of CoCl2 -induced damage, which highlighted the involvement of PPP in regulating the response of endothelial cell CoCl2 . Treatment with NAC may be a potential strategy to treat hypoxia or ischemia, which are widely observed in vascular diseases.}, } @article {pmid35663445, year = {2022}, author = {Park, C and Choi, EO and Hwangbo, H and Lee, H and Jeong, JW and Han, MH and Moon, SK and Yun, SJ and Kim, WJ and Kim, GY and Hwang, HJ and Choi, YH}, title = {Induction of apoptotic cell death in human bladder cancer cells by ethanol extract of Zanthoxylum schinifolium leaf, through ROS-dependent inactivation of the PI3K/Akt signaling pathway.}, journal = {Nutrition research and practice}, volume = {16}, number = {3}, pages = {330-343}, pmid = {35663445}, issn = {1976-1457}, abstract = {BACKGROUND/OBJECTIVES: Zanthoxylum schinifolium is traditionally used as a spice for cooking in East Asian countries. This study was undertaken to evaluate the anti-proliferative potential of ethanol extracts of Z. schinifolium leaves (EEZS) against human bladder cancer T24 cells.

MATERIALS/METHODS: Subsequent to measuring the cytotoxicity of EEZS, the anti-cancer activity was measured by assessing apoptosis induction, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). In addition, we determined the underlying mechanism of EEZS-induced apoptosis through various assays, including Western blot analysis.

RESULTS: EEZS treatment concentration-dependently inhibited T24 cell survival, which is associated with apoptosis induction. Exposure to EEZS induced the expression of Fas and Fas-ligand, activated caspases, and subsequently resulted to cleavage of poly (ADP-ribose) polymerase. EEZS also enhanced the expression of cytochrome c in the cytoplasm by suppressing MMP, following increase in the ratio of Bax:Bcl-2 expression and truncation of Bid. However, EEZS-mediated growth inhibition and apoptosis were significantly diminished by a pan-caspase inhibitor. Moreover, EEZS inhibited activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the apoptosis-inducing potential of EEZS was promoted in the presence of PI3K/Akt inhibitor. In addition, EEZS enhanced the production of ROS, whereas N-acetyl cysteine (NAC), a ROS scavenger, markedly suppressed growth inhibition and inactivation of the PI3K/Akt signaling pathway induced by EEZS. Furthermore, NAC significantly attenuated the EEZS-induced apoptosis and reduction of cell viability.

CONCLUSIONS: Taken together, our results indicate that exposure to EEZS exhibits anti-cancer activity in T24 bladder cancer cells through ROS-dependent induction of apoptosis and inactivation of the PI3K/Akt signaling pathway.}, } @article {pmid35661979, year = {2022}, author = {Bhattarai, N and Hytti, M and Reinisalo, M and Kaarniranta, K and Mysore, Y and Kauppinen, A}, title = {Hydroquinone predisposes for retinal pigment epithelial (RPE) cell degeneration in inflammatory conditions.}, journal = {Immunologic research}, volume = {70}, number = {5}, pages = {678-687}, pmid = {35661979}, issn = {1559-0755}, mesh = {*Ammonium Compounds/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Cells, Cultured ; Cysteine/metabolism/pharmacology ; Humans ; Hydroquinones/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/metabolism/pathology ; Retinal Pigments/metabolism/pharmacology ; *Tobacco Smoke Pollution ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {In addition to hypoxia, inflammation is capable of inducing vascular endothelial growth factor (VEGF) expression in human retinal pigment epithelial (RPE) cells. Excessive levels of VEGF promote choroidal neovascularization and thereby contribute to the pathogenesis of wet age-related macular degeneration (AMD). Intravitreal anti-VEGF injections ameliorate pathological vessel neoformation in wet AMD but excessive dampening of VEGF can result in a degeneration of the RPE. In the present study, we induced VEGF production by exposing human ARPE-19 cells to the pro-inflammatory IL-1α and subsequently to hydroquinone, a component of tobacco smoke that is a major environmental risk factor for AMD. Effects were monitored by measuring the levels of VEGF and anti-angiogenic pigment epithelium-derived factor (PEDF) using an enzyme-linked immunosorbent assay (ELISA) technique. In addition, we measured the production of reactive oxygen species (ROS) using the 2',7'-dichlorofluorescin diacetate (H2DCFDA) probe and studied the effects of two anti-oxidants, ammonium pyrrolidinedithiocarbamate (APDC) and N-acetyl-cysteine (NAC), on VEGF production. Cellular and secreted VEGF as well as secreted PEDF levels were reduced at all tested hydroquinone concentrations (10, 50, or 200 µM); these effects were evident prior to any reduction of cell viability evoked by hydroquinone. Cell viability was carefully explored in our previous study and verified by microscoping in the present study. APDC further reduced the VEGF levels, whereas NAC increased them. The 50 μM concentration of hydroquinone increased ROS production in ARPE-19 cells primed with IL-1α. Hydroquinone disturbs the regulatory balance of VEGF and PEDF in inflammatory conditions. These data support the idea that hydroquinone mediates RPE degeneration by reducing VEGF levels and may predispose to dry AMD since VEGF is as well important for retinal integrity.}, } @article {pmid35661091, year = {2022}, author = {Savran, F and Karabulut, B and Yılmaz, AS and Surmeli, M and Guler, EM and Genc, S and Ihvan, A}, title = {Mucolytic and Antioxidant Effects of Intranasal Acetylcysteine Use on Acute Rhinosinusitis in Rats with an Acute Rhinosinusitis Model.}, journal = {ORL; journal for oto-rhino-laryngology and its related specialties}, volume = {84}, number = {6}, pages = {447-452}, doi = {10.1159/000524869}, pmid = {35661091}, issn = {1423-0275}, mesh = {Rats ; Animals ; Mice ; *Acetylcysteine/pharmacology ; *Antioxidants/pharmacology ; Expectorants/pharmacology ; Oxidative Stress ; Sulfhydryl Compounds/pharmacology ; }, abstract = {INTRODUCTION: The aim of this study was to investigate whether N-acetylcysteine (NAC) is effective in the treatment murine model of acute rhinosinusitis in rats.

MATERIALS AND METHODS: Twelve rats were included in the study. The left nasal cavity of all rats was infected with Streptococcus pneumoniae. Group 1 was the group in which NAC was administered into the left nasal cavity twice daily. Group 2 was selected as the control group. All rats were then sterilely sacrificed under anesthesia after intracardiac blood sampling. After sacrifice, sterile culture samples were collected from the posterior nasal cavity.

RESULTS: Total oxidant status and oxidative stress index (OSI), interleukin 1β, interleukin 6, and tumor necrosis factor α levels decreased significantly in the treatment group. Total antioxidant status was significantly increased. There was a statistically significant increase in total serum thiol levels and native thiol levels. Histopathologic evaluation showed a statistically significant decrease in submucosal gland hypertrophy in the treatment group.

CONCLUSION: According to our study, intranasal application of NAC can decrease the inflammatory findings in murine acute rhinosinusitis.}, } @article {pmid35660452, year = {2022}, author = {Li, Q and Liao, J and Chen, W and Zhang, K and Li, H and Ma, F and Zhang, H and Han, Q and Guo, J and Li, Y and Hu, L and Pan, J and Tang, Z}, title = {NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway.}, journal = {Free radical biology & medicine}, volume = {187}, number = {}, pages = {158-170}, doi = {10.1016/j.freeradbiomed.2022.05.024}, pmid = {35660452}, issn = {1873-4596}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; *Diabetes Mellitus/metabolism ; *Diabetic Nephropathies/drug therapy/genetics/metabolism ; Dogs ; *Ferroptosis/genetics ; Homeostasis ; *Insulins/metabolism/pharmacology ; Mammals/metabolism ; Mitochondria/metabolism ; Oxidation-Reduction ; *Sirtuin 3/genetics/metabolism ; }, abstract = {Diabetic nephropathy (DN) is known as a major microvascular complication in type 1 diabetes. The effect of insulin treatment alone on controlling blood glucose is unsatisfactory. N-acetylcysteine (NAC), a chemical agent with thiol group, is found to confer a protective effect in renal injury. However, whether NAC combined with insulin treatment can further enhance the therapeutic effect in DN remains unclear. Here, we firstly used large mammal beagle as DN model to explore the effect of NAC combined with insulin treatment on DN during 120 d. Our results showed that NAC further alleviated mitochondrial oxidative damage and ferroptosis by enhancing activity of mitochondria GSH and maintaining mitochondrial redox homeostasis in DN. Additionally, the upregulated acetylation level of SOD2 was further abrogated by NAC treatment. In MDCK cells, NAC reduced high glucose (HG)-caused ferroptosis via activating Gpx4 expression. Of note, inhibition of Gpx4 by FIN56 abolished the protective effects of NAC on HG-induced ferroptosis. More importantly, 3-TYP reversed the effect of NAC on the mitochondria ROS under HG treatment, as well as eliminated its following beneficial effects for ferroptosis against HG-stimulated cells. These results reveal that NAC attenuated ferroptosis in DN via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2-Gpx4 signaling pathway.}, } @article {pmid35658749, year = {2022}, author = {Jin, S and Zhang, T and Fu, X and Duan, Z and Sun, J and Wang, Y}, title = {Aniline exposure activates receptor-interacting serine/threonineprotein kinase 1 and causes necroptosis of AML12 cells.}, journal = {Toxicology and industrial health}, volume = {38}, number = {8}, pages = {444-454}, doi = {10.1177/07482337221106751}, pmid = {35658749}, issn = {1477-0393}, mesh = {Aniline Compounds/toxicity ; Apoptosis ; *Chemical and Drug Induced Liver Injury ; Humans ; *Necroptosis ; Protein Serine-Threonine Kinases ; Reactive Oxygen Species/metabolism ; Serine ; }, abstract = {With the increased use of aniline, potential impacts on human health cannot be ignored. The hepatotoxicity of aniline is largely unknown and the underlying mechanism remains unclear. Therefore, the aim of the present study was to investigate the hepatotoxicity of aniline and elucidate the underlying mechanism. AML12 cells were exposed to different concentrations of aniline (0, 5, 10, or 20 mM) to observe changes to reactive oxygen species (ROS) production and the expression patterns of necroptosis-related proteins (RIPK1, RIPK3, and MLKL). The potential mechanism underlying aniline-induced hepatotoxicity was explored by knockout of RIPK1. The results showed that aniline induced cytotoxicity in AML12 cells in a dose-dependent manner in addition to the production of ROS and subsequent necroptosis of AML12 cells. Silencing of RIPK1 reversed upregulation of necroptosis-related proteins in AML12 cells exposed to aniline, demonstrating that aniline-induced ROS production was related to necroptosis of AML12. Moreover, aniline promoted intracellular RIPK1 activation, suggesting that the RIPK1/ROS pathway plays an important role in aniline-induced hepatotoxicity. NAC could quench ROS and inhibit necroptosis. These results provide a scientific basis for future studies of aniline-induced hepatotoxicity for the prevention and treatment of aniline-induced cytotoxicity.}, } @article {pmid35657279, year = {2022}, author = {Choi, SM and Lee, PH and An, MH and Yun-Gi, L and Park, S and Baek, AR and Jang, AS}, title = {N-acetylcysteine decreases lung inflammation and fibrosis by modulating ROS and Nrf2 in mice model exposed to particulate matter.}, journal = {Immunopharmacology and immunotoxicology}, volume = {44}, number = {6}, pages = {832-837}, doi = {10.1080/08923973.2022.2086138}, pmid = {35657279}, issn = {1532-2513}, mesh = {Female ; Mice ; Animals ; Acetylcysteine/pharmacology ; Particulate Matter/toxicity ; *Pulmonary Fibrosis/chemically induced/drug therapy ; Hyperplasia ; *Pneumonia/chemically induced/drug therapy ; *Respiratory Hypersensitivity ; }, abstract = {Background and Objectives: Air pollutants can induce and incite airway diseases such as asthma. N-acetylcysteine (NAC) affects signaling pathways involved in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and the inflammatory response. However, it is not known how NAC change redox-regulated gene expression in asthma mouse model exposed to particulate matter (PM). To investigate the effects of NAC on asthma mice exposed to PM through Reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), and mucin 5 (Muc5).Methods: To investigate the effects of NAC (100 mg/kg) on redox-regulated gene expression and lung fibrosis in a mouse model of asthma exposed to PM. A mice model of asthma induced by ovalbumin (OVA) or OVA plus titanium dioxide (OVA + TiO2) was established using wild-type BALB/c female mice, and the levels of Nrf2 and mucin 5AC (Muc5ac) proteins following NAC treatment were examined by Western blotting and immunostaining. In addition, the protein levels of ROS were checked.Results: Airway hyperresponsiveness and inflammation, goblet cell hyperplasia, and lung fibrosis were higher in OVA, OVA + TiO2 mice than in control mice. NAC diminished OVA + TiO2-induced airway hyperresponsiveness and inflammation, goblet cell hyperplasia, and lung fibrosis. Levels of ROS, Nrf2, and Muc5ac protein were higher in lung tissue from OVA + TiO2 mice than that from control mice and were decreased by treatment with NAC.Conclusions: NAC reduce airway inflammation and responsiveness, goblet cell hyperplasia, and lung fibrosis by modulating ROS and Nrf2.}, } @article {pmid35656297, year = {2022}, author = {Sanabria-Cabrera, J and Tabbai, S and Niu, H and Alvarez-Alvarez, I and Licata, A and Björnsson, E and Andrade, RJ and Lucena, MI}, title = {N-Acetylcysteine for the Management of Non-Acetaminophen Drug-Induced Liver Injury in Adults: A Systematic Review.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {876868}, pmid = {35656297}, issn = {1663-9812}, abstract = {Introduction: Idiosyncratic drug-induced liver injury (DILI) is a rare adverse reaction to drugs and other xenobiotics. DILI has different grades of severity and may lead to acute liver failure (ALF), for which there is no effective therapy. N-acetylcysteine (NAC) has been occasionally tested for the treatment of non-acetaminophen drug-induced ALF. However, limited evidence for its efficacy and safety is currently available. Our aim was to elucidate the benefit and safety of NAC in DILI and evaluate its hepatoprotective effect. Methods: We conducted a systematic review to evaluate the management and prevention focused on NAC in idiosyncratic DILI. The main outcomes included mortality due to DILI, time to normalization of liver biochemistry, transplant-free survival, and adverse events. We included clinical trials and observational studies, either prospective or retrospective. Results: A total of 11 studies were included after literature screening. All studies had different methodologies, and some of them had important risk of bias that may lead to interpreting their findings with caution. The majority of the studies proved NAC efficacy in a cohort of patients with ALF due to different etiologies, where DILI represented a subgroup. NAC seemed to improve transplant-free survival; however, its benefit was inconclusive in terms of overall survival. With regard to safety, NAC showed an adequate safety profile. In prevention studies, NAC showed a possible hepatoprotective effect; however, this finding is limited by the lack of studies and presence of bias. Conclusion: NAC treatment seems to have some benefit in non-acetaminophen drug-induced liver failure patients with acceptable safety; however, due to the lack of evidence and limitations detected across studies, its benefit must be corroborated in clinical trials with adequate methodology.}, } @article {pmid35655853, year = {2022}, author = {Wang, S and Liu, G and Jia, T and Wang, C and Lu, X and Tian, L and Yang, Q and Zhu, C}, title = {Protection Against Post-resuscitation Acute Kidney Injury by N-Acetylcysteine via Activation of the Nrf2/HO-1 Pathway.}, journal = {Frontiers in medicine}, volume = {9}, number = {}, pages = {848491}, pmid = {35655853}, issn = {2296-858X}, abstract = {BACKGROUND AND OBJECTIVE: Acute kidney injury (AKI), the common complication after cardiopulmonary resuscitation (CPR), seriously affects the prognosis of cardiac arrest (CA) patients. However, there are limited studies on post-resuscitation AKI. In addition, it has been demonstrated that N-acetylcysteine (N-AC) as an ROS scavenger, has multiorgan-protective effects on systemic and regional ischaemia-reperfusion injuries. However, no studies have reported its protective effects against post-resuscitation AKI and potential mechanisms. This study aimed to clarify the protective effects of N-AC on post-resuscitation AKI and investigate whether its potential mechanism was mediated by activating Nrf-2/HO-1 pathway in the kidney.

METHODS: We established cardiac arrest models in rats. All animals were divided into four groups: the sham, control, N-AC, and ZnPP groups. Animals in each group except for the ZnPP group were assigned into two subgroups based on the survival time: 6 and 48 h. The rats in the control, N-AC, and ZnPP groups underwent induction of ventricular fibrillation (VF), 8 min untreated VF and cardiopulmonary resuscitation. Renal function indicators, were detected using commercial kits. Renal pathologic changes were assessed by haematoxylin-eosin (HE) staining. Oxidative stress and inflammatory responses were measured using the corresponding indicators. Apoptosis was evaluated using terminal uridine nick-end labeling (TUNEL) staining, and expression of proteins associated with apoptosis and the Nrf-2/HO-1 pathway was measured by western blotting.

RESULTS: N-AC inhibited post-resuscitation AKI. We observed that N-AC reduced the levels of biomarkers of renal function derangement; improved renal pathological changes; and suppressed apoptosis, oxidative stress, and inflammatory response. Additionally, the production of ROS in the kidneys markedly decreased by N-AC. More importantly, compared with the control group, N-AC further upregulated the expression of nuclear Nrf2 and endogenous HO-1 in N-AC group. However, N-AC-determined protective effects on post-resuscitation AKI were markedly reversed after pretreatment of the HO-1 inhibitor zinc protoporphyrin (ZnPP).

CONCLUSIONS: N-AC alleviated renal dysfunction and prolonged survival in animal models of CA. N-AC partially exerts beneficial renal protection via activation of the Nrf-2/HO-1 pathway. Altogether, all these findings indicated that N-AC as a common clinical agent, may have the potentially clinical utility to improve patients the outcomes in cardiac arrest.}, } @article {pmid35647220, year = {2022}, author = {Popova, L and Mancuso, J}, title = {Dramatic Improvement of Trichotillomania with 6 Months of Treatment With N-Acetylcysteine.}, journal = {Global pediatric health}, volume = {9}, number = {}, pages = {2333794X221086576}, pmid = {35647220}, issn = {2333-794X}, abstract = {We present a case of a 17-year-old male with recurrent hair twirling resulting in patchy alopecia, who improved dramatically on N-acetylcysteine (NAC). Trichotillomania is characterized by repetitive hair pulling, twisting, or twirling and can vary from a mild habit to an impulse-control disorder. Standard treatment for pediatric trichotillomania includes cognitive behavioral therapy or medical therapy with selective serotonin reuptake inhibitors. NAC is a more recently utilized, safe, and well-tolerated over-the-counter supplement with some evidence of benefit for habitual skin and hair disorders. For this patient, we recommended 600 mg twice daily, increasing to 1200 mg twice daily as tolerated. After 6 months, our patient reported decreased desire to twirl his hair and his hair had almost completely regrown. Pediatricians who see patients with trichotillomania or other habitual disorders can consider treating these patients with NAC given its potential benefits and favorable side effect profile.}, } @article {pmid35640855, year = {2022}, author = {Promsan, S and Thongnak, L and Pengrattanachot, N and Phengpol, N and Sutthasupha, P and Lungkaphin, A}, title = {Agomelatine, a structural analog of melatonin, improves kidney dysfunction through regulating the AMPK/mTOR signaling pathway to promote autophagy in obese rats.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {165}, number = {}, pages = {113190}, doi = {10.1016/j.fct.2022.113190}, pmid = {35640855}, issn = {1873-6351}, mesh = {AMP-Activated Protein Kinases/metabolism ; Acetamides ; Animals ; Autophagy ; *Insulin Resistance ; Kidney ; Male ; *Melatonin/pharmacology ; Naphthalenes ; Obesity/metabolism ; Rats ; Rats, Wistar ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {This study aimed to investigate the renoprotective effect of agomelatine on kidney injury in an obese rat model and to understand the underlying mechanisms involving the AMPK-mTOR-autophagy signaling pathway. Male Wistar rats were fed either a normal (ND) or a high-fat diet (HF) for 16 weeks. The HF rats were divided into 4 groups: (1) HF control; (2) AGOM20 receiving agomelatine 20 mg. kg[-1] day[-1]; (3) AGOM40 receiving agomelatine 40 mg. kg[-1] day[-1]; and (4) NAC receiving N-acetylcysteine 100 mg. kg[-1] day[-1] by oral gavage for 4 weeks. HF rats demonstrated insulin resistance, impaired renal function and oxidative stress as evidenced by the elevation of MDA levels and expression of PKCα and NOX4. These alterations correlated with impaired autophagy, renal fibrosis and apoptosis. Agomelatine showed a greater efficacy than NAC treatment with regard to improving insulin resistance, dyslipidemia and renal dysfunction through alleviation of oxidative stress, fibrosis and apoptosis in kidney cells. Impaired autophagy was blunted after agomelatine or NAC administration, as demonstrated by the increased in Beclin-1, LC3B, Atg5, LAMP2, and AMPK, and decreased mTOR and CTSB expression. These data revealed that agomelatine protected against obesity-induced kidney injury via the regulation of ROS and AMPK-mTOR-autophagy signaling pathways.}, } @article {pmid35636024, year = {2022}, author = {Walker, H and Guthrie, GD and Lambourg, E and Traill, P and Zealley, I and Plumb, A and Bell, S}, title = {Systematic review and meta-analysis of prophylaxis use with intravenous contrast exposure to prevent contrast-induced nephropathy.}, journal = {European journal of radiology}, volume = {153}, number = {}, pages = {110368}, doi = {10.1016/j.ejrad.2022.110368}, pmid = {35636024}, issn = {1872-7727}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Contrast Media/adverse effects ; Humans ; *Kidney Diseases/chemically induced/prevention & control ; *Renal Insufficiency/chemically induced ; Sodium Bicarbonate/adverse effects ; }, abstract = {PURPOSE: Iodinated radiographic contrast media has been associated with an acute deterioration in renal function, termed contrast induced nephropathy (CIN). This review aims to establish the efficacy of prophylaxis interventions used in adult patients prior to intravenous exposure to iodinated contrast to reduce the risk of CIN.

METHODS: An electronic search for published peer-reviewed articles was performed, supplemented with manual review of references from previous systematic reviews and the National Institute for Health and Care Excellence guidelines. Risk of bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias. Random-effect meta-analyses were used to assess CIN incidence, need for kidney replacement therapy (KRT), mortality, fluid overload and persistent kidney dysfunction.

RESULTS: 22 studies assessing a range of interventions were included in the qualitative analysis. The incidence of CIN was reduced by the use of N-acetylcysteine compared to a control group of saline (risk difference = -0.07, 95% CI -0.13 to -0.01) but not by sodium bicarbonate compared to control group of saline (risk difference = -0.02, 95% CI -0.04 to 0.01). Published studies give no indication that prophylactic interventions have significant impact on the need for KRT, mortality or persistent renal impairment.

CONCLUSION: Evidence for prophylaxis against CIN in patients receiving intravenous iodinated contrast is limited. There was an association with the use of NAC with reduced incidence of CIN following intravenous contrast but there was no impact on other clinical outcomes assessed. The clinical significance of these findings remains unclear and further research focusing on these clinical outcomes is required.}, } @article {pmid35636015, year = {2022}, author = {Liu, W and Zhao, Y and Wang, G and Feng, S and Ge, X and Ye, W and Wang, Z and Zhu, Y and Cai, W and Bai, J and Zhou, X}, title = {TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling.}, journal = {Redox biology}, volume = {53}, number = {}, pages = {102344}, pmid = {35636015}, issn = {2213-2317}, mesh = {AMP-Activated Protein Kinases/genetics/metabolism ; Adolescent ; Autophagy/genetics ; *Bone Neoplasms ; Humans ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Minor Histocompatibility Antigens/pharmacology ; NF-E2-Related Factor 2/genetics/metabolism ; *Osteosarcoma/genetics ; Reactive Oxygen Species/metabolism ; Repressor Proteins/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Tripartite Motif Proteins/genetics/metabolism ; }, abstract = {Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.}, } @article {pmid35635082, year = {2022}, author = {Sun, Q and Zhen, P and Li, D and Liu, X and Ding, X and Liu, H}, title = {Amentoflavone promotes ferroptosis by regulating reactive oxygen species (ROS) /5'AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) to inhibit the malignant progression of endometrial carcinoma cells.}, journal = {Bioengineered}, volume = {13}, number = {5}, pages = {13269-13279}, pmid = {35635082}, issn = {2165-5987}, mesh = {AMP-Activated Protein Kinases/metabolism ; Biflavonoids ; *Endometrial Neoplasms ; Female ; *Ferroptosis ; Humans ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Thiobarbituric Acid Reactive Substances ; }, abstract = {It was reported that amentoflavone (AF) had anti-tumor ability. Therefore, this study aimed to investigate the role of AF in endometrial cancer as well as to discuss its underlying mechanism. The viability, proliferation, and apoptosis of endometrial carcinoma cells (KLE) with AF administration were detected by methyl tetrazolium (MTT) assay, clone formation, and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assays. Thiobarbituric acid reactive substance (TBARS) production and Fe[2+] level in AF-treated KLE cells were detected by TBARS assay and Iron assay. The expressions of proliferation- apoptosis-, ferroptosis-, and 5'AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling-related proteins in AF-treated KLE cells were detected by western blot analysis. Reactive oxygen species (ROS) expression in AF-treated KLE cells was determined by ROS assay kit. N-acetyl cysteine (NAC), which is an inhibitor of ROS, was used to confirm whether AF exerted its effects on KLE cells through ROS/AMPK/mTOR signaling. As a result, AF inhibited the viability and proliferation of KLE cells but promoted apoptosis and ferroptosis. The expressions of ROS and AMPK were increased, while mTOR expression was decreased in AF-treated KLE cells. NAC reversed the effects of AF on biological behaviors of KLE cells by inactivating ROS/AMPK/mTOR signaling. In conclusion, AF promoted ferroptosis by activating ROS/AMPK/mTOR to inhibit the viability and proliferation and promoted the apoptosis and ferroptosis of KLE cells.}, } @article {pmid35631736, year = {2022}, author = {He, W and Zhong, Q and He, B and Wu, B and Mohi Ud Din, A and Han, J and Ding, Y and Liu, Z and Li, W and Jiang, Y and Li, G}, title = {N-Acetylcysteine Priming Alleviates the Transplanting Injury of Machine-Transplanted Rice by Comprehensively Promoting Antioxidant and Photosynthetic Systems.}, journal = {Plants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {35631736}, issn = {2223-7747}, support = {BE2021361; BE2019377//Key Research and Development Program of Jiangsu Province/ ; CX (18) 1002//Jiangsu Agriculture Science and Technology Innovation Fund/ ; }, abstract = {The stress of transplanting injury adversely affects rice growth and productivity worldwide. N-acetylcysteine (NAC), the precursor of glutathione, is a potent ROS scavenger with powerful antioxidant activity. Previous studies on the application of NAC in plants mainly focused on alleviating the stress of heavy metals, UV-B, herbicides, etc. However, the role of NAC in alleviating transplanting injury is still not clear. A barrel experiment was carried out to explain the mechanism of NAC regulating the transplanting injury to machine-transplanted rice during the recovery stage. The results showed that NAC priming shortened the time of initiation of tillering and increased the tiller numbers within 3 weeks after transplanting. In addition, NAC priming increased the chlorophyll content, net photosynthetic rate, and sucrose content, thereby improving the dry weight at the recovery stage, especially root dry weight. At the same time, NAC priming significantly increased the activity of ascorbate peroxidase (APX), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD). In addition, it also regulated flavonoids and total phenols contents to reduce hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents, especially at the initial days after transplanting. These results suggest that NAC priming improves the tolerance of rice seedlings against transplanting injury by enhancing photosynthesis and antioxidant systems at initial days after transplanting, thereby promoting the accumulation of dry matter and tillering for higher yield returns.}, } @article {pmid35629355, year = {2022}, author = {Shih, SP and Lu, MC and El-Shazly, M and Lin, YH and Chen, CL and Yu, SS and Liu, YC}, title = {The Antileukemic and Anti-Prostatic Effect of Aeroplysinin-1 Is Mediated through ROS-Induced Apoptosis via NOX Activation and Inhibition of HIF-1a Activity.}, journal = {Life (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {35629355}, issn = {2075-1729}, support = {MOST 110-2320-B-259-001-MY3;110-2314-B-037-083//Ministry of Science and Technology/ ; NHRI-110A1-CACO-03212109//National Health Research Institutes/ ; 111T2560-5//National Dong Hwa University/ ; }, abstract = {Aeroplysinin-1 is a brominated isoxazoline alkaloid that has exhibited a potent antitumor cell effect in previous reports. We evaluated the cytotoxicity of aeroplysinin-1 against leukemia and prostate cancer cells in vitro. This marine alkaloid inhibited the cell proliferation of leukemia Molt-4, K562 cells, and prostate cancer cells Du145 and PC-3 with IC50 values of 0.12 ± 0.002, 0.54 ± 0.085, 0.58 ± 0.109 and 0.33 ± 0.042 µM, respectively, as shown by the MTT assay. Furthermore, in the non-malignant cells, CCD966SK and NR8383, its IC50 values were 1.54 ± 0.138 and 6.77 ± 0.190 μM, respectively. In a cell-free system, the thermal shift assay and Western blot assay verified the binding affinity of aeroplysinin-1 to Hsp90 and Topo IIα, which inhibited their activity. Flow cytometry analysis showed that the cytotoxic effect of aeroplysinin-1 is mediated through mitochondria-dependent apoptosis induced by reactive oxygen species (ROS). ROS interrupted the cellular oxidative balance by activating NOX and inhibiting HIF-1α and HO-1 expression. Pretreatment with N-acetylcysteine (NAC) reduced Apl-1-induced mitochondria-dependent apoptosis and preserved the expression of NOX, HO-1, and HIF-1a. Our findings indicated that aeroplysinin-1 targeted leukemia and prostate cancer cells through multiple pathways, suggesting its potential application as an anti-leukemia and prostate cancer drug lead.}, } @article {pmid35629096, year = {2022}, author = {Zisis, IE and Georgiadis, G and Docea, AO and Calina, D and Cercelaru, L and Tsiaoussis, J and Lazopoulos, G and Sofikitis, N and Tsatsakis, A and Mamoulakis, C}, title = {Renoprotective Effect of Vardenafil and Avanafil in Contrast-Induced Nephropathy: Emerging Evidence from an Animal Model.}, journal = {Journal of personalized medicine}, volume = {12}, number = {5}, pages = {}, pmid = {35629096}, issn = {2075-4426}, abstract = {The potential renoprotective effects of vardenafil (VAR) have been evaluated in a very limited number of studies using acute kidney injury animal models other than contrast-induced nephropathy (CIN) with promising results, while avanafil (AVA) has not been evaluated in this respect before. The purpose of this study was to evaluate for the first time the potential renoprotective effect of VAR and AVA in a rat model of CIN. Twenty-five male Wistar rats were equally assigned into five groups: control, CIN, CIN+N-acetyl cysteine (NAC) (100 mg/kg/day) as a positive control, CIN+VAR (10 mg/kg/day) and CIN+AVA (50 mg/kg/day). CIN was induced by dehydration, inhibition of prostaglandin and nitric oxide synthesis as well as exposure to the contrast medium (CM). Serum Cr (sCr) levels were measured at 24 and 48 h after CIN induction. At 48 h of CM exposure, animals were sacrificed. Matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, kidney injury molecule 1 (KIM-1) and cystatin-C (Cys-C) were measured on renal tissue. Histopathological findings were evaluated on kidney tissue. All treatment groups had close to normal kidney appearance. sCr levels subsided in all treatment groups compared to CIN group at 48 h following CIN induction. A significant decline in the levels of MMP-2, MMP-9, KIM-1 and Cys-C compared to CIN group was observed. These results provide emerging evidence that VAR and AVA may have the potential to prevent CIN.}, } @article {pmid35628435, year = {2022}, author = {Lai, KM and Wang, JH and Lin, SC and Wen, Y and Wu, CL and Su, JH and Chen, CC and Lin, CC}, title = {Crassolide Induces G2/M Cell Cycle Arrest, Apoptosis, and Autophagy in Human Lung Cancer Cells via ROS-Mediated ER Stress Pathways.}, journal = {International journal of molecular sciences}, volume = {23}, number = {10}, pages = {}, pmid = {35628435}, issn = {1422-0067}, support = {(MOE-110-S-0023-E//iEGG and Animal Biotechnology Center of the Feature Areas Research Center Program within the framework of the Higher Education Sprout Project by the Taiwan Ministry of Education/ ; TCVGH-1117307C//Taichung Veterans General Hospital/ ; }, mesh = {Apoptosis ; Autophagy ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Cell Cycle Checkpoints ; Cell Line, Tumor ; *Diterpenes/pharmacology ; G2 Phase Cell Cycle Checkpoints ; Humans ; *Lung Neoplasms/drug therapy ; Reactive Oxygen Species/metabolism ; }, abstract = {Crassolide, a cembranoid diterpene extracted from the soft coral Lobophytum crissum, has been proven to possess antioxidant and immunomodulatory properties. In the present study, we assessed the anticancer effects of crassolide on human H460 non-small-cell lung cancer (NSCLC) cells. We found that crassolide exerted cytotoxic effects on H460 cancer cells in vitro, inducing G2/M phase arrest and apoptosis. In addition, in H460 cells exposed to crassolide, the expression of the autophagy-related proteins LC3-II and beclin was increased, while the expression of p62 was decreased. Moreover, inhibiting autophagy with chloroquine (CQ) suppressed the crassolide-induced G2/M arrest and apoptosis of H460 cells. Moreover, we also found that crassolide induced endoplasmic reticulum (ER) stress in lung cancer cells by increasing the expression of ER stress marker proteins and that the crassolide-induced G2/M arrest, apoptosis, and autophagy were markedly attenuated by the ER stress inhibitor 4-phenylbutyric acid (4-PBA). Furthermore, we found that crassolide promoted reactive oxygen species (ROS) production by H460 cells and that the ROS inhibitor N-acetylcysteine (NAC) decreased the crassolide-induced ER stress, G2/M arrest, apoptosis, and autophagy. In conclusion, our findings show that crassolide inhibits NSCLC cell malignant biological behaviors for the first time, suggesting that this effect may be mechanistically achieved by inducing G2/M arrest, apoptosis, and autophagy through ROS accumulation, which activates the ER stress pathway. As a result of our findings, we now have a better understanding of the molecular mechanism underlying the anticancer effect of crassolide, and we believe crassolide might be a candidate for targeted cancer therapy.}, } @article {pmid35628239, year = {2022}, author = {Petricca, S and Celenza, G and Luzi, C and Cinque, B and Lizzi, AR and Franceschini, N and Festuccia, C and Iorio, R}, title = {Synergistic Activity of Ketoconazole and Miconazole with Prochloraz in Inducing Oxidative Stress, GSH Depletion, Mitochondrial Dysfunction, and Apoptosis in Mouse Sertoli TM4 Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {10}, pages = {}, pmid = {35628239}, issn = {1422-0067}, support = {07-RIA 2021 IORIO ROBERTO//DISCAB GRANT 2021/ ; CUP E11I18000300005//MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca, Italy)/ ; }, mesh = {Animals ; Apoptosis ; Glutathione/metabolism ; Imidazoles/metabolism/pharmacology ; *Ketoconazole/pharmacology ; Male ; Mammals/metabolism ; Mice ; *Miconazole/pharmacology ; Mitochondria/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Triazole and imidazole fungicides represent an emerging class of pollutants with endocrine-disrupting properties. Concerning mammalian reproduction, a possible causative role of antifungal compounds in inducing toxicity has been reported, although currently, there is little evidence about potential cooperative toxic effects. Toxicant-induced oxidative stress (OS) may be an important mechanism potentially involved in male reproductive dysfunction. Thus, to clarify the molecular mechanism underlying the effects of azoles on male reproduction, the individual and combined potential of fluconazole (FCZ), prochloraz (PCZ), miconazole (MCZ), and ketoconazole (KCZ) in triggering in vitro toxicity, redox status alterations, and OS in mouse TM4 Sertoli cells (SCs) was investigated. In the present study, we demonstrate that KCZ and MCZ, alone or in synergistic combination with PCZ, strongly impair SC functions, and this event is, at least in part, ascribed to OS. In particular, azoles-induced cytotoxicity is associated with growth inhibitory effects, G0/G1 cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, imbalance of the superoxide dismutase (SOD) specific activity, glutathione (GSH) depletion, and apoptosis. N-acetylcysteine (NAC) inhibits ROS accumulation and rescues SCs from azole-induced apoptosis. PCZ alone exhibits only cytostatic and pro-oxidant properties, while FCZ, either individually or in combination, shows no cytotoxic effects up to 320 µM.}, } @article {pmid35624761, year = {2022}, author = {Rodríguez-Agudo, R and Goikoetxea-Usandizaga, N and Serrano-Maciá, M and Fernández-Tussy, P and Fernández-Ramos, D and Lachiondo-Ortega, S and González-Recio, I and Gil-Pitarch, C and Mercado-Gómez, M and Morán, L and Bizkarguenaga, M and Lopitz-Otsoa, F and Petrov, P and Bravo, M and Van Liempd, SM and Falcon-Perez, JM and Zabala-Letona, A and Carracedo, A and Castell, JV and Jover, R and Martínez-Cruz, LA and Delgado, TC and Cubero, FJ and Lucena, MI and Andrade, RJ and Mabe, J and Simón, J and Martínez-Chantar, ML}, title = {Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {5}, pages = {}, pmid = {35624761}, issn = {2076-3921}, support = {DTS20/00138//Instituto de Salud Carlos III/ ; RTC2019-007125//Ministerio de Ciencia e Innovación/ ; PID2020-117116RB-100//Ministerio de Ciencia, Innovación y Universidades/ ; RTI2018-096759//Ministerio de Ciencia, Innovación y Universidades/ ; //BIOEF and AECC/ ; Rare Tumor Calls 2017//Asociación Española Contra el Cáncer/ ; Umbrella 2018//La Caixa Foundation Program/ ; BFU2015-70067-REDC, BFU2016-77408-R and BES-2017-080435//MINECO/FEDER/ ; FIGHT-CNNM2//EJP RD Joint Transnational Call 2019/ ; }, abstract = {Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.}, } @article {pmid35624744, year = {2022}, author = {Chen, H and Ma, N and Song, X and Wei, G and Zhang, H and Liu, J and Shen, X and Zhuge, X and Chang, G}, title = {Protective Effects of N-Acetylcysteine on Lipopolysaccharide-Induced Respiratory Inflammation and Oxidative Stress.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {5}, pages = {}, pmid = {35624744}, issn = {2076-3921}, support = {31702301//National Natural Science Foundation of China/ ; 21BEF02019//the National Key R&D Program of Ningxia Hui Autonomous Region of China/ ; 2017YFD0502205//the National Key R&D Program of China/ ; PAPD//the Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; }, abstract = {As the leading cause of bovine respiratory disease (BRD), bacterial pneumonia can result in tremendous losses in the herd farming industry worldwide. N-acetylcysteine (NAC), an acetylated precursor of the amino acid L-cysteine, has been reported to have anti-inflammatory and antioxidant properties. To explore the protective effect and underlying mechanisms of NAC in ALI, we investigated its role in lipopolysaccharide (LPS)-induced bovine embryo tracheal cells (EBTr) and mouse lung injury models. We found that NAC pretreatment attenuated LPS-induced inflammation in EBTr and mouse models. Moreover, LPS suppressed the expression of oxidative-related factors in EBTr and promoted gene expression and the secretion of inflammatory cytokines. Conversely, the pretreatment of NAC alleviated the secretion of inflammatory cytokines and decreased their mRNA levels, maintaining stable levels of antioxidative gene expression. In vivo, NAC helped LPS-induced inflammatory responses and lung injury in ALI mice. The relative protein concentration, total cells, and percentage of neutrophils in BALF; the level of secretion of IL-6, IL-8, TNF-α, and IL-1β; MPO activity; lung injury score; and the expression level of inflammatory-related genes were decreased significantly in the NAC group compared with the LPS group. NAC also ameliorated LPS-induced mRNA level changes in antioxidative genes. In conclusion, our findings suggest that NAC affects the inflammatory and oxidative response, alleviating LPS-induced EBTr inflammation and mouse lung injury, which offers a natural therapeutic strategy for BRD.}, } @article {pmid35624495, year = {2022}, author = {Zeng, X and Zhang, YD and Ma, RY and Chen, YJ and Xiang, XM and Hou, DY and Li, XH and Huang, H and Li, T and Duan, CY}, title = {Activated Drp1 regulates p62-mediated autophagic flux and aggravates inflammation in cerebral ischemia-reperfusion via the ROS-RIP1/RIP3-exosome axis.}, journal = {Military Medical Research}, volume = {9}, number = {1}, pages = {25}, pmid = {35624495}, issn = {2054-9369}, mesh = {Animals ; *Brain Ischemia ; Cerebral Infarction ; DNA, Mitochondrial ; *Exosomes/metabolism ; Glucose ; Humans ; Inflammation ; Male ; Mice ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Reperfusion ; *Reperfusion Injury ; Tumor Necrosis Factor-alpha ; }, abstract = {BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that can occur when the blood supply to the ischemic brain tissue is restored. However, the mechanism underlying such injury remains elusive.

METHODS: The 150 male C57 mice underwent middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h, Among them, 50 MCAO mice were further treated with Mitochondrial division inhibitor 1 (Mdivi-1) and 50 MCAO mice were further treated with N-acetylcysteine (NAC). SH-SY5Y cells were cultured in a low-glucose culture medium for 4 h under hypoxic conditions and then transferred to normal conditions for 12 h. Then, cerebral blood flow, mitochondrial structure, mitochondrial DNA (mtDNA) copy number, intracellular and mitochondrial reactive oxygen species (ROS), autophagic flux, aggresome and exosome expression profiles, cardiac tissue structure, mitochondrial length and cristae density, mtDNA and ROS content, as well as the expression of Drp1-Ser616/Drp1, RIP1/RIP3, LC3 II/LC3 I, TNF-α, IL-1β, etc., were detected under normal or Drp1 interference conditions.

RESULTS: The mtDNA content, ROS levels, and Drp1-Ser616/Drp1 were elevated by 2.2, 1.7 and 2.7 times after CIRI (P < 0.05). However, the high cytoplasmic LC3 II/I ratio and increased aggregation of p62 could be reversed by 44% and 88% by Drp1 short hairpin RNA (shRNA) (P < 0.05). The low fluorescence intensity of autophagic flux and the increased phosphorylation of RIP3 induced by CIRI could be attenuated by ROS scavenger, NAC (P < 0.05). RIP1/RIP3 inhibitor Necrostatin-1 (Nec-1) restored 75% to a low LC3 II/LC3 I ratio and enhanced 2 times to a high RFP-LC3 after Drp1 activation (P < 0.05). In addition, although CIRI-induced ROS production caused no considerable accumulation of autophagosomes (P > 0.05), it increased the packaging and extracellular secretion of exosomes containing p62 by 4 - 5 times, which could be decreased by Mdivi-1, Drp1 shRNA, and Nec-1 (P < 0.05). Furthermore, TNF-α and IL-1β increased in CIRI-derived exosomes could increase RIP3 phosphorylation in normal or oxygen-glucose deprivation/reoxygenation (OGD/R) conditions (P < 0.05).

CONCLUSIONS: CIRI activated Drp1 and accelerated the p62-mediated formation of autophagosomes while inhibiting the transition of autophagosomes to autolysosomes via the RIP1/RIP3 pathway activation. Undegraded autophagosomes were secreted extracellularly in the form of exosomes, leading to inflammatory cascades that further damaged mitochondria, resulting in excessive ROS generation and the blockage of autophagosome degradation, triggering a vicious cycle.}, } @article {pmid35622622, year = {2022}, author = {Lee, JL and Wang, YC and Hsu, YA and Chen, CS and Weng, RC and Lu, YP and Chuang, CY and Wan, L}, title = {Bisphenol A Coupled with a High-Fat Diet Promotes Hepatosteatosis through Reactive-Oxygen-Species-Induced CD36 Overexpression.}, journal = {Toxics}, volume = {10}, number = {5}, pages = {}, pmid = {35622622}, issn = {2305-6304}, abstract = {Bisphenol A (BPA) is an endocrine-disrupting chemical that affects lipid metabolism and contributes to non-alcoholic fatty liver disease (NAFLD). The mechanism of BPA exposure in hepatic lipid accumulation and its potential effect on NAFLD remain unclear. This study investigated the effect of BPA-exposure-induced hepatic lipid deposition on the pathology of NAFLD and its underlying mechanism in vitro and in vivo. BPA increased intracellular reactive oxygen species (ROS) levels, and promoted fatty acid uptake through upregulation of a free fatty acid uptake transporter, cluster of differentiation 36 (CD36), in HUH-7 cells. Additionally, C57BL/6 mice administered a high-fat/high-cholesterol/high-cholic acid diet (HFCCD) and BPA (50 mg/kg body weight) for 8 weeks developed a steatohepatitis-like phenotype, characterized by alpha-smooth muscle actin (α-SMA, an indicator of hepatic fibrosis) and cleaved caspase 3 (an indicator of apoptosis) in hepatic tissue; moreover, they had a higher oxidative stress index of 8-hydroxydeoxyguanosine (8-OHdG) in liver tissue compared to the control group. Treatment with ROS scavenger n-acetylcysteine (NAC) ameliorated BPA-mediated HFCCD-induced lipid accumulation and steatohepatitis in the livers of treated mice. Our study indicates that BPA acts synergistically to increase hepatic lipid uptake and promote NAFLD development by stimulating ROS-induced CD36 overexpression.}, } @article {pmid35621139, year = {2022}, author = {Xu, Y and Bu, H and Jiang, Y and Zhuo, X and Hu, K and Si, Z and Chen, Y and Liu, Q and Gong, X and Sun, H and Zhu, Q and Cui, L and Ma, X and Cui, Y}, title = {N‑acetyl cysteine prevents ambient fine particulate matter‑potentiated atherosclerosis via inhibition of reactive oxygen species‑induced oxidized low density lipoprotein elevation and decreased circulating endothelial progenitor cell.}, journal = {Molecular medicine reports}, volume = {26}, number = {1}, pages = {}, pmid = {35621139}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Atherosclerosis/drug therapy ; *Endothelial Progenitor Cells ; Lipoproteins, LDL/pharmacology ; Mice ; Particulate Matter/toxicity ; Reactive Oxygen Species ; }, abstract = {Ambient fine particulate matter (PM) serves an important role in the development of cardiovascular disease, including atherosclerosis. Antioxidant N‑acetyl cysteine (NAC) has protective effects in the cardiovascular system. However, it is unknown if NAC prevents PM‑potentiated atherosclerosis in hyperlipidemia. Low‑density lipoprotein (LDL) receptor knockout mice were pretreated with 1 mg/ml NAC in drinking water for 1 week and continued to receive NAC, high‑fat diet and intranasal instillation of PM for 1 week or 6 months. Blood plasma was collected for lipid profile, oxidized (ox‑)LDL, blood reactive oxygen species (ROS) and inflammatory cytokine (TNF‑α, IL‑1β and IL‑6) measurement. Blood cells were harvested for endothelial progenitor cell (EPC) population and intracellular ROS analysis. Murine aorta was isolated for atherosclerotic plaque ratio calculation. NAC treatment maintained circulating EPC level and significantly decreased blood ox‑LDL and ROS, inflammatory cytokines, mononuclear and EPC intracellular ROS levels as well as aortic plaque ratio. NAC prevented PM‑potentiated atherosclerosis by inhibiting plasma ROS‑induced ox‑LDL elevation, mononuclear cell and EPC intracellular ROS‑induced circulating EPC reduction and inflammatory cytokine production.}, } @article {pmid35619297, year = {2023}, author = {Li, W and Zhang, H and Chen, J and Tan, Y and Li, A and Guo, L}, title = {N-acetyl Cysteine Inhibits Cell Proliferation and Differentiation of LPSInduced MC3T3-E1 Cells Via Regulating Inflammatory Cytokines.}, journal = {Current pharmaceutical biotechnology}, volume = {24}, number = {3}, pages = {450-459}, doi = {10.2174/1389201023666220520102001}, pmid = {35619297}, issn = {1873-4316}, mesh = {Cell Line ; *Cytokines ; *Acetylcysteine/pharmacology ; Lipopolysaccharides/pharmacology ; Cell Differentiation ; Osteogenesis ; Cell Proliferation ; }, abstract = {BACKGROUND: Peri-implantitis is one of the most common complications in oral implantation and could lead to the loss of the function of bone tissues around implants.

METHODS: This study used lipopolysaccharide (LPS) as a stimulant for MC3T3-E1 cells and N-acetyl cysteine (NAC) as an inhibitor to inhibit the effect of LPS to investigate the effect of NAC on the expression of bone formation related factors and inflammatory-related factors of osteoblasts under the action of LPS.

RESULTS: In this study, we found that the cell proliferation and cell differentiation were significantly promoted when NAC concentrations were between 0 ~ 0.5 mM, but were inhibited when the concentration exceeded 0.5 mM. LPS had a slightly promoting effect on the cell proliferation before 20 μg/mL but inhibited the cell proliferation after 20 μg/mL. LPS reduced protein and gene expressions of Runx2, ALP and BGP and increased protein and gene expressions of NF-κB and TNF-α. NAC reversibly regulated the LPS's regulation on the expression of MC3T3-E1 cell cytokine gene and protein.

CONCLUSION: The optimal NAC concentration for treating MC3T3-E1 cells is 0.5 mM, and the optimal LPS concentration for stimulating MC3T3-E1 cells is 20 μg/mL. NAC plays an active role in regulating the differentiation of MC3T3-E1 cells, and can inhibit LPS to regulate the differentiation of MC3T3-E1 cells. NAC promotes the expression of an osteogenic factor of MC3T3-E1cells and inhibits the expression of inflammatory cytokines.}, } @article {pmid35615243, year = {2022}, author = {Arshad, MA and Bangash, MN}, title = {Acute liver failure following paracetamol overdose.}, journal = {Journal of the Intensive Care Society}, volume = {23}, number = {2}, pages = {244-251}, pmid = {35615243}, issn = {1751-1437}, abstract = {Acute liver failure is a rare syndrome comprising a coagulopathy of liver origin, jaundice and encephalopathy in a patient with no prior history of liver disease. Paracetamol overdose is the leading cause of acute liver failure in the United Kingdom and often presents with extrahepatic organ dysfunction requiring critical care. Presentation: We present the case of a patient with hyper acute liver failure secondary to paracetamol overdose. Management and discussion: Management focused on ensuring the correct diagnosis had been made, administering N-acetyl cysteine, fluid resuscitation and broad spectrum antimicrobials. Early intubation and transfer to a transplant centre were undertaken following development of hepatic encephalopathy. Neuroprotective measures and hypertonic saline were instituted to reduce the risk of intracranial hypertension. High dose haemofiltration was also started to help reduce ammonia levels. Aggressive critical care therapies with specialised input results in good outcomes for patients admitted with paracetamol induced hyper acute liver failure. Liver transplant is reserved for those patients unlikely to survive with medical treatment alone.}, } @article {pmid35615146, year = {2022}, author = {Xu, T and Jiang, Y and Yuan, S and Zhang, L and Chen, X and Zhao, W and Cai, L and Xiao, B and Jia, L}, title = {Andrographolide Inhibits ER-Positive Breast Cancer Growth and Enhances Fulvestrant Efficacy via ROS-FOXM1-ER-α Axis.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {899402}, pmid = {35615146}, issn = {2234-943X}, abstract = {Estrogen receptor (ER)-positive breast cancer is the main subtype of breast cancer (BRCA) with high incidence and mortality. Andrographolide (AD), a major active component derived from the traditional Chinese medicine Andrographis paniculate, has substantial anti-cancer effect in various tumors. However, the antitumor efficacy and the underlying molecular mechanisms of AD on ER-positive breast cancer are poorly understood. In the present study, we demonstrated that andrographolide (AD) significantly inhibited the growth of ER-positive breast cancer cells. Mechanistically, AD suppressed estrogen receptor 1 (ESR1, encodes ER-α) transcription to inhibit tumor growth. Further studies revealed that AD induced ROS production to down-regulate FOXM1-ER-α axis. Conversely, inhibiting ROS production with N-acetylcysteine (NAC) elevated AD-decreased ER-α expression, which could be alleviated by FOXM1 knockdown. In addition, AD in combination with fulvestrant (FUL) synergistically down-regulated ER-α expression to inhibit ER-positive breast cancer both in vitro and in vivo. These findings collectively indicate that AD suppresses ESR1 transcription through ROS-FOXM1 axis to inhibit ER-positive breast cancer growth and suggest that AD might be a potential therapeutic agent and fulvestrant sensitizer for ER-positive breast cancer treatment.}, } @article {pmid35609854, year = {2022}, author = {Kanazawa, J and Kakisaka, K and Suzuki, Y and Yonezawa, T and Abe, H and Wang, T and Takikawa, Y}, title = {Excess fructose enhances oleatic cytotoxicity via reactive oxygen species production and causes necroptosis in hepatocytes.}, journal = {The Journal of nutritional biochemistry}, volume = {107}, number = {}, pages = {109052}, doi = {10.1016/j.jnutbio.2022.109052}, pmid = {35609854}, issn = {1873-4847}, mesh = {Animals ; Diet, High-Fat/adverse effects ; Fructose/adverse effects/metabolism ; Hepatocytes/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Necroptosis ; *Non-alcoholic Fatty Liver Disease/metabolism ; Oleic Acid/metabolism/toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Non-alcoholic fatty liver disease (NAFLD), the hepatic phenotype of metabolic syndrome, has been identified as a major health concern as the number of cirrhosis and deaths associated with NAFLD is expected to increase. Although fructose intake has been considered to be a progressive factor in the pathophysiology of NAFLD, it remains unclear how fructose contributes to hepatocellular damage during lipotoxicity. In the present study, we aimed to analyze the hepatotoxicity of fructose in steatosis. Fructose effects on lipotoxicity were evaluated in HepG2 cells, primary mouse hepatocytes, and in mice fed a high-fat diet with or without sucrose (HFDS/HFD). Oleate induced caspase 3-independent cell death in HepG2 cells and primary mouse hepatocytes cultured in fructose-supplemented medium, and induced cleavage of caspase-1 in primary mouse hepatocytes. In addition, the number of cells stained positive for reactive oxygen species (ROS) was significantly increased, and N-acetyl cysteine was found to inhibit ROS production and cell death. Cell death was confirmed to be through necrotic cell death, and phosphorylation of mixed lineage kinase domain-like (MLKL) protein was observed. Taken together, hepatocyte cytotoxicity was due to excess fructose with oleate-induced ROS-mediated necroptosis. HFDS mice showed progressive hepatic fibrosis and inflammation and a higher NAS score than HFD mice or mice fed a control diet. The expression of hemoxygenase-1, phosphorylation of MLKL, cleavage of caspase1, and apoptosis were significantly increased in the livers of mice fed a HFDS. Overall, excess fructose intake induces necroptosis through the production of ROS and enhances the toxicity of oleatic cytotoxicity.}, } @article {pmid35608368, year = {2022}, author = {Wang, Q and Zhu, B and Han, Y and Yang, X and Xu, Y and Cheng, Y and Liu, T and Wu, J and Li, S and Ding, L and Bai, J and Niu, Y}, title = {Metal ion-mediated carbon dot nanoprobe for fluorescent turn-on sensing of N-acetyl-l-cysteine.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {37}, number = {8}, pages = {1267-1274}, doi = {10.1002/bio.4292}, pmid = {35608368}, issn = {1522-7243}, support = {//Fund for Shanxi '1331' Project/ ; 2021 L535//Scientific and Technological Innovation Programmes of Higher Education Institutions in Shanxi/ ; 2020 L0654//Scientific and Technological Innovation Programmes of Higher Education Institutions in Shanxi/ ; CSREP2019KJ038//Cultivate Scientific Research Excellence Programmes of Higher Education Institutions in Shanxi/ ; 2020XS02//Project for the Young Academic Leaders of Taiyuan Institute of Technology/ ; 201901D211454//Applied Basic Research Project of Shanxi Province/ ; }, mesh = {Acetylcysteine ; *Carbon ; Fluorescent Dyes ; Humans ; Ions ; *Quantum Dots ; Spectrometry, Fluorescence/methods ; }, abstract = {In this work, carbon dots (CDs) was easily synthesized from aspartic acid through a pyrolysis method. Based on their favourable fluorescence properties, CDs were utilized to design a metal ion-mediated fluorescent probe for N-acetyl-l-cysteine (NAC) detection. The fluorescence intensity of CDs was firstly quenched by manganese ions (Mn[2+]) through static quenching effect and subsequently restored by NAC via the combination with Mn[2+] due to the coordination effect. Therefore, the fluorescent turn-on sensing of NAC was actuated based on the fluorescence quenching stimulated by Mn[2+] and recovery induced by coordination. The fluorescence recovery efficiencies showed a proportional range to the concentration of NAC in the range 0.04-5 mmol L[-1] and the detection limit was 0.03 mmol L[-1] . Furthermore, this metal ion-mediated fluorescent nanoprobe was applied to human urine sample detection and the standard recovery rates were located in the range 97.62-102.34%. This was the first time that Mn[2+] was used to construct a fluorescent nanoprobe for NAC. Compared with other heavy metal ions, Mn[2+] with good biosecurity prevented the risk of application, which made the nanoprobe green and biopractical. The facile synthesis of CDs and novel metal ion-mediated sensing mode made it a promising method for pharmaceutical analysis.}, } @article {pmid35608150, year = {2023}, author = {Gabriel, FC and Oliveira, M and Bruna De M Martella, and Berk, M and Brietzke, E and Jacka, FN and Lafer, B}, title = {Nutrition and bipolar disorder: a systematic review.}, journal = {Nutritional neuroscience}, volume = {26}, number = {7}, pages = {637-651}, doi = {10.1080/1028415X.2022.2077031}, pmid = {35608150}, issn = {1476-8305}, mesh = {Humans ; *Bipolar Disorder ; Diet ; Vitamins ; Micronutrients ; *Fatty Acids, Omega-3 ; Acetylcysteine ; }, abstract = {INTRODUCTION: Individuals with bipolar disorder (BD) have higher rates of unhealthy lifestyles and risk for medical comorbidities Research currently suggests that dietary factors may play a role in the development of depression and anxiety. Therefore, nutritional approaches are potential strategies for the treatment of BD. The aim of this review is to summarize the available evidence on nutrition and BD.

MATERIALS AND METHODS: The paper was developed based on PRISMA 2020 guidelines. The search was conducted in Sep-2021 using PubMed and Cochrane Library, augmented by manually checked references lists. The search found 986 studies, of which 47 were included, combined with 13 from reference lists, totaling 60 studies.

RESULTS: There were 33 observational trials, of which 15 focused on fatty acids, 9 on micronutrients, 5 on specific foods, 4 on macro and micronutrients. The 27 interventional studies mainly focused on fatty acids, micronutrients and N-acetylcysteine (NAC).

DISCUSSION: Dietary intake or supplementation of unsaturated fatty acids, mainly Omega-3 seems to be associated with improved BD symptoms, along with seafood, folic acid and zinc. Studies found variable, mainly non-significant impacts of creatine, carnitine, vitamin D, inositol or NAC supplementation on BD. There are promising results associated with Coenzyme Q10 (Coq10) and probiotics. Taken together, these preliminary findings suggest that dietetic approaches might be included as part of BD treatment. Also considering the high risk of metabolic disorders in individuals with BD, they should be encouraged to choose healthy dietary lifestyles, including daily intake of fruits, vegetables, seafood and whole grains.}, } @article {pmid35603121, year = {2022}, author = {Khan, MSA and Kumar, KV and Kumar, RA and Prasannan, B and Urs, V and Unni, VN}, title = {A Study of Estimated Glomerular Filtration Rate in Patients Undergoing Diagnostic or Interventional Coronary Contrast Procedures.}, journal = {Indian journal of nephrology}, volume = {32}, number = {2}, pages = {132-137}, pmid = {35603121}, issn = {0971-4065}, abstract = {INTRODUCTION: Angiographic procedures are underused in patients with chronic kidney disease (CKD), who present with acute coronary syndromes, due to risk of contrast-induced acute kidney injury (CI-AKI). In this study, we assessed the change in estimated glomerular filtration rate (eGFR) over 3 months following coronary procedures in CKD patients.

METHODS: This observational study was done from July 2017 to January 2019 in patients undergoing elective coronary procedures with an eGFR <60 mL/min/1.73 m[2]. CKD-EPI equation was used to calculate eGFR pre and post coronary procedure at 24, 48, and 72 hours as well as 30, 90 days. AKI was diagnosed and patients were given prophylaxis for CI-AKI as per KDIGO recommendation (intravenous normal saline and oral N-acetyl cysteine).

RESULTS: Patients studied were 282 (225 males, 57 females) of which 68.1% were diabetics. Mean eGFR was 42.91 ± 10.51 mL/min/1.73 m[2] and mean hemoglobin was 12.08 ± 1.51 gm/dL. Coronary angiogram (CAG) was done in 174; percutaneous transluminal coronary angioplasty (PTCA) was done in 108. Mean contrast volume in CAG was 55.17 ± 34.45 mL and in PTCA was 156.94±±47.99 mL. CI-AKI was seen in 66 (23.4%) patients. The incidence of CI-AKI increased with severity of underlying CKD. The variability of eGFR at 1 and 3 months after coronary procedures showed no significant change from baseline, even in the patients who developed CI-AKI.

CONCLUSIONS: CI-AKI is self-limiting and has no major detrimental effects on eGFR at 1 and 3 months after contrast exposure.}, } @article {pmid35602237, year = {2022}, author = {Gill, G and Blakley, BW}, title = {Does N-acetylcysteine Improve Established Hearing Loss in Guinea Pigs?.}, journal = {OTO open}, volume = {6}, number = {2}, pages = {2473974X221100545}, pmid = {35602237}, issn = {2473-974X}, abstract = {OBJECTIVE: To assess whether multiple injections of a powerful antioxidant can improve established sensorineural hearing loss in guinea pigs.

STUDY DESIGN: Animal study.

SETTING: Animal science laboratory, University of Manitoba.

METHODS: A total of 16 guinea pigs were used in our study: 8 underwent unilateral intracochlear neomycin injection, and 8 underwent unilateral saline to serve as controls. After a period of 3 weeks for hearing loss to stabilize, 4 guinea pigs from each group received weekly intraperitoneal injections of N-acetylcysteine (NAC) for 4 weeks. Click auditory brainstem response (ABR) testing was conducted at baseline, weekly after the start of NAC injections, and after the last injection. Pure tone ABR tests were conducted prior to intracochlear injections and at completion of the study.

RESULTS: Click ABR thresholds were significantly worse in ears treated with neomycin (P < .001), as expected, but not significantly different when treated with NAC (P = .664). Thresholds for pure tone ABR were also not statistically different in neomycin-treated ears with or without NAC (P > .99).

CONCLUSIONS: The aggressive antioxidant therapy performed in this study was not successful in improving established hearing loss via an antioxidant regimen that is known to change the oxidation-reduction potential in the cochlea.}, } @article {pmid35598440, year = {2022}, author = {Miyashita, L and Shears, R and Foley, G and Semple, S and Kadioglu, A and Grigg, J}, title = {Underground railway particulate matter and susceptibility to pneumococcal infection.}, journal = {EBioMedicine}, volume = {80}, number = {}, pages = {104063}, pmid = {35598440}, issn = {2352-3964}, support = {MR/P011284/1/MRC_/Medical Research Council/United Kingdom ; MR/R002592/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Cell Line ; Cysteine/metabolism ; Humans ; Lung/metabolism ; Mice ; *Particulate Matter/adverse effects/metabolism ; *Pneumococcal Infections ; Streptococcus pneumoniae/metabolism ; }, abstract = {BACKGROUND: Concentrations of particulate matter less than 10 microns (PM10) on underground railways are higher than those near urban roads. Traffic-related PM10 increases pneumococcal infection via increasing the expression of platelet-activating factor receptor (PAFR), a receptor co-opted by pneumococci to adhere to cells. To date, it is unknown whether underground railway PM10 increases pneumococcal infection. This study sought to determine the effect of London Underground (LU) PM10 on; i) pneumococcal adhesion to airway cells, and ii) susceptibility to pneumococcal disease.

METHODS: A549 cells and human primary airway epithelial cells were cultured with 20 µg/mL PM10 from the Bakerloo (B-PM10) and Jubilee (J-PM10) line platforms of Baker Street station. PAFR expression was assessed by flow cytometry, and pneumococcal adhesion by colony forming unit (CFU) counts. Traffic-related PM10 was collected next to a main road near the station's entrance. The PAFR blocker CV3988 and the antioxidant N-acetyl cysteine were used to assess the role of PAFR-mediated pneumococcal adhesion and oxidative stress respectively. Pneumococcal infection of mice was done after exposure to 3×80 μg doses of intranasal LU-PM10.

FINDINGS: In A549 cells, human primary nasal cells, and human primary bronchial epithelial cells, B-PM10 and J-PM10 increased PAFR expression and pneumococcal adhesion. Stimulated adhesion was abrogated by CV3988 and N-acetyl cysteine. Traffic-related PM10 stimulated increased adhesion compared with B-PM10. B-PM10 and J-PM10 increased lung and blood CFU and mortality in mice. Treatment of B-PM10-exposed mice with CV3988 reduced blood CFU.

INTERPRETATION: LU-PM10 increases pneumococcal adhesion to airway cells and susceptibility to invasive disease in mice.

FUNDING: The Medical College of Saint Bartholomew's Hospital Trust, and the UK Medical Research Council Programme Grant (MR/P011284/1).}, } @article {pmid35598122, year = {2022}, author = {Sengupta, P and Biswas, S and Roy, T}, title = {Comparative Study to Evaluate the Effect of Low-Protein Diet Supplementation with Taurine and N-Acetylcysteine, N-Acetylcysteine and Pyridoxamine Dihydrochloride in Preventing the Progression of Chronic Renal Failure in Patients with Non-Diabetic Kidney Disease.}, journal = {The Journal of the Association of Physicians of India}, volume = {70}, number = {5}, pages = {11-12}, pmid = {35598122}, issn = {0004-5772}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Aged ; Diet, Protein-Restricted ; Dietary Supplements ; Disease Progression ; Female ; Humans ; *Kidney Failure, Chronic/prevention & control ; Male ; Middle Aged ; Pyridoxamine/analogs & derivatives/therapeutic use ; *Renal Insufficiency, Chronic/complications/diagnosis/drug therapy ; Taurine/therapeutic use ; }, abstract = {UNLABELLED: Chronic Kidney Disease(CKD) has multifactorial etiology and there are lots of grey zone in understanding its complex pathophysiology. There is no silver bullet for optimal care of CKD. Oxidative stress being well understood and considered as an important common progressive factor for CKD of different etiology. Several research studies focused on reducing oxidative stress and have shown diverse outcomes. In this randomized, open-label, three arms, controlled, single center study we evaluated the role of N acetylcysteine which is a direct scavenger of free radical, in combination with taurine and pyridoxamine in retarding the progression of non-diabetic kidney disease.

METHODS: 69 non-dialysis, non-diabetic patients diagnosed with chronic renal failure with GFR more than 15 ml/min/1.73m2 and less than 60ml/min/1.73m2 receiving standard of care were enrolled in the study, of which 22 were in the placebo arm, 23 treated with NT (500 mg Taurine + 150 mg NAC) arm and 24 in the NP (300mg NAC+ 50mg pyridoxamine di-hydrochloride) arm. The subjects in the treatment arm received the study drug twice a day along with low protein (0.6gm protein per Kg body weight) isocaloric diet with 25-30 Kcal/Kg/D and were evaluated monthly up to 6 months. Change in eGFR accorss 3 groups over 6 months were compared.

RESULT: Mean age of the subjects was 57 ± 13 years of 56.25% were male and 43.75% were female. 69 patients completed the study. The Empirical Distribution Function (EDF) of NP group was dominant over control and NT group indicating a positive effect of NT on non-diabetic CKD at 10% level of significance. In the subgroup analysis a significant effect was observed in the cases of patients receiving NP with baseline eGFR more than 45 ml/min. The mean increase in eGFR readings over six months was 8.15 units higher in the NP group than in the control group. The two-sided p-values of the t-test, the Wilcoxon test and the Kolmogorov-Smirnov test were 0.0496, 0.0316 and 0.0354, respectively. Thus, all the three tests reject the hypothesis of identical changes in eGFR at the 5% level. In subjects with bicarbonate more than 22 mg/dl, the mean increase in eGFR over six months was 10.86 units higher in the NP group than in the control group indicating NP has a positive effect on increasing eGFR over 6 months, in patients without the presence of any metabolic acidosis. The two-sided p-vales of the t-test, the Wilcoxon test and the Kolmogorov-Smirnov test were 0.0325, 0.0205 and 0.1495, respectively. Thus, two of the three tests reject the hypothesis of identical changes in eGFR at the 5% level which clearly indicates that NP had better efficacy than other groups.

CONCLUSION: N-acetyl cysteine along with pyridoxine may be a useful intervention along with a low protein diet in retarding progression of CKD in the nondiabetic population in early CKD.}, } @article {pmid35594827, year = {2022}, author = {Lin, CM and Huang, TH and Chi, MC and Guo, SE and Lee, CW and Hwang, SL and Shi, CS}, title = {N-acetylcysteine alleviates fine particulate matter (PM2.5)-induced lung injury by attenuation of ROS-mediated recruitment of neutrophils and Ly6C[high] monocytes and lung inflammation.}, journal = {Ecotoxicology and environmental safety}, volume = {239}, number = {}, pages = {113632}, doi = {10.1016/j.ecoenv.2022.113632}, pmid = {35594827}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Interleukin-6/metabolism ; Lung ; *Lung Injury/chemically induced/drug therapy/metabolism ; Mice ; Mice, Inbred C57BL ; Monocytes ; Neutrophils/metabolism ; Nitrites/metabolism ; Particulate Matter/adverse effects ; *Pneumonia/chemically induced/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {BACKGROUND: Exposure to particulate matter (PM) may contribute to lung inflammation and injury. The therapeutic effect of N-acetylcysteine (NAC), a well-known antioxidant, with regards to the prevention and treatment of fine PM (PM2.5)-induced lung injury is poorly understood. This study aimed to determine the effect of PM2.5 on the recruitment of neutrophils and Ly6C[high] monocytes into lung alveoli and the production of proinflammatory proteins by stimulating the generation of reactive oxygen species (ROS), and to investigate the therapeutic effect of NAC on PM2.5-induced lung injury.

METHODS: C57BL/6 mice were exposed to a single administration of PM2.5 (200 μg/100 μl/mouse) or phosphate-buffered saline (control) via intratracheal instillation. The mice were injected intratracheally via a microsprayer aerosolizer with NAC (20 or 40 mg/kg) 1 h before PM2.5 instillation and 24 h after PM2.5 instillation. Total protein, VEGF, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF) were measured. Oxidative stress was evaluated by determining levels of malondialdehyde (MDA) and nitrite in BALF. Flow cytometric analysis was used to identify and quantify neutrophils and Ly6C[high] and Ly6Clow monocyte subsets.

RESULTS: Neutrophil count, total protein, and VEGF content in BALF significantly increased after PM2.5 exposure and reached the highest level on day 2. Increased levels of TNF-alpha, IL-6, nitrite, and MDA in BALF were also noted. Flow cytometric analysis showed increased recruitment of neutrophils and Ly6C[high], but not Ly6C[low] monocytes, into lung alveoli. Treatment with NAC via the intratracheal spray significantly attenuated the recruitment of neutrophils and Ly6C[high] monocytes into lung alveoli in PM2.5-treated mice in a dose-dependent manner. Furthermore, NAC significantly attenuated the production of total protein, VEGF, nitrite, and MDA in the mice with PM2.5-induced lung injury in a dose-dependent manner.

CONCLUSION: PM2.5-induced lung injury caused by the generation of oxidative stress led to the recruitment of neutrophils and Ly6C[high] monocytes, and production of inflammatory proteins. NAC treatment alleviated PM2.5-induced lung injury by attenuating the ROS-mediated recruitment of neutrophils and Ly6C[high] monocytes and lung inflammation.}, } @article {pmid35594763, year = {2022}, author = {Wołosowicz, M and Dajnowicz-Brzezik, P and Łukaszuk, B and Żebrowska, E and Maciejczyk, M and Zalewska, A and Kasacka, I and Chabowski, A}, title = {Diverse impact of N-acetylcysteine or alpha-lipoic acid supplementation during high-fat diet regime on fatty acid transporters in visceral and subcutaneous adipose tissue.}, journal = {Advances in medical sciences}, volume = {67}, number = {2}, pages = {216-228}, doi = {10.1016/j.advms.2022.05.001}, pmid = {35594763}, issn = {1898-4002}, mesh = {Male ; Rats ; Animals ; *Thioctic Acid/pharmacology/metabolism ; Acetylcysteine/pharmacology/metabolism ; Fatty Acids/metabolism ; Antioxidants/pharmacology/metabolism ; Diet, High-Fat/adverse effects ; Reactive Oxygen Species/metabolism ; Rats, Wistar ; Subcutaneous Fat/metabolism ; Adipose Tissue/metabolism/pathology ; Dietary Supplements ; RNA, Messenger/metabolism ; Carrier Proteins/metabolism ; }, abstract = {PURPOSE: Adipose tissue's (AT) structural changes accompanying obesity may alter lipid transport protein expression and, thus, the fatty acids (FAs) transport and lipid balance of the body. Metabolic abnormalities within AT contribute to the elevated production of reactive oxygen species and increased oxidative/nitrosative stress. Although compounds such as N-acetylcysteine (NAC) and α-lipoic acid (ALA), which restore redox homeostasis, may improve lipid metabolism in AT, the mechanism of action of these antioxidants on lipid metabolism in AT is still unknown. This study aimed to examine the impact of NAC and ALA on the level and FA composition of the lipid fractions, and the expression of FA transporters in the visceral and subcutaneous AT of high-fat diet-fed rats.

MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups. The mRNA levels and protein expression of FA transporters were assessed using real-time PCR and Western Blot analyses. The collected samples were subjected to histological evaluation. The level of lipids (FFA, DAG, and TAG) was measured using gas-liquid chromatography.

RESULTS: We found that antioxidants affect FA transporter expressions at both the transcript and protein levels, and, therefore, they promote changes in AT's lipid pools. One of the most remarkable findings of our research is that different antioxidant molecules may have a varying impact on AT phenotype.

CONCLUSION: NAC and ALA exert different influences on AT, which is reflected in histopathological images, FA transport proteins expression patterns, or even the lipid storage capacity of adipocytes.}, } @article {pmid35593216, year = {2022}, author = {Ma, Z and Wang, W and Pan, C and Fan, C and Li, Y and Wang, W and Lan, T and Gong, F and Zhao, C and Zhao, Z and Yu, S and Yuan, M}, title = {N-acetylcysteine improves diabetic associated erectile dysfunction in streptozotocin-induced diabetic mice by inhibiting oxidative stress.}, journal = {Journal of cellular and molecular medicine}, volume = {26}, number = {12}, pages = {3527-3537}, pmid = {35593216}, issn = {1582-4934}, support = {2019SDRX-xx//Rongxiang Regenemiceive Medicine Foundation of Shandong University/ ; 2018YFC1003600//National Health Commission of the People Republic of China/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; *Diabetes Mellitus, Experimental/complications/drug therapy/metabolism ; *Erectile Dysfunction/complications/drug therapy ; Humans ; Male ; Mice ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Streptozocin/pharmacology ; }, abstract = {Oxidative stress appears to play a role in the pathogenesis of diabetes mellitus erectile dysfunction (DMED). This study aimed to investigate the effect of N-acetylcysteine (NAC) on DMED in streptozotocin-induced diabetic mice and to explore potential mechanisms. In the present study, we show that an erectile dysfunction is present in the streptozotocin-induced mouse model of diabetes as indicated by decreases in intracavernous pressure responses to electro-stimulation as well as from results of the apomorphine test of erectile function. After treatment of NAC, the intracavernous pressure was increased. In these DMED mice, oxidative stress and inflammatory responses were significantly reduced within the cavernous microenvironment, while activity of antioxidant enzymes in this cavernous tissue was enhanced after NAC treatment. These changes protected mitochondrial stress damage and a significant decreased in apoptosis within the cavernous tissue of DMED mice. This appears to involve activation of the nuclear factor erythroid 2-like-2 (Nrf2) signalling pathway, as well as suppression of the mitogen-activated protein kinase (MAPK) p38/ NF-κB pathway within cavernous tissue. In conclusion, NAC can improve erectile function through inhibiting oxidative stress via activating Nrf2 pathways and reducing apoptosis in streptozotocin-induced diabetic mice. NAC might provide a promising therapeutic strategy for individuals with DMED.}, } @article {pmid35588920, year = {2022}, author = {Limansubroto, N and Chung, WO and Johnson, JD and Paranjpe, A}, title = {Immunomodulatory Effects of N-Acetyl Cysteine Treated SCAP.}, journal = {Journal of endodontics}, volume = {48}, number = {8}, pages = {1055-1062}, doi = {10.1016/j.joen.2022.05.005}, pmid = {35588920}, issn = {1878-3554}, mesh = {*Acetylcysteine/pharmacology ; Cell Differentiation ; Cytokines ; Dental Papilla ; Humans ; *Leukocytes, Mononuclear ; Stem Cells ; }, abstract = {INTRODUCTION: Stem cells of the apical papilla (SCAP) play an important role in regenerative endodontic procedures (REPs). Previous studies have shown that during REPs, bacteria can activate the innate immune system and cause indirect stem cell toxicity, leading to the lysis of SCAP. N-acetylcysteine (NAC)-treated cells are resistant to apoptosis and have increased differentiation capabilities. The immunomodulatory properties of NAC-treated SCAP are still unknown. Hence, the aim of this study is to evaluate the interactions of SCAP pretreated with and without NAC with the immune system.

METHODS: Flow cytometric analysis was performed to assess the effects of NAC on SCAP viability. Human SCAP were then cultured and were either pretreated with NAC or non-treated and co-cultured with human peripheral blood mononuclear cells. A lactate dehydrogenase assay was performed to evaluate the levels of immune cell mediated apoptosis, followed by an enzyme-linked immunosorbent assay (ELISA) to measure levels of proinflammatory cytokines for these co-cultures. Data were analyzed using analysis of variance with post hoc Tukey test.

RESULTS: Cells treated with NAC had similar levels of viability as the controls. SCAP pretreated with NAC had significantly lower immune cell-mediated cytotoxicity to nonactivated and activated peripheral blood mononuclear cells. The ELISA results showed that SCAP pretreated with NAC induced lower levels of proinflammatory cytokines.

CONCLUSIONS: SCAP pretreated with NAC have a higher chance of surviving the activated immune system. This information may provide a better insight into the properties of these stem cells and may be the key to making REPs more predictable.}, } @article {pmid35587328, year = {2022}, author = {Dhillon, T and Kumar, A and Kumar, V}, title = {Neuroprotective Effect of N-acetylcysteine Against Monocrotophos-Induced Oxidative Stress in Different Brain Regions of Rats.}, journal = {Applied biochemistry and biotechnology}, volume = {194}, number = {9}, pages = {4049-4065}, pmid = {35587328}, issn = {1559-0291}, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism/pharmacology ; Brain ; Lipid Peroxidation ; Male ; Mammals/metabolism ; *Monocrotophos/metabolism/toxicity ; *Neuroprotective Agents/metabolism/pharmacology ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {Monocrotophos (MCP) is systemic organophosphate insecticide used against crop pests. It is reported to cause mammalian toxicity through both acute and chronic exposure. In the present study, we have shown the protective role of N-acetylcysteine (NAC) against MCP-induced oxidative stress in frontal cortex, corpus striatum and hippocampus brain regions of rats. Male Albino Wistar rats were divided into control, NAC-treated, MCP and NAC + MCP-treated groups. An oral dose of MCP (0.9 mg/kg b.wt) and NAC (200 mg/kg b.wt) was administered for 28 days. Results showed an increase in lipid peroxidation (LPO) and protein oxidation followed by decreased antioxidant enzymes after 28 days of MCP exposure. Histopathological analysis showed that monocrotophos exposure caused neurodegenerative changes as evident by neurons with dystrophic changes in the form of shrunken hyperchromatic nuclei in all the regions of the rat brain. N-acetylcysteine supplementation to MCP-treated rats showed a reduction in oxidative stress and ameliorated cellular alterations in all of the three regions. The results of the study indicate that N-acetylcysteine offers neuroprotection by improving antioxidant response and decreasing oxidative stress in different regions of the rat brain.}, } @article {pmid35587124, year = {2023}, author = {Sudanagunta, S and Camarena-Michel, A and Pennington, S and Leonard, J and Hoyte, C and Wang, GS}, title = {Comparison of Two-Bag Versus Three-Bag N-Acetylcysteine Regimens for Pediatric Acetaminophen Toxicity.}, journal = {The Annals of pharmacotherapy}, volume = {57}, number = {1}, pages = {36-43}, doi = {10.1177/10600280221097700}, pmid = {35587124}, issn = {1542-6270}, mesh = {Adult ; Child ; Humans ; Adolescent ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; Antidotes/therapeutic use ; Cohort Studies ; *Drug-Related Side Effects and Adverse Reactions ; *Drug Overdose/drug therapy ; Retrospective Studies ; *Analgesics, Non-Narcotic/therapeutic use ; }, abstract = {BACKGROUND: Acetaminophen overdose is a leading cause of liver failure, and a leading cause of pediatric poisoning requiring hospital admission. The antidote, N-acetylcysteine (NAC), is traditionally administered as a three-bag intravenous infusion. Despite its efficacy, NAC is associated with high incidence of nonallergic anaphylactoid reactions (NAARs). Adult evidence demonstrates that alternative dosing regimens decrease NAARs and medication errors (MEs).

OBJECTIVES: To compare NAARs and MEs associated with two- versus three-bag NAC for acetaminophen overdose in a pediatric population.

METHODS: This is a retrospective observational cohort study comparing pediatric patients who received three- versus two-bag NAC for acetaminophen toxicity. The primary outcome was incidence of NAARs. Secondary outcomes were rates of MEs and relevant hospital outcomes (length of stay [LOS], intensive care unit (ICU) admission, liver transplant, death).

RESULTS: Two hundred forty-three patients met inclusion criteria (median age of 15 years): 150 (62%) three-bag NAC and 93 (38%) two-bag NAC. There was no difference in overall NAARs (p = 0.54). Fewer cutaneous NAARs were observed in the two-bag group, three-bag: 15 (10%), two-bag: 2 (2%), p = 0.02. MEs were significantly decreased with the two-bag regimen, three-bag: 59 (39%), two-bag: 21 (23%), p = 0.01. No statistical differences were observed in LOS, ICU admissions, transplant, or death.

CONCLUSION AND RELEVANCE: A significant decrease in cutaneous NAARs and MEs was observed in pediatric patients by combining the first two bags of the traditional three-bag NAC regimen. In pediatric populations, a two-bag NAC regimen for acetaminophen overdose may improve medication tolerance and safety.}, } @article {pmid35583464, year = {2022}, author = {Zhang, M and Hu, Y and Li, W and Sun, C and Guan, C and Peng, Y and Zheng, J}, title = {In Vitro and In Vivo Metabolic Activation and Hepatotoxicity of Environmental Pollutant 2,6-Dimethylphenol.}, journal = {Chemical research in toxicology}, volume = {35}, number = {6}, pages = {1036-1044}, doi = {10.1021/acs.chemrestox.2c00048}, pmid = {35583464}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; *Chemical and Drug Induced Liver Injury ; *Environmental Pollutants/toxicity ; Glutathione/metabolism ; Mice ; Xylenes ; }, abstract = {2,6-Dimethylphenol (2,6-DMP) is an environmental pollutant found in industrial wastewater. Exposure to 2,6-DMP is of increasing concern as it endangered reportedly some aquatic animals. In this study, we investigated the metabolic activation and hepatotoxicity of 2,6-DMP. 2,6-DMP was metabolized to an o-quinone methide intermediate in vitro and in vivo. The electrophilic metabolite was reactive to the sulfhydryl groups of glutathione, N-acetyl cysteine, and cysteine. NADPH was required for the formation of the reactive metabolite. The quinone methide intermediate reacted with cysteine residues to form hepatic protein adduction. A single dose of 2,6-DMP induced marked elevation of serum ALT and AST in mice. Both the protein adduction and hepatotoxicity of 2,6-DMP showed dose dependency.}, } @article {pmid35582415, year = {2022}, author = {Yu, P and Luo, J and Song, H and Qian, T and He, X and Fang, J and Dong, W and Bian, X}, title = {N-acetylcysteine Ameliorates Vancomycin-induced Nephrotoxicity by Inhibiting Oxidative Stress and Apoptosis in the in vivo and in vitro Models.}, journal = {International journal of medical sciences}, volume = {19}, number = {4}, pages = {740-752}, pmid = {35582415}, issn = {1449-1907}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; *Acute Kidney Injury/chemically induced/drug therapy ; Animals ; Anti-Bacterial Agents/adverse effects ; Apoptosis ; Caspase 3/metabolism ; Kidney/pathology ; Lipocalin-2/metabolism/pharmacology ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; *Vancomycin/adverse effects/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Background: Oxidative stress-related apoptosis is considered as the key mechanism implicated in the pathophysiology of nephrotoxicity with vancomycin (VCM) therapy. We evaluated the possible effects of N-acetylcysteine (NAC) on VCM-induced nephrotoxicity and the underlying mechanism. Methods: VCM-induced nephrotoxicity was established using HK-2 cells and SD rats and observed by measuring cell survival, kidney histological changes, renal function and kidney injury related markers (KIM-1 and NGAL). Oxidative stress, renal cell apoptosis and the involved signaling pathways were also evaluated. Results: In model rats, NAC could protect against VCM-induced acute kidney injury with histological damage, renal dysfunction, and increased Cre and BUN levels. In HK-2 cells, VCM-induced decreased cell viability was restored by NAC. In addition, increased expression of caspase-3, KIM-1 and NGAL suffering from VCM was also reversed by NAC in vivo and in vitro. NAC inhibited ROS production, decreased cell apoptosis by decreasing the Bax/Bcl-2 ratio and caspase-3 expression in HK-2 cells and regulated oxidative stress indicators in the kidney by decreasing GSH, SOD and CAT activity and increasing MDA levels. Furthermore, NAC could effectively reverse VCM-associated increased P38 MAPK/JNK phosphorylation. Conclusions: The results demonstrated that NAC had a protective effect against nephrotoxicity from VCM by inhibiting oxidative stress and apoptosis via P38 MAPK/JNK.}, } @article {pmid35580081, year = {2022}, author = {Moens, C and Muller, CJF and Bouwens, L}, title = {In vitro comparison of various antioxidants and flavonoids from Rooibos as beta cell protectants against lipotoxicity and oxidative stress-induced cell death.}, journal = {PloS one}, volume = {17}, number = {5}, pages = {e0268551}, pmid = {35580081}, issn = {1932-6203}, mesh = {Antioxidants/analysis/pharmacology ; *Aspalathus ; Cell Death ; *Diabetes Mellitus, Type 2/drug therapy ; Exenatide/pharmacology ; Flavonoids/analysis/pharmacology ; *Insulin-Secreting Cells ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; Oxidative Stress ; Plant Extracts/pharmacology/therapeutic use ; Protective Agents/pharmacology ; }, abstract = {Oxidative stress and lipotoxicity effects on pancreatic β cells play a major role in the pathogenesis of type 2 diabetes (T2D). Flavonoids and antioxidants are under study for their cytoprotective effects and antidiabetic potential. In this study, we aimed to compare the protective effect of the Rooibos components aspalathin, isoorientin, 3-hydroxyphloretin (3-OH) and green Rooibos extract (GRT) itself, and exendin-4 and N-acetylcysteine (NAC) as reference molecules, against lipotoxicity and oxidative stress. The insulin-producing β cell line INS1E was exposed to hydrogen peroxide or streptozotocin (STZ) to induce oxidative stress, and palmitate to induce lipotoxicity. Cell viability was assessed by a MTS cell viability assay. Antioxidant response and antiapoptotic gene expression was performed by qRT-PCR. Glucose transporter 2 (GLUT 2) transporter inhibition was assessed through 2-NBDG uptake. GRT and the flavonoids aspalathin and 3-hydroxyphloretin offered significant protection against oxidative stress and lipotoxicity. GRT downregulated expression of pro-apoptotic genes Txnip and Ddit3. The flavonoids aspalathin and 3-hydroxyphloretin also downregulated these genes and in addition upregulated expression of antioxidant response genes Hmox1, Nqo1 and Sod1. Isoorientin gave no cytoprotection. Cytoprotection by Rooibos components was significantly higher than by NAC or exendin-4. Rooibos components strongly protect INS1E β cells against diabetogenic stress. Cytoprotection was associated with the upregulation of antioxidant response genes of the NRF2/KEAP1 pathway or suppression of the TXN system. The Rooibos molecules offered better protection against these insults than exendin-4 and NAC, making them interesting candidates as β cell cytoprotectants for therapeutic or nutraceutical applications.}, } @article {pmid35578630, year = {2022}, author = {Khurana, P and Varshney, R and Gupta, A}, title = {A network-biology led computational drug repurposing strategy to prioritize therapeutic options for COVID-19.}, journal = {Heliyon}, volume = {8}, number = {5}, pages = {e09387}, pmid = {35578630}, issn = {2405-8440}, abstract = {The alarming pandemic situation of novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection, high drug development cost and slow process of drug discovery have made repositioning of existing drugs for therapeutics a popular alternative. It involves the repurposing of existing safe compounds which results in low overall development costs and shorter development timeline. In the present study, a computational network-biology approach has been used for comparing three candidate drugs i.e. quercetin, N-acetyl cysteine (NAC), and 2-deoxy-glucose (2-DG) to be effectively repurposed against COVID-19. For this, the associations between these drugs and genes of Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) diseases were retrieved and a directed drug-gene-gene-disease interaction network was constructed. Further, to quantify the associations between a target gene and a disease gene, the shortest paths from the target gene to the disease genes were identified. A vector DV was calculated to represent the extent to which a disease gene was influenced by these drugs. Quercetin was quantified as the best among the three drugs, suited for repurposing with DV of -70.19, followed by NAC with DV of -39.99 and 2-DG with DV of -13.71. The drugs were also assessed for their safety and efficacy balance (in terms of therapeutic index) using network properties. It was found that quercetin was a forerunner than other two drugs.}, } @article {pmid35575346, year = {2022}, author = {Li, X and Xing, G and Guo, X and Wang, Y and Hu, Z and Cheng, M and Peng, Y and Zheng, J}, title = {Identification of Metoprolol Tartrate-Derived Reactive Metabolites Possibly Correlated with Its Cytotoxicity.}, journal = {Chemical research in toxicology}, volume = {35}, number = {6}, pages = {1059-1069}, doi = {10.1021/acs.chemrestox.2c00052}, pmid = {35575346}, issn = {1520-5010}, mesh = {Animals ; Rats ; Acetylcysteine/metabolism/pharmacology ; Glutathione/metabolism ; *Metoprolol/metabolism/pharmacology ; *Microsomes, Liver/metabolism ; }, abstract = {As a selective β1-receptor antagonist, metoprolol tartrate (MTA) is commonly used to treat cardiovascular diseases such as hypertension and angina pectoris. There have been cases of liver injury induced by MTA, but the mechanism of hepatotoxicity induced by MTA is not clear. The purposes of this study were to identify the reactive metabolites of MTA, to determine the pathway for the metabolic activation of MTA, and to define a possible correlation between the metabolic activation and cytotoxicity of MTA. Three oxidative metabolites (M1-M3), a glutathione (GSH) conjugate (M4), and an N-acetyl cysteine (NAC) conjugate (M5) were detected in rat liver microsomal incubations containing MTA and GSH or NAC. M4 was also detected in cultured rat primary hepatocytes and bile of rats given MTA, and M5 was detected in the urine of MTA-treated rats. A quinone methide intermediate may be produced from the metabolic activation process in vitro and in vivo. The metabolite was reactive to glutathione and N-acetyl cysteine. MTA induced marked cytotoxicity in cultured rat primary hepatocytes. Pretreatment of aminobenzotriazole, a nonselective P450 enzyme inhibitor, attenuated the susceptibility of hepatocytes to MTA cytotoxicity.}, } @article {pmid35575100, year = {2023}, author = {Motafeghi, F and Mortazavi, P and Salman Mahiny, AH and Abtahi, MM and Shokrzadeh, M}, title = {The role of ginger's extract and N-acetylcysteine against docetaxel-induced oxidative stress and genetic disorder.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {4}, pages = {617-624}, doi = {10.1080/01480545.2022.2075377}, pmid = {35575100}, issn = {1525-6014}, mesh = {*Acetylcysteine/pharmacology ; *Zingiber officinale ; Docetaxel/toxicity ; Reactive Oxygen Species ; Oxidative Stress ; Plant Extracts/pharmacology ; Antioxidants/pharmacology ; Flavonoids/pharmacology ; Phenols/pharmacology ; }, abstract = {Oxidative stress plays a prominent role in expanding toxicity and various diseases. This study investigated the potential protective effects of ginger (Zingiber officinale) rhizome extract and NAC on docetaxel induced genotoxicity and oxidative stress. The antioxidant power of NAC and ginger extract on the genetic toxicity induced by docetaxel was assessed by micronucleus test. The ROS test with DCFH reagent was used to assess the reactive oxygen species. The thiobarbituric acid method was used to evaluate the amount of MDA produced by docetaxel. The amounts of phenol and flavonoids in the ginger extracts were also evaluated. The amount of phenol in the ginger extract was 0.886 mg of gallic acid per gram of dry extract. The amount of flavonoids were 0.242 mg/mL of quercetin per gram of dry extract. As shown by the micronucleus results, concentrations of 100 and 500 μM NAC and all concentrations of the ginger extract significantly reduced the number of micronuclei produced by docetaxel. On the other hand, the results of oxidative stress tests (ROS and LPO) showed that docetaxel in HGF cells increased the production of ROS and LPO, and the concentrations of ginger extract and NAC decreased oxidative stress in HGF cells in a dose-dependent manner. The results indicate that using these two antioxidants helps inhibit genetic toxicity and oxidative stress caused by docetaxel.}, } @article {pmid35573789, year = {2022}, author = {Gu, J and Lin, Y and Wang, Z and Pan, Q and Cai, G and He, Q and Xu, X and Cai, X}, title = {Campylobacter jejuni Cytolethal Distending Toxin Induces GSDME-Dependent Pyroptosis in Colonic Epithelial Cells.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {853204}, pmid = {35573789}, issn = {2235-2988}, mesh = {Bacterial Toxins ; *Campylobacter jejuni/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Epithelial Cells/metabolism ; Humans ; *Pyroptosis ; Reactive Oxygen Species/metabolism ; Receptors, Estrogen/metabolism ; }, abstract = {BACKGROUND: Cytolethal distending toxin (CDT) is a critical virulence factor of Campylobacter jejuni, and it induces cell death and regulates inflammation response in human epithelial cells. Pyroptosis is an inflammatory form of programmed cell death (PCD), but whether it is involved in CDT-mediated cytotoxicity remains elusive.

AIMS: This study explores the role and mechanism of pyroptosis in CDT-mediated cytotoxicity.

METHODS: HCT116 and FHC cell lines were treated with CDT. Cell Counting Kit-8 (CCK-8) assay was used to detect cell viability. Western blotting was used to measure the expression of related proteins in the pathway, and cell morphology observation, annexin V/propidium iodide (PI) staining and lactate dehydrogenase (LDH) release assay were performed to evaluate the occurrence of pyroptosis.

RESULT: Our results show that C. jejuni CDT effectively induces pyroptosis in a dose- and time- dependent manner in human colonic epithelial cells owing to its DNase activity. Specific pyroptotic features including large bubbles emerging from plasma membrane and LDH release were observed upon CDT treatment. Moreover, CDT-induced pyroptosis involves the caspase-9/caspase-3 axis, which is followed by gasdermin E (GSDME) cleavage rather than gasdermin D (GSDMD). N-acetyl cysteine (NAC), a reactive oxygen species (ROS) inhibitor, attenuates the activation of caspase-9/3, the cleavage of GSDME and pyroptotic characteristic, therefore demonstrating ROS initiates pyroptotic signaling.

CONCLUSIONS: We first clarify a molecular mechanism that CDT induces pyroptosis via ROS/caspase-9/caspase-3/GSDME signaling. These findings provide a new insight on understanding of CDT-induced pathogenesis at the molecular level.}, } @article {pmid35571469, year = {2022}, author = {Krishnamurthy, V and Joseph, A and Venkataraman, S and Kurian, G}, title = {Simethicone and N-acetyl cysteine combination as premedication before esophagogastroduodenoscopy: Double-blind randomized controlled trial.}, journal = {Endoscopy international open}, volume = {10}, number = {5}, pages = {E585-E592}, pmid = {35571469}, issn = {2364-3722}, abstract = {Background and study aims Esophagogastroduodenoscopy (EGD), the most common method used for diagnosing upper gastrointestinal diseases, is often limited by the presence of foam and mucous. Thus, this study was designed to detect whether the combination of simethicone with N-acetyl cysteine (NAC) as premedication before EGD improves mucosal visualization. Patients and methods A total of 768 consenting patients were enrolled in this prospective, double-blind, randomized placebo-controlled trial in four groups (A: simethicone + N-acetyl cysteine; B: simethicone alone; C: NAC alone; and D: placebo). After 20 minutes of consuming the corresponding solution, EGD was done and multiple images were obtained from the esophagus, stomach, and duodenum. Based on the various images obtained, the study parameters were calculated. Statistical Analysis Software (SAS) was used to analyze the results using Kruskal-Wallis with the Bonferroni correction method. Results The study population consisted of 57 % men and the mean age was 44.18 years. Each group was randomized with 192 participants. Group A (combination of simethicone + NAC) premedication had the lowest total mucosal visibility score of 8.31, a significantly lower score for mucous/bubbles obscuring the vision, and less time to complete the procedure. Also, 81 % of the participants in group A did not require flushing to clear the mucous/bubbles. There were no side effects due to this premedication in any of the groups. Conclusions Using simethicone and NAC combined for premedication may improve the quality of EGD.}, } @article {pmid35571453, year = {2022}, author = {Chen, Q and Hou, Y and Li, D and Ding, Z and Xu, X and Hao, B and Xia, Q and Li, M and Fan, L}, title = {Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway.}, journal = {Annals of translational medicine}, volume = {10}, number = {8}, pages = {485}, pmid = {35571453}, issn = {2305-5839}, abstract = {BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), an isoquinoline alkaloid, is commonly used in traditional Chinese medicine. Previous studies have shown that BBR has a potential anti-tumor effect. However, the mechanisms of BBR on mitochondrial function in anti-lung cancer remain unknown. The aim of this study was to explore mitochondrial function in anti-tumor mechanisms of BBR in NSCLC.

METHODS: The NSCLCs were cultured and treated with various doses (40, 80, 120 µg/mL) of BBR for 24 and 48 h. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8). Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Relative protein expression was examined by western blot and immunohistochemical (IHC) analysis.

RESULTS: BBR potently suppressed NSCLC cells growth by inducing apoptosis in a dose-and time-dependent manner. BBR induced apoptosis in NSCLC cells as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of c-jun-NH2-kinase (JNK) and the JNK inhibitor (SP600125) significantly suppressed BBR-induced apoptosis, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction.

CONCLUSIONS: The results suggest that BBR induces apoptosis of NSCLC cells via ROS-mediated ASK1/JNK activation and the mitochondrial pathway.}, } @article {pmid35571237, year = {2022}, author = {Zhu, M and Ye, L and Zhu, G and Zeng, Y and Yang, C and Cai, H and Mo, Y and Song, X and Gao, X and Peng, W and Wang, J and Jin, M}, title = {ROS-Responsive miR-150-5p Downregulation Contributes to Cigarette Smoke-Induced COPD via Targeting IRE1α.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5695005}, pmid = {35571237}, issn = {1942-0994}, mesh = {3' Untranslated Regions ; Animals ; Biomarkers/metabolism ; *Cigarette Smoking/adverse effects ; Down-Regulation ; Endoribonucleases/metabolism ; Humans ; Inositol ; Mice ; *MicroRNAs/genetics/metabolism ; Protein Serine-Threonine Kinases ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {MicroRNAs (miRNAs) have been reported in human diseases, in which chronic obstructive pulmonary disease (COPD) is included. Herein, we assessed the role along with the possible mechanisms of miR-150-5p in cigarette smoke- (CS-) induced COPD. The plasma miR-150-5p expression was lower in patients with COPD and acute exacerbation of COPD (AECOPD) and was related to disease diagnosis, disease severity, and lung function. Consistently, exposure to CS for 3 months or 3 days reduced miR-150-5p in the plasma and lung tissues of mice, and CS extract (CSE) inhibited miR-150-5p in human bronchial epithelial cells (HBECs) in a concentration along with time-dependent approach. In vitro, miR-150-5p overexpression decreased the contents of inflammatory factors interleukin- (IL-) 6, IL-8 along with cyclooxygenase-2 (COX-2), and endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) and promoted cell migrate. Mechanistically, miR-150-5p could bind with the 3'-untranslated region (UTR) of inositol requiring enzyme 1α (IRE1α), while IRE1α overexpression obliterated the impacts of miR-150-5p. Besides, N-acetyl-cysteine (NAC) reversed CSE-induced miR-150-5p downregulation and its downstream effects. In vivo, miR-150-5p overexpression counteracted CS-triggered IRE1α upregulation, inflammation, and ER stress in the lung tissues of mice. In conclusion, our findings illustrated that ROS-mediated downregulation of miR-150-5p led to CS-induced COPD by inhibiting IRE1α expression, suggesting to serve as a useful biomarker for diagnosing and treating COPD.}, } @article {pmid35566133, year = {2022}, author = {Currie, TL and Engler, MM and Olsen, CH and Krauthamer, V and Scott, JM and Deuster, PA and Flagg, TP}, title = {The Effects of Berry Extracts on Oxidative Stress in Cultured Cardiomyocytes and Microglial Cells: A Potential Cardioprotective and Neuroprotective Mechanism.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {9}, pages = {}, pmid = {35566133}, issn = {1420-3049}, mesh = {Anthocyanins/pharmacology ; Antioxidants/pharmacology ; Fruit ; Microglia ; Myocytes, Cardiac ; Oxidative Stress ; Plant Extracts/pharmacology ; *Ribes ; *Vaccinium macrocarpon ; }, abstract = {Oxidative stress is a key underlying factor in cognitive decline and atherosclerosis. Oxidative stress occurs at the cellular level with an imbalance between reactive oxygen species and reactive nitrogen species and a deficiency in antioxidants. Mounting evidence suggests that berry flavonoids may promote cellular health by exerting antioxidant properties. Black currant and various berry extracts were tested in microglia (BV-2) and cardiomyocyte (HL-1) cell lines to study their biological effects. The principal ingredients in black currant and cranberry extract-delphinidin 3-rutinoside (D3R) and cyanidin 3-glucoside (C3G), were also assessed. A menadione-induced oxidative stressor was used, and its output was quantified to detect oxidative stress (CellROX[TM]). Black currant extract had similar antioxidant effects as N-acetylcysteine (NAC) in HL-1 cells with regard to cellular protection, whereas cranberry extract was ineffective. In contrast, cranberry extract was comparable in effectiveness to black currant extract in BV-2 cells. D3R and C3G also reduced oxidative stress similarly to whole berry extracts, which indicates that these ingredients may confer the antioxidant effects of berries. Black currant and cranberry extracts inhibit oxidative stress in microglial and cardiomyocyte cell lines. Black currant extract was more effective in reducing oxidative stress in the HL-1 cells, whereas cranberry extract was comparable in reducing oxidative stress in the BV-2 cells. The results suggest that berry flavonoids exert neuro- and cardioprotective effects.}, } @article {pmid35564261, year = {2022}, author = {Nozdrenko, D and Prylutska, S and Bogutska, K and Cherepanov, V and Senenko, A and Vygovska, O and Khrapatyi, S and Ritter, U and Prylutskyy, Y and Piosik, J}, title = {Analysis of Biomechanical and Biochemical Markers of Rat Muscle Soleus Fatigue Processes Development during Long-Term Use of C60 Fullerene and N-Acetylcysteine.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {12}, number = {9}, pages = {}, pmid = {35564261}, issn = {2079-4991}, abstract = {The development of an effective therapy aimed at restoring muscle dysfunctions in clinical and sports medicine, as well as optimizing working activity in general remains an urgent task today. Modern nanobiotechnologies are able to solve many clinical and social health problems, in particular, they offer new therapeutic approaches using biocompatible and bioavailable nanostructures with specific bioactivity. Therefore, the nanosized carbon molecule, C60 fullerene, as a powerful antioxidant, is very attractive. In this study, a comparative analysis of the dynamic of muscle soleus fatigue processes in rats was conducted using 50 Hz stimulation for 5 s with three consistent pools after intraperitoneal administration of the following antioxidants: C60 fullerene (a daily dose of 1 mg/kg one hour prior to the start of the experiment) and N-acetylcysteine (NAC; a daily dose of 150 mg/kg one hour prior to the start of the experiment) during five days. Changes in the integrated power of muscle contraction, levels of the maximum and minimum contraction force generation, time of reduction of the contraction force by 50% of its maximum value, achievement of the maximum force response, and delay of the beginning of a single contraction force response were analyzed as biomechanical markers of fatigue processes. Levels of creatinine, creatine phosphokinase, lactate, and lactate dehydrogenase, as well as pro- and antioxidant balance (thiobarbituric acid reactive substances, hydrogen peroxide, reduced glutathione, and catalase activity) in the blood of rats were analyzed as biochemical markers of fatigue processes. The obtained data indicate that applied therapeutic drugs have the most significant effects on the 2nd and especially the 3rd stimulation pools. Thus, the application of C60 fullerene has a (50-80)% stronger effect on the resumption of muscle biomechanics after the beginning of fatigue than NAC on the first day of the experiment. There is a clear trend toward a positive change in all studied biochemical parameters by about (12-15)% after therapeutic administration of NAC and by (20-25)% after using C60 fullerene throughout the experiment. These findings demonstrate the promise of using C60 fullerenes as potential therapeutic nanoagents that can reduce or adjust the pathological conditions of the muscular system that occur during fatigue processes in skeletal muscles.}, } @article {pmid35563172, year = {2022}, author = {Gao, M and Hu, J and Zhu, Y and Wang, X and Zeng, S and Hong, Y and Zhao, G}, title = {Ferroptosis and Apoptosis Are Involved in the Formation of L-Selenomethionine-Induced Ocular Defects in Zebrafish Embryos.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35563172}, issn = {1422-0067}, support = {2018YFD0901700//National Key R&D Program of China/ ; 2018ACF60014//The Fundamental Research Funds for the Key Scientific and Technological Projects in Jiangxi Province/ ; }, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis ; *Ferroptosis ; *Microphthalmos ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; *Selenium/metabolism ; Selenomethionine ; Zebrafish/genetics ; }, abstract = {Selenium is an essential trace element for humans and other vertebrates, playing an important role in antioxidant defense, neurobiology and reproduction. However, the toxicity of excessive selenium has not been thoroughly evaluated, especially for the visual system of vertebrates. In this study, fertilized zebrafish embryos were treated with 0.5 µM L-selenomethionine to investigate how excessive selenium alters zebrafish eye development. Selenium-stressed zebrafish embryos showed microphthalmia and altered expression of genes required for retinal neurogenesis. Moreover, ectopic proliferation, disrupted mitochondrial morphology, elevated ROS-induced oxidative stress, apoptosis and ferroptosis were observed in selenium-stressed embryos. Two antioxidants-reduced glutathione (GSH) and N-acetylcysteine (NAC)-and the ferroptosis inhibitor ferrostatin (Fer-1) were unable to rescue selenium-induced eye defects, but the ferroptosis and apoptosis activator cisplatin (CDDP) was able to improve microphthalmia and the expression of retina-specific genes in selenium-stressed embryos. In summary, our results reveal that ferroptosis and apoptosis might play a key role in selenium-induced defects of embryonic eye development. The findings not only provide new insights into selenium-induced cellular damage and death, but also important implications for studying the association between excessive selenium and ocular diseases in the future.}, } @article {pmid35553365, year = {2023}, author = {Kaya, S and Yalçın, T and Boydak, M and Dönmez, HH}, title = {Protective Effect of N-Acetylcysteine Against Aluminum-Induced Kidney Tissue Damage in Rats.}, journal = {Biological trace element research}, volume = {201}, number = {4}, pages = {1806-1815}, pmid = {35553365}, issn = {1559-0720}, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology ; Aluminum/toxicity ; Rats, Wistar ; Kidney ; *Kidney Diseases/chemically induced/prevention & control/pathology ; *Renal Insufficiency/pathology ; Oxidative Stress ; }, abstract = {Aluminum (AL) is an important nephrotoxic agent with a high daily exposure rate and property of accumulation in tissues. This study aimed to investigate the potential protective efficacy of N-acetylcysteine (NAC) against AL exposure-induced nephrotoxicity in rats. Twenty-eight rats were randomly divided into 4 groups as control, N-acetylcysteine group (NC), AL, and AL + NC, with an equal number of rats in each group (n = 7). No application was made to the control group. A total of 150 mg/kg/day NAC was administered to the NC group and 30 mg/kg/day AL was administered to the AL group intraperitoneally (i.p.). The AL + NC group received 30 mg/kg/day AL and 150 mg/kg/day NAC i.p. Biochemical parameters in blood serum and histopathological changes in kidney tissue, oxidative stress parameters, spexin (SPX), and apoptotic protein levels were examined after 15 days. Histopathological changes, biochemical parameters, oxidative stress parameters, and apoptotic protein levels were significantly irregular in the AL group compared to the control group. Moreover, SPX levels increased in the AL group. However, NAC treatment regulated AL exposure-related changes in the AL + NC group. NAC treatment may have a prophylactic effect against nephrotoxicity due to AL exposure. SPX may play a role in AL-induced nephrotoxicity.}, } @article {pmid35551047, year = {2022}, author = {Liu, H and Li, MJ and Zhang, XN and Wang, S and Li, LX and Guo, FF and Zeng, T}, title = {N,N-dimethylformamide-induced acute liver damage is driven by the activation of NLRP3 inflammasome in liver macrophages of mice.}, journal = {Ecotoxicology and environmental safety}, volume = {238}, number = {}, pages = {113609}, doi = {10.1016/j.ecoenv.2022.113609}, pmid = {35551047}, issn = {1090-2414}, mesh = {Animals ; *Chemical and Drug Induced Liver Injury/etiology ; Dimethylformamide ; Inflammasomes ; Liver ; *Liver Diseases ; Macrophages ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; }, abstract = {N,N-dimethylformamide (DMF) is a non-negligible volatile hazardous material in indoor and outdoor environments. Although the hepatotoxicity of DMF has been well recognized, the underlying mechanisms remain unclear and prophylactic medicine is still lacking. Herein, we established a DMF-induced acute liver injury mouse model and investigated the underlying mechanisms focusing on oxidative stress and the nucleotide-binding domain and leucine-rich repeat receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome. DMF was found to induce oxidative stress, evidenced by the elevation of hepatic malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) adducts levels, and the decline of reduced glutathione (GSH) levels. However, neither N-acetyl cysteine (NAC) nor sulforaphane (SF) ameliorated the hepatoxicity induced by DMF in mice. Interestingly, DMF exposure led to focal necrosis of hepatocytes and NLRP3 inflammasome activation before the onset of obvious liver damage. In addition, DMF exposure induced infiltration and proinflammatory/M1 polarization of macrophages in mice livers. Furthermore, the inactivation of hepatic macrophages by GdCl3 significantly suppressed DMF-induced elevation of serum aminotransferase activities, neutrophile infiltration, and activation of NLRP3 inflammasome in mice liver. Collectively, these results suggest that DMF-induced acute hepatotoxicity may be attributed to the activation of NLRP3 inflammasome in liver macrophages, but not oxidative stress.}, } @article {pmid35550579, year = {2022}, author = {Zhan, Y and Chen, J and Wu, J and Gu, Y and Huang, Q and Deng, Z and Chen, S and Wu, X and Lv, Y and Zeng, Z and Xie, J}, title = {Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease.}, journal = {Respiratory research}, volume = {23}, number = {1}, pages = {120}, pmid = {35550579}, issn = {1465-993X}, support = {81800041//National Natural Science Foundation of China/ ; 82170049//National Natural Science Foundation of China/ ; 81973986//National Natural Science Foundation of China,China/ ; WX21Q07//Health Research Fund of Wuhan/ ; WJ2019M116//Health and family planning research project of Hubei/ ; }, mesh = {Airway Remodeling ; Animals ; Cell Line ; Epithelial Cells/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Inflammation/metabolism ; *Interleukin-6/metabolism ; Mice ; *Pulmonary Disease, Chronic Obstructive ; WAP Four-Disulfide Core Domain Protein 2 ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by chronic inflammation and airway remodeling. Human epididymis protein 4 (HE4) plays a critical role in various inflammatory or fibrotic diseases. However, the role of HE4 in COPD remains unidentified.

METHODS: HE4 expression was determined in the lung tissues from COPD patients and cigarette smoke (CS)-exposed mice using immunohistochemical staining, qPCR, or western blot. The plasma level of HE4 was detected by ELISA. The regulations of HE4 in the expressions of CS extract (CSE)-induced inflammatory cytokines in human bronchial epithelial cells (HBE) were investigated through knockdown or overexpression of HE4. The role of secretory HE4 (sHE4) in the differentiation and proliferation in human pulmonary fibroblast cells (HPF) was explored via qPCR, western blot, CCK8 assay or 5-ethynyl-2'-deoxyuridine (EdU) staining. The probe of related mechanism in CSE-induced HE4 increase in HBE was conducted by administrating N-acetylcysteine (NAC).

RESULTS: HE4 was up-regulated in both the lung tissue and plasma of COPD patients relative to controls, and the plasma HE4 was negatively associated with lung function in COPD patients. The same enhanced HE4 expression was verified in CS-exposed mice and CSE-induced HBE, but CSE failed to increase HE4 expression in HPF. In vitro experiments showed that reducing HE4 expression in HBE alleviated CSE-induced IL-6 release while overexpressing HE4 facilitated IL-6 expression, mechanistically through affecting phosphorylation of NFκB-p65, whereas intervening HE4 expression had no distinctive influence on IL-8 secretion. Furthermore, we confirmed that sHE4 promoted fibroblast-myofibroblast transition, as indicated by promoting the expression of fibronectin, collagen I and α-SMA via phosphorylation of Smad2. EdU staining and CCK-8 assay demonstrated the pro-proliferative role of sHE4 in HPF, which was further confirmed by enhanced expression of survivin and PCNA. Pretreatment of NAC in CSE or H2O2-induced HBE mitigated HE4 expression.

CONCLUSIONS: Our study indicates that HE4 may participate in airway inflammation and remodeling of COPD. Cigarette smoke enhances HE4 expression and secretion in bronchial epithelium mediated by oxidative stress. Increased HE4 promotes IL-6 release in HBE via phosphorylation of NFκB-p65, and sHE4 promotes fibroblastic differentiation and proliferation.}, } @article {pmid35547461, year = {2022}, author = {Arunpriyandan, V and Sundaresan, KT}, title = {Fulminant Hepatic Failure in Dengue Fever Without Plasma Leakage: A Case Report.}, journal = {Cureus}, volume = {14}, number = {4}, pages = {e23964}, pmid = {35547461}, issn = {2168-8184}, abstract = {Dengue is an important arboviral disease in the tropics and subtropics. Although mild to moderate elevation of liver transaminases is a common phenomenon, dengue infection leading to hepatic failure is a rare complication in adults. We present a case of dengue fever in a young adult, leading to the rare complication of acute liver failure, without dengue shock syndrome. We tried evidence-based management with therapeutic plasma exchange, which led to a significant improvement in liver function.}, } @article {pmid35546602, year = {2022}, author = {Ponnusamy, S and Ali, HH and Dutt, F and Rahman, SU and Salah, AA and Pipalia, M and Baier, RE and Arany, PR}, title = {Redox signaling induces laminin receptor ribosomal protein-SA expression to improve cell adhesion following radiofrequency glow discharge treatments.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {7742}, pmid = {35546602}, issn = {2045-2322}, mesh = {Biocompatible Materials/pharmacology ; Catalase/pharmacology ; Cell Adhesion ; *Laminin/pharmacology ; Oxidation-Reduction ; Porphyromonas gingivalis ; Receptors, Laminin ; Ribosomal Proteins ; *Streptococcus gordonii ; }, abstract = {Current biomaterials effectively replace biological structures but are limited by infections and long-term material failures. This study examined the molecular mechanisms of radio frequency glow discharge treatments (RFGDT) in mediating the disinfection of biomaterial surfaces and concurrently promoting cell attachment and proliferation. Dental biomaterials were subjected to RFGDT, and viability of oral microbial species, namely Streptococcus mutants (SM), Streptococcus gordonii (SG), Moraxella catarrhalis (MC), and Porphyromonas gingivalis (PG), were assessed. Cell attachment and survival of a pre-odontoblast cell line, MDPC-23, was examined. Finally, mechanistic investigations into redox generation and biological signaling were investigated. Based on their compositions, dental biomaterials induced reactive oxygen species (ROS) following dose-dependent RFGDT. Reduced microbial viability was evident following RFGDT in the catalase-negative (SM and SG) species more prominently than catalase-positive (MC and PG) species. Cell adhesion assays noted improved MDPC-23 attachment and survival. Pretreatments with N-acetylcysteine (NAC) and catalase abrogated these responses. Immunoassays noted redox-induced downstream expression of a laminin receptor, Ribosomal Protein SA, following RFGDT. Thus, RFGDT-induced redox mediates antimicrobial and improves cell responses such as adhesion and proliferation. These observations together provide a mechanistic rationale for the clinical utility of RFGDT with dental biomaterials for regenerative clinical applications.}, } @article {pmid35543385, year = {2022}, author = {Wen, X and Li, S and Zhang, Y and Zhu, L and Xi, X and Zhang, S and Li, Y}, title = {Recombinant human klotho protects against hydrogen peroxide-mediated injury in human retinal pigment epithelial cells via the PI3K/Akt-Nrf2/HO-1 signaling pathway.}, journal = {Bioengineered}, volume = {13}, number = {5}, pages = {11767-11781}, pmid = {35543385}, issn = {2165-5987}, mesh = {Antioxidants/pharmacology ; Apoptosis ; Cell Survival ; Epithelial Cells/metabolism ; *Heme Oxygenase-1/genetics/metabolism ; Humans ; Hydrogen Peroxide/metabolism/toxicity ; *NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigments/metabolism/pharmacology ; Signal Transduction ; }, abstract = {Globally, age-related macular degeneration (AMD) is a common irreversible ophthalmopathy. Oxidative stress of retinal pigment epithelial cells is involved in AMD occurrence and development. Klotho is an anti-aging protein with antioxidant properties. We investigated the protective properties of Klotho on hydrogen peroxide (H2O2)-induced injury of retinal pigment epithelial cells (ARPE-19 cells) and its associated pathomechanisms. We found that Klotho pretreatment for 24 h could up-regulate Bcl-2 levels, decrease the cleaved-caspase-3 and Bax levels, inhibit H2O2-induced ARPE-19 cell apoptosis, and promote cell proliferation. Klotho pretreatment inhibited the H2O2-mediated elevations of reactive oxygen species (ROS) in ARPE-19 cells. It enhanced antioxidant activities of the cells and restored the glutathione peroxidase (GPX), superoxide dismutase (SOD2), catalase (CAT), as well as malondialdehyde (MDA) levels to close to the normal level. N-acetylcysteine (NAC), a reactive oxygen scavenger, could reverse the harmful effects of H2O2 on proliferation, apoptosis, and oxidative stress of ARPE-19 cells. Further, Klotho pretreatment enhanced Akt phosphorylation and expression as well as nuclear translocation of Nrf2 in H2O2-treated ARPE-19 cells. This indicates that Klotho protects cells from oxidative stress by activating phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)-nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway. Klotho is, therefore, a potential preventive or treatment option for AMD.}, } @article {pmid35535444, year = {2022}, author = {Rafiee, B and Karbalay-Doust, S and Tabei, SMB and Azarpira, N and Alaee, S and Lohrasbi, P and Bahmanpour, S}, title = {Effects of N-acetylcysteine and metformin treatment on the stereopathological characteristics of uterus and ovary.}, journal = {European journal of translational myology}, volume = {32}, number = {2}, pages = {}, pmid = {35535444}, issn = {2037-7452}, abstract = {In this study, the stereo-pathological effect of metformin and N-acetyl cysteine is evaluated on the uterus and ovary of polycystic ovary syndrome (PCOS) mice. 96 mature females (8-weekold, weight of 20-30 gr) BALB/c mice were classified into 6 groups including the control group (n= 16), letrozole-induced PCOS group (n=16), PCOS + metformin (n=16), PCOS+NAC (n=16) and a separate control group for NAC (n=16). Another PCOS group was maintained for a month to make sure that features remain till the end of the study. Testosterone level, vaginal cytology and stereological evaluations were assessed. Vaginal cytology in letrozole-receiving mice showed a diestrus phase continuity. Testosterone level, body weight, uterine weight, endometrial volume, myometrial volume, gland volume, stromal volume, epithelial volume, vessel volume, daughter and conglomerate glands, endometrial thickness, and myometrial thickness exhibited an increasing trend in the uterus of PCOS mice. While normal gland and vessel length decreased in the PCOS group. Ovarian volume, corticomedullary volume, primary follicles, secondary follicles, and ovarian cysts were increased in PCOS ovaries. While corpus luteum, primordial, graafian, and atretic follicles showed a decline in the PCOS group. NAC and metformin, however, managed to restore the condition to normal. Given the prevalence of PCOS and its impact on fertility, the use of noninvasive methods is of crucial significance. NAC can control and treat pathological parameters and help as a harmless drug in the treatment of women with PCOS.}, } @article {pmid35535093, year = {2022}, author = {Praharaj, DL and Anand, AC and Acharya, SK}, title = {Dosage of N-Acetyl Cysteine in Acute Liver Failure Not Related to Acetaminophen.}, journal = {Journal of clinical and experimental hepatology}, volume = {12}, number = {2}, pages = {726-728}, pmid = {35535093}, issn = {0973-6883}, } @article {pmid35535082, year = {2022}, author = {Mishra, S}, title = {Dose of N-acetyl Cysteine in INASL Consensus on Acute Liver Failure (Part 2)-Management.}, journal = {Journal of clinical and experimental hepatology}, volume = {12}, number = {2}, pages = {725}, pmid = {35535082}, issn = {0973-6883}, } @article {pmid35533555, year = {2022}, author = {Wang, L and Ji, T and Yuan, Y and Fu, H and Wang, Y and Tian, S and Hu, J and Wang, L and Wang, Z}, title = {High-fructose corn syrup promotes proinflammatory Macrophage activation via ROS-mediated NF-κB signaling and exacerbates colitis in mice.}, journal = {International immunopharmacology}, volume = {109}, number = {}, pages = {108814}, doi = {10.1016/j.intimp.2022.108814}, pmid = {35533555}, issn = {1878-1705}, mesh = {Animals ; *Colitis/chemically induced ; Dextran Sulfate/pharmacology ; Disease Models, Animal ; Fructose ; *High Fructose Corn Syrup/adverse effects ; *Inflammatory Bowel Diseases ; Macrophage Activation ; Mice ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Zea mays ; }, abstract = {The dramatically increasing incidence and prevalence of inflammatory bowel disease (IBD) are reportedly related to a Western diet, which is characterized by high sugar consumption. Dietary simple sugars aggravate IBD in animal models. However, the mechanisms underlying this effect remain unclear. Given that high-fructose corn syrup (HFCS) is a major added sugar in food and beverages, we focus on HFCS and investigated the effects of HFCS on a dextran sulfate sodium (DSS)-induced murine colitis model and in RAW264.7 macrophages. Our data demonstrate that short-term consumption of HFCS aggravates colitis and upregulates the proportion of macrophages in IBD mice but not in healthy mice. We find that HFCS promotes proinflammatory cytokine production through reactive oxygen species (ROS)-mediated nuclear factor-κB (NF-κB) signaling in RAW264.7 macrophages. Furthermore, N-acetylcysteine (NAC), an ROS scavenger, alleviates HFCS-aggravated colitis in mice and inhibits the ROS-mediated NF-κB signaling pathway in RAW264.7 macrophages. Our work unveils the important role of macrophages in HFCS-induced exacerbation of colitis and reveals the mechanism of how HFCS immunologically aggravates IBD.}, } @article {pmid35532240, year = {2022}, author = {Wykoff, JA and Shaffer, KM and Araba, KC and Markovetz, MR and Patarin, J and Robert de Saint Vincent, M and Donaldson, SH and Ehre, C}, title = {Rapid Viscoelastic Characterization of Airway Mucus Using a Benchtop Rheometer.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {182}, pages = {}, pmid = {35532240}, issn = {1940-087X}, support = {P30 DK065988/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Mucus ; Reproducibility of Results ; Respiratory System ; Rheology ; Sputum ; Viscosity ; }, abstract = {In muco-obstructive lung diseases (e.g., asthma, chronic obstructive pulmonary disease, cystic fibrosis) and other respiratory conditions (e.g., viral/bacterial infections), mucus biophysical properties are altered by goblet cell hypersecretion, airway dehydration, oxidative stress, and the presence of extracellular DNA. Previous studies showed that sputum viscoelasticity correlated with pulmonary function and that treatments affecting sputum rheology (e.g., mucolytics) can result in remarkable clinical benefits. In general, rheological measurements of non-Newtonian fluids employ elaborate, time-consuming approaches (e.g., parallel/cone-plate rheometers and/or microbead particle tracking) that require extensive training to perform the assay and interpret the data. This study tested the reliability, reproducibility, and sensitivity of Rheomuco, a user-friendly benchtop device that is designed to perform rapid measurements using dynamic oscillation with a shear-strain sweep to provide linear viscoelastic moduli (G', G", G[*], and tan δ) and gel point characteristics (γc and σc) for clinical samples within 5 min. Device performance was validated using different concentrations of a mucus simulant, 8 MDa polyethylene oxide (PEO), and against traditional bulk rheology measurements. A clinical isolate harvested from an intubated patient with status asthmaticus (SA) was then assessed in triplicate measurements and the coefficient of variation between measurements is <10%. Ex vivo use of a potent mucus reducing agent, TCEP, on SA mucus resulted in a five-fold decrease in elastic modulus and a change toward a more "liquid-like" behavior overall (e.g., higher tan δ). Together, these results demonstrate that the tested benchtop rheometer can make reliable measures of mucus viscoelasticity in clinical and research settings. In summary, the described protocol could be used to explore the effects of mucoactive drugs (e.g., rhDNase, N-acetyl cysteine) onsite to adapt treatment on a case-by-case basis, or in preclinical studies of novel compounds.}, } @article {pmid35527020, year = {2022}, author = {Chen, G and Lu, H}, title = {Oral high-dose acetylcysteine: Effective against the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?.}, journal = {Drug discoveries & therapeutics}, volume = {16}, number = {3}, pages = {139-141}, doi = {10.5582/ddt.2022.01032}, pmid = {35527020}, issn = {1881-784X}, mesh = {*Acetylcysteine/therapeutic use ; Antioxidants/therapeutic use ; Expectorants/therapeutic use ; Glutathione ; Humans ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a high rate of transmission and it exhibits immune escape characteristics. N-acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH), which can enter cells to play an antioxidant role, so it is better than glutathione. Patients tolerate NAC well, and adverse reactions are rare and mild, so this type of drug with multiple actions is considered to be a mucolytic agent as well as a drug for the prevention/treatment of various diseases, including COVID-19. Previous studies indicated that the clinical effectiveness of NAC is dose-dependent. Low-dose NAC (0.2 g tid for adults) is a mucolytic expectorant, high-dose NAC (0.6 g bid or tid) has expectorant action as well as antioxidant action, and extreme-dose NAC (300 mg/kg.d) is used for detoxification in cases of an acetaminophen overdose. Presumably, orally administered high-dose NAC (0.6 g tid for adults and 10 mg/kg tid for children) could be used as an adjuvant to treat an Omicron infection. It should reduce the time to negative conversion and prevent severe COVID-19, reducing the duration of hospitalization and increasing the bed turnover rate.}, } @article {pmid35526290, year = {2022}, author = {Rakhtshah, J and Shirkhanloo, H and Dehghani Mobarake, M}, title = {Simultaneously speciation and determination of manganese (II) and (VII) ions in water, food, and vegetable samples based on immobilization of N-acetylcysteine on multi-walled carbon nanotubes.}, journal = {Food chemistry}, volume = {389}, number = {}, pages = {133124}, doi = {10.1016/j.foodchem.2022.133124}, pmid = {35526290}, issn = {1873-7072}, mesh = {Acetylcysteine ; Adsorption ; Hydrogen-Ion Concentration ; Ions ; Limit of Detection ; *Manganese ; *Nanotubes, Carbon ; Solid Phase Extraction/methods ; Vegetables ; Water ; }, abstract = {A novel method based on the immobilization of N-acetylcysteine on chloro-functionalized multi-walled carbon nanotubes (MWCNTs@NAC) was used for the speciation of manganese ions [Mn (II) and Mn(VII)] in water samples. Also, the total manganese (TMn) in vegetables and food samples was determined by the AT-FAAS. By ultrasound-assisted-dispersive ionic liquid trap micro solid-phase extraction (UA-DILT-μ-SPE), the Mn (II)/Mn(VII) ions were extracted in the presence of MWCNTs@NAC for 50 mL of water samples at a pH of 6.5 and 3.0, respectively. The adsorption capacity of MWCNTs@NAC for Mn(II) and Mn(VII) ions was obtained at 146.7 mg g[-1] and 138.8 mg g[-1], respectively. Under the optimized conditions, the detection limits (LOD), linear range (LR), and enrichment factor (EF) for Mn(II) and Mn(VII) ions were obtained (0.12 μg L[-1]; 0.14 μg L[-1]), (0.48-36 μg L[-1]; 0.55-38.1 μg L[-1]) and (100.2; 94.5), respectively. The proposed methodology was successfully validated by the CRM samples.}, } @article {pmid35523509, year = {2022}, author = {Raghu, K and Berry, MJ}, title = {Acute liver failure secondary to therapeutic paracetamol dosing in an extremely preterm neonate.}, journal = {BMJ case reports}, volume = {15}, number = {5}, pages = {}, pmid = {35523509}, issn = {1757-790X}, mesh = {Acetaminophen/therapeutic use ; *Ductus Arteriosus, Patent ; Humans ; Ibuprofen/therapeutic use ; Infant ; Infant, Extremely Premature ; Infant, Newborn ; *Liver Failure, Acute/chemically induced/drug therapy ; Male ; }, abstract = {We report the first case of standard therapeutic dose paracetamol for patent ductus arteriosus closure causing acute liver failure in an extremely preterm infant. After 5 days of treatment, he presented with jaundice, acute severe hepatitis and coagulopathy. Treatment with N-acetyl cysteine resulted in full recovery.}, } @article {pmid35517780, year = {2022}, author = {Chen, HC and Chiou, HC and Tsai, ML and Chen, SC and Lin, MH and Chuang, TC and Hung, CH and Kuo, CH}, title = {Effects of Montelukast on Arsenic-Induced Epithelial-Mesenchymal Transition and the Role of Reactive Oxygen Species Production in Human Bronchial Epithelial Cells.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {877125}, pmid = {35517780}, issn = {1663-9812}, abstract = {Background: Epithelial-mesenchymal transition (EMT) of airway lung epithelial cells is considered a major driver of fibrosis and airway remodeling. Arsenic exposure is well known to cause the malignant transformation of cells, including those in the lung. Accumulating studies have shown that arsenic exposure is associated with chronic pulmonary diseases. However, clinical treatment for arsenic-induced pulmonary damage has not been well investigated. Materials and Methods: The therapeutic effects of montelukast and its combination with fluticasone on sodium arsenite-induced EMT changes in normal human bronchial cells were investigated. The cell migration ability was evaluated by Transwell and wound healing assays. EMT marker expression was determined by immunoblotting. Furthermore, the role of reactive oxygen species (ROS) generation in arsenic-induced EMT and the effect of montelukast on this process were determined by ROS inhibitor treatment and ROS measurement, respectively. Results: Montelukast was effective at reducing arsenic-induced cell migration and mesenchymal protein (fibronectin, MMP-2, N-cadherin, β-catenin, and SMAD2/3) expression. Arsenic-induced ROS production was attenuated by pretreatment with montelukast. Treatment with the ROS inhibitor N-acetyl cysteine reduced arsenic-induced NF-kB phosphorylation and the mesenchymal protein expression, indicating that ROS production is critical for arsenic-induced EMT. In addition, combined treatment with montelukast and fluticasone reversed the inhibitory effects of montelukast on cell migration. The expression of fibronectin, MMP-2 induced by arsenic was further enhanced by the combination treatment compared with montelukast treatment only. Conclusion: This study demonstrated that montelukast is effective at reducing arsenic-induced EMT in human bronchial epithelial cells. Through the inhibition of arsenic-induced ROS generation and NF-kB activation, which is critical for arsenic-induced EMT, montelukast inhibited arsenic-induced cell migration and the expression of extracellular matrix proteins and several EMT-regulating transcription factors. The combination of fluticasone with montelukast reversed the inhibitory effect of montelukast on arsenic-induced EMT. This study provides therapeutic strategies and mechanisms for arsenic-induced pulmonary epithelial damage.}, } @article {pmid35513370, year = {2022}, author = {Fan, L and Guan, F and Ma, Y and Zhang, Y and Li, L and Sun, Y and Cao, C and Du, H and He, M}, title = {N-Acetylcysteine improves oocyte quality through modulating the Nrf2 signaling pathway to ameliorate oxidative stress caused by repeated controlled ovarian hyperstimulation.}, journal = {Reproduction, fertility, and development}, volume = {34}, number = {10}, pages = {736-750}, doi = {10.1071/RD22020}, pmid = {35513370}, issn = {1448-5990}, mesh = {Animals ; Female ; Mice ; *Acetylcysteine/pharmacology ; NF-E2-Related Factor 2/metabolism ; Oocytes/metabolism ; *Ovarian Hyperstimulation Syndrome/metabolism ; Oxidative Stress ; Signal Transduction ; }, abstract = {CONTEXT: N -acetyl-cysteine (NAC) is a potent antioxidant that can be used for many gynecological diseases such as polycystic ovary syndrome and endometriosis. Controlled ovarian hyperstimulation (COH) is a critical step in infertility treatment. Our previous clinical studies have shown that repeated COH led to oxidative stress in follicle fluid and ovarian granulosa cells.

AIMS: In this study, we investigated whether NAC could inhibit oxidative stress in mice caused by repeated COH and improve the mitochondrial function of oocytes.

METHODS: Female Institute of Cancer Research (ICR) mice were randomly assigned into three groups: normal group, model (repeated COH) group, NAC group. We examined the morphology, number and quality of mitochondria. The mechanism of regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) by NAC to ameliorate oxidative stress was also investigated.

KEY RESULTS: Repeated COH caused oxidative damage in ovaries and oocytes and decreased oocyte quality, while NAC prevented oxidative damage and increased oocyte mitochondrial function. In in vitro experiments, it was verified that NAC can promote the nuclear translocation of Nrf2, which transcriptionally activates the expression of superoxide dismutase and glutathione peroxidase, which removed excessive reactive oxygen species that causes mitochondria damage.

CONCLUSIONS: The results suggest that NAC raises mitochondrial function in oocytes and improves oocyte quality through decreasing oxidative stress in mice with repeated COH. The underlying mechanism is related to the regulation of the Nrf2 signaling pathway.

IMPLICATION: This study provides a meaningful foundation for the future clinical application of NAC during repeated COH.}, } @article {pmid35510880, year = {2022}, author = {Filip, AB and Berg, SE and Mullins, ME and Schwarz, ES and , }, title = {Fomepizole as an adjunctive therapy for acetaminophen poisoning: cases reported to the toxicology investigators consortium (ToxIC) database 2015-2020.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {9}, pages = {1006-1011}, doi = {10.1080/15563650.2022.2070071}, pmid = {35510880}, issn = {1556-9519}, mesh = {*Acetaminophen ; Acetylcysteine/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; Databases, Factual ; Fomepizole ; Humans ; }, abstract = {INTRODUCTION: Fomepizole inhibits formation of toxic acetaminophen (APAP) metabolites and may prevent or reverse mitochondrial toxicity. Given these mechanisms, it may be beneficial in patients with severe APAP toxicity. Current patterns of use for this indication are not well-studied.

METHODS: This is a secondary analysis of patients enrolled in the Toxicology Investigators Consortium (ToxIC) database from January 2015 to July 2020. We queried cases in which APAP was listed as an ingested agent and fomepizole was also administered. We excluded cases in which APAP was not the primary agent, N-acetylcysteine (NAC) was not administered, or fomepizole was explicitly administered for another indication. Additionally, we sent a survey to each ToxIC site that administered fomepizole for APAP toxicity to better understand when, why, and how they were using it for this indication.

RESULTS: Twenty-five cases of fomepizole administration following an APAP ingestion met our inclusion criteria. There were one to four cases per year between 2015 and 2019 and eight cases in 2020. Seventeen of 25 (68%) cases were for a known acute ingestion. Eighteen of 25 (72%) patients developed hepatotoxicity (AST or ALT > 1000 IU/L) and 10 of 25 (40%) developed coagulopathy (PT > 15s). This was an ill patient population, with 18 of 25 (72%) developing metabolic acidosis (pH <7.20), 12 of 25 (48%) were intubated, 9 of 25 (36%) receiving vasopressors, and 6 of 25 (24%) receiving continuous renal replacement therapy. Overall, mortality was 24%.

CONCLUSION: The use of fomepizole is increasing in frequency in a small subset of critically ill and acutely APAP-poisoned patients.}, } @article {pmid35505312, year = {2022}, author = {Wozniak, J and DiSalvo, M and Farrell, A and Vaudreuil, C and Uchida, M and Ceranoglu, TA and Joshi, G and Cook, E and Faraone, SV and Biederman, J}, title = {Findings from a pilot open-label trial of N-acetylcysteine for the treatment of pediatric mania and hypomania.}, journal = {BMC psychiatry}, volume = {22}, number = {1}, pages = {314}, pmid = {35505312}, issn = {1471-244X}, mesh = {Acetylcysteine/therapeutic use ; Adolescent ; Antimanic Agents/therapeutic use ; *Bipolar Disorder/complications/drug therapy ; Child ; Child, Preschool ; Humans ; *Mania ; Pilot Projects ; }, abstract = {BACKGROUND: Pediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder.

METHODS: We conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5-17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores ≥ 20 and < 40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children's Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression.

RESULTS: This study had a high drop-out rate with only 53% completing all 12 weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS ≥ 30% and 46% had a CGI-I mania score ≤ 2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS ≥ 30%, 31% had an anti-depressive response measured by a reduction in CDRS ≥ 30%, and 38% had a CGI-I depression score ≤ 2 at endpoint.

CONCLUSIONS: These pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02357290 . First Registration 06/02/2015.}, } @article {pmid35504863, year = {2022}, author = {Hoang, DV and Thuy, LTT and Hai, H and Hieu, VN and Kimura, K and Oikawa, D and Ikura, Y and Dat, NQ and Hoang, TH and Sato-Matsubara, M and Dong, MP and Hanh, NV and Uchida-Kobayashi, S and Tokunaga, F and Kubo, S and Ohtani, N and Yoshizato, K and Kawada, N}, title = {Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species.}, journal = {Oncogenesis}, volume = {11}, number = {1}, pages = {23}, pmid = {35504863}, issn = {2157-9024}, support = {19H03641//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K08428//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; AMED- JP21fk0210050//Japan Agency for Medical Research and Development (AMED)/ ; 21gm1010009h0004//Japan Agency for Medical Research and Development (AMED)/ ; 21gm1010009h0004//Japan Agency for Medical Research and Development (AMED)/ ; FY2019-2021//Gilead Sciences (Gilead)/ ; }, abstract = {Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.}, } @article {pmid35504402, year = {2022}, author = {Jung, YY and Baek, SH and Ha, IJ and Ahn, KS}, title = {Regulation of apoptosis and autophagy by albendazole in human colon adenocarcinoma cells.}, journal = {Biochimie}, volume = {198}, number = {}, pages = {155-166}, doi = {10.1016/j.biochi.2022.04.014}, pmid = {35504402}, issn = {1638-6183}, mesh = {*Adenocarcinoma/drug therapy/metabolism ; Albendazole/pharmacology ; Apoptosis ; Autophagy ; Cell Line, Tumor ; *Colonic Neoplasms/drug therapy ; Humans ; }, abstract = {Albendazole (ABZ) was initially introduced as an anthelmintic, however, many studies have reported with its anticancer effects. We investigated the anti-tumor effects of ABZ in vitro in human colon adenocarcinoma HCT-15, HCT-116, HT-29, and SW480 cell lines in this study. The cytotoxicity of ABZ was analyzed in colon adenocarcinoma cell lines and normal CCD18Co cells. We found that ABZ induced the subG1 arrest during cell cycle progression, increased the late apoptotic cells, shifted of peak TUNEL-labeled cells peak, and induced apoptosis. Then effects on autophagy activation was confirmed by acridine orange (AO), MDC staining, and immunocytochemistry of LC3. It was observed that ABZ can induce the autophagy activation through modulating the levels of LC3, Atg7, and beclin-1. For mechanistic studies, apoptosis blocker (Z-DEVD-FMK) and autophagy inhibitor (3-MA) were used to confirm that whether ABZ has apoptosis and autophagy specific effects, and reversal in both these cell death processes were noted. The effects of ABZ on AMPK, MAPKs, and ULK induction was also evaluated. We noticed that N-acetyl cysteine (NAC), a broad spectrum antioxidant, can effectively inhibit both apoptosis and autophagy. However, ABZ could even recover suppression of apoptosis and autophagy caused by NAC in colon cancer cells. Therefore, ABZ can potentially up-regulate both the apoptosis and autophagy to significantly suppress tumorigenesis in colorectal cancer cell lines.}, } @article {pmid35504092, year = {2022}, author = {Liao, C and Zhang, L and Jiang, R and Xu, J and Tang, J and Hu, K and Jiang, S and Li, L and Yang, Y and Huang, J and Tang, L and Li, L}, title = {Inhibition of NAD kinase elevates the hepatic NAD[+] pool and alleviates acetaminophen-induced acute liver injury in mice.}, journal = {Biochemical and biophysical research communications}, volume = {612}, number = {}, pages = {70-76}, doi = {10.1016/j.bbrc.2022.04.079}, pmid = {35504092}, issn = {1090-2104}, mesh = {*Acetaminophen/adverse effects ; Animals ; *Chemical and Drug Induced Liver Injury/drug therapy ; Liver ; Mice ; Mice, Inbred C57BL ; NAD ; Phosphotransferases (Alcohol Group Acceptor) ; }, abstract = {Acetaminophen (APAP) overdose induces acute liver injury (ALI), even acute liver failure (ALF). There is a significant unmet need to furtherly elucidate the mechanisms and find new therapeutic target. Recently, emerging evidence indicates that nicotinamide adenine dinucleotide (NAD[+]) plays a crucial role in APAP-induced ALI. Herein, we firstly investigated the protein expression of NAD kinase (NADK), as the rate-limiting enzyme converting NAD[+] to nicotinamide adenine dinucleotide phosphate (NADP[+]), and found it was positively correlated with APAP-induced ALI in a dose- and time-dependent manner. Additionally, supplementation of N-acetylcysteine (NAC), known as an antidote of APAP, mitigated the ALI and downregulated the expression of NADK which was also in a dose-dependent manner. Moreover, pretreatment with methotrexate (MTX), the inhibitor of NADK, attenuated the levels of transaminases, alleviated morphological abnormalities, and improved oxidative stress triggered by APAP overdose, which was attributed to elevated hepatic NAD[+] pool. Subsequently, the increased NAD[+] upregulated the expression of Sirt1, SOD2 and attenuated DNA damage. Collectively, elevated expression of NADK is related to APAP-induced ALI, and inhibition of NADK alleviates the ALI through elevating liver NAD[+] level and improving antioxidant capacity.}, } @article {pmid35502492, year = {2023}, author = {Gungor, H and Ekici, M and Ates, MB}, title = {Lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on acetaminophen-induced hepatotoxicity in mice.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {3}, pages = {566-574}, doi = {10.1080/01480545.2022.2069256}, pmid = {35502492}, issn = {1525-6014}, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; Antioxidants/pharmacology/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Interleukin-6 ; *Chemical and Drug Induced Liver Injury/etiology/prevention & control/metabolism ; Anti-Inflammatory Agents/pharmacology ; Liver ; Oxidative Stress ; Acetylcysteine/pharmacology ; Mice, Inbred C57BL ; Lipids ; }, abstract = {Isorhamnetin is a hepatoprotective flavonoid molecule derived from the leaves and fruits of Hippophae rhamnoides L. However, the protective effect of isorhamnetin on acetaminophen (APAP) induced hepatotoxicity is still unknown. Thus, we aimed to investigate the lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on APAP-induced hepatotoxicity in mice. Hepatotoxicity was induced by a single injection of APAP (300 mg/kg, intraperitoneally). Isorhamnetin (50 or 100 mg/kg, orally) and N-acetylcysteine (NAC) (200 mg/kg, orally), or vehicle control, were administered 1 h before the administration of APAP. Total antioxidant status (TAS) and total oxidative status (TOS) of liver tissue and levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were analyzed by ELISA. Lipid profiles and liver function parameters were measured using an autoanalyzer. In addition, liver tissue was examined histopathologically. Isorhamnetin treatment significantly reduced the APAP-induced increase in the liver weight and liver index; it also reduced the APAP-induced increase in serum liver parameters (ALT, AST, ALP, and LDH) (p < 0.05). Isorhamnetin significantly reduced APAP-induced oxidative stress and inflammation by increasing TAS levels and decreasing TOS, TNF-α, IL-1β, and IL-6 levels (p < 0.05). Moreover, isorhamnetin treatment significantly regulated lipid profiles (TG, T-C, LDL-C, and HDL-C levels) that changed in response to APAP administration (p < 0.05). In histopathological examination, liver degeneration observed in the APAP group was significantly reduced in the NAC and isorhamnetin-treated groups (p < 0.05). This study suggests that isorhamnetin has a significant protective effect on APAP-induced hepatotoxicity in mice through its lipid-lowering, antioxidant, and anti-inflammatory effects.}, } @article {pmid35499714, year = {2022}, author = {Singh, S and Maurya, P and Rani, S and Mishra, N and Nisha, R and Singh, P and Saraf, SA}, title = {Development of doxorubicin hydrochloride-loaded whey protein nanoparticles and its surface modification with N-acetyl cysteine for triple-negative breast cancer.}, journal = {Drug delivery and translational research}, volume = {12}, number = {12}, pages = {3047-3062}, pmid = {35499714}, issn = {2190-3948}, mesh = {Humans ; Mice ; Animals ; Doxorubicin/pharmacology ; *Triple Negative Breast Neoplasms/drug therapy/metabolism ; Whey Proteins/therapeutic use ; Acetylcysteine ; Cell Line, Tumor ; *Nanoparticles ; }, abstract = {Limited targeted therapies are available for triple-negative breast cancer (TNBC). Thus, the current research focused on developing a targeted protein nanoparticle for TNBC. First, the doxorubicin hydrochloride (Dox)-loaded genipin-crosslinked whey protein nanoparticles (WD) were prepared and optimised by the QbD method using BBD. The hydrodynamic diameter of WD was found to be 364.38 ± 49.23 nm, zeta potential -27.59 ± 1.038 mV, entrapment 63.03 ± 3.625% and Dox loading was found to be 1.419 ± 0.422%. The drug recovery after 18 months of storage was 69%. Then, it was incubated with NAC to obtain modified WD (CyWD). WD followed first-order release kinetics, whereas CyWD followed the Higuchi model. Hemagglutination and hemolysis were not found qualitatively in WD and CyWD. Upon injecting the nanoformulations to 4T1-induced mice, the highest efficacy was found to be in CyWD followed by WD and Dox injection. Upon histopathological observance, it was found that the CyWD group gave the most significant damage to the 4T1 tumour tissue. Thus, NAC-modified protein nanoparticles carrying chemotherapeutic agents can be an excellent targeted therapeutic system against TNBC.}, } @article {pmid35498128, year = {2022}, author = {Li, X and Yin, C and Hu, Q and Wang, J and Nie, H and Liu, B and Tai, Y and Fang, J and Du, J and Shao, X and Fang, J and Liu, B}, title = {Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8035109}, pmid = {35498128}, issn = {1942-0994}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology ; Antioxidants ; *Chronic Pain ; *Complex Regional Pain Syndromes ; *Electroacupuncture ; Inflammation ; *NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Rats, Sprague-Dawley ; }, abstract = {Complex regional pain syndrome type-I (CRPS-I) represents a type of neurovascular condition featured by severe pain in affected extremities. Few treatments have proven effective for CRPS-I. Electroacupuncture (EA) is an effective therapy for pain relief. We explored the mechanism through which EA ameliorates pain in a rat CRPS-I model. The chronic postischemic pain (CPIP) model was established using Sprague-Dawley rats to mimic CRPS-I. We found that oxidative stress-related biological process was among the predominant biological processes in affected hindpaw of CPIP rats. Oxidative stress occurred primarily in local hindpaw but not in the spinal cord or serum of model rats. Antioxidant N-acetyl cysteine (NAC) attenuated mechanical allodynia and spinal glia overactivation in CPIP model rats, whereas locally increasing oxidative stress is sufficient to induce chronic pain and spinal glia overactivation in naive rats. EA exerted remarkable antiallodynia on CPIP rats by reducing local oxidative stress via enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Pharmacological blocking Nrf2 abolished antioxidative and antiallodynic effects of EA. EA reduced spinal glia overactivation, attenuated the upregulation of inflammatory cytokines, reduced the enhanced TRPA1 channel activity in dorsal root ganglion neurons innervating the hindpaws, and improved blood flow dysfunction in hindpaws of CPIP rats, all of which were mimicked by NAC treatment. Thus, we identified local oxidative injury as an important contributor to pathogenesis of animal CRPS-I model. EA targets local oxidative injury by enhancing endogenous Nrf2-mediated antioxidative mechanism to relieve pain and inflammation. Our study indicates EA can be an alternative option for CRPS-I management.}, } @article {pmid35489181, year = {2022}, author = {Ezquer, F and Quintanilla, ME and Morales, P and Santapau, D and Munita, JM and Moya-Flores, F and Ezquer, M and Herrera-Marschitz, M and Israel, Y}, title = {A dual treatment blocks alcohol binge-drinking relapse: Microbiota as a new player.}, journal = {Drug and alcohol dependence}, volume = {236}, number = {}, pages = {109466}, doi = {10.1016/j.drugalcdep.2022.109466}, pmid = {35489181}, issn = {1879-0046}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Alcohol Drinking ; *Alcohol-Related Disorders ; *Alcoholism/drug therapy ; Animals ; Aspirin ; Chronic Disease ; Ethanol ; Humans ; Mice ; *Microbiota ; Rats ; Recurrence ; }, abstract = {RATIONALE: Gut microbiota communicates information to the brain. Some animals are born with a gut microbiota that predisposes to high alcohol consumption, and transplantation of fecal material from alcoholics to mice increases animal preference for ethanol. Alcohol-use-disorders are chronic conditions where relapse is the hallmark. A predictive animal model of relapse is the "alcohol deprivation effect" where ethanol re-access is allowed following chronic alcohol intake and a long alcohol deprivation. The present study evaluates the effect of gut microbiota modification on relapse, as an adjunct to N-acetylcysteine + Acetylsalicylic acid administration, which inhibits the alcohol-induced hyper-glutamatergic condition.

METHODS: Rats bred as heavy alcohol consumers (UChB) were allowed ethanol intake for one month, were deprived of alcohol for two-weeks and subsequently offered re-access to ethanol. Prior to ethanol re-access animals received orally either (i) vehicle-control, (ii) Lactobacillus-rhamnosus-GG after antibiotic treatment (LGG); (iii) N-acetylcysteine+Acetylsalicylic acid (NAC/ASA) or (iv) both treatments: LGG+ (NAC/ASA).

RESULTS: Marked binge drinking (1.75 g ethanol/kg in 60 min) and blood alcohol levels exceeding 80 mg/dl were observed in the control group upon ethanol-re-access. Lactobacillus-GG or (NAC+ASA) treatments inhibited alcohol intake by 66-80%. The combination of both treatments virtually suppressed (inhibition of 90%) the re-access binge-like drinking, showing additive effects. Treatment with NAC+ASA increased the levels of glutamate transporters xCT and GLT-1 in nucleus accumbens, while Lactobacillus-GG administration increased those of the dopamine transporter (DAT).

CONCLUSIONS: The administration of a well-accepted probiotic may be of value as an adjunct in the treatment of alcohol-use-disorders.}, } @article {pmid35487270, year = {2022}, author = {Hammerschmidt, TG and Donida, B and Faverzani, JL and Moura, AP and Dos Reis, BG and Machado, AZ and Kessler, RG and Sebastião, FM and Reinhardt, LS and Moura, DJ and Vargas, CR}, title = {Cytokine profile and cholesterol levels in patients with Niemann-Pick type C disease presenting neurological symptoms: in vivo effect of miglustat and in vitro effect of N-acetylcysteine and coenzyme Q10.}, journal = {Experimental cell research}, volume = {416}, number = {2}, pages = {113175}, doi = {10.1016/j.yexcr.2022.113175}, pmid = {35487270}, issn = {1090-2422}, mesh = {1-Deoxynojirimycin/analogs & derivatives ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cholesterol ; Cytokines ; Enzyme Inhibitors/pharmacology/therapeutic use ; Humans ; Inflammation/drug therapy ; *Niemann-Pick Disease, Type C/drug therapy ; Ubiquinone/analogs & derivatives ; }, abstract = {Niemann Pick type C is an inborn error of metabolism (IEM), classified as a lysosomal storage disease (LSD) caused by a dysfunction in NPC transport protein, that leads to intracellular accumulation of non-esterified cholesterol and other lipids. Clinical manifestations are ample, with visceral and neurological symptoms. Miglustat, a molecule that reversibly inhibits glucosylceramide synthase is used as treatment for this disorder. Studies demonstrated the influence of oxidative stress and inflammation in IEM, as well in animal model of NP-C disease. Nonetheless, literature lacks data on patients, so our work aimed to investigate if there is influence of chronic inflammation in the pathophysiology of NP-C disease, and the effect of miglustat, N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). We evaluated the plasmatic cytokines in NPC patients at diagnosis and during the treatment with miglustat. Additionally, we performed an in vitro study with antioxidants NAC (1 mM and 2.5 mM) and CoQ10 (5 μM and 10 μM), where we could verify its effect on inflammatory parameters, as well as in cholesterol accumulation. Our results showed that NP-C patients have higher plasmatic levels of pro and anti-inflammatory cytokines (IL-6, IL-8, and IL-10) at diagnosis and the treatment with miglustat was able to restore it. In vitro study showed that treatment with antioxidants in higher concentrations significantly decrease cholesterol accumulation, and NAC at 2.5 mM normalized the level of pro-inflammatory cytokines. Although the mechanism is not completely clear, it can be related to restoration in lipid traffic and decrease in oxidative stress caused by antioxidants.}, } @article {pmid35478127, year = {2022}, author = {Sun, HN and Xie, DP and Ren, CX and Guo, XY and Zhang, HN and Xiao, WQ and Han, YH and Cui, YD and Kwon, T}, title = {Ethyl β-Carboline-3-Carboxylate Increases Cervical Cancer Cell Apoptosis Through ROS-p38 MAPK Signaling Pathway.}, journal = {In vivo (Athens, Greece)}, volume = {36}, number = {3}, pages = {1178-1187}, pmid = {35478127}, issn = {1791-7549}, mesh = {Apoptosis ; Carbolines/pharmacology ; Female ; Humans ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; *Uterine Cervical Neoplasms/drug therapy ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {BACKGROUND/AIM: Ethyl β-carboline-3-carboxylate (β-CCE) is one of the effective ingredients of Picrasma quassioides (P. quassioides). As a β-carboline alkaloid, it can antagonize the pharmacological effects of benzodiazepines by regulating neurotransmitter secretion through receptors, thus affecting anxiety and physiology. However, its efficacy in cancer treatment is still unclear.

MATERIALS AND METHODS: We explored the effect of b-CCE on SiHa cells using MTT assay, western blot, flow cytometry, LDH release, T-AOC, SOD, and MDA assays.

RESULTS: We investigated the cytotoxicity of β-CCE in SiHa cells and verified that β-CCE could induce cell apoptosis in a time- and concentration-dependent manner. In this process, treatment with β-CCE significantly increased the levels of cytoplasmic and mitochondrial reactive oxygen species (ROS), which disturb the oxidation homeostasis by regulating the total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) production. Notably, the addition of N-acetylcysteine (NAC) (ROS scavenger) effectively alleviated β-CCE-induced apoptosis in SiHa cells. In addition, β-CCE might activate the p38/MAPK signaling pathway, as the pre-treatment with SB203580 (p38 inhibitor) significantly reduced β-CCE-induced apoptosis in SiHa cells.

CONCLUSION: β-CCE has an anti-tumor activity. It activates the p38/MAPK signaling pathway by increasing intracellular ROS levels, which subsequently induce SiHa cell apoptosis. Our results provide a novel therapeutic target for treatment of cervical cancer.}, } @article {pmid35475860, year = {2022}, author = {}, title = {The Potential Role of Efficacy and Safety Evaluation of N-Acetylcysteine Administration During Liver Procurement. The NAC-400 Single Center Randomized Controlled Trial: Erratum.}, journal = {Transplantation}, volume = {106}, number = {5}, pages = {e287}, doi = {10.1097/TP.0000000000004154}, pmid = {35475860}, issn = {1534-6080}, } @article {pmid35473933, year = {2022}, author = {Liu, C and Shen, Y and Huang, L and Wang, J}, title = {TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {232}, pmid = {35473933}, issn = {2058-7716}, support = {81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070709//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81270826//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070708//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070708//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070708//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Acute kidney injury (AKI) is characterized by necroinflammation formed by necrotic tubular epithelial cells (TECs) and interstitial inflammation. In necroinflammation, macrophages are key inflammatory cells and can be activated and polarized into proinflammatory macrophages. Membranous Toll-like receptors (TLRs) can cooperate with intracellular NOD-like receptor protein 3 (NLRP3) to recognize danger signals from necrotic TECs and activate proinflammatory macrophages by assembling NLRP3 inflammasome. However, the cooperation between TLRs and NLRP3 is still unclear. Using conditioned medium from necrotic TECs, we confirmed that necrotic TECs could release danger signals to activate NLRP3 inflammasome in macrophages. We further identified that necrotic TECs-induced NLRP3 inflammasome activation was dependent on ATP secretion via Pannexin-1 (Panx1) channel in macrophages. Next, we verified that TLR2 was required for the activation of Panx1 and NLRP3 in macrophages. Mechanistically, we indicated that caspase-5 mediated TLR2-induced Panx1 activation. In addition, we showed that necrotic TECs-induced activation of TLR2/caspase-5/Panx1 axis could be decreased in macrophages when TECs was protected by N-acetylcysteine (NAC). Overall, we demonstrate that danger signals from necrotic TECs could activate NLRP3 inflammasome in macrophages via TLR2/caspase-5/Panx1 axis during AKI.}, } @article {pmid35473809, year = {2022}, author = {Wang, Y and Kong, Y and Zhao, HY and Zhang, YY and Wang, YZ and Xu, LP and Zhang, XH and Liu, KY and Huang, XJ}, title = {Prophylactic NAC promoted hematopoietic reconstitution by improving endothelial cells after haploidentical HSCT: a phase 3, open-label randomized trial.}, journal = {BMC medicine}, volume = {20}, number = {1}, pages = {140}, pmid = {35473809}, issn = {1741-7015}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Endothelial Cells ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Thrombocytopenia/etiology ; }, abstract = {BACKGROUND: Poor graft function (PGF) or prolonged isolated thrombocytopenia (PT), which are characterized by pancytopenia or thrombocytopenia, have become serious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous single-arm trial suggests that N-acetyl-L-cysteine (NAC) prophylaxis reduced PGF or PT after allo-HSCT. Therefore, an open-label, randomized, phase 3 trial was performed to investigate the efficacy and tolerability of NAC prophylaxis to reduce PGF or PT after allo-HSCT.

METHODS: A phase 3, open-label randomized trial was performed. Based on the percentage of CD34[+]VEGFR2 (CD309)[+] endothelial cells (ECs) in bone marrow (BM) detected by flow cytometry at 14 days before conditioning, patients aged 15 to 60 years with acute leukemia undergoing haploidentical HSCT were categorized as low-risk (EC ≥ 0.1%) or high-risk (EC < 0.1%); patients at high risk were randomly assigned (2:1) to receive NAC prophylaxis or nonprophylaxis. The primary endpoint was PGF and PT incidence at +60 days post-HSCT.

RESULTS: Between April 18, 2019, and June 24, 2021, 120 patients with BM EC <0.1% were randomly assigned for NAC (group A, N = 80) or nonprophylaxis (group B, N = 40), and 105 patients with EC≥0.1% (group C) were also analyzed. The +60 days incidence of PGF and PT was 7.5% (95% CI, 1.7 to 13.3%) and 22.5% (95% CI, 9.1 to 35.9%) in group A and group B (hazard ratio, 0.317; 95% CI, 0.113 to 0.890; P = 0.021) and 11.4% (95% CI, 5.2 to 17.6%) in group C (hazard ratio, 0.643; 95% CI, 0.242 to 1.715; P = 0.373). Consistently, NAC prophylaxis gradually improved BM ECs and CD34[+] cells in group A, whereas reduced their reactive oxygen species (ROS) levels post-HSCT. Within 60 days post-HSCT, the most common grade 3 to 5 adverse events for the NAC and control groups were infections (19/80 [24%] vs. 10/40 [25%]) and gastrointestinal adverse events (16/80 [20%] vs. 7/40 [18%]). There were no treatment-related deaths.

CONCLUSIONS: N-Acetyl-L-cysteine prophylaxis can prevent the occurrence of poor hematopoietic function and is well tolerated in haploidentical HSCT. It may offer a potential pathogenesis-oriented therapeutic approach for patients with poor hematopoietic function.

TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov as #NCT03967665.}, } @article {pmid35470759, year = {2022}, author = {Gan, X and Zhao, J and Chen, Y and Li, Y and Xuan, B and Gu, M and Feng, F and Yang, Y and Yang, D and Sun, X}, title = {Plin5 inhibits proliferation and migration of vascular smooth muscle cell through interacting with PGC-1α following vascular injury.}, journal = {Bioengineered}, volume = {13}, number = {4}, pages = {10665-10678}, pmid = {35470759}, issn = {2165-5987}, mesh = {Animals ; Becaplermin ; Cell Movement/genetics ; Cell Proliferation ; Cells, Cultured ; Hyperplasia/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Muscle, Smooth, Vascular/pathology ; *Neointima/genetics/metabolism/pathology ; Perilipin-5/metabolism ; Reactive Oxygen Species/metabolism ; Transcription Factors/*metabolism ; *Vascular System Injuries/genetics/metabolism/pathology ; }, abstract = {Abnormal proliferation and migration of vascular smooth muscle cell (VSMC) is a hallmark of vascular neointima hyperplasia. Perilipin 5 (Plin5), a regulator of lipid metabolism, is also confirmed to be involved in vascular disorders, such as microvascular endothelial dysfunction and atherosclerosis. To investigate the regulation and function of plin5 in the phenotypic alteration of VSMC, -an animal model of vascular intima hyperplasia was established in C57BL/6 J and Plin5 knockdown (Plin5[±]) mice by wire injure. Immunohistochemical staining was used to analyze neointima hyperplasia in artery. Ki-67, dihydroethidium immunofluorescence staining and wound healing assay were used to measure proliferation, reactive oxygen species (ROS) generation and migration of VSMC, respectively. Plin5 was downregulated in artery subjected to vascular injury and in VSMC subjected to platelet-derived growth factor (PDGF)-BB. Plin5 knockdown led to accelerated neointima hyperplasia, excessive proliferation and migration of VSMC after injury. In vitro, we observed increased ROS content in VSMC isolated from Plin5[±] mice. Antioxidative N-acetylcysteine (NAC) inhibited VSMC proliferation and migration induced by PDGF-BB or plin5 knockdown. More importantly, plin5-peroxlsome proliferator-activated receptor-γ coactivator (PGC)-1α interaction was also attenuated in VSMC after knockdown of plin5. Overexpression of PGC-1α suppressed PDGF-BB-induced ROS generation, proliferation, and migration in VSMC isolated from Plin5[±] mice. These data suggest that plin5 serves as a potent regulator of VSMC proliferation, migration, and neointima hyperplasia by interacting with PGC-1α and affecting ROS generation.}, } @article {pmid35466412, year = {2022}, author = {Xie, Y and Zhu, X and Liu, P and Liu, Y and Geng, Y and Zhang, L}, title = {Xanthatin inhibits non-small cell lung cancer proliferation by breaking the redox balance.}, journal = {Drug development research}, volume = {83}, number = {5}, pages = {1176-1189}, doi = {10.1002/ddr.21941}, pmid = {35466412}, issn = {1098-2299}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Apoptosis ; *Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Furans ; Humans ; *Lung Neoplasms/drug therapy/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {Lung cancer is the cancer with the highest mortality, and non-small cell lung cancer (NSCLC) accounts for more than 80%. Tumor cells often have high reactive oxygen species (ROS) and antioxidant capacity. Redox balance is very important for tumor. The decline of antioxidant capacity and excessive ROS will induce the death of tumor cells. Destroying the redox balance of tumor cells is a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. We observed that xanthatin induced the up regulation of mitochondrial ROS and mitochondrial damage. Meanwhile, our results showed that xanthatin could inhibit system xc [-] and reduce glutathione (GSH) synthesis. Antioxidant GSH and N-acetyl- l-cysteine (NAC) significantly reversed cell proliferation inhibition and apoptosis induced by xanthatin. β-Mercaptoethanol (β-ME) which can avoid inhibition of system xc [-] can also reverse the inhibition of cell proliferation induced by xanthatin, si-SLC7A11 was the opposite. Based on these results, we believe that the inhibition of xanthatin on the proliferation of NSCLC cells may be related to breaking the intracellular redox balance. Our data suggest that xanthatin is a promising antitumor candidate for the treatment of NSCLC.}, } @article {pmid35466101, year = {2022}, author = {Russell, SE and Wrobel, AL and Dean, OM and Berk, M and Dodd, S and Ng, CH and Malhi, GS and Cotton, SM and Sarris, J and Turner, A}, title = {Mixed Methods Thematic Analysis of a Randomised Controlled Trial of Adjunctive Mitochondrial Agents for Bipolar Depression.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {20}, number = {2}, pages = {300-310}, pmid = {35466101}, issn = {1738-1088}, abstract = {OBJECTIVE: There is often a shortfall in recovery following treatment for an episode of bipolar disorder (BD). Exploration of participant's experience provides vital information to enhance statistical outcomes for novel therapy trials. This study used mixed-methods to explore participants' experience of a trial testing N -acetyl cysteine (NAC) and mitochondrially active nutraceuticals for BD depression.

CASE: report forms from a randomised controlled trial (RCT) of BD depression (n = 148) were analysed using a pragmatic adaption of grounded theory and thematic analysis.

RESULTS: Thematic analysis of 148 study participants indicated numerous changes in participant experience over time. For example, perceived environmental stressors reported by participants decreased over the trial in both treatment groups. Quantitative analysis of the themes revealed more positive theme reports in the combination treatment arm compared to the placebo arm and there were more negative themes identified in the placebo arm, compared to the NAC arm.

CONCLUSION: This approach revealed additional results not elucidated in the primary quantitative analysis. This emphasises the value of mixed-methods research in capturing participants' experiences in RCTs and detecting possible latent benefits and risks. Such methods can detect latent target signals in novel therapy trials conducted in BD and generate novel hypotheses.}, } @article {pmid35461321, year = {2022}, author = {Sempere, J and Llamosí, M and Román, F and Lago, D and González-Camacho, F and Pérez-García, C and Yuste, J and Domenech, M}, title = {Clearance of mixed biofilms of Streptococcus pneumoniae and methicillin-susceptible/resistant Staphylococcus aureus by antioxidants N-acetyl-L-cysteine and cysteamine.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {6668}, pmid = {35461321}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/pharmacology ; Antioxidants/pharmacology ; Biofilms ; Cysteamine/pharmacology ; Methicillin/pharmacology ; *Methicillin-Resistant Staphylococcus aureus ; Microbial Sensitivity Tests ; Staphylococcus aureus ; Streptococcus pneumoniae ; }, abstract = {Biofilm-associated infections are of great concern because they are associated with antibiotic resistance and immune evasion. Co-colonization by Staphylococcus aureus and Streptococcus pneumoniae is possible and a threat in clinical practice. We investigated the interaction between S. aureus and S. pneumoniae in mixed biofilms and tested new antibiofilm therapies with antioxidants N-acetyl-L-cysteine (NAC) and cysteamine (Cys). We developed two in vitro S. aureus-S. pneumoniae mixed biofilms in 96-well polystyrene microtiter plates and we treated in vitro biofilms with Cys and NAC analyzing their effect by CV staining and viable plate counting. S. pneumoniae needed a higher proportion of cells in the inoculum and planktonic culture to reach a similar population rate in the mixed biofilm. We demonstrated the effect of Cys in preventing S. aureus biofilms and S. aureus-S. pneumoniae mixed biofilms. Moreover, administration of 5 mg/ml of NAC nearly eradicated the S. pneumoniae population and killed nearly 94% of MSSA cells and 99% of MRSA cells in the mixed biofilms. The methicillin resistance background did not change the antioxidants effect in S. aureus. These results identify NAC and Cys as promising repurposed drug candidates for the prevention and treatment of mixed biofilms by S. pneumoniae and S. aureus.}, } @article {pmid35458581, year = {2022}, author = {Rotondo, R and Ragucci, S and Castaldo, S and Landi, N and Oliva, MA and Pedone, PV and Di Maro, A and Arcella, A}, title = {Ageritin-The Ribotoxin-like Protein from Poplar Mushroom (Cyclocybe aegerita) Sensitizes Primary Glioblastoma Cells to Conventional Temozolomide Chemotherapy.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {8}, pages = {}, pmid = {35458581}, issn = {1420-3049}, support = {//v:ALERE(VAnviteLli pEr la RicErca)program./ ; //Italian Ministry of Health with Ricerca Corrente/ ; }, mesh = {*Agaricales ; Antineoplastic Agents, Alkylating ; Cell Line, Tumor ; DNA Modification Methylases ; Drug Resistance, Neoplasm ; *Glioblastoma/drug therapy ; Humans ; Ribonucleases ; Temozolomide/pharmacology ; *Toxins, Biological ; }, abstract = {Here, we propose Ageritin, the prototype of the ribotoxin-like protein family, as an adjuvant treatment to control the growth of NULU and ZAR, two primary human glioblastoma cell lines, which exhibit a pharmacoresistance phenotype. Ageritin is able to inhibit NULU and ZAR growth with an IC50 of 0.53 ± 0.29 µM and 0.42 ± 0.49 µM, respectively. In this study, Ageritin treatment highlighted a macroscopic genotoxic response through the formation of micronuclei, which represents the morphological manifestation of genomic chaos induced by this toxin. DNA damage was not associated with either the deregulation of DNA repair enzymes (i.e., ATM and DNA-PK), as demonstrated by quantitative PCR, or reactive oxygen species. Indeed, the pretreatment of the most responsive cell line ZAR with the ROS scavenger N-acetylcysteine (NAC) did not follow the reverse cytotoxic effect of Ageritin, suggesting that this protein is not involved in cellular oxidative stress. Vice versa, Ageritin pretreatment strongly enhanced the sensitivity to temozolomide (TMZ) and inhibited MGMT protein expression, restoring the sensitivity to temozolomide. Overall, Ageritin could be considered as a possible innovative glioblastoma treatment, directly damaging DNA and downregulating the MGMT DNA repair protein. Finally, we verified the proteolysis susceptibility of Ageritin using an in vitro digestion system, and considered the future perspective use of this toxin as a bioconjugate in biomedicine.}, } @article {pmid35455407, year = {2022}, author = {Muduli, S and Golan-Goldhirsh, A and Gopas, J and Danilenko, M}, title = {Cytotoxicity of Thioalkaloid-Enriched Nuphar lutea Extract and Purified 6,6'-Dihydroxythiobinupharidine in Acute Myeloid Leukemia Cells: The Role of Oxidative Stress and Intracellular Calcium.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, pmid = {35455407}, issn = {1424-8247}, support = {226/16//Israel Science Foundation/ ; 3-0-7374//Israel Ministry of Health/ ; }, abstract = {Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid progenitors. Here, we report the in vitro antileukemic effects of the sesquiterpene thioalkaloid-enriched fraction of the Nuphar lutea leaf extract (NUP) and a purified thioalkaloid 6,6'-dihydroxythiobinupharidine (DTBN). Treatment with 0.3-10 µg/mL NUP caused a dose- and time-dependent reduction in proliferation and viability of human AML cells (KG-1a, HL60 and U937). This was associated with apoptosis induction manifested by annexin-V/propidium iodide binding as well as cleavage of caspases 8, 9, and 3 as well as poly (ADP-ribose) polymerase. Caspase-dependence of the apoptotic effect was confirmed using the pan-caspase inhibitor Q-VD-OPH. NUP induced significant biphasic changes in the cytosolic levels of reactive oxygen species (ROS) compared to untreated cells-a decrease at early time points (2-4 h) and an increase after a longer incubation (24 h). ROS accumulation was accompanied by lowering the cellular glutathione (GSH) levels. In addition, NUP treatment resulted in elevation of the cytosolic Ca[2+] (Ca[2+]cyt) levels. The thiol antioxidant and glutathione precursor N-acetyl cysteine prevented NUP-induced ROS accumulation and markedly inhibited apoptosis. A similar antiapoptotic effect was obtained by Ca[2+]cyt chelating using BAPTA. These data indicate that NUP-induced cell death is mediated, at least in part, by the induction of oxidative stress and Ca[2+]cyt accumulation. However, a substantial apoptotic activity of pure DTBN (0.05-0.25 µg/mL), was found to be independent of cytosolic ROS or Ca[2+], suggesting that alternative mechanisms are involved in DTBN-induced cytotoxicity. Notably, neither NUP nor DTBN treatment significantly induced cell death of normal human peripheral blood mononuclear cells. Our results provide the basis for further investigation of the antileukemic potential of NUP and its active constituents.}, } @article {pmid35453441, year = {2022}, author = {Kim, JE and Lee, DS and Kim, TH and Kang, TC}, title = {Glutathione Regulates GPx1 Expression during CA1 Neuronal Death and Clasmatodendrosis in the Rat Hippocampus following Status Epilepticus.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {4}, pages = {}, pmid = {35453441}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482 and 2021R1A2C4002003//National Research Foundation of Korea (NRF)/ ; }, abstract = {Glutathione peroxidase-1 (GPx1) catalyze the reduction of H2O2 by using glutathione (GSH) as a cofactor. However, the profiles of altered GPx1 expression in response to status epilepticus (SE) have not been fully explored. In the present study, GPx1 expression was transiently decreased in dentate granule cells, while it was temporarily enhanced and subsequently reduced in CA1 neurons following SE. GPx1 expression was also transiently declined in CA1 astrocytes (within the stratum radiatum) following SE. However, it was elevated in reactive CA1 astrocytes, but not in clasmatodendritic CA1 astrocytes, in chronic epilepsy rats. Under physiological condition, L-buthionine sulfoximine (BSO, an inducer of GSH depletion) increased GPx1 expression in CA1 neurons but decreased it in CA1 astrocytes. However, N-acetylcysteine (NAC, an inducer of GSH synthesis) did not influence GPx1 expression in these cell populations. Following SE, BSO aggravated CA1 neuronal death, concomitant with reduced GPx1 expression. Further. BSO also lowered GPx1 expression in CA1 astrocytes. NAC effectively prevented neuronal death and GPx1 downregulation in CA1 neurons, and restored GPx1 expression to the control level in CA1 astrocytes. In chronic epilepsy rats, BSO reduced GPx1 intensity and exacerbated clasmatodendritic degeneration in CA1 astrocytes. In contrast, NAC restored GPx1 expression in clasmatodendritic astrocytes and ameliorated this autophagic astroglial death. To the best of our knowledge, our findings report, for the first time, the spatiotemporal profiles of altered GPx1 expression in the rat hippocampus following SE, and suggest GSH-mediated GPx1 regulation, which may affect SE-induced neuronal death and autophagic astroglial degeneration.}, } @article {pmid35450505, year = {2023}, author = {Angelovski, M and Hadzi-Petrushev, N and Mitrokhin, V and Kamkin, A and Mladenov, M}, title = {Myocardial infarction and oxidative damage in animal models: objective and expectations from the application of cysteine derivatives.}, journal = {Toxicology mechanisms and methods}, volume = {33}, number = {1}, pages = {1-17}, doi = {10.1080/15376516.2022.2069530}, pmid = {35450505}, issn = {1537-6524}, mesh = {Animals ; *Antioxidants/pharmacology/metabolism ; Motivation ; Oxidative Stress ; *Myocardial Infarction/drug therapy/prevention & control ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; }, abstract = {Reactive oxygen species (ROS) and associated oxidative stress are the main contributors to pathophysiological changes following myocardial infarction (MI), which is the principal cause of death from cardiovascular disease. The glutathione (GSH)/glutathione peroxidase (GPx) system appears to be the main and most active cardiac antioxidant mechanism. Hence, enhancement of the myocardial GSH system might have protective effects in the setting of MI. It follows that by increasing antioxidant capacity, the heart will be able to reduce the damage associated with MI and even prevent/weaken the occurrence of oxidative stress, which is highly ranked among the factors responsible for the occurrence of acute MI. For these reasons, the primary goal of future investigations should be to address the effects of different antioxidative compounds and especially cysteine derivatives like N-acetyl cysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid (OTC) as precursors responsible for the enhancement of the GSH-related antioxidant system's capacity. It is assumed that this will lay down the basis for elucidation of the mechanisms throughout which applicable doses of OTC will manifest a potentially positive impact in the reduction of adverse effects of acute MI. The inclusion of OTC in the models for prediction of the distribution of oxygen in infarcted animal hearts can help to upgrade existing computational models. Such a model would be based on computational geometries of the heart, but the inclusion of biochemical redox features in addition to angiogenic therapy, despite improvement of the post-infarcted oxygenated outcome could enhance the accuracy of the predictive values of oxygenation.}, } @article {pmid35449013, year = {2022}, author = {Ju, S and Lim, L and Ki, YJ and Choi, DH and Song, H}, title = {Oxidative stress generated by polycyclic aromatic hydrocarbons from ambient particulate matter enhance vascular smooth muscle cell migration through MMP upregulation and actin reorganization.}, journal = {Particle and fibre toxicology}, volume = {19}, number = {1}, pages = {29}, pmid = {35449013}, issn = {1743-8977}, mesh = {Actins ; *Air Pollutants/analysis ; *Atherosclerosis ; Cell Movement ; Humans ; Matrix Metalloproteinases ; Muscle, Smooth, Vascular/chemistry ; Oxidative Stress ; Particulate Matter/analysis/toxicity ; *Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; Up-Regulation ; }, abstract = {BACKGROUND: Epidemiological studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with the incidence of atherosclerosis, however, the underlying cellular and molecular mechanisms of atherosclerosis by PM exposure and the components that are mainly responsible for this adverse effect remain to be established. In this investigation, we evaluated the effects of ambient PM on vascular smooth muscle cell (VSMC) behavior. Furthermore, the effects of polycyclic aromatic hydrocarbons (PAHs), major components of PM, on VSMC migration and the underlying mechanisms were examined.

RESULTS: VSMC migration was significantly increased by treatment with organic matters extracted from ambient PM. The total amount of PAHs contained in WPM was higher than that in SPM, leading to higher ROS generation and VSMC migration. The increased migration was successfully inhibited by treatment with the anti-oxidant, N-acetyl-cysteine (NAC). The levels of matrix metalloproteinase (MMP) 2 and 9 were significantly increased in ambient PM-treated VSMCs, with MMP9 levels being significantly higher in WPM-treated VSMCs than in those treated with SPM. As expected, migration was significantly increased in all tested PAHs (anthracene, ANT; benz(a)anthracene, BaA) and their oxygenated derivatives (9,10-Anthraquinone, AQ; 7,12-benz(a)anthraquinone, BAQ, respectively). The phosphorylated levels of focal adhesion kinase (FAK) and formation of the focal adhesion complex were significantly increased in ambient PM or PAH-treated VSMCs, and these effects were blocked by administration of NAC or α-NF, an inhibitor of AhR, the receptor that allows PAH uptake. Subsequently, the levels of phosphorylated Src and NRF, the downstream targets of FAK, were altered with a pattern similar to that of p-FAK.

CONCLUSIONS: PAHs, including oxy-PAHs, in ambient PM may have dual effects that lead to an increase in VSMC migration. One is the generation of oxidative stress followed by MMP upregulation, and the other is actin reorganization that results from the activation of the focal adhesion complex.}, } @article {pmid35442462, year = {2022}, author = {Žuža, O and Minić, R and Kotur-Stevuljević, J and Žujović, D and Đorđević, B and Ilić, A}, title = {A combination of N-acetyl cysteine and propolis attenuates oxidative-inflammatory parameters during COPD exacerbation.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {7}, pages = {2467-2477}, doi = {10.26355/eurrev_202204_28481}, pmid = {35442462}, issn = {2284-0729}, mesh = {Acetylcysteine/therapeutic use ; Antioxidants/metabolism/therapeutic use ; Aryldialkylphosphatase/metabolism ; Biomarkers/metabolism ; Humans ; Oxidation-Reduction ; Oxidative Stress ; *Propolis/metabolism/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; Serum Albumin/metabolism ; }, abstract = {OBJECTIVE: The aim of this study was to determine any differences in oxidative stress and inflammation parameters in COPD patients treated with either N-acetyl cysteine (NAC) alone or with NAC in combination with propolis (NACP).

PATIENTS AND METHODS: Forty COPD patients in the exacerbation phase were enrolled into the study and were treated with either NAC (NAC group; n=20) or NACP (NACP group; n=20) twice daily for one month. Redox status was determined by measuring superoxide anion (O2.-), advanced oxidation protein products (AOPP), total oxidative status (TOS), prooxidative-antioxidant balance (PAB), malondialdehyde (MDA), ischemia modified albumin (IMA) and several other antioxidant markers: superoxide dismutase (SOD), paraoxonase 1 (PON1), total sulfhydryl groups (SHG) and total antioxidant status (TAS). Interleukins 6, 8 and 17 were measured as markers of inflammatory status.

RESULTS: Both groups had similar socio-demographic and clinical characteristics. After treatment significantly higher SHG [0.446 (0.395-0.516) vs. 0.292 (0.270-0.325), p<0.001] and significantly lower TOS - 50.6 [49.7-53.4 vs. 73.2 (50.9-84.6), p<0.05] - and IMA [0.650 (0.629-0.682) vs. 0.709 (0.667-0.756), p<0.05] - were found in the NACP group compared to the NAC group. Factorial analysis indicated a larger oxidative stress-inflammatory load in the NAC group after treatment.

CONCLUSIONS: From an oxidative stress and inflammatory status perspective, treatment with NACP was more successful than with NAC. The inclusion of propolis into therapy for COPD patients, especially those in the exacerbation phase, could prove beneficial.}, } @article {pmid35442037, year = {2022}, author = {Li, J and Shi, J and Jia, C and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Propafenone Mediated by CYP2D6.}, journal = {Chemical research in toxicology}, volume = {35}, number = {5}, pages = {829-839}, doi = {10.1021/acs.chemrestox.2c00013}, pmid = {35442037}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; *Chemical and Drug Induced Liver Injury/metabolism ; *Cytochrome P-450 CYP2D6/metabolism ; Glutathione/metabolism ; Microsomes, Liver/metabolism ; Propafenone/metabolism/pharmacology ; Quinones/metabolism ; Rats ; }, abstract = {Propafenone (PPF) is a class IC antidysrhythmic drug, which is commonly used for the treatment of atrial fibrillation and other supraventricular arrhythmias. It is also a β-adrenoceptor antagonist that can cause bradycardia and bronchospasm. Hepatotoxicity is one of the adverse reactions reported, with clinical manifestations including acute cholestasis and hepatocyte necrosis. However, the mechanism of PPF-induced hepatotoxicity remains unclear. The present study was conducted to identify reactive metabolite(s) to determine related metabolic pathways and define the possible association of the bioactivation with PPF cytotoxicity. An O-demethylation phase I metabolite (M1), a further position C5 hydroxylation (para-position of the benzene ring) metabolite (M2), glutathione (GSH) conjugates (M3 and M4), and N-acetylcysteine (NAC) conjugates (M5 and M6) were detected in rat liver microsomal incubations containing PPF and GSH or NAC as trapping agents. The corresponding GSH conjugates and NAC conjugates were found in the bile and urine of rats after PPF administration, respectively. The observed GSH and NAC conjugates indicate that a quinone metabolite was generated in vitro and in vivo. Recombinant P450 enzyme incubations showed that CYP2D6 was the principal enzyme catalyzing this metabolic activation. Quinidine, a selective inhibitor of CYP2D6, attenuated the susceptibility of hepatocytes to the cytotoxicity of PPF. The results suggest that PPF was metabolized to a p-quinone intermediate which may be involved in PPF-induced hepatotoxicity.}, } @article {pmid35439594, year = {2022}, author = {Wu, X and Ciminieri, C and Bos, IST and Woest, ME and D'Ambrosi, A and Wardenaar, R and Spierings, DCJ and Königshoff, M and Schmidt, M and Kistemaker, LEM and Gosens, R}, title = {Diesel exhaust particles distort lung epithelial progenitors and their fibroblast niche.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {305}, number = {}, pages = {119292}, pmid = {35439594}, issn = {1873-6424}, support = {R01 HL141380/HL/NHLBI NIH HHS/United States ; }, mesh = {Epithelial Cells ; Fibroblasts/pathology ; Humans ; Lung/metabolism ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Vehicle Emissions/toxicity ; *beta Catenin/metabolism ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by inflammation and impaired tissue regeneration, and is reported as the fourth leading cause of death worldwide by the Centers for Disease Control and Prevention (CDC). Environmental pollution and specifically motor vehicle emissions are known to play a role in the pathogenesis of COPD, but little is still known about the molecular mechanisms that are altered following diesel exhaust particles (DEP) exposure. Here we used lung organoids derived from co-culture of alveolar epithelial progenitors and fibroblasts to investigate the effect of DEP on the epithelial-mesenchymal signaling niche in the distal lung, which is essential for tissue repair. We found that DEP treatment impaired the number as well as the average diameter of both airway and alveolar type of lung organoids. Bulk RNA-sequencing of re-sorted epithelial cells and fibroblasts following organoid co-culture shows that the Nrf2 pathway, which regulates antioxidants' activity, was upregulated in both cell populations in response to DEP; and WNT/β-catenin signaling, which is essential to promote epithelial repair, was downregulated in DEP-exposed epithelial cells. We show that pharmacological treatment with anti-oxidant agents such as N-acetyl cysteine (NAC) or Mitoquinone mesylate (MitoQ) reversed the effect of DEP on organoids growth. Additionally, a WNT/β-catenin activator (CHIR99021) successfully restored WNT signaling and promoted organoid growth upon DEP exposure. We propose that targeting oxidative stress and specific signaling pathways affected by DEP in the distal lung may represent a strategy to restore tissue repair in COPD.}, } @article {pmid35434015, year = {2022}, author = {Chen, W and Teng, X and Ding, H and Xie, Z and Cheng, P and Liu, Z and Feng, T and Zhang, X and Huang, W and Geng, D}, title = {Nrf2 protects against cerebral ischemia-reperfusion injury by suppressing programmed necrosis and inflammatory signaling pathways.}, journal = {Annals of translational medicine}, volume = {10}, number = {6}, pages = {285}, pmid = {35434015}, issn = {2305-5839}, abstract = {BACKGROUND: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated neuroinflammation is linked to neuronal necroptosis in cerebral ischemia-reperfusion (I/R) injury, especially in cerebral ischemic penumbra. This study was designed to investigate the regulation of nuclear factor E2-related factor-2 (Nrf2) on NLRP3 inflammasome in necroptosis signal pathway induced by I/R injury.

METHODS: We investigated the mechanisms of Nrf2-negative regulation in necroptosis signaling pathway by using middle cerebral artery occlusion (MCAO) with Q-VD-OPH injected intraperitoneally. The protein level of the NLRP3 inflammasome was detected by western blot with Nrf2 knockdown and overexpression. NLRP3 inflammasome activation was Reactive oxygen species (ROS) dependent, and the protein level was regulated when N-acetylcysteine (NAC) and adenosine triphosphate (ATP) were selected as tools for regulating ROS.

RESULTS: We demonstrated the negative regulation of Nrf2 on NLRP3 inflammasome activation in Q-VD-OPH-induced necroptosis in cerebral artery I/R injury through Lentivirus-mediated RNA Interferenc, which mediated knockdown and overexpression of Nrf2. NLRP3 inflammasome activation was sensitive to both ATP-mediated ROS level increases and NAC-mediated ROS inhibition, suggesting that ROS is associated with the activation of NLRP3 inflammasome in necroptosis. In addition, Nrf2-induced NAD(P)H quinone dehydrogenase 1 (NQO1) was involved in the inhibition of NLRP3 inflammasome activation. These results suggest that Nrf2 regulates NQO1 to attenuate ROS, which negatively regulates NLRP3 inflammasome.

CONCLUSIONS: Nrf2/NQO1 was an inhibitor of ROS-induced NLRP3 inflammasome activation in Q-VD-OPH-induced necroptosis following cerebral I/R injury. Therefore, NLRP3 inflammasome could be a potential therapeutic target for cerebral ischemia.}, } @article {pmid35433335, year = {2022}, author = {Kapur, A and Sharma, M and Sageena, G}, title = {Therapeutic potential of N-acetyl cysteine during COVID-19 epoch.}, journal = {World journal of virology}, volume = {11}, number = {2}, pages = {104-106}, pmid = {35433335}, issn = {2220-3249}, abstract = {N-acetyl cysteine (NAC) is a promising drug for prophylaxis and treatment of coronavirus disease 2019 (COVID-19) based on antioxidant and anti-inflammatory mechanisms. Further studies with cautious approach are needed to establish the benefits and risks before considering NAC as an adjuvant treatment for COVID-19.}, } @article {pmid35430258, year = {2022}, author = {Barzegari, A and Omidi, Y and Landon, R and Gueguen, V and Parvizpour, S and Meddahi-Pellé, A and Anagnostou, F and Pavon-Djavid, G}, title = {The protective effect of N-acetylcysteine on antimycin A-induced respiratory chain deficiency in mesenchymal stem cells.}, journal = {Chemico-biological interactions}, volume = {360}, number = {}, pages = {109937}, doi = {10.1016/j.cbi.2022.109937}, pmid = {35430258}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Antimycin A/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Apoptosis ; Humans ; *Mesenchymal Stem Cells ; *Mitochondrial Diseases/metabolism ; Oxidative Stress ; }, abstract = {Transplantation of mesenchymal stem cells (MSCs) is an effective treatment in tissue injuries though it is limited due to the early death of stem cells within the first few days. The main reason could be a deficiency in the respiratory chain of injured tissues which is linked to the oxidative stress (OS) and disruption of energy metabolism. The disruption in energy metabolism and OS both inhibit the homing of stem cells in the hypoxic micro-environment, however on other hand, the key functions of stem cells are mainly regulated by their cellular redox status and energy metabolism. Because of that, strategies are being developed to improve the bio-functional properties of MSCs, including preconditioning of the stem cells in hypoxic conditions and pretreatment of antioxidants. To achieve this purpose, in this study N-acetylcysteine (NAC) was used for the protection of cells from oxidative stress and the disruption in energy metabolism was induced by Antimycin A (AMA) via blocking the cytochrome C complex. Then several parameters were analyzed, including cell viability/apoptosis, mitochondrial membrane potential, and redox molecular homeostasis. Based on our findings, upon the exposure of the MSCs to the conditions of deficient respiratory chain, the cells failed to scavenge the free radicals, and energy metabolism was disrupted. The use of NAC was found to alleviate the DNA damage, cell apoptosis, and oxidative stress via Nrf2/Sirt3 pathway though without any effect on the mitochondrial membrane potential. It means that antioxidants protect the cells from OS but the problem of ATP metabolism yet remains unresolved in the hypoxic conditions.}, } @article {pmid35429732, year = {2022}, author = {Berthou, M and Pallotta, A and Beurton, J and Chaigneau, T and Athanassiou, A and Marcic, C and Marchioni, E and Boudier, A and Clarot, I}, title = {Gold nanostructured membranes to concentrate low molecular weight thiols, a proof of concept study.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1198}, number = {}, pages = {123244}, doi = {10.1016/j.jchromb.2022.123244}, pmid = {35429732}, issn = {1873-376X}, mesh = {Acetylcysteine ; Animals ; Glutathione/metabolism ; Gold/chemistry ; *Metal Nanoparticles/chemistry ; Molecular Weight ; Oxidation-Reduction ; Proof of Concept Study ; Rats ; *Sulfhydryl Compounds/chemistry ; }, abstract = {Thiols are very important molecules in the biomedical field involved for example in redox homeostasis. Their detection and quantification remain difficult due to their poor stability (oxidation) linked to their strong reactivity towards other thiols (by the formation of S-S bonds) or other interfering molecules in the medium. Cellulose membranes with immobilized gold nanoparticles (AuNP) were developed to capture and quantify thiols in simple and complex matrices. This device was first optimized and characterized in terms of nanostructuration and thiol adsorption. N-Acetylcysteine (NAC) and reduced glutathione (GSH), chosen as model molecules, were filtered through the device demonstrating a maximal adsorption capacity of 270 and 60 nmol respectively. In a second step, the adsorbed species were subjected to ligand exchange using a more reactive thiol, dithiothreitol. The results showed release rates of approximately 90% for NAC and GSH. Finally, the amount of endogenous GSH in rat plasma was determined without any pretreatment. For the first time to our knowledge, a nanostructured device for the capture, selective and sensitive quantification of thiols is proposed. This device is easy to handle and overcomes matrix effects. Moreover, the very large concentration factor induced by this technology will be a valuable asset to decrease the quantification limits of analytical methods.}, } @article {pmid35428374, year = {2022}, author = {Erfani, R and Carmichael, C and Sofokleous, T and Wang, Q}, title = {Nanosecond-pulsed DBD plasma treatment on human leukaemia Jurkat cells and monoblastic U937 cells in vitro.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {6270}, pmid = {35428374}, issn = {2045-2322}, mesh = {Apoptosis ; Humans ; Jurkat Cells ; *Leukemia ; *Plasma Gases/pharmacology ; U937 Cells ; }, abstract = {Plasma therapy offers an exciting and novel way of cancer treatment. Specifically, it is shown that Jurkat death rates are closely governed by the plasma treatment time. However, apart from time, alterations to different parameters of treatment process may yield better results. Here, Dielectric barrier discharge (DBD) reactors excited by a nanosecond-pulse energy source are used to investigate cell viability for longer exposure times as well as the effects of polarity of reactor on treatment. Plasma discharge regimes are discussed and assessed using imaging and thermal imaging methods. We found that by changing the polarity of reactor i.e. changing the direction of plasma discharge, the plasma discharge regime changes influencing directly the effectiveness of treatment. Our results showed that ns-DBD- reactor could induce both apoptosis and necrosis of human Jurkat and U937 cells, and this cytotoxic effect of plasma was not completely antagonized by N-acetyl cysteine. It indicates that plasma could induce ROS-independent cell death. Gene expression analyses revealed that p53, BAD, BID and caspase 9 may play vital roles in plasma caused cell death. In addition, our findings demonstrate how different parameters can influence the effectiveness of our reactors. Our assay reveals the custom ability nature of plasma reactors for hematologic cancer therapy and our findings can be used for further development of such reactors using multi-objective optimisation techniques.}, } @article {pmid35425932, year = {2021}, author = {Lana, JFSD and Lana, AVSD and Rodrigues, QS and Santos, GS and Navani, R and Navani, A and da Fonseca, LF and Azzini, GOM and Setti, T and Mosaner, T and Simplicio, CL and Setti, TM}, title = {Nebulization of glutathione and N-Acetylcysteine as an adjuvant therapy for COVID-19 onset.}, journal = {Advances in redox research}, volume = {3}, number = {}, pages = {100015}, pmid = {35425932}, issn = {2667-1379}, abstract = {Ever since its emergence, the highly transmissible and debilitating coronavirus disease spread at an incredibly fast rate, causing global devastation in a matter of months. SARS-CoV-2, the novel coronavirus responsible for COVID-19, infects hosts after binding to ACE2 receptors present on cells from many structures pertaining to the respiratory, cardiac, hematological, neurological, renal and gastrointestinal systems. COVID-19, however, appears to trigger a severe cytokine storm syndrome in pulmonary structures, resulting in oxidative stress, exacerbated inflammation and alveolar injury. Due to the recent nature of this disease no treatments have shown complete efficacy and safety. More recently, however, researchers have begun to direct some attention towards GSH and NAC. These natural antioxidants play an essential role in several biological processes in the body, especially the maintenance of the redox equilibrium. In fact, many diseases appear to be strongly related to severe oxidative stress and deficiency of endogenous GSH. The high ratios of ROS over GSH, in particular, appear to reflect severity of symptoms and prolonged hospitalization of COVID-19 patients. This imbalance interferes with the body's ability to detoxify the cellular microenvironment, fold proteins, replenish antioxidant levels, maintain healthy immune responses and even modulate apoptotic events. Oral administration of GSH and NAC is convenient and safe, but they are susceptible to degradation in the digestive tract. Considering this drawback, nebulization of GSH and NAC as an adjuvant therapy may therefore be a viable alternative for the management of the early stages of COVID-19.}, } @article {pmid35422571, year = {2022}, author = {Ripani, U and Bisaccia, M and Meccariello, L}, title = {Dexamethasone and Nutraceutical Therapy Can Reduce the Myalgia Due to COVID-19 - a Systemic Review of the Active Substances that Can Reduce the Expression of Interlukin-6.}, journal = {Medical archives (Sarajevo, Bosnia and Herzegovina)}, volume = {76}, number = {1}, pages = {66-71}, pmid = {35422571}, issn = {1986-5961}, mesh = {Humans ; *COVID-19 Drug Treatment ; Dexamethasone/therapeutic use ; Dietary Supplements ; Inflammation ; Interleukin-6 ; Myalgia/etiology ; SARS-CoV-2 ; }, abstract = {BACKGROUND: Myalgia reflects generalized inflammation and cytokine response and can be the onset symptom of 36% of patients with COVID-19. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) levels in plasma and upper respiratory secretions directly correlate with the magnitude of viral replication, fever, and respiratory and systemic symptoms, including musculoskeletal clinical manifestations.

OBJECTIVE: The aim of our work is to report literature scientific investigation clinical protocol to reduce the immunomodulation and inflammatory response nutraceutical therapy associated with dexamethasone and how can reduce the expression of Interlukina-6(IL-6) and myalgia due to COVID-19.

METHODS: We searched in Pubmed and Cochrane the nautriceutical drugs to treat the immune modulation of organism to COVID-19. We put these keywords: immune inflammation, desease descriptions, epidemiology COVID-19; immunomodulations; IL-6; Rheumatic Symptoms; Joint; Musculoskeletal Disorders; dexamethasone; Polydatin; Zinc; Melatonin; N- Acetyl Cysteine; Colostrum; L- Glutamine; Vitamin D3.

RESULTS: We found 61 papers. All the authors analyze them. After the Analyze we suggest the use of response nutraceutical therapy associated with dexamethasone can reduce the expression of Interlukina-6(IL-6) and myalgia due to COVID-19.

CONCLUSION: According the scientific literature nutraceutical therapy associated with dexamethasone can reduce the expression of Interlukina-6(IL-6) and myalgia due to COVID-19.}, } @article {pmid35422124, year = {2022}, author = {Vind, K and Maffioli, S and Fernandez Ciruelos, B and Waschulin, V and Brunati, C and Simone, M and Sosio, M and Donadio, S}, title = {N-Acetyl-Cysteinylated Streptophenazines from Streptomyces.}, journal = {Journal of natural products}, volume = {85}, number = {5}, pages = {1239-1247}, pmid = {35422124}, issn = {1520-6025}, mesh = {Anti-Bacterial Agents/metabolism ; *Biological Products/metabolism ; Metabolomics ; Multigene Family ; *Streptomyces/genetics ; }, abstract = {Here, we describe two N-acetyl-cysteinylated streptophenazines (1 and 2) produced by the soil-derived Streptomyces sp. ID63040 and identified through a metabolomic approach. These metabolites attracted our interest due to their low occurrence frequency in a large library of fermentation broth extracts and their consistent presence in biological replicates of the producer strain. The compounds were found to possess broad-spectrum antibacterial activity while exhibiting low cytotoxicity. The biosynthetic gene cluster from Streptomyces sp. ID63040 was found to be highly similar to the streptophenazine reference cluster in the MIBiG database, which originates from the marine Streptomyces sp. CNB-091. Compounds 1 and 2 were the main streptophenazine products from Streptomyces sp. ID63040 at all cultivation times but were not detected in Streptomyces sp. CNB-091. The lack of obvious candidates for cysteinylation in the Streptomyces sp. ID63040 biosynthetic gene cluster suggests that the N-acetyl-cysteine moiety derives from cellular functions, most likely from mycothiol. Overall, our data represent an interesting example of how to leverage metabolomics for the discovery of new natural products and point out the often-neglected contribution of house-keeping cellular functions to natural product diversification.}, } @article {pmid35422087, year = {2022}, author = {Zhang, Y and Liu, Z and Wang, X and Jian, H and Xiao, H and Wen, T}, title = {SHMT2 promotes cell viability and inhibits ROS-dependent, mitochondrial-mediated apoptosis via the intrinsic signaling pathway in bladder cancer cells.}, journal = {Cancer gene therapy}, volume = {29}, number = {10}, pages = {1514-1527}, pmid = {35422087}, issn = {1476-5500}, mesh = {Apoptosis/genetics ; Carbon ; Caspase 3/genetics/metabolism ; Cell Line, Tumor ; Cell Survival/genetics ; Cysteine ; Cytochromes c/metabolism ; Formates ; Glutathione Disulfide ; Glycine ; *Glycine Hydroxymethyltransferase/genetics/metabolism ; Humans ; NAD/metabolism ; NADP/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Serine/metabolism ; Signal Transduction ; *Urinary Bladder Neoplasms/genetics ; }, abstract = {Mitochondrial serine hydroxymethyltransferase (SHMT2) catalyzes the conversion of serine to glycine and concomitantly produces one-carbon units to support cell growth and is upregulated in various cancer cells. SHMT2 knockdown triggers cell apoptosis; however, the detailed mechanism of apoptosis induced by SHMT2 inactivation remains unknown. Here, we demonstrate that SHMT2 supports the proliferation of bladder cancer (BC) cells by maintaining redox homeostasis. SHMT2 knockout decreased the pools of purine and one-carbon units and delayed cell cycle progression in a manner that was rescued by formate, demonstrating that SHMT2-mediated one-carbon units are essential for BC cell proliferation. SHMT2 deficiency promoted the accumulation of intracellular reactive oxygen species (ROS) by decreasing the NADH/NAD[+], NADPH/NADP[+], and GSH/GSSG ratios, leading to a loss in mitochondrial membrane potential, release of cytochrome c, translocation of Bcl-2 family protein and activation of caspase-3. Notably, blocking ROS production with the one-carbon donor formate and the ROS scavenger N-acetyl-cysteine (NAC) effectively rescued SHMT2 deficiency-induced cell apoptosis via the intrinsic signaling pathway. Treatment with the SHMT inhibitor SHIN1 resulted in a significant inhibitory effect on cell proliferation and induced cell apoptosis. Formate and NAC rescued SHIN1-induced cell apoptosis. Our findings reveal an important mechanism by which the loss of SHMT2 triggers ROS-dependent, mitochondrial-mediated apoptosis, which gives insight into the link between serine metabolism and cell apoptosis and provides a promising target for BC treatment and drug discovery.}, } @article {pmid35420738, year = {2022}, author = {Wołosowicz, M and Łukaszuk, B and Kasacka, I and Chabowski, A}, title = {Diverse Impact of N-Acetylcysteine or Alpha-Lipoic Acid Supplementation during High-Fat Diet Regime on Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Visceral and Subcutaneous Adipose Tissue.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {56}, number = {2}, pages = {166-179}, doi = {10.33594/000000511}, pmid = {35420738}, issn = {1421-9778}, support = {SUB/1/DN/21/008/1118//Medical University of Bialystok (MUB)/Poland ; }, mesh = {*Acetylcysteine/therapeutic use ; Animals ; Antioxidants/metabolism ; Diet, High-Fat/adverse effects ; Dietary Supplements ; Male ; Matrix Metalloproteinase 2/genetics/metabolism ; Matrix Metalloproteinase 9/genetics/metabolism ; Obesity/drug therapy/etiology/metabolism ; Rats ; Rats, Wistar ; Subcutaneous Fat/metabolism ; *Thioctic Acid/pharmacology/therapeutic use ; }, abstract = {BACKGROUND/AIMS: The high-fat diet (HFD) regime causes obesity and contributes to the development of oxidative stress in the cells by the production of reactive oxygen species and the occurrence and progress of inflammation. Despite years of studies, there is no data explaining the mechanism of action of N-acetylcysteine (NAC) or alpha-lipoic acid (ALA) on matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) in visceral and subcutaneous adipose tissue of HFD-fed rats. Our experiment aimed to evaluate for the first time the influence of chronic antioxidants administration on MMPs biology after an HFD regime as a potential therapeutic strategy for obesity-related complications prevention.

METHODS: Male Wistar rats were fed a standard rodent chow or an HFD with intragastric administration of NAC or ALA for ten weeks. The collected samples were subjected to pathohistological evaluation. Real-time PCR and western blot approaches were used to check whether NAC or ALA impacts MMP2/9 expression.

RESULTS: Antioxidant supplementation markedly reduced the number of circulating inflammatory cytokines, and tissue macrophage infiltration. Moreover, NAC and ALA have a divergent impact on MMP2 and MMP9 expression in different adipose tissue localization.

CONCLUSION: Based on our results, we speculate that NAC and ALA have a prominent effect on the MMP2/9 functions under obesity conditions.}, } @article {pmid35417724, year = {2022}, author = {Pan, N and Gao, K and Zhang, B and Fan, X and Lu, L and Wang, X}, title = {Inhibitory effects of zinc chloride (ZnCl2), n-acetyl-L-cysteine (NAC), and calcium/calmodulin dependent protein kinase II inhibitor (KN93) on Cd[2+]-induced abnormal cell morphology and membrane permeability.}, journal = {The Science of the total environment}, volume = {833}, number = {}, pages = {155208}, doi = {10.1016/j.scitotenv.2022.155208}, pmid = {35417724}, issn = {1879-1026}, mesh = {*Acetylcysteine/pharmacology ; Benzylamines ; *Cadmium/toxicity ; Calcium ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 ; Cell Membrane Permeability ; Chlorides ; Permeability ; Sulfonamides ; Zinc Compounds ; }, abstract = {Cadmium (Cd) could reduce abnormal cell morphology and membrane permeability, however, there are few studies on the detoxification of Cd-reduced cell membrane toxicity. In the present study, we firstly studied the effects of zinc chloride (ZnCl2), n-acetyl-L-cysteine (NAC), and calcium/calmodulin dependent protein kinase II inhibitor (KN93) on cell membrane permeability, respectively; then, we studied the inhibitory effects of ZnCl2, NAC, and KN93 on Cd[2+]-induced abnormal cell membrane permeability by scanning electrochemical microscopy (SECM) scanning imaging, transverse scanning curve and DPV technology. Our results showed that 10 μmol·L[-1] ZnCl2, 0.5 mmol·L[-1] NAC and 5 μmol·L[-1] KN93 could significantly improve the activity of MCF-7 cells, while did not destroy the cell morphology and membrane permeability. 0.5 mmol·L[-1] NAC and 5 μmol·L[-1] KN93 could significantly inhibit the effects of Cd[2+] on the morphology and membrane permeability of MCF-7 cells (p < 0.01). 10 μmol·L[-1] ZnCl2 could significantly inhibit the effect of Cd on the membrane permeability of MCF-7 cells, however, it cannot completely eliminate the morphological changes of MCF-7 cells caused by Cd[2+]. The results of cell activity experiment showed that 10 μmol·L[-1] ZnCl2, 0.5 mmol·L[-1] NAC and 5 μmol·L[-1] KN93 could inhibit the effect of Cd[2+] on the activity of MCF-7 cells. By comparing the inhibitory effects of ZnCl2, NAC and KN93 on Cd[2+]- induced cytotoxicity, 5 μmol·L[-1] KN93 had the robust effect on the maintenance of MCF-7 cell morphology and cell membrane integrity. Our research provided evidence on Zn supplement, NAC as antioxidant drugs, and KN93 as special inhibitor for the detoxification of Cd[2+]-reduced abnormal cell morphology and membrane permeability.}, } @article {pmid35413622, year = {2022}, author = {Wang, Y and Chi, H and Xu, F and He, Z and Li, Z and Wu, F and Li, Y and Zhang, G and Peng, X and Yu, S and Yang, J and Zhang, W and Yang, X}, title = {Cadmium chloride-induced apoptosis of HK-2 cells via interfering with mitochondrial respiratory chain.}, journal = {Ecotoxicology and environmental safety}, volume = {236}, number = {}, pages = {113494}, doi = {10.1016/j.ecoenv.2022.113494}, pmid = {35413622}, issn = {1090-2414}, mesh = {*Apoptosis ; Cadmium/toxicity ; *Cadmium Chloride/toxicity ; Electron Transport ; Humans ; Membrane Potential, Mitochondrial ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Cadmium could induce cell apoptosis, probably related to the dysfunction of the mitochondrial respiratory chain. The human renal proximal tubule (HK-2) was used to explore the mechanism of mitochondrial respiratory chain dysfunction during apoptosis induced by cadmium chloride (CdCl2). Cell viability was evaluated by cell proliferation assay and different concentrations of 60, 80 and 100 μM were selected to evaluate the mitochondrial toxicity of CdCl2 respectively. Under the CdCl2 treatment for 24 h, the mitochondrial reactive oxygen species (ROS) of HK-2 cells increased and the superoxide dismutase (SOD) activity was inhibited at the above three concentrations separately. Both ATP content and mitochondrial membrane potential decreased significantly at 100 μM concentration. The levels of procaspase-3 and Bcl-2 had fallen in a concentration-dependent manner and Bax was significantly increased at 60, 80 and 100 μM concentration compared with no CdCl2 treatment respectively, which activated the mitochondrial apoptosis pathway. N-acetyl-cysteine (NAC) could partially resist CdCl2-induced cell apoptosis, while myxothiazol (Myx) promoted the process. Mitochondria relative alterations manifested as inhibition of complex III and V. In addition, both the quantity of mitochondrial coenzyme Q-binding protein CoQ10 homolog B (CoQ10B) and cytochrome c (Cyt c) had decreased significantly. Taken together, CdCl2 induced HK-2 apoptosis due to the mitochondrial respiratory chain dysfunction by reducing the CoQ10B level, offering a novel evaluating indicator for the environmental toxicity of CdCl2.}, } @article {pmid35408692, year = {2022}, author = {Mostafa, SM and Aly, AA and Bräse, S and Nieger, M and Abdelhafez, SMN and Abdelzaher, WY and Abdelhafez, EMN}, title = {Synthesis, Characterization, and In Vivo Study of Some Novel 3,4,5-Trimethoxybenzylidene-hydrazinecarbothioamides and Thiadiazoles as Anti-Apoptotic Caspase-3 Inhibitors.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {7}, pages = {}, pmid = {35408692}, issn = {1420-3049}, mesh = {Animals ; Apoptosis ; *Caspase 3/metabolism ; *Caspase Inhibitors/chemistry ; Cytochromes c/metabolism ; Molecular Docking Simulation ; Rats ; Structure-Activity Relationship ; *Thiadiazoles/chemistry ; }, abstract = {The present study aims to discover novel derivatives as antiapoptotic agents and their protective effects against renal ischemia/reperfusion. Therefore, a series of new thiadiazole analogues 2a-g was designed and synthesized through cyclization of the corresponding opened hydrazinecarbothioamides 1a-g, followed by confirmation of the structure via spectroscopic tools (NMR, IR and mass spectra) and elemental analyses. The antiapoptotic activity showed alongside decreasing of tissue damage induced by I/R in the kidneys of rats using N-acetylcysteine (NAC) as an antiapoptotic reference. Most of the cyclized thiadiazoles are better antiapoptotic agents than their corresponding opened precursors. Particularly, compounds 2c and 2g were the most active antiapoptotic compounds with significant biomarkers. A preliminary mechanistic study was performed through caspase-3 inhibition. Compound 2c was selected along with its corresponding opened precursor 1c. An assay of cytochrome C revealed that there is an attenuation of cytochrome C level of about 5.5-fold, which was better than 1c with a level of 4.1-fold. In caspases-3, 8 and 9 assays, compound 2c showed more potency and selectivity toward caspase-3 and 9 compared with 1c. The renal histopathological investigation indicated normal renal tissue for most of the compounds, especially 2c and 2g, relative to the control. Finally, a molecular docking study was conducted at the caspase-3 active site to suggest possible binding modes.}, } @article {pmid35403558, year = {2022}, author = {Singh, J and Phogat, A and Kumar, V and Malik, V}, title = {N-acetylcysteine ameliorates monocrotophos exposure-induced mitochondrial dysfunctions in rat liver.}, journal = {Toxicology mechanisms and methods}, volume = {32}, number = {9}, pages = {686-694}, doi = {10.1080/15376516.2022.2064258}, pmid = {35403558}, issn = {1537-6524}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Liver/metabolism ; Male ; Mammals/metabolism ; Mitochondria/metabolism ; *Monocrotophos/metabolism/toxicity ; Oxidative Stress ; *Pesticides/toxicity ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Background: Monocrotophos (MCP) is an organophosphate pesticide with well-known toxicity in mammals. Exposure of MCP is associated with altered molecular physiology at sub-cellular levels. This study investigated the efficacy of N-acetylcysteine (NAC) against MCP exposure mediated mitochondrial dysfunctions in hepatic tissue of rats.Methods: Male Wistar rats were given NAC (200 mg/kg b.wt), MCP (0.9 mg/kg b.wt) and NAC together with MCP, intragastrically for 28 consecutive days. Mitochondrial complexes activities were evaluated using biochemical analysis. mRNA expression of mitochondrial complexes subunits, PGC-1α and its downstream regulators were analyzed using polymerase chain reaction.Results: Exposure of MCP (0.9 mg/kg b.wt, intragastrically, 28 d) decreased mitochondrial complexes activities and gene expression of complexes subunits. The expression of PGC-1α, NRF-1, NRF-2, and Tfam was also reduced significantly. The administration of NAC (200 mg/kg b.wt, intragastrically, 28 d) significantly increased mitochondrial complexes activities and gene expression of complexes subunits. Additionally, NAC also maintained mitochondrial functions, and enhanced the gene expression of PGC-1α and its downstream regulators.Conclusion: The results of this study indicate that NAC prevents hepatic mitochondrial dysfunctions and maintains PGC-1α signaling. In conclusion, NAC might be speculated as a therapeutic agent for mitochondrial dysfunctions following toxic exposures.}, } @article {pmid35401119, year = {2022}, author = {Wang, X and Han, Y and Chen, F and Wang, M and Xiao, Y and Wang, H and Xu, L and Liu, W}, title = {Glutathione Peroxidase 1 Protects Against Peroxynitrite-Induced Spiral Ganglion Neuron Damage Through Attenuating NF-κB Pathway Activation.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {841731}, pmid = {35401119}, issn = {1662-5102}, abstract = {Glutathione peroxidase 1 (GPX1) is a crucial antioxidant enzyme that prevented the harmful accumulation of intra-cellular hydrogen peroxide. GPX1 might contribute in limiting cochlear damages associated with aging or acoustic overexposure, but the function of GPX1 in the inner ear remains unclear. The present study was designed to investigate the effect of GPX1 on cochlear spiral ganglion neurons (SGNs) against oxidative stress induced by peroxynitrite, a versatile oxidant generated by the reaction of superoxide anion and nitric oxide. Here, we first found that the expression of GPX1 in cultured SGNs was downregulated after peroxynitrite exposure. Then, the GPX1 mimic ebselen and the gpx1 knockout (gpx1 [-/-]) mice were used to investigate the role of GPX1 in SGNs treated with peroxynitrite. The pretreatment with ebselen significantly increased the survived SGN numbers, inhibited the apoptosis, and enhanced the expression of 4-HNE in the cultured SGNs of peroxynitrite + ebselen group compared with the peroxynitrite-only group. On the contrary, remarkably less survived SGNs, more apoptotic SGNs, and the higher expression level of 4-HNE were detected in the peroxynitrite + gpx1 [-/-] group compared with the peroxynitrite-only group. Furthermore, rescue experiments with antioxidant N-acetylcysteine (NAC) showed that the expression of 4-HNE and the apoptosis in SGNs were significantly decreased, while the number of surviving SGNs was increased in peroxynitrite + NAC group compared the peroxynitrite-only group and in peroxynitrite + gpx1 [-/-] + NAC group vs. peroxynitrite + gpx1 [-/-] group. Finally, mechanistic studies showed that the activation of nuclear factor-kappa B (NF-κB) was involved in the SGNs damage caused by peroxynitrite and that GPX1 protected SGNs against peroxynitrite-induced damage, at least in part, via blocking the NF-κB pathway activation. Collectively, our findings suggest that GPX1 might serve as a new target for the prevention of nitrogen radical-induced SGNs damage and hearing loss.}, } @article {pmid35396503, year = {2022}, author = {Wang, YW and Dong, HZ and Tan, YX and Bao, X and Su, YM and Li, X and Jiang, F and Liang, J and Huang, ZC and Ren, YL and Xu, YL and Su, Q}, title = {HIF-1α-regulated lncRNA-TUG1 promotes mitochondrial dysfunction and pyroptosis by directly binding to FUS in myocardial infarction.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {178}, pmid = {35396503}, issn = {2058-7716}, abstract = {Myocardial infarction (MI) is a fatal heart disease that affects millions of lives worldwide each year. This study investigated the roles of HIF-1α/lncRNA-TUG1 in mitochondrial dysfunction and pyroptosis in MI. CCK-8, DHE, lactate dehydrogenase (LDH) assays, and JC-1 staining were performed to measure proliferation, reactive oxygen species (ROS), LDH leakage, and mitochondrial damage in hypoxia/reoxygenation (H/R)-treated cardiomyocytes. Enzyme-linked immunoassay (ELISA) and flow cytometry were used to detect LDH, creatine kinase (CK), and its isoenzyme (CK-MB) levels and caspase-1 activity. Chromatin immunoprecipitation (ChIP), luciferase assay, and RNA-immunoprecipitation (RIP) were used to assess the interaction between HIF-1α, TUG1, and FUS. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were used to measure HIF-1α, TUG1 and pyroptosis-related molecules. Hematoxylin and eosin (HE), 2,3,5-triphenyltetrazolium chloride (TTC), and terminal deoxynucleotidyl transferase dUTP risk end labelling (TUNEL) staining were employed to examine the morphology, infarction area, and myocardial injury in the MI mouse model. Mitochondrial dysfunction and pyroptosis were induced in H/R-treated cardiomyocytes, accompanied by an increase in the expression of HIF-α and TUG1. HIF-1α promoted TUG1 expression by directly binding to the TUG1 promoter. TUG1 silencing inhibited H/R-induced ROS production, mitochondrial injury and the expression of the pyroptosis-related proteins NLRP3, caspase-1 and GSDMD. Additionally, H/R elevated FUS levels in cardiomyocytes, which were directly inhibited by TUG1 silencing. Fused in sarcoma (FUS) overexpression reversed the effect of TUG1 silencing on mitochondrial damage and caspase-1 activation. However, the ROS inhibitor N-acetylcysteine (NAC) promoted the protective effect of TUG1 knockdown on H/R-induced cardiomyocyte damage. The in vivo MI model showed increased infarction, myocardial injury, ROS levels and pyroptosis, which were inhibited by TUG1 silencing. HIF-1α targeting upregulated TUG1 promotes mitochondrial damage and cardiomyocyte pyroptosis by combining with FUS, thereby promoting the occurrence of MI. HIF-1α/TUG1/FUS may serve as a potential treatment target for MI.}, } @article {pmid35394351, year = {2022}, author = {Shen, J and Dong, J and Shao, F and Zhao, J and Gong, L and Wang, H and Chen, W and Zhang, Y and Cai, Y}, title = {Graphene oxide induces autophagy and apoptosis via the ROS-dependent AMPK/mTOR/ULK-1 pathway in colorectal cancer cells.}, journal = {Nanomedicine (London, England)}, volume = {17}, number = {9}, pages = {591-605}, doi = {10.2217/nnm-2022-0030}, pmid = {35394351}, issn = {1748-6963}, mesh = {*AMP-Activated Protein Kinases/metabolism/pharmacology ; Apoptosis ; Autophagy ; Cell Line, Tumor ; *Colorectal Neoplasms/drug therapy/metabolism ; Graphite ; Humans ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Aim: To investigate the anticancer effects and action mechanism of graphene oxide (GO) in colorectal cancer (CRC). Materials & methods: Anticancer effects and mechanisms of GO in CRC were investigated both in vivo and in vitro. Results: GO significantly inhibited tumor growth both in vitro and in vivo. GO was able to enter HCT116 cells through endocytosis. GO treatment resulted in cytotoxicity, reactive oxygen species (ROS) production, apoptosis, autophagy and activation of the AMPK/mTOR/ULK1 signal pathway. However, ROS scavenger N-acetylcysteine (NAC) attenuated the above effects and restored the effects of GO on protein expressions related to apoptosis, autophagy and AMPK/mTOR/ULK1 signal pathways. Conclusion: GO exerts anticancer effects against CRC via ROS-dependent AMPK/mTOR/ULK-1 pathway-related autophagy and apoptosis.}, } @article {pmid35393384, year = {2022}, author = {Mcpherson, RA and Mangram, AJ and Barletta, JF and Dzandu, JK}, title = {N -acetylcysteine is associated with reduction of postconcussive symptoms in elderly patients: A pilot study.}, journal = {The journal of trauma and acute care surgery}, volume = {93}, number = {5}, pages = {644-649}, doi = {10.1097/TA.0000000000003639}, pmid = {35393384}, issn = {2163-0763}, mesh = {Humans ; Aged ; Aged, 80 and over ; Pilot Projects ; Acetylcysteine/therapeutic use ; Prospective Studies ; *Post-Concussion Syndrome/diagnosis/drug therapy/complications ; Glasgow Coma Scale ; *Brain Concussion/complications/psychology ; }, abstract = {INTRODUCTION: N -acetylcysteine (NAC) may be neuroprotective by minimizing postconcussion symptoms after mild traumatic brain injury (TBI), but limited data exist. This study evaluated the effects of NAC on postconcussion symptoms in elderly patients diagnosed with mild TBI.

METHODS: This prospective, quasirandomized, controlled trial enrolled patients 60 years or older who suffered mild TBI. Patients were excluded if cognitive function could not be assessed within 3-hours postinjury. Patients were allocated to receive NAC plus standard care, or standard care alone, based on the trauma center where they presented. The primary study outcome was the severity of concussive symptoms measured using the Rivermeade Postconcussion Symptoms Questionnaire (RPQ). Symptoms were evaluated on days 0, 7, and 30. The RPQ scores were compared both within and between treatment groups.

RESULTS: There were 65 patients analyzed (NAC, n = 34; control, n = 31) with an average age of 76 ± 10 years. Baseline demographics and clinical variables were similar. No group differences in head Abbreviated Injury Scale score or Glasgow Coma Scale score were observed. Baseline RPQ scores (6 [0-20] vs. 11 [4-20], p = 0.300) were indistinguishable. The RPQ scores on day 7 (2 [0-8] vs. 10 [3-18], p = 0.004) and 30 (0 [0-4] vs. 4 [0-13], p = 0.021) were significantly lower in the NAC group. Within-group differences were significantly lower in the NAC (p < 0.001) but not control group (p = 0.319).

CONCLUSION: N -acetylcysteine was associated with significant improvements in concussion symptoms in elderly patients with mild TBI. These results justify further research into using NAC to treat TBI.

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.}, } @article {pmid35388968, year = {2022}, author = {Bai, G and Zhou, R and Jiang, X and Zou, Y and Shi, B}, title = {Glyphosate-based herbicides induces autophagy in IPEC-J2 cells and the intervention of N-acetylcysteine.}, journal = {Environmental toxicology}, volume = {37}, number = {8}, pages = {1878-1890}, doi = {10.1002/tox.23534}, pmid = {35388968}, issn = {1522-7278}, support = {32072776//National Natural Science Foundation of China/ ; JQ2019C002//Provincial Science Fund for Distinguished Young Scholars/ ; }, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Autophagy ; Cell Line ; Cell Survival ; Epithelial Cells ; Glycine/analogs & derivatives ; *Herbicides/toxicity ; Interleukin-6/metabolism ; RNA, Messenger/metabolism ; Swine ; Glyphosate ; }, abstract = {Glyphosate-based herbicides (GBHs) are the most widely used pesticide in the world, and its extensive use has increased pressures on environmental safety and potential human and livestock health risks. This study investigated the effects of GBHs on antioxidant capacity, inflammatory cytokines, and autophagy of porcine intestinal epithelial cells (IPEC-J2) and its molecular mechanism. Also, the protective effects of N-acetylcysteine (NAC) against the toxicity of GBHs were evaluated. Our results showed that the activities of antioxidant enzymes (SOD, GSH-Px) were decreased by GBHs. GBHs increased inflammatory factors (IL-1β, IL-6, TNF-α) and the mRNA expression of iNOS and COX-2. GBHs induced the up-regulation of Nrf2/HO-1 pathway and the phosphorylation of IκB-α and NFκB p65, up-regulation of LC3-II/LC3-I, and down-regulation of P62, and NFκB inhibitor decreased the mRNA expression of inflammatory cytokines (IL-1β, IL-6, IL-8). Moreover, NAC reduced the cytotoxicity by suppressing ROS levels, and changed the autophagy-related proteins such as the suppression of LC3-II conversion and up-regulation of P62. Our findings unveil a novel mechanism of GBHs effects on IPEC-J2 cells and NAC can reverse cytotoxicity to some extent.}, } @article {pmid35383148, year = {2022}, author = {Wu, D and Yan, L and Zheng, C and Ren, X and Pan, Y and Huang, S and Pan, L and Li, Z}, title = {Akt-GSK3β-mPTP pathway regulates the mitochondrial dysfunction contributing to odontoblasts apoptosis induced by glucose oxidative stress.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {168}, pmid = {35383148}, issn = {2058-7716}, support = {Y20180704//Wenzhou Municipal Science and Technology Bureau (Wenzhou Municipal Sci - Tech Bureau)/ ; Y20190503//Wenzhou Municipal Science and Technology Bureau (Wenzhou Municipal Sci - Tech Bureau)/ ; 81870757//National Natural Science Foundation of China (National Science Foundation of China)/ ; GF21H140019//Zhejiang Province Public Welfare Technology Application Research Project (Public Welfare Technology Application Research Project of Zhejiang Province)/ ; }, abstract = {Diabetes Mellitus can cause dental pulp cells apoptosis by oxidative stress, and affect the integrity and function of dental pulp tissue. Mitochondria are the main attack targets of oxidative stress and have a critical role in apoptosis. However, whether mitochondria are involved in dental pulp damage caused by diabetes mellitus remains unclear. This study aimed to investigate the role of mitochondria in the apoptosis of odontoblast-like cell line (mDPC6T) induced by glucose oxidative stress, and to explore its possible mechanism. We established an oxidative stress model in vitro using glucose oxidase/glucose to simulate the pathological state under diabetic conditions. We found that the opening of mitochondrial permeability transition pore (mPTP) contributed to the apoptosis of mDPC6T treated with glucose oxidase, as evidenced by enhanced mitochondrial reactive oxygen species (mtROS) and intracellular Ca[2+] disorder, significantly reduced mitochondrial membrane potential (MMP) and ATP production. Antioxidant N-acetylcysteine (NAC) or Cyclosporine A (mPTP inhibitor) blocked the mPTP opening, which significantly attenuated mitochondrial dysfunction and apoptosis induced by glucose oxidative stress. In addition, we found that glucose oxidative stress stimulated mPTP opening may through inhibition of Akt-GSK3β pathway. This study provides a new insight into the mitochondrial mechanism underlying diabetes-associated odontoblast-like cell apoptosis, laying a foundation for the prevention and treatment of diabetes-associated pulp injury.}, } @article {pmid35372029, year = {2022}, author = {Fan, Y and Wang, J and Fang, Z and Pierce, SR and West, L and Staley, A and Tucker, K and Yin, Y and Sun, W and Kong, W and Prabhu, V and Allen, JE and Zhou, C and Bae-Jump, VL}, title = {Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {789450}, pmid = {35372029}, issn = {2234-943X}, abstract = {ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP). The present study was to explore the anti-tumor potential effect of ONC201 in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer under obese (high fat diet) and lean (low fat diet) conditions. ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial-mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial-mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. These results suggest that ONC201 may be a promising therapeutic agent to be explored in future clinical trials in high-grade serous ovarian cancer.}, } @article {pmid35371352, year = {2022}, author = {Amjad, W and Thuluvath, P and Mansoor, M and Dutta, A and Ali, F and Qureshi, W}, title = {N-acetylcysteine in non-acetaminophen-induced acute liver failure: a systematic review and meta-analysis of prospective studies.}, journal = {Przeglad gastroenterologiczny}, volume = {17}, number = {1}, pages = {9-16}, pmid = {35371352}, issn = {1895-5770}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: There are discordant reports on N-acetylcysteine (NAC) efficacy in non-acetaminophen acute liver failure (ALF).

AIM: To determine whether NAC is beneficial in non-acetaminophen ALF.

MATERIAL AND METHODS: We performed a systemic review and meta-analysis of published data to address the question. PubMed and MEDLINE were searched using the terms non-acetylcysteine and ALF due to non-acetaminophen, viral infection, drug-induced or autoimmune hepatitis. The primary outcome was overall mortality. Secondary outcomes were transplant-free survival and length of hospital stay. Risk ratios were calculated using a random model for meta-analysis.

RESULTS: A total of 672 patients were included in this meta-analysis from 5 prospective studies (NAC group: n = 334; control group: n = 338). Viral hepatitis (45.8% vs. 32.8%) followed by drug-induced liver injury (24.6% vs. 27.5%), indeterminate cause (13.2% vs. 21.6%) and autoimmune hepatitis (6.6% vs. 8.9%) were the most common etiologies of ALF in the treatment group and control group respectively. Treatment with N-acetylcysteine improved the transplant-free survival significantly (55.1% vs. 28.1%; RR = 0.56; 95% CI: 0.33-0.94) whereas the overall survival was not improved with NAC (71% vs. 59.8%; RR = 0.73; 95% CI: 0.48-1.09). The NAC treatment was associated with shorter hospital stay (standard difference in means (SMD) = -1.62; 95% CI: -1.84 to -1.40, p < 0.001).

CONCLUSIONS: The treatment of patients with acute liver failure with N-acetylcysteine improved transplant-free survival and length of stay.}, } @article {pmid35368869, year = {2022}, author = {Despotović, A and Mirčić, A and Misirlić-Denčić, S and Harhaji-Trajković, L and Trajković, V and Zogović, N and Tovilović-Kovačević, G}, title = {Combination of Ascorbic Acid and Menadione Induces Cytotoxic Autophagy in Human Glioblastoma Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {2998132}, pmid = {35368869}, issn = {1942-0994}, mesh = {Ascorbic Acid/pharmacology ; Autophagy/physiology ; *Glioblastoma/drug therapy ; Humans ; TOR Serine-Threonine Kinases/metabolism ; *Vitamin K 3/pharmacology ; }, abstract = {We investigated the ability of the ascorbic acid (AA) and menadione (MD) combination, the well-known reactive oxidative species- (ROS-) generating system, to induce autophagy in human U251 glioblastoma cells. A combination of AA and MD (AA+MD), in contrast to single treatments, induced necrosis-like cell death mediated by mitochondrial membrane depolarization and extremely high oxidative stress. AA+MD, and to a lesser extent MD alone, prompted the appearance of autophagy markers such as autophagic vacuoles, autophagosome-associated LC3-II protein, degradation of p62, and increased expression of beclin-1. While both MD and AA+MD increased phosphorylation of AMP-activated protein kinase (AMPK), the well-known autophagy promotor, only the combined treatment affected its downstream targets, mechanistic target of rapamycin complex 1 (mTORC1), Unc 51-like kinase 1 (ULK1), and increased the expression of several autophagy-related genes. Antioxidant N-acetyl cysteine reduced both MD- and AA+MD-induced autophagy, as well as changes in AMPK/mTORC1/ULK1 activity and cell death triggered by the drug combination. Pharmacological and genetic autophagy silencing abolished the toxicity of AA+MD, while autophagy upregulation enhanced the toxicity of both AA+MD and MD. Therefore, by upregulating oxidative stress, inhibiting mTORC1, and activating ULK1, AA converts MD-induced AMPK-dependent autophagy from nontoxic to cytotoxic. These results suggest that AA+MD or MD treatment in combination with autophagy inducers could be further investigated as a novel approach for glioblastoma therapy.}, } @article {pmid35361640, year = {2022}, author = {Luo, A and Liu, X and Hu, Q and Yang, M and Jiang, H and Liu, W}, title = {Efficacy of N-acetylcysteine on idiopathic or postinfective non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis protocol.}, journal = {BMJ open}, volume = {12}, number = {3}, pages = {e053625}, pmid = {35361640}, issn = {2044-6055}, mesh = {*Acetylcysteine/therapeutic use ; *Bronchiectasis/drug therapy ; Humans ; Meta-Analysis as Topic ; Quality of Life ; Research Design ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Non-cystic fibrosis (non-CF) bronchiectasis is a chronic pulmonary disorder that causes destruction and permanent dilatation of the airways, resulting in excessive sputum production, repeated infection and inflammation. A need for high-quality and specialised care has been highlighted in recent years. N-acetylcysteine (NAC) is a widely used mucolytic agent in respiratory diseases that not only possesses a property to enhance secretion clearance, but also exhibits antioxidant and anti-inflammatory effects. However, the efficacy and safety of NAC are not well described in idiopathic or postinfective non-CF bronchiectasis.

OBJECTIVE: This study aims to evaluate the efficacy and safety of NAC in patients with idiopathic or postinfective non-CF bronchiectasis.

METHODS AND ANALYSIS: PubMed/Medline, Embase, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials will be searched from inception to 1 March 2022 for eligible randomised controlled trials that investigating the effects of NAC on exacerbations, health-related quality of life, lung functions, sputum volume and colour, inflammation markers, exercise capacity and adverse events in patients with idiopathic or postinfective non-CF bronchiectasis, with ongoing trials being identified by searches on the websites of Chinese Clinical Trial Registry and ClinicalTrials.gov. Two independent reviewers will identify eligible studies, two will fulfil the data extraction and three will perform the quality appraisal. To generate more accurate analyses, the Grading of Recommendations Assessment, Development and Evaluation will be used to grade the evidence. χ[2] test and I[2] statistic will be used to assess heterogeneity. Subgroup analyses and meta-regression will be used to explore potential sources of heterogeneity. The potential publication bias will be examined using funnel plots.

ETHICS AND DISSEMINATION: No research ethics approval is required in this study because it is a systematic review. The results of this study are expected to be disseminated through peer-reviewed journals and conferences.

TRIAL REGISTRATION NUMBER: CRD42021239438.}, } @article {pmid35361025, year = {2023}, author = {Haroun, RA and Abdel-Aziz, N and Saad, S}, title = {The protective effect of N-acetyl cysteine against selenium toxicity and gamma irradiation in rats.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {3}, pages = {482-490}, doi = {10.1080/01480545.2022.2058010}, pmid = {35361025}, issn = {1525-6014}, mesh = {Animals ; Rats ; *Acetylcysteine/metabolism/pharmacology ; Adenosine Triphosphate/metabolism ; *Antioxidants/pharmacology/metabolism ; Cholesterol/metabolism/pharmacology ; Corticosterone/metabolism/pharmacology ; *Liver/drug effects/metabolism/radiation effects ; Oxidative Stress ; *Selenium/toxicity ; *Gamma Rays/adverse effects ; Adrenal Glands/drug effects/metabolism/radiation effects ; }, abstract = {N-acetyl cysteine (NAC) is a nutritional supplement and greatly applied as an antioxidant in vivo and in vitro. Therefore, this study aimed to assess the metabolic and antioxidant protective effect of NAC against selenium (Se) toxicity and gamma irradiation in rats by measuring biochemical and molecular parameters. This study was conducted on sixty rats divided into six equal different groups; control, NAC, Rad, Se, Rad + NAC, and Se + NAC groups. Oxidative/nitrosative makers (LPO, NO, and NOS), antioxidants status markers (GSH, GPx, and SOD), liver metabolic markers (LDH, SDH, and ATP), and plasma metabolic markers (Glucose, total cholesterol, and total proteins) were measured using commercial colorimetric kits while plasma corticosterone concentration was measured using commercial ELISA kit. Also, Levels of NR3C1 and Glut-2 genes expression using reverse transcription-quantitative polymerase chain reaction were done. Our results revealed that Se toxicity and gamma irradiation induced significant increases in oxidative/nitrosative stress markers and a significant decrease in antioxidant status markers in the liver and adrenal tissues. Moreover, metabolic disorders were recorded as manifested by elevation of plasma ALT, Albumin, glucose and cholesterol, and decrease in protein levels associated with a significant increase in corticosterone concentration. This was also accompanied by a significant decrease in SDH activity and ATP production in the hepatic tissue. Molecular analysis showed a marked increase in NR3C1 mRNA and decrease in Glut-2 mRNA in liver tissue. However, NAC supplementation attenuated the changes induced by these toxins. Finally, we could conclude that, oral supplementation of NAC can modulate the metabolic disturbances and has protective effects in rats exposed to Se toxicity and gamma irradiation.}, } @article {pmid35358610, year = {2022}, author = {Arber Raviv, S and Alyan, M and Egorov, E and Zano, A and Harush, MY and Pieters, C and Korach-Rechtman, H and Saadya, A and Kaneti, G and Nudelman, I and Farkash, S and Flikshtain, OD and Mekies, LN and Koren, L and Gal, Y and Dor, E and Shainsky, J and Shklover, J and Adir, Y and Schroeder, A}, title = {Lung targeted liposomes for treating ARDS.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {346}, number = {}, pages = {421-433}, pmid = {35358610}, issn = {1873-4995}, support = {680242/ERC_/European Research Council/International ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *COVID-19 ; Humans ; Inflammation/drug therapy ; Lipopolysaccharides/pharmacology ; Liposomes/therapeutic use ; Lung ; *Lung Diseases ; Mice ; Mice, Inbred C57BL ; Nanoparticles ; *Respiratory Distress Syndrome/drug therapy ; Tumor Necrosis Factor-alpha ; }, abstract = {Acute Respiratory Distress Syndrome (ARDS), associated with Covid-19 infections, is characterized by diffuse lung damage, inflammation and alveolar collapse that impairs gas exchange, leading to hypoxemia and patient' mortality rates above 40%. Here, we describe the development and assessment of 100-nm liposomes that are tailored for pulmonary delivery for treating ARDS, as a model for lung diseases. The liposomal lipid composition (primarily DPPC) was optimized to mimic the lung surfactant composition, and the drug loading process of both methylprednisolone (MPS), a steroid, and N-acetyl cysteine (NAC), a mucolytic agent, reached an encapsulation efficiency of 98% and 92%, respectively. In vitro, treating lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages with the liposomes decreased TNFα and nitric oxide (NO) secretion, while NAC increased the penetration of nanoparticles through the mucus. In vivo, we used LPS-induced lung inflammation model to assess the accumulation and therapeutic efficacy of the liposomes in C57BL/6 mice, either by intravenous (IV), endotracheal (ET) or IV plus ET nanoparticles administrations. Using both administration methods, liposomes exhibited an increased accumulation profile in the inflamed lungs over 48 h. Interestingly, while IV-administrated liposomes distributed widely throughout the lung, ET liposomes were present in lungs parenchyma but were not detected at some distal regions of the lungs, possibly due to imperfect airflow regimes. Twenty hours after the different treatments, lungs were assessed for markers of inflammation. We found that the nanoparticle treatment had a superior therapeutic effect compared to free drugs in treating ARDS, reducing inflammation and TNFα, IL-6 and IL-1β cytokine secretion in bronchoalveolar lavage (BAL), and that the combined treatment, delivering nanoparticles IV and ET simultaneously, had the best outcome of all treatments. Interestingly, also the DPPC lipid component alone played a therapeutic role in reducing inflammatory markers in the lungs. Collectively, we show that therapeutic nanoparticles accumulate in inflamed lungs holding potential for treating lung disorders. SIGNIFICANCE: In this study we compare intravenous versus intratracheal delivery of nanoparticles for treating lung disorders, specifically, acute respiratory distress syndrome (ARDS). By co-loading two medications into lipid nanoparticles, we were able to reduce both inflammation and mucus secretion in the inflamed lungs. Both modes of delivery resulted in high nanoparticle accumulation in the lungs, intravenously administered nanoparticles reached lung endothelial while endotracheal delivery reached lung epithelial. Combining both delivery approaches simultaneously provided the best ARDS treatment outcome.}, } @article {pmid35352469, year = {2022}, author = {Yang, Y and Han, C and Sheng, Y and Wang, J and Li, W and Zhou, X and Ruan, S}, title = {Antrodia camphorata polysaccharide improves inflammatory response in liver injury via the ROS/TLR4/NF-κB signal.}, journal = {Journal of cellular and molecular medicine}, volume = {26}, number = {9}, pages = {2706-2716}, pmid = {35352469}, issn = {1582-4934}, support = {LYY20H280005//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Animals ; *Antrodia/metabolism ; Liver/metabolism ; Mice ; NF-E2-Related Factor 2/metabolism ; *NF-kappa B/metabolism ; Polyporales ; Polysaccharides/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 4/metabolism ; }, abstract = {Antrodia Camphorata Polysaccharide (ACP) refers to a kind of polysaccharide extracted from the natural porous fungus Antrodia camphorata. This study investigated the mechanism of action of ACP in protecting the liver. The results showed that ACP suppressed the LPS-induced KC cell activation, reduced the expression of inflammatory factors, increased the SOD level and suppressed ROS expression. In addition, N-acetylcysteine (NAC) was adopted for pre-treatment to suppress ROS. The results indicated that NAC synergistically exerted its effect with ACP, suggesting that ACP played its role through suppressing ROS. Further detection revealed that ACP activated the Nrf2 signal. It was discovered in the mouse model that, ACP effectively improved liver injury in mice, decreased ALT and AST levels, and suppressed the expression of inflammatory factors. This study suggests that ACP can exert its effect against oxidative stress via the Nrf2-ARE signalling, which further improves the production of ROS and the activation of TLR4-NF-κB signalling, and protects the liver against liver injury.}, } @article {pmid35350335, year = {2022}, author = {Li, C and He, Q and Xu, Y and Lou, H and Fan, P}, title = {Synthesis of 3-O-Acetyl-11-keto-β-boswellic Acid (AKBA)-Derived Amides and Their Mitochondria-Targeted Antitumor Activities.}, journal = {ACS omega}, volume = {7}, number = {11}, pages = {9853-9866}, pmid = {35350335}, issn = {2470-1343}, abstract = {In this study, we synthesized a series of amide and mitochondria-targeted derivatives with 3-O-acetyl-11-keto-β-boswellic acid (AKBA) as the parent structure and an ethylenediamine moiety as the link chain. Compound 5e, a mitochondrial-targeting potential derivative, showed significantly stronger antitumor activity than that of AKBA, and it could induce vacuolization of A549 cells and stimulate the production of reactive oxygen species (ROS) in a time- and concentration-dependent manner. The antioxidant N-acetylcysteine (NAC) could inhibit the ROS level but could not suppress vacuolization and cell death induced by 5e. Further studies demonstrated that 5e caused abnormal opening of mitochondrial permeability transition pore (MPTP) and a decrease of mitochondrial membrane potential; additionally, it caused cell cycle arrest in G0/G1 but did not induce apoptosis. 5e represented a compound with improved antiproliferative effects for cancer therapy working through new mechanisms.}, } @article {pmid35346799, year = {2022}, author = {Wang, W and Chen, E and Ding, X and Lu, P and Chen, J and Ma, P and Lu, L}, title = {N-acetylcysteine protect inner hair cells from cisplatin by alleviated celluar oxidative stress and apoptosis.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {81}, number = {}, pages = {105354}, doi = {10.1016/j.tiv.2022.105354}, pmid = {35346799}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Antineoplastic Agents/toxicity ; Apoptosis ; *Cisplatin/toxicity ; Hair Cells, Auditory, Inner ; Humans ; Oxidative Stress ; Rats ; Zebrafish ; }, abstract = {Cisplatin is a well-known platinum-based chemotherapy drug widely used to treat a variety of malignant tumors. However, cisplatin has serious side-effects include nephrotoxicity and ototoxicity, Cisplatin chemotherapy causes permanent hearing loss at least 40% of treated patients. Our results showed that 20 mM N-acetylcysteine (NAC) can completely protect 50 μM cisplatin-induced hair cell loss in rat cochlear culture and protects against cisplatin-induced hair cell loss in zebrafish in vivo. The fluorescence intensity of mitochondrial ROS significantly increased after the cultures were treated with 15 μM cisplatin for 48 h and was decreased in the group treated with 15 μM cisplatin add 20 mM NAC. In addition, the number of TUNEL positive hair cells was increased after the cultures were treated with 15 μM cisplatin for 48 h and there are null in cisplatin and NAC co-treated group.}, } @article {pmid35345710, year = {2022}, author = {Philipose, J and Suchman, KI and Aronsky, D and Lee, TP}, title = {A Case of Acute Liver Failure in a Patient on Isoniazid Prophylaxis for Latent Tuberculosis.}, journal = {Cureus}, volume = {14}, number = {2}, pages = {e22452}, pmid = {35345710}, issn = {2168-8184}, abstract = {Isoniazid (INH) is widely used for latent Mycobacterium tuberculosis despite the known risk of liver injury, with severe hepatitis occurring in up to 1% of patients. We report a patient who presented with two weeks of anorexia, nausea, and jaundice following six months of INH monotherapy for latent tuberculosis (TB). After other causes of liver injury were ruled out, she underwent a liver biopsy showing submassive necrosis, hepatocellular dropout, and lobular inflammation with no evidence of fibrosis. She was also found to have acute portal hypertension. She was diagnosed with drug-induced liver injury (DILI) and was treated with n-acetyl cysteine (NAC), ursodiol, and vitamin K. She recovered without the need for a liver transplant. This case supports the need for monitoring of liver tests in high-risk individuals on INH therapy to reduce the risk of hepatotoxicity.}, } @article {pmid35345568, year = {2022}, author = {Shaikh, N and Chanda, AH and Rahman, MA and Nainthramveetil, MM and Kumar, A and Mathias, RM and Nashwan, AJ}, title = {Inhalational injury and use of heparin & N-acetylcysteine nebulization: A case report.}, journal = {Respiratory medicine case reports}, volume = {37}, number = {}, pages = {101640}, pmid = {35345568}, issn = {2213-0071}, abstract = {Inhalational injury to the upper and lower airway occurs due to thermal or chemical irritation causing airway edema, capillary leak, mucin, and fibrin debris forming clots and soot. The use of unfractionated heparin (UFH) nebulization was found to be effective by dissolving airway clots. We report a case of inhalational burn injury where UFH nebulization led to a better outcome. A healthy male was trapped in a residential room during a fire in the building. He sustained facial, neck, upper chest, and left upper extremity burns accounting for 25% of body surface area. He was intubated at the site and started on supportive care. In the surgical intensive care unit, bronchoscopy showed severe tracheobronchial burn injury; a thorough lavage was done, started on UFH and N-acetylcysteine nebulization (NAC). The patient improved, and his trachea was extubated on day 6. In our patient, unfractionated heparin nebulization was beneficial as the patient was extubated early without landing to acute respiratory distress syndrome.}, } @article {pmid35344072, year = {2022}, author = {Xu, X and Wang, X and Yang, Y and Ares, I and Martínez, M and Lopez-Torres, B and Martínez-Larrañaga, MR and Wang, X and Anadón, A and Martinez, MA}, title = {Neonicotinoids: mechanisms of systemic toxicity based on oxidative stress-mitochondrial damage.}, journal = {Archives of toxicology}, volume = {96}, number = {6}, pages = {1493-1520}, pmid = {35344072}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Antidotes/pharmacology ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; *Curcumin ; Glutathione/metabolism ; Mammals/metabolism ; Neonicotinoids ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Resveratrol/pharmacology ; }, abstract = {Neonicotinoids are the most widely used pesticides in the world. However, research studies have shown that it can affect the cognitive abilities and health of non-target bees and other wild pollinators by inducing DNA damage, apoptosis and mitochondrial damage, injure to its central nervous system, and it is even developmentally neurotoxic to mammals and humans, with mitochondria being an important target of neonicotinoids. Therefore, this article reviews the role of mitochondrial morphology, calcium ions (Ca[2+]) homeostasis, respiratory function, apoptosis, and DNA damage in neonicotinoids-induced systemic toxicity. Additionally, it evaluates the protective effects of various active substances including vitamin C, N-acetylcysteine (NAC), curcumin (CUR), glutathione reduced (GSH), caffeic acid phenethyl ester (CAPE), resveratrol, and thymoquinone (TQ) on neonicotinoids-induced toxicity. This review manuscript found that mitochondria are important targets to neonicotinoids. Neonicotinoids can cause DNA damage, apoptosis, protein oxidation, and lipid peroxidation in non-target organisms by altering mitochondrial Ca[2+] homeostasis, inhibiting mitochondrial respiration, and inducing reactive oxygen species (ROS) production. Several active substances (vitamin C, NAC, CUR, GSH, resveratrol, CAPE, and TQ) play a protective role against neonicotinoid-induced systemic toxicity by inhibiting ROS signaling pathways, apoptosis, and lipid peroxidation. This review manuscript emphasizes the importance and urgency of the development of neonicotinoid antidotes, emphasizes the prospect of the application of targeted mitochondrial antidotes, and prospects the development of neonicotinoid antidotes in order to provide some strategies for the prevention of neonicotinoid toxicity.}, } @article {pmid35342347, year = {2022}, author = {Gao, Z and Yi, W and Tang, J and Sun, Y and Huang, J and Lan, T and Dai, X and Xu, S and Jin, ZG and Wu, X}, title = {Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2.}, journal = {International journal of biological sciences}, volume = {18}, number = {5}, pages = {2146-2162}, pmid = {35342347}, issn = {1449-2288}, mesh = {Animals ; Mice ; *Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism ; *Coumarins/pharmacology ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Liver/metabolism ; Molecular Docking Simulation ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress ; }, abstract = {Acetaminophen overdose is a leading cause of acute live failure worldwide. N-acetylcysteine (NAC), as the only antidote, is limited due to its narrow therapeutic time window. Here we demonstrated that Urolithin A (UA), a metabolite of ellagitannin natural products in the gastrointestinal flora, protected against acetaminophen-induced liver injury (AILI) and is superior to NAC in terms of dosage and therapeutical time window. Transcriptomics assay revealed that UA promotes mitophagy and activated Nrf2/ARE signaling in the liver. Consistent with that, mitophagy and Nrf2/ARE signaling were activated, with less oxidative stress in UA-treated liver. Subsequently, molecular docking and dynamics simulation study revealed a binding mode between UA and Nrf-2/Keap1 including the hydrogen-bonding network among oxygen atoms in UA with the Nrf-2/Keap1 residues Arg 415, Ser 508 and Ser 602, which in turn trigger Nrf2 nuclear translocation, subsequently leading to activation of Nrf-2 target genes (HO-1, NQO1). Of note, mitophagy inhibition failed to prevent the protection of UA against AILI, which instead was compromised with Nrf2 gene silencing both in vivo and in vitro. Collectively, our data indicate that UA alleviated acetaminophen-induced oxidative stress and hepatic necrosis via activating Nrf2/ARE signaling pathway, highlighting a therapeutical potential of UA for AILI.}, } @article {pmid35341601, year = {2022}, author = {Schweikl, H and Weissenberger, S and Gallorini, M and Bolay, C and Waha, C and Hiller, KA and Buchalla, W}, title = {Influence of HEMA on LPS- and LTA-stimulated IL-6 release from human dental pulp cells.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {38}, number = {5}, pages = {886-897}, doi = {10.1016/j.dental.2022.03.008}, pmid = {35341601}, issn = {1879-0097}, mesh = {Dental Pulp/metabolism ; Humans ; Interleukin-6 ; *Lipopolysaccharides/pharmacology ; Methacrylates ; *Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVE: Dental pulp cells interact with immunogenic components such as LPS (lipopolysaccharide) or LTA (lipoteichoic acid) released from microorganisms in carious lesions. In the present investigation, the formation of the pro-inflammatory cytokines TNFα and IL-6 in LPS- or LTA-stimulated cells from the dental pulp interface and pulp fibroblasts was analyzed in the presence of the resin monomer 2-hydroxyethyl methacrylate (HEMA) under varying cellular redox conditions.

METHOD: Human pulp fibroblasts (HPC) or cells from the dental pulp interface expressing an odontoblast phenotype (hOD-1) were exposed to LTA, LPS or HEMA for 1 h or 24 h. Redox homeostasis was modified by the prooxidant BSO (L-buthionine sulfoximine) or the antioxidant NAC (N-acetyl cysteine). Formation of TNFα or IL-6 was analyzed by ELISA, and cell survival was determined by a crystal violet assay. Statistical analyses were performed using the Mann-Whitney-U-test.

RESULTS: Secretion of TNFα was not detected in LPS- or LTA-stimulated HPC or hOD-1, and IL-6 was not found after a short exposure (1 h). After a 24 h exposure, LPS induced a 3-fold increase in IL-6 formation in HPC, while LTA stimulated IL-6 release about 20-fold. Likewise, LTA was more effective than LPS in hOD-1 stimulating IL-6 levels about 50-fold. HEMA inhibited the LPS- and LTA-induced IL-6 release, and this effect was enhanced by BSO but counteracted by NAC in both cell types. IL-6 release was independent of cell survival rates.

CONCLUSIONS: The protective immune response in odontoblasts and pulp fibroblasts is impaired by monomers such as HEMA through the disturbance of the redox homeostasis.}, } @article {pmid35339751, year = {2022}, author = {Sapmaz, T and Sevgin, K and Topkaraoglu, S and Tekayev, M and Aktas, S and Coskun, G and Polat, S and Sapmaz, E and Irkorucu, O}, title = {Comparison of melatonin, oxytetracycline, and N-acetylcysteine pre-treatments in autologous intraperitoneal ovarian transplantation in rats.}, journal = {Biochemical and biophysical research communications}, volume = {606}, number = {}, pages = {49-54}, doi = {10.1016/j.bbrc.2022.03.065}, pmid = {35339751}, issn = {1090-2104}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Female ; *Melatonin/pharmacology ; *Ovary/transplantation ; *Oxytetracycline/pharmacology ; Rats ; Rats, Wistar ; bcl-2-Associated X Protein ; }, abstract = {This study was aimed at investigating the effects of melatonin, oxytetracycline and N-acetylcysteine on the ovarian follicle reserves and surface epithelium in autologous intraperitoneal ovarian transplantation in rats. Thirty adult female Wistar Albino were selected and randomly divided into six groups (n = 5). Group 1, which was the control group, only had their abdomens opened and closed while Group 2 underwent ovarian transplantation. Group 3, 4, 5 and 6 received 20 μg/kg/IM melatonin, 10 mg/kg/IM oxytetracycline, 150 mg/kg/IP N-Asetil sistein (NAC) and 1% ethanol respectively 15 min before the ovarian transplantation. Vaginal cytology was performed to monitor the estrus phase and the follicle reserve and changes in the surface epithelium were histopathologically evaluated during the preparations. Moreover, cellular apoptosis in tissues was evaluated with immunofluorescence staining of Bcl-2 and Bax. The Bax/Bcl-2 ratio was then calculated as the mean fluorescence intensity (MFI) of Bax and Bcl-2 MFI. Dysplastic change was found only significantly higher in the transplantation group (G2) (p < 0.01). Histopathologically, it was found that the follicle reserve was preserved significantly in the oxytetracycline and melatonin treated group (G3, G4) (p < 0.01). It was also observed that the oxytetracycline treated group (G4) were able to show better preventive effects against dysplastic changes of the surface epithelium. Moreover, the melatonin treated group depicted a low Bax/Bcl-2 ratio compared to the group that only underwent transplantation (G2) (p < 0.01). This study indicated that oxytetracycline and melatonin might be more effective than N-acetylcysteine in protecting against oxidative stress during ovarian transplantation.}, } @article {pmid35338924, year = {2022}, author = {Phan, H and Cossutta, M and Houppe, C and Le Cœur, C and Prevost, S and Cascone, I and Courty, J and Penelle, J and Couturaud, B}, title = {Polymerization-Induced Self-Assembly (PISA) for in situ drug encapsulation or drug conjugation in cancer application.}, journal = {Journal of colloid and interface science}, volume = {618}, number = {}, pages = {173-184}, doi = {10.1016/j.jcis.2022.03.044}, pmid = {35338924}, issn = {1095-7103}, mesh = {Doxorubicin/metabolism/pharmacology ; Drug Carriers ; Humans ; Methacrylates ; Micelles ; *Nanoparticles ; *Neoplasms ; Polymerization ; Polymers ; }, abstract = {HYPOTHESIS: We describe the possibility of using the same block copolymer carriers prepared by PISA for in situ drug encapsulation or drug conjugation.

EXPERIMENTS: Block copolymers containing poly((ethylene glycol) methacrylate)-co-poly(pentafluorophenyl methacrylate)-b-poly(hydroxypropyl methacrylate) (P((PEGMA-co-PFBMA)-b-PHPMA)) were synthesized at 10 wt% using PISA. The first approach involved in situ Doxorubicin (DOX) loading during PISA, while the second exhibited surface functionalization of PISA-made vesicles with dual drug therapies, N-acetyl cysteine (NAC) and DOX using para-fluoro-thiol reaction (PFTR) and carbodiimide chemistry, respectively. Cytotoxicity, cell uptake, and cell apoptosis were assessed on MDA-MB-231 cell lines.

FINDINGS: P((PEGMA-co-PFBMA)-b-PHPMA) nanocarriers were prepared, showing size and shape transformations from spheres, cylinders to raspberry-forming vesicles. DOX was readily loaded into NPs during PISA with relatively high encapsulation efficiency of 70 %, whereas the plain PISA-made vesicles could be functionalized with NAC and DOX at high yields. DOX-free NPs showed biocompatibility, whilst DOX-conjugated NPs imparted a concentration-dependent cytotoxicity, as well as an enhanced cell uptake compared to free DOX. The results demonstrated that the same PISA-derived self-assemblies enabled either in situ drug encapsulation, or post-polymerization surface engineering with useful functionalities upon tuning the macro-CTA block, thus holding promises for future drug delivery and biomedical applications.}, } @article {pmid35331045, year = {2023}, author = {Chen, B and Raja, K and Pierre-Louis, F and Patel, M and Patel, R and Kang, S and Daniel, N and Attalla, M and Philips, M}, title = {Intravenous N-Acetylcysteine in Management of COVID-19: A Case Series.}, journal = {Journal of pharmacy practice}, volume = {36}, number = {4}, pages = {1008-1014}, pmid = {35331045}, issn = {1531-1937}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *COVID-19 ; NF-kappa B ; Cytokine Release Syndrome/drug therapy ; Glutathione Reductase ; Retrospective Studies ; Glutathione ; SARS-CoV-2 ; }, abstract = {A novel coronavirus, severe acute respiratory syndrome coronavirus-2, was isolated from patients' lower respiratory tracts in December 2019. As of May 19, 2021, there were over 33 million reported infections and almost 600,000 deaths in the United States. The infection, coronavirus disease-19 (COVID-19), can lead to cytokine storm, with elevations in interleukin-6 (IL-6), IL-10, tumor necrosis factor-α, nuclear factor-kappaB (NF-kappaB), and glutathione reductase. NF-kappaB activation is necessary for further transcription of other pro-inflammatory markers. Glutathione may play a role in modulation of NF-kappaB activation and elevated glutathione reductase may indicate glutathione depletion. Administration of N-acetylcysteine (NAC) may replenish spent glutathione and attenuate over-activation of NF-kappaB. This retrospective case series included 10 patients who were COVID-19 positive and received intravenous NAC in an attempt to attenuate the cytokine storm. Patients' outcomes were graded based on the World Health Organization symptom severity scale from 0, no evidence of infection, to 8, death. Overall, the median WHO Scale prior to NAC was 6.5, and increased by day seven, which indicated clinical worsening. This retrospective case series showed no benefit of NAC; however, further studies are needed to elucidate if differences in drug regimens would lead to positive results.}, } @article {pmid35328386, year = {2022}, author = {Argaev-Frenkel, L and Rosenzweig, T}, title = {Complexity of NAC Action as an Antidiabetic Agent: Opposing Effects of Oxidative and Reductive Stress on Insulin Secretion and Insulin Signaling.}, journal = {International journal of molecular sciences}, volume = {23}, number = {6}, pages = {}, pmid = {35328386}, issn = {1422-0067}, support = {3-11350//D-Cure/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; *Diabetes Mellitus, Experimental/complications/drug therapy ; *Diabetes Mellitus, Type 2/complications/drug therapy ; Hydrogen Peroxide/pharmacology ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin/metabolism ; Insulin Secretion ; Mice ; Oxidation-Reduction ; Oxidative Stress ; }, abstract = {Dysregulated redox balance is involved in the pathogenesis of type 2 diabetes. While the benefit of antioxidants in neutralizing oxidative stress is well characterized, the potential harm of antioxidant-induced reductive stress is unclear. The aim of this study was to investigate the dose-dependent effects of the antioxidant N-acetylcysteine (NAC) on various tissues involved in the regulation of blood glucose and the mechanisms underlying its functions. H2O2 was used as an oxidizing agent in order to compare the outcomes of oxidative and reductive stress on cellular function. Cellular death in pancreatic islets and diminished insulin secretion were facilitated by H2O2-induced oxidative stress but not by NAC. On the other hand, myotubes and adipocytes were negatively affected by NAC-induced reductive stress, as demonstrated by the impaired transmission of insulin signaling and glucose transport, as opposed to H2O2-stimulatory action. This was accompanied by redox balance alteration and thiol modifications of proteins. The NAC-induced deterioration of insulin signaling was also observed in healthy mice, while both insulin secretion and insulin signaling were improved in diabetic mice. This study establishes the tissue-specific effects of NAC and the importance of the delicate maintenance of redox balance, emphasizing the challenge of implementing antioxidant therapy in the clinic.}, } @article {pmid35326237, year = {2022}, author = {Yu, TJ and Tang, JY and Shiau, JP and Hou, MF and Yen, CH and Ou-Yang, F and Chen, CY and Chang, HW}, title = {Gingerenone A Induces Antiproliferation and Senescence of Breast Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {35326237}, issn = {2076-3921}, support = {MOST 108-2320-B-037-015-MY3; MOST 110-2314-B-037-074-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 111-P20//National Sun Yat-sen University-KMU Joint Research Project/ ; KMUH110-0M39//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Ginger is a popular spice and consists of several bioactive antioxidant compounds. Gingerenone A (Gin A), a novel compound isolated from Zingiber officinale, is rarely investigated for its anti-breast-cancer properties. Some ginger extracts have been reported to initiate senescence, an anticancer strategy. However, the anticancer effects of Gin A on breast cancer cells remain unclear. The present study aims to assess the modulating impact of Gin A acting on proliferation and senescence to breast cancer cells. Gin A diminished the cellular ATP content and decreased the cell viability of the MTS assay in several breast cancer cell lines. It also showed a delayed G2/M response to breast cancer cells (MCF7 and MDA-MB-231). N-acetylcysteine (NAC), an oxidative stress inhibitor, can revert these responses of antiproliferation and G2/M delay. The oxidative stress and senescence responses of Gin A were further validated by increasing reactive oxygen species, mitochondrial superoxide, and β-galactosidase activity, which were reverted by NAC. Gin A also upregulated senescence-associated gene expressions. In addition to oxidative stress, Gin A also induced DNA damage responses by increasing γH2AX level and foci and generating 8-hydroxyl-2'-deoxyguanosine in breast cancer cells, which were reverted by NAC. Therefore, Gin A promotes antiproliferation and senescence of breast cancer cells induced by oxidative stress.}, } @article {pmid35326096, year = {2022}, author = {Eligini, S and Porro, B and Aldini, G and Colli, S and Banfi, C}, title = {N-Acetylcysteine Inhibits Platelet Function through the Regeneration of the Non-Oxidative Form of Albumin.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {35326096}, issn = {2076-3921}, support = {Ricerca Corrente RC 2021 MPP1A ID 2746191.//Italian Ministry of Health Ricerca Corrente RC 2021 MPP1A ID 2746191)./ ; }, abstract = {N-acetylcysteine (NAC) is able to break down protein disulfides, generating free thiols. This mechanism occurs on mixed disulfides of albumin (HSA) to form mercaptoalbumin (HMA), the main antioxidant species in the plasma. Circulating HSA exists in two main forms: the reduced form (HMA), and the oxidized forms, whose predominant modification is cystenylation (HSA-Cys). Increased levels of oxidized HSA have been detected in several diseases associated with oxidative stress. This study showed that NAC inhibits platelet aggregation by restoring HMA. In addition, the regeneration of HMA by NAC inhibits platelet functions such as intracellular calcium mobilization, reactive oxygen species generation, arachidonic acid metabolites synthesis, and adhesion to the collagen matrix. In our conditions, the exposure of platelets to NAC did not increase GSH levels. However, the inhibition of platelet aggregation was also detected following treatment of platelet-rich plasma with GSH, which, similarly to NAC, reduced HSA-Cys levels. Furthermore, this study showed that cysteine, another compound able to restore HMA by reducing the HSA-Cys content, inhibited platelet aggregation to a similar extent as NAC. The results obtained in this study suggest a new mechanism by which NAC can modulate platelet activation and suggest its possible use as an antiplatelet drug in conditions associated with oxidative stress.}, } @article {pmid35320665, year = {2022}, author = {Hur, J and Rhee, CK and Jo, YS}, title = {Effects of Antioxidant on Oxidative Stress and Autophagy in Bronchial Epithelial Cells Exposed to Particulate Matter and Cigarette Smoke Extract.}, journal = {Tuberculosis and respiratory diseases}, volume = {85}, number = {3}, pages = {237-248}, pmid = {35320665}, issn = {1738-3536}, support = {//The Korean Academy of Tuberculosis and Respiratory Diseases/ ; }, abstract = {BACKGROUND: We evaluated the effect of particulate matter (PM) and cigarette smoke extract (CSE) on bronchial epithelial cell survival, as well as oxidative stress and autophagy levels. Moreover, we aimed to assess the effect of the antioxidant N-acetylcysteine (NAC) on the adverse effects of PM and CSE exposure.

METHODS: Normal human bronchial epithelial cells (BEAS-2B cells) were exposed to urban PM with or without CSE, after which cytotoxic effects, including oxidative stress and autophagy levels, were measured. After identifying the toxic effects of urban PM and CSE exposure, the effects of NAC treatment on cell damage were evaluated.

RESULTS: Urban PM significantly decreased cell viability in a concentration-dependent manner, which was further aggravated by simultaneous treatment with CSE. Notably, pretreatment with NAC at 10 mM for 1 hour reversed the cytotoxic effects of PM and CSE co-exposure. Treatment with 1, 5, and 10 mM NAC was shown to decrease reactive oxygen species levels induced by exposure to both PM and CSE. Additionally, the autophagy response assessed via LC3B expression was increased by PM and CSE exposure, and this also attenuated by NAC treatment.

CONCLUSION: The toxic effects of PM and CSE co-exposure on human bronchial epithelial cells, including decreased cell viability and increased oxidative stress and autophagy levels, could be partly prevented by NAC treatment.}, } @article {pmid35316693, year = {2022}, author = {Chen, Q and Huang, J and Tong, W and Gui, X and Zheng, J and Hu, G}, title = {The geometry-dependent regulation of hepatic stellate cells by graphene oxide nanomaterials.}, journal = {Biochemical and biophysical research communications}, volume = {604}, number = {}, pages = {179-184}, doi = {10.1016/j.bbrc.2022.03.050}, pmid = {35316693}, issn = {1090-2104}, mesh = {Fibrosis ; *Graphite/pharmacology ; Hepatic Stellate Cells/metabolism ; Humans ; Liver/metabolism ; Liver Cirrhosis/metabolism ; *Nanostructures ; Transforming Growth Factor beta1/metabolism ; }, abstract = {Nanomaterials are widely used in biomedical applications such as drug delivery, bioimaging, and photothermal therapy. For example, graphene oxide (GO) nanomaterials are among the most popular drug delivery vehicles in treating liver diseases due to their tunable chemical/physical properties, and biocompatibility. However, it has been reported that nanomaterials tend to accumulate in livers. The biophysical impact of the accumulation in liver cells remains unclear, and it may cause the liver fibrosis in the long run. The activation of hepatic stellate cells (HSCs) is one of the key initial steps of liver fibrosis. In this paper, we explored the geometric effect (nanosheets vs. quantum dots) of GO nanomaterials on human HSCs, in terms of cell viability, fibrotic degree, mobility and regulation pathways. Our study showed that GO nanosheets could significantly reduce HSCs cell viability and mobility. The protein expression levels of TGFβRⅡ/Smad2/Smad3 decreased, corresponding to a trend of attenuating fibrotic degree. However, the expression level of α-SMA, a maker protein of fibrosis, increased and contradicted with the projection. Further investigation on mitochondria showed that GO nanosheets disrupted mitochondria membrane and membrane potentials. We found that while modulating fibrotic effect through the TGF-β pathway, GO nanosheets induced oxidative stress and activated HSCs through reactive oxygen species(ROS)pathway. This was confirmed by the decreased expression level of α-SMA after co-incubation of GO nanosheets and n-acetyl cysteine (NAC) with HSCs. GO quantum dots decreased α-SMA expression level at 100 mg/l, along with decrease in GAPDH expression level and constant expression level of β-actin. The correlation between GAPDH and α-SMA remains to be explored. Our study suggested that the biophysical impacts of GO nanomaterials on HSCs are geometry-dependent. Both GO nanosheets and quantum dots can be adapted for attenuating liver fibrosis with further investigation on mechanisms.}, } @article {pmid35316513, year = {2022}, author = {Bradlow, RCJ and Berk, M and Kalivas, PW and Back, SE and Kanaan, RA}, title = {The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders.}, journal = {CNS drugs}, volume = {36}, number = {5}, pages = {451-482}, pmid = {35316513}, issn = {1179-1934}, mesh = {Acetylcysteine/therapeutic use ; Anxiety Disorders/drug therapy ; *Bipolar Disorder/drug therapy ; Humans ; *Obsessive-Compulsive Disorder/drug therapy ; *Schizophrenia/drug therapy ; }, abstract = {N-acetyl-L-cysteine (NAC) is a compound of increasing interest in the treatment of psychiatric disorders. Primarily through its antioxidant, anti-inflammatory, and glutamate modulation activity, NAC has been investigated in the treatment of neurodevelopmental disorders, schizophrenia spectrum disorders, bipolar-related disorders, depressive disorders, anxiety disorders, obsessive compulsive-related disorders, substance-use disorders, neurocognitive disorders, and chronic pain. Whilst there is ample preclinical evidence and theoretical justification for the use of NAC in the treatment of multiple psychiatric disorders, clinical trials in most disorders have yielded mixed results. However, most studies have been underpowered and perhaps too brief, with some evidence of benefit only after months of treatment with NAC. Currently NAC has the most evidence of having a beneficial effect as an adjuvant agent in the negative symptoms of schizophrenia, severe autism, depression, and obsessive compulsive and related disorders. Future research with well-powered studies that are of sufficient length will be critical to better understand the utility of NAC in the treatment of psychiatric disorders.}, } @article {pmid35316061, year = {2022}, author = {Shi, J and Zhao, M and Li, K and Zhao, Y and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Fungicide Carbendazim Mediated by CYP1A2.}, journal = {Journal of agricultural and food chemistry}, volume = {70}, number = {13}, pages = {4092-4101}, doi = {10.1021/acs.jafc.1c08144}, pmid = {35316061}, issn = {1520-5118}, mesh = {Activation, Metabolic ; Animals ; Benzimidazoles ; Carbamates/metabolism/toxicity ; *Cytochrome P-450 CYP1A2/metabolism ; Glutathione/metabolism ; Microsomes, Liver/metabolism ; Rats ; *Zebrafish/metabolism ; }, abstract = {Carbendazim (CBZ) is a broad-spectrum fungicide widely used in many nations for foliar spray as well as seed and soil treatment. The resulting contamination and environmental pollution have been drawing public attention. In particular, CBZ was reported to cause liver damage in rats and zebrafish, and the mechanisms of its toxicity have not been clarified. The purposes of this study were to investigate the metabolic activation of CBZ and to determine a possible role of the reactive metabolites in CBZ-induced liver injury reported. One oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetyl cysteine conjugate (M3) were detected in human and rat liver microsomal incubations fortified with glutathione or N-acetyl cysteine after exposure to CBZ. CYP1A2 was the major enzyme responsible for the metabolic activation of CBZ. Biliary M2 and urinary M3 were detected in rats treated with CBZ. CBZ-derived protein adduction was found in cultured rat primary hepatocytes treated with CBZ. The increase of administration concentration intensified not only the cytotoxicity but also protein adduction induced by CBZ, suggesting a correlation of the cytotoxicity with the observed protein modification. The findings facilitate the understanding of the mechanisms of toxic action of CBZ.}, } @article {pmid35311615, year = {2022}, author = {Sarris, J and Ravindran, A and Yatham, LN and Marx, W and Rucklidge, JJ and McIntyre, RS and Akhondzadeh, S and Benedetti, F and Caneo, C and Cramer, H and Cribb, L and de Manincor, M and Dean, O and Deslandes, AC and Freeman, MP and Gangadhar, B and Harvey, BH and Kasper, S and Lake, J and Lopresti, A and Lu, L and Metri, NJ and Mischoulon, D and Ng, CH and Nishi, D and Rahimi, R and Seedat, S and Sinclair, J and Su, KP and Zhang, ZJ and Berk, M}, title = {Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {23}, number = {6}, pages = {424-455}, doi = {10.1080/15622975.2021.2013041}, pmid = {35311615}, issn = {1814-1412}, mesh = {Adolescent ; Humans ; *Biological Psychiatry ; Canada ; *Mental Disorders/drug therapy ; Anxiety ; Dietary Supplements ; *Fatty Acids, Omega-3 ; Vitamin D ; Zinc ; }, abstract = {OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations.

METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed.

RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy.

CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.}, } @article {pmid35310492, year = {2022}, author = {Wang, R and Chan, JF and Wang, S and Li, H and Zhao, J and Ip, TK and Zuo, Z and Yuen, KY and Yuan, S and Sun, H}, title = {Orally administered bismuth drug together with N-acetyl cysteine as a broad-spectrum anti-coronavirus cocktail therapy.}, journal = {Chemical science}, volume = {13}, number = {8}, pages = {2238-2248}, pmid = {35310492}, issn = {2041-6520}, abstract = {The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs, e.g. colloidal bismuth subcitrate (CBS) or bismuth subsalicylate (BSS), and N-acetyl-l-cysteine (NAC). Oral administration of the cocktail reduced viral loads in the lung and ameliorated virus-induced pneumonia in a hamster infection model. The mechanistic studies showed that NAC prevented the hydrolysis of bismuth drugs at gastric pH via the formation of the stable component [Bi(NAC)3], and optimized the pharmacokinetics profile of CBS in vivo. Combination of bismuth drugs with NAC suppressed the replication of a panel of medically important coronaviruses including Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus 229E (HCoV-229E) and SARS-CoV-2 Alpha variant (B.1.1.7) with broad-spectrum inhibitory activities towards key viral cysteine enzymes/proteases including papain-like protease (PL[pro]), main protease (M[pro]), helicase (Hel) and angiotensin-converting enzyme 2 (ACE2). Importantly, our study offered a potential at-home treatment for combating SARS-CoV-2 and future coronavirus infections.}, } @article {pmid35305384, year = {2022}, author = {Zhang, Y and Yan, M and Niu, W and Mao, H and Yang, P and Xu, B and Sun, Y}, title = {Tricalcium phosphate particles promote pyroptotic death of calvaria osteocytes through the ROS/NLRP3/Caspase-1 signaling axis in amouse osteolysis model.}, journal = {International immunopharmacology}, volume = {107}, number = {}, pages = {108699}, doi = {10.1016/j.intimp.2022.108699}, pmid = {35305384}, issn = {1878-1705}, mesh = {Animals ; Calcium Phosphates ; Caspase 1/metabolism ; Inflammasomes/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; NLR Proteins/metabolism ; *Osteocytes ; *Osteolysis/metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Skull/metabolism ; }, abstract = {Wear particles-induced inflammatory osteolysis, a major factor of aseptic loosening affects the long-term survival of orthopedic prostheses. Increasing observations have demonstrated that osteocytes, making up over 95% of all the bone cells, is involved in wear particle-induced periprosthetic osteolysis, but its mechanism remains unclear. In the present study, we embedded micro-sized tricalcium phosphate (TCP) particles (30 mg) under the periosteum around the middle suture of the mouse calvaria to establish a calvarial osteolysis model and investigated the biological effects of the particles on calvaria osteocytes in vivo. Results showed that TCP particles induced pyroptosis and activated the NLRP3 inflammasome in calvaria osteocytes, which was confirmed by obvious increases in empty lacunae, protein expressions of speck-like protein containing CARD (ASC), NOD-like receptor protein 3 (NLRP3), cleaved caspase-1 (Casp-1 p20) and cleaved gasdermin D (GSDMD-N), and resulted in elevated ratios of Casp-1 p20/Casp-1 and interleukin (IL)-1β/pro-IL-1β. Simultaneously, TCP particles enhanced serum levels of lactate dehydrogenase (LDH) and IL-1β. Furthermore, the pyroptotic effect was reversed by the Casp-1 inhibitor VX765 or the NLRP3 inhibitor MCC950. In addition, TCP particles increased the levels of intracellular reactive oxygen species (ROS) and malonaldehyde (MDA), whereas decreased the antioxidant enzyme nuclear factor E2-related factor 2 (Nrf2) level, leading to oxidative stress in calvaria osteocytes; the ROS scavenger N-acetylcysteine (NAC) attenuated these effects of pyroptotic death and the NLPR3 activation triggered by TCP particles. Collectively, our data suggested that TCP particles promote pyroptotic death of calvaria osteocytes through the ROS/NLRP3/Caspase-1 signaling axis, contributing to osteoclastogenesis and periprosthetic osteolysis.}, } @article {pmid35304155, year = {2022}, author = {Sarris, J and Byrne, G and Castle, D and Bousman, C and Oliver, G and Cribb, L and Blair-West, S and Brakoulias, V and Camfield, D and Ee, C and Chamoli, S and Boschen, M and Dean, OM and Dowling, N and Menon, R and Murphy, J and Metri, NJ and Nguyen, TP and Wong, A and Jordan, R and Karamacoska, D and Rossell, SL and Berk, M and Ng, CH}, title = {N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {117}, number = {}, pages = {110550}, doi = {10.1016/j.pnpbp.2022.110550}, pmid = {35304155}, issn = {1878-4216}, mesh = {*Acetylcysteine/therapeutic use ; Double-Blind Method ; Humans ; *Obsessive-Compulsive Disorder/therapy ; Quality of Life ; Treatment Outcome ; }, abstract = {OBJECTIVE: Preliminary evidence has suggested that adjunctive N-acetylcysteine (NAC), an antioxidant precursor to glutathione, may reduce symptoms of obsessive-compulsive disorder (OCD). We conducted a 20-week, multi-site, randomized controlled trial to investigate the safety and efficacy of the adjunctive use of NAC in OCD.

METHODS: The study was a phase III, 20-week, double-blind, randomized controlled trial across multiple sites in Australia investigating 2 g to 4 g per day of NAC (titrated according to response) in 98 participants with DSM-5 diagnosed OCD. Data were analysed using linear mixed effects models for the 89 participants who attended at least one follow-up visit.

RESULTS: A modified intention-to-treat analysis of the primary outcome found no evidence that NAC reduced symptoms of OCD measured on the Yale-Brown Obsessive-Compulsive Scale, relative to placebo (mean difference at week 20 = 0.53, 95% compatibility interval = -2.18, 3.23; p = 0.70; favouring placebo). There was also no evidence that NAC, compared to placebo, improved outcomes on the secondary measures including anxiety, depression, quality of life, functioning, or clinician/participant impression. NAC was well-tolerated with only mild gastrointestinal adverse events associated with the treatment.

CONCLUSION: We found no evidence supporting the efficacy of the adjunctive use of NAC in OCD.}, } @article {pmid35296207, year = {2022}, author = {Zhao, L and Zhang, R and Zhang, S and Zhang, H and Yang, Q and Xu, Z}, title = {Upregulation of p67[phox] in response to ischemia/reperfusion is cardioprotective by increasing ZIP2 expression via STAT3.}, journal = {Free radical research}, volume = {56}, number = {1}, pages = {115-126}, doi = {10.1080/10715762.2022.2052057}, pmid = {35296207}, issn = {1029-2470}, mesh = {Animals ; Mice ; Cation Transport Proteins ; Ischemia ; NADPH Oxidase 2/genetics/metabolism ; *NADPH Oxidases/metabolism ; Phosphoproteins ; Reactive Oxygen Species/metabolism ; Reperfusion ; *Reperfusion Injury ; STAT3 Transcription Factor ; Up-Regulation ; }, abstract = {While the zinc transporter ZIP2 (Slc39a2) is upregulated via STAT3 as an adaptive response to protect the heart from ischemia/reperfusion (I/R) injury, the precise mechanism underlying its upregulation remains unclear. The purpose of this study was to investigate the role of NADPH oxidase (NOX) isoform NOX2-derived ROS in the regulation of ZIP2 expression, focusing on the role of the NOX2 cytosolic factor p67[phox]. Mouse hearts or H9c2 cells were subjected to I/R. Protein expression was detected with Western blotting. Infarct size was measured with TTC staining. The cardiac-specific p67[phox] conditional knockout mice (p67[phox] cKO) were generated by adopting the CRISPR/Cas9 system. I/R-induced upregulation of STAT3 phosphorylation and ZIP2 expression was reversed by the ROS scavenger N-acetylcysteine (NAC) and the NOX inhibitor diphenyleneiodonium (DPI). p67[phox] but not NOX2 expression was increased 30 min after the onset of reperfusion, and downregulation of p67[phox] by siRNA or cKO invalidated I/R-induced upregulation of STAT3 phosphorylation and ZIP2 expression. Both NAC and DPI prevented upregulation of STAT3 phosphorylation and ZIP2 expression induced by overexpression of p67[phox], whereas the STAT3 inhibitor stattic abrogated upregulation ZIP2 expression, indicating that the increase of p67[phox] at reperfusion is an upstream signaling event responsible for ZIP2 upregulation via STAT3. Experiments also showed that chelation of Zn[2+] markedly enhanced p67[phox] and ZIP2 expression as well as STAT3 phosphorylation, whereas supplementation of Zn[2+] had the opposite effects, indicating that cardiac Zn[2+] loss upon reperfusion triggers p67[phox] upregulation. Furthermore, ischemic preconditioning (IPC) upregulated ZIP2 via p67[phox], and cKO of p67[phox] aggravated cardiac injury after I/R, indicating that p67[phox] upregulation is cardioprotective against I/R injury. In conclusion, an increase of p67[phox] expression in response to Zn[2+] is an intrinsic adaptive response to I/R and leads to cardioprotection against I/R by upregulating ZIP2 via STAT3.}, } @article {pmid35292969, year = {2022}, author = {}, title = {Editor's Note: Aghaamoo, S., Zandbina, A., Saffarieh, E. and Nassiri, S. (2021), The effect of N-acetyl cysteine on the volume of uterine leiomyoma: A randomized clinical trial. Int J Gynecol Obstet, 154: 521-525. https://doi.org/10.1002/ijgo.13611.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijgo.14124}, pmid = {35292969}, issn = {1879-3479}, } @article {pmid35292334, year = {2022}, author = {Duan, L and Sanchez-Guerrero, G and Jaeschke, H and Ramachandran, A}, title = {Activation of the adenosine A2B receptor even beyond the therapeutic window of N-acetylcysteine accelerates liver recovery after an acetaminophen overdose.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {163}, number = {}, pages = {112911}, pmid = {35292334}, issn = {1873-6351}, support = {P30 GM103326/GM/NIGMS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Animals ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention & control ; *Drug Overdose/drug therapy ; Female ; Liver ; Male ; Mice ; Mice, Inbred C57BL ; Receptor, Adenosine A2B/therapeutic use ; }, abstract = {Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the USA. The short therapeutic window of the current antidote, N-acetylcysteine (NAC) highlights the need for novel late acting therapeutics. The neuronal guidance cue netrin-1 provides delayed protection against APAP hepatotoxicity through the adenosine A2B receptor (A2BAR). The clinical relevance of this mechanism was investigated here by administration of the A2BAR agonist BAY 60-6583, after an APAP overdose (300 or 600 mg/kg) in fasted male and female C57BL/6J mice with assessment of liver injury 6 or 24 h after APAP in comparison to NAC. BAY 60-6583 treatment 1.5 h after APAP overdose (600 mg/kg) protected against liver injury at 6 h by preserving mitochondrial function despite JNK activation and its mitochondrial translocation. Gender independent protection was sustained when BAY 60-6583 was given 6 h after APAP overdose (300 mg/kg), when NAC administration did not show benefit. This protection was accompanied by enhanced infiltration of macrophages with the reparative anti-inflammatory phenotype by 24 h, accompanied by a decrease in neutrophil infiltration. Thus, our data emphasize the remarkable therapeutic utility of using an A2BAR agonist, which provides delayed protection long after the standard of care NAC ceased to be effective.}, } @article {pmid35292112, year = {2022}, author = {Lin, YC and Lin, YC and Tsai, ML and Liao, WT and Hung, CH}, title = {TSLP regulates mitochondrial ROS-induced mitophagy via histone modification in human monocytes.}, journal = {Cell & bioscience}, volume = {12}, number = {1}, pages = {32}, pmid = {35292112}, issn = {2045-3701}, support = {MOST109-2320-B-037-013//Ministry of Science and Technology, Taiwan/ ; MOST108-2314-B-037-071-//Ministry of Science and Technology, Taiwan/ ; 103-CCH-KMU-005//Kaohsiung Medical University/ ; KMU-TC109A01-1//Kaohsiung Medical University/ ; KMUH107-7R86//Kaohsiung Medical University Hospital/ ; S-109-05//Kaohsiung Municipal Siaogang Hospital/ ; I109-02//Kaohsiung Municipal Siaogang Hospital/ ; }, abstract = {BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a Th2-like cytokine involved in asthma pathogenesis. Excessive reactive oxygen species (ROS) production can lead to airway inflammation, hyperresponsiveness and remodeling. Mitophagy, followed by ROS production, is the selective degradation of mitochondria by autophagy and often occurs in defective mitochondria. In the present study, we aimed to examine the effects of TSLP on ROS production and mitophagy in human monocytes and to investigate the underlying mechanisms, including epigenetic regulation.

RESULTS: TSLP induced ROS generation, and the effects were reversed by the antioxidant N-acetylcysteine (NAC) in THP-1 cells. Transmission electron microscopy images showed donut-shaped mitochondria that lost the cristae ultrastructure after TSLP stimulation. A decrease in mitochondrial membrane potential, decreased MTCO2 expression, and increased mitochondrial DNA release after TSLP stimulation were found. TSLP enhanced mitochondrial complex I and complex II/III activity and increased mitochondrial copy numbers and the expression of the complex II SHDA gene. TSLP-induced SHDA expression was inhibited by the histone acetyltransferase inhibitor anacardic acid (AA) and the histone methyltransferase inhibitor methylthioadenosine (MTA), and chromatin immunoprecipitation assays revealed that TSLP enhanced H3 acetylation, H4 acetylation, and H3K4 and H3K36 trimethylation in the SHDA promoter. Confocal laser microscopy showed that TSLP treatment increased the signals of the mitophagy-related proteins PINK1, LC3, phospho-parkin and phospho-ubiquitin, and pretreatment with AA and MTA reduced TSLP-induced PINK1 and LC3 accumulation in mitochondria. Western blot analysis showed that TSLP significantly increased phosphor-AMPK signal intensity, and the effects were inhibited by the antioxidant NAC. The increased signal intensities of the mitophagy-related proteins PINK1, Parkin and LC3 I/II were decreased by dorsomorphin, an AMPK inhibitor. TSLP decreased M1-related cytokine CXCL-10 production and increased M2-related cytokine CCL-1 and CCL-22 production, which was suppressed by the mitophagy inhibitor Mdivi-1 and PINK1 gene knockdown.

CONCLUSIONS: Epithelial-derived TSLP regulates ROS production and mitophagy through AMPK activation and histone modification and alters M1/M2 chemokine expression in human monocytes.}, } @article {pmid35288263, year = {2022}, author = {Cheng, WC and Wen, Y and Chiu, YS and Chou, CH and Lim, CJ and Lin, SH and Chang, JM and Lin, CC}, title = {Pendulone induces apoptosis via the ROS-mediated ER-stress pathway in human non-small cell lung cancer cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {81}, number = {}, pages = {105346}, doi = {10.1016/j.tiv.2022.105346}, pmid = {35288263}, issn = {1879-3177}, mesh = {Apoptosis ; *Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Endoplasmic Reticulum Stress ; Humans ; *Isoflavones/pharmacology ; *Lung Neoplasms/metabolism ; Membrane Potential, Mitochondrial ; Quinones ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: Pendulone, an isoflavone compound, is known to act against human cancer cells. However, its role in human non-small cell lung cancer (NSCLC) and the exact molecular mechanisms of action have never been reported.

METHODS: We investigated the effects of pendulone on cell proliferation and apoptosis in human NSCLC H1299 cells. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was employed to evaluate apoptotic indices such as the cell cycle, mitochondrial membrane potential, cytochrome c release, caspase activity, and death receptor expression. The expression of proteins related to the cell cycle and apoptosis were analyzed by Western blot analysis.

RESULTS: Pendulone significantly decreased H1299 cell viability by inducing endoplasmic reticulum (ER) stress through the accumulation of reactive oxygen species (ROS). Pendulone induced the expression of ER stress-associated proteins, such as ATF4 and CHOP, which promoted the expression of death receptors. Activation of caspase 8 induced extrinsic pathway apoptosis. Pendulone also caused the loss of mitochondrial membrane potential, inhibited the anti-apoptotic proteins BCL-2 and activated the pro-apoptotic protein BAX, which promoted the release of cytochrome c to activate caspase 9. Antioxidant N-acetylcysteine (NAC), with its ROS-suppressive property, reversed pendulone-induced ER stress and cell apoptosis.

CONCLUSION: Our findings provide evidence that pendulone induces apoptosis by inducing ER stress through ROS accumulation and mitochondrial dysfunction in NSCLC cell lines.}, } @article {pmid35287541, year = {2022}, author = {Chen, BC and Lin, LJ and Lin, YC and Lee, CF and Hsu, WC}, title = {Optimal N-acetylcysteine concentration for intratympanic injection to prevent cisplatin-induced ototoxicity in guinea pigs.}, journal = {Acta oto-laryngologica}, volume = {142}, number = {2}, pages = {127-131}, doi = {10.1080/00016489.2022.2038796}, pmid = {35287541}, issn = {1651-2251}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Cisplatin/toxicity ; Evoked Potentials, Auditory, Brain Stem ; Guinea Pigs ; Injection, Intratympanic ; *Ototoxicity ; }, abstract = {BACKGROUND: Cisplatin is a chemotherapy drug that can induce sensorineural hearing loss. At present, no otoprotective agent is approved for use.

OBJECTIVES: This study investigated the optimal concentration of intratympanic N-acetylcysteine (NAC) to prevent cisplatin-induced ototoxicity in a guinea pig model.

MATERIALS AND METHODS: Guinea pigs (n = 64) were treated with a single intratympanic injection containing different NAC concentrations or saline (control) 3 days prior to intraperitoneal injection with cisplatin. The threshold change in the auditory brainstem response was assessed.

RESULTS: Four weeks after intraperitoneal cisplatin injection, only the group that received 2% NAC exhibited significant otoprotection (p < .05) compared with the control. Otoprotection was observed at all the frequencies tested (1k, 2k, 4k, and 8k Hz). The 2% NAC group also exhibited significant otoprotection (p < .05) compared with the other NAC groups (at 1k, 2k, 4k, and 8k Hz). The 4% NAC group exhibited significantly reduced hearing capacity (p < .05) in the fourth week compared with controls.

CONCLUSIONS AND SIGNIFICANCE: Intratympanic NAC administration is an efficient and safe means of preventing cisplatin-induced ototoxicity. In our animal model, the optimal intratympanic NAC concentration was 2%; concentrations of 4% loss of otoprotection.}, } @article {pmid35287043, year = {2022}, author = {Xu, X and Shao, G and Zhang, X and Hu, Y and Huang, J and Su, Y and Zhang, M and Cai, Y and Zhou, H}, title = {The efficacy of nutritional supplements for the adjunctive treatment of schizophrenia in adults: A systematic review and network meta-analysis.}, journal = {Psychiatry research}, volume = {311}, number = {}, pages = {114500}, doi = {10.1016/j.psychres.2022.114500}, pmid = {35287043}, issn = {1872-7123}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Dietary Supplements ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Humans ; Network Meta-Analysis ; *Schizophrenia/drug therapy ; Vitamin B 12/therapeutic use ; Vitamin D/therapeutic use ; Vitamins ; }, abstract = {Nutritional supplementations have been widely used as adjunctive treatments for schizophrenia. However, among these supplementations, of which the most beneficial is currently unknown. This study aimed to compare and rank the effectiveness of nutritional supplementations in the adjunctive treatments of schizophrenia. The four nutritional supplementations evaluated were: 1) folate acid or vitamin B12; 2) vitamin D; 3) N-acetyl cysteine (NAC); 4) Omega-3 polyunsaturated fatty acid, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). 17 eligible RCTs with 1165 participants were included in this network meta-analysis based on study criteria. NAC supplementation was significantly more efficacious than folic acid or vitamin B12 [MD (95% CI): -6.6 (-10.8, -2.4)] and omega-3 polyunsaturated fatty acid [MD (95% CI): -5.1(-9.9, -0.8)] supplementation in the term of PANSS score changes. There were no significant differences in the PANSS score changes between NAC and vitamin D [MD (95% CI): -5.2 (-10.9, 0.5)] supplementations. The estimated ranking probabilities of treatments showed that NAC might be the most effective adjunctive intervention over all nutritional supplementations. These results indicate that NAC could improve PANSS score and it may be among the most effective nutritional supplementations in schizophrenia patients.}, } @article {pmid35281576, year = {2022}, author = {Piktel, E and Wnorowska, U and Depciuch, J and Łysik, D and Cieśluk, M and Fiedoruk, K and Mystkowska, J and Parlińska-Wojtan, M and Janmey, PA and Bucki, R}, title = {N-Acetyl-Cysteine Increases Activity of Peanut-Shaped Gold Nanoparticles Against Biofilms Formed by Clinical Strains of Pseudomonas aeruginosa Isolated from Sputum of Cystic Fibrosis Patients.}, journal = {Infection and drug resistance}, volume = {15}, number = {}, pages = {851-871}, pmid = {35281576}, issn = {1178-6973}, abstract = {BACKGROUND: Extracellular polymeric substances (EPS) produced by bacteria, as they form a biofilm, determine the stability and viscoelastic properties of biofilms and prevent antibiotics from penetrating this multicellular structure. To date, studies demonstrated that an appropriate optimization of the chemistry and morphology of nanotherapeutics might provide a favorable approach to control their interaction with EPS and/or diffusion within the biofilm matrix. Targeting the biofilms' EPS, which in certain conditions can adopt liquid crystal structure, was demonstrated to improve the anti-biofilm activity of antibiotics and nanoparticles. A similar effect is achievable by interfering EPS' production by mucoactive agents, such as N-acetyl-cysteine (NAC). In our previous study, we demonstrated the nanogram efficiency of non-spherical gold nanoparticles, which due to their physicochemical features, particularly morphology, were noted to be superior in antimicrobial activity compared to their spherical-shaped counterparts.

METHODS: To explore the importance of EPS matrix modulation in achieving a suitable efficiency of peanut-shaped gold nanoparticles (AuP NPs) against biofilms produced by Pseudomonas aeruginosa strains isolated from cystic fibrosis patients, fluorescence microscopy, as well as resazurin staining were employed. Rheological parameters of AuP NPs-treated biofilms were investigated by rotational and creep-recovery tests using a rheometer in a plate-plate arrangement.

RESULTS: We demonstrated that tested nanoparticles significantly inhibit the growth of mono- and mixed-species biofilms, particularly when combined with NAC. Notably, gold nanopeanuts were shown to decrease the viscosity and increase the creep compliance of Pseudomonas biofilm, similarly to EPS-targeting NAC. Synergistic activity of AuP NPs with tobramycin was also observed, and the AuP NPs were able to eradicate bacteria within biofilms formed by tobramycin-resistant isolates.

CONCLUSION: We propose that peanut-shaped gold nanoparticles should be considered as a potent therapeutic agent against Pseudomonas biofilms.}, } @article {pmid35280167, year = {2022}, author = {Schiavi, S and La Rosa, P and Petrillo, S and Carbone, E and D'Amico, J and Piemonte, F and Trezza, V}, title = {N-Acetylcysteine Mitigates Social Dysfunction in a Rat Model of Autism Normalizing Glutathione Imbalance and the Altered Expression of Genes Related to Synaptic Function in Specific Brain Areas.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {851679}, pmid = {35280167}, issn = {1664-0640}, abstract = {Prenatal exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD) in humans and it induces autistic-like behaviors in rodents. Imbalances between GABAergic and glutamatergic neurotransmission and increased oxidative stress together with altered glutathione (GSH) metabolism have been hypothesized to play a role in both VPA-induced embriotoxicity and in human ASD. N-acetylcysteine (NAC) is an antioxidant precursor of glutathione and a modulator of glutamatergic neurotransmission that has been tested in ASD, although the clinical studies currently available provided controversial results. Here, we explored the effects of repeated NAC (150 mg/kg) administration on core autistic-like features and altered brain GSH metabolism in the VPA (500 mg/kg) rat model of ASD. Furthermore, we measured the mRNA expression of genes encoding for scaffolding and transcription regulation proteins, as well as the subunits of NMDA and AMPA receptors and metabotropic glutamate receptors mGLUR1 and mGLUR5 in brain areas that are relevant to ASD. NAC administration ameliorated the social deficit displayed by VPA-exposed rats in the three-chamber test, but not their stereotypic behavior in the hole board test. Furthermore, NAC normalized the altered GSH levels displayed by these animals in the hippocampus and nucleus accumbens, and it partially rescued the altered expression of post-synaptic terminal network genes found in VPA-exposed rats, such as NR2a, MGLUR5, GLUR1, and GLUR2 in nucleus accumbens, and CAMK2, NR1, and GLUR2 in cerebellum. These data indicate that NAC treatment selectively mitigates the social dysfunction displayed by VPA-exposed rats normalizing GSH imbalance and reestablishing the expression of genes related to synaptic function in a brain region-specific manner. Taken together, these data contribute to clarify the behavioral impact of NAC in ASD and the molecular mechanisms that underlie its effects.}, } @article {pmid35278063, year = {2022}, author = {Ek-Eudomsuk, P and Chalermrujinanant, C and Soontrapa, K}, title = {N-acetylcysteine potentiates the tumor cytotoxicity of cytokine-induced killer cells.}, journal = {Asian Pacific journal of allergy and immunology}, volume = {}, number = {}, pages = {}, doi = {10.12932/AP-280921-1245}, pmid = {35278063}, issn = {0125-877X}, abstract = {BACKGROUND: Cytokine-induced killer (CIK) cells are an ex vivo expanded heterogeneous population of natural killer (NK)-like T cells that can exert potent MHC-unrestricted antitumor activity. A number of pre-clinical and clinical studies have demonstrated that CIK cells can serve as a safe and potent immunotherapy of malignant tumors. N-acetylcysteine (NAC) has been demonstrated to enhance the T-cell functions by increasing their proliferation and cytokine production.

OBJECTIVE: To investigate whether the incorporation of NAC to CIK cell culture could enhance the antitumor activity of CIK cells.

METHODS: The phenotypes of human CIK cells, including CD3+CD56+, IFN-γ, granzyme B, and perforin, were determined by flow cytometry. The cytotoxic activity against the human erythroleukemic cell line (K562) and cholangiocarcinoma cell line (CL6) prelabeled with CFSE was investigated by flow cytometry. The mRNA expression levels of IFNG, PRF1, and GZMB were measured by real-time PCR.

RESULTS: By adding NAC into CIK cell culture, the percentage of CD3+CD56+ cells along with the expression of Th1 cytokines and cytolytic granules increased significantly, resulting in an improvement of cytotoxicity against the cancer cell lines CL6 and K562.

CONCLUSIONS: The incorporation of NAC into CIK culture can markedly improve the cytotoxicity against cancer cells due to the significant increase in the major effector population of CIK cells expressing Th1 cytokines and cytolytic granules.}, } @article {pmid35277478, year = {2022}, author = {Wiesen, T and Atlas, D}, title = {Novel anti-apoptotic L-DOPA precursors SuperDopa and SuperDopamide as potential neuroprotective agents for halting/delaying progression of Parkinson's disease.}, journal = {Cell death & disease}, volume = {13}, number = {3}, pages = {227}, pmid = {35277478}, issn = {2041-4889}, mesh = {Animals ; Antioxidants/metabolism ; Dopaminergic Neurons/metabolism ; HEK293 Cells ; Humans ; Levodopa/metabolism/pharmacology ; *Neuroprotective Agents/metabolism/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy/metabolism ; Rats ; Rotenone/pharmacology ; }, abstract = {Parkinson's disease (PD) is characterized by a gradual degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpC). Levodopa, the standard PD treatment, provides the missing dopamine in SNpC, but ultimately after a honeymoon with levodopa treatment the neurodegenerative process and the progression of the disease continue. Aimed at prolonging the life of dopaminergic cells, we prepared the levodopa precursors SuperDopa (SD) and SueprDopamide (SDA), in which levodopa is merged with the antioxidant N-acetylcysteine (NAC) into a single molecule. Rotenone is a mitochondrial complex inhibitor often used as experimental model of PD. In vivo, SD and SDA treatment show a significant relief of motor disabilities in rotenone-injected rats. SD and SDA also lower rotenone-induced-α-synuclein (α-syn) expression in human SH-SY5Y cells, and α-syn oligomerization in α-syn-overexpressing-HEK293 cells. In the neuronal SH-SY5Y cells, SD and SDA reverse oxidative stress-induced phosphorylation of cJun-N-terminal kinase (JNK) and p38-mitogen-activated kinase (p38[MAPK]). Attenuation of the MAPK-inflammatory/apoptotic pathway in SH-SY5Y cells concurrent with protection of rotenone-triggered motor impairment in rats, is a manifestation of the combined antioxidant/anti-inflammatory activity of SD and SDA together with levodopa release. The concept of joined therapies into a single molecule, where levodopa precursors confer antioxidant activity by enabling NAC delivery across the BBB, provides a potential disease-modifying treatment for slowing PD progression.}, } @article {pmid35272139, year = {2022}, author = {Coelho Dos Reis, JGA and Ferreira, GM and Lourenço, AA and Ribeiro, ÁL and da Mata, CPDSM and de Melo Oliveira, P and Marques, DPA and Ferreira, LL and Clarindo, FA and da Silva, MF and Filho, HPP and Oliveira, NRR and Sodré, MMD and Gadelha, SR and Albuquerque, GR and Maciel, BM and Mariano, APM and Silva, MM and Fontana, R and Marin, LJ and Carlos, RSA and Lopes, ATS and Ferreira, FB and Dos Santos, UR and Santana, ÍTS and Fehlberg, HF and Rezende, RP and Dias, JCT and Gross, E and Goulart, GAC and Santiago, MG and de Lemos, APML and da Conceição, AO and Romano, CC and de Carvalho, LD and Martins Filho, OA and Quadros, CA and Morris, DL and Valle, SJ}, title = {Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {148}, number = {}, pages = {112753}, pmid = {35272139}, issn = {1950-6007}, mesh = {Acetylcysteine/administration & dosage/*pharmacology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anti-Inflammatory Agents/administration & dosage/pharmacology ; Bromelains/administration & dosage/*pharmacology ; COVID-19/*pathology ; Chemokines/*drug effects ; Cytokine Release Syndrome/pathology ; Cytokines/*drug effects ; Dose-Response Relationship, Drug ; Down-Regulation ; Drug Combinations ; Expectorants/pharmacology ; Female ; Humans ; Inflammation Mediators/metabolism ; Male ; Middle Aged ; Respiration, Artificial ; Rheology ; SARS-CoV-2 ; Sputum/*cytology ; Trachea/pathology ; Young Adult ; }, abstract = {UNLABELLED: COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation.

METHOD: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed.

RESULTS: BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg.

CONCLUSION: These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19.}, } @article {pmid35270019, year = {2022}, author = {Le, AN and Park, SS and Le, MX and Lee, UH and Ko, BK and Lim, HR and Yu, R and Choi, SH and Lee, BJ and Ham, SY and Ha, CM and Park, JW}, title = {DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35270019}, issn = {1422-0067}, support = {NRF- 2014R1A6A1030318//National Research Foundation of Korea/ ; NRF-2020R1F1A1058459//National Research Foundation of Korea/ ; }, mesh = {Animals ; Cellular Senescence/genetics ; *Endothelial Cells/metabolism ; Mice ; Mice, Knockout ; Reactive Oxygen Species/metabolism ; *Vascular Diseases/metabolism ; }, abstract = {Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-β-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.}, } @article {pmid35270009, year = {2022}, author = {Yang, CY and Liu, SH and Su, CC and Fang, KM and Yang, TY and Liu, JM and Chen, YW and Chang, KC and Chuang, HL and Wu, CT and Lee, KI and Huang, CF}, title = {Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35270009}, issn = {1422-0067}, support = {MOST 110-2320-B-303-004-//Ministry of Science and Technology, Taiwan/ ; MOST 109-2320-B-039-039//Ministry of Science and Technology, Taiwan/ ; TTCRD 109-13//Buddhist Tzuchi Medical Foundation of the Taichung Tzu chi Hospital, Taiwan/ ; CSH-2015-C-027//Chung Shan Medical University Hospital, Taichung, Taiwan/ ; Grants No. 109018//Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan/ ; CMU110-S-36//China Medical University, Taiwan/ ; }, mesh = {Animals ; Apoptosis ; Caspase 3/metabolism ; *Endoplasmic Reticulum Stress ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Mammals/metabolism ; *Methylmercury Compounds/pharmacology ; Mitochondria/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic β-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 μM) significantly decreased insulin secretion and cell viability in pancreatic β-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic (Bax, Bak, p53)/antiapoptotic (Bcl-2) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 μM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 μM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 μM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to β-cell death.}, } @article {pmid35267162, year = {2022}, author = {Liu, X and Li, F and Zhu, Z and Peng, G and Huang, D and Xie, M}, title = {4-[1-Ethyl-1-methylhexy]-phenol induces apoptosis and interrupts Ca[2+] homeostasis via ROS pathway in Sertoli TM4 cells.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {35}, pages = {52665-52674}, pmid = {35267162}, issn = {1614-7499}, support = {81803193//National Natural Science Foundation of China/ ; 2018A030310033//Natural Science Foundation of Guangdong Province/ ; GC300502-33//Research Start-up Funds of DGUT/ ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphatases/metabolism ; *Apoptosis ; *Homeostasis ; Humans ; Male ; *Phenols/pharmacology ; Reactive Oxygen Species/metabolism ; *Sertoli Cells/cytology/drug effects ; }, abstract = {Biological effect of an individual nonylphenol (NP) isomer extremely relies upon the side chain structure. This research was designed to evaluate the impact of NP isomer, 4-[1-ethyl-1-methylhexy]-phenol (NP65), on Sertoli cells in vitro. Sertoli TM4 cells were exposed to various concentration (0, 0.1, 1, 10, or 20 μM) of NP65 for 24 h, and the outcomes indicated that treatment of NP65 induced reactive oxygen species (ROS) generation, oxidative stress, and apoptosis for Sertoli TM4 cells. In addition, it was found that NP65 exposure affected homeostasis of Ca[2+] in Sertoli TM4 cells by increasing cytoplasm [Ca[2+]]i, inhibiting Ca[2+]-ATPase activity and decreasing cyclic adenosine monophosphate (cAMP) concentration. Pretreatment with ROS scavenger, N-acetylcysteine (NAC), attenuated NP65-induced oxidative stress as well as apoptosis for TM4 cells. Furthermore, NAC blocked NP65-induced disorders of Ca[2+] homeostasis by attenuating the growth of intracellular [Ca[2+]]i and the inhibition of Ca[2+]-ATPase and cAMP activities. Thus, we have demonstrated that NP65 induced apoptosis as well as acted as a potent inhibitor of Ca[2+]-ATPase activity and resulted in disorder of Ca[2+] homeostasis in Sertoli TM4 cells; ROS participated in the process. Our results supported the view that oxidative stress acted an essential role within the development of apoptosis and Ca[2+] overload in TM4 cells as a consequence of NP65 stimulation.}, } @article {pmid35261035, year = {2022}, author = {Nejati, M and Dehghan, P and Jamilian, P and Zarezadeh, M}, title = {The effects of N-acetylcysteine on recovery biomarkers: A systematic review and meta-analysis of controlled trials.}, journal = {Journal of food biochemistry}, volume = {46}, number = {7}, pages = {e14116}, doi = {10.1111/jfbc.14116}, pmid = {35261035}, issn = {1745-4514}, support = {//Tabriz University of Medical Sciences/ ; }, mesh = {*Acetylcysteine ; Antioxidants ; Biomarkers ; *Dietary Supplements ; Humans ; Lactates ; Randomized Controlled Trials as Topic ; }, abstract = {N-acetylcysteine (NAC) is one of the antioxidant supplements which is thought to improve recovery. Existing studies regarding NAC and recovery presented conflicting results. This systematic review and meta-analysis evaluated the existing trials and determined the efficacy of acute and chronic NAC administration on recovery biomarkers. PubMed, Web of Science, and Scopus were searched up to July 2021. The random effects or fixed effects model was applied in the meta-analysis. Sensitivity and subgroup analyses were performed. In case of the presence of publication bias, standard methods were applied. The meta-analysis comprised 37 papers (1,388 participants). All included studies were in English language. Acute NAC administration indicated no significant effects on lactate, pH, VO2 , and CPK-MB ([SMD = -0.06 mmol/L; 95% CI: -0.40, 0.28; p = .714], [SMD = 0.17; 95% CI: -0.28, 0.62; p = .454], [SMD = -0.11 L/min; 95% CI: -0.63, 0.41; p = .686], and [SMD = -0.19 units/L; 95% CI: -0.62, 0.24; p = .395]). Additionally, no evidence of significant influence of chronic NAC administration on lactate, pH, VO2 , and CK was revealed ([SMD = 0.01 mmol/L; 95% CI: -0.25, 0.27; p = .950], [SMD = -0.51; 95% CI: -1.73, 0.70; p = .424], [SMD = -0.18 L/min; 95% CI: -0.56, 0.20; p = .361], and [SMD = -0.04 units/L; 95% CI: -0.36, 0.29; p = .821]). No considerable effect of NAC on recovery was found. PRACTICAL APPLICATIONS: Previous studies on the influence of NAC administration on recovery biomarkers have presented conflicting results. This systematic review and meta-analysis offers a broad range of detailed information on the influence of chronic and acute NAC supplementation outcomes regarding recovery biomarkers. Overall, the results support that NAC supplementation may not be effective in improving recovery biomarkers. However, subgroup analyses based on NAC dosage indicated the meaningful effect of NAC on CK-MB at the dosage of ≥100 mg/kg.}, } @article {pmid35259475, year = {2022}, author = {Shou, P and Li, J and Zhang, P and Wei, Y and Yan, M and Zhang, M and Feng, K and Lin, N and Zhao, H and Yang, B}, title = {Pharmacophore-probe reaction guided purification to precisely identify electrophilic withanolides from Tubocapsicum anomalum Makino and their anti-TNBC activity.}, journal = {Fitoterapia}, volume = {158}, number = {}, pages = {105169}, doi = {10.1016/j.fitote.2022.105169}, pmid = {35259475}, issn = {1873-6971}, mesh = {Cell Line, Tumor ; Humans ; Molecular Structure ; Signal Transduction ; *Solanaceae/chemistry ; *Triple Negative Breast Neoplasms/metabolism/pathology ; *Withanolides/chemistry/pharmacology ; }, abstract = {Pharmacophore-probe reaction guided purification strategy can reduce the workload of natural product chemistry and raise the probability of obtaining undescribed and high-bioactive target compounds. In this study, a probe of N-acetyl cysteine (NAC) was used to confirm the pharmacophore of Tubocapsicum anomalum (Franch. et Sav.) Makino. Furthermore, a thiol probe named 4-bromothiophenol (BTP) guided the discovery of three undescribed (1-3) and nine known (4-12) electrophilic withanolides (EWs) featured potential anti-triple negative breast cancer (TNBC) pharmacophore. Notably, co-incubation with BTP made the single crystals of EW conjugates much more accessible, which facilitated the absolute configuration determination of EWs. Electrophilic natural products with the potential of thio-alkylation modification and covalent inhibition key proteins in tumor cell signal transduction pathways may display significant antitumor activity. The MTT results indicated that most EWs showed anti-TNBC activity and were expected to develop anti-TNBC candidate drugs with high selectivity and novel mechanism.}, } @article {pmid35258392, year = {2022}, author = {Magalhaes-Novais, S and Blecha, J and Naraine, R and Mikesova, J and Abaffy, P and Pecinova, A and Milosevic, M and Bohuslavova, R and Prochazka, J and Khan, S and Novotna, E and Sindelka, R and Machan, R and Dewerchin, M and Vlcak, E and Kalucka, J and Stemberkova Hubackova, S and Benda, A and Goveia, J and Mracek, T and Barinka, C and Carmeliet, P and Neuzil, J and Rohlenova, K and Rohlena, J}, title = {Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.}, journal = {Autophagy}, volume = {18}, number = {10}, pages = {2409-2426}, pmid = {35258392}, issn = {1554-8635}, mesh = {AMP-Activated Protein Kinases/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; *Autophagy ; Cysteine/metabolism ; DNA, Mitochondrial/metabolism ; Dextrans/metabolism ; Endothelial Cells/metabolism ; Fibroblasts/metabolism ; Formaldehyde/metabolism ; Humans ; *Inflammatory Bowel Diseases/metabolism ; Isothiocyanates ; Lipopolysaccharides/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Phosphatidylethanolamines/metabolism ; Reactive Oxygen Species/metabolism ; Respiration ; Sirolimus ; }, abstract = {Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A1; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.}, } @article {pmid35257042, year = {2022}, author = {Shirakawa, K and Kobayashi, E and Ichihara, G and Kitakata, H and Katsumata, Y and Sugai, K and Hakamata, Y and Sano, M}, title = {H2 Inhibits the Formation of Neutrophil Extracellular Traps.}, journal = {JACC. Basic to translational science}, volume = {7}, number = {2}, pages = {146-161}, pmid = {35257042}, issn = {2452-302X}, abstract = {Neutrophil extracellular traps (NETs) contribute to inflammatory pathogenesis in numerous conditions, including infectious and cardiovascular diseases, and have attracted attention as potential therapeutic targets. H2 acts as an antioxidant and has been clinically and experimentally proven to ameliorate inflammation. This study was performed to investigate whether H2 could inhibit NET formation and excessive neutrophil activation. Neutrophils isolated from the blood of healthy volunteers were stimulated with phorbol-12-myristate-13-acetate (PMA) or the calcium ionophore A23187 in H2-exposed or control media. Compared with control neutrophils, PMA- or A23187-stimulated human neutrophils exposed to H2 exhibited reduced neutrophil aggregation, citrullination of histones, membrane disruption by chromatin complexes, and release of NET components. CXCR4[high] neutrophils are highly prone to NETs, and H2 suppressed Ser-139 phosphorylation in H2AX, a marker of DNA damage, thereby suppressing the induction of CXCR4 expression. H2 suppressed both myeloperoxidase chlorination activity and production of reactive oxygen species to the same degree as N-acetylcysteine and ascorbic acid, while showing a more potent ability to inhibit NET formation than these antioxidants do in PMA-stimulated neutrophils. Although A23187 formed NETs in a reactive oxygen species-independent manner, H2 inhibited A23187-induced NET formation, probably via direct inhibition of peptidyl arginine deiminase 4-mediated histone citrullination. Inhalation of H2 inhibited the formation and release of NET components in the blood and bronchoalveolar lavage fluid in animal models of lipopolysaccharide-induced sepsis (mice and aged mini pigs). Thus, H2 therapy can be a novel therapeutic strategy for NETs associated with excessive neutrophil activation.}, } @article {pmid35253534, year = {2022}, author = {Wei, AH and Zeng, L and Ruan, JL and Zhou, DN}, title = {Apoptosis induced by DICO, a novel non-aromatic B-ring flavonoid via a ROS-dependent mechanism in human colon cancer cells.}, journal = {Natural product research}, volume = {36}, number = {23}, pages = {6050-6055}, doi = {10.1080/14786419.2022.2042283}, pmid = {35253534}, issn = {1478-6427}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Flavonoids/pharmacology/chemistry ; Apoptosis ; STAT3 Transcription Factor/metabolism ; NF-kappa B/metabolism ; *Colonic Neoplasms/drug therapy ; Cell Line, Tumor ; }, abstract = {5,7-Dihydroxy-2-(1,2-isopropyldioxy-4-oxo-cyclohex-5-enyl)-chromen-4-one (DICO) is a novel non-aromatic B-ring flavonoid, isolated mainly from Macrothelypteris viridifrons and has anti-tumour properties. In this study, we investigated the cytotoxicity and underlying biochemical pathways leading to cell death, in response to DICO treatment of a human colon cancer cell line HT-29. Our results indicated that DICO induced apoptosis by elevating the generation of reactive oxygen species, which could be quenched by the antioxidants N-acetyl cysteine. In addition, activation of signal transducer and activator of transcription 3 and suppression of nuclear factor kappa B played a crucial role in DICO-induced apoptosis. Overall, our results provide mechanistic insights into the apoptotic action of a potential anti-tumour drug, DICO.}, } @article {pmid35249877, year = {2022}, author = {Feng, Y and Yang, D and Zhi, X and Deng, H and Zhang, W and Wang, R and Wu, W}, title = {[Role of interaction between reactive oxygen species and ferroptosis pathway in methylglyoxal-induced injury in mouse embryonic osteoblasts].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {42}, number = {1}, pages = {108-115}, pmid = {35249877}, issn = {1673-4254}, mesh = {Animals ; Cell Survival ; *Ferroptosis ; Mice ; Osteoblasts ; Pyruvaldehyde/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: To explore the interaction between reactive oxygen species (ROS) and ferroptosis in methylglyoxalinduced injury of mouse embryonic osteoblasts (MC3T3-E1 cells).

METHODS: MC3T3-E1 cells were treated with methylglyoxal to establish a cell model of diabetic osteoporosis. CCK-8 assay was used to detect the viability of MC3T3-E1 cells. Rhodamine 123 staining followed by photofluorography was used to examine mitochondrial membrane potential (MMP). The intracellular ROS level was detected by 2', 7'-dichlorodihydrofluorescein diacetate staining with photofluorograph. Alkaline phosphatase (ALP) activity in the cells was detected using an ALP kit, the number of mineralized nodules was determined with alizarin red S staining, and the level of iron ions was detected using a detection kit. The expression level of glutathione peroxidase 4 (GPX4, a marker protein that inhibits ferroptosis) in the osteoblasts was determined using Western blotting.

RESULTS: Treatment of MC3T3-E1 cells with 0.6 mmol/L methylglyoxal for 24 h significantly inhibited the expression level of GPX4 (P < 0.001), increased intracellular iron ion concentration, decreased the cell viability, increased the loss of MMP and intracellular ROS level, decreased both ALP activity and the number of mineralized nodules in the cells (P < 0.001). Co-treatment of MC3T3-E1 cells with 2 mmol/L N-acetylcysteine (NAC, a ROS scavenger) and methylglyoxal significantly increased the expression level of GPX4 (P < 0.01); co-treatment with 4 mmo/L FER-1 (a ferroptosis inhibitor) and methylglyoxal obviously decreased the intracellular ROS level (P < 0.001). Co-treatment of the cells either with NAC and methylglyoxal or with FER-1 and methylglyoxal attenuated methylglyoxal-induced injuries in the osteoblasts (P < 0.001).

CONCLUSION: The interaction between ROS and ferroptosis pathway plays an important role in methylglyoxal-induced injury of mouse embryonic osteoblasts.}, } @article {pmid35246254, year = {2022}, author = {Wang, P and Cui, Y and Wang, J and Liu, D and Tian, Y and Liu, K and Wang, X and Liu, L and He, Y and Pei, Y and Li, L and Sun, L and Zhu, Z and Chang, D and Jia, J and You, H}, title = {Mesenchymal stem cells protect against acetaminophen hepatotoxicity by secreting regenerative cytokine hepatocyte growth factor.}, journal = {Stem cell research & therapy}, volume = {13}, number = {1}, pages = {94}, pmid = {35246254}, issn = {1757-6512}, mesh = {Acetaminophen/toxicity ; Animals ; *Chemical and Drug Induced Liver Injury/metabolism/therapy ; Hepatocyte Growth Factor/metabolism ; Liver/metabolism ; *Mesenchymal Stem Cells ; Mice ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Acetaminophen (APAP) overdose is a major cause of the morbidity of acute liver failure. The current clinically approved treatment for APAP poisoning, N-acetylcysteine (NAC), has a limited therapeutic window, and prolonged treatment with NAC delays liver regeneration. Mesenchymal stem cells (MSCs) also have therapeutic effects on APAP-induced mouse liver failure, but whether the effects are comparable to those of NAC has not been determined, and the mechanism still needs further exploration.

METHODS: Fasted C57BL/6 mice that received 500 mg/kg APAP were treated intravenously with 300 mg/kg NAC or different amounts of MSCs at 2 h after APAP to investigate survival, hepatocyte necrosis and neutrophil/macrophage recruitment. In vitro co-culture was performed to study the anti-necrotic effects of MSCs on the APAP-injured hepatocyte cell line L-O2.

RESULTS: MSCs dose-dependently rescued the C57BL/6J mice from APAP-induced liver failure, with 87.5% of MSCs (1 × 10[6]) surviving similar to that of NAC (90%). MSC has similar effects on reduced hepatocyte necrosis and granulocytic myeloid-derived suppressor cells (MDSC) infiltration but enhanced the proportion of regenerative monocytic MDSC when compared to NAC. Mechanistically, MSCs attenuate hepatocyte necrosis by secreting hepatocyte growth factor (HGF). When HGF was knocked down, the protective effects of MSCs were reduced on APAP-induced hepatocyte necrosis and mouse liver failure.

CONCLUSIONS: MSCs are comparable to NAC against APAP-induced liver failure by secreting HGF with less regenerative retardation concerns, thus facilitating the application of MSCs in clinical therapy for APAP liver failure.}, } @article {pmid35245527, year = {2022}, author = {Aggarwal, H and Gupta, S and Sharma, P and Sharma, BM and Sharma, B}, title = {Neurobehavioral and neurobiochemical effect of atomoxetine and N-acetylcysteine in streptozotocin diabetes induced endothelial dysfunction and related dementia.}, journal = {Physiology & behavior}, volume = {249}, number = {}, pages = {113767}, doi = {10.1016/j.physbeh.2022.113767}, pmid = {35245527}, issn = {1873-507X}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Atomoxetine Hydrochloride/pharmacology/therapeutic use ; Body Weight ; Brain/metabolism ; *Dementia, Vascular/drug therapy ; *Diabetes Mellitus, Experimental/complications/drug therapy/metabolism ; Glucose/metabolism ; Male ; Maze Learning ; Oxidative Stress ; Rats ; Streptozocin/toxicity ; }, abstract = {Metabolic conditions like diabetes, is a major risk factor for the development of dementia of vascular origin. This study investigates the efficacy of atomoxetine (ATX) and N-acetylcysteine (NAC) in streptozotocin (STZ) diabetes induced vascular endothelium dysfunction and related dementia. Single dose STZ (50 mg/kg i.p) was administered to Albino Wistar rats (male, 200-250 g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests (ASST) were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-α, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE and histopathological changes were also assessed. Atomoxetine - ATX (2 mg kg[-1]/ 4 mg kg[-1]) and N-acetylcysteine- NAC (250 mg kg[-1]/ 500 mg kg[-1]) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg kg-[1]) was used as a positive control. STZ administered rats showed increase in serum glucose levels and decrease in body weight. Rats administered with STZ also showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress, inflammation, AChE activity and histopathological changes. Administration of ATX and NAC in two different doses as well as in combination, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, biochemical parameters and histopathological changes. Co-treatment of ATX and NAC was better in comparison to the doses when given alone. Hence, STZ administration caused diabetes induced dementia of vascular origin which was attenuated by the administration of ATX and NAC. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced dementia of vascular origin conditions.}, } @article {pmid35245333, year = {2022}, author = {Pang, Q and Li, G and Cao, F and Liu, H and Wei, W and Jiao, Y}, title = {Clinical efficacy of Chinese herbs for supplementing qi and activating blood circulation combined with N-acetylcysteine in the treatment of idiopathic pulmonary fibrosis: A systematic review and network meta-analysis.}, journal = {PloS one}, volume = {17}, number = {3}, pages = {e0265006}, pmid = {35245333}, issn = {1932-6203}, mesh = {Acetylcysteine/therapeutic use ; Humans ; *Idiopathic Pulmonary Fibrosis/drug therapy ; Network Meta-Analysis ; Oxygen/therapeutic use ; Qi ; Treatment Outcome ; }, abstract = {BACKGROUND: Chinese herbs for supplementing qi and activating blood circulation (CH) combined with N-acetylcysteine (NAC) is widely used for idiopathic pulmonary fibrosis (IPF) in China, but there is a lack of literature to evaluate its efficacy and clinical value.

PURPOSE: This study compared CH + NAC with other treatments by network meta-analysis to clarify its clinical value.

METHODS: Cochrane Library, PubMed, Embase, Web of Science, China National Knowledge Infrastructure, WanFang Data, VIP Database, and China Biology Medicine were searched. Outcomes included lung function (DLCO (%), VC (%), FVC (%), FVC (L)), 6-min walking distance (6MWD), score of St George's respiratory questionnaire (SGRQ), blood gas analysis (PaO2, PaCO2). The data were analyzed by Review Manager 5.4, Stata 12.0 and ADDIS 1.16.5.

RESULTS: 23 studies including 1390 patients (702 in intervention group and 688 in control group) were collected to compare 8 outcome indicators among different treatments involving CH, CH+NAC, CH+PFD, NAC, PFD and PFD+NAC on IPF. Network meta-analysis showed that CH was better than NAC in terms of DLCO (%) (MD = 5.14, 95%CI: 1.01 to 8.68) and 6MWD (MD = 49.17, 95%CI: 25.97 to 71.36) as well as PFD + NAC was better than NAC in terms of FVC (L) (MD = -0.56, 95%CI: -0.83 to -0.31). In rankings results, CH + NAC is the best in terms of FVC (%), SGRQ, PaO2 and PaCO2; CH is the best in terms of DLCO (%), VC (%) and 6MWD; CH + PFD is the best in terms of FVC (L).

CONCLUSION: CH related treatments may have advantages in the treatment of IPF and CH + NAC may have clinical application value. However, limited by the quality and quantity of researches included, more rational and scientific randomized controlled trials containing large sample sizes need to be conducted to further verify our conclusions.}, } @article {pmid35244883, year = {2022}, author = {Elshal, M and Abdelmageed, ME}, title = {Diacerein counteracts acetaminophen-induced hepatotoxicity in mice via targeting NLRP3/caspase-1/IL-1β and IL-4/MCP-1 signaling pathways.}, journal = {Archives of pharmacal research}, volume = {45}, number = {3}, pages = {142-158}, pmid = {35244883}, issn = {1976-3786}, mesh = {*Acetaminophen/metabolism/toxicity ; Animals ; Anthraquinones ; Caspase 1/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism/prevention & control ; Interleukin-4/metabolism ; Liver/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidative Stress ; Signal Transduction ; }, abstract = {The current study aims at repurposing the anti-arthritic drug diacerein (DCN) for the treatment of acetaminophen hepatotoxicity and investigating the potential underlying mechanisms. Mice were randomly divided into six groups receiving either no treatment (control group), 20 mg/kg DCN i.p, 400 mg/kg acetaminophen i.p, DCN 4 h before acetaminophen, DCN 2 h after acetaminophen, or 400 mg/kg N-acetylcysteine (NAC) i.p, 2 h after acetaminophen. Biomarkers of liver dysfunction, oxidative stress, and apoptosis were assessed. Hepatic necroinflammatory changes were evaluated along with hepatic expression of NF-κB and caspase-1. The levels of NLRP3, IL-1β, IL-4, MCP-1, and TNF-α in the liver, as well as CYP2E1 mRNA expression, were measured. Diacerein significantly reduced biomarkers of liver dysfunction, oxidative stress, hepatocyte necrosis, and infiltration of neutrophils and macrophages whether administered 4 h before or 2 h after acetaminophen. Further, the effects were comparable to those of NAC. Diacerein also counteracted acetaminophen-induced hepatocellular apoptosis by increasing Bcl-2 and decreasing Bax and caspase-3 expression levels. Moreover, DCN normalized hepatic TNF-α and significantly decreased NF-κB p65 expression. Accordingly, DCN can prevent or reverse acetaminophen hepatotoxicity in mice, suggesting potential utility as a repurposed drug for clinical treatment.}, } @article {pmid35238867, year = {2022}, author = {Chen, C and Zhang, B and Xue, J and Li, Z and Dou, S and Chen, H and Wang, Q and Qu, M and Wang, H and Zhang, Y and Wan, L and Zhou, Q and Xie, L}, title = {Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction.}, journal = {Investigative ophthalmology & visual science}, volume = {63}, number = {3}, pages = {4}, pmid = {35238867}, issn = {1552-5783}, mesh = {Acetylcysteine/adverse effects ; Animals ; Cells, Cultured ; *Corneal Edema/metabolism ; *Diabetes Mellitus, Experimental/metabolism ; Endoplasmic Reticulum Stress/physiology ; Endothelial Cells/metabolism ; Humans ; *Hyperglycemia/metabolism ; Mice ; }, abstract = {PURPOSE: Progressive corneal edema and endothelial cell loss represent the major corneal complications observed in diabetic patients after intraocular surgery. However, the underlying pathogenesis and potential treatment remain incompletely understood.

METHODS: We used streptozotocin-induced type 1 diabetic mice and db/db type 2 diabetic mice as diabetic animal models. These mice were treated with the endoplasmic reticulum (ER) stress agonist thapsigargin; 60-mmHg intraocular pressure (IOP) with the ER stress antagonist 4-phenylbutyric acid (4-PBA); mitochondria-targeted antioxidant SkQ1; or reactive oxygen species scavenger N-acetyl-l-cysteine (NAC). Corneal thickness and endothelial cell density were measured before and after treatment. Human corneal endothelial cells were treated with high glucose with or without 4-PBA. The expression of corneal endothelial- and ER stress-related genes was detected by western blot and immunofluorescence staining. Mitochondrial bioenergetics were measured with an Agilent Seahorse XFp Analyzer.

RESULTS: In diabetic mice, the appearance of ER stress preceded morphological changes in the corneal endothelium. The persistent ER stress directly caused corneal edema and endothelial cell loss in normal mice. Pharmacological inhibition of ER stress was sufficient to mitigate corneal edema and endothelial cell loss in both diabetic mice after high IOP treatment. Mechanistically, inhibiting ER stress ameliorated the hyperglycemia-induced mitochondrial bioenergetic deficits and improved the barrier and pump functional recovery of the corneal endothelium. When compared with NAC, 4-PBA and SkQ1 exhibited better improvement of corneal edema and endothelial cell loss in diabetic mice.

CONCLUSIONS: Hyperglycemia-induced ER stress contributes to the dysfunction of diabetic corneal endothelium, and inhibiting ER stress may offer therapeutic potential by improving mitochondrial bioenergetics.}, } @article {pmid35236897, year = {2022}, author = {Saijo, S and Ohno, M and Iwasaki, H and Matsuda, S and Nishi, K and Hiraoka, Y and Ide, N and Kimura, T and Nishi, E}, title = {Nardilysin in adipocytes regulates UCP1 expression and body temperature homeostasis.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {3449}, pmid = {35236897}, issn = {2045-2322}, mesh = {Adipocytes/metabolism ; Adipose Tissue, Brown/metabolism ; Animals ; Body Temperature ; *Body Temperature Regulation/physiology ; *Metalloendopeptidases/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Reactive Oxygen Species/metabolism ; *Thermogenesis/genetics ; *Uncoupling Protein 1/biosynthesis/genetics/metabolism ; }, abstract = {Brown adipose tissue (BAT) dissipates chemical energy as heat through uncoupling protein 1 (UCP1). The induction of mitochondrial reactive oxygen species (ROS) in BAT was recently identified as a mechanism that supports UCP1-dependent thermogenesis. We previously demonstrated that nardilysin (NRDC) plays critical roles in body temperature homeostasis. Global NRDC-deficient (Nrdc[-/-]) mice show hypothermia due to a lower set point for body temperature, whereas BAT thermogenesis at room temperature (RT) is enhanced mainly to compensate for poor thermal insulation. To examine the primary role of NRDC in BAT thermogenesis, we generated adipocyte-specific NRDC-deficient (Adipo-KO) mice by mating Nrdc floxed (Nrdc[flox/flox]) mice with adiponectin-Cre mice. Adipo-KO mice showed hyperthermia at both RT and thermoneutrality. They were also more cold-tolerant than Nrdc[flox/flox] mice. However, UCP1 mRNA levels were significantly lower in Adipo-KO BAT at RT, thermoneutrality, and 4 °C, whereas no significant differences were observed in UCP1 protein levels at RT and 4 °C. We examined the protein stability of UCP1 using the cycloheximide chase assay and found that NRDC negatively regulated its stability via the ubiquitin-proteasome pathway. NRDC may be also involved in ROS-mediated in vivo thermogenesis because the inhibitory effects of N-acetyl cysteine, an ROS scavenger, on β3 agonist-induced thermogenesis were stronger in Adipo-KO mice. Collectively, the present results demonstrate that NRDC in BAT controls adaptive thermogenesis and body temperature homeostasis possibly via the regulation of UCP1 protein stability and ROS levels.}, } @article {pmid35235429, year = {2022}, author = {Honda, M and Segawa, T and Ishikawa, K and Maeda, M and Saito, Y and Kon, S}, title = {Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species.}, journal = {American journal of physiology. Cell physiology}, volume = {322}, number = {4}, pages = {C699-C711}, doi = {10.1152/ajpcell.00376.2021}, pmid = {35235429}, issn = {1522-1563}, mesh = {Animals ; *Encephalomyelitis, Autoimmune, Experimental/immunology ; Extracellular Matrix Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; *T-Lymphocytes, Regulatory ; *Th17 Cells/metabolism ; }, abstract = {Blood levels of the extracellular matrix protein nephronectin (Npnt), a protein critical for kidney development, are elevated in autoimmune experimental autoimmune encephalitis (EAE) mice, which are a model for multiple sclerosis. We found here that treatment with anti-Npnt antibody directed against the α8β1 integrin-binding site (Npnt-blocking antibody) inhibits EAE development. The selenium transporter selenoprotein P (SeP) was identified as a novel Npnt-binding partner. In EAE, Npnt induced SeP and glutathione peroxidase 1 (GPx1) expression, followed by reactive oxygen species (ROS) inhibition in CD4[+] T cells; these changes were disturbed by Npnt-blocking antibody treatment, which also caused suppressed differentiation of interleukin (IL)-17-producing CD4[+] T-helper cells (Th17s) and elevated differentiation of regulatory T cells (Tregs). Treatment of EAE mice with the ROS scavenger N-acetyl cysteine (NAC) blocked the Npnt-blocking antibody-induced decrease in Th17 differentiation and increase in Treg differentiation. In conclusion, the interaction between Npnt and SeP contributes to EAE development by regulating the Th17/Treg balance via the ROS level.}, } @article {pmid35229943, year = {2022}, author = {Nall, RW and Beloate, LN and Meyerink, ME and Penaloza, T and Doolittle, J and Froeliger, B and Kalivas, PW and Garcia-Keller, C}, title = {Assessing combined effects of varenicline and N-acetylcysteine on reducing nicotine seeking in rats.}, journal = {Addiction biology}, volume = {27}, number = {2}, pages = {e13151}, pmid = {35229943}, issn = {1369-1600}, support = {I01 BX004727/BX/BLRD VA/United States ; K99 DA047426/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; R01 DA038700/DA/NIDA NIH HHS/United States ; P50 DA046373/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Nicotine/pharmacology ; Rats ; *Smoking Cessation ; *Tobacco Use Disorder/drug therapy/prevention & control ; Varenicline/pharmacology/therapeutic use ; }, abstract = {Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.}, } @article {pmid35229847, year = {2022}, author = {Ding, Q and Guo, R and Pei, L and Lai, S and Li, J and Yin, Y and Xu, T and Yang, W and Song, Q and Han, Q and Dou, X and Li, S}, title = {N-Acetylcysteine alleviates high fat diet-induced hepatic steatosis and liver injury via regulating the intestinal microecology in mice.}, journal = {Food & function}, volume = {13}, number = {6}, pages = {3368-3380}, doi = {10.1039/d1fo03952k}, pmid = {35229847}, issn = {2042-650X}, mesh = {1-Acylglycerol-3-Phosphate O-Acyltransferase ; Acetylcysteine/pharmacology ; Animals ; *Diet, High-Fat/adverse effects ; Liver ; Mice ; Mice, Inbred C57BL ; *Non-alcoholic Fatty Liver Disease/etiology/microbiology ; }, abstract = {N-Acetylcysteine (NAC), a well-accepted antioxidant, has been shown to protect against high fat diet (HFD)-induced obesity-associated non-alcoholic fatty liver disease (NAFLD) in mice. However, the underlying mechanism(s) of the beneficial role of NAC is still not fully understood. Our study aimed to evaluate the protective effect of NAC against NAFLD in terms of gut microbiota homeostasis. Thirty-two C57BL/6 mice were divided into four groups, including chow diet (CHOW), high-fat diet (HFD), CHOW + NAC (2 g L[-1] in the drinking water), and HFD + NAC groups, and fed for 12 weeks. NAC supplementation significantly improved HFD-induced obesity, dyslipidemia, and liver dysfunction in mice. NAC also rescued HFD-caused disorder of the gut microbiota. Intriguingly, removing intestinal microorganisms by antibiotics (ABX) obviously abolished NAC supplementation-rescued hepatic steatosis and liver injury, indicating the involvement of the gut microbiota in the beneficial role of NAC. The profiles of 1145 expressed hepatic mRNAs were analyzed by whole transcriptome sequencing. Among those, 5 up-expressed mRNAs induced by a HFD, including Cidea, CD36, Acnat2, Mogat1, and GPAT3, were reversed by NAC treatment, which was further verified by a quantitative real-time polymerase chain reaction (qRT-PCR). Meanwhile, those 5 mRNAs exhibited a significant (negative or positive) association with bacterial phyla or genera, including phyla Firmicutes and Bacteroidetes and genera norank_f_Erysipelotrichaceae and Lachnoclostridium, by Spearman's correlation analysis. These results suggested that the homeostasis of the gut microbiota plays an important role in NAC-improved NAFLD by affecting the enterohepatic axis.}, } @article {pmid35225941, year = {2022}, author = {Poli, V and Madduru, R and Aparna, Y and Kandukuri, V and Motireddy, SR}, title = {Amelioration of Cadmium-Induced Oxidative Damage in Wistar Rats by Vitamin C, Zinc and N-Acetylcysteine.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {10}, number = {1}, pages = {}, pmid = {35225941}, issn = {2076-3271}, mesh = {*Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Ascorbic Acid/pharmacology/therapeutic use ; *Cadmium/toxicity ; Oxidative Stress ; Rats ; Rats, Wistar ; Vitamins/pharmacology ; Zinc/pharmacology/therapeutic use ; }, abstract = {The present study was performed to determine the protective effects of vitamin C, zinc, and N-acetylcysteine, individually or in combination with Cd, to monitor their amelioration capability against Cd-induced oxidative damage in Wistar rats. We investigated and demonstrated that cadmium is a toxic element that damages rat liver and kidney tissues. Vitamin C, zinc, and NAC have been proven to have protective roles against Cd toxic effects. Nine groups of rats were studied as the experimental group. The present experiment was conducted for 45 days. Liver and kidneys were excised for biochemical evaluation by assaying antioxidant enzymes and lipid oxidation products to assess the impact of Cd toxicity and its amelioration by co-administration of vitamin C, zinc, and NAC along with Cd. Basal metabolic rates and tissue respiration rates of liver and kidney were significantly decreased (p < 0.05) during Cd toxicity. Serum biochemical parameters were also found to be significantly altered to cope with Cd toxicity. All the antioxidant enzymes and products were significant inhibited (p < 0.05) or elevated in rat liver and kidney tissues during Cd-induced toxicity. Our results suggest that co-administration of vitamin C, zinc, and NAC to rats ameliorates oxidative damage induced by Cd toxicity. From the results obtained in the present study, all the agents tested had protective effects against Cd-induced oxidative damage.}, } @article {pmid35217818, year = {2022}, author = {Fu, H and Shen, QR and Zhao, Y and Ni, M and Zhou, CC and Chen, JK and Chi, C and Li, DJ and Liang, G and Shen, FM}, title = {Activating α7nAChR ameliorates abdominal aortic aneurysm through inhibiting pyroptosis mediated by NLRP3 inflammasome.}, journal = {Acta pharmacologica Sinica}, volume = {43}, number = {10}, pages = {2585-2595}, pmid = {35217818}, issn = {1745-7254}, mesh = {Acetylcysteine ; Angiotensin II/metabolism ; Animals ; *Aortic Aneurysm, Abdominal/drug therapy/metabolism/prevention & control ; Apolipoproteins E/metabolism ; Caspase 1/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Elastin ; *Inflammasomes/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pyroptosis ; Tumor Necrosis Factor-alpha/metabolism ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; }, abstract = {Abdominal aortic aneurysm (AAA) is defined as a dilated aorta in diameter at least 1.5 times of a normal aorta. Our previous studies found that activating α7 nicotinic acetylcholine receptor (α7nAChR) had a protective effect on vascular injury. This work was to investigate whether activating α7nAChR could influence AAA formation and explore its mechanisms. AAA models were established by angiotensin II (Ang II) infusion in ApoE[-][/-] mice or in wild type and α7nAChR[-/-] mice. In vitro mouse aortic smooth muscle (MOVAS) cells were treated with tumor necrosis factor-α (TNF-α). PNU-282987 was chosen to activate α7nAChR. We found that cell pyroptosis effector GSDMD and NLRP3 inflammasome were activated in abdominal aorta, and inflammatory cytokines in serum were elevated in AAA models of ApoE[-/-] mice. Activating α7nAChR reduced maximal aortic diameters, preserved elastin integrity and decreased inflammatory responses in ApoE[-/-] mice with Ang II infusion. While α7nAChR[-/-] mice led to aggravated aortic injury and increased inflammatory cytokines with Ang II infusion when compared with wild type. Moreover, activating α7nAChR inhibited NLRP3/caspase-1/GSDMD pathway in AAA model of ApoE[-/-] mice, while α7nAChR deficiency promoted this pathway. In vitro, N-acetylcysteine (NAC) inhibited NLRP3 inflammasome activation and NLRP3 knockdown reduced GSDMD expression, in MOVAS cells treated with TNF-α. Furthermore, activating α7nAChR inhibited oxidative stress, reduced NLRP3/GSDMD expression, and decreased cell pyroptosis in MOVAS cells with TNF-α. In conclusion, our study found that activating α7nAChR retarded AAA through inhibiting pyroptosis mediated by NLRP3 inflammasome. These suggested that α7nAChR would be a potential pharmacological target for AAA.}, } @article {pmid35216241, year = {2022}, author = {Rogóż, Z and Kamińska, K and Lech, MA and Lorenc-Koci, E}, title = {N-Acetylcysteine and Aripiprazole Improve Social Behavior and Cognition and Modulate Brain BDNF Levels in a Rat Model of Schizophrenia.}, journal = {International journal of molecular sciences}, volume = {23}, number = {4}, pages = {}, pmid = {35216241}, issn = {1422-0067}, support = {UMO-2016/23/B/NZ7/01280//the National Science Centre of Poland/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antipsychotic Agents/pharmacology ; Aripiprazole/*pharmacology ; Behavior, Animal/drug effects ; Brain-Derived Neurotrophic Factor/*metabolism ; Cognition/*drug effects ; Cognition Disorders/drug therapy/metabolism ; Disease Models, Animal ; Female ; Hippocampus/*drug effects/metabolism ; Prefrontal Cortex/*drug effects/metabolism ; Pregnancy ; Quinolones/pharmacology ; Rats ; Rats, Sprague-Dawley ; Schizophrenia/*drug therapy/metabolism ; Social Behavior ; }, abstract = {Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5-p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.}, } @article {pmid35215851, year = {2022}, author = {Zeng, W and Ren, J and Li, Z and Jiang, C and Sun, Q and Li, C and Li, W and Li, W and He, Q}, title = {Levistolide A Inhibits PEDV Replication via Inducing ROS Generation.}, journal = {Viruses}, volume = {14}, number = {2}, pages = {}, pmid = {35215851}, issn = {1999-4915}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antiviral Agents/*pharmacology ; Benzofurans/*pharmacology ; Cell Line ; Chlorocebus aethiops ; Endoplasmic Reticulum Stress ; Porcine epidemic diarrhea virus/*drug effects/physiology ; RNA, Viral/metabolism ; Reactive Oxygen Species/*metabolism ; Sus scrofa ; Vero Cells ; Viral Proteins/metabolism ; Virus Replication/drug effects ; }, abstract = {Porcine epidemic diarrhea virus (PEDV) variant strains adversely affect the production of pigs globally. Vaccines derived from PEDV traditional strains impart less protection against the variant strains. Moreover, sequence diversity among different PEDV variant strains is also complicated. This necessitates developing alternative antiviral strategies for defending against PEDV. This study explored a natural product, Levistolide A (LA), to possess antiviral activity against PEDV. LA was found to suppress PEDV replication in a dose-dependent manner. And the inhibitory effect of LA against PEDV was maintained in the course of time. In terms of viral RNA and protein production, LA also showed a strong inhibitory effect. In addition, LA was indicated to inhibit PEDV from attaching to the cellular membrane or penetrating the cells. Further study revealed that LA can induce the generation of reactive oxygen species (ROS), and the corresponding inhibitor, NAC, was found to antagonize the effect of LA on inhibiting PEDV replication. This illustrated that the LA-induced ROS generation played an important role in its anti-PEDV activity. LA was also identified to stimulate ER stress, which is an important consequence of ROS production and was proven to be able to inhibit PEDV replication. To conclude, this study revealed that LA can inhibit PEDV replication via inducing ROS generation.}, } @article {pmid35215328, year = {2022}, author = {Guerini, M and Condrò, G and Friuli, V and Maggi, L and Perugini, P}, title = {N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A Review.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {2}, pages = {}, pmid = {35215328}, issn = {1424-8247}, abstract = {N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have been discovered over the years, making it a promising drug for diseases such as cystic fibrosis (CF). Its antioxidant activity plays a key role in CF airway inflammation and redox imbalance. Furthermore, this molecule appears to play an important role in the prevention and eradication of biofilms resulting from CF airway infections, in particular that of Pseudomonas aeruginosa. The aim of this review is to provide an overview of CF and the role that NAC could play in preventing and eliminating biofilms, as a modulator of inflammation and as an antioxidant, restoring the redox balance within the airways in CF patients. To do this, NAC can act alone, but it can also be used as an adjuvant molecule to known drugs (antibiotics/anti-inflammatories) to increase their activity.}, } @article {pmid35204298, year = {2022}, author = {Martinez-Banaclocha, M}, title = {N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204298}, issn = {2076-3921}, abstract = {In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use.}, } @article {pmid35204201, year = {2022}, author = {Bădilă, AE and Rădulescu, DM and Ilie, A and Niculescu, AG and Grumezescu, AM and Rădulescu, AR}, title = {Bone Regeneration and Oxidative Stress: An Updated Overview.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204201}, issn = {2076-3921}, abstract = {Bone tissue engineering is a complex domain that requires further investigation and benefits from data obtained over past decades. The models are increasing in complexity as they reveal new data from co-culturing and microfluidics applications. The in vitro models now focus on the 3D medium co-culturing of osteoblasts, osteoclasts, and osteocytes utilizing collagen for separation; this type of research allows for controlled medium and in-depth data analysis. Oxidative stress takes a toll on the domain, being beneficial as well as destructive. Reactive oxygen species (ROS) are molecules that influence the differentiation of osteoclasts, but over time their increasing presence can affect patients and aid the appearance of diseases such as osteoporosis. Oxidative stress can be limited by using antioxidants such as vitamin K and N-acetyl cysteine (NAC). Scaffolds and biocompatible coatings such as hydroxyapatite and bioactive glass are required to isolate the implant, protect the zone from the metallic, ionic exchange, and enhance the bone regeneration by mimicking the composition and structure of the body, thus enhancing cell proliferation. The materials can be further functionalized with growth factors that create a better response and higher chances of success for clinical use. This review highlights the vast majority of newly obtained information regarding bone tissue engineering, such as new co-culturing models, implant coatings, scaffolds, biomolecules, and the techniques utilized to obtain them.}, } @article {pmid35203827, year = {2022}, author = {De Angelis, M and Mascellino, MT and Miele, MC and Al Ismail, D and Colone, M and Stringaro, A and Vullo, V and Venditti, M and Mastroianni, CM and Oliva, A}, title = {High Activity of N-Acetylcysteine in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae and Acinetobacter baumannii.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35203827}, issn = {2079-6382}, abstract = {AIM: The aim of the study was to evaluate the in vitro activity of N-acetylcysteine (NAC), alone or in combination with beta-lactams, against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Acinetobacter baumannii (CR-Ab).

METHODS: The antibacterial activity of each compound was tested by broth microdilution and the synergism was evaluated by the checkerboard method. Killing studies of NAC alone and in combination with beta-lactams were performed. Bacterial morphological changes were investigated with scanning electron microscopy (SEM).

RESULTS: Overall, 30 strains were included (15 CR-Kp and 15 CR-Ab). The NAC Minimal Inhibitory Concentrations (MIC)50/90 were 5/5 and 2.5/5 mg/mL for CR-Kp and CR-Ab, respectively. For both microorganisms, NAC, in addition to beta-lactams (meropenem for CR-Kp, meropenem and ampicillin/sulbactam for CR-Ab, respectively), was able to enhance their activity. The killing studies showed a rapid and concentration-dependent activity of NAC alone; the addition of NAC to meropenem or ampicillin/sulbactam at subinhibitory concentrations induced a fast and lasting bactericidal activity that persisted over time. The SEM analyses showed evident morphological alterations of the bacterial cells following incubation with NAC, alone and in combination with meropenem.

CONCLUSIONS: NAC demonstrated a high in vitro activity against CR-Kp and CR-Ab and was able to enhance beta-lactams' susceptibility in the tested strains. The preliminary data on the SEM analyses confirmed the in vitro results.}, } @article {pmid35203350, year = {2022}, author = {Tanwar, J and Saurav, S and Basu, R and Singh, JB and Priya, A and Dutta, M and Santhanam, U and Joshi, M and Madison, S and Singh, A and Nair, N and Gokhale, RS and Motiani, RK}, title = {Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation.}, journal = {Cells}, volume = {11}, number = {4}, pages = {}, pmid = {35203350}, issn = {2073-4409}, support = {IA/I/19/2/504651/WTDBT_/DBT-Wellcome Trust India Alliance/India ; IA/I/19/2/504651//Wellcome Trust/DBT India Alliance/ ; CLP0027//Unilever R and D, India/ ; SRG/2019/000495//Science and Engineering Research Board/ ; }, mesh = {Animals ; Melanins/metabolism ; Melanocytes/metabolism ; *Melanoma, Experimental/metabolism ; *Melanosomes/metabolism ; Mice ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Inter-organellar communication is emerging as one of the most crucial regulators of cellular physiology. One of the key regulators of inter-organellar communication is Mitofusin-2 (MFN2). MFN2 is also involved in mediating mitochondrial fusion-fission dynamics. Further, it facilitates mitochondrial crosstalk with the endoplasmic reticulum, lysosomes and melanosomes, which are lysosome-related organelles specialized in melanin synthesis within melanocytes. However, the role of MFN2 in regulating melanocyte-specific cellular function, i.e., melanogenesis, remains poorly understood. Here, using a B16 mouse melanoma cell line and primary human melanocytes, we report that MFN2 negatively regulates melanogenesis. Both the transient and stable knockdown of MFN2 leads to enhanced melanogenesis, which is associated with an increase in the number of mature (stage III and IV) melanosomes and the augmented expression of key melanogenic enzymes. Further, the ectopic expression of MFN2 in MFN2-silenced cells leads to the complete rescue of the phenotype at the cellular and molecular levels. Mechanistically, MFN2-silencing elevates mitochondrial reactive-oxygen-species (ROS) levels which in turn increases melanogenesis. ROS quenching with the antioxidant N-acetyl cysteine (NAC) reverses the MFN2-knockdown-mediated increase in melanogenesis. Moreover, MFN2 expression is significantly lower in the darkly pigmented primary human melanocytes in comparison to lightly pigmented melanocytes, highlighting a potential contribution of lower MFN2 levels to higher physiological pigmentation. Taken together, our work establishes MFN2 as a novel negative regulator of melanogenesis.}, } @article {pmid35202279, year = {2022}, author = {Chen, H and Carty, RK and Bautista, AC and Hayakawa, KA and Lein, PJ}, title = {Triiodothyronine or Antioxidants Block the Inhibitory Effects of BDE-47 and BDE-49 on Axonal Growth in Rat Hippocampal Neuron-Glia Co-Cultures.}, journal = {Toxics}, volume = {10}, number = {2}, pages = {}, pmid = {35202279}, issn = {2305-6304}, support = {T32 ES007059/ES/NIEHS NIH HHS/United States ; R01 ES014901/ES/NIEHS NIH HHS/United States ; P30 ES023513/ES/NIEHS NIH HHS/United States ; P42 ES04699/ES/NIEHS NIH HHS/United States ; }, abstract = {We previously demonstrated that polybrominated diphenyl ethers (PBDEs) inhibit the growth of axons in primary rat hippocampal neurons. Here, we test the hypothesis that PBDE effects on axonal morphogenesis are mediated by thyroid hormone and/or reactive oxygen species (ROS)-dependent mechanisms. Axonal growth and ROS were quantified in primary neuronal-glial co-cultures dissociated from neonatal rat hippocampi exposed to nM concentrations of BDE-47 or BDE-49 in the absence or presence of triiodothyronine (T3; 3-30 nM), N-acetyl-cysteine (NAC; 100 µM), or α-tocopherol (100 µM). Co-exposure to T3 or either antioxidant prevented inhibition of axonal growth in hippocampal cultures exposed to BDE-47 or BDE-49. T3 supplementation in cultures not exposed to PBDEs did not alter axonal growth. T3 did, however, prevent PBDE-induced ROS generation and alterations in mitochondrial metabolism. Collectively, our data indicate that PBDEs inhibit axonal growth via ROS-dependent mechanisms, and that T3 protects axonal growth by inhibiting PBDE-induced ROS. These observations suggest that co-exposure to endocrine disruptors that decrease TH signaling in the brain may increase vulnerability to the adverse effects of developmental PBDE exposure on axonal morphogenesis.}, } @article {pmid35200000, year = {2022}, author = {Ding, Z and Wang, X and Zhang, N and Sun, C and Zhao, G and Peng, Y and Zheng, J}, title = {Metabolic Activation of Perampanel Mediated by CYP1A2.}, journal = {Chemical research in toxicology}, volume = {35}, number = {3}, pages = {490-498}, doi = {10.1021/acs.chemrestox.1c00396}, pmid = {35200000}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; *Cytochrome P-450 CYP1A2/metabolism ; *Glutathione/metabolism ; Humans ; Microsomes, Liver/metabolism ; Nitriles ; Pyridones ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Perampanel (PRP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist with high selectivity, has been used as a new adjuvant for the treatment of fractional seizures with or without primary generalized tonic-clonic seizures and secondary generalized seizures in epilepsy patients over the age of 12. Adverse events such as liver injury have been reported during the clinical application of PRP. The purpose of the study is to explore the in vitro and in vivo metabolic activation of PRP. Two GSH conjugates were detected in rat liver microsomal incubations containing PRP, GSH, and NADPH. The two GSH conjugates were both obtained from the bile of rats and rat primary hepatocytes after exposure to PRP. Similar microsomal incubations complemented with N-acetylcysteine (NAC) in place of GSH offered two NAC conjugates. As expected, the NAC conjugates were detected in the urine of PRP-treated rats. One of the two NAC conjugates was identified as NAC conjugate 12 verified by chemical synthesis. The individual human recombinant P450 enzyme incubation assay demonstrated that CYP1A2 dominated the catalysis for the metabolic activation of PRP. Pretreatment with α-naphthoflavone (NTF) decreased the formation of PRP-derived GSH conjugates in both livers of rats and cultured primary hepatocytes after being treated with PRP. Additionally, NTF was found to decrease the susceptibility of primary hepatocytes to the cytotoxicity of PRP. The findings indicate that PRP was metabolized to the corresponding epoxide, which could participate in PRP-induced cytotoxicity.}, } @article {pmid35193023, year = {2022}, author = {Narai-Kanayama, A and Chiku, K and Ono, H and Momoi, T and Hiwatashi-Kanno, M and Kobayashi, A and Matsuda, H and Yoshida, M and Nakayama, T}, title = {Inhibitory effects of thiol compounds on theaflavin browning and structural analysis of the causative substances.}, journal = {Food chemistry}, volume = {384}, number = {}, pages = {132488}, doi = {10.1016/j.foodchem.2022.132488}, pmid = {35193023}, issn = {1873-7072}, mesh = {Acetylcysteine ; Antioxidants/chemistry ; *Biflavonoids/chemistry ; Catechin ; *Cysteine/chemistry ; Glutathione/chemistry ; Oxidation-Reduction ; Sulfhydryl Compounds/chemistry ; }, abstract = {Theaflavin, a polyphenol responsible for the bright orange color and various bioactivities of black tea exudates, is susceptible to autoxidation at neutral and mild alkaline pH, changing its color to brown. In the presence of cysteine (Cys), glutathione (GSH), or N-acetyl cysteine (NAC), the browning of theaflavin solution was inhibited concomitantly with time-dependent decreases in the concentrations of both theaflavin and thiol group. The rank order of the decrease was Cys ≅ GSH > NAC, suggesting the relevance of the nucleophilic property of the thiol group to its reaction with theaflavin. LC-MS analysis of the reaction products indicated formation of novel derivatives that were mono- or di-molecular adducts of thiol compounds. We determined the chemical structures of theaflavin-Cys and theaflavin-GSH adducts by NMR and proposed the reaction mechanisms. It was found that the theaflavin-Cys adduct was not a simple adduct, to which a new cyclic structure was added.}, } @article {pmid35191764, year = {2022}, author = {Zhang, Z and Zhang, J and Liu, J and Zhao, H and Zhao, Y and Sun, D}, title = {The effect of different drugs on hard metal lung disease in a rat model.}, journal = {Toxicology and industrial health}, volume = {38}, number = {2}, pages = {92-99}, doi = {10.1177/07482337211062973}, pmid = {35191764}, issn = {1477-0393}, mesh = {Alloys ; Animals ; Bronchoalveolar Lavage Fluid ; Cobalt ; Female ; *Lung ; *Lung Diseases ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/metabolism ; Tungsten ; }, abstract = {Hard metal lung disease (HMLD) drugs include dexamethasone sodium phosphate (Dex), methylprednisolone (MP) injection, N-acetylcysteine injection (NAC), and a mix of Dex, MP, and NAC (MIX). In this study, we compared the effects of these drugs on different cytokines of hard metal lung disease in a rat model. Thirty-six adult female Sprague Dawley rats were distributed equally into the control group, hard metal (HM) group, Dex group, MP group, NAC group, and MIX group. HM powder (0.5 mL, 20 mg/mL; one time) was administered by intraperitoneal injection to the HM group through the pulmonary endotracheal tube, while the control group received normal saline (0.5 mL, 20 mg/mL; one time). After 4 weeks, the drugs were administered to the experimental groups (0.5 mL, 20 mg/mL; one time). After 8 weeks, bronchoalveolar lavage fluid (BALF) and serum were examined for cytokine levels. Biochemical analysis indicated that the Dex, MP, NAC, and MIX did not improve TGF-β1, TGF-β2, KL-6, and MMP-1 in the BALF, while MIX increased TIMP-1 in BALF. In addition, the NAC treatment significantly increased the expression levels of TGF-β1, TGF-β2, KL-6, and MMP-1. The MIX treatment significantly increased the expression levels of TGF-β1, TGF-β2, and KL-6. The MP treatment significantly increased the expression levels of KL-6, and MMP-1. The Dex treatment significantly increased the expression levels of TGF-β1, KL-6, and MMP-1. This study demonstrated that administered with NAC and MIX could improve TGF-β1, TGF-β2, and KL-6 in serum of hard metal lung disease in a rat model. Therefore, NAC injection may be considered a useful candidate in the development of a preventive agent against HMLD.}, } @article {pmid35189496, year = {2022}, author = {Sharma, R and Tikka, SK and Bhute, AR and Bastia, BK}, title = {N-acetyl cysteine in the treatment of cannabis use disorder: A systematic review of clinical trials.}, journal = {Addictive behaviors}, volume = {129}, number = {}, pages = {107283}, doi = {10.1016/j.addbeh.2022.107283}, pmid = {35189496}, issn = {1873-6327}, mesh = {Acetylcysteine/therapeutic use ; *Cannabis ; Humans ; *Marijuana Abuse/therapy ; }, abstract = {BACKGROUND AND AIM: Cannabis is the most consumed illicit drug globally, with a high risk of developing cannabis use disorder (CUD). No approved pharmacological treatment exists for CUD, but N-Acetyl Cysteine (NAC) has shown promising results in different clinical studies. This study aims to conduct a systematic review of NAC clinical trials for the treatment of CUD.

METHODS: Systematic review of randomized controlled trials (RCTs) was conducted to determine the effect of NAC for the treatment of cannabis dependence/cannabis use disorder (CUD). Articles were electronically searched across different databases using PubMed, Google Scholar, EMBASE, Cochrane Library, Medline and PsycINFO from inception to June 2021. Several study characteristics, including study duration, sample size, study population and age group, intervention, adverse effects, and outcome measure were extracted. A PICO table was used for data extraction.

RESULTS: We included 08 RCTs in the qualitative analysis. The risk of bias (RoB) was assessed according to Cochrane RoB criteria, and a 5 point grading system according to the Oxford Centre for Evidence-Based Medicine was used to rate the methodological quality (level of evidence) of the included articles. Mild and well-tolerated adverse events were reported in the placebo and NAC group.

CONCLUSIONS: The studies collectively offer mixed results, although the strength of the evidence available on which to make a recommendation is strong. NAC has shown to be effective in promoting abstinence, medication adherence and reducing cannabis use and craving among cannabis dependent users. This review also suggests recommendations for future research.}, } @article {pmid35187102, year = {2021}, author = {Huang, M and Yang, Z and Li, Y and Lan, H and Cyganek, L and Yuecel, G and Lang, S and Bieback, K and El-Battrawy, I and Zhou, X and Borggrefe, M and Akin, I}, title = {Dopamine D1/D5 Receptor Signaling Is Involved in Arrhythmogenesis in the Setting of Takotsubo Cardiomyopathy.}, journal = {Frontiers in cardiovascular medicine}, volume = {8}, number = {}, pages = {777463}, pmid = {35187102}, issn = {2297-055X}, abstract = {BACKGROUND: Previous studies suggested involvement of non-ß-adrenoceptors in the pathogenesis of Takotsubo cardiomyopathy (TTC). This study was designed to explore possible roles and underlying mechanisms of dopamine D1/D5 receptor coupled signaling in arrhythmogenesis of TTC.

METHODS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were challenged by toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) for mimicking the catecholamine excess in setting of TTC. Specific receptor blockers and activators were used to unveil roles of D1/D5 receptors. Patch clamp, qPCR, and FACS analyses were performed in the study.

RESULTS: High concentration Epi and two dopamine D1/D5 receptor agonists [(±)-SKF 38393 and fenoldopam] reduced the depolarization velocity and prolonged the duration of action potentials (APs) and caused arrhythmic events in iPSC-CMs, suggesting involvement of dopamine D1/D5 receptor signaling in arrhythmogenesis associated with QT interval prolongation in the setting of TTC. (±)-SKF 38393 and fenoldopam enhanced the reactive oxygen species (ROS)-production. H2O2 (100 μM) recapitulated the effects of (±)-SKF 38393 and fenoldopam on APs and a ROS-blocker N-acetylcysteine (NAC, 1 mM) abolished the effects, suggesting that the ROS-signaling is involved in the dopamine D1/D5 receptor actions. A NADPH oxidases blocker and a PKA- or PKC-blocker suppressed the effects of the dopamine receptor agonist, implying that PKA, NADPH oxidases and PKC participated in dopamine D1/D5 receptor signaling. The abnormal APs resulted from dopamine D1/D5 receptor activation-induced dysfunctions of ion channels including the Na[+] and L-type Ca[2+] and IKr channels.

CONCLUSIONS: Dopamine D1/D5 receptor signaling plays important roles for arrhythmogenesis of TTC. Dopamine D1/D5 receptor signaling in cardiomyocytes might be a potential target for treating arrhythmias in patients with TTC.}, } @article {pmid35186974, year = {2021}, author = {Yu, L and Wang, Y and Guo, YH and Wang, L and Yang, Z and Zhai, ZH and Tang, L}, title = {HIF-1α Alleviates High-Glucose-Induced Renal Tubular Cell Injury by Promoting Parkin/PINK1-Mediated Mitophagy.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {803874}, pmid = {35186974}, issn = {2296-858X}, abstract = {It is well-established that mitophagy leads to Diabetic Nephropathy (DN) and renal failure. Mitophagy mediated by a Hypoxia-inducible factor-1α (HIF-1α) plays a beneficial role in many diseases. Nevertheless, the mechanisms underlying HIF-1α-mediated mitophagy in DN remain unclear. This study defines the role of HIF-1α mediated mitophagy in DN. The expression of HIF-1α was upregulated in HK-2 cells in an High-Glucose (HG) environment, and the YC-1 (a specific inhibitor of HIF-1α) further exacerbated the hypoxia-induced mitochondrial dysfunction. Conversely, the HIF-1α-mediated protective effect was strengthened by scavenger N-acetylcysteine (NAC), a type of reactive oxygen species. Moreover, HIF-1α-Parkin/PINK1-mediated mitophagy prevented apoptosis and ROS production in HK-2 cells subjected to HG exposure. In summary, HIF-1α mediated mitophagy on HK-2 cells under HG conditions could alleviate DN, suggesting that it has huge prospects for DN treatment.}, } @article {pmid35185289, year = {2022}, author = {Pan, T and Qian, Y and Li, T and Zhang, Z and He, Y and Wang, J and Li, L and Hu, Y and Lin, M}, title = {Acetyl l-carnitine protects adipose-derived stem cells against serum-starvation: regulation on the network composed of reactive oxygen species, autophagy, apoptosis and senescence.}, journal = {Cytotechnology}, volume = {74}, number = {1}, pages = {105-121}, pmid = {35185289}, issn = {0920-9069}, abstract = {Adipose-derived stem cells (ADSCs) play an important role in cell therapy and regenerative medicine. However, local nutritional deficiency often limits therapeutical effect of the transplanted cells. Acetyl l-carnitine (ALC) is a common energy metabolism regulator and free radical scavenger. This study investigated the effect of ALC on ADSCs exposed to severe serum-deprivation and explored the relative machanisms. Treating with 1 mM ALC improved proliferation and alleviated senescence of starved cells, accompanied with reduced reactive oxygen species (ROS) and increased protein expression of SOD1 and catalase. In addition, ALC inhibited apoptosis but increased starvation-induced autophagy, which might be related to the regulation of phases of dissociation of Bcl-2-Beclin1 and Bcl-2-Bax complexes. Evidence obtained by replacing ALC with N-acetylcysteine (N-AC) suggested that ROS might be the central inducer of autophagy, apoptosis and senescence. There was a difference between ALC and N-AC in the protection mechanism, that was, compared with N-AC, ALC maintained autophagy well at the same time as anti-oxidation. Inhibition of autophagy by 3-methyladenine (3-MA) partially offset the protective effect of ALC. However, despite low-level ROS and enhanced autophagy, ALC with high concentration (10 mM) markedly aggravated cell apoptosis and senescence, thus losing cytoprotection and even causing damage.}, } @article {pmid35177589, year = {2022}, author = {Lv, J and Yi, Y and Qi, Y and Yan, C and Jin, W and Meng, L and Zhang, D and Jiang, W}, title = {Mitochondrial homeostasis regulates definitive endoderm differentiation of human pluripotent stem cells.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {69}, pmid = {35177589}, issn = {2058-7716}, support = {31970608//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2019CFA092//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; }, abstract = {Cellular organelles play fundamental roles in almost all cell behaviors. Mitochondria have been reported to be functionally linked to various biological processes, including reprogramming and pluripotency maintenance. However, very little about the role of mitochondria has been revealed in human early development and lineage specification. Here, we reported the characteristics and function of mitochondria during human definitive endoderm differentiation. Using a well-established differentiation system, we first investigated the change of mitochondrial morphology by comparing undifferentiated pluripotent stem cells, the intermediate mesendoderm cells, and differentiated endoderm cells, and found that mitochondria were gradually elongated and matured along differentiation. We further analyzed the expression pattern of mitochondria-related genes by RNA-seq, indicating that mitochondria became active during differentiation. Supporting this notion, the production of adenosine triphosphate (ATP) and reactive oxygen species (ROS) was increased as well. Functionally, we utilized chemicals and genome editing techniques, which could interfere with mitochondrial homeostasis, to determine the role of mitochondria in human endoderm differentiation. Treatment with mitochondrial inhibitors, or genetic depletion of mitochondrial transcription factor A (TFAM), significantly reduced the differentiation efficiency of definitive endoderm. In addition, the defect in endoderm differentiation due to dysfunctional mitochondria could be restored to some extent by the addition of ATP. Moreover, the clearance of excessive ROS due to dysfunctional mitochondria by N-acetylcysteine (NAC) improved the differentiation as well. We further found that ATP and NAC could partially replace the growth factor activin A for definitive endoderm differentiation. Our study illustrates the essential role of mitochondria during human endoderm differentiation through providing ATP and regulating ROS levels, which may provide new insight for metabolic regulation of cell fate determination.}, } @article {pmid35174928, year = {2022}, author = {Hashim, AR and Bashir, DW and Yasin, NAE and Rashad, MM and El-Gharbawy, SM}, title = {Ameliorative effect of N-acetylcysteine on the testicular tissue of adult male albino rats after glyphosate-based herbicide exposure.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {4}, pages = {e22997}, doi = {10.1002/jbt.22997}, pmid = {35174928}, issn = {1099-0461}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Glycine/analogs & derivatives ; *Herbicides/toxicity ; Male ; Oxidative Stress ; Rats ; Glyphosate ; }, abstract = {Glyphosate (GLP) is a broad-spectrum herbicide that is frequently used in crop production, but its residues remain in foodstuffs. This, in turn, has led to potential adverse effects on both human and animal health. Recent studies emphasized that GLP induces teratogenic effects and reproductive disorders, but its mechanism of toxicity is highly debated. N-acetylcysteine (NAC) is well known for its potent antioxidant capacity in addition to anti-inflammatory and cytoprotective properties. Therefore, our study aimed to investigate the reproductive toxicity of GLP in mature rats and evaluate the possible ameliorative effect of NAC against this toxicity. To this end, 30 adult male rats were assigned into three groups (10 rats per group) as follows: Group I, negative control; group II, GLP-exposed; 375 mg/kg GLP, orally; group III, NAC-cotreated, 160 mg/kg NAC 1 h before GLP, plus GLP, 375 mg/kg orally for 6 weeks. At the end of the experiment, the testicles were collected for semen analysis and biochemical, histopathological, and immunohistochemical studies. GLP-exposed rats exhibited disturbances in seminal parameters and a significant increase in malondialdehyde levels and expression of apoptotic markers. Several histopathological changes were observed, including strong immunoreactions for caspase-3 and proliferating cell nuclear antigen. Conversely, the administration of NAC before GLP was able to improve seminal parameters, attenuate the induced oxidative stress and apoptosis in addition to the regeneration of testicular damage. In conclusion, NAC can ameliorate the reproductive toxicity induced by GLP to an acceptable degree.}, } @article {pmid35171079, year = {2022}, author = {Urso, CJ and Zhou, H}, title = {Palmitic acid-induced defects in cell cycle progression and cytokinesis in Neuro-2a cells.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {21}, number = {10}, pages = {1048-1057}, pmid = {35171079}, issn = {1551-4005}, mesh = {Animals ; Apoptosis ; Cell Line, Tumor ; Cytokinesis ; DNA ; Fatty Acids/metabolism/pharmacology ; *Fatty Acids, Nonesterified/metabolism/pharmacology ; Fatty Acids, Unsaturated/metabolism/pharmacology ; G2 Phase Cell Cycle Checkpoints ; Linoleic Acids/pharmacology ; Mice ; Oleic Acids/pharmacology ; *Palmitic Acid/pharmacology ; alpha-Linolenic Acid/pharmacology ; }, abstract = {Obesity is associated with elevated levels of free fatty acids (FFAs). Excessive saturated fatty acids (SFAs) exhibit significant deleterious cytotoxic effects in many types of cells. However, the effects of palmitic acid (PA), the most common circulating SFA, on cell cycle progression in neuronal cells have not been well-examined. The aim of this study was to examine whether PA affects the proliferation and cell cycle progression in mouse neuroblastoma Neuro-2a (N2a) cells. Our studies found that 200 µM PA significantly decreased DNA synthesis and mitotic index in N2a cells as early as 4 h following treatment. 24 h treatment with 200 µM PA significantly decreased the percentage of diploid (2 N) cells while dramatically increasing the percentage of tetraploid (4 N) cells as compared to the BSA control. Moreover, our studies found that 24 h treatment with 200 µM PA increased the percentage of binucleate cells as compared to the BSA control. Our studies also found that unsaturated fatty acids (UFAs), including linoleic acid, oleic acid, α-linolenic acid, and docosahexaenoic acid, were able to abolish PA-induced decrease of 2 N cells, increase of 4 N cells, and accumulation of binucleate cells. Taken together, these results suggest that PA may affect multiple aspects of the cell cycle progression in N2a cells, including decreased DNA synthesis, G2/M arrest, and cytokinetic failure, which could be abolished by UFAs.Abbreviations: 4-PBA, 4-Phenylbutyric Acid; ALA, α-linolenic acid; BrdU, 5-bromo-2'-deoxyuridine; DAPI, 4',6-diamidino-2-phenylindole; ER, endoplasmic reticulum; FFA, free fatty acids; FITC, fluorescein isothiocyanate; LA, linoleic acid; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; N2a, Neuro-2a; NAC, N-acetyl cysteine; OA, oleic acid; PA, palmitic acid; pHH3, Phosphorylation of histone H3; PI, propidium iodide; SFA, saturated fatty acids; PUFA, polyunsaturated fatty acids; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; UFA, unsaturated fatty acids.}, } @article {pmid35169555, year = {2022}, author = {Hwang, S and Kim, JK}, title = {N-Acetylcysteine Induces Apoptotic, Oxidative and Excitotoxic Neuronal Death in Mouse Cortical Cultures.}, journal = {Chonnam medical journal}, volume = {58}, number = {1}, pages = {18-23}, pmid = {35169555}, issn = {2233-7385}, abstract = {N-acetylcysteine (NAC) has been used as an antioxidant to prevent oxidative cell death. However, we found NAC itself to induce neuronal death in mouse cortical cultures. Therefore, the current study was performed to investigate the mechanism of neuronal death caused by NAC. Cell death was assessed by measuring lactate dehydrogenase efflux to bathing media after 24-48 h exposure to NAC. NAC (0.1-10 mM) induced neuronal death in a concentration- and exposure time-dependent manner. However, NAC did not injure astrocytes even at a concentration of 10 mM. Also, 10 mM NAC markedly attenuated oxidative astrocyte death induced by 0.5 mM diethyl maleate or 0.25 mM H2O2. The NMDA receptor antagonist MK-801 (10 µM) markedly attenuated the neuronal death caused by 10 mM NAC, while NBQX did not affect the neuronal death. Cycloheximide (a protein synthesis inhibitor, 0.1 µg/mL) and z-VAD-FMK (a caspase inhibitor, 100 µM) also significantly attenuated neuronal death. Apoptotic features such as chromatin condensation, nuclear fragmentation, and caspase 3 activation were observed 1 h after the NAC treatment. The neuronal death induced by 1 or 10 mM NAC was significantly attenuated by the treatment with 100 µM Trolox or 1 mM ascorbic acid. NAC induced the generation of intracellular reactive oxygen species (ROS), as measured by the fluorescent dye 2',7'-dichlorofluorescein diacetate. The ROS generation was almost completely abolished by treatment with Trolox or ascorbic acid. These findings demonstrate that NAC can cause oxidative, apoptotic, and excitotoxic neuronal death in mouse neuronal cultures.}, } @article {pmid35167014, year = {2022}, author = {Tallarico, M and Leo, A and Guarnieri, L and Zito, MC and De Caro, C and Nicoletti, F and Russo, E and Constanti, A and De Sarro, G and Citraro, R}, title = {N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy.}, journal = {Molecular neurobiology}, volume = {59}, number = {5}, pages = {2702-2714}, pmid = {35167014}, issn = {1559-1182}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Cognitive Dysfunction ; Disease Models, Animal ; Electroencephalography/methods ; *Epilepsy, Absence/chemically induced/complications/drug therapy ; Humans ; Rats ; Seizures/chemically induced/complications/drug therapy ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant with some demonstrated efficacy in a range of neuropsychiatric disorders. NAC has shown anticonvulsant effects in animal models. NAC effects on absence seizures are still not uncovered, and considering its clinical use as a mucolytic in patients with lung diseases, people with epilepsy are also likely to be exposed to the drug. Therefore, we aimed to study the effects of NAC on absence seizures in the WAG/Rij rat model of absence epilepsy with neuropsychiatric comorbidities. The effects of NAC chronic treatment in WAG/Rij rats were evaluated on: absence seizures at 15 and 30 days by EEG recordings and animal behaviour at 30 days on neuropsychiatric comorbidities. Furthermore, the mechanism of action of NAC was evaluated by analysing brain expression levels of some possible key targets: the excitatory amino acid transporter 2, cystine-glutamate antiporter, metabotropic glutamate receptor 2, the mechanistic target of rapamycin and p70S6K as well as levels of total glutathione. Our results demonstrate that in WAG/Rij rats, NAC treatment significantly increased the number and duration of SWDs, aggravating absence epilepsy while ameliorating neuropsychiatric comorbidities. NAC treatment was linked to an increase in brain mGlu2 receptor expression with this being likely responsible for the observed absence seizure-promoting effects. In conclusion, while confirming the positive effects on animal behaviour induced by NAC also in epileptic animals, we report the aggravating effects of NAC on absence seizures which could have some serious consequences for epilepsy patients with the possible wider use of NAC in clinical therapeutics.}, } @article {pmid35163042, year = {2022}, author = {Suzuki-Karasaki, M and Ando, T and Ochiai, Y and Kawahara, K and Suzuki-Karasaki, M and Nakayama, H and Suzuki-Karasaki, Y}, title = {Air Plasma-Activated Medium Evokes a Death-Associated Perinuclear Mitochondrial Clustering.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163042}, issn = {1422-0067}, support = {JP21K0927//Japan Society for the Promotion of Science/ ; JP21K10128//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; Bone Neoplasms/*drug therapy/metabolism ; Cell Death ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cluster Analysis ; Humans ; Lipid Peroxides/metabolism ; Male ; Mice ; Mitochondria/drug effects/*metabolism ; Mitochondrial Dynamics/drug effects ; Mouth Neoplasms/*drug therapy/metabolism ; Osteosarcoma/*drug therapy/metabolism ; Plasma Gases/*administration & dosage/pharmacology ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy, which eliminates cancers effectively and safely, is the current clinical choice. Since aggressive tumors are substantially resistant to multidisciplinary therapies that target apoptosis, tumor-specific activation of another cell death modality is a promising avenue for meeting this goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can kill OS and OC by causing a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) based on its characteristic unipolar mitochondrial perinuclear accumulation. The APAM caused apoptotic and nonapoptotic cell death. The APAM increased mitochondrial ROS (mROS) and cell death, and the antioxidants such as N-acetylcysteine (NAC) prevented them. MPMC occurred following mitochondrial fragmentation, which coincided with nuclear damages. MPMC was accompanied by mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC, Ferrostatin-1, and Nocodazole. In contrast, the APAM induced minimal cell death, mROS generation, mLPO accumulation, and MPMC in fibroblasts. These results suggest that MPMC occurs in a tumor-specific manner via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC induction might serve as a promising target for exerting tumor-specific cytotoxicity.}, } @article {pmid35157342, year = {2022}, author = {Mansouri, MD and Ramanthan, V and Mansouri, DL and Hull, RA}, title = {In vitro activities of N-acetyl cysteine and levofloxacin as a catheter lock therapy against catheter-associated infections.}, journal = {Journal of applied microbiology}, volume = {132}, number = {5}, pages = {3915-3924}, doi = {10.1111/jam.15490}, pmid = {35157342}, issn = {1365-2672}, support = {R21 AI074010/AI/NIAID NIH HHS/United States ; AI074010/NH/NIH HHS/United States ; AI133037/NH/NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/pharmacology/therapeutic use ; *Anti-Infective Agents ; Biofilms ; *Catheter-Related Infections/drug therapy/microbiology/prevention & control ; Catheters/microbiology ; Escherichia coli ; Humans ; Levofloxacin/pharmacology ; *Methicillin-Resistant Staphylococcus aureus ; Staphylococcus aureus ; }, abstract = {AIMS: Since management of catheter-associated infections, which are generally biofilm-based, is attempted in certain patients such as older and frail patients by using a catheter lock solution (CLS), we examined the combination of N-acetyl cysteine (NAC), an antibiofilm agent, and levofloxacin, a broad-spectrum antimicrobial agent, for this purpose.

METHODS AND RESULTS: Intravascular catheters were colonized with methicillin-resistant Staphylococcus epidermidis, levofloxacin-sensitive/methicillin-resistant Staph. aureus, levofloxacin-resistant/methicillin-resistant Staph. aureus, vancomycin-resistant Enterococcus, Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa and treated with a CLS containing normal saline, NAC, levofloxacin or NAC plus levofloxacin (NACLEV) and then cultured to assess their antimicrobial activities. We also examined antibiofilm and antimicrobial activities of each CLS by scanning electron microscopy (SEM) and the mechanical integrity of catheters exposed to CLS. Treatment of colonized catheters with NACLEV-CLS significantly reduced colonization (p < 0.005) against all pathogens. SEM images also indicate reduction in colonization with NACLEV-CLS with considerable reduction in both visible bacteria and the associated biofilm. Mean tensile strength of catheters exposed to CLS was not significantly different compared to controls (p > 0.05).

CONCLUSIONS: These in vitro results suggest that NACLEV-CLS can significantly reduce all bacterial colonization and potentially help salvage infected catheters without affecting the catheter's mechanical integrity.

This study presents a novel CLS with a broad spectrum of antimicrobial activity against catheter-associated infections, particularly in long-term catheters.}, } @article {pmid35156589, year = {2022}, author = {Jouzdani, AF and Ganjirad, Z and Firozian, F and Soleimani-Asl, S and Ranjbar, A}, title = {Protective Effects of N-acetylcysteine Niosome Nanoparticles on Paraquatinduced Nephrotoxicity in Male Rats.}, journal = {Pharmaceutical nanotechnology}, volume = {10}, number = {2}, pages = {137-145}, doi = {10.2174/2211738510666220214102034}, pmid = {35156589}, issn = {2211-7393}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/pharmacology ; Creatinine ; Liposomes ; Male ; *Nanoparticles ; Paraquat/toxicity ; Rats ; Rats, Wistar ; }, abstract = {INTRODUCTION: Paraquat (PQ), as a bipyridyl compound, is widely used as an effective herbicide that produces reactive oxygen species (ROS), affecting the unsaturated lipids of cell membranes leading to cell mortality. N-acetylcysteine (NAC) is a medication that has a beneficial role in reducing the intoxication of kidneys caused by PQ. Niosomes are bilayer vesicles that enhance the bioavailability of drugs. This study aimed to compare the effects of NAC and niosome of NAC (NACNPs) on PQ-induced kidney toxicity concerning its antioxidant activity.

METHODS: In this experimental study, after formulating NACNP, 30 Wistar male rats weighing 180 to 250 gm were classified into five groups: the control group was treated with normal saline, while the other four groups received 35mg/kg/day of PQ via intraperitoneal route and, was treated with 25mg/kg/day NAC, 25mg/kg/day niosome and 25 mg/kg/day NACNP by gavage, Then, oxidative stress biomarkers such as total antioxidant capacity (TAC), catalase activity (CAT), lipid peroxidation (LPO), and total thiol group (TTG), plus blood urea nitrogen (BUN) and creatinine levels were evaluated in kidney tissue homogenate and examined histopathologically.

RESULTS: The results revealed that TTG increased significantly in NAC & NACNP groups than in the PQ group. Further, in the PQ group, LPO increased significantly compared with the control, NAC, and NACNP groups, while in the NAC and NACNP group, LPO diminished compared with the PQ group. There was no significant difference in TAC between groups. Blood urea nitrogen (BUN) and creatinine levels dropped in NACNP compared with the PQ group and the NAC. Histological studies also approved PQ-induced damage and the protective effect of NACNP.

CONCLUSION: The results indicated that NACNP could modulate oxidative stress status and kidney function against PQ toxicity.}, } @article {pmid35155393, year = {2022}, author = {Liu, Y and Na, Q and Liu, J and Liu, A and Oppong, A and Lee, JY and Chudnovets, A and Lei, J and Sharma, R and Kannan, S and Kannan, RM and Burd, I}, title = {Dendrimer-Based N-Acetyl Cysteine Maternal Therapy Ameliorates Placental Inflammation via Maintenance of M1/M2 Macrophage Recruitment.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {10}, number = {}, pages = {819593}, pmid = {35155393}, issn = {2296-4185}, support = {P50 HD103538/HD/NICHD NIH HHS/United States ; }, abstract = {Intrauterine inflammation (IUI) is the primary cause of spontaneous preterm birth and predisposes neonates to long-term sequelae, including adverse neurological outcomes. N-acetyl-L-cysteine (NAC) is the amino acid L-cysteine derivative and a precursor to the antioxidant glutathione (GSH). NAC is commonly used clinically as an antioxidant with anti-inflammatory properties. Poor bioavailability and high protein binding of NAC necessitates the use of high doses resulting in side effects including nausea, vomiting, and gastric disruptions. Therefore, dendrimer-based therapy can specifically target the drug to the cells involved in inflammation, reducing side effects with efficacy at much lower doses than the free drug. Towards development of the new therapies for the treatment of maternal inflammation, we successfully administered dendrimer-based N-Acetyl Cysteine (DNAC) in an animal model of IUI to reduce preterm birth and perinatal inflammatory response. This study explored the associated immune mechanisms of DNAC treatment on placental macrophages following IUI, especially on M1/M2 type macrophage polarization. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the pro-inflammatory cytokine mRNA of Il1β and Nos2, and decreased CD45[+] leukocyte infiltration in the placenta following IUI. Furthermore, we found that DNAC altered placental immune profile by stimulating macrophages to change to the M2 phenotype while decreasing the M1 phenotype, thus suppressing the inflammatory responses in the placenta. Our study provides evidence for DNAC therapy to alleviate IUI via the maintenance of macrophage M1/M2 imbalance in the placenta.}, } @article {pmid35154590, year = {2021}, author = {Mahmoodzadeh, Y and Mahmoudi, J and Gorgani-Firuzjaee, S and Mohtavinejad, N and Namvaran, A}, title = {Effects of N-acetylcysteine on Noise Exposure-induced Oxidative Stress and Depressive- and Anxiety-like Behaviors in Adult Male Mice.}, journal = {Basic and clinical neuroscience}, volume = {12}, number = {4}, pages = {499-510}, pmid = {35154590}, issn = {2008-126X}, abstract = {INTRODUCTION: Depression and anxiety are the most common psychiatric disorders. These conditions widely occur in industrial societies and severely affect individuals' lives. N-Acetylcysteine (NAC) is a mucolytic compound with antioxidant and anti-inflammatory effects. This study aimed to investigate the potential therapeutic effects of NAC on chronic noise-induced depression- and anxiety-like behaviors in mice.

METHODS: Fifty male BALB/c mice were randomly divided into 5 groups, as follows: control, noise90 dB, noise110 dB, noise 90+NAC, and noise 110+NAC groups. Animals in the noise groups were exposed to 90 dB 2 h/day and 110 dB 2 h/day for 30 days. The NAC groups received NAC (325 mg/kg P.O.) 20 min after being exposed to noise. To evaluate depressive- and anxiety-like behaviors, the examined mice were subjected to the Open Field Test (OFT), Sucrose Preference Test (SPT), Tail Suspension Test (TST), and Elevated Plus Maze (EPM) tasks. At the end of the behavioral tests, the study animals were sacrificed. Accordingly, the levels of Malondialdehyde (MDA), Total Antioxidant Capacity (TAC), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx) were determined in the Hippocampus (HIP) and the Prefrontal Cortex (PFC).

RESULTS: The obtained results suggested that noise exposure would induce anxiety- and depressive-like behaviors, being reversed by NAC administration. Moreover, chronic administration of NAC significantly increased antioxidant enzyme activities and reduced lipid peroxidation (MDA levels) in the PFC and HIP of noise-exposed mice.

CONCLUSION: Our findings revealed that administrating NAC would reduce the adverse effects of noise on the brain and would exert anti-depressant and anxiolytic effects.}, } @article {pmid35153010, year = {2022}, author = {Jin, Z and Hu, G and Zhao, K}, title = {Mannose-anchored quaternized chitosan/thiolated carboxymethyl chitosan composite NPs as mucoadhesive carrier for drug delivery.}, journal = {Carbohydrate polymers}, volume = {283}, number = {}, pages = {119174}, doi = {10.1016/j.carbpol.2022.119174}, pmid = {35153010}, issn = {1879-1344}, mesh = {Acetylcysteine/chemistry ; Administration, Mucosal ; Chemical Phenomena ; Chitosan/analogs & derivatives/*chemistry ; Drug Carriers/administration & dosage/*chemistry ; Drug Delivery Systems/*methods ; Drug Liberation ; HEK293 Cells ; Humans ; Hydrophobic and Hydrophilic Interactions ; Macrophages/drug effects ; Mannose/*chemistry ; Mucins/metabolism ; Nanoparticles/*chemistry ; Particle Size ; }, abstract = {There are various challenges for the mucosal delivery of drug, which is largely attributed to the absence of effective drug carriers that can make delivery to mucosal sites. In the present study, we aimed to synthesize bifunctional mucoadhesive nanoparticles (NPs) that could be used for mucosal delivery. N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (M-N-2-HACC) was modified with D-mannose, and N-acetyl-L-cysteine (NAC) was immobilized on the carboxymethyl chitosan (N-CMCS). The electrostatic interaction between the two substances was used to produce mannose-modified thiolated chitosan NPs (M-N-2-HACC/N-CMCS NPs). The NPs showed a particle size of 196.72 ± 0.45 nm and zeta potential of 17.12 ± 0.50 mV. Moreover, it demonstrated high hydrophilicity, enduring drug release, stability, safety, and mucosal adhesion, which contributed to the effectiveness of mucosal administration. Additionally, the NPs could be instantly absorbed by macrophages. Collectively, these results suggested that M-N-2-HACC/N-CMCS NPs could be used as a promising candidate for mucosal delivery.}, } @article {pmid35151835, year = {2022}, author = {Wang, X and He, MJ and Chen, XJ and Bai, YT and Zhou, G}, title = {Glaucocalyxin A impairs tumor growth via amplification of the ATF4/CHOP/CHAC1 cascade in human oral squamous cell carcinoma.}, journal = {Journal of ethnopharmacology}, volume = {290}, number = {}, pages = {115100}, doi = {10.1016/j.jep.2022.115100}, pmid = {35151835}, issn = {1872-7573}, mesh = {Activating Transcription Factor 4/*drug effects ; Animals ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Diterpenes, Kaurane/*pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Isodon ; Male ; Mice ; Mice, Inbred BALB C ; Mitochondria/drug effects ; Mouth Neoplasms/*pathology ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Transcription Factor CHOP/*drug effects ; Xenograft Model Antitumor Assays ; gamma-Glutamylcyclotransferase/*drug effects ; }, abstract = {The natural extract glaucocalyxin A (GLA), purified from the aboveground sections of the Chinese traditional medicinal herb Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, has various pharmacological benefits, such as anti-bacterial, anti-coagulative, anti-neoplastic, and anti-inflammatory activities. Although GLA has shown anti-tumor activity against various cancers, the therapeutic potential and biological mechanisms of GLA remain to be further explored in oral squamous cell carcinoma (OSCC).

AIM OF THE STUDY: This study aimed to elucidate the therapeutic potential and regulatory mechanisms of GLA in OSCC.

MATERIALS AND METHODS: The cell proliferation and apoptosis effects of GLA were analyzed by CCK-8, clone formation, Annexin V/PI staining, and apoptotic protein expression in vitro. An OSCC xenograft model was applied to confirm the anti-neoplastic effect in vivo. Furthermore, the changes of reactive oxygen species (ROS) were determined by DCFH-DA probe and GSH/GSSG assay, and inhibited by the pan-caspase inhibitor Z-VAD(OMe)-FMK and the ROS scavenger N-acetylcysteine (NAC). The modulation of GLA on mitochondria and ER-dependent apoptosis pathways was analyzed by JC-1 probe, quantitative real-time PCR, and Western blot. Finally, public databases, clinical samples, and transfection cells were analyzed to explore the importance of GLA's indirect targeting molecule CHAC1 in OSCC.

RESULTS: GLA significantly inhibited cell proliferation and induced apoptosis in vitro and in vivo. GLA perturbed the redox homeostasis, and cell apoptosis was totally rescued by Z-VAD(OMe)-FMK and NAC. Furthermore, GLA activated the mitochondrial apoptosis pathway. Simultaneously, the overexpression and knockdown of CHAC1 dramatically affected GLA-mediated apoptosis. The endoplasmic reticulum stress-associated ATF4/CHOP signal was identified to participate in GLA-upregulated CHAC1 expression. Finally, we found that CHAC1 expression was lower in OSCC compared with normal tissues and positively correlated with 4-Hydroxynonenal (4-HNE) level. High CHAC1 expression also indicated better overall survival. Moreover, CHAC1 selectively regulated the viability of oral cancer cells.

CONCLUSION: GLA is a promising therapeutic agent that activates the ROS-mediated ATF4/CHOP/CHAC1 axis in OSCC patients.}, } @article {pmid35151470, year = {2022}, author = {Zhang, B and Ma, X and Loor, JJ and Jiang, Q and Guo, H and Zhang, W and Li, M and Lv, X and Yin, Y and Wen, J and Wang, J and Xu, C and Yang, W}, title = {Role of ORAI calcium release-activated calcium modulator 1 (ORAI1) on neutrophil extracellular trap formation in dairy cows with subclinical hypocalcemia.}, journal = {Journal of dairy science}, volume = {105}, number = {4}, pages = {3394-3404}, doi = {10.3168/jds.2021-21044}, pmid = {35151470}, issn = {1525-3198}, mesh = {Animals ; Calcium ; Cattle ; *Cattle Diseases ; *Extracellular Traps/metabolism ; Female ; *Hypocalcemia/veterinary ; Lactation ; Neutrophils/metabolism ; ORAI1 Protein/genetics ; }, abstract = {Hypocalcemia in dairy cows is associated with decreased neutrophil phagocytosis, adhesion capacity, migration, and reactive oxygen species (ROS) production through alterations in ORAI calcium release-activated calcium modulator 1 (ORAI1). Neutrophils can resist the invasion of pathogenic microorganisms by releasing neutrophil extracellular traps (NET). However, the mechanisms controlling NET formation during hypocalcemia are unknown. To address the role of ORAI1 in NET formation, neutrophils were isolated at 2 d postcalving from lactating Holstein dairy cows (n = 10 per group) diagnosed as clinically healthy (control) or with plasma concentrations of Ca[2+] <2.0 mmol/L as a criterion for diagnosing subclinical hypocalcemia (SCH). A series of ex vivo experiments were conducted as follows: first, neutrophils isolated from both groups of cows were treated with phorbol 12-myristate 13-acetate (PMA) to stimulate NET formation; second, neutrophils from control and SCH were pretreated with or without the ROS scavenger N-acetylcysteine (NAC), the sarcoendoplasmic Ca[2+] ATPase inhibitor thapsigargin, or ORAI1 blocker 2APB and then treated with PMA to stimulate NET formation; and third, neutrophils were transfected with small interfering (si)ORAI1 or nontarget siRNA (siNEG) and then stimulated with PMA to induce formation of NET. A one-way ANOVA was used for statistical analysis of individual experiments. In the first experiment, neutrophils from SCH cows formed NET with fewer DNA filaments, more diffused nuclei, and reduced translocation of myeloperoxidase (MPO) and neutrophil elastase (NE) to the nucleus. Neutrophils from SCH cows stimulated with PMA had a lower mitochondrial permeability, the state of mitochondrial permeability transition pore was open, ROS production was lower and there was increased mitochondrial damage. In the second experiment, in both control and SCH-PMA stimulated neutrophils, exogenous NAC decreased NET formation (assessed via Hoechst 33342 dye; Beyotime). Furthermore, following the challenge with PMA, thapsigargin increased NET formation and ROS production, but blocking ORAI1 with 2APB decreased NADPH oxidase activation, ROS production, and NET formation. In the third experiment, neutrophils transfected with siORAI1 before stimulation with PMA had lower intracellular concentrations of Ca[2+], NET formation, and ROS production. Overall, the data indicated that SCH reduces NET formation in neutrophils partly due to damaged mitochondria. The reduction in ORAI1 abundance in neutrophils of dairy cows with hypocalcemia also decreases ROS production.}, } @article {pmid35148231, year = {2022}, author = {Joyjamras, K and Chaotham, C and Chanvorachote, P}, title = {Response surface optimization of enzymatic hydrolysis and ROS scavenging activity of silk sericin hydrolysates.}, journal = {Pharmaceutical biology}, volume = {60}, number = {1}, pages = {308-318}, pmid = {35148231}, issn = {1744-5116}, mesh = {Antioxidants/*pharmacology ; Cell Line, Tumor ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; HaCaT Cells ; Humans ; Hydrogen-Ion Concentration ; Hydrolysis/drug effects ; Keratinocytes/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Sericins/*pharmacology ; Subtilisins/metabolism ; Temperature ; }, abstract = {CONTEXT: Sericin, a protein found in wastewater from the silk industry, was shown to contain a variety of biological activities, including antioxidant. The enzymatic conditions have been continuously modified to improve antioxidant effect and scavenging capacity against various free radicals of silk sericin protein.

OBJECTIVE: Variables in enzymatic reactions, including pH, temperature and enzyme/substrate ratio were analysed to discover the optimum conditions for antioxidant activity of sericin hydrolysates.

MATERIALS AND METHODS: Hydrolysis reaction catalysed by Alcalase[®] was optimized through response surface methodology (RSM) in order to generate sericin hydrolysates possessing potency for % inhibition on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, ferric-reducing power and peroxyl scavenging capacity. Flow cytometry was performed to evaluate cellular ROS level in human HaCaT keratinocytes and melanin-generating MNT1 cells pre-treated either with 20 mg/mL RSM-optimized sericin hydrolysates or 5 mM N-acetyl cysteine (NAC) for 60 min prior exposure with 1 mM hydrogen peroxide (H2O2).

RESULTS: Among these three variables, response surface plots demonstrate the major role of temperature on scavenging capacity of sericin hydrolysates. Sericin hydrolysates prepared by using Alcalase[®] at RSM-optimized condition (enzyme/substrate ratio: 1.5, pH: 7.5, temperature: 70 °C) possessed % inhibition against H2O2 at 99.11 ± 0.54% and 73.25 ± 8.32% in HaCaT and MNT1 cells, respectively, while pre-treatment with NAC indicated the % inhibition only at 30.26 ± 7.62% in HaCaT and 51.05 ± 7.14% in MNT1 cells.

DISCUSSION AND CONCLUSIONS: The acquired RSM information would be of benefit for further developing antioxidant peptide from diverse resources, especially the recycling of waste products from silk industry.}, } @article {pmid35142656, year = {2022}, author = {Jiang, SX and Hussaini, T and Yoshida, EM}, title = {N-acetylcysteine for non-acetaminophen induced acute liver failure: A review.}, journal = {Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association}, volume = {28}, number = {2}, pages = {85-91}, pmid = {35142656}, issn = {1998-4049}, mesh = {Acetaminophen/adverse effects ; Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/pharmacology/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy ; Humans ; *Liver Failure, Acute/chemically induced/drug therapy ; Mice ; Prospective Studies ; }, abstract = {The use of N-acetylcysteine (NAC) for non-acetaminophen-induced acute liver failure (NAI-ALF) has been increasing despite controversy in its efficacy. National guidelines are in disagreement for NAC use as standard of care; however, many healthcare centers continue to adopt the use of NAC outside of acetaminophen poisoning. While NAC may have multiple mechanisms of action in treatment of ALF, this has not translated to clinical benefit. Murine models have reported antioxidant and anti-inflammatory properties, as well as improvement in liver-specific microcirculation. Multiple case studies and series have reported positive outcomes of NAC treatment for ALF of various etiologies. While prospective studies suggested the benefit of NAC treatment, these studies have methodological and statistical shortcomings that affect the validity of the results. In this review, we aimed to summarize the existing literature on the efficacy of NAC for NAI-ALF including mechanism of action, case studies and series demonstrating outcomes, and prospective studies that have led to its current widespread use, along with the reported rate of adverse events.}, } @article {pmid35140209, year = {2022}, author = {Kang, D and Lee, J and Jung, J and Carlson, BA and Chang, MJ and Chang, CB and Kang, SB and Lee, BC and Gladyshev, VN and Hatfield, DL and Lee, BJ and Kim, JH}, title = {Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {779}, pmid = {35140209}, issn = {2041-1723}, mesh = {Aging ; Animals ; Cartilage, Articular/metabolism ; Chondrocytes/metabolism ; Disease Models, Animal ; *Homeostasis ; Male ; Mice ; Mice, Knockout ; Osteoarthritis/*genetics/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Phosphotransferases/*deficiency/*genetics ; Reactive Oxygen Species ; Selenium/metabolism ; Selenoproteins ; Transcriptome ; }, abstract = {Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis. The resulting state of oxidative stress drives the pathological transition of chondrocytes during OA development. However, the specific molecular pathways involved in disrupting chondrocyte redox homeostasis remain unclear. Here, we show that selenophosphate synthetase 1 (SEPHS1) expression is downregulated in human and mouse OA cartilage. SEPHS1 downregulation impairs the cellular capacity to synthesize a class of selenoproteins with oxidoreductase functions in chondrocytes, thereby elevating the level of reactive oxygen species (ROS) and facilitating chondrocyte senescence. Cartilage-specific Sephs1 knockout in adult mice causes aging-associated OA, and augments post-traumatic OA, which is rescued by supplementation of N-acetylcysteine (NAC). Selenium-deficient feeding and Sephs1 knockout have synergistic effects in exacerbating OA pathogenesis in mice. Therefore, we propose that SEPHS1 is an essential regulator of selenium metabolism and redox homeostasis, and its dysregulation governs the progression of OA.}, } @article {pmid35133468, year = {2022}, author = {Esalatmanesh, K and Jamali, A and Esalatmanesh, R and Soleimani, Z and Khabbazi, A and Malek Mahdavi, A}, title = {Effects of N-acetylcysteine supplementation on disease activity, oxidative stress, and inflammatory and metabolic parameters in rheumatoid arthritis patients: a randomized double-blind placebo-controlled trial.}, journal = {Amino acids}, volume = {54}, number = {3}, pages = {433-440}, pmid = {35133468}, issn = {1438-2199}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; *Arthritis, Rheumatoid/drug therapy ; Biomarkers ; C-Reactive Protein ; Dietary Supplements ; Double-Blind Method ; Humans ; Oxidative Stress ; }, abstract = {Considering the importance of inflammation and oxidative stress in the development of rheumatoid arthritis (RA) as well as anti-inflammatory and antioxidant features of N-acetylcysteine (NAC), this study was conducted to evaluate the effect of NAC supplementation on disease activity, oxidative stress, and inflammatory and metabolic parameters in RA patients. In a randomized double-masked placebo-controlled trial, 74 RA subjects were chosen and randomly divided into two groups to take 600 mg of NAC or placebo twice daily for 3 months. Before and after the study, disease activity was assessed via disease activity score-28 (DAS-28), and serum malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (GPX) activity, nitric oxide (NO), high-sensitivity C-reactive protein (hs-CRP), fasting blood sugar (FBS), lipid profile, and erythrocyte sedimentation rate (ESR) were measured. Seventy patients completed the trial. Compared to baseline, NAC significantly reduced morning stiffness (P < 0.001), DAS-28 (P < 0.001), ESR (P = 0.004), MDA (P < 0.001), NO (P < 0.001), hs-CRP (P = 0.006), FBS (P < 0.001), and low-density lipoprotein cholesterol (LDL-C) (P = 0.023) and significantly increased GPx activity (P = 0.015) and high-density lipoprotein cholesterol (HDL-C) level (P = 0.001). After treatment, remarkable differences were only seen between the two groups in serum NO (P = 0.003), FBS (P = 0.010), and HDL-C (P < 0.001) adjusted for baseline measures. There were no significant changes in morning stiffness, DAS-28, ESR, hs-CRP, MDA, TAC, GPx activity, triglyceride, total cholesterol, and LDL-C levels compared to the placebo group. In conclusion, NAC did not improve RA disease activity, but reduced NO and FBS and increased HDL-C levels. It appears that NAC should not be consumed as a replacement for routine medications prescribed in RA therapy, but it can be used as an adjunctive therapy.}, } @article {pmid35132919, year = {2022}, author = {Hussein, RM and Kandeil, MA and Mohammed, NA and Khallaf, RA}, title = {Evaluation of the hepatoprotective effect of curcumin-loaded solid lipid nanoparticles against paracetamol overdose toxicity: Role of inducible nitric oxide synthase.}, journal = {Journal of liposome research}, volume = {32}, number = {4}, pages = {365-375}, doi = {10.1080/08982104.2022.2032737}, pmid = {35132919}, issn = {1532-2394}, mesh = {Animals ; Rats ; *Curcumin/pharmacology ; Liposomes ; Acetaminophen ; Nitric Oxide Synthase Type II ; Rats, Wistar ; *Nanoparticles ; Acetylcysteine ; }, abstract = {Curcumin (Cur) is a natural compound that exhibited therapeutic effects against various liver injuries however Cur showed poor water solubility and bioavailability. This study aimed to design Cur-loaded solid lipid nanoparticles (SLNs) and to evaluate the hepatoprotective and antioxidant effects in a model of acute hepatotoxicity induced by paracetamol (PCM) overdose compared to the raw Cur and N-acetylcysteine (NAC). SLNs were prepared by emulsion/solvent evaporation method and 3[2] factorial design was employed. Wistar rats were divided into Control, PCM, PCM + NAC, PCM + raw Cur, and PCM + Cur-SLNs groups and treated orally for 14 days before receiving a single PCM dose. The Cur-loaded SLNs showed high entrapment efficiency % ranging between 69.1 and 92.1%, particle size (PS) between 217 and 506 nm, and zeta potential values between -17.9 and -25.5 mV. The in vivo results revealed that the PCM group exhibited deterioration of liver functions, pathological lesions on the liver tissues, severe oxidative stress, and increases in both the serum and hepatic iNOS levels. Remarkably, the PCM + Cur-SLNs group showed significantly better liver functions and tissue integrity compared to the PCM group. Furthermore, higher reduced glutathione and catalase but lower malondialdehyde and iNOS levels were observed. In conclusion, Cur-loaded SLNs effectively prevented the liver damage induced by PCM overdose through alleviating the oxidative stress and inhibiting the serum and hepatic iNOS expression in an effect comparable to NAC and better than raw Cur.}, } @article {pmid35129469, year = {2022}, author = {Lee, JV and Engel, C and Tay, S and DeSilva, G and Desai, K and Cashin, J and Semenkovich, CF and Zayed, MA}, title = {Impact of N-Acetyl-Cysteine on Ischemic Stumps Following Major Lower Extremity Amputation: A Pilot Randomized Clinical Trial.}, journal = {Annals of surgery}, volume = {276}, number = {5}, pages = {e302-e310}, pmid = {35129469}, issn = {1528-1140}, support = {R01 DK101392/DK/NIDDK NIH HHS/United States ; P30 DK020579/DK/NIDDK NIH HHS/United States ; R01 HL157154/HL/NHLBI NIH HHS/United States ; R01 HL153262/HL/NHLBI NIH HHS/United States ; K08 HL132060/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Amputation, Surgical ; *Amputation Stumps/surgery ; Humans ; Ischemia/etiology/surgery ; Lower Extremity/surgery ; *Peripheral Arterial Disease/surgery ; Pilot Projects ; Risk Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the impact of N-acetyl-cysteine (NAC) on amputation stump perfusion and healing in patients with critical limb-threatening ischemia (CLTI).

BACKGROUND: Patients with CLTI are at increased risk of poor amputation site healing leading to increased procedure-associated morbidity.

METHODS: In a pilot, double-blind, placebo-controlled, randomized controlled trial, patients with CLTI undergoing major elective lower extremity amputation were randomized 1:1 to intravenous NAC (1200 mg twice-daily) or placebo for up to 5 days postoperatively. Primary outcomes were change in stump perfusion at postoperative day 3 (POD3) and POD5, and healing at POD30. Stumps were serially evaluated for wound healing, and tissue perfusion was evaluated using noninvasive laser-assisted fluorescent angiography.

RESULTS: Thirty-three patients were randomized to NAC (n = 16) or placebo (n = 17). Thirty-one patients were eligible for intent-to-treat analysis (NAC14; placebo17). Twenty patients (NAC7; placebo13) had amputation stump perfusion defects at POD0 and were considered high-risk for poor healing. Intent-to-treat analysis revealed no significant differences between treatment groups. Subgroup analysis of high-risk patients revealed differences in stump perfusion defect size (NAC-0.53-fold, placebo +0.71-fold; 95% confidence interval -2.11 to-0.35; P < 0.05) and healing (NAC [100%], placebo [46%]; P < 0.01) between study treatments.

CONCLUSIONS: Postoperative NAC administration may improve amputation stump perfusion and healing in patients with CLTI and tissue perfusion defects at the time of amputation. Intraoperative laser-assisted fluorescent angiogra-phy may help surgeons identify high-risk patients with stump perfusion defects and provide early adjunctive interventions. Future studies can further explore the therapeutic benefits of NAC in the healing and perfusion of other surgical operative sites in high-risk individuals.

TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT03253328.}, } @article {pmid35128081, year = {2022}, author = {Pfaff, A and Chernatynskaya, A and Vineyard, H and Ercal, N}, title = {Thiol antioxidants protect human lens epithelial (HLE B-3) cells against tert-butyl hydroperoxide-induced oxidative damage and cytotoxicity.}, journal = {Biochemistry and biophysics reports}, volume = {29}, number = {}, pages = {101213}, pmid = {35128081}, issn = {2405-5808}, support = {R15 EY029813/EY/NEI NIH HHS/United States ; }, abstract = {Oxidative damage to lens epithelial cells plays an important role in the development of age-related cataract, and the health of the lens has important implications for overall ocular health. As a result, there is a need for effective therapeutic agents that prevent oxidative damage to the lens. Thiol antioxidants such as tiopronin or N-(2-mercaptopropionyl)glycine (MPG), N-acetylcysteine amide (NACA), N-acetylcysteine (NAC), and exogenous glutathione (GSH) may be promising candidates for this purpose, but their ability to protect lens epithelial cells is not well understood. The effectiveness of these compounds was compared by exposing human lens epithelial cells (HLE B-3) to the chemical oxidant tert-butyl hydroperoxide (tBHP) and treating the cells with each of the antioxidant compounds. MTT cell viability, apoptosis, reactive oxygen species (ROS), and levels of intracellular GSH, the most important antioxidant in the lens, were measured after treatment. All four compounds provided some degree of protection against tBHP-induced oxidative stress and cytotoxicity. Cells treated with NACA exhibited the highest viability after exposure to tBHP, as well as decreased ROS and increased intracellular GSH. Exogenous GSH also preserved viability and increased intracellular GSH levels. MPG scavenged significant amounts of ROS, and NAC increased intracellular GSH levels. Our results suggest that both scavenging ROS and increasing GSH may be necessary for effective protection of lens epithelial cells. Further, the compounds tested may be useful for the development of therapeutic strategies that aim to prevent oxidative damage to the lens.}, } @article {pmid35125047, year = {2022}, author = {Yurttaş, GN and Özdemir, ZC and Tanrıkut, C and Kar, E and Küskü Kiraz, Z and Alataş, Ö and Dönmez, DB and Bör, Ö}, title = {The effects of N-acetylcysteine on experimentally created l-asparaginase-induced liver and pancreatic damage in rats.}, journal = {Leukemia & lymphoma}, volume = {63}, number = {6}, pages = {1445-1454}, doi = {10.1080/10428194.2022.2030474}, pmid = {35125047}, issn = {1029-2403}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; *Asparaginase/pharmacology ; Glutathione/metabolism/pharmacology ; Humans ; Liver ; Male ; Oxidative Stress ; Pancreas/metabolism ; Rats ; Rats, Wistar ; }, abstract = {In this study, oxidative stress marker (malondialdehyde, MDA) and antioxidant enzymes (glutathione (GSH), catalase (CAT)) levels in the liver and pancreas tissue and the histopathological effects of N-acetylcysteine (NAC) were investigated in l-asparaginase (l-ASP) induced liver and pancreatic damage in rats. Forty male albino rats were divided into four groups. The control group was intraperitoneally injected physiological saline (0.02 mL/g); NAC group was injected NAC (200 mg/kg, five days); l-ASP group was injected single-dose l-ASP (10,000 U/kg), and l-ASP + NAC group was injected NAC for five days following single-dose l-ASP (10,000 U/kg). The surgical operation was performed on all animals on the fifth day. There was no difference between the groups regarding tissue MDA, GSH, and CAT levels (p>.05, for all). In the group receiving NAC after l-ASP, there was a significant improvement in the liver and pancreas damage score than the l-ASP group. NAC was effective in reducing organ damage caused by l-ASP.}, } @article {pmid35124906, year = {2021}, author = {Ijaz, N and Waheed, A and Tayyab, M and Mumal, S and Iftikhar, R and Rehman, A and Akram, E}, title = {Reno Protective Role Of N Acetyl Cysteine And Aqueous Extract Of Berberis Lycium Royale Root Bark On Rats.}, journal = {Journal of Ayub Medical College, Abbottabad : JAMC}, volume = {33}, number = {4}, pages = {553-557}, pmid = {35124906}, issn = {1819-2718}, mesh = {Acetylcysteine ; Animals ; *Berberis ; Kidney ; *Lycium ; Plant Bark ; Plant Extracts/pharmacology ; Rats ; Rats, Wistar ; Uric Acid ; Water ; }, abstract = {BACKGROUND: N acetyl cysteine and Berberis lycium Royale root bark have been used to treat kidney diseases. Objectives of the study were to evaluate the individual and combined effect of N acetyl cysteine and aqueous extract of Berberis lycium Royale root bark in Gentamicin induced nephrotoxicity in rats. This randomized control trial conducted at Islamic International Medical College, Rawalpindi in collaboration with NIH, Islamabad in 1 month from Sep to Oct 2020.

METHODS: Fifty Wister albino rats of 10-12 weeks old were divided into five groups with 10 in each group. Group 1 was normal control given food and water only and remaining 40 were in treatment groups. Nephrotoxicity was induced by intraperitoneal injection of Gentamicin (80mg/kg) for 6 days in group 2, 3, 4 and 5. After induction of nephrotoxicity, Group 3 was administered N acetyl cysteine 140mg/kg per oral, Group 4 was given aqueous extract of Berberis lycium Royale root bark 400 mg/kg per oral and Group 5 was given both N acetyl cysteine 140mg/kg per oral and aqueous extract of Berberis lycium Royale root bark 400 mg/kg per oral for 21 days. Serum uric acid was measured in all groups after 30 days to observe the reversal of renal injury.

RESULTS: The results of this study indicate that Group 3, Group 4 and Group 5 showed a decrease in serum uric acid level as compared to Disease Control Group (Group 2). However, Group 5 significantly reduced uric acid (p-0.05).

CONCLUSIONS: Combined effect of N acetyl cysteine and aqueous extract of Berberis lycium Royale root bark showed improvement in uric acid level in Gentamicin induced nephrotoxicity in rats.}, } @article {pmid35123994, year = {2022}, author = {Thompson, B and Davidson, EA and Chen, Y and Orlicky, DJ and Thompson, DC and Vasiliou, V}, title = {Oxidative stress induces inflammation of lens cells and triggers immune surveillance of ocular tissues.}, journal = {Chemico-biological interactions}, volume = {355}, number = {}, pages = {109804}, pmid = {35123994}, issn = {1872-7786}, support = {P30 EY026878/EY/NEI NIH HHS/United States ; TL1 TR001864/TR/NCATS NIH HHS/United States ; K01 AA025093/AA/NIAAA NIH HHS/United States ; R01 EY022313/EY/NEI NIH HHS/United States ; R01 EY017963/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Chemokine CCL7/genetics/metabolism ; Cytokines/genetics/metabolism ; Down-Regulation/drug effects ; Epithelial Cells/cytology/metabolism ; Epithelial-Mesenchymal Transition/genetics ; Eye/*anatomy & histology/metabolism ; Glutamate-Cysteine Ligase/deficiency/genetics ; *Immunity, Innate ; Lens, Crystalline/cytology/*metabolism ; Leukocytes/cytology/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects ; }, abstract = {Recent reports have challenged the notion that the lens is immune-privileged. However, these studies have not fully identified the molecular mechanism(s) that promote immune surveillance of the lens. Using a mouse model of targeted glutathione (GSH) deficiency in ocular surface tissues, we have investigated the role of oxidative stress in upregulating cytokine expression and promoting immune surveillance of the eye. RNA-sequencing of lenses from postnatal day (P) 1-aged Gclc[f/f];Le-Cre[Tg/-] (KO) and Gclc[f/f];Le-Cre[-/-] control (CON) mice revealed upregulation of many cytokines (e.g., CCL4, GDF15, CSF1) and immune response genes in the lenses of KO mice. The eyes of KO mice had a greater number of cells in the aqueous and vitreous humors at P1, P20 and P50 than age-matched CON and Gclc[w/w];Le-Cre[Tg/-] (CRE) mice. Histological analyses revealed the presence of innate immune cells (i.e., macrophages, leukocytes) in ocular structures of the KO mice. At P20, the expression of cytokines and ROS content was higher in the lenses of KO mice than in those from age-matched CRE and CON mice, suggesting that oxidative stress may induce cytokine expression. In vitro administration of the oxidant, hydrogen peroxide, and the depletion of GSH (using buthionine sulfoximine (BSO)) in 21EM15 lens epithelial cells induced cytokine expression, an effect that was prevented by co-treatment of the cells with N-acetyl-l-cysteine (NAC), a antioxidant. The in vivo and ex vivo induction of cytokine expression by oxidative stress was associated with the expression of markers of epithelial-to-mesenchymal transition (EMT), α-SMA, in lens cells. Given that EMT of lens epithelial cells causes posterior capsule opacification (PCO), we propose that oxidative stress induces cytokine expression, EMT and the development of PCO in a positive feedback loop. Collectively these data indicate that oxidative stress induces inflammation of lens cells which promotes immune surveillance of ocular structures.}, } @article {pmid35123993, year = {2022}, author = {Yang, X and Li, C and Yu, G and Sun, L and Guo, S and Sai, L and Bo, C and Xing, C and Shao, H and Peng, C and Jia, Q}, title = {Ligand-independent activation of AhR by hydroquinone mediates benzene-induced hematopoietic toxicity.}, journal = {Chemico-biological interactions}, volume = {355}, number = {}, pages = {109845}, doi = {10.1016/j.cbi.2022.109845}, pmid = {35123993}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Basic Helix-Loop-Helix Transcription Factors/chemistry/genetics/*metabolism ; Benzene/toxicity ; Cell Line ; Cell Survival/drug effects ; Cytochrome P-450 CYP1A1/genetics/metabolism ; DNA Damage/drug effects ; HSP90 Heat-Shock Proteins/genetics/metabolism ; Humans ; Hydroquinones/*pharmacology ; *Ligands ; Lymphocytes/cytology/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/chemistry/genetics/*metabolism ; }, abstract = {Although it has been well recognized that benzene exposure can cause hematopoietic disorders such as aplastic anemia and leukemia, the underlying molecular mechanism remains to be fully understood. Emerging evidence indicated that aryl hydrocarbon receptor (AhR) plays important roles in hematopoietic and immune systems. This study investigated the activation of aryl hydrocarbon receptor (AhR) by hydroquinone (HQ) and its role in HQ-induced DNA damage and apoptosis in cultured human lymphocytes (JHP cells). We also investigated the effect of ROS on AhR activation and functions in JHP cells exposed to HQ with and without regulator including N-acetyl-l-cysteine (NAC), a potent antioxidant, and tert-butylhydroquinone (TBHQ), a Nrf2 activator. Results showed that HQ can cause oxidative stress, DNA damage and apoptosis. Pretreatment of an AhR antagonist (CH223191) can significantly increase the cell survival and mitigate HQ-induced toxicities such as DNA damage and apoptosis. We found that HQ can obviously increase expressions of total protein of AhR and prompt nuclear translocation compared to the control group. Interestingly, NAC can block HQ-induced AhR activation and DNA damage and apoptosis. Conclusively, our results indicated that HQ toxicity is mediated by AhR which is in turn regulated by ROS generated by HQ. The interaction between AhR and ROS drive and amplify the hematopoietic toxicity of HQ. This study provided new insights of mechanism and potential targets for the prevention and treatment to benzene-induced hematopoietic toxicity.}, } @article {pmid35123263, year = {2022}, author = {Murae, M and Shimizu, Y and Yamamoto, Y and Kobayashi, A and Houri, M and Inoue, T and Irie, T and Gemba, R and Kondo, Y and Nakano, Y and Miyazaki, S and Yamada, D and Saitoh, A and Ishii, I and Onodera, T and Takahashi, Y and Wakita, T and Fukasawa, M and Noguchi, K}, title = {The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione.}, journal = {Biochemical and biophysical research communications}, volume = {597}, number = {}, pages = {30-36}, pmid = {35123263}, issn = {1090-2104}, abstract = {Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor angiotensin converting enzyme-2 (ACE2) via its receptor-binding domain (RBD). The cysteine residue at position 488, consisting of a disulfide bridge with cysteine 480 is located in an important structural loop at ACE2-binding surface of RBD, and is highly conserved among SARS-related coronaviruses. We showed that the substitution of Cys-488 with alanine impaired pseudotyped SARS-CoV-2 infection, syncytium formation, and cell-cell fusion triggered by SARS-CoV-2 spike expression. Consistently, in vitro binding of RBD and ACE2, spike-mediated cell-cell fusion, and pseudotyped viral infection of VeroE6/TMPRSS2 cells were inhibited by the thiol-reactive compounds N-acetylcysteine (NAC) and a reduced form of glutathione (GSH). Furthermore, we demonstrated that the activity of variant spikes from the SARS-CoV-2 alpha and delta strains were also suppressed by NAC and GSH. Taken together, these data indicate that Cys-488 in spike RBD is required for SARS-CoV-2 spike functions and infectivity, and could be a target of anti-SARS-CoV-2 therapeutics.}, } @article {pmid35122928, year = {2022}, author = {Ou, YC and Li, JR and Wu, CC and Yu, TM and Chen, WY and Liao, SL and Kuan, YH and Chen, YF and Chen, CJ}, title = {Cadmium induces the expression of Interleukin-6 through Heme Oxygenase-1 in HK-2 cells and Sprague-Dawley rats.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {161}, number = {}, pages = {112846}, doi = {10.1016/j.fct.2022.112846}, pmid = {35122928}, issn = {1873-6351}, mesh = {Acetylcysteine ; Animals ; Antioxidants/pharmacology ; Cadmium Chloride/*toxicity ; Carbazoles ; Cell Line ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/*drug effects ; Heme Oxygenase (Decyclizing)/genetics/*metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Interleukin-6/genetics/*metabolism ; Kidney Diseases/chemically induced ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress/drug effects ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Cadmium is toxic to the kidney through mechanisms involving oxidative stress and inflammation. We studied reciprocal crosstalk among the oxidative stress, inflammation, and the nuclear Nrf2 pathway in cadmium-induced nephrotoxicity on HK-2 human renal proximal tubular epithelial cells. Cadmium chloride (CdCl2) caused cell viability loss, Reactive Oxygen Species (ROS) generation, glutathione reduction, and Interleukin-6 (IL-6) expression, accompanied by Nrf2 activation and Heme Oxygenase-1 (HO-1) expression. Pharmacological treatments demonstrated cytotprotective and anti-inflammatory effects of Nrf2 activation. Intriguingly, inhibition of HO-1 activity mitigated cell viability loss and IL-6 expression in CdCl2-treated cells. Parallel attenuation by HO-1 inhibitor was demonstrated in cadmium-induced ROS generation and glutathione reduction. CdCl2-treated cells also increased levels of ferrous iron, cGMP, Mitogen-Activated Protein Kinases phosphorylation, as well as NF-κB DNA-binding activity. These increments were mitigated by antioxidant N-Acetyl Cysteine, HO-1 inhibitor SnPP, and PKG inhibitor KT5823, and were mimicked by the Carbon Monoxide-releasing compound. In the kidney cortex of CdCl2-exposed Sprague-Dawley rats, we found similar renal injury, histological changes, ROS generation, IL-6 expression, and accompanied pro-oxidant and pro-inflammatory changes. These observations indicated that cadmium-induced nephrotoxicity was associated with oxidative stress and inflammation, and HO-1 likely acts as a linking molecule to induce nephrotoxicity-associated IL-6 expression upon cadmium exposure.}, } @article {pmid35122656, year = {2022}, author = {Chapela, SP and Burgos, HI and Stella, CA}, title = {N-Acetyl cysteine improves cellular growth in respiratory-deficient yeast.}, journal = {Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]}, volume = {53}, number = {2}, pages = {791-794}, pmid = {35122656}, issn = {1678-4405}, mesh = {*Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Oxidative Stress ; Reactive Oxygen Species ; *Saccharomyces cerevisiae/genetics ; }, abstract = {BACKGROUND: Reactive oxygen species (ROS) is a main factor that alters cellular physiology and functionality. Many strategies are used in order to control excessive oxidative stress. One strategy includes the use of antioxidants like N-acetyl cysteine (NAC). The aim of this study was to compare the effect of this antioxidant on ROS production and cellular growth of a wild-type and a respiratory-deficient Saccharomyces cerevisiae strain.

METHODS: Using a simple system such as yeast allows oxidative stress investigations on which numerous factors are more manageable or circumscribed than in a higher organism. We grew cells in a complex medium and incubated them during 72 h. Later, cellular viability and ROS production was evaluated. ROS level was estimated by use of fluorescence signal with 2',7'-dichlorofluorescein diacetate (DCFH-DA).

RESULTS: As it is found in the present work, a reducing environment exerted by NAC presence during incubation of the cells allows a respiratory-deficient Saccharomyces cerevisiae strain to improve its cellular growth.

CONCLUSIONS: It seems likely that the energy production or the phenotype which characterizes a deficient strain is incapable of palliating ROS growth inhibition while NAC helps to overcome this limitation.}, } @article {pmid35120950, year = {2022}, author = {Paithankar, JG and Kushalan, S and S, N and Hegde, S and Kini, S and Sharma, A}, title = {Systematic toxicity assessment of CdTe quantum dots in Drosophila melanogaster.}, journal = {Chemosphere}, volume = {295}, number = {}, pages = {133836}, doi = {10.1016/j.chemosphere.2022.133836}, pmid = {35120950}, issn = {1879-1298}, mesh = {Animals ; *Cadmium Compounds/chemistry/toxicity ; Drosophila melanogaster ; *Quantum Dots/chemistry/toxicity ; Tellurium/chemistry/toxicity ; }, abstract = {The risk assessment of cadmium (Cd)-based quantum dots (QDs) used for biomedical nanotechnology applications has stern toxicity concerns. Despite cytotoxicity studies of cadmium telluride (CdTe) QDs, the systematic in vivo study focusing on its organismal effects are more relevant to public health. Therefore, the present study aims to investigate the effect of chemically synthesized 3-mercapto propionic acid-functionalized CdTe QDs on organisms' survival, development, reproduction, and behaviour using Drosophila melanogaster as a model. The sub-cellular impact on the larval gut was also evaluated. First/third instar larvae or the adult Drosophila were exposed orally to green fluorescence emitting CdTe QDs (0.2-100 μM), and organisms' longevity, emergence, reproductive performance, locomotion, and reactive oxygen species (ROS), and cell death were assessed. Uptake of semiconductor CdTe QDs was observed as green fluorescence in the gut. A significant decline in percentage survivability up to 80% was evident at high CdTe QDs concentrations (25 and 100 μM). The developmental toxicity was marked by delayed and reduced fly emergence after CdTe exposure. The teratogenic effect was evident with significant wing deformities at 25 and 100 μM concentrations. However, at the reproductive level, adult flies' fecundity, fertility, and hatchability were highly affected even at low concentrations (1 μM). Surprisingly, the climbing ability of Drosophila was unaffected at any of the used CdTe QDs concentrations. In addition to organismal toxicity, the ROS level and cell death were elevated in gut cells, confirming the sub-cellular toxicity of CdTe QDs. Furthermore, we observed a significant rescue in CdTe QDs-associated developmental, reproductive, and survival adversities when organisms were co-exposed with N-acetyl-cysteine (NAC, an antioxidant) and CdTe QDs. Overall, our findings indicate that the environmental release of aqueously dispersible CdTe QDs raises a long-lasting health concern on the development, reproduction, and survivability of an organism.}, } @article {pmid35117973, year = {2022}, author = {Finsterer, J and Scorza, FA and Scorza, CA and Fiorini, AC}, title = {Repurposing the antioxidant and anti-inflammatory agent N-acetyl cysteine for treating COVID-19.}, journal = {World journal of virology}, volume = {11}, number = {1}, pages = {82-84}, pmid = {35117973}, issn = {2220-3249}, abstract = {Although several considerations have been raised suggesting a beneficial effect of N-acetyl cysteine (NAC) for the treatment of severe acute respiratory syndrome coronavirus 2 infection, there is currently no clinical evidence that NAC truly prevents coronavirus disease 2019 (COVID-19), reduces the severity of the disease, or improves the outcome. Appropriately designed clinical trials are warranted to prove or disprove a therapeutic effect of NAC for COVID-19 patients.}, } @article {pmid35116094, year = {2022}, author = {Jia, F and Liu, Y and Dou, X and Du, C and Mao, T and Liu, X}, title = {Liensinine Inhibits Osteosarcoma Growth by ROS-Mediated Suppression of the JAK2/STAT3 Signaling Pathway.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8245614}, pmid = {35116094}, issn = {1942-0994}, mesh = {Animals ; Apoptosis/drug effects ; Bone Neoplasms/drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Female ; G1 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/metabolism ; Humans ; Isoquinolines/*pharmacology/therapeutic use ; Janus Kinase 2/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Osteosarcoma/drug therapy/metabolism/pathology ; Phenols/*pharmacology/therapeutic use ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/*drug effects ; Transplantation, Heterologous ; }, abstract = {Osteosarcoma (OS) is the most common malignancy of bone. Liensinine exerts antitumor effects on cancers of the colon, breast, and gallbladder. However, its antitumor activity in OS remains unclear. This study is aimed at investigating the efficacy of liensinine against OS and the underlying mechanism of action. Cell proliferation, apoptosis, and cycle arrest in OS were detected using the Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays, respectively. The production of reactive oxygen species (ROS), glutathione (GSH) and glutathione disulfide (GSSG) concentrations, and mitochondrial membrane potential (MMP) of OS cells were measured by flow cytometry, colorimetry, and JC-1 staining. The expressions of factors related to apoptosis, cell cycle, and activation of the JAK2/STAT3 pathway were determined by Western blotting. To examine the potential role of ROS, an antioxidant (N-acetyl cysteine, NAC) was used in combination with liensinine. In vivo, we generated a xenograft mouse model to assess its antitumor efficacy. Tissue level expressions of factors related to apoptosis and activation of the JAK2/STAT3 pathway were assessed by immunohistochemistry or Western blotting. Liensinine inhibited the proliferation and induced G0/G1 phase arrest and apoptosis of OS cells in a dose-dependent manner. Additionally, liensinine promoted intracellular ROS production, enhanced the GSSG/GSH ratio, and induced MMP loss and ROS-mediated suppression of the JAK2/STAT3 pathway. NAC significantly attenuated the liensinine-induced antitumor activities and activated the JAK2/STAT3 pathway. In vivo, liensinine effectively inhibited the OS growth and promoted apoptosis; however, it had no negative effect on the internal organs. In conclusion, liensinine-induced ROS production could suppress the activation of the JAK2/STAT3 pathway and inhibit the OS growth both in vivo and in vitro. Our findings provided a new rationale for subsequent academic and clinical research on OS treatment.}, } @article {pmid35113447, year = {2022}, author = {Di Marco, F and Foti, G and Corsico, AG}, title = {Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19?.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {2}, pages = {715-721}, doi = {10.26355/eurrev_202201_27898}, pmid = {35113447}, issn = {2284-0729}, mesh = {Acetylcysteine/chemistry/*therapeutic use ; Antioxidants/chemistry ; COVID-19/metabolism/virology ; Glutathione/chemistry/metabolism ; Humans ; Oxidative Stress ; Randomized Controlled Trials as Topic ; Reactive Oxygen Species/metabolism ; SARS-CoV-2/isolation & purification ; Virus Diseases/drug therapy/metabolism ; *COVID-19 Drug Treatment ; }, abstract = {OBJECTIVE: As N-acetylcysteine (NAC) is promising as a re-purposed drug for the adjunctive or supportive treatment of serious COVID-19, this article aimed to describe current evidence.

MATERIALS AND METHODS: A search was performed in PubMed/Medline for "NAC", "viral Infection", COVID-19", oxidative stress", "inflammation", retrieving preclinical and clinical studies.

RESULTS: NAC is a pleiotropic molecule with a dual antioxidant mechanism; it may neutralize free radicals and acts as a donor of cysteine, restoring the physiological pool of GSH. Serious COVID-19 patients have increased levels of reactive oxygen species (ROS) and free radicals and often present with glutathione depletion, which prompts a cytokine storm. NAC, which acts as a precursor of GSH inside cells, has been currently used in many conditions to restore or protect against GSH depletion and has a wide safety margin. In addition, NAC has anti-inflammatory activity independently of its antioxidant activity.

CONCLUSIONS: Clinical and experimental data suggest that NAC may act on the mechanisms leading to the prothrombotic state observed in severe COVID-19.}, } @article {pmid35112077, year = {2022}, author = {Puri, V and Chaudhary, KR and Singh, A and Singh, C}, title = {Inhalation potential of N-Acetylcysteine loaded PLGA nanoparticles for the management of tuberculosis: In vitro lung deposition and efficacy studies.}, journal = {Current research in pharmacology and drug discovery}, volume = {3}, number = {}, pages = {100084}, pmid = {35112077}, issn = {2590-2571}, abstract = {Several studies have stated that mucus is a critical hurdle for drug delivery to the mucosal tissues. As a result, Polymeric nanoparticles that can overcome mucus barriers are gaining popularity for controlled drug delivery into intra-macrophages to attain high intracellular drug concentration. The present study was aimed to fabricate inhalable N-acetylcysteine (NAC) modified PLGA mucus penetrating particles using the double emulsion method (w/o/w) for target delivery to alveolar macrophages and minimize the dose-related adverse effects, efficiently encapsulate hydrophilic drug, sustain the release profile and prolong the retention time for the management of tuberculosis. Among the numerous formulations, the drug/polymer ratio of 1:10 with 0.50% PVA concentration and sonication time for 2 min s was chosen for further research. The formulated nanoparticles had a mean particle size of 307.50 ± 9.54 nm, PDI was 0.136 ± 0.02, zeta potential about -11.3 ± 0.4 mV, decent entrapment efficiency (55.46 ± 2.40%), drug loading (9.05 ± 0.22%), and excellent flowability. FTIR confirmed that NAC and PLGA were compatible with each other. SEM graphs elucidated that the nanoparticles were spherically shaped with a slightly rough surface whereas TEM analysis ensured the nanometer size nanoparticles and coating of lipid over NPs surface. PXRD spectrum concluded the transformation of the drug from crystalline to amorphous state in the formulation. In vitro release pattern was biphasic started with burst release (64.67 ± 1.53% within 12hrs) followed by sustained release over 48hrs thus enabling the prolonged replenishing of NAC. In vitro lung deposition study pronounced that coated NAC-PLGA-MPPs showed favorable results in terms of emitted dose (86.67 ± 2.52%), MMAD value (2.57 ± 0.12 μm), GSD value (1.55 ± 0.11 μm), and FPF of 62.67 ± 2.08% for the deposition and targeting the lungs. Finally, in vitro efficacy studies demonstrated that NAC-PLGA-MPPs presented more prominent antibacterial activity against MTB H37Rv strain as compared to NAC. Hence, PLGA based particles could be a better strategy to deliver the NAC for lung targeting.}, } @article {pmid35111421, year = {2021}, author = {Khan, Z and Abumedian, M and Ibekwe, M and Musa, K and Mlawa, G}, title = {Acute Renal Impairment in Patients Due to Paracetamol Overdose in the Absence of Hepatic Impairment.}, journal = {Cureus}, volume = {13}, number = {12}, pages = {e20727}, pmid = {35111421}, issn = {2168-8184}, abstract = {In general, paracetamol poisoning is associated with hepatotoxicity and very rarely with renal impairment in the absence of significant hepatic impairment. Paracetamol poisoning associated with renal impairment is rare, and it is mostly associated with hepatotoxicity. Most patients with acute renal impairment show a pattern of acute tubular necrosis or injury based on their blood, clinical presentation, and imaging. The level of injury was found to be associated with the dose of paracetamol taken. We describe a case of a 22-year-old patient presenting to the hospital with abdominal pain, back pain, and two episodes of vomiting after 36 hours of an intentional paracetamol overdose of 60 tablets. His lab results showed raised creatinine levels and C-reactive protein (CRP) despite normal liver function tests. His paracetamol and salicylate levels were not checked on his initial presentation. He was given N-acetyl cysteine (NAC) treatment for paracetamol overdose and had computed tomography of kidneys, ureters, and bladder (CT KUB) the following day, which showed mild, uncomplicated sigmoid diverticula. He was discharged the next day, but was readmitted two days later with severe abdominal pain and worsening renal function. He had an magnetic resonance imaging (MRI) abdomen that showed coronal/axial wedge like areas of relative hypo-intense change in the T2 acquisition. He received intravenous fluids and antibiotics, and his renal function improved. He was discharged home with outpatient follow-up and appeared to be fully recovered.}, } @article {pmid35110025, year = {2021}, author = {Kumar, R and Bansal, M and Nath, SS and Kumar, V and Malviya, D and Srivastava, D}, title = {N-Acetylcysteine Supplementation for the Prevention of Postoperative Liver Dysfunction after On-Pump Cardiac Surgery.}, journal = {Turkish journal of anaesthesiology and reanimation}, volume = {49}, number = {6}, pages = {460-469}, pmid = {35110025}, issn = {2667-677X}, abstract = {INTRODUCTION: Incidence of postoperative liver dysfunction continues to be high (ranging from 10-35%) in those who underwent cardiac surgeries using cardiopulmonary bypass (CPB) and is associated with considerable morbidity and mortality. Prolonged cardiopulmonary bypass time (CPBT) was found to be an independent predictor of postoperative liver dysfunction. So, the aim of the study was to evaluate the effect of prophylactic use of N-acetylcysteine (NAC) in patients undergoing on-pump cardiac surgery with expected prolonged CPBT in prevention of liver dysfunction.

METHODS: 60 consenting adult patients undergoing cardiac surgeries using CPB with CPBT more than 120 mins were included in this single-centre, randomized, parallel-group, double blind interventional study. Study group patients received NAC as per protocol. Liver transferases, alkaline phosphatase, serum bilirubin, kidney function tests and coagulation parameters were measured preoperatively, on the day of surgery and for three days postoperatively.

RESULTS: Values for serum ALT, AST and ALP were significantly raised in the control group compared to the study group, starting from the day of surgery till 3rd postoperative day. Serum bilirubin level (total and direct) were comparable till first postoperative day and were significantly raised on second and third postoperative days in the control group. Duration of mechanical ventilation, total chest tube drainage, duration of ICU and hospital stay were significantly shorter in study group compared to control group.

CONCLUSION: Prophylactic intravenous NAC has a protective role in preventing postoperative hepatic dysfunction in patients undergoing cardiac surgery with cardiopulmonary bypass.}, } @article {pmid35105269, year = {2023}, author = {de Souza, GR and De-Oliveira, ACAX and Soares, V and De-Souza, TP and Barbi, NS and Paumgartten, FJR and da Silva, AJR}, title = {Protective effects of a chemically characterized extract from solanum torvum leaves on acetaminophen-induced liver injury.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {1}, pages = {122-135}, doi = {10.1080/01480545.2021.2012905}, pmid = {35105269}, issn = {1525-6014}, mesh = {Mice ; Animals ; Acetaminophen/toxicity ; *Solanum ; Hydrogen Peroxide/toxicity ; *Chemical and Drug Induced Liver Injury, Chronic ; Plant Extracts ; Mice, Inbred C57BL ; Antioxidants/pharmacology/therapeutic use ; Liver ; Phenols/pharmacology ; Flavonoids/pharmacology/analysis ; *Chemical and Drug Induced Liver Injury/etiology/prevention & control/drug therapy ; }, abstract = {Distinct parts of Solanum torvum Swartz. (Solanaceae) are popularly used for a variety of therapeutic purposes. This study determined the phytochemical composition of a phenolic fraction of S. torvum leaf aqueous extract and investigated its antioxidant and liver-protective properties. A phenolic compound-enriched fraction, or phenolic fraction (STLAE-PF) of an infusion (STLAE) of S. torvum leaves, was tested in vitro (antagonism of H2O2 in cytotoxicity and DCF assays with HepG2/C3A cells), and in vivo for antioxidant activity and protective effects against acetaminophen (APAP)-induced liver injury in mice. Thirty-eight compounds (flavonoids, esters of hydroxycinnamic acid, and chlorogenic acid isomers) were tentatively identified (high-performance liquid chromatography coupled to high-resolution electrospray mass spectrometry) in the STLAE-PF fraction. In vitro assays in HepG2/C3A cells showed that STLAE-PF and some flavonoids contained in this phenolic fraction, at noncytotoxic levels, antagonized in a concentration-dependent manner the effects of a powerful oxidant agent (H2O2). In C57BL/6 mice, oral administration of STLAE (600 and 1,200 mg/kg bw) or STLAE-PF (300 mg/kg bw) prevented the rise in serum transaminases (ALT and AST), depletion of reduced glutathione (GSH) and elevation of thiobarbituric acid reactive species (TBARs) levels in the liver caused by APAP (600 mg/kg bw, i.p.). The hepatoprotective effects of STLAE-PF (300 mg/kg bw) against APAP-caused liver injury were comparable to those of N-acetyl-cysteine (NAC 300 or 600 mg/kg bw i.p.). These findings indicate that a phenolic fraction of S. torvum leaf extract (STLAE-PF) is a new phytotherapeutic agent potentially useful for preventing/treating liver injury caused by APAP overdosing.}, } @article {pmid35099714, year = {2022}, author = {Okuni, N and Honma, Y and Urano, T and Tamura, K}, title = {Romidepsin and tamoxifen cooperatively induce senescence of pancreatic cancer cells through downregulation of FOXM1 expression and induction of reactive oxygen species/lipid peroxidation.}, journal = {Molecular biology reports}, volume = {49}, number = {5}, pages = {3519-3529}, pmid = {35099714}, issn = {1573-4978}, support = {SUIGAN project//Shimane University/ ; }, mesh = {Animals ; Cell Line, Tumor ; Cell Proliferation ; Cysteine/metabolism ; *Depsipeptides/pharmacology ; Down-Regulation ; *Forkhead Box Protein M1/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Lipid Peroxidation ; *Pancreatic Neoplasms/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Tamoxifen/pharmacology ; alpha-Tocopherol/pharmacology ; }, abstract = {BACKGROUND: Although improvement has been made in therapeutic strategies against pancreatic carcinoma, overall survival has not significantly enhanced over the past decade. Thus, the establishment of better therapeutic regimens remains a high priority.

METHODS: Pancreatic cancer cell lines were incubated with romidepsin, an inhibitor of histone deacetylase, and tamoxifen, and their effects on cell growth, signaling and gene expression were analyzed. Xenografts of human pancreatic cancer CFPAC1 cells were medicated with romidepsin and tamoxifen to evaluate their effects on tumor growth.

RESULTS: The inhibition of the growth of pancreatic cancer cells induced by romidepsin and tamoxifen was effectively reduced by N-acetyl cysteine and α-tocopherol, respectively. The combined treatment greatly induced reactive oxygen species production and mitochondrial lipid peroxidation, and these effects were prevented by N-acetyl cysteine and α-tocopherol. Tamoxifen enhanced romidepsin-induced cell senescence. FOXM1 expression was markedly downregulated in pancreatic cancer cells treated with romidepsin, and tamoxifen further reduced FOXM1 expression in cells treated with romidepsin. Siomycin A, an inhibitor of FOXM1, induced senescence in pancreatic cancer cells. Similar results were obtained in knockdown of FOXM1 expression by siRNA.

CONCLUSION: Since FOXM1 is used as a prognostic marker and therapeutic target for pancreatic cancer, a combination of the clinically available drugs romidepsin and tamoxifen might be considered for the treatment of patients with pancreatic cancer.}, } @article {pmid35098531, year = {2022}, author = {Sandilands, EA and Rees, JMB and Raja, K and Dhaun, N and Morrison, EE and Hickson, K and Wraight, J and Gray, T and Briody, L and Cameron, S and Thompson, AP and Johnston, NR and Uren, N and Goddard, J and Treweeke, A and Rushworth, G and Webb, DJ and Bateman, DN and Norrie, J and Megson, IL and Eddleston, M}, title = {Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.}, journal = {Clinical pharmacology and therapeutics}, volume = {111}, number = {6}, pages = {1222-1238}, pmid = {35098531}, issn = {1532-6535}, support = {CZB/4/459/CSO_/Chief Scientist Office/United Kingdom ; }, mesh = {Acetylcysteine/therapeutic use ; Antioxidants ; Contrast Media/adverse effects ; Creatinine ; Cross-Over Studies ; Humans ; *Kidney Diseases ; *Renal Insufficiency, Chronic/drug therapy ; Treatment Outcome ; }, abstract = {Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m[2], P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.}, } @article {pmid35094812, year = {2022}, author = {Yamamoto, H and Shibuya, K and Fukushima, T and Hashizume, T}, title = {Effects of antioxidant capacity on micronucleus induction by cigarette smoke in mammalian cells.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {873}, number = {}, pages = {503427}, doi = {10.1016/j.mrgentox.2021.503427}, pmid = {35094812}, issn = {1879-3592}, mesh = {Animals ; *Antioxidants/metabolism ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Glutathione ; Micronucleus Tests ; Rats ; Reactive Oxygen Species ; *Smoke/adverse effects ; Sulfhydryl Compounds ; Nicotiana ; }, abstract = {We have compared micronucleus (MN) induction by cigarette smoke in the L5178Y, TK6, and CHL/IU cell lines. The test sample was total particulate matter of 3R4F reference cigarette smoke, suspended in DMSO. After 3-h treatment, with or without a rat liver S9 metabolic activation system, followed by 24-h recovery, dose-dependent MN increases were seen in all cell lines. However, CHL/IU and TK6 cells were more resistant than L5178Y cells (comparison by Benchmark Doses with PROAST software). 3R4F smoke generates reactive oxygen species (ROS). Therefore, we explored the relationship between the sensitivities to 3R4F smoke and the antioxidant capacities of the cell lines. While the total antioxidant capacities were not significantly different among the cell lines, cellular glutathione (GSH) was higher in CHL/IU cells than in L5178Y cells. Pretreatment of CHL/IU cells with a GSH precursor, N-acetylcysteine (NAC), reduced the genotoxicity/cytotoxicity of 3R4F, whereas an inhibitor of GSH biosynthesis, buthionine sulfoximine (BSO), enhanced it. The effects of NAC and BSO were also seen after treatment with allyl isothiocyanate, a ROS-generating chemical, but not with mitomycin C, a ROS-independent genotoxicant. Pretreatment with NAC increased cellular thiol levels. From the present results, the genotoxicity and cytotoxicity of cigarette smoke differs among these cell lines in a manner that may be related to their antioxidant thiol levels.}, } @article {pmid35090586, year = {2022}, author = {Duelen, R and Costamagna, D and Gilbert, G and De Waele, L and Goemans, N and Desloovere, K and Verfaillie, CM and Sipido, KR and Buyse, GM and Sampaolesi, M}, title = {Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy.}, journal = {Stem cell reports}, volume = {17}, number = {2}, pages = {352-368}, pmid = {35090586}, issn = {2213-6711}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; CRISPR-Cas Systems/genetics ; Cell Differentiation ; Cell Survival/drug effects ; Dystrophin/genetics/metabolism ; Gene Editing ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Mitochondria/drug effects/physiology ; Muscular Dystrophy, Duchenne/genetics/*pathology ; Myocytes, Cardiac/cytology/metabolism ; NADPH Oxidase 4/*metabolism ; Oxadiazoles/pharmacology ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Duchenne muscular dystrophy (DMD) is a progressive muscle disorder caused by mutations in the Dystrophin gene. Cardiomyopathy is a major cause of early death. We used DMD-patient-specific human induced pluripotent stem cells (hiPSCs) to model cardiomyopathic features and unravel novel pathologic insights. Cardiomyocytes (CMs) differentiated from DMD hiPSCs showed enhanced premature cell death due to significantly elevated intracellular reactive oxygen species (ROS) resulting from depolarized mitochondria and increased NADPH oxidase 4 (NOX4). CRISPR-Cas9 correction of Dystrophin restored normal ROS levels. ROS reduction by N-acetyl-L-cysteine (NAC), ataluren (PTC124), and idebenone improved hiPSC-CM survival. We show that oxidative stress in DMD hiPSC-CMs was counteracted by stimulating adenosine triphosphate (ATP) production. ATP can bind to NOX4 and partially inhibit the ROS production. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose targeting ROS production and preventing detrimental effects of NOX4 on DMD CMs as promising therapeutic strategy.}, } @article {pmid35089954, year = {2022}, author = {Hans, D and Rengel, A and Hans, J and Bassett, D and Hood, S}, title = {N-Acetylcysteine as a novel rapidly acting anti-suicidal agent: A pilot naturalistic study in the emergency setting.}, journal = {PloS one}, volume = {17}, number = {1}, pages = {e0263149}, pmid = {35089954}, issn = {1932-6203}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; *Emergency Service, Hospital ; Female ; Humans ; Male ; Middle Aged ; Outcome Assessment, Health Care ; Pilot Projects ; Psychiatric Status Rating Scales ; Young Adult ; *Suicide Prevention ; }, abstract = {OBJECTIVE: N-acetylcysteine has a demonstrated role as an adjunctive therapy in psychotic and affective disorders as a treatment to reduce symptoms of Bipolar Affective Disorder, Major Depressive Disorder and Schizophrenia. However, its potential as a rapidly acting anti-suicidal agent has not yet been assessed. This naturalistic study evaluates its effect in thirty patients presenting following intentional medication overdose.

METHODS: Eighteen patients who ingested toxic doses of paracetamol received NAC whilst twelve other patients with other overdoses received standard supportive treatment in the emergency department setting. Symptoms were measured using the Montgomery-Asberg Depression Rating Scale and Clinical Global Impression scale at time of presentation, 24 hours, and seven days.

RESULTS: Baseline characteristics between groups were similar. Both groups showed a significant reduction in suicidality, as measured by the suicide item of the MADRS, over time (p < 0.001). However, there was a greater reduction in suicidality in the 'NAC group' compared to the 'no-NAC group' one-week post presentation (p = 0.014). A greater proportion of the 'no-NAC group' still exhibited severe depressive symptoms (MADRS >32) compared to the 'NAC group' (p = 0.044).

CONCLUSION: This naturalistic study suggests NAC may have potential use as a rapidly acting treatment adjunct in major depressive disorder, warranting further investigation of its effects.}, } @article {pmid35084258, year = {2022}, author = {Izquierdo, JL and Soriano, JB and González, Y and Lumbreras, S and Ancochea, J and Echeverry, C and Rodríguez, JM}, title = {Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19.}, journal = {Science progress}, volume = {105}, number = {1}, pages = {368504221074574}, pmid = {35084258}, issn = {2047-7163}, mesh = {Acetylcysteine/therapeutic use ; *COVID-19 ; Hospitalization ; Humans ; Male ; Retrospective Studies ; SARS-CoV-2 ; Treatment Outcome ; }, abstract = {Infection by SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) can be associated with serious and life-threatening conditions, including acute respiratory distress syndrome (ARDS). Severity and mortality have been related to a cytokine storm, an imbalance of oxidative stress, and a pro-thrombotic state.We conducted an observational retrospective cohort study from a community-based large population of hospitalized COVID-19 PCR + patients admitted from March 01, 2020, to January 24, 2021, with integrated primary to tertiary care information in Castilla la Mancha, Spain. We explored the potential benefits of the antioxidant, anti-inflammatory and anti-thrombotic drug N-acetylcysteine (NAC) administered orally in high doses (600 mg every 8 h), added to standard of care in COVID-19 patients by using the free text information contained in their electronic health records (EHRs).Out of 19,208 patients with a diagnosis of COVID-19 hospitalized, we studied 2071 (10.8%) users of oral NAC at high doses. COVID-19 patients treated with NAC were older, predominantly male, and with more comorbidities such as hypertension, dyslipidemia, diabetes, and COPD when compared with those not on NAC (all p < 0.05). Despite greater baseline risk, use of NAC in COVID-19 patients was associated with significantly lower mortality (OR 0.56; 95%CI 0.47-0.67), a finding that remained significant in a multivariate analysis adjusting by baseline characteristics and concomitant use of corticosteroids. There were no significant differences with the use of NAC on the mean duration of hospitalization, admission to the intensive care unit or use of invasive mechanical ventilation. The observed association signaling to better relevant outcomes in COVID-19 patients treated with NAC at high doses should be further explored in other settings and populations and in randomized controlled trials.}, } @article {pmid35079634, year = {2022}, author = {Modi, HR and Wang, Q and Olmstead, SJ and Khoury, ES and Sah, N and Guo, Y and Gharibani, P and Sharma, R and Kannan, RM and Kannan, S and Thakor, NV}, title = {Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.}, journal = {Bioengineering & translational medicine}, volume = {7}, number = {1}, pages = {e10259}, pmid = {35079634}, issn = {2380-6761}, support = {R01 HL071568/HL/NHLBI NIH HHS/United States ; R01 HL139158/HL/NHLBI NIH HHS/United States ; }, abstract = {Cardiac arrest (CA), the sudden cessation of effective cardiac pumping function, is still a major clinical problem with a high rate of early and long-term mortality. Post-cardiac arrest syndrome (PCAS) may be related to an early systemic inflammatory response leading to exaggerated and sustained neuroinflammation. Therefore, early intervention with targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. Using a clinically relevant asphyxia CA model, we demonstrate that a single (i.p.) dose of dendrimer-N-acetylcysteine conjugate (D-NAC), can target "activated" microglial cells following CA, leading to an improvement in post-CA survival rate compared to saline (86% vs. 45%). D-NAC treatment also significantly improved gross neurological score within 4 h of treatment (p < 0.05) and continued to show improvement at 48 h (p < 0.05). Specifically, there was a substantial impairment in motor responses after CA, which was subsequently improved with D-NAC treatment (p < 0.05). D-NAC also mitigated hippocampal cell density loss seen post-CA in the CA1 and CA3 subregions (p < 0.001). These results demonstrate that early therapeutic intervention even with a single D-NAC bolus results in a robust sustainable improvement in long-term survival, short-term motor deficits, and neurological recovery. Our current work lays the groundwork for a clinically relevant therapeutic approach to treating post-CA syndrome.}, } @article {pmid35076219, year = {2022}, author = {Wang, X and Ding, Z and Ma, K and Sun, C and Zheng, X and You, Y and Zhang, S and Peng, Y and Zheng, J}, title = {Cysteine-Based Protein Covalent Binding and Hepatotoxicity Induced by Emodin.}, journal = {Chemical research in toxicology}, volume = {35}, number = {2}, pages = {293-302}, doi = {10.1021/acs.chemrestox.1c00358}, pmid = {35076219}, issn = {1520-5010}, mesh = {Animals ; Binding Sites/drug effects ; Cells, Cultured ; Cysteine/chemistry/*toxicity ; Emodin/chemistry/*toxicity ; Fallopia multiflora/chemistry ; Hepatocytes/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred Strains ; Molecular Structure ; Proteins/*chemistry ; }, abstract = {Emodin (EMD) is a major ingredient of Polygonum multiflorum Thunb. (PMT), which has shown adverse liver reactions. Despite multiple pharmacological activities, EMD is reported to show various toxicities. Our early study demonstrated the reactivity of EMD to glutathione. This study aimed to determine the covalent interaction of hepatic protein with EMD and the correlation of the protein modification with hepatotoxicity induced by EMD. EMD-derived protein adduction was detected in an incubation mixture containing mouse liver homogenates and EMD. Such protein adduction was also observed in hepatic protein obtained from mice exposed to EMD. The protein covalent binding occurred in time- and dose-dependent manners. Pre-treatment of l-buthionine-sulfoximine significantly potentiated EMD-induced adduction and hepatotoxicity caused by EMD and lipopolysaccharide co-treatment. As expected, EMD-derived protein modification was observed in mouse primary hepatocytes treated with EMD. The increase in EMD exposure concentration intensified EMD-derived protein adduction and increased EMD-induced cell death. The susceptibility of hepatocytes to EMD cytotoxicity and the intensity of EMD-induced protein adduction were attenuated by the co-treatment of hepatocytes with N-acetyl cysteine. A good association of protein modification with hepatotoxicity induced by EMD was illustrated, which facilitates the understanding of the mechanism of hepatotoxicity induced by EMD.}, } @article {pmid35068061, year = {2022}, author = {Yaryari, AM and Mousavibahar, SH and Amirhassani, S and Bagheri, M and Mohammadi, Y and Mehrpooya, M}, title = {Men suffering from category III chronic prostatitis may benefit from N-acetylcysteine as an adjunct to alpha-blockers.}, journal = {Lower urinary tract symptoms}, volume = {14}, number = {3}, pages = {199-207}, doi = {10.1111/luts.12425}, pmid = {35068061}, issn = {1757-5672}, mesh = {Acetylcysteine/therapeutic use ; Adrenergic alpha-Antagonists/therapeutic use ; Chronic Disease ; Humans ; Male ; Pelvic Pain/drug therapy ; *Prostatitis/diagnosis/drug therapy ; Quality of Life ; Tamsulosin/therapeutic use ; }, abstract = {OBJECTIVE: We designed this study to investigate the potential use of N-acetylcysteine (NAC) as an adjunct to alpha-blockers in the treatment of category III chronic prostatitis (CP).

METHODS: Sixty-three men with category III CP with a National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score of 15 or more were randomized to either the NAC treatment group or the placebo treatment group. Besides tamsulosin at a dose of 0.4 mg once daily, participants based on their allocation group received NAC or placebo at a dose of 600 mg twice daily for 12 weeks. The efficacy of the medications was assessed by measuring changes in the NIH-CPSI total score and its subscales, including pain, urinary symptoms, and quality of life.

RESULTS: Based on the general linear model analysis of the data, over the 12-week treatment, NAC+tamsulosin was statistically superior to placebo+tamsulosin in reducing the total NIH-CPSI score, pain subscore, and quality-of-life subscore (P value <.001). Further, after 12 weeks, more patients in the NAC+tamsulosin group than in the placebo+tamsulosin group met the responder criterion, defined as a decrease of at least 6 points in the NIH-CPSI total score (65.6% vs 29.0%). A more favorable outcome was also noted in the NAC+tamsulosin group regarding the number of patients reporting moderate or marked improvement in symptoms (62.5% vs 25.80%). No significant difference was seen between the groups concerning changes in urinary symptoms.

CONCLUSIONS: Our study provided clinical evidence that men with category III CP might benefit from NAC treatment. Further studies are needed for the validation of these findings.}, } @article {pmid35065218, year = {2022}, author = {Karlsson, T and Gustafsson, Å and Ekstrand-Hammarström, B and Elfsmark, L and Jonasson, S}, title = {Chlorine exposure induces Caspase-3 independent cell death in human lung epithelial cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {80}, number = {}, pages = {105317}, doi = {10.1016/j.tiv.2022.105317}, pmid = {35065218}, issn = {1879-3177}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Caspase 3 ; Cell Physiological Phenomena/drug effects ; Chlorine/*toxicity ; Cytokines/metabolism ; Humans ; Lung/*cytology ; Oxidants/*toxicity ; }, abstract = {Chlorine (Cl2) is a common toxic industrial gas and human inhalation exposure causes tissue damage with symptoms ranging from wheezing to more severe symptoms such as lung injury or even death. Because the mechanism behind Cl2-induced cell death is not clearly understood, the present study aimed to study the cellular effects in vitro after Cl2 exposure of human A549 lung epithelial cells. In addition, the possible treatment effects of the anti-inflammatory antioxidant N-acetyl cysteine (NAC) were evaluated. Exposure of A549 cells to Cl2 (100-1000 ppm) in the cell medium induced cell damage and toxicity within 1 h in a dose-dependent manner. The results showed that 250 ppm Cl2 increased cell death and formation of apoptotic-like bodies, while 500 ppm Cl2 exposure resulted in predominantly necrotic death. Pre-treatment with NAC was efficient to prevent cell damage at lower Cl2 concentrations in part by averting the formation of apoptotic-like bodies and increasing the expression of the anti-apoptotic proteins clusterin and phosphorylated tumour protein p53(S46). Analysis showed that Cl2 induced cell death by a possibly caspase-independent mechanism, since no cleavage of caspase-3 could be detected after exposure to 250 ppm. Currently, these results justifies further research into new treatment strategies for Cl2-induced lung injury.}, } @article {pmid35065167, year = {2022}, author = {Ali, M and Tabassum, H and Alam, MM and Parvez, S}, title = {N-acetyl-L-cysteine ameliorates mitochondrial dysfunction in ischemia/reperfusion injury via attenuating Drp-1 mediated mitochondrial autophagy.}, journal = {Life sciences}, volume = {293}, number = {}, pages = {120338}, doi = {10.1016/j.lfs.2022.120338}, pmid = {35065167}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Autophagy/*drug effects/physiology ; Brain Ischemia/metabolism/pathology/*prevention & control ; Dynamins/*antagonists & inhibitors/metabolism ; Free Radical Scavengers/pharmacology/therapeutic use ; Male ; Mitochondria/*drug effects/metabolism ; Mitochondrial Dynamics/drug effects/physiology ; Rats ; Rats, Wistar ; Reperfusion Injury/metabolism/pathology/*prevention & control ; }, abstract = {BACKGROUND AND PURPOSE: Ischemic reperfusion (I/R) injury causes a wide array of functional and structure alternations of mitochondria, associated with oxidative stress and increased the severity of injury. Despite the previous evidence for N-acetyl-L-cysteine (NAC) provide neuroprotection after I/R injury, it is unknown to evaluate the effect of NAC on altered mitochondrial autophagy forms an essential axis to impaired mitochondrial quality control in cerebral I/R injury.

METHODS: Male wistar rats subjected to I/R injury were used as transient Middle Cerebral Artery Occlusion (tMCAO) model. After I/R injury, the degree of cerebral tissue injury was detected by infarct volume, H&E staining and behavioral assessment. We also performed mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometry and mitochondrial respiratory complexes to evaluate the mitochondrial dysfunction. Finally, we performed the western blotting analysis to measure the apoptotic and autophagic marker.

RESULTS: We found that NAC administration significantly ameliorates brain injury, improves neurobehavioral outcome, decreases neuroinflammation and mitochondrial mediated oxidative stress. We evaluated the neuroprotective effect of NAC against neuronal apoptosis by assessing its ability to sustained mitochondrial integrity and function. Further studies revealed that beneficial effects of NAC is through targeting the mitochondrial autophagy via regulating the GSK-3β/Drp1mediated mitochondrial fission and inhibiting the expression of beclin-1 and conversion of LC3, as well as activating the p-Akt pro-survival pathway.

CONCLUSION: Our results suggest that NAC exerts neuroprotective effects to inhibit the altered mitochondrial changes and cell death in I/R injury via regulation of p-GSK-3β mediated Drp-1 translocation to the mitochondria.}, } @article {pmid35063860, year = {2022}, author = {Ntamo, Y and Ziqubu, K and Chellan, N and Nkambule, BB and Nyambuya, TM and Mazibuko-Mbeje, SE and Gabuza, KB and Orlando, P and Tiano, L and Dludla, PV}, title = {Clinical use of N-acetyl cysteine during liver transplantation: Implications of oxidative stress and inflammation as therapeutic targets.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {147}, number = {}, pages = {112638}, doi = {10.1016/j.biopha.2022.112638}, pmid = {35063860}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Humans ; Inflammation/*drug therapy/pathology ; Liver Failure/pathology ; Liver Transplantation/*adverse effects ; Oxidative Stress/*drug effects/physiology ; Randomized Controlled Trials as Topic ; Reperfusion Injury/pathology/prevention & control ; }, abstract = {Currently, liver transplantation is considered as the definitive treatment option for individuals with complete liver failure. However, the detrimental effects of oxidative stress and inflammation remain the predominant feature that drives hepatic ischemia-reperfusion injury during liver transplantation. As such, therapeutic drugs that hinder oxidative stress and attenuate inflammation, have become ideal targets to curb liver injuries during transplantation. The current review analyses available clinical evidence on the importance of using N-acetyl cysteine (NAC) during liver transplantation. Thus, prominent online search engines such as PubMed and Google Scholar were accessed to retrieve literature from randomized clinical trials reporting on the use of NAC during liver transplantation. Overwhelming evidence suggests that established therapeutic properties of NAC, through enhancing endogenous antioxidants like glutathione to block oxidative stress and attenuate inflammation, remain essential to improve liver function in patients undergoing liver transportation. However, to the contrary, some clinical studies did not show any beneficial effects in patients receiving NAC during liver transplantation. Thus, such controversies, in addition to discussing the implications of oxidative stress and inflammation in relation to hepatic ischemia-reperfusion injury remain the major subject of the current review.}, } @article {pmid35057065, year = {2022}, author = {Guerini, M and Condrò, G and Perugini, P}, title = {Evaluation of the Mucoadhesive Properties of Chitosan-Based Microstructured Lipid Carrier (CH-MLC).}, journal = {Pharmaceutics}, volume = {14}, number = {1}, pages = {}, pmid = {35057065}, issn = {1999-4923}, abstract = {Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) with a new approach which requires chitosan and mucin to be compacted into a tablet and mucoadhesion to be assessed on a non-mucoadhesive substrate. This type of test showed that chitosan maintains a close bond with mucin even in the presence of a fluid and even encapsulated in microparticles. After this, using a bioreactor, the release of N-acetylcysteine (NAC) from the microparticles (NA-CH-MLC) through a layer of mucus mimicking the pathological conditions of a patient with cystic fibrosis was tested. The release of the active from NAC-CH-MLC demonstrated how the chitosan inside the microparticles acts as a penetration enhancer and how the microparticles can impart a prolonged release over time.}, } @article {pmid35055458, year = {2022}, author = {Allam, A and Abdeen, A and Devkota, HP and Ibrahim, SS and Youssef, G and Soliman, A and Abdel-Daim, MM and Alzahrani, KJ and Shoghy, K and Ibrahim, SF and Aboubakr, M}, title = {N-Acetylcysteine Alleviated the Deltamethrin-Induced Oxidative Cascade and Apoptosis in Liver and Kidney Tissues.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {2}, pages = {}, pmid = {35055458}, issn = {1660-4601}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis ; *Chickens/metabolism ; Humans ; Kidney ; Liver ; Nitriles ; Oxidative Stress ; Pyrethrins ; }, abstract = {Deltamethrin (DLM) is a synthetic pyrethroid with anti-acaricide and insecticidal properties. It is commonly used in agriculture and veterinary medicine. Humans and animals are exposed to DLM through the ingestion of polluted food and water, resulting in severe health issues. N-acetylcysteine (NAC) is a prodrug of L-cysteine, the precursor to glutathione. It can restore the oxidant-antioxidant balance. Therefore, this research aimed to examine whether NAC may protect broiler chickens against oxidative stress, at the level of biochemical and molecular alterations caused by DLM intoxication. The indicators of liver and kidney injury in the serum of DLM-intoxicated and NAC-treated groups were examined. Furthermore, lipid peroxidation, antioxidant markers, superoxide dismutase activity, and apoptotic gene expressions (caspase-3 and Bcl-2) were investigated. All parameters were significantly altered in the DLM-intoxicated group, suggesting that DLM could induce oxidative damage and apoptosis in hepato-renal tissue. The majority of the changes in the studied parameters were reversed when NAC therapy was used. In conclusion, by virtue of its antioxidant and antiapoptotic properties, NAC enabled the provision of significant protection effects against DLM-induced hepato-renal injury.}, } @article {pmid35052593, year = {2021}, author = {Singh, J and Phogat, A and Prakash, C and Chhikara, SK and Singh, S and Malik, V and Kumar, V}, title = {N-Acetylcysteine Reverses Monocrotophos Exposure-Induced Hepatic Oxidative Damage via Mitigating Apoptosis, Inflammation and Structural Changes in Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052593}, issn = {2076-3921}, abstract = {Oxidative stress-mediated tissue damage is primarily involved in hepatic injuries and dysfunctioning. Natural antioxidants have been shown to exert hepatoprotective, anti-inflammatory and antiapoptotic properties. The present study evaluated the effect of N-acetylcysteine (NAC) against monocrotophos (MCP) exposure-induced toxicity in the rat liver. Albino Wistar rats were divided into four groups: (1) control, (2) NAC-treated, (3) MCP-exposure, (4) NAC and MCP-coexposure group. The dose of MCP (0.9 mg/kg b.wt) and NAC (200 mg/kg b.wt) were administered orally for 28 days. Exposure to MCP caused a significant increase in lipid peroxidation, protein oxidation and decreased glutathione content along with the depletion of antioxidant enzyme activities. Further MCP exposure increased pro-inflammatory cytokines levels and upregulated Bax and Caspase-3 expressions. MCP exposure also caused an array of structural alternations in liver tissue, as depicted by the histological and electron microscopic analysis. Thepretreatment of NAC improved glutathione content, restored antioxidant enzyme activities, prevented oxidation of lipids and proteins, decreased pro-inflammatory cytokines levels and normalized apoptotic protein expression. Treatment of NAC also prevented histological and ultrastructural alternations. Thus, the study represents the therapeutic efficacy and antioxidant potential of NAC against MCP exposure in the rat liver.}, } @article {pmid35051378, year = {2022}, author = {Ning, Z and Lan, J and Jiang, X and Zhong, G and Zhang, H and Wan, F and Wu, S and Tang, Z and Bilal, RM and Hu, L and Huang, R}, title = {Arsenic trioxide-induced autophagy affected the antioxidant capacity and apoptosis rate of chicken hepatocytes.}, journal = {Chemico-biological interactions}, volume = {354}, number = {}, pages = {109821}, doi = {10.1016/j.cbi.2022.109821}, pmid = {35051378}, issn = {1872-7786}, mesh = {Animals ; *Arsenic Trioxide/toxicity/pharmacology ; *Autophagy/drug effects ; *Hepatocytes/drug effects/metabolism ; *Chickens ; *Apoptosis/drug effects ; *Oxides/toxicity ; *Antioxidants/pharmacology ; Arsenicals ; Oxidative Stress/drug effects ; Sirolimus/pharmacology ; Cells, Cultured ; Acetylcysteine/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Adenine/analogs & derivatives ; }, abstract = {Arsenic has recently received widespread attention due to its high toxicological effects on multiple animals; however, the mechanism underlying this toxicity is unclear. We investigated the damaging effects of arsenic trioxide (ATO) on hepatocytes and the effects of regulating autophagy on the hepatocyte damage induced by ATO exposure. First, we investigated the effects of ATO exposure (0, 0.6, 1.2, 2.4, and 4.8 μM) on the biochemical function and autophagy of chicken hepatocytes. The findings showed that as the concentration of ATO increased, the lactate dehydrogenase (LDH) concentration increased, more autophagosomes were observed via transmission electron microscopy (TEM), and the gene and protein expression levels of P62, LC3Ⅱ, and Beclin1 increased. Adding N-acetyl-l-cystine (NAC, 1 mM) attenuated autophagy and the hepatocyte damage induced by ATO. Then, we used rapamycin (Rapa) and 3-methylpurine (3-MA) to regulate the autophagy induced by exposure to 4.8 μM ATO and observed changes in the antioxidant capacity and apoptosis rate of chicken hepatocytes. Induction of autophagy reduced ATO-induced hepatocyte apoptosis but caused no significant effect on oxidative stress in chicken hepatocytes. Inhibition of autophagy exacerbated ATO-induced hepatocyte oxidative stress and apoptosis. These findings demonstrate that autophagy plays an important role in ATO-induced cell damage.}, } @article {pmid35044038, year = {2022}, author = {Hu, Q and Zheng, J and Xu, XN and Gu, C and Li, W}, title = {Uranium induces kidney cells apoptosis via reactive oxygen species generation, endoplasmic reticulum stress and inhibition of PI3K/AKT/mTOR signaling in culture.}, journal = {Environmental toxicology}, volume = {37}, number = {4}, pages = {899-909}, doi = {10.1002/tox.23453}, pmid = {35044038}, issn = {1522-7278}, support = {82160627//National Natural Science Foundation of China/ ; 2020GXNFSAA297262//Natural Science Foundation of Guangxi Autonomous Region/ ; }, mesh = {Apoptosis ; *Endoplasmic Reticulum Stress ; Kidney/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; *Uranium/pharmacology ; }, abstract = {Uranium (U) induces generation of excessive intracellular reactive oxygen species (ROS), which is generally considered as a possible mediator of U-triggered kidney tubular cells injury and nephrotoxicity. Our goal is designed to elucidate that the precise molecular mechanism in ROS downstream is association with U-induced NRK-52[E] cells apoptosis. The results show that U intoxication in NRK-52[E] cells reduced cell activity and triggered apoptosis, as demonstrated by flow cytometry and apoptotic marker cleaved Caspase-3 expression. U exposure triggered endoplasmic reticulum (ER) stress, which is involvement of apoptosis determined by marker molecules including GRP78, PERK, IRE1, ATF6, CHOP, cleaved Caspase-12, and Caspase-3. Administration of antioxidant N-acetylcysteine (NAC) effectively blocked U-triggered ROS generation, ER stress, and apoptosis. U contamination evidently decreased the expression of phosphorylation PI3K, AKT, and mTOR and ratios of their respective phosphorylation to the corresponding total proteins. Application of a PI3K activator IGF-1 significantly abolished these adverse effects of U intoxication on PI3K/AKT/mTOR signaling and subsequently abrogated U-triggered apoptosis. NAC also effectively reversed down-regulation of phosphorylated PI3K induced by U exposure. Taken together, these data strongly suggest that U treatment induces NRK-52[E] cells apoptosis through ROS production, ER stress, and down-regulation of PI3K/AKT/mTOR signaling. Targeting ROS formation-, ER stress-, and PI3K/AKT/mTOR pathway-mediated apoptosis could be a novel approach for attenuating U-triggered nephrotoxicity.}, } @article {pmid35043378, year = {2022}, author = {Lai, L and Wang, Y and Peng, S and Guo, W and Wei, G and Li, L and Xia, Z and Li, F and Xu, S}, title = {Bupivacaine Induces ROS-Dependent Autophagic Damage in DRG Neurons via TUG1/mTOR in a High-Glucose Environment.}, journal = {Neurotoxicity research}, volume = {40}, number = {1}, pages = {111-126}, pmid = {35043378}, issn = {1476-3524}, support = {81501082//National Natural Science Foundation of China/ ; 81771315//National Natural Science Foundation of China/ ; 82171357//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Apoptosis ; Autophagy ; *Bupivacaine/toxicity ; *Ganglia, Spinal/metabolism ; Glucose/metabolism ; Humans ; Mammals/metabolism ; Mice ; Neurons/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Taurine/metabolism ; }, abstract = {Bupivacaine (BP) is a commonly clinically used local anesthetic (LA). Current studies suggest that neurological complications are increased in diabetic patients after LA application, but the molecular mechanism is poorly understood. LA-induced autophagy and neuronal injury have been reported. We hypothesized that a high-glucose environment aggravates BP-induced autophagic damage. Mouse dorsal root ganglion (DRG) neurons were treated with BP in a high-glucose environment, and the results showed that reactive oxygen species (ROS) levels increased, autophagy was activated, autophagy flux was blocked, and cell viability decreased. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) attenuated ROS-mediated autophagy regulation. Moreover, the expression of the long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) increased, and NAC and TUG1 siRNA inhibited the expression of TUG1/mammalian target of rapamycin (mTOR) in DRGs treated with BP in a high-glucose environment. Intriguingly, contrary to previous reports on a positive effect on neurons, we found that rapamycin, an autophagy activator, and chloroquine, an autophagy and lysosome inhibitor, both exacerbated autophagic damage. These data suggest that a high-glucose environment exacerbated BP induced ROS-dependent autophagic damage in DRG neurons through the TUG1/mTOR signaling pathway, which provides a theoretical basis and target for the clinical prevention and treatment of BP neurotoxicity in diabeties.}, } @article {pmid35039188, year = {2022}, author = {Karaarslan, U and Çolak, M and Topal, S and Atakul, G and Soydan, E and Çağlar, A and Ağın, H}, title = {The association between N-acetylcysteine treatment and hepatic healing in patients with non-acetaminophen-induced liver injury in pediatric intensive care: A single-center retrospective study.}, journal = {Archives de pediatrie : organe officiel de la Societe francaise de pediatrie}, volume = {29}, number = {2}, pages = {140-144}, doi = {10.1016/j.arcped.2021.11.006}, pmid = {35039188}, issn = {1769-664X}, mesh = {Acetaminophen ; Acetylcysteine/*therapeutic use ; Analgesics, Non-Narcotic/therapeutic use ; *Chemical and Drug Induced Liver Injury/etiology ; Child ; Critical Care ; Female ; Humans ; Liver Failure, Acute/*drug therapy/etiology ; Male ; Retrospective Studies ; Transaminases/blood ; Treatment Outcome ; }, abstract = {OBJECTIVE: The aim of this study was to determine the association between the use of intravenous N-acetylcysteine (NAC) and hepatic healing in pediatric intensive care unit (PICU) patients with non-acetaminophen-induced hepatic injury, except for acute liver failure.

METHODS: The data of patients who received intravenous NAC as adjuvant therapy for transaminase levels more than sixfold normal values during their PICU stay between 2010 and 2014 were retrospectively collected from the medical records database. The patients who did not receive NAC with elevated transaminase levels during their PICU stay between 2014 and 2018 were also collected as the standard of care (SOC) cohort.

RESULTS: More than 50% of the liver injuries were secondary to acute hypoxia, hypotension, sepsis, and inflammation. The median number of elevated transaminase period (ETP) days of the NAC and SOC groups were 5 (IQR: 4) and 4 (IQR: 4), respectively (p = 0.17). There was no significant difference between the groups in terms of minimum and maximum laboratory values during ETP. There was no significant difference in terms of ETP and maximum ALT levels between the NAC and SOC groups in the hypoxia-hypotension subgroup.

CONCLUSION: This study did not show an association between indirect measures of hepatic healing and post-insult use of NAC in pediatric liver injury in the PICU setting.}, } @article {pmid35037248, year = {2022}, author = {Saito, N and Mikami, R and Mizutani, K and Takeda, K and Kominato, H and Kido, D and Ikeda, Y and Buranasin, P and Nakagawa, K and Takemura, S and Ueno, T and Hosaka, K and Hanawa, T and Shinomura, T and Iwata, T}, title = {Impaired dental implant osseointegration in rat with streptozotocin-induced diabetes.}, journal = {Journal of periodontal research}, volume = {57}, number = {2}, pages = {412-424}, doi = {10.1111/jre.12972}, pmid = {35037248}, issn = {1600-0765}, support = {//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Dental Implants ; *Diabetes Mellitus, Experimental/metabolism ; Osseointegration ; Osteogenesis ; Rats ; Streptozocin ; Titanium/pharmacology ; }, abstract = {OBJECTIVE: Few studies have reported on the impact of oxidative stress on the dental implant failure. The aim of this study was to investigate the impact of hyperglycemia-induced oxidative stress on dental implant osseointegration in diabetes mellitus (DM).

METHODS: Acid-treated titanium implants were bilaterally placed in the maxillary alveolar ridge of streptozotocin-induced diabetic (DM group) and control rats after extraction of first molars. Histological analysis and micro-push-out test were performed 4 weeks after surgery. Oxidative stress and osteogenic markers in the surrounding bone were quantified by real-time polymerase chain reaction. In the in vitro study, rat bone marrow-derived mesenchymal stem cells (BMMSCs) were cultured on acid-treated titanium discs in a high-glucose (HG) or normal environment. Intracellular reactive oxygen species (ROS), cell proliferation, alkaline phosphatase (ALP) activity, and extracellular calcification were evaluated following antioxidant treatment with N-acetyl-L-cysteine (NAC).

RESULTS: The implant survival rate was 92.9% and 75.0% in control and DM group, respectively. Bone-implant contact and push-out loads were significantly lower in the DM group. Expression of superoxide dismutase 1 at the mRNA level and on immunohistochemistry was significantly lower in the DM group. In vitro experiments revealed that the HG condition significantly increased ROS expression and suppressed the proliferation and extracellular calcification of BMMSCs, while NAC treatment significantly restored ROS expression, cell proliferation, and calcification. The ALP activity of both groups was not significantly different.

CONCLUSION: In diabetes, high-glucose-induced oxidative stress downregulates proliferation and calcification of BMMSCs, impairing osseointegration and leading to implant failure.}, } @article {pmid35035668, year = {2022}, author = {Chen, W and Huang, W and Yang, Y and Li, K}, title = {Methylglyoxal Scavengers Attenuate Angiogenesis Dysfunction Induced by Methylglyoxal and Oxygen-Glucose Deprivation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8854457}, pmid = {35035668}, issn = {1942-0994}, mesh = {Angiogenesis Inhibitors/pharmacology/*therapeutic use ; Animals ; Chick Embryo ; Glucose/*metabolism ; Humans ; Oxidative Stress/*drug effects ; Oxygen/*metabolism ; Pyruvaldehyde/pharmacology/*therapeutic use ; }, abstract = {Cerebral endothelial cells play an essential role in brain angiogenesis, and their function has been found to be impaired in diabetes. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite of glucose formed mainly during glycolysis, and its levels can be elevated in hyperglycemic conditions. MG is a potent precursor of AGEs (advanced glycation end-products). In this study, we investigated if MG can induce angiogenesis dysfunction and whether MG scavengers can ameliorate angiogenesis dysfunction induced by MG. Here, we used cultured human brain microvascular endothelial cells (HBMECs) treated with MG and oxygen-glucose deprivation (OGD) to mimic diabetic stroke in vitro. We also used the MG challenged chicken embryo chorioallantoic membrane (CAM) to study angiogenesis in vivo. Interestingly, administration of MG significantly impaired cell proliferation, cell migration, and tube formation and decreased protein expression of angiogenesis-related factors, which was rescued by three different MG scavengers, glyoxalase 1 (GLO1), aminoguanidine (AG), and N-acetyl cysteine (NAC). In cultured CAM, MG exposure significantly reduced angiogenesis and the angiogenesis-related dysfunction could be attenuated by pretreatment with AG or NAC. Treatment of cultured HBMECs with MG plus OGD increased cellular apoptosis significantly, which could be prevented by exposure to GLO1, AG, or NAC. We also noted that administration of MG increased cellular oxidative stress as measured by reactive oxygen species (ROS) generation, enhanced AGE accumulation, and receptor for advanced glycation end-product (RAGE) expression in the cultured HBMECs, which were partially reversed by GLO1, AG, or NAC. Taken together, our findings demonstrated that GLO1, AG, or NAC administration can ameliorate MG-induced angiogenesis dysfunction, and this can be mainly attributed to attenuated ROS production, reduced cellular apoptosis, and increased levels of angiogenic factors. Overall, this study suggested that GLO1, AG, or NAC may be promising candidate compounds for the treatment of angiogenesis dysfunction caused by hyperglycemia in diabetic ischemic stroke.}, } @article {pmid35035661, year = {2022}, author = {Hseu, YC and Tseng, YF and Pandey, S and Shrestha, S and Lin, KY and Lin, CW and Lee, CC and Huang, ST and Yang, HL}, title = {Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {4266214}, pmid = {35035661}, issn = {1942-0994}, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Humans ; Inflammasomes/*drug effects ; Lipopolysaccharides/*metabolism ; Macrophages/*metabolism ; Mice ; Mitophagy/*immunology ; Transfection ; Ubiquinone/pharmacology/*therapeutic use ; }, abstract = {Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ0's non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ0 led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ0 increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ0 inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ0, Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1β expression. Interestingly, treatment with CoQ0 or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ0-inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ0 inhibited ROS-mediated NLRP3 inflammasome activation and IL1β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ0 might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties.}, } @article {pmid35029525, year = {2022}, author = {Khoshdel, AR and Emami Aleagha, O and Shahriary, A and Aghamollaei, H and Najjar Asiabani, F}, title = {Topical Effects of N-Acetyl Cysteine and Doxycycline on Inflammatory and Angiogenic Factors in the Rat Model of Alkali-Burned Cornea.}, journal = {Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research}, volume = {42}, number = {2}, pages = {82-89}, doi = {10.1089/jir.2021.0150}, pmid = {35029525}, issn = {1557-7465}, mesh = {Acetylcysteine/metabolism/pharmacology ; Alkalies/metabolism/pharmacology ; Angiogenesis Inducing Agents/metabolism/pharmacology ; Animals ; *Burns, Chemical/complications/drug therapy/metabolism ; Cornea/metabolism ; *Corneal Neovascularization/etiology/genetics ; Disease Models, Animal ; Doxycycline/metabolism/pharmacology ; *Eye Burns/chemically induced/complications/drug therapy ; Rats ; Sodium Hydroxide/metabolism/pharmacology ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {The aim of this study was to analyze the single and combined effects of N-acetyl cysteine (NAC) and doxycycline (Dox) on the inflammatory and angiogenic factors in the rat model of alkali-burned cornea. Rats were treated with a single and combined 0.5% NAC and 12.5 μg/mL Dox eye drops and evaluated on days 3, 7, and 28. In the corneas of various groups, the activity of Catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzymes was assessed. The expression of inflammatory factors (TNF-α, Rel-a, and CXCL-1) and angiogenic factors (VEGF-a, MMP2, and MMP9) was measured using real-time polymerase chain reaction. The antioxidant enzyme activities decreased substantially 3 days after injury with sodium hydroxide (NaOH). NAC and combined NAC+ Dox topical treatments increased the SOD enzyme activity on day 28 (P < 0.05). The expression of TNF-α and Rel-a genes following single and combined treatment of NAC and Dox decreased significantly on days 7 and 28 (P < 0.05). The mRNA level of angiogenic factors and corneal neovascularization (CNV) level declined in NaOH-injured rats treated with Dox (P < 0.05). The topical treatment of Dox could attenuate inflammation and CNV complications. However, NAC treatment may not reduce the expression of angiogenic genes.}, } @article {pmid35024307, year = {2021}, author = {Qian, H and Bai, Q and Yang, X and Akakpo, JY and Ji, L and Yang, L and Rülicke, T and Zatloukal, K and Jaeschke, H and Ni, HM and Ding, WX}, title = {Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {12}, pages = {3791-3805}, pmid = {35024307}, issn = {2211-3835}, support = {R01 AA020518/AA/NIAAA NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; R37 AA020518/AA/NIAAA NIH HHS/United States ; U01 AA024733/AA/NIAAA NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; R21 AA017421/AA/NIAAA NIH HHS/United States ; R01 AG072895/AG/NIA NIH HHS/United States ; }, abstract = {Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.}, } @article {pmid35024303, year = {2021}, author = {Jaeschke, H and Adelusi, OB and Akakpo, JY and Nguyen, NT and Sanchez-Guerrero, G and Umbaugh, DS and Ding, WX and Ramachandran, A}, title = {Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {12}, pages = {3740-3755}, pmid = {35024303}, issn = {2211-3835}, support = {R01 DK070195/DK/NIDDK NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, abstract = {Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.}, } @article {pmid35024183, year = {2021}, author = {Fatima, K and Masood, N and Ahmad Wani, Z and Meena, A and Luqman, S}, title = {Neomenthol prevents the proliferation of skin cancer cells by restraining tubulin polymerization and hyaluronidase activity.}, journal = {Journal of advanced research}, volume = {34}, number = {}, pages = {93-107}, pmid = {35024183}, issn = {2090-1224}, mesh = {Animals ; Cell Proliferation ; HEK293 Cells ; Humans ; Hyaluronoglucosaminidase ; Mice ; Molecular Docking Simulation ; Polymerization ; *Skin Neoplasms/drug therapy ; *Tubulin ; }, abstract = {INTRODUCTION: Neomenthol, a cyclic monoterpenoid, is a stereoisomer of menthol present in the essential oil of Mentha spp. It is used in food as a flavoring agent, in cosmetics and medicines because of its cooling effects. However, neomenthol has not been much explored for its anticancer potential. Additionally, targeting hyaluronidase, Cathepsin-D, and ODC by phytochemicals is amongst the efficient approach for cancer prevention and/or treatment.

OBJECTIVES: To investigate the molecular and cell target-based antiproliferative potential of neomenthol on human cancer (A431, PC-3, K562, A549, FaDu, MDA-MB-231, COLO-205, MCF-7, and WRL-68) and normal (HEK-293) cell lines.

METHODS: The potency of neomenthol was evaluated on human cancer and normal cell line using SRB, NRU and MTT assays. The molecular target based study of neomenthol was carried out in cell-free and cell-based test systems. Further, the potency of neomenthol was confirmed by quantitative real-time PCR analysis and molecular docking studies. The in vivo anticancer potential of neomenthol was performed on mice EAC model and the toxicity examination was accomplished through in silico, ex vivo and in vivo approaches.

RESULTS: Neomenthol exhibits a promising activity (IC50 17.3 ± 6.49 μM) against human epidermoid carcinoma (A431) cells by arresting the G2/M phase and increasing the number of sub-diploid cells. It significantly inhibits hyaluronidase activity (IC50 12.81 ± 0.01 μM) and affects the tubulin polymerization. The expression analysis and molecular docking studies support the in vitro molecular and cell target based results. Neomenthol prevents EAC tumor formation by 58.84% and inhibits hyaluronidase activity up to 10% at 75 mg/kg bw, i.p. dose. The oral dose of 1000 mg/kg bw was found safe in acute oral toxicity studies.

CONCLUSION: Neomenthol delayed the growth of skin carcinoma cells by inhibiting the tubulin polymerization and hyaluronidase activity, which are responsible for tumor growth, metastasis, and angiogenesis.}, } @article {pmid35023144, year = {2022}, author = {Wang, XJ and Ni, XQ and Zhao, S and Zhao, RZ and Wang, XH and Xia, SJ and Sun, XW and Zhuo, J}, title = {ROS-NLRP3 signaling pathway induces sterile inflammation after thulium laser resection of the prostate.}, journal = {Journal of cellular physiology}, volume = {237}, number = {3}, pages = {1923-1935}, doi = {10.1002/jcp.30663}, pmid = {35023144}, issn = {1097-4652}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspase 1/genetics/metabolism ; Dogs ; Humans ; Inflammasomes/metabolism ; *Inflammation ; Interleukin-18 ; Interleukin-1beta/metabolism ; Lasers ; Male ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Prostate/metabolism/surgery ; *Reactive Oxygen Species/metabolism ; Signal Transduction ; Thulium ; }, abstract = {The sterile inflammation (SI) of the urinary tract is a common problem requiring serious consideration after prostatectomy. This study mainly focuses on the role of the reactive oxygen species-NLR family, pyrin domain-containing 3 (ROS-NLRP3) signaling pathway in SI after thulium laser resection of the prostate (TmLRP). Urinary cytokines were determined in patients who received TmLRP, and heat shock protein 70 (HSP70) was detected in the resected tissues. The involvement of ROS signaling in HSP70-induced inflammation was explored in THP-1 cells with or without N-acetyl- l-cysteine (NAC) pretreatment. The function of NLRP3 and Caspase-1 was determined by Western blot analysis, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction. These phenomena and mechanisms were verified by the beagle models that received TmLRP. Clinical urine samples after TmLRP showed high expression of inflammatory factors and peaked 3-5 days after surgery. The high expression of HSP70 in the resected tissues was observed. After HSP70 stimulation, the expression of ROS, NLRP3, Caspase-1, and interleukin-18 (IL-18) increased significantly and could be reduced by ROS inhibitor NAC. The expression of IL-1β and IL-18 could be inhibited by NLRP3 or Caspase-1 inhibitors. In beagle models that received TmLRP, HSP70, NLRP3, Caspase-1, IL-1β, and IL-18 were highly expressed in the wound tissue or urine, and could also be reduced by NAC pretreatment. Activation of the ROS-NLRP3 signaling pathway induces SI in the wound after prostatectomy. Inhibition of this pathway may be effective for clinical prevention and treatment of SI and related complications after prostatectomy.}, } @article {pmid35020164, year = {2023}, author = {Çoban, FK and İnce, S and Demirel, HH and İslam, İ and Aytuğ, H}, title = {Acetaminophen-Induced Nephrotoxicity: Suppression of Apoptosis and Endoplasmic Reticulum Stress Using Boric Acid.}, journal = {Biological trace element research}, volume = {201}, number = {1}, pages = {242-249}, pmid = {35020164}, issn = {1559-0720}, mesh = {Rats ; Animals ; *Acetaminophen/toxicity/metabolism ; Boron/pharmacology ; Acetylcysteine/pharmacology ; Apoptosis ; *Kidney Diseases/chemically induced ; Endoplasmic Reticulum Stress ; }, abstract = {Acetaminophen (APAP) is one of the popular and safe pain medications worldwide. However, due its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure. Boron is a bioactive trace element, found naturally as boric acid (BA) and borate. In this study, the effects of boric acid on the acute renal toxicity induced by APAP in rats were researched in comparison with N-acetyl cysteine (NAC). In the study, 7 groups were formed and 2 g/kg dose of paracetamol per rat was prepared by suspending in 1% Carboxy Methyl Cellulose (CMC) solution of phosphate buffer saline (PBS). Boric acid dissolved in saline was administered to experimental animals by gavage at doses of 50, 100, and 200 mg/kg. In this study, ER stress and apoptosis formed by paracetamol-induced nephrotoxicity were investigated. This purpose determined iNOS, PERK, ATF6, NFkB p53, caspases 3, 12, bcl-2, and bcl-xL gene mRNA expression kidney tissue. Also, the levels of kidney injury molecule-1 (KIM-1), Cysteine (Cys), and IL-18 levels, which are mentioned today as kidney damage markers were compared with BUN and creatine levels. The effect of boron on kidney damage was determined by histopathologic. Data were statistically analyzed by using SPSS-20 ANOVA and stated as means and standard deviation. According to the data obtained in our study, we believe that boric acid has a protective effect on the negative effects of paracetamol on the kidney. We believe that our study will provide useful data to the literature on the possibility of a supplement to be used as an active compound in paracetamol for the prophylaxis of boric acid and it can also be converted into a useful product.}, } @article {pmid35017325, year = {2021}, author = {Alrowaie, FA and Almatham, KI and Alsamadi, F and Bashir, MS and Munshi, HH}, title = {Could Omega 3 fatty acids reduce the risk of contrast-induced nephropathy in patients undergoing coronary angiography? A randomized controlled trial.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {32}, number = {2}, pages = {328-335}, doi = {10.4103/1319-2442.335443}, pmid = {35017325}, issn = {1319-2442}, mesh = {Acetylcysteine/administration & dosage/*pharmacology ; Acute Kidney Injury/*chemically induced/diagnosis/metabolism ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Fatty Acids, Omega-3/administration & dosage/*pharmacology ; Female ; Free Radical Scavengers/*administration & dosage ; Humans ; Kidney Diseases/*chemically induced/diagnosis/metabolism ; Male ; Middle Aged ; Treatment Outcome ; }, abstract = {Contrast medium-induced nephropathy (CIN) is a leading cause of acquired acute kidney injury and has been associated with prolonged hospitalization and adverse clinical outcomes. This study aimed to determine if omega 3 fatty acids reduce the risk of CIN in patients with chronic kidney disease undergoing coronary angiography. A total of 130 consecutive patients undergoing coronary angiography were randomly assigned to one of two groups as follows: 67 patients were assigned to the N-acetylcysteine (NAC; 1200 mg) and 63 patients were assigned to the omega 3 fatty acid (4 g). Both drugs were administered orally twice per day one day before and on the day of contrast administration. Of the 130 patients enrolled in this study, 10 (7.7%) experienced an increase of at least 0.5 mg/dL (44 μmol/L) in serum creatinine levels 48 h after administration of the contrast agent including 5 of the 67 patients in the NAC group (7.5%) and 5 of the 63 patients in the omega 3 fatty acids group (7.9%; P = 0.919). There were no significant differences in the need for renal replacement therapy (3.0% vs. 9.5%, P = 0.121) or in the mortality rate (3.0% vs. 6.3%, P = 0.361) between the two groups. Short-term prophylactic omega 3 fatty acid treatment with hydration does not reduce the risk of CIN in patients with chronic kidney disease undergoing coronary angiography.}, } @article {pmid35014505, year = {2021}, author = {Beltrame, JM and Guindani, C and Novy, MG and Felipe, KB and Sayer, C and Pedrosa, RC and Hermes de Araújo, PH}, title = {Covalently Bonded N-Acetylcysteine-polyester Loaded in PCL Scaffolds for Enhanced Interactions with Fibroblasts.}, journal = {ACS applied bio materials}, volume = {4}, number = {2}, pages = {1552-1562}, doi = {10.1021/acsabm.0c01404}, pmid = {35014505}, issn = {2576-6422}, mesh = {Acetylcysteine/*chemistry ; Caproates/*metabolism ; Fibroblasts/*metabolism ; Lactones/*metabolism ; Polyesters/*chemistry ; Tissue Engineering/*methods ; }, abstract = {Poly(ε-caprolactone) (PCL) is commonly used in devices for tissue reconstruction due to its biocompatibility and suitable mechanical properties. However, its high crystallinity and hydrophobicity do not favor cell adhesion and difficult polymer bioresorption. To improve these characteristics, the development of engineered scaffolds for tissue regeneration, based on poly(globalide-co-ε-caprolactone) (PGlCL) covalently bonded with N-acetylcysteine (PGlCL-NAC) was proposed. The scaffolds were obtained from polymer blends of PCL and PGlCL-NAC, using the electrospinning technique. The use of PGlCL-NAC allowed for the modification of the physical and chemical properties of PCL electrospun scaffolds, including an expressive reduction in the fiber's diameter, hydrophobicity, and crystallinity. All electrospun scaffolds showed no cytotoxicity against fibroblasts (McCoy cells). In vitro biocompatibility assays showed that all tested scaffolds provided high cell viability and proliferation in short-term (NRU, MTT, and nuclear morphology assays) and long-term (clonogenic assay) assays. Nevertheless, PGlCL-NAC based scaffolds have favored the survival and proliferation of the cells in comparison to PCL scaffolds. Cell adhesion on the scaffolds assessed by electronic microscopy images confirmed this behavior. These results suggest that the incorporation of PGlCL-NAC in scaffolds for tissue regeneration could be a promising strategy to improve cell-surface interactions and contribute to the development of more efficiently engineered biomedical devices.}, } @article {pmid35011309, year = {2021}, author = {Liao, CY and Wu, TC and Yang, SF and Chang, JT}, title = {Effects of NAC and Gallic Acid on the Proliferation Inhibition and Induced Death of Lung Cancer Cells with Different Antioxidant Capacities.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {1}, pages = {}, pmid = {35011309}, issn = {1420-3049}, support = {MOST 108-2320-B-040-004 (Taiwan, R.O.C.)//Ministry of Science and Technology Taiwan, R.O.C./ ; }, mesh = {Acetylcysteine/chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Antioxidants/chemistry/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Gallic Acid/chemistry/*pharmacology ; Humans ; Lung Neoplasms ; Molecular Structure ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {N-acetylcysteine (NAC) is a recognized antioxidant in culture studies and treatments for oxidative stress-related diseases, but in some cases, NAC is a pro-oxidant. To study the effect of NAC on cell proliferation in the presence or absence of ROS stress, we used the stable ROS generator gallic acid (GA) to treat CL1-0 lung cancer cell models with different antioxidant activities. Different antioxidant activities were achieved through the ectopic expression of different PERP-428 single nucleotide polymorphisms. GA increased ROS levels in CL1-0/PERP-428C cells and caused cell death but had no effect on CL1-0/PERP-428G cells within 24 h. We found that 0.1 mM NAC eliminated GA-induced growth inhibition, but 0.5 mM NAC enhanced GA-induced CL1-0/PERP-428C cell death. However, in the absence of GA, NAC exceeding 2 mM inhibited the growth of CL1-0/PERP-428G cells more significantly than that of CL1-0/PERP-428C cells. Without GA, NAC has an antioxidant effect. Under GA-induced ROS stress, NAC may have pro-oxidant effects. Each cell type has a unique range of ROS levels for survival. The levels of ROS in the cell determines the sensitivity of the cell to an antioxidant or pro-oxidant. Cells with different antioxidant capacities were used to show that the intracellular ROS level affects NAC function and provides valuable information for the adjuvant clinical application of NAC.}, } @article {pmid35008006, year = {2022}, author = {Xu, D and Zhou, X and Chen, J and Li, N and Ruan, S and Zuo, A and Lei, S and Li, L and Guo, Y}, title = {C1q/tumour necrosis factor-related protein-9 aggravates lipopolysaccharide-induced inflammation via promoting NLRP3 inflammasome activation.}, journal = {International immunopharmacology}, volume = {104}, number = {}, pages = {108513}, doi = {10.1016/j.intimp.2021.108513}, pmid = {35008006}, issn = {1878-1705}, mesh = {Adiponectin/genetics/*immunology ; Animals ; Female ; Glycoproteins/genetics/*immunology ; Inflammasomes/genetics/*immunology ; Inflammation/chemically induced/genetics/*immunology ; Interleukin-1beta/blood/genetics/immunology ; Lipopolysaccharides ; Macrophages, Peritoneal/immunology ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidase 2/genetics/immunology ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*immunology ; Pyroptosis ; Reactive Oxygen Species/immunology ; Mice ; }, abstract = {The NLRP3 inflammasome plays a vital role in inflammation by increasing the maturation of interleukin-1β (IL-1β) and promoting pyroptosis. Given that C1q/tumour necrosis factor-related protein-9 (CTRP9) has been shown to be involved in diverse inflammatory diseases, we sought to assess the underlying impact of CTRP9 on NLRP3 inflammasome activation. In vitro, macrophages isolated from murine peritonea were stimulated with exogenous CTRP9, followed by lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP). We demonstrated that CTRP9 markedly augmented the activation of the NLRP3 inflammasome, as shown by increased mature IL-1β secretion, triggering ASC speck formation and promoting pyroptosis. Mechanistically, CTRP9 increased the levels of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). Suppressing ROS with N-acetylcysteine (NAC) or interfering with NOX2 by small interfering RNA weakened the promoting effect of CTRP9 on the NLRP3 inflammasome. Furthermore, NLRP3 inflammasome activation, pyroptosis and secretion of mature IL-1β were significantly decreased in macrophages from CTRP9-KO mice compared to those from WT mice with the same treatment. In vivo, we established a sepsis model by intraperitoneal injection of LPS into WT and CTRP9-KO mice. CTRP9 knockout improved the survival rates of the septic mice and attenuated NLRP3 inflammasome-mediated inflammation. In conclusion, our study indicates that CTRP9 aggravates LPS-induced inflammation by promoting NLRP3 inflammasome activation via the NOX2/ROS pathway. CTRP9 could be a promising target for NLRP3 inflammasome-driven inflammatory diseases.}, } @article {pmid35006548, year = {2022}, author = {Baum, RA and Su, MK and Weant, KA}, title = {The Cents of the Dosage Cap in Patients Greater than 100 Kilograms Receiving N-Acetylcysteine for Acetaminophen Toxicity.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {18}, number = {1}, pages = {67-68}, pmid = {35006548}, issn = {1937-6995}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; }, } @article {pmid35006546, year = {2022}, author = {Berland, NG and Leonard, J and Calello, DP}, title = {Should the Dosage Cap Be Used in Patients Greater than 100 kg Receiving N-acetylcysteine for Acetaminophen Toxicity?.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {18}, number = {1}, pages = {65-66}, pmid = {35006546}, issn = {1937-6995}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; }, } @article {pmid35000568, year = {2022}, author = {Guo, X and He, J and Zhang, R and Wang, T and Chen, J and Wang, J and Wang, Z and Chang, G and Niu, Y and Niu, Z and Song, J}, title = {N-Acetylcysteine alleviates spinal cord injury in rats after early decompression surgery by regulating inflammation and apoptosis.}, journal = {Neurological research}, volume = {44}, number = {7}, pages = {605-613}, doi = {10.1080/01616412.2021.2024737}, pmid = {35000568}, issn = {1743-1328}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; Apoptosis ; Decompression ; Inflammation/drug therapy/pathology ; Rats ; Recovery of Function ; Spinal Cord/pathology ; *Spinal Cord Injuries/drug therapy/pathology/surgery ; }, abstract = {OBJECTIVE: Decompression surgery in patients with spinal cord injury (SCI) has a neuroprotective effect by alleviating secondary injury and improving neurological outcomes. N-Acetylcysteine (NAC), a drug approved by the United States Food and Drug Administration, has been shown to play neuroprotective roles via attenuation of apoptosis and inflammation. The purpose of the present study was to investigate the effects of early or late decompression surgery in combination with NAC administration on acute SCI, as well as investigate the underlying mechanisms of its actions.

METHODS: In this study, an acute SCI model was established in rats. The rats were treated with decompression surgery 24/48 h post-SCI in combination with or without NAC.

RESULTS: The results showed that decompression surgery in combination with NAC lead to a better outcome than decompression alone, as demonstrated by the higher Basso, Beattie, and Bresnahan scores. Histopathological examination demonstrated that early decompression surgery in combination with NAC exerted the best therapeutic effect on spinal cord recovery, which was further confirmed by the extent of inflammation and apoptosis. Additionally, we found that NAC might compensate for a lack of late surgery.

CONCLUSIONS: Collectively, early decompression surgery and NAC could be a promising combination for the treatment of acute SCI, and its therapeutic effects may be associated with the regulation of inflammation and apoptosis.}, } @article {pmid34995428, year = {2021}, author = {Elsayed, S and Gohar, A and Omar, M}, title = {A Review Article on 5-Oxoproline Induced High Anion Gap Metabolic Acidosis.}, journal = {South Dakota medicine : the journal of the South Dakota State Medical Association}, volume = {74}, number = {10}, pages = {468-470}, pmid = {34995428}, issn = {0038-3317}, mesh = {Acetaminophen ; Acid-Base Equilibrium ; *Acidosis/chemically induced ; Adult ; *Analgesics, Non-Narcotic ; Female ; Humans ; Pyrrolidonecarboxylic Acid/metabolism ; }, abstract = {In 1989, an acquired high anion gap metabolic acidosis due to elevated 5-oxoproline (pyroglutamic acid) was first reported. This is related to chronic acetaminophen use in malnourished patients and women with chronic medical conditions, it could happen even using therapeutic or low doses. The mainstay of treatment is cessation of acetaminophen use along with the administration of intravenous fluids. N-acetyl cysteine might accelerate improvement. The best explanation of the disorder is glutathione depletion and activation of a key enzyme in the γ-glutamyl cycle. This review article aims to highlight the mechanism and management of acquired high anion gap metabolic acidosis caused by 5-oxoproline in the adult population.}, } @article {pmid34994286, year = {2022}, author = {Asgari, Z and Moini, A and Montazeri, A and Tavoli, Z and Hosseini, L and Hosseini, R and Tehranian, A and Karimi, R}, title = {Comparing the effect of adjunctive N-acetylcysteine plus low dose contraceptive with low dose contraceptive alone on recurrence of ovarian endometrioma and chronic pelvic pain after conservative laparoscopic surgery: a randomised clinical trial study.}, journal = {Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology}, volume = {42}, number = {5}, pages = {1493-1497}, doi = {10.1080/01443615.2021.2006165}, pmid = {34994286}, issn = {1364-6893}, mesh = {Acetylcysteine/therapeutic use ; *Chronic Pain ; Contraceptive Agents ; *Endometriosis/drug therapy/surgery ; Female ; Humans ; *Laparoscopy ; *Ovarian Diseases/surgery ; Pelvic Pain/drug therapy/etiology/surgery ; Recurrence ; }, abstract = {This study aimed to compare the effectiveness of NAC plus low dose contraceptive with low dose contraceptives alone. This was a randomised trial on a sample of women who underwent conservative laparoscopic surgery for ovarian endometrioma. Patients were randomly assigned either to the NAC plus low dose contraceptive group (n = 48) or low dose contraceptive alone (n = 52). To evaluate the recurrence rate transvaginal ultrasound was performed. Pelvic pain was assessed using a visual analogue scale (VAS). All assessments were performed at two points in time: 3 and 6 months post-surgery and compared between the two regimens. The findings indicated that reduction in the recurrence rate of endometrioma and pelvic pain were similar between both groups. The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone.Impact statementWhat is already known on this subject? Endometriosis is a frequent benign disease-producing inflammatory response with mild to severe symptoms. Although surgical removal of ectopic lesions is the first-line intervention, the recurrence rate of the disease is high. Thus this study aimed to compare the effectiveness of N-acetylcysteine plus low dose contraceptive with low dose contraceptive alone.What do the results of this study add? The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone.What are the implications of these findings for clinical practice and/or further research? It is recommended to increase the duration of drug administration in future studies.}, } @article {pmid34993544, year = {2022}, author = {Chen, CA and Chang, JM and Chen, HC and Chang, EE}, title = {Generation of endoplasmic reticulum stress-dependent reactive oxygen species mediates TGF-β1-induced podocyte migration.}, journal = {Journal of biochemistry}, volume = {171}, number = {3}, pages = {305-314}, doi = {10.1093/jb/mvab128}, pmid = {34993544}, issn = {1756-2651}, mesh = {Apoptosis ; Cell Movement ; *Endoplasmic Reticulum Stress ; *Podocytes/metabolism ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/metabolism/pharmacology ; }, abstract = {Podocyte migration results in proteinuria and glomerulonephropathy. Transforming growth factor-β1 (TGF-β1), endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) can mediate podocyte migration; however, the crosstalk between them is unclear. This study determined the relationships between these factors. ER stress biomarkers (GRP78, p-eIF2α or CHOP), intracellular ROS generation, integrin-β3 and cell adhesion and migration were studied in a treatment of experiment using TGF-β1 with and without the ER stress inhibitors: 4-phenylbutyric acid (4-PBA, a chemical chaperone), salubrinal (an eIF2α dephosphorylation inhibitor) and N-acetylcysteine (NAC, an antioxidant). ER stress biomarkers (p-eIF2α/eIF2α and GRP78), ROS generation and intergrin-β3 expression increased after TGF-β1 treatment. NAC down-regulated the expression of GRP78 after TGF-β1 treatment. 4-PBA attenuated TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation and intergrin-β3 expression. However, salubrinal did not inhibit TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation or integrin-β3 expression. NAC abrogated TGF-β1-induced integrin-β3 expression. At 24 h after treatment with TGF-β1, podocyte adhesion and migration increased. Furthermore, NAC, 4-PBA and an anti-interin-β3 antibody attenuated TGF-β1-induced podocyte adhesion and migration. This study demonstrated that TGF-β1-induced ER stress potentiates the generation of intracellular ROS to a high degree through the PERK/eIF2α/CHOP pathway. This intracellular ROS then mediates integrin-β3 expression, which regulates podocyte migration.}, } @article {pmid34987729, year = {2021}, author = {Khalili, F and Khosravi, MB and Sahmeddini, MA and Eghbal, MH and Kazemi, K and Nikeghbalian, S and Ghazanfar Tehran, S and Khosravi, B}, title = {The Effect of Perioperative N-acetylcysteine on the Short and Long Term Outcomes in Pediatrics Undergoing Living-Donor Liver Transplantation.}, journal = {International journal of organ transplantation medicine}, volume = {12}, number = {1}, pages = {12-20}, pmid = {34987729}, issn = {2008-6482}, abstract = {BACKGROUND: Ischemia-reperfusion injury during transplantation can cause post-operative graft dysfunction.

OBJECTIVE: To assess the efficacy of N-acetylcysteine in preventing hepatic ischemia-reperfusion injury and post-transplant outcomes.

METHODS: In this retrospective study on pediatrics undergoing living-donor (from one of their parents) liver transplantation, N-acetylcysteine was administered to one group (n=20) after induction in the donors until graft harvest, and in the recipients during implantation, which was maintained for 19 hours. The second group (n=20) did not receive NAC. Early allograft dysfunction was determined in the presence of alanine aminotransferase or aspartate aminotransferase ≥2000 IU/L and bilirubin ≥10 mg/dL within the first 7 days, and an international normalized ratio ≥1.6 on day 7. Data were collected from a retrospectively maintained database.

RESULTS: The incidence of post-reperfusion syndrome was lower in N-acetylcysteine group compared with the other group (5% vs. 30%, p=0.037). Serum creatinine level was significantly (p=0.04) different in the N-acetylcysteine group during the second post-operative week (0.14 vs. 0.15 mg/dL). There was no significant difference in the incidence of early allograft dysfunction (21% vs. 14%, p=0.327), and the survival rate (p=0.409).

CONCLUSION: Peri-operative infusion of N-acetylcysteine in both donor and recipient would effectively prevent post-reperfusion syndrome and renal insufficiency. However, it might not affect the early allograft dysfunction, ICU stay, and mortality. NAC increases the chance of re-operation due to non-surgical bleeding in the first post-operative day.}, } @article {pmid34984698, year = {2022}, author = {Huang, G and Zhu, Y and Yong, C and Tian, F and Liu, L and Wu, Q and Shu, Y and Yao, M and Tang, C and Wang, X and Chen, W and Zhou, E}, title = {Artemisia capillaris Thunb. water extract attenuates adriamycin-induced renal injury by regulating apoptosis through the ROS/MAPK axis.}, journal = {Journal of food biochemistry}, volume = {46}, number = {2}, pages = {e14065}, doi = {10.1111/jfbc.14065}, pmid = {34984698}, issn = {1745-4514}, mesh = {Animals ; Apoptosis ; *Artemisia ; *Doxorubicin/adverse effects ; Kidney/physiology ; Plant Extracts/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Renal Insufficiency/chemically induced/drug therapy ; Water ; }, abstract = {Artemisia capillaris Thunb. is widely used in the treatment of kidney diseases, but the underlying mechanism remain elusive. Therefore, this study aimed to elucidate the mechanism of Artemisia capillaris Thunb. in alleviating renal injury. And renoprotective effects of freeze-dried powder of Artemisia capillaris Thunb. water extract (WAC) were assessed using adriamycin (ADR)-induced renal injury to the NRK-52E cells and ADR-induced renal injury Sprague-Dawley rats (SD rats) models. The results show that WAC could alleviate ADR-induced renal injury in SD rats and the NRK-52E cell line, improved renal function (BUN 9.73 ± 0.35 vs 7.13 ± 0.15, SCR 80.60 ± 1.68 vs 60.50 ± 1.42, ACR 11.50 ± 0.50 vs 8.526 ± 0.15) or cell viability (IC50 = 1.08 µg/ml (ADR), cell viability increase 36.38% ± 6.74% (added 4 mg/ml WAC)), and reduced the apoptosis. Moreover, WAC inhibited the MAPK signal transduction, increased the expression of superoxide dismutase 1 (SOD1), and decreased the production of ROS. The treatment of N-acetylcysteine (NAC, antioxidant) in vitro showed that NAC inhibited apoptosis and alleviated renal injury by inhibiting oxidative stress and reducing the phosphorylation of proteins related to the MAPK signaling pathway. Therefore, these results suggested that WAC can alleviate ADR-induced renal injury and apoptosis by regulating the ROS/MAPK axis and has potential to be used as a renoprotective drug. PRACTICAL APPLICATIONS: Artemisia capillaris Thunb., which is a medicinal and edible plant, is widely used to treat kidney diseases in traditional Chinese medicine. The present research examined the renal protective effect of Artemisia capillaris Thunb. The results show that Artemisia capillaris Thunb. can effectively reduce renal tubular cell apoptosis through the ROS/MAPK axis in vivo and in vitro. In general, Artemisia capillaris Thunb. can be used as a potential herb to attenuate renal injury and further research can be conducted to explore its renoprotective mechanisms.}, } @article {pmid34982438, year = {2021}, author = {Spartalis, M and Siasos, G and Mastrogeorgiou, M and Spartalis, E and Kaminiotis, VV and Mylonas, KS and Kapelouzou, A and Kontogiannis, C and Doulamis, IP and Toutouzas, K and Nikiteas, N and Iliopoulos, DC}, title = {The effect of per os colchicine administration in combination with fenofibrate and N-acetylcysteine on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits.}, journal = {European review for medical and pharmacological sciences}, volume = {25}, number = {24}, pages = {7765-7776}, doi = {10.26355/eurrev_202112_27623}, pmid = {34982438}, issn = {2284-0729}, mesh = {Acetylcysteine/*administration & dosage ; Administration, Oral ; Animals ; Anti-Inflammatory Agents/*administration & dosage ; Aorta/drug effects/pathology ; Atherosclerosis/blood/*drug therapy/pathology ; C-Reactive Protein/analysis ; Cholesterol/administration & dosage ; Colchicine/*administration & dosage ; Drug Therapy, Combination ; Fenofibrate/*administration & dosage ; Hypolipidemic Agents/*administration & dosage ; Interleukin-6/antagonists & inhibitors/blood ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors ; Rabbits ; Triglycerides/blood ; }, abstract = {OBJECTIVE: Atherosclerosis is a chronic inflammatory disease promoted by pro-inflammatory cytokines produced by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP 3) inflammasome. Colchicine is an anti-inflammatory agent that inhibits inflammasome's action and stabilizes atherosclerotic lesions. N-acetylcysteine (NAC) reduces low-density lipoprotein (LDL) oxidation, metalloproteinase levels, and foam cell count and volume. Fenofibrate also has antioxidant, anti-inflammatory, and anticoagulant properties while also having a beneficial effect on the vasomotor function of the endothelium. The purpose of this study is to investigate the effect of per os colchicine administration in combination with fenofibrate and NAC on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits.

MATERIALS AND METHODS: Twenty-eight male, 2 months old New Zealand White rabbits were separated into four groups and were fed with different types of diet for 7 weeks: standard, cholesterol 1% w/w, cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 250 mg/kg body weight/day fenofibrate, and cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 15 mg/kg body weight/day NAC. Blood samples were drawn from all animals. Lipid profiles were assessed, and interleukin 6 (IL-6) measurements were performed using an enzyme-linked immunosorbent assay (ELISA) kit. Histologic examination was performed on aorta specimens stained with eosin and hematoxylin. Aortic intimal thickness was evaluated using image analysis.

RESULTS: Colchicine administration in combination with fenofibrate or NAC statistically significantly reduced the extent of atherosclerotic lesions in aortic preparations. Co-administration of colchicine with NAC has a stronger anti-atherogenic effect than the colchicine plus fenofibrate regimen. Triglerycide levels were decreased in the colchicine plus fenofibrate group and the colchicine plus NAC group at the end of the experiment (p < 0.05), whereas the Cholesterol group had increased levels. A favorable significant lower concentration of IL-6 was detected in the colchicine plus NAC group vs. the other groups.

CONCLUSIONS: In an experimental rabbit model, it appears that colchicine statistically significantly reduces the development of atherosclerosis of the aorta, especially in combination with NAC. Colchicine, as an NLRP3 inflammasome inhibitor, and NAC, as an agent that directly targets IL-6 signaling, can reduce the inflammatory risk. Fenofibrate enhances the attenuating role of colchicine on triglyceride levels. Clinical studies should investigate whether similar effects can be observed in humans.}, } @article {pmid34981600, year = {2022}, author = {Philippot, Q and Kannengiesser, C and Debray, MP and Gauvain, C and Ba, I and Vieri, M and Gondouin, A and Naccache, JM and Reynaud-Gaubert, M and Uzunhan, Y and Bondue, B and Israël-Biet, D and Dieudé, P and Fourrage, C and Lainey, E and Manali, E and Papiris, S and Wemeau, L and Hirschi, S and Mal, H and Nunes, H and Schlemmer, F and Blanchard, E and Beier, F and Cottin, V and Crestani, B and Borie, R and , }, title = {Interstitial lung diseases associated with mutations of poly(A)-specific ribonuclease: A multicentre retrospective study.}, journal = {Respirology (Carlton, Vic.)}, volume = {27}, number = {3}, pages = {226-235}, doi = {10.1111/resp.14195}, pmid = {34981600}, issn = {1440-1843}, mesh = {Exoribonucleases ; Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; *Lung Diseases, Interstitial/genetics ; Mutation/genetics ; Retrospective Studies ; }, abstract = {BACKGROUND AND OBJECTIVE: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations.

METHODS: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network.

RESULTS: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation.

CONCLUSION: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed.}, } @article {pmid34981453, year = {2022}, author = {Yamasaki, T and Okada, M and Hiraishi, A and Mori, W and Zhang, Y and Fujinaga, M and Wakizaka, H and Kurihara, Y and Nengaki, N and Zhang, MR}, title = {Upregulation of Striatal Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Rats with Excessive Glutamate Release Induced by N-Acetylcysteine.}, journal = {Neurotoxicity research}, volume = {40}, number = {1}, pages = {26-35}, pmid = {34981453}, issn = {1476-3524}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Glutamic Acid/metabolism ; Rats ; *Receptors, Metabotropic Glutamate ; Up-Regulation ; }, abstract = {The aim of this study is to investigate the changes in expression of metabotropic glutamate (Glu) receptor subtype 1 (mGluR1), a key molecule involved in neuroexcitetoxicity, during excessive Glu release in the brain by PET imaging. An animal model of excessive Glu release in the brain was produced by intraperitoneally implanting an Alzet osmotic pump containing N-acetylcysteine (NAC), an activator of the cysteine/Glu antiporter, into the abdomen of rats. Basal Glu concentration in the brain was measured by microdialysis, which showed that basal Glu concentration in NAC-treated rats (0.31 µM) was higher than that in saline-treated rats (0.17 µM) at day 7 after the implantation of the osmotic pump. Similarly, PET studies with [[11]C]ITDM, a useful radioligand for mGluR1 imaging exhibited that the striatal binding potential (BPND) of [[11]C]ITDM for mGluR1 in PET assessments was increased in NAC-treated animals at day 7 after implantation (2.30) compared with before implantation (1.92). The dynamic changes in striatal BPND during the experimental period were highly correlated with basal Glu concentration. In conclusion, density of mGluR1 is rapidly upregulated by increases in basal Glu concentration, suggesting that mGluR1 might to be a potential biomarker of abnormal conditions in the brain.}, } @article {pmid34979873, year = {2022}, author = {El-Shal, LM and El-Star, AAA and Azmy, AM and Elnegris, HM}, title = {The possible protective role of N-acetyl cysteine on duodenal mucosa of high fat diet and orlistat treated adult male albino rats and the active role of tumor necrosis factor α (TNFα) and Interleukin 6 (IL6) (histological and biochemical study).}, journal = {Ultrastructural pathology}, volume = {46}, number = {1}, pages = {18-36}, doi = {10.1080/01913123.2021.2007194}, pmid = {34979873}, issn = {1521-0758}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Diet, High-Fat/adverse effects ; Interleukin-6 ; Male ; Mucous Membrane/drug effects ; Orlistat/adverse effects ; Oxidative Stress ; Rats ; Tumor Necrosis Factor-alpha ; }, abstract = {BACKGROUND: Obesity is a major universal health issue linked to a majority of illness.

AIM: To evaluate the histological and biochemical changes occurred in the duodenal mucosa of high fat diet HFD and orlistat fed rats and to assess the possible protective role of N-acetyl cysteine NAC supplementation.

MATERIAL AND METHOD: Sixty male albino rats weighing 180-200 g were classified randomly into control group I and three experimental groups (HFD group II, HFD + orlistat group III, and HFD + orlistat + NAC group IV). All experimental groups received HFD alone/and treatment for 6 weeks. Group III received orlistat (32 mg/kg/day) before meals and group IV received the same regimen as group III in addition to NAC (230 mg/kg/day) after meals. After completion of the experiment, duodenal sections were processed for histological examination, oxidative stress parameters, and semiqualitative real time PCR for proinflammatory mediators TNFα and IL6 evaluation. Also, plasma lipid parameters were assessed and morphometric duodenal results were analyzed statistically.

RESULTS: By histological examination of HFD and (HFD + orlistat) groups, we found severe to moderate duodenal structural disturbances, increased goblet cells, collagen fibers, and BAX and iNOS immunostaining. By Biochemical examination, both groups showed increased proinflammatory markers level (TNFα and IL6) with decreased all antioxidant parameters and increased MDA. Moreover, NAC treatment in group IV significantly reduced all structural changes, levels of proinflammatory mediators and increased all antioxidant parameter levels and decreased MDA.

CONCLUSION: All findings elucidated that NAC could be accounted to be a useful drug for protection of duodenal mucosa of HFD and orlistat treated animals.}, } @article {pmid34979328, year = {2022}, author = {Qi, J and Hu, S and He, X and Pan, T and Yang, L and Zhang, R and Tang, Y and Wu, D and Han, Y}, title = {N-Acetyl-L-Cysteine Potentially Inhibits Complement Activation in Transplantation-Associated Thrombotic Microangiopathy.}, journal = {Transplantation and cellular therapy}, volume = {28}, number = {4}, pages = {216.e1-216.e5}, doi = {10.1016/j.jtct.2021.12.018}, pmid = {34979328}, issn = {2666-6367}, mesh = {Acetylcysteine/pharmacology ; Adult ; Complement Activation ; Female ; *Hematopoietic Stem Cell Transplantation ; Humans ; *Thrombotic Microangiopathies/drug therapy ; Treatment Outcome ; }, abstract = {Transplant-associated thrombotic microangiopathy (TA-TMA) has a high mortality rate and lacks effective treatments. We searched the GEO database and analyzed RNA-seq data and whole-genome sequencing data from patients' blood samples. We identified N-acetyl-L-cysteine (NAC) as a possible therapeutic target for TA-TMA. In vitro experiments showed that NAC reduced complement activation and VWF multimerization in HUVECs. We also treated a 36-year-old female TA-TMA patient with NAC. Hemoglobin, platelet counts, lactate dehydrogenase levels, and sC5b-9 levels and schistocytes were normalized after using NAC. It shows that NAC may be an effective drug to improve TA-TMA symptoms by inhibiting complement activation.}, } @article {pmid34978586, year = {2022}, author = {Akakpo, JY and Ramachandran, A and Curry, SC and Rumack, BH and Jaeschke, H}, title = {Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose.}, journal = {Archives of toxicology}, volume = {96}, number = {2}, pages = {453-465}, pmid = {34978586}, issn = {1432-0738}, support = {R01 DK070195/DK/NIDDK NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; GM103549/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; DK102142/DK/NIDDK NIH HHS/United States ; DK120194/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; GM118247/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic/poisoning ; Animals ; Antidotes/*pharmacology ; Chemical and Drug Induced Liver Injury/etiology/*prevention & control ; Drug Overdose ; Fomepizole/pharmacology ; Hepatocytes/drug effects/pathology ; Humans ; Mice ; }, abstract = {Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.}, } @article {pmid34976966, year = {2021}, author = {Li, X and Xiong, F and Wang, S and Zhang, Z and Dai, J and Chen, H and Wang, J and Wang, Q and Yuan, H}, title = {N-Acetyl-Cysteine-Loaded Biomimetic Nanofibrous Scaffold for Osteogenesis of Induced-Pluripotent-Stem-Cell-Derived Mesenchymal Stem Cells and Bone Regeneration.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {9}, number = {}, pages = {767641}, pmid = {34976966}, issn = {2296-4185}, abstract = {To regenerate bone tissues, we investigated the osteogenic differentiation of induced-pluripotent-stem-cell-derived mesenchymal stem cells (iPSC-MSCs) and bone regeneration capacities using N-acetyl cysteine (NAC)-loaded biomimetic nanofibers of hydroxyapatite/silk fibroin (HAp/SF). The addition of HAp and NAC decreased the diameters of the electrospun fibers and enhanced the mechanical properties of the silk scaffold. The release kinetic curve indicated that NAC was released from NAC/HAp/SF nanofibers in a biphasic pattern, with an initial burst release stage and a later sustained release stage. This pattern of release of NAC encapsulated on the NAC/HAp/SF scaffolds prolonged the release of high concentrations of NAC, thereby largely affecting the osteogenic differentiation of iPSC-MSCs and bone regeneration. Thus, a new silk electrospun scaffold was developed. HAp was used as a separate nanocarrier for recharging the NAC concentration, which demonstrated the promising potential for the use of NAC/HAp/SF for bone tissue engineering.}, } @article {pmid34976186, year = {2022}, author = {Qi, H and Zhang, X and Liu, H and Han, M and Tang, X and Qu, S and Wang, X and Yang, Y}, title = {Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells.}, journal = {Journal of Cancer}, volume = {13}, number = {1}, pages = {243-252}, pmid = {34976186}, issn = {1837-9664}, abstract = {Shikonin is a naphthoquinone pigment isolated from the root of Lithospermum erythrorhizon, which has displayed potent anti-tumor properties. However, the effects of shikonin in colorectal cancer cells have not been yet fully investigated. In this study, we demonstrated that shikonin significantly inhibited the activity of colorectal cancer cells in a time- and dose-dependent manner. The flow cytometry and western blot results indicated that shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP. The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment. The pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin. Taken together, shikonin could inhibit proliferation of the colorectal cancer cell through the activation of ROS mediated-ER stress. The in vivo results showed that shikonin effectively inhibited tumor growth in the HCT-116 and HCT-15 xenograft models. In conclusion, shikonin inhibited the proliferation of colorectal cancer cells in vitro and in vivo and warrants future investigation.}, } @article {pmid34972717, year = {2022}, author = {Lee, EJ and Park, SJ and Lee, C and Yim, GW and Kim, JW and Kim, HS}, title = {Hypoxia-induced Maspin Expression Affects the Prognosis of Ovarian Clear Cell Carcinoma.}, journal = {In vivo (Athens, Greece)}, volume = {36}, number = {1}, pages = {212-220}, pmid = {34972717}, issn = {1791-7549}, mesh = {*Adenocarcinoma, Clear Cell/genetics ; Female ; Humans ; Hypoxia/genetics ; *Ovarian Neoplasms/drug therapy/genetics ; Prognosis ; *Serpins/genetics ; }, abstract = {BACKGROUND/AIM: To investigate the role of the expression of hypoxia-related genes on the prognosis of ovarian clear cell carcinoma (OCCC).

MATERIALS AND METHODS: Basal mRNA levels of eight hypoxia-related genes were compared. Cell viability was assayed after treating ES-2 cells under hypoxic conditions. The mRNA and protein levels were evaluated after the induction of hypoxia and administration of increased doses of N-acetylcysteine (NAC). Finally, the prognostic role of their expression levels was evaluated in 61 patients with OCCC.

RESULTS: The mRNA and protein levels of maspin increased gradually with the induction of hypoxia. Maspin protein expression decreased after treatment with paclitaxel and NAC. High expression of maspin was related to poor progression-free and overall survival in patients with OCCC (adjusted hazard ratios, 3.97 and 7.47; 95% confidence intervals=1.34-11.81, and 1.98-28.13).

CONCLUSION: High expression of maspin induced by hypoxia might be associated with poor prognosis of OCCC.}, } @article {pmid34970573, year = {2021}, author = {Zhou, X and Dai, Y and Zhai, Z and Hong, J}, title = {WAY-100635 Alleviates Corneal Lesions Through 5-HT1A Receptor-ROS-Autophagy Axis in Dry Eye.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {799949}, pmid = {34970573}, issn = {2296-858X}, abstract = {Purpose: To explore whether 5-HT1A receptors are involved in the dry eye disease (DED) mouse model and reveal its underlying mechanism. Methods: A C57BL/6J mouse DED model was established via the administration of 0.2% benzalkonium chloride twice a day for 14 days. Corneal fluorescein sodium staining score and Schirmer I test were checked before, and on days 7, 14, and 21 after treatment. The experiment was randomly divided into control, DED, 5-HT1A receptor agonist with or without N-acetylcysteine (NAC) and 5-HT1A receptor antagonist with or without NAC groups. The mRNA expression of inflammatory cytokines was measured by reverse transcription-quantitative polymerase chain reaction. Cellular reactive oxygen species (ROS) were detected by 2', 7'-dichlorodihydrofluorescein diacetate assays. Western blot analysis was used to measure the expression levels of autophagic proteins microtubule-associated protein 1 light chain 3 (LC3B-I/II) and autophagy-related gene 5 (ATG5). Results: 5-HT1A receptor agonist (8-OH-DPAT) increased corneal fluorescein sodium staining spots and 5-HT1A receptor antagonist (WAY-100635) decreased them. Treatment with 8-OH-DPAT was associated with the gene expression of more inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) compared with treatment with WAY-100635. An increased expression of LC3B-I/II and ATG5 was observed in corneal epithelial cells in the mouse model of DED. 8-OH-DPAT significantly enhanced the expression of LC3B-I/II and ATG5 by disrupting ROS levels. WAY-100635 alleviates autophagy by inhibiting ROS production. Conclusion: Excessive ROS release through 8-OH-DPAT induction can lead to impaired autophagy and increased inflammatory response in DED. WAY-100635 reduces corneal epithelial defects and inflammation in DED, as well as alleviates autophagy by inhibiting ROS production. The activation of the 5-HT1A receptor-ROS-autophagy axis is critically involved in DED development.}, } @article {pmid34965485, year = {2022}, author = {Wen, E and Xin, G and Su, W and Li, S and Zhang, Y and Dong, Y and Yang, X and Wan, C and Chen, Z and Yu, X and Zhang, K and Niu, H and Huang, W}, title = {Activation of TLR4 induces severe acute pancreatitis-associated spleen injury via ROS-disrupted mitophagy pathway.}, journal = {Molecular immunology}, volume = {142}, number = {}, pages = {63-75}, doi = {10.1016/j.molimm.2021.12.012}, pmid = {34965485}, issn = {1872-9142}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/physiology ; Immunologic Factors/therapeutic use ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mitochondria/pathology ; Mitophagy/*physiology ; Pancreas/pathology ; Pancreatitis/chemically induced/*pathology ; Phosphatidylinositol 3-Kinase/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/physiology ; Spleen/injuries/*pathology ; TOR Serine-Threonine Kinases/metabolism ; Taurocholic Acid/toxicity ; Toll-Like Receptor 4/genetics/*metabolism ; Tuftsin/therapeutic use ; }, abstract = {Severe acute pancreatitis (SAP) is complicated by systemic inflammatory response syndrome and multiple organ dysfunction, the disease will eventually result in death in almost half of the case. The spleen, as the largest immune organ adjacent to the pancreas, is prone to damage in SAP, thereby aggravating the damage of other organs and increasing mortality. However, to date, the research on the mechanism and treatment of spleen injury caused by SAP is still in its infancy. Herein, we investigated the mechanism of spleen injury, and explored the application potential of tuftsin for relieving spleen damage in SAP mice. Firstly, SAP mice model was constructed via the retrograde infusion of 3.5 % sodium taurocholate into the biliopancreatic duct. Then, we proved that the up-regulation of Toll-like receptor 4 (TLR4) in spleen would lead to the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction under SAP conditions. The splenic ROS and mitochondrial dysfunction could be improved by N-acetylcysteine (NAC) treatment or knocking out TLR4 in SAP mice. Meanwhile, we found that NAC treatment could also improve the autophagy of spleen tissue, suggesting that splenic ROS may affect impaired autophagy, causing the accumulation of damaged mitochondria, aggravating spleen damage. Furthermore, we verified the mechanism of spleen injury is caused by splenic ROS affecting PI3K/p-AKT/mTOR pathway-mediated autophagy. In addition, we detected the spleen injury caused by SAP could decrease the concentration of tuftsin in the serum of mice. Whereas, exogenous supplementation of tuftsin ameliorated the pathological damage, ROS accumulation, impaired autophagy, inflammation expression and apoptosis in damaged spleen. In summary, we verified the new mechanism of SAP-caused spleen damage that TLR4-induced ROS provoked mitophagy impairment and mitochondrial dysfunction in spleen via PI3K/p-AKT mTOR signaling, and the application potential of tuftsin in treating spleen injury, which might expand novel ideas and methods for the treatment of pancreatitis.}, } @article {pmid34964212, year = {2022}, author = {Bhardwaj, JK and Kumar, V and Saraf, P and Panchal, H and Rathee, V and Sachdeva, SN}, title = {Efficacy of N-acetyl- l-cysteine against glyphosate induced oxidative stress and apoptosis in testicular germ cells preventing infertility.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {4}, pages = {e22979}, doi = {10.1002/jbt.22979}, pmid = {34964212}, issn = {1099-0461}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Apoptosis ; Germ Cells/metabolism ; Glycine/analogs & derivatives ; Goats/metabolism ; *Infertility/metabolism ; Male ; Oxidative Stress ; Testis/metabolism ; Glyphosate ; }, abstract = {The present era's demand for continuous pesticides' use to increase the agriculture outcome, has caused numerous health effects among which mammalian infertility, owing to reproductive toxicity, is serious. Thus, the present study emphasizes upon glyphosate (GLY) induced toxicity and mitigating effects of N-acetyl cysteine (NAC) in testicular cells of caprine by using various cytotoxic and biochemical parameters. GLY was found to induce several apoptotic attributes such as pyknotic nuclei, tubular degeneration, increased vacuolization, and so on, in testicular cells. GLY also decreased the cell viability and increased the incidence of apoptosis in testicular cells in a dose- and time-dependent manner as revealed by MTT assay and Fluorescence (ethidium bromide/acridine orange) assay, respectively. It also increased the level of oxidative stress as evident with an increase in lipid peroxidation and decline in antioxidant power along with the decreased enzymatic activity of different antioxidant enzymes (SOD, CAT, and GST). However, NAC supplementation showed antagonistic results in GLY-treated testicular tissues with maximum amelioration at the highest dose, thereby decreasing GLY-mediated apoptosis rate and oxidative stress. Maximum amelioration was reported at 10 mM NAC concentration. Reduced GLY toxicity due to NAC will prove NAC to be an excellent approach for dealing with male reproductive toxicity at the cellular level, benefiting the mammalian reproductive status.}, } @article {pmid34964128, year = {2022}, author = {Bai, X and Lian, Y and Hu, C and Yang, S and Pei, B and Yao, M and Zhu, X and Shang, L and Li, Z}, title = {Cyanidin-3-glucoside protects against high glucose-induced injury in human nucleus pulposus cells by regulating the Nrf2/HO-1 signaling.}, journal = {Journal of applied toxicology : JAT}, volume = {42}, number = {7}, pages = {1137-1145}, doi = {10.1002/jat.4281}, pmid = {34964128}, issn = {1099-1263}, support = {2041ZF092//Baoding Science and Technology Plan Project/ ; }, mesh = {Aggrecans/metabolism/pharmacology ; *Anthocyanins/metabolism/pharmacology ; Apoptosis ; Caspase 3/metabolism ; Glucose/metabolism/toxicity ; Humans ; Matrix Metalloproteinase 13/metabolism/pharmacology ; Matrix Metalloproteinase 3/metabolism/pharmacology ; NF-E2-Related Factor 2/genetics/metabolism ; *Nucleus Pulposus/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Cyanidin-3-glucoside (C3G) is a well-known natural anthocyanin with antioxidant and anti-inflammatory properties. In this study, we explored the role and action mechanism of C3G in high glucose (HG)-induced damage of human nucleus pulposus cells (HNPCs). Cell viability was assessed by CCK-8 assay. TUNEL assay was performed for detecting apoptotic rate. Western blot was performed to determine the expression levels of cl-caspase-3, caspase-3, Bax, Bim, collagen II, aggrecan, MMP-3, MMP-13, and ADAMTS5. Reactive oxygen species (ROS) generation was analyzed using DCFH-DA staining. The Nrf2 was knocked down or overexpressed in HNPCs through transfection with si-Nrf2 or pcDNA3.0-Nrf2. C3G treatment (12.5, 25, and 50 μM) improved cell viability of HNPCs under HG condition. HG-induced cell apoptosis of HNPCs was attenuated by C3G with decreased apoptotic rate and relative levels of cl-caspase-3/caspase-3, Bax, and Bim. C3G treatment caused significant increase in expression levels of collagen II and aggrecan and decrease in the relative levels of MMP-3, MMP-13, and ADAMTS5. After treatment with C3G, ROS generation in HNPCs was markedly reduced. Treatment with N-acetylcysteine (NAC) reversed HG-induced cell apoptosis and extracellular matrix (ECM) degradation. C3G treatment induced the expression of Nrf2 and HO-1 in HG-induced HNPCs. Moreover, knockdown of Nrf2 reversed the inhibitory effect of C3G on ROS production. Summarily, C3G exerted a protective effect on ROS-mediated cellular damage in HNPCs under HG condition, which was attributed to the induction of the Nrf2/HO-1 signaling pathway.}, } @article {pmid34958912, year = {2022}, author = {Virel, A and Johansson, J and Axelsson, J and Ericsson, M and Laterveer, R and Ögren, M and Orädd, G and Jakobson Mo, S and Af Bjerkén, S}, title = {N-acetylcysteine decreases dopamine transporter availability in the non-lesioned striatum of the 6-OHDA hemiparkinsonian rat.}, journal = {Neuroscience letters}, volume = {770}, number = {}, pages = {136420}, doi = {10.1016/j.neulet.2021.136420}, pmid = {34958912}, issn = {1872-7972}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Corpus Striatum/drug effects/*metabolism ; Dopamine Plasma Membrane Transport Proteins/*metabolism ; Female ; Nortropanes/pharmacokinetics ; Oxidopamine/toxicity ; Parkinson Disease/diagnostic imaging/etiology/*metabolism ; Positron-Emission Tomography ; Radiopharmaceuticals/pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; }, abstract = {This study aimed to explore the beneficial effects of the antioxidant N-acetylcysteine (NAC) on the degenerated dopamine system. The short- and long-term regulatory mechanisms of NAC on the 6-OHDA hemiparkinsonian rat model were longitudinally investigated by performing positron emission tomography (PET) imaging using the specific dopamine transporter (DAT) radioligand [[18]F]FE-PE2I. The results demonstrate that after a unilateral dopamine insult NAC has a strong influence on the non-lesioned hemisphere by decreasing the levels of DAT in the striatum early after the lesion. We interpret this early and short-term decrease of DAT in the healthy striatum of NAC-treated animals as a beneficial compensatory effect induced by NAC.}, } @article {pmid34958803, year = {2022}, author = {Liu, D and Cheng, Y and Chen, J and Mei, X and Tang, Z and Cao, X and Liu, J}, title = {Exploring the molecular mechanisms of the inhibition of acrolein-induced BEAS-2B cytotoxicity by luteolin using network pharmacology and cell biology technology.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {160}, number = {}, pages = {112779}, doi = {10.1016/j.fct.2021.112779}, pmid = {34958803}, issn = {1873-6351}, mesh = {Acrolein/*toxicity ; Air Pollutants/*toxicity ; Apoptosis/drug effects ; Bronchi/cytology/drug effects/metabolism ; DNA Damage/drug effects ; Epithelial Cells/cytology/*drug effects/metabolism ; Glutathione/metabolism ; Humans ; Luteolin/*pharmacology ; Network Pharmacology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Acrolein is a highly reactive unsaturated hazardous air pollutant, which is extremely irritating to the respiratory tract. Luteolin, an active flavonoid compound, possesses multiple biological activities. The purpose of this study was to evaluate the mechanism of the inhibition of acrolein-induced human bronchial epithelial (BEAS-2B) cells cytotoxicity by luteolin using network pharmacology and cell biology technology. Firstly, network pharmacology results indicated that oxidative stress processes might play an important role in luteolin inhibiting lung injury. Next, it was verified at the cellular level. Reactive oxygen species (ROS) generation increased, glutathione (GSH) level decreased after exposure to acrolein. MAPK signaling pathways were activated, which activated downstream IκBα/NF-κB signaling pathways. Meanwhile, acrolein caused oxidative DNA damage and double-strand breaks, induced DNA damage response (DDR) and apoptosis. These adverse effects were significantly reversed by luteolin, which inhibited the activation of MAPK/IκBα/NF-κB and DDR pathways, and reduced the ratio of Bax/Bcl-2. Moreover, luteolin also had a similar effect to antioxidant N-acetyl cysteine (NAC) in the regulation of signaling transduction mechanisms, which indicated that the regulation of oxidative stress played an important role in the process. These results provide an experimental basis for elucidating the molecular mechanisms of the inhibition of acrolein-induced BEAS-2B cytotoxicity with luteolin.}, } @article {pmid34957591, year = {2023}, author = {Bateman, DN}, title = {Large paracetamol overdose-Higher dose acetylcysteine is required.}, journal = {British journal of clinical pharmacology}, volume = {89}, number = {1}, pages = {34-38}, doi = {10.1111/bcp.15201}, pmid = {34957591}, issn = {1365-2125}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Acetaminophen ; Antidotes/therapeutic use ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury ; *Drug-Related Side Effects and Adverse Reactions ; *Analgesics, Non-Narcotic ; }, abstract = {Paracetamol poisoning continues to be a worldwide problem and, despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from high doses of paracetamol, even in those receiving prompt NAC therapy, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.}, } @article {pmid34954677, year = {2022}, author = {Zhang, Y and Yan, M and Kuang, S and Lou, Y and Wu, S and Li, Y and Wang, Z and Mao, H}, title = {Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO-Y4: Involvement of ROS-mediated mTOR/ULK1 pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {230}, number = {}, pages = {113119}, doi = {10.1016/j.ecoenv.2021.113119}, pmid = {34954677}, issn = {1090-2414}, abstract = {Bisphenol A (BPA) is a widely environmental endocrine disruptor. The accumulated BPA in humans is toxic to osteoblasts and osteoclasts, but few studies focused on the effects of BPA on osteocytes, the most abundant bone cell type, contributing to the development and metabolism of bone. Here, we reported that BPA (50, 100, 200 μmol/L) inhibited the cell viability of osteocytes MLO-Y4, promoted G0/G1 phase arrest and apoptosis in a dose-dependent manner. BPA treatment significantly increased the levels of autophagy-regulated proteins including Beclin-1 and LC3-II along with the decrease of p62, accompanied by the elevation of autophagy flux and the accumulation of acidic vacuoles, which was blocked by the autophagy inhibitor bafilomycin A1 (BafA1). Furthermore, BPA significantly inhibited the mammalian target of rapamycin (mTOR) and activated Unc-51 like autophagy activating kinase 1 (ULK1) signaling, leading to the decreased p-mTOR/mTOR ratio and the increased p-ULK1/ULK1 ratio. The mTOR activator MHY1485 (MHY) or the ULK1 inhibitor SBI-0206965 (SBI) prevented autophagy and enhanced apoptosis caused by BPA, respectively. In addition, BPA increased the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased antioxidant enzymes nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels, resulting in oxidative stress. The ROS scavenger N-acetylcysteine (NAC) attenuated BPA-induced the mTOR/ULK1 pathway activation, apoptosis and autophagy. Collectively, ROS-mediated mTOR/ULK1 signaling is involved in BPA-induced apoptosis and autophagy in osteocytes MLO-Y4. Our data first provide in vitro evidence that apoptosis and autophagy as cellular mechanisms for the toxic effect of BPA on osteocytes, thereby advancing our understanding of the potential role of osteocytes in the adverse effect of BPA on bone health.}, } @article {pmid34953289, year = {2022}, author = {Manohar, S and Ding, D and Jiang, H and Li, L and Chen, GD and Kador, P and Salvi, R}, title = {Combined antioxidants and anti-inflammatory therapies fail to attenuate the early and late phases of cyclodextrin-induced cochlear damage and hearing loss.}, journal = {Hearing research}, volume = {414}, number = {}, pages = {108409}, doi = {10.1016/j.heares.2021.108409}, pmid = {34953289}, issn = {1878-5891}, support = {R01 DC014693/DC/NIDCD NIH HHS/United States ; R01 DC014452/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Cochlea ; *Cyclodextrins/pharmacology ; Hair Cells, Auditory, Outer/physiology ; *Hearing Loss/chemically induced/prevention & control ; *Neurodegenerative Diseases ; Otoacoustic Emissions, Spontaneous ; Rats ; }, abstract = {Niemann-Pick C1 (NPC1) is a fatal neurodegenerative disease caused by aberrant cholesterol metabolism. The progression of the disease can be slowed by removing excess cholesterol with high-doses of 2-hyroxypropyl-beta-cyclodextrin (HPβCD). Unfortunately, HPβCD causes hearing loss; the initial first phase involves a rapid destruction of outer hair cells (OHCs) while the second phase, occurring 4-6 weeks later, involves the destruction of inner hair cells (IHCs), pillar cells, collapse of the organ of Corti and spiral ganglion neuron degeneration. To determine whether the first and/or second phase of HPβCD-induced cochlear damage is linked, in part, to excess oxidative stress or neuroinflammation, rats were treated with a single-dose of 3000 mg/kg HPβCD alone or together with one of two combination therapies. Each combination therapy was administered from 2-days before to 6-weeks after the HPβCD treatment. Combination 1 consisted of minocycline, an antibiotic that suppresses neuroinflammation, and HK-2, a multifunctional redox modulator that suppresses oxidative stress. Combination 2 was comprised of minocycline plus N-acetyl cysteine (NAC), which upregulates glutathione, a potent antioxidant. To determine if either combination therapy could prevent HPβCD-induced hearing impairment and cochlear damage, distortion product otoacoustic emissions (DPOAE) were measured to assess OHC function and the cochlear compound action potential (CAP) was measured to assess the function of IHCs and auditory nerve fibers. Cochleograms were prepared to quantify the amount of OHC, IHC and pillar cell (PC) loss. HPβCD significantly reduced DPOAE and CAP amplitudes and caused significant OHC, IHC and OPC losses with losses greater in the high-frequency base of the cochlea than the apex. Neither minocycline + HK-2 (MIN+ HK-2) nor minocycline + NAC (MIN+NAC) prevented the loss of DPOAEs, CAPs, OHCs, IHCs or IPCs caused by HPβCD. These results suggest that oxidative stress and neuroinflammation are unlikely to play major roles in mediating the first or second phase of HPβCD-induced cochlear damage. Thus, HPβCD-induced ototoxicity must be mediated by some other unknown cell-death pathway possibly involving loss of trophic support from damaged support cells or disrupted cholesterol metabolism.}, } @article {pmid34951044, year = {2023}, author = {Thanacoody, HKR}, title = {Large paracetamol overdose - Higher dose NAC is NOT required.}, journal = {British journal of clinical pharmacology}, volume = {89}, number = {1}, pages = {39-42}, doi = {10.1111/bcp.15199}, pmid = {34951044}, issn = {1365-2125}, mesh = {Humans ; Acetaminophen ; *Analgesics, Non-Narcotic/therapeutic use ; Acetylcysteine/therapeutic use ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury ; *Drug-Related Side Effects and Adverse Reactions ; Retrospective Studies ; }, abstract = {Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30 g or 500 mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. A small study in patients with paracetamol overdoses of 40 g or more and paracetamol concentrations above the 300 mg/L nomogram line showed that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22 h may reduce the risk of hepatotoxicity (peak ALT > 1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.}, } @article {pmid34948425, year = {2021}, author = {Gutziet, O and Iluz, R and Ben Asher, H and Segal, L and Ben Zvi, D and Ginsberg, Y and Khatib, N and Zmora, O and Ross, MG and Weiner, Z and Beloosesky, R}, title = {Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948425}, issn = {1422-0067}, mesh = {Acetylcysteine/*metabolism ; Animals ; Animals, Newborn ; Antioxidants/metabolism ; Asphyxia Neonatorum/*complications ; Brain/*metabolism ; Gene Expression Regulation ; Hypoxia, Brain/etiology/metabolism/*prevention & control ; In Situ Nick-End Labeling ; *Inflammation ; Interleukin-6/genetics ; Nitric Oxide Synthase Type I/genetics ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Transcription Factor RelA/genetics ; Tumor Necrosis Factor-alpha/genetics ; }, abstract = {Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality. N-Acetyl-Cysteine (NAC) is a powerful antioxidant that acts directly as a scavenger of free radicals. We hypothesized that maternal-antenatal and offspring-postnatal NAC can protect offspring brains from hypoxic brain damage.Sixty six newborn rats were randomized into four study groups. Group 1: Control (CON) received no hypoxic intervention. Group 2: Hypoxia (HYP)-received hypoxia protocol. Group 3: Hypoxia-NAC (HYP-NAC). received hypoxia protocol and treated with NAC following each hypoxia episode. Group 4: NAC Hypoxia (NAC-HYP) treated with NAC during pregnancy, pups subject to hypoxia protocol. Each group was evaluated for: neurological function (Righting reflex), serum proinflammatory IL-6 protein levels (ELISA), brain protein levels: NF-κB p65, neuronal nitric oxide synthase (nNOS), TNF-α, and IL-6 (Western blot) and neuronal apoptosis (histology evaluation with TUNEL stain). Hypoxia significantly increased pups brain protein levels compared to controls. NAC administration to dams or offspring demonstrated lower brain NF-κB p65, nNOS, TNF-α and IL-6 protein levels compared to hypoxia alone. Hypoxia significantly increased brain apoptosis as evidenced by higher grade of brain TUNEL reaction. NAC administration to dams or offspring significantly reduce this effect. Hypoxia induced acute sensorimotor dysfunction. NAC treatment to dams significantly attenuated hypoxia-induced acute sensorimotor dysfunction. Prophylactic NAC treatment of dams during pregnancy confers long-term protection to offspring with hypoxia associated brain injury, measured by several pathways of injury and correlated markers with pathology and behavior. This implies we may consider prophylactic NAC treatment for patients at risk for hypoxia during labor.}, } @article {pmid34948343, year = {2021}, author = {Kim, B and Yoon, H and Kim, T and Lee, S}, title = {Role of Klotho as a Modulator of Oxidative Stress Associated with Ovarian Tissue Cryopreservation.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948343}, issn = {1422-0067}, support = {NRF-2016R1C1B3015250//The Korean Government/ ; Research Fund//The Catholic University of Korea/ ; }, mesh = {Animals ; Antioxidants/pharmacology ; *Cryopreservation ; Female ; Fertility Preservation/*methods ; Klotho Proteins/*metabolism ; Mice ; Mice, Inbred BALB C ; Ovary/*metabolism ; *Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {Ovarian tissue cryopreservation is the only option for preserving fertility in adult and prepubertal cancer patients who require immediate chemotherapy or do not want ovarian stimulation. However, whether ovarian tissue cryopreservation can ameliorate follicular damage and inhibit the production of reactive oxygen species in cryopreserved ovarian tissue remains unclear. Oxidative stress is caused by several factors, such as UV exposure, obesity, age, oxygen, and cryopreservation, which affect many of the physiological processes involved in reproduction, from maturation to fertilization, embryonic development, and pregnancy. Here, freezing and thawing solutions were pre-treated with N-acetylcysteine (NAC) and klotho protein upon the freezing of ovarian tissue. While both NAC and klotho protein suppressed DNA fragmentation by scavenging reactive oxygen species, NAC induced apoptosis and tissue damage in mouse ovarian tissue. Klotho protein inhibited NAC-induced apoptosis and restored cellular tissue damage, suggesting that klotho protein may be an effective antioxidant for the cryopreservation of ovarian tissue.}, } @article {pmid34948311, year = {2021}, author = {Kwon, JH and Lee, NG and Kang, AR and Song, JY and Hwang, SG and Um, HD and Kim, J and Park, JK}, title = {Radiosensitizer Effect of β-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948311}, issn = {1422-0067}, support = {505312021//National Research Foundation of Korea/ ; NRF-2021R1F1A1055981//National Research Foundation of Korea/ ; NRF-2020M2D9A2094153//National Research Foundation of Korea/ ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colorectal Neoplasms/*drug therapy/metabolism ; HCT116 Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Podophyllin/*pharmacology ; Radiation-Sensitizing Agents/*pharmacology ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays/methods ; }, abstract = {β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.}, } @article {pmid34944962, year = {2021}, author = {Tian, Y and Riquelme, MA and Tu, C and Quan, Y and Liu, X and Sun, LZ and Jiang, JX}, title = {Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth.}, journal = {Cancers}, volume = {13}, number = {24}, pages = {}, pmid = {34944962}, issn = {2072-6694}, support = {R01 CA196214/CA/NCI NIH HHS/United States ; CA196214/NH/NIH HHS/United States ; BC161273//Department of Defence/ ; AQ-1507//Welch Foundation/ ; }, abstract = {Osteocytes, the most abundant bone cell types embedded in the mineral matrix, express connexin 43 (Cx43) hemichannels that play important roles in bone remodeling and osteocyte survival. Estrogen deficiency decreases osteocytic Cx43 hemichannel activity and causes a loss in osteocytes' resistance to oxidative stress (OS). In this study, we showed that OS reduced the growth of both human (MDA-MB-231) and murine (Py8119) breast cancer cells. However, co-culturing these cells with osteocytes reduced the inhibitory effect of OS on breast cancer cells, and this effect was ablated by the inhibition of Cx43 hemichannels. Py8119 cells were intratibially implanted in the bone marrow of ovariectomized (OVX) mice to determine the role of osteocytic Cx43 hemichannels in breast cancer bone metastasis in response to OS. Two transgenic mice overexpressing dominant-negative Cx43 mutants, R76W and Δ130-136, were adopted for this study; the former inhibits gap junctions while the latter inhibits gap junctions and hemichannels. Under normal conditions, Δ130-136 mice had significantly more tumor growth in bone than that in WT and R76W mice. OVX increased tumor growth in R76W but had no significant effect on WT mice. In contrast, OVX reduced tumor growth in Δ130-136 mice. To confirm the role of OS, WT and Δ130-136 mice were administered the antioxidant N-acetyl cysteine (NAC). NAC increased tumor burden and growth in Δ130-136 mice but not in WT mice. Together, the data suggest that osteocytes and Cx43 hemichannels play pivotal roles in modulating the oxidative microenvironment and breast cancer growth in the bone.}, } @article {pmid34944701, year = {2021}, author = {Kolomaznik, M and Mikolka, P and Hanusrichterova, J and Kosutova, P and Matasova, K and Mokra, D and Calkovska, A}, title = {N-Acetylcysteine in Mechanically Ventilated Rats with Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: The Effect of Intravenous Dose on Oxidative Damage and Inflammation.}, journal = {Biomedicines}, volume = {9}, number = {12}, pages = {}, pmid = {34944701}, issn = {2227-9059}, support = {APVV-17-0250//Slovak Research and Development Agency/ ; VEGA 1/0055/19//Scientific Grant Agency of the Slovak Republic/ ; VEGA 1/0004/21//Scientific Grant Agency of the Slovak Republic/ ; }, abstract = {Treatment of acute respiratory distress syndrome (ARDS) is challenging due to its multifactorial aetiology. The benefit of antioxidant therapy was not consistently demonstrated by previous studies. We evaluated the effect of two different doses of intravenous (i.v.) N-acetylcysteine (NAC) on oxidative stress, inflammation and lung functions in the animal model of severe LPS-induced lung injury requiring mechanical ventilation. Adult Wistar rats with LPS (500 μg/kg; 2.2 mL/kg) were treated with i.v. NAC 10 mg/kg (NAC10) or 20 mg/kg (NAC20). Controls received saline. Lung functions, lung oedema, total white blood cell (WBC) count and neutrophils count in blood and bronchoalveolar lavage fluid, and tissue damage in homogenized lung were evaluated. NAC significantly improved ventilatory parameters and oxygenation, reduced lung oedema, WBC migration and alleviated oxidative stress and inflammation. NAC20 in comparison to NAC10 was more effective in reduction of oxidative damage of lipids and proteins, and inflammation almost to the baseline. In conclusion, LPS-instilled and mechanically ventilated rats may be a suitable model of ARDS to test the treatment effects at organ, systemic, cellular and molecular levels. The results together with literary data support the potential of NAC in ARDS.}, } @article {pmid34944641, year = {2021}, author = {Zhou, J and Terluk, MR and Orchard, PJ and Cloyd, JC and Kartha, RV}, title = {N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy.}, journal = {Biomedicines}, volume = {9}, number = {12}, pages = {}, pmid = {34944641}, issn = {2227-9059}, support = {Grant-in Aid of Research, Artistry and Scholarship award//University of Minnesota Office of Vice President of Research/ ; }, abstract = {The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N-acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1-100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.}, } @article {pmid34943939, year = {2021}, author = {Sønstevold, T and Engedal, N and Torgersen, ML}, title = {Perturbation of Cellular Redox Homeostasis Dictates Divergent Effects of Polybutyl Cyanoacrylate (PBCA) Nanoparticles on Autophagy.}, journal = {Cells}, volume = {10}, number = {12}, pages = {}, pmid = {34943939}, issn = {2073-4409}, support = {274574//The Research Council of Norway/ ; 198016-2018//Norwegian Cancer Society/ ; 2021088//Southern and Eastern Norway Regional Health Authority/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Autophagy/*drug effects/genetics ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Proteins/genetics ; Beclin-1/genetics ; Class III Phosphatidylinositol 3-Kinases/genetics ; *Drug Delivery Systems ; Enbucrilate/chemistry/*pharmacology ; Epithelial Cells/drug effects ; Gene Expression Regulation/drug effects ; Homeostasis/drug effects ; Humans ; Hydrogen Peroxide/metabolism/pharmacology ; MAP Kinase Kinase 4/genetics ; Nanoparticles/*chemistry ; Oxidation-Reduction/drug effects ; p38 Mitogen-Activated Protein Kinases/genetics ; }, abstract = {Nanoparticles (NPs) are used in our everyday life, including as drug delivery vehicles. However, the effects of NPs at the cellular level and their impacts on autophagy are poorly understood. Here, we demonstrate that the NP drug delivery vehicle poly(butyl cyanoacrylate) (PBCA) perturbs redox homeostasis in human epithelial cells, and that the degree of redox perturbation dictates divergent effects of PBCA on autophagy. Specifically, PBCA promoted functional autophagy at low concentrations, whereas it inhibited autophagy at high concentrations. Both effects were completely abolished by the antioxidant N-acetyl cysteine (NAC). High concentrations of PBCA inhibited MAP1LC3B/GABARAP lipidation and LC3 flux, and blocked bulk autophagic cargo flux induced by mTOR inhibition. These effects were mimicked by the redox regulator H2O2. In contrast, low concentrations of PBCA enhanced bulk autophagic cargo flux in a Vps34-, ULK1/2- and ATG13-dependent manner, yet interestingly, without an accompanying increase in LC3 lipidation or flux. PBCA activated MAP kinase signaling cascades in a redox-dependent manner, and interference with individual signaling components revealed that the autophagy-stimulating effect of PBCA required the action of the JNK and p38-MK2 pathways, whose activities converged on the pro-autophagic protein Beclin-1. Collectively, our results reveal that PBCA exerts a dual effect on autophagy depending on the severity of the NP insult and the resulting perturbation of redox homeostasis. Such a dual autophagy-modifying effect may be of general relevance for redox-perturbing NPs and have important implications in nanomedicine.}, } @article {pmid34943083, year = {2021}, author = {Raiteri, T and Zaggia, I and Reano, S and Scircoli, A and Salvadori, L and Prodam, F and Filigheddu, N}, title = {The Atrophic Effect of 1,25(OH)2 Vitamin D3 (Calcitriol) on C2C12 Myotubes Depends on Oxidative Stress.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {34943083}, issn = {2076-3921}, support = {N/A//Italian Ministry of University and Research program "Departments of Excellence 2018-2022", AGING Project - Department of Translational Medicine, Università del Piemonte Orientale./ ; }, abstract = {Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle loss, the efficacy of VD supplementation to overcome muscle wasting is debated. Investigations on the direct effects of VD metabolites on skeletal muscle using C2C12 myotubes have revealed an unexpected pro-atrophic activity of calcitriol (1,25VD), while its upstream metabolites cholecalciferol (VD3) and calcidiol (25VD) have anti-atrophic effects. Here, we investigated if the atrophic effects of 1,25VD on myotubes depend on its activity on mitochondrial metabolism. The impact of 1,25VD and its upstream metabolites VD3 and 25VD on mitochondria dynamics and the activity of C2C12 myotubes was evaluated by measuring mitochondrial content, architecture, metabolism, and reactive oxygen species (ROS) production. We found that 1,25VD induces atrophy through protein kinase C (PKC)-mediated ROS production, mainly of extramitochondrial origin. Consistent with this, cotreatment with the antioxidant N-acetylcysteine (NAC), but not with the mitochondria-specific antioxidant mitoTEMPO, was sufficient to blunt the atrophic activity of 1,25VD. In contrast, VD3 and 25VD have antioxidant properties, suggesting that the efficacy of VD supplementation might result from the balance between atrophic pro-oxidant (1,25VD) and protective antioxidant (VD3 and 25VD) metabolites.}, } @article {pmid34942984, year = {2021}, author = {Kim, TW and Ko, SG}, title = {The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {34942984}, issn = {2076-3921}, support = {2020R1A5A2019413//National Research Foundation of Korea/ ; }, abstract = {Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.}, } @article {pmid34939440, year = {2021}, author = {Alduraywish, AA}, title = {Cardiorespiratory and metabolic fitness indicators in novice volleyball trainees: effect of 1-week antioxidant supplementation with N-acetyl-cysteine/zinc/vitamin C.}, journal = {The Journal of international medical research}, volume = {49}, number = {12}, pages = {3000605211067125}, pmid = {34939440}, issn = {1473-2300}, mesh = {Acetylcysteine/pharmacology ; Angiopoietin-Like Protein 8/blood ; *Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Dietary Supplements ; Hepatocyte Growth Factor/blood ; Humans ; Insulin/blood ; Male ; *Sports Nutritional Physiological Phenomena ; *Volleyball ; Zinc/pharmacology ; }, abstract = {OBJECTIVES: This study aimed to determine the effect of 7-day dietary supplementation of N-acetylcysteine (NAC)/zinc/vitamin C on the time-to-exhaustion (TTE), the cardiorespiratory fitness (CRF) index, and metabolic indicators.

METHODS: This study enrolled volleyball student trainees (n = 18 men) who took NAC/zinc/vitamin C (750 mg/5 mg/100 mg) for 7 days at Jouf University, Saudi Arabia. The CRF index and TTE were determined. Serum concentrations of metabolic regulators (insulin, betatrophin, and hepatocyte growth factor), biomarkers of cellular damage/hypoxia, and indicators of lipid and glycemic control were measured.

RESULTS: Supplementation improved the TTE and CRF index, and lowered cytochrome c, C-reactive protein, hypoxia-inducible factor-1α (HIF-1α), total cholesterol, insulin, and glycated hemoglobin values. Before and after supplementation, the CRF index was negatively correlated with body mass index and positively correlated with the TTE. Before supplementation, the CRF index was positively correlated with betatrophin concentrations, and hepatocyte growth factor concentrations were positively correlated with betatrophin concentrations and negatively correlated with the homeostasis model assessment of insulin resistance index. After supplementation, the CRF index was negatively correlated with HIF-1α concentrations and metabolites. Additionally, the TTE was negatively correlated with HIF-1α, cytochrome c, and triacylglycerol concentrations.

CONCLUSION: Supplementation of NAC/zinc/vitamin C improves metabolic and CRF performance.}, } @article {pmid34936178, year = {2022}, author = {Cecire, J and Adams, K and Pham, H and Pang, T and Burnett, D}, title = {Pharmacological prevention of post-operative pancreatitis: systematic review and meta-analysis of randomized controlled trials on animal studies.}, journal = {ANZ journal of surgery}, volume = {92}, number = {6}, pages = {1338-1346}, doi = {10.1111/ans.17417}, pmid = {34936178}, issn = {1445-2197}, mesh = {Amylases ; Animals ; Humans ; *Interleukin-6 ; Necrosis/complications ; *Pancreatitis/etiology/prevention & control ; Postoperative Complications/etiology/prevention & control ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Postoperative pancreatic fistula (POPF) remains a significant complication of pancreatic resection with recent evidence showing a strong association between post-operative pancreatitis and subsequent development of POPF. Incidence and severity of pancreatitis following endoscopic therapy has been effectively reduced with indomethacin prophylaxis, however further agents require evaluation. We present a systematic literature review and meta-analysis of the prophylactic treatment with corticosteroids or n-acetyl cysteine (NAC) of induced pancreatitis in rodent models.

METHODS: A systematic literature search was conducted using Pubmed, Medline, Embase and Cochrane library to identify eligible randomized control trials (RCT) involving animal models that examined NAC or corticosteroids. The primary outcome was the subsequent effect on serum amylase and IL-6 and the histopathological markers of severity such as pancreatic oedema and necrosis.

RESULTS: Four RCTs (n = 178) met inclusion criteria examining NAC and eight RCTs (n = 546) examining corticosteroid agents (dexamethasone, hydrocortisone, methylprednisolone). Prophylactic administration of all corticosteroid agents showed a net effect in favour of reducing markers of severity of pancreatitis. NAC showed a significant reduction in severity of amylase and necrosis.

CONCLUSION: The RCTs examined suggest that prophylactic administration of corticosteroid agents and NAC can reduce the severity of pancreatitis as indicated by histopathologic markers, serum amylase and IL-6 levels.}, } @article {pmid34933532, year = {2021}, author = {Rafiee, B and Bagher Tabei, SM}, title = {The effect of N-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of COVID-19 in the last three months.}, journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica}, volume = {93}, number = {4}, pages = {465-467}, doi = {10.4081/aiua.2021.4.465}, pmid = {34933532}, issn = {2282-4197}, mesh = {Acetylcysteine/therapeutic use ; *COVID-19 ; Female ; Humans ; *Infertility, Male/drug therapy ; Male ; SARS-CoV-2 ; Semen ; Semen Analysis ; Sperm Count ; Sperm Motility ; Spermatozoa ; }, abstract = {Male infertility is an important factor accounting for 40-50% of infertility cases that may be due to disturbance in one of the parameters as concentration, motility and morphology observed in one or two semen analysis with an interval of 1 and 4 weeks. COVID-19 may affect male fertility through virus division, cytotoxic effects on testicular tissue and immunopathological effect. N-acetyl cysteine (NAC) improved sperm concentration and acrosome reaction while reducing reactive oxygen species (ROS) and oxidation of sperm DNA. This interventional study was conducted on 200 men who were referred to private infertility clinics for female factor (their previous semen analysis was normal) and got COVID-19 infection in the last 3 months showing an impairment of the latest semen analysis due to COVID. Men were placed in two groups of control (n = 100) and intervention (NAC consumption). Subjects who got COVID-19 infection had a significant impairment of sperm quality (sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis evaluated before the COVID-19 infection. NAC consumption significantly improved sperm total motility, sperm morphology and sperm concentration. COVID-19 infection has a negative effect on sperm parameters. NAC supplementation may have positive effect on sperm parameters.}, } @article {pmid34929351, year = {2022}, author = {Zhang, Y and Yan, M and Shan, W and Zhang, T and Shen, Y and Zhu, R and Fang, J and Mao, H}, title = {Bisphenol A induces pyroptotic cell death via ROS/NLRP3/Caspase-1 pathway in osteocytes MLO-Y4.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {159}, number = {}, pages = {112772}, doi = {10.1016/j.fct.2021.112772}, pmid = {34929351}, issn = {1873-6351}, mesh = {Animals ; Benzhydryl Compounds/*toxicity ; Caspase 1/metabolism ; Cell Line ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Osteocytes/*drug effects/metabolism ; Phenols/*toxicity ; Pyroptosis/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, is commonly used as a plasticizer to manufacture various food packaging materials. Evidence has demonstrated that BPA disturbed bone health. However, few studies focused on the effect of BPA on osteocytes, making up over 95% of all the bone cells. Here, we reported that BPA inhibited the cell viability of MLO-Y4 cells, and increased apoptosis in a dose-dependent manner. Furthermore, BPA up-regulated protein expressions of speck-like protein containing CARD (ASC), NLRP3, cleaved caspase-1 (Casp-1 p20) and cleaved gasdermin D (GSDMD-N), and increased the ratios of interleukin (IL)-1β/pro-IL-1β and IL-18/pro-IL-18 in MLO-Y4 cells. BPA enhanced levels of lactate dehydrogenase (LDH), IL-1β and IL-18 in culture supernatants. This pyroptotic death and the NLPR3 inflammasome activation were reversed by the caspase-1 inhibitor VX765 or the NLRP3 inflammasome inhibitor MCC950. Furthermore, BPA stimulated the production of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), elevated malondialdehyde (MDA) level and decreased superoxide dismutase (SOD) activity, which led to oxidative damage in MLO-Y4 cells. The ROS scavenger N-acetylcysteine (NAC) or the mitochondrial antioxidant Mito-TEMPO inhibited the NLPR3 inflammasome activation and pyroptotic death induced by BPA. Collectively, our data suggest that BPA causes pyroptotic death of osteocytes via ROS/NLRP3/Caspase-1 pathway.}, } @article {pmid34926192, year = {2021}, author = {Hwang, SB and Park, JH and Park, JY and Kang, SS and Chung, HS and Lee, H and Kim, JY and Tchah, H}, title = {Anti-inflammatory and anti-apoptotic effects of N-acetylcysteine in diabetic rat corneal epithelium.}, journal = {International journal of ophthalmology}, volume = {14}, number = {12}, pages = {1805-1812}, pmid = {34926192}, issn = {2222-3959}, abstract = {AIM: To characterize the anti-inflammatory and anti-apoptotic effects of N-acetylcysteine (NAC) in streptozotocin (STZ)-induced diabetic rat corneal epithelium and human corneal epithelial cells (HCECs) exposed to a high-glucose environment.

METHODS: HCECs were incubated in 0, 5, 50 mmol/L glucose medium, or 50 mmol/L glucose medium with NAC for 24h. Diabetes was induced in rats by intraperitoneal injection of 65 mg/kg STZ and some of these rats were topically administered NAC to corneas with 3 mice per group. We characterized receptor for advanced glycation end-products (RAGE) expression using immunofluorescence, and interleukin (IL)-1β and cleaved caspase-3 (CCAP-3) expression using immunohistochemistry. Circulating tumor necrosis factor (TNF)-α concentration was measured by ELISA and cleaved poly-ADP ribose polymerase (PARP) concentration was quantified by Western blotting. Apoptotic cells were detected using TUNEL assay and annexin V and propidium iodide staining.

RESULTS: Diabetic rats had higher expression of RAGE (2.46±0.13 fold), IL-1β, and CCAP-3 in apoptotic cells of their corneas than control rats. The expression of RAGE (1.83±0.11 fold), IL-1β, and CCAP-3, and the number of apoptotic cells, were reduced by topical NAC treatment. HCECs incubated in 50 mmol/L glucose medium showed high concentrations of TNF-α (310±2.00 pg/mL) and cleaved PARP (7.43±0.56 fold), and more extensive apoptosis than cells in 50 mmol/L glucose medium. However, the addition of NAC reduced the concentrations of TNF-α (153.67±2.31 pg/mL) and cleaved PARP (5.55±0.31 fold) and the number of apoptotic cells.

CONCLUSION: NAC inhibits inflammation and apoptosis in the corneas of diabetic rats and HCECs maintained in a high-glucose environment.}, } @article {pmid34924003, year = {2021}, author = {Zhang, VX and Sze, KM and Chan, LK and Ho, DW and Tsui, YM and Chiu, YT and Lee, E and Husain, A and Huang, H and Tian, L and Wong, CC and Ng, IO}, title = {Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1.}, journal = {Cell & bioscience}, volume = {11}, number = {1}, pages = {217}, pmid = {34924003}, issn = {2045-3701}, support = {04152336//Health and Medical Research Fund/ ; T12-704/16-R//Hong Kong Research Grants Council Theme-based Research Scheme/ ; 81872222//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth.

METHODS: Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets.

RESULTS: In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo.

CONCLUSIONS: Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.}, } @article {pmid34916980, year = {2021}, author = {Palaniyappan, L and Sabesan, P and Li, X and Luo, Q}, title = {Schizophrenia Increases Variability of the Central Antioxidant System: A Meta-Analysis of Variance From MRS Studies of Glutathione.}, journal = {Frontiers in psychiatry}, volume = {12}, number = {}, pages = {796466}, pmid = {34916980}, issn = {1664-0640}, abstract = {Patients with schizophrenia diverge in their clinical trajectories. Such diverge outcomes may result from the resilience provided by antioxidant response system centered on glutathione (GSH). Proton Magnetic Resonance Spectroscopy (1H-MRS) has enabled the precise in vivo measurement of intracortical GSH; but individual studies report highly variable results even when GSH levels are measured from the same brain region. This inconsistency could be due to the presence of distinct subgroups of schizophrenia with varying GSH-levels. At present, we do not know if schizophrenia increases the interindividual variability of intracortical GSH relative to matched healthy individuals. We reviewed all 1H-MRS GSH studies in schizophrenia focused on the Anterior Cingulate Cortex published until August 2021. We estimated the relative variability of ACC GSH levels in patients compared to control groups using the variability ratio (VR) and coefficient of variation ratio (CVR). The presence of schizophrenia significantly increases the variability of intracortical GSH in the ACC (logVR = 0.12; 95% CI: 0.03-0.21; log CVR = 0.15; 95% CI = 0.06-0.23). Insofar as increased within-group variability (heterogeneity) could result from the existence of subtypes, our results call for a careful examination of intracortical GSH distribution in schizophrenia to seek redox-deficient and redox-sufficient subgroups. An increase in GSH variability among patients also indicate that the within-group predictability of adaptive response to oxidative stress may be lower in schizophrenia. Uncovering the origins of this illness-related reduction in the redox system stability may provide novel treatment targets in schizophrenia.}, } @article {pmid34916780, year = {2021}, author = {Zhang, BH and Liu, H and Yuan, Y and Weng, XD and Du, Y and Chen, H and Chen, ZY and Wang, L and Liu, XH}, title = {Knockdown of TRIM8 Protects HK-2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Inhibiting Oxidative Stress-Mediated Apoptosis and Pyroptosis via PI3K/Akt Signal Pathway.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {4973-4983}, pmid = {34916780}, issn = {1177-8881}, mesh = {Acute Kidney Injury/*metabolism ; Apoptosis/drug effects ; Carrier Proteins/*metabolism ; Cell Survival ; Cells, Cultured ; Humans ; Hydrogen Peroxide/metabolism ; Hypoxia ; Nerve Tissue Proteins/*metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Pyroptosis/drug effects ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/*prevention & control ; Signal Transduction ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) emerges as an acute and critical disease. Tripartite motif 8 (TRIM8), one number of the TRIM protein family, is proved to participate in ischemia/reperfusion (I/R) injury. However, whether TRIM8 is involved in renal I/R injury and the associated mechanisms are currently unclear.

PURPOSE: This study aimed to investigate the precise role of TRIM8 and relevant mechanisms in renal I/R injury.

MATERIALS AND METHODS: In this study, human renal proximal tubular epithelial cells (HK-2 cells) underwent 12 hours of hypoxia and 2 h, 3 h or 4 h of reoxygenation to establish an in vitro hypoxia/reoxygenation (H/R) model. The siRNAs specific to TRIM8 (si-TRIM8) were transfected into HK-2 cells to knockdown TRIM8. The cell H/R model included various groups including Control, H/R, H/R+DMSO, H/R+NAC, si-NC+H/R, si-TRIM8+H/R and si-TRIM8+LY294002+H/R. The cell viability and levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2), mRNA, apoptotic proteins, pyroptosis-related proteins and PI3K/AKT pathway-associated proteins were assessed.

RESULTS: In vitro, realtime-quantitative PCR and western-blot analysis showed that the mRNA and protein expression of TRIM8 were obviously upregulated after H/R treatment in HK-2 cells. Compared with the H/R model group, knockdown of TRIM8 significantly increased cell viability and reduced the levels of ROS, H2O2, apoptotic proteins (Cleaved caspasebase-3 and BAX) and pyroptosis-related proteins (NLRP3, ASC, Caspase-1, Caspase-11, IL-1β and GSDMD-N). Western-blot analysis also authenticated that PI3K/AKT pathway was activated after TRIM8 inhibition. The application of 5 mM N-acetyl-cysteine, one highly efficient ROS inhibitor, significantly suppressed the expression of apoptotic proteins and pyroptosis-related proteins. Moreover, the combined treatment of TRIM8 knockdown and LY294002 reversed the effects of inhibiting oxidative stress.

CONCLUSION: Knockdown of TRIM8 can alleviate H/R-induced oxidative stress by triggering the PI3K/AKT pathway, thus attenuating pyropyosis and apoptosis in vitro.}, } @article {pmid34912495, year = {2021}, author = {Ntamo, Y and Ziqubu, K and Chellan, N and Nkambule, BB and Nyambuya, TM and Mazibuko-Mbeje, SE and Gabuza, KB and Marcheggiani, F and Tiano, L and Dludla, PV}, title = {Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {3320325}, pmid = {34912495}, issn = {1942-0994}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chemical and Drug Induced Liver Injury/etiology/pathology/*prevention & control ; Free Radical Scavengers/*pharmacology ; Humans ; }, abstract = {Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.}, } @article {pmid34907710, year = {2021}, author = {Thida, M and Li, B and Zhang, X and Chen, C and Zhang, X}, title = {Echinacoside alleviates acetaminophen-induced liver injury by attenuating oxidative stress and inflammatory cytokines in mice.}, journal = {Journal of applied biomedicine}, volume = {19}, number = {2}, pages = {105-112}, pmid = {34907710}, issn = {1214-0287}, mesh = {Acetaminophen/adverse effects ; Animals ; Antioxidants/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy ; Cytochrome P-450 CYP2E1/metabolism ; *Cytokines/drug effects/metabolism ; *Glycosides/pharmacology/therapeutic use ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Malondialdehyde/metabolism ; Mice ; Molecular Docking Simulation ; *Oxidative Stress/drug effects ; Sulfotransferases/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Uridine Diphosphate/metabolism ; }, abstract = {This study evaluates the protective effect of Echinacoside on acute liver toxicity induced by acetaminophen in mice and the mechanism behind it. Echinacoside and N-Acetyl Cysteine were intragastrically administrated for 7 days, and acetaminophen was intraperitoneally injected into mice 1 h after the last treatment on day 7. At the end of the experimental period, histological examination, parameters for the level of oxidative damage, hepatic malondialdehyde, serum pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β), UDP-glucuronosyltransferases, and sulfotransferases changes were examined using enzyme-linked immunosorbent assay and standard biochemical procedures. The expression of cytochrome P450 2E1 protein was assessed by western blot, followed by in silico molecular docking. Acetaminophen treatment obviously increased the levels of ALT and AST, changed hepatic histopathology, promoted oxidative stress, decreased antioxidant enzyme activities, and elevated the pro-inflammatory cytokines. Echinacoside significantly attenuated Acetaminophen-induced liver damage in a dose-dependent manner, with the most effective dose at 100 mg/kg. The pretreatments of Echinacoside in different concentrations altered the Acetaminophen-induced hepatotoxicity levels by decreasing the level of liver enzymes, reducing the liver necrosis with vacuolization, decreasing the hepatic malondialdehyde formation, increasing hepatic antioxidants activities, suppressing the pro-inflammatory cytokines (Tumor Necrosis Factor, Interleukin-6 and Interleukin-1beta), inhibiting Nitric Oxide production, enhancing sulfotransferases and UDP-glucuronosyltransferases activities. Notably, the expression of cytochrome P450 2E1 was inhibited by Echinacoside in a dose-dependent manner and the binding energy was -214.3 MeV. Echinacoside showed a significant protective effect against Acetaminophen-induced hepatotoxicity through the inhibition of oxidative stress, the expression of pro-inflammatory cytokines and cytochrome P450 2E1 protein expression.}, } @article {pmid34906805, year = {2022}, author = {Yao, Y and Xiong, W and Chen, L and Ju, X and Wang, L}, title = {Synergistic growth-inhibition effect of quercetin and N-Acetyl-L-cysteine against HepG2 cells relying on the improvement of quercetin stability.}, journal = {Food chemistry}, volume = {374}, number = {}, pages = {131729}, doi = {10.1016/j.foodchem.2021.131729}, pmid = {34906805}, issn = {1873-7072}, mesh = {*Acetylcysteine ; Hep G2 Cells ; Humans ; *Quercetin ; }, abstract = {In this study, N-Acetyl-l-cysteine (NAC) as a widely-used antioxidant was first applied to improve the stability of Que in medium. The stability of Que in medium was analyzed, and the growth-inhibition effect of Que and NAC against HepG2 cells was estimated. The results showed NAC could significantly improve the stability of Que in medium (more than 80%), while Que alone in medium was totally degraded within 4 h. Besides, it was found that Que together with NAC could significantly enhance the growth-inhibition effect against HepG2 cells compared with Que alone, with the IC50 value of 40 μM and 200 μM for Que together with NAC and Que alone. Moreover, NAC could inhibit the depletion of GSH induced by Que. The synergistic growth-inhibition effect of Que and NAC against HepG2 cells was attributed to NAC improving Que stability in medium accompanied by NAC inhibiting the depletion of GSH induced by Que. The results showed that NAC could improve the stability of Que and reduce the degradation rate of Que in culture medium. This study can provide a reference for the further study of the mechanism of NAC enhancing the stability of quercetin and the development of broad-spectrum stabilizers.}, } @article {pmid34901531, year = {2022}, author = {Sun, L and Ouyang, J and Zeng, Z and Zeng, C and Ma, Y and Zeng, F and Wu, S}, title = {Targeted and activatable nanosystem for fluorescent and optoacoustic imaging of immune-mediated inflammatory diseases and therapy via inhibiting NF-κB/NLRP3 pathways.}, journal = {Bioactive materials}, volume = {10}, number = {}, pages = {79-92}, pmid = {34901531}, issn = {2452-199X}, abstract = {Immune-mediated inflammatory diseases (IMIDs) represent a diverse group of diseases and challenges remain for the current medications. Herein, we present an activatable and targeted nanosystem for detecting and imaging IMIDs foci and treating them through blocking NF-κB/NLRP3 pathways. A ROS-activatable prodrug BH-EGCG is synthesized by coupling a near-infrared chromophore with the NF-κB/NLRP3 inhibitor epigallocatechin-3-gallate (EGCG) through boronate bond which serves as both the fluorescence quencher and ROS-responsive moiety. BH-EGCG molecules readily form stable nanoparticles in aqueous medium, which are then coated with macrophage membrane to ensure the actively-targeting capability toward inflammation sites. Additionally, an antioxidant precursor N-acetylcysteine is co-encapsulated into the coated nanoparticles to afford the nanosystem BH-EGCG&NAC@MM to further improve the anti-inflammatory efficacy. Benefiting from the inflammation-homing effect of the macrophage membrane, the nanosystem delivers payloads (diagnostic probe and therapeutic drugs) to inflammatory lesions more efficiently and releases a chromophore and two drugs upon being triggered by the overexpressed in-situ ROS, thus exhibiting better theranostic performance in the autoimmune hepatitis and hind paw edema mouse models, including more salient imaging signals and better therapeutic efficacy via inhibiting NF-κB pathway and suppressing NLRP3 inflammasome activation. This work may provide perceptions for designing other actively-targeting theranostic nanosystems for various inflammatory diseases.}, } @article {pmid34899969, year = {2021}, author = {Liu, X and Lu, X and Hu, Z}, title = {N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells.}, journal = {Computational and mathematical methods in medicine}, volume = {2021}, number = {}, pages = {7596343}, pmid = {34899969}, issn = {1748-6718}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Animals ; Case-Control Studies ; Computational Biology ; Cytokines/blood ; Disease Models, Animal ; Female ; Humans ; Interferon-gamma/*biosynthesis ; Interleukin-18/antagonists & inhibitors/*biosynthesis ; Killer Cells, Natural/*drug effects/*immunology ; Lung/drug effects/immunology/pathology ; Macrophages/drug effects/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists & inhibitors ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*immunology/pathology ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) had exerted antioxidation and anti-inflammation effects on chronic obstructive pulmonary disease (COPD) patients. However, its effect in regulating interleukin- (IL-) 18 was not fully understood. This study was designed to evaluate the specific mechanism of NAC regulating IL-18.

MATERIALS AND METHODS: A total of 112 COPD patients and 103 health individuals were recruited in the study. Cytokine level in patients' serum was measured by enzyme-linked immunosorbent assay (ELISA). A COPD mouse model was established by administration of lipopolysaccharide (LPS) and cigarette smoke. The expression of cytokines was measured by ELISA and flow cytometry. Inflammasome-related protein was measured by Western blot.

RESULT: NAC could effectively improve the immune status of COPD patients as well as the COPD mouse model by downregulating proinflammation and inflammation cytokines including IL-1β, interferon- (IFN-) γ, tumor necrosis factor- (TNF-) α, and IL-18. It also had the capability to suppress synthesis of IL-18 in macrophage to inhibit the secretion of IFN-γ from natural killer (NK) cells through influencing the inflammasome-related protein in macrophages.

CONCLUSION: NAC could effectively inhibit the production of IL-18 by suppressing NLRP3 expression in macrophages to reduce the production of IFN-γ in NK cells.}, } @article {pmid34895315, year = {2021}, author = {Gao, FF and Quan, JH and Lee, MA and Ye, W and Yuk, JM and Cha, GH and Choi, IW and Lee, YH}, title = {Trichomonas vaginalis induces apoptosis via ROS and ER stress response through ER-mitochondria crosstalk in SiHa cells.}, journal = {Parasites & vectors}, volume = {14}, number = {1}, pages = {603}, pmid = {34895315}, issn = {1756-3305}, support = {NRF-2019R1A2C1088346//National Research Foundation of Korea/ ; 81771612//National Natural Science Foundation of China/ ; 81971389//National Natural Science Foundation of China/ ; }, mesh = {*Apoptosis ; Cell Line, Tumor ; Endoplasmic Reticulum/metabolism ; *Endoplasmic Reticulum Stress ; Female ; Humans ; Membrane Potential, Mitochondrial ; Mitochondria/metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; Trichomonas vaginalis/*physiology ; Uterine Cervical Neoplasms/*parasitology ; }, abstract = {BACKGROUND: Trichomonas vaginalis causes lesions on the cervicovaginal mucosa in women; however, its pathogenesis remains unclear. We have investigated the involvement of the endoplasmic reticulum (ER) in the induction of apoptosis by T. vaginalis and its molecular mechanisms in human cervical cancer SiHa cells.

METHODS: Apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), ER stress response and Bcl-2 family protein expression were evaluated using immunocytochemistry, flow cytometry, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide dye staining and western blotting.

RESULTS: Trichomonas vaginalis induced mitochondrial ROS production, apoptosis, the ER stress response and mitochondrial dysfunction, such as MMP depolarization and an imbalance in Bcl-2 family proteins, in SiHa cells in a parasite burden- and infection time-dependent manner. Pretreatment with N-acetyl cysteine (ROS scavenger) or 4-phenylbutyric acid (4-PBA; ER stress inhibitor) significantly alleviated apoptosis, mitochondrial ROS production, mitochondrial dysfunction and ER stress response in a dose-dependent manner. In addition, T. vaginalis induced the phosphorylation of apoptosis signal regulating kinase 1 (ASK1) and c-Jun N-terminal kinases (JNK) in SiHa cells, whereas 4-PBA or SP600125 (JNK inhibitor) pretreatment significantly attenuated ASK1/JNK phosphorylation, mitochondrial dysfunction, apoptosis and ER stress response in SiHa cells, in a dose-dependent manner. Furthermore, T. vaginalis excretory/secretory products also induced mitochondrial ROS production, apoptosis and the ER stress response in SiHa cells, in a time-dependent manner.

CONCLUSIONS: Trichomonas vaginalis induces apoptosis through mitochondrial ROS and ER stress responses, and also promotes ER stress-mediated mitochondrial apoptosis via the IRE1/ASK1/JNK/Bcl-2 family protein pathways in SiHa cells. These data suggest that T. vaginalis-induced apoptosis is affected by ROS and ER stress response via ER-mitochondria crosstalk.}, } @article {pmid34887597, year = {2021}, author = {Ielmini, M and Caselli, I and Ceccon, F and Diurni, M and Poloni, N and Callegari, C}, title = {Selective Serotonin Reuptake Inhibitors and Nutraceutical Combination in Major Depression Disorder: A Case-Control Study.}, journal = {Psychopharmacology bulletin}, volume = {51}, number = {4}, pages = {31-39}, pmid = {34887597}, issn = {2472-2448}, mesh = {Adult ; Case-Control Studies ; *Depressive Disorder, Major/drug therapy ; *Dietary Supplements ; Humans ; Quality of Life ; Selective Serotonin Reuptake Inhibitors/*therapeutic use ; }, abstract = {INTRODUCTION: Major depressive disorder (MDD) is a primary cause of disability in adults, affecting daily functioning and decreasing quality of life. The focus on the role of nutraceuticals as adjunctive treatments to improve antidepressant response is paying growing interest. The study aims to compare the antidepressants response in the utilization of selective serotonin reuptake inhibitors (SSRIs) versus a combination of SSRIs and nutraceutical supplements based on S-Adenosyl methionine (SAMe), N-acetylcysteine (NAC) and folate in terms of efficacy and tolerability.

METHODS: A case-control study was carried out between March 2018 and September 2019. Cases and controls were evaluated through the following scales: Hospital Anxiety Depression Scale (HADS); Clinical Global Impression (CGI); Patient Global Impression of Improvement (PGI-I); Antidepressant Adverse Events checklist (AES).

RESULTS: A significant difference between the two groups of patients emerged at T1 in the HADS-A (p = 0.004) score and in the CGI score (p = 0.01), due to a major improvement in patients with a nutraceutical co-prescription. At T3 a significant statistical difference emerged, showing a greater improvement at HADS-D in the case group (p = 0.006), confirmed by a higher remission rate in patients taking a nutraceutical co-prescription. No differences in terms of adverse events emerged.

CONCLUSION: This study shows promising data about the role of nutraceuticals as adjunctive treatment in major depressive disorder to improve SSRIs efficacy, with good tolerability. More data are needed to confirm these results, particularly about the role of nutraceuticals to decrease the latency of SSRIs response.}, } @article {pmid34885867, year = {2021}, author = {Mushtaq, I and Bashir, Z and Sarwar, M and Arshad, M and Ishtiaq, A and Khan, W and Khan, U and Tabassum, S and Ali, T and Fatima, T and Valadi, H and Nawaz, M and Murtaza, I}, title = {N-Acetyl Cysteine, Selenium, and Ascorbic Acid Rescue Diabetic Cardiac Hypertrophy via Mitochondrial-Associated Redox Regulators.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {23}, pages = {}, pmid = {34885867}, issn = {1420-3049}, support = {2018-2022//Higher Education Commission (HEC) Pakistan (to Iram Murtaza)/ ; 2019-2021//University research fund (URF), Quaid-i-Azam University (to Iram Murtaza)/ ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Ascorbic Acid/*therapeutic use ; Biomarkers/blood ; Blood Glucose/metabolism ; Body Weight/drug effects ; Calcium/blood ; Cardiomegaly/blood/complications/*drug therapy/pathology ; Cardiotonic Agents/pharmacology/therapeutic use ; Cytochromes c/metabolism ; Diabetic Cardiomyopathies/blood/complications/*drug therapy/pathology ; Disease Models, Animal ; Down-Regulation ; GATA4 Transcription Factor/metabolism ; Lipid Peroxidation/drug effects ; Lipids/blood ; Mitochondria, Heart/drug effects/*metabolism ; Myocardium/pathology ; Oxidation-Reduction ; Oxidative Stress ; PPAR alpha/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Selenium/pharmacology/*therapeutic use ; Rats ; }, abstract = {Metabolic disorders often lead to cardiac complications. Metabolic deregulations during diabetic conditions are linked to mitochondrial dysfunctions, which are the key contributing factors in cardiac hypertrophy. However, the underlying mechanisms involved in diabetes-induced cardiac hypertrophy are poorly understood. In the current study, we initially established a diabetic rat model by alloxan-administration, which was validated by peripheral glucose measurement. Diabetic rats displayed myocardial stiffness and fibrosis, changes in heart weight/body weight, heart weight/tibia length ratios, and enhanced size of myocytes, which altogether demonstrated the establishment of diabetic cardiac hypertrophy (DCH). Furthermore, we examined the expression of genes associated with mitochondrial signaling impairment. Our data show that the expression of PGC-1α, cytochrome c, MFN-2, and Drp-1 was deregulated. Mitochondrial-signaling impairment was further validated by redox-system dysregulation, which showed a significant increase in ROS and thiobarbituric acid reactive substances, both in serum and heart tissue, whereas the superoxide dismutase, catalase, and glutathione levels were decreased. Additionally, the expression levels of pro-apoptotic gene PUMA and stress marker GATA-4 genes were elevated, whereas ARC, PPARα, and Bcl-2 expression levels were decreased in the heart tissues of diabetic rats. Importantly, these alloxan-induced impairments were rescued by N-acetyl cysteine, ascorbic acid, and selenium treatment. This was demonstrated by the amelioration of myocardial stiffness, fibrosis, mitochondrial gene expression, lipid profile, restoration of myocyte size, reduced oxidative stress, and the activation of enzymes associated with antioxidant activities. Altogether, these data indicate that the improvement of mitochondrial dysfunction by protective agents such as N-acetyl cysteine, selenium, and ascorbic acid could rescue diabetes-associated cardiac complications, including DCH.}, } @article {pmid34884459, year = {2021}, author = {Cela-López, JM and Camacho Roldán, CJ and Gómez-Lizarraga, G and Martínez, V}, title = {Effects of Itxasol© Components on Gene Expression in Bacteria Related to Infections of the Urinary Tract and to the Inflammation Process.}, journal = {International journal of molecular sciences}, volume = {22}, number = {23}, pages = {}, pmid = {34884459}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Arbutin/pharmacology/therapeutic use ; Bacteria/drug effects/*genetics ; Bacterial Proteins/*genetics ; Drug Combinations ; Gene Expression Regulation, Bacterial/drug effects ; Humans ; Molecular Mimicry ; Umbelliferones/pharmacology/therapeutic use ; Urinary Tract Infections/drug therapy/*microbiology ; }, abstract = {Urinary tract infections (UTIs) represent a health problem of the first magnitude since they affect large segments of the population, cause increased mortality and comorbidity, and have a high incidence of relapse. Therefore, UTIs cause a major socioeconomic concern. Current antibiotic treatments have various limitations such as the appearance of resistance to antibiotics, nephrotoxicity, and side effects such as gastrointestinal problems including microbiota alterations that contribute to increasing antibiotic resistance. In this context, Itxasol© has emerged, approved as an adjuvant for the treatment of UTIs. Designed with biomimetic principles, it is composed of arbutin, umbelliferon, and N-acetyl cysteine. In this work, we review the activities of these three compounds concerning the changes they produce in the expression of bacterial genes and those related to inflammation as well as assess how they are capable of affecting the DNA of bacteria and fungi.}, } @article {pmid34884437, year = {2021}, author = {Mlejnek, P and Dolezel, P and Kriegova, E and Pastvova, N}, title = {N-acetylcysteine Can Induce Massive Oxidative Stress, Resulting in Cell Death with Apoptotic Features in Human Leukemia Cells.}, journal = {International journal of molecular sciences}, volume = {22}, number = {23}, pages = {}, pmid = {34884437}, issn = {1422-0067}, support = {IGA_LF 2021_006//Palacký University, Olomouc/ ; }, mesh = {Acetylcysteine/*pharmacology ; Catalase/genetics ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; HL-60 Cells ; Humans ; Leukemia/drug therapy/*genetics/metabolism ; NADPH Oxidase 2/*genetics ; Oxidative Stress/*drug effects ; Peroxidase/*genetics ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*genetics ; U937 Cells ; }, abstract = {N-acetylcysteine (NAC), often used as an antioxidant-scavenging reactive oxygen species (ROS) in vitro, was recently shown to increase the cytotoxicity of other compounds through ROS-dependent and ROS-independent mechanisms. In this study, NAC itself was found to induce extensive ROS production in human leukemia HL-60 and U937 cells. The cytotoxicity depends on ROS-modulating enzyme expression. In HL-60 cells, NAC activated NOX2 to produce superoxide (O2•[-]). Its subsequent conversion into H2O2 by superoxide dismutase 1 and 3 (SOD1, SOD3) and production of ClO[-] from H2O2 by myeloperoxidase (MPO) was necessary for cell death induction. While the addition of extracellular SOD potentiated NAC-induced cell death, extracellular catalase (CAT) prevented cell death in HL-60 cells. The MPO inhibitor partially reduced the number of dying HL-60 cells. In U937 cells, the weak cytotoxicity of NAC is probably caused by lower expression of NOX2, SOD1, SOD3, and by the absence of MOP expression. However, even here, the addition of extracellular SOD induced cell death in U937 cells, and this effect could be reversed by extracellular CAT. NAC-induced cell death exhibited predominantly apoptotic features in both cell lines. Conclusions: NAC itself can induce extensive production of O2•[-] in HL-60 and U937 cell lines. The fate of the cells then depends on the expression of enzymes that control the formation and conversion of ROS: NOX, SOD, and MPO. The mode of cell death in response to NAC treatment bears apoptotic and apoptotic-like features in both cell lines.}, } @article {pmid34880073, year = {2023}, author = {Dayasiri, K and Rao, S}, title = {Fifteen-minute update: International normalised ratio as the treatment end point in children with acute paracetamol poisoning.}, journal = {Archives of disease in childhood. Education and practice edition}, volume = {108}, number = {3}, pages = {181-183}, doi = {10.1136/archdischild-2020-320190}, pmid = {34880073}, issn = {1743-0593}, mesh = {Humans ; Child ; *Acetaminophen ; International Normalized Ratio ; *Liver Diseases ; Acetylcysteine/therapeutic use ; Vitamin K/therapeutic use ; }, abstract = {Paracetamol is one of the most frequent reasons for poisonings across the UK with an estimated 90,000 patients and 150 deaths annually. International normalised ratio (INR) may be elevated due to hepatocellular damage and is frequently used to monitor progress on N-acetyl cysteine. N-acetyl cysteine is associated with reduced activity of vitamin K dependent clotting factors leading to a benign elevation of INR. In asymptomatic children with normal aspartate transaminase/alanine transaminase, isolated borderline elevation of INR following paracetamol overdose should be reviewed for possible N-acetyl cysteine induced elevation of INR. Due to these factors, in those with borderline persistent elevation of INR, N-acetyl cysteine can be safety stopped if INR is falling on two or more consecutive tests and is <3.0.}, } @article {pmid34875739, year = {2021}, author = {Ghorbani, F and Nasiri, Z and Koohestanidehaghi, Y and Lorian, K}, title = {The antioxidant roles of L-carnitine and N-acetyl cysteine against oxidative stress on human sperm functional parameters during vitrification.}, journal = {Clinical and experimental reproductive medicine}, volume = {48}, number = {4}, pages = {316-321}, pmid = {34875739}, issn = {2233-8233}, abstract = {OBJECTIVE: Amino acids can protect sperm structure in cryopreservation due to their antioxidant properties. Therefore, the present study aimed to investigate the protective effect of L-carnitine (LC) and N-acetyl cysteine (NAC) on motility parameters, plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), DNA damage, and human sperm intracellular reactive oxygen species (ROS) during vitrification.

METHODS: Twenty normal human sperm samples were examined. Each sample was divided into six equal groups: LC (1 and 10 mM), NAC (5 and 10 mM), and cryopreserved and fresh control groups.

RESULTS: The groups treated with LC and NAC showed favorable findings in terms of motility parameters, DNA damage, and MMP. Significantly higher levels of intracellular ROS were observed in all cryopreserved groups than in the fresh group (p≤0.05). The presence of LC and NAC at both concentrations caused an increase in PMI, MMP, and progressive motility parameters, as well as a significant reduction in intracellular ROS compared to the control group (p≤0.05). The concentrations of the amino acids did not show any significant effect.

CONCLUSION: LC and NAC are promising as potential additives in sperm cryopreservation.}, } @article {pmid34869660, year = {2021}, author = {Khan, SA and Campbell, AM and Lu, Y and An, L and Alpert, JS and Chen, QM}, title = {N-Acetylcysteine for Cardiac Protection During Coronary Artery Reperfusion: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {Frontiers in cardiovascular medicine}, volume = {8}, number = {}, pages = {752939}, pmid = {34869660}, issn = {2297-055X}, support = {R01 GM125212/GM/NIGMS NIH HHS/United States ; R01 GM126165/GM/NIGMS NIH HHS/United States ; }, abstract = {Coronary artery reperfusion is essential for the management of symptoms in the patients with myocardial ischemia. However, the benefit of reperfusion often comes at an expense of paradoxical injury, which contributes to the adverse events, and sometimes heart failure. Reperfusion is known to increase the production of reactive oxygen species (ROS). We address whether N-acetylcysteine (NAC) reduces the ROS and alleviates reperfusion injury by improving the clinical outcomes. A literature search for the randomized controlled trials (RCTs) was carried out in the five biomedical databases for testing the effects of NAC in patients undergoing coronary artery reperfusion by percutaneous coronary intervention, thrombolysis, or coronary artery bypass graft. Of 787 publications reviewed, 28 RCTs were identified, with a summary of 2,174 patients. A meta-analysis using the random effects model indicated that NAC administration during or prior to the reperfusion procedures resulted in a trend toward a reduction in the level of serum cardiac troponin (cTn) [95% CI, standardized mean difference (SMD) -0.80 (-1.75; 0.15), p = 0.088, n = 262 for control, 277 for NAC group], and in the incidence of postoperative atrial fibrillation [95% CI, relative risk (RR) 0.57 (0.30; 1.06), p = 0.071, n = 484 for control, 490 for NAC group]. The left ventricular ejection fraction or the measures of length of stay in intensive care unit (ICU) or in hospital displayed a positive trend that was not statistically significant. Among the nine trials that measured ROS, seven showed a correlation between the reduction of lipid peroxidation and improved clinical outcomes. These lines of evidence support the potential benefit of NAC as an adjuvant therapy for cardiac protection against reperfusion injury.}, } @article {pmid34868392, year = {2021}, author = {Zhou, J and Xu, J and Sun, S and Guo, M and Li, P and Cheng, A}, title = {N-Acetylcysteine Slows Down Cardiac Pathological Remodeling by Inhibiting Cardiac Fibroblast Proliferation and Collagen Synthesis.}, journal = {Disease markers}, volume = {2021}, number = {}, pages = {3625662}, pmid = {34868392}, issn = {1875-8630}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Collagen/*biosynthesis ; Male ; Myocytes, Cardiac/metabolism/*pathology ; NF-kappa B/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Ventricular Remodeling/*drug effects ; }, abstract = {OBJECTIVE: By observing the effect of N-acetylcysteine (NAC) on the proliferation and collagen synthesis of rat cardiac fibroblasts (CFs) to explore the effect of NAC on cardiac remodeling (CR).

METHODS: In vivo, first, the Sprague Dawley (SD) rat myocardial hypertrophy model was constructed, and the effect of NAC on cardiac structure and function was detected by echocardiography, serological testing, and Masson staining. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression level of antioxidant enzymes, and flow cytometry was used to detect the intracellular reactive oxygen species (ROS) content. In vitro, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining were used to detect cell proliferation, and the expression level of the NF-κB signaling pathway was detected.

RESULTS: Compared with the control group, the model group had disordered cardiac structure, reduced cardiac function, and obvious oxidative stress (OS) response. However, after NAC treatment, it could obviously improve the rat cardiac structure and cardiac function and alleviate redox imbalance and cardiology remodeling. At the same time, NAC can inhibit the activation of the NF-κB signaling pathway and reduce the proliferation level of CFs and the amount of [3]H proline incorporated.

CONCLUSIONS: NAC can inhibit AngII-induced CF proliferation and collagen synthesis through the NF-κB signaling pathway, alleviate the OS response of myocardial tissue, inhibit the fibrosis of myocardial tissue, and thus slow down the pathological remodeling of the heart.}, } @article {pmid34867200, year = {2021}, author = {Singh-Mallah, G and Kawamura, T and Ardalan, M and Chumak, T and Svedin, P and Arthur, PG and James, C and Hagberg, H and Sandberg, M and Mallard, C}, title = {N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {743093}, pmid = {34867200}, issn = {1662-5102}, abstract = {Inflammation and neonatal hypoxia-ischemia (HI) are important etiological factors of perinatal brain injury. However, underlying mechanisms remain unclear. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases. Sirtuin-6 is thought to regulate inflammatory and oxidative pathways, such as the extracellular release of the alarmin high mobility group box-1 (HMGB1). The expression and role of sirtuin-6 in neonatal brain injury are unknown. In a well-established model of neonatal brain injury, which encompasses inflammation (lipopolysaccharide, LPS) and hypoxia-ischemia (LPS+HI), we investigated the protein expression of sirtuin-6 and HMGB1, as well as thiol oxidation. Furthermore, we assessed the effect of the antioxidant N-acetyl cysteine (NAC) on sirtuin-6 expression, nuclear to cytoplasmic translocation, and release of HMGB1 in the brain and blood thiol oxidation after LPS+HI. We demonstrate reduced expression of sirtuin-6 and increased release of HMGB1 in injured hippocampus after LPS+HI. NAC treatment restored sirtuin-6 protein levels, which was associated with reduced extracellular HMGB1 release and reduced thiol oxidation in the blood. The study suggests that early reduction in sirtuin-6 is associated with HMGB1 release, which may contribute to neonatal brain injury, and that antioxidant treatment is beneficial for the alleviation of these injurious mechanisms.}, } @article {pmid34856342, year = {2022}, author = {Ghaffarian-Bahraman, A and Arabnezhad, MR and Keshavarzi, M and Davani-Davari, D and Jamshidzadeh, A and Mohammadi-Bardbori, A}, title = {Influence of cellular redox environment on aryl hydrocarbon receptor ligands induced melanogenesis.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {79}, number = {}, pages = {105282}, doi = {10.1016/j.tiv.2021.105282}, pmid = {34856342}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzo(a)pyrene/pharmacology ; Carbazoles/pharmacology ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Ligands ; Melanins/*biosynthesis ; Melanoma/metabolism/*physiopathology ; Mice ; Onium Compounds/pharmacology ; *Oxidation-Reduction ; Oxidative Stress/drug effects ; Receptors, Aryl Hydrocarbon/*drug effects/metabolism ; }, abstract = {Many environmental pollutants, natural compounds, as well as endogenous chemicals exert their biological/toxicological effects by reacting with the aryl hydrocarbon receptor (AhR). Previous evidence shed new light on the role of AhR in skin physiology by regulating melanin production. In this study, we investigated the effect of oxidative imbalance induced by AhR ligands on the melanogenesis process in B16 murine melanoma cells. Exposure to 6-formylindolo[3,2-b] carbazole (FICZ) or benzo-α-pyrene (BαP) led to enhanced expression of CTNNB1, MITF, and TYR genes following increased tyrosinase enzyme activity and melanin content in an AhR-dependent manner. Analysis of the presence of reactive oxygen species (ROS) as well as reduced glutathione (GSH) / oxidized glutathione (GSSG) ratio revealed that treatment with AhR ligands is associated with oxidative stress which can be ameliorated with NAC (N-acetyl cysteine) or diphenyleneiodonium chloride (DPI). On the other hand, NAC and DPI enhanced melanogenesis induced by AhR ligands by reducing the level of ROS. We have shown for the first time that a cellular redox status is a critical event during AhR ligand-induced melanogenesis.}, } @article {pmid34854886, year = {2021}, author = {Huynh, TPN and Bowater, RP and Bernuzzi, F and Saha, S and Wormstone, IM}, title = {GSH Levels Serve As a Biological Redox Switch Regulating Sulforaphane-Induced Cell Fate in Human Lens Cells.}, journal = {Investigative ophthalmology & visual science}, volume = {62}, number = {15}, pages = {2}, pmid = {34854886}, issn = {1552-5783}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 6/metabolism ; Aged ; Aged, 80 and over ; Anticarcinogenic Agents/*pharmacology ; Apoptosis/drug effects ; Biomarkers/*metabolism ; Cell Line ; Cell Survival ; Chromatography, Liquid ; Epithelial Cells/*drug effects/metabolism/pathology ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Glutathione Reductase/metabolism ; Humans ; Immunoblotting ; Isothiocyanates/*pharmacology ; Lens, Crystalline/*cytology ; Membrane Potential, Mitochondrial/physiology ; Middle Aged ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Sulfoxides/*pharmacology ; Tandem Mass Spectrometry ; }, abstract = {PURPOSE: Sulforaphane (SFN) is a therapeutic phytochemical agent for many health conditions. SFN-induced cytotoxicity is shown to have promise in preventing posterior capsule opacification (PCO). In the current study, we aimed to elucidate key processes and mechanisms linking SFN treatment to lens cell death.

METHODS: The human lens epithelial cell line FHL124 and central anterior epithelium were used as experimental models. Cell death was assessed by microscopic observation and cell damage/viability assays. Gene or protein levels were assessed by TaqMan RT-PCR or immunoblotting. Mitochondrial networks and DNA damage were assessed by immunofluorescence. Mitochondrial membrane potential, activating transcription factor 6 (ATF6) activity, ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and glutathione reductase (GR) activity were measured using different light reporter assays. SFN metabolites were analyzed by LC-MS/MS.

RESULTS: Treatment with N-acetylcysteine (NAC), a reactive oxygen species scavenger, prevented SFN-induced cell death in both models. NAC also significantly protected FHL124 cells from SFN-induced mitochondrial dysfunctions, endoplasmic reticulum stress (ERS), DNA damage and autophagy. SFN significantly depleted GSH, the major antioxidant in the eye, and reduced GR activity, despite doubling its protein levels. The most abundant SFN conjugate detected in lens cells following SFN application was SFN-GSH. The addition of GSH protected lens cells from all SFN-induced cellular events.

CONCLUSIONS: SFN depletes GSH levels in lens cells through conjugation and inhibition of GR activity. This leads to increased reactive oxygen species and oxidative stress that trigger mitochondrial dysfunction, ERS, autophagy, and DNA damage, leading to cell death. In summary, the work presented provides a mechanistic understanding to support the therapeutic application of SFN for PCO and other disorders.}, } @article {pmid34854203, year = {2022}, author = {Wieting, J and Deest, M and Bleich, S and Frieling, H and Eberlein, C}, title = {N-Acetylcysteine provides limited efficacy as treatment option for skin picking in Prader-Willi syndrome.}, journal = {American journal of medical genetics. Part A}, volume = {188}, number = {3}, pages = {828-835}, doi = {10.1002/ajmg.a.62589}, pmid = {34854203}, issn = {1552-4833}, mesh = {Acetylcysteine/therapeutic use ; Female ; Humans ; Male ; *Mental Disorders ; *Prader-Willi Syndrome/complications/drug therapy/genetics ; Retrospective Studies ; *Self-Injurious Behavior/drug therapy/genetics ; }, abstract = {Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed genes in chromosome region 15q11-13. In addition to typical characteristics such as hyperphagia, PWS is evidenced by a certain behavioral phenotype. Common indicators are repetitive behaviors, temper tantrums, and self-injurious behaviors such as skin- and/or rectal picking. N-Acetylcysteine (NAC) was previously described as a promising therapeutic option for skin picking in PWS. In this case series, we retrospectively investigated the effect of pharmacotherapy with NAC in 14 individuals with PWS suffering from skin- and/or rectal picking. Treatment success was determined using the Clinical Global Impression-Improvement scale (CGI-I). The Clinical Global Impression-Efficacy index (CGI-EI) was used to put treatment success and side effects into perspective. Six of fourteen patients, all of which were female, showed improvement in symptoms (dosage 1800-2400 mg/day), whereas six patients did not show any change during treatment. Moreover, two male patients treated for solitary rectal picking showed new onset of skin picking. Across all cases, a CGI-I of 3 (corresponding to minimal improvement) was seen after 3 months of treatment, with a CGI-EI of 1.6 (corresponding to moderate efficacy). NAC remains a reasonable therapeutic option in certain cases of skin picking in PWS but provides only limited efficacy compared to previous studies on the topic. There was a higher rate of adverse drug reactions than previously reported. The results particularly suggest caution in future treatment in individuals with solitary rectal picking and reduced efficacy when coadministered with neuroleptics.}, } @article {pmid34850077, year = {2021}, author = {Hu, M and Zhang, Y and Ma, S and Li, J and Wang, X and Liang, M and Sferruzzi-Perri, AN and Wu, X and Ma, H and Brännström, M and Shao, LR and Billig, H}, title = {Suppression of uterine and placental ferroptosis by N-acetylcysteine in a rat model of polycystic ovary syndrome.}, journal = {Molecular human reproduction}, volume = {27}, number = {12}, pages = {}, doi = {10.1093/molehr/gaab067}, pmid = {34850077}, issn = {1460-2407}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Dihydrotestosterone ; Disease Models, Animal ; Female ; Ferroptosis/*drug effects ; Glutathione/metabolism ; Insulin Resistance ; Iron/metabolism ; Malondialdehyde/metabolism ; Mitochondria/*drug effects/metabolism/ultrastructure ; Oxidative Phosphorylation ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Placenta/*drug effects/metabolism/ultrastructure ; Polycystic Ovary Syndrome/chemically induced/metabolism/pathology/*prevention & control ; Pregnancy ; Rats, Sprague-Dawley ; Signal Transduction ; Uterus/*drug effects/metabolism/ultrastructure ; Rats ; }, abstract = {The mechanisms that link hyperandrogenism and insulin (INS) resistance (HAIR) to the increased miscarriage rate in women with polycystic ovary syndrome (PCOS) remain elusive. Previous studies demonstrate that increased uterine and placental ferroptosis is associated with oxidative stress-induced fetal loss in a pre-clinical PCOS-like rat model. Here, we investigated the efficacy and molecular mechanism of action of the antioxidant N-acetylcysteine (NAC) in reversing gravid uterine and placental ferroptosis in pregnant rats exposed to 5α-dihydrotestosterone (DHT) and INS. Molecular and histological analyses showed that NAC attenuated DHT and INS-induced uterine ferroptosis, including dose-dependent increases in anti-ferroptosis gene content. Changes in other molecular factors after NAC treatment were also observed in the placenta exposed to DHT and INS, such as increased glutathione peroxidase 4 protein level. Furthermore, increased apoptosis-inducing factor mitochondria-associated 2 mRNA expression was seen in the placenta but not in the uterus. Additionally, NAC was not sufficient to rescue DHT + INS-induced mitochondria-morphological abnormalities in the uterus, whereas the same treatment partially reversed such abnormalities in the placenta. Finally, we demonstrated that NAC selectively normalized uterine leukemia inhibitory factor, osteopontin/secreted phosphoprotein 1, progesterone receptor, homeobox A11 mRNA expression and placental estrogen-related receptor beta and trophoblast-specific protein alpha mRNA expression. Collectively, our data provide insight into how NAC exerts beneficial effects on differentially attenuating gravid uterine and placental ferroptosis in a PCOS-like rat model with fetal loss. These results indicate that exogenous administration of NAC represents a potential therapeutic strategy in the treatment of HAIR-induced uterine and placental dysfunction.}, } @article {pmid34841761, year = {2021}, author = {Ji, LW and Deng, Y and Li, T}, title = {[Effect of Ketone Body β-Hydroxybutyrate to Attenuate Inflammation-Induced Mitochondrial Oxidative Stress in Vascular Endothelial Cells].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {52}, number = {6}, pages = {954-959}, pmid = {34841761}, issn = {1672-173X}, mesh = {3-Hydroxybutyric Acid ; Cells, Cultured ; Human Umbilical Vein Endothelial Cells ; Humans ; *Inflammation ; *Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {OBJECTIVE: To investigate the regulatory function and mechanism of β-hydroxybutyrate (β-OHB), a ketone body, on the mitochondrial oxidative stress of inflammatory human umbilical vein endothelial cells (HUVECs).

METHODS: Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were used to induce macrophages to release proinflammatory factors, and the culture supernatant was collected as a macrophage-conditioned medium (MCM) to culture HUVECs. A total of 7 groups of cells were used in the study: ①control group, or normal cultured HUVECs; ②MCM group, or the MCM-cultured HUVECs; groups ③ to ⑦ were all HUVECs co-cultured with different reagents, including ③MCM+β-OHB group, ④MCM+N-acetylcysteine (NAC) group, ⑤MCM+β-OHB+NAC group, ⑥MCM+β-OHB+histone deacetylase agonist ITSA1 group, and ⑦MCM+β-OHB+histone deacetylase inhibitor Entinostat group. MitoSOX immunofluorescence staining was conducted to analyzes the mitochondrial superoxide levels, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was performed to examine the mRNA expression of antioxidant genes, and Seahorse mitochondrial energy analyzer was used to measure mitochondrial aerobic respiration capacity.

RESULTS: Compared with the control group, mitochondrial superoxide production was significantly increased in the MCM cultured HUVECs cells, while β-OHB treatment significantly inhibited mitochondrial superoxide production, which was accompanied by an increase in the mRNA expression of antioxidant genes, and significant increase in the basal mitochondrial oxygen consumption rate and respiratory reserve capacity. NAC treatment did not further enhance the protective effect of β-OHB on mitochondrial functions. In addition, ITSA1 treatment could completely offset the antioxidant and mitochondrial protective effects of β-OHB, and these stated effects were still maintained after Entinostat treatment.

CONCLUSION: The ketone body β-OHB attenuates the mitochondrial oxidative stress of vascular endothelial cells through activating the antioxidant pathway and inhibiting histone deacetylase activity.}, } @article {pmid34840312, year = {2022}, author = {Laoprasopwattana, K and Khantee, P and Saelim, K and Geater, A}, title = {Mortality Rates of Severe Dengue Viral Infection Before and After Implementation of a Revised Guideline for Severe Dengue.}, journal = {The Pediatric infectious disease journal}, volume = {41}, number = {3}, pages = {211-216}, pmid = {34840312}, issn = {1532-0987}, mesh = {Acute Kidney Injury/etiology/mortality ; Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Liver Failure, Acute/epidemiology/etiology ; Liver Function Tests ; Male ; *Mortality ; Multiple Organ Failure/etiology/mortality ; Respiratory Distress Syndrome/epidemiology/mortality ; Severe Dengue/complications/diagnosis/*mortality/*physiopathology ; Shock/etiology/mortality ; }, abstract = {OBJECTIVES: To compare the mortality rate of severe dengue (SD) before and after implementation of a revised SD guideline.

METHODS: Medical records of SD patients <15 years of age hospitalized during 1998-2020 were reviewed. The revised SD guidelines were implemented in 2016, including intensive monitoring of vital signs and intra-abdominal pressure, the release of intra-abdominal pressure in cases of abdominal compartment syndrome (ACS) and the use of N-acetyl cysteine in cases of acute liver failure.

RESULTS: On initial admission, organ failure including severe bleeding, acute respiratory failure, acute kidney injury and acute liver failure was not significantly different between 78 and 23 patients treated in the pre- and postrevised guideline periods, respectively. After hospitalization, the proportions of patients who developed profound shock (68.8% vs. 41.2%), multiorgan failures (60.4% vs. 73.3%), ACS (37.2% vs. 26.1%) and fatal outcome (33.3% vs. 13.0%) were also not significantly different between the pre- and postrevised guideline periods, respectively. In subgroup analysis, the mortality rates in patients with multiorgan failure (44.1% vs. 15.8%), acute respiratory failure and active bleeding (78.1% vs. 37.5%) and ACS (82.8% vs. 33.3%), respectively, were significantly higher in the pre- than the postrevised guideline periods. The durations of time before the liver function tests returned to normal levels, and the mortality rates in acute liver failure patients treated with and without N-acetyl cysteine were not significantly different.

CONCLUSIONS: Although following the revised guidelines could not prevent organ failure, the mortality rates in patients with multiorgan failure and/or ACS decreased significantly when following the revised guidelines.}, } @article {pmid34834918, year = {2021}, author = {Mendonça-Vieira, LR and Aníbal-Silva, CE and Menezes-Neto, A and Azevedo, EAN and Zanluqui, NG and Peron, JPS and Franca, RFO}, title = {Reactive Oxygen Species (ROS) Are Not a Key Determinant for Zika Virus-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells.}, journal = {Viruses}, volume = {13}, number = {11}, pages = {}, pmid = {34834918}, issn = {1999-4915}, mesh = {*Apoptosis ; Cell Line, Tumor ; Humans ; Mitochondria/genetics/metabolism ; Neuroblastoma/metabolism/*physiopathology/virology ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Zika Virus/genetics/*physiology ; Zika Virus Infection/metabolism/*physiopathology/virology ; }, abstract = {INTRODUCTION: ZIKV is a highly neurotropic virus that can cause the death of infected neuroprogenitor cells through mitochondrial damage and intrinsic apoptotic signaling. In this context, the role of reactive oxygen species (ROS) in neuronal cell death caused by ZIKV still remains elusive.

OBJECTIVE: We aimed at evaluating the role of these cellular components in the death of human undifferentiated neuroblastoma cell line infected with ZIKV.

RESULTS: ZIKV infection resulted in the extensive death of SH-SY5Y cells with the upregulation of several genes involved in survival and apoptotic responses as well as the colocalization of mitochondrial staining with ZIKV Envelope (E) protein. Notably, levels of intracellular reactive oxygen species (ROS) were not altered during ZIKV infection in undifferentiated SH-SY5Y cells, and consistent with these results, the treatment of infected cells with the widely studied ROS scavenger N-acetylcysteine (NAC) did not prevent cell death in these cells.

CONCLUSION: Altogether, our results suggest that excessive ROS production is not the main trigger of SH-SY5Y cells death in ZIKV infection.}, } @article {pmid34834129, year = {2021}, author = {Wang, KC and Lu, MC and Hsu, KC and El-Shazly, M and Shih, SP and Lien, ST and Kuo, FW and Yang, SC and Chen, CL and Yang, YSH}, title = {The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {22}, pages = {}, pmid = {34834129}, issn = {1420-3049}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; HSP90 Heat-Shock Proteins/*metabolism ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Mitochondria/drug effects/metabolism ; Quinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC50 values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 μM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 μg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.}, } @article {pmid34833436, year = {2021}, author = {Teder, K and Maddison, L and Soeorg, H and Meos, A and Karjagin, J}, title = {The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {57}, number = {11}, pages = {}, pmid = {34833436}, issn = {1648-9144}, support = {DoRa 3//Archimedes Foundation/ ; PUT1197, IUT34-24//Estonian Research Council/ ; }, mesh = {*Acetylcysteine ; Biological Availability ; Critical Illness ; Humans ; Intensive Care Units ; *Pneumonia, Ventilator-Associated/drug therapy/prevention & control ; }, abstract = {Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC's pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3-16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.}, } @article {pmid34831255, year = {2021}, author = {Wang, Y and Pandak, WM and Lesnefsky, EJ and Hylemon, PB and Ren, S}, title = {25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models.}, journal = {Cells}, volume = {10}, number = {11}, pages = {}, pmid = {34831255}, issn = {2073-4409}, support = {1I01BX003656/VA/VA/United States ; Research aggrement//Durect corporation/ ; }, mesh = {Animals ; Apoptosis/drug effects/genetics ; Chemical and Drug Induced Liver Injury/*drug therapy/genetics/physiopathology ; Cholesterol Esters/pharmacology/*therapeutic use ; CpG Islands/genetics ; DNA Demethylation ; Disease Models, Animal ; Female ; Gene Expression Regulation/drug effects ; Hydroxycholesterols/pharmacology/*therapeutic use ; Liver/drug effects/injuries/metabolism/pathology ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Models, Biological ; Organ Specificity/drug effects ; Oxidants/metabolism ; Mice ; }, abstract = {Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure (ALF). N-acetylcysteine (NAC) is currently being used as part of the standard care in the clinic but its usage has been limited in severe cases, in which liver transplantation becomes the only treatment option. Therefore, there still is a need for a specific and effective therapy for APAP induced ALF. In the current study, we have demonstrated that treatment with 25-Hydroxycholesterol 3-Sulfate (25HC3S) not only significantly reduced mortality but also decreased the plasma levels of liver injury markers, including LDH, AST, and ALT, in APAP overdosed mouse models. 25HC3S also decreased the expression of those genes involved in cell apoptosis, stabilized mitochondrial polarization, and significantly decreased the levels of oxidants, malondialdehyde (MDA), and reactive oxygen species (ROS). Whole genome bisulfite sequencing analysis showed that 25HC3S increased demethylation of [5m]CpG in key promoter regions and thereby increased the expression of those genes involved in MAPK-ERK and PI3K-Akt signaling pathways. We concluded that 25HC3S may alleviate APAP induced liver injury via up-regulating the master signaling pathways and maintaining mitochondrial membrane polarization. The results suggest that 25HC3S treatment facilitates the recovery and significantly decreases the mortality of APAP induced acute liver injury and has a synergistic effect with NAC in propylene glycol (PG) for the injury.}, } @article {pmid34830394, year = {2021}, author = {Phoo, NLL and Dejkriengkraikul, P and Khaw-On, P and Yodkeeree, S}, title = {Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death.}, journal = {International journal of molecular sciences}, volume = {22}, number = {22}, pages = {}, pmid = {34830394}, issn = {1422-0067}, support = {Grant no. 14/2564//Chiang Mai University, the Center for Research and Development of Natural Products for Health/ ; Grant No. 163/2563//by Faculty of Medicine Research Fund/ ; }, mesh = {20-Hydroxysteroid Dehydrogenases/*genetics ; Aldo-Keto Reductase Family 1 Member C3/*genetics ; Autophagic Cell Death/drug effects/genetics ; Carcinoma, Signet Ring Cell/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Cisplatin/pharmacology ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Stomach Neoplasms/*drug therapy/genetics/pathology ; Transcriptome/drug effects ; }, abstract = {Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin-resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying cisplatin resistance. Transcriptomic and bioinformatic analyses were used to identify the candidate gene. This was confirmed by qPCR and Western blot. Aldoketoreductase1C1 and 1C3 (AKR1C1 and AKR1C3) were the most promising molecules in KATO/DDP cells. A specific inhibitor of AKR1C1 (5PBSA) and AKR1C3 (ASP9521) was used to enhance cisplatin-induced KATO/DPP cell death. Although cisplatin alone induced KATO/DDP apoptosis, a combination treatment of cisplatin and the AKR1C inhibitors had no influence on percent cell apoptosis. In conjunction with the autophagy inhibitor, 3MA, attenuated the effects of 5PBSA or ASP9521 to enhance cisplatin-induced cell death. These results indicated that AKR1C1 and 1C3 regulated cisplatin-induced KATO/DDP cell death via autophagy. Moreover, cisplatin in combination with AKR1C inhibitors and N-acetyl cysteine increased KATO/DDP cells' viability when compared with a combination treatment of cisplatin and the inhibitors. Taken together, our results suggested that AKR1C1 and 1C3 play a crucial role in cisplatin resistance of SRCGC by regulating redox-dependent autophagy.}, } @article {pmid34830376, year = {2021}, author = {Kang, J and Bishayee, K and Huh, SO}, title = {Azoxystrobin Impairs Neuronal Migration and Induces ROS Dependent Apoptosis in Cortical Neurons.}, journal = {International journal of molecular sciences}, volume = {22}, number = {22}, pages = {}, pmid = {34830376}, issn = {1422-0067}, support = {2019M3C7A1032601//National Research Foundation of Korea/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Autistic Disorder/chemically induced/genetics/pathology ; Cell Movement/drug effects ; Cell Survival/drug effects ; Female ; Fungicides, Industrial/toxicity ; Humans ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mice ; Mitochondria/drug effects ; Neurogenesis/*drug effects ; Neuronal Outgrowth/drug effects ; Neurons/*drug effects/pathology ; Pregnancy ; Prenatal Exposure Delayed Effects ; Pyrimidines/*pharmacology/toxicity ; Reactive Oxygen Species/antagonists & inhibitors ; Strobilurins/*pharmacology/toxicity ; }, abstract = {Fungicides often cause genotoxic stress and neurodevelopmental disorders such as autism (ASD). Fungicide-azoxystrobin (AZOX) showed acute and chronic toxicity to various organisms, and remained a concern for ill effects in developing neurons. We evaluated the neurotoxicity of AZOX in developing mouse brains, and observed prenatal exposure to AZOX reduced neuronal viability, neurite outgrowth, and cortical migration process in developing brains. The 50% inhibitory concentration (IC50) of AZOX for acute (24 h) and chronic (7 days) exposures were 30 and 10 μM, respectively. Loss in viability was due to the accumulation of reactive oxygen species (ROS), and inhibited neurite outgrowth was due to the deactivation of mTORC1 kinase activity. Pretreatment with ROS scavenger- N-acetylcysteine (NAC) reserved the viability loss and forced activation of mTORC1 kinase revived the neurite outgrowth in AZOX treated neurons. Intra-amniotic injection of AZOX coupled with in utero electroporation of GFP-labelled plasmid in E15.5 mouse was performed and 20 mg/kg AZOX inhibited radial neuronal migration. Moreover, the accumulation of mitochondria was significantly reduced in AZOX treated primary neurons, indicative of mitochondrial deactivation and induction of apoptosis, which was quantified by Bcl2/Bax ratio and caspase 3 cleavage assay. This study elucidated the neurotoxicity of AZOX and explained the possible cure from it.}, } @article {pmid34829701, year = {2021}, author = {Tsai, MF and Chen, SM and Ong, AZ and Chung, YH and Chen, PN and Hsieh, YH and Kang, YT and Hsu, LS}, title = {Shikonin Induced Program Cell Death through Generation of Reactive Oxygen Species in Renal Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {34829701}, issn = {2076-3921}, support = {109-2320-B-040-022-//Ministry of Science and Technology/ ; }, abstract = {Shikonin mitigated tumor cell proliferation by elevating reactive oxygen species (ROS) levels. Herein, we investigated the effects of shikonin on renal cancer cell (RCC) cell proliferation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that shikonin dose-dependently reduced the proliferation of Caki-1 and ACHN cells. Shikonin remarkably triggered necrosis and apoptosis in Caki-1 and ACHN cells in proportion to its concentration. Moreover, necrostatin-1 recovered cell viability in the presence of shikonin. Elevated ROS levels and mitochondrial dysfunction were also found in shikonin treatment groups. Pretreatment with N-acetyl cysteine remarkably mitigated shikonin-induced cell death and ROS generation. Western blot analysis revealed that shikonin reduced pro-PARP, pro-caspase-3, and Bcl-2 expression and increased cleavage PARP expression. Enhanced autophagy was also found in the shikonin-treated group as evidenced by acridine orange staining. Moreover, light chain 3B (LC3B)-II accumulation and enhanced p62 expression indicated that autophagy occurred in the shikonin-treated group. LC3B knockdown considerably recovered cell viability in the presence of shikonin. Shikonin treatment elevated p38 activity in a dose-dependent manner. In conclusion, our results revealed that shikonin triggered programmed cell death via the elevation of ROS level and p38 activity in different types of RCC cells. These findings suggested that shikonin may be a potential anti-RCC agent.}, } @article {pmid34829610, year = {2021}, author = {Henry, ML and Velez-Irizarry, D and Pagan, JD and Sordillo, L and Gandy, J and Valberg, SJ}, title = {The Impact of N-Acetyl Cysteine and Coenzyme Q10 Supplementation on Skeletal Muscle Antioxidants and Proteome in Fit Thoroughbred Horses.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {34829610}, issn = {2076-3921}, support = {N/A//McPhail Equine Endowment, Michigan State University/ ; N/A//Kentucky Equine Research, Versailles, KY/ ; N/A//Martha Wolfson Endowment, Michigan State University/ ; }, abstract = {Horses have one of the highest skeletal muscle oxidative capacities amongst mammals, which, combined with a high glycolytic capacity, could perturb redox status during maximal exercise. We determined the effect of 30 d of oral coenzyme Q10 and N-acetyl-cysteine supplementation (NACQ) on muscle glutathione (GSH), cysteine, ROS, and coenzyme Q10 concentrations, and the muscle proteome, in seven maximally exercising Thoroughbred horses using a placebo and randomized cross-over design. Gluteal muscle biopsies were obtained the day before and 1 h after maximal exercise. Concentrations of GSH, cysteine, coenzyme Q10, and ROS were measured, and citrate synthase, glutathione peroxidase, and superoxide dismutase activities analyzed. GSH increased significantly 1 h post-exercise in the NACQ group (p = 0.022), whereas other antioxidant concentrations/activities were unchanged. TMT proteomic analysis revealed 40 differentially expressed proteins with NACQ out of 387 identified, including upregulation of 13 mitochondrial proteins (TCA cycle and NADPH production), 4 Z-disc proteins, and down regulation of 9 glycolytic proteins. NACQ supplementation significantly impacted muscle redox capacity after intense exercise by enhancing muscle glutathione concentrations and increasing expression of proteins involved in the uptake of glutathione into mitochondria and the NAPDH-associated reduction of oxidized glutathione, without any evident detrimental effects on performance.}, } @article {pmid34826043, year = {2022}, author = {Liu, XD and Song, CY and Kong, CC and Tian, X}, title = {Bufalin Induces Programmed Necroptosis in Triple-Negative Breast Cancer Drug-Resistant Cell Lines through RIP1/ROS-Mediated Pathway.}, journal = {Chinese journal of integrative medicine}, volume = {28}, number = {10}, pages = {900-908}, pmid = {34826043}, issn = {1993-0402}, mesh = {Antioxidants/pharmacology ; Apoptosis ; Bufanolides ; Caspase 3/metabolism ; Cell Line ; Cell Line, Tumor ; Cysteine/pharmacology ; Docetaxel/pharmacology ; Doxorubicin/pharmacology ; Fluorescein-5-isothiocyanate/pharmacology ; Humans ; *Necroptosis ; Propidium/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor ; *Triple Negative Breast Neoplasms/drug therapy ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {OBJECTIVE: To explore the effect and mechanism of action of bufalin in triple-negative breast cancer (TNBC) drug-resistant cell lines.

METHODS: The normal human mammary epithelial cell line, TNBC cell line, TNBC adriamycin-resistant cell line, and TNBC docetaxel-resistant cell line were treated with different doses of bufalin (0-1,000 nmol/L) at different time points (0-72 h). Propidium iodide staining, AV-FITC/PI double staining, Hoechst 33342/PI double staining and transmission electron microscopy (TEM) were used to evaluate the death patterns of the cell lines.

RESULTS: Bufalin killed the TNBC cell line and its drug-resistant cell lines in a dose/time-dependent manner (all P<0.01). After treatment with bufalin for 24 h, the adriamycin-resistant cell line showed a co-existing pattern of necroptosis and apoptosis. However, at 48 h, necroptosis was the main manifestation. After treatment with bufalin, the expressions of tumor necrosis factor α, phospho-tumor necrosis factor receptor 1, phospho-receptor interacting protein 1 and c-caspase 3 increased (all P<0.01), the killing effect of bufalin could be mostly inhibited by NEC-1, and by z-VAD-fmk (both P<0.01). Besides, the intracellular reactive oxygen species (ROS) levels increased considerably (P<0.01), the antioxidant N-acetyl cysteine or Nec-1 could inhibit the increase of ROS level and the killing effect of bufalin (all P<0.01). The adriamycin-resistant cell line exhibited necroptosis characteristic after 48 h of bufalin treatment under TEM.

CONCLUSIONS: Bufalin could induce necroptosis through RIP1/ROS-mediated pathway to kill the drug-resistant TNBC cell lines. This finding provides critical experimental data and theoretical basis for the clinical application of bufalin to overcome the difficulties in the treatment of TNBC.}, } @article {pmid34825328, year = {2022}, author = {Elsayed, A and Elkomy, A and Alkafafy, M and Elkammar, R and El-Shafey, A and Soliman, A and Aboubakr, M}, title = {Testicular toxicity of cisplatin in rats: ameliorative effect of lycopene and N-acetylcysteine.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {16}, pages = {24077-24084}, pmid = {34825328}, issn = {1614-7499}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; *Cisplatin/toxicity ; Lycopene/metabolism/pharmacology ; Male ; Oxidative Stress ; Rats ; Spermatozoa ; Superoxide Dismutase/metabolism ; *Testis ; }, abstract = {Lycopene (LP) and N-acetylcysteine (NAC) protective effects were assessed for testicular toxicity mediated by cisplatin (CP) in rats. Forty-nine rats were divided into 7 groups (n = 7); these groups included the control group (saline, PO), LP (10 mg/kg, PO), NAC (150 mg/kg, PO), CP (7.5 mg/kg, IP) on the 27th day of the study, LP + CP, NAC+CP, and LP + NAC + CP. Serum levels of testosterone were decreased following CP injection. Malondialdehyde (MDA) has been increased with considerable glutathione (GSH), and dismutase superoxide (SOD) and catalase (CAT) decline in the testis tissues after CP injection. CP caused severe alterations in testicular tissues and elevated caspase-3 expression. Besides that, LP and/or NAC administration improved CP-induced testicular toxicity and apoptosis, probably via their antioxidant properties.}, } @article {pmid34822616, year = {2021}, author = {Petkova, T and Milanova, A}, title = {Absorption of N-acetylcysteine in Healthy and Mycoplasma gallisepticum-Infected Chickens.}, journal = {Veterinary sciences}, volume = {8}, number = {11}, pages = {}, pmid = {34822616}, issn = {2306-7381}, abstract = {N-acetylcysteine (NAC) is widely used as a mucolytic agent in cases with inflammation of the lungs. NAC is applied in poultry with aflatoxin B1 intoxication as an antioxidant, but its pharmacokinetics are not known. The present study was conducted to characterize the population pharmacokinetics of orally administered NAC in broilers. It included 32 chickens, divided into four groups, treated with NAC at a dose rate of 100 mg/kg/day mixed with the feed: healthy broilers (n = 6); chickens infected with Mycoplasma gallisepticum (n = 10); healthy broilers (n = 6); and diseased chickens (n = 10) treated with NAC and doxycycline (via drinking water, 20 mg/kg body weight (b.w.)). Plasma concentrations were analyzed by Liquid Chromatography -Mass Spectrometry (MS)/MS. NAC was absorbed after oral administration in all four groups of chickens. In healthy chickens treated solely with NAC, maximum plasma concentrations of 2.26 ± 0.91 µg mL[-1] were achieved at 2.47 ± 0.45 h after dosing. The value of absorption half-life was 1.04 ± 0.53 h. The population pharmacokinetic analysis showed that dose adjustment of NAC is not required in M. gallisepticum-infected broilers or when it is combined with doxycycline.}, } @article {pmid34820428, year = {2021}, author = {Zhang, J and Feng, W and Li, M and Chen, P and Ning, X and Ou, C and Chen, M}, title = {Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis.}, journal = {Frontiers in cardiovascular medicine}, volume = {8}, number = {}, pages = {737652}, pmid = {34820428}, issn = {2297-055X}, abstract = {Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. In this study, we aimed to investigate Cd-mediated AS through macrophage polarization and know the mechanisms of Cd-caused mitochondrial homeostasis imbalance. In vitro, flow cytometry shows that Cd exposure promotes M1-type polarization of macrophages, manifested as the increasing expressions of nuclear Factor kappa-light-chain-enhancer of activated B (NF-kB) and NLR family pyrin domain containing 3 (NLRP3). Mitochondrial homeostasis tests revealed that decreasing mitochondrial membrane potential and mitophage, increasing the mitochondrial superoxide (mROS), and mitochondrial fission are involved in the Cd-induced macrophage polarization. The upregulated expressions of receptor-interacting protein kinase 3 (RIPK3) and pseudokinase-mixed lineage kinase domain-like protein (p-MLKL) were observed. Knocking out RIPK3, followed by decreasing the expression of p-MLKL, improves the mitochondrial homeostasis imbalance which effectively reverses macrophage polarization. In vivo, the oil red O staining showed that Cd with higher blood significantly aggravates AS. Besides, M1-type polarization of macrophages and mitochondrial homeostasis imbalance were observed in the aortic roots of the mice through immunofluorescence and western blot. Knocking out RIPK3 restored the changes above. Finally, the administered N-acetyl cysteine (NAC) or mitochondrial division inhibitor-1 (Mdivi-1), which decreased the mROS or mitochondrial fission, inhibited the expressions of RIPK3 and p-MLKL, attenuating AS and macrophage M1-type polarization in the Cd-treated group. Consequently, the Cd exposure activated the RIPK3 pathway and impaired the mitochondrial homeostasis, resulting in pro-inflammatory macrophage polarization and subsequent AS. Knocking out RIPK3 provided a potential therapeutic target for Cd-caused macrophage polarization and subsequent AS.}, } @article {pmid34816377, year = {2022}, author = {Jaafarzadeh, M and Mahjoob Khaligh, R and Mohsenifar, Z and Shabani, A and Rezvani Gilkalaei, M and Rajabi Keleshteri, S and Beigi Harchegani, A}, title = {Protecting Effects of N-acetyl Cysteine Supplementation Against Lead and Cadmium-Induced Brain Toxicity in Rat Models.}, journal = {Biological trace element research}, volume = {200}, number = {10}, pages = {4395-4403}, pmid = {34816377}, issn = {1559-0720}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Brain/metabolism ; Cadmium/toxicity ; Dietary Supplements ; Lead/toxicity ; Male ; *Metals, Heavy/pharmacology ; Oxidative Stress ; Rats ; }, abstract = {We aimed to investigate mitigating effects of N-acetylcysteine (NAC) on the oxidative stress, apoptosis and Parkinson's disease (PD)-related genes in the brain tissue of male rats exposed to continuous doses of cadmium and lead. Rats were randomly divided into five groups, including G1 (control), G2 (continuous dose of Cd), G3 (continuous dose of Pb), G4 (continuous dose of Cd + NAC), and G5 (continuous dose of Pb + NAC). Biomarkers of oxidative stress, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured. Expression of PD- and apoptosis-related genes was considered using RT-PCR. Chronic exposure to these heavy metals was associated with accumulation of Pb and Cd in the brain and blood and caused severe morphological changes in the brain, as well as decreased body and brain weights. Continuous exposure to Cd and Pb significantly decreased TAC content and SOD expression but increased MDA level in the brain tissues (P < 0.001). A significant increase was observed in expression of PD-related genes, Parkin, Pink1, LRRK2, SNCA, and Caspase-3 in the brain tissues following exposure to Cd and Pb. Pb exhibited stronger toxicity on the brain tissue compared to Cd. NAC supplementation not only improved morphological changes, but also compensated antioxidant capacity and expression of apoptosis- and PD-related genes in the brain tissues when compared to rats exposed to Pb and Cd alone. Chronic exposure to Pb and Cd is strongly associated with accumulation of these heavy metals in the brain, morphological changes, antioxidants depletion, oxidative stress, and brain cells apoptosis. Changes in expression of PD-related genes indicate the higher risk of PD among individuals who are chronically exposed to these heavy metals. NAC can protect brain tissue against Pb and Cd toxicity by elevating antioxidants capacity, mitigating oxidative stress, apoptosis, and down-regulating of PD-related genes.}, } @article {pmid34815794, year = {2021}, author = {Zhang, DY and Tu, T and Younis, MR and Zhu, KS and Liu, H and Lei, S and Qu, J and Lin, J and Huang, P}, title = {Clinically translatable gold nanozymes with broad spectrum antioxidant and anti-inflammatory activity for alleviating acute kidney injury.}, journal = {Theranostics}, volume = {11}, number = {20}, pages = {9904-9917}, pmid = {34815794}, issn = {1838-7640}, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/*drug therapy ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Disease Models, Animal ; Drug Delivery Systems/*methods ; Female ; Gold/chemistry ; HEK293 Cells ; Humans ; Kidney/drug effects ; Male ; Metal Nanoparticles/administration & dosage/chemistry/*therapeutic use ; Mice ; Mice, Inbred BALB C ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Rationale: Acute kidney injury (AKI) is associated with aberrant generation of oxidative species and inflammation, leading to high mortality of in-hospitalized patients. Although N-acetylcysteine (NAC) showed positive effects in alleviating contrast-induced AKI, the clinical applications are strongly restrained due to the low bioavailability, low renal accumulation, short renal retention time, and high dosage-induced toxicity. Methods: We addressed the clinical dilemma of NAC by developing ultrasmall gold nanoclusters (1-2 nm) capped with NAC (denoted as Au NCs-NAC) as a nanozyme-based antioxidant defense system for AKI alleviation. Rhabdomyolysis-induced AKI mice model was developed, and the same dose of free NAC (as a control) and NAC onto Au NCs (Au NCs-NAC) was used for in vivo investigation of AKI restoration. Results: The as-developed gold nanozyme exhibited high bioavailability and good physicochemical stability as compared to NAC. Meanwhile, Au NCs-NAC showed broad-spectrum antioxidant activity of Au NCs-NAC, offering in vitro renoprotective effects, as well as macrophages by relieving inflammation under hydrogen peroxide or lipopolysaccharide stimulation. Notably, owing to the smaller size than kidney threshold (5.5 nm), Au NCs-NAC displayed preferential renal enrichment (< 2 h) and longer retention (> 24 h) in AKI mice as revealed by fluorescence imaging, thereby largely enhancing the restoration of renal function in AKI mice than free NAC by protecting the kidneys from oxidative injury and inflammation without systemic toxicity, as demonstrated by tissues staining, inflammatory cytokines and biomarkers detection, and mice survival rate. Conclusion: Owing to the synergistic anti-inflammatory/antioxidative effects, and enhanced bioavailability and renal accumulation/retention, Au NCs-NAC displayed far superior therapeutic performance than NAC alone. This work will facilitate the development of high-performance antioxidative nanoplatforms, as well as overcome the clinical limitations of small molecular drugs for AKI treatment and other inflammatory diseases.}, } @article {pmid34814783, year = {2021}, author = {Hada, B and Karmacharya, MB and Park, SR and Choi, BH}, title = {Low-intensity ultrasound (LIUS) differentially modulates mitochondrial reactive oxygen species (mtROS) generation by three different chemicals in PC12 cells.}, journal = {Free radical research}, volume = {55}, number = {11-12}, pages = {1037-1047}, doi = {10.1080/10715762.2021.2010730}, pmid = {34814783}, issn = {1029-2470}, mesh = {Animals ; Glutathione/metabolism ; Ionomycin/metabolism ; *Mitochondria/metabolism ; PC12 Cells ; Rats ; Reactive Oxygen Species/metabolism ; *Rotenone/pharmacology ; }, abstract = {We have previously shown that low-intensity ultrasound (LIUS) can modulate mitochondrial complex I activity and the generation of mitochondrial reactive oxygen species (mtROS) in PC12 cells. This study investigated the mechanism of LIUS by comparing its effect on mitochondrial dysfunction by three different pathways. LIUS was shown to reverse the effects of rotenone, a Q-site blocker, on the complex I inhibition, mtROS generation, and drop of mitochondrial membrane potential (Δψm). In contrast, common antioxidants, N-acetyl cysteine (NAC), and uric acid (UA) blocked rotenone-induced mtROS generation and Δψm drop without recovering the complex I activity, which suggested that Δψm drop is correlated with mtROS generation rather than complex I inhibition itself. Ionomycin, an ionophore for Ca[2+], and L-buthionine-S,R-sulfoximine (BSO), an inhibitor of glutathione (GSH) biosynthesis, induced mtROS generation and Δψm drop without inhibiting complex I activity via different mechanisms. LIUS showed no effect on ionomycin-induced Δψm drop but showed partial inhibition on the other effects of ionomycin and BSO. These results suggest that LIUS might have redundant mechanisms but acted mainly on the complex I activity thereby modulating mtROS and Δψm levels. LIUS appeared to act on the Q-module of complex I because it showed no inhibitory effect on Zn[2+], an inhibitor of the proton transporting P-module of complex I. Interestingly, pretreatment of LIUS for up to an hour in advance blocked the rotenone effect as efficiently as the co-treatment. Further studies are needed to reveal the exact mechanism of LIUS to inhibit complex I activity.}, } @article {pmid34811378, year = {2021}, author = {Kim, S and Kim, SY and Rho, SJ and Kim, SH and Song, SH and Kim, CH and Lee, H and Kim, SK}, title = {Biocompatible N-acetyl-nanoconstruct alleviates lipopolysaccharide-induced acute lung injury in vivo.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {22662}, pmid = {34811378}, issn = {2045-2322}, support = {2020M3A9I4038197//Ministry of Science and ICT, South Korea/ ; 2020R1A6A3A01098476//Ministry of Education, South Korea/ ; 2E30341//Korea Institute of Science and Technology/ ; }, mesh = {Acute Lung Injury/*drug therapy ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; *Biocompatible Materials ; Biotechnology/methods ; Cytokines/metabolism ; Drug Delivery Systems ; Inflammation ; Lipopolysaccharides/*chemistry ; Lung/metabolism ; Male ; Microscopy, Electron, Transmission ; Nanoparticles ; Nanotechnology/methods ; Nitrogen ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; }, abstract = {Oxidative stress plays important roles in inflammatory responses during acute lung injury (ALI). Recently, nanoconstruct (Nano)-based drug-delivery systems have shown promise in many models of inflammation. In this study, we evaluated the anti-inflammatory effects of N-acetylcysteine (NAC) loaded in a biocompatible Nano using a rat model of ALI. We synthesized a Nano with a good NAC-releasing capacity using porous silica Nano, which was used to produce Nano/NAC complexes. For in vivo experiments, Sprague-Dawley rats were intraperitoneally administered NAC or Nano/NAC 30 min after intratracheal instillation of lipopolysaccharide. After 6 h, bronchoalveolar lavage fluids and lung tissues were collected. The anti-oxidative effect of the Nano/NAC complex was confirmed by demonstrating reduced levels of reactive oxygen species after treatment with the Nano/NAC in vitro. In vivo experiments also showed that the Nano/NAC treatment may protect against LPS-induced ALI thorough anti-oxidative and anti-inflammatory effects, which may be attributed to the inactivation of the NF-κB and MAPK pathways. In addition, the effects of Nano/NAC treatment were shown to be superior to those of NAC alone. We suggest the therapeutic potential of Nano/NAC treatment as an anti-inflammatory agent against ALI. Furthermore, our study can provide basic data for developing nanotechnology-based pharmacotherapeutics for ALI.}, } @article {pmid34801537, year = {2022}, author = {Jacobsen, J and Adomako-Bonsu, AG and Maser, E}, title = {Induction of carbonyl reductase 1 (CR1) gene expression in Daphnia magna by TNT, but not its key metabolites 2-ADNT and 4-ADNT.}, journal = {Chemico-biological interactions}, volume = {351}, number = {}, pages = {109752}, doi = {10.1016/j.cbi.2021.109752}, pmid = {34801537}, issn = {1872-7786}, mesh = {Aniline Compounds/pharmacology ; Animals ; Biomarkers/metabolism ; Carbonyl Reductase (NADPH)/genetics/*metabolism ; Daphnia/*drug effects ; Trinitrotoluene/*pharmacology ; Up-Regulation/*drug effects ; Water Pollutants, Chemical/*pharmacology ; }, abstract = {2,4,6-trinitrotoluene (TNT) is a known source of reactive oxygen species (ROS), which cause oxidative stress in aquatic ecosystems. Carbonyl reductases (CRs) are one of several possible defense mechanisms induced against ROS products, especially those that result in the 'so-called' carbonyl stress. Daphnia magna, a freshwater organism living in stagnant freshwater bodies, expresses four copies of the CR gene (Dma_CR1, Dma_CR2, Dma_CR3 and Dma_CR4). In this study, induction of all four copies of Dma_CR by 2-amino-4,6-dinitrotoluene (2-ADNT) and 4-amino-2,6-dinitrotoluene (4-ADNT), was investigated. Reverse transcription polymerase chain reaction (RT-PCR) analysis of treated daphnids revealed up-regulation of Dma_CR1 alone in response to TNT, but not 2-ADNT and 4-ADNT (which are key metabolites of TNT). This concentration- and time-dependent up-regulation in mRNA-expression was observed both in the presence and absence of light, in the same magnitude. Moreover, significant change in mRNA-expression could be observed 8 h after treatment with TNT. In the presence of TNT, the antioxidant N-acetylcysteine (NAc) could not reverse TNT-induced up-regulation of Dma_CR1 mRNA-expression. On the other hand, withdrawal of TNT from the culture medium caused a significant reduction in the TNT-induced mRNA-expression of Dma_CR1 within 24 h. These findings highlight the potential of Dma_CR1 as a biomarker for biomonitoring of TNT levels in freshwater bodies.}, } @article {pmid34801356, year = {2022}, author = {Parpoudi, S and Mantzoros, I and Gkiouliava, A and Kyziridis, D and Makrantonakis, A and Chatzakis, C and Gekas, C and Konstantaras, D and Ioannidis, O and Bitsianis, S and Miliaras, D and Aggelopoulos, S}, title = {Effect of N-acetyl-L-cysteine on inflammation after intraperitoneal mesh placement in a potentially contaminated environment: An experimental study in the rat.}, journal = {Asian journal of surgery}, volume = {45}, number = {11}, pages = {2191-2196}, doi = {10.1016/j.asjsur.2021.11.001}, pmid = {34801356}, issn = {0219-3108}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Ciprofloxacin ; Inflammation/prevention & control ; Interleukin-6 ; Male ; Rats ; Rats, Wistar ; *Surgical Mesh ; Tissue Adhesions/etiology/pathology/prevention & control ; }, abstract = {BACKGROUND: The use of prosthetic meshes in abdominal wall reconstruction is a well-established approach; however, in certain cases where a bowel resection coexists its application is disputed. Any underlying inflammatory process may augment adhesion formation which is a major postoperative complication. In this animal study, our aim was to investigate the effect of N-acetyl-l-cysteine (NAC) on adhesion formation and the expression of inflammatory markers when a mesh was used in a clean or a potentially contaminated environment.

METHODS: Sixty male Wistar rats were randomly and equally allocated in 3 groups: A, B and C. Animals in all groups underwent laparotomy, a prosthetic mesh was placed and chemoprophylaxis with ciprofloxacin was administered. In groups B and C an enterectomy was also performed. NAC was injected intraperitoneally in group C. Adhesion formation, IL-1a, IL-6, TNF-a and histological data including fibrosis, neutrophils' infiltration and neovascularization were assessed. Mesh samples were sent for cultivation.

RESULTS: Adhesion formation was significantly less and inflammation markers were also lower in group C compared to group B (p<0.05). Histological findings were significant for greater fibrosis, neutrophils' infiltration and neovascularization in group B compared to both group A and C. Regarding mesh cultures, more specimens were tested positive in group B (p <0.05). Outcomes between group A and C did not differ.

CONCLUSION: NAC effectively ameliorated adhesion formation and inflammation in a potentially septic environment where a prosthetic mesh was placed.}, } @article {pmid34793863, year = {2022}, author = {Liu, Y and Yang, Z and Du, Y and Shi, S and Cheng, Y}, title = {Antioxidant interventions in autism spectrum disorders: A meta-analysis.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {113}, number = {}, pages = {110476}, doi = {10.1016/j.pnpbp.2021.110476}, pmid = {34793863}, issn = {1878-4216}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Autism Spectrum Disorder/*therapy ; Humans ; Oxidative Stress ; Randomized Controlled Trials as Topic ; Stereotyped Behavior ; }, abstract = {BACKGROUND: Autism spectrum disorder (ASD) might be associated with oxidative stress, and antioxidants are commonly used in the treatment of young people with ASD. However, the evidence about the effectiveness of these interventions remains debatable. We performed a meta-analysis to evaluate the effect of antioxidants on the symptoms of patients with autism.

METHODS: Data sources: PubMed and Web of Science databases.

STUDY SELECTION: We selected placebo-controlled, double-blind, randomized clinical trials published until February 2021 to evaluate the efficacy of antioxidant interventions on ASD.

DATA ANALYSIS: Aberrant Behavior Checklist (ABC), Repetitive Behavior Scale-Revised (RBS), Social Responsiveness Scale (SRS), Developmental Behavior Checklist (DBC) and Clinical Global Impressions Severity scale (CGIS) were used to evaluate the 22 different symptom outcomes. The Hedges-adjusted g value was used to estimate the effect of each dietary intervention relative to the placebo.

RESULTS: In this meta-analysis, we examined 13 double-blind randomized clinical trials, comprising a total of 570 patients with ASD: 293 in the intervention group and 277 in the placebo group. Antioxidants (N-acetylcysteine (NAC), other antioxidants) are more effective than placebos in improving the irritability among symptoms in the ABC and communication disturbance symptoms in the DBC. There was a good trend of improvement in the stereotypic behavior symptoms in the ABC. Treatment with NAC antioxidants showed a good trend of improvement in irritability in the ABC and symptoms of hyperactivity. The effect size was small, and there was a low risk of statistical heterogeneity and publication bias.

LIMITATIONS: The number of studies in this meta-analysis was small and the sample size was small.

CONCLUSION: This meta-analysis suggests that antioxidant intervention has a potential role in the management of some symptoms in patients with ASD, and indicates the feasibility of using antioxidants to treat autism in the future.}, } @article {pmid34785568, year = {2022}, author = {Qin, X and Hakenjos, JM and MacKenzie, KR and Barzi, M and Chavan, H and Nyshadham, P and Wang, J and Jung, SY and Guner, JZ and Chen, S and Guo, L and Krishnamurthy, P and Bissig, KD and Palmer, S and Matzuk, MM and Li, F}, title = {Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {50}, number = {2}, pages = {128-139}, pmid = {34785568}, issn = {1521-009X}, support = {P01 HD087157/HD/NICHD NIH HHS/United States ; R01 DK121970/DK/NIDDK NIH HHS/United States ; R01 GM115622/GM/NIGMS NIH HHS/United States ; R61 HD099995/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; *Depressive Disorder, Major/metabolism ; Duloxetine Hydrochloride/metabolism ; Mice ; Microsomes, Liver/metabolism ; Serotonin/metabolism ; *Serotonin and Noradrenaline Reuptake Inhibitors/metabolism ; }, abstract = {Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five N-acetyl cysteine adducts and one reduced glutathione (GSH) adduct associated with DLX. Additionally, the species differences of certain metabolites were observed between human and mouse liver microsomes. CYP1A2 and CYP2D6 are primary enzymes responsible for the formation of DLX metabolites in liver microsomes, including DLX-GSH adducts. In summary, a total of 39 DLX metabolites were identified, and species differences were noticed in vitro. The roles of CYP450s in DLX metabolite formation were also verified using human recombinant cytochrome P450 (P450) enzymes and corresponding chemical inhibitors. Further studies are warranted to address the exact role of DLX metabolism in its adverse effects in vitro (e.g., human primary hepatocytes) and in vivo (e.g., Cyp1a2-null mice). SIGNIFICANCE STATEMENT: This current study systematically investigated Duloxetine (DLX) metabolism and bioactivation in liver microsomes and mice. This study provided a global view of DLX metabolism and bioactivation in liver microsomes and mice, which are very valuable to further elucidate the mechanistic study of DLX-related adverse effects and drug-drug interaction from metabolic aspects.}, } @article {pmid34785186, year = {2022}, author = {Pourbagher-Shahri, AM and Schimmel, J and Shirazi, FM and Nakhaee, S and Mehrpour, O}, title = {Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review.}, journal = {Toxicology letters}, volume = {355}, number = {}, pages = {47-61}, doi = {10.1016/j.toxlet.2021.11.005}, pmid = {34785186}, issn = {1879-3169}, mesh = {Acetaminophen/*toxicity ; Antidotes/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; Fomepizole/*therapeutic use ; Humans ; }, abstract = {INTRODUCTION: Acetaminophen (paracetamol, APAP) poisoning is a prominent global cause of drug-induced liver injury. While N-acetylcysteine (NAC) is an effective antidote, it has therapeutic limitations in massive overdose or delayed presentation. The objective is to comprehensively review the literature on fomepizole as a potential adjunct antidote for acetaminophen toxicity.

METHODS: A scoping review was performed using standardized search terms from inception through July 2021.

RESULTS: Reports on fomepizole as a therapeutic adjunct for APAP toxicity span heterogeneous types of evidence. Eleven preclinical studies (in vitro and animal), fourteen case reports/series, and one human volunteer study were included. Fomepizole's action is mediated by inhibition of CYP2E1 to prevent oxidant stress generation, and inhibition of c-Jun N-terminal kinase (JNK) to decrease amplification of oxidant stress signaling to mitochondria. Studies have shown a reduction in oxidative metabolites likely by shunting metabolism away from CYP2E1 and a resultant decrease in liver injury in animals, independent of CYP2E1 interactions. Fomepizole has been linked to few adverse effects.

CONCLUSION: Based on in vitro and animal studies, and bolstered by case reports, fomepizole likely offers benefit as an adjunct antidote for APAP toxicity, however this remains to be shown in a human trial. NAC remains the standard of care antidote, but given that fomepizole is approved and generally safe, it may be considered for APAP toxicity as off-label use by experienced clinicians, in rare circumstances associated with increased risk of hepatotoxicity despite standard NAC dosing. The marginal clinical benefit of fomepizole adjunct therapy beyond NAC monotherapy remains to be clearly defined, and routine use for APAP overdose is premature based on current evidence.}, } @article {pmid34781617, year = {2021}, author = {Singh, K and Bhargava, V and Brar, JE and Bhargava, M and Kaushal, R and Khullar, D}, title = {Contrast Induced Acute Kidney Injury (CI- AKI) - Myths and Realities.}, journal = {The Journal of the Association of Physicians of India}, volume = {69}, number = {11}, pages = {11-12}, pmid = {34781617}, issn = {0004-5772}, mesh = {Acetylcysteine/therapeutic use ; *Acute Kidney Injury/chemically induced ; *Contrast Media/adverse effects ; Humans ; Renal Dialysis ; Risk Factors ; }, abstract = {Contrast Induced Acute Kidney Injury (CI-AKI) is one of the most common causes of acute kidney injury in hospitalized patients. These days, contrast agents are widely being used in both cardiology and radiology procedures. Old age, history of diabetes, heart failure, proteinuria and low blood pressure are some important risk factors in the pathogenesis of CI-AKI. Apart from risk stratification and the use of low and iso-osmolar contrast agents, intravenous fluid hydration with crystalloids is the only recommended strategy for the prevention of CI-AKI. Agents like N-acetylcysteine (NAC), atrial natriuretic peptide, ascorbic acid, theophylline, and fenoldopam have failed to show any proven beneficial role in the prevention of CI-AKI. Though hemodialysis is still being perceived by many clinicians as the modality for contrast removal but prophylactic hemodialysis is now not recommended for the prevention of CI-AKI.}, } @article {pmid34776986, year = {2021}, author = {Xiang, Y and Chen, X and Wang, W and Zhai, L and Sun, X and Feng, J and Duan, T and Zhang, M and Pan, T and Yan, L and Jin, T and Gao, Q and Wen, C and Ma, W and Liu, W and Wang, D and Wu, Q and Xie, T and Sui, X}, title = {Natural Product Erianin Inhibits Bladder Cancer Cell Growth by Inducing Ferroptosis via NRF2 Inactivation.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {775506}, pmid = {34776986}, issn = {1663-9812}, abstract = {Erianin, a natural product derived from Dendrobium chrysotoxum Lindl, has been proved to play antitumor activity in various cancers. However, the effects and molecular mechanisms of erianin in bladder cancer cells remain unexplored. In this study, we found that erianin triggered cell death and cell cycle arrest in bladder cancer cells. Then we demonstrated that erianin could promote the accumulation of lethal lipid-based reactive oxygen species (ROS) and the depletion of glutathione (GSH), suggesting the induction of ferroptosis. In the further study, the ferroptosis inhibitor deferoxamine (DFO), N-Acetylcysteine (NAC) and GSH but not necrostatin-1, CQ or Z-VAD-FMK rescued erianin-caused cell death, showing ferroptosis played a major role in erianin-caused cell death. In vivo, we also showed that erianin suppressed the tumor growth by inducing ferroptosis. Mechanistically, we demonstrated that nuclear factor E2-related factor 2 (NRF2) inactivation was a key determinant of ferroptosis caused by erianin. In bladder cancer cells, the compound tert-butylhydro-quinone (TBHQ), an activator of NRF2, suppressed erianin-induced ferroptosis. Whereas, NRF2 inhibition used shRNA augmented the ferroptosis response induced by erianin treatment. In conclusion, our data provide the first evidence that erianin can initiate ferroptosis-like cell death and lipid peroxidation in bladder cancer, which will hopefully become a promising anticancer compound for the treatment of bladder cancer.}, } @article {pmid34775122, year = {2022}, author = {Biswas, DP and Tk, DS}, title = {The efficacy of adjuvant N acetyl cysteine for the eradication of H pylori infections: A systematic review and meta-analysis of randomized clinical trials.}, journal = {Clinics and research in hepatology and gastroenterology}, volume = {46}, number = {3}, pages = {101832}, doi = {10.1016/j.clinre.2021.101832}, pmid = {34775122}, issn = {2210-741X}, mesh = {Adult ; Anti-Bacterial Agents/therapeutic use ; Clarithromycin/therapeutic use ; Cysteine/therapeutic use ; Drug Therapy, Combination ; *Helicobacter Infections/drug therapy ; *Helicobacter pylori ; Humans ; Proton Pump Inhibitors/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Biofilm-producing bacteria are relatively resistant to antibiotics, as the penetration of antibiotics into the endopolysaccharide envelope is incomplete. N Acetyl cysteine (NAC) is known to destabilize the biofilms, as it cleaves the disulfide bonds of mucus glycoproteins, reducing the viscosity and thickness of mucus. This allows NAC to act synergistically with antibiotics for the eradication of H Pylori. The meta-analysis evaluates the evidence of the efficacy of adjuvant N acetyl cysteine (NAC) compared to standard therapies in the eradication of H. Pylori infections.

METHODS: We searched randomized clinical trials in MEDLINE, Cochrane Central Register of Clinical Trials (CENTRAL), EBSCO, Database of Abstracts of Reviews of Effects (DARE), and Google Scholar. We included trials comparing standard treatment protocols plus adjuvant NAC and the same regimen without NAC. These studies included adults with a diagnosis of Helicobacter pylori infection. Our primary outcome was the successful eradication of H. Pylori. The results were pooled using a random-effects model, and data were analyzed using RevMan 5.0 software. Cochrane collaboration's tool was used to assess the risk of bias. Publication bias and other inconsistencies were assessed. Sensitivity analyses and grading of evidence were performed.

FINDINGS: Eight studies, comprising 1167 patients, were included in the meta-analysis, the pooled outcomes of patients on adjuvant NAC+ standard eradication therapy noted an eradication rate of 76.1% (n=581) compared to the patients in standard eradication therapy with a rate of 72.18% (n=586), RR 1.17 [95% CI (0.99, 1.39); I2= 64%; p value=0.07]. Moderate to severe heterogeneity was noted. These pooled results show that adjuvant NAC plus standard treatment protocols are not superior to standard treatment protocols for H pylori eradication. Similar results were seen in the use of adjuvant NAC with 'currently used standard treatment protocols' (78.3% versus 76.3%, RR 1.08, [95% CI 0.94 to 1.25]; I2=55%; p=0.28; n= 829 patients], as well as in the treatment of naïve patients (79.8% versus 80.9%, RR 1.00[95% CI 0.87 to 1.15]; i2=27%; P=-0.98; n= 775 patients].

CONCLUSION: Adjuvant NAC plus standard treatment protocols are not superior to standard treatment protocols for H. pylori eradication. These findings are consistent with the use of adjuvant NAC with 'currently used standard treatment protocols' (clarithromycin-based triple therapies) and also with adjuvant NAC used in the treatment of naïve patients. We are moderately certain of these findings. Future studies could explore the use of NAC as a pretreatment before using the current standard therapies in the eradication of H. Pylori rather than NAC as adjuvant therapy.

FUNDING: None.}, } @article {pmid34771053, year = {2021}, author = {Balaji, K and Vijayakumar, J and Sankaran, PK and Senthilkumar, S and Vijayaraghavan, R and Selvaraj, J and Yuvaraj, MF}, title = {Molecular Studies on the Nephroprotective Potential of Celastrus paniculatus against Lead-Acetate-Induced Nephrotoxicity in Experimental Rats: Role of the PI3K/AKT Signaling Pathway.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {21}, pages = {}, pmid = {34771053}, issn = {1420-3049}, mesh = {Animals ; Biomarkers ; Celastrus/*chemistry ; Female ; Gene Expression ; Immunohistochemistry ; Kidney/*drug effects/*metabolism/pathology/ultrastructure ; Organometallic Compounds/*adverse effects ; Phosphatidylinositol 3-Kinases/metabolism ; Plant Extracts/chemistry/*pharmacology ; Protective Agents/chemistry/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Signal Transduction/drug effects ; }, abstract = {Chemicals can induce nephrotoxicity, with damage to different segments of the nephron and deterioration of renal function. Nephrotoxicity due to exposure to a toxin such as carbon tetrachloride, sodium oxalate, or heavy metals is the most common cause of kidney injury. The current study aimed to evaluate the protective effects of Celastrus paniculatus seed extract against lead-acetate-induced nephrotoxicity by evaluating the histopathology, immunohistochemistry, ultrastructure, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Twenty-four rats were divided into four groups (n = 6 per group): group 1 contained normal animals and served as the control; group 2 received lead acetate (30 mg/kg body weight (b.w.)/day, oral); group 3 received lead acetate and the standard drug N-acetylcysteine (NAC, 200 mg/kg b.w./day, oral); and group 4 received lead acetate and the ethanolic extract of C. paniculatus seed (EECP; 800 mg/kg b.w./day, oral). Treatment was given for 28 consecutive days. The data were analyzed using one-way analysis of variance with SIGMA PLOT 13 using SYSTAT software followed by Newman-Keul's test for comparison between the groups. EECP ameliorated the adverse changes caused by lead acetate. PI3K and AKT messenger RNA (mRNA) levels were diminished in lead-acetate-treated rats. Treatment with EECP inhibited the occurrence of shrunken cells, the atrophy of glomeruli, and degenerative changes in renal tubules caused by lead acetate. Interestingly, the PI3K and AKT mRNA levels were significantly increased in EECP-treated animals. Our results clearly evidence for the first time that C. paniculatus seed extract inhibits lead-acetate-induced detrimental changes in kidneys by regulating PI3K/AKT signaling pathways.}, } @article {pmid34770989, year = {2021}, author = {Beck, C and Gren, T and Ortiz-López, FJ and Jørgensen, TS and Carretero-Molina, D and Martín Serrano, J and Tormo, JR and Oves-Costales, D and Kontou, EE and Mohite, OS and Mingyar, E and Stegmann, E and Genilloud, O and Weber, T}, title = {Activation and Identification of a Griseusin Cluster in Streptomyces sp. CA-256286 by Employing Transcriptional Regulators and Multi-Omics Methods.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {21}, pages = {}, pmid = {34770989}, issn = {1420-3049}, support = {NNF20CC0035580//Novo Nordisk Foundation/ ; NNF16OC0021746//Novo Nordisk Foundation/ ; 9.818//German Center for Infection Research/ ; 398967434//German Research Foundation (DFG), TRR261/ ; }, mesh = {*Computational Biology ; Molecular Structure ; Naphthoquinones/analysis/metabolism ; Streptomyces/*chemistry/metabolism ; Transcription Factors/genetics/*metabolism ; Transcription, Genetic/genetics ; }, abstract = {Streptomyces are well-known producers of a range of different secondary metabolites, including antibiotics and other bioactive compounds. Recently, it has been demonstrated that "silent" biosynthetic gene clusters (BGCs) can be activated by heterologously expressing transcriptional regulators from other BGCs. Here, we have activated a silent BGC in Streptomyces sp. CA-256286 by overexpression of a set of SARP family transcriptional regulators. The structure of the produced compound was elucidated by NMR and found to be an N-acetyl cysteine adduct of the pyranonaphtoquinone polyketide 3'-O-α-d-forosaminyl-(+)-griseusin A. Employing a combination of multi-omics and metabolic engineering techniques, we identified the responsible BGC. These methods include genome mining, proteomics and transcriptomics analyses, in combination with CRISPR induced gene inactivations and expression of the BGC in a heterologous host strain. This work demonstrates an easy-to-implement workflow of how silent BGCs can be activated, followed by the identification and characterization of the produced compound, the responsible BGC, and hints of its biosynthetic pathway.}, } @article {pmid34768986, year = {2021}, author = {Ramburrun, P and Kumar, P and Ndobe, E and Choonara, YE}, title = {Gellan-Xanthan Hydrogel Conduits with Intraluminal Electrospun Nanofibers as Physical, Chemical and Therapeutic Cues for Peripheral Nerve Repair.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34768986}, issn = {1422-0067}, support = {n/a//National Research Foundation of South Africa/ ; n/a//NRF South African Research Chairs Initiative/ ; n/a//University Research Committee of the University of the Witwatersrand/ ; }, mesh = {Animals ; Axons/drug effects ; Cell Line ; Cues ; Female ; Guided Tissue Regeneration/methods ; Hydrogels/*chemistry ; Male ; Nanofibers/*chemistry ; Nerve Regeneration/*drug effects ; Neurons/drug effects ; Peripheral Nerve Injuries/*drug therapy ; Polysaccharides, Bacterial/*chemistry ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve/*drug effects ; Tissue Engineering/methods ; Tissue Scaffolds/chemistry ; }, abstract = {Optimal levels of functional recovery in peripheral nerve injuries remain elusive due to the architectural complexity of the neuronal environment. Commercial nerve repair conduits lack essential guidance cues for the regenerating axons. In this study, the regenerative potential of a biosimulated nerve repair system providing three types of regenerative cues was evaluated in a 10 mm sciatic nerve-gap model over 4 weeks. A thermo-ionically crosslinked gellan-xanthan hydrogel conduit loaded with electrospun PHBV-magnesium oleate-N-acetyl-cysteine (PHBV-MgOl-NAC) nanofibers was assessed for mechanical properties, nerve growth factor (NGF) release kinetics and PC12 viability. In vivo functional recovery was based on walking track analysis, gastrocnemius muscle mass and histological analysis. As an intraluminal filler, PHBV-MgOl-NAC nanofibers improved matrix resilience, deformation and fracture of the hydrogel conduit. NGF release was sustained over 4 weeks, governed by Fickian diffusion and Case-II relaxational release for the hollow conduit and the nanofiber-loaded conduit, respectively. The intraluminal fibers supported PC12 proliferation by 49% compared to the control, preserved up to 43% muscle mass and gradually improved functional recovery. The combined elements of physical guidance (nanofibrous scaffolding), chemical cues (N-acetyl-cysteine and magnesium oleate) and therapeutic cues (NGF and diclofenac sodium) offers a promising strategy for the regeneration of severed peripheral nerves.}, } @article {pmid34768739, year = {2021}, author = {Chlumsky, O and Smith, HJ and Parker, AE and Brileya, K and Wilking, JN and Purkrtova, S and Michova, H and Ulbrich, P and Viktorova, J and Demnerova, K}, title = {Evaluation of the Antimicrobial Efficacy of N-Acetyl-l-Cysteine, Rhamnolipids, and Usnic Acid-Novel Approaches to Fight Food-Borne Pathogens.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34768739}, issn = {1422-0067}, support = {No. 17-15936S//Grantová Agentura České Republiky/ ; DMR-1455247//The National Science Foundation/ ; MSMT No 21-SVV/2020//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; }, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/pharmacology ; Anti-Infective Agents/pharmacology ; Benzofurans/*pharmacology ; Biofilms/drug effects ; Cell Line ; Escherichia coli/drug effects ; Food Contamination/prevention & control ; Food Microbiology/methods ; Foodborne Diseases/*drug therapy/microbiology ; Glycolipids/*pharmacology ; Humans ; Listeria monocytogenes/drug effects ; Microbial Sensitivity Tests ; Salmonella enterica/drug effects ; Staphylococcus aureus/drug effects ; }, abstract = {In the food industry, the increasing antimicrobial resistance of food-borne pathogens to conventional sanitizers poses the risk of food contamination and a decrease in product quality and safety. Therefore, we explored alternative antimicrobials N-Acetyl-l-cysteine (NAC), rhamnolipids (RLs), and usnic acid (UA) as a novel approach to prevent biofilm formation and reduce existing biofilms formed by important food-borne pathogens (three strains of Salmonella enterica and two strains of Escherichia coli, Listeria monocytogenes, Staphylococcus aureus). Their effectiveness was evaluated by determining minimum inhibitory concentrations needed for inhibition of bacterial growth, biofilm formation, metabolic activity, and biofilm reduction. Transmission electron microscopy and confocal scanning laser microscopy followed by image analysis were used to visualize and quantify the impact of tested substances on both planktonic and biofilm-associated cells. The in vitro cytotoxicity of the substances was determined as a half-maximal inhibitory concentration in five different cell lines. The results indicate relatively low cytotoxic effects of NAC in comparison to RLs and UA. In addition, NAC inhibited bacterial growth for all strains, while RLs showed overall lower inhibition and UA inhibited only the growth of Gram-positive bacteria. Even though tested substances did not remove the biofilms, NAC represents a promising tool in biofilm prevention.}, } @article {pmid34765973, year = {2021}, author = {Yamamoto, M and Sanomachi, T and Suzuki, S and Togashi, K and Sugai, A and Seino, S and Sato, A and Okada, M and Kitanaka, C}, title = {Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax.}, journal = {Neuro-oncology advances}, volume = {3}, number = {1}, pages = {vdab148}, pmid = {34765973}, issn = {2632-2498}, abstract = {BACKGROUND: Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We recently reported that malignant meningioma cells are highly sensitive to gemcitabine; however, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells.

METHODS: We examined the radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts and explored the underlying mechanisms.

RESULTS: Gemcitabine sensitized malignant meningioma cells to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug that inhibits Bcl-2 proteins, further enhanced the effects of the combination of gemcitabine and IR by strongly inducing apoptotic cell death in senescent cells.

CONCLUSION: These results not only indicate the potential of gemcitabine as a candidate radiosensitizer for malignant meningioma, but also reveal a novel role for gemcitabine radiosensitization as a means to create a therapeutic vulnerability of senescent meningioma cells to senolytics.}, } @article {pmid34762917, year = {2021}, author = {Khurana, H and Srivastava, M and Chaudhary, D and Gosain, TP and Kumari, R and Bean, AC and Chugh, S and Maiti, TK and Stephens, CE and Asthana, S and Singh, R}, title = {Identification of diphenyl furan derivatives via high throughput and computational studies as ArgA inhibitors of Mycobacterium tuberculosis.}, journal = {International journal of biological macromolecules}, volume = {193}, number = {Pt B}, pages = {1845-1858}, doi = {10.1016/j.ijbiomac.2021.11.017}, pmid = {34762917}, issn = {1879-0003}, mesh = {*Amino-Acid N-Acetyltransferase/antagonists & inhibitors/chemistry ; Antitubercular Agents/*chemistry/therapeutic use ; *Bacterial Proteins/antagonists & inhibitors/chemistry ; Enzyme Inhibitors/*chemistry/therapeutic use ; Furans ; Mycobacterium bovis/enzymology ; Mycobacterium tuberculosis/*enzymology ; }, abstract = {Microbial amino acid biosynthetic pathways are underexploited for the development of anti-bacterial agents. N-acetyl glutamate synthase (ArgA) catalyses the first committed step in L-arginine biosynthesis and is essential for M. tuberculosis growth. Here, we have purified and optimized assay conditions for the acetylation of l-glutamine by ArgA. Using the optimized conditions, high throughput screening was performed to identify ArgA inhibitors. We identified 2,5-Bis (2-chloro-4-guanidinophenyl) furan, a dicationic diaryl furan derivatives, as ArgA inhibitor, with a MIC99 values of 1.56 μM against M. tuberculosis. The diaryl furan derivative displayed bactericidal killing against both M. bovis BCG and M. tuberculosis. Inhibition of ArgA by the lead compound resulted in transcriptional reprogramming and accumulation of reactive oxygen species. The lead compound and its derivatives showed micromolar binding with ArgA as observed in surface plasmon resonance and tryptophan quenching experiments. Computational and dynamic analysis revealed that these scaffolds share similar binding site residues with L-arginine, however, with slight variations in their interaction pattern. Partial restoration of growth upon supplementation of liquid cultures with either L-arginine or N-acetyl cysteine suggests a multi-target killing mechanism for the lead compound. Taken together, we have identified small molecule inhibitors against ArgA enzyme from M. tuberculosis.}, } @article {pmid34762904, year = {2021}, author = {Xue, Y and Ren, X and Zhu, Z and Lei, P and Liu, M and Wan, M and Zhong, D and Huang, H and Diao, X}, title = {Site-specific protein modification by 3-n-butylphthalide in primary hepatocytes: Covalent protein adducts diminished by glutathione and N-acetylcysteine.}, journal = {Life sciences}, volume = {287}, number = {}, pages = {120125}, doi = {10.1016/j.lfs.2021.120125}, pmid = {34762904}, issn = {1879-0631}, mesh = {Acetylcysteine/*metabolism ; Animals ; Benzofurans/*metabolism/*toxicity ; Binding Sites/physiology ; Cells, Cultured ; Cytochrome P-450 CYP3A Inducers/metabolism/toxicity ; Dose-Response Relationship, Drug ; Glutathione/*metabolism ; Hepatocytes/drug effects/*metabolism ; Humans ; Protein Structure, Tertiary ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIMS: 3-n-Butylphthalide (NBP) is widely used for the treatment of cerebral ischaemic stroke but can causeliver injury in clinical practice. This study aims to elucidate the underlying mechanisms and propose potential preventive strategies.

MAIN METHODS: NBP and its four major metabolites, 3-hydroxy-NBP (3-OH-NBP), 10-hydroxy-NBP, 10-keto-NBP and NBP-11-oic acid, were synthesized and evaluated in primary human or rat hepatocytes (PHHs, PRHs). NBP-related substances or amino acid adducts were identified and semi-quantitated by ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). The target proteins and binding sites were identified by shotgun proteomics based on peptide mass fingerprinting coupled with tandem mass spectrometry and verified by molecular docking.

KEY FINDINGS: The toxicity of NBP and its four major metabolites were compared in both PHHs and PRHs, and 3-OH-NBP was found to be the most toxic metabolite. 3-OH-NBP induced remarkable cell death and oxidative stresses in hepatocytes, which correlated well with the levels of glutathione and N-acetylcysteine adducts (3-GSH-NBP and 3-NAC-NBP) in cell supernatants. Additionally, 3-OH-NBP covalently conjugated with intracellular Cys, Lys and Ser, with preferable binding to Cys sites at Myh9 Cys1380, Prdx4 Cys53, Vdac2 Cys48 and Vdac3 Cys36. Furthermore, we found that CYP3A4 induction by rifampicin augmented NBP-induced cell toxicity and supplementing with GSH or NAC alleviated the oxidative stresses and reactive metabolites caused by 3-OH-NBP.

SIGNIFICANCE: Our work suggests that glutathione depletion, mitochondrial injury and covalent protein modification are the main causes of NBP-induced hepatotoxicity, which may be prevented by exogenous GSH or NAC supplementation and avoiding concomitant use of CYP3A4 inducers.}, } @article {pmid34757312, year = {2021}, author = {Arancini, L and Mohebbi, M and Berk, M and Dean, OM and Bortolasci, CC and Spolding, B and Zazula, R and Dodd, S}, title = {A placebo-controlled, randomised pilot trial of N-acetylcysteine or placebo for cessation of tobacco smoking.}, journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology}, volume = {53}, number = {}, pages = {120-126}, doi = {10.1016/j.euroneuro.2021.10.002}, pmid = {34757312}, issn = {1873-7862}, mesh = {*Acetylcysteine/therapeutic use ; Australia ; Humans ; Pilot Projects ; *Smoking Cessation ; Tobacco Smoking ; Treatment Outcome ; }, abstract = {Smoking represents a significant health threat to the population, however there remains a core group of consistent smokers that are largely unable to break the addiction. Novel therapies are required to assist this group with cessation. N-acetylcysteine (NAC) is a nutraceutical supplement that has shown efficacy compared to placebo in previous pilot studies for assisting smokers to quit or reduce their consumption of cigarettes. A double-blind, randomised trial with a treatment period of 16 weeks and a final follow-up at 42 weeks was conducted comparing 1.8g of effervescent NAC per day (n=47) with placebo (n=47) as an aide to smoking cessation. Both study arms received adjunctive online support through the QuitCoach program. Participants reported smoking at each timepoint (baseline and weeks 8, 16 & 42), which was confirmed through salivary cotinine and exhaled carbon monoxide testing. Primary and secondary analyses were undertaken using a modified intent-to-treat basis, including all participants with at least one valid post baseline outcome, regardless of treatment received or their withdrawal from the study. There was no significant difference in smoking outcomes between intervention groups among the 24 participants that competed follow-up. There were no significant differences in age, gender, or body mass index (BMI) between the groups lost to follow-up or recorded at follow-up. This study found no evidence to support NAC as a therapy for smoking cessation. The negative outcome could be the result of lack of treatment efficacy, or alternatively, small sample size, participant retention difficulties, dose, or duration of follow-up. Trial Registration: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303. Registered on 19 October 2017.}, } @article {pmid34753902, year = {2021}, author = {Anna, Z and Joanna, K and Sara, Z and Jan, M and Paula, KS and Izabela, S and Robert, ŁJ and Małgorzata, ŻP and Mateusz, M}, title = {N-acetylcysteine supplementation did not reverse mitochondrial oxidative stress, apoptosis, and inflammation in the salivary glands of hyperglycemic rats.}, journal = {Nutrition & diabetes}, volume = {11}, number = {1}, pages = {35}, pmid = {34753902}, issn = {2044-4052}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Citrate (si)-Synthase/metabolism ; Diet, High-Fat ; Dietary Supplements ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Hyperglycemia/*drug therapy/metabolism ; Inflammation/metabolism ; Male ; Mitochondria/*metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Salivary Glands/drug effects/*metabolism ; }, abstract = {BACKGROUND/OBJECTIVES: Previous studies have shown that N-acetylcysteine (NAC) supplementation with the simultaneous inclusion of HFD prevents salivary glands from oxidative stress and mitochondrial dysfunction. In this experiment, we examined if NAC supplementation could reverse the harmful effect of HFD on mitochondrial function, reduce the severity of apoptosis, and the activity of pro-oxidative enzymes in the salivary glands of rats with confirmed hyperglycemia.

SUBJECTS/METHODS: Wistar rats were fed the standard or high-fat (HFD) diet for 10 weeks. After 6 weeks of the experiment, HFD rats were diagnosed with hyperglycemia and for the next 4 weeks, the animals were given NAC intragastrically. In the mitochondrial fraction of the parotid (PG) and submandibular salivary glands (SMG), we assessed redox status, inflammation, and apoptosis.

RESULTS: The inclusion of NAC increased the activity of mitochondrial complexes I and II + III as well as decreased the concentration of interleukin-1β, tumor necrosis factor α, and caspase-3, but only in the parotid glands of rats with hyperglycemia compared to the HFD group. However, N-acetylcysteine supplementation did not reduce the activity of caspase-9 or the Bax/Bcl-2 ratio in PG and SMG mitochondria. In both salivary glands we observed reduced activity of cytochrome c oxidase, NADPH oxidase, and xanthine oxidase, as well as hindered production of ROS and lower ADP/ATP radio, but the levels of these parameters were not comparable to the control group.

CONCLUSIONS: We demonstrated that NAC supplementation restores the glutathione ratio only in the mitochondria of the submandibular salivary glands. The supply of NAC did not significantly affect the other measured parameters. Our results indicate that NAC supplementation provides little protection against free radicals, apoptosis, and inflammation in the salivary gland mitochondria of HFD rats. Stimulated salivary secretion in hyperglycaemic rats supplemented with NAC seems to be closely related to mitochondrial respiratory capacity and appropriate ATP level.}, } @article {pmid34753839, year = {2021}, author = {Pawar, M and Pawar, V and Thete, SG and Dutta, SD and Sadan, PP and Maria, R and Kulkarni, D}, title = {Enhancement of Odontoblastic Differentiation of Stem Cells from Exfoliated Deciduous Tooth Using N-acetylcysteine-An In Vitro Study.}, journal = {The journal of contemporary dental practice}, volume = {22}, number = {8}, pages = {882-889}, pmid = {34753839}, issn = {1526-3711}, mesh = {*Acetylcysteine/pharmacology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; *Dental Pulp ; Humans ; Odontoblasts ; Stem Cells ; Tooth, Deciduous ; }, abstract = {AIM AND OBJECTIVE: The study was conducted to evaluate the effects of N-acetylcysteine (NAC) on the propagation and differentiation of stem cells from human exfoliated deciduous teeth(SHED).

MATERIALS AND METHODS: SHEDs were isolated by explant culture method and characterized for stem cell properties using flow cytometry method. MTT assay and Cell Counting Kit-8 (CCK-8) assay were used to examine the viability and proliferation of the SHEDs. The effects of NAC-induced osteo/odontoblastic differentiation of SHEDs were determined by functional staining for mineralization, and the gene expression of osteo/odontoblastic transcription factors and proteins was evaluated by real-time quantitative reverse transcription-polymerase chain reaction(qRT-PCR) analyses. Protein levels of collagen type 1 (COL1), dentin sialophosphoprotein (DSPP), and dentin matrix acidic phosphoprotein 1(DMP-1) were calculated by the Western blot method to assess the osteo/odontogenic differentiation.

RESULTS: SHEDs presented mesenchymal stem cell (MSC)-like characteristics on flow cytometric analysis. The cell viability and metabolic activity of SHEDs were increased with an increase in the concentrations of NAC from 0.5 to 10 nM. However, the concentrations of NAC from 0.5 to 2.5 mM did not affect cell proliferation. NAC incorporated at a concentration of 2.5 mM showed higher mineralization and considerably increased gene expression levels of runt-related transcription factor 2 (RUNX2), COL1A1, DSPP, and DMP-1. It significantly increased the protein expression of odontoblast-related matrix proteins like COL1, DSPP, and DMP-1.

CONCLUSION: NAC regulates the healthy propagation of dental stem cells in vitro. Its effects on the differentiation of dental pulp SHEDs remain unidentified. This study explores that NAC can encourage the mineralization of SHEDs and differentiate them into the odontoblastic lineage.

CLINICAL SIGNIFICANCE: The results propose that NAC could have a significant pharmacological role in activating and enhancing odontogenic differentiation of dental stem cells and possibly a prospect in regenerative dentistry.}, } @article {pmid34753573, year = {2021}, author = {Zhan, Z and Chai, L and Lei, Q and Zhou, X and Wang, Y and Deng, H and Lv, Y and Li, W}, title = {Two-photon ratiometric fluorescent probe for imaging of hypochlorous acid in acute lung injury and its remediation effect.}, journal = {Analytica chimica acta}, volume = {1187}, number = {}, pages = {339159}, doi = {10.1016/j.aca.2021.339159}, pmid = {34753573}, issn = {1873-4324}, mesh = {*Acute Lung Injury/diagnostic imaging ; Diagnostic Tests, Routine ; Fluorescent Dyes ; Humans ; *Hypochlorous Acid ; Photons ; }, abstract = {Acute lung injury (ALI) is a pulmonary inflammatory disease with high morbidity and mortality rates. However, owing to the unknown etiology and rapid progression of the disease, the diagnosis of ALI is full of challenges with no effective treatment. Since the inflammatory response and oxidative stress played vital roles in the development of ALI, we herein developed the largest emission cross-shift (△λ = 145 nm) two-photon ratiometric fluorescent probe of TPRS-HOCl with high selectivity and short response time toward hypochlorous acid (HOCl) for exploring the relevance between the degree of ALI and HOCl concentration in the development process of the disease. In addition, the inhibition effect of HOCl during different treatment periods was also evaluated. Moreover, the tendency of imaging results was basically in accordance with that of hematoxylin and eosin (H&E) staining and the treatment effect became better in the early stage when using N-acetylcysteine (NAC), demonstrating the sensitivity of TPRS-HOCl toward ALI response. Thus, TPRS-HOCl has great potential to diagnose ALI in the early stage and guide for effective treatment.}, } @article {pmid34751803, year = {2021}, author = {Maiti, R and Mishra, A and Mishra, BR and Jena, M}, title = {Comparative efficacy of mitochondrial agents for bipolar disorder during depressive episodes: a network meta-analysis using frequentist and Bayesian approaches.}, journal = {Psychopharmacology}, volume = {238}, number = {12}, pages = {3347-3356}, pmid = {34751803}, issn = {1432-2072}, mesh = {Acetylcarnitine ; Bayes Theorem ; *Bipolar Disorder/drug therapy ; Humans ; Network Meta-Analysis ; Treatment Outcome ; }, abstract = {RATIONALE: Mitochondrial dysfunctions have emerged as new biological hypothesis and therapeutic target for bipolar disorder. This network meta-analysis has been done to evaluate the comparative efficacy of mitochondrial agents in bipolar depression.

METHODS: After a comprehensive literature search on PubMed/MEDLINE, Cochrane databases, and International Trials Registry Platform, efficacy data were extracted from 15 randomized controlled trials. Random-effects meta-analysis was done following both frequentist and Bayesian approaches to pool the effects across the interventions. A network graph was built, relative effects of interventions in respect to one another and placebo were calculated, and treatments were ranked as per P- and SUCRA scores. Change in depression rating score was the primary outcome. Data was entered in contrast level and arm level for frequentist and Bayesian approaches, respectively.

RESULTS: Amongst mitochondrial agents, N-acetylcysteine (NAC) was shown to have the highest probability of being the best treatment, followed by coenzyme Q10 and combination therapy of alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) as depicted by P- and SUCRA scores. In the Bayesian approach, none of the treatments had better efficacy than placebo, but in the frequentist approach, NAC (effect estimate: - 1.18 (95% CI: - 2.05; - 0.31)) was significantly better than placebo.

CONCLUSION: Methodically, there may be a difference of magnitude in frequentist and Bayesian approaches, but the direction of effect and ranking probabilities do not differ. We conclude that none of the existing mitochondrial agents showed better efficacy than placebo in bipolar depression regarding depression rating scores.}, } @article {pmid34748318, year = {2021}, author = {Lu, K and Li, Y and Cheng, Y and Li, W and Zeng, B and Gu, C and Zeng, R and Song, Y}, title = {Activation of the ROS/CncC and 20-Hydroxyecdysone Signaling Pathways Is Associated with Xanthotoxin-Induced Tolerance to λ-Cyhalothrin in Spodoptera litura.}, journal = {Journal of agricultural and food chemistry}, volume = {69}, number = {45}, pages = {13425-13435}, doi = {10.1021/acs.jafc.1c04519}, pmid = {34748318}, issn = {1520-5118}, mesh = {Animals ; *Ecdysterone ; Insect Proteins/metabolism ; *Insecticides/pharmacology ; Larva/genetics/metabolism ; Methoxsalen ; Nitriles ; Pyrethrins ; Reactive Oxygen Species ; Signal Transduction ; Spodoptera/genetics/metabolism ; }, abstract = {Adaptation to phytochemicals in herbivorous insects can influence tolerance to insecticides. However, it is unclear how insects use phytochemicals as cues to activate their metabolic detoxification systems. In this study, we found that dietary exposure to xanthotoxin enhanced tolerance of Spodoptera litura larvae to λ-cyhalothrin. Xanthotoxin ingestion significantly elevated the mRNA levels of 35 detoxification genes as well as the transcription factors Cap 'n' collar isoform-C (CncC) and its binding factor small muscle aponeurosis fibromatosis isoform-K (MafK). Additionally, xanthotoxin exposure increased the levels of reactive oxygen species (ROS), while ROS inhibitor N-acetylcysteine (NAC) treatment blocked xanthotoxin-induced expression of CncC, MafK, and detoxification genes and also prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. The 20-hydroxyecdysone (20E) signaling pathway was effectively activated by xanthotoxin, while blocking of 20E signaling transduction prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. Application of 20E induced the expression of multiple xanthotoxin-induced detoxification genes and enhanced λ-cyhalothrin tolerance in S. litura. NAC treatment blocked xanthotoxin-induced 20E synthesis, while the CncC agonist curcumin activated the 20E signaling pathway. These results indicate that the ROS/CncC pathway controls the induction of metabolic detoxification upon exposure to xanthotoxin, at least in part, through its regulation of the 20E signaling pathway.}, } @article {pmid34746455, year = {2021}, author = {Harahap, Y and Nurahman, F and Purwanto, DJ and Yanuar, A}, title = {The correlation between the level of 3-hydroxypropyl mercapturic acid, CYP2B6 polymorphisms, and hematuria occurrences after cyclophosphamide administration and its bioanalytical methods: A systematic review.}, journal = {Heliyon}, volume = {7}, number = {10}, pages = {e08126}, pmid = {34746455}, issn = {2405-8440}, abstract = {BACKGROUND: Cyclophosphamide (CPA) is a cytotoxic prodrug that needs to be metabolized by cytochrome P450 enzymes, like CYP2B6. Unfortunately, CYP2B6 is a very polymorphic enzyme and can cause a change in 3-hydroxypropyl mercapturic acid (3-HPMA), the most found CYP metabolite in urine levels. Change in 3-HPMA levels can also indicate the level change in its precursor, acrolein, which is responsible for the hematuria incidence after CPA administration.This review's purpose is to obtain a conclusion about the optimal 3-HPMA analysis method in urine after the administration of cyclophosphamide using liquid chromatography-tandem mass spectrometry (LC-MS/MS) through literature review from previous studies. Also, this review was written to examine the relationship between levels of 3-HPMA in urine, polymorphisms of CYP2B6 enzymes, and the incidence of hematuria after cyclophosphamide administration in cancer patients.

METHODS: Major databases, such as Universitas Indonesia's library database ScienceDirect, PubMed/Medline, Frontiers Media, and Google Scholar database, were used to find both published and unpublished studies without a time limit until 2020. Studies on pharmacokinetics, pharmacodynamics, drug therapy monitoring of cyclophosphamide, bioanalysis, and polymerase chain reaction (PCR) published in Indonesian and English were included. Meanwhile, non-related studies or studies written in other languages besides Indonesian and English were excluded. Two independent reviewers screened the titles, abstracts, and full-text manuscripts. Data obtained from eligible sources were used to answer the purpose of this review in a narrative form.

RESULTS: The authors found 436 related studies from various databases and websites. Then, the authors narrowed it down into 62 pieces of literature by removing the duplicates and reviewing the abstracts and full-text manuscripts. Out of 62 sources, the authors found 30 studies that explained 3-HPMA analysis using LC/MS-MS, CYP2B6 polymorphisms, and hematuria occurrences. The authors used those 30 studies to build a conclusion regarding the purpose of this study. We strengthened the results with some additional information from the other 32 eligible sources.

CONCLUSIONS: The authors conclude that according to literature searches from previous studies, the optimal 3-HPMA analysis method in urine after cyclophosphamide administration using LC-MS/MS is using triple quadrupole LC-MS/MS; source of positive ion electrospray ionization (ESI); mobile phase combination of 0.1% formic acid in water (A) - 0.1% formic acid in acetonitrile (90:10 v/v) (B); the Acquity® BEH C18 column (2.1 × 100 mm; 1.7 μm); injection volume of 10 μl; flow rate of 0.2 ml/minute; gradient elution method. Detection was carried out using mass spectrometry with m/z ratio of 222.10 > 90 for 3-HPMA and m/z 164.10 > 122 for n-acetylcysteine (NAC). The optimum sample preparation method is acidification and dilution ratio of 1:5 v/v. Also, there is a relationship between 3-HPMA levels, CYP2B6 polymorphisms, and the occurrences of hematuria after the administration of cyclophosphamide, which is a type of CYP2B6 polymorph, namely CYP2B6∗6, can increase cyclophosphamide hydroxylation so that it can increase the levels of acrolein and 3-HPMA, as its metabolites, and risk of hematuria.

ETHICS AND DISSEMINATION: This research does not use human participants, human data, or human tissue for being directly studied for the review. Therefore, ethics approval and consent to participate are not applicable.

REGISTRATION: This research has not been registered yet.}, } @article {pmid34745415, year = {2021}, author = {Guo, M and Huang, YL and Wu, Q and Chai, L and Jiang, ZZ and Zeng, Y and Wan, SR and Tan, XZ and Long, Y and Gu, JL and Teng, FY and Xu, Y}, title = {Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {3027954}, pmid = {34745415}, issn = {1942-0994}, mesh = {Alcohol Drinking/*adverse effects ; Animals ; Bone Diseases, Metabolic/etiology/metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; *Necroptosis ; Osteoblasts/*pathology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Chronic high-dose alcohol consumption impairs bone remodeling, reduces bone mass, and increases the risk of osteoporosis and bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are yet to be elucidated. In this study, we showed that excess intake of ethyl alcohol (EtOH) resulted in osteopenia and osteoblast necroptosis in mice that led to necrotic lesions and reduced osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). We found that EtOH treatment led to the activation of the RIPK1/RIPK3/MLKL signaling, resulting in increased osteoblast necroptosis and decreased osteogenic differentiation and bone formation both in vivo and in vitro. We further discovered that excessive EtOH treatment-induced osteoblast necroptosis might partly depend on reactive oxygen species (ROS) generation; concomitantly, ROS contributed to necroptosis of osteoblasts through a positive feedback loop involving RIPK1/RIPK3. In addition, blocking of the RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 kinase in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS, could decrease the activation of osteoblast necroptosis and ameliorate alcohol-induced osteopenia both in vivo and in vitro. Collectively, we demonstrated that chronic high-dose alcohol consumption induced osteopenia via osteoblast necroptosis and revealed that RIPK1 kinase may be a therapeutic target for alcohol-induced osteopenia.}, } @article {pmid34739934, year = {2021}, author = {Guo, H and Yin, H and Zuo, Z and Yang, Z and Yang, Y and Wei, L and Cui, H and Deng, H and Chen, X and Chen, J and Zhu, Y and Ouyang, P and Geng, Y and Du, Z and Tang, H and Wang, F and Fang, J}, title = {Oxidative stress-mediated apoptosis and autophagy involved in Ni-induced nephrotoxicity in the mice.}, journal = {Ecotoxicology and environmental safety}, volume = {228}, number = {}, pages = {112954}, doi = {10.1016/j.ecoenv.2021.112954}, pmid = {34739934}, issn = {1090-2414}, abstract = {As an extensively environmental pollution, Nickel (Ni) represents a serious hazard to human health. The present study focused on exploring the mechanism of Ni-mediated nephrotoxicity, such as apoptosis, autophagy and oxidative stress. In the current work, NiCl2 treatment could induce kidney damage. Meanwhile, NiCl2 treatment elevated ROS production and MDA content and suppressed the antioxidant activity, which was characterized by reducing T-AOC, CAT, SOD activity and GSH content. For investigating the role of oxidative stress on NiCl2-mediated nephrotoxicity, N-acetyl cysteine (NAC, effective antioxidant and free radical scavenger) was co-treated with NiCl2. The results showed that NAC significantly suppressed the NiCl2-mediated oxidative stress and mitigated NiCl2-induced the kidney damage. Then, whether oxidative stress-induced autophagy and apoptosis were involved in NiCl2-induced nephrotoxicity was explored. The findings demonstrated that NAC relieved NiCl2-induced autophagy and reversed the activation of Akt/AMPK/mTOR pathway. Concurrently, the results indicated that NAC attenuated NiCl2-induced apoptosis, as evidenced by reduction of apoptotic cells and cleaved-caspase-3/- 8/- 9 together with cleaved-PARP protein levels. To sum up, our findings suggested that NiCl2-mediated renal injury was associated with oxidative stress-induced apoptosis and autophagy. This study provides new theoretical basis for excess Ni exposure nephrotoxic researches.}, } @article {pmid34736541, year = {2021}, author = {Hadi, F and Kashefinejad, S and Kamalzadeh, L and Hoobehfekr, S and Shalbafan, M}, title = {Glutamatergic medications as adjunctive therapy for moderate to severe obsessive-compulsive disorder in adults: a systematic review and meta-analysis.}, journal = {BMC pharmacology & toxicology}, volume = {22}, number = {1}, pages = {69}, pmid = {34736541}, issn = {2050-6511}, mesh = {Adult ; Drug Therapy, Combination ; Excitatory Amino Acid Agents/*therapeutic use ; Humans ; Obsessive-Compulsive Disorder/*drug therapy ; Selective Serotonin Reuptake Inhibitors/*therapeutic use ; }, abstract = {BACKGROUND: Obsessive-compulsive disorder (OCD) is among the most disabling neuropsychiatric conditions characterized by the presence of repetitive intrusive thoughts, impulses, or images (obsessions) and/or ritualized mental or physical acts (compulsions). Serotonergic medications, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), are the first-line treatments for patients with OCD. Recently, dysregulation of glutamatergic system has been proposed to be involved in the etiology of OCD. We designed this systematic review and meta-analysis to evaluate clinical efficacy of glutamatergic medications in patients with OCD, according to the guidelines of Cochrane collaboration.

METHOD: We searched Medline, Scopus, and Cochrane library without applying any language filter. Two of the authors independently reviewed search results for irrelevant and duplicate studies and extracted data and assessed methodological quality of the studies. We transformed data into a common rubric and calculated a weighted treatment effect across studies using Review Manager.

RESULTS: We found 476 references in 3 databases, and after exclusion of irrelevant and duplicate studies, 17 studies with total number of 759 patients with OCD were included. In the present review we found evidence for several drugs such as memantine, N-acetylcysteine (NAC), Minocycline, L-carnosine and riluzole. Glutamaterigic drug plus SSRIs were superior to SSRI+ Placebo with regard to Y-BOCS scale [standardized mean difference (SMD = - 3.81 95% CI = - 4.4, - 3.23).

CONCLUSION: Augmentation of glutamatergic medications with SSRIs are beneficial in obsessive-compulsive patients, no harmful significant differences in any safety outcome were found between the groups.}, } @article {pmid34733484, year = {2021}, author = {Mohammed, N and Ahmed, SA and Hegazy, NI and Kashishy, K}, title = {Ameliorative effects of hesperidin and N-acetylcysteine against formaldehyde-induced-hemato- and genotoxicity.}, journal = {Toxicology research}, volume = {10}, number = {5}, pages = {992-1002}, pmid = {34733484}, issn = {2045-452X}, abstract = {This study investigated the hemato- and genotoxic effects of formaldehyde (FA) and the possible mitigating role of hesperidin (HP) and N-acetylcysteine (NAC), each alone and in combination. Sixty-four adult male albino rats were divided into eight equal groups; the study was conducted for 8 weeks; Group I (negative control: received no medication), Group II (positive control: received distilled water), Group III (received HP 50 mg/kg/day), Group IV (received NAC 50 mg/kg/day), Group V (received FA 10 mg/kg/day), Group VI (FA + HP), Group VII (FA + NAC), and Group VIII (FA + HP + NAC). Groups VI, VII, VIII received the same previously mentioned doses and for the same duration. All treatments were given by intraperitoneal administration. At the end of the study, complete blood count, oxidative stress, histopathological changes, immunohistochemical staining of inducible nitric oxide synthase, and proliferating cell nuclear antigen and genotoxicity by comet assay in the bone marrow of treated rats were assessed. FA administration caused significant hematotoxicity represented by elevated white blood cell numbers and serum malondialdehyde levels and reduced red blood cell numbers, platelets, and serum superoxide dismutase values. Histologically, it induced an increase in fat cell numbers in bone marrow tissue with a widening of marrow spaces and decreased cellularity of hematopoietic cells, megakaryocytes, and granulocytes. FA exposure significantly decreased immunoreactivity for proliferating cell nuclear antigen, whereas the immunoreactivity for inducible nitric oxide synthase was increased. Genotoxicity, as measured by comet assay, revealed a significant increase in comet% and tail length in FA-treated group when compared with other groups. The cotreatment with HP and NAC revealed their ability to protect against hematological changes, oxidative damage, histopathological, and immunohistochemical changes, and genotoxicity induced by FA.}, } @article {pmid34732600, year = {2022}, author = {Tan, YK and Luo, H and Kang, GS and Teoh, KL and Kofidis, T}, title = {N-Acetylcysteine's Renoprotective Effect in Cardiac Surgery: A Systematic Review and Meta-Analysis.}, journal = {Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia}, volume = {28}, number = {2}, pages = {138-145}, pmid = {34732600}, issn = {2186-1005}, mesh = {Acetylcysteine/adverse effects ; *Acute Kidney Injury/diagnosis/epidemiology/etiology ; Adult ; *Cardiac Surgical Procedures/adverse effects ; Female ; Humans ; Male ; Odds Ratio ; Treatment Outcome ; }, abstract = {OBJECTIVE: To examine N-acetylcysteine's (NAC's) renoprotective effect in adult cardiac surgeryMethods: PubMed, Ovid Medline, and Embase were searched for randomized controlled trials published between January 1990 and May 2021 that investigated the effect of NAC in preventing acute kidney injury (AKI) in patients undergoing cardiac surgery. The inclusion criterion was studies that assessed the effect of NAC in comparison to placebo by measuring the incidence of AKI.

RESULTS: Overall meta-analytic estimates of all 10 included trials showed that NAC did not have a significant effect (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.64-1.10) on AKI. Further subgroup analysis did not show a significant benefit of NAC in preventing AKI.

CONCLUSION: This meta-analysis suggests that NAC does not have a significant effect in reducing the incidence of AKI. However, there is notable heterogeneity among the included studies that could possibly account for the non-significant effect observed. It is worth noting that only one trial administered NAC high dosages perioperatively, and it is the only included trial to show a significant benefit in reducing the incidence of AKI (OR: 0.30, 95% CI: 0.11-0.81). Further studies on this dosage and duration of administration should be conducted to best elucidate the effect of administering NAC.}, } @article {pmid34729372, year = {2021}, author = {Saeed, H and Osama, H and Abdelrahman, MA and Madney, YM and Harb, HS and Abdelrahim, MEA and Ali, F}, title = {Vitamins and other immune-supportive elements as cofactors for passing the COVID-19 pandemic.}, journal = {Beni-Suef University journal of basic and applied sciences}, volume = {10}, number = {1}, pages = {71}, pmid = {34729372}, issn = {2314-8543}, abstract = {BACKGROUND: Coronavirus disease 2019 (COVID-19) is a viral disease that causes a respiratory disorder, started in December of 2019 in China. Several vitamins and trace elements could help in enhancing host immunity producing antioxidant or anti-inflammatory action. This work aimed to identify the role of different nutrition, vitamins, and trace elements on the immunity status of the infected subject and the possibility of the beneficial role of these elements in the management of COVID-19.

MAIN BODY: After collecting (PubMed, scholar, OVID, Embase, Cochrane Library) and investigating published articles, testing the effect of these elements on viral infection, it was found that most of these elements have a significant role during viral infection through a different mechanism, like antioxidant, anti-inflammatory, and immunomodulation. Nutritional interventions in COVID-19 infections are very important currently, and it was reported that vitamin C and D reduce the risk of acute respiratory infections. In addition, low vitamin A diets compromise the effectiveness of inactivated bovine coronavirus vaccines. Administration of N-acetyl cysteine showed a beneficial inhibitory effect in viral infections and enhanced glutathione production. The deficiency of selenium on COVID-19 subjects has a significant impact on the clinical outcome of the subjects. In addition, supplementation with vitamins proved to enhance immune response during viral infection. Vitamins and trace elements not only showed a beneficial effect but also Omega 3 fatty acids showed an immunomodulating effect during infections.

SHORT CONCLUSIONS: Assessment of levels for these trace elements at the baseline and providing supplementation containing different vitamins and elements could result in better control and clinical outcomes in the case of COVID-19.}, } @article {pmid34727343, year = {2022}, author = {Yazdi, A and Khansari, N and Mehrpooya, M and Mohammadi, Y and Zareie, S}, title = {Oral N-acetylcysteine as an adjunct to standard medical therapy improved heart function in cases with stable class II and III systolic heart failure.}, journal = {Irish journal of medical science}, volume = {191}, number = {5}, pages = {2063-2075}, pmid = {34727343}, issn = {1863-4362}, mesh = {Acetylcysteine/therapeutic use ; *Heart Failure/therapy ; *Heart Failure, Systolic/drug therapy ; Humans ; Iran ; Stroke Volume ; Ventricular Function, Left ; Ventricular Function, Right ; }, abstract = {BACKGROUND: This research attempted to assess whether N-acetylcysteine (NAC) as adjunctive therapy can be useful in the treatment of patients with heart failure (HF).

METHODS: Fifty-five cases with diagnosed systolic HF and stable symptomatic New York Heart Association (NYHA) functional class II and III and on optimal medical treatment of HF for at least 3 months were assigned for receiving oral NAC (600 mg twice daily) or placebo for 12 weeks. The outcomes were changes in the echocardiographic hemodynamic indices as well as the patients' functional capacity assessed by NYHA classification over a 12-week treatment.

RESULTS: Compared to placebo, NAC more significantly improved the systolic left ventricular (LV) function expressed as the ejection fraction and Tei index. These changes are accompanied by more improvement in other LV echocardiographic indices including LV end-diastolic volume index and LV global longitudinal strain in the patients receiving NAC in comparison with those receiving placebo. In parallel with the improvement of LV function, right ventricular (RV) function expressed as RV fractional area change and RV Tei-index also got more improvement in those receiving NAC than those receiving placebo. However, the change in RV global longitudinal strain did not show a significant difference between study groups. Additionally, at week 12, the distribution of the NYHA functional class also shifted toward a better outcome in the NAC group in comparison with the placebo group; however, it was not significant.

CONCLUSIONS: These preliminary data support experimental findings showing that NAC supplementation is able to improve heart function.

TRIAL REGISTRATION: The registration of the trial was done at the Iranian Registry of Clinical Trials (www.irct.ir). Identifier code: IRCT20120215009014N333. Registration date: 2020-01-11.}, } @article {pmid34726248, year = {2021}, author = {Shi, W and Men, L and Pi, X and Jiang, T and Peng, D and Huo, S and Luo, P and Wang, M and Guo, J and Jiang, Y and Peng, L and Lin, L and Li, S and Lv, J}, title = {Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL‑6/STAT3 signaling pathway.}, journal = {International journal of oncology}, volume = {59}, number = {6}, pages = {}, pmid = {34726248}, issn = {1791-2423}, mesh = {ADAM17 Protein/genetics/*metabolism ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Apoptosis ; Cell Proliferation ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Interleukin-6/genetics/*metabolism ; Naphthoquinones/*pharmacology ; STAT3 Transcription Factor/genetics/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Signal transducer and activator of transcription 3 (STAT3) activation is associated with drug resistance induced by anti‑epidermal growth factor receptor (anti‑EGFR) therapy in the treatment of colon cancer. Thus, the combined inhibition of EGFR and STAT3 may prove beneficial for this type of cancer. STAT3 has been proven to play a critical role in colon cancer initiation and progression, and is considered the primary downstream effector driven by interleukin‑6 (IL‑6). A disintegrin and metalloproteinase 17 (ADAM17), documented as an oncogene, catalyzes the cleavage of both EGF and IL‑6R, inducing EGFR signaling and enabling IL‑6 trans‑signaling to activate STAT3 in a wide range of cell types to promote inflammation and cancer development. As a natural product, shikonin (SKN) has been found to function as an antitumor agent; however, its role in the regulation of ADAM17 and IL‑6/STAT3 signaling in colon cancer cells remains unknown. In the present study, it was found that SKN inhibited colon cancer cell growth, suppressed both constitutive and IL‑6‑induced STAT3 phosphorylation, and downregulated the expression of ADAM17. ADAM17 expression was not altered in response to STAT3 knockdown, while IL‑6‑induced STAT3 activation did not induce ADAM17 transcripts. Furthermore, it was demonstrated that SKN did not affect the expression of key proteins involved in the maturation and degradation of ADAM17. SKN decreased ADAM17 expression possibly through reactive oxygen species (ROS)‑mediated translational inhibition, as evidenced by the increased ADAM17 mRNA and phosphorylation levels of eukaryotic initiation factor 2α (eIF2α). The expression of ADAM17 and p‑eIF2α was reversed by N‑acetylcysteine (NAC, a ROS scavenger). Taken together, these results indicate that the concurrent inhibition of ADAM17 and IL‑6/STAT3 signaling by SKN may synergistically contribute to the suppression of colon cancer cell growth.}, } @article {pmid34725845, year = {2022}, author = {Brown, LE and Reyes, G and Albrecht, EA}, title = {Crotalus atrox venom-induced cellular toxicity: Early wound progression involves reactive oxygen species.}, journal = {Journal of applied toxicology : JAT}, volume = {42}, number = {5}, pages = {852-863}, pmid = {34725845}, issn = {1099-1263}, support = {//Kennesaw State University Office of Research/ ; }, mesh = {Animals ; *Crotalid Venoms/chemistry/toxicity ; *Crotalus/physiology ; HEK293 Cells ; Humans ; Reactive Oxygen Species ; }, abstract = {Understanding the mechanisms that produce cellular cytotoxicity is fundamental in the field of toxicology. Cytotoxic stimuli can include organic toxins such as hemorrhagic snake venom, which can lead to secondary complications such as the development of necrotic tissue and profuse scarring. These clinical manifestations mimic cytotoxic responses induce by other organic compounds such as organic acids. We used hemorrhagic snake venom and human embryonic kidney cells (HEK 293T) as a model system to better understand the cellular responses involved in venom induced cytotoxicity. Cells stimulated with Crotalus atrox (CA) (western diamondback) venom for 4 or 10 h demonstrated significant cytotoxicity. Results from 2',7'-Dichlorodihydrofluorescein diacetate (H2 DCF-DA) assays determine CA venom stimulation induces a robust production of reactive oxygen species (ROS) over a 3-h time course. In contrast, pretreatment with polyethylene glycol (PEG)-catalase or N-acetyl cysteine (NAC) prior to CA venom stimulation significantly blunted H2 DCFDA fluorescence fold changes and showed greater cytoprotective effects than cells stimulated with CA venom alone. Pre- incubating HEK293T cells with the NADPH oxidase (NOX) pan-inhibitor VAS2870 prior venom stimulation significantly minimized the venom-induced oxidative burst at early timepoints (≤2 h). Collectively, our experiments show that pre-application of antioxidants reduces CA venom induce cellular toxicity. This result highlights the importance of ROS in the early stages of cytotoxicity and suggests muting ROS production in noxious injuries may increase positive clinical outcomes.}, } @article {pmid34722507, year = {2021}, author = {Ma, S and Fu, X and Liu, L and Liu, Y and Feng, H and Jiang, H and Liu, X and Liu, R and Liang, Z and Li, M and Tian, Z and Hu, B and Bai, Y and Liang, B and Liu, X}, title = {Iron-Dependent Autophagic Cell Death Induced by Radiation in MDA-MB-231 Breast Cancer Cells.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {723801}, pmid = {34722507}, issn = {2296-634X}, abstract = {In radiation oncology, ionizing radiation is used to kill cancer cells, in other words, the induction of different types of cell death. To investigate this cellular death and the associated iron accumulation, the transfer, release, and participation of iron after radiation treatment was analyzed. We found that radiation-induced cell death varied in different breast cancer cells and autophagy was induced in MDA-MB-231 and BT549 cells (triple negative breast cancer cell line) rather than in MCF-7 and zr-75 cells. Iron chelator deferoxamine (DFO), the autophagy inhibitor 3MA, silencing of the autophagy-related genes ATG5, and Beclin 1 could decrease radiation induced cell death in MDA-MB-231 cells, while inhibitors of apoptosis such as Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1 (Fer-1), and necroptosis inhibitor Necrostatin-1 showed no change. This suggests the occurrence of autophagic cell death. Furthermore, we found that iron accumulation and iron regulatory proteins, including transferrin (Tf), transferrin receptor (CD71), and Ferritin (FTH), increased after radiation treatment, and the silencing of transferrin decreased radiation-induced cell death. In addition, radiation increased lysosomal membrane permeabilization (LMP) and the release of lysosomal iron and cathepsins, while cathepsins silencing failed to change cell viability. Radiation-induced iron accumulation increased Reactive oxygen species (ROS) generation via the Fenton reaction and increased autophagy in a time-dependent manner. DFO, N-acetylcysteine (NAC), and overexpression of superoxide dismutase 2 (SOD2) decreased ROS generation, autophagy, and cell death. To summarize, for the first time, we found that radiation-induced autophagic cell death was iron-dependent in breast cancer MDA-MB-231 cells. These results provide new insights into the cell death process of cancers and might conduce to the development and application of novel therapeutic strategies for patients with apoptosis-resistant breast cancer.}, } @article {pmid34718251, year = {2021}, author = {Cao, Q and Wang, T and Xiao, M and Bai, L}, title = {Increased endogenous reactive oxygen species normalizes proliferation defects of Bmi1 heterozygous knockout neural stem cells.}, journal = {Neuroreport}, volume = {32}, number = {17}, pages = {1388-1394}, doi = {10.1097/WNR.0000000000001740}, pmid = {34718251}, issn = {1473-558X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Cell Proliferation/drug effects/*genetics ; Free Radical Scavengers/pharmacology ; Heterozygote ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Knockout ; Neural Stem Cells/drug effects/*metabolism ; Oxidants/pharmacology ; Polycomb Repressive Complex 1/*genetics ; Proto-Oncogene Proteins/*genetics ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/drug effects/metabolism ; }, abstract = {OBJECTIVES: The Bmi1gene, one of transcriptional suppressor genes in multi-comb family, maintains proliferation of neural stem cells (NSCs) and redox homeostasis. However, heterozygous deletion of the Bmi1 gene (Bmi1+/-) does not reduce the proliferative ability of NSCs. The aim of the present study was to reveal the underlying mechanism of this phenotype.

METHODS: NSCs derived from the cortex of newborn Bmi1+/- and wild-type (WT) mice were treated with different concentrations of hydrogen peroxide (H2O2) and antioxidant N-acetyl-L-cysteine (NAC) for 24 h followed by analyses of NSC proliferation and oxidative stress-related indexes.

RESULTS: The levels of reactive oxygen species (ROS) of Bmi1+/--NSCs were slightly higher than that of WT-NSCs at baseline. H2O2 increased ROS and NAC reduced ROS in a concentration-dependent pattern, but the change was significantly greater in Bmi1+/--NSCs than WT-NSCs. The proliferation and self-renewal ability of Bmi1+/--NSCs and WT-NSCs were comparable in a basic state. After 1 μM H2O2 treatment, Brdu incorporation ratio, cell viability, total antioxidant capacity (T-AOC) and total superoxide dismutase activity were increased slightly in WT-NSCs, but decreased in Bmi1+/--NSCs. H2O2 at 10 μM decreased proliferation and self-renewal ability of both genotype NSCs, with greater effect in Bmi1+/-. After treatment with 1 mM NAC, the number and diameter of neurospheres, Brdu incorporation rate, cell viability, T-AOC and total superoxide dismutase activity of Bmi1+/--NSCs were lower than those of WT-NSCs.

CONCLUSION: These results suggest that Bmi1+/--NSCs exhibit normal proliferation and self-renewal due to a slight increase in ROS, but are more vulnerable to changes in redox status.}, } @article {pmid34712416, year = {2021}, author = {Tousian, H and Razavi, BM and Hosseinzadeh, H}, title = {In search of elixir: Pharmacological agents against stem cell senescence.}, journal = {Iranian journal of basic medical sciences}, volume = {24}, number = {7}, pages = {868-880}, pmid = {34712416}, issn = {2008-3866}, abstract = {Stem cell senescence causes different complications. In addition to the aging phenomenon, stem cell senescence has been investigated in various concepts such as cancer, adverse drug effects, and as a limiting factor in cell therapy. This manuscript examines protective medicines and supplements which are capable of hindering stem cell senescence. We searched the databases such as EMBASE, PubMed, and Web of Science with the keywords "stem cell," "progenitor cell," "satellite," "senescence" and excluded the keywords "cancer," "tumor," "malignancy" and "carcinoma" until June 2020. Among these results, we chose 47 relevant studies. Our investigation indicates that most of these studies examined endothelial progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose-derived stem cells, and a few others were about less-discussed types of stem cells such as cardiac stem cells, myeloblasts, and induced pluripotent stem cells. From another aspect, 17β-Estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C were the most studied agents, while the main protective mechanism was through telomerase activity enhancement or oxidative damage ablation. Although many of these studies are in vitro, they are still worthwhile. Stem cell senescence in the in vitro expansion stage is an essential concern in clinical procedures of cell therapy. Moreover, in vitro studies are the first step for further in vivo and clinical studies. It is noteworthy to mention the fact that these protective agents have been used in the clinical setting for various purposes for a long time. Given that, we only need to examine their systemic anti-senescence effects and effective dosages.}, } @article {pmid34711021, year = {2021}, author = {Aala, J and Harchegani, AB and Monsef, HA and Mohsenifar, Z and Ebrahimi, P and Parvizi, MR}, title = {N-Acetyl cysteine mitigates histopathological changes and inflammatory genes expressions in the liver of cadmium exposed rats.}, journal = {Environmental analysis, health and toxicology}, volume = {36}, number = {4}, pages = {e2021024-0}, pmid = {34711021}, issn = {2671-9525}, abstract = {This study aimed to consider the expression of Nrf2, NLRP3 and caspase 1 genes, as well as oxidative stress, and the protective role of N-acetyl cysteine (NAC) in the liver of rats treated with cadmium (Cd). Male rats were randomly divided into five groups including G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd + NAC), and G5 (continuous dose of Cd + NAC). Levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Expression of Nrf2, NLRP3 and caspase 1 genes was considered using RT-PCR. NAC treatments significantly improved TAC, but decreased MDA values in rats that exposed to continuous dose of Cd (p<0.05). Exposure to continuous dose of Cd caused a significant decrease in Nrf2 expression by 2.46-fold (p<0.001), but enhanced expression of NLRP3 and Caspase 1 genes by 3.13-fold and 3.16-fold), respectively (p<0.001). Compared to rats that treated to continuous dose of Cd, NAC supplementation enhanced the expression of Nrf2 by 1.67-fold (p<0.001) and reduced the expression of NLRP3 and Caspase 1 genes by 1.39-fold (p<0.001) and 1.58-fold (p<0.001), respectively. Down-regulation of Nrf2 and overexpression of NLRP3 and caspase 1 seems to be one of the main mechanisms of Cd toxicity on liver tissue. NAC protects liver tissue against Cd-induced oxidative injuries via enhancement of Nrf2 expression and reduction of NLRP3 and caspase 1 genes.}, } @article {pmid34709101, year = {2022}, author = {Link, SL and Rampon, G and Osmon, S and Scalzo, AJ and Rumack, BH}, title = {Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {472-477}, doi = {10.1080/15563650.2021.1996591}, pmid = {34709101}, issn = {1556-9519}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; Antidotes ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose/drug therapy ; Fomepizole ; Humans ; }, abstract = {INTRODUCTION: Acetaminophen (N-acetyl-para-aminophenol or APAP) is the leading cause of acute liver failure worldwide. Standard therapy for APAP overdose is with IV N-acetylcysteine (NAC). However, overdose patients treated with NAC can still incur hepatotoxicity in some circumstances. Fomepizole has proven safety in methanol and ethylene glycol poisoning and is a potent CYP2E1 and c-Jun-N-terminal Kinase (JNK) inhibitor that is effective even in the metabolic phase.

METHODS: We present a prospective case series of 14 consecutive, high-risk patients who had elevated APAP levels after overdose who were treated with fomepizole as an adjunct to standard IV-NAC. The attending toxicologist utilized clinical judgement to determine the use of fomepizole, especially if APAP levels persisted due to altered half-life or risk factors for toxicity.

RESULTS: There were no unfavorable outcomes in any patient, which were better than expected.

CONCLUSIONS: This case series has demonstrated the safety of fomepizole in high-risk APAP overdose. The efficacy of fomepizole needs to be further elucidated through controlled clinical trials on a larger scale. In massive APAP overdoses, fomepizole should be considered as an adjunct due to the known failure rate of NAC and the safety profile of fomepizole.}, } @article {pmid34703944, year = {2021}, author = {Oszajca, K and Szemraj, J}, title = {Assessment of the correlation between oxidative stress and expression of MMP-2, TIMP-1 and COX-2 in human aortic smooth muscle cells.}, journal = {Archives of medical sciences. Atherosclerotic diseases}, volume = {6}, number = {}, pages = {e158-e165}, pmid = {34703944}, issn = {2451-0629}, abstract = {INTRODUCTION: Smooth muscle cells (SMCs) are considered to be the main producer of matrix metalloproteinase-2 (MMP-2) participating primarily in extracellular matrix (ECM) remodeling. Any disturbances in ECM structure may underlie the pathogenesis of many cardiovascular diseases and contribute to angiogenesis, cancer development, invasion or metastasis. The purpose of the study was to examine the effect of oxidative stress on the expression of MMP-2, its tissue inhibitor type 1 (TIMP-1) and cyclooxygenase-2 (COX-2) in human aortic smooth muscle cells (HASMCs).

MATERIAL AND METHODS: HASMCs were treated with exogenously applied H2O2 or TNF-α. N-acetylcysteine (NAC) was used as an antioxidant. Gene expression levels were measured by real-time PCR and the protein levels were determined using ELISA assay.

RESULTS: The studies revealed no association between oxidative stress and either mRNA quantity or protein secretion of MMP-2 and TIMP-1. However, we found markedly reduced (p < 0.001) MMP-2 secretion in cells incubated with NAC. HASMCs stimulated with TNF-α demonstrated a significantly increased COX-2 mRNA level as well as enzyme activity. H2O2-induced cells showed lowered COX-2 activity in comparison to untreated cells. MMP-2 and TIMP-1 expression did not change after COX-2 inhibition with DuP-697.

CONCLUSIONS: We did not find any effect of oxidative stress on expression of MMP-2 and TIMP-1 in HASMCs. However, COX-2 mRNA and protein level were elevated in these conditions. There was no correlation between COX-2 activity and MMP-2 and TIMP-1 mRNA expression or protein secretion.}, } @article {pmid34703822, year = {2021}, author = {Chung, SA and Lim, JW and Kim, H}, title = {Docosahexaenoic Acid Inhibits Cytokine Expression by Reducing Reactive Oxygen Species in Pancreatic Stellate Cells.}, journal = {Journal of cancer prevention}, volume = {26}, number = {3}, pages = {195-206}, pmid = {34703822}, issn = {2288-3649}, abstract = {Pancreatic stellate cells (PSCs) are activated by inflammatory stimuli, such as TNF-α or viral infection. Activated PSCs play a crucial role in the development of chronic pancreatitis. Polyinosinic-polycytidylic acid (poly (I:C)) is structurally similar to double-stranded RNA and mimics viral infection. Docosahexaenoic acid (DHA) exhibits anti-inflammatory activity. It inhibited fibrotic mediators and reduced NF-κB activity in the pancreas of mice with chronic pancreatitis. The present study aimed to investigate whether DHA could suppress cytokine expression in PSCs isolated from rats. Cells were pre-treated with DHA or the antioxidant N-acetylcysteine (NAC) and stimulated with TNF-α or poly (I:C). Treatment with TNF-α or poly (I:C) increased the expression of monocyte chemoattractant protein 1 (MCP-1) and chemokine C-X3-C motif ligand 1 (CX3CL1), which are known chemoattractants, and enhanced intracellular and mitochondrial reactive oxygen species (ROS) production and NF-κB activity, but reduced mitochondrial membrane potential (MMP). Increased intracellular and mitochondrial ROS accumulation, cytokine expression, MMP disruption, and NF-κB activation were all prevented by DHA in TNF-α- or poly (I:C)-treated PSCs. NAC suppressed TNF-α- or poly (I:C)-induced expression of MCP-1 and CX3CL1. In conclusion, DHA inhibits poly (I:C)- or TNF-α-induced cytokine expression and NF-κB activation by reducing intracellular and mitochondrial ROS in PSCs. Consumption of DHA-rich foods may be beneficial in preventing chronic pancreatitis by inhibiting cytokine expression in PSCs.}, } @article {pmid34698588, year = {2021}, author = {Bhardwaj, JK and Kumar, V and Panchal, H and Sachdeva, SN}, title = {Transmission electron microscopic analysis of glyphosate induced cytotoxicity and its attenuation by N-acetyl-L-cysteine in caprine testicular germ cells in vitro.}, journal = {Ultrastructural pathology}, volume = {45}, number = {6}, pages = {407-413}, doi = {10.1080/01913123.2021.1993400}, pmid = {34698588}, issn = {1521-0758}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Electrons ; Germ Cells ; Glycine/analogs & derivatives ; *Goats ; Male ; Microscopy, Electron, Transmission ; Oxidative Stress ; Glyphosate ; }, abstract = {The agricultural pesticide poisoning is currently the most thrust area of human health concern. Pesticide-induced cytotoxicity and the corresponding reproductive toxicity in today's scenario is not a concealed reality that has to be considered for the continuation of respective race. Here, the transmission electron microscopy (TEM) technique was employed to investigate the adverse impact of glyphosate (GLY) and its mitigation by N-acetyl-L-cysteine (NAC) in goat testicular germ cells under in vitro conditions. The ultrastructural observations of testicular tissue from GLY-treated groups at different concentrations (0.1 and 4 mg/ml) and exposure durations (8 and 12 h) revealed that this organophosphate herbicide induced different apoptotic characteristics in testicular germ cells in a time- and dose-dependent manner. However, NAC (10 mM), being a potent antioxidant, was found to mitigate GLY-induced cytotoxicity in testicular cells as evidenced by fewer apoptotic characteristics in GLY plus NAC-treated groups, suggesting its beneficial potential in alleviating the GLY-induced gonadotoxicity in males.Abbreviations: GLY (Glyphosate), NAC (N-acetyl-L-cysteine), TEM (Transmission electron microscopic), GE (genetic engineered), Organophosphate (OPs).}, } @article {pmid34697592, year = {2021}, author = {Abdelhafez, D and Aboelkomsan, E and El Sadik, A and Lasheen, N and Ashur, S and Elshimy, A and Morcos, GNB}, title = {The Role of Mesenchymal Stem Cells with Ascorbic Acid and N-Acetylcysteine on TNF-α, IL 1β, and NF-κβ Expressions in Acute Pancreatitis in Albino Rats.}, journal = {Journal of diabetes research}, volume = {2021}, number = {}, pages = {6229460}, pmid = {34697592}, issn = {2314-6753}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Blood Glucose/drug effects/metabolism ; Body Weight/drug effects ; Caspase 3/drug effects/metabolism ; Cell Proliferation/drug effects ; Ceruletide ; Fluorescent Dyes ; Insulin/metabolism ; Interleukin-1beta/*drug effects/metabolism ; Islets of Langerhans/*drug effects/metabolism/pathology ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; NF-kappa B/*drug effects/metabolism ; Organic Chemicals ; Pancreatitis/chemically induced/*metabolism/pathology ; Proliferating Cell Nuclear Antigen/drug effects/metabolism ; Rats ; Regeneration/drug effects ; Tumor Necrosis Factor-alpha/*drug effects/metabolism ; }, abstract = {Severe acute pancreatitis (SAP) is a necrotic pancreatic inflammation associated with high mortality rate (up to 70%). Bone marrow (BM) mesenchymal stem cells (MSCs) have been investigated in pancreatic cellular regeneration, but still their effects are controversial. Therefore, the present study is aimed at examining the enrichment of the stem cells with ascorbic acid (AA) and N-acetylcysteine (NAC) and explore their combined action on the expression of the inflammatory cytokines: interleukin 1β (IL 1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κβ (NF-κβ). A total of twenty adult male Sprague-Dawley albino rats were divided into four groups: the control group, cerulein group (to induce acute pancreatitis), BM-MSCs group, and combined BM-MSCs with AA and NAC group. Homing and proliferation of stem cells were revealed by the appearance of PKH26-labelled BM-MSCs in the islets of Langerhans. AA and NAC combination with BM-MSCs (group IV) was demonstrated to affect the expression of the inflammatory cytokines: IL 1β, TNF-α, and NF-κβ. In addition, improvement of the biochemical and histological parameters is represented in increasing body weight, normal blood glucose, and insulin levels and regeneration of the islet cells. Immunohistochemical studies showed an increase in proliferating cell nuclear antigen (PCNA) and decrease in caspase-3 reactions, detected markedly in group IV, after the marked distortion of the classic pancreatic lobular architecture was induced by cerulein. It could be concluded that treatment with BM-MSCs combined with antioxidants could provide a promising therapy for acute pancreatitis and improve the degeneration, apoptosis, necrosis, and inflammatory processes of the islets of Langerhans. TNF-α, IL 1β, and NF-κβ are essential biomarkers for the evaluation of MSC regenerative effectiveness.}, } @article {pmid34690806, year = {2021}, author = {Zhu, X and Zhan, Y and Gu, Y and Huang, Q and Wang, T and Deng, Z and Xie, J}, title = {Cigarette Smoke Promotes Interleukin-8 Production in Alveolar Macrophages Through the Reactive Oxygen Species/Stromal Interaction Molecule 1/Ca[2+] Axis.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {733650}, pmid = {34690806}, issn = {1664-042X}, abstract = {Chronic obstructive pulmonary disease (COPD), primarily attributed to cigarette smoke (CS), is characterized by multiple pathophysiological changes, including oxidative stress and inflammation. Stromal interaction molecule 1 (STIM1) is a Ca[2+] sensor that regulates Ca[2+] entry in different types of cells. The present study aimed to explore the relationship between CS-induced oxidative stress and inflammation, as well as the functional role of STIM1 thereinto. Our results showed that the reactive oxygen species (ROS)/STIM1/Ca[2+] axis played a critical role in CS-induced secretion of interleukin (IL)-8 in human alveolar macrophages. Specifically, smokers with COPD (SC) showed higher levels of ROS in the lung tissues compared with healthy non-smokers (HN). STIM1 was upregulated in the lung tissues of COPD patients. The expression of STIM1 was positively associated with ROS levels and negatively correlated with pulmonary function. The expression of STIM1 was also increased in the bronchoalveolar lavage fluid (BALF) macrophages of COPD patients and PMA-differentiated THP-1 macrophages stimulated by cigarette smoke extract (CSE). Additionally, CSE-induced upregulation of STIM1 in PMA-differentiated THP-1 macrophages was inhibited by pretreatment with N-acetylcysteine (NAC), a ROS scavenger. Transfection with small interfering RNA (siRNA) targeting STIM1 and pretreatment with NAC alleviated CSE-induced increase in intracellular Ca[2+] levels and IL-8 expression. Furthermore, pretreatment with SKF-96365 and 2-APB, the inhibitors of Ca[2+] influx, suppressed CSE-induced secretion of IL-8. In conclusion, our study demonstrates that CSE-induced ROS production may increase the expression of STIM1 in macrophages, which further promotes the release of IL-8 by regulating Ca[2+] entry. These data suggest that STIM1 may play a crucial role in CSE-induced ROS production and inflammation, and participate in the pathogenesis of COPD.}, } @article {pmid34687865, year = {2021}, author = {Wang, XH and Song, TZ and Zheng, HY and Li, YH and Zheng, YT}, title = {Jejunal epithelial barrier disruption triggered by reactive oxygen species in early SIV infected rhesus macaques.}, journal = {Free radical biology & medicine}, volume = {177}, number = {}, pages = {143-155}, doi = {10.1016/j.freeradbiomed.2021.10.026}, pmid = {34687865}, issn = {1873-4596}, mesh = {Animals ; Humans ; Hydrogen Peroxide ; Intestinal Mucosa ; Macaca mulatta ; Reactive Oxygen Species ; *Simian Acquired Immunodeficiency Syndrome ; *Simian Immunodeficiency Virus ; }, abstract = {Intestinal epithelial barrier destruction occurs earlier than mucosal immune dysfunction in the acute stage of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. At present, however, the cause of compromised gastrointestinal integrity in early SIV infection remains unknown. In the current study, we investigated the effects of SIV infection on epithelial barrier integrity and explored oxidative stress-mediated DNA damage and apoptosis in epithelial cells from early acute SIVmac239-infected Chinese rhesus macaques (Macaca mulatta). Results showed that the sensitive molecular marker of small intestinal barrier dysfunction, i.e., intestinal fatty acid-binding protein (IFABP), was significantly increased in plasma at 14 days post-SIV infection. SIV infection induced a profound decrease in the expression of tight junction proteins, including claudin-1, claudin-3, and zonula occludens (ZO)-1, as well as a significant increase in the active form of caspase-3 level in epithelial cells. RNA sequencing (RNA-seq) analysis suggested that differentially expressed genes between pre- and post-SIV-infected jejuna were enriched in pathways involved in cell redox homeostasis, oxidoreductase activity, and mitochondria. Indeed, a SIV-mediated increase in reactive oxygen species (ROS) in the epithelium and macrophages, as well as an increase in hydrogen peroxide (H2O2) and decrease in glutathione (GSH)/glutathione disulfide (GSSG) antioxidant defense, were observed in SIV-infected jejuna. In addition, the accumulation of mitochondrial dysfunction and DNA oxidative damage led to an increase in senescence-associated β-galactosidase (SA-β-gal) and early apoptosis in intestinal epithelial cells. Furthermore, HIV-1 Tat protein-induced epithelial monolayer disruption in HT-29 cells was rescued by antioxidant N-acetylcysteine (NAC). These results indicate that mitochondrial dysfunction and oxidative stress in jejunal epithelial cells are primary contributors to gut epithelial barrier disruption in early SIV-infected rhesus macaques.}, } @article {pmid34687363, year = {2021}, author = {Berkel, C and Cacan, E}, title = {A collective analysis of lifespan-extending compounds in diverse model organisms, and of species whose lifespan can be extended the most by the application of compounds.}, journal = {Biogerontology}, volume = {22}, number = {6}, pages = {639-653}, pmid = {34687363}, issn = {1573-6768}, mesh = {Aging ; Animals ; Caenorhabditis elegans ; *Caenorhabditis elegans Proteins ; Drosophila melanogaster ; *Longevity ; Mice ; }, abstract = {Research on aging and lifespan-extending compounds has been carried out using diverse model organisms, including yeast, worms, flies and mice. Many studies reported the identification of novel lifespan-extending compounds in different species, some of which may have the potential to translate to the clinic. However, studies collectively and comparatively analyzing all the data available in these studies are highly limited. Here, by using data from the DrugAge database, we first identified top compounds in terms of their effects on percent change in average lifespan of diverse organisms, collectively (n = 1728). We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average. We showed that minocycline led to the highest percent increase in average lifespan among other compounds, in both Drosophila melanogaster (28.09%) and Caenorhabditis elegans (26.67%), followed by curcumin (11.29%) and gluconic acid (5.51%) for D. melanogaster and by metformin (26.56%), resveratrol (15.82%) and quercetin (9.58%) for C. elegans. Moreover, we found that top 5 species whose lifespan can be extended the most by compounds with lifespan-extending properties are Philodina acuticornis, Acheta domesticus, Aeolosoma viride, Mytilina brevispina and Saccharomyces cerevisiae (211.80%, 76%, 70.26%, 55.18% and 45.71% in average, respectively). This study provides novel insights on lifespan extension in model organisms, and highlights the importance of databases with high quality content curated by researchers from multiple resources, in aging research.}, } @article {pmid34684533, year = {2021}, author = {Quesada-Vázquez, S and Colom-Pellicer, M and Navarro-Masip, È and Aragonès, G and Del Bas, JM and Caimari, A and Escoté, X}, title = {Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease, Hepatic Fibrosis, and Insulin Resistance in Mice.}, journal = {Nutrients}, volume = {13}, number = {10}, pages = {}, pmid = {34684533}, issn = {2072-6643}, support = {ACCIÓ-Eurecat//ACCIÓ/ ; CER-20191010//TECNOMIFOOD; Centre for the Development of Industrial Technology (CDTI)/ ; }, mesh = {Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Biomarkers/metabolism ; *Dietary Supplements ; Fatty Acids/metabolism ; Gene Expression Regulation ; *Insulin Resistance ; Lipid Metabolism ; Liver/injuries/pathology ; Liver Cirrhosis/blood/*metabolism ; Male ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/blood/*metabolism ; Oxidation-Reduction ; RNA, Messenger/genetics/metabolism ; Mice ; }, abstract = {Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD[+]) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.}, } @article {pmid34684414, year = {2021}, author = {Hodun, K and Sztolsztener, K and Chabowski, A}, title = {Antioxidants Supplementation Reduces Ceramide Synthesis Improving the Cardiac Insulin Transduction Pathway in a Rodent Model of Obesity.}, journal = {Nutrients}, volume = {13}, number = {10}, pages = {}, pmid = {34684414}, issn = {2072-6643}, support = {SUB/1/DN/20/004/1118//Uniwersytet Medyczny w Bialymstoku/ ; }, mesh = {Animal Feed ; Animals ; Antioxidants/*pharmacology ; Biomarkers/blood/metabolism ; Body Weight ; Ceramides/*biosynthesis ; Diet, High-Fat ; *Dietary Supplements ; Glucose/metabolism ; Insulin/*metabolism ; Insulin Resistance ; Male ; Metabolic Networks and Pathways ; Models, Animal ; Myocardium/*metabolism ; Obesity/etiology/*metabolism ; Phosphorylation ; Rats ; Rodentia ; Signal Transduction/*drug effects ; Sphingolipids/metabolism ; }, abstract = {Obesity-related disruption in lipid metabolism contributes to cardiovascular dysfunction. Despite numerous studies on lipid metabolism in the left ventricle, there is no data describing the influence of n-acetylcysteine (NAC) and α-lipoic acid (ALA), as glutathione precursors, on sphingolipid metabolism, and insulin resistance (IR) occurrence. The aim of our experiment was to evaluate the influence of chronic antioxidants administration on myocardial sphingolipid state and intracellular insulin signaling as a potential therapeutic strategy for obesity-related cardiovascular IR. The experiment was conducted on male Wistar rats fed a standard rodent chow or a high-fat diet with intragastric administration of NAC or ALA for eight weeks. Cardiac and plasma sphingolipid species were assessed by high-performance liquid chromatography (HPLC). The proteins expressed from sphingolipid and insulin signaling pathways were determined by Western blot. Antioxidant supplementation markedly reduced ceramide accumulation by lowering the expression of selected proteins from the sphingolipid pathway and simultaneously increased the myocardial sphingosine-1-phosphate level. Moreover, NAC and ALA augmented the expression of GLUT4 and the phosphorylation state of Akt (Ser473) and GSK3β (Ser9), which improved the intracellular insulin transduction pathway. Based on our results, we may postulate that NAC and ALA have a beneficial influence on the cardiac ceramidose under IR conditions.}, } @article {pmid34681725, year = {2021}, author = {Tsymbal, SA and Moiseeva, AA and Agadzhanian, NA and Efimova, SS and Markova, AA and Guk, DA and Krasnovskaya, OO and Alpatova, VM and Zaitsev, AV and Shibaeva, AV and Tatarskiy, VV and Dukhinova, MS and Ol'shevskaya, VA and Ostroumova, OS and Beloglazkina, EK and Shtil, AA}, title = {Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst.}, journal = {International journal of molecular sciences}, volume = {22}, number = {20}, pages = {}, pmid = {34681725}, issn = {1422-0067}, support = {Project 19-29-08007//Russian Foundation for Basic Research/ ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Coordination Complexes/chemical synthesis/*pharmacology ; Copper/*chemistry ; Drug Resistance, Neoplasm/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Liposomes/chemistry/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/chemistry/*toxicity ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Superoxides/metabolism ; }, abstract = {Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu[2+] in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2-3 orders of magnitude determined by IC50 values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1-1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2-6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu-organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu-organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu[+1] complexes can generate a superoxide anion in a Fenton-like reaction Cu[+1]L + O2 → O2[-.] + Cu[+2]L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds.}, } @article {pmid34681647, year = {2021}, author = {Wang, S and Xu, X and Che, D and Fan, R and Gao, M and Cao, Y and Ge, C and Feng, Y and Li, J and Xie, S and Wang, C and Dai, F and Gao, L and Wang, Y}, title = {Reactive Oxygen Species Mediate 6c-Induced Mitochondrial and Lysosomal Dysfunction, Autophagic Cell Death, and DNA Damage in Hepatocellular Carcinoma.}, journal = {International journal of molecular sciences}, volume = {22}, number = {20}, pages = {}, pmid = {34681647}, issn = {1422-0067}, support = {U1904151, 81703004, 32000271 and 81772832//National Natural Science Foundation of China/ ; 2019M652527, 2020M672214//China Postdoctoral Science Foundation Funded Project/ ; 1901009//Start-up Fund of Postdoctoral Research Program of Henan Province/ ; 2019SJGLX081Y//Postgraduate Education Reform Project of Henan Province/ ; }, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs & derivatives/pharmacology ; Antioxidants/chemistry/pharmacology ; Autophagic Cell Death/*drug effects ; Autophagosomes/metabolism ; Carcinoma, Hepatocellular/metabolism/pathology ; DNA Damage/*drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism/pathology ; Lysosomes/*metabolism ; Microtubule-Associated Proteins/metabolism ; Mitochondria/*metabolism ; Naphthalimides/chemistry/*pharmacology ; Proteome/analysis ; Proteomics/methods ; Reactive Oxygen Species/*metabolism ; Sequestosome-1 Protein/metabolism ; }, abstract = {Increasing the level of reactive oxygen species (ROS) in cancer cells has been suggested as a viable approach to cancer therapy. Our previous study has demonstrated that mitochondria-targeted flavone-naphthalimide-polyamine conjugate 6c elevates the level of ROS in cancer cells. However, the detailed role of ROS in 6c-treated cancer cells is not clearly stated. The biological effects and in-depth mechanisms of 6c in cancer cells need to be further investigated. In this study, we confirmed that mitochondria are the main source of 6c-induced ROS, as demonstrated by an increase in 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox fluorescence. Compound 6c-induced mitochondrial ROS caused mitochondrial dysfunction and lysosomal destabilization confirmed by absolute quantitation (iTRAQ)-based comparative proteomics. Compound 6c-induced metabolic pathway dysfunction and lysosomal destabilization was attenuated by N-acetyl-L-cysteine (NAC). iTRAQ-based comparative proteomics showed that ROS regulated the expression of 6c-mediated proteins, and treatment with 6c promoted the formation of autophagosomes depending on ROS. Compound 6c-induced DNA damage was characterized by comet assay, p53 phosphorylation, and γH2A.X, which was diminished by pretreatment with NAC. Compound 6c-induced cell death was partially reversed by 3-methyladenine (3-MA), bafilomycin (BAF) A1, and NAC, respectively. Taken together, the data obtained in our study highlighted the involvement of mitochondrial ROS in 6c-induced autophagic cell death, mitochondrial and lysosomal dysfunction, and DNA damage.}, } @article {pmid34681610, year = {2021}, author = {Khoi, CS and Lin, YW and Chen, JH and Liu, BH and Lin, TY and Hung, KY and Chiang, CK}, title = {Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells.}, journal = {International journal of molecular sciences}, volume = {22}, number = {20}, pages = {}, pmid = {34681610}, issn = {1422-0067}, support = {108-FTN16//Far-Eastern Memorial Hospital/ ; 108-FTN16//National Taiwan University Hospital/ ; NTUH- 108-S4373//National Taiwan University Hospital/ ; NTUH-UN-109-S4785//National Taiwan University Hospital/ ; NTUH-110-S5074//National Taiwan University Hospital/ ; MOST- 110-2314-B-002 -130//Ministry of Science and Technology, Taiwan/ ; MOST-107-2314-B-002-027-MY3//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Endoribonucleases/metabolism ; Epithelial Cells/cytology/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Kidney Tubules, Proximal/cytology/metabolism ; Ochratoxins/*pharmacology ; Oxidative Stress/drug effects ; Protein Serine-Threonine Kinases/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.}, } @article {pmid34681218, year = {2021}, author = {Yang, KH and Lin, YS and Wang, SC and Lee, MY and Tang, JY and Chang, FR and Chuang, YT and Sheu, JH and Chang, HW}, title = {Soft Coral-Derived Dihydrosinularin Exhibits Antiproliferative Effects Associated with Apoptosis and DNA Damage in Oral Cancer Cells.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {34681218}, issn = {1424-8247}, support = {MOST 108-2320-B-037-015-MY3 and 110-2314-B-037-074-MY3//Ministry of Science and Technology Taiwan/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; KMUH109-9M56//Kaohsiung Medical University Hospital/ ; }, abstract = {Dihydrosinularin (DHS) is an analog of soft coral-derived sinularin; however, the anticancer effects and mechanisms of DHS have seldom been reported. This investigation examined the antiproliferation ability and mechanisms of DHS on oral cancer cells. In a cell viability assay, DHS showed growth inhibition against several types of oral cancer cell lines (Ca9-22, SCC-9, OECM-1, CAL 27, OC-2, and HSC-3) with no cytotoxic side effects on non-malignant oral cells (HGF-1). Ca9-22 and SCC-9 cell lines showing high susceptibility to DHS were selected to explore the antiproliferation mechanisms of DHS. DHS also causes apoptosis as detected by annexin V, pancaspase, and caspase 3 activation. DHS induces oxidative stress, leading to the generation of reactive oxygen species (ROS)/mitochondrial superoxide (MitoSOX) and mitochondrial membrane potential (MitoMP) depletion. DHS also induced DNA damage by probing γH2AX phosphorylation. Pretreatment with the ROS scavenger N-acetylcysteine (NAC) can partly counter these DHS-induced changes. We report that the marine natural product DHS can inhibit the cell growth of oral cancer cells. Exploring the mechanisms of this cancer cell growth inhibition, we demonstrate the prominent role DHS plays in oxidative stress.}, } @article {pmid34680757, year = {2021}, author = {Aiyer, A and Visser, SK and Bye, P and Britton, WJ and Whiteley, GS and Glasbey, T and Kriel, FH and Farrell, J and Das, T and Manos, J}, title = {Effect of N-Acetylcysteine in Combination with Antibiotics on the Biofilms of Three Cystic Fibrosis Pathogens of Emerging Importance.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {10}, number = {10}, pages = {}, pmid = {34680757}, issn = {2079-6382}, support = {CT20584//University of Sydney and Whiteley Corporation/ ; grant number CT20584//COMMERCIAL DEVELOPMENT & INDUSTRY PARTNERSHIP, grant number CT20584-University of Sydney and Whiteley Corporation/ ; }, abstract = {Cystic fibrosis (CF) is a genetic disorder causing dysfunctional ion transport resulting in accumulation of viscous mucus that fosters chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans and Stenotrophomonas maltophilia are increasingly prevalent CF pathogens and while Burkholderia cencocepacia is slowly decreasing; all are complicated by multidrug resistance that is enhanced by biofilm formation. This study investigates potential synergy between the antibiotics ciprofloxacin (0.5-128 µg/mL), colistin (0.5-128 µg/mL) and tobramycin (0.5-128 µg/mL) when combined with the neutral pH form of N-Acetylcysteine (NACneutral) (0.5-16.3 mg/mL) against 11 cystic fibrosis strains of Burkholderia, Stenotrophomonas and Achromobacter sp. in planktonic and biofilm cultures. We screened for potential synergism using checkerboard assays from which fraction inhibitory concentration indices (FICI) were calculated. Synergistic (FICI ≤ 0.5) and additive (0.5 > FICI ≥ 1) combinations were tested on irreversibly attached bacteria and 48 h mature biofilms via time-course and colony forming units (CFU/mL) assays. This study suggests that planktonic FICI analysis does not necessarily translate to reduction in bacterial loads in a biofilm model. Future directions include refining synergy testing and determining further mechanisms of action of NAC to understand how it may interact with antibiotics to better predict synergy.}, } @article {pmid34680063, year = {2021}, author = {Moreno-Gómez-Toledano, R and Sánchez-Esteban, S and Cook, A and Mínguez-Moratinos, M and Ramírez-Carracedo, R and Reventún, P and Delgado-Marín, M and Bosch, RJ and Saura, M}, title = {Bisphenol A Induces Accelerated Cell Aging in Murine Endothelium.}, journal = {Biomolecules}, volume = {11}, number = {10}, pages = {}, pmid = {34680063}, issn = {2218-273X}, mesh = {Acetylcysteine/metabolism ; Activating Transcription Factor 4/*genetics ; Aging/drug effects/genetics ; Animals ; Aorta/drug effects ; Apoptosis/drug effects ; Benzhydryl Compounds/pharmacology ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; Endothelium/drug effects/pathology ; Mice ; Necroptosis/drug effects/genetics ; Oxidative Stress/drug effects ; Phenols/pharmacology ; Transcription Factor CHOP/genetics ; eIF-2 Kinase/*genetics ; }, abstract = {Bisphenol A (BPA) is a widespread endocrine disruptor affecting many organs and systems. Previous work in our laboratory demonstrated that BPA could induce death due to necroptosis in murine aortic endothelial cells (MAECs). This work aims to evaluate the possible involvement of BPA-induced senescence mechanisms in endothelial cells. The β-Gal assays showed interesting differences in cell senescence at relatively low doses (100 nM and 5 µM). Western blots confirmed that proteins involved in senescence mechanisms, p16 and p21, were overexpressed in the presence of BPA. In addition, the UPR (unfolding protein response) system, which is part of the senescent phenotype, was also explored by Western blot and qPCR, confirming the involvement of the PERK-ATF4-CHOP pathway (related to pathological processes). The endothelium of mice treated with BPA showed an evident increase in the expression of the proteins p16, p21, and CHOP, confirming the results observed in cells. Our results demonstrate that oxidative stress induced by BPA leads to UPR activation and senescence since pretreatment with N-acetylcysteine (NAC) in BPA-treated cells reduced the percentage of senescent cells prevented the overexpression of proteins related to BPA-induced senescence and reduced the activation of the UPR system. The results suggest that BPA participates actively in accelerated cell aging mechanisms, affecting the vascular endothelium and promoting cardiovascular diseases.}, } @article {pmid34679638, year = {2021}, author = {Lee, HA and Chu, KB and Moon, EK and Quan, FS}, title = {Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {10}, pages = {}, pmid = {34679638}, issn = {2076-3921}, support = {2018R1A6A1A03025124 and 2020R1I1A1A01066748//National Research Foundation of Korea/ ; HV20C0085 and HV20C0142//the Ministry of Health & Welfare, Republic of Korea/ ; }, abstract = {Histone deacetylase inhibitors (HDACi) are emerging as anti-hepatocellular carcinoma (HCC) agents. However, the molecular mechanisms underlying HDACi-induced sensitization to oxidative stress and cell death of HCC remain elusive. We hypothesized that HDACi reduces the anti-oxidative stress capacity of HCC, rendering it more susceptible to oxidative stress and cell death. Change in the transcriptome of HCC was analyzed by RNA-seq and validated using real-time quantitative polymerase chain reaction (qPCR) and Western blot. Cell death of HCC was analyzed by fluorescence-activated cell sorting (FACS). Protein localization and binding on the target gene promoters were investigated by immunofluorescence (IF) and chromatin immunoprecipitation (ChIP), respectively. Glutathione peroxidase 8 (GPX8) was highly down-regulated in HCC upon oxidative stress and HDACi co-treatment. Oxidative stress and HDACi enhanced the expression and transcriptional activities of ER-stress-related genes. N-acetyl-cysteine (NAC) supplementation reversed the oxidative stress and HDACi-induced apoptosis in HCC. HDACi significantly enhanced the effect of ER stressors on HCC cell death. GPX8 overexpression reversed the activation of ER stress signaling and apoptosis induced by oxidative stress and HDACi. In conclusion, HDACi suppresses the expression of GPX8, which sensitizes HCC to ER stress and apoptosis by oxidative stress.}, } @article {pmid34672197, year = {2021}, author = {Weng, J and Wang, Y and Zhang, Y and Ye, D}, title = {An Activatable Near-Infrared Fluorescence Probe for in Vivo Imaging of Acute Kidney Injury by Targeting Phosphatidylserine and Caspase-3.}, journal = {Journal of the American Chemical Society}, volume = {143}, number = {43}, pages = {18294-18304}, doi = {10.1021/jacs.1c08898}, pmid = {34672197}, issn = {1520-5126}, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/chemically induced/*diagnostic imaging/drug therapy/metabolism ; Animals ; Apoptosis/physiology ; Biomarkers/metabolism ; Caspase 3/*metabolism ; Cell Line ; Cisplatin ; Coordination Complexes/chemical synthesis/chemistry/radiation effects ; Female ; Fluorescent Dyes/chemical synthesis/*chemistry/radiation effects ; Indoles/chemical synthesis/chemistry/radiation effects ; Infrared Rays ; Mice, Inbred BALB C ; Mice, Nude ; Optical Imaging ; Phosphatidylserines/*metabolism ; Zinc/chemistry ; Mice ; }, abstract = {Renal-clearable and target-responsive near-infrared (NIR) fluorescent imaging probes have been promising for in vivo diagnosis of acute kidney injury (AKI). However, designing an imaging probe that is renal-clearable and concurrently responsive toward multiple molecular targets to facilitate early detection of AKI with improved sensitivity and specificity is challenging. Herein, by leveraging the receptor-mediated binding and retention effect along with enzyme-triggered fluorescence activation, we design and synthesize an activatable small-molecule NIR fluorescent probe (1-DPA2) using a "one-pot sequential click reaction" approach. 1-DPA2 can target both the externalized phosphatidylserine (PS) and active caspase-3 (Casp-3), two essential biomarkers of apoptosis, producing enhanced 808 nm NIR fluorescence and a high signal-to-background ratio (SBR) amenable to detecting the onset of cisplatin-induced AKI in mice as early as 24 h post-treatment with cisplatin. We not only monitor the gradual activation of Casp-3 in the kidney of mice upon AKI progression but also can report on the progressive recovery of kidney functions in AKI mice following N-acetyl-l-cysteine (NAC) therapy via real-time fluorescence imaging by 1-DPA2. This study demonstrates the ability of 1-DPA2 for longitudinal monitoring of renal cell apoptosis by concurrently targeting PS externalization and Casp-3 activation, which is efficient for early diagnosis of AKI and useful for prediction of potential drug nephrotoxicity as well as in vivo screening of anti-AKI drugs' efficacy.}, } @article {pmid34665895, year = {2022}, author = {El Shehaby, DM and Sayed, SA and Abd El-Kareem, DM and Elsherif, R and Almaz, D}, title = {Trimetazedine with hyperinsulinimea-euoglycemia, N-acetyl cysteine, and vitamin C: A new approach concept for management of aluminum phosphide poisoning.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {1}, pages = {e22931}, doi = {10.1002/jbt.22931}, pmid = {34665895}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Aluminum Compounds/*poisoning ; Animals ; Ascorbic Acid/*pharmacology ; *Hyperinsulinism/chemically induced/drug therapy/metabolism ; Male ; Phosphines/*poisoning ; Rabbits ; Trimetazidine/*pharmacology ; }, abstract = {Aluminum phosphide (AlP) is commonly used as a powerful suicidal tool. The exact mechanism of acute toxicity has not been well defined despite high mortality rates as well as its supportive treatment including rapid decontamination and institution of resuscitative measures. The current study aimed to investigate a new combination therapy using trimetazidine, N-acetyl cysteine, vitamin C, and hyperinsulinemia-euglycemia to manage acute AlP poisoning. Acute AlP-induced cardiotoxicity, hemodynamic changes, and hepatotoxicity were evaluated using electrocardiogram, creatinine kinase MB iso-enzyme, troponin-1, blood pressure, random blood glucose level, liver function tests, and histopathological changes in both the heart and liver in a rabbit model of AlP poisoning. The results showed that the new regimen therapy ameliorates the toxic effect of AlP with significant improvement in survival, cardiovascular and hemodynamic parameters in addition to histopathological changes. These results highlight the strong cardioprotective, antioxidant, hepatoprotective effects of the new combined therapy along with correction of hemodynamic changes and hyperglycemia as a potential target in the management of acute AlP poisoning.}, } @article {pmid34664816, year = {2021}, author = {Jamali, F and Ahmadzadeh, A and Sahraei, Z and Salamzadeh, J}, title = {Study of the Effects of N-acetylcysteine on Inflammatory Biomarkers and Disease Activity Score in Patients with Rheumatoid Arthritis.}, journal = {Iranian journal of allergy, asthma, and immunology}, volume = {20}, number = {5}, pages = {574-583}, doi = {10.18502/ijaai.v20i5.7407}, pmid = {34664816}, issn = {1735-5249}, mesh = {Acetylcysteine/*administration & dosage ; Administration, Oral ; Arthritis, Rheumatoid/diagnosis/*drug therapy/etiology/*metabolism ; *Biomarkers ; Blood Sedimentation ; C-Reactive Protein ; Cytokines/blood/metabolism ; Disease Management ; Disease Susceptibility ; Humans ; Inflammation Mediators/*metabolism ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {Rheumatoid arthritis (RA) is considered as an autoimmune-related condition in which the overproduction of pro-inflammatory cytokines leads to an inflammatory cascade. N-acetylcysteine (NAC) is a potent anti-inflammatory and anti-oxidant agent. We aimed to explore the impact of oral NAC on cytokines activities and clinical indicators in RA patients. In this placebo-controlled randomized double-blind clinical trial, 41 active RA patients were allocated in either NAC (600 mg, twice a day) or placebo group, as add-on therapy to the routine regimen, for 8 weeks. Disease activity score with an erythrocyte sedimentation rate (DAS28-ESR), and serum concentrations of interleukin (IL)-1β and IL-17 were assessed at baseline and end of the trial for all participants in the test and control groups. The reduction of the DAS28-ESR was higher considerably in the NAC group compared to that of the control group. No statistically significant differences were seen in the reduction of IL-1β and IL-17 cytokines between the NAC and control groups. In addition, improvements in the patient global assessment, number of tender joints, number of swollen joints, and the ESR rates were in favor of the NAC group. Our findings reveal that NAC may have a beneficial effect on all of the clinical features of RA. However, non-significant variations in the IL-1β and IL-17 levels suggest an alternative way of NAC effectiveness without influencing the measured cytokines. Nevertheless, these results need to be confirmed by further investigations.}, } @article {pmid34660086, year = {2021}, author = {Sandhu, JK and Waqar, A and Jain, A and Joseph, C and Srivastava, K and Ochuba, O and Alkayyali, T and Ruo, SW and Poudel, S}, title = {Oxidative Stress in Polycystic Ovarian Syndrome and the Effect of Antioxidant N-Acetylcysteine on Ovulation and Pregnancy Rate.}, journal = {Cureus}, volume = {13}, number = {9}, pages = {e17887}, pmid = {34660086}, issn = {2168-8184}, abstract = {Polycystic ovarian syndrome (PCOS) is an endocrinological condition that leads to infertility in many females. N-acetylcysteine (NAC), a novel antioxidant, is being used as an adjuvant to treat infertility in females suffering from PCOS. This review aims to evaluate oxidative stress in females suffering from PCOS and assess whether the anti-oxidizing properties of NAC are beneficial in enhancing the rate of ovulation and pregnancy in infertile PCOS females. A literature search was conducted manually on PubMed and Google Scholar databases using the following keywords: "N-Acetylcysteine," "PCOS," "Oxidative stress," "Antioxidants," and "infertility" alone and/or in combination for data collection. The studies were manually screened and, after applying inclusion-exclusion criteria, 32 studies consisting of 2466 females of the reproductive age group are included in this review. Our review revealed that females suffering from PCOS tend to show elevated levels of inflammatory markers and a decrease in antioxidant capacity. When used in combination with clomiphene citrate or letrozole, NAC increases ovulation and pregnancy rate in infertile females suffering from PCOS and positively affects the quality of oocytes and number of follicles ≥18mm. Moreover, its side effect profile is low. It also results in a mild increase in endometrial thickness in some females. Future studies on a large sample size using NAC alone are highly recommended to evaluate its role as a single-drug therapy for treating infertility in females suffering from PCOS.}, } @article {pmid34658034, year = {2022}, author = {Bourne, LE and Patel, JJ and Davies, BK and Neven, E and Verhulst, A and D'Haese, PC and Wheeler-Jones, CPD and Orriss, IR}, title = {N-acetylcysteine (NAC) differentially affects arterial medial calcification and bone formation: The role of l-cysteine and hydrogen sulphide.}, journal = {Journal of cellular physiology}, volume = {237}, number = {1}, pages = {1070-1086}, doi = {10.1002/jcp.30605}, pmid = {34658034}, issn = {1097-4652}, support = {PG/15/13/31296/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {*Acetylcysteine/pharmacology ; Arteries/metabolism ; Glutathione/metabolism ; *Hydrogen Sulfide/metabolism/pharmacology ; Osteoblasts/metabolism ; Osteogenesis ; }, abstract = {Arterial medial calcification (AMC) is the deposition of calcium phosphate in the arteries. AMC is widely thought to share similarities with physiological bone formation; however, emerging evidence suggests several key differences between these processes. N-acetylcysteine (NAC) displays antioxidant properties and can generate hydrogen sulphide (H2 S) and glutathione (GSH) from its deacetylation to l-cysteine. This study found that NAC exerts divergent effects in vitro, increasing osteoblast differentiation and bone formation by up to 5.5-fold but reducing vascular smooth muscle cell (VSMC) calcification and cell death by up to 80%. In vivo, NAC reduced AMC in a site-specific manner by 25% but had no effect on the bone. The actions of l-cysteine and H2 S mimicked those of NAC; however, the effects of H2 S were much less efficacious than NAC and l-cysteine. Pharmacological inhibition of H2 S-generating enzymes did not alter the actions of NAC or l-cysteine; endogenous production of H2 S was also unaffected. In contrast, NAC and l-cysteine increased GSH levels in calcifying VSMCs and osteoblasts by up to 3-fold. This suggests that the beneficial actions of NAC are likely to be mediated via the breakdown of l-cysteine and the subsequent GSH generation. Together, these data show that while the molecular mechanisms driving the actions of NAC appear similar, the downstream effects on cell function differ significantly between osteoblasts and calcifying VSMCs. The ability of NAC to exert these differential actions further supports the notion that there are differences between the development of pathological AMC and physiological bone formation. NAC could represent a therapeutic option for treating AMC without exerting negative effects on bone.}, } @article {pmid34653248, year = {2022}, author = {Docampo, MD and da Silva, MB and Lazrak, A and Nichols, KB and Lieberman, SR and Slingerland, AE and Armijo, GK and Shono, Y and Nguyen, C and Monette, S and Dwomoh, E and Lee, N and Geary, CD and Perobelli, SM and Smith, M and Markey, KA and Vardhana, SA and Kousa, AI and Zamir, E and Greenfield, I and Sun, JC and Cross, JR and Peled, JU and Jenq, RR and Stein-Thoeringer, CK and van den Brink, MRM}, title = {Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.}, journal = {Blood}, volume = {139}, number = {15}, pages = {2392-2405}, pmid = {34653248}, issn = {1528-0020}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; R01 CA228308/CA/NCI NIH HHS/United States ; R01 HL147584/HL/NHLBI NIH HHS/United States ; R01 HL124112/HL/NHLBI NIH HHS/United States ; U01 AI124275/AI/NIAID NIH HHS/United States ; R01 HL125571/HL/NHLBI NIH HHS/United States ; R01 CA228358/CA/NCI NIH HHS/United States ; K08 HL143189/HL/NHLBI NIH HHS/United States ; R01 HL123340/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 AG052359/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Butyrates ; Fatty Acids, Volatile/physiology ; *Graft vs Host Disease ; *Hematopoietic Stem Cell Transplantation ; Mice ; T-Lymphocytes ; }, abstract = {The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.}, } @article {pmid34652584, year = {2022}, author = {Song, L and Yao, S and Zheng, D and Xuan, Y and Li, W}, title = {Astaxanthin attenuates contrast-induced acute kidney injury in rats via ROS/NLRP3 inflammasome.}, journal = {International urology and nephrology}, volume = {54}, number = {6}, pages = {1355-1364}, pmid = {34652584}, issn = {1573-2584}, support = {2014-YY007//Six Talent Peaks Project in Jiangsu Province/ ; }, mesh = {*Acute Kidney Injury/chemically induced/metabolism/prevention & control ; Animals ; Caspase 1 ; Female ; Humans ; *Inflammasomes/metabolism ; Interleukin-18 ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Xanthophylls ; }, abstract = {OBJECTIVE: To explore the protective effect and mechanism of astaxanthin on the kidney of rats with contrast-induced acute kidney injury.

METHODS: Forty SD rats were randomly divided into five groups: Control group (CON); Astaxanthin control group (AST); Contrast media group (CM); Astaxanthin pre-treatment group (AST + CM); N-acetylcysteine pre-treatment group (NAC + CM), each group with eight rats. The rats were killed 72 h after the modeling, the blood supernatant and kidneys were collected, and then the serum creatinine and blood urea nitrogen levels were measured; HE staining was used to observe the pathological changes in kidney tissue; TUNEL was used to detect apoptosis level in renal tubular epithelial cells; frozen section was used to observe the expression of ROS in renal tissue by reactive oxygen staining; the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 were detected by immunohistochemistry and western blot.

RESULTS: The CI-AKI rat model was induced by iohexol. Then the elevated level of ROS activated the inflammatory response mediated by NLRP3 inflammasome (NLRP3, ASC, caspase-1). Subsequently, the increase in renal tubular epithelial cell apoptosis caused the destruction of the pathological structure of the kidney and finally led to renal impairment. While after the pretreatment of astaxanthin, the level of ROS was decreased. The activation level of NLRP3 inflammasome and its mediated inflammatory response were alleviated significantly. Eventually, the level of renal tubular epithelial cell apoptosis and renal damage were significantly mitigated.

CONCLUSION: Astaxanthin can protect the kidney in CI-AKI by inhibiting the activation of NLRP3 inflammasome-IL-1β/IL-18 through inhibition of the production of ROS.}, } @article {pmid34652265, year = {2022}, author = {Atilgan, FA and Atescelik, M and Yilmaz, M and Turk, A and Gurger, M and Goktekin, MC and Kuloglu, T}, title = {Effects of N-acetyl cysteine on TRPM2 expression in kidney and liver tissues following malathion intoxication.}, journal = {Biotechnic & histochemistry : official publication of the Biological Stain Commission}, volume = {97}, number = {5}, pages = {340-346}, doi = {10.1080/10520295.2021.1986639}, pmid = {34652265}, issn = {1473-7760}, mesh = {Acetylcysteine/pharmacology ; Animals ; Atropine Derivatives/metabolism/pharmacology ; Kidney/metabolism ; Liver ; *Malathion/metabolism/toxicity ; Male ; Oxidative Stress ; Rats ; Rats, Wistar ; *TRPM Cation Channels/metabolism ; }, abstract = {We investigated the effects of N-acetyl cysteine (NAC) on transient receptor potential melastatin 2 (TRPM2) channel expression in rat kidney and liver tissues following experimental malathion intoxication. We used seven groups of six male Wistar albino rats: control group, NAC, pralidoxime + atropine, malathion, malathion + pralidoxime + atropine, malathion + pralidoxime + atropine + NAC, and malathion + NAC. Single doses of 100 mg/kg N-acetyl cysteine, 40 mg/kg pralidoxime, 2 mg/kg atropine and 1/3 the lethal dose of malathion were administered. No difference in malondialdehyde (MDA) levels, apoptosis or TRPM2 immunoreactivity was found in liver tissue among the groups. In kidney tissue, MDA levels, apoptosis and TRPM2 immunoreactivity were increased significantly in the malathion and malathion + NAC groups compared to the control group. We found that organophosphate intoxication did not affect MDA, apoptosis or TRPM2 immunoreactivity in rat liver during the acute period. By contrast, we found that in kidney tissue, MDA, apoptosis, and TRPM2 immunoreactivity were increased significantly following administration of malathion. Also, NAC given in addition to pralidoxime and atropine reduced MDA to control levels.}, } @article {pmid34647812, year = {2022}, author = {Crisol, M and Yong, KW and Wu, K and Laouar, L and Elliott, JAW and Jomha, NM}, title = {Effectiveness of Clinical-Grade Chondroitin Sulfate and Ascorbic Acid in Mitigating Cryoprotectant Toxicity in Porcine Articular Cartilage.}, journal = {Biopreservation and biobanking}, volume = {20}, number = {4}, pages = {401-408}, doi = {10.1089/bio.2021.0083}, pmid = {34647812}, issn = {1947-5543}, mesh = {Animals ; Ascorbic Acid/metabolism/pharmacology ; *Cartilage, Articular/metabolism ; Cell Survival ; Chondrocytes/metabolism ; Chondroitin Sulfates/metabolism/pharmacology ; Cryopreservation/methods ; *Cryoprotective Agents/pharmacology ; Humans ; Swine ; }, abstract = {High concentrations of cryoprotective agents (CPAs) are required to achieve successful vitrification of articular cartilage; however, CPA cytotoxicity causes chondrocyte death. To reduce CPA toxicity, supplementation with research-grade additives, in particular chondroitin sulfate (CS) and ascorbic acid (AA), have previously been shown to improve chondrocyte recovery and metabolic function after exposure to CPAs at hypothermic conditions. However, it is necessary to evaluate the pharmaceutical equivalent clinical grade of these additives to facilitate the supplementation of additives into future vitrification protocols, which will be designed for vitrifying human articular cartilage in tissue banks. We sought to investigate the effectiveness of clinical-grade CS, AA, and N-acetylcysteine (NAC) in mitigating toxicity to chondrocytes during CPA exposure and removal, and determine whether a combination of two additives would further improve chondrocyte viability. We hypothesized that clinical-grade additives would exert chondroprotective effects comparable to those of research-grade additives, and that this protective effect would be enhanced if two additives were combined when compared with a single additive. The results indicated that both clinical-grade and research-grade additives significantly improved cell viability (p < 0.10) compared with the negative control (CPA with no additives). CS, AA, and NAC+AA increased cell viability significantly (p < 0.10) compared with the negative control. However, NAC, NAC+CS, and CS+AA did not improve cell viability when compared with the negative control (p > 0.10). We demonstrated that supplementation with clinical-grade CS or AA significantly improved chondrocyte viability in porcine cartilage subjected to high CPA concentrations, whereas supplementation with clinical-grade NAC did not benefit chondrocyte viability. Supplementation with clinical-grade additives in CPA solutions can mitigate CPA toxicity, which will be important in translating previously developed effective protocols for the vitrification of articular cartilage to human tissue banks.}, } @article {pmid34645105, year = {2021}, author = {Vukovic, R and Selakovic, D and Stankovic, JSK and Kumburovic, I and Jovicic, N and Rosic, G}, title = {Alteration of Oxidative stress and apoptotic markers alterations in the rat prefrontal cortex influence behavioral response induced by cisplatin and N-acetylcysteine in the tail suspension test.}, journal = {Journal of integrative neuroscience}, volume = {20}, number = {3}, pages = {711-718}, doi = {10.31083/j.jin2003076}, pmid = {34645105}, issn = {0219-6352}, mesh = {Acetylcysteine/administration & dosage/*pharmacology ; Animals ; Antineoplastic Agents/administration & dosage/*pharmacology ; Antioxidants/administration & dosage/*pharmacology ; Apoptosis/*drug effects ; Behavior, Animal/*drug effects ; Cisplatin/administration & dosage/*pharmacology ; Male ; Oxidative Stress/*drug effects ; Prefrontal Cortex/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Cisplatin therapy is often accompanied by neurotoxicity manifestation, and since the prefrontal cortex is strongly involved in emotion regulation, the aim of this study was to analyze the alterations in the oxidative and apoptotic status of this brain region, with its behavioral impact in rats, following cisplatin administration, with or without N-acetylcysteine supplementation. Thirty-two male Wistar albino rats were randomly divided into four equal experimental groups: control, cisplatin group (single dose of 7.5 mg/kg, intraperitoneally (i.p.), on the fifth day), N-acetylcysteine group (500 mg/kg i.p., on the first and the fifth day), cisplatin + N-acetylcysteine group. Behavioral testing was performed in the tail suspension test. Oxidative stress and apoptotic markers were determined in the prefrontal cortex tissue samples. Cisplatin administration increased lipid peroxidation and decreased the activity of antioxidant enzymes in the prefrontal cortex. Also, cisplatin induced increase in Bax and decrease in Bcl-2 relative gene expression. Simultaneous application of N-acetylcysteine diminished cisplatin-induced alterations in oxidative stress and apoptotic markers. The results obtained in the tail suspension test that nominally resembles antidepressant action of cisplatin (attenuated by N-acetylcysteine), should be attributed to strong motor expression of anxiogenic response to cisplatin (also reversed by N-acetylcysteine). The antioxidant supplementation with NAC diminished cisplatin-induced oxidative damage and pro-apoptotic action in the prefrontal cortex, and significantly influenced specific behavioral alterations.}, } @article {pmid34644184, year = {2021}, author = {Mohammadi-Sardoo, M and Mandegary, A and Nematollahi-Mahani, SN and Moballegh Nasery, M and Nabiuni, M and Amirheidari, B}, title = {Cytotoxicity of mancozeb on Sertoli-germ cell co-culture system: Role of MAPK signaling pathway.}, journal = {Toxicology and industrial health}, volume = {37}, number = {11}, pages = {674-684}, doi = {10.1177/07482337211044028}, pmid = {34644184}, issn = {1477-0393}, mesh = {Animals ; Apoptosis/*drug effects ; Germ Cells/drug effects ; Male ; Maneb/*toxicity ; Mice ; Mitogen-Activated Protein Kinases/*pharmacology ; Oxidative Stress/drug effects ; Sertoli Cells/*drug effects ; Zineb/*toxicity ; }, abstract = {Mancozeb (MZB) is a worldwide fungicide for the management of fungal diseases in agriculture and industrial contexts. Human exposure occurs by consuming contaminated plants, drinking water, and occupational exposure. There are reports on MZB's reprotoxicity such as testicular structure damage, sperm abnormalities, and decrease in sperm parameters (number, viability, and motility), but its molecular mechanism on apoptosis in testis remains limited. To investigate the molecular mechanisms involved in male reprotoxicity induced by MZB, we used primary cultures of mouse Sertoli-germ cells. Cells were exposed to MZB (1.5, 2.5, and 3.5 μM) for 3 h to evaluate viability by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, reactive oxygen species (ROS) generation, and oxidative stress parameters (lipid peroxidation). Cell death and mitogen-activated protein kinase (MAPK) signaling were measured in these cells using flow cytometry and western blotting. In addition, some groups were exposed to N-acetylcysteine (NAC, 5 mM) in the form of co-treatment with MZB. Mancozeb reduced viability and increased the level of intracellular ROS, p38 and c-Jun N-terminal kinases (JNK) MAPK proteins phosphorylation, and apoptotic cell death, which could be blocked by NAC as an inhibitor of oxidative stress. The present study indicated for the first time the toxic manifestations of MZB on the Sertoli-germ cell co-culture. Redox imbalance and p38 and JNK signaling pathway activation might play critical roles in MZB-induced apoptosis in the male reproductive system.}, } @article {pmid34641738, year = {2022}, author = {Khaleel, EF}, title = {l-Thyroxine induces left ventricular remodeling and fibrosis in rats by upregulating miR-21 in a reactive oxygen-dependent mechanism: a protective role of N-acetylcysteine.}, journal = {Drug and chemical toxicology}, volume = {45}, number = {6}, pages = {2758-2768}, doi = {10.1080/01480545.2021.1986251}, pmid = {34641738}, issn = {1525-6014}, mesh = {Rats ; Male ; Animals ; *Ventricular Remodeling ; Transforming Growth Factor beta1/genetics/metabolism ; Acetylcysteine/pharmacology ; NF-kappa B ; Tumor Necrosis Factor-alpha/metabolism ; Interleukin-6 ; Reactive Oxygen Species ; Thyroxine ; Actins ; Rats, Sprague-Dawley ; Antagomirs ; Inflammasomes ; Fibrosis ; Glutathione ; *MicroRNAs/genetics ; Collagen ; RNA, Messenger ; Oxygen ; Mammals/metabolism ; }, abstract = {miR-21 is the most studied pro-fibrotic marker in the majority of mammalian tissues. The precise mechanism by which hyperthyroidism induces left ventricular LV fibrosis and remodeling remains unclear. In this study, we have investigated the role of miR-21 on l-thyroxine (l-Thy)-induced cardiac fibrosis in rats. Adult male Sprague-Dawley rats were divided into four groups as control, l-Thy, l-Thy + miR antagomir (inhibitor), and l-Thy + N-acetylcysteine (NAC/glutathione (GSH) precursor). Administration of l-Thy significantly increased mRNA levels of miR-21 in the LVs of the treated rats. Also, it impaired the LV systolic and diastolic function and increased the production of reactive oxygen species (ROS), the transactivation of NF-κB p65, the expression of NRLP3 inflammasome, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in these LVs. Concomitantly, l-Thy increased the ventricular collagen deposition, and stimulated the expression of collagen 1/3, alpha-smooth actin (α-SMA), transforming growth factor-β1, and Smad3/p-Smad3 but suppressed the expression of Smad7. All these effects were reversed by pre-treatment with miR-21 antagomir or co-administration of NAC. In conclusion, l-Thy-induced LV remodeling and fibrosis include a ROS-dependent upregulation of miR-21 which in turns activates NF-κB/NRLP3 inflammasome and suppresses SMad7.}, } @article {pmid34638900, year = {2021}, author = {Kyyriäinen, J and Kajevu, N and Bañuelos, I and Lara, L and Lipponen, A and Balosso, S and Hämäläinen, E and Das Gupta, S and Puhakka, N and Natunen, T and Ravizza, T and Vezzani, A and Hiltunen, M and Pitkänen, A}, title = {Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury.}, journal = {International journal of molecular sciences}, volume = {22}, number = {19}, pages = {}, pmid = {34638900}, issn = {1422-0067}, support = {272249//Academy of Finland/ ; 273909//Academy of Finland/ ; 2285733-9//Academy of Finland/ ; 307866//Academy of Finland/ ; 0000//Sigrid Juséliuksen Säätiö/ ; 0000//Strategic Neuroscience Funding of the University of Eastern Finland/ ; 602102//FP7-HEALTH project 602102 (EPITARGET)/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Brain/drug effects/metabolism/pathology ; Brain Injuries, Traumatic/*drug therapy/genetics/metabolism ; Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; Gene Expression/drug effects ; Heme Oxygenase-1/genetics/metabolism ; Isothiocyanates/*pharmacology ; Male ; Mice, Inbred C57BL ; Microglia/cytology/*drug effects/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Neurons/cytology/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Sulfoxides/*pharmacology ; Mice ; Rats ; }, abstract = {We assessed the effect of antioxidant therapy using the Food and Drug Administration-approved respiratory drug N-acetylcysteine (NAC) or sulforaphane (SFN) as monotherapies or duotherapy in vitro in neuron-BV2 microglial co-cultures and validated the results in a lateral fluid-percussion model of TBI in rats. As in vitro measures, we assessed neuronal viability by microtubule-associated-protein 2 immunostaining, neuroinflammation by monitoring tumor necrosis factor (TNF) levels, and neurotoxicity by measuring nitrite levels. In vitro, duotherapy with NAC and SFN reduced nitrite levels to 40% (p < 0.001) and neuroinflammation to -29% (p < 0.001) compared with untreated culture. The treatment also improved neuronal viability up to 72% of that in a positive control (p < 0.001). The effect of NAC was negligible, however, compared with SFN. In vivo, antioxidant duotherapy slightly improved performance in the beam walking test. Interestingly, duotherapy treatment decreased the plasma interleukin-6 and TNF levels in sham-operated controls (p < 0.05). After TBI, no treatment effect on HMGB1 or plasma cytokine levels was detected. Also, no treatment effects on the composite neuroscore or cortical lesion area were detected. The robust favorable effect of duotherapy on neuroprotection, neuroinflammation, and oxidative stress in neuron-BV2 microglial co-cultures translated to modest favorable in vivo effects in a severe TBI model.}, } @article {pmid34638698, year = {2021}, author = {Vanin, AF}, title = {Physico-Chemistry of Dinitrosyl Iron Complexes as a Determinant of Their Biological Activity.}, journal = {International journal of molecular sciences}, volume = {22}, number = {19}, pages = {}, pmid = {34638698}, issn = {1422-0067}, mesh = {Acetylcysteine/chemistry/metabolism ; *Iron/chemistry/metabolism ; *Models, Biological ; *Models, Chemical ; *Nitrogen Oxides/chemistry/metabolism ; Oxidation-Reduction ; }, abstract = {In this article we minutely discuss the so-called "oxidative" mechanism of mononuclear form of dinitrosyl iron complexes (M-DNICs) formations proposed by the author. M-DNICs are proposed to be formed from their building material-neutral NO molecules, Fe[2+] ions and anionic non-thiol (L[-]) and thiol (RS[-]) ligands based on the disproportionation reaction of NO molecules binding with divalent ion irons in pairs. Then a protonated form of nitroxyl anion (NO[-]) appearing in the reaction is released from this group and a neutral NO molecule is included instead. As a result, M-DNICs are produced. Their resonance structure is described as [(L[-])2Fe[2+](NO)(NO[+])], in which nitrosyl ligands are represented by NO molecules and nitrosonium cations in equal proportions. Binding of hydroxyl ions with the latter causes conversion of these cations into nitrite anions at neutral pH values and therefore transformation of DNICs into the corresponding high-spin mononitrosyl iron complexes (MNICs) with the resonance structure described as [(L[-])2Fe[2+](NO)]. In case of replacing L[-] by thiol-containing ligands, which are characterized by high π-donor activity, electron density transferred from sulfur atoms to iron-dinitrosyl groups neutralizes the positive charge on nitrosonium cations, which prevents their hydrolysis, ensuring relatively a high stability of the corresponding M-DNICs with the resonance structure [(RS[-])2Fe[2+] (NO, NO[+])]. Therefore, M-DNICs with thiol-containing ligands, as well as their binuclear analogs (B-DNICs, respective resonance structure [(RS[-])2Fe[2+]2 (NO, NO[+])2]), can serve donors of both NO and NO[+]. Experiments with solutions of B-DNICs with glutathione or N-acetyl-L-cysteine (B-DNIC-GSH or B-DNIC-NAC) showed that these complexes release both NO and NO[+] in case of decomposition in the presence of acid or after oxidation of thiol-containing ligands in them. The level of released NO was measured via optical absorption intensity of NO in the gaseous phase, while the number of released nitrosonium cations was determined based on their inclusion in S-nitrosothiols or their conversion into nitrite anions. Biomedical research showed the ability of DNICs with thiol-containing ligands to be donors of NO and NO[+] and produce various biological effects on living organisms. At the same time, NO molecules released from DNICs usually have a positive and regulatory effect on organisms, while nitrosonium cations have a negative and cytotoxic effect.}, } @article {pmid34637923, year = {2021}, author = {Seong, JB and Kim, B and Kim, S and Kim, MH and Park, YH and Lee, Y and Lee, HJ and Hong, CW and Lee, DS}, title = {Macrophage peroxiredoxin 5 deficiency promotes lung cancer progression via ROS-dependent M2-like polarization.}, journal = {Free radical biology & medicine}, volume = {176}, number = {}, pages = {322-334}, doi = {10.1016/j.freeradbiomed.2021.10.010}, pmid = {34637923}, issn = {1873-4596}, mesh = {Animals ; Cell Line, Tumor ; Humans ; *Lung Neoplasms/genetics ; Macrophage Activation ; Macrophages ; Mice ; *Peroxiredoxins/genetics ; Reactive Oxygen Species ; Tumor Microenvironment ; }, abstract = {Strategies for cancer treatment have traditionally focused on suppressing cancer cell behavior, but many recent studies have demonstrated that regulating the tumor microenvironment (TME) can also inhibit disease progression. Macrophages are major TME components, and the direction of phenotype polarization is known to regulate tumor behavior, with M2-like polarization promoting progression. It is also known that reactive oxygen species (ROS) in macrophages drive M2 polarization, and M2 polarization promote lung cancer progression. Lung cancer patients with lower expression of the antioxidant enzyme peroxiredoxin 5 (Prx5) demonstrate poorer survival. This study revealed that Prx5 deficiency in macrophages induced M2 macrophage polarization by lung cancer. We report that injection of lung cancer cells produced larger tumors in Prx5-deficit mice than wild-type mice independent of cancer cell Prx5 expression. Through co-culture with lung cancer cell lines, Prx5-deficient macrophages exhibited M2 polarization, and reduced expression levels of the M1-associated inflammatory factors iNOS, TNFα, and Il-1β. Moreover, these Prx5-deficient macrophages promoted the proliferation and migration of co-cultured lung cancer cells. Conversely, suppression of ROS generation by N-acetyl cysteine (NAC) inhibited the M2-like polarization of Prx5-deficient macrophages, increased expression levels of inflammatory factors, inhibited the proliferation and migration of co-cultured lung cancer cells, and suppressed tumor growth in mice. These findings suggest that blocking the M2 polarization of macrophages may promote lung cancer regression.}, } @article {pmid34627931, year = {2021}, author = {Raut, PK and Lee, HS and Joo, SH and Chun, KS}, title = {Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2/STAT3 signaling pathway in human melanoma cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {157}, number = {}, pages = {112604}, doi = {10.1016/j.fct.2021.112604}, pmid = {34627931}, issn = {1873-6351}, mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology/therapeutic use ; Blotting, Western ; Cell Line, Tumor ; Down-Regulation/drug effects ; Humans ; Janus Kinase 2/*metabolism ; Melanoma/*drug therapy/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Melanoma is a highly aggressive and treatment-resistant cancer, and the incidence and mortality rates are increasing worldwide. Thymoquinone (TQ) is the active component of Nigella sativa seed extracts and exerts anticancer effects in various cancer cells. However, the anticancer effects of TQ on melanoma and the underlying molecular mechanisms remain elusive. In this study, TQ treatment induced apoptosis in SK-MEL-28 cells. Interestingly, constitutive phosphorylation of Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) was markedly decreased following TQ treatment. Furthermore, TQ treatment downregulated STAT3-dependent genes including cyclin D1, D2, and D3 and survivin. Moreover, inhibition of Jak2/STAT3 using AG490, an inhibitor of Jak2 or genetic ablation of STAT3, abrogated the expression of target genes. TQ increased the levels of reactive oxygen species (ROS), whereas pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, prevented the suppressive effect of TQ on Jak2/STAT3 activation and protected SK-MEL-28 cells from TQ-induced apoptosis. TQ administration further attenuated the growth of SK-MEL-28 tumor xenografts. Taken together, TQ induced apoptosis of SK-MEL-28 by hindering the Jak2/STAT3 signaling pathway through ROS generation. Our results support further development of TQ as a potential anticancer therapeutic agent for treating melanoma.}, } @article {pmid34619980, year = {2024}, author = {Subrahmanian, S and Varshney, R and Subramani, K and Murphy, B and Woolington, S and Ahamed, J}, title = {N-Acetylcysteine Inhibits Aortic Stenosis Progression in a Murine Model by Blocking Shear-Induced Activation of Platelet Latent Transforming Growth Factor Beta 1.}, journal = {Antioxidants & redox signaling}, volume = {41}, number = {16-18}, pages = {e1187-e1196}, pmid = {34619980}, issn = {1557-7716}, support = {P30 GM114731/GM/NIGMS NIH HHS/United States ; R01 HL123605/HL/NHLBI NIH HHS/United States ; R01 HL148123/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Acetylcysteine/pharmacology ; *Transforming Growth Factor beta1/metabolism ; *Aortic Valve Stenosis/metabolism/drug therapy/pathology ; *Disease Models, Animal ; *Blood Platelets/metabolism/drug effects ; Disease Progression ; Receptors, LDL/metabolism/genetics ; Mice, Knockout ; Stress, Mechanical ; }, abstract = {Objective: Aortic stenosis (AS) is characterized by narrowing of the aortic valve opening, resulting in peak blood flow velocity that induces high wall shear stress (WSS) across the valve. Severe AS leads to heart failure and death. There is no treatment available for AS other than valve replacement. Platelet-derived transforming growth factor beta 1 (TGF-β1) partially contributes to AS progression in mice, and WSS is a potent activator of latent TGF-β1. N-acetylcysteine (NAC) inhibits WSS-induced TGF-β1 activation in vitro. We hypothesize that NAC will inhibit AS progression by inhibiting WSS-induced TGF-β1 activation. Approach: We treated a cohort of Ldlr(-/-)Apob(100/100) low density lipoprotein receptor (LDLR) mice fed a high-fat diet with NAC (2% in drinking water) at different stages of disease progression and measured its effect on AS progression and TGF-β1 activation. Results: Short-term NAC treatment inhibited AS progression in mice with moderate and severe AS relative to controls, but not in LDLR mice lacking platelet-derived TGF-β1 (TGF-β1[platlet-KO]-LDLR). NAC treatment reduced TGF-β signaling, p-Smad2 and collagen levels, and mesenchymal transition from isolectin B4 and CD45-positive cells in LDLR mice. Mechanistically, NAC treatment resulted in plasma NAC concentrations ranging from 75.5 to 449.2 ng/mL, which were sufficient to block free thiol labeling of plasma proteins and reduce active TGF-β1 levels without substantially affecting reactive oxygen species-modified products in valvular cells. Conclusions: Short-term treatment with NAC inhibits AS progression by inhibiting WSS-induced TGF-β1 activation in the LDLR mouse model of AS, motivating a clinical trial of NAC and/or other thiol-reactive agent(s) as a potential therapy for AS.}, } @article {pmid34617640, year = {2022}, author = {Adl, A and Motamedifar, M and Malekzadeh, P and Sedigh-Shams, M}, title = {Disinfection of dentinal tubules with diclofenac sodium and N-Acetylcysteine compared with calcium hydroxide as intracanal medicaments against Enterococcus faecalis.}, journal = {Australian endodontic journal : the journal of the Australian Society of Endodontology Inc}, volume = {48}, number = {3}, pages = {386-391}, doi = {10.1111/aej.12575}, pmid = {34617640}, issn = {1747-4477}, support = {19832//Shiraz University of Medical Sciences/ ; }, mesh = {*Calcium Hydroxide/pharmacology ; *Enterococcus faecalis ; Root Canal Irrigants/pharmacology ; Diclofenac/pharmacology ; Acetylcysteine/pharmacology ; Dentin ; Anti-Bacterial Agents/pharmacology ; Dental Pulp Cavity/microbiology ; }, abstract = {The purpose of this study was to evaluate the disinfection of dentinal tubules with diclofenac sodium (DS), N-acetylcysteine (NAC) and calcium hydroxide (CH). Contaminated dentinal blocks were divided into two control and seven experimental groups (n = 15): CH, DS, NAC, CH + 5% DS, 50% CH + 50% DS, CH + 5% NAC and 50% CH + 50% NAC. After seven days, dentine debris was obtained from two depths of 100 and 200 µm. The bacterial load was assessed by counting the number of colony-forming units (CFUs). Pure DS exhibited maximum antibacterial activity at both depths. At 200 µm, it showed statistically significant differences with all the other groups (P < 0.05). Mixing CH with either 5% or 50% of DS and NAC did not increase the antibacterial efficacy (P > 0.05). Pure DS was most effective in disinfecting dentinal tubules, and mixing CH with DS or NAC is not recommended.}, } @article {pmid34614473, year = {2021}, author = {Pang, Y and Wu, D and Ma, Y and Cao, Y and Liu, Q and Tang, M and Pu, Y and Zhang, T}, title = {Reactive oxygen species trigger NF-κB-mediated NLRP3 inflammasome activation involvement in low-dose CdTe QDs exposure-induced hepatotoxicity.}, journal = {Redox biology}, volume = {47}, number = {}, pages = {102157}, pmid = {34614473}, issn = {2213-2317}, mesh = {*Cadmium Compounds/toxicity ; *Chemical and Drug Induced Liver Injury/etiology ; Humans ; Inflammasomes ; NF-kappa B ; *NLR Family, Pyrin Domain-Containing 3 Protein ; *Quantum Dots/toxicity ; Reactive Oxygen Species ; Tellurium/toxicity ; }, abstract = {Cadmium telluride (CdTe) quantum dots (QDs) can be employed as imaging and drug delivery tools; however, the toxic effects and mechanisms of low-dose exposure are unclear. Therefore, this pioneering study focused on hepatic macrophages (Kupffer cells, KCs) and explored the potential damage process induced by exposure to low-dose CdTe QDs. In vivo results showed that both 2.5 μM/kg·bw and 10 μM/kg·bw could both activate KCs to cause liver injury, and produce inflammation by disturbing antioxidant levels. Abnormal liver function further verified the risks of low-dose exposure to CdTe QDs. The KC model demonstrated that low-dose CdTe QDs (0 nM, 5 nM and 50 nM) can be absorbed by cells and cause severe reactive oxygen species (ROS) production, oxidative stress, and inflammation. Additionally, the expression of NF-κB, caspase-1, and NLRP3 were decreased after pretreatment with ROS scavenging agent N-acetylcysteine (NAC, 5 mM pretreated for 2 h) and the NF-κB nuclear translocation inhibitor Dehydroxymethylepoxyquinomicin (DHMEQ, 10 μg/mL pretreatment for 4 h) respectively. The results indicate that the activation of the NF-κB pathway by ROS not only directly promotes the expression of inflammatory factors such as pro-IL-1β, TNF-α, and IL-6, but also mediates the assembly of NLRP3 by ROS activation of NF-κB pathway, which indirectly promotes the expression of NLRP3. Finally, a high-degree of overlap between the expression of the NF-κB and NLRP3 and the activated regions of KCs, further support the importance of KCs in inflammation induced by low-dose CdTe QDs.}, } @article {pmid34608499, year = {2021}, author = {Kim, S and Lee, H and Lim, JW and Kim, H}, title = {Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells.}, journal = {Molecular medicine reports}, volume = {24}, number = {6}, pages = {}, pmid = {34608499}, issn = {1791-3004}, mesh = {Adenocarcinoma/metabolism ; Animals ; Antitubercular Agents/pharmacology ; Apoptosis ; Cell Death ; Cell Line, Tumor ; Epithelial Cells ; Humans ; Imidazoles ; Indoles ; L-Lactate Dehydrogenase/metabolism ; NADPH Oxidases/drug effects/*metabolism ; *Necroptosis ; Protein Kinases/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; Stomach Neoplasms/*metabolism ; Xanthophylls/pharmacology ; }, abstract = {Astaxanthin (ASX), a red‑colored xanthophyll carotenoid, functions as an antioxidant or pro‑oxidant. ASX displays anticancer effects by reducing or increasing oxidative stress. Reactive oxygen species (ROS) promote cancer cell death by necroptosis mediated by receptor‑interacting protein kinase 1 (RIP1) and RIP3. NADPH oxidase is a major source of ROS that may promote necroptosis in some cancer cells. The present study aimed to investigate whether ASX induces necroptosis by increasing NADPH oxidase activity and ROS levels in gastric cancer AGS cells. AGS cells were treated with ASX with or without ML171 (NADPH oxidase 1 specific inhibitor), N‑acetyl cysteine (NAC; antioxidant), z‑VAD (pan‑caspase inhibitor) or Necrostatin‑1 (Nec‑1; a specific inhibitor of RIP1). As a result, ASX increased NADPH oxidase activity, ROS levels and cell death, and these effects were suppressed by ML171 and NAC. Furthermore, ASX induced RIP1 and RIP3 activation, ultimately inducing mixed lineage kinase domain‑like protein (MLKL) activation, lactate dehydrogenase (LDH) release and cell death. Moreover, the ASX‑induced decrease in cell viability was reversed by Nec‑1 treatment and RIP1 siRNA transfection, but not by z‑VAD. ASX did not increase the ratio of apoptotic Bax/anti‑apoptotic Bcl‑2, the number of Annexin V‑positive cells, or caspase‑9 activation, which are apoptosis indices. In conclusion, ASX induced necroptotic cell death by increasing NADPH oxidase activity, ROS levels, LDH release and the number of propidium iodide‑positive cells, as well as activating necroptosis‑regulating proteins, RIP1/RIP3/MLKL, in gastric cancer AGS cells. The results of this study demonstrated the necroptotic effect of ASX on gastric cancer AGS cells, which required NADPH oxidase activation and RIP1/RIP3/MLKL signaling in vitro.}, } @article {pmid34603718, year = {2021}, author = {Katwal, S and Malbul, K and Mandal, SK and Kc, S and Alam, MZ and Karki, P and Pant, C}, title = {Successfully managed aluminum phosphide poisoning: A case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {70}, number = {}, pages = {102868}, pmid = {34603718}, issn = {2049-0801}, abstract = {INTRODUCTION: and Importance: Aluminum phosphide (ALP) is a commonly available pesticide in agricultural countries like Nepal. Upon ingestion, this releases highly toxic phosphine gas in the gastrointestinal tract when it comes in contact with humidity. This leads to refractory shock, metabolic acidosis, cardiac arrhythmia, renal failure, and hepato-biliary impairment.

CASE PRESENTATION: We present a successfully managed case of a 17-year-old girl who ingested 6 g (2 tablets) of ALP tablets with suicidal intent. Although the mortality has been reported as 70-100% with mere ingestion of 150-500 mg of ALP, this case survived even after developing severe metabolic acidosis, acute renal failure, refractory shock, and ventricular tachycardia.

CLINICAL DISCUSSION: ALP poisoning is most often lethal. However, there is an emerging evidence of successful use of various drugs such as magnesium sulfate, trimetazidine, and other interventions such as intra-aortic balloon pump and extra corporeal membrane oxygenation in case of ALP poisoning.

CONCLUSION: Owing to the unavailability of an effective antidote of ALP to date, we emphasize early initiation of supportive management, intensive monitoring, and potential role of membrane stabilizers like magnesium sulfate, and cardio-protective agents like trimetazidine, N-Acetyl cysteine, thiamine, vitamin C, and hydrocortisone in decreasing the likelihood of fatal outcome.}, } @article {pmid34603395, year = {2021}, author = {Rodríguez, E and Grover Thomas, F and Camus, MF and Lane, N}, title = {Mitonuclear Interactions Produce Diverging Responses to Mild Stress in Drosophila Larvae.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {734255}, pmid = {34603395}, issn = {1664-8021}, abstract = {Mitochondrial function depends on direct interactions between respiratory proteins encoded by genes in two genomes, mitochondrial and nuclear, which evolve in very different ways. Serious incompatibilities between these genomes can have severe effects on development, fitness and viability. The effect of subtle mitonuclear mismatches has received less attention, especially when subject to mild physiological stress. Here, we investigate how two distinct physiological stresses, metabolic stress (high-protein diet) and redox stress [the glutathione precursor N-acetyl cysteine (NAC)], affect development time, egg-to-adult viability, and the mitochondrial physiology of Drosophila larvae with an isogenic nuclear background set against three mitochondrial DNA (mtDNA) haplotypes: one coevolved (WT) and two slightly mismatched (COX and BAR). Larvae fed the high-protein diet developed faster and had greater viability in all haplotypes. The opposite was true of NAC-fed flies, especially those with the COX haplotype. Unexpectedly, the slightly mismatched BAR larvae developed fastest and were the most viable on both treatments, as well as control diets. These changes in larval development were linked to a shift to complex I-driven mitochondrial respiration in all haplotypes on the high-protein diet. In contrast, NAC increased respiration in COX larvae but drove a shift toward oxidation of proline and succinate. The flux of reactive oxygen species was increased in COX larvae treated with NAC and was associated with an increase in mtDNA copy number. Our results support the notion that subtle mitonuclear mismatches can lead to diverging responses to mild physiological stress, undermining fitness in some cases, but surprisingly improving outcomes in other ostensibly mismatched fly lines.}, } @article {pmid34602622, year = {2021}, author = {Friciu, MM and Monfort, A and Dubé, PA and Leclair, G}, title = {Stability of N-Acetylcysteine 60 mg/mL in Extemporaneously Compounded Injectable Solutions.}, journal = {The Canadian journal of hospital pharmacy}, volume = {74}, number = {4}, pages = {344-349}, pmid = {34602622}, issn = {1920-2903}, abstract = {BACKGROUND: N-Acetylcysteine (NAC) administered by the IV route is the current treatment of choice for acetaminophen overdose. However, the protocol approved by health authorities in most countries has a complex dosing regimen, which leads to dosage errors in one-third of cases. Therefore, the Canadian Antidote Guide in Acute Care Toxicology and individual poison centres have begun to recommend a simplified regimen using continuous IV infusion. Unfortunately, no study has demonstrated the stability of IV solutions of NAC at concentrations above 30 mg/mL or in solutions other than 5% dextrose.

OBJECTIVE: To evaluate the stability of solutions of NAC 60 mg/mL in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose, stored for up to 72 hours in polyvinyl chloride (PVC) bags at 25°C.

METHODS: Solutions of the desired concentration were prepared from a commercial solution of NAC 200 mg/mL, with dilution in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose, and were then stored at room temperature in PVC bags for up to 72 hours. At predetermined time points (0, 16, 24, 40, 48 and 72 h), samples were collected and analyzed using a stability-indicating high-performance liquid chromatography method. A solution was considered stable if it maintained at least 90.0% of its initial concentration. Particulate matter count was also evaluated to confirm chemical stability. Finally, organoleptic properties, such as odour and colour, were evaluated to assess the stability of the solutions.

RESULTS: All solutions maintained at least 98.7% of their initial concentration. No obvious changes in odour or colour were observed. Moreover, particle counts remained acceptable throughout the study, according to the criteria specified in United States Pharmacopeia (USP) General Chapter <788>.

CONCLUSIONS: NAC 60 mg/mL, diluted in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose and stored in PVC bags at 25°C, was chemically and physically stable for a period of at least 72 hours.}, } @article {pmid34602393, year = {2021}, author = {Shao, Z and Meng, X and Meng, F}, title = {Efficacy and safety of mesenchymal stem cell in Chinese patients with chronic renal failure: A pilot study in Shandong province, China.}, journal = {Pakistan journal of pharmaceutical sciences}, volume = {34}, number = {3(Special)}, pages = {1227-1231}, pmid = {34602393}, issn = {1011-601X}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; China ; Creatinine/metabolism ; Female ; Free Radical Scavengers/*therapeutic use ; Glomerular Filtration Rate ; Humans ; Kidney Failure, Chronic/metabolism/*therapy ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Middle Aged ; Pilot Projects ; Transplantation, Autologous/methods ; Treatment Outcome ; }, abstract = {This study designed to evaluate efficacy and safety profile of Mesenchymal stem cells (MSCs) versus Acetyl cysteine (NACys) in the Chinese patients with Chronic renal failure (CRF). The CRF patients having eGFR less than 60ml per minute per 1.73m2 randomly assigned to MSCs (N=100) or NACys (N=100) (1:1) for 8 weeks. MSCs administered as intravenous infusion of marrow-derived autologous MSCs (1 × 106 to 2 × 106/kg) reperfusion, whereas, another group received NACys 600mg orally twice a day for 8 weeks. The efficacy variables include: creatinine; cystatin C; TGF-β levels; oxidants/reactive oxygen species production induced by TGF-β; collagen levels (type 1 and 4); urinary albumin/creatinine ratio and Glomerular area. Safety was also assesed. Both the treatments significantly decreased creatinine, cystatin C and reactive oxygen species from baseline, however, reduction in creatinine, cystatin C, and reactive oxygen species level from baseline was significantly higher in patient treated with MSCs (N=100) as compared to NACys (N=100). Moreover, improvement in renal and systemic functional parameters from baseline was significantly higher in patient treated with MSCs as compared to NACys. Overall, MSCs offer significantly greater improvement in renal function as compared to NACys in Chinese CRF patients.}, } @article {pmid34601074, year = {2021}, author = {Zhao, X and Zhao, X and Wang, Z}, title = {Synergistic neuroprotective effects of hyperbaric oxygen and N-acetylcysteine against traumatic spinal cord injury in rat.}, journal = {Journal of chemical neuroanatomy}, volume = {118}, number = {}, pages = {102037}, doi = {10.1016/j.jchemneu.2021.102037}, pmid = {34601074}, issn = {1873-6300}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Count ; Combined Modality Therapy ; Cytokines/metabolism ; Electromyography ; Female ; *Hyperbaric Oxygenation ; Neuroglia/pathology ; Neuroprotective Agents/*therapeutic use ; Rats ; Rats, Wistar ; Spinal Cord/metabolism/pathology ; Spinal Cord Injuries/*drug therapy/metabolism/pathology ; }, abstract = {BACKGROUND: The mitochondrial dysfunction and following oxidative stress, as well as the spread of inflammation plays major roles in the failure to regenerate following severe spinal cord injury (SCI). In this regard, we investigated the neuroprotective effects of hyperbaric oxygen (HBO), as an anti-apoptotic and anti-inflammatory agent, and N-acetylcysteine (NAC), as a mitochondrial enhancer, in SCI.

MATERIAL AND METHODS: Seventy-five female adult Wistar rats divided into five groups (n = 15): laminectomy alone (Sham) group, SCI group, HBO group (underwent SCI and received HBO), NAC group (underwent SCI and received NAC), and HBO+NAC group (underwent SCI and simultaneously received NAC and HBO). At the end of study, spinal cord tissue samples were taken for evaluation of biochemical profiles including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) levels, immunohistochemistry for caspase-3 as well as gene expressions of interleukin (IL)-10, tumor necrosis factor alpha (TNF-α), and IL-1β. Stereological assessments were performed to determine the total volumes, central cavity volumes and as well as numerical density of the neural and glial cells in traumatic area. Moreover, neurological functions were evaluated by the Basso-Beattie-Bresnehan (BBB) and electromyography (EMG).

RESULTS: Our results showed that the stereological parameters, biochemical profiles (except MDA) and neurological function were significantly higher in each HBO, NAC and HBO+NAC groups compared to the SCI group, and were highest in HBO+NAC ones. The transcript for IL-10 gene was significantly upregulated in all treatment regimens compared to SCI group, and was highest in HBO+NAC ones. While expression of TNF-α and IL-1β, latency, as well as density of apoptosis cells in caspase-3 evaluation significantly more decreased in HBO+NAC group compared to other groups.

CONCLUSION: Overall, using combined therapy with HBO and NAC has synergistic neuroprotective effects in SCI treatment.}, } @article {pmid34599149, year = {2021}, author = {Huang, C and Santofimia-Castaño, P and Liu, X and Xia, Y and Peng, L and Gotorbe, C and Neira, JL and Tang, D and Pouyssegur, J and Iovanna, J}, title = {NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner.}, journal = {Cell death discovery}, volume = {7}, number = {1}, pages = {269}, pmid = {34599149}, issn = {2058-7716}, abstract = {Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.}, } @article {pmid34597721, year = {2021}, author = {Huang, Y and Zhang, J and Tao, Y and Ji, C and Aniagu, S and Jiang, Y and Chen, T}, title = {AHR/ROS-mediated mitochondria apoptosis contributes to benzo[a]pyrene-induced heart defects and the protective effects of resveratrol.}, journal = {Toxicology}, volume = {462}, number = {}, pages = {152965}, doi = {10.1016/j.tox.2021.152965}, pmid = {34597721}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Azo Compounds/pharmacology ; Benzo(a)pyrene/administration & dosage/*toxicity ; Dose-Response Relationship, Drug ; Heart Defects, Congenital/chemically induced/*prevention & control ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Pyrazoles/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/*metabolism ; Resveratrol/*pharmacology ; Zebrafish ; }, abstract = {Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon, is widely present in the environment. BaP-induced heart defects have been frequently reported, but the underlying molecular mechanisms remain elusive. Here, we found that BaP increased heart malformations in zebrafish embryos in a concentration-dependent manner, which were attenuated by supplementation with either CH223191 (CH), an aryl hydrocarbon receptor (AHR) inhibitor, or N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger. While CH and NAC both inhibited BaP-induced ROS generation, NAC had no effect on BaP-induced AHR activation. We further demonstrated that BaP increased mitochondrial ROS, decreased mitochondrial membrane potential, and caused endogenous apoptosis, with all these effects being counteracted by supplementation with either CH or NAC. Resveratrol (RSV), a natural AHR antagonist and ROS scavenger, also counteracted the heart malformations caused by BaP. Further experiments showed that RSV attenuated BaP-induced oxidative stress, mitochondrial damage and apoptosis, but had no significant effect on AHR activation. In conclusion, our findings show that BaP induces oxidative stress via AHR activation, which causes mitochondria-mediated intrinsic apoptosis, resulting in heart malformations in zebrafish embryos, and that RSV had a protective effect against BaP-induced heart defects mainly by inhibiting oxidative stress rather than through antagonism of AHR activity.}, } @article {pmid34597422, year = {2021}, author = {Yokoo, K and Yamamoto, Y and Suzuki, T}, title = {Ammonia impairs tight junction barriers by inducing mitochondrial dysfunction in Caco-2 cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {35}, number = {11}, pages = {e21854}, doi = {10.1096/fj.202100758R}, pmid = {34597422}, issn = {1530-6860}, mesh = {Adenosine Triphosphate/metabolism ; Ammonia/*pharmacology ; Caco-2 Cells ; Glutathione/metabolism ; Humans ; Interleukin-8/biosynthesis ; Intestinal Mucosa/metabolism ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/*metabolism ; NADP/metabolism ; Oxidative Stress/drug effects ; Permeability/drug effects ; Renal Insufficiency, Chronic/metabolism ; Signal Transduction/*drug effects ; Tight Junction Proteins/*metabolism ; Tight Junctions/*drug effects/*metabolism ; }, abstract = {Ammonia is one of the major metabolites produced by intestinal microorganisms; however, its role in intestinal homeostasis is poorly understood. The present study investigated the regulation of intestinal tight junction (TJ) proteins by ammonia and the underlying mechanisms in human intestinal Caco-2 cells. Ammonia (15, 30, and 60 mM) increased the permeability of the cells in a dose-dependent manner, as indicated by reduced transepithelial electrical resistance and increased dextran flux. Immunoblot and immunofluorescence analyses revealed that the ammonia-induced increase in TJ permeability reduced the membrane localization of TJ proteins such as zonula occludens (ZO)1, ZO2, occludin, claudin-1, and claudin-3. DNA microarray analysis identified a biological pathway "response to reactive oxygen species" enriched by ammonia treatment, indicating the induction of oxidative stress in the cells. Ammonia treatment also increased the malondialdehyde content and decreased the ratio of reduced to oxidized glutathione. Meanwhile, ammonia treatment-induced mitochondrial dysfunction, as indicated by the downregulation of genes associated with the electron transport chain, reduction of the cellular ATP, NADH, and tricarboxylic acid cycle intermediate content, and suppression of the mitochondrial membrane potential. In contrast, N-acetyl cysteine reversed the ammonia-induced impairment of TJ permeability and structure without affecting the mitochondrial parameters. Collectively, ammonia impaired the TJ barrier by increasing oxidative stress in Caco-2 cells. A mitochondrial dysfunction is possibly an event preceding ammonia-induced oxidative stress. The findings of this study could potentially improve our understanding of the interplay between intestinal microorganisms and their hosts.}, } @article {pmid34592079, year = {2020}, author = {Devi, N and Boya, C and Chhabra, M and Bansal, D}, title = {N-acetyl-cysteine as adjuvant therapy in female infertility: a systematic review and meta-analysis.}, journal = {Journal of basic and clinical physiology and pharmacology}, volume = {32}, number = {5}, pages = {899-910}, doi = {10.1515/jbcpp-2020-0107}, pmid = {34592079}, issn = {2191-0286}, mesh = {*Abortion, Spontaneous/prevention & control ; *Acetylcysteine/therapeutic use ; Female ; Humans ; *Infertility, Female/drug therapy/etiology ; Live Birth ; Ovulation Induction ; *Polycystic Ovary Syndrome/complications ; Pregnancy ; Pregnancy Rate ; }, abstract = {OBJECTIVES: The objective of this study is to explore the efficacy and safety of N-acetyl-cysteine (NAC) as adjuvant therapy in female infertility.

CONTENT: We performed a systematic literature search of PubMed, Cochrane Library, Embase, and Ovid databases through April 2019 for Randomized Controlled Trials (RCTs) evaluating the effectiveness and safety of NAC as adjuvant therapy in female infertility. The outcomes assessed were rates of ovulation, pregnancy, miscarriage and multiple pregnancy, presented as pooled odds ratio with 95% confidence interval (CI) using the random-effects model. Heterogeneity and inconsistency of the measurements were identified through Cochrane's Q statistic and I2 statistic. We also performed a sensitivity analysis, publication bias (using funnel plot and Begg's test), and subgroup analysis.

SUMMARY: Fifteen RCTs recruiting 2330 female receiving NAC were included. The pooled estimate showed the statistically insignificant improvement in outcomes; clinical pregnancy rate 1.55 (95% CI 0.98-2.47; I2=68%; p<0.01), ovulation rate 1.77 (95% CI 0.76-4.14; I2=90%; p<0.01), multiple pregnancy rate 0.83 (95% CI 0.34-1.99; I2=10%; p=0.31) and miscarriage rate 0.76 (95% CI= 0.37, 1.53; I2=0%; p=0.69) . NAC was found less efficacious and safe than metformin in all outcomes. Overall, NAC showed statistically insignificant (OR=0.98-2.47).

OUTLOOK: NAC can be an effective adjuvant in PCOS related and unexplained female infertility. The effect could be more profound in women with high BMI, insulin resistance, and oxidative stress. However, the findings need further confirmation in well-designed randomized controlled trials to examine clinical outcomes such as live birth rate in more extended follow-up periods.}, } @article {pmid34590731, year = {2022}, author = {Yi, SY and Barnett, BR and Poetzel, MJ and Stowe, NA and Yu, JJ}, title = {Clinical translational neuroimaging of the antioxidant effect of N-acetylcysteine on neural microstructure.}, journal = {Magnetic resonance in medicine}, volume = {87}, number = {2}, pages = {820-836}, pmid = {34590731}, issn = {1522-2594}, support = {U54 AI117924/AI/NIAID NIH HHS/United States ; P30 HD003352/HD/NICHD NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; T32 GM008692/GM/NIGMS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; T32 GM140935/GM/NIGMS NIH HHS/United States ; F30 AG066329/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Antioxidants/pharmacology ; Brain/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; *Diffusion Tensor Imaging ; Female ; Male ; Nerve Tissue Proteins ; Neuroimaging ; Rats ; Rats, Sprague-Dawley ; }, abstract = {PURPOSE: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness.

METHODS: Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how gene-environment interactions might alter effectiveness of NAC therapy.

RESULTS: The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits.

CONCLUSION: These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.}, } @article {pmid34589369, year = {2021}, author = {Orozco, E and Birnbrich, A and Liberman, SR}, title = {The Role of N-acetylcysteine in the Treatment of Accidental Submersion of the Hands in Liquid Nitrogen.}, journal = {Cureus}, volume = {13}, number = {9}, pages = {e18129}, pmid = {34589369}, issn = {2168-8184}, abstract = {N-acetylcysteine (NAC) is a compound with numerous uses, especially in cases which require prevention of cellular damage. To the authors' knowledge, no reports of NAC as treatment for liquid nitrogen (LN2) injuries currently exist. We present a case in which a 40-year-old woman accidentally submerged her hands in LN2 while working in a lab. The patient was treated with NAC, antibiotics, and wound care. Six months post-injury, the patient had full range of motion, full sensation, full function, and no pain. Therefore, NAC, in combination with dressing changes and antibiotics, can be used to successfully treat patients with LN2 burns.}, } @article {pmid34588976, year = {2021}, author = {Hang, W and Shu, H and Wen, Z and Liu, J and Jin, Z and Shi, Z and Chen, C and Wang, DW}, title = {N-Acetyl Cysteine Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease and Intracellular Triglyceride Accumulation by Preserving Mitochondrial Function.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {636204}, pmid = {34588976}, issn = {1663-9812}, abstract = {Rationale: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic disease characterized by liver steatosis. Excessive reactive oxygen species (ROS) originating from dysfunctional mitochondria is the major pathophysiological contributor in the development of NAFLD and is thought to be a promising therapeutic target. A few reports demonstrate the antioxidative treatments for NAFLD. Methods: Male C57 mice were fed on a normal chow diet (ND) or high-fat diet (HFD) for 8 weeks. PBS or N-acetyl cysteine (NAC) was gavaged to mice. LO2 human liver cell line treated with palmitic acid (PA) was applied as a cellular model. Western blot, immunofluorescence, biochemistry assay, and pathological staining were used to investigate the mechanism of suppressing lipid accumulation of NAC. Results: NAC treatment was able to prevent HFD-induced NAFLD, as evidenced by less hepatic triglyceride accumulation and lipid droplet formation compared with that of mice in the HFD group. NAC could preserve mitochondrial function by inhibiting excessive mitophagy and promoting mitochondria biogenesis to prevent ROS production. NAC also activated Sirt1 and preserved its protein level and subsequently promoted mitochondria biogenesis via deacetylating PGC1a. Conclusion: We demonstrated that NAC may be an effective drug to treat NAFLD, which was related to its antioxidative and mitochondrial protective effect.}, } @article {pmid34585633, year = {2021}, author = {Peng, M and Liu, Y and Xu, Y and Li, L and Li, Y and Yang, H}, title = {Cathelicidin-WA ameliorates diabetic cardiomyopathy by inhibiting the NLRP3 inflammasome.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {20}, number = {21}, pages = {2278-2290}, pmid = {34585633}, issn = {1551-4005}, mesh = {Animals ; Antimicrobial Cationic Peptides ; Cell Cycle Proteins ; *Diabetes Mellitus ; *Diabetic Cardiomyopathies/metabolism ; Inflammasomes/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Stroke Volume ; Ventricular Function, Left ; Cathelicidins ; }, abstract = {Cathelicidin-WA (CWA) is a novel cathelicidin peptide isolated from snakes that has been suggested to exert anti-inflammatory effects. The aim of our study was to investigate whether cathelicidin-WA (CWA) could protect the heart from diabetic cardiomyopathy (DCM). Streptozotocin (STZ) injection was used to establish a mouse model of DCM. CWA peptide (2 mg/kg or 8 mg/kg) was continuously administered to the mice from 10 weeks to 16 weeks after STZ injection. The mice in the DCM group exhibited cardiac dysfunction, while 8 mg/kg CWA ameliorated this cardiac dysfunction. Cardiac fibrosis, inflammation, and oxidative stress as well as cardiomyocyte apoptosis in the DCM mice were decreased by treatment with 8 mg/kg CWA. We isolated neonatal rat cardiomyocytes and stimulated the cells with high glucose to establish an in vitro model of myocyte cell injury. Consistently, CWA inhibited high glucose-induced cell death, inflammation and oxidative stress in the myocytes. Moreover, CWA reduced the formation of the NLR family pyrin domain-containing 3 (NRLP3) inflammasome by regulating thioredoxin-interacting protein expression and p65 activation. NLRP3 overexpression inhibited the beneficial effects of CWA on the heart during DCM and on high glucose-induced myocyte injury. In summary, CWA attenuates cardiac injury and preserves cardiac function during DCM by targeting the NLRP3 pathway.Abbreviations: AAV9: Adeno associated virus; AGE: Advanced Glycation End products; CWA: Cathelicidin-WA; DCM: diabetic cardiomyopathy; Gpx: glutathione peroxidase; HG: high glucose; IL: Interleukin; NLR: Family Pyrin Domain Containing 3 (NRLP3); TXNIP: Thioredoxin interacting protein; LVEF: left ventricular ejection fraction; MDA: Malondialdehyde; MnSOD: manganese superoxide dismutase; NADPH: Nicotinamide adenine dinucleotide phosphate; NAC: N-acetyl-cysteine; NRCMs: Neonatal rat cardiomyocytes; ROS: reactive oxygen species; STZ: Streptozotocin; TNFa: tumor necrosis factor a.}, } @article {pmid34581655, year = {2022}, author = {Lewis, JC and Lim, M and Lai, L and Mendoza, E and Albertson, TE and Chenoweth, JA}, title = {Evaluation of N-acetylcysteine dose for the treatment of massive acetaminophen ingestion.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {507-513}, doi = {10.1080/15563650.2021.1984503}, pmid = {34581655}, issn = {1556-9519}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose/drug therapy ; Eating ; Humans ; Retrospective Studies ; }, abstract = {METHODS: The use of N-acetylcysteine (NAC) remains the standard of care for treatment of acetaminophen (APAP) toxicity and overdose. Currently, there is growing evidence to suggest that massive acetaminophen overdose is associated with increased hepatotoxicity despite timely administration of NAC. This raises the question as to whether an increased dose of intravenous (IV) NAC should be used in the setting of massive APAP ingestion. This study aimed to evaluate the rate of hepatotoxicity after massive APAP overdose treated with 3 different NAC treatment regimens.

METHODS: This was a retrospective cohort study conducted by electronic medical record review of cases reported to a statewide poison control system between 2007 and 2020. Inclusion criteria were single APAP or APAP combination-medication ingestion; acute massive acetaminophen (APAP) ingestion (defined as APAP concentration ≥ 2 times above the Rumack-Matthew 150 nomogram); received one of the three NAC regimens: standard dose IV NAC, oral (PO) NAC, or high dose IV NAC. The risk of hepatotoxicity was evaluated using a multivariate logistic regression model with standard dose IV NAC as the base variable for comparison.

RESULTS: A total of 373 patients met inclusion for the study. Of those, 135 cases were treated with standard dose IV NAC, 121 cases treated with PO NAC, and 117 cases treated with high dose IV NAC. The risk of developing hepatotoxicity was not statistically significant between the high dose IV NAC (OR 1.05, 95% CI 0.52 - 2.09) or oral NAC (OR 0.69, 95% CI 0.33 - 1.46) when compared to standard dose IV NAC. When adjusted for APAP combination medications, initial APAP ratio, initial elevated AST/ALT, and treatment within 8 h, there remained no difference between treatment regimens.

CONCLUSION: This study was unable to detect a large absolute reduction in the rate of hepatotoxicity after massive APAP ingestion in patients treated with high dose IV NAC or PO NAC when compared to standard dose IV NAC; even when treatment was initiated within 8 h of ingestion.}, } @article {pmid34576256, year = {2021}, author = {Lacerda-Abreu, MA and Russo-Abrahão, T and Rocco-Machado, N and Cosentino-Gomes, D and Dick, CF and Carvalho-Kelly, LF and Cunha Nascimento, MT and Rocha-Vieira, TC and Meyer-Fernandes, JR}, title = {Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34576256}, issn = {1422-0067}, support = {401134/2014-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 0012017//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; e-26/201.300/2014//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; }, mesh = {Acetylcysteine/pharmacology ; Breast Neoplasms/*drug therapy ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Cell Survival ; Epithelial-Mesenchymal Transition ; Female ; Humans ; Hydrogen Peroxide/*chemistry ; MCF-7 Cells ; Membrane Potential, Mitochondrial ; NADPH Oxidases/metabolism ; Neoplasm Metastasis ; Oxygen Consumption ; *Phosphates ; Protein Kinase C/metabolism ; Reactive Oxygen Species ; }, abstract = {According to the growth rate hypothesis (GRH), tumour cells have high inorganic phosphate (Pi) demands due to accelerated proliferation. Compared to healthy individuals, cancer patients present with a nearly 2.5-fold higher Pi serum concentration. In this work, we show that an increasing concentration of Pi had the opposite effect on Pi-transporters only in MDA-MB-231 when compared to other breast cell lines: MCF-7 or MCF10-A (non-tumoural breast cell line). Here, we show for the first time that high extracellular Pi concentration mediates ROS production in TNBC (MDA-MB-231). After a short-time exposure (1 h), Pi hyperpolarizes the mitochondrial membrane, increases mitochondrial ROS generation, impairs oxygen (O2) consumption and increases PKC activity. However, after 24 h Pi-exposure, the source of H2O2 seems to shift from mitochondria to an NADPH oxidase enzyme (NOX), through activation of PKC by H2O2. Exogenous-added H2O2 modulated Pi-transporters the same way as extracellular high Pi, which could be reversed by the addition of the antioxidant N-acetylcysteine (NAC). NAC was also able to abolish Pi-induced Epithelial-mesenchymal transition (EMT), migration and adhesion of MDA-MB-231. We believe that Pi transporters support part of the energy required for the metastatic processes stimulated by Pi and trigger Pi-induced H2O2 production as a signalling response to promote cell migration and adhesion.}, } @article {pmid34576128, year = {2021}, author = {Song, Y and Hu, S and Zhang, J and Zhu, L and Zhao, X and Chen, Q and Zhang, J and Bai, Y and Pan, Y and Shao, C}, title = {Fractionated Irradiation of Right Thorax Induces Abscopal Damage on Bone Marrow Cells via TNF-α and SAA.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34576128}, issn = {1422-0067}, support = {31770910, 11775052, and 81672985//National Natural Science Foundation of China/ ; 2017YFC0108604//National Key R&D Program of China/ ; 19411950902//Shanghai Science and Technology Commission/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Proteins/metabolism ; Bone Marrow Cells/*metabolism/*radiation effects ; Cell Cycle/radiation effects ; DNA Damage ; *Dose Fractionation, Radiation ; Free Radical Scavengers/pharmacology ; Lung Injury/pathology ; Male ; Mesenchymal Stem Cells/metabolism/radiation effects ; Mice, Inbred C57BL ; Proteomics ; Reactive Oxygen Species/metabolism ; Serum Amyloid A Protein/*metabolism ; Thorax/*radiation effects ; Tumor Necrosis Factor-alpha/*metabolism ; Mice ; }, abstract = {Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1-6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice.}, } @article {pmid34575651, year = {2021}, author = {Yang, KH and Tang, JY and Chen, YN and Chuang, YT and Tsai, IH and Chiu, CC and Li, LJ and Chien, TM and Cheng, YB and Chang, FR and Yen, CY and Chang, HW}, title = {Nepenthes Extract Induces Selective Killing, Necrosis, and Apoptosis in Oral Cancer Cells.}, journal = {Journal of personalized medicine}, volume = {11}, number = {9}, pages = {}, pmid = {34575651}, issn = {2075-4426}, support = {MOST 108-2314-B-384-002; MOST 108-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 110-P016//National Sun Yat-sen University-KMU Joint Research Project/ ; KMUH-109-9M56//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Ethyl acetate Nepenthes extract (EANT) from Nepenthes thorellii × (ventricosa × maxima) shows antiproliferation and apoptosis but not necrosis in breast cancer cells, but this has not been investigated in oral cancer cells. In the present study, EANT shows no cytotoxicity to normal oral cells but exhibits selective killing to six oral cancer cell lines. They were suppressed by pretreatment of the antioxidant inhibitor N-acetylcysteine (NAC), demonstrating that EANT-induced cell death was mediated by oxidative stress. Concerning high sensitivity to EANT, Ca9-22 and CAL 27 oral cancer cells were chosen for exploring detailed selective killing mechanisms. EANT triggers a mixture of necrosis and apoptosis as determined by annexin V/7-aminoactinmycin D analysis. Still, they show differential switches from necrosis at a low (10 μg/mL) concentration to apoptosis at high (25 μg/mL) concentration of EANT in oral cancer cells. NAC induces necrosis but suppresses annexin V-detected apoptosis in oral cancer cells. Necrostatin 1 (NEC1), a necroptosis inhibitor, moderately suppresses necrosis but induces apoptosis at 10 μg/mL EANT. In contrast, Z-VAD-FMK, a pancaspase inhibitor, slightly causes necrosis but suppresses apoptosis at 10 μg/mL EANT. Furthermore, the flow cytometry-detected pancaspase activity is dose-responsively increased but is suppressed by NAC and ZVAD, although not for NEC1 in oral cancer cells. EANT causes several oxidative stress events such as reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization. In response to oxidative stresses, the mRNA for antioxidant signaling, such as nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), heme oxygenase 1 (HMOX1), and thioredoxin (TXN), are overexpressed in oral cancer cells. Moreover, EANT also triggers DNA damage, as detected by γH2AX and 8-oxo-2'-deoxyguanosine adducts. The dependence of oxidative stress is validated by the evidence that NAC pretreatment reverts the changes of cellular and mitochondrial stress and DNA damage. Therefore, EANT exhibits antiproliferation involving an oxidative stress-dependent necrosis/apoptosis switch and DNA damage in oral cancer cells.}, } @article {pmid34575034, year = {2021}, author = {Suzuki, S and Yamamoto, M and Sanomachi, T and Togashi, K and Sugai, A and Seino, S and Yoshioka, T and Okada, M and Kitanaka, C}, title = {Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction.}, journal = {Life (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {34575034}, issn = {2075-1729}, support = {15K18437//Ministry of Education, Culture, Sports, Science and Technology/ ; NA//Takeda Science Foundation/ ; }, abstract = {Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression.}, } @article {pmid34573138, year = {2021}, author = {Song, WJ and Yun, JH and Jeong, MS and Kim, KN and Shin, T and Kim, HC and Wie, MB}, title = {Inhibitors of Lipoxygenase and Cyclooxygenase-2 Attenuate Trimethyltin-Induced Neurotoxicity through Regulating Oxidative Stress and Pro-Inflammatory Cytokines in Human Neuroblastoma SH-SY5Y Cells.}, journal = {Brain sciences}, volume = {11}, number = {9}, pages = {}, pmid = {34573138}, issn = {2076-3425}, support = {520170377//Kangwon National University/ ; }, abstract = {Trimethyltin (TMT) is an environmental neurotoxin that mediates dopaminergic neuronal injury in the brain. In this study, we characterized the toxic mechanism and possible protective compounds against TMT-induced neurotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. Antioxidants such as melatonin, N-acetylcysteine (NAC), α-tocopherol, and allopurinol alleviated TMT toxicity. Apoptosis induced by TMT was identified by altered expression of cleaved caspase-3, Bax, Bcl-2, and Bcl-xL through Western blot analysis. The iron chelator deferoxamine ameliorated the alteration of apoptosis-related proteins through TMT exposure. TMT also induced delayed ultrastructural necrotic features such as mitochondrial swelling and cytoplasmic membrane rupture; NAC reduced these necrotic injuries. Esculetin, meloxicam, celecoxib, and phenidone decreased TMT toxicity. Elevation of the pro-inflammatory cytokines IL-1β, TNF-α, and NF-ĸB and reduction of the antioxidant enzymes catalase and glutathione peroxidase-1 (GPx-1) were induced by TMT and ameliorated by inhibitors of LOX and COX-2 enzymes. Both NMDA and non-NMDA antagonists attenuated TMT toxicity. The free calcium ion modulators nimodipine and BAPTA/AM contributed to neuronal survival against TMT toxicity. Inhibitors of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway, an autophagy regulator, decreased TMT toxicity. These results imply that TMT neurotoxicity is the chief participant in LOX- and COX-2-mediated apoptosis, partly via necrosis and autophagy in SH-SY5Y cells.}, } @article {pmid34572976, year = {2021}, author = {Jenkins, DD and Moss, HG and Brown, TR and Yazdani, M and Thayyil, S and Montaldo, P and Vento, M and Kuligowski, J and Wagner, C and Hollis, BW and Wiest, DB}, title = {NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {9}, pages = {}, pmid = {34572976}, issn = {2076-3921}, support = {MR/R001375/1/MRC_/Medical Research Council/United Kingdom ; F31NS108623/NS/NINDS NIH HHS/United States ; P60743//National Institute for Health Research/ ; EC11-246//Spanish Ministry of Health/ ; FISPI14/0433//Instituto Carlos III,/ ; Neuroscience Insitute Discovery Grant//Medical University of South Carolina/ ; }, abstract = {N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24-48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.}, } @article {pmid34564600, year = {2021}, author = {Liu, J and Liu, Q and Han, J and Feng, J and Guo, T and Li, Z and Min, F and Jin, R and Peng, X}, title = {N-Acetylcysteine Inhibits Patulin-Induced Apoptosis by Affecting ROS-Mediated Oxidative Damage Pathway.}, journal = {Toxins}, volume = {13}, number = {9}, pages = {}, pmid = {34564600}, issn = {2072-6651}, mesh = {Acetylcysteine/*metabolism/*pharmacology ; Apoptosis/*drug effects ; Cells, Cultured/drug effects ; HEK293 Cells/drug effects ; Humans ; Metabolic Networks and Pathways ; Mitochondria/metabolism ; Mycotoxins/toxicity ; Oxidative Phosphorylation/*drug effects ; Oxidative Stress/*drug effects ; Patulin/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Patulin (PAT) belongs to the family of food-borne mycotoxins. Our previous studies revealed that PAT caused cytotoxicity in human embryonic kidney cells (HEK293). In the present research, we systematically explored the detailed mechanism of ROS production and ROS clearance in PAT-induced HEK293 cell apoptosis. Results showed that PAT treatment (2.5, 5, 7.5, 10 μM) for 10 h could regulate the expression of genes and proteins involved in the mitochondrial respiratory chain complex, resulting in dysfunction of mitochondrial oxidative phosphorylation and induction of ROS overproduction. We further investigated the role of N-acetylcysteine (NAC), an ROS scavenger, in promoting the survival of PAT-treated HEK293 cells. NAC improves PAT-induced apoptosis of HEK293 cells by clearing excess ROS, modulating the expression of mitochondrial respiratory chain complex genes and proteins, and maintaining normal mitochondrial function. In addition, NAC protects the activity of antioxidant enzymes, maintains normal GSH content, and relieves oxidative damage. Additionally, 4 mM NAC alleviated 7.5 μM PAT-mediated apoptosis through the caspase pathway in HEK293 cells. In summary, our study demonstrated that ROS is significant in PAT-mediated cytotoxicity, which provides valuable insight into the management of PAT-associated health issues.}, } @article {pmid34563228, year = {2021}, author = {Zhao, X and Wang, S and Hong, X and Lu, S and Tang, S and Shen, Y and Feng, M and Guo, P and Fang, Y}, title = {A case of trichotillomania with binge eating disorder: combined with N-acetylcysteine synergistic therapy.}, journal = {Annals of general psychiatry}, volume = {20}, number = {1}, pages = {46}, pmid = {34563228}, issn = {1744-859X}, support = {2019KY681//Project of Health Department in Zhejiang Province/ ; 2018GY20//Huzhou Municipal Science and Technology Bureau/ ; 2018GYB16//Huzhou Municipal Science and Technology Bureau/ ; }, abstract = {BACKGROUND: Obsessive-compulsive and related disorders (OCRDs) are a group of intractable and chronic mental disorders. Trichotillomania (TTM) is a common type of OCRDs characterized by repetitive hair pulling, driven by escalating tension before the action and during the attempts to resist it. Binge eating disorder (BED) is a common type of eating disorder characterized by recurrent compulsive episodes of binge eating. Both have common psychological processes (tension or impulsion) and pathological manifestations (out of control), but the pathological mechanisms are still unclear and the current clinical treatments are often unsatisfactory for these two disorders.

CASE PRESENTATION: A 25-year-old woman with TTM comorbid BED came to our hospital for treatment. She had accepted systematic cognitive behavioral therapy (CBT) and also monotherapy or multidrug therapy with sertraline, fluvoxamine, bupropion, risperidone in full dosage and duration for 2 years, but all of them did not work. We treated this case with N-acetylcysteine (NAC) as a synergist on the basis of recent treatment (fluvoxamine 150 mg/day and bupropion 300 mg/day). The pathological hair plucking behavior and binge eating symptoms were both significantly and rapidly improved, and the follow-up in next 14 weeks showed that the effect was still maintained.

CONCLUSION: To our knowledge, this may be the first case report of using NAC as a synergist to treat TTM comorbid BED successfully, which suggest that these two disorders may have a common pathophysiological mechanism. Moreover, NAC can be one choice as a synergistic treatment for OCRDs.}, } @article {pmid34549670, year = {2022}, author = {Shah, KR and Beuhler, MC}, title = {Single bag high dose intravenous N-acetylcysteine associated with decreased hepatotoxicity compared to triple bag intravenous N-acetylcysteine in high-risk acetaminophen ingestions.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {493-498}, doi = {10.1080/15563650.2021.1979231}, pmid = {34549670}, issn = {1556-9519}, mesh = {Acetaminophen/therapeutic use ; Acetylcysteine/therapeutic use ; Administration, Intravenous ; *Analgesics, Non-Narcotic/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose/drug therapy ; Eating ; Humans ; Retrospective Studies ; }, abstract = {INTRODUCTION: There is controversy that the triple bag intravenous (IV) N-acetylcysteine (NAC) regimen may be underdosing the sickest patients in its current, common usage. We hypothesize that a higher dose IV NAC regimen improves some outcomes.

METHODS: We conducted a poison center based retrospective observational study from January 1, 2016 to December 31, 2017 comparing a single bag higher dose IV NAC regimen (150 mg/kg over 1 h, 15 mg/kg/hour) to the triple bag IV NAC regimen (150 mg/kg over 1 h, 12.5 mg/kg/hour for 4 h, 6.25 mg/kg/hour). In a high-risk population of patients with acetaminophen ingestion (defined as multiplication product ≥ 10,000 mg/L IU/L, not acute ingestions receiving NAC within 8 h, and not hepatotoxic on first contact), we evaluated the rate of hepatotoxicity, peak transaminase, and rate of laboratory coagulopathy.

RESULTS: 89 patients met the inclusion criteria. 12 of the 23 patients (52%) who received triple bag NAC became hepatotoxic and 10 (43%) became coagulopathic, while only 19 of 66 patients (29%) who received single bag NAC became hepatotoxic and 15 (23%) became coagulopathic; p = .043 and .057, resp. Mean peak transaminase was 4481 IU/L vs 2143 IU/L in those receiving triple bag NAC vs single bag NAC, difference of means 2338 IU/L; p = .026.

CONCLUSION: In this exploratory study of a high-risk population of patients with acetaminophen ingestions, the single bag IV NAC regimen was associated with lower peak transaminase and fewer patients becoming hepatotoxic as compared to the triple bag IV NAC regimen.}, } @article {pmid34549665, year = {2022}, author = {Minhaj, FS and Leonard, JB and Seung, H and Anderson, BD and Klein-Schwartz, W and King, JD}, title = {In vitro analysis of n-acetylcysteine (NAC) interference with the international normalized ratio (INR).}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {489-492}, doi = {10.1080/15563650.2021.1979232}, pmid = {34549665}, issn = {1556-9519}, mesh = {*Acetaminophen ; *Acetylcysteine/therapeutic use ; Administration, Intravenous ; Adult ; Female ; Humans ; International Normalized Ratio ; Male ; Middle Aged ; Prothrombin Time ; }, abstract = {BACKGROUND: Previous literature suggests a laboratory interference of n-acetylcysteine (NAC) with prothrombin time (PT) and the international normalized ratio (INR). Early publications focused on this interaction in the setting of an acetaminophen overdose and evaluated the INR of patients receiving intravenous NAC. However, there is limited literature describing the concentration-effect relationship of NAC to INR measurement in the absence of acetaminophen-induced hepatotoxicity at therapeutic NAC concentrations. The purpose of the study is to quantify the degree of interference of NAC on INR values at therapeutic concentrations correlating to each infusion of the regimen (ex. bag 1: 550 mcg/mL, bag 2: 200 mcg/mL, bag 3: 35 mcg/mL, double bag 3: 70 mcg/mL) and at supratherapeutic concentrations in vitro.

METHODS: Blood samples were obtained from study volunteers. Each blood sample was transferred into vials containing 0.3 mL buffered sodium citrate 3.2% and spiked with various concentrations of NAC for final concentrations of 0, 35, 70, 200, 550, 1000, 2000, and 4000 mcg/mL. The samples were centrifuged and tested to determine PT and INR on two separate machines: Siemens CS-2500 and Stago SN1114559. We would require a sample size of 6 to achieve a power of 80% and a level of significance of 1.7% (two-sided). Differences between INRs at varying concentrations were determined by Friedman's test. For multiple comparisons, post hoc analysis was performed using Wilcoxon signed-rank test with Bonferroni adjustment. Analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC).

RESULTS: Participants included 11 healthy subjects: 8 males, 3 females, median age 30 years (range 25 - 58). Median and interquartile ranges (IQR) INR for the baseline samples were 1.09 (IQR 1.05, 1.16) for Siemens and 1.03 (IQR 0.99, 1.11) for Stago analyzers. There was a significant difference in INR between the therapeutic concentrations (baseline, 35, 70,200, or 550 µg/mL) (Siemens p = .0008, Stago p < .0001). The 550 µg/mL concentration with the Siemens analyzer was the only one compared separately and found to be significantly greater than the baseline (1.07 vs 1.22, p = .02). For the Stago analyzer the 200 µg/mL and 500 µg/mL were compared and found to be significantly different from baseline (1.00 vs 1.07 and 1.19, adjusted p = .02 and p = .03, respectively). The largest INR increase seen was in one subject from a baseline of 1.07-1.32 with the 550 µg/mL concentration. Increases in concentrations to supratherapeutic levels resulted in a statistically significant non-linear increase in INR for all concentrations (Siemens p < .0001, Stago p < .0001). All of these concentrations were found to be significantly different from baseline (all adjusted p < .05).

CONCLUSION: Although it was found that at therapeutic concentrations the in vitro presence of NAC affects INR measurements on two different machines, the change is of little clinical relevance. Supratherapeutic concentrations of NAC affect INR significantly, but the clinical utility of those results is limited by the rarity of those concentrations being measured.}, } @article {pmid34544380, year = {2021}, author = {Dissanayake, DMDIB and Gunaratne, WMSN and Kumarihamy, KWMPP and Kularatne, SAM and Kumarasiri, PVR}, title = {Use of intravenous N-acetylcysteine in acute severe hepatitis due to severe dengue infection: a case series.}, journal = {BMC infectious diseases}, volume = {21}, number = {1}, pages = {978}, pmid = {34544380}, issn = {1471-2334}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; Adult ; Animals ; *Hepatitis ; Humans ; Infant, Newborn ; Male ; Retrospective Studies ; *Severe Dengue/drug therapy ; }, abstract = {BACKGROUND: Dengue fever is a common mosquito borne viral infection. Severe dengue fever associated severe hepatitis carries high mortality. Based on the beneficial effect of N-acetylcysteine (NAC) in paracetamol poisoning and non-acetaminophen induced liver failure, it is used in dengue fever associated hepatitis in clinical practice. We aim to study the reversal of liver enzymes with NAC in the setting of severe hepatitis due to severe dengue infection.

METHODS: A retrospective analysis was conducted on hospitalized 30 adults with severe dengue fever with severe hepatitis. These 30 patients had aspartate transaminase (AST) and alanine transaminases (ALT) more than 500 U/L and/or PT INR (prothrombin time and international normalized ratio) more than 1.5. They were treated with NAC infusion of 100 mg/h for 3 to 5 days.

RESULTS: The mean age of the group was 49.9 ± 11.46 years and 18 (60%) patients were males. Nineteen patients (63%) developed dengue shock. Of them 12 patients (40%) developed hepatic encephalopathy. Median AST on the day of administration of NAC was 1125 U/L interquartile range (IQR) 1653.25 while median ALT was 752 (IQR 459.25). There was a statistically significant reduction of both ALT (p = 0.034) and AST (p = 0.049) from day 1 to 4 after NAC infusion. Rise of platelet count between day 1 and day 4 also showed statistically significant difference (p = 0.011) but the reduction of prothrombin time and international normalized ratio (PT/INR) from 1 to day 4 did not show statistical significance difference. Mean duration of treatment with NAC was 3.61 ± 0.75 days while mean length of hospital stay was 6.2 ± 1.27 days. Only one patient died (3.3%). None of the patients reported adverse drug reaction due to NAC.

CONCLUSION: Majority of patients demonstrated marked clinical and biochemical improvements and they recovered fully. We observed faster and significant recovery of liver enzymes following administration of NAC. Based on the above findings, this study provides preliminary evidence for the beneficial effect of NAC in severe hepatitis in dengue infection with greater survival benefits.}, } @article {pmid34544266, year = {2021}, author = {Maartens, M and Kruger, MJ and van de Vyver, M}, title = {The Effect of N-Acetylcysteine and Ascorbic Acid-2-Phosphate Supplementation on Mesenchymal Stem Cell Function in B6.C-Lep[ob]/J Type 2 Diabetic Mice.}, journal = {Stem cells and development}, volume = {30}, number = {23}, pages = {1179-1189}, doi = {10.1089/scd.2021.0139}, pmid = {34544266}, issn = {1557-8534}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Ascorbic Acid/pharmacology ; *Diabetes Mellitus, Experimental/metabolism ; *Diabetes Mellitus, Type 2/pathology ; Dietary Supplements ; Humans ; Male ; *Mesenchymal Stem Cells/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Phosphates ; Quality of Life ; }, abstract = {Diabetes is a complex multifactorial disorder associated with hyperglycemia, oxidative stress, and inflammation. The pathological microenvironment impairs mesenchymal stem cell (MSC) viability and dysregulates their proregenerative and immune-modulatory function causing maladaptive tissue damage. Targeting stem cells to protect them against impairment could thus delay the onset of complications and enhance the quality of life in diabetes mellitus patients. The aim of this study was to investigate the efficacy of N-acetylcysteine (NAC) and ascorbic-acid-2-phosphate (AAP) oral supplementation as preventative measure against MSC impairment. Healthy wild-type control (C57BL/6J) (male, n = 24) and obese diabetic (B6.C-Lep[ob]/J) (ob/ob) (male, n = 24) mice received either placebo or antioxidant (NAC/AAP) supplementation for a period of 6 weeks. Metabolic parameters (weight and blood glucose) and the oxidative status (serum total serum antioxidant capacity, malondialdehyde) of animals were assessed. At the end of the 6-week supplementation period, bone marrow MSCs were isolated and their functionality (growth rate, viability, adipogenesis, and osteogenesis) assessed ex vivo. Real time quantitative polymerase chain reaction microarray analysis was also performed to assess the expression of 84 genes related to oxidative stress in MSCs. Despite no change in the metabolic profile, NAC/AAP supplementation improved the antioxidant status of diabetic animals and reduced lipid peroxidation, which is indicative of cellular damage. NAC/AAP also improved the population doubling time of MSCs (first 6-days postisolation) and significantly downregulated the expression of two genes (Nox1 and Rag2) associated with oxidative stress compared to placebo treatment. Taken together, this study has shown reduced oxidative stress and improvements in MSC function following in vivo antioxidant supplementation in healthy control and type 2 diabetic mice.}, } @article {pmid34541370, year = {2021}, author = {Lewis, JE and Poles, J and Shaw, DP and Karhu, E and Khan, SA and Lyons, AE and Sacco, SB and McDaniel, HR}, title = {The effects of twenty-one nutrients and phytonutrients on cognitive function: A narrative review.}, journal = {Journal of clinical and translational research}, volume = {7}, number = {4}, pages = {575-620}, pmid = {34541370}, issn = {2424-810X}, abstract = {BACKGROUND AND AIM: Brain health is becoming more important to the average person as the number of people with cognitive impairments, such as Alzheimer's disease (AD), is rising significantly. The current Food and Drug Administration-approved pharmacotherapeutics for dementia neither cure nor halt cognitive decline; they just delay the worsening cognitive impairment. This narrative review summarizes the effects of nutrients and phytonutrients on cognitive function.

METHODS: A comprehensive literature search of PubMed was performed to find clinical trials in humans that assessed the effects of nutrients and phytonutrients on cognitive function published in English between 2000 and 2021. Six independent reviewers evaluated the articles for inclusion in this review.

RESULTS: Ninety-six articles were summarized in this narrative review. In total 21 categories of nutrients and phytonutrients were included, i.e., α-lipoic acid, Bacopa monnieri, B vitamins, cholinergic precursors, vitamin D, vitamin E, Ginkgo biloba, ginseng, lion's mane mushroom, N-acetyl cysteine, omega-3 fatty acids, aloe polysaccharides, Rhodiola rosea, rosemary, saffron, tart cherries, turmeric, wild yam, Withania somnifera, xanthines, and zinc. Particular noteworthy effects on cognition included memory, recollection, attention, intelligence, vocabulary, recognition, response inhibition, arousal, performance enhancement, planning, creative thinking, reaction time, vigilance, task switching, orientation to time, place, and person, reading, writing, comprehension, accuracy, learning, information processing speed, executive function, mental flexibility, daily functioning, decrease in mental fatigue, and freedom from distractibility. Some nutrients and phytonutrients also improved mood and contentedness and reduced anxiety and the need for caregiving. These effects are not completely consistent or ubiquitous across all patient populations or health statuses. Adverse effects were minimal or nonexistent.

CONCLUSION: Due to the growing population of people with cognitive impairment and the lack of effective pharmacotherapeutics, it is prudent for those afflicted or their caregivers to find alternative treatments. Our narrative review shows that many of these nutrients and phytonutrients may be promising for treating some aspects of cognitive impairment, especially for people afflicted with AD.

RELEVANCE FOR PATIENTS: As demonstrated in a number of clinical trials, healthy adults and patients with various health challenges (e.g., AD, mild cognitive impairment, multiple sclerosis, and Parkinson's disease) exhibiting a wide range of severity in cognitive defects would be best served to consider multiple nutrients and phytonutrients to improve aspects of their cognitive function.}, } @article {pmid34540868, year = {2021}, author = {Fukutsu, K and Murata, M and Kikuchi, K and Yoshida, S and Noda, K and Ishida, S}, title = {ROCK1 Mediates Retinal Glial Cell Migration Promoted by Acrolein.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {717602}, pmid = {34540868}, issn = {2296-858X}, abstract = {Objective: Acrolein is a highly reactive aldehyde that covalently binds to cellular macromolecules and subsequently modulates cellular function. Our previous study demonstrated that acrolein induces glial cell migration, a pathological hallmark of diabetic retinopathy; however, the detailed cellular mechanism remains unclear. The purpose of this study was to investigate the role of acrolein in retinal glial cell migration by focusing on rho-associated coiled-coil-containing protein kinases (ROCKs). Methods: Immunofluorescence staining for ROCK isoforms was performed using sections of fibrovascular tissue obtained from the eyes of patients with proliferative diabetic retinopathy (PDR). Rat retinal Müller glial cell line, TR-MUL5, was stimulated with acrolein and the levels of ROCK1 were evaluated using real-time PCR and western blotting. Phosphorylation of the myosin-binding subunit of myosin light chain phosphatase [myosin phosphatase target subunit 1, (MYPT1)] and myosin light chain 2 (MLC2) was assessed. The cell migration rate of TR-MUL5 cells exposed to acrolein and/or ripasudil, a non-selective ROCK inhibitor, was measured using the Oris cell migration assay. Results: ROCK isoforms, ROCK1 and ROCK2, were positively stained in the cytosol of glial cells in fibrovascular tissues. In TR-MUL5 cells, the mRNA expression level of Rock1, but not Rock2, was increased following acrolein stimulation. In line with the PCR data, western blotting showed increase in ROCK1 and cleaved ROCK1 protein in TR-MUL5 cells stimulated with acrolein. N-acetylcysteine (NAC) suppressed acrolein-associated Rock1 upregulation in TR-MUL5 cells. Acrolein augmented the phosphorylation of MYPT1 and MLC2 and increased the cell migration rate of TR-MUL5 cells, both of which were abrogated by ripasudil. Conclusions: Our study demonstrated that ROCK1 mediates the migration of retinal glial cells promoted by the unsaturated aldehyde acrolein.}, } @article {pmid34536564, year = {2022}, author = {Li, HY and Tang, ZM and Wang, Z and Lv, JM and Liu, XL and Liang, YL and Cheng, B and Gao, N and Ji, SR and Wu, Y}, title = {C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement Overactivation.}, journal = {Cellular and molecular gastroenterology and hepatology}, volume = {13}, number = {1}, pages = {289-307}, pmid = {34536564}, issn = {2352-345X}, mesh = {Acetaminophen/adverse effects ; Animals ; C-Reactive Protein ; *Chemical and Drug Induced Liver Injury ; *Chemical and Drug Induced Liver Injury, Chronic ; Mice ; Mice, Inbred C57BL ; Rats ; }, abstract = {BACKGROUND AND AIMS: C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI).

METHODS: The effects of CRP in AILI were investigated using CRP knockout mice and rats combined with human CRP rescue. The mechanisms of CRP action were investigated in vitro and in mice with Fcγ receptor 2B knockout, C3 knockout, or hepatic expression of CRP mutants defective in complement interaction. The therapeutic potential of CRP was investigated by intraperitoneal administration at 2 or 6 hours post-AILI induction in wild-type mice.

RESULTS: CRP knockout exacerbated AILI in mice and rats, which could be rescued by genetic knock-in, adeno-associated virus-mediated hepatic expression or direct administration of human CRP. Mechanistically, CRP does not act via its cellular receptor Fcγ receptor 2B to inhibit the early phase injury to hepatocytes induced by acetaminophen; instead, CRP acts via factor H to inhibit complement overactivation on already injured hepatocytes, thereby suppressing the late phase amplification of inflammation likely mediated by C3a-dependent actions of neutrophils. Importantly, CRP treatment effectively alleviated AILI with a significantly extended therapeutic time window than that of N-acetyl cysteine.

CONCLUSION: Our results thus identify CRP as a crucial checkpoint that limits destructive activation of complement in acute liver injury, and we argue that long-term suppression of CRP expression or function might increase the susceptibility to AILI.}, } @article {pmid34534560, year = {2021}, author = {Gilardoni, M and Léonço, D and Caffin, F and Gros-Désormeaux, F and Eldin, C and Béal, D and Ouzia, S and Junot, C and Fenaille, F and Piérard, C and Douki, T}, title = {Evidence for the systemic diffusion of (2-chloroethyl)-ethyl-sulfide, a sulfur mustard analog, and its deleterious effects in brain.}, journal = {Toxicology}, volume = {462}, number = {}, pages = {152950}, doi = {10.1016/j.tox.2021.152950}, pmid = {34534560}, issn = {1879-3185}, mesh = {Administration, Cutaneous ; Animals ; Brain/*drug effects ; Chemical Warfare Agents/pharmacokinetics/*toxicity ; DNA Damage/*drug effects ; Glutathione/metabolism ; Metabolomics ; Mice ; Mice, Hairless ; Mustard Gas/administration & dosage/*analogs & derivatives/pharmacokinetics/toxicity ; Skin/metabolism ; Time Factors ; Tissue Distribution ; }, abstract = {Sulfur mustard, a chemical warfare agent known to be a vesicant of skin, readily diffuses in the blood stream and reaches internal organs. In the present study, we used the analog (2-chloroethyl)-ethyl-sulfide (CEES) to provide novel data on the systemic diffusion of vesicants and on their ability to induce brain damage, which result in neurological disorders. SKH-1 hairless mice were topically exposed to CEES and sacrificed at different time until 14 days after exposure. A plasma metabolomics study showed a strong systemic impact following a self-protection mechanism to alleviate the injury of CEES exposure. This result was confirmed by the quantification of specific biomarkers in plasma. Those were the conjugates of CEES with glutathione (GSH-CEES), cysteine (Cys-CEES) and N-acetyl-cysteine (NAC-CEES), as well as the guanine adduct (N7Gua-CEES). In brain, N7Gua-CEES could be detected both in DNA and in organ extracts. Similarly, GSH-CEES, Cys-CEES and NAC-CEES were present in the extracts until day14. Altogether, these results, based on novel exposure markers, confirm the ability of vesicants to induce internal damage following dermal exposure. The observation of alkylation damage to glutathione and DNA in brain provides an additional mechanism to the neurological insult of SM.}, } @article {pmid34531444, year = {2021}, author = {Mukherjee, I and Dhar, R and Singh, S and Sharma, JB and Nag, TC and Mridha, AR and Jaiswal, P and Biswas, S and Karmakar, S}, title = {Oxidative stress-induced impairment of trophoblast function causes preeclampsia through the unfolded protein response pathway.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {18415}, pmid = {34531444}, issn = {2045-2322}, mesh = {Adult ; Biomarkers/metabolism ; Cell Differentiation/drug effects ; Cell Line ; Cell Movement/drug effects ; Endoribonucleases/metabolism ; Female ; Humans ; Hydrogen Peroxide/toxicity ; Models, Biological ; *Oxidative Stress/drug effects ; Pre-Eclampsia/*pathology ; Pregnancy ; Protein Serine-Threonine Kinases/metabolism ; Trophoblasts/drug effects/*pathology/ultrastructure ; *Unfolded Protein Response/drug effects ; X-Box Binding Protein 1/metabolism ; Young Adult ; }, abstract = {Pre-eclampsia (PE) is a pregnancy-specific disorder, characterized by hypertension and proteinuria. In PE, trophoblasts mediated inadequate remodeling of uterine spiral arteries seem to interrupt uteroplacental blood flow, one of the hallmarks in the early onset of PE (EO-PE). This, in turn, results in placental ischemia-reperfusion injury during hypoxia and reoxygenation episodes, leading to the generation of reactive oxygen species (ROS) and oxidative stress (OS). But still it is debatable if OS is a cause or consequence of PE. In this present study, we have investigated the effects of OS on PE placentae and trophoblast cell functions using BeWo and HTR8/SVneo cell lines. PE placental tissues showed abnormal ultrastructure, high level of reactive oxygen species (ROS) with altered unfolded protein responses (UPR) in compare with term placental tissues. Similar to PE placentae, during OS induction, the trophoblast cells showed altered invasion and migration properties with significantly variable expression of differentiation and invasion markers, e.g., syncytin and MMPs. The effect was rescued by antioxidant, N-acetyl cysteine, thereby implying a ROS-specific effect and in the trophoblast cells, OS triggers UPR pathway through IRE1α-XBP1 axis. Taken together, these findings highlight the harmful effect of unfolded protein response, which was induced due to OS on trophoblast cells and deformed invasion and differentiation programme and can be extended further to clinical settings to identify clinically approved antioxidants during pregnancy as a therapeutic measure to reduce the onset of PE.}, } @article {pmid34530696, year = {2021}, author = {Zhu, QY and Tai, S and Tang, L and Xiao, YC and Tang, JJ and Chen, YQ and Shen, L and He, J and Ouyang, MQ and Zhou, SH}, title = {N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice.}, journal = {Redox report : communications in free radical research}, volume = {26}, number = {1}, pages = {170-175}, pmid = {34530696}, issn = {1743-2928}, mesh = {*Acetylcysteine/pharmacology ; Aging ; Animals ; Aorta ; Fibrosis ; *Macrophages/pathology ; Mice ; Mice, Inbred C57BL ; }, abstract = {Background: Vascular fibrosis is a universal phenomenon associated with aging, and oxidative stress plays an important role in the genesis of vascular damage in line with the aging process. However, whether antioxidants can ameliorate vascular fibrosis remains unclear.Objectives: The present study was to determine antioxidant N-acetylcysteine (NAC) could ameliorates aortic fibrosis in aging wild-type C57BL/6 mice.Methods: The aortas were harvested from both 12-week and 60-week wild-type mice. The 60-week mice were treated with and without the NAC for 12 weeks starting at the age of 48 weeks. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining of aortic samples were performed, and the levels of reactive oxygen species (ROS), RNA expression of GAPDH, TNF-α, MCP-1, IL-6, IL-10, IL-4, SIRT-1, SIRT-3, FOXO-1, and macrophage polarization were determined.Results: There is a positive relationship between collagen deposition and the M1/M2 macrophage ratio in the aortic wall of aged wild-type C57BL/6 mice. The higher collagen area percentage in the aortas of 60-week-old mice than in 12-week-old mice was reversed by NAC. NAC could not impact the total number of macrophages, but partly promoted M2 macrophage polarization. By performing qRT-PCR using aortic samples from these mice, we identified that SIRT-1, SIRT-3, FOXO-1 could be somehow responsible for aging-related fibrosis.Conclusions: NAC ameliorates aortic fibrosis in aging wild type mice partly by promoting M2 macrophage polarization.}, } @article {pmid34511825, year = {2021}, author = {Allen, BJW and Abu Shanab, AA and Anderson, MR and Fogden, EN}, title = {Recurrent Pyroglutamic Acidosis in the Context of Undiagnosed Liver Cirrhosis-A Case Report.}, journal = {Journal of clinical and experimental hepatology}, volume = {11}, number = {5}, pages = {623-627}, pmid = {34511825}, issn = {0973-6883}, abstract = {Metabolic associated fatty liver disease, previously known as nonalcoholic fatty liver disease, is the most common cause of chronic liver disease across all ethnic groups; however, it remains enormously underestimated.[1] [,] [2] Sepsis, hepatotoxic medications and malnutrition in the acute settings on top of unknown cirrhosis can lead to decompensation and various metabolic complications. Pyroglutamic acidosis is a rarely recognised cause for unexplained high anion gap metabolic acidosis that is felt to be frequently underdiagnosed. Particular patients at risk include women, the elderly, those on regular paracetamol and those suffering with malnourishment or sepsis. Other risk factors include alcohol abuse and chronic liver disease (3). We present the case of a patient with recurrent episodes of pyroglutamic acidosis and encephalopathy in the context of undiagnosed nonalcoholic fatty liver disease with cirrhosis.}, } @article {pmid34511433, year = {2021}, author = {Tan, T and Fu, X and Qu, J and Zhang, M and Chen, H and Wang, Y and Wang, B and Li, J and Liu, J and Liu, P}, title = {2,5-dimethyl celecoxib induces apoptosis and autophagy via activation of ROS/JNK axis in nasopharyngeal carcinoma cells.}, journal = {Aging}, volume = {13}, number = {17}, pages = {21483-21496}, pmid = {34511433}, issn = {1945-4589}, mesh = {Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Celecoxib ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nasopharyngeal Carcinoma/*pathology ; Nasopharyngeal Neoplasms/*pathology ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {2,5-dimethyl celecoxib (DMC), a close derivative of celecoxib, has also been reported to have anticancer effects. However, the effects and underlying molecular mechanisms of DMC with respect to nasopharyngeal carcinoma are still largely unknown. In this study, we present that DMC has displayed anticancer potency in nasopharyngeal carcinoma in vitro and in vivo. Mechanistically, we found DMC induced apoptosis and autophagy for anticancer therapy against nasopharyngeal carcinoma. Furthermore, DMC-induced autophagy could remarkably attenuate after the treatment of reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (SP). Taken together, these results suggested DMC induced apoptosis and autophagic death via activation of ROS/JNK axis in NPC cells, which providing us new insights into developing potential therapeutic agents for nasopharyngeal carcinoma patients.}, } @article {pmid34510229, year = {2021}, author = {Li, Z and Chi, H and Zhu, W and Yang, G and Song, J and Mo, L and Zhang, Y and Deng, Y and Xu, F and Yang, J and He, Z and Yang, X}, title = {Cadmium induces renal inflammation by activating the NLRP3 inflammasome through ROS/MAPK/NF-κB pathway in vitro and in vivo.}, journal = {Archives of toxicology}, volume = {95}, number = {11}, pages = {3497-3513}, pmid = {34510229}, issn = {1432-0738}, support = {2018YFC1603101//national key r&d program of china/ ; 2019B020210002//guangdong key r&d program/ ; 81872642//national natural science foundation of china/ ; 82073599//national natural science foundation of china/ ; }, mesh = {Acute Kidney Injury/*chemically induced ; Animals ; Cadmium/*toxicity/urine ; Cell Line, Transformed ; Female ; Humans ; Inflammasomes ; Inflammation/*etiology ; Kidney/*drug effects/pathology ; Kidney Tubules, Proximal ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Rats ; }, abstract = {Cadmium (Cd) has been reported to induce kidney damage by triggering oxidative stress and inflammation. The NLR family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated a role in the pathogenesis of inflammation. However, the connection between Cd and NLRP3 inflammasome in the development of renal inflammation remains unknown. In this study, in vitro experiments based on the telomerase-immortalized human renal proximal-tubule epithelial cell line (RPTEC/TERT1) were carried out. Results revealed that CdCl2 (2-8 μM) increased ROS production and activated NLRP3, thereby enhancing secretion of IL-1β and IL-18 (P < 0.05). Knock-down of NLRP3 rescued the RPTEC/TERT1 cells from Cd-induced inflammatory damage. Cd activated the MAPK/NF-κB signaling pathway in RPTEC/TERT1 cells (P < 0.05). In addition, treatment with N-acetylcysteine (NAC) improved inflammation and blocked the upregulation of the MAPK/NF-κB signaling pathway. Pre-treatment with MAPK and NF-κB inhibitors also suppressed NLRP3 inflammasome activation (P < 0.05). Moreover, CdCl2 (25-00 mg/L) stimulated the MAPK/NF-κB signaling pathway, activated the NLRP3 inflammasome, and increased inflammatory response (P < 0.05) leading to renal injury in rats. Exposure to cadmium elevated serum levels of NLRP3 and IL-1β in populations (P < 0.05). Further analysis found that serum NLRP3 and IL-1β levels were positively correlated with urine cadmium (UCd) and urine N-acetyl-β-D-glucosaminidase (UNAG). Overall, Cd induced renal inflammation through the ROS/MAPK/NF-κB signaling pathway by activating the NLRP3 inflammasome. Our research thus provides new insights into the molecular mechanism that NLRP3 contributes to Cd-induced kidney damage.}, } @article {pmid34499870, year = {2021}, author = {Baron, JM and Heaney, DL and John, A and Fantz, CR}, title = {Real evidence to assess clinical testing interference risk (REACTIR): A strategy using real world data to assess the prevalence of interfering substances in patients undergoing clinical laboratory testing.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {523}, number = {}, pages = {178-184}, doi = {10.1016/j.cca.2021.09.001}, pmid = {34499870}, issn = {1873-3492}, mesh = {*Blood Glucose ; Humans ; Laboratories, Clinical ; *Point-of-Care Systems ; Point-of-Care Testing ; Prevalence ; }, abstract = {INTRODUCTION: Laboratory test interferences can cause spurious test results and patient harm. Knowing the frequency of various interfering substances in patient populations likely to be tested with a particular laboratory assay may inform test development, test utilization and strategies to mitigate interference risk.

METHODS: We developed REACTIR (Real Evidence to Assess Clinical Testing Interference Risk), an approach using real world data to assess the prevalence of various interfering substances in patients tested with a particular type of assay. REACTIR uses administrative real world data to identify and subgroup patient cohorts tested with a particular laboratory test and evaluate interference risk.

RESULTS: We demonstrate the application REACTIR to point of care (POC) blood glucose testing. We found that exposure to several substances with the potential to interfere in POC blood glucose tests, including N-acetyl cysteine (NAC) and high dose vitamin C was uncommon in most patients undergoing POC glucose tests with several key exceptions, such as burn patients receiving high dose IV-vitamin C or acetaminophen overdose patients receiving NAC.

CONCLUSIONS: Findings from REACTIR may support risk mitigation strategies including targeted clinician education and clinical decision support. Likewise, adaptations of REACTIR to premarket assay development may inform optimal assay design and assessment.}, } @article {pmid34495252, year = {2021}, author = {Watanabe, M and Borges, FT and Pessoa, EA and Fonseca, CD and Fernandes, SM and Drew, RC and Volpini, RA and Vattimo, MFF}, title = {Renoprotective effect of N-acetylcysteine depends upon the severity of the ischemia reperfusion injury.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {54}, number = {11}, pages = {e9941}, pmid = {34495252}, issn = {1414-431X}, mesh = {Acetylcysteine/therapeutic use ; *Acute Kidney Injury/prevention & control ; Animals ; Humans ; Kidney ; Oxidative Stress ; Rats ; Rats, Wistar ; *Reperfusion Injury/prevention & control ; }, abstract = {Acute kidney injury (AKI) is a common complication in seriously ill patients, while renal ischemia-reperfusion (I/R) injury is the most frequent event in this oxidative renal injury. N-acetylcysteine (NAC) is a small molecule containing a thiol group that has antioxidant properties, promoting detoxification and acting directly as a free radical scavenger. In this study, the protective effect of NAC was investigated in short-term (30 min) and long-term (45 min) ischemic AKI. This was achieved via clamping of the renal artery for 30 or 45 min in Wistar rats to induce I/R injury. AKI worsened with a longer period of ischemia (45 compared to 30 min) due to probable irreversible damage. Preconditioning with NAC in short-term ischemia improved renal blood flow and increased creatinine clearance by reducing oxidative metabolites and increasing antioxidant capacity. Otherwise, NAC did not change these parameters in the long-term ischemia. Therefore, this study demonstrated that the period of ischemia determines the severity of the AKI, and NAC presented antioxidant effects in short-term ischemia but not in long-term ischemia, confirming that there is a possible therapeutic window for its renoprotective effect.}, } @article {pmid34486746, year = {2021}, author = {Luo, G and Liu, J and Bian, T and Zhang, Z and Li, M}, title = {The mechanism of N-acetyl-l-cysteine in improving the secretion of porcine follicle-stimulating hormone in Pichia pastoris.}, journal = {Yeast (Chichester, England)}, volume = {38}, number = {11}, pages = {601-611}, doi = {10.1002/yea.3668}, pmid = {34486746}, issn = {1097-0061}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Follicle Stimulating Hormone ; Humans ; Pichia/genetics ; Saccharomycetales ; *Serum Albumin ; Swine ; }, abstract = {Our previous study revealed that N-acetyl-l-cysteine (NAC) could enhance the secretion of recombinant proteins by Pichia pastoris, but the corresponding molecular mechanisms are still unclear. In the present study, we explored whether other thiols have a similar action on the secretion of recombinant human serum albumin and porcine follicle-stimulating hormone fusion protein (HSA-pFSHβ), to reveal the mechanism of NAC on HSA-pFSHβ secretion. Transcriptome analysis showed that genes involved in oxidoreductase activity and oxidation-reduction process were upregulated in cells supplemented with NAC. The other three thiol-reducing regents including dimercaptopropanol (DT), thioglycolic acid, and mercaptolactic acid could improve HSA-pFSHβ production in the culture supernatant. Among them, only DT had similar effect as NAC on HSA-pFSHβ secretion and the increase of GSH content. Moreover, 1-20 mM GSH, 1-10 mM cysteine, or 1-20 mM N-acetyl-d-cysteine supplementation could improve the secretion of HSA-pFSHβ. Furthermore, 0.4-3.2 mM ethacrynic acid, rather than 1-16 mM BSO could inhibit the effect of NAC on the production of HSA-pFSHβ. These results indicated that NAC improved the secretion of HSA-pFSHβ by increasing the intracellular GSH content through its thiol activity rather than as a precursor for GSH synthesis. In conclusion, our results demonstrate, for the first time, that the secretion of recombinant HSA-pFSHβ in Pichia pastoris could be improved through thiol-reducing agent supplementation, and the mechanism of the effect NAC has on HSA-pFSHβ secretion is associated with improving the intracellular GSH content.}, } @article {pmid34482039, year = {2021}, author = {Darvishi, FZ and Saadat, M}, title = {Morphine treatment is associated with diminished telomere length together with down-regulated TERT and TERF2 mRNA levels.}, journal = {Drug and alcohol dependence}, volume = {227}, number = {}, pages = {108982}, doi = {10.1016/j.drugalcdep.2021.108982}, pmid = {34482039}, issn = {1879-0046}, mesh = {Down-Regulation ; Humans ; Morphine/pharmacology ; RNA, Messenger/genetics ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; }, abstract = {BACKGROUND: Drug dependence promotes accelerated aging and higher mortality compare with the general population. Telomere length is a biomarker of determination of cellular aging. Telomere attrition has been reported in heroin dependent patients. To investigate whether telomere length is affected by morphine or not, the expressions of hTERT and TERF2 in morphine treated human SH-SY5Y cells were determined and compared with untreated cells.

METHODS: The SH-SY5Y cells were treated with 1 and 5 μM concentrations of morphine for different exposure times (1d, 2d, 3d, 7d and 60 days). The mRNA levels of hTERT and TERF2 were determined using quantitative real-time RCR. The relative telomere length was measured as the ratio of telomere/36B4.

RESULTS: The hTERT and TERF2 mRNA levels were down regulated in morphine treated cells as a function of exposure duration. These alterations were reversible if morphine was removed from the culture medium. No reduction in the relative expression of hTERT and TERF2 in the cells exposed to N-acetyl cysteine (NAC) plus morphine was observed. In the SH-SY5Y cells treated by 5 μM morphine for 60 consecutive days, the hTERT and TERF2 mRNA levels and relative telomere lengths remarkably decreased.

CONCLUSIONS: Reversible alteration of mRNA levels by removing morphine from culture medium, and effect of NAC in co-treatment of morphine plus NAC, emphasize the role of reactive oxygen species in down-regulation of the expression of hTERT and TERF2 by morphine. Telomere attrition in morphine treated cells is a consequence of down-regulation of the expression of hTERT and TERF2.}, } @article {pmid34481340, year = {2021}, author = {Hung, SY and Chen, WF and Lee, YC and Su, JH and Juan, YS and Lin, IP and Zhang, YH and Chang, MK and Lin, MY and Chen, CY and Lee, CH}, title = {Rhopaloic acid A induces apoptosis, autophagy and MAPK activation through ROS-mediated signaling in bladder cancer.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {92}, number = {}, pages = {153720}, doi = {10.1016/j.phymed.2021.153720}, pmid = {34481340}, issn = {1618-095X}, mesh = {Animals ; Apoptosis ; Autophagy ; Cell Line, Tumor ; Cell Proliferation ; Humans ; MAP Kinase Signaling System ; Male ; Pyrans ; Reactive Oxygen Species ; *Urinary Bladder Neoplasms/drug therapy ; Zebrafish ; }, abstract = {BACKGROUND: Bladder cancer (BC) is a very common type of malignant cancer in men and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that Rhopaloic acid A (RA), a compound isolated from marine sponges, fights cancer but its potential anti-tumor effect on BC is still unknown.

PURPOSE: The present study was aimed to explore the potential anti-tumor effects of RA against human BC cells and the underlying molecular mechanism.

METHODS: Cell cytotoxicity was determined using the MTT and colony formation assays. Cell cycle distribution, apoptosis induction and generation of mitochondrial reactive oxygen species (ROS) were analyzed by flow cytometry. Mitochondrial membrane potential, acridine orange staining and intracellular ROS levels were observed using fluorescence microscopy. Levels of various signaling proteins were assessed using Western blotting. Furthermore, a zebrafish BC xenotransplantation model was used to confirm the anti-tumor effect of RA in vivo.

RESULTS: Treatment with RA significantly suppressed the proliferation of BC cells that resulted from G2/M cycle arrest. Additionally, RA induced mitochondrial-mediated apoptosis and autophagy in BC cells. The death of BC cells induced by RA was rescued by treatment with inhibitors of apoptosis (Z-VAD-FMA) or autophagy (3-MA). RA activated the MAPK pathway and increased the production of cellular and mitochondrial ROS. Treatment with the ROS scavenger N-acetyl cysteine, effectively reversed the induction of apoptosis, autophagy, JNK activation and DNA damage elicited by RA. Finally, RA significantly inhibited tumor growth in a zebrafish BC xenotransplantation model.

CONCLUSION: Taken together, our findings indicate that RA induces apoptosis and autophagy and activates the MAPK pathway through ROS-mediated signaling in human BC cells. This RA-induced pathway offers insights into the molecular mechanism of its antitumor effect and shows that RA is a promising candidate for the treatment of BC.}, } @article {pmid34481041, year = {2021}, author = {Atlas, D}, title = {Emerging therapeutic opportunities of novel thiol-amides, NAC-amide (AD4/NACA) and thioredoxin mimetics (TXM-Peptides) for neurodegenerative-related disorders.}, journal = {Free radical biology & medicine}, volume = {176}, number = {}, pages = {120-141}, doi = {10.1016/j.freeradbiomed.2021.08.239}, pmid = {34481041}, issn = {1873-4596}, mesh = {Acetylcysteine/analogs & derivatives ; Amides ; Humans ; *Neurodegenerative Diseases/drug therapy ; Peptides ; *Sulfhydryl Compounds ; Thioredoxins ; }, abstract = {Understanding neurodegenerative diseases have challenged scientists for decades. It has become apparent that a decrease in life span is often correlated with the development of neurodegenerative disorders. Oxidative stress and the subsequent inflammatory damages appear to contribute to the different molecular and biochemical mechanisms associated with neurodegeneration. In this review, I examine the protective properties of novel amino acid based compounds, comprising the AD series (AD1-AD7) in particular N-acetylcysteine amide, AD4, also called NACA, and the series of thioredoxin mimetic (TXM) peptides, TXM-CB3-TXM-CB16. Designed to cross the blood-brain-barrier (BBB) and permeate the cell membrane, these antioxidant/anti-inflammatory compounds may enable effective treatment of neurodegenerative related disorders. The review addresses the molecular mechanism of cellular protection exhibited by these new reagents, focusing on the reversal of oxidative stress, mitochondrial stress, inflammatory damages, and prevention of premature cell death. In addition, it will cover the outlook of the clinical prospects of AD4/NACA and the thioredoxin-mimetic peptides, which are currently in development.}, } @article {pmid34479835, year = {2021}, author = {Han, S and Lim, JH and Bang, J and Cho, JH}, title = {Use of a combination of N-acetylcysteine and clonazepam to treat burning mouth syndrome.}, journal = {Oral surgery, oral medicine, oral pathology and oral radiology}, volume = {132}, number = {5}, pages = {532-538}, doi = {10.1016/j.oooo.2021.07.016}, pmid = {34479835}, issn = {2212-4411}, mesh = {Acetylcysteine/therapeutic use ; *Burning Mouth Syndrome/drug therapy ; *Clonazepam ; Humans ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: This study was intended to evaluate the clinical efficacy of a combination of N-acetylcysteine (NAC) and clonazepam for treatment of burning mouth syndrome (BMS).

STUDY DESIGN: A total of 160 patients with BMS were divided into 3 groups: group 1 received NAC (400 mg/d), group 2 received clonazepam (0.5 mg/d), and group 3 received both NAC and clonazepam. We evaluated symptom relief after 8 weeks of treatment using a visual analog scale (VAS). To assess oral health-related quality of life, we used the validated Korean version of an oral health impact profile (OHIP-14K).

RESULTS: The overall response rates of the 3 groups were 60.3%, 51.3%, and 80.0%, respectively. The mean VAS and OHIP-14K scores significantly decreased in all groups after the 8-week treatments. The VAS score changes were -12.2 ± 19.5, -10.0 ± 14.1, and -21.0 ± 24.6, respectively (P = .001), in the 3 groups and the OHIP-14K changes were -2.3 ± 9.2, -4.4 ± 6.9, and -8.7 ± 10.3, respectively (P = .020). Group 3 showed significantly larger differences in VAS and OHIP-14K scores than group 2, before and after treatment.

CONCLUSIONS: In the treatment of BMS, the NAC/clonazepam combination therapy was more effective than either monotherapy.}, } @article {pmid34479474, year = {2021}, author = {Zhu, L and Xu, F and Kang, X and Zhou, J and Yao, Q and Lin, Y and Zhang, W}, title = {The antioxidant N-acetylcysteine promotes immune response and inhibits epithelial-mesenchymal transition to alleviate pulmonary fibrosis in chronic obstructive pulmonary disease by suppressing the VWF/p38 MAPK axis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {27}, number = {1}, pages = {97}, pmid = {34479474}, issn = {1528-3658}, mesh = {Antioxidants/*pharmacology ; Biomarkers ; Disease Susceptibility ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; Immunomodulation/*drug effects ; Pulmonary Disease, Chronic Obstructive/diagnosis/*etiology/*metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/*metabolism ; von Willebrand Factor/*metabolism ; }, abstract = {BACKGROUND/AIM: N-Acetylcysteine (NAC) demonstrates applications in the prevention of exacerbation of chronic obstructive pulmonary disease (COPD). COPD is often characterized by fibrosis of the small airways. This study aims at investigating the physiological mechanisms by which NAC might mediate the pulmonary fibrosis in COPD.

METHODS: A total of 10 non-smokers without COPD and 10 smokers with COPD were recruited in this study, and COPD rat models were established. Cigarette smoke extract (CSE) cell models were constructed. The gain- or loss-of-function experiments were adopted to determine the expression of VWF and the extent of p38 MAPK phosphorylation, levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and immunoglobulins (IgG, IgM and IgA) in the serum of COPD rats and supernatant of alveolar epithelial cells and to detect cell invasion and migration and the ratio of CD3[+], CD4[+], CD8[+] and CD4[+]/CD8[+]T lymphocytes.

RESULTS: Expression of VWF and the extent of p38 MAPK phosphorylation were increased in COPD. NAC inhibited p38 MAPK phosphorylation by reducing the VWF expression. NAC could inhibit cell migration and invasion, elevate E-cadherin expression, the ratio of CD3[+], CD4[+], CD8[+] and CD4[+]/CD8[+]T lymphocytes, and levels of IgG, IgA, and IgM, and reduce N-cadherin expression and levels of IL-6 and TNF-α in CSE cells and serum of COPD rats. NAC promoted immune response and suppressed epithelial-mesenchymal transformation (EMT) to relieve COPD-induced pulmonary fibrosis in vitro and in vivo by inhibiting the VWF/p38 MAPK axis.

CONCLUSIONS: Collectively, NAC could ameliorate COPD-induced pulmonary fibrosis by promoting immune response and inhibiting EMT process via the VWF/p38 MAPK axis, therefore providing us with a potential therapeutic target for treating COPD.}, } @article {pmid34478974, year = {2021}, author = {Yang, X and Liu, P and Zhang, X and Zhang, J and Cui, Y and Song, M and Li, Y}, title = {T-2 toxin causes dysfunction of Sertoli cells by inducing oxidative stress.}, journal = {Ecotoxicology and environmental safety}, volume = {225}, number = {}, pages = {112702}, doi = {10.1016/j.ecoenv.2021.112702}, pmid = {34478974}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Humans ; Leydig Cells ; Male ; Oxidative Stress ; Sertoli Cells ; *T-2 Toxin/toxicity ; }, abstract = {T-2 toxin is an inevitable mycotoxin in food products and feeds. It is a proven toxicant impairing the male reproductive system. However, previous studies have concentrated on the toxic effect of T-2 toxin on Leydig cells, with little attention on the Sertoli cell cytotoxicity. Therefore, this study aimed to establish the toxic mechanism of T-2 toxin on Sertoli cells. The Sertoli cell line (TM4 cell) was cultured and exposed to different concentrations of T-2 toxin with/without N-acetyl-L-cysteine (NAC) for 24 h. A CCK-8 assay then measured the cell viability. In addition, the expression of TM4 cell biomarkers (FSHR and ABP) and functional factors (occludin (Ocln), zonula occluden-1 (ZO-1), Connexin 43 (Cx-43), and N-Cadherin (N-cad)) were measured by qRT-PCR and Western blotting. The oxidative stress status (ROS, MDA, CAT, and SOD) and apoptosis rate, including the caspase-9, 8, and 3 activities in TM4 cells, were analyzed. We established that (1): T-2 toxin decreased TM4 cells viability and the half-maximal inhibitory concentration was 8.10 nM. (2): T-2 toxin-induced oxidative stress, evidenced by increased ROS and MDA contents, and inhibited CAT and SOD activities. (3): T-2 toxin inhibited FSHR, ABP, ocln, ZO-1, Cx-43, and N-Cad expressions. (4): T-2 toxin promoted TM4 cell apoptosis and caspase-9, 8, and 3 activities. (5): N-acetyl-L-cysteine relieved oxidative stress, functional impairment, and apoptosis in TM4 cells treated with T-2 toxin. Thus, T-2 toxin induced TM4 cell dysfunction through ROS-induced apoptosis.}, } @article {pmid34478011, year = {2021}, author = {Mohammadlou, H and Hamzeloo-Moghadam, M and Mohammadi, MH and Yami, A and Gharehbaghian, A}, title = {Britannin, a sesquiterpene lactone induces ROS-dependent apoptosis in NALM-6, REH, and JURKAT cell lines and produces a synergistic effect with vincristine.}, journal = {Molecular biology reports}, volume = {48}, number = {9}, pages = {6249-6258}, pmid = {34478011}, issn = {1573-4978}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/isolation & purification/*pharmacology ; Apoptosis/*drug effects ; Catharanthus/*chemistry ; Cell Survival/drug effects ; Drug Synergism ; Free Radical Scavengers/pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Inula/*chemistry ; Jurkat Cells ; Lactones/isolation & purification/*pharmacology ; Leukocytes, Mononuclear/drug effects/metabolism ; Phytochemicals/isolation & purification/*pharmacology ; Plant Extracts/isolation & purification/*pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/isolation & purification/*pharmacology ; Signal Transduction/drug effects ; Vincristine/*pharmacology ; }, abstract = {BACKGROUND: Britannin, a Sesquiterpene Lactone isolated from Inula aucheriana, has recently gained attraction in the therapeutic fields due to its anti-tumor properties. This study was designed to evaluate the effect of this agent on Acute Lymphoblastic Leukemia (ALL) cell lines, either as a monotherapy or in combination with Vincristine (VCR).

METHODS AND RESULTS: To determine the anti-leukemic effects of Britannin on ALL-derived cell lines and suggest a mechanism of action for the agent, we used MTT assay, Annexin-V/PI staining, ROS assay, and real-time PCR analysis. Moreover, by using a combination index (CI), we evaluated the synergistic effect of Britannin on Vincristine. We found that unlike normal Peripheral Blood Mononuclear Cells (PBMCs) and L929 cells, Britannin reduced the viability of NALM-6, REH, and JURKAT cells. Among tested cells, NALM-6 cells had the highest sensitivity to Britannin, and this agent was able to induce p21/p27-mediated G1 cell cycle arrest and Reactive Oxygen Specious (ROS)-mediated apoptotic cell death in this cell line. When NALM-6 cells were treated with Nacetyl-L-Cysteine (NAC), a scavenger of ROS, Britannin could induce neither apoptosis nor reduce the survival of the cells suggesting that the cytotoxic effect of Britannin is induced through ROS-dependent manner. Moreover, we found that a low dose of Britannin enhanced the effect of Vincristine in NALM-6 cells by inducing apoptotic cell death via altering the expression of apoptotic-related genes.

CONCLUSIONS: Overall, our results proposed a mechanism for the cytotoxic effect of Britannin, either as a single agent or in combination with Vincristine, in NALM-6 cells.}, } @article {pmid34474340, year = {2021}, author = {Liang, Y and Du, R and Chen, R and Chu, PH and Ip, MSM and Zhang, KYB and Mak, JCW}, title = {Therapeutic potential and mechanism of Dendrobium officinale polysaccharides on cigarette smoke-induced airway inflammation in rat.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {143}, number = {}, pages = {112101}, doi = {10.1016/j.biopha.2021.112101}, pmid = {34474340}, issn = {1950-6007}, mesh = {Animals ; Antioxidants/isolation & purification/*pharmacology ; *Dendrobium/chemistry ; Disease Models, Animal ; Inflammation Mediators/metabolism ; Lung/*drug effects/immunology/metabolism ; Male ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Phosphorylation ; Plant Extracts/isolation & purification/*pharmacology ; Pneumonia/etiology/immunology/metabolism/*prevention & control ; Polysaccharides/isolation & purification/*pharmacology ; Rats, Sprague-Dawley ; Signal Transduction ; Smoke/*adverse effects ; Tobacco Products/*adverse effects ; Rats ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide, and is characterized by persistent respiratory symptoms and airflow limitation due to chronic airway inflammation. Cigarette smoking is a major risk factor for COPD. This study aims to determine the therapeutic effects of polysaccharides extracted from Dendrobium officinale (DOPs), a valuable traditional Chinese Medicinal herb, on cigarette smoke (CS)-induced airway inflammation in a rat passive smoking model. Male Sprague-Dawley rats were exposed to CS or sham air (SA) as control for a 56-day period. On Day 29, rats were subdivided and given water, DOPs or N-acetylcysteine (NAC) via oral gavage on a daily basis for the remaining duration. DOPs reduced CS-induced oxidative stress as evidenced by reducing malondialdehyde (MDA) levels in the lung. DOPs also exerted potent anti-inflammatory properties as evidenced by a reduction in the number of lymphocytes and monocytes in serum, significantly attenuating infiltration of inflammatory cells in lung tissue, as well as pro-inflammatory mediators in serum, bronchoalveolar lavage (BAL) and lung. Additionally, DOPs inhibited the CS-induced activation of ERK, p38 MAPK and NF-κB signaling pathways. These findings suggest that DOPs may have potentially beneficial effects in limiting smoking-related lung oxidative stress, and inflammation mediated via the inhibition of MAPK and NF-κB signaling pathways in smokers, without or with COPD.}, } @article {pmid34466155, year = {2021}, author = {Jang, JH and Lee, TJ and Sung, EG and Song, IH and Kim, JY}, title = {Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP(L) expression and reducing Bcl-2 protein stability.}, journal = {Oncology letters}, volume = {22}, number = {4}, pages = {743}, pmid = {34466155}, issn = {1792-1082}, abstract = {Pioglitazone is an anti-diabetic agent used in the treatment of type 2 diabetes, which belongs to the thiazolidinediones (TZDs) group. TZDs target peroxisome proliferator-activated receptor γ (PPARγ), which functions as a transcription factor of the nuclear hormone receptor. Pioglitazone has antitumor effects in several cancer types and could be a tool for drug therapy in various cancer treatments. Nevertheless, the molecular basis for pioglitazone-induced anticancer effects in renal cancer (RC) has not yet been elucidated. Thus, the aim of the present study was to investigate the detailed signaling pathway underlying pioglitazone-induced apoptosis in Caki cells derived from human clear cell renal cell carcinoma. As a result, it was demonstrated by flow cytometry analysis and Annexin V-propidium iodide staining that pioglitazone treatment induced apoptotic cell death in a dose-dependent manner in Caki cells. The protein expression levels of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP)(L) and Bcl-2, which were determined by western blotting, decreased after pioglitazone treatment in Caki cells. Flow cytometry and western blot analyses demonstrated that pioglitazone-mediated apoptosis was blocked following pretreatment with the pan-caspase inhibitor, z-VAD-fmk, indicating that pioglitazone-induced apoptosis was mediated via a caspase-dependent signaling pathway. However, the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), did not affect pioglitazone-mediated apoptosis and degradation of c-FLIP(L) and Bcl-2 protein. Of note, it was found by western blot analysis that Bcl-2 protein expression was downregulated by the decreased protein stability of Bcl-2 in pioglitazone-treated Caki cells. In conclusion, these findings indicated that pioglitazone-induced apoptosis is regulated through caspase-mediated degradation of FLIP(L) and reduction of Bcl-2 protein stability, suggesting that pioglitazone is a feasible apoptotic agent that could be used in the treatment of human RC.}, } @article {pmid34464076, year = {2021}, author = {Pinto, RM and Monteiro, C and Costa Lima, SA and Casal, S and Van Dijck, P and Martins, MCL and Nunes, C and Reis, S}, title = {N-Acetyl-l-cysteine-Loaded Nanosystems as a Promising Therapeutic Approach Toward the Eradication of Pseudomonas aeruginosa Biofilms.}, journal = {ACS applied materials & interfaces}, volume = {13}, number = {36}, pages = {42329-42343}, doi = {10.1021/acsami.1c05124}, pmid = {34464076}, issn = {1944-8252}, mesh = {Acetylcysteine/chemistry/toxicity ; Animals ; Anti-Bacterial Agents/chemistry/*pharmacology/toxicity ; Biofilms/*drug effects ; Cell Line ; Drug Carriers/chemistry/*pharmacology/toxicity ; Drug Synergism ; Humans ; Liposomes/*chemistry/toxicity ; Mice ; Microbial Sensitivity Tests ; Moxifloxacin/pharmacology ; Nanoparticles/*chemistry/toxicity ; Palmitates/chemistry/toxicity ; Phosphatidylethanolamines/chemistry/toxicity ; Polyethylene Glycols/chemistry/toxicity ; Pseudomonas aeruginosa/*drug effects/physiology ; }, abstract = {Bacterial biofilms are a major health concern, mainly due to their contribution to increased bacterial resistance to well-known antibiotics. The conventional treatment of biofilms represents a challenge, and frequently, eradication is not achieved with long-lasting administration of antibiotics. In this context, the present work proposes an innovative therapeutic approach that is focused on the encapsulation of N-acetyl-l-cysteine (NAC) into lipid nanoparticles (LNPs) functionalized with d-amino acids to target and disrupt bacterial biofilms. The optimized formulations presented a mean hydrodynamic diameter around 200 nm, a low polydispersity index, and a high loading capacity. These formulations were stable under storage conditions up to 6 months. In vitro biocompatibility studies showed a low cytotoxicity effect in fibroblasts and a low hemolytic activity in human red blood cells. Nevertheless, unloaded LNPs showed a higher hemolytic potential than NAC-loaded LNPs, which suggests a safer profile of the latter. The in vitro antibiofilm efficacy of the developed formulations was tested against Staphylococcus epidermidis (Gram-positive) and Pseudomonas aeruginosa (Gram-negative) mature biofilms. The results showed that the NAC-loaded LNPs were ineffective against S. epidermidis biofilms, while a significant reduction of biofilm biomass and bacterial viability in P. aeruginosa biofilms were observed. In a more complex therapeutic approach, the LNPs were further combined with moxifloxacin, revealing a beneficial effect between the LNPs and the antibiotic against P. aeruginosa biofilms. Both alone and in combination with moxifloxacin, unloaded and NAC-loaded LNPs functionalized with d-amino acids showed a great potential to reduce bacterial viability, with no significant differences in the presence or absence of NAC. However, the presence of NAC in NAC-loaded functionalized LNPs shows a safer profile than the unloaded LNPs, which is beneficial for an in vivo application. Overall, the developed formulations present a potential therapeutic approach against P. aeruginosa biofilms, alone or in combination with antibiotics.}, } @article {pmid34456713, year = {2021}, author = {Ruiz-Torres, V and Forsythe, N and Pérez-Sánchez, A and Van Schaeybroeck, S and Barrajón-Catalán, E and Micol, V}, title = {A Nudibranch Marine Extract Selectively Chemosensitizes Colorectal Cancer Cells by Inducing ROS-Mediated Endoplasmic Reticulum Stress.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {625946}, pmid = {34456713}, issn = {1663-9812}, abstract = {The present study shows the putative antiproliferative mechanism of action of the previously analytically characterized nudibranch extract (Dolabella auricularia, NB) and its different effects in colon cancer cells vs. nontumor colon cells. NB extract increased the accumulation of reactive oxygen species (ROS) and increased endoplasmic reticulum (ER) stress via stimulation of the unfolded protein response. Stress scavengers, N-acetylcysteine (NAC) and 4-phenylbutyric acid (4-PBA), decreased the stress induced by NB. The results showed that NB extract increased ER stress through overproduction of ROS in superinvasive colon cancer cells, decreased their resistance threshold, and produced a nonreturn level of ER stress, causing DNA damage and cell cycle arrest, which prevented them from achieving hyperproliferative capacity and migrating to and invading other tissues. On the contrary, NB extract had a considerably lower effect on nontumor human colon cells, suggesting a selective effect related to stress balance homeostasis. In conclusion, our results confirm that the growth and malignancy of colon cancer cells can be decreased by marine compounds through the modification of one of the most potent resistance mechanisms present in tumor cells; this characteristic differentiates cancer cells from nontumor cells in terms of stress balance.}, } @article {pmid34455951, year = {2022}, author = {Rashid, M and Chandran, VP and Nair, S and Muthu, DS and Pappuraj, J and Jacob, KA and Sridhar, B and Mark, K and Hyder, S and Khan, S and Thunga, G}, title = {N-Acetyl Cysteine in Rodenticide Poisoning: A Systematic Review and Meta-Analysis.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {17}, number = {3}, pages = {192-204}, doi = {10.2174/2772432816666210825102726}, pmid = {34455951}, issn = {2772-4336}, mesh = {Acetylcysteine/therapeutic use ; Humans ; Prospective Studies ; Retrospective Studies ; *Rodenticides ; }, abstract = {BACKGROUND: Treatment with N-Acetyl Cysteine (NAC) in rodenticide poisoning has not been well established due to mixed study results and insufficient evidence. This review aimed to summarize the clinical benefits of NAC in the management of rodenticide poisoning.

METHODS: This review follows the PICOS framework and the PRISMA guidelines. Pub- Med/MEDLINE, Scopus, and the Cochrane library were searched to identify the published literature from inception to September 2020, and a reference search was performed for additional relevant studies. The English language studies addressing the use of NAC in rodenticide poisoning were considered for the review. We considered all experimental and observational studies due to the insufficient number of interventional studies.

RESULTS: Ten studies (two RCTs, four observational, and four descriptive) out of 2,178 studies with 492 participants were considered for the review. Only six studies (two RCTs, one prospective, and three retrospective studies) reported recovery and mortality. Pooled results of RCTs (n=2) showed a significant recovery rate (Odds Ratio [OR]: 3.97; 95% Confidence Interval [CI]:1.69-9.30), whereas summary estimates of prospective and retrospective studies recorded a non-significant effect. Metaanalysis of RCTs (OR: 0.25; 95% CI: 0.11-0.59; n=2) and retrospective studies (OR: 0.34; 95% CI: 0.15-0.78; n=3) showed a significant reduction in mortality, whereas pooled analysis of prospective studies recorded a non-significant effect. A significant reduction in intubation or ventilation (OR: 0.25; 95% CI: 0.11-0.60; 2 RCTs) and a non-significant (P=0.41) difference in duration of hospitalization was observed with NAC when compared to the non-NAC treated group. The quality of the included studies appeared to be moderate to high.

CONCLUSION: Our findings indicate that NAC showed better survival and lower mortality rate when compared to non-NAC treated group; hence NAC can be considered for the management of rodenticide poisoning.}, } @article {pmid34454534, year = {2021}, author = {Yang, M and Luo, Q and Chen, X and Chen, F}, title = {Bitter melon derived extracellular vesicles enhance the therapeutic effects and reduce the drug resistance of 5-fluorouracil on oral squamous cell carcinoma.}, journal = {Journal of nanobiotechnology}, volume = {19}, number = {1}, pages = {259}, pmid = {34454534}, issn = {1477-3155}, support = {81803088//National Natural Science Foundation of China/ ; 81870762//National Natural Science Foundation of China/ ; 20ZR1431500//Natural Science Foundation of Shanghai/ ; 19YF1427500//Shanghai Sailing Program/ ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy ; Cell Cycle ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/*drug effects ; Extracellular Vesicles/*metabolism ; Fluorouracil/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Head and Neck Neoplasms/drug therapy ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Momordica charantia/*metabolism ; Mouth Neoplasms/*drug therapy ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Squamous Cell Carcinoma of Head and Neck/*drug therapy ; }, abstract = {BACKGROUND: Plant-derived extracellular vesicles (PDEVs) have been exploited for cancer treatment with several benefits. Bitter melon is cultivated as a vegetable and folk medicine with anticancer and anti-inflammatory activities. 5-Fluorouracil (5-FU) is widely used for cancer treatment. However, 5-FU-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammation activation induced the resistance of oral squamous cell carcinoma (OSCC) cells to 5-FU. In this study, we explored the potential of bitter melon-derived extracellular vesicles (BMEVs) for enhancing the therapeutic efficacy and reduce the resistance of OSCC to 5-FU.

RESULTS: Herein, we demonstrate that bitter melon derived extracellular vesicles (BMEVs), in addition to their antitumor activity against OSCC have intrinsic anti-inflammatory functions. BMEVs induced S phase cell cycle arrest and apoptosis. Apoptosis induction was dependent on reactive oxygen species (ROS) production and JUN protein upregulation, since pretreatment with N-acetyl cysteine or catechin hydrate could prevent apoptosis and JUN accumulation, respectively. Surprisingly, BMEVs significantly downregulated NLRP3 expression, although ROS plays a central role in NLRP3 activation. We further assessed the underlying molecular mechanism and proposed that the RNAs of BMEVs, at least in part, mediate anti-inflammatory bioactivity. In our previous studies, NLRP3 activation contributed to the resistance of OSCC cells to 5-FU. Our data clearly indicate that BMEVs could exert a remarkable synergistic therapeutic effect of 5-FU against OSCC both in vitro and in vivo. Most notably, NLRP3 downregulation reduced the resistance of OSCC to 5-FU.

CONCLUSIONS: Together, our findings demonstrate a novel approach to enhance the therapeutic efficacy and reduce the drug resistance of cancer cells to chemotherapeutic agents, which provides proof-of-concept evidence for the future development of PDEVs-enhanced therapy.}, } @article {pmid34453856, year = {2022}, author = {Chi, RF and Li, L and Wang, AL and Yang, H and Xi, J and Zhu, ZF and Wang, K and Li, B and Yang, LG and Qin, FZ and Zhang, C}, title = {Enhanced oxidative stress mediates pathological autophagy and necroptosis in cardiac myocytes in pressure overload induced heart failure in rats.}, journal = {Clinical and experimental pharmacology & physiology}, volume = {49}, number = {1}, pages = {60-69}, doi = {10.1111/1440-1681.13583}, pmid = {34453856}, issn = {1440-1681}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Autophagy/drug effects ; Blood Pressure ; Echocardiography ; Heart Failure/metabolism/*pathology/physiopathology ; Male ; Myocytes, Cardiac/drug effects/metabolism/*pathology/physiology ; *Necroptosis/drug effects ; *Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Ventricular Dysfunction, Left ; }, abstract = {In cardiac myocytes in vitro, hydrogen peroxide induces autophagic cell death and necroptosis. Oxidative stress, myocyte autophagy and necroptosis coexist in heart failure (HF). In this study, we tested the hypothesis that excessive oxidative stress mediates pathological autophagy and necroptosis in myocytes in pressure overload-induced HF. HF was produced by chronic pressure overload induced by abdominal aortic constriction (AAC) in rats. Rats with AAC or sham operation were randomised to orally receive an antioxidant N-acetylcysteine (NAC) or placebo for 4 weeks. Echocardiography was performed for the assessments of left ventricular (LV) structure and function. AAC rats exhibited decreased LV fractional shortening (FS) at 4 weeks after surgery. NAC treatment attenuated decreased LV FS in AAC rats. In AAC rats, myocardial level of 8-hydroxydeoxyguanosine assessed by immunohistochemical staining, indicative of oxidative stress, was increased, LC3 II protein, a marker of autophagy, Beclin1 protein and Atg4b, Atg5, Atg7 and Atg12 mRNA expression were markedly increased, RIP1, RIP3 and MLKL expression, indicative of necroptosis, was increased, and all of the alterations in AAC rats were prevented by the NAC treatment. NAC treatment also attenuated myocyte cross-sectional area and myocardial fibrosis in AAC rats. In conclusion, NAC treatment prevented the increases in oxidative stress, myocyte autophagy and necroptosis and the decrease in LV systolic function in pressure overload-induced HF. These findings suggest that enhanced oxidative stress mediates pathological autophagy and necroptosis in myocytes, leading to LV systolic dysfunction, and antioxidants may be of value to prevent HF through the inhibition of excessive autophagy and necroptosis.}, } @article {pmid34448938, year = {2021}, author = {Cazzola, M and Rogliani, P and Salvi, SS and Ora, J and Matera, MG}, title = {Use of Thiols in the Treatment of COVID-19: Current Evidence.}, journal = {Lung}, volume = {199}, number = {4}, pages = {335-343}, pmid = {34448938}, issn = {1432-1750}, mesh = {COVID-19/epidemiology/metabolism ; Humans ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; SARS-CoV-2 ; Sulfhydryl Compounds/*pharmacology ; *COVID-19 Drug Treatment ; }, abstract = {There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients.}, } @article {pmid34445365, year = {2021}, author = {Paskal, W and Kopka, M and Stachura, A and Paskal, AM and Pietruski, P and Pełka, K and Woessner, AE and Quinn, KP and Galus, R and Wejman, J and Włodarski, P}, title = {Single Dose of N-Acetylcysteine in Local Anesthesia Increases Expression of HIF1α, MAPK1, TGFβ1 and Growth Factors in Rat Wound Healing.}, journal = {International journal of molecular sciences}, volume = {22}, number = {16}, pages = {}, pmid = {34445365}, issn = {1422-0067}, support = {MNiSW/2019/106/DIR/NN3//Ministerstwo Nauki i Szkolnictwa Wyższego/ ; 1M15/NM1/17//Warszawski Uniwersytet Medyczny/ ; }, mesh = {Acetylcysteine/*administration & dosage/pharmacology ; Anesthesia, Local ; Animals ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Hypoxia-Inducible Factor 1, alpha Subunit/*genetics ; Mitogen-Activated Protein Kinase 1/*genetics ; Oxidative Stress/drug effects ; Peroxidase/metabolism ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/*genetics ; Wound Healing/*drug effects ; }, abstract = {In this study, we aimed to investigate the influence of N-acetylcysteine (NAC) on the gene expression profile, neoangiogenesis, neutrophils and macrophages in a rat model of incisional wounds. Before creating wounds on the backs of 24 Sprague-Dawley rats, intradermal injections were made. Lidocaine-epinephrin solutions were supplemented with 0.015%, 0.03% or 0.045% solutions of NAC, or nothing (control group). Scars were harvested on the 3rd, 7th, 14th and 60th day post-surgery. We performed immunohistochemical staining in order to visualize macrophages (anti-CD68), neutrophils (anti-MPO) and newly formed blood vessels (anti-CD31). Additionally, RT-qPCR was used to measure the relative expression of 88 genes involved in the wound healing process. On the 14th day, the number of cells stained with anti-CD68 and anti-CD31 antibodies was significantly larger in the tissues treated with 0.03% NAC compared with the control. Among the selected genes, 52 were upregulated and six were downregulated at different time points. Interestingly, NAC exerted a significant effect on the expression of 45 genes 60 days after its administration. In summation, a 0.03% NAC addition to the pre-incisional anesthetic solution improves neovasculature and increases the macrophages' concentration at the wound site on the 14th day, as well as altering the expression of numerous genes that are responsible for the regenerative processes.}, } @article {pmid34443480, year = {2021}, author = {Cozma, V and Rosca, I and Radulescu, L and Martu, C and Nastasa, V and Varganici, CD and Ursu, EL and Doroftei, F and Pinteala, M and Racles, C}, title = {Antibacterial Polysiloxane Polymers and Coatings for Cochlear Implants.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {16}, pages = {}, pmid = {34443480}, issn = {1420-3049}, support = {PN-III-P4-ID-PCCF-2016-0050//Ministery of Research and Innovation, CNCS-UEFISCDI/ ; }, mesh = {Acetylcysteine/chemistry/pharmacology/therapeutic use ; Animals ; Anti-Bacterial Agents/*chemistry/pharmacology/therapeutic use ; Bacterial Adhesion/drug effects ; Biofilms/drug effects ; Coated Materials, Biocompatible/*chemistry/pharmacology/therapeutic use ; Cochlear Implants/adverse effects/*microbiology ; Otitis/*drug therapy ; Polymers/*chemistry/pharmacology/therapeutic use ; Rats, Wistar ; Siloxanes/*chemistry/pharmacology/therapeutic use ; Streptococcus pneumoniae/drug effects ; Sulfhydryl Compounds/chemistry ; Surface Properties ; Rats ; }, abstract = {Within this study, new materials were synthesized and characterized based on polysiloxane modified with different ratios of N-acetyl-l-cysteine (NAC) and crosslinked via UV-assisted thiol-ene addition, in order to obtain efficient membranes able to resist bacterial adherence and biofilm formation. These membranes were subjected to in vitro testing for microbial adherence against S. pneumoniae using standardized tests. WISTAR rats were implanted for 4 weeks with crosslinked siloxane samples without and with NAC. A set of physical characterization methods was employed to assess the chemical structure and morphological aspects of the new synthetized materials before and after contact with the microbiological medium.}, } @article {pmid34441854, year = {2021}, author = {Comino-Sanz, IM and López-Franco, MD and Castro, B and Pancorbo-Hidalgo, PL}, title = {The Role of Antioxidants on Wound Healing: A Review of the Current Evidence.}, journal = {Journal of clinical medicine}, volume = {10}, number = {16}, pages = {}, pmid = {34441854}, issn = {2077-0383}, abstract = {(1) Background: Reactive oxygen species (ROS) play a crucial role in the preparation of the normal wound healing response. Therefore, a correct balance between low or high levels of ROS is essential. Antioxidant dressings that regulate this balance are a target for new therapies. The purpose of this review is to identify the compounds with antioxidant properties that have been tested for wound healing and to summarize the available evidence on their effects. (2) Methods: A literature search was conducted and included any study that evaluated the effects or mechanisms of antioxidants in the healing process (in vitro, animal models or human studies). (3) Results: Seven compounds with antioxidant activity were identified (Curcumin, N-acetyl cysteine, Chitosan, Gallic Acid, Edaravone, Crocin, Safranal and Quercetin) and 46 studies reporting the effects on the healing process of these antioxidants compounds were included. (4) Conclusions: this review offers a map of the research on some of the antioxidant compounds with potential for use as wound therapies and basic research on redox balance and oxidative stress in the healing process. Curcumin, NAC, quercetin and chitosan are the antioxidant compounds that shown some initial evidence of efficacy, but more research in human is needed.}, } @article {pmid34440609, year = {2021}, author = {Liu, Z and Zhang, L and Liu, Y and Zhang, H and Chen, J and Feng, G and Yang, P and Sha, F and Cui, L and Sun, G}, title = {Identification of Compound CB-2 as a Novel Late-Stage Autophagy Inhibitor Exhibits Inhibitory Potency against A549 Cells.}, journal = {Life (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {34440609}, issn = {2075-1729}, support = {32070742 ;31471296//National Natural Science Foundation of China/ ; 192102310148;182102310270//Research Program for Science and Technology of Henan Province/ ; }, abstract = {Autophagy has been recognized as a stress tolerance mechanism that maintains cell viability, which contributes to tumor progression, dormancy, and treatment resistance. The inhibition of autophagy in cancer has the potential to improve the therapeutic efficacy. It is therefore of great significance to search for new autophagy inhibitors. In the present study, after screening a series of curcumin derivatives synthesized in our laboratory, (E)-3-((E)-4-chlorobenzylidene)-5-((5-methoxy-1H-indol-3-yl)methylene)-1-methylpiperidin-4-one (CB-2) was selected as a candidate for further study. We found that CB-2 increased the LC3B-II and SQSTM1 levels associated with the accumulation of autophagosomes in non-small cell lung cancer (NSCLC) A549 cells. The increased level of LC3B-II induced by CB-2 was neither eliminated when autophagy initiation was suppressed by wortmannin nor further increased when autophagosome degradation was inhibited by chloroquine (CQ). CB-2 enhanced the accumulation of LC3B-II under starvation conditions. Further studies revealed that CB-2 did not affect the levels of the key proteins involved in autophagy induction but significantly blocked the fusion of autophagosomes with lysosomes. High-dose CB-2 induced the apoptosis and necrosis of A549 cells, while a lower dose of CB-2 mainly impaired the migrative capacity of A549 cells, which only slightly induced cell apoptosis. CB-2 increased the levels of mitochondrial-derived reactive oxygen species (ROS) while decreasing the mitochondrial membrane potential (MMP). Scavenging ROS via N-acetylcysteine (NAC) reversed CB-2-induced autophagy inhibition and its inhibitory effect against A549 cells. In conclusion, CB-2 serves as a new late-stage autophagy inhibitor, which has a strong inhibitory potency against A549 cells.}, } @article {pmid34440602, year = {2021}, author = {Ko, YH and Jeong, M and Jang, DS and Choi, JH}, title = {Gomisin L1, a Lignan Isolated from Schisandra Berries, Induces Apoptosis by Regulating NADPH Oxidase in Human Ovarian Cancer Cells.}, journal = {Life (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {34440602}, issn = {2075-1729}, support = {NRF-2019R1A2C2011213//National Research Foundation of Korea/ ; }, abstract = {The fruits of Schisandra chinensis (Schisandra berries) are used as health food supplements and popular food ingredients in East Asia. Lignans, major and characteristic polyphenol compounds of Schisandra berries, possess various biological activities, including hepatoprotective and anticancer effects. However, the biological activities of gomisin L1, a lignan isolated from Schisandra berries, are less to be investigated. In this study, the antitumor activity of gomisin L1 and its underlying molecular mechanism in human ovarian cancer cells were investigated. Gomisin L1 exhibited potent cytotoxic activity against A2780 and SKOV3 ovarian cancer cells. Flow cytometry analysis revealed that the growth inhibitory effects of gomisin L1 were mediated by the induction of apoptosis. Furthermore, gomisin L1 induced an increase in intracellular reactive oxygen species (ROS) levels, and the antioxidant N-acetyl cysteine significantly negated gomisin L1-induced cell death. Moreover, inhibition of NADPH oxidase (NOX) using an inhibitor and siRNA attenuated gomisin L1-induced death of, and ROS production in, human ovarian cancer cells. Taken together, these data indicate that the lignan gomisin L1 from Schisandra berries induces apoptotic cell death by regulating intracellular ROS production via NOX.}, } @article {pmid34440143, year = {2021}, author = {Yan, M and Wang, Z and Xia, T and Jin, S and Liu, Y and Hu, H and Chang, Q}, title = {Enhancement of TEX264-Mediated ER-Phagy Contributes to the Therapeutic Effect of Glycycoumarin against APA Hepatotoxicity in Mice.}, journal = {Biomedicines}, volume = {9}, number = {8}, pages = {}, pmid = {34440143}, issn = {2227-9059}, support = {3332020048//Fundamental Research Funds for the Central Universities/ ; }, abstract = {Acetaminophen (APA)-induced hepatotoxicity is coupled with the activation of autophagy. We sought to determine whether selective autophagy of the endoplasmic reticulum (ER), termed ER-phagy, is involved in APA hepatotoxicity and to explore its potential as a therapeutic target for APA-induced liver injury (AILI). APA (300 or 600 mg/kg) was administered to male C57BL/6N mice, with and without rapamycin, glycycoumarin (GCM) and N-acetylcysteine (NAC). The results demonstrated that ER-phagy accompanied with ER stress was activated after APA overdose. The dynamic changes of LC3 and TEX264 revealed that ER-phagy was induced as early as 6 h and peaked at 24 h following the APA injection. A delayed treatment with GCM, but not rapamycin, considerably attenuated a liver injury and, consequently, reduced its mortality. This is probably due to the inhibition of ER stress and the acceleration of liver regeneration via enhanced ER-phagy. Unlike the impaired hepatocyte proliferation and more severe liver injury in mice that received prolonged treatment with NAC, liver recovery is facilitated by repeated treatment with GCM. These findings suggest that TEX264-mediated ER-phagy is a compensatory mechanism against ER stress provoked by an APA overdose. A delayed and prolonged treatment with GCM enhances ER-phagy, thus serving as a potential therapeutic approach for patients presenting at the late stage of AILI.}, } @article {pmid34439417, year = {2021}, author = {Botto, L and Bulbarelli, A and Lonati, E and Cazzaniga, E and Tassotti, M and Mena, P and Del Rio, D and Palestini, P}, title = {Study of the Antioxidant Effects of Coffee Phenolic Metabolites on C6 Glioma Cells Exposed to Diesel Exhaust Particles.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34439417}, issn = {2076-3921}, support = {ID 225155, CUP E47F17000020009//Regione Lombardia/ ; }, abstract = {The contributing role of environmental factors to the development of neurodegenerative diseases has become increasingly evident. Here, we report that exposure of C6 glioma cells to diesel exhaust particles (DEPs), a major constituent of urban air pollution, causes intracellular reactive oxygen species (ROS) production. In this scenario, we suggest employing the possible protective role that coffee phenolic metabolites may have. Coffee is a commonly consumed hot beverage and a major contributor to the dietary intake of (poly) phenols. Taking into account physiological concentrations, we analysed the effects of two different coffee phenolic metabolites mixes consisting of compounds derived from bacterial metabolization reactions or phase II conjugations, as well as caffeic acid. The results showed that these mixes were able to counteract DEP-induced oxidative stress. The cellular components mediating the downregulation of ROS included extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and uncoupling protein 2 (UCP2). Contrary to coffee phenolic metabolites, the treatment with N-acetylcysteine (NAC), a known antioxidant, was found to be ineffective in preventing the DEP exposure oxidant effect. These results revealed that coffee phenolic metabolites could be promising candidates to protect against some adverse health effects of daily exposure to air pollution.}, } @article {pmid34439408, year = {2021}, author = {Karmi, O and Sohn, YS and Marjault, HB and Israeli, T and Leibowitz, G and Ioannidis, K and Nahmias, Y and Mittler, R and Cabantchik, IZ and Nechushtai, R}, title = {A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34439408}, issn = {2076-3921}, support = {R01 GM111364/GM/NIGMS NIH HHS/United States ; NIDDK DK120986 (K.P.M.), DK101753 (K.P.M.), DK114464 (K.P.M.), and GM111364 (to R.M.)./NH/NIH HHS/United States ; }, abstract = {Decreased insulin secretion, associated with pancreatic β-cell failure, plays a critical role in many human diseases including diabetes, obesity, and cancer. While numerous studies linked β-cell failure with enhanced levels of reactive oxygen species (ROS), the development of diabetes associated with hereditary conditions that result in iron overload, e.g., hemochromatosis, Friedreich's ataxia, and Wolfram syndrome type 2 (WFS-T2; a mutation in CISD2, encoding the [2Fe-2S] protein NAF-1), underscores an additional link between iron metabolism and β-cell failure. Here, using NAF-1-repressed INS-1E pancreatic cells, we observed that NAF-1 repression inhibited insulin secretion, as well as impaired mitochondrial and ER structure and function. Importantly, we found that a combined treatment with the cell permeant iron chelator deferiprone and the glutathione precursor N-acetyl cysteine promoted the structural repair of mitochondria and ER, decreased mitochondrial labile iron and ROS levels, and restored glucose-stimulated insulin secretion. Additionally, treatment with the ferroptosis inhibitor ferrostatin-1 decreased cellular ROS formation and improved cellular growth of NAF-1 repressed pancreatic cells. Our findings reveal that suppressed expression of NAF-1 is associated with the development of ferroptosis-like features in pancreatic cells, and that reducing the levels of mitochondrial iron and ROS levels could be used as a therapeutic avenue for WFS-T2 patients.}, } @article {pmid34438950, year = {2021}, author = {Manoharan, A and Ognenovska, S and Paino, D and Whiteley, G and Glasbey, T and Kriel, FH and Farrell, J and Moore, KH and Manos, J and Das, T}, title = {N-Acetylcysteine Protects Bladder Epithelial Cells from Bacterial Invasion and Displays Antibiofilm Activity against Urinary Tract Bacterial Pathogens.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34438950}, issn = {2079-6382}, support = {IMCRC/WLY/08052019.1//Innovative Manufacturing CRC/ ; }, abstract = {Introduction: Urinary tract infections (UTIs) affect more than 150 million individuals annually. A strong correlation exists between bladder epithelia invasion by uropathogenic bacteria and patients with recurrent UTIs. Intracellular bacteria often recolonise epithelial cells post-antibiotic treatment. We investigated whether N-acetylcysteine (NAC) could prevent uropathogenic E. coli and E. faecalis bladder cell invasion, in addition to its effect on uropathogens when used alone or in combination with ciprofloxacin. Methods: An invasion assay was performed in which bacteria were added to bladder epithelial cells (BECs) in presence of NAC and invasion was allowed to occur. Cells were washed with gentamicin, lysed, and plated for enumeration of the intracellular bacterial load. Cytotoxicity was evaluated by exposing BECs to various concentrations of NAC and quantifying the metabolic activity using resazurin at different exposure times. The effect of NAC on the preformed biofilms was also investigated by treating 48 h biofilms for 24 h and enumerating colony counts. Bacteria were stained with propidium iodide (PI) to measure membrane damage. Results: NAC completely inhibited BEC invasion by multiple E. coli and E. faecalis clinical strains in a dose-dependent manner (p < 0.01). This was also evident when bacterial invasion was visualised using GFP-tagged E. coli. NAC displayed no cytotoxicity against BECs despite its intrinsic acidity (pH ~2.6), with >90% cellular viability 48 h post-exposure. NAC also prevented biofilm formation by E. coli and E. faecalis and significantly reduced bacterial loads in 48 h biofilms when combined with ciprofloxacin. NAC visibly damaged E. coli and E. faecalis bacterial membranes, with a threefold increase in propidium iodide-stained cells following treatment (p < 0.05). Conclusions: NAC is a non-toxic, antibiofilm agent in vitro and can prevent cell invasion and IBC formation by uropathogens, thus providing a potentially novel and efficacious treatment for UTIs. When combined with an antibiotic, it may disrupt bacterial biofilms and eliminate residual bacteria.}, } @article {pmid34438354, year = {2021}, author = {Bortolasci, CC and Turner, A and Mohebbi, M and Liu, ZS and Ashton, M and Gray, L and Marx, W and Walker, AJ and Kowalski, GM and Jacka, F and Berk, M and Dean, OM and Walder, K}, title = {Baseline serum amino acid levels predict treatment response to augmentation with N-acetylcysteine (NAC) in a bipolar disorder randomised trial.}, journal = {Journal of psychiatric research}, volume = {142}, number = {}, pages = {376-383}, doi = {10.1016/j.jpsychires.2021.08.034}, pmid = {34438354}, issn = {1879-1379}, mesh = {*Acetylcysteine/therapeutic use ; *Bipolar Disorder/drug therapy ; Depression ; Double-Blind Method ; Drug Therapy, Combination ; Humans ; Treatment Outcome ; }, abstract = {N-acetylcysteine (NAC) acts on glutamatergic and redox systems, two systems implicated in the pathophysiology of bipolar disorder (BD). This has led to the investigation of NAC as a potential candidate for the treatment of BD. The aim of this study was to investigate metabolomic markers to identify predictors of NAC response in a cohort of BD participants. This study is a secondary analysis of a 16-week, multi-site, randomized, double-blinded, parallel-group, placebo-controlled trial in BD participants with a current acute depressive episode. This study included trial participants who received either NAC 2000 mg/day, or placebo. Participants (NAC: n = 31, placebo: n = 29) were assessed at baseline and week 16 using the Montgomery Åsberg Depression Rating Scale (MADRS) and were dichotomised into "responders" (MADRS at week 16 < 50% of MADRS at baseline) and "non-responders" (MADRS at week 16 > 50% at baseline). Untargeted gas chromatography-mass spectrometry analysis was performed to analyse baseline levels of 68 serum metabolites. Of the nine metabolites that differentiated placebo and NAC groups, five were amino acids with lower levels in the NAC responder group compared with the NAC non-responders. Further analysis generated a predictive model of MADRS improvement including glycine, norleucine, threonine, proline, phenylalanine, tyrosine, glutamic acid, lysine and leucine (R[2] = 0.853; adjusted R[2] = 0.733). This prediction model predicted 85% of the variance in MADRS outcome after adjunctive treatment with NAC. BD participants with lower serum levels of free amino acids at baseline may be more likely to respond to adjunctive treatment with NAC.}, } @article {pmid34434429, year = {2021}, author = {Affas, S and Ayas, MF and Kassab, IA}, title = {Use of N-Acetylcysteine in Amphetamine-Induced Acute Liver Failure.}, journal = {Journal of medical cases}, volume = {12}, number = {2}, pages = {54-56}, pmid = {34434429}, issn = {1923-4155}, abstract = {Acute liver failure (ALF) is a serious complication of many drugs. Amongst recreational drugs, cocaine, amphetamines and ecstasy (methylenedioxymethamphetamine) have been known to cause ALF as a complication. However, the true effects and management on the liver of such cases have not been well reported and treatment of such conditions needs prompt action. N-acetylcysteine (NAC) is a known hepatoprotective agent but remains controversial in the use of recreational drug-induced acute liver injury. We present a case of ALF secondary to amphetamine ingestion, with a rapid recovery after administration of intravenous NAC.}, } @article {pmid34433910, year = {2021}, author = {Qiu, P and Hou, W and Wang, H and Lei, KKW and Wang, S and Chen, W and Pardeshi, LA and Prothro, K and Shukla, Y and Su, SSM and Schrump, DS and Chen, Q and Deng, CX and Xu, X and Wang, R}, title = {Sirt1 deficiency upregulates glutathione metabolism to prevent hepatocellular carcinoma initiation in mice.}, journal = {Oncogene}, volume = {40}, number = {41}, pages = {6023-6033}, pmid = {34433910}, issn = {1476-5594}, support = {ZIA BC011115/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Glutathione/*metabolism ; Liver Neoplasms, Experimental/*metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Sirtuin 1/*deficiency/metabolism ; Up-Regulation ; }, abstract = {Sirtuin-1 (SIRT1) is involved in various metabolic pathways, including fatty acid synthesis and gluconeogenesis in the liver. However, its role in initiation and progression of liver cancer remains unclear. Studying Sirt1 liver-specific knockout (LKO) mice in combination with diethylnitrosamine (DEN) treatment, we demonstrated that loss of Sirt1 rendered mice resistant to DEN-induced hepatocellular carcinoma (HCC) development. RNA-seq revealed that livers from LKO mice exhibited an enrichment in glutathione metabolism eight months after DEN challenge. Sirt1 deficiency elevated the expression of glutathione-s-transferase family genes by increasing the level of Nrf2, a key regulator of glutathione metabolism. Hence, LKO livers displayed a reductive environment with an increased ratio of GSH to GSSG and an elevated GSH level. Furthermore, using CRISPR knockout techniques, we confirmed that the impairment of HCC formation in LKO mice is mainly dependent on NRF2 signaling. Meanwhile, HCC induced by DEN could be blocked by the administration of N-acetyl cysteine (NAC) when administered one month after DEN challenge. However, NAC treatment starting five months after DEN injection was not able to prevent tumor development. In conclusion, our findings indicate that a reductive environment orchestrated by glutathione metabolism at an early stage can prevent the initiation of HCC.}, } @article {pmid34431675, year = {2021}, author = {You, Y and Wang, X and Ma, K and Li, J and Peng, Y and Zheng, J}, title = {Metabolic Activation of Atomoxetine Mediated by Cytochrome P450 2D6.}, journal = {Chemical research in toxicology}, volume = {34}, number = {9}, pages = {2135-2144}, doi = {10.1021/acs.chemrestox.1c00216}, pmid = {34431675}, issn = {1520-5010}, mesh = {Activation, Metabolic ; Animals ; Atomoxetine Hydrochloride/analogs & derivatives/analysis/*metabolism ; Cytochrome P-450 CYP2D6/*metabolism ; Glutathione/analogs & derivatives/analysis ; Hydroxylation ; Male ; Microsomes, Liver/metabolism ; Oxidation-Reduction ; Rats, Sprague-Dawley ; Rats ; }, abstract = {Atomoxetine (ATX) is a neurological drug widely used for the treatment of attention deficit-hyperactivity disorder. Liver injury has been documented in patients administered ATX. The mechanism of ATX's toxic action is less clear. This study is aimed to characterize reactive metabolites of ATX in vitro and in vivo to assist our understanding of the mechanisms of ATX hepatotoxicity. A hydroxylated metabolite, along with an O-dealkylation metabolite, was found in ATX-supplemented rat liver microsome incubations. Additionally, two glutathione (GSH) conjugates and two N-acetylcysteine (NAC) conjugates were observed in rat liver microsome incubations containing ATX, NADPH, and GSH or NAC. The corresponding GSH conjugates and NAC conjugates were found in bile and urine of ATX-treated rats, respectively. Recombinant P450 enzyme incubation study demonstrated that CYP2D6 dominated the metabolic activation of ATX. The insights gained from this study may be of assistance to illuminate the mechanisms of ATX-induced hepatotoxicity.}, } @article {pmid34425836, year = {2021}, author = {Niu, J and Wang, J and Zhang, Q and Zou, Z and Ding, Y}, title = {Cinobufagin-induced DNA damage response activates G2/M checkpoint and apoptosis to cause selective cytotoxicity in cancer cells.}, journal = {Cancer cell international}, volume = {21}, number = {1}, pages = {446}, pmid = {34425836}, issn = {1475-2867}, support = {(20180101237JC//Natural Science Foundation of Jilin Province/ ; }, abstract = {BACKGROUND: Processed extracts from toad skin and parotoid gland have long been used to treat various illnesses including cancer in many Asian countries. Recent studies have uncovered a family of bufadienolides as the responsible pharmacological compounds, and the two major molecules, cinobufagin and bufalin, have been shown to possess robust antitumor activity; however, the underlying mechanisms remain poorly understood.

METHODS: Intracellular reactive oxygen species (ROS) were measured by DCFH-DA staining and flow cytometry, and DNA damage was analyzed by immunofluorescent staining and the alkaline comet assay. Cytotoxicity was measured by MTT as well as colony formation assays, and cell cycle and apoptosis were analyzed by flow cytometry. In addition, apoptosis was further characterized by TUNEL and mitochondrial membrane potential assays.

RESULTS: Here we showed that sublethal doses of cinobufagin suppressed the viability of many cancer but not noncancerous cell lines. This tumor-selective cytotoxicity was preceded by a rapid, cancer-specific increase in cellular ROS and was significantly reduced by the ROS inhibitor N-acetyl cysteine (NAC), indicating oxidative stress as the primary source of cinobufagin-induced cancer cell toxicity. Sublethal cinobufagin-induced ROS overload resulted in oxidative DNA damage and intense replication stress in cancer cells, leading to strong DNA damage response (DDR) signaling. Subsequent phosphorylation of CDC25C and stabilization of p53 downstream of DDR resulted in activation of the G2/M checkpoint followed by induction of apoptosis. These data indicate that cinobufagin suppresses cancer cell viability via DDR-mediated G2 arrest and apoptosis.

CONCLUSION: As elevated oxidative pressure is shared by most cancer cells that renders them sensitive to further oxidative insult, these studies suggest that nontoxic doses of cinobufagin can be used to exploit a cancer vulnerability for induction of cancer-specific cytotoxicity.}, } @article {pmid34425541, year = {2021}, author = {Li, S and Cao, Y and Pan, Q and Xiao, Y and Wang, Y and Wang, X and Li, X and Li, Q and Tang, X and Ran, B}, title = {Neonicotinoid insecticides triggers mitochondrial bioenergetic dysfunction via manipulating ROS-calcium influx pathway in the liver.}, journal = {Ecotoxicology and environmental safety}, volume = {224}, number = {}, pages = {112690}, doi = {10.1016/j.ecoenv.2021.112690}, pmid = {34425541}, issn = {1090-2414}, abstract = {Extensive use of neonicotinoids insecticides (NNIs) rapidly garnered widespread attention in the toxicology, since they have been found in human samples, including urine, blood, breast milk and hair. However, the precise mechanism is not completely clear regarding the NNIs-induced hepatotoxicity. In this study, we exposed male mice to three neonicotinoids (dinotefuran (DIN), nitenpyram (NIT) and acetamiprid (ACET) for 30 days. Our results showed that NNIs remarkably induced morphological damage in the liver. Simultaneously, we found that three neonicotinoids could activate the store operated Ca[2+] entry (SOCE) in the liver. Further results confirmed that reactive oxide species (ROS) scavenger n-acetylcysteine (NAC) attenuated DIN-induced calcium ion (Ca[2+]) overload and S-phase arrest via restoring protein expression of SOCE and S phase related genes in L02 hepatocytes. Moreover, we found that NAC obviously combated mitochondrial dysfunction caused by DIN via restoring mitochondrial membrane potential. Meanwhile, DIN treatment significantly increased pyruvate content, impaired the activities of tricarboxylic acid (TCA) cycle rate-limiting enzymes and inhibited adenosine triphosphate (ATP) generation, but these effects were reversed by Serca specific activator CDN1163. Collectively, perturbation of redox states can be recognized as the center of S-phase arrest and Ca[2+] overload after NNIs exposure. In this regard, Ca[2+] homeostasis dysregulation is a causative event of mitochondrial bioenergetic dysfunction in the liver. These data provides a new perspective for understanding NNI-induced hepatotoxicity mechanisms.}, } @article {pmid34425170, year = {2021}, author = {Osman, KA and Ezz El-Din, EM and Ahmed, NS and El-Seedy, AS}, title = {Effect of N-acetylcysteine on attenuation of chlropyrifos and its methyl analogue toxicity in male rats.}, journal = {Toxicology}, volume = {461}, number = {}, pages = {152904}, doi = {10.1016/j.tox.2021.152904}, pmid = {34425170}, issn = {1879-3185}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/metabolism ; Chlorpyrifos/*analogs & derivatives/chemistry/toxicity ; Cholinesterase Inhibitors/chemistry/toxicity ; Chromosome Aberrations/chemically induced ; Cytochromes c/metabolism ; Erythrocytes/drug effects ; Lipid Peroxidation/drug effects ; Male ; Mutagenicity Tests ; Nitric Oxide/blood ; Pesticides/chemistry/*toxicity ; Rats ; }, abstract = {The attenuating effect of 150 mg/kg of N-acetylcysteine (NAC) against the oral administration of 7.88 and 202.07 mg/kg/day for 14 days of either chlropyrifos-ethyl (CPE-E) or chlropyrifos-methyl (CPF-M), respectively, in male rat was investigated using biochemical and genetic markers. Biomarkers such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), paraoxonase (PON), adenosine 5'-triphosphatase (ATP-ase), glutathione-S-transferase (GST), catalase (CAT), glutathione reduced (GSH) in serum showed a significant decline in their levels, while calcium (Ca[+2]), cytochrome C reduction (CYC-R), lipid peroxidation (LPO), nitric oxide (NO) levels showed a significant increase in serum of treated rats. Regarding the genotoxic parameters, when rats are treated either with CPE-E or CPF-M, liver DNA, chromosomal aberration (CA), and micronucleated polychromatic erythrocytes (MnPCE) significantly increased, while the mitotic index (MI) and polychromatic erythrocytes (PCE)/ normochromatic erythrocytes (NCE) ratio were significantly decreased. However, the administration of NAC following the intoxication of CPF-E or CPF-M attenuated the tested biochemical and genotoxic markers. It can be concluded that NAC can be used to ameliorate the toxicity of certain organophosphorus compounds such as CPF-E and CPF-M.}, } @article {pmid34424746, year = {2021}, author = {Li, J and Navarro, MA and Uzal, FA and McClane, BA}, title = {NanI Sialidase Contributes to the Growth and Adherence of Clostridium perfringens Type F Strain F4969 in the Presence of Adherent Mucus.}, journal = {Infection and immunity}, volume = {89}, number = {11}, pages = {e0025621}, pmid = {34424746}, issn = {1098-5522}, support = {R21 AI125796/AI/NIAID NIH HHS/United States ; R21 AI140010/AI/NIAID NIH HHS/United States ; R21 AI148911/AI/NIAID NIH HHS/United States ; }, mesh = {Bacterial Adhesion/*physiology ; Caco-2 Cells ; Clostridium perfringens/growth & development/*physiology ; HT29 Cells ; Humans ; Intestines/*microbiology ; Mucus/*physiology ; Neuraminidase/*physiology ; Virulence Factors/physiology ; }, abstract = {Clostridium perfringens type F strains causing nonfoodborne human gastrointestinal diseases (NFD) typically produce NanI sialidase as their major secreted sialidase. Type F NFDs can persist for several weeks, indicating their pathogenesis involves intestinal colonization, including vegetative cell growth and adherence, with subsequent sporulation that fosters enterotoxin production and release. We previously reported that NanI contributes to type F NFD strain adherence and growth using Caco-2 cells. However, Caco-2 cells make minimal amounts of mucus, which is significant because the intestines are coated with adherent mucus. Therefore, it was important to assess if NanI contributes to the growth and adherence of type F NFD strains in the presence of adherent mucus. Consequently, the current study first demonstrated greater growth of nanI-carrying versus non-nanI-carrying type F strains in the presence of HT29-MTX-E12 cells, which produce an adherent mucus layer, versus their parental HT29 cells, which make minimal mucus. Demonstrating the specific importance of NanI for this effect, type F NFD strain F4969 or a complementing strain grew and adhered better than an isogenic nanI null mutant in the presence of HT29-MTX-E12 cells versus HT29 cells. Those effects involved mucus production by HT29-MTX-E12 cells since mucus reduction using N-acetyl cysteine reduced F4969 growth and adherence. Consistent with those in vitro results, NanI contributed to growth of F4969 in the mouse small intestine. By demonstrating a growth and adherence role for NanI in the presence of adherent mucus, these results further support NanI as a potential virulence factor during type F NFDs.}, } @article {pmid34422872, year = {2021}, author = {Wang, ML and Yin, XJ and Li, XL and Wang, FD and Zhou, J and Tao, YC and Wang, YH and Wu, DB and Chen, EQ}, title = {Retrospective Analysis of the Clinical Efficacy of N-Acetylcysteine in the Treatment of Hepatitis B Virus Related Acute-on-Chronic Liver Failure.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {724224}, pmid = {34422872}, issn = {2296-858X}, abstract = {Objective: HBV-related acute-on-chronic liver failure (HBV-ACLF) has a high mortality due to severe intrahepatic cholestasis and coagulation dysfunction, thus new treatment measures are urgently needed to improve the therapeutic effect. This study aimed to observe the efficacy of N-acetylcysteine (NAC) in the treatment of HBV-ACLF. Methods: The data of patients with HBV-ACLF admitted to West China Hospital from October 2019 to August 2020 were collected retrospectively, and they were divided into treatment group and control group according to whether they had received additional NAC treatment. The improvement of biochemistry, coagulation function and disease severity score after 14 days of hospitalization were analyzed between two groups. Results: A total of 90 HBV-ACLF patients were included, including 42 patients in treatment group and 48 patients in control group. Compared with baseline, serum TBil, DBil, TBA, GGT and ALP in two groups both decreased significantly, while PTA increased significantly. Interesting, the decrease of serum TBil, DBil and TBA and the increase of PTA in treatment group were all significantly than these in control group. Additionally, more patients in treatment group than control group changed from CTP grade C to grade B. Subgroup analysis of CTP grade C patients showed that the decrease of serum TBil, DBil and TBA and the increase of PTA in treatment group were significantly than these in control group. Conclusion: The NAC treatment may help to improve intrahepatic cholestasis and coagulation dysfunction of HBV-ACLF.}, } @article {pmid34420083, year = {2021}, author = {Akakpo, JY and Jaeschke, MW and Ramachandran, A and Curry, SC and Rumack, BH and Jaeschke, H}, title = {Delayed administration of N-acetylcysteine blunts recovery after an acetaminophen overdose unlike 4-methylpyrazole.}, journal = {Archives of toxicology}, volume = {95}, number = {10}, pages = {3377-3391}, pmid = {34420083}, issn = {1432-0738}, support = {DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; GM103549/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; DK102142/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; GM118247/GM/NIGMS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK1200194/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration & dosage/*pharmacology ; Animals ; Antidotes/administration & dosage/*pharmacology ; Cell Proliferation/drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; Drug Overdose/drug therapy ; Fomepizole/administration & dosage/*pharmacology ; Hepatocytes/drug effects/pathology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Time Factors ; }, abstract = {N-acetylcysteine (NAC) is the only clinically approved antidote against acetaminophen (APAP) hepatotoxicity. Despite its efficacy in patients treated early after APAP overdose, NAC has been implicated in impairing liver recovery in mice. More recently, 4-methylpyrazole (4MP, Fomepizole) emerged as a potential antidote in the mouse APAP hepatotoxicity model. The objective of this manuscript was to verify the detrimental effect of NAC and its potential mechanism and assess whether 4MP has the same liability. C57BL/6J mice were treated with 300 mg/kg APAP; 9 h after APAP and every 12 h after that, the animals received either 100 mg/kg NAC or 184.5 mg/kg 4MP. At 24 or 48 h after APAP, parameters of liver injury, mitochondrial biogenesis and cell proliferation were evaluated. Delayed NAC treatment had no effect on APAP-induced liver injury at 24 h but reduced the decline of plasma ALT activities and prevented the shrinkage of the areas of necrosis at 48 h. This effect correlated with down-regulation of key activators of mitochondrial biogenesis (AMPK, PGC-1α, Nrf1/2, TFAM) and reduced expression of Tom 20 (mitochondrial mass) and PCNA (cell proliferation). In contrast, 4MP attenuated liver injury at 24 h and promoted recovery at 48 h, which correlated with enhanced mitochondrial biogenesis and hepatocyte proliferation. In human hepatocytes, 4MP demonstrated higher efficacy in preventing cell death compared to NAC when treated at 18 h after APAP. Thus, due to the wider treatment window and lack of detrimental effects on recovery, it appears that at least in preclinical models, 4MP is superior to NAC as an antidote against APAP overdose.}, } @article {pmid36457967, year = {2022}, author = {Chang, PH and Liu, CW and Hung, SH and Kang, YN}, title = {Effect of N-acetyl-cysteine in prevention of noise-induced hearing loss: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Archives of medical science : AMS}, volume = {18}, number = {6}, pages = {1535-1541}, pmid = {36457967}, issn = {1734-1922}, abstract = {INTRODUCTION: Noise-induced hearing loss is one of the most prevalent causes of hearing impairment and occupational diseases. Although multiple factors lead to noise-induced hearing loss, prevention and protection strategies remain limited. Studies in the past decade have employed antioxidants, especially N-acetyl-cysteine, to prevent noise-induced hearing loss. Therefore, this systematic review and meta-analysis of randomized controlled trials evaluated the effect of N-acetyl-cysteine on the prevention of noise-induced hearing loss.

MATERIAL AND METHODS: This systematic review and meta-analysis included relevant studies from the Cochrane Library, EMBASE, PubMed, ScienceDirect, Scopus, and Web of Science by using related terms. The study only included randomized controlled trials in meta-analyses and assessed the quality of the identified randomized controlled trials by using the Cochrane Risk of Bias tool. Two authors extracted and calculated data on characteristics and hearing threshold. The results are presented as weighted mean difference (WMD) with 95% confidence interval (CI).

RESULTS: This study identified five randomized controlled trials that randomized 1,115 patients into N-acetyl-cysteine and control groups. The meta-analysis evidenced that N-acetyl-cysteine has greater protective effects against hearing threshold shifts than the control in the 0 to 4 kHz (WMD = -3.39, 95% CI: -6.56 to -0.22) and 0 to 6 kHz (MD = -3.49, 95% CI: -6.57 to -0.41) subgroups.

CONCLUSIONS: The present review and meta-analysis recommends that N-acetyl-cysteine may be considered as an option for protective therapy for noise-induced hearing loss. Nonetheless, larger randomized controlled trials are requisite for further investigation and verification.}, } @article {pmid34909640, year = {2020}, author = {Abdoli, N and Sadeghian, I and Mousavi, K and Azarpira, N and Ommati, MM and Heidari, R}, title = {Suppression of cirrhosis-related renal injury by N-acetyl cysteine.}, journal = {Current research in pharmacology and drug discovery}, volume = {1}, number = {}, pages = {30-38}, pmid = {34909640}, issn = {2590-2571}, abstract = {Cirrhosis-induced renal injury or cholemic nephropathy (CN) is a serious clinical complication with poor prognosis. CN could finally lead to renal failure and the need for organ transplantation. Unfortunately, there is no specific pharmacological intervention against CN to date. On the other hand, various studies mentioned the role of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to evaluate the potential protective effects of NAC as a thiol-reducing agent and antioxidant in CN. Bile duct ligation (BDL) was used as a reliable animal model of cholestasis. BDL animals received NAC (0.25% and 1% w: v) in drinking water for 28 consecutive days. Finally, urine, blood, and kidney samples were collected and analyzed. Significant elevation in serum biomarkers of renal injury, along with urine markers of kidney damage, was evident in the BDL group. Moreover, markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, and increased oxidized glutathione (GSSG) were evident detected in the kidney of cholestatic rats. Renal tissue antioxidant capacity and reduced glutathione (GSH) were also significantly depleted in the BDL group. Significant mitochondrial depolarization, depleted ATP content, and mitochondrial permeabilization was also detected in mitochondria isolated from the kidney of cholestatic animals. Renal histopathological alterations consisted of significant tissue fibrosis, interstitial inflammation, and tubular atrophy. It was found that NAC (0.25 and 1% in drinking water for 28 consecutive days) blunted histopathological changes, decreased markers of oxidative stress, and improved mitochondrial indices in the kidney of cirrhotic rats. Moreover, serum and urine biomarkers of renal injury were also mitigated in upon NAC treatment. These data indicate a potential renoprotective role for NAC in cholestasis. The effects of NAC on cellular redox state and mitochondrial function seem to play a fundamental role in its renoprotective effects during CN.}, } @article {pmid36704111, year = {2020}, author = {Abu Hasna, A and Khoury, RD and Toia, CC and Gonçalves, GB and de Andrade, FB and Talge Carvalho, CA and Ribeiro Camargo, CH and Carneiro Valera, M}, title = {In vitro Evaluation of the Antimicrobial Effect of N-acetylcysteine and Photodynamic Therapy on Root Canals Infected with Enterococcus faecalis.}, journal = {Iranian endodontic journal}, volume = {15}, number = {4}, pages = {236-245}, pmid = {36704111}, issn = {2008-2746}, abstract = {INTRODUCTION: This study aimed to evaluate the in vitro effectiveness of N-acetylcysteine (NAC), photodynamic therapy (PDT) and NAC with supplemental PDT in optimizing the removal of bacteria from infected dentinal tubules of root canals infected with Enterococcus (E.) faecalis biofilm.

METHODS AND MATERIALS: Eighty human teeth were randomly divided into 5 groups (n=16) according to the intracanal medication used: saline solution (control); calcium hydroxide (CH); NAC; PDT; NAC+PDT. Ten samples from each group were prepared for microbiological culture analysis (CFU/mL) and were inoculated with E. faecalis suspension for 21 days for biofilm development; the other six samples from each group were prepared for scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) and submitted to a 5-days contamination protocol including eight centrifugation cycles on every other day for dentinal tubules infection. For antimicrobial activity analysis by microbiological culture (CFU/mL), the root canals were contaminated with E. faecalis biofilm, instrumented and then medicated according to the experimental groups. Three samples were collected from the root canals: after 21-days of contamination, immediately after the instrumentation and 14-days after the medication according to the experimental groups. The morphology of E. faecalis biofilm on the root canal walls and bacterial cells viability were assessed by means of SEM and CLSM, respectively. One-way ANOVA and Repeated Measures ANOVA tests were used to analyze the obtained data statistically.

RESULTS: CFU/mL analysis showed that CH, NAC and NAC+PDT promoted greater antibacterial activity with statistically significant difference compared to saline solution and PDT (P<0.0001). However, saline solution and PDT were statistically similar (P>0.07). Illustrative images by SEM confirmed partially the CFU/mL results. CLSM showed that all groups were effective eliminating E. faecalis except for the saline solution group.

CONCLUSIONS: Based on this in vitro study NAC was bactericidal against E. faecalis biofilms regardless PDT stimulation, presenting similar antimicrobial activity to CH.}, } @article {pmid34752548, year = {2020}, author = {Phelps, MK and Olson, LM and Patel, MAVB and Thompson, MJ and Murphy, CV}, title = {Nebulized Heparin for Adult Patients With Smoke Inhalation Injury: A Review of the Literature.}, journal = {The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians}, volume = {36}, number = {4}, pages = {130-140}, pmid = {34752548}, issn = {8755-1225}, abstract = {Objective: To review the clinical effects of nebulized heparin and N-acetylcysteine (NAC) in patients with smoke inhalation injury (IHI) and provide recommendations for use. Data Sources: A search of PubMed, MEDLINE, and Scopus databases was completed from database inception through April 15, 2020, using terms: heparin, acetylcysteine, smoke inhalation injury, and burn injury. Study Selection and Data Extraction: All studies pertaining to efficacy and safety of nebulized heparin and/or NAC for IHI in adult patients were evaluated. Reference lists were reviewed for additional publications. Nonhuman studies, non-English, and case report publications were excluded. Data Synthesis: Eight studies were included. Four demonstrated positive outcomes, 3 demonstrated no benefit or possible harm, and 1 assessed safety. Supporting trials treated patients within 48 hours of injury with 10 000 units of nebulized heparin with NAC for 7 days or until extubation. Two trials with negative findings treated patients within 72 hours, or unspecified, with 5000 units of nebulized heparin with NAC for 7 days, while the third used 25 000 units within 36 hours but was grossly underpowered for analysis. Clinical findings include reduced duration of mechanical ventilation and improved lung function with possible increase risk of pneumonia and no evidence of increased bleeding risk. Conclusions: Nebulized heparin may improve oxygenation and reduce duration of mechanical ventilation in IHI. If nebulized heparin is used, 10 000 units every 4 hours alternating with NAC and albuterol at 4-hour intervals is recommended. Sterile technique should be emphasized. Monitoring for bronchospasm or new-onset pneumonia should be considered.}, } @article {pmid34909638, year = {2020}, author = {Ommati, MM and Farshad, O and Niknahad, H and Mousavi, K and Moein, M and Azarpira, N and Mohammadi, H and Jamshidzadeh, A and Heidari, R}, title = {Oral administration of thiol-reducing agents mitigates gut barrier disintegrity and bacterial lipopolysaccharide translocation in a rat model of biliary obstruction.}, journal = {Current research in pharmacology and drug discovery}, volume = {1}, number = {}, pages = {10-18}, pmid = {34909638}, issn = {2590-2571}, abstract = {It has been well documented that cirrhosis is associated with the intestinal injury. Intestinal injury in cirrhosis could lead to bacterial lipopolysaccharide (LPS) translocation to the systemic circulation. It has been found that high plasma LPS is connected with higher morbidity and mortality in cirrhotic patients. Therefore, finding therapeutic approaches to mitigate this complication has great clinical value. Several investigations mentioned the pivotal role of oxidative stress in cirrhosis-associated intestinal injury. It has been well-known that the redox balance of enterocytes is disturbed in cirrhotic patients. In the current study, the effects of thiol-reducing agents N-acetylcysteine (NAC) (0.5 and 1% w: v) and dithiothreitol (DTT) (0.5 and 1% w: v) on biomarkers of oxidative stress, tissue histopathological alterations, and LPS translocation is investigated in a rat model of cirrhosis. Bile duct ligation (BDL) surgery was used to induce cirrhosis in male Sprague-Dawley rats. Animals (n = 48; 8 animals/group) were supplemented with NAC and DTT for 28 consecutive days. Significant changes in ileum and colon markers of oxidative stress were evident in BDL rats as judged by increased reactive oxygen species (ROS), lipid peroxidation, oxidized glutathione (GSSG), and protein carbonylation along with decreased antioxidant capacity and glutathione (GSH) content. Blunted villus, decreased villus number, and inflammation was also detected in the intestine of BDL animals. Moreover, serum LPS level was also significantly higher in BDL rats. NAC and DTT administration (0.5 and 1% w: v, gavage) significantly decreased biomarkers of oxidative stress, mitigated intestinal histopathological alterations, and restored tissue antioxidant capacity. Moreover, NAC and/or DTT significantly suppressed LPS translocation to the systemic circulation. The protective effects of thiol reducing agents in the intestine of cirrhotic rats could be attributed to the effect of these chemicals on the cellular redox environment and biomarkers of oxidative stress.}, } @article {pmid35519466, year = {2019}, author = {Bala Subramaniyan, S and Veerappan, A}, title = {Water soluble cadmium selenide quantum dots for ultrasensitive detection of organic, inorganic and elemental mercury in biological fluids and live cells.}, journal = {RSC advances}, volume = {9}, number = {39}, pages = {22274-22281}, pmid = {35519466}, issn = {2046-2069}, abstract = {Mercury exists in organic, inorganic, and elemental forms; all of them are highly toxic. A sensor which could detect all forms of mercury below the permissible level in environmental and biological samples would be advantageous. A facile method to synthesize N-acetyl cysteine capped cadmium selenide quantum dots (CdSe QDs) with an emission at 554 nm was reported. CdSe QDs showed high sensitivity and selectivity toward Hg in aqueous media as well as biological fluids like simulated cerebrospinal fluid, saliva, and urine, and also in natural fluids like juices of tomato, sugarcane, and lime. The sensing mechanism is attributed to the interactions between Hg and CdSe QDs inducing fluorescence quenching. The limit of detection is 1.62, 0.75, and 1.27 ppb for organic, inorganic and elemental mercury, respectively, which is below WHO guidelines. The suitability of the sensor for estimating Hg in biological fluids was demonstrated by recovery experiments. Besides sensing, a two color cell imaging method was developed employing CdSe QDs and acridine orange. Using this method, the uptake of Hg in living cells was demonstrated.}, } @article {pmid35517041, year = {2019}, author = {Zhao, K and Pi, B and Zhao, L and Tian, S and Ge, J and Yang, H and Sha, W and Wang, L}, title = {Influence of N-acetyl cysteine (NAC) and 2-methylene-1,3-dioxepane (MDO) on the properties of polymethyl methacrylate (PMMA) bone cement.}, journal = {RSC advances}, volume = {9}, number = {21}, pages = {11833-11841}, pmid = {35517041}, issn = {2046-2069}, abstract = {The properties of polymethyl methacrylate (PMMA) bone cement make it a popular bone filling material. However, its disadvantages, such as lack of biodegradability and osteogenesis, restrict its clinical application. Studies have indicated the osteogenic properties of N-acetyl cysteine (NAC) and the biodegradability of 2-methylene-1,3-dioxepane/methyl methacrylate-based (MDO/MMA) copolymers. In this study, we developed bioactive PMMA cements through modification with fixed concentrations of NAC and different proportions of MDO. The purpose of this study was to compare the mechanical properties, morphology, NAC release, biocompatibility, degradability and mineralization capability of modified bone cements with those of conventional cement. The specific-modified specimens (NAC-p (5% MDO-co-MMA)) exhibited a lower bending modulus but had little effect on compressive strength. This material was morphologically compact and nonporous, similar to conventional PMMA bone cement. NAC could be released from NAC-p (5% MDO-co-MMA) continuously and appropriately. NAC-p (5% MDO-co-MMA) was biologically safe and showed satisfactory tissue compatibility. Ester was introduced into the polymer, which reinforced the degradation properties of NAC-p (5% MDO-co-MMA). NAC-p (5% MDO-co-MMA) enhanced the mineralization capability of osteoblastic cells.}, } @article {pmid36879587, year = {2019}, author = {Rastegar Khosravi, M and Khonsha, M and Ramazanzadeh, R}, title = {Combined Effect of Levofloxacin and N-Acetylcysteine against Enterococcus faecalis Biofilm for Regenerative Endodontics: An in Vitro Study.}, journal = {Iranian endodontic journal}, volume = {14}, number = {1}, pages = {40-46}, pmid = {36879587}, issn = {2008-2746}, abstract = {INTRODUCTION: Endodontic treatment of necrotic immature teeth poses several clinical challenges. A major problem is the elimination of microorganisms from the root canal system. This study evaluates the in vitro antibacterial efficacy of ciprofloxacin (CIP), levofloxacin (LEV), and their combination with N-acetylcysteine (NAC) in root canals infected with Enterococcus faecalis (E. faecalis).

METHODS AND MATERIALS: A total of 120 human extracted teeth with single canals were prepared and randomly divided into six groups: Calcium hydroxide (CH), ciprofloxacin (CIP), levofloxacin (LEV), ciprofloxacin and N-acetylcysteine (CIP+NAC), levofloxacin and N-acetylcysteine (LEV+NAC), and normal saline as a positive control. According to the name of the groups, intracanal medicaments were placed into the canals and the teeth were restored with a temporary filling. After one week, intracanal medicament was removed and the final count of bacteria was measured. Antibacterial effect of medicament was assessed by measuring the percentage reduction in the colony counts (RCC) and scanning electron microscopy (SEM). The Mann-Whitney U test and the Kruskal-Wallis test were used to compare the overall antibacterial efficacy of the intracanal medicaments at significance level of 0.05.

RESULTS: All intracanal medicaments were significantly more effective than calcium hydroxide (P<0.05). The combination of LEV and NAC caused significantly higher reduction in colony count in comparison with other tested medicaments (P=0.001).

CONCLUSION: The combination of LEV and NAC showed greater antibacterial activity compared with other tested medicaments against biofilm of E. faecalis. Thus, it has the potential to be used in regenerative endodontic treatments.}, } @article {pmid35557821, year = {2018}, author = {Yue, Z and Zhang, X and Yu, Q and Liu, L and Zhou, X}, title = {Cytochrome P450-dependent reactive oxygen species (ROS) production contributes to Mn3O4 nanoparticle-caused liver injury.}, journal = {RSC advances}, volume = {8}, number = {65}, pages = {37307-37314}, pmid = {35557821}, issn = {2046-2069}, abstract = {Mn3O4 nanoparticles (NPs) are one of the most important nanomaterials, and have a wide range of applications (i.e., catalysis, solar-electron transformation and molecular adsorption). However, their biological effect remains to be detailed. In this study, we investigated the in vivo toxicity of the synthesized Mn3O4 NPs using a long-term exposure model. After exposure to the Mn3O4 NPs for 60-120 days, rats preferentially accumulated manganese in the livers. Histopathological observation and apoptosis assays revealed that the Mn3O4 NPs caused severe liver injury associated with apoptosis. Transcription profiling analysis, immune histochemistry (IHC) staining and western blotting showed that the NPs significantly up-regulated expression of the cytochrome P450 (CYP1A2). Accordingly, the NP-treated livers exhibited high levels of reactive oxygen species (ROS) and oxidative damage. Moreover, ROS scavenging by N-acetylcysteine (NAC) attenuated Mn3O4 NP-caused liver injury, but had no impact on the expression of CYP1A2. These results indicated that the toxicity of the Mn3O4 NPs was attributed to cytochrome P450-dependent ROS accumulation and consequent oxidative damage. This study uncovers the contribution of cytochrome P450-induced oxidative stress to nanotoxicity.}, } @article {pmid35547513, year = {2018}, author = {Jaiswal, A and Sabarwal, A and Narayan Mishra, JP and Singh, RP}, title = {Plumbagin induces ROS-mediated apoptosis and cell cycle arrest and inhibits EMT in human cervical carcinoma cells.}, journal = {RSC advances}, volume = {8}, number = {56}, pages = {32022-32037}, pmid = {35547513}, issn = {2046-2069}, abstract = {Plumbagin, an important phytochemical from the roots of the medicinal plant Plumbago zeylanica L. has shown many biological activities. The roots of this plant have been in use in the Indian system of medicine for more than twenty five centuries for treatments of various ailments. It has shown anticancer activities, however, the anticancer and anti-metastatic effects of plumbagin are largely unknown against cervical cancer cells. Herein, we investigated the molecular alterations associated with plumbagin-mediated inhibition of growth, survival and epithelial to mesenchymal transition of human cervical cancer SiHa and HeLa cells. Plumbagin (1-4 μM) caused a significant decrease in the cell viability and increased the cell death in SiHa and Hela cells after 24 and 48 h. Plumbagin also caused strong G2/M and S-G2/M phase cell cycle arrest in SiHa and HeLa cells, respectively which was accompanied by a decrease in the expression of cyclin and CDK levels. The expression levels of both mRNAs and proteins of cyclin B1, A and E2 and CDK 1 and 2 decreased after 24 and 48 h. Plumbagin strongly induced apoptosis along with increased ratio of Bax : Bcl2 and cleavage of caspase 3, 9, and PARP. Plumbagin caused a significant increase in reactive oxygen species generation which mediated cell death as it was attenuated by pre-treatment with N-acetyl cysteine. Additionally, we also report for the first time that plumbagin possesses an anti-metastatic effect at non-cytotoxic doses that was accompanied by the modulation of MMP-2, 9, E-cadherin, N-cadherin, β-catenin and vimentin. Taken together, our findings suggest that plumbagin has strong anticancer and anti-metastatic effects against human cervical cancer cells.}, } @article {pmid34419099, year = {2021}, author = {Ke, S and Liu, Q and Zhang, X and Yao, Y and Yang, X and Sui, G}, title = {Cytotoxicity analysis of biomass combustion particles in human pulmonary alveolar epithelial cells on an air-liquid interface/dynamic culture platform.}, journal = {Particle and fibre toxicology}, volume = {18}, number = {1}, pages = {31}, pmid = {34419099}, issn = {1743-8977}, support = {R01 AA020401/AA/NIAAA NIH HHS/United States ; }, mesh = {*Air Pollutants ; *Alveolar Epithelial Cells ; Biomass ; Cell Survival ; Epithelial Cells ; Humans ; Lung ; }, abstract = {BACKGROUND: Exposure to indoor air pollution from solid fuel combustion is associated with lung diseases and cancer. This study investigated the cytotoxicity and molecular mechanisms of biomass combustion-derived particles in human pulmonary alveolar epithelial cells (HPAEpiC) using a platform that combines air-liquid interface (ALI) and dynamic culture (DC) systems.

METHODS: HPAEpiC were cultured on the surface of polycarbonate (PC) membranes on the ALI-DC platform. The cells were sprayed with an aerosolized solution of biomass combustion soluble constituents (BCSCs) and simultaneously nourished with culture medium flowing beneath the permeable PC membranes. The ALI-DC method was compared with the traditional submerged culture approach. BCSC particle morphology and dosages deposited on the chip were determined for particle characterization. Flow cytometry, scanning electron microscopy, and transmission electron microscopy were used to investigate the apoptosis rate of HPAEpiC and changes in the cell ultrastructure induced by BCSCs. Additionally, the underlying apoptotic pathway was examined by determining the protein expression levels by western blotting.

RESULTS: Scanning electron microscope images demonstrated that the sample processing and delivering approach of the ALI-DC platform were suitable for pollutant exposure. Compared with the submerged culture method, a significant decline in cell viability and increase in apoptosis rate was observed after BCSC exposure on the ALI-DC platform, indicating that the ALI-DC platform is a more sensitive system for investigating cytotoxicity of indoor air pollutants in lung cells. The morphology and ultrastructure of the cells were damaged after exposure to BCSCs, and the p53 pathway was activated. The Bcl-2/Bax ratio was reduced, upregulating caspase-9 and caspase-3 expression and subsequently inducing apoptosis of HPAEpiC. The addition of N-acetyl cysteine antioxidant significantly alleviated the cytotoxicity induced by BCSCs.

CONCLUSION: A novel ALI-DC platform was developed to study the cytotoxicity of air pollutants on lung cells. Using the platform, we demonstrated that BCSCs could damage the mitochondria, produce reactive oxygen species, and activate p53 in HPAEpiC, ultimately inducing apoptosis.}, } @article {pmid34417577, year = {2022}, author = {Yang, CB and Liu, J and Tong, BC and Wang, ZY and Zhu, Z and Su, CF and Sreenivasmurthy, SG and Wu, JX and Iyaswamy, A and Krishnamoorthi, S and Huang, SY and Cheung, KH and Song, JX and Tan, JQ and Lu, JH and Li, M}, title = {TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2.}, journal = {Acta pharmacologica Sinica}, volume = {43}, number = {5}, pages = {1251-1263}, pmid = {34417577}, issn = {1745-7254}, mesh = {Apoptosis ; Autophagy ; Cyclopentanes ; *Prostaglandin D2/analogs & derivatives/pharmacology ; *Prostaglandins/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-∆-[12,14]-prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d-PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.}, } @article {pmid34416896, year = {2021}, author = {Chen, M and Yi, J and Zhao, Z}, title = {Biocompatible orthodontic cement with antibacterial capability and protein repellency.}, journal = {BMC oral health}, volume = {21}, number = {1}, pages = {412}, pmid = {34416896}, issn = {1472-6831}, mesh = {Anti-Bacterial Agents/pharmacology/therapeutic use ; Biofilms ; *Dental Bonding ; Dental Cements ; Dental Enamel ; Glass Ionomer Cements/pharmacology ; Humans ; Materials Testing ; *Orthodontic Brackets ; Resin Cements ; }, abstract = {BACKGROUND: White spot lesions (WSLs) often occur in orthodontic treatments. The objectives of this study were to develop a novel orthodontic cement using particles of nano silver (NAg), N-acetylcysteine (NAC) and 2-methacryloyloxyethyl phosphorylcholine (MPC), and to investigate the effects on bonding strength, biofilms and biocompatibility.

METHODS: A commercial resin-modified glass ionomer cement (RMGIC) was modified by adding NAg, NAC and MPC. The unmodified RMGIC served as the control. Enamel bond strength and cytotoxicity of the cements were investigated. The protein repellent behavior of cements was also evaluated. The metabolic assay, lactic acid production assay and colony-forming unit assay of biofilms were used to determine the antibacterial capability of cements.

RESULTS: The new bioactive cement with NAg, NAC and MPC had clinically acceptable bond strength and biocompatibility. Compared to commercial control, the new cement suppressed metabolic activity and lactic acid production of biofilms by 59.03% and 70.02% respectively (p < 0.05), reduced biofilm CFU by 2 logs (p < 0.05) and reduced protein adsorption by 76.87% (p < 0.05).

CONCLUSIONS: The new cement with NAg, NAC and MPC had strong antibacterial capability, protein-repellent ability and acceptable biocompatibility. The new cement is promising to protect enamel from demineralization during orthodontic treatments.}, } @article {pmid34411914, year = {2021}, author = {Rodrigues, ACBDC and Bomfim, LM and Neves, SP and Soares, MBP and Dias, RB and Valverde, LF and Rocha, CAG and Costa, EV and da Silva, FMA and Rocha, WC and Koolen, HHF and Bezerra, DP}, title = {Tingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {142}, number = {}, pages = {112034}, doi = {10.1016/j.biopha.2021.112034}, pmid = {34411914}, issn = {1950-6007}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Line ; Cell Line, Tumor ; DNA Breaks, Double-Stranded/drug effects ; Down-Regulation/drug effects ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics ; MAP Kinase Signaling System/drug effects ; Mice ; Oxidative Stress/drug effects ; Salacia/chemistry ; Thioredoxins/*genetics ; Triterpenes/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin, as a target for TG and 22-HTG. The application of N-acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin.}, } @article {pmid34402711, year = {2022}, author = {O'Callaghan, C and Graudins, A and Wong, A}, title = {A two-bag acetylcysteine regimen is associated with shorter delays and interruptions in the treatment of paracetamol overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {3}, pages = {319-323}, doi = {10.1080/15563650.2021.1966027}, pmid = {34402711}, issn = {1556-9519}, mesh = {Acetaminophen/therapeutic use ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic/therapeutic use ; Antidotes/therapeutic use ; Australia ; *Drug Overdose/drug therapy ; *Drug-Related Side Effects and Adverse Reactions/drug therapy ; Humans ; Retrospective Studies ; }, abstract = {BACKGROUND: The three-bag intravenous (IV) acetylcysteine regimen for paracetamol overdose is associated with frequent and long delays during treatment. This has not been previously studied in regard to the two-bag regimen.

AIMS: Our primary aim was to compare the cumulative duration of delays during IV acetylcysteine infusion between the three-bag and two-bag regimens. Secondary aims were to compare the frequency of delays and to identify causes for delay.

METHODS: This was a retrospective cohort study of patients receiving IV acetylcysteine for the treatment of paracetamol overdose, conducted at three Australian emergency departments. A cohort of patients treated with the three-bag regimen from October 2009 to October 2013 was compared to patients treated with the two-bag regimen from February 2014 to May 2020. Start times of each infusion were sourced from medical records and delays were calculated by comparing actual infusion time against prescribed time. Evidence of adverse drug reactions - gastrointestinal reactions and cutaneous and systemic non-allergic anaphylactoid reactions (NAARs) - were also recorded.

RESULTS: The three-bag cohort included 271 cases and the two-bag cohort included 598 cases. Delays were significantly shorter in the two-bag cohort, compared to the three-bag cohort: median delay 35 min (IQR: 15, 70) vs 65 min (IQR: 40, 105), p < 0.01. Delays longer than 1 h were less frequent in the two-bag cohort: 31% vs 51%, p < 0.01. NAARs were associated with significantly longer delays in both cohorts and were more frequent in the three-bag cohort.

CONCLUSIONS: The two-bag regimen was associated with significantly fewer and shorter delays. NAARs, which were more frequent in the three-bag cohort, were associated with significantly longer delays.}, } @article {pmid34402583, year = {2021}, author = {Ghosh, R and Siddarth, M and Kare, PK and Banerjee, BD and Kalra, OP and Tripathi, AK}, title = {β-Endosulfan-mediated induction of pro-fibrotic markers in renal (HK-2) cells in vitro: A new insight in the pathogenesis of chronic kidney disease of unknown etiology.}, journal = {Environmental toxicology}, volume = {36}, number = {11}, pages = {2354-2360}, doi = {10.1002/tox.23349}, pmid = {34402583}, issn = {1522-7278}, support = {//Department of Science and Technology, Ministry of Science and Technology, India/ ; }, mesh = {*Endosulfan/toxicity ; Epithelial Cells/pathology ; Epithelial-Mesenchymal Transition ; Fibrosis ; Humans ; Kidney/pathology ; Kidney Tubules, Proximal/pathology ; *Renal Insufficiency, Chronic/chemically induced/pathology ; Transforming Growth Factor beta1 ; }, abstract = {Chronic kidney disease of unknown etiology (CKDu), manifested clinically as tubulo interstitial fibrosis, has emerged as the second major cause of chronic kidney disease (CKD) in the Indian subcontinent and various agrochemicals have been implicated in its occurance. Among the agrochemicals organochlorine pesticides particularly endosulfan is well known for its toxicity and recent residue analysis have shown its presence in the blood samples of general population. In this present study, we have investigated the consequences of endosulfan exposure at a concentration (0.01 μM) equivalent to their highest reported presence in human blood sample of some CKDu patients, to human renal proximal tubular epithelial (HK-2) cell line with regard to ROS generation and expression of profibrotic and epithelial to mesenchymal (EMT) markers in order to find out endosulfan's ability to induce profibrotic changes in renal cell. We demonstrated a significant increase in intracellular ROS generation and increased expression of TGF-β1 when cells were incubated with β-endosulfan (0.01 μM) indicating occurrence of oxidative stress and fibrotic process. Again, decreased expression of epithelial marker E-cadherin and increase in the expression of mesenchymal marker α-smooth muscle actin (α-SMA) suggest possible onset of EMT process. Pre-treatment with 5 mM concentration of anti-oxidant N-acetyl cysteine partially attenuated the above process. In conclusion, these findings suggest possible involvement of β-endosulfan in the development of CKDu through oxidative stress and profibrotic signaling.}, } @article {pmid34399087, year = {2021}, author = {Zhan, X and Xie, Y and Sun, L and Si, Q and Shang, H}, title = {Dexamethasone may inhibit placental growth by blocking glucocorticoid receptors via phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin and reactive oxygen species/AMP-activated protein kinase signalling pathways in human placental JEG-3 cells.}, journal = {Reproduction, fertility, and development}, volume = {33}, number = {12}, pages = {700-712}, doi = {10.1071/RD21048}, pmid = {34399087}, issn = {1448-5990}, mesh = {AMP-Activated Protein Kinases/metabolism ; Apoptosis/drug effects ; Cell Line ; Dexamethasone/*pharmacology ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Placenta/*drug effects/metabolism ; Pregnancy ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Glucocorticoid/*metabolism ; Signal Transduction/*drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {This study explored the molecular mechanism underlying the effects of dexamethasone (DEX, 1 µM) on glucose transporters (GLUT) in JEG-3 human placental choriocarcinoma cells. JEG-3 cells were treated with DEX, an expression plasmid encoding human glucocorticoid receptor α (GRα), pcDNA3.1-GRα, GRα short interference (si) RNA, LY294002, xanthine oxidase (XO)/hypoxanthine (HX), rapamycin, insulin-like growth factor (IGF) 1, N-acetylcysteine (NAC) or phosphatidic acid (PA), and cell proliferation, apoptosis, mitochondrial membrane potential (MMP), human chorionic gonadotrophin (hCG) content, human placental lactogen (hPL) content, glucose uptake, reactive oxygen species levels and signalling pathway modulation were evaluated. Treatment of JEG-3 cells with DEX (1 µM), GRα siRNA, LY294002 (50 µM), XO/HX (7.2 µM/36 nM) or rapamycin (80 nM) inhibited cell proliferation, induced apoptosis, significantly decreased MMP and hCG and hPL content and increased ROS levels. In addition, glucose uptake was decreased through downregulation of the mRNA and protein expression of GRα, GLUT1 and GLUT3. Treatment of JEG-3 cells with GRα siRNA, LY294002, XO/HX or rapamycin inhibited phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, glycogen synthase kinase 3 and mammalian target of rapamycin (mTOR) and induced the phosphorylation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex 2. The effects of GRα overexpression and IGF1 (100 nM), NAC (5 nM) or PA (100 µM) treatment on JEG-3 cells contrasted with those of DEX treatment. DEX blocked glucose uptake by downregulating GRα expression, which reduced GLUT1 and GLUT3 mRNA and protein expression, which, in turn, may have inhibited the PI3K/AKT/mTOR pathway and activated the ROS/AMPK pathway.}, } @article {pmid34397062, year = {2021}, author = {Qu, L and Fu, R and Ma, X and Fan, D}, title = {Hepatoprotective effects of ginsenoside Rk3 in acetaminophen-induced liver injury in mice by activation of autophagy.}, journal = {Food & function}, volume = {12}, number = {19}, pages = {9128-9140}, doi = {10.1039/d1fo02081a}, pmid = {34397062}, issn = {2042-650X}, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; *Autophagy ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology/*prevention & control ; Chloroquine/pharmacology ; Cytokines/metabolism ; Ginsenosides/administration & dosage/*therapeutic use ; Liver/*drug effects/pathology ; Male ; Mice ; Mice, Inbred ICR ; Oxidative Stress ; }, abstract = {Acetaminophen (APAP)-induced acute liver injury (AIALI) is one of the most common causes of acute liver failure. Owing to the limitations of N-acetylcysteine (NAC), which is the only antidote currently used in clinical practice for APAP, there is a need to develop new therapies that can provide extensive protection against AIALI. Ginsenoside Rk3 is a rare ginsenoside extracted from Panax notoginseng and a previous study has reported its excellent hepatoprotective function. In this study, we explored the therapeutic potential of ginsenoside Rk3 in APAP-induced acute liver injury. We found that ginsenoside Rk3 could reduce APAP-induced hepatotoxicity by reducing serum alanine aminotransferase and aspartate aminotransferase activity and pathological damage to the liver. Moreover, ginsenoside Rk3 could inhibit APAP-induced liver inflammation and oxidative stress by inhibiting the production of oxidative molecules, increasing the production of antioxidant molecules, and reducing the infiltration of inflammatory cells and the production of pro-inflammatory cytokines. Further mechanistic investigations revealed that the therapeutic effect of ginsenoside Rk3 was mainly dependent on the continuous activation of autophagy. Chloroquine, an autophagy inhibitor, was found to inhibit these protective effects. Therefore, ginsenoside Rk3 shows potential as a novel hepatoprotective agent to prevent drug-induced liver injury.}, } @article {pmid34392569, year = {2021}, author = {Morgan, AM and Hassanen, EI and Ogaly, HA and Al Dulmani, SA and Al-Zahrani, FAM and Galal, MK and Kamel, S and Rashad, MM and Ibrahim, MA and Hussien, AM}, title = {The ameliorative effect of N-acetylcysteine against penconazole induced neurodegenerative and neuroinflammatory disorders in rats.}, journal = {Journal of biochemical and molecular toxicology}, volume = {35}, number = {10}, pages = {e22884}, doi = {10.1002/jbt.22884}, pmid = {34392569}, issn = {1099-0461}, mesh = {Acetylcysteine/*administration & dosage ; Animals ; Anti-Inflammatory Agents/*administration & dosage ; Antioxidants/*administration & dosage ; Apoptosis/drug effects ; Behavior, Animal/drug effects ; Brain/metabolism/pathology ; Caspase 3/metabolism ; Elevated Plus Maze Test ; Male ; Malondialdehyde/metabolism ; Neurodegenerative Diseases/*chemically induced/*drug therapy/metabolism/psychology ; Neuroinflammatory Diseases/*chemically induced/*drug therapy/metabolism/psychology ; Neuroprotective Agents/*administration & dosage ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Treatment Outcome ; Triazoles/*adverse effects ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Penconazole (PEN) is a widely used systemic fungicide to treat various fungal diseases in plants but it leaves residues in crops and food products causing serious environmental and health problems. N-acetylcysteine (NAC) is a precursor of the antioxidant glutathione in the body and exerts prominent antioxidant and anti-inflammatory effects. The present study aimed to explore the mechanistic way of NAC to ameliorate the PEN neurotoxicity in male rats. Twenty-eight male rats were randomly divided into four groups (n = 7) and given the treated material via oral gavage for 10 days as the following: Group I (distilled water), Group II (50 mg/kg body weight [bwt] PEN), Group III (200 mg/kg bwt NAC), and Group IV (NAC + PEN). After 10 days all rats were subjected to behavioral assessment and then euthanized to collect brain tissues to perform oxidative stress, molecular studies, and pathological examination. Our results revealed that PEN exhibits neurobehavioral toxicity manifested by alteration in the forced swim test, elevated plus maze test, and Y-maze test. There were marked elevations in malondialdehyde levels with reduction in total antioxidant capacity levels, upregulation of messenger RNA levels of bax, caspase 3, and caspase 9 genes with downregulation of bcl2 genes. In addition, brain sections showed marked histopathological alteration in the cerebrum and cerebellum with strong bax and inducible nitric oxide synthetase protein expression. On the contrary, cotreatment of rats with NAC had the ability to improve all the abovementioned neurotoxic parameters. The present study can conclude that NAC has a neuroprotective effect against PEN-induced neurotoxicity via its antioxidant, anti-inflammatory, and antiapoptotic effect. We recommend using NAC as a preventive and therapeutic agent for a wide variety of neurodegenerative and neuroinflammatory disorders.}, } @article {pmid34390848, year = {2021}, author = {Qiu, X and Yu, Y and Liu, H and Li, X and Sun, W and Wu, W and Liu, C and Miao, L}, title = {Remodeling the periodontitis microenvironment for osteogenesis by using a reactive oxygen species-cleavable nanoplatform.}, journal = {Acta biomaterialia}, volume = {135}, number = {}, pages = {593-605}, doi = {10.1016/j.actbio.2021.08.009}, pmid = {34390848}, issn = {1878-7568}, mesh = {Cell Differentiation ; Cells, Cultured ; Humans ; *Osteogenesis ; Periodontal Ligament ; *Periodontitis/drug therapy ; Reactive Oxygen Species ; }, abstract = {Modestly removing the excessive reactive oxygen species (ROS) plays a crucial role in regulating the microenvironment of periodontitis and provides favorable conditions for osteogenesis. However, the current strategy for scavenging ROS is not controllable, substantially limiting the outcomes in periodontitis. Herein, we introduced a controllable ROS-scavenging nanoplatform by encasing N-acetylcysteine (NAC, (a well-known ROS scavenger) into tailor-made ROS-cleavable amphiphilic polymer nanoparticles (PEG-ss-PCL NPs) as an intracellular delivery carrier. The existing ROS in the inflammatory microenvironment facilitated polymer degradation via breakage of thioketal bonds, and then led to encapsulated NAC release. NAC eliminated all ROS induced by lipopolysaccharide (LPS), while PssL-NAC adjusted the ROS level slightly higher than that of the control group. The percentage of apoptotic cells cultured with NAC and PssL-NAC decreased observably compared with that of cells cultured with 10 µg/ml LPS. The microenvironment regulated by PssL-NAC was highly suitable for osteogenic differentiation based on PCR and Western blot results, which showed higher expression levels of BMP2, Runx2, and PKA. Analysis of ALP activity and Alizarin red S staining showed consistent results. Additionally, the injection of PssL-NAC into the periodontitis area could alleviate the tissue destruction induced by ligation of the maxillary second molar. PssL-NAC showed a better ability to decrease osteoclast activity and inflammation, consequently improving the restoration of destroyed tissue. Our study suggests that ROS-responsive polymer nanoparticles loaded with NAC (PssL-NAC) can be new promising materials for the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: More and more studies indicate that periodontal tissue damage is closely related to the high reactive oxygen species (ROS) environment. Excessive ROS will aggravate periodontal tissue damage and is not conducive to tissue repair. However, as an essential signal molecule in human physiological activities, ROS absence is also useless for tissue repair. In this study, we proposed to improve ROS imbalance in the environment of periodontitis as a strategy to promote periodontal regeneration and successfully synthesized a smart drug-releasing nanoplatform that can respond to ROS. Besides, we validated its ability to regulate the ROS environment and promote osteogenesis through experimental data in vivo and in vitro.}, } @article {pmid34389427, year = {2021}, author = {Smiley, CE and Saleh, HK and Nimchuk, KE and Garcia-Keller, C and Gass, JT}, title = {Adolescent exposure to delta-9-tetrahydrocannabinol and ethanol heightens sensitivity to fear stimuli.}, journal = {Behavioural brain research}, volume = {415}, number = {}, pages = {113517}, pmid = {34389427}, issn = {1872-7549}, support = {K99 DA047426/DA/NIDA NIH HHS/United States ; R01 AA024526/AA/NIAAA NIH HHS/United States ; T32 AA007474/AA/NIAAA NIH HHS/United States ; }, mesh = {Age Factors ; Animals ; Behavior, Animal/*drug effects ; Cannabinoid Receptor Agonists/administration & dosage/*pharmacology ; Central Nervous System Depressants/administration & dosage/*pharmacology ; Conditioning, Classical/*drug effects ; Dronabinol/administration & dosage/*pharmacology ; Ethanol/administration & dosage/*pharmacology ; Fear/*drug effects ; Male ; Rats ; Rats, Wistar ; }, abstract = {Cannabis use disorder (CUD) has doubled in prevalence over the past decade as a nation-wide trend toward legalization allows for increased drug accessibility. As a result, marijuana has become the most commonly used illicit drug in the United States particularly among the adolescent population. This is especially concerning since there is greater risk for the harmful side effects of drug use during this developmental period due to ongoing brain maturation. Increasing evidence indicates that CUD often occurs along with other debilitating conditions including both alcohol use disorder (AUD) and anxiety disorders such post-traumatic stress disorder (PTSD). Additionally, exposure to cannabis, alcohol, and stress can induce alterations in glutamate regulation and homeostasis in the prefrontal cortex (PFC) that may lead to impairments in neuronal functioning and cognition. Therefore, in order to study the relationship between drug exposure and the development of PTSD, these studies utilized rodent models to determine the impact of adolescent exposure to delta-9-tetrahydrocannabinol (THC) and ethanol on responses to fear stimuli during fear conditioning and used calcium imaging to measure glutamate activity in the prelimbic cortex during this behavioral paradigm. The results from these experiments indicate that adolescent exposure to THC and ethanol leads to enhanced sensitivity to fear stimuli both behaviorally and neuronally. Additionally, these effects were attenuated when animals were treated with the glutamatergic modulator N-acetylcysteine (NAC). In summary, these studies support the hypothesis that adolescent exposure to THC and ethanol leads to alterations in fear stimuli processing through glutamatergic reliant modifications in PFC signaling.}, } @article {pmid34389161, year = {2021}, author = {Garcia, AA and Koperniku, A and Ferreira, JCB and Mochly-Rosen, D}, title = {Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives.}, journal = {Trends in pharmacological sciences}, volume = {42}, number = {10}, pages = {829-844}, pmid = {34389161}, issn = {1873-3735}, support = {F32 HD008442/HD/NICHD NIH HHS/United States ; R01 HD084422/HD/NICHD NIH HHS/United States ; T32 GM113854/GM/NIGMS NIH HHS/United States ; }, mesh = {*Glucosephosphate Dehydrogenase Deficiency/genetics ; Glutathione/metabolism ; Humans ; Mutation ; Oxidation-Reduction ; Oxidative Stress ; }, abstract = {Glucose-6-phosphate dehydrogenase (G6PD) maintains redox balance in a variety of cell types and is essential for erythrocyte resistance to oxidative stress. G6PD deficiency, caused by mutations in the G6PD gene, is present in ~400 million people worldwide, and can cause acute hemolytic anemia. Currently, there are no therapeutics for G6PD deficiency. We discuss the role of G6PD in hemolytic and nonhemolytic disorders, treatment strategies attempted over the years, and potential reasons for their failure. We also discuss potential pharmacological pathways, including glutathione (GSH) metabolism, compensatory NADPH production routes, transcriptional upregulation of the G6PD gene, highlighting potential drug targets. The needs and opportunities described here may motivate the development of a therapeutic for hematological and other chronic diseases associated with G6PD deficiency.}, } @article {pmid34387821, year = {2022}, author = {Zhao, H and Fu, L and Xiang, HX and Xiang, Y and Li, MD and Lv, BB and Tan, ZX and Gao, L and Zhang, C and Xu, DX}, title = {N-acetylcysteine alleviates pulmonary inflammatory response during benzo[a]pyrene-evoked acute lung injury.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {3}, pages = {3474-3486}, pmid = {34387821}, issn = {1614-7499}, support = {81670060//National Natural Science Foundation of China/ ; 91743105//National Natural Science Foundation of China/ ; 2020GQFY05//National Natural Science Foundation Incubation Program of the Second Affiliated Hospital of Anhui Medical University/ ; AHWJ2021b091//Scientific Research of Health Commission in Anhui Province/ ; }, mesh = {Acetylcysteine/pharmacology ; *Acute Lung Injury/chemically induced/drug therapy ; Animals ; Benzo(a)pyrene/toxicity ; Lung ; Mice ; NF-kappa B ; *Pneumonia ; }, abstract = {Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon, exists widely in automobile emissions and polluted atmosphere. The current study aimed to describe pulmonary inflammation during BaP-induced acute lung injury (ALI). All mice except controls were intratracheally instilled with a single dose of BaP (90 μg per mouse). The alveolar structure was damaged, accompanied by numerous inflammatory cell infiltration around pulmonary interstitium and small airway. Airway wall area and mean linear intercept were reduced in BaP-exposed mouse lungs. By contrast, airway wall thickness and destructive index were elevated in BaP-exposed mouse lungs. Several inflammatory genes, such as Tnf-α, Il-1β, Il-6, Mip-2, Kc, and Mcp-1, were upregulated in mouse lungs. Phosphorylated IκBα was elevated in BaP-exposed mouse lungs. Nuclear translocation of NF-κB p65 and p50 was accordingly observed in BaP-exposed mouse lungs. Several molecules of the MAPK pathway, including JNK, ERK1/2, and p38, were activated in mouse lungs. Of interest, pretreatment with N-acetylcysteine (NAC), an antioxidant, alleviated BaP-induced ALI. Moreover, NAC attenuated BaP-induced inflammatory cell infiltration in mouse lungs and inflammatory gene upregulation in A549 cells. In addition, NAC attenuated BaP-induced NF-κB activation in A549 cells and mouse lungs. These results suggest that NAC alleviates pulmonary inflammatory response during BaP-evoked ALI.}, } @article {pmid34387802, year = {2021}, author = {Aboalgasm, H and Ballo, R and Gwanyanya, A}, title = {Organisational alteration of cardiac myofilament proteins by hyperglycaemia in mouse embryonic stem cell-derived cardiomyocytes.}, journal = {Journal of muscle research and cell motility}, volume = {42}, number = {3-4}, pages = {419-428}, pmid = {34387802}, issn = {1573-2657}, mesh = {Actinin ; Animals ; Glucose ; *Hyperglycemia ; Mice ; Mouse Embryonic Stem Cells ; *Myocytes, Cardiac ; Myofibrils ; }, abstract = {The exposure of the developing foetal heart to hyperglycaemia in mothers with diabetes mellitus is a major risk factor for foetal cardiac complications that lead to heart failure. We studied the effects of hyperglycaemia on the layout of cardiac myofilament proteins in stem cell-derived cardiomyocytes and their possible underlying mechanisms. Mouse embryonic stem cells (mESCs) were differentiated into cardiac-like cells and cultured in media containing baseline- or high glucose concentrations. Cellular biomarkers were detected using Western blot analysis, immunocytochemistry, 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay, and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. High glucose decreased the proportion of cardiac troponin T and α-actinin 2 positive mESCs as well as disrupted the α-actinin 2 striated pattern and the distribution of the cardiac myosin heavy chain α- and β isoforms. However, there was no alteration of the cellular EdU uptake nor the expression of the receptor of advanced glycation end-product (RAGE). High glucose also increased the presence of the oxidative stress marker nitrotyrosine as well as the number of TUNEL-stained nuclei in cardiac-like cells. Treatment with the antioxidant N-acetyl cysteine decreased the number of TUNEL-stained cells in high glucose and improved the α-actinin 2 striated pattern. Hyperglycaemia negatively impacted the expression and cellular organisation of cardiac myofilament proteins in mESC-derived cardiomyocytes through oxidative stress. The results add further insights into the pathophysiological mechanisms of cardiac contractile dysfunction in diabetic cardiac developmental disease.}, } @article {pmid34387415, year = {2021}, author = {Luo, SY and Liu, C and Ding, J and Gao, XM and Wang, JQ and Zhang, YB and Du, C and Hou, CC and Zhu, JQ and Lou, B and Wu, XF and Shen, WL}, title = {Scavenging reactive oxygen species is a potential strategy to protect Larimichthys crocea against environmental hypoxia by mitigating oxidative stress.}, journal = {Zoological research}, volume = {42}, number = {5}, pages = {592-605}, pmid = {34387415}, issn = {2095-8137}, mesh = {Animals ; Antioxidants/*metabolism ; Cell Line ; Cell Survival ; Environment ; Fishes/*metabolism ; Homeostasis ; NADP ; Oxidative Stress/*physiology ; Oxygen/*chemistry/*metabolism ; *Reactive Oxygen Species ; }, abstract = {The large yellow croaker (Larimichthys crocea), which is an economically important mariculture fish in China, is often exposed to environmental hypoxia. Reactive oxygen species (ROS) homeostasis is essential for the maintenance of normal physiological conditions in an organism. Direct evidence that environmental hypoxia leads to ROS overproduction is scarce in marine fish. Furthermore, the sources of ROS overproduction in marine fish under hypoxic stress are poorly known. In this study, we investigated the effects of hypoxia on redox homeostasis in L. crocea and the impact of impaired redox homeostasis on fish. We first confirmed that hypoxia drove ROS production mainly via the mitochondrial electron transport chain and NADPH oxidase complex pathways in L. crocea and its cell line (large yellow croaker fry (LYCF) cells). We subsequently detected a marked increase in the antioxidant systems of the fish. However, imbalance between the pro-oxidation and antioxidation systems ultimately led to excessive ROS and oxidative stress. Cell viability showed a remarkable decrease while oxidative indicators, such as malondialdehyde, protein carbonylation, and 8-hydroxy-2 deoxyguanosine, showed a significant increase after hypoxia, accompanied by tissue damage. N-acetylcysteine (NAC) reduced ROS levels, alleviated oxidative damage, and improved cell viability in vitro. Appropriate uptake of ROS scavengers (e.g., NAC and elamipretide Szeto-Schiller-31) and inhibitors (e.g., apocynin, diphenylene iodonium, and 5-hydroxydecanoate) may be effective at overcoming hypoxic toxicity. Our findings highlight previously unstudied strategies of hypoxic toxicity resistance in marine fish.}, } @article {pmid34385060, year = {2021}, author = {Guan, M and Tang, S and Chang, H and Chen, Y and Chen, F and Mu, Y and Zhao, D and Fan, W and Tian, H and Darland, DC and Zhang, Y}, title = {Development of alveolar-capillary-exchange (ACE) chip and its application for assessment of PM2.5-induced toxicity.}, journal = {Ecotoxicology and environmental safety}, volume = {223}, number = {}, pages = {112601}, pmid = {34385060}, issn = {1090-2414}, support = {P20 GM104360/GM/NIGMS NIH HHS/United States ; }, mesh = {*Air Pollutants/toxicity ; Alveolar Epithelial Cells ; Endothelial Cells ; Humans ; Lung ; Particulate Matter/toxicity ; }, abstract = {Although standard two-dimensional (2D) cell culture is an effective tool for cell studies, monolayer cultivation can yield imperfect or misleading information about numerous biological functions. In this study, we developed an alveolar-capillary exchange (ACE) chip aiming to simulate the cellular microenvironment at the alveolar-capillary interface. The ACE chip was designed with two chambers for culturing alveolar epithelial cells and vascular endothelial cells separately, which are separated by a microporous polycarbonate film that allows for the exchange of soluble biomolecules. Using this model, we further tested the toxic effects of fine particulate matter (PM2.5), a form of airborne pollutant known to induce adverse effects on human respiratory system. These effects are largely associated with the ability of PM2.5 to penetrate the alveoli, where it negatively affects the pulmonary function. Our results indicate that alveolar epithelial cells cultured in the ACE chip in solo and coculture with vascular endothelial cells underwent oxidative injury-induced apoptosis mediated via the PEAK-eIF2α signaling pathway of endoplasmic reticulum stress. The use of ACE chip in an alveolar epithelial cell-vascular endothelial cell coculture model revealed cellular vulnerability to PM2.5. Therefore, this chip provides a feasible surrogate approach in vitro for investigating and simulating the cellular microenvironment responses associated with ACE in vivo.}, } @article {pmid34377857, year = {2021}, author = {Shahrampour, S and Heholt, J and Wang, A and Vedaei, F and Mohamed, FB and Alizadeh, M and Wang, Z and Zabrecky, G and Wintering, N and Bazzan, AJ and Leist, TP and Monti, DA and Newberg, AB}, title = {N-acetyl cysteine administration affects cerebral blood flow as measured by arterial spin labeling MRI in patients with multiple sclerosis.}, journal = {Heliyon}, volume = {7}, number = {7}, pages = {e07615}, pmid = {34377857}, issn = {2405-8440}, abstract = {BACKGROUND: The purpose of this study was to explore if administration of N-acetyl-cysteine (NAC) in patients with multiple sclerosis (MS) resulted in altered cerebral blood flow (CBF) based on Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI).

METHODS: Twenty-three patients with mild to moderate MS, (17 relapsing remitting and 6 primary progressive) were randomized to either NAC plus standard of care (N = 11), or standard of care only (N = 12). The experimental group received NAC intravenously (50 mg/kg) once per week and orally (500mg 2x/day) the other six days. Patients in both groups were evaluated initially and after 2 months (of receiving the NAC or waitlist control) with ASL MRI to measure CBF. Clinical symptom questionnaires were also completed at both time points.

RESULTS: The CBF data showed significant differences in several brain regions including the pons, midbrain, left temporal and frontal lobe, left thalamus, right middle frontal lobe and right temporal/hippocampus (p < 0.001) in the MS group after treatment with NAC, when compared to the control group. Self-reported scores related to cognition and attention were also significantly improved in the NAC group as compared to the control group.

CONCLUSIONS: The results of this study suggest that NAC administration alters resting CBF in MS patients, and this is associated with qualitative improvements in cognition and attention. Given these findings, large scale efficacy studies will be of value to determine the potential clinical impact of NAC over the course of illness in patients with MS, as well as the most effective dosages and differential effects across subpopulations.}, } @article {pmid34371004, year = {2022}, author = {Guo, Q and Fan, X and Zhu, S and Zhao, X and Fang, N and Guo, M and Liu, Z and Han, Y}, title = {Comparing N-acetylcysteine with sodium thiosulfate for relieving symptoms caused by Lugol's iodine chromoendoscopy: a randomized, double-blind trial.}, journal = {Gastrointestinal endoscopy}, volume = {95}, number = {2}, pages = {249-257}, doi = {10.1016/j.gie.2021.07.025}, pmid = {34371004}, issn = {1097-6779}, mesh = {Acetylcysteine/therapeutic use ; Coloring Agents ; *Esophageal Neoplasms ; *Esophageal Squamous Cell Carcinoma ; Esophagoscopy/methods ; Humans ; Iodides/therapeutic use ; Thiosulfates ; }, abstract = {BACKGROUND AND AIMS: Lugol's iodine chromoendoscopy is an important method to detect esophageal squamous cell carcinoma. Sodium thiosulfate solution (STS) has been used to neutralize iodine after Lugol's chromoendoscopy; however, it is not available in many medical centers. The aim of the current study was to assess the efficacy of N-acetylcysteine solution (NAC) for relieving symptoms caused by Lugol's iodine chromoendoscopy.

METHODS: Patients were randomized to receive either STS or NAC after spraying Lugol's iodine solution on the esophagus. The neutralizing effects for residual iodine in the esophagus and gastric mucous pool were observed. The primary endpoint was the intensity of retrosternal pain and/or heartburn measured by a visual analog scale (VAS) score 30 minutes after chromoendoscopy. Secondary endpoints were the rate of patients with any adverse symptom, rate of moderate to severe retrosternal discomfort occurring, and heart rate variability between time points before and after chromoendoscopy.

RESULTS: The neutralization rates for residual iodine between the NAC and STS groups were not significantly different (P > .999). The difference of median VAS scores between the NAC and STS groups 30 minutes after chromoendoscopy was .0 (P = .719; 95% confidence interval, .0-.0), and the 95% confidence interval higher limit was .0, which was less than our prespecified margin of .5, concluding an noninferiority of NAC with regard to STS. There was no significant difference between the 2 groups regarding the rate of patients with any adverse symptom, rate of moderate to severe retrosternal discomfort, or heart rate variability at 5 minutes or 30 minutes after chromoendoscopy.

CONCLUSION: As a very easily accessible reagent in clinical circumstances, NAC can also alleviate mucosal irritation symptoms induced by Lugol's chromoendoscopy at similar efficacy as STS and can be routinely recommended. (Clinical trial registration number: NCT04764643.).}, } @article {pmid34369229, year = {2021}, author = {Kuttikrishnan, S and Prabhu, KS and Khan, AQ and Alali, FQ and Ahmad, A and Uddin, S}, title = {Thiostrepton inhibits growth and induces apoptosis by targeting FoxM1/SKP2/MTH1 axis in B-precursor acute lymphoblastic leukemia cells.}, journal = {Leukemia & lymphoma}, volume = {62}, number = {13}, pages = {3170-3180}, doi = {10.1080/10428194.2021.1957873}, pmid = {34369229}, issn = {1029-2403}, mesh = {*Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; *Forkhead Box Protein M1/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; *Thiostrepton/pharmacology ; }, abstract = {Forkhead box M1 (FoxM1) is a transcription factor that plays an important role in the etiology of many cancers, however, its role has not been elucidated in B-precursor acute lymphoblastic leukemia (B-pre-ALL). In the current study, we showed that the downregulation of FoxM1 by its inhibitor thiostrepton inhibited cell viability and induced caspase-dependent apoptosis in a panel of B-pre-ALL cell lines. Thiostrepton led downregulation of FoxM1 accompanied by decreased expression of Aurora kinase A, B, matrix metalloproteinases, and oncogene SKP2 as well as MTH1. Downregulation of the FoxM1/SKP2/MTH1 axis led to increase in the Bax/Bcl2 ratio and suppression of antiapoptotic proteins. Thiostrepton-mediated apoptosis was prevented by N-acetyl cysteine, a scavenger of reactive oxygen species. Co-treatment of B-pre-ALL with subtoxic doses of thiostrepton and bortezomib potentiated the proapoptotic action. Altogether, our results suggest that targeting FoxM1expression could be an attractive strategy for the treatment of B-pre-ALL.}, } @article {pmid34367464, year = {2021}, author = {Zhou, XY and Zhang, J and Li, Y and Chen, YX and Wu, XM and Li, X and Zhang, XF and Ma, LZ and Yang, YZ and Zheng, KM and Liu, YD and Wang, Z and Chen, SL}, title = {Advanced Oxidation Protein Products Induce G1/G0-Phase Arrest in Ovarian Granulosa Cells via the ROS-JNK/p38 MAPK-p21 Pathway in Premature Ovarian Insufficiency.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6634718}, pmid = {34367464}, issn = {1942-0994}, mesh = {Advanced Oxidation Protein Products/genetics/*metabolism ; Animals ; Apoptosis ; *Cell Cycle Checkpoints ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism ; Female ; G1 Phase ; Gene Expression Regulation ; Granulosa Cells/metabolism/pathology ; Humans ; JNK Mitogen-Activated Protein Kinases/genetics/*metabolism ; Primary Ovarian Insufficiency/genetics/metabolism/*pathology ; Prognosis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Resting Phase, Cell Cycle ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {The mechanism underlying the role of oxidative stress and advanced oxidation protein products (AOPPs) in the aetiology of premature ovarian insufficiency (POI) is poorly understood. Here, we investigated the plasma AOPP level in POI patients and the effects of AOPPs on granulosa cells both in vitro and in vivo. KGN cells were treated with different AOPP doses, and cell cycle distribution, intracellular reactive oxygen species (ROS), and protein expression levels were measured. Sprague-Dawley (SD) rats were treated daily with PBS, rat serum albumin, AOPP, or AOPP+ N-acetylcysteine (NAC) for 12 weeks to explore the effect of AOPPs on ovarian function. Plasma AOPP concentrations were significantly higher in both POI and biochemical POI patients than in controls and negatively correlated with anti-Müllerian hormone and the antral follicle count. KGN cells treated with AOPP exhibited G1/G0-phase arrest. AOPP induced G1/G0-phase arrest in KGN cells by activating the ROS-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK)-p21 pathway. Pretreatment with NAC, SP600125, SB203580, and si-p21 blocked AOPP-induced G1/G0-phase arrest. In SD rats, AOPP treatment increased the proportion of atretic follicles, and NAC attenuated the adverse effects of AOPPs in the ovary. In conclusion, we provide mechanistic evidence that AOPPs may induce cell cycle arrest in granulosa cells via the ROS-JNK/p38 MAPK-p21 pathway and thus may be a novel biomarker of POI.}, } @article {pmid34366878, year = {2021}, author = {Ningappa, M and Adenuga, M and Ngo, KA and Mohamed, N and Narayanan, T and Prasadan, K and Ashokkumar, C and Das, J and Schmitt, L and Hartman, H and Sehrawat, A and Salgado, CM and Reyes-Mugica, M and Gittes, GK and Lo, CW and Subramaniam, S and Sindhi, R}, title = {Mechanisms of Impaired Lung Development and Ciliation in Mannosidase-1-Alpha-2 (Man1a2) Mutants.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {658518}, pmid = {34366878}, issn = {1664-042X}, support = {R01 DK109365/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Ciliary defects cause heterogenous phenotypes related to mutation burden which lead to impaired development. A previously reported homozygous deletion in the Man1a2 gene causes lethal respiratory failure in newborn pups and decreased lung ciliation compared with wild type (WT) pups. The effects of heterozygous mutation, and the potential for rescue are not known.

PURPOSE: We hypothesized that survival and lung ciliation, (a) would decrease progressively in Man1a2 [+/-] heterozygous and Man1a2 [-/-] null newborn pups compared with WT, and (b) could be enhanced by gestational treatment with N-Acetyl-cysteine (NAC), an antioxidant.

METHODS: Man1a2[+/-] adult mice were fed NAC or placebo from a week before breeding through gestation. Survival of newborn pups was monitored for 24 h. Lungs, liver and tails were harvested for morphology, genotyping, and transcriptional profiling.

RESULTS: Survival (p = 0.0001, Kaplan-Meier) and percent lung ciliation (p = 0.0001, ANOVA) measured by frequency of Arl13b[+] respiratory epithelial cells decreased progressively, as hypothesized. Compared with placebo, gestational NAC treatment enhanced (a) lung ciliation in pups with each genotype, (b) survival in heterozygous pups (p = 0.017) but not in WT or null pups. Whole transcriptome of lung but not liver demonstrated patterns of up- and down-regulated genes that were identical in living heterozygous and WT pups, and completely opposite to those in dead heterozygous and null pups. Systems biology analysis enabled reconstruction of protein interaction networks that yielded functionally relevant modules and their interactions. In these networks, the mutant Man1a2 enzyme contributes to abnormal synthesis of proteins essential for lung development. The associated unfolded protein, hypoxic and oxidative stress responses can be mitigated with NAC. Comparisons with the developing human fetal lung transcriptome show that NAC likely restores normal vascular and epithelial tube morphogenesis in Man1a2 mutant mice.

CONCLUSION: Survival and lung ciliation in the Man1a2 mutant mouse, and its improvement with N-Acetyl cysteine is genotype-dependent. NAC-mediated rescue depends on the central role for oxidative and hypoxic stress in regulating ciliary function and organogenesis during development.}, } @article {pmid34363627, year = {2021}, author = {An, J and Yang, J and Wei, Y and Liu, Y and Song, Y and Zhang, Z and Pan, Y}, title = {Identification of the metabolites of rhapontigenin in rat and human by ultra-high-performance liquid chromatography-high-resolution mass spectrometry.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {35}, number = {20}, pages = {e9180}, doi = {10.1002/rcm.9180}, pmid = {34363627}, issn = {1097-0231}, mesh = {Animals ; Chromatography, High Pressure Liquid/methods ; Hepatocytes/chemistry/metabolism ; Humans ; Male ; Microsomes, Liver/chemistry/metabolism ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization/methods ; Stilbenes/*chemistry/*metabolism/urine ; }, abstract = {RATIONALE: Rhapontigenin, a stilbene compound isolated from the medicinal plant of rhubarb rhizomes, has shown a variety of biological activities. The purpose of this study was to identify and characterize the metabolites of rhapontigenin in rat liver microsomes, hepatocytes, urine, and human liver microsomes and hepatocytes.

METHODS: The samples were analyzed by ultra-high-performance liquid chromatography combined with electrospray ionization quadrupole/orbitrap high-resolution mass spectrometry (UPLC-Q/Orbitrap-HRMS). The structures of the metabolites were interpreted by MS, MS/MS data, and elemental compositions.

RESULTS: A total of 11 metabolites were detected and tentatively identified. M1, identified as piceatannol, was unambiguously identified using reference standard. Our results suggested that rhapontigenin was metabolized through the following pathways: (a) demethylation to produce piceatannol (M1), which further underwent oxidation to form ortho-quinone intermediate. This intermediate was reactive and conjugated with GSH (M10 and M11), which were further converted into N-acetyl-cysteine and excreted in urine. M1 also underwent sulfation (M8) and glucuronidation (M5); (b) direct sulfation, forming M6 and M7; and (c) direct glucuronidation to form M2, M3, and M4. Glucuronidation was a major metabolic pathway in hepatocytes and urine.

CONCLUSIONS: The current study provides an overview of the metabolism of rhapontigenin, which is of great importance for us to understand the disposition of this compound.}, } @article {pmid34361723, year = {2021}, author = {Cela-López, JM and Camacho Roldán, CJ and Gómez-Lizarraga, G and Martínez, V}, title = {A Natural Alternative Treatment for Urinary Tract Infections: Itxasol©, the Importance of the Formulation.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {15}, pages = {}, pmid = {34361723}, issn = {1420-3049}, mesh = {Acetylcysteine/chemistry/*therapeutic use ; Anti-Bacterial Agents/chemistry/therapeutic use ; Anti-Inflammatory Agents/chemistry/therapeutic use ; Antifungal Agents/chemistry/therapeutic use ; Arbutin/chemistry/*therapeutic use ; Biofilms/drug effects/growth & development ; Biological Products/chemistry/*therapeutic use ; Biomimetic Materials/chemistry/therapeutic use ; Candida/drug effects/growth & development/pathogenicity ; Drug Combinations ; Female ; Gram-Negative Bacteria/drug effects/growth & development/pathogenicity ; Gram-Positive Bacteria/drug effects/growth & development/pathogenicity ; Humans ; Male ; Microbial Sensitivity Tests ; Umbelliferones/chemistry/*therapeutic use ; Urinary Tract Infections/*drug therapy/microbiology/pathology ; }, abstract = {Genito-urinary tract infections have a high incidence in the general population, being more prevalent among women than men. These diseases are usually treated with antibiotics, but very frequently, they are recurrent and lead to the creation of resistance and are associated with increased morbidity and mortality. For this reason, it is necessary to develop new compounds for their treatment. In this work, our objective is to review the characteristics of the compounds of a new formulation called Itxasol© that is prescribed as an adjuvant for the treatment of UTIs and composed of β-arbutin, umbelliferon and n-acetyl cysteine. This formulation, based on biomimetic principles, makes Itxasol© a broad-spectrum antibiotic with bactericidal, bacteriostatic and antifungal properties that is capable of destroying the biofilm and stopping its formation. It also acts as an anti-inflammatory agent, without the adverse effects associated with the recurrent use of antibiotics that leads to renal nephrotoxicity and other side effects. All these characteristics make Itxasol© an ideal candidate for the treatment of UTIs since it behaves like an antibiotic and with better characteristics than other adjuvants, such as D-mannose and cranberry extracts.}, } @article {pmid34358106, year = {2021}, author = {Chittasupho, C and Junmahasathien, T and Chalermmongkol, J and Wongjirasakul, R and Leesawat, P and Okonogi, S}, title = {Suppression of Intracellular Reactive Oxygen Species in Human Corneal Epithelial Cells via the Combination of Quercetin Nanoparticles and Epigallocatechin Gallate and In Situ Thermosensitive Gel Formulation for Ocular Drug Delivery.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {7}, pages = {}, pmid = {34358106}, issn = {1424-8247}, support = {JRCMU2564_014//Chiang Mai University/ ; }, abstract = {Oxidative stress can cause several severe ophthalmological diseases. In this study, we developed a thermosensitive gel as a delivery system for two antioxidant substances, namely, quercetin and epigallocatechin gallate. The quercetin was loaded in the PLGA nanoparticles using a solvent displacement method. The physical and chemical stability of the quercetin nanoparticles were evaluated, and the degradation kinetics of the quercetin in the nanoparticles was investigated. The in vitro antioxidant and intracellular reactive oxygen species inhibition of the quercetin nanoparticles, combined with the epigallocatechin gallate (EGCG), were determined using a 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and a 2,7-dichlorodihydrofluorescein fluorescent probes, respectively. The thermosensitive gel loaded with the quercetin nanoparticles and EGCG was formulated. We confirmed that quercetin nanoparticles displayed the desired physical characteristics, release kinetics, and stability. The combination of quercetin nanoparticles and EGCG suggested the additive effect of antioxidant activity. We also demonstrated the superior intracellular ROS inhibition activity of the quercetin nanoparticles and EGCG with n-acetyl cysteine. The thermosensitive gel showed an appropriate gelation temperature and time for ocular drug delivery. Our results provide promising prospects for applying the thermosensitive gel loaded with quercetin nanoparticles and EGCG as an efficient drug delivery system for antioxidant activity in human corneal epithelial cells.}, } @article {pmid34356340, year = {2021}, author = {Minati, MA and Libert, M and Dahou, H and Jacquemin, P and Assi, M}, title = {N-Acetylcysteine Reduces the Pro-Oxidant and Inflammatory Responses during Pancreatitis and Pancreas Tumorigenesis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {7}, pages = {}, pmid = {34356340}, issn = {2076-3921}, support = {n°1. B.017.19F//Fonds De La Recherche Scientifique - FNRS/ ; #2018-076//Fondation contre le Cancer/ ; #7.8515.18//Télévie/ ; }, abstract = {Pancreatitis, an inflammation of the pancreas, appears to be a main driver of pancreatic cancer when combined with Kras mutations. In this context, the exact redox mechanisms are not clearly elucidated. Herein, we treated mice expressing a Kras[G12D] mutation in pancreatic acinar cells with cerulein to induce acute pancreatitis. In the presence of Kras[G12D], pancreatitis triggered significantly greater redox unbalance and oxidative damages compared to control mice expressing wild-type&nbsp;Kras alleles. Further analyses identified the disruption in glutathione metabolism as the main redox event occurring during pancreatitis. Compared to the wild-type background, Kras[G12D]-bearing mice showed a greater responsiveness to treatment with a thiol-containing compound, N-acetylcysteine (NAC). Notably, NAC treatment increased the pancreatic glutathione pool, reduced systemic markers related to pancreatic and liver damages, limited the extent of pancreatic edema and fibrosis as well as reduced systemic and pancreatic oxidative damages. The protective effects of NAC were, at least, partly due to a decrease in the production of tumor necrosis factor-α (TNF-α) by acinar cells, which was concomitant with the inhibition of NF-κB(p65) nuclear translocation. Our data provide a rationale to use thiol-containing compounds as an adjuvant therapy to alleviate the severity of inflammation during pancreatitis and pancreatic tumorigenesis.}, } @article {pmid34351926, year = {2021}, author = {Kardos, P and Beeh, KM and Sent, U and Bissmann, G}, title = {Impact of guideline awareness on the counseling of patients with acute cough among general practitioners and pharmacy personnel.}, journal = {PloS one}, volume = {16}, number = {8}, pages = {e0254086}, pmid = {34351926}, issn = {1932-6203}, mesh = {Acute Disease ; Aged ; Cough/*drug therapy ; *Counseling ; Female ; *General Practitioners ; Guideline Adherence ; Humans ; Male ; Middle Aged ; Nonprescription Drugs/*administration & dosage ; *Pharmacies ; }, abstract = {OBJECTIVE: To explore the awareness and knowledge of applicable guidelines on acute cough among general practitioners, pharmacists and pharmacy technicians and to compare their recommendation behavior and clinical decision making to the evidence-based recommendation in the applicable guidelines.

METHODS: An anonymous online survey was performed among 303 members of an existing panel of healthcare professionals (HCPs). They were presented with a hypothetical case vignette representative of their daily practice and asked for their treatment recommendations. After being shown an excerpt from the applicable guidelines, these questions were repeated.

RESULTS: Forty-six % of participants reported to seek information on cough and respiratory conditions very often or often. Among 12 non-prescription treatments-commonly used over-the-counter-products for acute cough, HCPs most often recommended various plant extract-based products (phytotherapeutic remedies) for the acute cough case, whereas chemically defined options such as ambroxol or N-acetyl-cysteine were recommended less often. Following presentation of the guidelines excerpt, recommendations of the phytotherapeutic remedies decreased moderately whereas that of the guideline-recommended ambroxol more than doubled. Among stated reasons for the recommendation guideline conformity increased from 5% to 35% among the top-3 reasons.

CONCLUSIONS: The recommendations for the treatment of acute cough by professionals involved in primary healthcare deviated considerably from the applicable guideline recommendation but changed after presentation of a guidelines excerpt and knowledge thereof. We conclude that dissemination of applicable guideline knowledge is relevant to improve evidence-based healthcare and clinical decision making.}, } @article {pmid34349610, year = {2021}, author = {Kwak, MS and Lim, JW and Kim, H}, title = {Astaxanthin Inhibits Interleukin-6 Expression in Cerulein/Resistin-Stimulated Pancreatic Acinar Cells.}, journal = {Mediators of inflammation}, volume = {2021}, number = {}, pages = {5587297}, pmid = {34349610}, issn = {1466-1861}, mesh = {Acinar Cells/drug effects/*metabolism ; Adipokines/metabolism ; Animals ; Anti-Inflammatory Agents/chemistry ; Calcium/chemistry/metabolism ; Cell Line ; Ceruletide/*chemistry ; Chelating Agents/chemistry ; Interleukin-6/*metabolism ; NADPH Oxidases/metabolism ; Obesity/metabolism ; Oxidative Stress ; Pancreas/drug effects/*metabolism ; Rats ; Reactive Oxygen Species ; Resistin/*chemistry ; Xanthophylls/pharmacology ; }, abstract = {Acute pancreatitis is a common clinical condition with increasing the proinflammatory mediators, including interleukin-6 (IL-6). Obesity is a negative prognostic factor in acute pancreatitis. Obese patients with acute pancreatitis have a higher systemic inflammatory response rate. Levels of serum resistin, an adipocytokine secreted by fat tissues, increase with obesity. Cerulein, a cholecystokinin analog, induces calcium (Ca[2+]) overload, oxidative stress, and IL-6 expression in pancreatic acinar cells, which are hallmarks of acute pancreatitis. A recent study showed that resistin aggravates the expression of inflammatory cytokines in cerulein-stimulated pancreatic acinar cells. We aimed to investigate whether resistin amplifies cerulein-induced IL-6 expression and whether astaxanthin (ASX), an antioxidant carotenoid with anti-inflammatory properties, inhibits ceruelin/resistin-induced IL-6 expression in pancreatic acinar AR42J cells. We found that resistin enhanced intracellular Ca[2+] levels, NADPH oxidase activity, intracellular reactive oxygen species (ROS) production, NF-κB activity, and IL-6 expression in cerulein-stimulated AR42J cells, which were inhibited by ASX in a dose-dependent manner. The calcium chelator BAPTA-AM inhibited cerulein/resistin-induced NADPH oxidase activation and ROS production. Antioxidant N-acetyl cysteine (NAC) and ML171, a specific NADPH oxidase 1 inhibitor, suppressed cerulein/resistin-induced ROS production, NF-κB activation, and IL-6 expression. In conclusion, ASX inhibits IL-6 expression, by reducing Ca[2+] overload, NADPH oxidase-mediated ROS production, and NF-κB activity in cerulein/resistin-stimulated pancreatic acinar cells. Consumption of ASX-rich foods could be beneficial for preventing or delaying the incidence of obesity-associated acute pancreatitis.}, } @article {pmid34346781, year = {2021}, author = {Pascoe, CD and Roy, N and Turner-Brannen, E and Schultz, A and Vaghasiya, J and Ravandi, A and Halayko, AJ and West, AR}, title = {Oxidized phosphatidylcholines induce multiple functional defects in airway epithelial cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {321}, number = {4}, pages = {L703-L717}, doi = {10.1152/ajplung.00539.2020}, pmid = {34346781}, issn = {1522-1504}, support = {156616//CIHR/Canada ; }, mesh = {Asthma/*pathology ; Cell Line ; Cell Movement/physiology ; DNA/biosynthesis ; Epithelial Cells/*metabolism ; Humans ; Lipid Metabolism/physiology ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Phosphatidylcholines/*metabolism ; Phospholipids/metabolism ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/cytology/*pathology ; Respiratory System ; Tight Junctions/physiology ; }, abstract = {Oxidative stress is a hallmark of numerous airway diseases, contributing to extensive cell and tissue damage. Cell membranes and the airway mucosal lining are rich in phospholipids that are particularly susceptible to oxidative attack, producing bioactive molecules including oxidized phosphatidylcholines (OxPCs). With the recent discovery of elevated OxPCs in patients with asthma after allergen challenge, we hypothesized that OxPCs directly contribute to disease by inducing airway epithelial cell dysfunction. We found that OxPCs induced concentration-dependent cell stress and loss of viability in BEAS-2B and Calu-3 cell lines and primary human epithelial cells. These responses corresponded with significant epithelial barrier dysfunction, which was further compounded when combining OxPCs with an epithelial wound. OxPCs inhibited DNA synthesis and migration required to reestablish barrier function, but cells recovered if OxPCs were washed off soon after treatment. OxPCs induced generation of reactive oxygen species, lipid peroxidation, and mitochondrial dysfunction, raising the possibility that OxPCs cause pathological lipid metabolism in a self-propagating cycle. The oxidative stress induced by OxPCs could not be abrogated by putative OxPC receptor blockers, but partial recovery of barrier function, proliferation, and lipid peroxidation could be achieved with the antioxidant N-acetyl cysteine. In summary, we have identified OxPCs as a group of bioactive molecules that significantly impair multiple facets of epithelial cell function, consistent with pathological features of asthma. Further characterization of the mechanisms by which OxPCs affect epithelial cells could yield new insights into how oxidative stress contributes to the pathogenesis of airway disease.}, } @article {pmid34345305, year = {2021}, author = {Hattori, K and Takano, N and Kazama, H and Moriya, S and Miyake, K and Hiramoto, M and Tsukahara, K and Miyazawa, K}, title = {Induction of synergistic non-apoptotic cell death by simultaneously targeting proteasomes with bortezomib and histone deacetylase 6 with ricolinostat in head and neck tumor cells.}, journal = {Oncology letters}, volume = {22}, number = {3}, pages = {680}, pmid = {34345305}, issn = {1792-1082}, abstract = {Following surgery and chemoradiation, ~50% of patients with locally advanced head and neck tumors experience relapse within the first two years, with a poor prognosis. Therefore, a novel therapeutic approach is required. The aim of the present study was to investigate the effect of combination treatment with the proteasome inhibitor bortezomib (BTZ), and ricolinostat (RCS), a specific inhibitor of histone deacetylase 6 (HDAC6), on CAL27 and Detroit562 head and neck cancer cells. BTZ and RCS exhibited cytotoxicity in a dose- and time-dependent manner. Simultaneous treatment with BTZ and RCS resulted in the synergistic enhancement of non-apoptotic cell death and autophagy. The receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor, necrostatin, but not the autophagy inhibitor, 3-methyladenine, attenuated the cytotoxicity of combined BTZ and RCS treatment. Thus, necroptosis [type-III programmed cell death (PCD)], but not autophagic cell death (type-II PCD), appeared to contribute to the pronounced cytotoxicity. However, no phosphorylation of RIPK1 or mixed lineage kinase domain-like protein was detectable in response to BTZ or RCS. Furthermore, RCS induced α-tubulin acetylation and inhibited BTZ-induced aggresome formation along with endoplasmic reticulum stress loading. Combined treatment with BTZ and RCS enhanced the production of reactive oxygen species (ROS). The ROS scavenger, N-acetyl cysteine, abrogated the increase in cytotoxicity. These results suggest the potential therapeutic value of the dual targeting of the proteasome and HDCA6 for head and neck cancers through the induction of necroptosis-like cell death along with ROS generation.}, } @article {pmid34343907, year = {2021}, author = {Chen, C and Wang, S and Yu, L and Mueller, J and Fortunato, F and Rausch, V and Mueller, S}, title = {H2O2-mediated autophagy during ethanol metabolism.}, journal = {Redox biology}, volume = {46}, number = {}, pages = {102081}, pmid = {34343907}, issn = {2213-2317}, mesh = {Animals ; Autophagy ; Cytochrome P-450 CYP2E1/genetics ; Ethanol/toxicity ; *Hydrogen Peroxide ; *Liver Diseases, Alcoholic/genetics ; Mice ; }, abstract = {BACKGROUND: Alcoholic liver disease (ALD) is the most common liver disease worldwide and its underlying molecular mechanisms are still poorly understood. Moreover, conflicting data have been reported on potentially protective autophagy, the exact role of ethanol-metabolizing enzymes and ROS.

METHODS: Expression of LC3B, CYP2E1, and NOX4 was studied in a mouse model of acute ethanol exposure by immunoblotting and immunohistochemistry. Autophagy was further studied in primary mouse hepatocytes and huh7 cells in response to ethanol and its major intermediator acetaldehyde. Experiments were carried out in cells overexpressing CYP2E1 and knock down of NOX4 using siRNA. The response to external H2O2 was studied by using the GOX/CAT system. Autophagic flux was monitored using the mRFP-GFP-LC3 plasmid, while rapamycin and chloroquine served as positive and negative controls.

RESULTS: Acute ethanol exposure of mice over 24 h significantly induced autophagy as measured by LC3B expression but also induced the ROS-generating CYP2E1 and NOX4 enzymes. Notably, ethanol but not its downstream metabolite acetaldehyde induced autophagy in primary mouse hepatocytes. In contrast, autophagy could only be induced in huh7 cells in the presence of overexpressed CYP2E1. In addition, overexpression of NOX4 also significantly increased autophagy, which could be blocked by siRNA mediated knock down. The antioxidant N-acetylcysteine (NAC) also efficiently blocked CYP2E1-and NOX4-mediated induction of autophagy. Finally, specific and non-toxic production of H2O2 by the GOX/CAT system as evidenced by elevated peroxiredoxin (Prx-2) also induced LC3B which was efficiently blocked by NAC. H2O2 strongly increased the autophagic flux as measured by mRFP-GFP-LC3 plasmid.

CONCLUSION: We here provide evidence that short-term ethanol exposure induces autophagy in hepatocytes both in vivo and in vitro through the generation of ROS. These data suggest that suppression of autophagy by ethanol is most likely due to longer alcohol exposure during chronic alcohol consumption with the accumulation of e.g. misfolded proteins.}, } @article {pmid34340627, year = {2021}, author = {Dawra, S and Kumar, A and Kumar, D and Ari, B and Srivastava, S and Manrai, M}, title = {Rodenticide-induced acute liver failure - Uncommon presentation of commonly available poison.}, journal = {Tropical doctor}, volume = {51}, number = {4}, pages = {561-565}, doi = {10.1177/00494755211031019}, pmid = {34340627}, issn = {1758-1133}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Humans ; *Liver Failure, Acute/chemically induced/diagnosis ; Phosphorus ; *Poisons ; Rats ; *Rodenticides ; }, abstract = {Rodenticide or 'rat poison' is easily available in a predominantly agrarian economy such as India. Metal phosphides or yellow phosphorous are two common rodenticides. Acute liver failure caused by accidental or suicidal poisoning with rodenticides has been infrequently reported in literature. Liver transplantation offers the best chances of survival in severe intoxication. However, the availability of liver transplantation in resource-limited settings presents a challenge. N-acetyl cysteine has been successfully used in paracetamol poisoning. Its use in rodenticide-induced acute liver failure is not so well known. We report three cases of rodenticide-related acute liver failure, one of them being a pregnant lady. All three patients were given N-acetyl cysteine and two patients improved. It is possible that the administration of N-acetyl cysteine contributed to the improvement in these two.}, } @article {pmid34339721, year = {2022}, author = {Eghtedari, Y and Oh, LJ and Girolamo, ND and Watson, SL}, title = {The role of topical N-acetylcysteine in ocular therapeutics.}, journal = {Survey of ophthalmology}, volume = {67}, number = {2}, pages = {608-622}, doi = {10.1016/j.survophthal.2021.07.008}, pmid = {34339721}, issn = {1879-3304}, mesh = {*Acetylcysteine/administration & dosage/chemistry ; Administration, Topical ; Chitosan ; *Cornea/drug effects ; *Dry Eye Syndromes/drug therapy ; Humans ; }, abstract = {N-acetylcysteine (NAC) was first discovered as a mucolytic agent in 1960. We investigate the role of topical NAC in ocular therapeutics, including its mechanism of action, current applications, and adverse effects. A systematic search of peer-reviewed articles identified 106 references including in vitro, in vivo and clinical studies on the use of NAC in the treatment of ocular diseases. NAC can be synthetically manufactured, and its mechanisms of action include mucolysis, scavenging hydroxyl radicals, and modulation of inflammatory cascades. These unique properties contribute to the diverse applications of NAC, including its steroid-sparing potential. NAC has been used topically in the treatment of corneal wounds, chemical injuries, keratitis, dry eye disease and meibomian gland dysfunction. The clinical benefits of NAC are evident over a wide range of concentrations, the most common being 5-10% topical NAC applied four times daily. Adverse effects such as corneal necrosis are rare, but have been reported with higher doses. NAC also has potential applications in laser epithelial keratomileusis, diabetic eye disease, retinitis pigmentosa, senile nuclear cataracts, macular degeneration, and cigarette smoke-induced corneal damage. Recently, chitosan-NAC has been used as a nanocarrier for the topical administration of medications to the ocular surface. Owing to its potent antioxidant, anti-inflammatory and mucolytic properties, topical NAC has had extensive use in the treatment of ocular pathology.}, } @article {pmid34336301, year = {2021}, author = {Chiu, MH and Jaworska, N and Li, NL and Yarema, M}, title = {Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis.}, journal = {Case reports in critical care}, volume = {2021}, number = {}, pages = {6695967}, pmid = {34336301}, issn = {2090-6420}, abstract = {Acetaminophen overdose is one of the most common causes of acute hepatic failure in the developed world. There is strong evidence for N-acetylcysteine (NAC) as a safe and effective antidote for acetaminophen toxicity. However, there is less clarity in the management of massive overdoses (acute, single ingestions > 500 mg/kg with 4-hour equivalent concentrations ~6000 μmol/L) which are often associated with metabolic acidosis and multiorgan dysfunction. In such ingestions, the role of adjuvant treatments such as fomepizole and extracorporeal removal is unclear. We present a case of a 20-year-old female presenting with an acute ingestion of over 120 grams (1764.7 mg/kg) and an acetaminophen concentration of 5880 μmol/L who developed refractory shock, decreased level of consciousness, and metabolic acidosis requiring mechanical ventilation and vasopressor support. She was treated with gastric decontamination with activated charcoal, IV NAC, fomepizole, and hemodialysis. The patient had complete clearance of acetaminophen by 32 hours after presentation and normalization of her acid base and hemodynamic status without any organ failure. This case highlights the potential benefit of a triple strategy of NAC, fomepizole, and early hemodialysis in massive acetaminophen overdose, potentially sparing complications of prolonged intubation and ICU hospitalization.}, } @article {pmid34332981, year = {2021}, author = {Sun, L and Jiang, Y and Yan, X and Dai, X and Huang, C and Chen, L and Li, T and Zhang, Y and Xiao, H and Yang, M and Xiang, L and Zhang, Y and Chen, S and Li, S and Chen, A and He, F and Lian, J}, title = {Dichloroacetate enhances the anti-tumor effect of sorafenib via modulating the ROS-JNK-Mcl-1 pathway in liver cancer cells.}, journal = {Experimental cell research}, volume = {406}, number = {1}, pages = {112755}, doi = {10.1016/j.yexcr.2021.112755}, pmid = {34332981}, issn = {1090-2422}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/drug effects ; Cell Line, Tumor ; Dichloroacetic Acid/*pharmacology ; Drug Resistance, Neoplasm/drug effects/*genetics ; Drug Synergism ; Gene Expression Regulation, Neoplastic ; Hepatocytes/drug effects/metabolism/pathology ; Humans ; Liver Neoplasms/*drug therapy/genetics/metabolism/pathology ; MAP Kinase Kinase 4/antagonists & inhibitors/*genetics/metabolism ; Male ; Mice, Nude ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors/*genetics/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/antagonists & inhibitors/metabolism ; Signal Transduction ; Sorafenib/*pharmacology ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; Mice ; }, abstract = {Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically up-regulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor 'SP'600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be beneficial for further clinical application of sorafenib in liver cancer treatment.}, } @article {pmid34332247, year = {2021}, author = {He, Z and Zhang, Y and Zhang, H and Zhou, C and Ma, Q and Deng, P and Lu, M and Mou, Z and Lin, M and Yang, L and Li, Y and Yue, Y and Pi, H and Lu, Y and He, M and Zhang, L and Chen, C and Zhou, Z and Yu, Z}, title = {NAC antagonizes arsenic-induced neurotoxicity through TMEM179 by inhibiting oxidative stress in Oli-neu cells.}, journal = {Ecotoxicology and environmental safety}, volume = {223}, number = {}, pages = {112554}, doi = {10.1016/j.ecoenv.2021.112554}, pmid = {34332247}, issn = {1090-2414}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Apoptosis ; *Arsenic/metabolism/toxicity ; Mice ; Mitochondria/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Arsenic is one of the most common environmental pollutants. Neurotoxicity induced by arsenic has become a major public health concern. However, the effects of arsenic-induced neurotoxicity in the brain and the underlying molecular mechanisms are not well understood. N-acetyl-cysteine (NAC) is a thiol-based antioxidant that can antagonize heavy metal-induced neurotoxicity by scavenging reactive oxygen species (ROS). Here, we used the mouse oligodendrocyte precursor cell (OPC) line Oli-neu to explore the neurotoxic effects of arsenic and the protective effects of NAC. We found that arsenic exposure decreased cell viability, increased oxidative stress, caused mitochondrial dysfunction, and led to apoptosis of Oli-neu cells. Furthermore, we revealed that NAC treatment reversed these neurotoxic effects of arsenic. TMEM179, a key membrane protein, was found highly expressed in OPCs and to be an important factor in maintaining mitochondrial functions. We found that TMEM179 played a critical role in mediating the neurotoxic effects of arsenic and the protective role of NAC. PKCβ is a downstream factor through which TMEM179 regulates the expression of apoptosis-related proteins. This study improves our understanding of the neurotoxic effects and mechanisms of arsenic exposure and the protective effects of NAC. It also identifies a potential molecular target, TMEM179, for the treatment of arsenic-induced neurotoxicity.}, } @article {pmid34332028, year = {2021}, author = {Schulte, MHJ and Goudriaan, AE and Boendermaker, WJ and van den Brink, W and Wiers, RW}, title = {The effect of N-acetylcysteine and working memory training on glutamate concentrations in the dACC and rACC in regular cocaine users - A randomized proof of concept study.}, journal = {Neuroscience letters}, volume = {762}, number = {}, pages = {136146}, doi = {10.1016/j.neulet.2021.136146}, pmid = {34332028}, issn = {1872-7972}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cocaine-Related Disorders/*therapy ; Double-Blind Method ; Glutamic Acid/*drug effects/metabolism ; Gyrus Cinguli/*drug effects/metabolism ; Humans ; *Learning ; Male ; Memory, Short-Term ; Middle Aged ; Proof of Concept Study ; }, abstract = {INTRODUCTION: Current treatments for cocaine use disorder (CUD) are not very effective and better treatments are needed. This study investigates the effectiveness of a combined intervention that targets the assumed underlying glutamate pathology in cocaine users. To this end, the combined effects of N-acetylcysteine (NAC) and working memory (WM) training on glutamate concentrations in the dorsal and rostral ACC were investigated in a randomized, double-blind placebo-controlled design.

METHODS: In this study, 38 regular cocaine-using men were randomized to either 25-days with 2400 mg/day NAC and WM-training or 25 days with placebo with WM-training. Cocaine use, impulsivity, and glutamate concentrations in the dACC and rACC using proton Magnetic Resonance Spectroscopy were assessed at baseline and after treatment.

RESULTS: Twenty-four participants completed the study, of which 9 received NAC and 15 received placebo. There were no baseline correlations of glutamate concentrations in the dACC or rACC with cocaine use measures or impulsivity. Additionally, there were no effects of NAC, WM-training, or the combination thereof on (changes in) glutamate concentrations in the dACC or rACC.

DISCUSSION: This randomized proof of concept study could not confirm our hypotheses. Possible explanations are insufficient power and the possible absence of deviant baseline glutamate concentrations in the included participants. Future studies should consider larger samples and a non-using control group to confirm baseline deviations in glutamate in cocaine users.}, } @article {pmid34330957, year = {2021}, author = {Picchi, SC and de Souza E Silva, M and Saldanha, LL and Ferreira, H and Takita, MA and Caldana, C and de Souza, AA}, title = {GC-TOF/MS-based metabolomics analysis to investigate the changes driven by N-Acetylcysteine in the plant-pathogen Xanthomonas citri subsp. citri.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {15558}, pmid = {34330957}, issn = {2045-2322}, mesh = {Acetylcysteine/*metabolism ; Amino Acids/metabolism ; Cell Membrane/metabolism ; Citrus/metabolism ; Gas Chromatography-Mass Spectrometry/*methods ; Glutamine/metabolism ; Metabolomics/*methods ; Xanthomonas/*metabolism ; }, abstract = {N-Acetylcysteine (NAC) is an antioxidant, anti-adhesive, and antimicrobial compound. Even though there is much information regarding the role of NAC as an antioxidant and anti-adhesive agent, little is known about its antimicrobial activity. In order to assess its mode of action in bacterial cells, we investigated the metabolic responses triggered by NAC at neutral pH. As a model organism, we chose the Gram-negative plant pathogen Xanthomonas citri subsp. citri (X. citri), the causal agent of citrus canker disease, due to the potential use of NAC as a sustainable molecule against phytopathogens dissemination in citrus cultivated areas. In presence of NAC, cell proliferation was affected after 4 h, but damages to the cell membrane were observed only after 24 h. Targeted metabolite profiling analysis using GC-MS/TOF unravelled that NAC seems to be metabolized by the cells affecting cysteine metabolism. Intriguingly, glutamine, a marker for nitrogen status, was not detected among the cells treated with NAC. The absence of glutamine was followed by a decrease in the levels of the majority of the proteinogenic amino acids, suggesting that the reduced availability of amino acids affect protein synthesis and consequently cell proliferation.}, } @article {pmid34329734, year = {2021}, author = {Gaisina, IN and Hushpulian, DM and Gaisin, AM and Kazakov, EH and Ammal Kaidery, N and Ahuja, M and Poloznikov, AA and Gazaryan, IG and Thatcher, GRJ and Thomas, B}, title = {Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs.}, journal = {Neurochemistry international}, volume = {149}, number = {}, pages = {105148}, pmid = {34329734}, issn = {1872-9754}, support = {R01 NS101967/NS/NINDS NIH HHS/United States ; }, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Aspirin/*pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Humans ; NF-E2-Related Factor 2/agonists/*metabolism ; Prodrugs/*pharmacology ; Protein Structure, Tertiary ; }, abstract = {Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other conditions. A library of aspirin derivatives of various scaffolds potentially activating Nrf2 has been tested in Neh2-luc reporter assay which screens for direct Nrf2 protein stabilizers working via disruption of Nrf2-Keap1 interaction. Most aspirin prodrugs had a pro-alkylating or pro-oxidant motif in the structure and, therefore, were toxic at high concentrations. However, among the active compounds, we identified a molecule resembling a well-known Nrf2 displacement activator, bis-1,4-(4-methoxybenzenesulfonamidyl) naphthalene (NMBSA). The direct comparison of the newly identified compound with NMBSA and its improved analog in the reporter assay showed no quenching with N-acetyl cysteine, thus pointing to Nrf2 stabilization mechanism without cysteine alkylation. The potency of the newly identified compound in the reporter assay was much stronger than NMBSA, despite its inhibitory action in the commercial fluorescence polarization assay was observed only in the millimolar range. Molecular docking predicted that mono-deacetylation of the novel prodrug should generate a potent displacement activator. The time-course of reporter activation with the novel prodrug had a pronounced lag-period pointing to a plausible intracellular transformation leading to an active product. Treatment of the novel prodrug with blood plasma or cell lysate demonstrated stepwise deacetylation as judge by liquid chromatography-mass spectrometry (LC-MS). Hence, the esterase-catalyzed hydrolysis of the prodrug liberates only acetyl groups from aspirin moiety and generates a potent Nrf2 activator. The discovered mechanism of prodrug activation makes the newly identified compound a promising lead for future optimization studies.}, } @article {pmid34326284, year = {2021}, author = {Keshtkarjahromi, M and Mariscal, J and Dempsey, K and Tonarelli, S}, title = {Treatment of Severe Excoriation Disorder With Mirtazapine: A Case Report.}, journal = {Clinical neuropharmacology}, volume = {44}, number = {5}, pages = {189-190}, doi = {10.1097/WNF.0000000000000467}, pmid = {34326284}, issn = {1537-162X}, mesh = {Antidepressive Agents ; *Antipsychotic Agents/therapeutic use ; Female ; Humans ; *Mental Disorders/drug therapy ; Middle Aged ; Mirtazapine/therapeutic use ; Selective Serotonin Reuptake Inhibitors ; }, abstract = {OBJECTIVE: Excoriation disorder is a disabling behavioral disorder characterized by compulsive and repetitive picking of the skin. Excoriation disorder has a lifetime prevalence of 3% to 5% in the general population, and it is most common in females. Its course is chronic, and it is characterized by fluctuating and frequent periods of exacerbation. Excoriation disorder is commonly comorbid with several psychiatric disorders. The treatment of this disorder is challenging and requires a multidisciplinary approach. Current literature has described an improvement in skin picking when patients are treated with fluoxetine or escitalopram; other studies have involved augmentation strategies using antipsychotics, such as olanzapine and aripiprazole; serotonin norepinephrine reuptake inhibitors; and N-acetyl-cysteine. Other pharmacological therapies include lamotrigine and opioid antagonists. Psychotherapies are additional nonpharmacological treatment modalities to consider in this condition.

METHODS: We report the case of a 60-year-old Hispanic woman with severe excoriation disorder and several psychiatric comorbidities who responded remarkably to augmentation treatment with mirtazapine.

CONCLUSION: Mirtazapine is a noradrenergic and specific serotonergic antidepressant, and its antihistaminergic effect can relieve skin itching and pain.}, } @article {pmid34325504, year = {2021}, author = {Lee, JY and Kim, DA and Choi, E and Lee, YS and Park, SJ and Kim, BJ}, title = {Aldosterone Inhibits In Vitro Myogenesis by Increasing Intracellular Oxidative Stress via Mineralocorticoid Receptor.}, journal = {Endocrinology and metabolism (Seoul, Korea)}, volume = {36}, number = {4}, pages = {865-874}, pmid = {34325504}, issn = {2093-5978}, mesh = {*Aldosterone/metabolism/pharmacology ; Animals ; Humans ; Mice ; Muscle Development/physiology ; Myoblasts/metabolism ; Oxidative Stress/physiology ; *Receptors, Mineralocorticoid/metabolism ; }, abstract = {BACKGROUND: Despite clinical evidence indicating poor muscle health in subjects with primary aldosteronism (PA), it is still unclear whether the role of aldosterone in muscle metabolism is direct or mediated indirectly via factors, such as electrolyte imbalance or impaired glucose uptake. As one approach to clarify this issue, we investigated the effect of aldosterone on in vitro myogenesis and the potential mechanism explaining it.

METHODS: Myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. Immunofluorescence, quantitative reversetranscription polymerase chain reaction, Western blot, viability, and migration analyses were performed for experimental research.

RESULTS: Recombinant aldosterone treatment suppressed muscle differentiation from mouse C2C12 myoblasts in a dose-dependent manner, and consistently reduced the expression of myogenic differentiation markers. Furthermore, aldosterone significantly increased intracellular reactive oxygen species (ROS) levels in myotubes, and treatment with N-acetyl cysteine, a potent biological thiol antioxidant, reversed the decrease of myotube area, myotube area per myotube, nucleus number per myotube, and fusion index due to aldosterone through decreasing oxidative stress. A binding enzyme-linked immunosorbent assay confirmed that mineralocorticoid receptor (MR) interacted with aldosterone in C2C12 myoblasts, while eplerenone, an MR inhibitor, blocked aldosterone-stimulated intracellular ROS generation during myogenesis and markedly attenuated the suppression of in vitro myogenesis by aldosterone.

CONCLUSION: These findings support the hypothesis that hypersecretion of aldosterone, like PA, directly contributes to muscular deterioration and suggest that antioxidants and/or MR antagonists could be effective therapeutic options to reduce the risk of sarcopenia in these patients.}, } @article {pmid34325292, year = {2022}, author = {Chen, X and Bi, M and Yang, J and Cai, J and Zhang, H and Zhu, Y and Zheng, Y and Liu, Q and Shi, G and Zhang, Z}, title = {Cadmium exposure triggers oxidative stress, necroptosis, Th1/Th2 imbalance and promotes inflammation through the TNF-α/NF-κB pathway in swine small intestine.}, journal = {Journal of hazardous materials}, volume = {421}, number = {}, pages = {126704}, doi = {10.1016/j.jhazmat.2021.126704}, pmid = {34325292}, issn = {1873-3336}, mesh = {Animals ; Cadmium/toxicity ; Inflammation/chemically induced ; Intestine, Small/metabolism ; *NF-kappa B/genetics/metabolism ; *Necroptosis ; Oxidative Stress ; Swine ; Tumor Necrosis Factor-alpha ; }, abstract = {Cadmium (Cd) is a toxic environmental pollutant and induces toxic effects to organism. Nevertheless, the mechanism of Cd-induced toxicity in swine remains obscure. To explore this, 10 healthy 6-week-old weaned swine were placed into two groups stochastically, the Cd group was treated with a commercial diet containing 20 mg/kg Cd for 40 days. The results of histopathological and ultrastructural observations showed typical necrosis features and inflammatory cell infiltration in Cd group. Excessive Cd suppressed T-AOC and SOD activities, increased MDA content and ROS levels. Cd diet elevated the expression of RIPK1, RIPK3, and MLKL to activate the RIPK3-dependent necroptosis pathway. Results of Th1 and Th2 cytokines indicated that the levels of IL-4, IL-6 and IL10 was increased, while the level of IFN-γ was decreased, illustrating Th1/Th2 immune imbalance leads to aggravate inflammatory responses. Cd activated the TNF-α/NF-κB pathway and induced inflammatory responses via increasing the expression of HO-1, IL-1β, iNOS, COX2. Heat shock proteins were notably elevated in response to inflammatory reactions. And these effects were inhibited by necrostatin-1 (Nec-1) and N-acetyl-cysteine (NAC). Altogether, these data demonstrated that Cd induced necroptosis and inflammation to aggravate small intestine injury in swine by increasing the excessive accumulation of ROS and imbalanced Th1/Th2, respectively.}, } @article {pmid34315111, year = {2021}, author = {Ho, MH and Yen, CH and Hsieh, TH and Kao, TJ and Chiu, JY and Chiang, YH and Hoffer, BJ and Chang, WC and Chou, SY}, title = {CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury.}, journal = {Redox biology}, volume = {46}, number = {}, pages = {102067}, pmid = {34315111}, issn = {2213-2317}, mesh = {Animals ; *Brain Concussion ; Chemokine CCL5 ; Glutathione Peroxidase/metabolism ; Hippocampus/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Glutathione Peroxidase GPX1 ; }, abstract = {Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C-C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor - N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1-3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.}, } @article {pmid34310944, year = {2021}, author = {Whitney, K and Nikulina, E and Rahman, SN and Alexis, A and Bergold, PJ}, title = {Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury.}, journal = {Experimental neurology}, volume = {345}, number = {}, pages = {113816}, pmid = {34310944}, issn = {1090-2430}, support = {R01 NS108190/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration & dosage ; Animals ; Brain/*drug effects/metabolism/pathology ; Brain Injuries, Traumatic/*drug therapy/metabolism/pathology ; Drug Administration Schedule ; Drug Therapy, Combination ; Free Radical Scavengers/administration & dosage ; Male ; Memory Disorders/drug therapy/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Minocycline/*administration & dosage ; Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Neuroprotective Agents/*administration & dosage ; Spatial Memory/*drug effects/physiology ; }, abstract = {Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials. Few drugs have been developed with therapeutic time windows sufficiently long enough to treat TBI because little is known about which brain functions can be targeted if therapy is delayed hours to days after injury. We identified multiple injury parameters that are improved by first initiating treatment with the drug combination minocycline (MINO) plus N-acetylcysteine (NAC) at 72 h after injury (MN72) in a mouse closed head injury (CHI) experimental TBI model. CHI produces spatial memory deficits resulting in impaired performance on Barnes maze, hippocampal neuronal loss, and bilateral damage to hippocampal neurons, dendrites, spines and synapses. MN72 treatment restores Barnes maze acquisition and retention, protects against hippocampal neuronal loss, limits damage to dendrites, spines and synapses, and accelerates recovery of microtubule associated protein 2 (MAP2) expression, a key protein in maintaining proper dendritic architecture and synapse density. These data show that in addition to the structural integrity of the dendritic arbor, spine and synapse density can be successfully targeted with drugs first dosed days after injury. Retention of substantial drug efficacy even when first dosed 72 h after injury makes MINO plus NAC a promising candidate to treat clinical TBI.}, } @article {pmid34308314, year = {2021}, author = {McKetin, R and Dean, OM and Turner, A and Kelly, PJ and Quinn, B and Lubman, DI and Dietze, P and Carter, G and Higgs, P and Sinclair, B and Reid, D and Baker, AL and Manning, V and Pas, NT and Thomas, T and Bathish, R and Raftery, DK and Wrobel, A and Saunders, L and Arunogiri, S and Cordaro, F and Hill, H and Hall, S and Clare, PJ and Mohebbi, M and Berk, M}, title = {N-acetylcysteine (NAC) for methamphetamine dependence: A randomised controlled trial.}, journal = {EClinicalMedicine}, volume = {38}, number = {}, pages = {101005}, pmid = {34308314}, issn = {2589-5370}, abstract = {BACKGROUND: Methamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence.

METHODS: A parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400 mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were p < 0.025 for primary outcomes and p < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257.

RESULTS: Participants (N = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo (n = 77) or NAC (n = 76). Both groups had a median (IQR) of 24 (15-28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean [SE] reduction of 7.3 [1.2]) days for placebo, 6.8 [1.2] for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4-4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6-7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or psychotic symptoms relative to placebo. Adverse events did not differ significantly between placebo and NAC groups.

INTERPRETATION: These findings suggest that take-home oral NAC has no significant effect on methamphetamine use or most clinically related outcomes amongst people who are dependent on the drug.}, } @article {pmid34307672, year = {2021}, author = {Dou, Q and Tong, H and Yang, Y and Zhang, H and Gan, H}, title = {PICK1 Deficiency Exacerbates Sepsis-Associated Acute Kidney Injury.}, journal = {BioMed research international}, volume = {2021}, number = {}, pages = {9884297}, pmid = {34307672}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/*etiology/*metabolism/pathology ; Animals ; Apoptosis ; Carrier Proteins/*metabolism ; Cell Cycle Proteins/antagonists & inhibitors/*deficiency/metabolism ; Cell Line ; Disease Models, Animal ; Epithelial Cells/drug effects/metabolism/pathology ; Humans ; Kidney Tubules, Proximal/pathology ; Lipopolysaccharides ; MAP Kinase Kinase Kinase 5/metabolism ; Male ; Mice, Inbred C57BL ; Nuclear Proteins/*metabolism ; Peroxides/metabolism ; Sepsis/*complications ; p38 Mitogen-Activated Protein Kinases/metabolism ; Mice ; }, abstract = {We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.}, } @article {pmid34306311, year = {2021}, author = {Yu, L and Yang, X and Li, X and Qin, L and Xu, W and Cui, H and Jia, Z and He, Q and Wang, Z}, title = {Pink1/PARK2/mROS-Dependent Mitophagy Initiates the Sensitization of Cancer Cells to Radiation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {5595652}, pmid = {34306311}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Autophagy/drug effects/*physiology ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mitochondria/*drug effects/metabolism ; Mitophagy/*drug effects/physiology ; Neoplasms/drug therapy/metabolism ; *Radiation, Ionizing ; Reactive Oxygen Species/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Autophagy plays a double-edged sword for cancer; particularly, mitophagy plays important roles in the selective degradation of damaged mitochondria. However, whether mitophagy is involved in killing effects of tumor cells by ionizing radiation (IR) and its underlying mechanism remain elusive. The purpose is to evaluate the effects of mitochondrial ROS (mROS) on autophagy after IR; furthermore, we hypothesized that KillerRed (KR) targeting mitochondria could induce mROS generation, subsequent mitochondrial depolarization, accumulation of Pink1, and recruitment of PARK2 to promote the mitophagy. Thereby, we would achieve a new strategy to enhance mROS accumulation and clarify the roles and mechanisms of radiosensitization by KR and IR. Our data demonstrated that IR might cause autophagy of both MCF-7 and HeLa cells, which is related to mitochondria and mROS, and the ROS scavenger N-acetylcysteine (NAC) could reduce the effects. Based on the theory, mitochondrial targeting vector sterile α- and HEAT/armadillo motif-containing protein 1- (Sarm1-) mtKR has been successfully constructed, and we found that ROS levels have significantly increased after light exposure. Furthermore, mitochondrial depolarization of HeLa cells was triggered, such as the decrease of Na[+]K[+] ATPase, Ca[2+]Mg[2+] ATPase, and mitochondrial respiratory complex I and III activities, and mitochondrial membrane potential (MMP) has significantly decreased, and voltage-dependent anion channel 1 (VDAC1) protein has significantly increased in the mitochondria. Additionally, HeLa cell proliferation was obviously inhibited, and the cell autophagic rates dramatically increased, which referred to the regulation of the Pink1/PARK2 pathway. These results indicated that mitophagy induced by mROS can initiate the sensitization of cancer cells to IR and might be regulated by the Pink1/PARK2 pathway.}, } @article {pmid34301364, year = {2021}, author = {Ham, J and Yun, BH and Lim, W and Song, G}, title = {Folpet induces mitochondrial dysfunction and ROS-mediated apoptosis in mouse Sertoli cells.}, journal = {Pesticide biochemistry and physiology}, volume = {177}, number = {}, pages = {104903}, doi = {10.1016/j.pestbp.2021.104903}, pmid = {34301364}, issn = {1095-9939}, mesh = {Animals ; *Apoptosis ; Male ; Mice ; Mitochondria ; Phthalimides/metabolism ; Reactive Oxygen Species/metabolism ; *Sertoli Cells/metabolism ; }, abstract = {Folpet is a phthalimide type of fungicide and has been used to control several crop diseases. Although it has adverse effects on the gastrointestinal tract, its mechanism and toxic effects on testis have not been demonstrated. In the present study, we elucidated the cytotoxic effect of folpet on the mouse Sertoli cell line, TM4. Our results revealed that folpet suppressed viability and proliferative capacity of TM4 cells and further inhibited 3D spheroid formation. Moreover, folpet impeded appropriate cell cycle progression and induced apoptotic cell death in TM4 cells. It disrupted the electrochemical gradient of mitochondria and calcium homeostasis in TM4 cells. Furthermore, endoplasmic reticulum stress-related proteins were activated in folpet-treated TM4 cells, and relative reactive oxygen species (ROS) production was also increased. N-acetylcysteine (NAC) treatment reinstated the folpet-induced ROS generation in TM4 cells. Additionally, NAC restored the proliferative capacity and reduced the apoptotic cells in folpet-treated TM4 cells. Collectively, we demonstrated that folpet causes ROS-mediated apoptotic cell death with mitochondrial dysfunction and calcium dysregulation in TM4 cells.}, } @article {pmid34299175, year = {2021}, author = {Paskal, W and Paskal, AM and Pietruski, P and Stachura, A and Pełka, K and Woessner, AE and Quinn, KP and Kopka, M and Galus, R and Wejman, J and Włodarski, P}, title = {N-Acetylcysteine Added to Local Anesthesia Reduces Scar Area and Width in Early Wound Healing-An Animal Model Study.}, journal = {International journal of molecular sciences}, volume = {22}, number = {14}, pages = {}, pmid = {34299175}, issn = {1422-0067}, support = {MNiSW/2019/106/DIR/NN3//Ministerstwo Nauki i Szkolnictwa Wyższego/ ; 1M15/NM1/17//Warszawski Uniwersytet Medyczny/ ; }, mesh = {Acetylcysteine/*pharmacology ; Anesthesia, Local/*methods ; Anesthetics, Local/*pharmacology ; Animals ; Cicatrix/*drug therapy/pathology ; *Disease Models, Animal ; Drug Therapy, Combination ; Free Radical Scavengers/*pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Wound Healing/*drug effects ; }, abstract = {The aim of the study was to evaluate if a pre-incisional N-acetylcysteine (NAC) treatment altered the process of wound healing in a rat model. The dorsal skin of 24 Sprague-Dawley rats was incised in six locations. Before the incisions were made, skin was injected either with lidocaine and epinephrine (one side) or with these agents supplemented with 0.015%, 0.03%, or 0.045% NAC (contralaterally). Photographic documentation of the wound healing process was made at 11 time points. Rats were sacrificed 3, 7, 14, or 60 days after incision to excise scars for histological analysis. They included: Abramov scale scoring, histomorphometry analysis, and collagen fiber arrangement assessment. Skin pretreated with 0.03% NAC produced the shortest scars at all analyzed time points, though this result was statistically insignificant. At this NAC concentration the scars had smaller areas on the third day and were narrower on the day 4 compared with all the other groups (p < 0.05). On day 7, at the same concentration of NAC, the scars had a higher superficial concentration index (p = 0.03) and larger dermal proliferation area (p = 0.04). NAC addition to pre-incisional anesthetic solution decreased wound size and width at an early stage of scar formation at all concentrations; however, with optimal results at 0.03% concentration.}, } @article {pmid34295982, year = {2021}, author = {Jawaid, H and Ali, MM and Khan, MU and Sami, S and Shaikh, MA}, title = {Efficacy and safety of N-acetylcysteine for the treatment of non-acetaminophen-induced acute liver failure: an updated systematic review and meta-analysis.}, journal = {Clinical and experimental hepatology}, volume = {7}, number = {2}, pages = {156-164}, pmid = {34295982}, issn = {2392-1099}, abstract = {AIM OF THE STUDY: N-acetylcysteine (NAC) is the treatment of choice for acetaminophen-induced liver injury. However, recent years have witnessed growing interest in its role in the treatment of acute liver failure (ALF) due to other aetiologies. This study aims to determine both its safety and efficacy by pooling data from multiple studies.

MATERIAL AND METHODS: A search was conducted for all controlled randomized/non-randomized studies that measured the efficacy and safety of NAC in adult patients with non-acetaminophen-induced acute liver failure (NAI-ALF). Transplant-free survival (TFS) was considered the primary endpoint, while secondary endpoints such as length of hospital stay, and incidence of adverse events during treatment, were included in our analysis. Data were pooled via a random-effects model, I [2] was used as a measure of heterogeneity, and publication bias was assessed via a funnel plot.

RESULTS: A total of 3 studies [2 randomized controlled trials (RCTs) and 1 non-randomized cohort] were pooled in this meta-analysis. TFS was significantly higher in patients given NAC, when compared to the placebo/control (PBO) group (RR = 1.54, CI = 1.19-1.98, p = 0.01, I [2] = 0.0%). No secondary endpoint was observed to have improved significantly in patients prescribed NAC: length of hospital stay (SMD = -0.405, CI = -1.44-0.63, p = 0.445, I [2] = 91.1%), renal failure (RR = 1.01, CI = 0.65-1.57, p = 0.967, I [2] = 21.3%), infections (RR = 1.18, CI = 0.91-1.52, p = 0.208, I [2] = 2.3%), pulmonary failure (RR = 1.19, CI = 0.57-2.49, p = 0.649, I [2] = 84.6%). Minimal side effects were reported in around 10-14% of the patients prescribed NAC.

CONCLUSIONS: NAC was shown to significantly improve TFS in adult patients with NAI-ALF, while no significant benefit was observed concerning the secondary endpoints of length of hospital stay and incidence of adverse effects.}, } @article {pmid34291011, year = {2021}, author = {Ghorbi, M and Rashidi, M and Olapour, A and Javaherforooshzadeh, F and Akhondzadeh, R}, title = {Effect of N-Acetylcysteine on the treatment of acute respiratory distress syndrome in mechanically ventilated patients admitted to the intensive care unit.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {35}, number = {}, pages = {87}, pmid = {34291011}, issn = {1016-1430}, abstract = {Background: N-acetylcysteine (NAC) is an antioxidant derived from the amino acid cysteine and is one of the drugs used in the treatment of respiratory diseases. The aim of this study was to investigate the effect of NAC on the treatment of acute respiratory distress syndrome in mechanically ventilated patients admitted to the intensive care unit. Methods: This study was a randomized clinical trial. Patients under mechanical ventilation admitted to the intensive care unit were examined. Patients in the intervention group received daily 150 mg/kg of NAC on the first day of admission and then 50 mg/kg up to the fourth day of admission. Patients in the control group received routine care. The vital signs, level of consciousness, and other important variables were recorded. Data were analyzed using statistical tests and SPSS software version 24. Results: There was no significant difference between MAP, heart rate, respiratory rate, O2Sat, APACHE II score, and pulmonary capacity of the patients in the two groups on the first, second, third and fourth days after the intervention (p>0.05). There was no significant difference between the level of consciousness (according to GCS criteria), respiratory index (PAO2/FIO2) and PEEP of patients in the two study groups within 1 to 2 days after the intervention (p>0.05). There was a significant difference between the level of consciousness (based on GCS criteria), respiratory index (PAO2/FIO2) and PEEP of patients in the two study groups within 3 to 4 days after the intervention (p<0.05). There was no significant difference between the duration of hospitalization in the ICU, the time required for mechanical ventilation and the mortality rate of the patients in the two groups (p>0.05). Conclusion: It seems that N-acetylcysteine has a positive effect on the treatment of acute respiratory distress syndrome in mechanically ventilated patients admitted to the intensive care unit.}, } @article {pmid34290603, year = {2021}, author = {Qing, C and Xinyi, Z and Xuefei, Y and Xindong, X and Jianhua, F}, title = {The Specific Connexin 43-Inhibiting Peptide Gap26 Improved Alveolar Development of Neonatal Rats With Hyperoxia Exposure.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {587267}, pmid = {34290603}, issn = {1663-9812}, abstract = {Bronchopulmonary dysplasia (BPD) is a common devastating pulmonary complication in preterm infants. Alveolar maldevelopment is the crucial pathological change of BPD highly associated with oxidative stress-mediated excessive apoptosis. Cellular injury can be propagated and amplified by gap junction (GJ)-mediated intercellular communication. Connexin 43 (Cx43) is the most ubiquitous and critical GJ protein. Gap26 is a specific Cx43 mimic peptide, playing as a Cx43-GJ inhibitor. We hypothesized that Cx43-GJ was involved in alveolar maldevelopment of BPD via amplifying oxidative stress signaling and inducing excessive apoptosis. Neonatal Sprague Dawley rats were kept in either normoxia (21% O2) or hyperoxia (85% O2) continuously from postnatal day (PN) 1 to 14 in the presence or absence of Gap26. Moreover, RLE-6TN cells (type II alveolar epithelial cells of rats) were cultured in vitro under normoxia (21% O2) or hyperoxia (85% O2). RLE-6TN cells were treated by N-acetyl cysteine (NAC) (a kind of reactive oxygen species (ROS) scavenger) or Gap26. Morphological properties of lung tissue are detected. Markers associated with Cx43 expression, ROS production, the activity of the ASK1-JNK/p38 signaling pathway, and apoptotic level are detected in vivo and in vitro, respectively. In vitro, the ability of GJ-mediated intercellular communication was examined by dye-coupling assay. In vitro, our results demonstrated ROS increased Cx43 expression and GJ-mediated intercellular communication and Gap26 treatment decreased ROS production, inhibited ASK1-JNK/p38 signaling, and decreased apoptosis. In vivo, we found that hyperoxia exposure resulted in increased ROS production and Cx43 expression, activated ASK1-JNK/p38 signaling, and induced excessive apoptosis. However, Gap26 treatment reversed these changes, thus improving alveolar development in neonatal rats with hyperoxia exposure. In summary, oxidative stress increased Cx43 expression and Cx43-GJ-mediated intercellular communication. And Cx43-GJ-mediated intercellular communication amplified oxidative stress signaling, inducing excessive apoptosis via the ASK1-JNK/p38 signaling pathway. The specific connexin 43-inhibiting peptide Gap26 was a novel therapeutic strategy to improve the alveolar development of BPD.}, } @article {pmid34284670, year = {2023}, author = {Shah, J and Muir, J and Furfaro, D and Beitler, JR and Dzierba, AL}, title = {Use of N-Acetylcysteine for Clozapine-Induced Acute Liver Injury: A Case Report and Literature Review.}, journal = {Journal of pharmacy practice}, volume = {36}, number = {2}, pages = {463-467}, doi = {10.1177/08971900211034007}, pmid = {34284670}, issn = {1531-1937}, mesh = {Humans ; Female ; Middle Aged ; Acetylcysteine/therapeutic use ; *Clozapine/adverse effects ; *Liver Failure, Acute/drug therapy ; *Drug-Related Side Effects and Adverse Reactions/drug therapy ; *Chemical and Drug Induced Liver Injury/diagnosis/drug therapy/etiology ; }, abstract = {Purpose: To report a case of clozapine-induced hepatotoxicity managed with intravenous (IV) N-acetylcysteine (NAC) and summarize the available literature. Summary: A 46-year-old woman with history of bipolar disorder with psychotic features presented to the intensive care unit with asterixis and elevations in liver enzymes. The patient had been initiated on risperidone, clozapine, and lithium approximately 1 month prior to admission. After ruling out other possible non-drug etiologies, clozapine was suspected as the likeliest cause of the acute liver injury. Her acute liver injury was managed with the discontinuation of all antipsychotics, administration of IV NAC, and other standard of care supportive measures. Conclusion: Although clozapine has been associated with hepatitis and acute liver failure, there are no reports of NAC used in the management of clozapine-induced hepatotoxicity. NAC was used in our patient after considering the potential benefit and limited adverse effects. The role of NAC in non-acetaminophen-induced acute liver failure remains promising, but more research is warranted.}, } @article {pmid34281260, year = {2021}, author = {Liu, X and Xiao, Y and Zhu, Q and Cui, Y and Hao, H and Wang, M and Cowan, PJ and Korthuis, RJ and Li, G and Sun, Q and Liu, Z}, title = {Circulating Endothelial Progenitor Cells Are Preserved in Female Mice Exposed to Ambient Fine Particulate Matter Independent of Estrogen.}, journal = {International journal of molecular sciences}, volume = {22}, number = {13}, pages = {}, pmid = {34281260}, issn = {1422-0067}, support = {R01 ES026200/ES/NIEHS NIH HHS/United States ; ES026200/NH/NIH HHS/United States ; AA022108/NH/NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cardiovascular Diseases/etiology/metabolism ; Cytokines/blood ; Endothelial Progenitor Cells/*drug effects/*metabolism/pathology ; Estrogens/metabolism ; Female ; Inflammation Mediators/blood ; Male ; Mice ; Mice, Inbred C57BL ; Ovariectomy ; Oxidative Stress/drug effects ; Particulate Matter/*toxicity ; Reactive Oxygen Species/metabolism ; Sex Factors ; }, abstract = {Males have a higher risk for cardiovascular diseases (CVDs) than females. Ambient fine particulate matter (PM) exposure increases CVD risk with increased reactive oxygen species (ROS) production and oxidative stress. Endothelial progenitor cells (EPCs) are important to vascular structure and function and can contribute to the development of CVDs. The aims of the present study were to determine if sex differences exist in the effect of PM exposure on circulating EPCs in mice and, if so, whether oxidative stress plays a role. Male and female C57BL/6 mice (8-10 weeks old) were exposed to PM or a vehicle control for six weeks. ELISA analysis showed that PM exposure substantially increased the serum levels of IL-6 and IL-1β in both males and females, but the concentrations were significantly higher in males. PM exposure only increased the serum levels of TNF-α in males. Flow cytometry analysis demonstrated that ROS production was significantly increased by PM treatment in males but not in females. Similarly, the level of circulating EPCs (CD34[+]/CD133[+] and Sca-1[+]/Flk-1[+]) was significantly decreased by PM treatment in males but not in females. Antioxidants N-acetylcysteine (NAC) effectively prevented PM exposure-induced ROS and inflammatory cytokine production and restored circulating EPC levels in male mice. In sharp contrast, circulating EPC levels remained unchanged in female mice with PM exposure, an effect that was not altered by ovariectomy. In conclusion, PM exposure selectively decreased the circulating EPC population in male mice via increased oxidative stress without a significant impact on circulating EPCs in females independent of estrogen.}, } @article {pmid34278450, year = {2021}, author = {He, Y and Shi, Y and Yang, Y and Huang, H and Feng, Y and Wang, Y and Zhan, L and Wei, B}, title = {Chrysin induces autophagy through the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in endometrial cancer.}, journal = {International journal of molecular medicine}, volume = {48}, number = {3}, pages = {}, pmid = {34278450}, issn = {1791-244X}, mesh = {Antineoplastic Agents/*pharmacology ; Autophagy/*drug effects ; Cell Line, Tumor ; Endometrial Neoplasms/*drug therapy/metabolism ; Female ; Flavonoids/*pharmacology ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Endometrial cancer (EC) is widely known as an aggressive malignancy. Due to the limited therapeutic options and poor prognosis of patients with advanced‑stage EC, there is a need to identify effective alternative treatments. Chrysin is a naturally active flavonoid (5,7‑dihydroxyflavone), which has been demonstrated to exert anticancer effects and may present a novel strategy for EC treatment. However, the role of chrysin in EC remains largely unclear. The aim of the present study was to examine the anticancer effects of chrysin on EC. The results revealed that, in addition to apoptosis, chrysin increased the LC3II expression levels and markedly accelerated the autophagic flux, suggesting that chrysin induced both the autophagy and apoptosis of EC cells. Furthermore, the inhibition of autophagy by chloroquine enhanced the inhibitory effect on cell proliferation and the promotion of the chrysin‑induced apoptosis of EC cells, indicating that chrysin‑induced autophagy was a cytoprotective mechanism. Additionally, chrysin led to the production of intracellular reactive oxygen species (ROS). N‑acetylcysteine (NAC) pretreatment significantly inhibited chrysin‑induced autophagy, suggesting that ROS activated autophagy induced by chrysin in EC cells. Furthermore, the phosphorylated (p‑)Akt and p‑mTOR levels were significantly decreased in a concentration‑dependent manner following treatment with chrysin, while NAC blocked these effects. Taken together, these findings demonstrated that chrysin‑induced autophagy via the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in EC cells.}, } @article {pmid34276378, year = {2021}, author = {Hang, X and Zhang, Y and Li, J and Li, Z and Zhang, Y and Ye, X and Tang, Q and Sun, W}, title = {Comparative Efficacy and Acceptability of Anti-inflammatory Agents on Major Depressive Disorder: A Network Meta-Analysis.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {691200}, pmid = {34276378}, issn = {1663-9812}, abstract = {Background: With the growing importance of research about the association between neuroinflammation and major depressive disorder (MDD), anti-inflammatory agents have been used as a new antidepressant therapy in clinical practice. We conducted a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents for improving the treatment of MDD patients. Methods: To identify eligible randomized clinical trials, four databases (i.e, the Cochrane Library, Web of Science, PubMed and Embase) were searched from inception date to May 31, 2020. Anti-inflammatory agents were defined as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, cytokine inhibitors, statins, pioglitazone, minocycline, N-acetylcysteine (NAC) and omega-3 fatty acid (Omega-3 FA). The main outcomes of this NMA were efficacy, acceptability and remission rate. Risk ratio (RR) was adopted for dichotomous outcomes, and the confidence interval (CI) was set at 95%. STATA 14.0 and R 3.6.3 were used to conduct the NMA. The study protocol was registered with PROSPERO (CRD42020182531). Results: A total of 39 studies, involving 2871 participants, were included in quantitative data synthesis. For efficacy, NSAIDs (RR=0.50, 95%CI: 0.26-0.73) and pioglitazone (RR=0.45, 95%CI: 0.20-0.84) were more favorable than placebo. With respect to acceptability, NSAIDs were more acceptable than placebo (RR=0.89, 95%CI: 0.77-0.99) and minocycline (RR=1.22, 95%CI: 1.03-1.49). For remission, NSAIDs were more superior than placebo (RR=0.48, 95%CI: 0.27-0.79) and Omega-3 FA (RR=2.01, 95%CI: 1.09-3.90), while NACs were more favorable than placebo (RR=0.39, 95%CI: 0.13-0.99). Based on the surface under the cumulative ranking curve (SUCRA) value, corticosteroids (0.86) were the best anti-inflammatory agent for MDD patients in terms of efficacy, but the head-to-head comparisons for the efficacy of glucocorticoids and other agents were not statistically significant. As for acceptability, NSAIDs (0.81) were much better than other anti-inflammatory agents. Besides, NAC (0.80) was the best anti-inflammatory agent in the terms of remission. Conclusions: In summary, we found that corticosteroids were more superior than other agents in terms of efficacy according to the SUCRA value. However, this result must be interpreted with caution because the head-to-head comparisons for the efficacy of glucocorticoids and other agents did not reach statistical significance. NSAIDs were recommended for acceptability and NAC for remission rate.}, } @article {pmid34275660, year = {2021}, author = {Pang, KH and Chapple, CR and Chatters, R and Downey, AP and Harding, CK and Hind, D and Watkin, N and Osman, NI}, title = {A Systematic Review and Meta-analysis of Adjuncts to Minimally Invasive Treatment of Urethral Stricture in Men.}, journal = {European urology}, volume = {80}, number = {4}, pages = {467-479}, doi = {10.1016/j.eururo.2021.06.022}, pmid = {34275660}, issn = {1873-7560}, mesh = {Captopril ; Humans ; Injections, Intralesional ; Male ; Mitomycin ; Recurrence ; Tamoxifen ; Triamcinolone ; Urethra ; *Urethral Stricture/surgery ; }, abstract = {CONTEXT: Urethral stricture disease (USD) is initially managed with minimally invasive techniques such as urethrotomy and urethral dilatation. Minimally invasive techniques are associated with a high recurrence rate, especially in recurrent USD. Adjunctive measures, such as local drug injection, have been used in an attempt to reduce recurrence rates.

OBJECTIVE: To systematically review evidence for the efficacy and safety of adjuncts used alongside minimally invasive treatment of USD.

EVIDENCE ACQUISITION: A systematic review of the literature published between 1990 and 2020 was conducted in accordance with the PRISMA checklist.

EVIDENCE SYNTHESIS: A total of 26 studies were included in the systematic review, from which 13 different adjuncts were identified, including intralesional injection (triamcinolone, n = 135; prednisolone, n = 58; mitomycin C, n = 142; steroid-mitomycin C-hyaluronidase, n = 103, triamcinolone-mitomycin C-N-acetyl cysteine, n = 50; platelet-rich plasma, n = 44), intraluminal instillation (mitomycin C, n = 20; hyaluronic acid and carboxymethylcellulose, n = 70; captopril, n = 37; 192-iridium brachytherapy, n = 10), application via a lubricated catheter (triamcinolone, n = 124), application via a coated balloon (paclitaxel, n = 106), and enteral application (tamoxifen, n = 30; deflazacort, n = 36). Overall, 13 randomised controlled trials were included in the meta-analysis. Use of any adjunct was associated with a lower rate of USD recurrence (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.27-0.50; p <  0.001) compared to no adjunct use. Of all the adjuncts, mitomycin C was associated with the lowest rate of USD recurrence (intralesional injection: OR 0.23, 95% CI 0.11-0.48; p <  0.001; intraluminal injection: OR 0.11, 95% CI 0.02-0.61; p =  0.01). Urinary tract infection (2.9-14%), bleeding (8.8%), and extravasation (5.8%) were associated with steroid injection; pruritis of the urethra (61%) occurred after instillation of captopril; mild gynaecomastia (6.7%) and gastrointestinal side effects (6.7%) were associated with oral tamoxifen.

CONCLUSIONS: Adjuncts to minimally invasive treatment of USD appear to lower the recurrence rate and are associated with a low adjunct-specific complication rate. However, the studies included were at high risk of bias. Mitomycin C is the adjunct supported by the highest level of evidence.

PATIENT SUMMARY: We reviewed studies on additional therapies (called adjuncts) to minimally invasive treatments for narrowing of the urethra in men. Adjuncts such as mitomycin C injection result in a lower recurrence rate compared to no adjunct use. The use of adjuncts appeared to be safe and complications are uncommon; however, the studies were small and of low quality.}, } @article {pmid34275158, year = {2021}, author = {Sahasrabudhe, SA and Kartha, RV and Ng, M and Basso, LM and Mishra, U and Cloyd, JC and Orchard, PJ and Brundage, RC and Coles, LD}, title = {Population Pharmacokinetic Analysis of N-Acetylcysteine in Pediatric Patients With Inherited Metabolic Disorders Undergoing Hematopoietic Stem Cell Transplant.}, journal = {Journal of clinical pharmacology}, volume = {61}, number = {12}, pages = {1638-1645}, doi = {10.1002/jcph.1943}, pmid = {34275158}, issn = {1552-4604}, mesh = {Acetylcysteine/*pharmacokinetics ; Adolescent ; Child ; Child, Preschool ; Female ; Half-Life ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Metabolic Clearance Rate ; Metabolism, Inborn Errors/*metabolism ; Models, Biological ; Prospective Studies ; Time Factors ; Young Adult ; }, abstract = {N-acetylcysteine (NAC) has been used in patients with cerebral adrenoleukodystrophy as an antioxidant agent in association with hematopoietic stem cell transplant (HSCT). However, an understanding of the pharmacokinetic characteristics of intravenous NAC dosing in these patients is limited. If and how NAC pharmacokinetics change following the transplant is unknown. Toward that end, a total of 260 blood samples obtained from 18 pediatric patients with inherited metabolic disorders who underwent HSCT were included in a population pharmacokinetic analysis using nonlinear mixed-effects modeling. NAC clearance (CL) and volume of distribution (V) were explored on 3 occasions: -7, +7, and +21 days relative to transplant. Additionally, the effect of transplant procedure on NAC disposition was explored by accounting for between-occasion variability. The covariate OCC was modeled as a fixed-effect parameter on CL and/or V1. A 2-compartment model adequately described the pharmacokinetics of total NAC. Weight-based allometric scaling on pharmacokinetic parameters was assumed using standard coefficients. Estimates for CL, central (V1), and peripheral volume (V2), and intercompartment clearance were 14.7 L/h, 23.2 L, 17.1 L, 3.99 L/h, respectively, for a 70-kg person. The data only supported between-subject variability in CL (12%) and V1 (41%). Residual variability was estimated to be 16%. HSCT did not change CL and V1 significantly, and analysis across occasions did not reveal any trends. Pharmacokinetic parameter estimates were in general comparable to those reported previously in different populations. These results suggest that dosing of NAC does not need to be altered following HSCT.}, } @article {pmid34267823, year = {2021}, author = {Jiang, D and Xu, J and Liu, S and Nasser, MI and Wei, W and Mao, T and Liu, X and Zou, X and Li, J and Li, X}, title = {Rosmanol induces breast cancer cells apoptosis by regulating PI3K/AKT and STAT3/JAK2 signaling pathways.}, journal = {Oncology letters}, volume = {22}, number = {2}, pages = {631}, pmid = {34267823}, issn = {1792-1082}, abstract = {Breast cancer is one of the most frequently diagnosed cancers amongst women; however, there is currently no effective treatment. Natural compounds are considered to contribute to cancer prevention and have a pivotal role in modulating apoptosis. Rosmanol is a phenolic diterpene compound with antioxidant and anti-inflammatory properties. In the present study, the effects of Rosmanol on breast cancer cell proliferation/apoptosis were investigated, and it was demonstrated that it inhibited the proliferation of MCF-7 and MDA-MB 231 cells but did not have a significant effect on normal human breast MCF-10A cells. In addition, the apoptotic process was accelerated by Rosmanol, through mitochondrial pathways and reactive oxygen species (ROS) production caused by DNA damage, which function further demonstrated by the attenuation and addition of the ROS inhibitor, N-acetyl-cysteine. It was also demonstrated that Rosmanol accelerated cell apoptosis, and arrested breast cancer cells in the S phase. Moreover, Rosmanol inhibited proliferation and promoted apoptosis of cancer cells via the inhibition of ERK and STAT3 signals, attributable to the increase in p-p38, the overexpression of protein inhibitor of activated STAT3, and the decrease in PI3K/AKT, ERK and JAK2/STAT3.}, } @article {pmid34267196, year = {2021}, author = {Gusarov, I and Shamovsky, I and Pani, B and Gautier, L and Eremina, S and Katkova-Zhukotskaya, O and Mironov, A and Makarov, AА and Nudler, E}, title = {Dietary thiols accelerate aging of C. elegans.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {4336}, pmid = {34267196}, issn = {2041-1723}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aging/*drug effects/genetics/physiology ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/*drug effects/*physiology ; Caenorhabditis elegans Proteins/genetics ; DNA-Binding Proteins/genetics ; Dietary Supplements ; Escherichia coli ; Female ; Fibroblasts/metabolism ; Gene Expression Regulation/drug effects ; Glutathione/metabolism/*pharmacology ; Humans ; Male ; Paraquat/pharmacology ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; Transcription Factors/genetics ; Unfolded Protein Response/physiology ; }, abstract = {Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1-mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.}, } @article {pmid34262291, year = {2021}, author = {Xia, Y and Wang, G and Jiang, M and Liu, X and Zhao, Y and Song, Y and Jiang, B and Zhu, D and Hu, L and Zhang, Z and Cao, T and Wang, JM and Hu, J}, title = {A Novel Biological Activity of the STAT3 Inhibitor Stattic in Inhibiting Glutathione Reductase and Suppressing the Tumorigenicity of Human Cervical Cancer Cells via a ROS-Dependent Pathway.}, journal = {OncoTargets and therapy}, volume = {14}, number = {}, pages = {4047-4060}, pmid = {34262291}, issn = {1178-6930}, abstract = {INTRODUCTION: Glutathione reductase (GSR) provides reduced glutathione (GSH) to maintain redox homeostasis. Inhibition of GSR disrupts this balance, resulting in cell damage, which benefits cancer therapy. However, the effect of GSR inhibition on the tumorigenicity of human cervical cancer is not fully understood.

MATERIALS AND METHODS: Tissue microarray analysis was employed to determine GSR expression in cervical cancer tissues by immunohistochemical staining. Cell death was measured with PI/FITC-annexin V staining. mRNA levels were measured via quantitative RT-PCR. Protein expression was measured by Western blotting and flow cytometry. STAT3 deletion was performed with CRISPR/Cas9 technology. GSR knockdown was achieved by RNA interference. Reactive oxygen species (ROS) levels were measured by DCF staining. GSR enzymatic activity was measured with a GSR assay kit. The effect of GSR inhibition on the growth of tumors formed by cervical cancer cells was investigated using a xenograft model.

RESULTS: The expression of GSR was increased in human cervical cancer tissues, as shown by immunohistochemical staining. GSR knockdown by RNA interference in human cervical cancer cell lines resulted in cell death, suggesting the ability of GSR to maintain cancer cell survival. The STAT3 inhibitor 6-nitrobenzo[b]thiophene 1,1-dioxide (Stattic) also inhibited the enzymatic activity of GSR and induced the death of cervical cancer cells. More importantly, Stattic decreased the growth of xenograft tumors formed by cervical cancer cells in nude mice. Mechanistically, tumor cell death induced by Stattic-mediated GSR inhibition was ROS-dependent, since the ROS scavengers GSH and N-acetyl cysteine (NAC) reversed the effect of Stattic. In contrast, pharmacological and molecular inhibition of STAT3 did not induce the death of cervical cancer cells, suggesting a STAT3-independent activity of Stattic.

CONCLUSION: Stattic inhibits the enzymatic activity of GSR and induces STAT3-independent but ROS-dependent death of cervical cancer cells, suggesting its potential application as a therapeutic agent for human cervical cancers.}, } @article {pmid34262087, year = {2021}, author = {Zhang, T and Ni, C and Li, C and Lu, P and Chen, D and Dong, Y and Whetstine, JR and Zhang, Y and Xie, Z}, title = {Isoflurane impairs oogenesis through germ cell apoptosis in C. elegans.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {14481}, pmid = {34262087}, issn = {2045-2322}, support = {R01GM088801/NH/NIH HHS/United States ; R01 HD086977/HD/NICHD NIH HHS/United States ; P30 CA006927/CA/NCI NIH HHS/United States ; }, mesh = {Anesthetics, Inhalation/toxicity ; Animals ; Apoptosis/*drug effects ; Caenorhabditis elegans/cytology/*drug effects/embryology/genetics ; Caenorhabditis elegans Proteins/genetics ; Caspases/genetics ; Embryo, Nonmammalian/drug effects ; Female ; Hermaphroditic Organisms ; Isoflurane/*toxicity ; Male ; Oogenesis/*drug effects ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-abl/genetics ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics ; }, abstract = {Anesthetic isoflurane has been reported to induce toxicity. However, the effects of isoflurane on fecundity remain largely unknown. We established a system in C. elegans to investigate the effects of isoflurane on oogenesis. Synchronized L4 stage C. elegans were treated with 7% isoflurane for 4 h. Dead cells, ROS, embryos, and unfertilized eggs laid by hermaphrodites were measured by fluorescence imaging and counting. The C. elegans with losses of ced-3, cep-1, abl-1, male C. elegans, and oxidative stress inhibitor N-acetyl-cysteine were used in the interaction studies. We found that isoflurane decreased the numbers of embryos and unfertilized eggs and increased the levels of dead cells and ROS in C. elegans. The isoflurane-induced impairment of oogenesis was associated with abl-1, ced-3, but not cep-1. N-acetyl-cysteine attenuated the isoflurane-in