@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.<br><br>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).<br><br>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&#xb1;0.47) and the control group (0.33&#xb1;0.21, p=0.026). The combination of NAC and glycine significantly reduced peribronchial and peribronchiolar infiltrates (0.33&#xb1;0.33, p=0.026) compared to the diabetic group. Similarly, septal inflammatory infiltrates were significantly lower in the NAC+glycine group (1&#xb1;0.36) compared to diabetic rats (3.33&#xb1;0.33, p=0.004). Total airway inflammatory infiltration was also significantly reduced in the NAC+glycine group (1.33&#xb1;0.33, p=0.002) compared to the diabetic group (5.5&#xb1;0.5).<br><br>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 = {2024}, 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 = {}, number = {}, pages = {}, pmid = {39626181}, issn = {1530-0374}, 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.<br><br>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 &#x3bc;g/kg/d), low-dose estrogen (e; 25 &#x3bc;g/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.<br><br>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.<br><br>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 = {2024}, 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 = {}, number = {}, pages = {117180}, doi = {10.1016/j.taap.2024.117180}, pmid = {39617257}, issn = {1096-0333}, 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.<br><br>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.<br><br>RESULTS: The levels of reactive oxygen species (ROS), malondialdehyde (MDA), apoptosis rate, and LC3II/ &#x3b2;-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/&#x3b2;-actin ratio 48 hours after NAC treatment, compared to the H37Rv group.<br><br>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.<br><br>RESULTS: Implementing cyclic chronic HS (34&#xa0;&#xb0;C for 7&#xa0;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&#xa0;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-&#x3ba;B 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.<br><br>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 = {}, pages = {CD012905}, pmid = {39607014}, issn = {1469-493X}, mesh = {*Fenoldopam/therapeutic use ; Humans ; *Acute Kidney Injury/prevention &amp; control ; *Randomized Controlled Trials as Topic ; Child ; Adult ; *Bias ; *Dopamine Agonists/therapeutic use ; Postoperative Complications/prevention &amp; control ; Cardiac Surgical Procedures/adverse effects ; Sepsis/prevention &amp; 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.<br><br>OBJECTIVES: This review aimed to assess the benefits and harms of fenoldopam for the prevention or treatment of AKI in children and adults.<br><br>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.<br><br>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.<br><br>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.<br><br>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).<br><br>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.<br><br>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.<br><br>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.<br><br>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 = {}, doi = {10.3390/nu16223803}, 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 = {}, doi = {10.3390/pharmaceutics16111454}, 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.<br><br>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.<br><br>METHODS: The nanoparticles were formulated using &#x3b1;,&#x3b2;-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).<br><br>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 &#xb5;m. Inclusion of LPHNPs@MePD (0.25% w/v) resulted in FPF and MMAD values of 56.7% and 4.4 &#xb5;m. 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 = {}, doi = {10.3390/life14111361}, 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 = {}, doi = {10.3390/ijms252212096}, 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 = {}, doi = {10.3390/antiox13111390}, 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 = {}, doi = {10.3390/antiox13111379}, 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 = {}, doi = {10.3390/antiox13111295}, 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}, 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 = {}, doi = {10.3390/toxics12110779}, 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}, 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}, 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.<br><br>PURPOSE: This study aims to investigate the protective effects of R-Rg3 on diabetes-induced retinal injury and the associated molecular mechanisms of action.<br><br>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 &#x3bc;M), antioxidant N-Acetylcysteine (NAC, 1 mM) and Nrf2 inhibitor ML385 (5 &#x3bc;M). 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.<br><br>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.<br><br>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.<br><br>METHODS: We conducted a retrospective analysis of consecutive patients aged&#x2009;&#x2265;&#x2009;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.<br><br>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&#x2009;=&#x2009;0.005) and fewer ventilator-free days (18.5 (0-23.0) versus 22.0 (18.3-24.0), p&#x2009;=&#x2009;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.<br><br>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 = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.4c03807}, pmid = {39570044}, issn = {1520-6882}, 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 = {}, number = {}, pages = {}, doi = {10.1021/acsabm.4c01143}, pmid = {39564655}, issn = {2576-6422}, 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}, doi = {10.1111/adb.70001}, pmid = {39556483}, issn = {1369-1600}, support = {R01AA030041/AA/NIAAA NIH HHS/United States ; HU0001-22-2-0066//Department of Defense/ ; }, mesh = {*Acetylcysteine/therapeutic use ; Humans ; *Craving/drug effects ; *Substance-Related Disorders/drug therapy ; Randomized Controlled Trials as Topic ; }, 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 Pol&#xed;ticas Sobre Drogas/Brazil ; 2015-0488/FIPE/HCPA/Fundo de Incentivo &#xe0; Pesquisa e Eventos/Hospital de Cl&#xed;nicas de Porto Alegre/Brazil ; 001/CAPES/Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel 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.<br><br>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.<br><br>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.<br><br>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 {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 {pmid39549915, year = {2024}, 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 = {}, number = {}, pages = {154001}, doi = {10.1016/j.tox.2024.154001}, pmid = {39549915}, issn = {1879-3185}, 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 20mg/m[3] for 6hours/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 2.0mg/m[3] for 6hours/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 20mg/m[3] CL-PAA included intraperitoneal injections of the antioxidant N-acetylcysteine (NAC) (200mg/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 0.2mg/m[3]. Oxidative stress linked to CL-PAA-induced inflammation was mitigated by NAC administration.}, }
@article {pmid39549861, year = {2024}, 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 &amp; pharmacology : CBP}, volume = {}, number = {}, pages = {110071}, doi = {10.1016/j.cbpc.2024.110071}, pmid = {39549861}, issn = {1532-0456}, 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-acetyl cysteine.}, journal = {Respiratory medicine}, volume = {}, number = {}, pages = {107865}, doi = {10.1016/j.rmed.2024.107865}, pmid = {39549856}, issn = {1532-3064}, 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, A and Gorelkin, P and Barykin, E and Kolmogorov, V and Timoshenko, R and Mitkevich, V and Petrushanko, I and Varshavskaya, K and Salikhov, S and Klyachko, N and Makarov, A and Erofeev, A}, 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}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.toxlet.2024.11.002}, pmid = {39547318}, issn = {1879-3169}, 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}, 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}, 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.<br><br>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 &#x3b2;-galactosidase activity and p21 protein level, and ROS and pro-inflammatory factors were upregulated, and NF-&#x3ba;B p65 phosphorylation was enhanced. However, the use of VC or NAC can significantly ameliorate these effects and improve HEI-OC1 cell senescence.<br><br>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-&#x3ba;B 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}, 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}, doi = {10.22038/ijbms.2024.78543.16982}, 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.<br><br>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.<br><br>RESULTS: In the co-culture model, AD-derived LCL triggered excessive A&#x3b2;1-42 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 A&#x3b2;1-42 overproduction and reduced the level of &#x3b2;-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.<br><br>CONCLUSION: Catalpol affects the anti-A&#x3b2; 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 {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 &amp; 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 {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.<br><br>SETTING: Outpatient medicine center.<br><br>PARTICIPANTS: Fifty patients with chronic PCS for at least 3 months post injury.<br><br>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.<br><br>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.<br><br>RESULTS: The results demonstrated significant (P <&#xa0;.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<&#xa0;.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.<br><br>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.<br><br>DATA SOURCES: PubMed, Embase, Web of Science, and ClinicalTrials.gov.<br><br>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.<br><br>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&#x2009;weeks after administration while one study tested subjects' hearing after 1&#x2009;year. In pooled analysis, two studies assessing NAC showed the greatest reduction in ototoxicity (RR 0.112, 95% CI, 0.032-0.395; p&#x2009;=&#x2009;0.0007; I[2]&#x2009;=&#x2009;18%), followed by two studies examining aspirin (RR 0.229, 95% CI, 0.080-0.650; p&#x2009;=&#x2009;0.0057; I[2]&#x2009;=&#x2009;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&#x2009;=&#x2009;0.8416).<br><br>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.<br><br>LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.}, }
@article {pmid39526680, year = {2024}, author = {Baune, BT and Fromme, SE}, title = {The role of immunomodulators in severe mental disorders: future perspectives.}, journal = {Current opinion in psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1097/YCO.0000000000000976}, pmid = {39526680}, issn = {1473-6578}, 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.<br><br>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.<br><br>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 = {2024}, 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}, 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 = {}, number = {}, pages = {}, doi = {10.1093/gerona/glae271}, pmid = {39506899}, issn = {1758-535X}, 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 were 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}, 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.<br><br>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.<br><br>RESULTS: This review included 12 studies (904 patients with depression). The daily dose of NAC in the included studies ranged from 1000 to 3000&#xa0;mg. The duration of NAC treatment ranged from 8 to 24&#xa0;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&#xa0;=&#xa0;-0.24; 95&#xa0;% confidence interval (CI)&#xa0;=&#xa0;-0.44 to -0.05; I[2]&#xa0;=&#xa0;45&#xa0;%; P&#xa0;=&#xa0;.02).<br><br>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 = {}, number = {}, pages = {}, 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.<br><br>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.<br><br>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/&#x251; 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.<br><br>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/&#x251; 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.<br><br>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 &amp; 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.<br><br>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&#xa0;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.<br><br>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.<br><br>CONCLUSIONS: Oral NAC at a dose of 1200&#xa0;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 = {Humans ; *Acetylcysteine/pharmacology ; *Mucin 5AC/metabolism/genetics ; *Pulmonary Disease, Chronic Obstructive/drug therapy/metabolism/physiopathology ; *Expectorants/pharmacology/therapeutic use ; Animals ; *Mucus/metabolism ; *Goblet Cells/drug effects/metabolism ; *Mucin-5B/metabolism/genetics ; *Lung/drug effects/metabolism ; Mucociliary Clearance/drug effects ; Hyperplasia ; }, 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.<br><br>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&#xa0;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.<br><br>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.<br><br>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 &amp; 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.<br><br>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.<br><br>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.<br><br>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 ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Liver Cirrhosis/drug therapy/pathology/metabolism ; *Mice, Knockout ; Mice ; *ATP-Binding Cassette Sub-Family B Member 4 ; *ATP Binding Cassette Transporter, Subfamily B/genetics/metabolism ; Administration, Oral ; Liver/drug effects/metabolism/pathology ; Disease Models, Animal ; Liver Regeneration/drug effects ; Male ; }, 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 = {}, number = {}, pages = {111114}, doi = {10.1016/j.brainresbull.2024.111114}, pmid = {39489186}, issn = {1873-2747}, 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}, 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.<br><br>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, &#x3b1;&#x2161;b&#x3b2;3 activation, mitochondrial membrane potential depolarization, phosphatidylserine (PS) externalization, ROS expression and platelet aggregation.<br><br>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 &#x3b1;&#x2161;b&#x3b2;3 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 &#x3b1;&#x2161;b&#x3b2;3 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.<br><br>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 Ci&#xea;ncias e da Tecnologia/ ; 0077/2020/A2//Fundo para o Desenvolvimento das Ci&#xea;ncias e da Tecnologia/ ; 0099/2022/AFJ//Fundo para o Desenvolvimento das Ci&#xea;ncias 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 {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 {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 &amp; 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, &#xc9; 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}, doi = {10.1371/journal.pone.0312828}, pmid = {39471200}, issn = {1932-6203}, mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; *Antioxidants/pharmacology/administration &amp; dosage ; *Rats, Wistar ; Rats ; *Morphine/pharmacology/administration &amp; dosage ; Male ; *Oxidative Stress/drug effects ; *Pyridines/pharmacology/administration &amp; dosage ; *Self Administration ; *Anti-Inflammatory Agents/pharmacology/administration &amp; 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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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}, doi = {10.1111/jcmm.70127}, 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 = {2024}, 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}, 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 = {}, doi = {10.3390/antiox13101162}, 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 = {}, doi = {10.3390/antibiotics13100985}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.jconrel.2024.10.046}, pmid = {39447843}, issn = {1873-4995}, 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}, 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 &amp; 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.<br><br>METHODS: We constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8&#x2009;+&#x2009;T cell differentiation and its potential mechanism were explored using cell flow assay and other studies in vitro and ex vivo.<br><br>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.<br><br>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.<br><br>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&#xa0;mg/kg NAC (PCOS&#x2009;+&#x2009;NAC group), 200&#xa0;mg/kg metformin (PCOS&#x2009;+&#x2009;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&#xa0;g/day oral NAC, n&#x2009;=&#x2009;115) or the control group (n&#x2009;=&#x2009;115). Patients in both groups underwent&#x2009;&#x2264;&#x2009;3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups.<br><br>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&#x2009;<&#x2009;0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p&#x2009;<&#x2009;0.005).<br><br>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 = {}, doi = {10.3390/ani14192852}, 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 = {}, doi = {10.3390/ijms251910858}, 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 Innovaci&#xf3;n/ ; 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}, 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 = {}, number = {}, pages = {123128}, doi = {10.1016/j.lfs.2024.123128}, pmid = {39393575}, issn = {1879-0631}, 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.<br><br>MATERIALS AND METHODS: In this study, we used bleomycin (BLM)-induced PF mouse model and TGF-&#x3b2;-induced collagen deposition cells for in vivo and in vitro experiments, respectively. Additionally, we employed BSO, a glutathione synthesis inhibitor, to induce excess ROS.<br><br>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-&#x3b2;, as indicated by the increased levels of p53 and p21, along with an increase in &#x3b2;-galactosidase-positive cells. Moreover, inflammatory responses, including inflammatory cells, inflammatory cytokines, and ROS levels were dramatically increased with the BSO and BLM or TGF-&#x3b2; combination. Mechanistically, we found that NLRP3 inflammasome was activated more significantly by the combined treatments of BSO with BLM or TGF-&#x3b2;. 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.<br><br>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 = {2024}, 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 = {}, number = {}, pages = {148992}, doi = {10.1016/j.gene.2024.148992}, pmid = {39389326}, issn = {1879-0038}, 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 = {}, number = {}, pages = {123109}, doi = {10.1016/j.lfs.2024.123109}, pmid = {39384146}, issn = {1879-0631}, 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.<br><br>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.<br><br>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-1&#x3b1; 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.<br><br>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.<br><br>METHODS: The review included articles published before 2024 that investigated the effects of NAC on oxidative stress in individuals with &#x3b2;-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.<br><br>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&#x2009;mg/kg/day (equivalent to 600&#x2009;mg/day) over a period of 3-6 months. All the studies assessing the impact of NAC on oxidative stress indicators in &#x3b2;-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.<br><br>CONCLUSION: The current potency of NAC alone appears to be effective in ameliorating oxidative stress in patients with &#x3b2;-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 {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 ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology ; *NF-kappa B/metabolism ; Humans ; Mice ; *Lung Neoplasms/drug therapy/pathology ; *Signal Transduction/drug effects ; Cell Line, Tumor ; *Antineoplastic Agents/pharmacology/administration &amp; dosage ; Acetylcysteine/pharmacology ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; Epithelial-Mesenchymal Transition/drug effects ; A549 Cells ; Mice, Nude ; Xenograft Model Antitumor Assays ; Ditiocarb/pharmacology ; Mice, Inbred BALB C ; }, 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 {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}, doi = {10.1002/cam4.70279}, 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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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 = {}, number = {}, pages = {123104}, doi = {10.1016/j.lfs.2024.123104}, pmid = {39366552}, issn = {1879-0631}, 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.<br><br>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&#x202f;mg/kg BW of BPA, 1&#x202f;mg/kg BW Es-37 and L-37 and 50&#x202f;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.<br><br>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 averted and 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.<br><br>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 &amp; 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 &amp; numerical data ; Liver Function Tests ; Aged ; Elective Surgical Procedures ; Liver Diseases/prevention &amp; 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.<br><br>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).<br><br>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.<br><br>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}, doi = {10.4103/aca.aca_156_24}, 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 = {}, number = {}, pages = {e6012}, doi = {10.1002/bmc.6012}, pmid = {39363690}, issn = {1099-0801}, 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 = {}, number = {}, pages = {}, doi = {10.55563/clinexprheumatol/dmd5dv}, pmid = {39360368}, issn = {0392-856X}, 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.<br><br>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 Sj&#xf6;gren'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.<br><br>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&#x2265;1 in ESSPRI in the NAC compared with placebo group on D30 (p=0.045), a result not found on D90 (p=0.696).<br><br>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.<br><br>CLINICALTRIALS: gov-NCT04793646.}, }
@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 = {}, number = {}, pages = {}, doi = {10.1016/j.burns.2024.09.012}, pmid = {39353794}, issn = {1879-1409}, 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.<br><br>METHODS: A descriptive cross-sectional study examining SII guidelines provided by adult burn units and centres in England, Scotland and Wales.<br><br>RESULTS: All 16 adult burn units and centres responded. Fourteen (87.5&#xa0;%) 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&#xa0;% 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&#xa0;=&#xa0;8); N-acetyl cysteine (NAC) (n&#xa0;=&#xa0;8); or salbutamol (n&#xa0;=&#xa0;8). All guidelines included advice on carbon monoxide poisoning; however, carboxyhaemoglobin (COHb) cut-off levels for treatment varied (5&#xa0;% [n-4], 10&#xa0;% [n&#xa0;=&#xa0;3], 15&#xa0;% [n&#xa0;=&#xa0;1]). All recommended high-flow oxygen. Seven (70&#xa0;%) guidelines offered guidance on cyanide poisoning. Reduced/altered consciousness was the only consistent diagnostic criterion. Five (50&#xa0;%) 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&#xa0;=&#xa0;8); oxygenation goals (n&#xa0;=&#xa0;3); and permissive hypercapnia (n&#xa0;=&#xa0;3). Within lung-protective ventilation, advice on tidal volume (6, or 6-8&#xa0;ml/kg) and plateau pressures (>30 cmH2O) were presented most commonly (n&#xa0;=&#xa0;7).<br><br>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 {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.<br><br>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.<br><br>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.<br><br>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 {pmid39357253, year = {2024}, 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}, 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 {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 &amp; 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}, doi = {10.1371/journal.pone.0307212}, pmid = {39348347}, issn = {1932-6203}, mesh = {Animals ; *Antioxidants/metabolism/pharmacology ; *Acetylcysteine/pharmacology ; *Dietary Supplements ; Hydrocortisone/metabolism ; Cichlids/growth &amp; development/immunology/metabolism ; Superoxide Dismutase/metabolism ; Animal Feed/analysis ; Catalase/metabolism ; Tilapia/growth &amp; 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 {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 = {}, doi = {10.3390/v16091503}, pmid = {39339978}, issn = {1999-4915}, mesh = {*Peptide Elongation Factor 1/metabolism/genetics ; *Virus Replication/drug effects ; *Enterovirus B, Human/drug effects/physiology ; Animals ; *Acetylcysteine/pharmacology ; Humans ; Mice ; *Coxsackievirus Infections/drug therapy/virology ; *Down-Regulation/drug effects ; Antiviral Agents/pharmacology ; Cell Line ; Myocarditis/virology/drug therapy ; Male ; }, 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 = {}, doi = {10.3390/pharmaceutics16091123}, 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 = {}, doi = {10.3390/ijms251810198}, 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 &amp; development ; *Gene Expression Regulation, Plant ; *Pigmentation/genetics ; *Oleaceae/genetics/metabolism/growth &amp; 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 = {}, doi = {10.3390/ijms25189986}, pmid = {39337474}, issn = {1422-0067}, support = {1MN/2/MG/N/20//Medical University of Warsaw/ ; }, mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; 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 = {}, doi = {10.3390/ijms25189857}, 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 &amp; medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2024.09.042}, pmid = {39332540}, issn = {1873-4596}, 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.<br><br>MATERIALS AND METHODS: A multispecies biofilm was grown on the surface of AR and Co-Cr specimens (&#xd8; 12&#xd7;3mm). After biofilm maturation, the specimens were immersed in experimental solutions and evaluated through biofilm viability (CFU) (n&#61;9), biofilm metabolic activity (XTT) (n&#61;9), biofilm-covered areas (Live/Dead) (n&#61;2), effects on the extracellular polymeric substance (EPS) (n&#61;2) and biofilm morphology (n&#61;1). Data were analyzed by ANOVA and the Tukey post-test or Kruskal-Wallis followed by the Dunn post-test (&#x3b1;&#61;.05).<br><br>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&#61;.006) and Co-Cr (P&#61;.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.<br><br>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 = {2024}, 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 = {}, number = {}, pages = {115261}, doi = {10.1016/j.bbr.2024.115261}, pmid = {39313073}, issn = {1872-7549}, 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 to 51. Rats were trained to self-administer intravenous amphetamine (0.1mg/kg/infusion) during twelve 6-hour sessions. During the abstinence period, NAC (100mg/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, &#xd6;C}, 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}, doi = {10.1097/MD.0000000000039742}, 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 &amp; 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.<br><br>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&#x2009;<&#x2009;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&#xa0;mg/mL NAC compared to the D-gal treatment group. Furthermore, 10 mg/mL D-gal significantly (p&#x2009;<&#x2009;0.01) reduced GSH, T-SOD, and catalase (CAT) levels in the ovaries. However, 0.1 mg/mL NAC effectively (p&#x2009;<&#x2009;0.01) suppressed these adverse effects. Moreover, the current results showed that 10 mg/mL D-gal alone significantly (p&#x2009;<&#x2009;0.01) downregulated the expression of Nrf2, GPX, PRDX4, GSR, SOD1, and TAF4B, whereas 0.1 mg/mL NAC counteracted these suppressive effects (p&#x2009;<&#x2009;0.01).<br><br>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.<br><br>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).<br><br>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%).<br><br>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 = {}, number = {}, pages = {}, doi = {10.3233/JAD-240709}, pmid = {39302378}, issn = {1875-8908}, 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.<br><br>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.<br><br>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.<br><br>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&#xa0;+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2&#xa0;+]i levels in muscle cells.<br><br>CONCLUSIONS: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2&#xa0;+]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 = {}, doi = {10.3892/mmr.2024.13330}, 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 = {}, number = {}, pages = {107340}, doi = {10.1016/j.ijantimicag.2024.107340}, pmid = {39299599}, issn = {1872-7913}, abstract = {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. 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. 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. 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. 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}, doi = {10.1192/bjo.2024.740}, 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 = {}, doi = {10.21203/rs.3.rs-4947457/v1}, pmid = {39281865}, issn = {2693-5015}, 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 (x c [-]) 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 = {}, number = {}, pages = {110096}, doi = {10.1016/j.exer.2024.110096}, pmid = {39278392}, issn = {1096-0007}, 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.<br><br>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.<br><br>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-1&#x3b2; (IL-1&#x3b2;), 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.<br><br>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}, doi = {10.12122/j.issn.1673-4254.2024.08.14}, 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.<br><br>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 &#x3bc;mol/L) and DDP (0, 4, 8, 16, 32, 64, 128 &#x3bc;mol/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.<br><br>RESULTS: Different concentrations of DHA and DDP alone both significantly inhibited the viability of HNE1/DDP cells. The combination index of DHA (5 &#x3bc;mol/L) combined with DDP (8, 16, 32, 64, 128 &#x3bc;mol/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).<br><br>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 = {}, doi = {10.3390/cancers16173108}, 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.<br><br>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.<br><br>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.<br><br>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 = {2024}, 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 = {}, number = {}, pages = {1-19}, doi = {10.1080/15548627.2024.2395142}, pmid = {39265983}, issn = {1554-8635}, 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, &#xd6; and Hümeyra Taşkin Kafa, A and Taş, A and Keklikçioğlu 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 = {}, number = {}, pages = {106934}, doi = {10.1016/j.micpath.2024.106934}, pmid = {39265812}, issn = {1096-1208}, abstract = {BACKGROUND: The increasing prevalence of antibiotic-resistant bacterial infections has led to the search for new approaches.<br><br>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.<br><br>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.<br><br>RESULTS: While Minimum inhibitory concentration and minimum bactericidal concentration values for carvacrol varied between 250-500 &#x3bc;g/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 hours. 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.<br><br>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}, doi = {10.21037/cdt-24-19}, 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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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).<br><br>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 = {}, number = {}, pages = {124922}, doi = {10.1016/j.envpol.2024.124922}, pmid = {39260547}, issn = {1873-6424}, 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 livers 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-acetyl-cysteine (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 = {}, number = {}, pages = {1-10}, doi = {10.1080/10715762.2024.2396909}, pmid = {39258904}, issn = {1029-2470}, 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}, doi = {10.1016/j.bpsgos.2024.100361}, 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.<br><br>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.<br><br>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.<br><br>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 {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 {pmid39251120, year = {2024}, author = {Wood, JPM and Chidlow, G and Wall, GM and Casson Franzco, RJ}, title = {N-ACETYLCYSTEINE AMIDE AND DI- N-ACETYLCYSTEINE AMIDE PROTECT RETINAL CELLS IN CULTURE VIA AN ANTIOXIDANT ACTION.}, journal = {Experimental eye research}, volume = {}, number = {}, pages = {110074}, doi = {10.1016/j.exer.2024.110074}, pmid = {39251120}, issn = {1096-0007}, 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 = {}, number = {}, pages = {114988}, doi = {10.1016/j.fct.2024.114988}, pmid = {39251036}, issn = {1873-6351}, 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 to 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 = {}, number = {}, pages = {}, doi = {10.1002/em.22627}, pmid = {39248027}, issn = {1098-2280}, 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 = {}, number = {}, pages = {135418}, doi = {10.1016/j.ijbiomac.2024.135418}, pmid = {39245103}, issn = {1879-0003}, 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 = {acetylcysteine promotes doxycycline resistance in the bacterial pathogen edwardsiella tarda.}, journal = {Virulence}, volume = {}, number = {}, pages = {2399983}, doi = {10.1080/21505594.2024.2399983}, pmid = {39239906}, issn = {2150-5608}, 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.<br><br>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.<br><br>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 = {2024}, 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 = {}, number = {}, pages = {}, doi = {10.1002/biof.2117}, pmid = {39225404}, issn = {1872-8081}, 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 &amp; 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 &amp; 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.<br><br>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&#x2009;&#x2265;&#x2009;40 years with post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC)&#x2009;<&#x2009;0.7 and COPD assessment test (CAT) phlegm score&#x2009;&#x2265;&#x2009;2; the patients were current or ex-smoker with smoking pack-years&#x2009;&#x2265;&#x2009;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.<br><br>RESULTS: In total, 100 COPD patients were enrolled from 10 hospitals. The mean age of the patients was 71.42&#x2009;&#xb1;&#x2009;8.20 years, with 19.78% being current-smokers and 80.22% being ex-smokers. The mean smoking pack-years was 40.32&#x2009;&#xb1;&#x2009;35.18. The mean FVC, FEV1, and FEV1/FVC were 3.94&#xa0;L (75.44%), 2.22&#xa0;L (58.50%), and 0.53, respectively. The CAT phlegm score at baseline was 3.47&#x2009;&#xb1;&#x2009;1.06, whereas after 12 weeks of nebulized NAC it significantly decreased to 2.62&#x2009;&#xb1;&#x2009;1.30 (p&#x2009;<&#x2009;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.<br><br>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}, 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}, doi = {10.1016/j.clinsp.2024.100476}, pmid = {39208656}, issn = {1980-5322}, mesh = {Humans ; *Ambroxol/therapeutic use/administration &amp; 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.<br><br>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.<br><br>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).<br><br>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}, 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 = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.4c03060}, pmid = {39196852}, issn = {1520-5118}, 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 &amp; dosage/therapeutic use ; Male ; *Tuberculosis, Pulmonary/drug therapy ; Female ; Adult ; Prospective Studies ; *Antitubercular Agents/therapeutic use/administration &amp; 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.<br><br>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&#x2009;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.<br><br>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 &#xd7; 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 &#xd7; 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.<br><br>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, &#x15e;}, 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}, doi = {10.52312/jdrs.2024.1784}, 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.<br><br>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.<br><br>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).<br><br>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 &amp; 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 = {}, number = {}, pages = {104959}, doi = {10.1016/j.cryobiol.2024.104959}, pmid = {39182712}, issn = {1090-2392}, 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}, 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 {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}, 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}, 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 = {}, number = {}, pages = {1-12}, doi = {10.1080/17581869.2024.2388504}, pmid = {39166871}, issn = {1758-1877}, 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}, doi = {10.1016/j.tranon.2024.102101}, 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 = {}, number = {}, pages = {}, doi = {10.1097/SHK.0000000000002438}, pmid = {39158930}, issn = {1540-0514}, 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.<br><br>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.<br><br>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 &#x3b3;-H2AX. Therefore, the pharmacologic antioxidant NAC exhibited significant hepato-protective effects.<br><br>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.<br><br>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.<br><br>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).<br><br>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&#xff1b;YJSCX202290Y//Medical Science and Technology Tackling Program of Henan Province (SB201901060) and Postgraduate research innovation program (YJSCX202290Y)./ ; SB201901060&#xff1b;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.<br><br>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 &#x3b1;-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.<br><br>CONCLUSIONS: Catalpol inhibits HHcy-induced EndMT, and the underlying mechanism may be related to the ROS/NF-&#x3ba;B 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 &amp; 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.<br><br>STUDY DESIGN: A multicenter, 12 weeks, 2&#x2005;&#xd7;&#x2005;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.<br><br>STUDY RESULTS: We recruited our desired sample (n&#x2005;=&#x2005;68) and retained 78% (n&#x2005;=&#x2005;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.<br><br>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.<br><br>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.<br><br>STUDY DESIGN: In this double-blind, randomized, controlled multicenter trial, a 2&#x2005;&#xd7;&#x2005;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.<br><br>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&#x2005;+&#x2005;NAC: 72.7&#x2005;&#xb1;&#x2005;13.4%, PSM&#x2005;+&#x2005;NAC: 72.7&#x2005;&#xb1;&#x2005;13.4%) as compared to patients receiving PLC (IPPI&#x2005;+&#x2005;PLC: 56.1&#x2005;&#xb1;&#x2005;15.3%, PSM&#x2005;+&#x2005;PLC: 39.0&#x2005;&#xb1;&#x2005;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.<br><br>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}, 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.<br><br>OBJECTIVES: We aimed to study the male reproductive toxicity of EHDPP and its related mechanism.<br><br>METHODS: Human spermatocyte cell line GC-2 was treated with 10&#x202f;&#xb5;M, 50&#x202f;&#xb5;M or 100&#x202f;&#xb5;M EHDPP for 24&#x202f;h. Male CD-1 mice aged 6 weeks were given 1, 10, or 100&#x202f;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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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}, 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 = {2024}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.biochi.2024.08.009}, pmid = {39128490}, issn = {1638-6183}, 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.<br><br>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-&#x3b2;) to investigate the effect of DAPA.<br><br>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.<br><br>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.<br><br>METHODS: This is a double-blind randomized controlled trial. Patients will be randomized in 1:1 ratio to receive oral NAC at 600&#x2009;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&#x2009;mg twice daily or placebo for 7&#x2009;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&#x2009;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.<br><br>DISCUSSION: We hypothesize that NAC use in COPD exacerbation can provide benefits in clinical and laboratory parameters.<br><br>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 Cient&#xed;fico e Tecnol&#xf3;gico/ ; 307280/2022-5//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 2021/10923-5//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o 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 &amp; 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).<br><br>METHODS: Six-month-old male SHR were divided into sedentary (S, n&#x2009;=&#x2009;12), concurrent training (T, n&#x2009;=&#x2009;13), sedentary supplemented with NAC (SNAC, n&#x2009;=&#x2009;13), and concurrent training with NAC supplementation (TNAC, n&#x2009;=&#x2009;14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120&#xa0;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.<br><br>RESULTS: Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40&#x2009;&#xb1;&#x2009;0.04; T 0.39&#x2009;&#xb1;&#x2009;0.03; SNAC 0.40&#x2009;&#xb1;&#x2009;0.04; TNAC 0.43&#x2009;&#xb1;&#x2009;0.04 *; * p&#x2009;<&#x2009;0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50&#x2009;&#xb1;&#x2009;0.12; T 1.52&#x2009;&#xb1;&#x2009;0.10; SNAC 1.56&#x2009;&#xb1;&#x2009;0.12; TNAC 1.62&#x2009;&#xb1;&#x2009;0.14 * mm; * p&#x2009;<&#x2009;0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4&#x2009;&#xb1;&#x2009;5.01; T 36.4&#x2009;&#xb1;&#x2009;2.96; SNAC 39.7&#x2009;&#xb1;&#x2009;3.44; TNAC 41.6&#x2009;&#xb1;&#x2009;3.57 * mm/s; * p&#x2009;<&#x2009;0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210&#x2009;&#xb1;&#x2009;48; T 182&#x2009;&#xb1;&#x2009;43; SNAC 159&#x2009;&#xb1;&#x2009;33 *; TNAC 110&#x2009;&#xb1;&#x2009;23 *[#] nmol/g tissue; * p&#x2009;<&#x2009;0.05 vs S, [#] p&#x2009;<&#x2009;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&#x2009;<&#x2009;0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups.<br><br>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 &amp; 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 de Farias Cabral, VP and Barbosa, AD and do Amaral Valente Sá, LG 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 = {}, number = {}, pages = {1-12}, doi = {10.1080/17460913.2024.2380601}, pmid = {39101446}, issn = {1746-0921}, 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 &amp; 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 = {}, number = {}, pages = {}, doi = {10.1111/ans.19183}, pmid = {39101362}, issn = {1445-2197}, 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.<br><br>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).<br><br>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]&#x2009;=&#x2009;67%). There were, however, no differences in the post-operative INR (WMD -0.04, 95% CI -0.19 to 0.12, I[2]&#x2009;=&#x2009;96%) and ALT (WMD -94.94, 95% CI -228.46 to 40.38; I[2]&#x2009;=&#x2009;67%). More importantly, there were no statistically significant differences in length of stay, transfusion rates, and morbidity between the two groups.<br><br>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.<br><br>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.<br><br>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-&#x3b1;, IL-6 and IL-1&#x3b2;). 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.<br><br>CONCLUSION: Overall, this study revealed that BUN&#xa0;+&#xa0;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}, 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 = {}, number = {}, pages = {}, doi = {10.1016/j.jpedsurg.2024.06.024}, pmid = {39089892}, issn = {1531-5037}, abstract = {INTRODUCTION: This study aimed to investigate the effects of N-acetylcysteine (NAC) and selenium (Se) on vesicoureteral reflux (VUR) nephropathy.<br><br>METHODS: A total of 44 rabbits in 7 groups, namely group 1 (Control), group 2 (VUR&#xa0;+&#xa0;sterile urine), group 3 (VUR&#xa0;+&#xa0;sterile urine&#xa0;+&#xa0;NAC), group 4 (VUR&#xa0;+&#xa0;sterile urine&#xa0;+&#xa0;Se), group 5 (VUR&#xa0;+&#xa0;infected urine), group 6 (VUR&#xa0;+&#xa0;infected urine&#xa0;+&#xa0;NAC) and group 7 (VUR&#xa0;+&#xa0;infected urine&#xa0;+&#xa0;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.&#xa0;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.<br><br>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&#xa0;=&#xa0;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&#xa0;<&#xa0;0.001). Left kidney CRSs were significantly higher in group 5 compared to group 2 (p&#xa0;=&#xa0;0.026), group 6 (p&#xa0;<&#xa0;0.001) and group 7 (p&#xa0;=&#xa0;0.006).<br><br>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.<br><br>TYPE OF STUDY: Experimental animal study.<br><br>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.<br><br>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.<br><br>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&#xa0;%, P&#xa0;<&#xa0;0.05), NLRP3 (46.8&#xa0;%, P&#xa0;<&#xa0;0.05), and p-P38/P38 (37.1&#xa0;%, P&#xa0;<&#xa0;0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0&#xa0;%, P&#xa0;<&#xa0;0.01), TNF-&#x3b1; (30.3&#xa0;%, P&#xa0;<&#xa0;0.05), and NLRP3 (43.3&#xa0;%, P&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-&#x3ba;B 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 = {}, number = {}, pages = {e2451053}, doi = {10.1002/eji.202451053}, pmid = {39072707}, issn = {1521-4141}, support = {G78I18000930007//Progetto "SeNSO/ ; //P.O. FESR Regione Siciliana/ ; //Fondazione Ri.MED./ ; }, 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, &#x160; 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 &amp; 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&amp;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 Innovaci&#xf3;n, MCINN, Gobierno de Espa&#xf1;a, Plan Estatal de I+D+i, PID2020-117266RB-C22-1, Cluster of Excellence "Hearing4All" EXC 2177/1, ID:390895286, part of the Germany&#xb4;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 = {}, number = {}, pages = {}, pmid = {39060756}, issn = {1865-7265}, 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 &amp; medicine}, volume = {223}, number = {}, pages = {30-41}, doi = {10.1016/j.freeradbiomed.2024.07.021}, pmid = {39053861}, issn = {1873-4596}, 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 &amp; dosage/pharmacology ; *Parasitemia/drug therapy ; Mice ; *Malaria/drug therapy ; *Acetylcysteine/administration &amp; dosage/therapeutic use/pharmacology ; *Plasmodium berghei/drug effects ; *Antioxidants/therapeutic use/administration &amp; dosage ; *Dietary Supplements ; Oxidative Stress/drug effects ; Carotenoids/therapeutic use/administration &amp; 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.<br><br>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, IRE1&#x3b1;, p-IRE1&#x3b1; and XBP1s were measured by Western blotting. Gene silencing was achieved by using small-interfering RNAs.<br><br>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.<br><br>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 &amp; 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.<br><br>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.<br><br>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&#xa0;&#xd7;&#xa0;10[6] colony forming units/mL. The concentrations of the test compounds ketoconazole (KTZ), terbinafine (TER), nystatin (NYS) and NAC were 0.02-300&#xa0;&#xb5;g/mL, 0.04-80&#xa0;&#xb5;g/mL, 0.16-40&#xa0;&#xb5;g/mL and 1.25-20&#xa0;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.<br><br>RESULTS: The MIC90 values of M. pachydermatis were 4.6875-9.375&#xa0;&#xb5;g/mL, 1.25&#xa0;&#xb5;g/mL, 5-10&#xa0;&#xb5;g/mL and 10&#xa0;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.<br><br>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 &amp; 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 = {}, number = {}, pages = {}, doi = {10.1002/iub.2899}, pmid = {39038059}, issn = {1521-6551}, support = {JCB/2019/000016//Department of Science and Technology, Ministry of Science and Technology, India (The J.C. Bose fellowship)/ ; }, abstract = {Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.}, }
@article {pmid39037665, year = {2024}, author = {Gao, C and Wang, L and Fu, K and Cheng, S and Wang, S and Feng, Z and Yu, S and Yang, Z}, title = {N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells.}, journal = {Inflammation}, volume = {}, number = {}, pages = {}, pmid = {39037665}, issn = {1573-2576}, support = {GSWS2021036//Gusu Talent Program/ ; SKY2022181//Science and Technology Project of Suzhou/ ; LGY2020045//Jiangsu Commission of Health/ ; SYH-32034-0103(2024007)//Jiangsu Medical Association Pediatric Medical Research Special Fund Project/ ; }, abstract = {Abstract-Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in neonates, and effective strategies to prevent and treat NEC are still lacking. Studies have shown that N-acetylcysteine (NAC) has protective effects against NEC, however, the specific mechanism underlying its effects on intestinal functions remains unclear. Recently, NAC has been shown to suppress ferroptosis in many diseases, while it is unclear whether the beneficial effects of NAC on NEC are related to ferroptosis. In this study, we revealed that ferroptosis was significantly induced in intestinal samples from infants with NEC. NAC alleviated intestinal inflammation, barrier damage and ferroptosis in multifactorial NEC models in vivo and in vitro. Sestrin2 (SESN2) was identified as an important mediator of NAC-induced ferroptosis resistance in intestinal epithelial cells. Furthermore, SESN2 knockdown inhibited the inflammatory response, alleviated barrier damage and ferroptosis in intestinal epithelial cells and enhanced the protective effects of NAC to a certain extent. Conversely, cells overexpressing SESN2 showed the opposite changes. In summary, our study demonstrated that NAC attenuates NEC progression by decreasing SESN2 expression to inhibit ferroptosis in intestinal epithelial cells, suggesting that NAC might be an effective clinical treatment for NEC.}, }
@article {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 = {}, number = {}, pages = {}, doi = {10.1002/tox.24377}, pmid = {39031462}, issn = {1522-7278}, support = {NCHU-CCH-11007//National Chung Hsing University/Changhua Christian Hospital Joint Research Program/ ; TCVGH-1107304D//Taichung Veterans General Hospital Research Program/ ; MOST-109-2320-B-371-003//Ministry of Science and Technology, Taiwan/ ; }, abstract = {In sepsis, bacterial components, particularly lipopolysaccharide (LPS), trigger organ injuries such as liver dysfunction. Although sepsis induces hepatocyte damage, the mechanisms underlying sepsis-related hepatic failure remain unclear. In this study, we demonstrated that the LPS-treated rat hepatocyte cell line Clone 9 not only induced reactive oxygen species (ROS) generation and apoptosis but also increased the expression of the autophagy marker proteins LC3-II and p62, and decreased the expression of intact Lamp2A, a lysosomal membrane protein. Additionally, LPS increased lysosomal membrane permeability and galectin-3 puncta formation, and promoted lysosomal alkalization in Clone 9 cells. Pharmacological inhibition of caspase-8 and cathepsin D (CTSD) suppressed the activation of caspase-3 and rescued the viability of LPS-treated Clone 9 cells. Furthermore, LPS induced CTSD release associated with lysosomal leakage and contributed to caspase-8 activation. Pretreatment with the antioxidant N-acetylcysteine (NAC) not only diminished ROS generation and increased the cell survival rate, but also decreased the expression of activated caspase-8 and caspase-3 and increased the protein level of Lamp2A in LPS-treated Clone 9 cells. These results demonstrate that LPS-induced ROS causes lysosomal membrane permeabilization and lysosomal cell death, which may play a crucial role in hepatic failure in sepsis. Our results may facilitate the development of new strategies for sepsis management.}, }
@article {pmid39028629, year = {2024}, author = {Ye, JJ and Chen, ZY and Wang, QH and Liao, XY and Wang, XY and Zhang, CC and Liu, LR and Wei, Q and Bao, YG}, title = {Current treatment for male infertility: an umbrella review of systematic reviews and meta-analyses.}, journal = {Asian journal of andrology}, volume = {}, number = {}, pages = {}, doi = {10.4103/aja202428}, pmid = {39028629}, issn = {1745-7262}, abstract = {This umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments for male infertility and assess the quality of evidence and possible biases. An umbrella review of systematic reviews and meta-analyses available in PubMed, Web of Science, and Scopus, covering studies published up to October 2023, was conducted. Sperm concentration, morphology, and motility were used as endpoints to evaluate the effectiveness of the treatments. Of 2998 studies, 18 published meta-analyses were extracted, yielding 90 summary effects on sperm concentration (n = 36), sperm morphology (n = 26), and sperm motility (n = 28) on 28 interventions. None of the meta-analyses were classified as having low methodological quality, whereas 12 (66.7%) and 6 (33.3%) had high and moderate quality, respectively. Of the 90 summary effects, none were rated high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23), and 21.1% (n = 19) were rated moderate, low, and very low, respectively. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (N-acetyl-cysteine, antioxidant therapy, aromatase inhibitors, selective estrogen receptor modulators, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (varicocele repair and redo varicocelectomy). In addition, vitamin supplementation had no significant positive effects on sperm concentration, motility, or morphology. Treatments for male infertility are increasingly diverse; however, the current evidence is poor because of the limited number of patients. Further well-designed studies on single treatment and high-quality meta-analysis of intertreatment comparisons are recommended.}, }
@article {pmid39028412, year = {2024}, author = {Zolnourian, A and Garland, P and Holton, P and Arora, M and Rhodes, J and Uff, C and Birch, T and Howat, D and Franklin, S and Galea, I and Bulters, D}, title = {A Randomised Controlled Trial of SFX-01 After Subarachnoid Haemorrhage - The SAS Study.}, journal = {Translational stroke research}, volume = {}, number = {}, pages = {}, pmid = {39028412}, issn = {1868-601X}, abstract = {SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R[2] = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.}, }
@article {pmid39028033, year = {2024}, author = {Arenhoevel, J and Kuppe, A and Addante, A and Wei, LF and Boback, N and Butnarasu, C and Zhong, Y and Wong, C and Graeber, SY and Duerr, J and Gradzielski, M and Lauster, D and Mall, MA and Haag, R}, title = {Thiolated polyglycerol sulfate as potential mucolytic for muco-obstructive lung diseases.}, journal = {Biomaterials science}, volume = {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 &amp; 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.<br><br>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.<br><br>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.<br><br>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, &#xd6;}, 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 &amp; clinical pharmacology &amp; toxicology}, volume = {135}, number = {3}, pages = {285-294}, pmid = {39004668}, issn = {1742-7843}, mesh = {*Acetylcysteine/administration &amp; dosage/therapeutic use ; Humans ; *Acetaminophen/poisoning/administration &amp; dosage ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control ; Analgesics, Non-Narcotic/poisoning/administration &amp; dosage ; Antidotes/administration &amp; 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}, 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 = {}, number = {}, pages = {105388}, doi = {10.1016/j.micinf.2024.105388}, pmid = {38997833}, issn = {1769-714X}, }
@article {pmid38992233, year = {2024}, author = {Glass, KA and Stoecker, ZR and LeRoy, J and Palmer, CL and Stipek, J and Boley, S}, title = {Investigating a Novel Two-Bag N-Acetylcysteine Regimen for Acetaminophen Toxicity.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {}, number = {}, pages = {}, pmid = {38992233}, issn = {1937-6995}, abstract = {BACKGROUND: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors.<br><br>OBJECTIVE: We aimed to assess whether switching to a novel two-bag protocol (150&#xa0;mg/kg over 1&#xa0;h followed by 150&#xa0;mg/kg over 20&#xa0;h) reduced administration errors while not increasing liver injury or anaphylactoid reactions.<br><br>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.<br><br>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.<br><br>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 &amp; dosage ; }, abstract = {PURPOSE: To investigate the protective effect of intravesical glucosamine in treating overactive bladder (OAB).<br><br>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&#xa0;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&#x2009;=&#x2009;48) and inter-contractile interval, the duration between two voids (ICI, n&#x2009;=&#x2009;32).<br><br>RESULTS: LPP was significantly elevated in the GPS group (mean&#x2009;&#xb1;&#x2009;SD: 110.9&#x2009;&#xb1;&#x2009;6.2 mmHg) compared to the NC (81.0&#x2009;&#xb1;&#x2009;32.5 mmHg), PS (40.3&#x2009;&#xb1;&#x2009;10.9 mmHg), and NAC group (70.3&#x2009;&#xb1;&#x2009;19.4 mmHg). The cystometrogram data also reveals a prolonged ICI in the GPS group (241.3&#x2009;&#xb1;&#x2009;40.2&#xa0;s) compared to the NC group (216.0&#x2009;&#xb1;&#x2009;41.7&#xa0;s), PS group (128.8&#x2009;&#xb1;&#x2009;23.6&#xa0;s), and NAC group (193.8&#x2009;&#xb1;&#x2009;28.3&#xa0;s).<br><br>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 Cient&#xed;fico y Tecnol&#xf3;gico/ ; 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 = {}, number = {}, pages = {}, doi = {10.1002/jpn3.12312}, pmid = {38973318}, issn = {1536-4801}, support = {1-14-CE-04//American Diabetes Association/ ; //Nemours Biomedical Research/ ; }, abstract = {BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction-associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N-acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and (LS) in children with obesity and biopsy-confirmed MASLD.<br><br>METHODS: Thirteen children (n&#x2009;=&#x2009;13; age: 13.6&#x2009;&#xb1;&#x2009;2.8 years; NAS score >2) underwent a double-blind, placebo-controlled trial of NAC (either 600 or 1200&#x2009;mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high-sensitivity c-reactive protein (hs-CRP), and interleukin-6 (IL-6) were also measured. HOMA-IR was calculated.<br><br>RESULTS: Sixteen-week NAC treatment improved (baseline adjusted between-group p&#x2009;<&#x2009;.05 for all) markers of inflammation (IL-6 and hs-CRP), oxidative stress (GSH), and insulin resistance (HOMA-IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes.<br><br>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 &amp; 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 {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 &amp; 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.<br><br>CASE PRESENTATION: We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48&#xa0;h after she had taken 10&#xa0;g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20&#xa0;mg/dL on admission, with a peak at 3.67&#xa0;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.<br><br>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 = {}, number = {}, pages = {1-21}, doi = {10.1080/15548627.2024.2374692}, pmid = {38953310}, issn = {1554-8635}, abstract = {Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca[2+]. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H[+]-translocating ATPase.}, }
@article {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 &amp; 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.<br><br>METHODS: Forty-eight rats were divided into six groups (n&#x2009;=&#x2009;8) as follows: Group A (control) (0.5 mL saline administered intraperitoneally [IP]), Group B (a single 10&#xa0;mg/kg dose of DOX administered IP on day 1), Group C (a single 10&#xa0;mg/kg dose of DOX administered IP 24&#xa0;h before sacrifice), Group D (100&#xa0;mg/kg of NAC administered IP for 21 days), Group E (a single 10&#xa0;mg/kg dose of DOX administered IP on day 1 and 100&#xa0;mg/kg of NAC administered IP for 21 days), and Group F (100&#xa0;mg/kg of NAC administered IP for 21 days and a single 10&#xa0;mg/kg dose of DOX administered IP 24&#xa0;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.<br><br>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-m&#xfc;llerian hormone (AMH) level was the highest in Group F.<br><br>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 &amp; 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 &amp; 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 ; Nicotiana/chemistry ; Calcium/metabolism ; Cell Survival/drug effects ; }, abstract = {BACKGROUND: The increasing prevalence of heated tobacco products (HTPs) has heightened concerns regarding their potential health risks. Previous studies have demonstrated the toxicity of cigarette smoke extract (CSE) from traditional tobacco's mainstream smoke, even after the removal of nicotine and tar. Our study aimed to investigate the cytotoxicity of CSE derived from HTPs and traditional tobacco, with a particular focus on the role of reactive oxygen species (ROS) and intracellular Ca[2+].<br><br>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.<br><br>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.<br><br>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 = {}, number = {}, pages = {1-18}, doi = {10.1080/15548627.2024.2370751}, pmid = {38910554}, issn = {1554-8635}, abstract = {Excessive macroautophagy/autophagy leads to pancreatic β-cell failure that contributes to the development of diabetes. Our previous study proved that the occurrence of deleterious hyperactive autophagy attributes to glucolipotoxicity-induced NR3C1 activation. Here, we explored the potential protective effects of (-)-epigallocatechin 3-gallate (EGCG) on β-cell-specific NR3C1 overexpression mice in vivo and NR3C1-enhanced β cells in vitro. We showed that EGCG protects pancreatic β cells against NR3C1 enhancement-induced failure through inhibiting excessive autophagy. RNA demethylase FTO (FTO alpha-ketoglutarate dependent dioxygenase) caused diminished m[6]A modifications on mRNAs of three pro-oxidant genes (Tlr4, Rela, Src) and, hence, oxidative stress occurs; by contrast, EGCG promotes FTO degradation by the ubiquitin-proteasome system in NR3C1-enhanced β cells, which alleviates oxidative stress, and thereby prevents excessive autophagy. Moreover, FTO overexpression abolishes the beneficial effects of EGCG on β cells against NR3C1 enhancement-induced damage. Collectively, our results demonstrate that EGCG protects pancreatic β cells against NR3C1 enhancement-induced excessive autophagy through suppressing FTO-stimulated oxidative stress, which provides novel insights into the mechanisms for the anti-diabetic effect of EGCG.Abbreviation 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ad: adenovirus; ALD: aldosterone; AUC: area under curve; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; Ctrl: control; CHX: cycloheximide; DEX: dexamethasone; DHE: dihydroethidium; EGCG: (-)-epigallocatechin 3-gallate; FTO: FTO alpha-ketoglutarate dependent dioxygenase; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; HG: high glucose; i.p.: intraperitoneal; IOD: immunofluorescence optical density; KSIS: potassium-stimulated insulin secretion; m[6]A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NO: nitric oxide; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NAC: N-acetylcysteine; NC: negative control; PBS: phosphate-buffered saline; PI: propidium iodide; OCR: oxygen consumption rate; Palm.: palmitate; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RNA-seq: RNA sequencing; O2[.-]: superoxide anion; SRC: Rous sarcoma oncogene; ROS: reactive oxygen species; T2D: type 2 diabetes; TEM: transmission electron microscopy; TLR4: toll-like receptor 4; TUNEL: terminal dUTP nick-end labeling; UTR: untranslated region; WT: wild-type.}, }
@article {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 &amp; 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.<br><br>METHODS: BV-2 cells were pre-incubated with 10&#xa0;&#x3bc;M N-acetyl-L-cysteine (NAC) for 2&#xa0;h, which were then reacted with 1&#xa0;&#x3bc;g/mL LPS for 24&#xa0;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.<br><br>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-1&#x3b2;, 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.<br><br>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//Jos&#xe9; Carreras Leuk&#xe4;mie-Stiftung/ ; }, mesh = {*DNA Repair ; *Caenorhabditis elegans/genetics/drug effects/growth &amp; 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 &amp; 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.<br><br>OBJECTIVES: In this study, we aim to determine the mechanisms regulating the damaging effects of POPs in pancreatic &#x3b2;-cells, which have a central role in the development of diabetes.<br><br>METHODS: We treated INS-1E pancreatic &#x3b2;-cells with PCB-153, p,p'-DDE, PCB-126, or TCDD at doses ranging from 1&#xa0;&#xd7;&#xa0;10[-15]to 5&#xa0;&#xd7;&#xa0;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.<br><br>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&#xa0;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[&#x2022;-]) 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.<br><br>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 &amp; derivatives ; Rats, Wistar ; Sulfides/pharmacology/administration &amp; 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.<br><br>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.<br><br>METHODS: Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&amp;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.<br><br>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-&#x3ba;B) 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.<br><br>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 &amp; 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 = {}, number = {}, pages = {1-21}, doi = {10.1080/15548627.2024.2367191}, pmid = {38873925}, issn = {1554-8635}, abstract = {Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3[-/-]) mice and edil3[-/-] bone marrow chimeric mice exhibited a considerable exacerbation in β-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/β3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: β-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-β-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&amp;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 &amp; 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 L&#xfc;liang/ ; 2020ZDSYS17//the Key Laboratory Platform Construction Projects of L&#xfc;liang/ ; 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.<br><br>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.<br><br>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&#xa0;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.<br><br>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&#xa0;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 = {}, number = {}, pages = {e202400110}, doi = {10.1002/cmdc.202400110}, pmid = {38847101}, issn = {1860-7187}, support = {2018CXGC1411//Key R&amp;D Programs of Shandong Province/ ; 2021CXGC010514//Key R&amp;D Programs of Shandong Province/ ; }, 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.<br><br>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&#x2009;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.<br><br>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, E&#x130;}, 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).<br><br>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.<br><br>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.<br><br>CONCLUSIONS: Atrial fibrillation is a significant postoperative complication, particularly in cardiothoracic surgery. This study highlights the need for further research on optimal NAC dosing and timing, with evidence suggesting that preoperative and postoperative NAC administration may significantly decrease postoperative atrial fibrillation in cardiothoracic surgery patients, although limitations and variability in study designs need to be considered.}, }
@article {pmid38841121, year = {2024}, author = {Jenkins, DD and Garner, SS and Brennan, A and Morris, J and Bonham, K and Adams, L and Hunt, S and Moss, H and Badran, BW and George, MS and Wiest, DB}, title = {Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1373543}, pmid = {38841121}, issn = {1662-5161}, abstract = {OBJECTIVE: This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.<br><br>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&#x2009;mg/kg/dose) was given by nasogastric (NG) administration every 6&#x2009;h for 4&#x2009;days, then combined with taVNS paired with 2 daily feeds for another 14&#x2009;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.<br><br>RESULTS: NAC 100&#x2009;mg/kg/dose every 6&#x2009;h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13&#x2009;&#xb1;&#x2009;0.08&#x2009;mM (p&#x2009;=&#x2009;0.01, compared to baseline). Mean daily feeding volumes increased over 14&#x2009;days of NAC&#x2009;+&#x2009;taVNS compared to the 14&#x2009;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.<br><br>CONCLUSION: In IDM failing oral feeds, NAC 100&#x2009;mg/kg/dose every 6&#x2009;h NG for 4&#x2009;days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.}, }
@article {pmid38836732, year = {2024}, author = {Chen, J and Zhu, Y and Zheng, C and Zhao, W and Liu, Q}, title = {Influence Factors of the Therapeutic Effect of Budesonide Combined with N-Acetylcysteine in Children with Mycoplasma Pneumoniae Infection Analyzed by Lasso-Logistic and Construction of a Nomogram Prediction Model.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {38836732}, issn = {1078-6791}, abstract = {OBJECTIVE: This study aims to analyze the factors influencing the efficacy of budesonide (BUD) combined with N-acetylcysteine (NAC) treatment in children with Mycoplasma pneumoniae (MP) infection through Lasso-Logistic analysis, construct a Nomogram predictive model, and provide personalized treatment plans for clinicians. Additionally, it aims to fill the knowledge gap regarding the treatment of MP-infected children with BUD combined with NAC.<br><br>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.<br><br>RESULTS: Logistic regression identified prolonged fever (&#x2265;7 days), high fever, and elevated levels of TNF-&#x3b1;, 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.<br><br>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 = {}, number = {}, pages = {}, doi = {10.1002/jsfa.13620}, pmid = {38828636}, issn = {1097-0010}, support = {No.32172725//National Natural Science Foundation of China/ ; 2023AAC02013//Ningxia Natural Science Foundation of China/ ; 2021YFC2101403//National Key Research and Development Program of China/ ; }, abstract = {BACKGROUND: Heat stress (HS) has been shown to affect reproductive performance and muscle development negatively in animals. N-Acetylcysteine (NAC) plays a pivotal role in enhancing the antioxidant performance in animals as a recognized antioxidant. The present study assesses the potential of NAC to modulate the reproductive performance and antioxidant function in pregnant mice exposed to HS. The role of NAC in muscle development of offspring mice was also explored.<br><br>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&#x2009;<&#x2009;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.<br><br>CONCLUSION: The results of the present study support the use of NAC at a dose of 100&#x2009;mg&#x2009;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. &#xa9; 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 &amp; 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.<br><br>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.<br><br>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.<br><br>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 &amp; 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 &amp; redox signaling}, volume = {}, number = {}, pages = {}, doi = {10.1089/ars.2023.0383}, pmid = {38814824}, issn = {1557-7716}, abstract = {Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury.}, }
@article {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 &amp; clinical pharmacology &amp; 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.<br><br>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.<br><br>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.<br><br>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.<br><br>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 (IKK&#x3b2;), inhibitor of Kappa B&#x3b1; (I&#x3ba;B&#x3b1;), 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.<br><br>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, I&#x3ba;B&#x3b1;, IKK&#x3b2;, 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, I&#x3ba;B&#x3b1;, IKK&#x3b2;, 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.<br><br>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.<br><br>ABSTRACT: This case report presents a unique manifestation of severe hepatic involvement in a 4-year-old girl with thalassemia minor and COVID-19. Despite the absence of prominent respiratory symptoms, the patient exhibited jaundice, elevated liver enzymes, and coagulopathy. Initial suspicion of viral hepatitis was replaced by the discovery of significantly elevated SARS-CoV-2 antibodies. A multidisciplinary approach, including gastroenterology consultation and an extensive workup, was pivotal in ruling out alternative etiologies. Unconventional use of N-acetyl cysteine contributed to clinical improvement, highlighting the need for adaptable treatment strategies. This case underscores the importance of heightened awareness in recognizing atypical presentations of COVID-19 in pediatric patients, especially those with underlying health conditions. Further exploration into nuanced manifestations and treatment approaches is warranted for comprehensive clinical management.}, }
@article {pmid38798604, year = {2024}, author = {Winterlind, EL and Malone, SG and Setzer, MR and Murphy, MA and Saunders, D and Gray, JC}, title = {N-acetylcysteine as a treatment for substance use cravings: A meta-analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.13.24306839}, pmid = {38798604}, abstract = {N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. There were no between-group differences in risk of AEs. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.}, }
@article {pmid38797057, year = {2024}, author = {Li, Y and Guo, M and Wang, Q and Zhou, H and Wu, W and Lin, H and Fan, H}, title = {Glaesserella parasuis serotype 5 induces pyroptosis via the RIG-I/MAVS/NLRP3 pathway in swine tracheal epithelial cells.}, journal = {Veterinary microbiology}, volume = {294}, number = {}, pages = {110127}, doi = {10.1016/j.vetmic.2024.110127}, pmid = {38797057}, issn = {1873-2542}, 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 = {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 &amp; 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.<br><br>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-&#x3ba;B/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.<br><br>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&#xa0;<&#xa0;0.01), accompanied by substantially enhanced serum levels of TNF-&#x3b1;, IL-6, and IL-1&#x3b2;, significantly reduced serum levels of IL-10, and remarkably augmented TLR4, NLRP3, p-NF-&#x3ba;B p65, NF-&#x3ba;B p65 mRNA, and Caspase-1 expression in lung tissues (all P&#xa0;<&#xa0;0.01). Furthermore, treatment with NAC or MCC950 alone or in combination prominently lowered the W/D of lung tissues (P&#xa0;<&#xa0;0.01), serum levels of TNF-&#x3b1; (P&#xa0;<&#xa0;0.05), IL-6 (P&#xa0;<&#xa0;0.05), and IL-1&#x3b2; (P&#xa0;<&#xa0;0.01), and NF-&#x3ba;B p65 expression and phosphorylation (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) while significantly increasing SOD and GSH concentrations (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) and serum levels of IL-10 (P&#xa0;<&#xa0;0.01) in modeled rats. Meanwhile, treatment of NAC alone or combined with MCC950 significantly reduced MDA concentration and ROS levels (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;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&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01).<br><br>CONCLUSION: Inhibition of oxidative stress and the TLR4/NF-&#x3ba;B/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.<br><br>OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD.<br><br>SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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-&#x3ba;B expression and raised Nrf-2 expression, inhibiting the synthesis of pro-inflammatory cytokines and chemokines.<br><br>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.<br><br>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).<br><br>RESULTS: Strobilurin X significantly decreased the viability of A549 and HeLa cells compared to that in the WI-38 cells after 48&#xa0;h of exposure. The EC50 values for cytotoxicity in the A549, HeLa, and WI-38 cells were 3.4, 5.4, and 16.8&#xa0;&#x3bc;g/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&#xa0;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.<br><br>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 &amp; 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 &amp; 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 {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.<br><br>MATERIALS AND METHODS: AC16 cells were treated with 2 &#xb5;mol/L of doxorubicin (DOX) for 12, 24, and 48&#xa0;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.<br><br>RESULTS: Increased DUOX1 expression levels were observed after DOX treatment for 24&#xa0;h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1&#x3b2;, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1&#x3b2;, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors.<br><br>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).<br><br>METHODS: Cystathione &#x3b3;-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).<br><br>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 &#x3b2;-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.<br><br>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 &amp; breathing = Schlaf &amp; 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.<br><br>METHODS: Pubmed and Embase databases were searched for human studies evaluating the utility of antioxidant therapies in patients with OSA.<br><br>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.<br><br>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 &amp; pharmacotherapy = Biomedecine &amp; 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 &amp; 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 &amp; 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 &amp; 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 <sc>l</sc>-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.<br><br>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 m<sc>m</sc>). To evaluate adipose tissue senescence, beta-galactosidase (&#x3b2;-gal) activity and the expression of P16, P21, P53, IL-6, and TNF-&#x3b1; were determined. ANOVA test was employed to analyze the varying markers of cellular senescence and inflammation between treatment groups.<br><br>RESULTS: The NAC at concentrations of 5 m<sc>m</sc> and 10 m<sc>m</sc> resulted in a noteworthy reduction &#x3b2;-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 m<sc>m</sc>) and NAC (10 m<sc>m</sc>) compared to the control group (All p < 0.001).<br><br>DISCUSSION/CONCLUSION: Taken together, these data suggest the senotherapeutic effect of NAC, as it effectively reduces the activity of SA-&#x3b2;-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.<br><br>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 &#x3bc;g/mL emerged with 89% sensitivity and 93% specificity (area under the curve, 0.951).<br><br>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.<br><br>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.<br><br>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 &amp; dosage ; Male ; Female ; Middle Aged ; Apoptosis/drug effects ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Tumor Cells, Cultured ; Mitomycin/pharmacology/administration &amp; 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.<br><br>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&#xa0;&#xb0;C and 42&#xa0;&#xb0;C with and without bromelain pretreatment.<br><br>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&#x2009;=&#x2009;0.0009) or NAC alone (47% versus 12.8%, p&#x2009;=&#x2009;0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p&#x2009;<&#x2009;0.001) and > 66% in 48 h (p&#x2009;<&#x2009;0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p&#x2009;=&#x2009;0.0001) and 35.5% (p&#x2009;=&#x2009;0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p&#x2009;=&#x2009;0.009) and Bcl-xL (p&#x2009;=&#x2009;0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p&#x2009;<&#x2009;0.03) and II (p&#x2009;<&#x2009;0.031) were increased; while ATG7 (p&#x2009;<&#x2009;0.01), ATG 12 (p&#x2009;<&#x2009;0.04), and Becline 1(p&#x2009;<&#x2009;0.03), expression decreased in bromelain-treated PTOs.<br><br>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 Innovaci&#xf3;n/ ; VA244P20//Junta de Castilla y Le&#xf3;n/ ; 23CO1/002570//Ministerio de Ciencia e Innovaci&#xf3;n 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 &amp; 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.<br><br>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&#xa0;mg of NAC (n&#x2009;=&#x2009;22) or placebo (n&#x2009;=&#x2009;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, THR&#x3b1; and &#x3b2;, and 18s RNA (as an internal control) using the provided instructions to investigate the expression of the respective genes.<br><br>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 THR&#x3b1; expression and decrease in THR&#x3b2; expression). In addition, after adjustment of possible confounders, no significant effect was observed on anthropometric factors and serum levels of thyroid hormones.<br><br>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 &amp; 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.<br><br>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.<br><br>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.<br><br>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 &amp; 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).<br><br>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 GPIb&#x3b1;, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21.<br><br>RESULTS: Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIb&#x3b1; were all increased several-fold (p&#x2009;<&#x2009;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 >&#x2009;50% (p&#x2009;<&#x2009;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&#x2009;<&#x2009;0.05), approximately 20-fold greater platelet adhesion (p&#x2009;<&#x2009;0.05), and increased staining for markers of platelet transforming growth factor-&#x3b2;1 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.<br><br>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 &amp; pharmacotherapy = Biomedecine &amp; 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 &amp; 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 &amp; 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 &amp; development ; *Candida albicans/drug effects/growth &amp; development ; *Antifungal Agents/pharmacology ; *Reactive Oxygen Species/metabolism ; *Benzylisoquinolines/pharmacology ; *Microbial Sensitivity Tests ; Hyphae/drug effects/growth &amp; 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.<br><br>PURPOSE: To investigate the potential anti-tumor mechanism of extracts of EHL on hemangioendothelioma and melanoma.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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&#x202f;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).<br><br>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.<br><br>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.<br><br>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 &#xb0;C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.<br><br>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&#x2005;nm after submersion in saline over approximately 8&#x2005;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 &amp; 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 &amp; 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 Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; }, mesh = {*Xylella/drug effects/physiology ; *Acetylcysteine/pharmacology ; *Plant Diseases/microbiology/prevention &amp; 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.<br><br>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.<br><br>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. &#xa9; 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 &amp; derivatives ; Rats, Sprague-Dawley ; *Substance Withdrawal Syndrome ; Naloxone/pharmacology ; Narcotic Antagonists/pharmacology ; *Morphine Dependence ; Lysine/*analogs &amp; 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.<br><br>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.<br><br>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.<br><br>DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects.<br><br>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 &amp; 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 = {}, number = {}, pages = {}, doi = {10.1089/bio.2023.0103}, pmid = {38634668}, issn = {1947-5543}, 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.<br><br>AIM: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats.<br><br>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.<br><br>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-&#x3b1;, and TGF-&#x3b2;1 levels, and marked elevation in the IgM levels.<br><br>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 &amp; 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.<br><br>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&#xa0;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.<br><br>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.<br><br>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.<br><br>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.<br><br>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 &amp; 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 &amp; 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.<br><br>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&#xa0;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.<br><br>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.<br><br>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).<br><br>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.<br><br>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.<br><br>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 &amp; 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).<br><br>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.<br><br>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.<br><br>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.<br><br>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 ; 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 &amp; 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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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).<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>METHODS: The current study evaluated the efficacy and safety of Abivisor[&#xae;], 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.<br><br>RESULTS: Abivisor[&#xae;] 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.<br><br>CONCLUSIONS: The present study suggests that Abivisor[&#xae;] 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.<br><br>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.<br><br>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.<br><br>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, &#xd3; 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 "Ram&#xf3;n 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&amp;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 ; 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.<br><br>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.<br><br>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.<br><br>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.<br><br>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-1&#x3b2; 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.<br><br>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.<br><br>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.<br><br>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.&#xa0;Subjects recruited from the smoking cessation clinic were screened for eligibility and were&#xa0;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.&#xa0;Adverse events (AEs) have also been observed on each visit.<br><br>RESULTS: A total of 90&#xa0;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&#xa0;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)&#xa0;(9.59&#xa0;&#xb1;7.4 vs 13,4&#xa0;&#xb1;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&#xa0;NAC&#xa0;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.<br><br>CONCLUSIONS: &#xa0;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.<br><br>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 &#x3b1;-synuclein, by using qPCR and Western blot techniques. Moreover, we quantified the effect of NAC on total dopamine levels using a dopamine ELISA assay.<br><br>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 &#x3b1;-synuclein.<br><br>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.<br><br>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 &amp; redox signaling}, volume = {40}, number = {16-18}, pages = {968-989}, doi = {10.1089/ars.2023.0524}, pmid = {38497734}, issn = {1557-7716}, 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 &amp; control ; Anti-Inflammatory Agents ; Inflammation ; Calcitriol/*analogs &amp; 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.<br><br>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.<br><br>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.<br><br>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 &amp; inhibitors/analysis/chemistry ; *Virulence Factors/antagonists &amp; 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 &amp; 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.<br><br>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.<br><br>RESULTS: Twenty patients with a mean age of 36.4&#x2009;years were recruited. The mean percentage of lesions and their intensity were significantly improved 2&#x2009;weeks after the third session and 1&#x2009;month after the end of the treatment (p&#x2009;<&#x2009;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&#x2009;>&#x2009;0.05).<br><br>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.<br><br>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&#x2009;weeks of ATT, subsequently received a diagnosis of severe dengue. Laboratory evidence indicated markedly elevated transaminases (AST 4335&#x2009;U/L, ALT 1958&#x2009;U/L), total bilirubin (72&#x2009;&#x3bc;mol/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 &amp; 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 &amp; 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 &amp; 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.<br><br>OBJECTIVE: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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.<br><br>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 An&#xe6;stesiologi 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.<br><br>OBJECTIVES: In this study, we investigated the effect of F. subpinnata extract on MCF-7 breast cancer cells.<br><br>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.<br><br>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 &#x3bc;g/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.<br><br>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.<br><br>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.<br><br>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%.<br><br>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).<br><br>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.<br><br>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.<br><br>METHODS: Biofilm formation and the efficacy of these agents on the biofilm layer were demonstrated using colony counting and laser-screened confocal microscopy.<br><br>RESULTS: NAC at a final concentration of 2 &#x3bc;g/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 &#x3bc;g/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 &#x2265; 2 log10.<br><br>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.<br><br>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-1&#x3b2;, IL-18, IL-6, and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) 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.<br><br>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-1&#x3b2;, IL-18, IL-6, and TNF-&#x3b1;, and promoted the expression of active IL-1&#x3b2;, 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.<br><br>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.<br><br>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.<br><br>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.<br><br>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&#xb1;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).<br><br>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 a