@article {pmid40359441,
year = {2025},
author = {Goldin, D and Salani, DA and Valdes, B},
title = {N-Acetylcysteine (NAC) for Trichotillomania and Excoriation Disorder: An Overview.},
journal = {Journal of psychosocial nursing and mental health services},
volume = {},
number = {},
pages = {1-9},
doi = {10.3928/02793695-20250506-04},
pmid = {40359441},
issn = {0279-3695},
abstract = {Trichotillomania and excoriation/skin-picking disorder involve repetitive behaviors, such as hair pulling leading to hair loss or skin picking leading to skin lesions, that cause physical complications, significant mental distress, and functional impairment despite attempts to stop. Currently, no first-line pharmacological treatments are approved for these disorders, although glutamatergic agents, select antidepressants, and other medications have demonstrated some benefit. The therapeutic potential of N-acetylcysteine (NAC) is promising. NAC helps maintain glutamate homeostasis in the brain, thereby reducing compulsive and habitual behaviors. In addition, NAC is recognized as a low-risk, well-tolerated, and accessible dietary supplement with valuable therapeutic potential. Deficiencies in pharmacological protocols and lack of government controls place individuals at risk; therefore, health care providers are well positioned to provide reliable information and educate individuals to make informed decisions about their health. [Journal of Psychosocial Nursing and Mental Health Services, xx(x), xx-xx.].},
}

@article {pmid40356978,
year = {2025},
author = {Zhang, M and Yuan, W and Li, C and Chen, C and Liu, X and Ma, Z and Xiang, Y and Chen, G and Wang, C and Li, L and Wang, L and Xu, Z and Xu, C},
title = {Resveratrol and N-acetylcystein reduce hepatic steatosis but enhance initiation and progression of hepatocellular carcinoma by inhibiting GST-pi-MAPK axis in mice.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1574039},
pmid = {40356978},
issn = {1663-9812},
abstract = {INTRODUCTION: Accumulating evidence indicates that antioxidants promote tumor growth and metastasis after tumor onset in several cancer types. However, whether antioxidants prevent or accelerate hepatic tumorigenesis during steatosis remains unknown. Therefore, we investigated the effects of resveratrol (RES) and N-acetylcysteine (NAC) on hepatocellular carcinoma (HCC) development using two fatty liver mouse models.

METHODS: High-fat diet (HFD) plus diethylnitrosamine (DEN)- and AKT/Ras-induced primary HCC mouse models were used. The weight, liver weight ratio and the number of HCC tumors were calculated and histological features of mouse HCC tissues were analyzed using immumohistochemical staining such as hematoxylin and eosin staining. Proteomic analysis was used to screen for differences in liver cancer progression between antioxidant-treated HCC and models. Protein inhibitor recovery experiments in mice and in vitro cells validate the targets screened by proteomic analysis. The expression of GST-pi, p-JNK and p-p38 signaling molecules in HCC were investigated using Western blotting.

RESULTS: RES and NAC enhance HCC formation in both DEN/HFD and AKT/Ras mice. RES and NAC alleviate hepatosteatosis, and reduce ROS and DNA damage in mice. Proteomic analysis and protein inhibitor recovery assay demonstrated that GST-pi is a therapeutic target for antioxidant-induced hepatocellular carcinoma growth. Mechanistically, RES and NAC decreased p-JNK and p-p38, the two major mitogen-activated protein kinases, in HCC cells. Blockade of GST-pi abrogated the reduction in p-JNK and p-p38 levels and increased apoptosis of HCC cells.

CONCLUSION: Antioxidants may increase the incidence of HCC in a population with fatty liver, despite reduction in ROS production, by inhibiting GST-pi-MAPK axis.},
}

@article {pmid40311609,
year = {2025},
author = {Zheng, J and Zhang, W and Ito, J and Henkelmann, B and Xu, C and Mishima, E and Conrad, M},
title = {N-acetyl-l-cysteine averts ferroptosis by fostering glutathione peroxidase 4.},
journal = {Cell chemical biology},
volume = {32},
number = {5},
pages = {767-775.e5},
doi = {10.1016/j.chembiol.2025.04.002},
pmid = {40311609},
issn = {2451-9448},
mesh = {*Ferroptosis/drug effects ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Acetylcysteine/pharmacology/chemistry/metabolism ; Humans ; Lipid Peroxidation/drug effects ; },
abstract = {N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc[-], glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.},
}

*Ferroptosis/drug effects
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
*Acetylcysteine/pharmacology/chemistry/metabolism
Humans
Lipid Peroxidation/drug effects

@article {pmid40021515,
year = {2025},
author = {Dong, L and Hao, X and Liu, M and Zhai, Y and Wang, X and Tian, X and Li, W and Peng, Y and Zheng, J},
title = {Metabolic activation and cytotoxicity of ibudilast mediated by CYP3A4.},
journal = {Archives of toxicology},
volume = {99},
number = {5},
pages = {2023-2038},
pmid = {40021515},
issn = {1432-0738},
mesh = {Animals ; *Cytochrome P-450 CYP3A/metabolism ; Humans ; Microsomes, Liver/drug effects/metabolism/enzymology ; Glutathione/metabolism ; *Pyridines/toxicity/metabolism/pharmacokinetics ; Mice ; Male ; Activation, Metabolic ; *Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology ; Hepatocytes/drug effects/metabolism ; Cysteine/metabolism ; Mice, Inbred C57BL ; Cell Survival/drug effects ; Acetylcysteine/metabolism ; Indolizines ; Pyrazoles ; },
abstract = {Ibudilast (IBD) is a relatively nonselective inhibitor of phosphodiesterase, commonly used for treating asthma, progressive multiple sclerosis and other neuropathological pain conditions. Although IBD was considered safe and harmless to human health, its clinical use might be associated with reported increases of serum AST and ALT as well as liver weight. However, the mechanisms behind such liver injury are still unknown. The purpose of this work was to investigate metabolic activation of IBD and to define correlation between bioactivation and hepatotoxicity of IBD. Two oxidative metabolites, IBD-derived glutathione (GSH) conjugates (M1, M2), N-acetyl-L-cysteine (NAC) conjugates (M3, M4), and cysteine (Cys) conjugates (M5, M6) were detected in mouse liver microsomes fortified with IBD (100 μM) and trapping agents GSH, NAC, or Cys, respectively, and two GSH conjugates (M1 and M2), one NAC conjugate (M4) and one Cys conjugate (M5) were detected. Similar observation was obtained in human liver microsomal incubations. The formation of M1-M6 was NADPH-dependent. Moreover, biliary GSH conjugates and urinary NAC conjugates derived from IBD were detected in mice given IBD intragastrically at 100 mg/kg. The metabolism study suggested the formation of an epoxide intermediate. In addition, the epoxide intermediate was found to react with cysteine residues of hepatic protein in a dose-dependent manner. Further studies indicate that CYP3A4 dominated the metabolic activation of IBD. Exposure of primary hepatocytes to IBD resulted in decreased cell survival. Pretreatment of mice hepatocytes with ketoconazole attenuated the susceptibility to the cytotoxicity of IBD (25-400 μM). The reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD. This work revealed the reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD, and would provide new insights into the mechanisms behind the adverse reactions taking place in clinical use of IBD, especially for the reported liver injury.},
}

Animals
*Cytochrome P-450 CYP3A/metabolism
Humans
Microsomes, Liver/drug effects/metabolism/enzymology
Glutathione/metabolism
*Pyridines/toxicity/metabolism/pharmacokinetics
Mice
Male
Activation, Metabolic
*Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology
Hepatocytes/drug effects/metabolism
Cysteine/metabolism
Mice, Inbred C57BL
Cell Survival/drug effects
Acetylcysteine/metabolism
Indolizines
Pyrazoles

@article {pmid40352229,
year = {2025},
author = {Nasrun, MW and Ginting, TT and Siste, K and Pandelaki, J and Kekalih, A and Louisa, M and Susanto, AD and Utami, DS and Tarigan, IN and Trishna, AR and Halim, K},
title = {Efficacy of N-acetylcysteine and motivational enhancement therapy for nicotine addiction: A randomized clinical trial.},
journal = {Narra J},
volume = {5},
number = {1},
pages = {e2178},
pmid = {40352229},
issn = {2807-2618},
mesh = {Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Male ; Female ; Adult ; *Tobacco Use Disorder/drug therapy/therapy ; Middle Aged ; Magnetic Resonance Spectroscopy ; Motivation ; Treatment Outcome ; Brain/metabolism/drug effects ; Creatine/metabolism ; Glutamine ; Prefrontal Cortex ; Aspartic Acid/analogs & derivatives ; },
abstract = {N-acetylcysteine (NAC) is known to enhance neuroplasticity and help reduce smoking addiction by modulating brain metabolites. The use of magnetic resonance spectroscopy (MRS) in smokers receiving NAC as an adjuvant to motivational enhancement therapy (MET) represents a novel approach to understanding how this combination therapy influences brain chemistry. By utilizing MRS, the effectiveness of NAC can be quantitatively assessed by analyzing changes in smoking-affected brain metabolites. The aim of this study was to evaluate the efficacy of NAC combined with MET for nicotine addiction, using MRS to assess neurochemical alterations associated with treatment response. A stratified, randomized, parallel-group clinical trial was conducted, comparing NAC and MET combination to MET only among smokers. The study analyzed the effectiveness of NAC by evaluating glutamate-glutamine (Glx) to creatine ratio (Glx/creatine ratio) and N-acetylaspartate (NAA) to creatine ratio (NAA/creatine ratio) in the nucleus accumbens, bilateral cerebellum, medial prefrontal cortex, ventromedial prefrontal cortex, and bilateral precuneus. Our data indicated that the Glx/creatine ratios for the intervention versus control groups were as follows: nucleus accumbens (0.68 vs 0. 43), bilateral cerebellum (0.68 vs 0.43), left medial prefrontal cortex (1.11 vs 0.82), ventromedial prefrontal cortex (0.32 vs 0.86), and bilateral precuneus (0.75 vs 0.58). The NAA/creatine ratios for the intervention versus control groups were as follows: nucleus accumbens (3.55 vs 8.35), bilateral cerebellum (7.82 vs 4.02), left medial prefrontal cortex (5.47 vs 5.20), ventromedial prefrontal cortex (3.55 vs 7.46), and bilateral precuneus (4.73 vs 4.00). Our analysis indicated that the Glx/creatine ratio was higher in the intervention group than in the control group in the medial prefrontal cortex (p = 0.02), while the NAA/creatine ratio was higher in the intervention group than in the control group in the bilateral cerebellum (p < 0.001). The reported side effects were mild to moderate discomfort and well-tolerated across both groups. These findings highlight the potential of NAC and MET combination in promoting neuroplasticity and supporting nicotine addiction treatment.},
}

Humans
*Acetylcysteine/therapeutic use/pharmacology
Male
Female
Adult
*Tobacco Use Disorder/drug therapy/therapy
Middle Aged
Magnetic Resonance Spectroscopy
Motivation
Treatment Outcome
Brain/metabolism/drug effects
Creatine/metabolism
Glutamine
Prefrontal Cortex
Aspartic Acid/analogs & derivatives

@article {pmid40350672,
year = {2025},
author = {Ma, X and Yang, Y and Liu, S and Cui, Y and Wu, J},
title = {Meta-analysis of the efficacy and safety of L-carnitine and N-acetylcysteine monotherapy for male idiopathic infertility.},
journal = {Revista internacional de andrologia},
volume = {23},
number = {1},
pages = {1-12},
doi = {10.22514/j.androl.2025.004},
pmid = {40350672},
issn = {1698-0409},
support = {82370690, 82303813//National Natural Science Foundation of China/ ; ZR2023MH241, ZR2023QH271//Shandong Science and Technology Program/ ; tsqn201909199, tsqn202306403//Taishan Scholars Program of Shandong Province/ ; },
mesh = {Male ; *Acetylcysteine/therapeutic use/adverse effects ; Humans ; *Infertility, Male/drug therapy ; *Carnitine/therapeutic use/adverse effects ; Sperm Motility/drug effects ; Randomized Controlled Trials as Topic ; *Antioxidants/therapeutic use/adverse effects/administration & dosage ; Sperm Count ; Testosterone/blood ; Treatment Outcome ; Ejaculation/drug effects ; },
abstract = {BACKGROUND: Oral antioxidants especially L-carnitine (LC) and N-Acetylcysteine (NAC) are commonly used as the drug treatment method for idiopathic male infertility (IMI).

METHODS: Randomized controlled trials (RCTs) of LC and NAC monotherapy for IMI were searched systematically by using MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of retrieved studies were also perused. We analyzed the sperm concentration, normal morphology, sperm motility, and ejaculation volume.

RESULTS: Seven Randomized controlled trials were included. Four trials compared the efficacy of LC with placebo, and three trials compared the efficacy of NAC with placebo. In the efficacy analysis, LC increased sperm concentration (p < 0.001), normal morphology (p = 0.03), and sperm motility (p = 0.02); NAC improved the first three indicators while also increasing ejaculation volume (p = 0.002). In hormone level analysis, LC increased serum testosterone levels (p < 0.001), but the changes in other hormone levels were not statistically significant.

CONCLUSIONS: Both LC and NAC can improve sperm motility, sperm concentration, and normal morphology, and increase serum testosterone concentration, but have no significant effect on other serum hormones.

THE PROSPERO REGISTRATION: CRD42024552120.},
}

Male
*Acetylcysteine/therapeutic use/adverse effects
Humans
*Infertility, Male/drug therapy
*Carnitine/therapeutic use/adverse effects
Sperm Motility/drug effects
Randomized Controlled Trials as Topic
*Antioxidants/therapeutic use/adverse effects/administration & dosage
Sperm Count
Testosterone/blood
Treatment Outcome
Ejaculation/drug effects

@article {pmid40348944,
year = {2025},
author = {Kosonen, JP and Eskelinen, ASA and Orozco, GA and Coleman, MC and Goetz, JE and Anderson, DD and Grodzinsky, AJ and Tanska, P and Korhonen, RK},
title = {Mechanobiochemical finite element model to analyze impact-loading-induced cell damage, subsequent proteoglycan loss, and anti-oxidative treatment effects in articular cartilage.},
journal = {Biomechanics and modeling in mechanobiology},
volume = {},
number = {},
pages = {},
pmid = {40348944},
issn = {1617-7940},
support = {240098//Sigrid Juselius Foundation/ ; 354916//Strategic funding of the University of Eastern Finland, Academy of Finland/ ; 363459//Strategic funding of the University of Eastern Finland, Academy of Finland/ ; 240074//Päivikki and Sakari Sohlberg Foundation/ ; NNF21OC0065373//Novo Nordisk Foundation (the Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA))/ ; },
abstract = {Joint trauma often leads to articular cartilage degeneration and post-traumatic osteoarthritis (PTOA). Pivotal determinants include trauma-induced excessive tissue strains that damage cartilage cells. As a downstream effect, these damaged cells can trigger cartilage degeneration via oxidative stress, cell death, and proteolytic tissue degeneration. N-acetylcysteine (NAC) has emerged as an antioxidant capable of inhibiting oxidative stress, cell death, and cartilage degeneration post-impact. However, the temporal effects of NAC are not fully understood and remain difficult to assess solely by physical experiments. Thus, we developed a computational finite element analysis framework to simulate a drop-tower impact of cartilage in Abaqus, and subsequent oxidative stress-related cell damage, and NAC treatment upon cartilage proteoglycan content in Comsol Multiphysics, based on prior ex vivo experiments. Model results provide evidence that immediate NAC treatment can reduce proteoglycan loss by mitigating oxidative stress, cell death (improved proteoglycan biosynthesis), and enzymatic proteoglycan depletion. Our simulations also indicate that delayed NAC treatment may not inhibit cartilage proteoglycan loss despite reduced cell death after impact. These results enhance understanding of the temporal effects of impact-related cell damage and treatment that are critical for the development of effective treatments for PTOA. In the future, our modeling framework could increase understanding of time-dependent mechanisms of oxidative stress and downstream effects in injured cartilage and aid in developing better treatments to mitigate PTOA progression.},
}

@article {pmid40348128,
year = {2025},
author = {Modanlo, N and Yan, X and Bourgeois, JA},
title = {Pharmacologic Management of Skin-Picking Disorder: An Updated Review.},
journal = {Journal of the Academy of Consultation-Liaison Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaclp.2025.05.002},
pmid = {40348128},
issn = {2667-2960},
abstract = {INTRODUCTION: Skin-picking disorder (SPD), defined as a psychocutaneous condition that involves excessive picking at the skin causing marked impairment in quality of life, is commonly seen in both dermatology and psychiatry. As such, therapeutic intervention - both non-pharmacologic and pharmacologic - is essential. Given the rising prevalence of SPD and the tremendous impact it can have on quality of life, an updated review, specifically on pharmacologic options, is very much needed.

METHODS: A search through PubMed was conducted using the key words "treatment" and "skin picking" or "excoriation" in November 2024. Articles were limited to those that solely address pharmacologic treatments in skin-picking for individuals > 18-years-old, were published in the last 20 years, in the English language, and can be classified as either a clinical trial, case report/series, or cohort study.

FINDINGS: Of the 192 articles extracted from PubMed, 13 studies (289 patients) met the inclusion criteria. These articles consist of 7 case reports/series and 6 randomized controlled trials. The following medications were evaluated for treatment of SPD: selective serotonin reuptake inhibitors (SSRIs), glutamatergic drugs (N-acetyl cysteine, memantine), antiepileptics (lamotrigine, topiramate), lithium, antipsychotics (olanzapine, aripiprazole), opioid antagonists (naltrexone), and mirtazapine.

CONCLUSION: Of the medications evaluated for use in SPD, SSRIs show the most promising results in terms of mitigating the severity and frequency of skin-picking symptoms. Although habit-reversal psychotherapy has traditionally been first-line treatment, SSRIs are now increasingly being used in combination with psychotherapy when a patient presents with SPD. N-acetyl cysteine has also been well-established in the treatment of SPD. Other classes of medications that have been studied in SPD include the use of antipsychotics (often combined with antidepressants) and naltrexone. Additional studies are indicated to further expand on the current research and definitively establish the role of the less common medications, such as antiepileptics, in SPD.},
}

@article {pmid40347530,
year = {2025},
author = {Chetcuti, L and Uljarević, M and Schuck, RK and Hardan, AY and Gengoux, GW and Trembath, D and Vadgama, Y and Varcin, KJ and Vivanti, G and Whitehouse, AJO and Helton, M and Frazier, TW},
title = {Characterizing predictors of response to behavioral interventions for children with autism spectrum disorder: A meta-analytic approach.},
journal = {Clinical psychology review},
volume = {119},
number = {},
pages = {102588},
doi = {10.1016/j.cpr.2025.102588},
pmid = {40347530},
issn = {1873-7811},
abstract = {A comprehensive understanding of specific factors contributing to variability in responsiveness of children with autism to interventions is paramount for making evidence-based clinical and policy decisions. This meta-analysis examined child and family characteristics, as well as intervention design factors, associated with outcomes of behavioral interventions for children with autism. A systematic review identified 95 studies published between 1987 and 2024, encompassing 6780 children on the autism spectrum and 2150 independent effect sizes. Results indicated that stronger post-intervention effects were observed across intervention approaches for children with higher cognitive, language, and other developmental abilities, greater adaptive functioning, and fewer autism-related features. Additionally, interventions of longer duration and greater total hours were associated with stronger post-intervention outcomes. In contrast, intervention approach (Early Intensive Behavioral Intervention, Naturalistic Developmental Behavioral Interventions, or Developmental Interventions), delivery agent, and child age at intervention onset did not significantly predict the strength of post-intervention outcomes. While study methodology and reporting quality were marginally associated with predictive strength, adjusting for these factors had minimal impact on the reported findings. The insights from this meta-analysis have significant implications for the development of personalized intervention models for children with autism. These models have the potential to optimize outcomes and offer critical guidance for decision-making in both the service and policy levels, ensuring efficient and equitable allocation of resources.},
}

@article {pmid40345318,
year = {2025},
author = {Låg, M and Skuland, T and Ballangby, J and Grytting, VS and Jørgensen, RB and Snilsberg, B and Øvrevik, J and Holme, JA and Refsnes, M},
title = {Mechanisms involved in pro-inflammatory responses to traffic-derived particulate matter (PM) in THP-1 macrophages compared to HBEC3-KT bronchial epithelial cells.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154174},
doi = {10.1016/j.tox.2025.154174},
pmid = {40345318},
issn = {1879-3185},
abstract = {The pro-inflammatory responses in THP-1-derived macrophages and human bronchial epithelial cells (HBEC3-KT) were examined after exposure to size-fractioned particulate matter (PM) sampled in two road tunnels. All tunnel PM samples induced release and expression of CXCL8 and IL-1β in THP-1 macrophages (50µg/mL) and HBEC3-KT cells (100µg/mL), but the potency of the samples differed between the cell types. The road tunnel PM induced pro-inflammatory responses in the macrophages to a much higher extent than diesel exhaust particles (DEP) and particles derived from the stone materials used in the asphalt. Tunnel PM induced a markedly higher increase in cytochrome P450 (CYP)1A1 expression in HBEC3-KT cells than in THP-1 macrophages. The content of organic carbon (OC) in PM correlated to the release of CXCL8 in HBEC3-KT cells, but not in THP-1 macrophages. Moreover, the aryl hydrocarbon receptor (AhR)-inhibitor CH223191 and the antioxidant N-acetyl cysteine (NAC) reduced the PM-induced cytokine release in the macrophages to a lower extent than in HBEC3-KT. In contrast, a toll-like receptor (TLR)2 antibody markedly reduced the PM-induced responses in THP-1 macrophages, but not in HBEC3-KT. A TLR4 antibody was without effect in both cell types. The levels of the microbial TLR2-ligand β-glucan in the PM samples were in a range that might be sufficient to induce pro-inflammatory responses. However, a microbial-independent mechanism could also be involved. In support of such a mechanism, the pro-inflammatory responses to a sample of α-quartz (Min-U-Sil 5), with low levels of β-glucan, were reduced by anti-TLR2. In conclusion, our results indicate that traffic-derived PM exert pro-inflammatory responses in THP-1 macrophages and HBEC3-KT cells via different PM constituents and mechanisms. OC/AhR-dependent mechanisms appeared to be important for PM-induced CXCL8 responses in HBEC3-KT cells, while the cytokine responses in THP-1 macrophages seemed to involve TLR2-mediated activation, either via β-glucan-dependent or -independent mechanisms.},
}

@article {pmid40342610,
year = {2025},
author = {Ebid, AIM and Mohamed, HS and Mohammed, YMM and Mohamed Abdel Motaleb, SM},
title = {Efficacy, Safety, and Cost-Effectiveness of N-Acetylcysteine in Preventing Amphotericin B Nephrotoxicity in Egyptian Patients with Hematological Malignancies: A Randomized Controlled Trial.},
journal = {Hospital pharmacy},
volume = {},
number = {},
pages = {00185787251337615},
pmid = {40342610},
issn = {0018-5787},
abstract = {Introduction: Amphotericin B (AmB-d) is one of the most common agents for treating fatal systemic fungal infections in patients with hematologic malignancies. However, its severe adverse effects, especially nephrotoxicity, limited its use. This study evaluated the efficacy, safety, and cost-effectiveness of oral N-acetylcysteine (NAC) in preventing AmB-d nephrotoxicity and promoting renal recovery in Egyptian hematological malignancy patients. Methods: A prospective open-label randomized controlled trial was conducted. Patients were randomized to receive AmB-d plus 600 mg NAC twice daily (intervention group) or AmB-d alone (control group). The primary outcome was the incidence of acute kidney injury (AKI), with secondary outcomes including electrolyte imbalances (hypokalemia, hypomagnesemia) and renal recovery from AKI. A cost-effectiveness analysis was performed, supported by one-way and probabilistic sensitivity analyses (PSA). Results: NAC co-treatment significantly reduced AmB-d-induced AKI (odds ratio = 0.415, 95% CI: 0.174-0.992, P = .041). Renal recovery rates were higher in the NAC group (73.33% vs 53.85%), though not statistically significant (P = .322); the number needed to treat (NNT) was 6, indicating clinical relevance. No significant differences were observed in hypokalemia (P = .547) or hypomagnesemia (P = .768). NAC was cost-effective, with an effectiveness gain of 0.22 and cost savings of 2742.678 EGP per patient. Sensitivity analyses confirmed robustness, with NAC being dominant in 942 out of 1000 PSA scenarios. NAC was well-tolerated, with only mild gastrointestinal side effects reported. Conclusion: NAC co-administration with AmB-d effectively prevents nephrotoxicity, reduces costs, and may promote renal recovery in Egyptian hematological malignancy patients. The favorable NNT for renal recovery suggests clinical relevance, warranting further investigation in larger studies. Trial registration: ClinicalTrials.gov identifier, NCT06122311.},
}

@article {pmid40341677,
year = {2025},
author = {Zhao, Y and Zhu, L and Lin, X and Li, B and Miu, B and Qiu, J and Gao, S and Liu, J},
title = {JS-K induces ferroptosis in renal carcinoma cells by regulating the c-Myc-GSTP1 Axis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {15987},
pmid = {40341677},
issn = {2045-2322},
support = {81272833//National Natural Science Funds/ ; },
mesh = {*Ferroptosis/drug effects ; Humans ; Animals ; *Carcinoma, Renal Cell/metabolism/drug therapy/pathology ; *Kidney Neoplasms/metabolism/drug therapy/pathology ; Mice ; *Proto-Oncogene Proteins c-myc/metabolism/genetics ; Cell Line, Tumor ; *Glutathione S-Transferase pi/metabolism/genetics ; Lipid Peroxidation/drug effects ; Mice, Nude ; Glutathione/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Xenograft Model Antitumor Assays ; Piperazines/pharmacology ; },
abstract = {JS-K is a precursor drug of nitric oxide (NO) and inhibits tumor growth through various mechanisms. Ferroptosis, a form of cell death closely related to lipid peroxidation, is increasingly being recognized for its role in cancer biology. However, the relevance of ferroptosis in the anti-tumor effects of JS-K is yet to be defined. The cytotoxic effects of erastin and JS-K were evaluated in various renal cell carcinoma (RCC) cell lines and normal human renal epithelial cells. Cell viability and the intracellular levels of ferrous ions, glutathione (GSH), lipid peroxides, and malondialdehyde (MDA) were measured using standard in vitro assays. The expression levels of specific proteins were analyzed by western blotting. Subcutaneous xenografts of RCC were established in a nude mouse model, and the anti-tumor effects of JS-K were assessed by histological and immunohistochemical methods. Erastin selectively inhibited the growth of RCC cells without affecting normal renal cells. In addition, JS-K induced ferroptosis in RCC cells by reducing cellular GSH levels, increasing lipid peroxidation, and elevating ferrous ion levels, and the effects of JS-K were neutralized by N-acetylcysteine (NAC). At the molecular level, JS-K downregulated GSTP1 by blocking the transcription factor c-Myc. Finally, JS-K inhibited tumor growth in a mouse model by inducing ferroptosis. JS-K induces ferroptosis in RCC cells by depleting glutathione through the inhibition of the c-Myc-GSTP1 axis.},
}

*Ferroptosis/drug effects
Humans
Animals
*Carcinoma, Renal Cell/metabolism/drug therapy/pathology
*Kidney Neoplasms/metabolism/drug therapy/pathology
Mice
*Proto-Oncogene Proteins c-myc/metabolism/genetics
Cell Line, Tumor
*Glutathione S-Transferase pi/metabolism/genetics
Lipid Peroxidation/drug effects
Mice, Nude
Glutathione/metabolism
Gene Expression Regulation, Neoplastic/drug effects
Xenograft Model Antitumor Assays
Piperazines/pharmacology

@article {pmid40340690,
year = {2025},
author = {Yang, N and Lai, Y and Yu, G and Zhang, X and Shi, J and Xiang, L and Zhang, J and Wu, Y and Jiang, X and Zhang, X and Yang, L and Gao, W and Ding, J and Wang, X and Xiao, J and Zhou, K},
title = {METTL3-dependent m[6]A modification of SNAP29 induces "autophagy-mitochondrial crisis" in the ischemic microenvironment after soft tissue transplantation.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-24},
doi = {10.1080/15548627.2025.2493455},
pmid = {40340690},
issn = {1554-8635},
abstract = {Necrosis at the ischemic distal end of flap transplants increases patients' pain and economic burden. Reactive oxygen species (ROS) and mitochondrial damage are crucial in regulating parthanatos, but the mechanisms linking disrupted macroautophagic/autophagic flux to parthanatos in ischemic flaps remain unclear. The results of western blotting, immunofluorescence staining, and a proteomic analysis revealed that the autophagic protein SNAP29 was deficient in ischemic flaps, resulting in disrupted autophagic flux, increased ROS-induced parthanatos, and aggravated ischemic flap necrosis. The use of AAV vector to restore SNAP29 in vivo mitigated the disruption of autophagic flux and parthanatos. Additionally, quantification of the total m[6]A level and RIP-qPCR, MeRIP-qPCR, and RNA stability assessments were performed to determine differential Snap29 mRNA m[6]A methylation levels and mRNA stability in ischemic flaps. Various in vitro and in vivo tests were conducted to verify the ability of METTL3-mediated m[6]A methylation to promote SNAP29 depletion and disrupt autophagic flux. Finally, we concluded that restoring SNAP29 by inhibiting METTL3 and YTHDF2 reversed the "autophagy-mitochondrial crisis", defined for the first time as disrupted autophagic flux, mitochondrial damage, mitochondrial protein leakage, and the occurrence of parthanatos. The reversal of this crisis ultimately promoted the survival of ischemic flaps.Abbreviations: AAV = adeno-associated virus; ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta; AIFM/AIF = apoptosis-inducing factor, mitochondrion-associated; ALKBH5 = alkB homolog, RNA demythelase; Baf A1 = bafilomycin A1; CQ = chloroquine; DHE = dihydroethidium; ECs = endothelial cells; F-CHP = 5-FAM-conjugated collagen-hybridizing peptide; GO = gene ontology; HUVECs = human umbilical vein endothelial cells; KEGG = Kyoto Encyclopedia of Genes and Genomes; LC-MS/MS = liquid chromatography-tandem mass spectrometry; LDBF = laser doppler blood flow; m[6]A = N6-methyladenosine; MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3; MeRIP = methylated RNA immunoprecipitation; METTL3 = methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; NAC = N-acetylcysteine; OGD = oxygen glucose deprivation; PAR = poly (ADP-ribose); PARP1 = poly (ADP-ribose) polymerase family, member 1; PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1; ROS = reactive oxygen species; RT-qPCR = reverse transcription quantitative polymerase chain reaction; RIP = RNA immunoprecipitation; SNAP29 = synaptosomal-associated protein 29; SNARE = soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1 = sequestosome 1; SRAMP = sequence-based RNA adenosine methylation site predicting; STX17 = syntaxin 17; TMT = tandem mass tag; TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling; VAMP8 = vesicle-associated membrane protein 8; WTAP = WT1 associating protein; YTHDF2 = YTH N6-methyladenosine RNA binding protein 2; 3' UTR = 3'-untranslated region.},
}

@article {pmid40340419,
year = {2025},
author = {Stutts, J and Clatterbuck, K and Duckworth, C and Pemberton, T and Elkins, A and Patra, P and Stoecker, W and Geria, N and Nosoudi, N},
title = {Synergistic impact of antioxidant combinations on collagen and elastin synthesis in human dermal fibroblasts.},
journal = {Bio-medical materials and engineering},
volume = {},
number = {},
pages = {9592989251341159},
doi = {10.1177/09592989251341159},
pmid = {40340419},
issn = {1878-3619},
abstract = {The restoration of collagen and elastin in human dermal fibroblasts plays a crucial role in anti-aging and skin rejuvenation therapies. Numerous studies have examined the effects of various antioxidants on skin health, but there is limited research comparing their combined effects on collagen and elastin synthesis in human dermal fibroblasts. Objective: The objective of this study was to evaluate the individual and combined effects of N-acetylcysteine (NAC), Coenzyme Q10 (CoQ10), Niacinamide (NIAC), Gamma Cyclodextrin (GAMMA), Retinol (RET), Epigallocatechin Gallate (EGCG), and Ellagic Acid (ELA) on collagen type I and elastin synthesis in human dermal fibroblasts (HDFs). Methods: Human dermal fibroblasts were treated with individual and combined antioxidants. The expression of collagen type I and elastin was measured using mRNA analysis, immunofluorescence staining, and matrix protein assays. The study focused on the effects of EGCG in combination with other antioxidants like RET, CoQ10, and NAC to identify synergistic effects. Results: The combination of EGCG + RET and EGCG + CoQ10 showed the most significant increase in both elastin and collagen type I synthesis, surpassing the effects of individual antioxidants. EGCG demonstrated the highest fold change in elastin mRNA expression, while the combination treatments notably enhanced the extracellular matrix restoration in HDFs. Conclusion: The combination of EGCG with CoQ10, Retinol, or NAC presents a promising strategy for enhancing skin elasticity and firmness by promoting both elastin and collagen synthesis. These findings suggest that antioxidant combinations can be developed for effective anti-aging skincare formulations.},
}

@article {pmid40337403,
year = {2025},
author = {Pasam, SS and Majety, SK and Nayeem, O and Mishra, D and Chakra G, S and Singh, R and Karuchola, MP and Anumolu, A},
title = {Paraquat poisoning: a case series of 15 survivors and narrative review.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {5},
pages = {2537-2546},
pmid = {40337403},
issn = {2049-0801},
abstract = {BACKGROUND: Paraquat (PQ) poisoning is a grave concern in developing countries due to its wide availability. Acute paraquat poisoning can have both systemic and local manifestations, with mortality rates that can reach as high as 90%; pulmonary complications and multiple organ dysfunction syndromes being major causes. This case series is a unique retrospective observational study of 15 survivors from South India.

CASE PRESENTATION: The case series consists of 15 cases, with a mean age of 24.6 years (excluding outliers), that were alleged to have taken varying amounts of paraquat dichloride. Patients exhibited a diverse range of symptoms affecting multiple organ systems, with particular emphasis on kidney, liver, and lung function. Treatments included a combination of hemodialysis, targeted drug therapy in the form of N-acetyl cysteine, anti-inflammatory therapy with corticosteriods and symptomatic therapy. The case descriptions also include the details of the amount of paraquat allegedly ingested, the ingestion to hospitalization time, demographics, etc, that further help in determination of prognosis.

OVERVIEW: PQ can cause a variety of clinical signs and symptoms, including gastrointestinal, renal, hepatic, and pulmonary problems. Less commonly, it can also affect the neurological and cardiac systems. Treatment is mainly focused on reducing the effective PQ concentration in blood, as no antidote has been named till date. The paper also discusses the various treatments available, drugs and procedures, and their mechanisms. Also prognostic factors like age, amount, ingestion to hospitalization time, etc.

CONCLUSION: The study underlines the need for defined treatment protocols, prognostic factors, and enforcing restrictions on availability of this deadly poison.},
}

@article {pmid40333203,
year = {2025},
author = {St John, A and Wang, X and Chen, J and Le, J and Ringgold, K and Klug, J and White, N and Stern, S and Chung, D and Lindner, JR and López, J},
title = {N-acetylcysteine reduces von Willebrand factor multimer size and improves renal microvascular blood flow in rats after severe trauma.},
journal = {Shock (Augusta, Ga.)},
volume = {},
number = {},
pages = {},
doi = {10.1097/SHK.0000000000002611},
pmid = {40333203},
issn = {1540-0514},
abstract = {BACKGROUND: Severe injury induces systemic microvascular impairment that reduces microvascular blood flow (MBF), even after resuscitation to normal blood pressure. These changes are associated with organ dysfunction and death, but the underlying causes and potential therapeutic approaches to address them remain unclear. Two possible contributors are hyperadhesive VWF secretion from an activated endothelium and oxidative modification of hemostatic proteins. N-acetylcysteine has been shown to address both of these processes and increase MBF in other disease states with similar features.

METHODS: Anesthetized, male Sprague-Dawley rats were subjected to a standardized polytrauma and pressure-targeted catheter hemorrhage. They then received either no treatment (Control) or a single bolus of NAC, followed by autologous whole blood transfusion. Renal MBF was measured using contrast-enhanced ultrasound (CEUS) at prespecified time points. von Willebrand factor (VWF) multimer gels and other laboratory studies were performed. Histologic analysis of vascular thrombi was also performed on uninjured tissue from rats undergoing either this trauma protocol or a sham procedure.

RESULTS: NAC increased MBF at 3 hours after resuscitation. This was accompanied by a decrease in VWF multimer size that was not seen in the Control group. Histologic data showed an overall increase in systemic thrombus burden associated with trauma.

CONCLUSIONS: NAC improves renal MBF, possibly by reducing VWF multimer size and reducing microthrombus burden. This is significant both mechanistically and therapeutically. It sheds light on the possible pathways involved in causing microvascular obstruction after trauma and identifies possible treatment approaches that could be developed further. Ultimately, targeting these pathways could move us closer to resuscitation strategies that optimize vital organ MBF.},
}

@article {pmid40333083,
year = {2025},
author = {Yang, S and Zhang, Y and Xu, J and Chen, Z and Ren, Y and Long, Y and Huang, X and Liu, J and Huang, H and Xie, S and Ma, R and Dong, Y and Fan, X and Hu, Z and Li, F},
title = {N-Acetylcysteine as a Host-Directed Therapy Against Clarithromycin-Resistant Mycobacterium abscessus.},
journal = {Pathogens (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {40333083},
issn = {2076-0817},
support = {21Y11901700//Science and Technology Commission of Shanghai Municipality/ ; 20Z11901002//Science and Technology Commission of Shanghai Municipality/ ; ZD2021CY001//Shanghai Municipal Science and Technology Major Project/ ; },
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; *Mycobacterium abscessus/drug effects ; *Clarithromycin/pharmacology ; Animals ; Humans ; *Mycobacterium Infections, Nontuberculous/drug therapy/microbiology/immunology ; Mice ; *Drug Resistance, Bacterial/drug effects ; *Anti-Bacterial Agents/pharmacology ; Disease Models, Animal ; THP-1 Cells ; Signal Transduction/drug effects ; Female ; },
abstract = {(1) Background: The treatment of Mycobacterium abscessus (M. abscessus) infections resistant to clarithromycin (CLR) is highly challenging. Traditional non-tuberculous mycobacteria (NTM) chemotherapy may disturb the immune homeostasis of the host by increasing oxidative stress; therefore, host-directed immunotherapy is an alternative option for infections caused by M. abscessus. (2) Method: A clinical isolate of CLR-resistant M. abscessus was screened, and then the therapeutic effects of N-acetylcysteine (NAC) against CLR-resistant M. abscessus infection were evaluated in Tohoku Hospital Pediatrics-1 (THP-1) cells and murine models. RNA sequencing and Western blot were used to profile the protective immune responses induced by NAC. The contribution of candidate signaling pathways was confirmed by the corresponding inhibitor and agonist. (3) Results: NAC immunotherapy led to a significant reduction in bacterial loads both in THP-1 cells and murine infection models, which was associated with enhanced antioxidant effects and downregulation of apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated protein ki-nase/extracellular signal-regulated kinase 3/6 (MKK3/6)-p38 mitogen-activated protein kinase (MAPK)-mediated inflammatory immune responses. The inhibitor of p38 signaling mimicked the protective effect of NAC, while the agonist attenuated it, suggesting that the p38 pathway is crucial in NAC-mediated immune protection against M. abscessus infection. (4) Conclusion: Our study suggests that NAC could be used as a host-directed therapy agent against drug-resistant M. abscessus infection.},
}

*Acetylcysteine/pharmacology/therapeutic use
*Mycobacterium abscessus/drug effects
*Clarithromycin/pharmacology
Animals
Humans
*Mycobacterium Infections, Nontuberculous/drug therapy/microbiology/immunology
Mice
*Drug Resistance, Bacterial/drug effects
*Anti-Bacterial Agents/pharmacology
Disease Models, Animal
THP-1 Cells
Signal Transduction/drug effects
Female

@article {pmid40328458,
year = {2025},
author = {Pfau, K and Callizo, J and Rossouw, P and Gabrani, C and Holz, F and Charbel Issa, P and Kellner, U and Strauss, R and Kühlewein, L and Stingl, K and Feltgen, N and Pfau, M},
title = {[Correction: N-Acetylcysteine (NAC) for Retinitis pigmentosa].},
journal = {Klinische Monatsblatter fur Augenheilkunde},
volume = {242},
number = {3},
pages = {e2},
doi = {10.1055/a-2587-6864},
pmid = {40328458},
issn = {1439-3999},
}

@article {pmid40327168,
year = {2025},
author = {Zatloukal, J and Page, C and Brat, K and Svoboda, M and Voláková, E and Plutinský, M and Kopecký, M and Koblížek, V},
title = {Effect of Treatment with Mucoactive Drugs on COPD Exacerbations During 5 years of Follow-up in the Czech Republic: A Real-World Study.},
journal = {Lung},
volume = {203},
number = {1},
pages = {61},
pmid = {40327168},
issn = {1432-1750},
support = {FNOl no. 00098892//Ministerstvo Zdravotnictví Ceské Republiky/ ; no. 15/14/NAP//Ministerstvo Zdravotnictví Ceské Republiky/ ; FNOl no. 00098892//Ministerstvo Zdravotnictví Ceské Republiky/ ; FNBr no. 65269705//Ministerstvo Zdravotnictví Ceské Republiky/ ; UHHK no. 00179906//Ministerstvo Zdravotnictví Ceské Republiky/ ; UHHK no. 00179906//Ministerstvo Zdravotnictví Ceské Republiky/ ; Research Area INDI//Cooperatio Charles University, Czechia/ ; Research Area INDI//Cooperatio Charles University, Czechia/ ; },
mesh = {Humans ; *Pulmonary Disease, Chronic Obstructive/drug therapy/physiopathology/diagnosis ; Male ; Czech Republic ; Female ; Aged ; Middle Aged ; Prospective Studies ; Disease Progression ; *Expectorants/therapeutic use ; Follow-Up Studies ; *Acetylcysteine/therapeutic use ; Treatment Outcome ; Forced Expiratory Volume ; Time Factors ; },
abstract = {INTRODUCTION: Studies indicate that chronic treatment with mucoactive drugs may reduce COPD exacerbation rates. This real-world, multicenter, prospective, observational study aimed to determine the effect of long-term mucoactive treatment on exacerbations in patients with COPD in the Czech Republic.

METHODS: 452 adult patients on the Czech Multicenter Research Database of COPD with post-bronchodilator FEV1 ≤ 60% of predicted value received standard of care and were followed up for 5 years. For the first 24 months, 81 patients received regular thiol-based mucoactive drugs (77 erdosteine, 4 N-acetylcysteine) at the discretion of the treating physician and 371 patients had no mucoactive treatment (control group). Erdosteine was fully reimbursed, and NAC was partially reimbursed for COPD patients. The annual number/rate of COPD exacerbations over 5 years was monitored.

RESULTS: Patients receiving mucoactive treatment for 24 months had a significantly larger reduction from baseline in all exacerbations compared to the control group (- 0.61 vs - 0.18, p = 0.026; - 0.54 vs - 0.09, p = 0.007; - 0.55 vs 0.04, p = 0.005; - 0.67 vs 0.13, p = 0.002; - 0.53 vs 0.10, p = 0.019 in the first to fifth year, respectively). The reduction in moderate exacerbations was also significantly larger in those receiving mucoactive treatment versus no mucoactive treatment. The exacerbation rate was reduced to a greater extent in the subgroups with cough or with stage 3‒4 COPD who received mucoactive treatment but was independent of the use of inhaled corticosteroids (ICS).

CONCLUSION: Mucoactive treatment for two years reduced the number of COPD exacerbations (all, moderate) over five years of follow-up. The reduction in exacerbations was more pronounced in patients with cough or with stage 3‒4 COPD but was independent of the use of ICS.},
}

Humans
*Pulmonary Disease, Chronic Obstructive/drug therapy/physiopathology/diagnosis
Male
Czech Republic
Female
Aged
Middle Aged
Prospective Studies
Disease Progression
*Expectorants/therapeutic use
Follow-Up Studies
*Acetylcysteine/therapeutic use
Treatment Outcome
Forced Expiratory Volume
Time Factors

@article {pmid40323204,
year = {2025},
author = {Plane, J and Cabral, TDD and Knoll, RM and Conrado, JEP and Vendramini, BDV and Jung, DH},
title = {N-acetylcysteine for the Prevention of Cisplatin-Induced Hearing Loss: A Systematic Review and Meta-analysis.},
journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery},
volume = {},
number = {},
pages = {},
doi = {10.1002/ohn.1272},
pmid = {40323204},
issn = {1097-6817},
abstract = {OBJECTIVE: Cisplatin is an effective antineoplastic drug used worldwide in the treatment of various malignancies. However, it is associated with side effects, including cisplatin-induced hearing loss (CIHL). N-acetylcysteine (NAC) has been suggested as a promising drug to prevent or reduce cisplatin-derived ototoxicity. To evaluate the evidence supporting the efficacy of NAC in preventing CIHL, we conducted a systematic review and meta-analysis of the literature.

DATA SOURCES: A systematic search was conducted on PubMed, Embase, Web of Science, Clinicaltrials.gov, and Cochrane Library.

REVIEW METHODS: Articles reporting the administration of systemic or transtympanic injection of NAC for CIHL prevention were considered. The outcomes of interest included the presence of hearing loss events and changes in hearing thresholds at 0.5 through 12 kHz following cisplatin treatment.

RESULTS: A total of 7 studies involving 217 patients met inclusion criteria. Of these patients, 175 received systemic administration of NAC, and the remaining received transtympanic injection of NAC. No significant differences were found in CIHL prevention between the use of either systemic or transtympanic NAC administration compared to placebo (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.54-1.19; P = .28, and RR 0.89; 95% CI 0.51-1.54; P = .67, respectively). No significant differences were found at 0.5 to 8 kHz between groups. Qualitative analyses suggested a tendency to otoprotection in ultra-high frequencies (10 and 12 kHz).

CONCLUSION: Our findings suggest that, regardless of administration route, current published evidence does not show that NAC is effective in preventing CIHL in the standard clinical audiogram range. Further studies with larger samples are needed to confirm our findings.

LEVEL OF EVIDENCE: I.},
}

@article {pmid40321407,
year = {2025},
author = {Hosseini, E and Beyranvand, Z and Schoenwaelder, SM and Farhid, F and Ghasemzadeh, M},
title = {The Reactive Oxygen Species Scavenger N-Acetyl-L-Cysteine Reduces Storage-Dependent Decline in Integrin α IIb β 3-Mediated Platelet Function, Inhibiting Pre-Activation of Integrin and Its β 3 Subunit Cleavage.},
journal = {Oxidative medicine and cellular longevity},
volume = {2025},
number = {},
pages = {7499648},
pmid = {40321407},
issn = {1942-0994},
mesh = {*Acetylcysteine/pharmacology ; Humans ; *Reactive Oxygen Species/metabolism ; *Blood Platelets/metabolism/drug effects/cytology ; *Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; *Integrin beta3/metabolism ; Platelet Activation/drug effects ; *Free Radical Scavengers/pharmacology ; Platelet Adhesiveness/drug effects ; },
abstract = {Background: Premature activation of integrin α IIb β 3 plays a central role in the induction and development of the platelet storage lesion (PSL) characterized by an exhausted platelet phenotype that affects adhesion and spreading on fibrinogen. Given the role of reactive oxygen species (ROS) in regulating platelet activation per se, we investigated the effects of a ROS scavenger on reducing the functional decline of platelet integrin α IIb β 3 during storage. Methods: Platelet-rich plasma-platelet concentrates (PRP-PCs) were either treated with ROS-reducing agents (1 mM N-acetyl-L-cysteine [NAC] or 30 μM NADPH oxidase [NOX] inhibitor, VAS2870) or kept untreated during storage. CD41/CD61 (total integrin α IIb β 3) expression and PAC-1 binding (specific to active integrin α IIb β 3 conformation) were analyzed by flow cytometry over a 5 day storage period. Molecular changes in integrin β 3 subunit were evaluated by western blotting. Platelet adhesion/spreading to fibrinogen in the presence of ROS inhibitors was also investigated during storage using fluorescence microscopy. Results: A decrease in the molecular weight of integrin β 3 subunit was observed during platelet storage, and was significantly reduced by NAC but not VAS2870, suggesting proteolytic cleavage of β 3 during storage. Further to this, ROS inhibitors decreased integrin activation and increased platelet adhesion to fibrinogen from day 3 of storage, while NAC but not VAS2870 improved platelet spreading. Conclusion: This is the first report of increasing β 3 cleavage of integrin during storage that was inversely correlated with integrin α IIb β 3-mediated platelet function. In this regard, as a generic ROS scavenger, NAC was shown to reduce defects in platelet spreading through inhibition of β 3 cleavage. This is in contrast to VAS2870 which selectively inhibits cytosolic NOX alone, suggesting that the reduced platelet function observed during storage may be due to cumulative effects of mitochondrial ROS. Taken together, these studies suggest that adding NAC to platelets may significantly preserve optimal integrin α IIb β 3 and platelet function during storage. Moreover, as a reversible scavenger, its inhibitory effect can be readily compensated after transfusion.},
}

*Acetylcysteine/pharmacology
Humans
*Reactive Oxygen Species/metabolism
*Blood Platelets/metabolism/drug effects/cytology
*Platelet Glycoprotein GPIIb-IIIa Complex/metabolism
*Integrin beta3/metabolism
Platelet Activation/drug effects
*Free Radical Scavengers/pharmacology
Platelet Adhesiveness/drug effects

@article {pmid40319292,
year = {2025},
author = {Eswaran, S and Mascarenhas, R and Kabekkodu, SP},
title = {The ester derivative Palmitoylcarnitine abrogates cervical cancer cell survival by enhancing lipotoxicity and mitochondrial dysfunction.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {213},
pmid = {40319292},
issn = {1478-811X},
support = {6242-P8/RGCB/PMD/DBT/ SPDK/2015//Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Ministry of Science and Technology, India/ ; },
mesh = {Humans ; *Uterine Cervical Neoplasms/pathology/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Female ; Cell Survival/drug effects ; HeLa Cells ; *Carnitine/analogs & derivatives/pharmacology ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Apoptosis/drug effects ; Extracellular Vesicles/metabolism/drug effects ; Esters ; },
abstract = {BACKGROUND: In cervical cancer (CC), Double C2 Like Domain Beta (DOC2B) functions as a metastatic suppressor. The present study aims to determine whether ectopic expression of DOC2B causes global metabolomic changes in extracellular vesicles (EVs) and corresponds with its tumor suppressive properties.

METHODS: Using a retroviral method, we first ectopically expressed DOC2B in SiHa cells, which do not normally express DOC2B.

RESULTS: We observed that ectopically expressed DOC2B significantly altered the global metabolite profile of EVs. Metabolomics identified significant enrichment of palmitoylcarnitine (PC) in EVs upon ectopic expression of DOC2B. We identified that SiHa and HeLa cells exhibited greater cytotoxicity to PC than gingival fibroblast, HaCaT, Cal27, and MCF7. PC treatment reduced the growth, proliferation, and migration of SiHa and HeLa cells, via increasing apoptosis and decreasing S-Phase cells. PC treatment resulted in morphological alterations, decreased length and number of filopodia, and expression of proteins related to cell cycle progression, proliferation, and the epithelial-to-mesenchymal transition. Further, PC treatment caused mitochondrial morphological changes, increased mitochondrial membrane potential, and decreased mtDNA content. The decreased GSH activity, glucose consumption rate, and lactate production upon PC treatment suggest that PC can induce metabolic reprogramming in CC cells. Increased oxidative stress, calcium overload, lipid droplet accumulation, mitochondrial lipotoxicity, and mitophagy suggest that PC can cause mitochondrial dysfunction. N-acetyl cysteine (NAC) treatment reversed the cytotoxic effect of PC, via decreasing lipid peroxidation rate and increasing GSH activity. PC treatment enhanced the cytotoxic effect of cisplatin in CC.

CONCLUSION: DOC2B restoration or the use of PC may be employed as a novel therapeutic approach for CC.},
}

Humans
*Uterine Cervical Neoplasms/pathology/metabolism
*Mitochondria/drug effects/metabolism/pathology
Female
Cell Survival/drug effects
HeLa Cells
*Carnitine/analogs & derivatives/pharmacology
Cell Proliferation/drug effects
Cell Line, Tumor
Apoptosis/drug effects
Extracellular Vesicles/metabolism/drug effects
Esters

@article {pmid40318637,
year = {2025},
author = {Paul, B and Merta, H and Ugrankar-Banerjee, R and Hensley, MR and Tran, S and do Vale, GD and Zacherias, L and Hewett, CK and McDonald, JG and Font-Burgada, J and Mathews, TP and Farber, SA and Henne, WM},
title = {Paraoxonase-like APMAP maintains endoplasmic-reticulum-associated lipid and lipoprotein homeostasis.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2025.04.008},
pmid = {40318637},
issn = {1878-1551},
abstract = {Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored when compared with mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuring Drosophila, zebrafish, and mammalian hepatocytes, here we characterize the paraoxonase-like C20orf3/adipocyte plasma-membrane-associated protein (APMAP) as an ER-localized antioxidant that suppresses ER lipid oxidation to safeguard ER function. APMAP-depleted cells exhibit defective ER morphology, ER stress, and lipid peroxidation dependent on ER-oxidoreductase 1α (ERO1A), as well as sensitivity to ferroptosis and defects in ApoB-lipoprotein homeostasis. Similarly, organismal APMAP depletion in Drosophila and zebrafish perturbs ApoB-lipoprotein homeostasis. Strikingly, APMAP loss is rescued with chemical antioxidant N-acetyl-cysteine (NAC). Lipidomics identifies that APMAP loss elevates phospholipid peroxidation and boosts ceramides-signatures of lipid stress. Collectively, we propose that APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis in the ER network.},
}

@article {pmid40316146,
year = {2025},
author = {Rogóż, Z and Kamińska, K and Wąsik, A},
title = {N-acetylcysteine enhances the antipsychotic effect of aripiprazole in the neurodevelopmental rat model of schizophrenia.},
journal = {Pharmacology, biochemistry, and behavior},
volume = {},
number = {},
pages = {174028},
doi = {10.1016/j.pbb.2025.174028},
pmid = {40316146},
issn = {1873-5177},
abstract = {Symptoms of schizophrenia are well characterized, but the mechanism underlying the pathogenesis of the disease still remains unknown. In addition, therapy of negative symptoms and cognitive deficits in schizophrenic patients is a serious clinical problem. Some clinical studies have shown that the atypical antipsychotic drug aripiprazole (ARI), and the antioxidant N-acetylcysteine (NAC) are effective in reducing positive and negative symptoms of schizophrenia in patients. The aim of the present study was to evaluate the influence of repeated co-treatment with low doses of ARI and NAC on the schizophrenia-like behavior in adult rats. The schizophrenia-like behavior was induced in Sprague-Dawley male pups in the neonatal days p5-p16 by repeated administration of the glutathione synthesis inhibitor L-butionine-(S,R)-sulfoximine (BSO) given together with the dopamine reuptake inhibitor 1-[2-[Bis-4(fluorophenyl)methoxy]ethyl]-4-3-(3-phenylpropyl) (GBR 12909). Adult rats received repeated co-treatment with ARI (0.1 mg/kg) and NAC (10 mg/kg) for 21 days, and their effects on schizophrenia-like behavior were assessed (on p90-91) using the social interaction test and novel object recognition test. The present data indicated that the studied drugs at higher doses: ARI (0.3 mg/kg but not 0.1 mg/kg) and NAC (30 mg/kg but not 10 mg/kg) reversed schizophrenia-like symptoms in the tested model. Moreover, repeated co-treatment with low doses of ARI with NAC also reversed schizophrenia-like behavior in the neurodevelopmental rat model of schizophrenia. The above results indicated that NAC enhanced the action of ARI in the used neurodevelopmental rat model of schizophrenia, and the mechanism of action of the used drugs in this model is discussed.},
}

@article {pmid40312270,
year = {2025},
author = {Ji, R and Yang, Y and Bian, B and Zhang, Y and Wang, F and Jia, Y},
title = {Exposure to Polyethylene Terephthalate Microplastic Induces Mouse Liver Fibrosis Through Oxidative Stress and p38 MAPK/p65 NF-κB Signaling Pathway.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4797},
pmid = {40312270},
issn = {1099-1263},
support = {42377430//National Natural Science Foundation of China/ ; 202201382//Inner Mongolia Autonomous Region Health Science and Technology Plan project/ ; HLJH202418//Bud Plan of Baotou Medical College/ ; },
abstract = {Microplastic (MP) pollution has garnered attention due to its potential impact on living organisms. Among these, polyethylene terephthalate microplastics (PET-MPs) are frequently detected in both environmental samples and human tissues. Despite this, the effects of PET-MPs on liver damage and fibrosis in mammals remain insufficiently understood. This study demonstrated that oral exposure to PET-MPs at doses of 1 mg/day (with a diameter of 1 μm) over 42 days resulted in inhibited weight gain and altered organ coefficients in male mice, suggesting possible liver damage. Using HE and Masson staining revealed pathological changes in the livers of exposed mice, such as hepatocyte swelling, inflammatory cell infiltration, and collagen deposition. Liver function tests confirmed elevated serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Further, the elevated levels of oxidative stress markers, along with the enhanced expression of proteins related to the p38 MAPK/p65 NF-κB signaling pathway as revealed by western blot analysis, both of which are strongly associated with liver damage and fibrosis. To further elucidate these mechanisms, experiments involving N-acetylcysteine (NAC) to counteract oxidative stress and SB203580 to inhibit p38 MAPK activation demonstrated that both interventions effectively mitigated liver fibrosis. Exposure to PET-MPs may trigger liver injury and fibrosis in mice. During this process, oxidative stress and the p38 MAPK/p65 NF-κB signaling pathway may play significant mediating roles.},
}

@article {pmid40311840,
year = {2025},
author = {Zhang, Z and Zhao, L and Wang, J and Chen, H and Lin, Y and Wang, F and Wang, L and Chen, J and Liu, J and Zhang, X},
title = {Luteolin, as a bidirectional ROS regulator, elevates mouse beige adipocyte browning.},
journal = {Biochimica et biophysica acta. Molecular and cell biology of lipids},
volume = {1870},
number = {5},
pages = {159620},
doi = {10.1016/j.bbalip.2025.159620},
pmid = {40311840},
issn = {1879-2618},
abstract = {In beige adipocytes, UCP1-dependent thermogenesis can be driven by intracellular reactive oxygen species (ROS) generation. While ROS elevation also induces mast cell activation, serotonin synthesis and release from mast cells inhibits beige progenitor cell proliferation and browning. As a natural antioxidant and mast cell stabilizer, luteolin promotes adipocyte thermogenesis and inhibits mast cell activation. Thus, to activate adipocyte thermogenesis, how luteolin regulates ROS level in beige adipocytes and mast cells needs to be further investigated. In this study, mouse subcutaneous stromal vascular fraction (SVF) cells are induced to differentiate into beige adipocytes, and mouse bone marrow-derived mast cells (BMMCs) are activated with hydrogen peroxide (H2O2). Intracellular ROS level is augmented in differentiated beige adipocytes and H2O2-activated BMMCs, and H2O2-activated BMMCs inhibited brown differentiation of SVF cells and thermogenesis of beige adipocytes. In beige adipocytes, unlike synthetic antioxidant N-acetylcysteine (NAC), luteolin elevates the expression of thermogenic and beige-selective marker genes and intracellular ROS generation. Contrarily, luteolin inhibits H2O2-induced mast cell activation and ROS generation. Further, luteolin partially reverses the inhibitory effects of H2O2-activated BMMCs on the brown differentiation of SVF cells and the thermogenesis of beige adipocytes. Molecular mechanistic studies demonstrate that luteolin regulates intracellular ROS level in beige adipocytes and mast cells via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Catalase pathway. Altogether, as a ROS regulator, luteolin contrarily affects intracellular ROS generation in beige adipocytes and mast cells, and hence elevates adipocyte browning.},
}

@article {pmid40302832,
year = {2025},
author = {Sunny, G and Doddwad, PK and Shenvi, S},
title = {Comparative evaluation of effect of N-acetyl cysteine, maleic acid, and ethylenediaminetetraacetic Acid on the depth of dentinal tubule penetration of an epoxy resin-based root canal sealer: A confocal laser scanning microscopy study.},
journal = {Journal of conservative dentistry and endodontics},
volume = {28},
number = {4},
pages = {309-313},
pmid = {40302832},
issn = {2950-4708},
abstract = {BACKGROUND: Effective root canal irrigation removes the smear layer for optimal sealer penetration. While 17% ethylenediaminetetraacetic Acid (EDTA) is effective, concerns about dentin erosion exist. Alternatives like 7% maleic acid (MA) and 20% N-acetylcysteine (NAC) show promise with fewer adverse effects.

AIM: To compare the effects of 20% NAC, 7% MA, and 17% EDTA as final irrigating solutions on the depth of sealer penetration into dentinal tubules at coronal, middle, and apical thirds of root canals using confocal laser scanning microscopy (CLSM).

MATERIALS AND METHODS: Sixty-six single-canal mandibular premolars free of caries, fractures, or prior treatment were selected. The teeth were decoronated to 14 mm root length using a diamond disk under water spray. Working length was determined by inserting a size 10 K-file until visible at the apical foramen, subtracting 1 mm. Root canals were instrumented up to F3 using ProTaper Universal rotary files with 1 mL of 2.5% NaOCl irrigation between files. Based on the final irrigation protocol, samples were divided into three groups (n = 22): Group 1-20% NAC, Group 2-7% MA, and Group 3-17% EDTA. Each group was irrigated with 5 mL of the respective irrigant, followed by a final rinse with 10 mL of distilled water. AH Plus sealer with 0.1% Rhodamine B was applied using a #25 Lentulo, and an F3 gutta-percha cone coated with the sealer was placed to working length, trimmed, and sealed with Cavit. Samples were incubated at 37°C and 100% humidity for 7 days to allow sealer setting. Roots were sectioned at 2, 5, and 8 mm from the apex to obtain 1 mm thick sections. Sealer penetration into dentinal tubules was evaluated using CLSM at ×10 magnification, measuring the penetration depth in micrometers from the canal wall to the point of maximum sealer infiltration using ImageJ software, measuring the longest penetration depth from the canal wall to the point of deepest sealer infiltration.

RESULTS: Sealer penetration was greatest in the coronal third, followed by the middle, with the least in the apical third (P < 0.0001). NAC demonstrated the highest mean in the coronal region (829.35 ± 85.36), while MA exhibited superior performance in the middle (522.92 ± 112.32) and apical (361.76 ± 49.03) regions. Intergroup comparisons showed superior penetration with 7% MA in the apical region (P < 0.0001). NAC and EDTA demonstrated comparable penetration across regions.

CONCLUSION: While all irrigants enhanced sealer penetration, 7% MA was most effective in the apical region. Both 7% MA and 20% NAC can serve as alternatives to 17% EDTA for final irrigation.},
}

@article {pmid40302321,
year = {2025},
author = {An, D and Jiang, X and Yang, Y},
title = {Sesamin Exerts Anti-Tumor Activity in Nasopharyngeal Carcinoma Through Inducing Autophagy and Reactive Oxygen Species Production.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {4},
pages = {26038},
doi = {10.31083/FBL26038},
pmid = {40302321},
issn = {2768-6698},
support = {81970864//National Natural Science Foundation of China/ ; Yu Wei (2018) No 2//Chongqing Middle and Youth Medical High-end Talent Studio Project/ ; Yu Wei (2021)//Chongqing Talents Project/ ; },
mesh = {*Reactive Oxygen Species/metabolism ; *Autophagy/drug effects ; Humans ; Animals ; *Lignans/pharmacology ; *Nasopharyngeal Carcinoma/metabolism/drug therapy ; Cell Line, Tumor ; Apoptosis/drug effects ; *Dioxoles/pharmacology/therapeutic use ; *Nasopharyngeal Neoplasms/metabolism/drug therapy/pathology ; Cell Proliferation/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Mice, Nude ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred BALB C ; Cell Movement/drug effects ; *Antineoplastic Agents/pharmacology ; Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: Sesamin can suppress many cancers, but its effect on nasopharyngeal carcinoma (NPC) is unclear. Herein, we set out to pinpoint the possible changes in NPC due to Sesamin.

METHODS: The biological function of NPC cells exposed to Sesamin/N-acetyl-L-cysteine (NAC)/3-Methyladenine (3-MA) was detected, followed by evaluation of reactive oxygen species (ROS) production (dichlorodihydrofluorescein diacetate staining) and mitochondrial membrane potential (MMP) (flow cytometry). Proteins pertinent to apoptosis (cleaved caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1)), cell cycle (Cyclin B1), and autophagy (microtubule-associated protein light chain 3 (LC3)-I, LC3-II, Beclin-1, P62) were quantified by Western blot. After the xenografted tumor model in mice was established, the tumor volume and weight were recorded, and Ki-67 and cleaved caspase-3 levels were determined by immunohistochemical analysis.

RESULTS: Sesamin inhibited viability, proliferation, cell cycle progression and migration, induced apoptosis, increased ROS production, and decreased MMP in NPC cells. Sesamin elevated cleaved caspase-3/caspase-3, cleaved PARP1/PARP1, and Beclin-1 expressions as well as LC3-II/LC3-I ratio, while diminishing Cyclin B1 and P62 levels. NAC and 3-MA abrogated Sesamin-induced changes as above in NPC cells. Sesamin inhibited the increase of the xenografted tumor volume and weight, down-regulated Ki-67, and up-regulated cleaved caspase-3 in xenografted tumors.

CONCLUSION: Sesamin exerts anti-tumor activity in NPC, as demonstrated by attenuated tumor proliferation and xenografted tumor volume and weight, as well as induced apoptosis in tumor tissues, consequent upon the promotion of autophagy and reactive oxygen species production.},
}

*Reactive Oxygen Species/metabolism
*Autophagy/drug effects
Humans
Animals
*Lignans/pharmacology
*Nasopharyngeal Carcinoma/metabolism/drug therapy
Cell Line, Tumor
Apoptosis/drug effects
*Dioxoles/pharmacology/therapeutic use
*Nasopharyngeal Neoplasms/metabolism/drug therapy/pathology
Cell Proliferation/drug effects
Mice
Xenograft Model Antitumor Assays
Mice, Nude
Membrane Potential, Mitochondrial/drug effects
Mice, Inbred BALB C
Cell Movement/drug effects
*Antineoplastic Agents/pharmacology
Acetylcysteine/pharmacology

@article {pmid40301453,
year = {2025},
author = {Karakoç, E and Halaçlı, SO and Hanelçi, RH and Ayhan, S and Eylem, CC and Nemutlu, E and Atilla, P},
title = {N-acetylcysteine stimulates organelle malfunction in endometriotic cells via IFN-gamma signaling.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {15120},
pmid = {40301453},
issn = {2045-2322},
support = {#TSA-2021-19011and # THD-2019-18110//Hacettepe University Scientific Research Unit/ ; #TSA-2021-19011and # THD-2019-18110//Hacettepe University Scientific Research Unit/ ; },
mesh = {Humans ; Female ; *Acetylcysteine/pharmacology ; *Endometriosis/metabolism/pathology/drug therapy ; *Interferon-gamma/metabolism ; *Signal Transduction/drug effects ; Endoplasmic Reticulum Stress/drug effects ; *Endometrium/metabolism/drug effects/pathology ; Mitochondria/drug effects/metabolism ; Cell Proliferation/drug effects ; *Organelles/drug effects/metabolism ; Interleukin-6/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {Endometriosis is a chronic inflammatory gynecologic disease characterized by the abnormal implantation of endometrial tissue outside the uterus. The inflammatory microenvironment of endometriosis is dominated by highly migratory endometriotic cells, inflammatory cells, and cytokines. There is no curative treatment other than oral contraceptives, painkillers, and surgery. N-acetyl-L-cysteine (NAC), an anti-inflammatory compound has been identified as a promising agent for endometriosis. However, it is still unclear how NAC interacts with interferon-gamma (IFN-ɣ) and common cytokines in the endometriotic microenvironment. This study aimed to investigate the effects of NAC, alone and in combination with IFN-ɣ and major cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-⍺) on endometriotic cells. For this purpose, we performed a real time-dependent cell impedance assay, Annexin V/PI and ER tracking by flow cytometry, immunofluorescence, western blotting, and metabolomic assays. Our results offered a new insight into the complex relationship between NAC and IFN-ɣ, both of which reduced endometriotic cells' proliferation, induced ER stress and mitochondrial dysfunction. In conclusion, NAC and IFN-ɣ, alter the metabolism of endometriotic cells, leading to endoplasmic reticulum stress and mitochondrial dysfunction. These findings suggest that NAC when combined with IFN-ɣ, has the potential to generate innovative therapeutic modalities for the treatment of endometriosis.},
}

Humans
Female
*Acetylcysteine/pharmacology
*Endometriosis/metabolism/pathology/drug therapy
*Interferon-gamma/metabolism
*Signal Transduction/drug effects
Endoplasmic Reticulum Stress/drug effects
*Endometrium/metabolism/drug effects/pathology
Mitochondria/drug effects/metabolism
Cell Proliferation/drug effects
*Organelles/drug effects/metabolism
Interleukin-6/metabolism
Tumor Necrosis Factor-alpha/metabolism

@article {pmid40298799,
year = {2025},
author = {Hu, J and Feng, J and Bai, Y and Yao, ZS and Wu, XY and Hong, XY and Lu, GD and Xue, K},
title = {Sucralose Promotes Benzo(a)Pyrene-Induced Renal Toxicity in Mice by Regulating P-glycoprotein.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
pmid = {40298799},
issn = {2076-3921},
support = {GWVI-11.1-41//Shanghai Municipal Health Commission/ ; GWVI-11.1-41//Shanghai Municipal Health Commission/ ; },
abstract = {BACKGROUND: Sucralose and benzo(a)pyrene (B[a]P) are widespread foodborne substances known to harm human health. However, the effects of their combined exposure on kidney function remain unclear. This study aimed to investigate the mechanisms by which sucralose and B[a]P induce kidney injury through P-glycoprotein (PGP/ABCB1), a crucial protein involved in cellular detoxification.

METHODS: C57BL/6N mice were co-treated with sucralose and B[a]P for 90 days to evaluate their impact on kidney histopathology and function. In vitro experiments assessed cell viability, reactive oxygen species (ROS) levels, and B[a]P accumulation by flow cytometry. Molecular docking and cellular thermal shift assay (CETSA) were used to determine the binding affinity of sucralose to PGP. Furthermore, PCR, Western blotting, and immunohistochemistry were performed to analyze the expression of PGP and its upstream transcription factors.

RESULTS: Ninety days of co-exposure to sucralose and B[a]P significantly exacerbated renal dysfunction in mice, as evidenced by the elevated level of serum creatinine and urea nitrogen, which could be reverted by ROS scavenger N-acetyl cysteine (NAC). In vitro, sucralose promoted cellular accumulation of B[a]P, consequently enhancing B[a]P-induced cell growth inhibition and ROS production. Consistently, B[a]P accumulation was enhanced by PGP knockdown in both HK2 and HEK-293 cells. Mechanistically, sucralose can directly bind to PGP, competitively inhibiting its efflux capacity and increasing intracellular B[a]P retention. Prolonged co-exposure further downregulated PGP expression, possibly through the reductions of its transcriptional regulators (PXR, NRF2, and NF-κB).

CONCLUSIONS: Co-exposure to sucralose and B[a]P exacerbates renal injury by impairing PGP function. Mechanistically, sucralose inhibits PGP activity, resulting in the accumulation of B[a]P within renal cells. This accumulation triggers oxidative stress and inhibits cell growth, which demonstrates that sucralose potentiates B[a]P-induced nephrotoxicity by directly inhibiting PGP-mediated detoxification pathways, thus underscoring the critical need to evaluate toxicity risks associated with combined exposure to these compounds.},
}

@article {pmid40296602,
year = {2025},
author = {Cheng, Y and Chen, HJ and Yang, T},
title = {[Influences of dihydromyricetin on proliferation and apoptosis of chondrocytes in osteoarthritis induced by H2O2 through ROS/p38-MAPK signal pathway].},
journal = {Zhongguo gu shang = China journal of orthopaedics and traumatology},
volume = {38},
number = {4},
pages = {396-402},
doi = {10.12200/j.issn.1003-0034.20230237},
pmid = {40296602},
issn = {1003-0034},
mesh = {Animals ; *Chondrocytes/drug effects/cytology/metabolism ; *Apoptosis/drug effects ; *Hydrogen Peroxide/toxicity ; *Osteoarthritis/metabolism/drug therapy/physiopathology ; Mice, Inbred C57BL ; *Reactive Oxygen Species/metabolism ; Mice ; *Flavonols/pharmacology ; *p38 Mitogen-Activated Protein Kinases/metabolism/genetics ; *Cell Proliferation/drug effects ; Male ; Signal Transduction/drug effects ; *MAP Kinase Signaling System/drug effects ; Cells, Cultured ; },
abstract = {OBJECTIVE: To analyze the influences of dihydromyricetin on the proliferation and apoptosis of chondrocytes in osteoarthritis induced by hydrogen peroxide (H2O2) through reactive oxygen species (ROS)/p38 mitogen activated protein kinase (p38-MAPK) pathway.

METHODS: Five C57BL/6J mice were euthanized by cervical dislocation after anesthesia. Chondrocytes were extracted and cultured.After passage, the chondrocytes were divided into control group, H2O2 group (0.8 μmol·L[-1] H2O2), dihydromyricetin low concentration group (0.8 μmol·L[-1] H2O2+20 μmol·L[-1] dihydromyricetin), dihydromyricetin high concentration group (0.8 μmol·L[-1] H2O2+80 μmol·L[-1] dihydromyricetin), and ROS inhibitor N-acetylcysteine (NAC) group (0.8 μmol·L[-1] H2O2+5 mmol·L[-1] NAC). The activity of chondrocytes was measured by methyl thiazolyl tetrazolium (MTT) assay. The apoptosis rate of chondrocytes was measured by Hoechst 33342 method. The level of ROS in chondrocytes was measured by 2, 7-dichlorofluorescein diacetate (DCFH-DA) fluorescence probe.The level of Type II collagen α1 (Col2α1) mRNA was measured by qRT-PCR.And the expression of Col2α1, p-p38-MAPK/p38-MAPK, B cell lymphoma gene-2 (Bcl-2) and Bcl-2 associated X protein (Bax) proteins was detected by Western blot.

RESULTS: The chondrocytes showed swirling fibrous mass, and the expression of COL2α was positive. Compared with the control group, the chondrocyte viability, apoptosis rate, ROS fluorescence intensity, p-p38-MAPK/p38-MAPK, and the expression of Bax protein in H2O22 group increased, the level of Col2α1 mRNA, and the expression of Col2α1 and Bcl-2 proteins decreased (P<0.05). Compared with H2O2 group, the chondrocyte viability, apoptosis rate, ROS fluorescence intensity, p-p38-MAPK/p38-MAPK, and the expression of Bax protein in dihydromyricetin low concentration group, dihydromyricetin high concentration group, and NAC group decreased, the level of Col2α1 mRNA, and the expression of Col2α1 and Bcl-2 proteins increased (P<0.05).

CONCLUSION: Dihydromyricetin may inhibit chondrocyte apoptosis, inflammatory reaction and oxidative stress by inhibiting ROS/p38-MAPK pathway. Dihydromyricetin may be a potential drug for treating osteoarthritis.},
}

Animals
*Chondrocytes/drug effects/cytology/metabolism
*Apoptosis/drug effects
*Hydrogen Peroxide/toxicity
*Osteoarthritis/metabolism/drug therapy/physiopathology
Mice, Inbred C57BL
*Reactive Oxygen Species/metabolism
Mice
*Flavonols/pharmacology
*p38 Mitogen-Activated Protein Kinases/metabolism/genetics
*Cell Proliferation/drug effects
Male
Signal Transduction/drug effects
*MAP Kinase Signaling System/drug effects
Cells, Cultured

@article {pmid39800517,
year = {2025},
author = {Wang, YS and Dong, C and Zou, L and Zhao, L and Qin, JH and Mo, HL},
title = {Ligand engineering boosts catalase-like activity of gold nanoclusters for cascade reactions combined with glucose oxidase in ZIF-8 matrix.},
journal = {Analytica chimica acta},
volume = {1337},
number = {},
pages = {343565},
doi = {10.1016/j.aca.2024.343565},
pmid = {39800517},
issn = {1873-4324},
mesh = {*Glucose Oxidase/metabolism/chemistry ; *Gold/chemistry/metabolism ; *Metal Nanoparticles/chemistry ; *Catalase/metabolism/chemistry ; *Zeolites/chemistry ; Glucose/metabolism/analysis ; *Metal-Organic Frameworks/chemistry ; Ligands ; Hydrogen Peroxide/chemistry/metabolism ; Acetylcysteine/chemistry ; Imidazoles ; },
abstract = {BACKGROUND: Integrating natural enzymes and nanomaterials exhibiting tailored enzyme-like activities is an effective strategy for the application of cascade reactions. It is essential to develop a highly efficient and robust glucose oxidase-catalase (GOx-CAT) cascade system featuring controllable enzyme activity, a reliable supply of oxygen, and improved stability for glucose depletion in cancer starvation therapy. However, the ambiguous relationship between structure and performance, and the difficulty in controlling enzyme-mimic activity, significantly hinder their broader application. Herein, the CAT-like activity of atomically precise Au25(MPA)18 (MPA = 3-mercaptopropionic acid) nanoclusters (AuNCs) was modulated by incorporating N-acetyl-l-cysteine (NAC) in a series of ratio.

RESULTS: It is found that Au25(NAC)14-17(MPA)4-1 exhibited superior CAT-like activity and structural stability than Au25(MPA)18 owing to the intramolecular hydrogen bond in NAC. Moreover, the synergetic effects of glucose-depletion catalyzed by GOx, oxygen generation from the intermediate hydrogen peroxide (H2O2) facilitated by Au25(NAC)14-17(MPA)4-1, and protective function and nanoconfinement effect of zeolitic imidazolate framework-8 (ZIF-8) enabled the GOx-Au25(NAC)14-17(MPA)4-1@ZIF-8 composite to degrade more glucose. Compared to that treated with a single enzyme or free enzymes, the residual intermediate H2O2 level after treatment with GOx-Au25(NAC)14-17(MPA)4-1@ZIF-8 was about 93 % lower than that after treatment with GOx alone. This composite showed higher catalytic activity, stability, and tolerance when applied to GOx-mediated glucose depletion.

SIGNIFICANCE: In brief, the study provides a feasible strategy for realizing robust and efficient cascade reaction by integrating the merits of natural enzymes and atomically precise metal NCs with adjustable enzyme-like activity. This research offers essential guidance for developing a biocompatible and tailored cascade system.},
}

*Glucose Oxidase/metabolism/chemistry
*Gold/chemistry/metabolism
*Metal Nanoparticles/chemistry
*Catalase/metabolism/chemistry
*Zeolites/chemistry
Glucose/metabolism/analysis
*Metal-Organic Frameworks/chemistry
Ligands
Hydrogen Peroxide/chemistry/metabolism
Acetylcysteine/chemistry
Imidazoles

@article {pmid40295625,
year = {2025},
author = {Lee, SO and Joo, SH and Lee, NY and Cho, SS and Yoon, G and Kim, KT and Choi, YH and Park, JW and Choi, JS and Shim, JH},
title = {Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {14912},
pmid = {40295625},
issn = {2045-2322},
support = {RS-2024-00336900//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; Oxaliplatin/pharmacology ; *Apoptosis/drug effects ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Colorectal Neoplasms/metabolism/pathology/drug therapy ; HCT116 Cells ; *Drug Resistance, Neoplasm/drug effects ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; *JNK Mitogen-Activated Protein Kinases/metabolism ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; Enzyme Activation/drug effects ; Caspases/metabolism ; Sesquiterpenes ; },
abstract = {Treating colorectal cancer (CRC) poses challenges due to the lack of specific molecular targets. Although oxaliplatin (Ox) is commonly used to treat CRC, resistance frequently develops, necessitating the discovery of new therapeutics. This study explored the anticancer effects of Isoalantolactone (IAL) on human CRC cells HCT116 and Ox-resistant HCT116 (HCT116-OxR). Apoptosis, ROS generation, cell cycle distribution, mitochondrial membrane potential (MMP), and caspase activation were assessed through flow cytometry. Protein levels were determined by Western blot analysis. IAL reduced cell viability, measured by MTT assay, and inhibited anchorage-independent colony formation in CRC cells in a time- and concentration-dependent manner. The IC50 values for 48 h of incubation were below 10 µM. Annexin V/7-AAD double staining demonstrated that IAL induced apoptosis in HCT116 and HCT116-OxR cells, and Western blot analysis confirmed increased phosphorylation of JNK and p38 mitogen-activated protein kinase (MAPK). The inhibition of these kinases by SP600125 or SB203580 blocked the antiproliferative effects of IAL. Additionally, IAL triggered ROS generation and disrupted mitochondrial membranes, leading to caspase activation. Pretreatment with N-acetylcysteine (NAC) or Z-VAD-FMK inhibited the antiproliferative effects of IAL, highlighting the crucial roles of ROS generation and caspase activation in IAL-induced apoptosis in CRC cells. In summary, IAL exhibited anticancer effects in CRC cells by inducing apoptosis by elevating ROS level and activating JNK and p38 MAPK. These findings warrant further study to evaluate the therapeutic potential of IAL in treating CRC with various resistances.},
}

Humans
*Reactive Oxygen Species/metabolism
Oxaliplatin/pharmacology
*Apoptosis/drug effects
*p38 Mitogen-Activated Protein Kinases/metabolism
*Colorectal Neoplasms/metabolism/pathology/drug therapy
HCT116 Cells
*Drug Resistance, Neoplasm/drug effects
Membrane Potential, Mitochondrial/drug effects
*Antineoplastic Agents/pharmacology
*JNK Mitogen-Activated Protein Kinases/metabolism
Cell Survival/drug effects
Cell Proliferation/drug effects
Enzyme Activation/drug effects
Caspases/metabolism
Sesquiterpenes

@article {pmid40292267,
year = {2025},
author = {Zolfaghari Farajerdi, M and Rajabian, F and Razavi, BM and Ghasemzadeh Rahbarda, M and Khajavi Rad, A and Amoueian, S and Hosseinzadeh, H},
title = {Evaluating the effect of crocin on contrast-induced nephropathy in rats.},
journal = {Avicenna journal of phytomedicine},
volume = {15},
number = {2},
pages = {920-932},
pmid = {40292267},
issn = {2228-7930},
abstract = {OBJECTIVE: Contrast-induced nephropathy (CIN) raises the risk of renal injury, but crocin, a saffron component, may improve kidney function. This study investigated crocin's protective effects against CIN in rats.

MATERIALS AND METHODS: Male Wistar rats were divided into eight groups: Sham, Control, Contrast medium (diatrizoate), Diatrizoate combined with crocin at 10, 20, or 40 mg/kg/day, Diatrizoate combined with N-acetylcysteine (NAC) at 125 mg/kg/day, and Crocin alone at 40 mg/kg/day. Water deprivation began on day 5 for 48 hr, except for the sham and crocin alone groups. Indomethacin and N(ω)-nitro-L-arginine methyl ester were administered after 40 hr of dehydration. Rats were sacrificed on the eighth day, and blood and kidney samples were collected.

RESULTS: Diatrizoate increased serum creatinine and blood urea nitrogen levels, elevated malondialdehyde levels, and reduced glutathione in renal tissue. Crocin reversed these effects. Diatrizoate caused severe tubular necrosis, proteinaceous casts, medullary congestion, and interstitial edema in kidney tissue. Crocin (20 and 40 mg/kg) significantly reduced tubular necrosis, and doses of 10 and 40 mg/kg reduced interstitial edema. NAC significantly improved histopathological damage, biochemical factors, and oxidative stress. The crocin alone group showed no significant changes.

CONCLUSION: Diatrizoate induces nephrotoxicity by enhancing oxidative stress in rats, and crocin has a protective effect against it. Crocin mitigates both tissue and biochemical damage inflicted by diatrizoate.},
}

@article {pmid40289970,
year = {2025},
author = {Jiang, L and Lu, Y and Zhao, H and He, W},
title = {Arctigenin Suppresses Melanoma via Mitophagy Activation In vitro and Enhances Dacarbazine Sensitivity In vivo.},
journal = {Current cancer drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680096373796250414062644},
pmid = {40289970},
issn = {1873-5576},
abstract = {OBJECTIVE: This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.

METHODS: In vitro experiments were conducted to explore the effects of ARG on the biologi-cal behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autoph-agy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were as-sessed.

RESULTS: CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. West-ern blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax in-creased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mito-chondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmis-sion electron microscopy. ARG inhibited the proliferation and induced the apoptosis of mel-anoma cells in vivo.

CONCLUSION: Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.},
}

@article {pmid40288286,
year = {2025},
author = {Dai, A and Liu, X and Chen, Y and Wang, Y and Qi, H and Zeng, Y and Li, J},
title = {Co-exposure to ozone and polystyrene nanoplastic exacerbates cognitive impairment and anxiety-like behavior by regulating neuronal pyroptosis in mice.},
journal = {Environment international},
volume = {199},
number = {},
pages = {109501},
doi = {10.1016/j.envint.2025.109501},
pmid = {40288286},
issn = {1873-6750},
abstract = {Ozone (O3) and nanoplastics (NPs) are pervasive environmental pollutants that frequently co-occur in our heavily industrialized era. While it has been documented that exposure to O3 or NPs individually has neurotoxic effects, studies investigating their combined impact and the hazardous mechanisms resulting from co-exposure are limited. In this study, we established a mouse model co-exposure to polystyrene nanoparticles (PS-NPs) and O3, focusing on the prefrontal cortex (PFC), a brain region crucial for cognition and emotion. We examined the effects of O3 and PS-NPs on behavioral changes related to learning, memory, and anxiety, employing transcriptome sequencing alongside molecular and histopathological methods. Our findings indicate that combined exposure to O3 and PS-NPs disrupts the integrity of the blood-brain barrier, reducing Claudin 5 expression and leading to increased accumulation of PS-NPs in the PFC. Transcriptome sequencing demonstrated the involvement of the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and oxidative stress in the pathological changes observed in the PFC. Through immunohistochemical and immunofluorescence analysis, we observed enhanced microglial activation, which correlates with increased production of inflammatory factors. Additionally, western blot and immunofluorescence co-labeling analyses revealed elevated expression levels of GSDMD-N, caspase-1, IL-1β, and IL-18 proteins, which are associated with neuronal pyroptosis. Finally, immunofluorescence co-labeling confirmed that the activation of the p38 MAPK pathway in neurons is involved in co-exposure-induced pyroptosis. Meanwhile, N-Acetylcysteine (NAC), a common antioxidant, can alleviate neuroinflammation and neuronal pyroptosis in the PFC, and it rescued the cognitive deficits and anxiety-like behaviors observed in the co-exposed mice. Our study illustrates that co-exposure to O3 and NPs can aggravate damage to the blood-brain barrier and elevate oxidative stress levels in the PFC, thereby increasing the occurrence of neuroinflammation and may mediate neuronal pyroptosis through activation of the p38 MAPK pathway, ultimately contributing to neurobehavioral toxicity.},
}

@article {pmid40284514,
year = {2025},
author = {Polo-Montalvo, A and Gómez-Cerezo, N and Cicuéndez, M and González, B and Izquierdo-Barba, I and Arcos, D},
title = {Osteogenic and Antibacterial Response of Levofloxacin-Loaded Mesoporous Nanoparticles Functionalized with N-Acetylcysteine.},
journal = {Pharmaceutics},
volume = {17},
number = {4},
pages = {},
pmid = {40284514},
issn = {1999-4923},
support = {PID2020-117091RB-I00, AEI /10.13039/501100011033//Ministerio de Ciencia e Innovación/ ; Nano4Infection, FD5/22_01//Fundación Ramón Areces, SPAIN/ ; PID2023-149093OB-I00, MCIU/AEI/10.13039/501100011033/FEDER,UE//Ministerio de Ciencia e Innovación/ ; },
abstract = {Background/Objectives: Bone infection is one of the most prevalent complications in orthopedic surgery. This pathology is mostly due to bacterial pathogens, among which S. aureus stands out. The formation of a bacterial biofilm makes systemic treatment with antibiotics ineffective. Herein we propose a nanosystem composed of mesoporous bioactive glass nanoparticles (MBGN) loaded with levofloxacin and functionalized with N-acetylcysteine (NAC), aiming to offer an alternative to current treatments. These nanoparticles would present antibacterial activity able to disintegrate the biofilm and regenerate the peri-implantar osseous tissue. Methods: MBGN of composition 82.5 SiO2-17.5 CaO have been synthesized, loaded with levofloxacin, and functionalized with NAC (MBGN-L-NAC). The antimicrobial activity against mature S. aureus biofilms and bioactivity of the nanosystem have been evaluated, as well as its biocompatibility and ability to promote murine pre-osteoblastic MC3T3-E1 differentiation. Results: MBGNs exhibited high surface areas and radial mesoporosity, allowing up to 23.1% (% w/w) of levofloxacin loading. NAC was covalently bound keeping the mucolytic thiol group, SH, available. NAC and levofloxacin combination enhances the activity against S. aureus by disrupting mature biofilm integrity. This nanosystem was biocompatible with pre-osteoblasts, enhanced their differentiation towards a mature osteoblast phenotype, and promoted bio-mimetic mineralization under in vitro conditions. MBGN-L-NAC nanoparticles induced greater osteogenic response of osteoprogenitor cells through increased alkaline phosphatase expression, increased mineralization, and stimulation of pre-osteoblast nodule formation. Conclusions: MBGN-L-NAC exhibits a more efficient antibacterial activity due to the biofilm disaggregation exerted by NAC, which also contributes to enhance the osteoinductive properties of MBGNs, providing a potential alternative to conventional strategies for the management of bone infections.},
}

@article {pmid40284511,
year = {2025},
author = {Meadows, I and Mvungi, H and Salim, K and Kaswaga, O and Mbelele, P and Liyoyo, A and Semvua, H and Ngoma, A and Heysell, SK and Mpagama, SG},
title = {N-Acetylcysteine to Reduce Kidney and Liver Injury Associated with Drug-Resistant Tuberculosis Treatment.},
journal = {Pharmaceutics},
volume = {17},
number = {4},
pages = {},
pmid = {40284511},
issn = {1999-4923},
support = {TMA2016SF-1463//EDCTP/ ; 1T32AI007046-24A44/NH/NIH HHS/United States ; },
abstract = {Background: New drug classes and regimens have shortened the treatment duration for drug-resistant tuberculosis, but adverse events (AEs) and organ toxicity remain unacceptably common. N-acetylcysteine (NAC) has demonstrated potential in reducing kidney and liver toxicity in other clinical settings, but efficacy in drug-resistant tuberculosis treatment has not been rigorously evaluated. Method: A randomized controlled trial was conducted at Kibong'oto Infectious Diseases Hospital in Tanzania to assess the efficacy of NAC in reducing AEs in patients undergoing rifampin-resistant pulmonary tuberculosis treatment. Participants received an all-oral standardized rifampin-resistant regimen alone, with NAC 900 mg daily, or NAC 900 mg twice daily for 6 months. AEs, severe AEs, and renal and liver toxicity were monitored monthly and classified according to the Risk, Injury, Failure, Loss, and End-stage kidney disease criteria and National Cancer Institute Common Terminology Criteria for Adverse Events. Incident ratios and Kaplan-Meier curves were employed to compare group event occurrences. Results: A total of 66 patients (mean age 47 ± 12 years; 80% male) were randomized into three groups of 22. One hundred and fifty-eight AEs were recorded: 52 (33%) in the standard treatment group, 55 (35%) in the NAC 900 mg daily group, and 51 (32%) in the NAC 900 mg twice-daily group (p > 0.99). Severe AEs were observed in four patients in the standard group, two in the NAC 900 mg daily group, and three in the NAC 900 mg twice-daily group. Renal toxicity was more prevalent in the standard treatment group compared to those that received NAC (45% vs. 23%; p = 0.058), with a shorter onset of time to toxicity (χ[2] = 3.199; p = 0.074). Liver injury events were rare across all groups. Conclusion: Among Tanzanian adults receiving rifampin-resistant tuberculosis treatment, NAC did not significantly reduce overall AEs but demonstrated important trends in reducing renal toxicity.},
}

@article {pmid40277294,
year = {2025},
author = {Li, F and Gao, S and Ma, R and Zhang, Y and Li, Y and Wu, D and Han, Z and Li, Q and He, Q and Li, J and Dai, Q and Xu, AD and Zhang, L and Liu, C and Lu, Y},
title = {Polymer-Encapsulated Catalase for Targeted Redox Regulation in Acute Liver Injury.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e2412349},
doi = {10.1002/smll.202412349},
pmid = {40277294},
issn = {1613-6829},
support = {YDZJSX2024B011//Shanxi Province Central Government Guidance Fund for Local Science and Technology Development/ ; 2024AOXIANG02//Project for Scientific Breakthroughs at Shanxi Bethune/ ; 2022YFC2104800//Key Technologies Research and Development Program/ ; L234016//National Natural Science Foundation of China-Nuclear Technology Innovation Joint Fund/ ; },
abstract = {The liver plays a critical role in maintaining homeostasis, and its dysfunction can lead to severe conditions like acute liver injury (ALI), which is primarily caused by viral infections, toxins, and oxidative stress. Reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), significantly drive hepatocyte injury, initiating oxidative stress and inflammation. Current antioxidants, such as N-acetylcysteine (NAC) and superoxide dismutase (SOD), show limited clinical efficacy due to poor targeting, instability, and toxicity. Catalase (CAT), an essential enzyme for H2O2 decomposition, represents a promising therapeutic for ALI; however, its clinical application faces challenges in stability, rapid degradation, and insufficient targeting. Here, a novel nanocapsule-based CAT delivery system (n(CAT)) is presented, formed through in situ radical polymerization using 2-methacryloyloxyethyl phosphorylcholine (MPC) and N-(3-aminopropyl)-methacrylamide hydrochloride (APM). This strategy significantly enhances CAT's stability, retains enzyme activity, and improves selective liver accumulation, particularly at inflammation sites. The results demonstrate that n(CAT) effectively reduces oxidative stress, minimizes inflammation, and facilitates liver repair in ALI and ischemia-reperfusion injury (IRI) models. These findings highlight the potential of n(CAT) as a promising platform for advanced antioxidant therapies targeting liver diseases, including hepatitis.},
}

@article {pmid40277148,
year = {2025},
author = {Tuset, MP and Cooper, JN and Ebode, D and Mittal, J and Garnham, C and Melchionna, T and Hessler, R and Schilp, S and Godur, D and McKenna, K and Mittal, R and Eshraghi, AA},
title = {Intracochlear Drug Delivery Using a Catheter and Dexamethasone-Eluting Electrode Preserves Residual Hearing Post-Cochlear Implantation.},
journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery},
volume = {},
number = {},
pages = {},
doi = {10.1002/ohn.1252},
pmid = {40277148},
issn = {1097-6817},
abstract = {OBJECTIVES: This study aims to assess the feasibility and safety of a cochlear catheter (cannula) for inner ear drug delivery during cochlear implantation. We evaluated the otoprotective effect of L-N-acetylcysteine (L-NAC) administered via a cannula in combination with a dexamethasone-eluting cochlear implant (CI).

STUDY DESIGN: An animal model study.

SETTING: Animal facility of an academic institution.

METHODS: Animals were divided into 8 groups: (1) implantation with a CI; (2) implantation with a dexamethasone-eluting CI (CIDexel); (3) cannula injection of artificial perilymph (Can+AP); (4) cannula injection of Ringer (Can+R); (5) cannula injection of R and CI (Can+CI); (6) cannula injection of R and Dexel (Can+Dexel); (7) cannula injection of 2 mM L-NAC and CI (Can L-NAC 2 mM+CI); or (8) cannula injection of 2mM L-NAC and Dexel (Can L-NAC 2 mM++Dexel). The contralateral ear served as the control group. Hearing thresholds were determined preoperatively, and at postoperative day (POD 7) and POD 30 post-cochlear implantation, using auditory brainstem responses (ABRs). The organ of Corti dissections were performed at POD 30 for hair cell (HC) viability, and oxidative stress assessment using immunostaining.

RESULTS: The L-NAC (2 mM) and dexamethasone-eluting electrode group had significantly lower hearing thresholds than the standard CI, Can L-NAC 2 mM, and Dexel groups. The animal group treated with L-NAC (2 mM) and dexamethasone-eluting electrode showed higher HC viability and reduced oxidative stress.

CONCLUSION: An intracochlear cannula can deliver pharmaceutical interventions without causing additional hearing loss. L-NAC presents strong anti-apoptotic potential and administration through a cannula together with Dexel implantation, and achieves a synergistic effect enhancing the otoprotection.},
}

@article {pmid39714274,
year = {2025},
author = {Huang, KT and Tsai, WH and Chen, CW and Hwang, YS and Cheng, HC and Yeh, CW and Lin, YH and Cheng, AJ and Chang, HC and Lin, SJ and Yen, MC and Chang, WT},
title = {Hyperoxia induces autophagy in pulmonary epithelial cells: insights from in vivo and in vitro experiments.},
journal = {Free radical research},
volume = {59},
number = {1},
pages = {9-22},
doi = {10.1080/10715762.2024.2446321},
pmid = {39714274},
issn = {1029-2470},
mesh = {*Autophagy/drug effects ; Humans ; Animals ; *Hyperoxia/pathology/metabolism ; Rats ; A549 Cells ; *Epithelial Cells/metabolism/pathology/drug effects ; Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology ; *Lung/pathology/metabolism ; Oxidative Stress ; Rats, Sprague-Dawley ; Membrane Potential, Mitochondrial/drug effects ; },
abstract = {Patients with hypoxemia require high-concentration oxygen therapy. However, prolonged exposure to oxygen concentrations 21% higher than physiological concentrations (hyperoxia) may cause oxidative cellular damage. Pulmonary alveolar epithelial cells are major targets for hyperoxia-induced oxidative stress. In this study, we evaluated the therapeutic potential of the antioxidant N-acetyl-L-cysteine (NAC) for preventing hyperoxia-induced cell death. In vitro experiments were performed using the human lung cancer cell line A549. In brief, NAC-treated and untreated cells were exposed to various concentrations of oxygen (hyperoxia) for different durations. The results indicated that hyperoxia inhibited proliferation and caused cell cycle arrest in A549 cells. It also induced necrosis and autophagy. Furthermore, hyperoxia increased intracellular reactive oxygen species levels and altered mitochondrial membrane potential. Co-treatment with NAC improved the survival of cells exposed to 95% oxygen for 24 h. Experiments performed using a neonatal rat model of acute lung injury confirmed that hyperoxia induced an autophagic response. This study provides evidence for hyperoxia-induced autophagy both in vitro and in vivo. NAC can protect A549 cells from death induced by short-term hyperoxia. Our findings may inform protective strategies against hyperoxia-induced injury in developing lungs-for example, bronchopulmonary dysplasia in premature infants.},
}

*Autophagy/drug effects
Humans
Animals
*Hyperoxia/pathology/metabolism
Rats
A549 Cells
*Epithelial Cells/metabolism/pathology/drug effects
Reactive Oxygen Species/metabolism
Acetylcysteine/pharmacology
*Lung/pathology/metabolism
Oxidative Stress
Rats, Sprague-Dawley
Membrane Potential, Mitochondrial/drug effects

@article {pmid40275972,
year = {2024},
author = {Keshavarz, S and Reisi, M and Keivanfar, M and Rabbani, F and Sabzghabaee, AM},
title = {Efficacy of Adding Oral N acetyl Cysteine Supplement to the Cystic Fibrosis Treatment Regimen: A Randomized Quasi-Experimental Trial.},
journal = {Journal of research in pharmacy practice},
volume = {13},
number = {3},
pages = {72-77},
pmid = {40275972},
issn = {2319-9644},
abstract = {OBJECTIVE: This study investigated the efficacy of adding the oral N-acetyl cysteine (NAC) supplement to the cystic fibrosis (CF) treatment regimen compared to adding a placebo. It also studied the quality of life and respiratory indicators of patients aged 6-18 with mild-to-moderate pulmonary involvement.

METHODS: This clinical trial was a randomized, quasi-experimental pilot and add-on therapy controlled with a placebo for 3 months. The case group received 200 mg of oral NAC three times a day. In contrast, the control group had a placebo in the same way. From the 2021 fall to the summer of 2022, 38 CF patients referred to Imam Hossein Children's Hospital Clinic were finally examined. They were clinically stable with a forced expiratory volume in the first second (FEV1) level of more than 50% and no history of underlying cardiovascular and renal diseases.

FINDINGS: The differences between the groups were not significant. In the placebo group, key measures remained unchanged, whereas the NAC group had an improvement in the CF Questionnaire-Revised score but no notable changes in other indices. Overall, comparisons of forced vital capacity (FVC) between the groups showed no variation.

CONCLUSION: The indicators of FEV1, FVC, FEV1/FVC, forced expiratory flow between 25% and 75% of vital capacity, and the quality of life of the case group were not significantly different from those of the placebo group, and no significant differences were observed between this medicine and placebo.},
}

@article {pmid40275970,
year = {2024},
author = {Shabani, AM and Alikhani, A and Heydari, F and Hosseinnataj, A and Sohrabi, M and Ramezaninejad, S and Ala, S and Kasgari, HA},
title = {Evaluation of the Effect of N-acetylcysteine in the Prevention of Colistin Nephrotoxicity in Critically Ill Patients: A Randomized Controlled Trial.},
journal = {Journal of research in pharmacy practice},
volume = {13},
number = {3},
pages = {85-91},
pmid = {40275970},
issn = {2319-9644},
abstract = {OBJECTIVE: The present study aimed to evaluate the efficacy of N-acetylcysteine (NAC) in preventing nephrotoxicity in critically ill patients receiving colistin.

METHODS: In a randomized, controlled clinical trial, eligible participants receiving colistin were divided into two groups: the drug group (n = 24) and the control group (n = 24). In the drug group, 2 g of NAC was administered intravenously daily for 5 days, simultaneously with colistin. The patients in the control group received only colistin. Serum creatinine (SCr), blood urea nitrogen (BUN), and creatinine clearance (CrCl) at baseline and on each day, and the number of cases of acute kidney injury during the study were recorded. Urinary N-acetyl-beta-D-glucosaminidase (NAG) was determined before the start of treatment and on day 5. The study outcomes were the mortality rate, length of intensive care unit (ICU) stay, and NAG levels. Finally, the values were compared between the groups.

FINDINGS: It was found that the 28-day mortality rate (P = 0.540) and length of ICU stay (P = 0.699) were not significantly improved by coadministration of intravenous N-acetylcysteine with colistin. SCr and BUN showed no significant reduction, and there were no changes in CrCl at the end of treatment. The changes in urinary NAG levels did not differ significantly between the two groups. There was also no difference in the stages of the RIFLE criteria (P = 0.641), and most patients were in the normal stage (58.3%).

CONCLUSION: Concomitant administration of intravenous NAC at a dose of 2 g daily does not prevent colistin-induced nephrotoxicity, 28-day mortality, and length of ICU stay in critically ill patients.},
}

@article {pmid40269590,
year = {2025},
author = {Liu, N and Liu, Y and Wang, X and Liu, M and Wang, Y and Feng, C and Piao, M},
title = {N-Acety-L-Cysteine Alleviates Isoflurane-Triggered Neuronal Cell Parthanatos by Suppressing Reactive Oxygen Species Accumulation Through the Induction of c-Jun N-Terminal Kinase Signaling Pathway Inhibition.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {5},
pages = {e70268},
pmid = {40269590},
issn = {1099-0461},
support = {//This investigation was supported by grants from the National Natural Science Foundation of China (Grant No. 81771141 and 82471221 to C. F.) and the Science and Technology Development Project of Jilin Province (Grant No. 20210101304JC to C. F.)./ ; },
mesh = {Animals ; *Isoflurane/adverse effects/pharmacology ; *Reactive Oxygen Species/metabolism ; Rats ; *Neurons/metabolism/drug effects/pathology ; *Acetylcysteine/pharmacology ; *JNK Mitogen-Activated Protein Kinases/metabolism ; *MAP Kinase Signaling System/drug effects ; Humans ; Hippocampus/metabolism/pathology ; *Parthanatos/drug effects ; *Anesthetics, Inhalation/adverse effects ; Rats, Sprague-Dawley ; Cell Line, Tumor ; Oxidative Stress/drug effects ; },
abstract = {In recent years, the potential neurotoxicity of inhaled anesthetics on the developing brain has increasingly garnered attention, yet its mechanism remains unclear. Parthanatos is a newly discovered form of programmed cell death dependent on PARP-1, and it is believed to be closely associated with cellular oxidative stress response. However, it is still to be proven whether isoflurane, a commonly used clinical anesthetic, can induce parthanatos in developing brain neurons and whether it activates the oxidative stress signaling pathway in neuronal cells. In this study, we treated SH-SY5Y cells and rat hippocampus neuron cells (RN-h) with isoflurane, measured cell viability using the MTT assay, examined the activation of the parthanatos-related PARP-1/AIF/PAR signaling pathway using western blot analysis, detected the accumulation of ROS using DCFH-DA, detected mitochondrial membrane potential (Δψm) by a JC-1 assay, and assessed the activation of the oxidative stress-related JNK signaling pathway using western blot. In vivo, we examined the damaging effects of inhaled isoflurane on neonatal rat hippocampal neurons using HE staining. The results showed that 2% and 4% concentrations of isoflurane significantly inhibited cell survival and upregulated the expression levels of PARP-1, AIF, and PAR in both types of neuronal cells. Moreover, isoflurane significantly enhanced ROS levels and decreased Δψm, and activated the JNK signaling pathway in both cell types. Importantly, we found that pretreatment with N-Acetylcysteine (NAC) could inhibit isoflurane-induced parthanatos and the accumulation of ROS in cells, as well as the activation of the JNK pathway. The experimental results in neonatal rats also demonstrated that isoflurane led to significant neuronal death in the hippocampal CA1 region. However, pretreatment with NAC significantly increased the survival rate of pyramidal neurons in this region. In summary, through our experiments, we confirmed that isoflurane can induce parthanatos in neuronal cells, and NAC can decrease ROS accumulation in neuronal cells and thus mitigate the damage isoflurane causes to neuronal cells.},
}

Animals
*Isoflurane/adverse effects/pharmacology
*Reactive Oxygen Species/metabolism
Rats
*Neurons/metabolism/drug effects/pathology
*Acetylcysteine/pharmacology
*JNK Mitogen-Activated Protein Kinases/metabolism
*MAP Kinase Signaling System/drug effects
Humans
Hippocampus/metabolism/pathology
*Parthanatos/drug effects
*Anesthetics, Inhalation/adverse effects
Rats, Sprague-Dawley
Cell Line, Tumor
Oxidative Stress/drug effects

@article {pmid40269151,
year = {2025},
author = {Liu, F and Lv, R and Qiao, X and Lv, G and Yuan, H and Han, J and Wang, X and Wan, J and Wang, M},
title = {Salinomycin and oxaliplatin synergistically enhances cytotoxic effect on human colorectal cancer cells in vitro and in vivo.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {14056},
pmid = {40269151},
issn = {2045-2322},
support = {SDYWZGKCJHLH2023095//Shandong Province Medical Staff Science and Technology Innovation Plan Project/ ; 2020NS160 and 2022NS319//Taian science and technology innovation and development project/ ; 2020NS160 and 2022NS319//Taian science and technology innovation and development project/ ; 2022MPM03//Nursery Project of the Affiliated Taian City Central Hospital of Qingdao University/ ; ZR2020MH239//Natural Science Foundation of Shandong Province, China/ ; },
mesh = {*Oxaliplatin/pharmacology ; Humans ; *Colorectal Neoplasms/drug therapy/metabolism/pathology ; *Pyrans/pharmacology/administration & dosage ; Drug Synergism ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Animals ; Cell Proliferation/drug effects ; Mice ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Cell Movement/drug effects ; *Antineoplastic Agents/pharmacology ; *Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Mice, Nude ; Polyether Polyketides ; },
abstract = {Oxaliplatin (OXA) is widely used for colorectal cancer (CRC) as a first-line chemotherapy. However, drug resistance and peripheral neurotoxicity prevail in colorectal cancer therapy. Salinomycin (SAL) makes cancer cells sensitive to ionizing radiation and chemotherapeutic drugs. Chemotherapy regimens that combine more than two drugs can improve the outcome of patients. In the present study, we detected apoptosis and mitochondrial function in CRC cells through MTT assays, Annexin V-FITC/PI staining, colony-forming assays, intracellular reactive oxygen species (ROS) measurements, western blotting and so on. We used CompuSyn software to calculate combination index (CI). The effect of SAL and OXA was synergistic. The combination treatment inhibited cell proliferation, migration and colony formation but increased the expression of proapoptotic proteins and promoted cell apoptosis of CRC cells. In vitro experiments demonstrated that the SAL and OXA cotreatment increased intracellular ROS levels in CRC cell lines, decreased the MMP and activated the mitogen-activated protein kinase (MAPK) pathway, thus inhibiting the proliferation of CRC cells and promoting the apoptosis of CRC cells. Pretreatment with N-acetylcysteine (NAC) reversed this effect. Cotreatment with SAL and OXA increases the apoptotic effects in OXA-treated CRC cell lines. In vivo, combined treatment of SAL and OXA markedly inhibited the tumor growth compared to either drug alone. SAL enhances OXA-induced antitumor effects in CRC both in vitro and in vivo by ROS-mediated mitochondrial apoptosis and activation of the MAPK pathway. These results may provide a rationale for combining SAL with OXA for CRC treatment.},
}

*Oxaliplatin/pharmacology
Humans
*Colorectal Neoplasms/drug therapy/metabolism/pathology
*Pyrans/pharmacology/administration & dosage
Drug Synergism
Apoptosis/drug effects
Reactive Oxygen Species/metabolism
Animals
Cell Proliferation/drug effects
Mice
Cell Line, Tumor
Xenograft Model Antitumor Assays
Cell Movement/drug effects
*Antineoplastic Agents/pharmacology
*Antineoplastic Combined Chemotherapy Protocols/pharmacology
Mice, Nude
Polyether Polyketides

@article {pmid40267072,
year = {2025},
author = {Oike, H and Yamasaki, K and Hashiguchi, K and Uehira, H},
title = {Evaluation of intake of aged garlic extract and organosulfur compounds on progressive hearing loss in DBA/2J mice.},
journal = {PloS one},
volume = {20},
number = {4},
pages = {e0322105},
pmid = {40267072},
issn = {1932-6203},
mesh = {Animals ; *Garlic/chemistry ; Mice ; *Hearing Loss/drug therapy/physiopathology ; Mice, Inbred DBA ; *Plant Extracts/pharmacology/administration & dosage/chemistry/therapeutic use ; *Cysteine/analogs & derivatives/pharmacology/administration & dosage ; Male ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Acetylcysteine/pharmacology ; *Sulfur Compounds/pharmacology/administration & dosage ; },
abstract = {Garlic is rich in organosulfur compounds with high antioxidant capacity and is known to have various health benefits. Aged garlic is a particularly effective source of these active compounds because it contains fewer toxic components. This study evaluated the effects of S-allyl cysteine (SAC), a major functional organosulfur compound in garlic, and aged garlic extract (AGE) on the suppression of progressive hearing loss. SAC and AGE were dissolved in drinking water at 1% (w/w) and administered to DBA/2J mice, a model of early progressive hearing loss, for 12 weeks, starting at 4 weeks of age. While the results revealed a trend toward weight loss in the SAC group, the weight of the AGE group was comparable to that of the control group, and no adverse events were observed in either group. The hearing ability of the mice was measured using auditory brainstem responses at 4, 8, 12, and 16 weeks of age. Hearing loss at 8 and 16 kHz progressed over the 12-week period, with neither sample inhibiting hearing loss. In contrast, another organosulfur compound, N-acetylcysteine (NAC), administered in 1% w/w drinking water and evaluated for hearing loss over time, significantly suppressed hearing loss progression in DBA/2J mice. These results indicate that the NAC and SAC differ in their ability to prevent hearing loss and demonstrate that the inhibitory effects of functional food components on hearing loss can be evaluated over a short period in DBA/2J mice.},
}

Animals
*Garlic/chemistry
Mice
*Hearing Loss/drug therapy/physiopathology
Mice, Inbred DBA
*Plant Extracts/pharmacology/administration & dosage/chemistry/therapeutic use
*Cysteine/analogs & derivatives/pharmacology/administration & dosage
Male
Evoked Potentials, Auditory, Brain Stem/drug effects
Acetylcysteine/pharmacology
*Sulfur Compounds/pharmacology/administration & dosage

@article {pmid40266430,
year = {2025},
author = {Chen, KL and Lu, HI and Yen, CY and Chen, CY and Chien, TM and Jeng, JH and Chen, BH and Chang, HW},
title = {Antioral cancer effects of ginger derivative 3-HDM exert oxidative stress-associated apoptosis and DNA damage.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {414},
pmid = {40266430},
issn = {1573-4978},
support = {112CM-KMU-05//Chimei-KMU jointed project/ ; MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; KMU-TC113A04//Kaohsiung Medical University Research Center/ ; KMU-DK(A)113003 and KMU-TB114009//Kaohsiung Medical University/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Zingiber officinale/chemistry ; *DNA Damage/drug effects ; *Mouth Neoplasms/drug therapy/metabolism/genetics/pathology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Cell Proliferation/drug effects ; Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: 3-Hydroxy-1-(3',5'-dimethoxy-4'-hydroxy-phenyl)-hexan-5-one (3-HDM), a novel ginger Zingiber officinale-derived compound, lacks anti-cancer investigation, especially for oral cancer. This study addresses the antioral function and mechanism of 3-HDM against oral cancer cells (Ca9-22 and CAL 27).

METHOD: MTS, flow cytometry, and western blotting were used to determine cell viability and antioral function and mechanism.

RESULTS: 3-HDM inhibits oral cancer cell viability without normal cell (S-G) toxicity. This selective antiproliferation relies on oxidative stress validated by N-acetylcysteine (NAC), a reactive oxygen species (ROS) remover. 3-HDM upregulates subG1 and annexin V proportions, enhances caspases 3 and 8 activation to a greater extent in oral cancer than in normal cells, reverted by NAC. This process demonstrates the ROS-dependent selective apoptotic character of 3-HDM. 3-HDM also upregulates more ROS and mitochondrial superoxide and downregulates the mitochondrial membrane potential and glutathione in oral cancer than in normal cells in a ROS-dependent manner. Moreover, 3-HDM suppresses antioxidant signaling mRNA expressions such as NFE2L2, NQO1, and TXN and inhibits NFE2L2 phosphorylation in oral cancer cells compared to normal cells. NAC also downregulates the 3-HDM-induced γH2AX and 8-hydroxy-2-deoxyguanosine DNA damage markers.

CONCLUSION: 3-HDM shows selective antioral cancer effects and mechanisms without toxicity to normal cells via oxidative stress regulation.},
}

Humans
*Oxidative Stress/drug effects
*Apoptosis/drug effects
*Zingiber officinale/chemistry
*DNA Damage/drug effects
*Mouth Neoplasms/drug therapy/metabolism/genetics/pathology
Cell Line, Tumor
Reactive Oxygen Species/metabolism
Cell Survival/drug effects
Membrane Potential, Mitochondrial/drug effects
Cell Proliferation/drug effects
Acetylcysteine/pharmacology

@article {pmid40262667,
year = {2025},
author = {Liu, R and Dai, L and Jia, S and Geng, S and Niu, Y and Chen, J and Dong, C and Li, C and Shi, Y and Wang, X and Zhang, J and Zhao, N and Gao, Z and Yang, X and Gao, S},
title = {Fut8 regulated Unc5b hyperfucosylation reduces macrophage emigration and accelerates atherosclerosis development via the ferroptosis pathway.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.04.025},
pmid = {40262667},
issn = {1873-4596},
abstract = {The accumulation of foam cells in the arterial walls is a defining characteristic of atherosclerosis. Enhancing their migration from plaques may represent a key strategy for slowing disease progression. Recent studies suggest that fucosyltransferase 8 (Fut8) impairs macrophage migration from the intima by modifying the Unc5b membrane receptor, thereby influencing the development of atherosclerosis. This study investigated the roles of Fut8 and Unc5b in foam cell migration using ApoE[-/-] mouse and foam cell models, employing techniques such as western blotting, mitochondrial function assays, wound healing experiments, and immunofluorescence staining. The findings indicate that Fut8 upregulation increases P53 expression and reduces SLC7A11 and GPX4 levels, leading to altered intracellular concentrations of GSH and Fe[2+], impaired mitochondrial function, and reduced migration capacity, all of which promote atherosclerosis. These mechanisms are closely associated with ferroptosis. Intervention with N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) demonstrated that NAC mitigates oxidative stress and migration inhibition,induced by oxidized low-density lipoprotein (ox-LDL). Additionally, inhibiting ferroptosis slowed the progression of atherosclerosis in ApoE[-/-] mice. Together, these results highlight that Fut8 exacerbates atherosclerosis through a P53/SLC7A11-mediated enhancement of ferroptosis in foam cells, offering a novel perspective on the pathophysiology of atherosclerosis.},
}

@article {pmid40257108,
year = {2025},
author = {He, W and Xu, L and Jiang, W and Yao, S and Fu, Y and Cheng, Z and Zhang, D and Huang, L},
title = {miR-223-3p Mitigates Mitochondrial Dysfunction and Cementoblast Apoptosis in Orthodontic Root Resorption via FoxO3.},
journal = {Journal of periodontal research},
volume = {},
number = {},
pages = {},
doi = {10.1111/jre.13384},
pmid = {40257108},
issn = {1600-0765},
support = {82170989//National Natural Science Foundation of China/ ; KQY202307//the Scientific Research and Innovation Project for Postgraduates of the Affiliated Stomatological Hospital of Chongqing Medical University/ ; CSTB2022NSCQ-MSX0794//Natural Science Foundation of Chongqing Municipality/ ; },
abstract = {AIM: The aim of this study was to elucidate the roles of miR-223-3p in orthodontically induced inflammatory root resorption (OIIRR).

METHODS: We used high-throughput miRNA sequencing and transcriptome sequencing to analyze the differentially expressed miRNAs and mRNAs in OCCM-30 cells under hypoxia. Real-time quantitative PCR (RT-qPCR) and Western blotting were used to assess the expression of genes and proteins related to apoptosis, oxidative stress, and mitochondrial dysfunction. Fluorescence staining was employed to detect changes in cellular ROS (reactive oxygen species), MMP (mitochondrial membrane potential), and mtROS (mitochondrial ROS) expression.

RESULTS: We found that miR-223-3p targeted FoxO3 to regulate apoptosis in cementoblasts under hypoxic conditions. Moreover, hypoxia-induced FoxO3 increased oxidative stress and induced mitochondrial dysfunction in cementoblasts, resulting in cell apoptosis. Administration of the ROS inhibitor NAC (N-acetyl cysteine) effectively reversed FoxO3-induced oxidative stress and mitochondrial dysfunction, thereby rescuing cell apoptosis.

CONCLUSIONS: miR-223-3p targets FoxO3 and regulates the apoptosis of cementoblasts by improving oxidative stress and mitochondrial dysfunction. These findings may offer new insights into the mechanism of OIIRR.},
}

@article {pmid40256695,
year = {2025},
author = {Narvekar, PS and Shivanand, S and Patil, S and Raikar, S and Mallick, A and Doddwad, PK},
title = {Dentinal tubule penetration of a silicone-based endodontic sealer following N-acetyl cysteine intracanal medicament removal using ultrasonic agitation and laser activated irrigation - An in vitro study.},
journal = {Journal of conservative dentistry and endodontics},
volume = {28},
number = {3},
pages = {231-236},
pmid = {40256695},
issn = {2950-4708},
abstract = {CONTEXT: The removal of intracanal medicament is essential for sealer penetration and the success of endodontic therapy.

AIMS: To evaluate and compare the dentinal tubule penetration of a silicone-based endodontic sealer following N-acetyl cysteine (NAC) intracanal medicament removal using ultrasonic agitation and laser-activated irrigation.

MATERIALS AND METHODS: Eighty-one extracted single-rooted mandibular premolars were decoronated and prepared with ProTaper Universal rotary files up to MAF F3. To prepare medicament, NAC powder was mixed with propylene glycol in the ratio of 1:1, placed using a size #30 Lentulospiral, and specimens stored in an incubator for 14 days. The specimens were then instrumented with #30 Hedström and divided into three groups according to final irrigant activation techniques: Group I: Diode laser activation, Group II: Passive Ultrasonic agitation, Group III: No agitation (positive control). Canals were obturated with GuttaFlow bioseal sealer mixed with 0.1% Rhodamine B dye and gutta-percha cones and incubated for 7 days. The specimens were sectioned horizontally to obtain 1 mm thick sections from 2, 5, and 8 mm from the apex. Sections were examined under Confocal Laser Scanning Microscope to measure the depth of sealer penetration (in µm).

STATISTICAL ANALYSIS: One-way analysis of variance and Tukeys multiple post hoc test.

RESULTS: The highest mean depth of penetration of 728.52 µm was seen with Group I, followed by Group II and least was seen in Group III.

CONCLUSIONS: Diode laser activation group was most effective in the removal of NAC intracanal medicament from all the three regions of the root canal.},
}

@article {pmid40253238,
year = {2025},
author = {Zhou, Q and Lin, J and Li, Q},
title = {Study of high-strength, low-shrinkage dental resin composites with bifunctional polysilsesquioxane.},
journal = {Dental materials : official publication of the Academy of Dental Materials},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.dental.2025.03.012},
pmid = {40253238},
issn = {1879-0097},
abstract = {OBJECTIVES: The aim of this study was to develop a new composite resin to solve the problem of volume shrinkage of conventional dental restorative composite resins during the curing process in order to improve their mechanical properties and reduce the risk of restoration failure.

METHODS: We synthesized the mercapto-alkenyl click chemical reaction product (MN-POSS) of acrylate-based POSS (MAP-POSS) with N-Acetylcysteine (NAC) using a bifunctional polysilsesquioxane modification technique and improved its dispersion in the resin matrix by physicochemical methods. In addition, methacrylate-based epoxy POSS (ME-POSS) was further synthesized and used to modify acrylate dental resins to form a free radical-cation hybrid light-curing system.

RESULTS: The results showed that the composites modified with MN-POSS significantly improved mechanical strength, while the application of ME-POSS effectively reduced polymerization shrinkage, improved the water absorption and dissolution properties of the materials, and enhanced mechanical properties and hardness. This study provides new ideas and material solutions to improve the performance of dental restorative materials.

SIGNIFICANCE: Both of these improved solutions demonstrate the potential of bifunctional POSS as a modified filler, providing new ideas and methods for the design of future dental restorative materials.},
}

@article {pmid40252905,
year = {2025},
author = {Ricardi, LL and Zecchinati, F and Perdomo, VG and Basiglio, CL and García, F and Arana, MR and Villanueva, SSM},
title = {Oxidative stress promotes post-translational down-regulation of MRP2 in Caco-2 Cells: involvement of proteasomal degradation and toxicological implications.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {115459},
doi = {10.1016/j.fct.2025.115459},
pmid = {40252905},
issn = {1873-6351},
abstract = {The intestinal tract is highly susceptible to oxidative stress (OS), which impairs gut barrier function. Multidrug Resistance-Associated Protein 2 (MRP2) is a key efflux pump in the intestinal transcellular barrier, regulating toxicant and drug disposition. We here evaluated the effects of OS on MRP2 in Caco-2 cells treated with tert-butyl hydroperoxide (TBH). After 24 h, TBH 250 μM increased ROS production and lipid peroxidation while decreasing GSH content and SOD activity, confirming OS induction. Under these conditions, total MRP2 protein levels decreased, while P-gp levels remained unchanged. Correspondingly, MRP2 efflux activity decreased, impairing barrier function against ochratoxin A (OTA), a substrate of MRP2, and exacerbating OTA toxicity. Localization analysis revealed reduced apical MRP2 signal in TBH 250 group, with unchanged mRNA levels, indicating post-transcriptional regulation. Mechanistically, TBH induced rapid MRP2 internalization (30 min), mediated by cPKC and clathrin, without microtubule involvement, followed by proteasomal degradation at 24 h. Both processes were dependent on GSH depletion, as treatment with N-Acetyl-L-Cysteine (NAC) restored GSH levels, MRP2 localization, and activity. We provide here the first evidence that human intestinal MRP2 is post-translationally downregulated under specific OS conditions, highlighting its potential role in exacerbating xenobiotic absorption and toxicity in OS-related human diseases.},
}

@article {pmid40251236,
year = {2025},
author = {Poojary, KK and Kunhiraman, JP and Madhvacharya, VV and Kumari, S and Krishna, N and S, SP and K, RG and Mutalik, S and Ghani, NK and Kabekkodu, SP and Prasad, TSK and Adiga, SK and Kalthur, G},
title = {Bromodomain and extraterminal protein inhibitor JQ1 induces maturation arrest and disrupts the cytoplasmic organization in mouse oocytes under in vitro conditions.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {13448},
pmid = {40251236},
issn = {2045-2322},
mesh = {Animals ; *Oocytes/drug effects/metabolism/cytology ; Mice ; *Azepines/pharmacology ; *Triazoles/pharmacology ; Female ; Endoplasmic Reticulum Chaperone BiP ; *Cytoplasm/drug effects/metabolism ; In Vitro Oocyte Maturation Techniques ; Oxidative Stress/drug effects ; Oogenesis/drug effects ; },
abstract = {JQ1, a small cell-permeable molecule is known for its potent inhibitory action on bromodomain and extraterminal (BET) proteins. Although earlier studies have shown its inhibitory effect on male gametogenesis, limited information is available about its influence on oocyte development. Since BET genes are known to exhibit regulatory functions on oocyte development and maturation, the present study aimed to investigate the effect of JQ1 on oocyte developmental competence under in vitro conditions. Germinal vesicle (GV) stage oocytes were collected from adult Swiss albino mice and subjected to in vitro maturation (IVM) in the presence of various concentrations of JQ1 (25, 50, and 100 μM). The metaphase II (MII) stage oocytes were assessed for cytoplasmic organization and functional competence at 24 h after IVM. A significant decrease in nuclear maturation (at 50 and 100 μM), symmetric cytokinesis, altered distribution of mitochondria and cortical granules, poorly organized actin and meiotic spindle, misaligned chromosomes, and elevated endoplasmic reticulum (ER) stress and oxidative stress was observed in JQ1-exposed oocytes. Presence of N-acetyl cysteine (NAC), in IVM medium resulted in significant reduction in JQ1-induced oxidative stress and symmetric cytokinesis. Administration of JQ1 (50 mg/kg, intra peritoneal) to adult Swiss albino mice primed with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) did not affect the ovulation. However, a high degree of oocyte degeneration, elevated intracellular reactive oxygen species (ROS), and GRP78 expression was observed in JQ1-administered mice. In conclusion, our study reveals that BET inhibitor JQ1 has detrimental effects on oocyte function and development.},
}

Animals
*Oocytes/drug effects/metabolism/cytology
Mice
*Azepines/pharmacology
*Triazoles/pharmacology
Female
Endoplasmic Reticulum Chaperone BiP
*Cytoplasm/drug effects/metabolism
In Vitro Oocyte Maturation Techniques
Oxidative Stress/drug effects
Oogenesis/drug effects

@article {pmid40243461,
year = {2025},
author = {Bilski, R and Nuszkiewicz, J},
title = {Antioxidant Therapies as Emerging Adjuncts in Rheumatoid Arthritis: Targeting Oxidative Stress to Enhance Treatment Outcomes.},
journal = {International journal of molecular sciences},
volume = {26},
number = {7},
pages = {},
pmid = {40243461},
issn = {1422-0067},
mesh = {Humans ; *Arthritis, Rheumatoid/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Antioxidants/therapeutic use/pharmacology ; Animals ; Reactive Oxygen Species/metabolism ; Antirheumatic Agents/therapeutic use/pharmacology ; Treatment Outcome ; },
abstract = {Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation and progressive joint destruction. Recent data underscore oxidative stress as a primary factor in the pathophysiology of rheumatoid arthritis, intensifying inflammatory processes and tissue damage via the overproduction of reactive oxygen species (ROS) and compromised antioxidant defenses. Current therapies, including disease-modifying antirheumatic drugs (DMARDs), primarily target immune dysregulation but fail to address oxidative stress, necessitating novel adjunctive treatment strategies. This review explores the potential of antioxidant-based therapies as complementary approaches to RA management. Natural compounds such as curcumin, resveratrol, sulforaphane, and propolis exhibit strong anti-inflammatory and antioxidative properties by modulating redox-sensitive pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase (HO-1). N-acetylcysteine (NAC) replenishes intracellular glutathione, enhancing cellular resilience against oxidative stress. Additionally, molecular hydrogen (H2) selectively neutralizes harmful ROS, reducing oxidative damage and inflammation. The role of vitamin supplementation (D, B12, C, and K) in regulating immune responses and protecting joint structures is also discussed. This review aims to evaluate the efficacy and potential clinical applications of antioxidant therapies in RA, emphasizing their role in mitigating oxidative damage and improving treatment outcomes. While preliminary findings are promising, further clinical trials are needed to establish standardized dosing, long-term safety, and their integration into current RA treatment protocols.},
}

Humans
*Arthritis, Rheumatoid/drug therapy/metabolism
*Oxidative Stress/drug effects
*Antioxidants/therapeutic use/pharmacology
Animals
Reactive Oxygen Species/metabolism
Antirheumatic Agents/therapeutic use/pharmacology
Treatment Outcome

@article {pmid40243112,
year = {2025},
author = {She, Z and Zeng, F and Wu, S},
title = {A zwitterionic chromophore as both a biomarker-activatable optical imaging probe and a therapeutic agent for the detection and treatment of acute lung injury with bacterial infection.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5bm00419e},
pmid = {40243112},
issn = {2047-4849},
abstract = {Acute lung injury (ALI), often complicated by bacterial infection, poses significant challenges in diagnosis and treatment. Nitric oxide (NO) plays a key role in the pathophysiology of ALI, making it an ideal biomarker for early detection. In this study, we developed a zwitterionic chromophore, ZW-N, designed as both a biomarker-activatable imaging probe and a therapeutic agent for ALI with bacterial infection. The chromophore ZW-N integrates quaternary ammonium groups for antimicrobial activity and zwitterionic sulfonate groups to enhance biocompatibility and water solubility. Built on a flexible propanyl linker that couples two heptamethine cyanine dyes, ZW-N enables biomarker-responsive dual-modal imaging via optoacoustic (OA) imaging and near-infrared second-window (NIR-II) fluorescence imaging. Moreover, the chromophore ZW-N demonstrates therapeutic efficacy when combined with the clinically used antioxidant N-acetylcysteine (NAC) to treat ALI with bacterial infection. This dual-functional chromophore offers a promising platform for non-invasive, real-time monitoring of ALI, providing significant potential for improved detection and a more effective treatment strategy.},
}

@article {pmid40240934,
year = {2025},
author = {Kim, JH and Lee, JH and Koo, YJ and Song, JW},
title = {N-actylcysteine inhibits diethyl phthalate-induced inflammation via JNK and STAT pathway in RAW264.7 macrophages.},
journal = {BMC molecular and cell biology},
volume = {26},
number = {1},
pages = {12},
pmid = {40240934},
issn = {2661-8850},
support = {2022R1I1A1A01068466//National Research Foundation of Korea/ ; 2022R1A2C1011500//National Research Foundation of Korea/ ; 2022R1F1A1075191//National Research Foundation of Korea/ ; },
mesh = {Animals ; Mice ; RAW 264.7 Cells ; *Phthalic Acids/toxicity ; *Macrophages/drug effects/metabolism ; *Inflammation/chemically induced/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; Cyclooxygenase 2/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Glutathione/metabolism ; Dinoprostone/metabolism ; *MAP Kinase Signaling System/drug effects ; Nitric Oxide/metabolism ; Signal Transduction/drug effects ; *STAT Transcription Factors/metabolism ; STAT3 Transcription Factor/metabolism ; *Acetylcysteine/pharmacology ; },
abstract = {BACKGROUND: Phthalates are plasticizers that cause inflammation in several cell types and adversely affect the health of humans and animals. Nacetylcysteine (NAC) has been shown to exert antioxidant effects in various diseases. However, the effect of NAC on diethyl phthalate (DEP)-induced toxicity in macrophages has not yet been elucidated. In this study, we investigated the effect and underlying mechanisms of NAC on DEP-induced inflammation in RAW264.7 macrophages. RAW264.7 macrophages were pretreated with NAC for 2 h followed by exposure to DEP. We investigated the effect of NAC on NO, reactive oxygen species (ROS), prostaglandin E2 (PGE2), and glutathione (GSH) levels following DEP exposure. In addition, pathway-related genes including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription (STAT) were evaluated using western blot.

RESULTS: Treatment with 100 and 300 µM DEHP, DBP, and DEP significantly increased the protein levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) compared with those in the control group. However, NAC pretreatment downregulated the levels of NO, PGE2, and ROS, elevated GSH levels, and suppressed the mRNA levels of inflammatory cytokines such as interleukin (IL)-1β, IL-6, COX-2, and iNOS compared with those in the DEP-treated group. In addition, NAC significantly reduced the levels of p-JNK and p-STAT1/3 in RAW264.7 macrophages treated with DEP.

CONCLUSIONS: NAC pretreatment inhibits DEP-induced inflammation via the MAPK/JNK and STAT1/3 pathways in macrophages.},
}

Animals
Mice
RAW 264.7 Cells
*Phthalic Acids/toxicity
*Macrophages/drug effects/metabolism
*Inflammation/chemically induced/metabolism/drug therapy
Reactive Oxygen Species/metabolism
Cyclooxygenase 2/metabolism
Nitric Oxide Synthase Type II/metabolism
Glutathione/metabolism
Dinoprostone/metabolism
*MAP Kinase Signaling System/drug effects
Nitric Oxide/metabolism
Signal Transduction/drug effects
*STAT Transcription Factors/metabolism
STAT3 Transcription Factor/metabolism
*Acetylcysteine/pharmacology

@article {pmid40236464,
year = {2024},
author = {Wu, J and Maller, B and Kaul, R and Galabow, A and Bryan, A and Neuwelt, A},
title = {High-Dose Acetaminophen as a Treatment for Cancer.},
journal = {Livers},
volume = {4},
number = {1},
pages = {84-91},
pmid = {40236464},
issn = {2673-4389},
support = {IK2 BX004914/BX/BLRD VA/United States ; },
abstract = {The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity-in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent "reverse translational" studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted.},
}

@article {pmid40235406,
year = {2025},
author = {Yildirim, B and Erturk, C and Buyukdogan, H and Saritas, TB and Yildirim Erdogan, N and Ertem, F},
title = {Effect of N-acetylcysteine on fracture healing in rat femoral diaphysis: A histopathological, radiological, and biomechanical analysis.},
journal = {Joint diseases and related surgery},
volume = {36},
number = {2},
pages = {283-292},
doi = {10.52312/jdrs.2025.1975},
pmid = {40235406},
issn = {2687-4792},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; Rats, Wistar ; *Fracture Healing/drug effects ; *Femoral Fractures/diagnostic imaging/pathology/physiopathology/drug therapy/surgery ; Rats ; Diaphyses/diagnostic imaging/drug effects/pathology/injuries ; Biomechanical Phenomena ; Disease Models, Animal ; *Antioxidants/pharmacology ; *Femur/diagnostic imaging/drug effects/pathology/physiopathology ; Radiography ; },
abstract = {OBJECTIVES: The aim of this study was to examine the effect of N-acetylcysteine (NAC), which has antioxidant properties, on healing in a rat femoral diaphysis fracture model.

MATERIALS AND METHODS: Twenty-four male Wistar-Hannover rats were randomly divided into two groups: experimental (n=12) and control groups (n=12). An open femur fracture model (osteotomy) was applied to the right femora of both groups. Fixation was performed with Kirschner wire. While intraperitoneal NAC treatment was given to the experimental group for 21 days after surgery, an equal volume of intraperitoneal saline injection was administered to the control group. At the end of this period, the femurs obtained from the sacrificed animals were examined histopathologically, radiologically, and biomechanically. Huo scoring was used for histopathological examination. The samples were examined radiologically according to the Radiographic Union Scale in Tibial Fractures (RUST) scoring system. The three-point bending test was used for the biomechanical examination.

RESULTS: According to the third-week results, NAC could histopathologically contribute positively to fracture healing in rats (p=0.003 and p<0.05, respectively). Considering radiological and biomechanical parameters, no significant difference was observed between the groups in terms of healing (p>0.05). However, a positive significant correlation (67.7%) was found between histopathological results and radiological findings (p=0.016 and p<0.05, respectively).

CONCLUSION: Our study results indicate that NAC may have a histopathologically positive effect on the healing process in rat traumatic fractures. Based on these findings, NAC preparations may be used as a supportive agent in the treatment of fractures. Further clinical studies are needed.},
}

Animals
*Acetylcysteine/pharmacology
Male
Rats, Wistar
*Fracture Healing/drug effects
*Femoral Fractures/diagnostic imaging/pathology/physiopathology/drug therapy/surgery
Rats
Diaphyses/diagnostic imaging/drug effects/pathology/injuries
Biomechanical Phenomena
Disease Models, Animal
*Antioxidants/pharmacology
*Femur/diagnostic imaging/drug effects/pathology/physiopathology
Radiography

@article {pmid40229128,
year = {2025},
author = {Li, P and Meng, X and Lu, T and Sun, C and Song, G},
title = {Synergistic Effect of ROS and p38 MAPK in Apoptosis of TM4 Cells Induced by Titanium Dioxide Nanoparticles.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4789},
pmid = {40229128},
issn = {1099-1263},
support = {82460651//National Natural Science Foundation of China/ ; 21966027//National Natural Science Foundation of China/ ; 2023AB049//Science and Technology Planning Project of Xinjiang Production and Construction Corps/ ; },
abstract = {The adverse effects of titanium dioxide nanoparticles (TiO2 NPs) on the integrity of the blood-testis barrier (BTB) are widely recognized. However, the underlying mechanisms remain incompletely understood. The integrity of the BTB is imperative for the preservation of male reproductive health. TM4 cells, which are major component of the BTB, play a critical role in its integrity. The apoptosis of TM4 cells is closely associated with the disruption of the BTB. Therefore, we selected TM4 cells as experimental models to investigate the apoptosis induced by TiO2 NPs and the underlying mechanisms. Cell viability, excessive production of reactive oxygen species (ROS), activation of p38 mitogen-activated protein kinase (MAPK) pathway, and apoptosis-related protein expression levels were determined under various concentrations (50, 100, 150, and 200 μg/mL) of TiO2 NPs exposure. The results indicate that TiO2 NPs induced the overproduction of ROS and activated the p38 MAPK signaling pathway, which subsequently led to apoptosis. The ROS scavenger N-acetylcysteine (NAC) was able to suppress the activation of p38 MAPK pathway induced by TiO2 NPs, while the p38 MAPK inhibitor SB203580 mitigated TiO2 NPs-induced ROS overproduction and subsequent apoptosis, suggesting an interplay between ROS overproduction and p38 MAPK pathway activation. In summary, TiO2 NPs induced mitochondrial apoptosis via the ROS-p38 MAPK axis. A positive feedback regulatory mechanism exists between the two processes, promoting apoptosis in TM4 cells through a synergistic effect.},
}

@article {pmid40227392,
year = {2025},
author = {Amador-Martínez, I and Aparicio-Trejo, OE and Aranda-Rivera, AK and Bernabe-Yepes, B and Medina-Campos, ON and Tapia, E and Cortés-González, CC and Silva-Palacios, A and Roldán, FJ and León-Contreras, JC and Hernández-Pando, R and Saavedra, E and Gonzaga-Sánchez, JG and Ceja-Galicia, ZA and Sánchez-Lozada, LG and Pedraza-Chaverri, J},
title = {Effect of N-Acetylcysteine in Mitochondrial Function, Redox Signaling, and Sirtuin 3 Levels in the Heart During Cardiorenal Syndrome Type 4 Development.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {3},
pages = {},
pmid = {40227392},
issn = {2076-3921},
support = {CBF2023-2024-190//CONAHCYT/ ; IN200922 and IN202725//PAPIIT-UNAM/ ; 21-1250//Instituto Nacional de Cardiología Ignacio Chávez/ ; },
abstract = {Type 4 cardiorenal syndrome (CRS-4) is a pathology in which chronic kidney disease (CKD) triggers the development of cardiovascular disease. CKD pathophysiology produces alterations that can affect the bioenergetics of heart mitochondria, causing oxidative stress and reducing antioxidant glutathione (GSH) levels. GSH depletion alters protein function by affecting post-translational modifications such as S-glutathionylation (RS-SG), exacerbating oxidative stress, and mitochondrial dysfunction. On the other hand, N-acetylcysteine (NAC) is an antioxidant GSH precursor that modulates oxidative stress and RS-SG. Moreover, recent studies have found that NAC can activate the Sirtuin 3 (SIRT3) deacetylase in diseases. However, the role of NAC and its effects on mitochondrial function, redox signaling, and SIRT3 modifications in the heart during CRS-4 have not been studied. This study aimed to investigate the role of NAC in mitochondrial function, redox signaling, and SIRT3 in the hearts of animals with CRS-4 at two months of follow-up. Our results showed that the oral administration of NAC (600 mg/kg/day) improved blood pressure and reduced cardiac fibrosis. NACs' protective effect was associated with preserving cardiac mitochondrial bioenergetics and decreasing these organelles' hydrogen peroxide (H2O2) production. Additionally, NAC increased GSH levels in heart mitochondria and regulated the redox state, which coincided with an increase in nicotinamide adenine dinucleotide oxidized (NAD[+]) levels and a decrease in mitochondrial acetylated lysines. Finally, NAC increased SIRT3 levels and the activity of superoxide dismutase 2 (SOD-2) in the heart. Thus, treatment with NAC decreases mitochondrial alterations, restores redox signaling, and decreases SIRT3 disturbances during CRS-4 through an antioxidant defense mechanism.},
}

@article {pmid40220949,
year = {2025},
author = {Sztolsztener, K and Michalak, D and Chabowski, A},
title = {N-acetylcysteine influence on PI3K/Akt/mTOR and sphingolipid pathways in rats with MASLD induced by HFD: a promising new therapeutic purpose.},
journal = {Molecular and cellular endocrinology},
volume = {603},
number = {},
pages = {112545},
doi = {10.1016/j.mce.2025.112545},
pmid = {40220949},
issn = {1872-8057},
abstract = {Sphingolipid and glucose metabolism play important roles in the induction and progression of severe liver disorders like metabolic dysfunction-associated steatotic liver disease (MASLD). The perturbation in sphingolipid formation may improve the liver structure and functioning and may constitute the potential therapeutic options for the development of simple steatosis and its progression to steatohepatitis. This study aims to assess the influence of N-acetylcysteine (NAC) on the sphingolipid and insulin signaling pathways in rats subjected to standard or high-fat diets. Sphingolipid level was measured using high-performance liquid chromatography (HPLC). A multiplex assay kit determined the level of phosphorylated form of proteins included in the PI3K/Akt/mTOR pathway. The immunoblotting estimated the expression of proteins from sphingolipid and insulin transduction pathways. A histological Oil red O staining was used to assess the hepatic accumulation of lipid droplets. Molecular docking was applied to showcase NAC interaction with PI3K/Akt/mTOR pathway proteins. NAC decreased dihydroceramide and ceramide levels and increased phosphorylation of sphingosine and sphinganine. This antioxidant also enhanced phosphorylated Akt, GSK3α/β, and P70 S6 kinase and decreased phosphorylated S6RP. In silico docking analysis of insulin signaling molecules evidenced the higher binding affinity of NAC with all tested proteins, i.e., IRS1, PTEN, Akt, GSK3α/β, P70 S6 kinase, and S6RP, suggesting a potential protective influence on insulin resistance development, which is one of the criteria for MASLD diagnosing. Based on these data, NAC improved the hepatic insulin sensitivity and sphingolipid synthesis and storage, improving and restoring glucose homeostasis.},
}

@article {pmid40220169,
year = {2025},
author = {Ciftel, E and Mercantepe, T and Ciftel, S and Karakas, SM and Aktepe, R and Yilmaz, A and Mercantepe, F},
title = {Somatostatin and N-acetylcysteine on testicular damage triggered by ischemia reperfusion: cellular protection and antioxidant effects.},
journal = {Hormones (Athens, Greece)},
volume = {},
number = {},
pages = {},
pmid = {40220169},
issn = {2520-8721},
abstract = {Ischemia-reperfusion (I/R) injury is a significant cause of testicular damage, leading to infertility and other reproductive dysfunctions. Antioxidant therapies have emerged as a potential intervention to mitigate oxidative stress and cellular damage. This study investigates the effects of somatostatin (SST) and N-acetylcysteine (NAC) on testicular damage induced by I/R, focusing on their antioxidant and cellular protective effects. Twenty-four male rats were divided into four groups, as follows: sham operated, I/R injury, I/R + somatostatin treatment, and I/R + NAC treatment. A testicular I/R injury was induced surgically, followed by either SST or NAC administration. Testicular tissues were assessed histopathologically using hematoxylin and eosin staining and employing Johnson's biopsy scoring. Immunohistochemical analyses were performed for caspase- 3, 8-hydroxy- 2'-deoxyguanosine (8-OHdG), testis-specific histone 2B, and testosterone to evaluate apoptosis, oxidative DNA damage, cellular proliferation, and steroidogenesis, respectively. Serum levels of testosterone and follicle-stimulating hormone (FSH) were measured by biochemical analysis. The results showed that both SST and NAC treatments significantly ameliorated histopathological damage and reduced the levels of caspase- 3 and 8-OHdG, indicating reduced apoptosis and oxidative DNA damage. Furthermore, increased testis-specific histone 2B positivity suggested enhanced cellular proliferation. Notably, administration of SST decreased testosterone positivity in the testis, whereas NAC treatment increased it. However, no significant differences in serum testosterone levels were observed between the NAC and SST groups. In addition, serum FSH levels of the I/R + SST group were found to be significantly higher than those of the control group. SST and NAC exhibit protective effects against testicular damage induced by I/R, as evidenced by their antioxidant and anti-apoptotic properties. The differential impact on testosterone positivity in the testis tissue highlights distinct underlying mechanisms, warranting further investigation. Despite these promising findings, the lack of significant changes in serum hormone levels calls for additional studies to fully elucidate the therapeutic potential and mechanistic pathways of SST and NAC in the context of testicular I/R injury.},
}

@article {pmid40218498,
year = {2025},
author = {Jensch, H and Setford, S and Thomé, N and Srikanthamoorthy, G and Weingärtner, L and Grady, M and Holt, E and Pfützner, A},
title = {Dynamic Interference Testing-Unexpected Results Obtained with the Abbott Libre 2 and Dexcom G6 Continuous Glucose Monitoring Devices.},
journal = {Sensors (Basel, Switzerland)},
volume = {25},
number = {7},
pages = {},
pmid = {40218498},
issn = {1424-8220},
support = {951933 (ForgetDiabetes)//European Union's Horizon 2020 research and innovation program/ ; Unrestricted grant//Lifescan Global Corp./ ; },
mesh = {*Blood Glucose Self-Monitoring/instrumentation/methods ; Humans ; *Blood Glucose/analysis ; *Biosensing Techniques/methods ; Continuous Glucose Monitoring ; },
abstract = {BACKGROUND: Sensors for continuous glucose monitoring (CGM) are now commonly used by people with type 1 and type 2 diabetes. However, the response of these devices to potentially interfering nutritional, pharmaceutical, or endogenous substances is barely explored. We previously developed an in vitro test method for continuous and dynamic CGM interference testing and herein explore the sensitivity of the Abbott Libre2 (L2) and Dexcom G6 (G6) sensors to a panel of 68 individual substances.

METHODS: In each interference experiment, L2 and G6 sensors were exposed in triplicate to substance gradients from zero to supraphysiological concentrations at a stable glucose concentration of 200 mg/dL. YSI Stat 2300 Plus was used as the glucose reference method. Interference was presumed if the CGM sensors showed a mean bias of at least ±10% from baseline with a tested substance at any given substance concentration.

RESULTS: Both L2 and G6 sensors showed interference with the following substances: dithiothreitol (maximal bias from baseline: L2/G6: +46%/-18%), galactose (>+100%/+17%), mannose (>+100%/+20%), and N-acetyl-cysteine (+11%/+18%). The following substances were found to interfere with L2 sensors only: ascorbic acid (+48%), ibuprofen (+14%), icodextrin (+10%), methyldopa (+16%), red wine (+12%), and xylose (>+100%). On the other hand, the following substances were found to interfere with G6 sensors only: acetaminophen (>+100%), ethyl alcohol (+12%), gentisic acid (+18%), hydroxyurea (>+100%), l-cysteine (-25%), l-Dopa (+11%), and uric acid (+33%). Additionally, G6 sensors could subsequently not be calibrated for use after exposure to dithiothreitol, gentisic acid, l-cysteine, and mesalazine (sensor fouling).

CONCLUSIONS: Our standardized dynamic interference testing protocol identified several nutritional, pharmaceutical and endogenous substances that substantially influenced L2 and G6 sensor signals. Clinical trials are now necessary to investigate whether our findings are of relevance during routine care.},
}

*Blood Glucose Self-Monitoring/instrumentation/methods
Humans
*Blood Glucose/analysis
*Biosensing Techniques/methods
Continuous Glucose Monitoring

@article {pmid40207512,
year = {2025},
author = {Zhou, Y and Sha, J and Xu, B and Zhang, K and Wang, Y and Jiang, S and Zhang, H and Xu, S},
title = {Identification and Characterization of Dacomitinib Metabolites in Rats by Liquid Chromatography Combined With Q-Exactive-Orbitrap High Resolution Mass Spectrometry.},
journal = {Biomedical chromatography : BMC},
volume = {39},
number = {5},
pages = {e70075},
doi = {10.1002/bmc.70075},
pmid = {40207512},
issn = {1099-0801},
mesh = {Animals ; Rats ; Microsomes, Liver/metabolism ; Rats, Sprague-Dawley ; Chromatography, Liquid/methods ; *Quinazolinones/metabolism/analysis/chemistry/urine/pharmacokinetics ; Male ; *Mass Spectrometry/methods ; Tandem Mass Spectrometry/methods ; },
abstract = {Dacomitinib is an irreversible inhibitor targeting epidermal growth factor receptor, which has been developed for the treatment of metastatic non-small cell lung cancer (NSCLC). The aim of this study was to establish a reliable liquid chromatography combined with high resolution mass spectrometric method to identify and characterize the metabolites of dacomitinib in rats. In vitro metabolism was investigated through 60-min incubation with rat liver microsomes, while in vivo analysis involved bile and urine sample collection following a single oral 10 mg/kg dose. A total of 18 metabolites, were structurally elucidated through accurate MS measurements, MS[2] spectral interpretation, and fragmentation pattern analysis, including two GSH conjugates and two N-acetyl-cysteine conjugates. Among these metabolites, a total of 12 metabolites were first reported, i.e., M1, M2, M3, M7, M9, M10, M11, M13, M14, M15, M16, and M17. The parent drug remained the predominant species across all metrices. The primary metabolic pathways included: oxidative defluorination, O-demethylation, N-dealkylation, oxidative deamination, piperidin ring opening, N-oxygenation, lactam formation, dehydrogenation, and hydroxylation. Phase II biotransformation pathways included GSH conjugation and N-acetyl-cysteine conjugation. These findings enhance understanding of dacomitinib's metabolic fate, providing critical insights into its elimination mechanisms, and supporting subsequent evaluation of therapeutic efficacy and safety profiles.},
}

Animals
Rats
Microsomes, Liver/metabolism
Rats, Sprague-Dawley
Chromatography, Liquid/methods
*Quinazolinones/metabolism/analysis/chemistry/urine/pharmacokinetics
Male
*Mass Spectrometry/methods
Tandem Mass Spectrometry/methods

@article {pmid40207489,
year = {2025},
author = {Efati, M and Sahebkar, A and Tavallaei, S and Alidadi, S and Hosseini, H and Hamidi-Alamdari, D},
title = {Protective effect of Leuco-methylene blue against acetaminophen-induced liver injury: an experimental study.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/01480545.2025.2485347},
pmid = {40207489},
issn = {1525-6014},
abstract = {Acetaminophen is a commonly used drug for mild to moderate pain relief; however, acetaminophen toxicity due to the formation of toxic metabolites is a major cause of drug-induced liver injury. Methylene blue is an FDA-approved drug for the treatment of methemoglobinemia and has potential applications in the treatment of carbon monoxide and cyanide poisoning. Leuco-methylene blue, a colorless form of methylene blue, is more effective in entering cells and counteracting oxidative stress, making it a valuable option in regulating mitochondrial function and ATP production. In this study, we aimed to evaluate the effect of LMB on liver damage caused by acetaminophen toxicity. Thirty-six rats were divided into six groups: control, APAP, NAC, LMB, MB, and NAC+LMB. All groups except the control received acetaminophen (1500 mg/kg), followed by treatments with NAC (100 mg/kg), LMB (5 mg/kg), MB (5 mg/kg), and NAC+LMB after 3 hours. The rats were sacrificed 24 hours post-acetaminophen administration. LMB significantly reduced serum levels of liver enzymes (ALT, AST, and ALP) and increased the expression of genes involved in mitochondrial biogenesis and antioxidant defense (PGC-1, Nrf2, and Tfam). Additionally, LMB significantly increased total antioxidant capacity and glutathione reductase levels, decreased the prooxidant-antioxidant balance (PAB), and reduced the expression of inflammatory cytokines (IL-6 and TNF-α) in the liver tissue. LMB effectively reduced the severity of acetaminophen-induced liver damage through antioxidant and anti-inflammatory effects. LMB can effectively ameliorate APAP-induced toxicity in rats, with comparable efficacy to N-acetylcysteine with respect to most complications of acetaminophen-induced toxicity in rats.},
}

@article {pmid40205270,
year = {2025},
author = {Gouda, AR and El-Bassiouny, NA and Salahuddin, A and Hamouda, EH and Kassem, AB},
title = {Repurposing of high-dose N-acetylcysteine as anti-inflammatory, antioxidant and neuroprotective agent in moderate to severe traumatic brain injury patients: a randomized controlled trial.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40205270},
issn = {1568-5608},
abstract = {INTRODUCTION: Traumatic brain injury (TBI) refers to an impact of the brain within the skull resulting in an altered mental state. The study aim is to determine the effect of a high dose of N-acetylcysteine (NAC) on biochemical and inflammatory markers of neuronal damage and clinical outcomes in patients with moderate to severe TBI.

METHODS: A randomized open label-controlled trial was conducted on 40 patients with moderate to severe TBI patients presented to the emergency unit within < 24 h since the trauma occurred and randomized into NAC and control groups 20 patients each. Serum samples for evaluation of biomarkers: malondialdehyde (MDA), interleukin-6 (IL-6), neuron-specific enolase (NSE), and S100B were withdrawn at baseline and on day 7. The patients were followed for 7 days and evaluated clinically by the Glasgow Coma Scale (GCS).

RESULTS: There was a significant decrease in NSE and MDA levels on day 7 from baseline in NAC group (p < 0.001 and p < 0.001). Also, S100B and IL-6 decreased significantly in NAC group on day 7 from baseline (p = 0.003 and p < 0.001 consequently) compared to control group. Moreover, patients in NAC group showed a significantly shorter length of stay at intensive care unit (ICU) (p = 0.038). There was a significant increase in GCS in NAC group on day 7 from baseline (p = 0.001).

CONCLUSION: Adjunctive early use of high-dose NAC significantly reduced inflammatory and oxidative markers and had neuroprotective effect which may be a novel treatment option for moderate to severe TBI patients.

TRIAL REGISTRATION: Pactr.org identifier: (PACTR202209548995270) on 14 September 2022.},
}

@article {pmid40202448,
year = {2025},
author = {Ommi, NB and Mattocks, DAL and Kalecký, K and Bottiglieri, T and Nichenametla, SN},
title = {Pharmacological recapitulation of the lean phenotype induced by the lifespan-extending sulfur amino acid-restricted diet.},
journal = {Aging},
volume = {17},
number = {},
pages = {},
doi = {10.18632/aging.206237},
pmid = {40202448},
issn = {1945-4589},
abstract = {Sulfur amino acid restriction (SAAR), lowering the dietary concentration of sulfur amino acids methionine and cysteine, induces strong anti-obesity effects in rodents. Due to difficulties in formulating the SAAR diet for human consumption, its translation is challenging. Since our previous studies suggest a mechanistic role for low glutathione (GSH) in SAAR-induced anti-obesity effects, we investigated if the pharmacological lowering of GSH recapitulates the lean phenotype in mice on a sulfur amino acid-replete diet. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (CD), 0.12% methionine (SAAR), SAAR diet supplemented with a GSH biosynthetic precursor, N-acetylcysteine in water (NAC), and CD supplemented with a GSH biosynthetic inhibitor, DL-buthionine-(S, R)-sulfoximine in water (BSO). The SAAR diet lowered hepatic GSH but increased Nrf2, Phgdh, and serine. These molecular changes culminated in lower hepatic lipid droplet frequency, epididymal fat depot weights, and body fat mass; NAC reversed all these changes. BSO mice exhibited all SAAR-induced changes, with two notable differences, i.e., a smaller effect size than that of the SAAR diet and a higher predilection for molecular changes in kidneys than in the liver. Metabolomics data indicate that BSO and the SAAR diet induce similar changes in the kidney. Unaltered plasma aspartate and alanine transaminases and cystatin-C indicate that long-term continuous administration of BSO is safe. Data demonstrate that BSO recapitulates the SAAR-induced anti-obesity effects and that GSH plays a mechanistic role. BSO dose-response studies in animals and pilot studies in humans to combat obesity are highly warranted.},
}

@article {pmid40201900,
year = {2025},
author = {Hu, X and Wu, JL and He, Q and Xiong, ZQ and Li, N},
title = {Strategy for cysteine-targeting covalent inhibitors screening using in-house database based LC-MS/MS and drug repurposing.},
journal = {Journal of pharmaceutical analysis},
volume = {15},
number = {3},
pages = {101045},
pmid = {40201900},
issn = {2214-0883},
abstract = {Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.},
}

@article {pmid40200382,
year = {2025},
author = {Kasai, H and Kawai, K and Fujisawa, K},
title = {Formation of the toxic furan metabolite 2-butene-1,4-dial through hemin-induced degradation of 2,4-alkadienals in fried foods.},
journal = {Genes and environment : the official journal of the Japanese Environmental Mutagen Society},
volume = {47},
number = {1},
pages = {8},
pmid = {40200382},
issn = {1880-7046},
abstract = {BACKGROUND: The mechanism of protein modification by 2,4-alkadienals (ADE), lipid peroxidation products prevalent in fried foods, was investigated through model reactions.

RESULTS: A mixture of 2,4-heptadienal (HDE) and hemin was initially incubated at pH 3.0-7.4, followed by treatment with acetyl-cysteine (AcCys) and acetyl-lysine (AcLys) at pH 7.4. Analysis via HPLC revealed a product with a characteristic UV spectrum as the primary peak. This product was identified as an AcCys-pyrrole-AcLys (CPL) crosslink derived from AcCys, 2-butene-1,4-dial (BDA), and AcLys. Increasing the HDE concentration in the initial reaction led to maximum CPL formation at pH 3.5 in the presence of hemin. Lowering the HDE concentration with a higher Cys/HDE ratio resulted in CPL formation, which was observed at pH 7.4 and 3.5 in the presence of hemin. Upon incubation of ADE and hemin at pH 3.0-3.5, BDA was directly identified as 2,4-dinitrophenylhydrazone. BDA was also detected in the 2,4-decadienal reaction mixture. Additionally, a notable propensity for high BDA-dC adduct formation with hemin under acidic conditions was observed, consistent with the results of CPL assay and BDA-2,4-dinitrophenylhydrazone analysis.

CONCLUSIONS: 1) BDA is efficiently generated from ADE in the presence of hemin under gastric conditions, and 2) BDA-derived CPL can also form under physiological conditions (pH 7.4) through the interaction of ADE, hemin, Cys, and Lys. BDA is recognized as the primary reactive metabolite of the suspected carcinogen furan (IARC, 2B). Given that human intake of ADE exceeds that of furan and acrylamide (IARC 2A) by several orders of magnitude, and the estimated hemin concentration in the stomach post-meal is comparable to the present study, a substantial amount of BDA may form in the stomach following consumption of fried foods and meat. The risk assessment of ADE warrants a thorough re-evaluation, based on the toxicity mechanism of BDA.},
}

@article {pmid40199136,
year = {2025},
author = {Chuang, YT and Liu, W and Chien, TM and Cheng, YB and Jeng, JH and Chen, CY and Tang, JY and Chang, HW},
title = {Antiproliferative and apoptotic effects of (1R*,12R*)-dolabella-4(16),7,10-triene-3,13-dione (CI-A) in oral cancer cells are mediated by oxidative stress and ERK activation.},
journal = {International immunopharmacology},
volume = {155},
number = {},
pages = {114615},
doi = {10.1016/j.intimp.2025.114615},
pmid = {40199136},
issn = {1878-1705},
abstract = {The anticancer effects and mechanisms of the main component (CI-A) of methanol extracts of Clavularia inflat have not been reported. This study explores the anti-oral cancer effect and mechanism of (1R*,12R*)-dolabella-4(16),7,10-triene-3,13-dione (CI-A) and compared with normal cells. CI-A shows oxidative-stress-dependent preferential antiproliferation of oral cancer cells without normal cell toxicity. CI-A triggers cell cycle dysregulation, apoptosis/caspase activation, cellular/mitochondrial ROS induction, glutathione depletion, and oxidative DNA damage in oral cancer but not normal cells. After testing with three MAPK (p38, JNK, and ERK) inhibitors, only the ERK inhibitor (PD98059) protects against CI-A-induced antiproliferation in oral cancer cells. CI-A upregulates phosphorylated ERK in oral cancer cells compared to normal cells. Notably, a ROS inhibitor, N-acetylcysteine (NAC), attenuates all CI-A-modulated changes. Moreover, the CI-A-triggered annexin V-detected apoptosis and caspase 3/8/9 activations of oral cancer cells were downregulated by PD98059. In conclusion, CI-A induces the oxidative-stress- and ERK-dependent antiproliferative and apoptotic mechanism in oral cancer cells and shows the benefit of non-cytotoxicity to normal cells.},
}

@article {pmid40199010,
year = {2025},
author = {Ashraf, R and Khalid, Z and Qin, QP and Iqbal, MA and Taskin-Tok, T and Bayil, İ and Quah, CK and Daud, NAM and Alqahtany, FZ and Amin, MA and El-Bahy, SM},
title = {Synthesis of N-heterocyclic carbene‑selenium complexes modulating apoptosis and autophagy in cancer cells: Probing the interactions with biomolecules and enzymes.},
journal = {Bioorganic chemistry},
volume = {160},
number = {},
pages = {108435},
doi = {10.1016/j.bioorg.2025.108435},
pmid = {40199010},
issn = {1090-2120},
abstract = {Growing cancer resistance is a global threat that calls for development of newer chemotherapeutic analogues especially targeted based therapy to enhance efficacy and selectivity. In this contribution, herein, we report synthesis of selenium incorporated N-heterocyclic carbene (NHC) compounds to explore their potential cytotoxicity against HeLa cells. Test compounds were assured for suitability as drug candidates through physiochemical properties that showed lipophilicity logP 0.85-1.45 for C1-C3 and found stable in biological media (DMEM), whereas, least reactive with N-acetyl cysteine (NAC) and L-glutathione. All the studied compounds showed good cytotoxicity against various cancer strains while compound C1 [3,3-(hexane-1,6-diyl)bis(1-phenethyl-1H-imidazole-2(3H)-selenone)] and C2 [3,3-(hexane-1,6-diyl)bis(1-decyl-1H-imidazole-2(3H)-selenone)] showed promising results with IC50 values of 14.65 ± 0.66 and 8.05 ± 0.35 μg/mL respectively as compared to positive control 21.5 ± 0.05 μg/mL against HeLa cell lines. These compounds showed six-fold higher apoptosis than control with higher accumulation of Ca[+] ions intracellularly that alters the expression level of autophagy proteins and increased capase-9 activity. Cell cycle analysis indicated an arrest of cycle in G1 phase of HeLa cells when treated with C1 & C2. Test compounds showed prominent affinity for binding with DNA and inhibiting thioredoxin reductase enzymes in time dependent manners. These findings indicate that Selenium NHC compounds are promising drug candidates to induce cytotoxicity via apoptosis, autophagy and mitochondrial membrane disruptions to manage tumor growth.},
}

@article {pmid40188524,
year = {2025},
author = {Yang, W and Wang, F and Liu, J and Wang, X and Zhang, H and Gao, D and Wang, A and Jin, Y and Chen, H},
title = {β-Hydroxybutyrate aggravates LPS-induced inflammatory response in bovine endometrial epithelial cells by activating the oxidative stress/NF-κB signaling pathway.},
journal = {International immunopharmacology},
volume = {154},
number = {},
pages = {114609},
doi = {10.1016/j.intimp.2025.114609},
pmid = {40188524},
issn = {1878-1705},
abstract = {Ketosis, a metabolic disorder characterized by elevated levels of ketone bodies in the blood or urine, is known to impair the health and productivity of dairy cows, leading to substantial economic losses in the dairy industry. When ketosis occurs in dairy cows, the levels of β-hydroxybutyrate (BHBA), an abundant form of ketone bodies, in the blood increase significantly. Elevated BHBA levels have been shown to negatively impact reproductive performance and increase the incidence of periparturient diseases in dairy cows, including mastitis and endometritis. However, the role of BHBA in the development of endometritis in dairy cows and its underlying mechanisms remain largely unclear. The present study was designed to investigate the specific role of BHBA in the development of endometritis using an inflammatory response model of the bovine endometrial epithelial cell line (BENDs). Escherichia coli lipopolysaccharide (LPS) treatment (1 μg/mL) significantly increased the expression levels of interleukin (IL)-6 and IL-1β, as well as the phosphorylation of p65 and IκB in BENDs. In addition, co-treatment with BHBA (2.4 mM) and LPS (1 μg/mL) significantly increased the expression levels of proinflammatory cytokines (IL-6, IL-1β, and IL-8), as well as the phosphorylation of p65 and IκB, compared to the LPS-only treatment group. Immunofluorescence staining showed that the addition of LPS altered the nuclear localization of p65, and co-treatment with BHBA and LPS further promoted the translocation of p65 to the nucleus. Additionally, the addition of BHBA significantly increased the levels of oxidation indicators (MDA), whereas the levels of antioxidative indicators, including heme oxygenase-1 (HO-1) and catalase (CAT), were markedly decreased in BENDs. As a representative antioxidant, N-acetylcysteine (NAC) treatment significantly reduced the phosphorylation of p65 and IκB in the BHBA and LPS co-treatment group. SC75741, an NF-κB signaling pathway inhibitor, significantly decreased the expression levels of proinflammatory cytokines (IL-6, IL-1β, IL-8, and CCL5) in the BHBA and LPS co-treatment group. In summary, the current study demonstrates that BHBA aggravates LPS-induced inflammatory response in BENDs through the activation of oxidative stress/NF-κB signaling pathway, unravelling the mechanism by which BHBA exacerbates the inflammatory response in the BENDs of dairy cattle. This study elucidates the role of ketosis and its key metabolite BHBA in the pathogenesis of endometritis in dairy cows, providing valuable insights for understanding this pathological process.},
}

@article {pmid40187375,
year = {2025},
author = {Bruschi, M and Masini, S and Biancucci, F and Piersanti, G and Canonico, B and Menotta, M and Magnani, M and Fraternale, A},
title = {Redox modulation via a synthetic thiol compound reshapes energy metabolism in endothelial cells and ameliorates angiogenic expression in a co-culture study with activated macrophages.},
journal = {Biochimica et biophysica acta. General subjects},
volume = {1869},
number = {6},
pages = {130803},
doi = {10.1016/j.bbagen.2025.130803},
pmid = {40187375},
issn = {1872-8006},
abstract = {The vascular endothelium is the first interface exposed to circulating compounds and oxidative as well as pro-inflammatory stimuli. Nowadays, cysteine pro-drugs are emerging as new and potential therapies in cardiovascular and inflammatory diseases due to their cytoprotective effects. In this study, the effects of redox modulation by a synthetic thiol compound, i.e., I-152, a precursor of N-acetylcysteine (NAC) and cysteamine (MEA), were evaluated after 6 h and 24 h treatment on human umbilical cord endothelial cell (HUVECs) energy metabolism. Following I-152 treatment, higher cysteine and glutathione (GSH) content were detected via HPLC, in concomitance with I-152 derivatives, i.e., NAC and MEA. Untargeted metabolomics confirmed GSH upregulation and NAC presence in addition to I-152 itself and other metabolites, such as dithiol compound (NACMEAA) and triacetylated I-152. Mass spectrometry revealed that I-152 boosted ATP production, specifically through the mitochondrial OXPHOS, as determined via Seahorse assay without inducing oxidative stress. Additionally, I-152 treatment of HUVECs before co-culture with LPS-stimulated macrophages provided GSH and cysteine sustainment and attenuated the transcription of adhesion molecules as well as iNOS expression. Identifying the impact of redox regulation in physiological conditions and the possible metabolic targets could aid the application of novel thiol-based therapeutics.},
}

@article {pmid40186271,
year = {2025},
author = {Zhang, J and Liu, T and Wu, H and Wei, J and Qu, Q},
title = {Target oxidative stress-induced disulfidptosis: novel therapeutic avenues in Parkinson's disease.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {29},
pmid = {40186271},
issn = {1756-6606},
support = {2021ZD0201808//Scientific and technological innovation 2030/ ; },
mesh = {*Oxidative Stress/genetics/drug effects ; *Parkinson Disease/genetics/pathology/drug therapy/therapy ; Animals ; Molecular Docking Simulation ; Humans ; Gene Expression Profiling ; Gene Regulatory Networks ; Mice ; *Molecular Targeted Therapy ; Gene Expression Regulation ; Reproducibility of Results ; Transcriptome/genetics ; Disulfidptosis ; },
abstract = {BACKGROUND: Parkinson's disease (PD), a globally prevalent neurodegenerative disorder, has been implicated with oxidative stress (OS) as a central pathomechanism. Excessive reactive oxygen species (ROS) trigger neuronal damage and may induce disulfidptosis-a novel cell death modality not yet characterized in PD pathogenesis.

METHOD: Integrated bioinformatics analyses were conducted using GEO datasets to identify PD-associated differentially expressed genes (DEGs). These datasets were subjected to: immune infiltration analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), intersection analysis of oxidative stress-related genes (ORGs) and disulfidptosis-related genes (DRGs) for functional enrichment annotation. Following hub gene identification, diagnostic performance was validated using independent cohorts. LASSO regression was applied for feature selection, with subsequent experimental validation in MPTP-induced PD mouse models. Single-cell transcriptomic profiling and molecular docking studies were performed to map target gene expression and assess drug-target interactions.

RESULT: A total of 1615 PD DEGs and 200 WGCNA DEGs were obtained, and the intersection with ORGs and DRGs resulted in 202 DEORGs, 11 DEDRGs, and 5 DED-ORGs (NDUFS2, LRPPRC, NDUFS1, GLUD1, and MYH6). These genes are mainly associated with oxidative stress, the respiratory electron transport chain, the ATP metabolic process, oxidative phosphorylation, mitochondrial respiration, and the TCA cycle. 10 hub genes have good diagnostic value, including in the validation dataset (AUC ≥ 0.507). LASSO analysis of hub genes yielded a total of 6 target genes, ACO2, CYCS, HSPA9, SNCA, SDHA, and VDAC1. In the MPTP-induced PD mice model, the expression of ACO2, HSPA9, and SDHA was decreased while the expression of CYCS, SNCA, and VDAC1 was increased, and the expression of the 5 DED-ORGs was decreased. Additionally, it was discovered that N-Acetylcysteine (NAC) could inhibit the occurrence of disulfidptosis in the MPTP-induced PD model. Subsequently, the distribution of target genes with AUC > 0.7 in different cell types of the brain was analyzed. Finally, molecular docking was performed between the anti-PD drugs entering clinical phase IV and the target genes. LRPPRC has low binding energy and strong affinity with duloxetine and donepezil, with binding energies of -7.6 kcal/mol and - 8.7 kcal/mol, respectively.

CONCLUSION: This study elucidates the pathogenic role of OS-induced disulfidptosis in PD progression. By identifying novel diagnostic biomarkers (e.g., DED-ORGs) and therapeutic targets (e.g., LRPPRC), our findings provide a mechanistic framework for PD management and lay the groundwork for future therapeutic development.},
}

*Oxidative Stress/genetics/drug effects
*Parkinson Disease/genetics/pathology/drug therapy/therapy
Animals
Molecular Docking Simulation
Humans
Gene Expression Profiling
Gene Regulatory Networks
Mice
*Molecular Targeted Therapy
Gene Expression Regulation
Reproducibility of Results
Transcriptome/genetics
Disulfidptosis

@article {pmid40183046,
year = {2025},
author = {Song, J and Qiao, J and Chen, M and Li, J and Wang, J and Yu, D and Zheng, H and Shi, L},
title = {Chaetoglobosin A induces apoptosis in T-24 human bladder cancer cells through oxidative stress and MAPK/PI3K-AKT-mTOR pathway.},
journal = {PeerJ},
volume = {13},
number = {},
pages = {e19085},
pmid = {40183046},
issn = {2167-8359},
mesh = {Humans ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Urinary Bladder Neoplasms/drug therapy/metabolism/pathology ; TOR Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Cell Line, Tumor ; Phosphatidylinositol 3-Kinases/metabolism ; *Indole Alkaloids/pharmacology ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Cell Movement/drug effects ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; },
abstract = {Chaetoglobosin A (ChA) is an antitumor compound produced by Chaetomium globosum. However, the mechanism of its antitumor effect has been rarely reported. In this study, we evaluated the anti-proliferative effect of ChA on T-24 human bladder cancer cells and explored its mechanism of action. ChA was found to have a good inhibitory effect on T-24 cells by MTT assay with an IC50 value of 48.14 ± 10.25 μΜ. Moreover, it was found to have a migration inhibitory ability and a sustained proliferation inhibitory effect on tumor cells by cell aggregation assay and cell migration assay. The cells morphological changes were determined by Hoechst33342 assay. While Annexin V-FITC/PI double-staining assay also demonstrated that the number of apoptotic cells increased with the increase of drug concentration. Flow cytometry results showed that ChA treatment increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in T-24 cells and inhibited cell mitosis, resulting in an increase in the number of sub-G1 phase cells. Further western blot experiments demonstrated that MAPK and PI3K-AKT-mTOR pathways were activated after drug treatment in addition to endogenous and exogenous apoptotic pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) upregulated the expression level of Bcl-2 protein, decreased p38 phosphorylation, increased ERK phosphorylation and restored the levels of PI3K and p-mTOR after ChA treatment. These suggest that ChA induces apoptosis by regulating oxidative stress, MAPK, and PI3K-AKT-mTOR signaling pathways in T-24 cells.},
}

Humans
*Apoptosis/drug effects
*Oxidative Stress/drug effects
*Urinary Bladder Neoplasms/drug therapy/metabolism/pathology
TOR Serine-Threonine Kinases/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Cell Line, Tumor
Phosphatidylinositol 3-Kinases/metabolism
*Indole Alkaloids/pharmacology
Signal Transduction/drug effects
Reactive Oxygen Species/metabolism
Cell Proliferation/drug effects
Cell Movement/drug effects
MAP Kinase Signaling System/drug effects
Membrane Potential, Mitochondrial/drug effects
*Antineoplastic Agents/pharmacology

@article {pmid40180519,
year = {2025},
author = {Oscullo, G and Méndez, R and Olveira, C and Girón, R and García-Clemente, M and Máiz, L and Sibila, O and Golpe, R and Rodríguez-Hermosa, J and Barreiro, E and Prados, C and Rodríguez-López, JL and de la Rosa-Carrillo, D and Martinez-García, MÁ},
title = {Effect of N-Acetylcysteine on Bronchiectasis in a Real-life Study. Data From the Spanish RIBRON Registry.},
journal = {Archivos de bronconeumologia},
volume = {61},
number = {4},
pages = {196-202},
doi = {10.1016/j.arbres.2025.02.015},
pmid = {40180519},
issn = {1579-2129},
mesh = {Humans ; *Bronchiectasis/drug therapy ; *Acetylcysteine/therapeutic use ; Male ; Female ; Middle Aged ; Aged ; Registries ; Spain ; *Expectorants/therapeutic use ; Longitudinal Studies ; Pseudomonas Infections/drug therapy/prevention & control ; Hospitalization/statistics & numerical data ; Sputum/metabolism ; Treatment Outcome ; Adult ; Pseudomonas aeruginosa/isolation & purification ; },
abstract = {INTRODUCTION: There is scarce information about the most used mucolytic drug in bronchiectasis N-acetylcysteine (N-AC). Our objective was to analyze the effect of N-AC with respect to some outcomes in bronchiectasis.

METHODS: Ambispective, longitudinal, observational, multi-center (43 centers) study of a cohort of 2461 adult patients diagnosed with bronchiectasis. Those patients treated in a stable situation with at least 600mg/d of N-AC (368; 15%) for at least 6 months were compared with patients not receiving this treatment. The variables analyzed and compared were those available two years before and after treatment. ANCOVA analysis was used to analyze the effect of N-AC as the inter-group difference of the basal intra-group difference for each variable, adjusted for relevant covariables.

RESULTS: The N-AC group showed a full adjusted improvement of 27% in exacerbations, 17% in hospitalizations, and 31% in total exacerbation rates compared with the no-N-AC group. Moreover, a decrease in the volume of sputum production of 59.7% was observed as well as a decrease of 12% of patients with bronchial infection by Pseudomonas aeruginosa (PA). The use of 1200mg/d (n=116) resulted in only a mild, albeit significative improvement in the exacerbation rate compared with the use of 600mg/d (-11% in absolute number). Both doses were well tolerated.

CONCLUSION: N-AC (in most cases at a dose of 600mg/d) is safe and effective and sufficient to reduce both the number of exacerbations and hospitalizations and the purulence and volume of sputum, as well as the isolation rate of PA in patients with bronchiectasis.},
}

Humans
*Bronchiectasis/drug therapy
*Acetylcysteine/therapeutic use
Male
Female
Middle Aged
Aged
Registries
Spain
*Expectorants/therapeutic use
Longitudinal Studies
Pseudomonas Infections/drug therapy/prevention & control
Hospitalization/statistics & numerical data
Sputum/metabolism
Treatment Outcome
Adult
Pseudomonas aeruginosa/isolation & purification

@article {pmid40177701,
year = {2025},
author = {Kamboj, SS and Sharma, SP and Mohamed, WMY and Sandhir, R},
title = {N-acetyl-L-cysteine mitigates diabetes-induced impairments in sciatic nerve.},
journal = {IBRO neuroscience reports},
volume = {18},
number = {},
pages = {512-519},
pmid = {40177701},
issn = {2667-2421},
abstract = {Diabetic neuropathy is a consequence of long-term hyperglycemia. The emergence of neuronal condition is a result of hyperglycemia-induced oxidative stress. In the present study, streptozotocin-induced diabetes exhibited notable decrease in the levels of phospholipids, glycolipids, gangliosides, and triglycerides in the sciatic nerve. The alterations in lipids resulted in increase in cholesterol to phospholipid ratio in sciatic nerve of diabetic animals. This ratio is crucial and determines the rheological properties of membranes and resulted in substantial reduction in the activity of membrane-bound enzymes; Ca[2 +] ATPase and acetylcholinesterase. Histological examination of the cross-section of the sciatic nerve in diabetic mice revealed axonal atrophy and disarrayed myelin sheath. The potential therapeutic impact of N-acetyl Cysteine (NAC), a powerful antioxidant, on a rat model of diabetic neuropathy was evaluated. NAC was administered to rats in drinking water for a period of 8 weeks. The results indicate that administration of NAC restored lipid composition; ratio of cholesterol to phospholipids, the activity of membrane linked enzymes, and improved the structural defects in sciatic nerve. NAC plays protective role against diabetes-induced alterations in lipid composition in sciatic nerve membranes leading to improvement in structure and function of membranes. Overall, the findings suggest NAC as a potential therapeutic strategy in preventing diabetic neuropathy and other diabetic complications.},
}

@article {pmid40170426,
year = {2025},
author = {Tang, H and Li, L},
title = {Effects of detergent component sodium dodecyl sulfate on growth hormone secretion in GH3 cells: Implications for pediatric exposure and accidental ingestion.},
journal = {Human & experimental toxicology},
volume = {44},
number = {},
pages = {9603271251332255},
doi = {10.1177/09603271251332255},
pmid = {40170426},
issn = {1477-0903},
mesh = {*Sodium Dodecyl Sulfate/toxicity ; *Oxidative Stress/drug effects ; *Cell Survival/drug effects ; Growth Hormone/metabolism ; NF-E2-Related Factor 2/metabolism/genetics ; Animals ; Detergents/toxicity ; Reactive Oxygen Species/metabolism ; Humans ; Rats ; Cell Line ; Human Growth Hormone ; },
abstract = {IntroductionSodium dodecyl sulfate (SDS), a widely used surfactant in detergents, has raised concerns due to its potential health risks, particularly in children. This study evaluates the impact of SDS exposure on GH secretion in GH3 cells, focusing on oxidative stress as a key mechanism.MethodsGH3 cells were treated with varying concentrations of SDS (0.001-10 mM) for 24 or 48 h. Cell viability was assessed using the MTT assay, while GH secretion was quantified via ELISA. Oxidative stress levels were evaluated through ROS fluorescence assays, and gene expression of Nrf2, IL-6, TNF-α, and caspase-3 was analyzed using qPCR. Additionally, the antioxidant N-acetylcysteine (NAC) was used to determine its protective effects against SDS-induced oxidative stress.ResultsSDS exposure led to a dose-dependent decrease in GH secretion and cell viability, with oxidative stress identified as a primary driver. Nrf2 exhibited a biphasic response, showing transient upregulation at low doses but suppression at higher concentrations, exacerbating oxidative damage. NAC treatment reduced ROS levels and partially restored GH secretion, confirming the role of oxidative stress in SDS-induced toxicity.DiscussionThese findings suggest that SDS exposure may disrupt endocrine function, warranting further risk assessment of its safety in consumer products. Given SDS's prevalence in household products, future research should focus on the long-term effects of SDS exposure to children and potential therapeutic interventions to mitigate oxidative damage.},
}

*Sodium Dodecyl Sulfate/toxicity
*Oxidative Stress/drug effects
*Cell Survival/drug effects
Growth Hormone/metabolism
NF-E2-Related Factor 2/metabolism/genetics
Animals
Detergents/toxicity
Reactive Oxygen Species/metabolism
Humans
Rats
Cell Line
Human Growth Hormone

@article {pmid40169142,
year = {2025},
author = {Kawaguchi, M and Yoshino, K and Ida, T and Moriyama, H and Ieda, N and Ohta, Y and Kasamatsu, S and Ihara, H and Nakagawa, H},
title = {Serendipitous Discovery of Photolytic Thiosulfoxide Formation: Application for Visible-Light-Inducible Manipulation of Supersulfide Level in Biological Systems.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c00196},
pmid = {40169142},
issn = {1520-5126},
abstract = {Tools to enable spatiotemporally controlled upregulation of supersulfides, which are highly reactive, unstable sulfur species, are needed to study the pathophysiological roles of post-translational protein modification with catenated sulfur atoms. Here, we set out to design N,N-diethylaminocoumarin (DEAC)-based visible-light-responsive N-acetylcysteine persulfide donors (NAC-SS-DEAC), and serendipitously found that upon visible light irradiation, they donate a sulfane sulfur (S[0]) atom to nucleophiles, including thiols and cyanate. Light-assisted tautomerization of the disulfide moiety of NAC-SS-DEAC to transiently afford unstable thiosulfoxide plays a key role in the S[0] donation. We show that this reaction can be utilized to achieve visible-light-inducible manipulation of supersulfide levels in living cells.},
}

@article {pmid40166462,
year = {2025},
author = {Zhang, Z and Yan, Z and Yuan, T and Zhao, X and Wang, M and Liu, G and Gan, L and Qin, W},
title = {PD-1 inhibition disrupts collagen homeostasis and aggravates cardiac dysfunction through endothelial-fibroblast crosstalk and EndMT.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1549487},
pmid = {40166462},
issn = {1663-9812},
abstract = {INTRODUCTION: Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects and mechanisms of PD-1 inhibitor on cardiac collagen remodeling remain poorly understood.

METHODS: C57BL/6 mice were injected with anti-mouse PD-1 antibody to create a PD-1 inhibitor-treated model. Cardiac function was measured by echocardiography, and collagen distribution was analyzed with Masson's trichrome staining and Sirius Red staining. Single-nucleus RNA sequencing was performed to examine the effects of PD-1 inhibition on gene expression in cardiac fibroblasts (CFs) and endothelial cells (ECs). EC-CF crosstalk was assessed using co-culture experiments and ELISA. ChIP assay was performed to analyze the regulation of TCF12 on TGF-β1 promoter. Western blot, qRT-PCR, and immunofluorescence staining were used to detect the expression of TCF12, TGF-β1, and endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels were evaluated by DHE staining, MDA content, and SOD activity assays.

RESULTS: We report a newly discovered cardiotoxic effect of PD-1 inhibitor, which causes aberrant collagen distribution in the heart, marked by a decrease in interstitial collagen and an increase in perivascular collagen deposition. Mechanistically, PD-1 inhibitor does not directly affect CFs but instead impact them through EC-CF crosstalk. PD-1 inhibitor reduces TGF-β1 secretion in ECs by downregulating TCF12, which we identify as a transcriptional promoter of TGF-β1. This subsequently decreases CF activity, leading to reduced interstitial collagen deposition. Additionally, PD-1 inhibitor induces EndMT, increasing perivascular collagen deposition. The endothelial dysfunction induced by PD-1 inhibitor results from ROS accumulation in ECs. Inhibiting ROS with N-acetylcysteine (NAC) preserves normal collagen distribution and cardiac function in PD-1 inhibitor-treated mice by reversing TCF12 downregulation and EndMT in ECs.

CONCLUSION: Our results suggest that PD-1 inhibitor causes ROS accumulation in cardiac ECs, leading to imbalanced collagen distribution (decrease in interstitial collagen and increase in perivascular collagen) in the heart by modulating TCF12/TGF-β1-mediated EC-CF crosstalk and EndMT. NAC supplementation could be an effective clinical strategy to mitigate PD-1 inhibitor-induced imbalanced collagen distribution and cardiac dysfunction.},
}

@article {pmid40163767,
year = {2025},
author = {Kruse, LD and Holte, C and Zapotoczny, B and Struck, EC and Schürstedt, J and Hübner, W and Huser, T and Szafranska, K},
title = {Hydrogen peroxide damage to rat liver sinusoidal endothelial cells is prevented by n-acetyl-cysteine but not GSH.},
journal = {Hepatology communications},
volume = {9},
number = {2},
pages = {},
pmid = {40163767},
issn = {2471-254X},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Hydrogen Peroxide/toxicity/pharmacology ; Rats ; *Glutathione/metabolism ; *Endothelial Cells/drug effects/metabolism ; *Oxidative Stress/drug effects ; *Reactive Oxygen Species/metabolism ; *Liver/drug effects/metabolism ; Male ; Cell Survival/drug effects ; Cells, Cultured ; Rats, Sprague-Dawley ; },
abstract = {BACKGROUND: Reactive oxygen species (ROS) are prevalent in the liver during intoxication, infection, inflammation, and aging. Changes in liver sinusoidal endothelial cells (LSEC) are associated with various liver diseases.

METHODS: Isolated rat LSEC were studied under oxidative stress induced by H2O2 at different concentrations (0.5-1000 µM) and exposure times (10-120 min). LSEC functions were tested in a dose-dependent and time-dependent manner.

RESULTS: (1) Cell viability, reducing potential, and scavenging function decreased as H2O2 concentration and exposure time increased; (2) intracellular ROS levels rose with higher H2O2 concentrations; (3) fenestrations exhibited a dynamic response, initially closing but partially reopening at H2O2 concentrations above 100 µM after about 1 hour; (4) scavenging function was affected after just 10 minutes of exposure, with the impact being irreversible and primarily affecting degradation rather than receptor-mediated uptake; (5) the tubulin network was disrupted in high H2O2 concentration while the actin cytoskeleton appears to remain largely intact. Finally, we found that reducing agents and thiol donors such as n-acetyl cysteine and glutathione (GSH) could protect cells from ROS-induced damage but could not reverse existing damage as pretreatment with n-acetyl cysteine, but not GSH, reduced the negative effects of ROS exposure.

CONCLUSIONS: The results suggest that LSEC does not store an excess amount of GSH but rather can readily produce it in the occurrence of oxidative stress conditions. Moreover, the observed thresholds in dose-dependent and time-dependent changes, as well as the treatments with n-acetyl cysteine/GSH, confirm the existence of a ROS-depleting system in LSEC.},
}

Animals
*Acetylcysteine/pharmacology
*Hydrogen Peroxide/toxicity/pharmacology
Rats
*Glutathione/metabolism
*Endothelial Cells/drug effects/metabolism
*Oxidative Stress/drug effects
*Reactive Oxygen Species/metabolism
*Liver/drug effects/metabolism
Male
Cell Survival/drug effects
Cells, Cultured
Rats, Sprague-Dawley

@article {pmid40163489,
year = {2025},
author = {Bao, Q and Wang, Z and Yang, T and Su, X and Chen, Y and Liu, L and Deng, Q and Liu, Q and Shao, C and Zhu, W},
title = {Curcumin induces mitochondrial dysfunction-associated oxidative DNA damage in ovarian cancer cells.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0319846},
pmid = {40163489},
issn = {1932-6203},
mesh = {*Curcumin/pharmacology ; Female ; Humans ; *Ovarian Neoplasms/drug therapy/pathology/metabolism/genetics ; *DNA Damage/drug effects ; Animals ; *Mitochondria/drug effects/metabolism ; Cell Line, Tumor ; *Oxidative Stress/drug effects ; Mice ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Mice, Nude ; Xenograft Model Antitumor Assays ; Antineoplastic Agents/pharmacology ; },
abstract = {Resistance to chemotherapeutic agents is a critical challenge for the clinical management of ovarian cancer. While curcumin has been reported to possess anti-cancer properties, how it exerts its anti-neoplastic effect on ovarian cancer cells remains to be explored. We here characterized the fate of human ovarian cancer cell lines HO8910 and OVCAR3 treated with curcumin. Cell proliferation, cell death, mitochondrial function, oxidative damage and tumor formation in nude mice were examined. Significant inhibition of proliferation and induction of apoptosis were observed in ovarian cells treated with curcumin. The cancer cells exhibit cell cycle arrest at G2/M phase, mitochondrial accumulation, mitochondrial oxidative stress and high level of DNA damage after curcumin treatment. This effect of curcumin is independent of the BRCA mutation status. Curcumin-induced proliferation inhibition and apoptosis were effectively attenuated by the application of antioxidant N-acetylcysteine (NAC), suggesting that curcumin exerts its anti-cancer effect by inflicting oxidative stress. Curcumin applied at 200 mg/kg intraperitoneal infusion daily also inhibited the growth, oxidative damage, and mitochondrial accumulation of tumor xenografts in vivo. Together, the results indicate that curcumin can exert its anti-tumor effect via inducing mitochondrial dysfunction-associated oxidative DNA damage and can be potentially used in combination with other DNA repair-interfering therapeutics, such as PARP inhibitor, in the treatment of ovarian cancer.},
}

*Curcumin/pharmacology
Female
Humans
*Ovarian Neoplasms/drug therapy/pathology/metabolism/genetics
*DNA Damage/drug effects
Animals
*Mitochondria/drug effects/metabolism
Cell Line, Tumor
*Oxidative Stress/drug effects
Mice
*Apoptosis/drug effects
*Cell Proliferation/drug effects
Mice, Nude
Xenograft Model Antitumor Assays
Antineoplastic Agents/pharmacology

@article {pmid40163249,
year = {2025},
author = {Snorradottir, AO and Gutierrez-Uzquiza, A and Bragado, P and March, ME and Kao, C and Arkink, EB and Jonsdottir, S and Sigurdardottir, A and Isaksson, HJ and Mariasdóttir, HL and Bjorgvinsdottir, OY and Kowal, NM and Heimisdottir, HL and Sverrisdottir, A and Palsdottir, A and Bjornsson, HT and Hakonarson, H},
title = {N-Acetylcysteine for Hereditary Cystatin C Amyloid Angiopathy: A Nonrandomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {40163249},
issn = {2168-6157},
abstract = {IMPORTANCE: Hereditary cystatin C amyloid angiopathy (HCCAA) is a lethal, dominantly inherited disease primarily affecting Icelandic young adults that leads to severe cerebral amyloid angiopathy, with no effective therapy.

OBJECTIVE: To investigate safety, tolerance, and therapeutic potential of N-acetylcysteine (NAC) in lowering disease-associated biomarkers in sequence variation carriers.

This phase 2a open-label clinical trial was conducted from March 2019 to December 2021 at a single study center at Landspitali University Hospital in Reykjavik, Iceland, and included 17 confirmed carriers of the L68Q-CST3 sequence variation.

INTERVENTION: High-dose NAC treatment was administered at 2400 mg daily for 9 months. Participants underwent regular monitoring for hemorrhages and disease progression, including blood and skin biopsy samples obtained every 3 months for biomarker testing.

MAIN OUTCOMES AND MEASURES: The primary outcomes were drug tolerability and safety, cognitive status, and reduction in disease-associated biomarkers in skin biopsies. Secondary outcomes included changes in blood and plasma biomarker levels.

RESULTS: Of 17 carriers treated, 6 were male and 11 were female, and mean (SD) participant age was 40.0 (4.2) years. Analysis of the primary outcomes showed that NAC was safe and well tolerated. Five cerebral bleeds occurred during the treatment period without permanent neurological sequela; no death occurred. There was significant reduction in median (IQR) disease-specific biomarker levels in skin after treatment, including collagen IV (baseline: 3.69% [2.48%-5.16%]; after treatment: 2.60% [1.99%-2.97%]; P < .001), fibronectin (baseline: 3.17% [2.09%-5.05%]; after treatment: 2.37% [1.87%-3.42%]; P = .01), vimentin (baseline: 1.60% [1.24%-2.37%]; after treatment: 1.31% [0.97%-1.68%]; P < .001), and SMAD (baseline: 2.25% [0.55%-4.36%]; after treatment: 1.56% [0.20%-2.54%]; P < .001) via Wilcoxon matched-pairs signed rank test. Secondary outcomes included a significant increase in reduced glutathione levels and decreased high-molecular-weight cystatin C aggregate levels in plasma after NAC treatment.

CONCLUSIONS AND RELEVANCE: In this single-center nonrandomized clinical trial, NAC was safe and well tolerated and decreased disease-associated biomarker and amyloid deposition, suggesting NAC may offer a preventive strategy against HCCAA.

TRIAL REGISTRATION: ClinicalTrialsRegister.eu Identifier: 2017-004776-56.},
}

@article {pmid40159744,
year = {2025},
author = {Adamczuk, P and Jamka, K and Bojar, H and Szala-Rycaj, J and Szewczyk, A and Sawicki, KB and Raszewski, G},
title = {The effect of the antioxidant N-acetylcysteine on cholinesterase activity in the brain and blood during Pirimiphos methyl poisoning in the course of treatment with atropine alone, and with atropine and obidoxime.},
journal = {Annals of agricultural and environmental medicine : AAEM},
volume = {32},
number = {1},
pages = {116-121},
doi = {10.26444/aaem/199716},
pmid = {40159744},
issn = {1898-2263},
mesh = {Animals ; *Atropine/pharmacology/administration & dosage ; *Acetylcysteine/pharmacology ; Male ; Mice ; *Antioxidants/metabolism ; *Brain/drug effects/metabolism ; *Obidoxime Chloride/pharmacology ; Organothiophosphorus Compounds ; Organophosphate Poisoning/drug therapy ; Butyrylcholinesterase/metabolism ; Acetylcholinesterase/metabolism ; Antidotes/pharmacology/administration & dosage ; Cholinesterases/metabolism/blood ; Cholinesterase Inhibitors ; },
abstract = {INTRODUCTION AND OBJECTIVE: The antioxidant N-acetylcysteine (NAC) may help in the treatment of organophosphates poisoning, including Pirymiphos methyl (PM). However, there is no information on the effect of NAC on target cholinesterases during the core treatment with atropine and obidoxime after acute and chronic exposure to PM. The impact was investigated of NAC on the functional status of target cholinesterases in the brain and blood during treatment with atropine (ATR) and/or obidoxime (OBID) in PM-induced toxicity.

MATERIAL AND METHODS: All experiments were performed on Male Swiss mice. The animals were intoxicated with PM and treated with OBID and/or ATR with or without and NAC, in various combinations (with 2-3 drugs) used simultaneously after intoxication. Total acetylcholinesterase activity (AChE) in brain and blood and plasma butyrylcholinesterase activity (BChE) were monitored at 2 and 72 h after intoxication. Enzyme activity was determined using Ellman's colorimetric method.

RESULTS: The applied therapies with OBID, ATR and NAC in various configurations significantly reactivated PM-inhibited AChE in the brain and erythrocytes and the BChE in the plasma. The benefits of NAC administration in combination with ATR and/or OBID therapy have also been reported to restore AChE activity in the brain. NAC may reduce the dose of ATR in the treatment of PM poisoning.

CONCLUSIONS: Adjunctive treatment offered by NAC can reduce or prevent the deleterious effects against PM-induced toxicity. Therefore, NAC remains a strong candidate for adjunct treatment for OP-poisoning, including PM, although additional preclinical and clinical studies are needed.},
}

Animals
*Atropine/pharmacology/administration & dosage
*Acetylcysteine/pharmacology
Male
Mice
*Antioxidants/metabolism
*Brain/drug effects/metabolism
*Obidoxime Chloride/pharmacology
Organothiophosphorus Compounds
Organophosphate Poisoning/drug therapy
Butyrylcholinesterase/metabolism
Acetylcholinesterase/metabolism
Antidotes/pharmacology/administration & dosage
Cholinesterases/metabolism/blood
Cholinesterase Inhibitors

@article {pmid40159690,
year = {2025},
author = {Chen, H and Wang, J and Zhao, B and Yang, Y and Yang, C and Zhao, Z and Ding, X and Li, Y and Zhang, T and Yingpai, Z and Huo, S},
title = {N-Acetylcysteine relieving hydrogen peroxide-induced damage in granulosa cells of sheep.},
journal = {Cell adhesion & migration},
volume = {19},
number = {1},
pages = {2484182},
doi = {10.1080/19336918.2025.2484182},
pmid = {40159690},
issn = {1933-6926},
mesh = {Animals ; *Hydrogen Peroxide/pharmacology/metabolism ; Female ; *Granulosa Cells/metabolism/drug effects ; *Oxidative Stress/drug effects ; Sheep ; *Acetylcysteine/pharmacology ; *Signal Transduction/drug effects ; *Phosphatidylinositol 3-Kinases/metabolism ; NF-E2-Related Factor 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; },
abstract = {Sheep ovarian granulosa cells (GCs) play a unique role in the ovary. Damage to GCs can affect the normal development of oocytes. The oxidative stress model was constructed by H2O2to study the biological changes. Specifically, pathological characteristic was assessed by immunohistochemistry (IHC), while signaling pathway was studied using western blot, quantitative RT-PCR, and immunofluorescence. Theresults showed that the oxidative damage model was successfully constructed by 200 μmol/LH2O2 for 12 h. NAC can protect the proliferation of GCs under H2O2-induced oxidative stress and reduce apoptosis. It can also promote the secretion of E2 and P4 by GCs and reduce the inflammatory response of GCs. NAC can enhance the expression of NRF2, PI3K and Akt. These findings suggest that NAC alleviates H2O2-induced oxidative stress injury through NRF2/PI3K/AKT signaling pathways. Provide ideas for studying the poor quality of mammalian oocytes.},
}

Animals
*Hydrogen Peroxide/pharmacology/metabolism
Female
*Granulosa Cells/metabolism/drug effects
*Oxidative Stress/drug effects
Sheep
*Acetylcysteine/pharmacology
*Signal Transduction/drug effects
*Phosphatidylinositol 3-Kinases/metabolism
NF-E2-Related Factor 2/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Apoptosis/drug effects
Cell Proliferation/drug effects

@article {pmid40156629,
year = {2025},
author = {Xu, Y and You, J and Yao, J and Hou, B and Wang, W and Hao, Z},
title = {Klotho alleviates oxidative stress and mitochondrial dysfunction through the Nrf2/HO-1 pathway, thereby reducing renal senescence induced by calcium oxalate crystals.},
journal = {Urolithiasis},
volume = {53},
number = {1},
pages = {61},
pmid = {40156629},
issn = {2194-7236},
support = {82070724//the National Natural Science Foundation of China/ ; },
mesh = {*Klotho Proteins ; *Oxidative Stress/drug effects ; Animals ; *Calcium Oxalate/metabolism/toxicity ; *NF-E2-Related Factor 2/metabolism ; Mice ; *Glucuronidase/metabolism/genetics ; *Heme Oxygenase-1/metabolism/genetics ; *Signal Transduction/drug effects ; *Kidney/drug effects/metabolism/pathology ; *Mitochondria/drug effects/metabolism ; Male ; Cellular Senescence/drug effects ; Humans ; Disease Models, Animal ; Mice, Inbred C57BL ; Cell Line ; Aging/drug effects ; Membrane Proteins ; },
abstract = {Klotho is an antiaging protein that is primarily secreted by the kidneys. This study aimed to explore the protective effects of Klotho against calcium oxalate (CaOx) crystal-induced renal aging and the underlying mechanisms involved. We established a mouse model of CaOx crystal deposition via the intraperitoneal injection of glyoxylate (Gly) and constructed an in vitro model by stimulating HK2 cells with calcium oxalate monohydrate (COM). Renal aging levels were assessed through β-galactosidase (SA-β-gal) staining and the detection of senescence-associated markers. By overexpressing Klotho both in vitro and in vivo, we examined oxidative stress, mitochondrial function, and renal aging levels. We then evaluated the role of Nrf2/HO-1 signalling pathway-mediated oxidative stress in CaOx crystal-induced renal aging by applying the oxidative stress scavenger N-acetylcysteine (NAC) and overexpressing or inhibiting Nrf2 in HK2 cells. We subsequently overexpressed Klotho while inhibiting Nrf2 to confirm that Klotho exerts its protective effects through the Nrf2/HO-1 pathway. Finally, we measured the methylation levels of the Klotho promoter and assessed the degree of renal aging induced by CaOx crystals after the inhibition of Klotho DNA methylation. We found that the overexpression of Klotho alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thereby reducing renal aging. NAC mitigated CaOx crystal-induced renal aging. The overexpression of Nrf2 alleviated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, thus reducing renal aging, whereas the knockdown of Nrf2 exacerbated CaOx crystal-induced oxidative stress and mitochondrial dysfunction, leading to more severe renal aging. The combination of Klotho overexpression and Nrf2 knockdown reversed the protective effects of Klotho. CaOx crystals induced an increase in the DNA methylation levels of Klotho in the kidneys, and the inhibition of DNA methylation alleviated CaOx-induced renal aging. This study revealed that Klotho plays a crucial role in calcium oxalate crystal-induced kidney senescence by influencing kidney oxidative stress and mitochondrial function through the Nrf2/HO-1 pathway.},
}

*Klotho Proteins
*Oxidative Stress/drug effects
Animals
*Calcium Oxalate/metabolism/toxicity
*NF-E2-Related Factor 2/metabolism
Mice
*Glucuronidase/metabolism/genetics
*Heme Oxygenase-1/metabolism/genetics
*Signal Transduction/drug effects
*Kidney/drug effects/metabolism/pathology
*Mitochondria/drug effects/metabolism
Male
Cellular Senescence/drug effects
Humans
Disease Models, Animal
Mice, Inbred C57BL
Cell Line
Aging/drug effects
Membrane Proteins

@article {pmid40155786,
year = {2025},
author = {Nasiri, MJ and Khoshdel, N and Venketaraman, V},
title = {Glutathione and N-acetylcysteine in TB management.},
journal = {The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease},
volume = {29},
number = {4},
pages = {171-177},
doi = {10.5588/ijtld.24.0604},
pmid = {40155786},
issn = {1815-7920},
mesh = {*Acetylcysteine/therapeutic use ; Humans ; *Glutathione ; Antitubercular Agents/administration & dosage/pharmacology ; Tuberculosis/drug therapy ; Oxidative Stress/drug effects ; Tuberculosis, Pulmonary/drug therapy ; },
abstract = {TB remains a major global health challenge. Glutathione (GSH) and N-acetylcysteine (NAC) have been proposed as adjunctive therapies with potential clinical and immunomodulatory benefits. This systematic review aims to evaluate the efficacy, safety, and immunomodulatory effects of GSH and NAC as adjunctive therapies in TB management.PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched until October 15, 2024. We included studies assessing the efficacy of GSH and NAC in TB management, focusing on clinical outcomes such as lung function recovery, sputum conversion, hepatoprotection, and immune response modulation. The quality of the studies was assessed using the Cochrane Risk of Bias tool.Eight controlled trials were included. GSH and NAC significantly improved lung function accelerated sputum conversion, and provided hepatoprotective effects. GSH, particularly in its liposomal form, enhanced immune responses by modulating cytokine levels and reducing oxidative stress. Most adverse effects reported were mild and manageable, indicating a favourable safety profile for both agents.GSH and NAC show promise as adjunctive therapies in TB management, demonstrating improvements in lung function, sputum conversion, and hepatoprotection while also enhancing immune responses..},
}

*Acetylcysteine/therapeutic use
Humans
*Glutathione
Antitubercular Agents/administration & dosage/pharmacology
Tuberculosis/drug therapy
Oxidative Stress/drug effects
Tuberculosis, Pulmonary/drug therapy

@article {pmid40153160,
year = {2025},
author = {Borovskaya, TG and Vychuzhanina, AV and Schemerova, YA and Stremlina, LA and Goldberg, VE and Dygai, AM and Zhdanov, VV},
title = {Genoprotective Properties of para-Tyrosol against Doxorubicin-Induced DNA Damage in Sperm and Testicular Tissue Cells of Rats.},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {40153160},
issn = {1573-8221},
abstract = {The effect of para-tyrosol (PT), a hydroxyalkylphenol exhibiting antioxidant properties, on the level of DNA damage in testicular tissue cells and sperm of rats treated with doxorubicin was studied using the DNA comet assay. N-acetylcysteine (NAC) was used as a reference drug. It was found that both drugs reduced the number of DNA breaks in rat testicular tissue cells (by 46-48%). The antigenotoxic effect, judging by %DNA in tail, in relation to spermatozoa was detected only in PT. The number of DNA damage in male germ cells after treatment with PT was reduced by 52% from the control (administration of doxorubicin alone). The results suggest that it is advisable to use PT in order to reduce the genotoxicity of doxorubicin, in the therapy of Hodgkin lymphoma (HL) in treatment regimens containing this anthracycline antibiotic.},
}

@article {pmid40143181,
year = {2025},
author = {Alhaddad, A and Mosalam, EM and AboShabaan, HS and Sallam, AS and Mahfouz, MM and Elhosary, E and Mohammed, AA and Metwally, EM and Shaldam, MA and Ghoneim, ME},
title = {Mechanistic and Molecular Insights into Empagliflozin's Role in Ferroptosis and Inflammation Trajectories in Acetaminophen-Induced Hepatotoxicity.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {3},
pages = {},
pmid = {40143181},
issn = {1424-8247},
abstract = {Background: Acetaminophen (APAP)-induced acute liver injury (ALI) is increasingly becoming a public health issue with high rate of morbidity and mortality. Therefore, there is a critical demand for finding protective modalities by understanding the underlying proposed mechanisms including, but not limited to, ferroptosis and inflammation. Objectives: This study seeks to investigate the possible hepatoprotective effect of empagliflozin (EMPA) against APAP-induced ALI through modulation of ferroptosis and inflammatory cascades. Methods: Mice were allocated into the following five groups: vehicle control, APAP, EMPA 10, EMPA 20 (10 and 20 mg/kg/day, respectively, P.O.), and N-acetylcysteine (NAC, hepatoprotective agent against APAP-induced ALI). The hepatic injury was detected by determining liver enzymes and by histopathological examination. Inflammation, oxidative stress, apoptosis, and ferroptosis were also evaluated. Results: The APAP group showed an elevated level of hepatic enzymes with disrupted hepatic architecture. This toxicity was promoted by inflammation, oxidative stress, apoptosis, and ferroptosis, as indicated by elevated cytokines, lipid peroxidation, reduced antioxidants, increased caspase-3, decreased Bcl-2, and activation of the NF-κB/STAT3/hepcidin pathway. Pretreatment with EMPA remarkably reversed these features, which was reflected by restoration of the histoarchitecture of hepatic tissue, but the higher dose of EMPA was more efficient. Conclusions: APAP can induce ALI through initiation of inflammatory and oxidative conditions, which favor ferroptosis. EMPA hindered these unfavorable consequences; an outcome which indicates its anti-inflammatory, antioxidant, anti-apoptotic, and anti-ferroptotic effects. This modulatory action advocated EMPA as a potential hepatoprotective agent.},
}

@article {pmid40143066,
year = {2025},
author = {Liu, Y and Yao, L and Liu, Y and Yang, Y and Liang, A and He, H and Lei, Y and Cao, W and Chen, Z},
title = {Micheliolide Alleviates Hepatic Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via the TrxR1/2-Mediated ROS/MEK/ERK Pathway.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {3},
pages = {},
pmid = {40143066},
issn = {1424-8247},
support = {82100131, 82004168//National Natural Science Foundation of China/ ; CSTB2023NSCQ-MSX0136//Natural Science Foundation Project of Chongqing/ ; KJQN202215101, KJZD-K202315101//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; W0066//CQMU Program for Youth Innovation in Future Medicine/ ; },
abstract = {Background: Hepatic fibrosis is a major global health issue without an optimal drug treatment, highlighting the urgent need to find effective therapies. This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl4-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl4-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition.},
}

@article {pmid40141299,
year = {2025},
author = {Mokra, D and Porvaznik, I and Mokry, J},
title = {N-Acetylcysteine in the Treatment of Acute Lung Injury: Perspectives and Limitations.},
journal = {International journal of molecular sciences},
volume = {26},
number = {6},
pages = {},
pmid = {40141299},
issn = {1422-0067},
support = {APVV-15-0075//Slovak Research and Development Agency/ ; APVV-18-0084//Slovak Research and Development Agency/ ; APVV-22-0342//Slovak Research and Development Agency/ ; VEGA 1/0131/22//Ministry of Education, Science, Research and Sport of the Slovak Republic/ ; VEGA 1/0093/22//Ministry of Education, Science, Research and Sport of the Slovak Republic/ ; },
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Acute Lung Injury/drug therapy ; Animals ; *Oxidative Stress/drug effects ; COVID-19 ; Antioxidants/therapeutic use/pharmacology ; COVID-19 Drug Treatment ; SARS-CoV-2/drug effects ; Respiratory Distress Syndrome/drug therapy ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; },
abstract = {N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies indicates that early administration of NAC may reduce markers of oxidative stress and alleviate inflammation in animal models of acute lung injury (ALI) and in patients suffering from distinct forms of acute respiratory distress syndrome (ARDS) or pulmonary infections including community-acquired pneumonia or Coronavirus Disease (COVID)-19. Besides low costs, easy accessibility, low toxicity, and rare side effects, NAC can also be combined with other drugs. This article provides a review of knowledge on the mechanisms of inflammation and oxidative stress in various forms of ALI/ARDS and critically discusses experience with the use of NAC in these disorders. For preparing the review, articles published in the English language from the PubMed database were used.},
}

*Acetylcysteine/therapeutic use/pharmacology
Humans
*Acute Lung Injury/drug therapy
Animals
*Oxidative Stress/drug effects
COVID-19
Antioxidants/therapeutic use/pharmacology
COVID-19 Drug Treatment
SARS-CoV-2/drug effects
Respiratory Distress Syndrome/drug therapy
Anti-Inflammatory Agents/therapeutic use/pharmacology

@article {pmid40139162,
year = {2025},
author = {Megan, L and Sanchez-Migallon Guzman, D and Knych, H and Beaufrère, H},
title = {Pharmacokinetics of single-dose oral acetaminophen with and without concurrent administration of silymarin or N-acetylcysteine in orange-winged Amazon parrots (Amazona amazonica).},
journal = {American journal of veterinary research},
volume = {},
number = {},
pages = {1-11},
doi = {10.2460/ajvr.24.12.0402},
pmid = {40139162},
issn = {1943-5681},
abstract = {OBJECTIVE: To determine the pharmacokinetics of acetaminophen (N-acetyl-para-aminophenol [APAP]) and its metabolites after oral administration of a single dose of APAP, with or without silymarin or N-acetylcysteine (NAC), to orange-winged Amazon parrots (Amazona amazonica).

METHODS: Eight parrots received, in 3 separate studies, 1 of the following oral treatments: (1) APAP (100 mg/kg) with silymarin (50 mg/kg, twice, q 12 h); (2) APAP (100 mg/kg) with NAC (400 mg/kg); or (3) APAP (100 mg/kg) alone. For each study, blood samples were collected over 24 hours after drug administration to evaluate plasma concentrations of APAP, APAP-glucuronide, and APAP-sulfate. Pharmacokinetic parameters were calculated. Plasma biochemistry panels were performed before and after each study. In a fourth study, a single oral dose of APAP (100 mg/kg) was administered to 8 additional parrots for adverse effects evaluation alone.

RESULTS: Pharmacokinetic parameters for APAP, APAP-glucuronide, and APAP-sulfate were established. The APAP maximum plasma concentration, time of maximal plasma concentration, and half-life across studies ranged from 2,016.9 to 2,917.2 ng/mL, 1.13 to 2.1 hours, and 1.3 to 1.45 hours, respectively. Acetaminophen had marked metabolism to APAP-glucuronide and negligible to APAP-sulfate. Concurrent administration of APAP with silymarin resulted in a mild but significant elevation in glutamate dehydrogenase.

CONCLUSIONS: Acetaminophen plasma concentrations were lower than in other avian species despite a relatively high dose. Acetaminophen has fast absorption, short half-life, and marked glucuronidation. Single oral dose administration of APAP, alone or with NAC, appears safe based on plasma biochemistries. Multidose and pharmacodynamic studies are needed.

CLINICAL RELEVANCE: This is the first pharmacokinetic study of APAP in psittacines, which has the potential to be an effective and safe component of multimodal analgesia in these species.},
}

@article {pmid40136229,
year = {2025},
author = {Sinigaglia, G and Fortunato, LM and Grillo, ML and Partata, WA},
title = {Potential of N-acetylcysteine in the management of low back pain: a scoping review of studies in humans and animal models.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {58},
number = {},
pages = {e14382},
doi = {10.1590/1414-431X2025e14382},
pmid = {40136229},
issn = {1414-431X},
mesh = {*Acetylcysteine/therapeutic use ; Humans ; *Low Back Pain/drug therapy ; Animals ; Disease Models, Animal ; },
abstract = {Low back pain (LBP) is a common type of pain that causes disability and impairs cognitive function. With over 80% of adults estimated to experience LBP during their lifetime, this type of pain not only has a significant impact on the individual, but also on public health systems and national economies. Unfortunately, there is no single standard of care for patients with LBP. N-acetylcysteine (NAC), which is used clinically to treat acetaminophen overdose, has recently been tested as a potential treatment for LBP. NAC is inexpensive and commercially available, and it has an established tolerance and safety profile. However, NAC's efficacy in LBP has not been established. This scoping review presents a summary of studies investigating the effects of NAC and the potential benefits in LBP treatment, and highlights its potential molecular mechanisms and side effects. A systematic literature search in Pubmed/MEDLINE, Embase, Scopus, Science Direct, Web of Science, Cinahl, and Lilacs databases was conducted. The PRISMA-ScR checklist was used to ensure integrity of the review. The scoping review protocol was registered in the Open Science Framework. No limit was set on study language and publication date. In total, 2357 articles were located, of which 16 were included. The studies show that NAC has potential for LBP treatment, but data are derived only from a few clinical trials and preclinical studies. Thus, there is much to learn and more clinical studies should be performed before NAC can be clinically recommended for the treatment of LBP.},
}

*Acetylcysteine/therapeutic use
Humans
*Low Back Pain/drug therapy
Animals
Disease Models, Animal

@article {pmid40136129,
year = {2024},
author = {Hardt, M and Mayr, A and Kutschera, E and Marciniak, J and Küchler, EC and Kirschneck, C and Deschner, J and Jäger, A and Beisel-Memmert, S},
title = {Rho Kinases and Reactive Oxygen Species in Autophagy Regulation by Pressure in Periodontal Ligament Cells.},
journal = {Brazilian dental journal},
volume = {35},
number = {},
pages = {e245944},
doi = {10.1590/0103-6440202405944},
pmid = {40136129},
issn = {1806-4760},
mesh = {*Periodontal Ligament/cytology ; *Autophagy/drug effects/physiology ; Humans ; *rho-Associated Kinases/metabolism ; *Reactive Oxygen Species/metabolism ; *Pyridines/pharmacology ; *Amides/pharmacology ; *Pressure ; Cells, Cultured ; Flow Cytometry ; Acetylcysteine/pharmacology ; },
abstract = {Autophagy is a self-digestion mechanism of cells, which is related to cell stress. It enables cell survival by maintaining cellular homeostasis or initiates cell death. This study aimed to investigate the intracellular signaling of pressure-induced autophagy regulation in human periodontal ligament (PDL) cells and to analyze the involvement of Rho kinases (ROCK) and reactive oxygen species (ROS) in particular. Human PDL cells were treated with the ROCK inhibitor Y-27632 and the ROS scavenger N-acetylcysteine (NAC) in combination with pressure magnitudes of 2, 6, and 8 g/cm2 over 16 hours. Cells treated with rapamycin served as a positive control and untreated cells as a control group. The Cyto-ID® Autophagy Detection Kit was used for flow cytometric analysis. Statistical analysis was performed using ANOVA and post-hoc tests. The results show that the pressure-induced autophagy was affected differently by the two inhibitors (p<0.05). The application of Y-27632 led to a significant reduction in autophagy in all pressure groups. The application of NAC led to reduced autophagy at pressures of 2 g/cm2 and 6 g/cm2. At 8 g/cm2, this effect was no longer present. In the control group, autophagy was significantly reduced by Y-27632 and significantly increased by NAC. Our data suggest that both Rho-kinase and reactive oxygen species could influence pressure-induced autophagy regulation in PDL cells.},
}

*Periodontal Ligament/cytology
*Autophagy/drug effects/physiology
Humans
*rho-Associated Kinases/metabolism
*Reactive Oxygen Species/metabolism
*Pyridines/pharmacology
*Amides/pharmacology
*Pressure
Cells, Cultured
Flow Cytometry
Acetylcysteine/pharmacology

@article {pmid40133146,
year = {2025},
author = {Xu, R and Zhang, G and Huang, H and Zhao, Y and Tan, WS and Cai, H},
title = {Polyvinyl alcohol, N-acetylcysteine, and methyl-β-cyclodextrin exhibit albumin functions in natural killer cell culture.},
journal = {Journal of bioscience and bioengineering},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jbiosc.2025.02.008},
pmid = {40133146},
issn = {1347-4421},
abstract = {Albumin is a crucial component of serum-free media, playing a significant role in ex vivo cell culture as a lipid carrier and antioxidant. However, purified albumin contains undefined substances, making it challenging to achieve clinical application standards for effector cell culture. This study used natural killer (NK)-92 cells as a model to investigate the effects of the albumin substitute replacing bovine serum albumin (BSA) on cell expansion and metabolism in an in-house-designed, chemically defined, serum-free medium. We selected polyvinyl alcohol (PVA), N-acetylcysteine (NAC), and methyl-β-cyclodextrin (M-β-CD) as an albumin substitute combination and optimized their concentrations by using response surface methodology. The optimized albumin substitute was named PVA-NAC-M-β-CD (PNM). After 8 days of culture, NK-92 cells cultured with the PNM exhibited phenotype and cytotoxic function comparable to cells cultured with different concentrations of BSA. The expansion fold was 89.22 ± 3.55, significantly higher than the 51.23 ± 6.57 observed in the 0.75 g/L BSA group (p < 0.05). Further verification of functions of PNM showed that intracellular fatty acid levels, cholesterol consumption rates, and the pSTAT5 level in the PNM group were significantly higher than those in the 0.75 g/L BSA group (p < 0.05). Reactive oxygen species levels remained controlled, and mitochondrial membrane potential was similar. These findings suggested that the PNM can effectively replace the functions of BSA as a fatty acid carrier, antioxidant, and, to some extent, a cholesterol carrier. This study provides insights for developing chemically defined media to prepare clinical-grade NK cells efficiently.},
}

@article {pmid40133121,
year = {2025},
author = {Lucas-Herald, AK and Hussain, S and McGinley, K and Alves-Lopes, R and Amjad, SB and Flett, M and Lee, B and Steven, M and O'Toole, S and Ahmed, SF},
title = {ROS scavengers and genital skin healing in boys with hypospadias.},
journal = {Journal of pediatric urology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpurol.2025.02.023},
pmid = {40133121},
issn = {1873-4898},
abstract = {INTRODUCTION: Hypospadias repair is associated with high complication rates. Vascular cells from boys with hypospadias have increased reactive oxygen species (ROS) compared to controls. It is not clear if ROS affects wound healing in hypospadias.

OBJECTIVES: The aim of this study is to identify if cell migration and proliferation in genital skin is altered in hypospadias, and whether this is altered by antioxidants.

STUDY DESIGN: Genital skin fibroblasts (GSFs) were grown from boys undergoing hypospadias repair or routine circumcision. Cells were imaged immediately after creating a wound scratch and 48 h later, in the presence/absence of ROS scavengers, N-acetylcysteine (NAC) or Tempol. Cell migration was determined using ImageJ software. Cell proliferation was measured using a Cell Count Kit-8 (Abcam, UK).

RESULTS: Twenty-four cases (median age (range) 1.8 (1.2, 6.3) years) and 28 controls (1.6 (1.2, 6.1) years) were recruited. Boys with hypospadias had impaired cell migration with reduced wound closure at 48 h (2.0 fold, p < 0.0001) and reduced cell proliferation (1.3 fold, p = 0.01). External Masculinisation Score was positively correlated with wound closure (r = 0.5, p < 0.0001) and cell proliferation (r = 0.3, p = 0.002). Exposure to NAC and Tempol improved wound closure (1.9 fold, p = 0.01, and 1.5 fold, p = 0.02 respectively) and cell proliferation (1.5 fold, p = 0.02 and 1.4 fold, p = 0.05 respectively).

DISCUSSION: There is an association between wound healing and virilisation of the external genitalia in boys. ROS scavengers increase cell migration and proliferation in GSFs from boys with hypospadias.

CONCLUSION: Translational studies are required to confirm whether ROS scavengers may represent a therapeutic option for improving surgical outcome in boys with hypospadias.},
}

@article {pmid40126496,
year = {2025},
author = {Syarif, S and Makkaraka, MAG and Zainal, ATF and Birowo, P and Atmoko, W},
title = {Unlocking the potential of antioxidant supplementation with n-acetylcysteine to improve seminal parameters and analysis of its safety: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica},
volume = {},
number = {},
pages = {13750},
doi = {10.4081/aiua.2025.13750},
pmid = {40126496},
issn = {2282-4197},
abstract = {INTRODUCTION AND OBJECTIVES: N-acetyl-cysteine (NAC) is one of the oldest and most powerful antioxidants used to treat various diseases. It plays an important role in protecting cells against oxidative damage and has the potential to improve seminal parameters in male with infertility. This systematic review and meta-analysis aim to comprehensively evaluate the efficacy and safety profile of antioxidant supplementation with NAC in male with infertility or impaired semen parameters.

MATERIALS AND METHODS: This systematic review and meta-analysis adhered to Cochrane Handbook guidelines. A literature search across PubMed, ScienceDirect, Cochrane Library and Scopus on February 21, 2024 of studies evaluating NAC supplementation for male infertility or impaired semen parameters was conducted. Study quality was assessed using Revised Cochrane's risk of bias (RoB 2.0) and RevMan 5.4 was used for meta-analysis.

RESULTS: Search yielded 1.106 articles and 5 studies were included in this meta-analysis. Our study showed that patients who received NAC had statistically significant results in improving sperm volume [MD: 0.69 (0.26-1.12), P = 0.002], sperm concentration [MD: 4.43 1.50-7.36), P = 0.003], sperm total motility [MD: 9.69 (6.61-12.77), P < 0.00001], and normal sperm morphology [MD: 1.36 (0.70-2.03), P < 0.0001] compared to control. Additionally, patients given NAC had no reported side effects based on our included studies.

CONCLUSIONS: We found NAC supplementation significantly improves seminal parameters and has a favorable safety profile. These findings highlight the potential role of NAC as a safe supplementation for male with infertility or in male with impaired semen parameters.},
}

@article {pmid40125296,
year = {2025},
author = {El-Sarnagawy, GN and Abd Eldayem, YB and Sobeeh, FG},
title = {Pattern and impact of antidotal administration in an Egyptian tertiary poison control center: A three-year retrospective study (2021-2023).},
journal = {Toxicology reports},
volume = {14},
number = {},
pages = {101973},
pmid = {40125296},
issn = {2214-7500},
abstract = {Timely antidote administration is a critical step in acute poisoning management. Awareness of poisoning patterns and the essential antidotal requirement could improve patient care with better hospital resource allocation. This study investigates the pattern and impact of antidotal administration on patient outcomes in an Egyptian tertiary poison control center, providing insights to optimize the antidote stocking of essential antidotes. A three-year cross-sectional study was conducted at Tanta University Poison Control Center from January 2021 to December 2023. Demographic data, poisoning characteristics, causative agents, and administered antidotal data were retrieved. The initial Poisoning Severity Score (PSS), total hospitalization period, and patient outcomes were also recorded. The included 447 antidote-treated poisoned patients showed near equal gender distribution and median age of 25 years. Atropine, oximes, N-acetylcysteine (NAC), and naloxone were the top administered antidotes among patients (48.3 %, 25.7 %, 19.9 %, and 11.2 %, respectively). Mortality and complications were recorded in 5.15 % and 20.8 %, respectively. Administration of atropine, oximes, NAC, and L-carnitine significantly improved all outcomes (p < 0.05). Although HBO therapy significantly improved mortality, it substantially increased intensive care unit admissions (p < 0.001). Despite folic acid administration significantly improved mortality and complication incidences (p < 0.05), its therapeutic efficiency is still questionable. Availability constraints of the digibind and botulinum antitoxin could affect patient outcomes. Administration of atropine, oximes, NAC, naloxone, and sodium bicarbonate was significantly linked to prolonged hospitalization (p < 0.001). Accordingly, the emergency department in each institution should regularly update the antidotal stock based on a review of the list of essential and commonly used antidotes.},
}

@article {pmid40122550,
year = {2025},
author = {Humphries, C and Clarke, E and Eddleston, M and Gillings, M and Irvine, S and Keating, L and Miell, A and Milne, L and Muir, L and O'Brien, R and Oatey, K and Raman, R and Thanacoody, R and Tuck, S and Weir, CJ and Wood, DM and Dear, JW and , },
title = {HiSNAP trial-a multicentre, randomised, open-label, blinded end point, safety and efficacy trial of conventional (300 mg/kg) versus higher doses of acetylcysteine (450 mg/kg and 600 mg/kg) in patients with paracetamol overdose in the UK: study protocol.},
journal = {BMJ open},
volume = {15},
number = {3},
pages = {e097432},
doi = {10.1136/bmjopen-2024-097432},
pmid = {40122550},
issn = {2044-6055},
mesh = {Humans ; *Acetaminophen/poisoning/administration & dosage ; *Acetylcysteine/administration & dosage/therapeutic use ; *Drug Overdose/drug therapy ; Analgesics, Non-Narcotic/poisoning/administration & dosage ; United Kingdom ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Antidotes/administration & dosage/therapeutic use ; Chemical and Drug Induced Liver Injury/drug therapy ; Glutathione/metabolism ; Dose-Response Relationship, Drug ; Male ; Adult ; },
abstract = {INTRODUCTION: In overdose, a larger proportion of paracetamol (acetaminophen) is converted in the liver to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Glutathione (GSH) is the endogenous antioxidant that protects cells from NAPQI-induced injury. In overdose, GSH stores may become depleted, leaving NAPQI free to produce liver damage. N-Acetylcysteine (NAC) helps prevent paracetamol toxicity by replenishing liver GSH. This protective effect of NAC produces specific metabolites in the circulation. Currently, regardless of the paracetamol dose ingested, patients in the UK receive a dose of NAC based only on their weight. Basic pharmacology, mathematical modelling and observational studies suggest that this dose may be insufficient in some patients (particularly those taking a large overdose).

METHODS AND ANALYSIS: A multicentre trial, taking place across several hospitals in Scotland, UK, within Emergency Departments and Acute Medical Units. Recruitment commenced on 19 February 2024 and is anticipated to run for approximately 2 years. This is a three-group dose-finding trial, in which participants are assigned in a 1:1:1 ratio to either Standard NAC (300 mg/kg) or higher doses of 450 mg/kg (Group 1) and 600 mg/kg (Group 2). The primary outcome is the proportion of paracetamol metabolites in the circulation that are directly produced by GSH/NAC detoxification of NAPQI. A higher proportion of these metabolites will indicate that the additional NAC is reducing the amount of toxic paracetamol metabolites in the body. The study will first test the primary outcome on the HiSNAP Group 2 against Standard NAC; only if that is significant will HiSNAP Group 1 be tested against Standard NAC.

ETHICS AND DISSEMINATION: The HiSNAP trial has been approved by the East Midlands (Derby) Research Ethics Committee (reference 23/EM/0129), NHS Lothian Research and Development Department, and the MHRA. Results will be disseminated by peer-reviewed publication, conferences and linked on isrctn.com.

TRIAL REGISTRATION NUMBER: ISRCTN17516192.},
}

Humans
*Acetaminophen/poisoning/administration & dosage
*Acetylcysteine/administration & dosage/therapeutic use
*Drug Overdose/drug therapy
Analgesics, Non-Narcotic/poisoning/administration & dosage
United Kingdom
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Antidotes/administration & dosage/therapeutic use
Chemical and Drug Induced Liver Injury/drug therapy
Glutathione/metabolism
Dose-Response Relationship, Drug
Male
Adult

@article {pmid40122511,
year = {2025},
author = {Peerapen, P and Rattananinsruang, P and Putpeerawit, P and Boonmark, W and Thongboonkerd, V},
title = {The direct inhibitory effects of an antioxidant, N-acetylcysteine, against calcium oxalate crystal growth, aggregation and adhesion to MDCK renal cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {115403},
doi = {10.1016/j.fct.2025.115403},
pmid = {40122511},
issn = {1873-6351},
abstract = {N-acetylcysteine (NAC), a potent antioxidant, can reduce nephrolithiatic pathogenesis by diminishing oxidative assault during crystalluria. However, its direct effects on calcium oxalate (CaOx) crystals that affect stone development were unknown. Herein, we examined the direct effects of NAC (at 1, 10 or 100 μM) on CaOx crystal formation, growth, aggregation, adhesion to MDCK renal cells, and internalization into the cells. The findings demonstrated that NAC at all these concentrations did not significantly affect size, number and mass of the newly generated CaOx crystals and their internalization into renal cells. However, NAC dose-dependently inhibited CaOx self-aggregation. Additionally, NAC at all concentrations significantly decreased the enlargement (growth) of the already-formed CaOx crystals and their adhesion to renal cells. Its dose-dependent inhibitory effects on crystal growth and adhesion were demonstrated at lower concentrations (0.01 and 0.1 μM). Measurement of adsorption energy (Eadsorption) between NAC molecule and Ca[2+] ion revealed adsorption or affinity between NAC and Ca[2+]. Their affinity/binding was also confirmed by an ion-selective electrode (ISE)-based titration assay. These data have shown, for the first time, the direct inhibitory effects of NAC against CaOx crystal growth, aggregation and crystal adhesion to renal cells via Ca[2+] binding that may impact the prevention of nephrolithiasis.},
}