@article {pmid40553255,
year = {2025},
author = {Chen, ZW and Li, YF and Qiu, HL and Xie, W and Chen, TY and Zhang, Y and Chen, JM and Zhuang, J and Wen, SS},
title = {Maternal Electronic Cigarette Exposure Induces Dysregulation of Autophagy via Oxidative Stress/DNA Methylation in Pulmonary Hypertension Offspring.},
journal = {Current medical science},
volume = {},
number = {},
pages = {},
pmid = {40553255},
issn = {2523-899X},
support = {82300268//National Natural Science Foundation of China/ ; 2023B03J1255//Guangzhou Municipal Science and Technology Project/ ; },
abstract = {OBJECTIVE: Electronic cigarettes (ECs) differ from traditional tobacco smoke but may contribute to cardiopulmonary remodeling. Pulmonary hypertension (PH), characterized by pulmonary artery and right ventricle remodeling, poses a significant risk of mortality in infants, children, and adolescents. However, the impact of maternal EC exposure on PH development in offspring remains unclear. To address this, we established a PH rat model with maternal EC exposure.

METHODS: Maternal EC exposure was initiated on gestation day 12 via electronic nicotine delivery systems. Offspring were administered monocrotaline (MCT) at 6 weeks of age (6-wo) to induce PH. Mechanistic experiments were conducted at 10-week-old (10-wo). Protein expression of NADPH oxidases, DNA methyltransferases, and autophagy-related markers was analyzed by Western blot. Morphological changes and the severity of PH were evaluated via hematoxylin and eosin (HE) staining and echocardiography, respectively. Furthermore, the involvement of the oxidative stress/DNA methylation/autophagy axis in response to maternal EC exposure was confirmed through a combination of ELISA, Western blot, HE staining, and echocardiography. Additionally, ATG5 mRNA expression was measured by qRT-PCR.

RESULTS: Compared with control conditions, maternal EC exposure significantly worsened MCT-induced PH in male offspring. This was associated with increased oxidative stress, DNA hypomethylation, and anomalous autophagy in the offspring. In vivo treatment with chloroquine inhibited autophagy and ameliorated PH development in offspring exposed to maternal EC. Furthermore, N-acetylcysteine (NAC), an antioxidant, attenuated maternal EC exposure-induced oxidative stress, DNA hypomethylation, and excessive autophagy, thereby improving PH. DNA hypermethylation also reversed PH development, accompanied by reduced oxidative stress and suppressed autophagy. ATG5, a key regulator of autophagy, was identified as a potential therapeutic target, as its repression mitigated PH in maternal EC-exposed offspring.

CONCLUSION: Maternal EC exposure induces oxidative stress and DNA hypomethylation in offspring, leading to anomalous autophagy and exacerbation of PH development. Targeting ATG5-mediated autophagy may represent a novel therapeutic approach for improving PH outcomes in offspring exposed to maternal EC.},
}

@article {pmid40553253,
year = {2025},
author = {Ding, WC and Chen, J and Li, Q and Ren, Y and Wang, MM and Zhang, W and Ji, XH and Wu, XY and Nie, SN and Huang, CB and Sun, ZR},
title = {Quercetin Confers Protection against Sepsis-Related Acute Respiratory Distress Syndrome by Suppressing ROS/p38 MAPK Pathway.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {40553253},
issn = {1993-0402},
abstract = {OBJECTIVE: To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS).

METHODS: In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 μmol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro.

RESULTS: Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01).

CONCLUSION: Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.},
}

@article {pmid40541897,
year = {2025},
author = {Karmarkar, C and Sarkar, D and Ghosh, A and Haldar, D and Chatterjee, M},
title = {Evaluating the leishmanicidal activity of m-Nitrocinnamic Acid containing Lipophilic Peptide against Leishmania donovani.},
journal = {Acta tropica},
volume = {},
number = {},
pages = {107703},
doi = {10.1016/j.actatropica.2025.107703},
pmid = {40541897},
issn = {1873-6254},
abstract = {Studies have demonstrated that m-Nitrocinnamic acid containing Lipophilic Peptide (LP) exhibits leishmanicidal activity against Leishmania major promastigotes; however, its efficacy against the amastigote form remains unclear. In this study, we evaluated the activity of LP against Leishmania donovani, the causative agent of Visceral Leishmaniasis (VL), wherein LP demonstrated both anti-promastigote and anti-amastigote activity, as measured by MTS cell viability assay and droplet digital PCR (ddPCR) respectively, the IC50 derived being 25.0 and 6.0 µM respectively, while the CC50 was >500 µM, which translated into a safety index >83. LP induced leishmanicidal activity by triggering a redox imbalance in promastigotes, by enhancing the generation of reactive oxygen species (ROS) and caused lipid peroxidation, but failed to impact on generation of mitochondrial superoxide. Furthermore, as N-acetyl cysteine (NAC) attenuated the parasiticidal properties of LP via scavenging the free radicals, it substantiated that the cytotoxicity of LP was mediated by inducing a redox imbalance. An apoptotic-like cell death was demonstrated in promastigotes, features being an enhanced annexin V positivity, altered mitochondrial membrane potential, and cell cycle arrest at sub G0/G1. Collectively, this study confirmed that LP exhibited leishmanicidal activity against L. donovani that was mediated by an apoptotic-like cell death via disruption of redox homeostasis, and could be considered as a compound worthy of further pharmacological consideration.},
}

@article {pmid40541750,
year = {2025},
author = {Lin, D and Li, G and Deng, H and Wang, S},
title = {The protective effect of Schisandra lignans on the hepatotoxicity induced by the metabolic activation of dictamnine.},
journal = {Journal of ethnopharmacology},
volume = {352},
number = {},
pages = {120170},
doi = {10.1016/j.jep.2025.120170},
pmid = {40541750},
issn = {1872-7573},
abstract = {Dictamnine (DIC) is the predominant pharmacological and hepatotoxic component of Cortex Dictamni (CD). CYP3A-mediated metabolic activation plays an important role in DIC-induced hepatotoxicity. Schisandra lignans (SCLs) are the major hepatoprotective ingredients of Schisandra chinensis (SC). CD and SC are frequently used as herb pairs in traditional Chinese medical formulas particularly for the treatment of eczema and urticarial. Our preliminary studies have shown that SC can protect against CD-induced liver injury. However, the underlying protective mechanism of SC against CD-induced liver injury has remained unknown.

AIM OF THE STUDY: This study aims to investigate the effects of SCLs on the hepatotoxicity and metabolic activation of DIC and elucidate the underlying hepatoprotective mechanism from the perspective of the inhibition of CYP3A-mediated metabolic activation.

MATERIAL AND METHODS: The protective effect of SCLs against DIC-induced hepatotoxicity was evaluated by biochemical analysis and liver histological observation. The effect of SCLs on the in vitro metabolic activation of DIC was assessed by detecting the level of DIC-N-acetylcysteine (NAC) conjugates in mouse liver microsomal incubations. The effect of SCLs on the metabolic activation in vivo of DIC was examined by monitoring the toxicokinetic behaviors of DIC, DIC-induced hepatic GSH depletion, the cumulative urine excretion of DIC, the levels of DIC-NAC conjugates in urine and liver of mice, and the formation of DIC-derived cysteine-protein adducts.

RESULTS: Our findings indicated that SCLs protected against DIC-induced hepatotoxicity in a dose-dependent manner. SCLs exhibited dose-dependent inhibitory effect on the formation of DIC-NAC conjugates in liver microsomal incubations, indicating SCLs inhibited the metabolic activation of DIC in vitro. SCLs increased Cmax and AUCs of DIC in the blood and liver of mice, leading to the enhancive accumulation of DIC in the circulation. Pretreatment with SCLs relieved hepatic GSH depletion induced by DIC, promoted the urinary excretion of DIC, inhibited the formation of reactive metabolite of DIC in urine and liver of mice, and reduced the production of DIC-derived cysteine-protein adducts, suggesting that SCLs influenced absorption, distribution, metabolism, and excretion (ADME) of DIC by suppressing the metabolic activation of DIC in vivo.

CONCLUSIONS: The study demonstrated the protective effect of SCLs against hepatotoxicity induced by DIC was related to the inhibition of CYP3A-mediated metabolic activation of DIC. Therefore, the study demonstrated that SCLs may serve as the candidate drugs for the intoxication of DIC. Moreover, our findings may interpret the protective mechanism of SC against CD-induced liver injury.},
}

@article {pmid40539306,
year = {2025},
author = {Zahaki Nosrat, F and Yari, S and Mahmoodi, B and Hasanein, P},
title = {Effects of N-acetylcysteine on rat sperm treated with hydrogen peroxide in in vitro conditions.},
journal = {Biotechnic & histochemistry : official publication of the Biological Stain Commission},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/10520295.2025.2516582},
pmid = {40539306},
issn = {1473-7760},
abstract = {Infertility affects around 15% of couples worldwide, with male factors being responsible for nearly half of these cases. Oxidative stress is a significant contributor to male infertility, leading to damaged sperm. This research examines the protective effects of Nacetylcysteine (NAC) on sperm exposed to hydrogen peroxide (H2O2) induced oxidative stress in rats. Sperm samples from adult male Wistar rats were divided into four groups: control, H2O2, NAC, and H2O2+NAC. Various parameters, including sperm viability, abnormal morphology, chromatin condensation, and plasma membrane integrity were evaluated after incubation using established assays. Exposure to H2O2 significantly decreased sperm viability, increased the rate of abnormal morphology, heightened chromatin condensation abnormalities, and compromised plasma membrane integrity. Treatment with NAC significantly ameliorated these effects, demonstrating its protective role against oxidative damage. NAC effectively counteracts oxidative damage in sperm, improving viability, morphology, chromatin integrity, and membrane integrity. These findings demonstrate the protective effects of NAC against oxidative stress-induced sperm damage under in vitro conditions, underscoring its potential as a subject for further investigation in the context of oxidative stress-related male infertility.},
}

@article {pmid40538547,
year = {2025},
author = {Shen, YC and Wang, YH and Liou, KT and Wei, WC and Cheng, JJ and Liu, HK and Huang, NK and Lo, IW and Chang, CC and Chiou, WF and Tsai, KC and Chiou, CT and Liaw, CC and Su, YC},
title = {Synergistic protective effects of TCM formula NRICM102 and N-acetylcysteine against hepatorenal injury in a mouse model of bongkrekic acid poisoning.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1596785},
pmid = {40538547},
issn = {1663-9812},
abstract = {Bongkrekic acid (BKA), a mitochondrial toxin produced by Burkholderia cocovenenans subsp. farinofermentans, is typically found in contaminated fermented rice products such as tempeh bongkrek, causing severe foodborne illnesses marked by systemic inflammation, multi-organ failure (MOF), and high mortality rates (40%-100%). A recent outbreak in Taiwan (2024) resulted in six fatalities among 33 affected individuals, underscoring the urgent clinical need for effective treatments. This study evaluated the therapeutic potential of NRICM102, a novel traditional Chinese medicine (TCM) formulation, combined with the antioxidant N-acetylcysteine (NAC), against BKA-induced hepatorenal toxicity in a mouse model. NRICM102 (1.5-3.0 g/kg), NAC (0.5 g/kg), and their combination significantly improved survival, reduced serum biomarkers (GOT, GPT, BUN), and alleviated liver and kidney histopathological damage following acute (5.0 mg/kg) and subacute (2.0 mg/kg) BKA exposure. RNA-seq analyses suggested that the NRICM102-NAC combination synergistically modulated critical pathways, including mitochondrial function, cytochrome P450 enzyme activity, oxidative stress, immune responses, and cell death regulation. Despite these promising findings, mechanistic conclusions remain associative and require further validation using targeted mitochondrial studies. Collectively, NRICM102 combined with NAC offers a promising, translationally relevant therapeutic strategy warranting additional preclinical safety and pharmacokinetic assessments to advance toward clinical application.},
}

@article {pmid40534932,
year = {2025},
author = {Brown, S and Kennard, B and Thigpen, J},
title = {Chemical Compatibility of N-Acetylcysteine After the Simultaneous Intravenous Administration of Ondansetron.},
journal = {The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG},
volume = {30},
number = {3},
pages = {362-366},
pmid = {40534932},
issn = {1551-6776},
abstract = {OBJECTIVE: This study evaluated the chemical compatibility of N-acetylcysteine (NAC) and ondansetron to simplify the treatment of acute nausea and vomiting during intravenous (IV) NAC administration. NAC is commonly used to treat acetaminophen overdose, but its 21-hour IV infusion is often interrupted for ondansetron administration, which can pose risks.

METHODS: High-performance liquid chromatography with ultraviolet detection was used to quantify NAC. To simulate IV administration, a closed-circuit pump with multiple independent lines, was plumbed with Y-sites to circulate NAC at concentrations matching 30- and 100-kg loading doses and 4-mg ondansetron was pushed into the flow paths. Control lines without ondansetron were also maintained. Samples were collected at 10, 20, and 30 minutes postondansetron introduction. NAC concentrations in single-drug and combination lines were compared using an unpaired t-test with Welch's correction (p = 0.05).

RESULTS: The mean concentrations for the 100-kg dose were 55.23 and 55.28 mg/mL for control and with ondansetron, respectively. The 30-kg cohort included 36.38 mg/mL for control and 36.49 mg/mL with ondansetron. The results of the unpaired t-test for either weight illustrated that no statistical significance was achieved. Furthermore, the t-values of 0.2013 for 100 kg and 0.8556 for 30 kg support a less likely chance of significant difference.

CONCLUSION: Based on this experiment, ondansetron can be introduced into an NAC infusion via IV push in vitro without affecting the NAC concentration in the solution. The likelihood of IV compatibility for NAC and ondansetron could permit no infusion interruptions, reducing unnecessary risk of acetaminophen toxicity.},
}

@article {pmid40533050,
year = {2025},
author = {Nakhaee, S and Kooshki, A and Mehrpour, O and Hosseini, M and Farrokhfall, K},
title = {Effects of anti-oxidants, NOX inhibitor (DPI), and anti-apoptotic pathways on carbohydrate metabolism and liver function in acute aluminum phosphide toxicity exposed rats.},
journal = {Regulatory toxicology and pharmacology : RTP},
volume = {162},
number = {},
pages = {105890},
doi = {10.1016/j.yrtph.2025.105890},
pmid = {40533050},
issn = {1096-0295},
abstract = {Aluminum phosphide (AlP) is widely used in suicide attempts. We evaluated the effects of Diphenylene iodonium (DPI), N- N-acetyl cysteine (NAC), and Nivocasan therapeutics on AlP toxicity. Thirty rats were kept in five groups: control (receiving normal saline); the remaining groups were exposed to oral AlP, and treatments (NAC, DPI, and Nivocasan). Liver function tests (LFTs), serum and liver oxidative markers, insulin, glucose, tumor necrosis factor-α (TNF-α), serum and islets interleukin 1β (IL-1β), and glucose-stimulated insulin secretion through islet isolation were assessed. LFTs significantly increased in AlP poisoned animals, and NAC, DPI, and Nivocasan decreased their levels to near control (P < 0.05). DPI and Nivocasan recovered AlP-induced hypoglycemia. Plasma catalase, GPx, and MDA increased in the AlP group, and NAC, DPI, and Nivocasan had protective effects (P < 0.05). DPI significantly decreased serum TNF-α, and NAC decreased IL-1β levels. NAC reversed AlP-induced lower insulin secretion (P < 0.05). Aluminum phosphide (AlP) induces hypoglycemia and liver damage. AlP-related hypoglycemia is associated with elevated inflammatory and oxidative stress markers and impaired insulin secretion from pancreatic islets which improved by NAC. DPI and Nivocasan treat hypoglycemia. DPI and NAC were effective in reducing inflammatory markers.},
}

@article {pmid40532836,
year = {2025},
author = {Zhou, X and Yan, H and Hong, Y and Ding, Y and Chen, J and Tang, H and Wei, Y and Long, C and Shen, L and Wei, G and Wu, S},
title = {PPARγ mediated lysosomal membrane permeabilization and lipophagy blockage were involved in microplastics and di (2-ethylhexyl) phthalate co-exposure induced immature testis injury.},
journal = {Free radical biology & medicine},
volume = {237},
number = {},
pages = {615-630},
doi = {10.1016/j.freeradbiomed.2025.06.023},
pmid = {40532836},
issn = {1873-4596},
abstract = {Polystyrene microplastics (PS-MPs) and di (2-ethylhexyl) phthalate (DEHP), two main composites of plastic products, are always exposed to human at the same time. However, most existing research has focused on single exposure, which is not consistent with the actual exposure circumstance. In this study, single and co-exposure animal model were established. C57/BL6J mice were exposed to corn oil, 20 mg/kg PS-MPs, 200 mg/kg DEHP and PS-MPs + DEHP for 28 days. The HE staining showed more serious seminiferous epithelium disorganization in co-exposed mice, indicating that PS-MPs and DEHP co-exposure could aggravate testicular injury. Compared with control group, integrative analysis of transcriptomics and proteomics revealed that PPARγ pathway played a crucial role in PS-MPs and DEHP co-exposure induced testis injury. In vitro, spermatocytes (GC-2) and leydig cells (TM3) were exposed to 50 μM MEHP, 10 mg/L PS-MPs and PS-MPs + MEHP for 48 h. Though PS-MPs and MEHP single exposure also triggered oxidative stress and PPAR pathway, the protein levels showed more remarkable difference in co-exposure group. Furthermore, co-exposure to PS-MPs and MEHP induced lysosomal membrane permeabilization (LMP), which significantly impaired lysosomal-mediated lipid degradation, thereby exacerbating lipid metabolism dysfunction in testicular cells. Treatment with N-Acetylcysteine (NAC) and knockdown of fatty acid-binding protein (FABP4) restored lipophagy flux and reduced lipid droplets deposition. Overall, co-exposure of PS-MPs and DEHP has synergistic toxic effect, inducing oxidative stress, PPARγ activation and lipophagy blockage, finally resulting in unbalanced lipid metabolism and testicular damage.},
}

@article {pmid40531753,
year = {2025},
author = {Assis, EIT and Godinho, AN and Freire, JMO and Lima Neto, MF and Costa, JJN and Souza, ALP and Monte, APOD and Matos, MHT and Sousa, ALM and Silva, JRV and Silva, AWB},
title = {Protective effects of Aloe vera extract against doxorubicin-induced degeneration in ovarian follicles and stromal cells in mice.},
journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas},
volume = {58},
number = {},
pages = {e14402},
pmid = {40531753},
issn = {1414-431X},
mesh = {Animals ; Female ; *Doxorubicin/toxicity ; *Aloe/chemistry ; *Plant Extracts/pharmacology ; *Ovarian Follicle/drug effects/pathology ; Mice ; *Stromal Cells/drug effects/pathology ; Random Allocation ; Antibiotics, Antineoplastic/toxicity ; Superoxide Dismutase/analysis ; },
abstract = {The present study aimed to evaluate the protective effects of Aloe vera on doxorubicin (DOX)-induced degeneration in ovarian follicles and stromal cells in mice. Mice (n=48) were randomly divided into six groups. The positive control group mice received pretreatment of N-acetylcysteine orally (po), followed by a single intraperitoneal (ip) dose of DOX after 1 h (NAC+DOX). The negative control group mice were pre-treated with saline (po) and administered a single DOX dose (ip) after 1 h (SAL+DOX). The other groups of mice were pre-treated with different concentrations (0.1, 1.0, or 10.0 mg/kg; po) of Aloe vera and then received a single dose of DOX (ip) after 1 h (AV0.1+DOX, AV1.0+DOX, and AV10.0+DOX). The control group received saline po and ip (SAL+SAL). Aloe vera was administered once daily for 3 consecutive days. On the fourth day, the ovaries were processed for histological analysis, immunohistochemistry, and real-time PCR (mRNA for superoxide dismutase (SOD), catalase (CAT), nuclear factor erythroid 2-related factor 2 (NRF2), and tumor necrosis factor-α (TNF-α). Results showed that 0.1 and 1.0 mg/kg Aloe vera protected ovarian follicles and stromal density against DOX-induced degeneration. Furthermore, 0.1 and 1.0 mg/kg Aloe vera reduced TNF-α protein expression and increased NRF2, SOD, and CAT mRNA levels. In conclusion, 0.1 and 1.0 mg/kg Aloe vera had protective effects against DOX-induced degeneration in ovarian follicles and stromal cells in mice.},
}

Animals
Female
*Doxorubicin/toxicity
*Aloe/chemistry
*Plant Extracts/pharmacology
*Ovarian Follicle/drug effects/pathology
Mice
*Stromal Cells/drug effects/pathology
Random Allocation
Antibiotics, Antineoplastic/toxicity
Superoxide Dismutase/analysis

@article {pmid40524738,
year = {2025},
author = {Duttenhefner, JN and Reindl, KM},
title = {GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.},
journal = {Molecular & cellular oncology},
volume = {12},
number = {1},
pages = {2518773},
pmid = {40524738},
issn = {2372-3556},
abstract = {Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.},
}

@article {pmid40523886,
year = {2025},
author = {Tang, G and Cao, X and Chen, J and Hui, F and Xu, N and Jiang, Y and Lu, H and Xiao, H and Liang, X and Ma, M and Qian, Y and Liu, D and Wang, Z and Liu, S and Yu, G and Sun, L},
title = {Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis.},
journal = {Cell death & disease},
volume = {16},
number = {1},
pages = {452},
pmid = {40523886},
issn = {2041-4889},
mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology/metabolism ; *Lung Neoplasms/drug therapy/genetics/pathology/metabolism ; *Tumor Suppressor Protein p53/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Pyroptosis/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; *Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors/metabolism ; Caspase 3/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Drug Repositioning ; Cell Line, Tumor ; Mutation/genetics ; Apoptosis/drug effects ; para-Aminobenzoates/pharmacology ; Phosphate-Binding Proteins/metabolism ; Gasdermins ; },
abstract = {Non-small cell lung cancer (NSCLC) is highly malignant with limited treatment options, largely due to the inherent tumoral heterogeneity and acquired resistance towards chemotherapy and immunotherapy. RG7388, a known MDM2 inhibitor, exhibited anticancer activity in TP53-wild-type (TP53[WT]) NSCLC by triggering the p53/PUMA axis-dependent apoptosis. However, our study uncovered previously unrecognized p53-independent anticancer effects of RG7388 in TP53-mutant (TP53[mutant]) NSCLC, although the underlying mechanisms remained elusive. Here, we demonstrated that RG7388 specifically induced the NOXA/caspase-3 axis-dependent apoptosis and gasdermin E (GSDME)-mediated secondary pyroptosis in TP53[mutant] NSCLC, as validated through in silico analyses and multiple biological assays. Mechanically, we identified reactive oxygen species (ROS) as the critical mediator in NOXA upregulation and p38 MAPK pathway activation in RG7388 treated TP53[mutant] NSCLC. This was further supported by the use of ROS scavengers, N-acetylcysteine (NAC), and Ferrostatin-1 (Fer-1), which attenuated these effects. Pharmacologic inhibition of p38 MAPK signaling by SB203580 rescued RG7388-induced ROS-dependent NOXA accumulation and subsequent apoptosis and pyroptosis, highlighting the central role of the ROS/phosphorylated p38 MAPK (p-p38)/NOXA/caspase-3 axis in RG7388-induced TP53[mutant] NSCLC cell death. Our findings revealed a novel mechanism for selectively targeting mutant p53-derived cancer through ROS/p-p38-mediated NOXA accumulation, offering potential therapeutic implications given the current lack of direct mutant p53 targeting strategies in cancer. Furthermore, immunohistochemical (IHC) analysis of an NSCLC tissue microarray confirmed a strong positive correlation between p-p38 and NOXA expression. Clinical data analysis further suggested that the p-p38/NOXA axis might be a potential prognostic biomarker for overall survival (OS) in NSCLC patients.},
}

Humans
*Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology/metabolism
*Lung Neoplasms/drug therapy/genetics/pathology/metabolism
*Tumor Suppressor Protein p53/genetics/metabolism
Reactive Oxygen Species/metabolism
*Pyroptosis/drug effects
p38 Mitogen-Activated Protein Kinases/metabolism
*Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors/metabolism
Caspase 3/metabolism
Proto-Oncogene Proteins c-bcl-2/metabolism
Drug Repositioning
Cell Line, Tumor
Mutation/genetics
Apoptosis/drug effects
para-Aminobenzoates/pharmacology
Phosphate-Binding Proteins/metabolism
Gasdermins

@article {pmid40522608,
year = {2025},
author = {Zhou, K and Wu, G and Dong, R and Kan, C and Xie, L and Gao, L and Li, H and Sun, J and Ning, W},
title = {Mitochondrial deoxyguanosine kinase depletion induced ROS causes melanocyte stem cell exhaustion and hair greying.},
journal = {Cell regeneration (London, England)},
volume = {14},
number = {1},
pages = {25},
pmid = {40522608},
issn = {2045-9769},
support = {32270846//National Natural Science Foundation of China/ ; 202401AT070443//Applied Basic Research Foundation of Yunnan Province/ ; 202501AT070205//Applied Basic Research Foundation of Yunnan Province/ ; },
abstract = {Hair pigmentation is regulated by melanocyte stem cells (MeSCs) within the hair follicle. Mitochondrial dysfunction is associated with hair depigmentation, primarily due to defects in melanogenesis. However, the mechanisms by which mitochondria support MeSCs during hair pigmentation remain obscure. In this study, we investigated the role of mitochondrial deoxyguanosine kinase (DGUOK), which provides guanosine and adenosine nucleotides for mitochondrial DNA (mtDNA) replication, in hair pigmentation and MeSCs maintenance. Dguok depleted and conditional knockout mice exhibit premature hair greying. This phenotype was not due to impaired melanin production by melanocytes but was associated with a significant loss of MeSCs and mature melanocytes. Notably, Dguok deficiency decreased the expression of 13 mtDNA-encoded genes, increased the levels of reactive oxygen species (ROS) and apoptosis in MeSCs. Treatment with N-acetylcysteine (NAC), an ROS inhibitor, effectively mitigated the depigmentation and rejuvenated the MeSCs population. These findings underscore the critical role of DGUOK in regulating mtDNA integrity, which is vital for sustaining MeSCs and ensuring hair pigmentation, providing valuable insights that may inform therapeutic strategies for combating hair greying.},
}

@article {pmid40516766,
year = {2025},
author = {Spilere, DA and Lodetti, G and de Farias, ACS and Teixeira, AG and Dondossola, ER and Rico, EP},
title = {Effects of N-acetylcysteine after repeated exposure to ethanol in memory and neurotransmission in zebrafish.},
journal = {Neurotoxicology and teratology},
volume = {110},
number = {},
pages = {107508},
doi = {10.1016/j.ntt.2025.107508},
pmid = {40516766},
issn = {1872-9738},
abstract = {INTRODUCTION: In the brain, alcohol metabolites alter the functioning of several neurotransmission systems, such as glutamatergic and cholinergic, in addition to impairing memory and learning. Medications for Alcohol Use Disorders (AUD) cause adverse effects and contraindications. N-acetylcysteine (NAC) has been shown to protect memory and restore acetylcholinesterase (AChE) levels. Additionally, it functions as an antioxidant that works alongside glutathione, which is associated with the glutamatergic synapse. In this context, the current research aimed to examine the neuroprotective effects of NAC in animals that underwent repeated ethanol exposure (REE), along with the impacts on memory and the cholinergic and glutamatergic signaling pathways in zebrafish.

METHODS: The animals were exposed to 1 % ethanol for 8 days for 20 min daily. They received treatment with NAC after the eighth exposure to ethanol for 10 or 60 min. Euthanasia occurred 24 h after the last exposure. Inhibitory avoidance and object recognition tests were performed. Also, the choline acetyltransferase (ChAT) enzyme activities, AChE activity, and glutamate uptake were evaluated.

RESULTS: The results show a significant AChE activity increase in the REE group and a decrease in those exposed to alcohol and treated with NAC for 10 min. No significant differences were found regarding ChAT activity. REE significantly reduced glutamate uptake. All groups except the ethanol group acquired aversive memory in inhibitory avoidance tests. Only the NAC-treated group demonstrated longer new object exploration in the recognition test. The study indicates that REE affects AChE, glutamate uptake, and aversive memory and that a single NAC treatment can mitigate these effects. These findings enhance the understanding of REE mechanisms and NAC's protective properties against ethanol-induced damage in zebrafish.},
}

@article {pmid40511989,
year = {2025},
author = {Rosenhall, U and Muhr, P and Duan, M},
title = {Is pharmaceutical treatment of noise-induced hearing loss a realistic option? Debate article.},
journal = {Acta oto-laryngologica},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/00016489.2025.2509662},
pmid = {40511989},
issn = {1651-2251},
abstract = {Essential conclusionsThe need for pharmaceutical treatment of noise-induced hearing loss (NIHL) is pronounced.Animal studies indicate that such treatment is possible.Clinical trials must be designed so that the participants are not exposed to harmful noise.This implicates that prospective, randomised studies of possible drug effects on permanent NIHL are difficult to perform of ethical reasons.Indirect outcome measures of noise effects on hearing are considered less reliable and informative than permanent NIHL for the evaluation of the efficacy of a drug therapy.If drug therapies aiming to reduce NIHL are looked for, issues related to the design of clinical trials must be discussed and possibly revised.},
}

@article {pmid40510771,
year = {2025},
author = {Muthmainah, M and Wiyono, N and Syah, FK and Purnianto, A and Yudhani, RD and Wasita, B},
title = {Current trends and future prospects of N-acetylcysteine utilizations in Parkinson's disease: A literature network analysis.},
journal = {Journal of Taibah University Medical Sciences},
volume = {20},
number = {3},
pages = {298-306},
pmid = {40510771},
issn = {1658-3612},
abstract = {Parkinson's disease (PD) is a prevalent neurodegenerative disorder without a definitive cure. Oxidative stress is significantly implicated in its pathogenesis, prompting interest in N-acetylcysteine (NAC), a strong antioxidant and cysteine precursor, as a potential therapeutic agent. We conducted a bibliometric analysis of 421 Scopus articles to assess current trend and future potential of research on the use of NAC in Parkinson's disease. The number of publications related to this topic reached the peaked in 2010 and gradually decreased afterward. We identified 4 main clusters of research theme related to the potential mechanism of NAC effects on Parkinson's disease progression. These include research focusing on NAC effects on oxidative stress, dysfunction of the mitochondria, aberrant protein accumulation and clearance and inflammation. Investigating NAC effect for Parkinson's disease in human is a potential research area.},
}

@article {pmid40509229,
year = {2025},
author = {Barbosa-Azevedo, M and Igreja-Cardoso, MB and Carvalho, F and Costa, VM},
title = {Comparative Neurotoxic Effects of Doxorubicin and Sunitinib: An In Vitro Study on Human Dopaminergic Neuronal Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {11},
pages = {},
pmid = {40509229},
issn = {1420-3049},
support = {UIDB/04046/2020 and UIDP/04046/2020//Fundação para a Ciência e tecnologia/ ; },
mesh = {Humans ; *Doxorubicin/pharmacology/adverse effects/toxicity ; *Sunitinib/pharmacology/toxicity/adverse effects ; Autophagy/drug effects ; *Dopaminergic Neurons/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Sulfoxides ; Isothiocyanates ; },
abstract = {Chemotherapy-induced cognitive impairment, commonly referred to as chemobrain, is a well-documented adverse outcome of anticancer treatments. While the neurotoxicity of doxorubicin (DOX) has been extensively studied, targeted therapies such as sunitinib (SUN) remain largely unexplored concerning this outcome. This study aimed to compare the neurotoxic effects of DOX and SUN in dopaminergic neuronal cells and to explore the involvement of oxidative stress and autophagy as potential mechanisms underlying their cytotoxicity. Human neuronal SH-SY5Y cells were differentiated into a dopaminergic phenotype and exposed to clinically relevant concentrations of DOX (0.1-10 µM) and SUN (1-10 µM) for 24 or 48 h. To investigate the involvement of oxidative stress in their cytotoxicity, redox modulators [N-acetylcysteine (NAC); dimethyl fumarate (DMF); sulforaphane (SFN); and cheirolin (CH)] were tested alongside DOX and SUN for their potential protective effects. The role of autophagy in SUN-induced toxicity was assessed using 3-methyladenine (3-MA; an early-stage inhibitor); chloroquine (CH; a late-stage inhibitor); and rapamycin (RAP; an autophagy inducer). Additionally, LC3-I and LC3-II expression levels were determined. Both DOX and SUN exhibited time- and concentration-dependent cytotoxicity and induced mitochondrial membrane depolarization. NAC conferred partial protection against SUN toxicity but enhanced DOX's cytotoxicity at the lowest concentration tested. DMF and SFN had dual effects, depending on the drug's concentration, while CH exhibited a consistent protective effect towards the cytotoxicity induced by both drugs. Regarding autophagy, 3-MA partially protected against SUN-induced toxicity, whereas CLQ and RAP exacerbated it. LC3-II levels were increased in some conditions, suggesting that SUN-induced toxicity involves autophagy. This study shows that SUN, though less studied in chemobrain, has a cytotoxic profile similar to DOX, which is a known contributor to chemobrain, in SH-SY5Y cells. These findings highlight the need for further research on neuroprotective strategies targeting oxidative stress and autophagy to reduce chemobrain in cancer patients and survivors.},
}

Humans
*Doxorubicin/pharmacology/adverse effects/toxicity
*Sunitinib/pharmacology/toxicity/adverse effects
Autophagy/drug effects
*Dopaminergic Neurons/drug effects/metabolism/pathology
Oxidative Stress/drug effects
Cell Line, Tumor
Cell Survival/drug effects
Sulfoxides
Isothiocyanates

@article {pmid40505349,
year = {2025},
author = {Asghar, MA and Wan, B and Li, L and Zhang, J and Tang, S and Han, H and Yang, Y and Chu, L and Zhang, Q and Zhang, X and Zhao, Q},
title = {Micronutrient antioxidant supplementation alleviates valproic acid-induced oxidative stress and male infertility via the NRF2/HO-1 pathway.},
journal = {Redox biology},
volume = {85},
number = {},
pages = {103685},
doi = {10.1016/j.redox.2025.103685},
pmid = {40505349},
issn = {2213-2317},
abstract = {BACKGROUND: Valproic Acid (VPA), a widely used anticonvulsant, is known to induce oxidative stress, contributing to male infertility. This study explores the potential of micronutrient antioxidants to improve fertility in VPA-treated individuals.

METHODS: Six-week-old male mice were treated with VPA and supplemented with antioxidants, including l-Arginine (120 mg/kg), N-Acetylcysteine (NAC) (2 mg/kg), Taurine (200 mg/kg), L-Tryptophan (0.5 mg/kg), Zinc chloride (ZnCl2) (1.5 mg/kg), and Selenium (0.5 mg/kg). The dosing regimen lasted for 34 days. Sperm quality, oxidative stress, and inflammatory biomarkers were assessed through gene expression analysis, western blotting, histological assessments, TUNEL assays, and immunohistochemistry. Additionally, GC-2spd(ts) and HepG2 cell lines were used to examine the testicular and systemic effects of VPA and antioxidants. Network pharmacology was applied to identify key molecular targets and pathways.

RESULTS: Antioxidant supplementation significantly improved sperm count, with l-Arginine showing an approximately 296.1 % increase, NAC a 270.7 % increase, and Taurine a 255.9 % increase compared to the VPA-only group. Furthermore, antioxidants enhanced semen volume, testosterone levels, sperm motility, morphology, and viability. Gene expression analysis revealed significant upregulation of key oxidative stress-related proteins such as SOD1, HO-1, NRF2, and NQO1. Western blot and histological analyses showed a reversal of oxidative stress and preservation of seminiferous tubule integrity. TUNEL assays demonstrated a reduction in apoptotic damage, and IHC confirmed an increase in HO-1 and SOD1. In vitro studies with GC-2spd(ts) and HepG2 cells confirmed that antioxidants alleviated VPA-induced oxidative stress. Network pharmacology identified key molecular targets, such as GPX4, SOD1, HO-1, and NRF2, which are involved in oxidative stress, apoptosis, and inflammation pathways, that were modulated by antioxidants.

CONCLUSION: Micronutrient antioxidants effectively reduce VPA-induced oxidative stress and improve male fertility. These results suggest that antioxidant supplementation could be a promising strategy to mitigate oxidative damage and enhance fertility in individuals undergoing VPA therapy.},
}

@article {pmid40501637,
year = {2025},
author = {Zhang, H and Valestil, K and Pierce, EA},
title = {Oxidative DNA Damage Drives Apoptotic Photoreceptor Loss in NMNAT1 -Associated Inherited Retinal Degeneration: A Therapeutic Opportunity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.05.658162},
pmid = {40501637},
issn = {2692-8205},
abstract = {Early-onset inherited retinal degenerations (IRDs), such as Leber congenital amaurosis (LCA) caused by pathogenic variants in the NMNAT1 gene, lead to severe vision loss in children. Despite its ubiquitous expression, reduced NMNAT1 function primarily affects photoreceptor cells (PRs) of the retina, yet the mechanisms underlying their heightened vulnerability remain incompletely understood. Here, we demonstrate that reduced NMNAT1 enzyme function due to the p.V9M mutation leads to DNA damage in PRs, characterized by the progressive accumulation of the oxidative DNA adduct 8-oxo-dG in Nmnat1 [V9M/V9M] mutant mice. Cells with oxidative DNA damage also demonstrate DNA double-strand breaks, as evidenced by co-staining with antibodies to phosphorylated H2AX (γH2A.X). This DNA damage correlates with apoptosis-driven PR degeneration, as evidenced by caspase-9 activation and TUNEL staining in the PRs of the Nmnat1 [V9M/V9M] mutant mice, while alternative cell death pathways such as necroptosis and parthanatos were not significantly activated. Treatment with the antioxidant N-acetylcysteine (NAC) effectively reduced oxidative DNA damage and retinal immune responses, mitigated apoptosis, and preserved cone PRs. Longitudinal assessment via optical coherence tomography (OCT) and electroretinography (ERG) revealed sustained structural and functional protection in NAC-treated mice. These findings establish oxidative DNA damage as a key driver of PR degeneration in the Nmnat1 [V9M/V9M] model and highlight NAC's potential as a causal gene variant-independent therapeutic strategy for NMNAT1 -associated IRD and potentially other IRDs in which oxidative DNA damage contributes to disease pathogenesis.},
}

@article {pmid40497192,
year = {2025},
author = {Abutineh, MA and Lodha, C and Mitchell, G},
title = {Multiorgan Failure Secondary to Intentional Acetaminophen Overdose-Induced Methemoglobinemia.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e83833},
pmid = {40497192},
issn = {2168-8184},
abstract = {Although acetaminophen toxicity has been reported to cause methemoglobinemia, its recognition remains limited in the clinical literature. Methemoglobinemia often necessitates a high index of clinical suspicion, as it may contribute to lactic acidosis and multiorgan dysfunction due to impaired tissue oxygenation. A 21-year-old man presented to the emergency department (ED) via emergency medical services (EMS) with reports of an intentional overdose of an unknown amount of bupropion, two pill bottles of acetaminophen, and an unknown amount of bleach. The patient was emergently intubated. Despite reported bleach ingestion, esophagogastroduodenoscopy (EGD) revealed no evidence of caustic injury or esophagitis. The poison center was contacted, and the patient was started on N-acetylcysteine (NAC). The exact time of acetaminophen ingestion was unknown; however, liver function tests were normal at presentation. Transaminases became abnormal 48 hours later (well after NAC administration had begun). Persistent lactic acidosis in the context of normal initial transaminase levels raised clinical suspicion for methemoglobinemia, given the potential for tissue hypoxia. Methemoglobin levels were confirmed to be elevated, potentially explaining tissue ischemia. The patient received methylene blue as the antidote. The liver transplant team was consulted and agreed with the poison center's recommendation of excluding acetaminophen-induced liver injury. Due to unexplained elevated lactic acid and multisystem organ failure, the family elected for a Do Not Resuscitate (DNR) status. The patient expired four days later with multisystem organ failure.},
}

@article {pmid40490445,
year = {2025},
author = {Kundukad, B and Rice, SA and Doyle, PS and Kjelleberg, S},
title = {Alginate exopolymer significantly modulates the viscoelastic properties and resilience of bacterial biofilms.},
journal = {NPJ biofilms and microbiomes},
volume = {11},
number = {1},
pages = {98},
pmid = {40490445},
issn = {2055-5008},
mesh = {*Biofilms/growth & development/drug effects ; *Alginates/metabolism/chemistry ; *Pseudomonas aeruginosa/physiology/drug effects/genetics ; Elasticity ; Viscosity ; *Polysaccharides, Bacterial/metabolism ; Extracellular Matrix/chemistry ; },
abstract = {Biofilms are viscoelastic gels with a cross-linked network of biopolymers forming an extracellular matrix that protects bacteria from most antimicrobial treatments. This study examines the physical role of the matrix in preventing recolonisation using a mucoid Pseudomonas aeruginosa (P. aeruginosa ΔmucA) and isogenic wild-type Pseudomonas aeruginosa PAO1. We investigated the recolonisation of pre-formed live biofilms and the residual matrix left behind after bacterial eradication with N-acetyl cysteine (NAC). P. aeruginosa ΔmucA, which overproduces alginate, prevented recolonisation through swelling and increased elastic modulus. In contrast, the wild-type P. aeruginosa biofilm matrix exhibited minimal swelling and decreased elasticity, suggesting crosslink breakage. These observations align with polymer physics theories where alginate's polyelectrolyte nature drives swelling through the Donnan effect, enhancing matrix stability. Meanwhile, the Psl-rich wild-type matrix limited swelling but showed reduced mechanical stability. This study underscores the critical role of matrix composition in biofilm mechanics, influencing bacterial protection regardless of viability.},
}

*Biofilms/growth & development/drug effects
*Alginates/metabolism/chemistry
*Pseudomonas aeruginosa/physiology/drug effects/genetics
Elasticity
Viscosity
*Polysaccharides, Bacterial/metabolism
Extracellular Matrix/chemistry

@article {pmid40489761,
year = {2025},
author = {Harpavat, S and Borovsky, KA and Scheurer, ME and Cavallo, L and Erhiawarie, FE and Vasudevan, S and Vogel, AM and Cerminara, D and Tessier, EM and Patel, KR and Devaraj, S and Shneider, BL},
title = {A phase 2 trial of short-term intravenous N-acetylcysteine in biliary atresia after Kasai portoenterostomy.},
journal = {Hepatology communications},
volume = {9},
number = {7},
pages = {},
pmid = {40489761},
issn = {2471-254X},
mesh = {Humans ; *Acetylcysteine/administration & dosage/adverse effects ; *Biliary Atresia/surgery/drug therapy/blood ; Male ; Female ; *Portoenterostomy, Hepatic ; Infant ; Treatment Outcome ; Administration, Intravenous ; },
abstract = {BACKGROUND: For infants with biliary atresia, the only treatment that can establish bile flow and delay need for liver transplant is the Kasai portoenterostomy (KP). Unfortunately, the KP has variable success. In this study, we hypothesized that intravenous N-acetylcysteine (IV NAC) treatment following KP would improve bile flow.

METHODS: This was a phase 2 study following the two-stage "minimax" trial design. Participants received IV NAC (150 mg/kg/day) for 7 days after KP, and the primary endpoint was achieving total serum bile acids (TSBA) ≤10 μmol/L within 24 weeks of KP. Secondary endpoints were clinical markers and the occurrence of sentinel events.

RESULTS: There were 12 participants in stage 1 who received treatment, with none achieving TSBAs ≤10 μmol/L within 24 weeks of KP. As a result, no participants were enrolled in stage 2. There were 32 adverse events in 11 participants, including 5 serious adverse events which were considered part of the participants' natural clinical course and not directly attributable to NAC treatment. Analyses of secondary outcomes demonstrated no difference in clinical markers or occurrence of sentinel events between study participants and matched historical controls.

CONCLUSIONS: This study demonstrates how the two-stage "minimax" trial design can be used to efficiently evaluate potential therapies for BA. Although the primary endpoint was not met, NAC therapy was generally well-tolerated. NAC therapy may prove efficacious in future trials with (i) a less stringent primary endpoint and/or (ii) a longer course of treatment (NCT03499249).},
}

Humans
*Acetylcysteine/administration & dosage/adverse effects
*Biliary Atresia/surgery/drug therapy/blood
Male
Female
*Portoenterostomy, Hepatic
Infant
Treatment Outcome
Administration, Intravenous

@article {pmid40488120,
year = {2025},
author = {Al-Younis, I and Martín-Jiménez, R and Khan, M and Baussan, Y and Jose, C and Thibeault, Y and Hebert-Chatelain, E},
title = {N-acetyl-L-cysteine improves mitochondrial and oxidative defects in the acadian variant of fanconi syndrome.},
journal = {Experimental biology and medicine (Maywood, N.J.)},
volume = {250},
number = {},
pages = {10448},
pmid = {40488120},
issn = {1535-3699},
mesh = {Humans ; *Acetylcysteine/pharmacology ; *Oxidative Stress/drug effects ; Fibroblasts/drug effects/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; *Fanconi Syndrome/drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; *Antioxidants/pharmacology ; Cells, Cultured ; Electron Transport Complex I/metabolism ; Cell Respiration/drug effects ; Malondialdehyde/metabolism ; },
abstract = {The Acadian variant of Fanconi Syndrome (AVFS) is a rare genetic disorder characterized by renal deficiencies. AVFS is caused by a mutation to NDUFAF6 encoding a complex I assembly factor, and leading to metabolic alterations. We confirmed that fibroblasts derived from AVFS patients have lower complex I activity, mitochondrial membrane potential and cellular respiration. These mitochondrial defects were accompanied by higher levels of 8-hydroxy-2'deoxyguanosine, malondialdehyde and carbonyl, which are markers of oxidative damage to DNA, lipids and proteins, respectively. Thus, we hypothesized that the antioxidant N-Acetyl-L-cysteine (NAC) would reduce oxidative stress and mitochondrial defects in AVFS fibroblasts. Treatment with NAC during 5 days partially restored complex I activity, mitochondrial membrane potential and cellular respiration in AVFS fibroblasts. NAC also prevented oxidative damage in AVFS fibroblasts. This work shows for the first time that the physiopathology of AVFS includes high oxidative stress. It also reveals that NAC and other antioxidant-based strategies might represent an effective pharmacological treatment for AVFS.},
}

Humans
*Acetylcysteine/pharmacology
*Oxidative Stress/drug effects
Fibroblasts/drug effects/metabolism
*Mitochondria/drug effects/metabolism/pathology
*Fanconi Syndrome/drug therapy/metabolism/pathology
Membrane Potential, Mitochondrial/drug effects
*Antioxidants/pharmacology
Cells, Cultured
Electron Transport Complex I/metabolism
Cell Respiration/drug effects
Malondialdehyde/metabolism

@article {pmid40485434,
year = {2025},
author = {Pandey, S and Arachchige, DL and Schwandt, RJ and Dwivedi, SK and Kathuria, I and Liu, H and Luck, RL},
title = {Rhodamine-derived ratiometric fluorescent probes for high-sensitivity detection and real-time imaging of mitochondrial pH and viscosity in HeLa cells and Drosophila melanogaster.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5tb00747j},
pmid = {40485434},
issn = {2050-7518},
abstract = {The spirolactam on/off switch attached to rhodamine dye is known to be a highly selective and sensitive fluorescent probe, yet few studies have explored extending the π-conjugation system within its skeleton for pH detection in live cells. An extended π-conjugated rhodamine section should enable ratiometric pH detection in the near-infrared region. In this study, we synthesized probes A and B by coupling a rhodamine derivative with 7-nitrobenzofurazan and 7-(diethylamino)-2-oxo-3,8a-dihydro-2H-chromene-3-carbaldehyde sections, respectively. Probe A exhibits emission via a Förster resonance energy transfer (FRET) mechanism. Under excitation at 370 nm, the conjugated 7-nitrobenzofurazan in probe A exhibits fluorescence at 465 nm in the ring-closed state, while fluorescence at 660 nm appears in the ring-open state due to increased conjugation in the rhodamine moiety. Excitation of probe B at 325 nm resulted in reduced emission around 350 nm and a significantly enhanced response at 525 nm. Probe A was evaluated for mitochondrial pH detection through ratiometric fluorescence emission measurements. Additional tests in living HeLa cells, including responses to stimuli such as carbonyl cyanide-4(trifluoromethoxy)phenylhydrazone (FCCP), hydrogen peroxide (H2O2), N-acetyl cysteine (NAC), mitophagy induced by nutrient deprivation, and hypoxia triggered by cobalt chloride (CoCl2) treatment, as well as pH changes in fruit fly larvae, further validated its applicability for ratiometric measurement of mitochondrial pH variations. Probe A's emission was dependent on the pH level under basic conditions, but under acidic conditions, the change in conformation upon ring opening resulted in the emission also being affected by viscosity.},
}

@article {pmid40482471,
year = {2025},
author = {Miller, A and Lombardo, GP and Spiccia, L and Natale, V and Migliorato, A and Bednarski, M and Iciek, M and Bilska-Wilkosz, A and Sablik, M and Lauriano, ER and Kotańska, M and Pergolizzi, S},
title = {Characterization of immune cells in the rat intestinal mucosa and liver involved in inflammation caused by LPS and evaluation of the effects of N-acetylcysteine and disulfiram (well-known sulfur drugs) for this inflammation.},
journal = {Acta histochemica},
volume = {127},
number = {3},
pages = {152272},
doi = {10.1016/j.acthis.2025.152272},
pmid = {40482471},
issn = {1618-0372},
abstract = {Lipopolysaccharide (LPS)-induced inflammation is an experimental rat model often used as a tool for testing new drugs as candidates for treating various diseases associated with inflammation. New methods now allow for precise imaging of tissues and changes induced by various factors. To increase knowledge about LPS-induced inflammation and promote strategies for investigating new therapies, this study aims to characterize immune cells involved in inflammation in the rat intestinal mucosa and liver and to evaluate the therapeutic effect of two well-known sulfur drugs N-acetylcysteine (NAC) and disulfiram (DSF) on this model LPS was administered intraperitoneally to rats once a day, for 10 days. NAC and DSF were administered 5 h after LPS. At the end of experiment, animals were euthanized, and the intestine and liver were collected. The immune cells of the intestinal mucosa and liver were characterized with the following antibodies: Toll-like receptors (TLR2 and TLR4), smooth muscle alpha-actin (α-SMA), major histocompatibility complex II (MHC-II), and serotonin (5-HT). In samples obtained from inflamed rat intestinal mucosa, it was possible to detect TLR2-positive and TLR4-positive cells, and numerous α-SMA-positive cells, indicating an inflammatory state. Furthermore, an increase in serotonin positive neuroendocrine cells compared to normal was demonstrated, which could be associated with intestinal inflammation. The number of these positive cells was much smaller in the samples derived from animals treated with NAC or DSF, suggesting anti-inflammatory action of these drugs. In the inflamed rat liver, several immune cells positive for these antibodies were observed and NAC or DSF decreased the amount of these positive cells. In conclusion, this study shows that bacterial LPS can activate various innate immune system cell populations, such as dendritic cells, neutrophils, Kupffer cells, myofibroblasts and enterocytes. Moreover, this study demonstrates the beneficial effects on NAC and DSF in alleviating inflammation and relieving tissue fibrosis in the LPS-induced inflammation in the rat intestinal mucosa and liver.},
}

@article {pmid40481912,
year = {2025},
author = {Bakirhan, EG and Yanilmaz, EMB and Tüfekci, KK and Bakirhan, F and Susam, S},
title = {Maternal high-fat diet impairs cognitive performance by altering hippocampal GRP78/PERK axis and BDNF expression in adult female rat offspring: the potential protective role of N acetylcysteine.},
journal = {Journal of molecular histology},
volume = {56},
number = {3},
pages = {189},
pmid = {40481912},
issn = {1567-2387},
mesh = {Animals ; Female ; *Brain-Derived Neurotrophic Factor/metabolism ; *Hippocampus/metabolism/drug effects ; *Diet, High-Fat/adverse effects ; Rats ; Pregnancy ; *Acetylcysteine/pharmacology ; *Heat-Shock Proteins/metabolism ; *eIF-2 Kinase/metabolism ; *Prenatal Exposure Delayed Effects ; Endoplasmic Reticulum Stress/drug effects ; *Cognition/drug effects ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Maze Learning/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Maternal high fat diet (HFD) affects the neurodevelopment of offspring and has long-term consequences on cognitive behavior. This study investigated changes occurring in GRP78 and PERK, important markers of endoplasmic reticulum stress (ERS) signaling, in the hippocampus of female adult rats exposed to maternal HFD, and in brain-derived neurotrophic factor (BDNF) signaling, with its important role in the regulation of cognitive behavior, and the potential neuroprotective effects of N-acetylcysteine (NAC) against these changes. A maternal obesity model was created with HFD (60% kcal). NAC (150 mg/kg) was administered intragastrically to both the NAC and HFD + NAC groups. The animals were mated at 12 weeks of age. The same diet was maintained throughout pregnancy and lactation. All female rat pups were subjected to the water maze test at eight weeks of age. Hippocampal GRP78 and PERK expressions increased in the HFD rats. However, maternal HFD suppressed hippocampal BDNF levels and reduced hippocampal neuronal volume. NAC supplementation reduced GRP78 and PERK expressions and increased BDNF and hippocampal volume values in the HFD + NAC group. At behavioral assessments, rats in the HFD group exhibited decreased memory and learning ability, but the HFD + NAC group exhibited stronger responses than the HFD group. Our findings suggest that the decrease in BDNF expression, which plays a role in memory and learning, after maternal HFD exposure may be due to ERS associated with increased GRP78 and PERK expressions. Furthermore, NAC supplementation may ameliorate the impairment in memory and spatial learning ability by attenuating hippocampal ERS in HFD rats.},
}

Animals
Female
*Brain-Derived Neurotrophic Factor/metabolism
*Hippocampus/metabolism/drug effects
*Diet, High-Fat/adverse effects
Rats
Pregnancy
*Acetylcysteine/pharmacology
*Heat-Shock Proteins/metabolism
*eIF-2 Kinase/metabolism
*Prenatal Exposure Delayed Effects
Endoplasmic Reticulum Stress/drug effects
*Cognition/drug effects
Neuroprotective Agents/pharmacology
Signal Transduction/drug effects
Endoplasmic Reticulum Chaperone BiP
Maze Learning/drug effects
Rats, Sprague-Dawley

@article {pmid40480879,
year = {2025},
author = {Zakaria, AY and Badawi, R and Osama, H and Abdelrahman, MA and El-Kalaawy, AM},
title = {New Approach Combination-Dosed Therapy for Nonalcoholic Steatohepatitis Versus Vitamin E: A Randomized Controlled Trial.},
journal = {Clinical therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clinthera.2025.05.006},
pmid = {40480879},
issn = {1879-114X},
abstract = {PURPOSE: There is currently no US Food and Drug Administration-approved remedy for nonalcoholic steatohepatitis (NASH). The present study evaluated the efficacy of N-acetyl cysteine (NAC) and rosuvastatin (RSV) compared with conventional vitamin E in patients with NASH.

METHODS: This study was designed as a parallel, double-blinded, randomized controlled trial. Ninety patients who met the eligibility criteria were enrolled in this study. Subsequently, 45 patients were allocated to each group as follows: group 1 reported consistent administration of vitamin E 400 IU[Ⓡ] (PHARCO-Pharmaceuticals) twice daily over a duration of 6 months. Group 2 included patients with NASH who received NAC, Gemacysteine 300 mg[Ⓡ] (GEMA-Pharma) at 1200 mg twice daily, along with RSV, Crestor 20 mg[Ⓡ] (AstraZeneca). To achieve the study's objective, FibroScan[Ⓡ] examination of liver tissue and fibrosis scores, as well as tests for liver aminotransferases, lipid profile, glycemic parameters, and hepatic and renal functions, besides health-related quality of life using the Short-Form 36 were evaluated before and after 6 months of treatment.

FINDINGS: In group 1, a statistically significant decrease in the mean value of steatosis was observed after 6 months by 6.05% (P = 0.017), whereas treated group 2 exhibited a reduction of 16.49% (P = 0.001). Group 2 reported a statistically significant decrease in the mean fibrosis value of approximately 19.5% (P = 0.001). Fibrosis-4 Index score's significance stated a reduction in the mean values within treatment group 2, with decreases of 51.70%. MACK-3 score which is a combination of homeostatic model assessment, aspartate aminotransferase, and cytokeratin-18, exhibited a notable reduction in mean values within treatment group 2 by 25.06% (P = 0.001). Concerning biological markers, malondialdehyde, both groups reported significant reductions in mean values of 11.90% (P = 0.006) and 27.43% (P = 0.001), respectively. Group 2 exhibited substantial reductions in mean levels of all biological markers: NOD-like receptor-associated protein 3 inflammasome decreased by 24.40%, tumor necrosis factor-α by 9.64%, tissue inhibitor of metalloproteinases 1 by 10.28%, N-terminal propeptide of procollagen type III by 14.58%, cytokeratin-18 by 23.44%, and fibroblast growth factor-21 by 15.08% (P < 0.05), whereas group 1 did not demonstrate significant differences. Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters.

IMPLICATIONS: Patients in group 2 treated with the combination of NAC/RSV exhibited tolerability and efficacy in improving liver steatosis and fibrosis, besides metabolic parameters, indicating a new combination approach to the management of NASH.

CLINICALTRIALS: gov identifier: NCT06105060.},
}

@article {pmid40478359,
year = {2025},
author = {Saniei, H and Naderi, R},
title = {The effect of N-acetylcysteine on apoptosis and NGF-Akt/Bad pathway in the hippocampus tissue of cerebral ischemia-reperfusion in male rats.},
journal = {Metabolic brain disease},
volume = {40},
number = {5},
pages = {217},
pmid = {40478359},
issn = {1573-7365},
mesh = {Animals ; Male ; *Apoptosis/drug effects/physiology ; *Hippocampus/drug effects/metabolism/pathology ; *Reperfusion Injury/metabolism/drug therapy/pathology ; *Nerve Growth Factor/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *bcl-Associated Death Protein/metabolism ; *Brain Ischemia/metabolism/drug therapy/pathology ; Signal Transduction/drug effects ; Rats, Sprague-Dawley ; },
abstract = {Apoptosis is the primary pathological feature of neuronal injury caused by cerebral ischemia-reperfusion (I/R). The detailed molecular mediators are still being debated. This study aims to examine the effects of cerebral ischemia-reperfusion on apoptosis and NGF-Akt/Bad axis in rat hippocampus alone and in combination with NAC (N-Acetylcysteine). Rats were subjected to common carotid artery occlusion (CCAO) for 20 min followed by 24 h reperfusion. NAC (150 mg/kg) was given intraperitoneally (ip) one hour before ischemia and five minutes before reperfusion. TUNEL staining of hippocampus neurons revealed that the number of apoptotic neurons was elevated 24 h after reperfusion. At the molecular levels, I/R injury resulted in an increased protein expression of cleaved caspase3/procaspase3 ratio and cytochrome c level with a concomitant down-regulation of NGF, p-AKT/AKT, p-Bad/Bad and p-Trk/Trk ratio. NAC treatment significantly reduced the apoptotic damage and also reversed NGF, p-AKT/AKT, p-Bad/Bad, and p-Trk/Trk ratio in hippocampus neurons in I/R rats. In conclusion, our data showed that NGF-Akt/Bad axis may play a regulatory role in hippocampus cell death, providing a new target for a novel therapeutic strategy during transit ischemic stroke. NAC has been shown to reverse molecular alterations, suggesting its potential as an effective agent against hippocampal apoptosis following acute I/R injury.},
}

Animals
Male
*Apoptosis/drug effects/physiology
*Hippocampus/drug effects/metabolism/pathology
*Reperfusion Injury/metabolism/drug therapy/pathology
*Nerve Growth Factor/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Acetylcysteine/pharmacology/therapeutic use
Rats
*bcl-Associated Death Protein/metabolism
*Brain Ischemia/metabolism/drug therapy/pathology
Signal Transduction/drug effects
Rats, Sprague-Dawley

@article {pmid40470288,
year = {2025},
author = {Wolff, HT and Piroth, AC and Oltmanns, H and Meißner, J and Verspohl, J and Volk, HA and Busse, C},
title = {Commercially available antiseptics show high in vitro efficacy against pathogens most commonly associated with canine and feline infectious keratitis.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1552230},
pmid = {40470288},
issn = {2297-1769},
abstract = {PURPOSE: To determine the minimal bactericidal concentration (MBC) of polyhexanide (PHMB), povidone-iodine (PVP-I), N-acetylcysteine (NAC), and hypochlorous acid (HOCl) for bacterial species commonly found in canine and feline infectious keratitis.

METHODS: MBCs for clinical isolates of Staphylococcus (S.) pseudintermedius (n = 11), including 3 methicillin-resistant strains, Pseudomonas (P.) aeruginosa (n = 8), and Streptococcus (Str.) canis (n = 11), including the corresponding control strains, were examined. All testing substances were serially diluted in phosphate-buffered saline (PBS) and cation-adjusted Mueller-Hinton Broth (CAMHB) and inoculated with the bacterial suspension for 10 min. Afterwards, a neutralisation with Dey-Engley neutralising broth was performed, followed by plating onto Columbia sheep-blood agar. After incubation, plates were visually examined for bacterial growth. Tests were carried out in triplicate.

RESULTS: MBCs in PBS for polyhexanide ranged 0.8-1.6 mg/L for S. pseudintermedius and 1.6-3.2 mg/L for P. aeruginosa and Str. canis. For povidone-iodine, MBCs in PBS were observed at concentrations ranging 8-32 mg/L for S. pseudintermedius and P. aeruginosa and 8-16 mg/L for Str. canis. MBCs in PBS for NAC were recorded at a range of 6,400-12,800 mg/L for S. pseudintermedius, whereas those for P. aeruginosa and Str. canis ranged 3,200-6,400 mg/L. Results for HOCl in PBS ranged 0.4-1.6 mg/L for S. pseudintermedius and 0.4-0.8 mg/L for P. aeruginosa and Str. canis. MBCs in CAMHB for polyhexanide were found in the range between 3.2 and >12.8 mg/L, those for povidone-iodine between 6,400 and >12,800 mg/L, and for NAC between 6,400 and >12,800 mg/L, across the tested species. When dissolved in CAMHB, no antimicrobial effect could be observed for HOCl in concentrations up to 137.5 mg/L.

CONCLUSION: All tested substances had an in vitro bactericidal effect against all three bacterial species with MBCs below known tolerated ocular concentrations when dissolved in PBS. Povidone-iodine and hypochlorous acid showed a marked reduction in their in vitro efficacy in the presence of protein. Nevertheless, our results provide a promising outlook on alternatives or adjuvants to antibiotics in ophthalmology that align with the One Health approach.},
}

@article {pmid40464516,
year = {2025},
author = {Ma, HY and Wu, HY and Xiang, YT and Liu, YY and Xie, J and Cai, PY and Zhang, B and Zhang, YH and Wu, MX},
title = {Mechanism of SLC1A5 Regulation of Glutamine Metabolism to Promote Ferroptosis Sensitivity in Endometriosis.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {5},
pages = {36781},
doi = {10.31083/FBL36781},
pmid = {40464516},
issn = {2768-6698},
mesh = {*Ferroptosis/drug effects ; Female ; *Glutamine/metabolism ; Humans ; Animals ; *Amino Acid Transport System ASC/metabolism/genetics ; Rats ; Reactive Oxygen Species/metabolism ; *Endometriosis/metabolism/pathology/drug therapy/genetics ; *Minor Histocompatibility Antigens/metabolism/genetics ; Piperazines/pharmacology ; Proto-Oncogene Proteins c-myc/metabolism ; Cell Line ; Rats, Sprague-Dawley ; Disease Models, Animal ; Stromal Cells/metabolism ; Endometrium/metabolism ; },
abstract = {BACKGROUND: Endometriosis (EMs) is a chronic gynecological disorder associated with ectopic endometrial tissue, inflammation, oxidative stress, and mitochondrial dysfunction. A promising strategy for treating EMs is to target ferroptosis, a programmed cell death mechanism regulated by reactive oxygen species (ROS) and glutamine metabolism. Solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, and c-Myc play key roles in ferroptosis, forming a "ROS/c-Myc/SLC1A5" feedback loop. The aim of this study was to investigate the regulatory role of SLC1A5 in ferroptosis. In addition, we evaluated the ferroptosis inducer Erastin as a potential therapeutic agent for EMs.

METHODS: The human endometrial stromal cells (ESCs) line hEM15A was used in this study, together with a rat model of EMs. hEM15A cells and rats were treated with Erastin, with or without SLC1A5 modulation or ROS scavenging with N-acetylcysteine (NAC). Cell viability, ROS levels, glutamine metabolism, mitochondrial function, and ferroptosis markers (glutathione peroxidase 4 (GPX4)) were subsequently analyzed by Cell Counting Kit-8 (CCK-8) assay, reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot, and fluorescent probes. Pathological changes, lesion volumes, and pelvic adhesions in the rat EM model were assessed using hematoxylin and eosin (HE) staining, ultrasound imaging, and Haber scoring.

RESULTS: Erastin treatment of ESCs induced ferroptosis by upregulating SLC1A5 and c-Myc expression, increasing ROS levels, and altering glutamine metabolism. Overexpression of SLC1A5 enhanced sensitivity to ferroptosis, whereas SLC1A5 knockdown and NAC treatment reversed these effects. Mechanistically, c-Myc bound to the SLC1A5 promoter, forming positive feedback with ROS. In the rat model of EMs, Erastin treatment reduced ectopic lesion volume, pelvic adhesions, and inflammatory markers (TNF-α, IL-6, IL-1β). These therapeutic effects were mitigated by NAC, highlighting the importance of the ROS/c-Myc/SLC1A5 pathway.

CONCLUSIONS: This study confirmed the involvement of the ROS/c-Myc/SLC1A5 pathway in regulating EMs sensitivity to ferroptosis and demonstrated the potential of Erastin as a therapeutic agent. Targeting this pathway offers a promising approach for the treatment of EMs.},
}

*Ferroptosis/drug effects
Female
*Glutamine/metabolism
Humans
Animals
*Amino Acid Transport System ASC/metabolism/genetics
Rats
Reactive Oxygen Species/metabolism
*Endometriosis/metabolism/pathology/drug therapy/genetics
*Minor Histocompatibility Antigens/metabolism/genetics
Piperazines/pharmacology
Proto-Oncogene Proteins c-myc/metabolism
Cell Line
Rats, Sprague-Dawley
Disease Models, Animal
Stromal Cells/metabolism
Endometrium/metabolism

@article {pmid40459775,
year = {2025},
author = {Singh, J and Phogat, A and Malik, V},
title = {N-acetylcysteine: a potential therapeutic agent against toxicity of pesticides.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {539},
pmid = {40459775},
issn = {1573-4978},
mesh = {*Acetylcysteine/pharmacology/therapeutic use/metabolism ; *Pesticides/toxicity ; Humans ; Oxidative Stress/drug effects ; Animals ; Antioxidants/pharmacology/metabolism ; Signal Transduction/drug effects ; },
abstract = {N-acetylcysteine (NAC) is a well-known health supplement that acts as a precursor to glutathione and exhibits antioxidative, anti-inflammatory, and modulatory activities. Several studies have extensively investigated the biological efficacy of NAC, including its effects on oxidative stress, cellular antioxidants, signal transduction, and structural anomalies caused by xenobiotics, including pesticides. This review summarizes the evidence of the ameliorative potential of NAC against oxidative stress and details its therapeutic potential in alleviating the toxicity of pesticides. Both in vivo and in vitro experiments have shown that NAC exerts its biological efficacy via regulation of TGF-β1/Smad3, MAPK, NF-κB, and PGC-1α/Tfam signaling pathways and rejuvenation of endogenous antioxidants.The present review provides insights into the recent findings and the mechanistic basis of the therapeutic potential of NAC for implementing it as an ameliorative agent against pesticide toxicity.},
}

*Acetylcysteine/pharmacology/therapeutic use/metabolism
*Pesticides/toxicity
Humans
Oxidative Stress/drug effects
Animals
Antioxidants/pharmacology/metabolism
Signal Transduction/drug effects

@article {pmid40456742,
year = {2025},
author = {Romero, JC and Tonapi, SS and Parihar, M and Loranc, E and Miller, HE and Lawrence, LA and Bassani, N and Robledo, DG and Cao, L and Nie, J and Kanda, K and Stoja, A and Garcia, N and Gorthi, A and Stoveken, BJ and Fan, TW and Cassel, TA and Zha, S and Lechleiter, JD and Musi, N and Dong, LQ and Lane, AN and Bishop, AJR},
title = {Loss of CD98HC phosphorylation by ATM impairs antiporter trafficking and drives glutamate toxicity in Ataxia telangiectasia.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5109},
pmid = {40456742},
issn = {2041-1723},
support = {T32 AG021890/AG/NIA NIH HHS/United States ; R01 CA241554/CA/NCI NIH HHS/United States ; F31 AG072902/AG/NIA NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; K22 ES012264/ES/NIEHS NIH HHS/United States ; P30 CA177558/CA/NCI NIH HHS/United States ; T32 CA148724/CA/NCI NIH HHS/United States ; },
mesh = {*Ataxia Telangiectasia Mutated Proteins/metabolism/genetics ; Animals ; Phosphorylation ; *Glutamic Acid/metabolism/toxicity ; *Ataxia Telangiectasia/metabolism/genetics/pathology ; Humans ; Mice ; *Fusion Regulatory Protein 1, Heavy Chain/metabolism/genetics ; *Antiporters/metabolism ; Endothelial Cells/metabolism ; Mice, Knockout ; Oxidative Stress ; Protein Transport ; },
abstract = {Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of this disorder is not understood. CD98HC chaperones cystine/glutamate and cationic/neutral amino acid antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on heterodimeric amino acid transporters relevant to Ataxia-telangiectasia phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes), with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance in ATM-deficient cells and mouse models. These findings provide insight into the long-known benefits of N-acetyl cysteine in Ataxia-telangiectasia cells beyond oxidative stress through removing glutamate excess by producing glutathione.},
}

*Ataxia Telangiectasia Mutated Proteins/metabolism/genetics
Animals
Phosphorylation
*Glutamic Acid/metabolism/toxicity
*Ataxia Telangiectasia/metabolism/genetics/pathology
Humans
Mice
*Fusion Regulatory Protein 1, Heavy Chain/metabolism/genetics
*Antiporters/metabolism
Endothelial Cells/metabolism
Mice, Knockout
Oxidative Stress
Protein Transport

@article {pmid40452041,
year = {2025},
author = {Pan, Y and Shih, HJ and Chuang, SH and Chang, CP and Hsiao, CH and Chiu, YH and Wang, PF and Lin, CC and Shih, PH},
title = {Effects of functional antioxidants on the expansion of gamma delta T-cells and their cellular cytotoxicity against bladder cancer cells.},
journal = {BMC cancer},
volume = {25},
number = {1},
pages = {980},
pmid = {40452041},
issn = {1471-2407},
support = {112-CCH-IRP-087//Changhua Christian Hospital, Taiwan/ ; 112-CCH-IRP-087//Changhua Christian Hospital, Taiwan/ ; 112-CCH-IRP-087//Changhua Christian Hospital, Taiwan/ ; },
mesh = {Humans ; *Urinary Bladder Neoplasms/immunology/pathology/drug therapy/metabolism ; *Antioxidants/pharmacology ; *Receptors, Antigen, T-Cell, gamma-delta/metabolism/immunology ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; *Intraepithelial Lymphocytes/immunology/drug effects ; Cell Survival/drug effects ; *Cytotoxicity, Immunologic/drug effects ; Acetylcysteine/pharmacology ; Lymphocyte Activation/drug effects ; Ascorbic Acid/pharmacology ; Vitamin E/pharmacology ; *T-Lymphocytes/drug effects/immunology ; Oxidative Stress/drug effects ; },
abstract = {PURPOSE: Results of previous studies have demonstrated that T-cell receptor cross-linking rapidly generates reactive oxygen species, which play essential signaling roles within mitochondria for the antigen-specific expansion of T-cells. However, oxidative stress also causes damage to cellular organelles. Thus, modulating ROS metabolism using antioxidants during naïve T-cell activation may promote the expansion and generation of functional T-cells. Notably, urothelial cancer is a sex-specific malignancy with high mortality rates worldwide. The present study aimed to evaluate the effects of various antioxidants on γδ T-cell proliferation, and the associated cytotoxicity against urothelial carcinoma cells (UCs).

METHODS: Over a period of cell induction and expansion, peripheral blood mononuclear cells were cultured with or without different antioxidants, including N-acetyl cysteine (NAC), vitamin C and vitamin E. Subsequently, phenotypic characterization of γδ T-cells and their cytolytic effects against UCs were analyzed by flow cytometry and cell viability assays, respectively.

RESULTS AND CONCLUSIONS: The results revealed that NAC partially inhibited T-cell expansion in a dose-dependent manner. In addition, CD3[+]/Vγ9[+] levels and natural killer group 2D receptor expression were mildly reduced following treatment with a high dose of NAC, whereas CD3[+]/CD56[+] levels and CD314 expression in natural killer-like cells were moderately decreased following treatment with vitamin E. Particularly, the direct co-incubation of bladder cancer cells with γδ T-cells supplemented with antioxidants significantly enhanced bladder cancer cytolysis. Collectively, results of the present study revealed that co-administration of functional antioxidants during γδ T-cell expansion may enhance the quality and efficacy of adoptive T-cell therapies for cancer treatment.},
}

Humans
*Urinary Bladder Neoplasms/immunology/pathology/drug therapy/metabolism
*Antioxidants/pharmacology
*Receptors, Antigen, T-Cell, gamma-delta/metabolism/immunology
Cell Proliferation/drug effects
Cell Line, Tumor
Reactive Oxygen Species/metabolism
*Intraepithelial Lymphocytes/immunology/drug effects
Cell Survival/drug effects
*Cytotoxicity, Immunologic/drug effects
Acetylcysteine/pharmacology
Lymphocyte Activation/drug effects
Ascorbic Acid/pharmacology
Vitamin E/pharmacology
*T-Lymphocytes/drug effects/immunology
Oxidative Stress/drug effects

@article {pmid40324675,
year = {2025},
author = {Li, Y and Li, N and Zhang, J and Liu, X and Xu, Y and Kong, L and Man, R and Li, J},
title = {FKBP51 protects hair cells of utricles from gentamicin-induced toxicity in vitro: possible relation to the activities of NF-κB signaling pathway.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {202},
number = {},
pages = {115513},
doi = {10.1016/j.fct.2025.115513},
pmid = {40324675},
issn = {1873-6351},
mesh = {Animals ; Mice ; *Anti-Bacterial Agents/toxicity ; Apoptosis/drug effects ; *Gentamicins/toxicity ; *Hair Cells, Auditory/drug effects/metabolism ; Mice, Knockout ; *NF-kappa B/metabolism/genetics ; Reactive Oxygen Species/metabolism ; *Saccule and Utricle/drug effects/cytology/metabolism ; *Signal Transduction/drug effects ; *Tacrolimus Binding Proteins/metabolism/genetics ; Acetylcysteine/chemistry/metabolism ; },
abstract = {FK506-binding protein 51 (FKBP51) belongs to the immunophilin family, which is related to regulation of cell growth and apoptosis. The present study was designed to explore the expression of FKBP51 in murine utricle hair cells (HCs) and the possible mechanisms underpinning the actions of FKBP51 relevant to gentamicin-mediated toxicity, with special attention given to nuclear factor-kappa B (NF-κB) activities in vitro. Here, we found, for the first time, that FKBP51 was widely expressed in both cytoplasm and cytomembrane. Moreover, the expression of FKBP51 in cultured HCs of utricle was downregulated after exposure to 1 mM gentamicin for 24 h. Then, the fkbp51 knockout mice were utilized to further investigate the role of FKBP51 in HCs in response to gentamicin. And the absence of FKBP51 led to severe HCs loss, accumulated ROS levels, and increased apoptotic factors, which could be alleviated by 2 mM N-acetyl-l-cysteine (NAC) to certain degree. In addition, mechanistic studies with 10 mM BAY 11-7082 showed that FKBP51 protected HCs against gentamicin-induced damage, at least in part, via blocking the NF-κB pathway activation. Taken together, our new findings suggest that FKBP51 might serve as a new target for the prevention of HCs of utricle from aminoglycoside-induced vestibular toxicity.},
}

Animals
Mice
*Anti-Bacterial Agents/toxicity
Apoptosis/drug effects
*Gentamicins/toxicity
*Hair Cells, Auditory/drug effects/metabolism
Mice, Knockout
*NF-kappa B/metabolism/genetics
Reactive Oxygen Species/metabolism
*Saccule and Utricle/drug effects/cytology/metabolism
*Signal Transduction/drug effects
*Tacrolimus Binding Proteins/metabolism/genetics
Acetylcysteine/chemistry/metabolism

@article {pmid40449641,
year = {2025},
author = {Ruangjaroon, T and Paricharttanakul, NM and Chokchaichamnankit, D and Srisomsap, C and Lirdprapamongkol, K and Svasti, J},
title = {Toxicoproteomic study of fipronil in SH-SY5Y cells reveals induction of endoplasmic reticulum stress and necrotic cell death as neurodegenerative mechanisms.},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {},
number = {},
pages = {106098},
doi = {10.1016/j.tiv.2025.106098},
pmid = {40449641},
issn = {1879-3177},
abstract = {Exposure to pesticides has been considered as a risk factor for developing neurodegenerative diseases. The increasing use of fipronil, a phenylpyrazole insecticide, poses a risk to human health. This study aims to use toxicoproteomics for exploring neurodegenerative mechanism of fipronil in SH-SY5Y human neuroblastoma cells. In this study, fipronil at sub-cytotoxic and cytotoxic concentrations (43 and 78 μM) caused increases in superoxide level from 3 to 48 h after treatment, while intracellular glutathione level was decreased at 48 h. Neurite outgrowth of the cells was impaired by fipronil at both concentrations, while significant increase of cell death via apoptosis and necrosis modes were observed with fipronil at cytotoxic concentration. Pretreatment with antioxidant N-acetylcysteine (NAC) effectively relieved impairment of neurite outgrowth and induction of cell death by fipronil. Proteomic analysis showed that expression of proteins involving endoplasmic reticulum (ER) stress and unfolded protein responses were predominantly affected by fipronil. Immunoblotting confirmed the increased expression of ER stress markers, GRP78/BiP (78 kDa glucose-regulated protein/Binding immunoglobulin protein) and PDI (protein disulfide isomerase), in fipronil-treated cells. Improved understanding of the neurotoxic mechanism of fipronil may help in developing a strategy for reducing risk of neurodegenerative development from intense and prolonged use of fipronil.},
}

@article {pmid40446373,
year = {2025},
author = {Fang, X and Pan, B and Xie, Y and Shao, W and Li, J and Han, D and Hong, X and Tu, W and Zhao, Y and Wu, J and Zhu, Y and Zhang, Y and Li, W and Xu, Y and Kan, H and Chen, R},
title = {Mechanistic insights into ozone-induced asthma exacerbation: role of oxidative stress and IL-33.},
journal = {Journal of hazardous materials},
volume = {494},
number = {},
pages = {138760},
doi = {10.1016/j.jhazmat.2025.138760},
pmid = {40446373},
issn = {1873-3336},
abstract = {Short-term exposure to ozone is linked to the onset and exacerbation of asthma, yet the underlying mechanisms remain unclear. This study aims to elucidate the molecular pathways and key mediators involved in ozone-induced asthma exacerbation. In a longitudinal epidemiological study, each 10 µg/m[3] increase in ozone is associated with decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF) of 26.24 ml (95 % confidence interval [CI]: 11.16 ml, 41.33 ml), 19.10 ml (95 % CI: 6.96 ml, 31.24 ml), and 41.65 ml/s (95 % CI: 3.87 ml/s, 79.43 ml/s), respectively. In asthmatic mice, ozone exposure induces oxidative stress and worsens pulmonary dysfunction, lung tissue damage, and inflammation, disrupting the balance of type 2 innate lymphoid cells (ILC2s), T helper type 2 (Th2), and T helper type 17 (Th17) cells. These effects are partially mitigated by N-acetylcysteine (NAC). Furthermore, ozone exposure significantly increases the interleukin (IL)-33 level, while treatment with an IL-33 neutralizing antibody markedly improves lung dysfunction, inflammatory cell infiltration, and immune response dysregulation. In conclusion, this study highlights that short-term exposure to ozone has deleterious effects on asthmatic patients and animals by inducing oxidative stress in lungs and disrupting immune function via IL-33.},
}

@article {pmid40443238,
year = {2025},
author = {Elangovan, A and Singh, A and Iyer, M and Kumar, SM and Kinoshita, M and Krishnan, J and Parkash, J and Verma, N and Yadav, MK and Wander, A and Reddy, DH and Vellingiri, B},
title = {Unravelling the Mechanistic Approach of Aflatoxin Contaminated Food on Neurodegenerative Diseases-A Novel Approach.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4817},
pmid = {40443238},
issn = {1099-1263},
abstract = {Aflatoxins (AFs) are a group of toxic secondary metabolites and a dietary toxin produced predominantly by Aspergillus species such as Aspergillus flavus and Aspergillus parasiticus. The four most common and harmful forms of AFs include Aflatoxin B1 (AFB1), Aflatoxin B2 (AFB2), Aflatoxin G1 (AFG1), and Aflatoxin G2 (AFG2), which pose a significant health threat due to their widespread contamination of food and feed products. Particularly, AFB1 has raised a major global health concern. Noxious neurological outcomes have been associated with chronic exposure to AF-contaminated food, contributing to development of neuropathies, demyelinating diseases, and cognitive decline. Disrupted tight junctions of blood-brain barrier (BBB) said to have implicated by AFs toxicity by directly damaging brain endothelial cells. Compromised BBB leads to the formation of DNA adducts, mitochondrial dysfunction, and impaired oxidative phosphorylation, contributing to oxidative stress in neuronal cells. AFs disrupt neuronal signaling pathways by generating reactive oxygen species (ROS) and initiating chronic inflammation, impairing cognitive function and motor control. Mounting evidences suggests that these factors trigger neurological disorders especially neurodegenerative disorders. Neuroprotective compounds, such as hesperetin, N-acetylcysteine (NAC), curcumin, and artichoke extract, have shown promise in counteracting AF-induced neurotoxicity. These compounds could reduce oxidative stress, attenuate inflammation, and support mitochondrial function, offering potential therapeutic strategies to mitigate AF-induced neurodegeneration. This review focuses on the molecular pathways through which AFs exert neurotoxic effects, highlighting their role in the onset of neurodegenerative diseases and potential neuroprotective compounds for therapies have been highlighted.},
}

@article {pmid40438181,
year = {2025},
author = {Liu, Y and Zhao, W and Huang, Q and Wan, L and Ren, Z and Zhang, B and Han, C and Yang, J and Zhang, H and Zhang, J},
title = {Advances in Research on the Release of von Willebrand Factor from Endothelial Cells through the Membrane Attack Complex C5b-9 in Sepsis.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {6719-6733},
pmid = {40438181},
issn = {1178-7031},
abstract = {Sepsis, a lethal organ dysfunction syndrome driven by aberrant host responses to infection, intertwines excessive inflammatory responses and dysregulated coagulation processes in its pathophysiology. Emerging research reveals the complement terminal membrane attack complex C5b-9 orchestrates ultralarge von Willebrand factor (ULVWF) release from vascular endothelial cells (ECs) through multifaceted mechanisms: C5b-9 compromises EC membrane integrity, activates calcium influx cascades, and provokes NLRP3 inflammasome signaling, triggering massive exocytosis of ULVWF stored within Weibel-Palade bodies (WPBs). When ADAMTS13 activity falters, undegraded ULVWF complexes with platelets to spawn microthrombi, precipitating microvascular occlusion and multiorgan collapse. Strikingly, elevated plasma von Willebrand factor (vWF) antigen levels in sepsis patients correlate robustly with endothelial injury, thrombocytopenia, and mortality-underscoring C5b-9-driven vWF release as a linchpin of septic coagulopathy. Current therapeutic strategies targeting these pathways, including recombinant ADAMTS13 (rhADAMTS13), N-acetylcysteine (NAC), and complement inhibitors like eculizumab, face limitations in clinical translation, necessitating further validation of their efficacy. Additionally, investigating complement regulatory molecules such as CD59 may unlock novel therapeutic avenues. Deciphering the intricate interplay within the C5b-9-vWF axis and advancing precision therapies hold transformative potential for ameliorating sepsis outcomes.},
}

@article {pmid40436274,
year = {2025},
author = {Marqués, J and Fernández-Irigoyen, J and Martínez-Azcona, M and Ainzúa, E and Marqués, V and Roncal, C and Orbe, J and Santamaría, E and Zalba, G},
title = {Endothelial NADPH oxidase 5 overexpression promotes thrombosis and alters thrombus composition by sex-dependent mechanisms in mice.},
journal = {Journal of thrombosis and haemostasis : JTH},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtha.2025.05.015},
pmid = {40436274},
issn = {1538-7836},
abstract = {BACKGROUND: Different members of the NADPH oxidases family (NOXs) participate in thrombosis. Nevertheless, the information about NOX5 in this process is scarce. The aim of this study was to test whether chronic expression of NOX5 may modulate thrombosis.

METHODS: To test this hypothesis, mice expressing human NOX5 at the endothelium and their control littermates underwent a FeCl3-induced thrombosis model in the carotid artery. The composition of the thrombi obtained from these mice was analysed by proteomics. The derived findings were corroborated by molecular analysis in vivo, in vitro and ex vivo. Finally, the antithrombic effects of N-acetylcysteine (NAC) and the pan-NOX inhibitor ML090 were tested.

RESULTS: The results from the present assay indicate that endothelial NOX5 expression promotes thrombosis in vivo in a sex-dependent manner. In female mice, NOX5 enhances prostaglandin E2 (PGE2) secretion and alters the expression of endothelial adhesion molecules. In male mice, NOX5 partially promotes the activation of circulating neutrophils. Both, NAC and ML090 protect against thrombosis in vivo.

CONCLUSIONS: In conclusion, our findings demonstrate that endothelial NOX5 plays a role in thrombosis, indicating that this oxidase should be considered as a therapeutic target to prevent thrombosis.},
}

@article {pmid40403956,
year = {2025},
author = {Hu, LJ and Li, CY and Xing, T and Wang, Y and Jiang, Q and Jiang, H and Wang, J and Tang, FF and Chang, YJ and Zhang, XH and Kong, Y and Huang, XJ},
title = {N-acetyl-L-cysteine promoted hematopoietic recovery in patients with acute myeloid leukemia after complete remission--A pilot study.},
journal = {Cancer letters},
volume = {625},
number = {},
pages = {217812},
doi = {10.1016/j.canlet.2025.217812},
pmid = {40403956},
issn = {1872-7980},
mesh = {Humans ; Pilot Projects ; *Leukemia, Myeloid, Acute/drug therapy/blood/pathology ; *Acetylcysteine/therapeutic use/administration & dosage/adverse effects ; Male ; Female ; Middle Aged ; Remission Induction ; *Hematopoiesis/drug effects ; Aged ; Adult ; Reactive Oxygen Species/metabolism ; Young Adult ; Treatment Outcome ; },
abstract = {Chemotherapy is a cornerstone treatment for acute leukemia (AL), but it often results in bone marrow (BM) failure, leading to infections, anemia, and bleeding, which significantly impact patient survival. Endothelial progenitor cells (EPCs) are critical elements of the BM microenvironment and are essential for hematopoiesis. Our previous research using in vitro and AML mouse models indicated that BM EPC dysfunction, characterized by impaired angiogenesis and elevated reactive oxygen species (ROS) levels in AML patients, could be partially reversed after complete remission (CR) and further improved with N-acetyl-L-cysteine (NAC) treatment. This pilot cohort study (NCT06024031, www.clinicaltrials.gov) evaluated the effects of NAC on hematopoietic recovery in 30 newly diagnosed AML patients after induction chemotherapy, compared to a propensity-matched control group of 60 patients. Patients received oral NAC (400 mg, three times daily) for 28 days post-chemotherapy alongside standard supportive care. NAC treatment did not affect CR rates (90 % vs. 80 %, P = 0.23), but significantly shortened platelet recovery time (19 vs. 22 days, P = 0.0001) among CR patients. NAC improved EPC percentages, reduced ROS, and enhanced EPC hematopoiesis-supporting functions in patients who achieved CR. NAC was safe and effective in promoting normal hematopoiesis recovery in AML patients in CR following chemotherapy.},
}

Humans
Pilot Projects
*Leukemia, Myeloid, Acute/drug therapy/blood/pathology
*Acetylcysteine/therapeutic use/administration & dosage/adverse effects
Male
Female
Middle Aged
Remission Induction
*Hematopoiesis/drug effects
Aged
Adult
Reactive Oxygen Species/metabolism
Young Adult
Treatment Outcome

@article {pmid40432447,
year = {2025},
author = {Máchalová, A and Landa, L and Máchal, J and Demlová, R and Slíva, J},
title = {The Effect of N-Acetylcysteine on Behavioral Sensitization to Methamphetamine in Mice.},
journal = {Physiological research},
volume = {74},
number = {2},
pages = {337-346},
pmid = {40432447},
issn = {1802-9973},
mesh = {Animals ; *Acetylcysteine/pharmacology/administration & dosage ; *Methamphetamine/pharmacology/administration & dosage ; Mice ; Male ; *Central Nervous System Stimulants/pharmacology ; *Behavior, Animal/drug effects ; },
abstract = {Behavioral sensitization is a phenomenon occurring after repeated administration of various psychotropic substances and it is characterized by gradually increasing response to the particular drug. It has been described for majority of addictive substances including amphetamines. It is considered to reinstate drug-seeking behaviour and plays important role in the processes associated with drug abuse and addiction. There are published reports, particularly on preclinical level, that N-acetylcysteine (NAC) may affect addictive properties of different classes of drugs (e.g., cocaine, heroin, alcohol, cannabinoids, nicotine). Since the lack of information on possible effects of NAC on amphetamine derivatives we decided to test possible influence of this substance on behavioral sensitization to methamphetamine (MET) in the mouse open field test. Our results have shown a decreased acute stimulatory effect of MET caused by NAC and moreover, there was a non-significant trend of attenuated development of behavioral sensitization to MET after simultaneous long-term administration of MET and NAC. This suppression of MET stimulatory effects therefore suggested on the preclinical level possible promising efficacy of NAC on addictive properties associated with MET similarly as it was demonstrated by other authors in association with cocaine or heroin. Key words: N-acetylcysteine, Methamphetamine, Behavioral sensitization.},
}

Animals
*Acetylcysteine/pharmacology/administration & dosage
*Methamphetamine/pharmacology/administration & dosage
Mice
Male
*Central Nervous System Stimulants/pharmacology
*Behavior, Animal/drug effects

@article {pmid40430469,
year = {2025},
author = {Zakaria, AY and Badawi, R and Osama, H and Abdelrahman, MA and El-Kalaawy, AM},
title = {A Comparative Study of N-Acetyl Cysteine, Rosuvastatin, and Vitamin E in the Management of Patients with Non-Alcoholic Steatohepatitis: A Randomized Controlled Trial.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {5},
pages = {},
pmid = {40430469},
issn = {1424-8247},
abstract = {Background: Non-alcoholic steatohepatitis (NASH) is characterized by increased production of proinflammatory cytokines, fibrosis, and hepatocyte apoptosis. This study aimed to assess the efficacy of N-acetyl cysteine (NAC), rosuvastatin (RSV), and vitamin E (VE) in patients with NASH. Methods: A double-blinded, parallel, randomized, controlled study was conducted and registered on clinicaltrials.gov (Identifier: NCT06105060), involving 135 NASH participants, who were divided into three groups: the control group (group 1), consisting of patients receiving standard therapy VE at a dosage of 400 IU twice daily. In the treated group (group 2), patients were administered NAC at a dosage of 1200 mg twice daily, while treatment (group 3) received RSV at a dosage of 20 mg once daily. FibroScan[®] examination of liver tissue and fibrosis scores, along with tests for liver aminotransferases, lipid profile, glycemic parameters, and renal and hepatic functions, were assessed before and after six months of treatment. Results: The analyzed groups demonstrated a significant reduction in steatosis and lipid peroxidation (p < 0.05). The NAC group demonstrated greater anti-inflammatory and anti-apoptotic effects compared to the RSV group, although this difference was not significant in the control group. NAC is conceded as the only significant antifibrotic agent in liver stiffness measurement (LSM), biological marker findings, and non-invasive liver fibrosis scores (p < 0.05), in addition to its improvement of several metabolic parameters and health-related quality of life. Conclusions: Patients receiving NAC demonstrated safety and efficacy in enhancing steatosis, fibrosis, and metabolic parameters, representing a novel strategy in the management of NASH.},
}

@article {pmid40429784,
year = {2025},
author = {Recinella, L and Pinti, M and Di Lodovico, S and Brenciani, A and Giovanetti, E and Diban, F and Di Giulio, M and Brunetti, L and Leone, S},
title = {A New Bromelain-Based Polyenzymatic Complex Plus N-Acetylcysteine: A Promising Approach for the Treatment of Urinary Tract Infections.},
journal = {International journal of molecular sciences},
volume = {26},
number = {10},
pages = {},
pmid = {40429784},
issn = {1422-0067},
support = {Difass International Spa 2024//Difass International Spa/ ; },
mesh = {Biofilms/drug effects ; *Urinary Tract Infections/drug therapy/microbiology ; Ciprofloxacin/pharmacology ; Animals ; Microbial Sensitivity Tests ; Escherichia coli/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Acetylcysteine/pharmacology/chemistry ; *Bromelains/chemistry/pharmacology ; Moths/microbiology ; Humans ; },
abstract = {Biofilm plays a crucial role in the pathogenesis and chronicity of urinary tract infections (UTIs). The present work aimed to evaluate the anti-biofilm effects of Formulation (DIF17BRO[®] plus NAC) in combination with ciprofloxacin (CPX) on Escherichia coli strains. The antimicrobial activity of ciprofloxacin was evaluated by minimum inhibitory concentration (MIC) determination, and the antibiofilm effects of ciprofloxacin alone and combined with Formulation were evaluated on E. coli ATCC700926, E. coli ATCC10536, E. coli PNT, and E. coli PCA mature biofilms in terms of CFU/mL and biomass quantifications. Moreover, the potential protective effects of Formulation plus ciprofloxacin was tested in a Galleria mellonella in vivo infection assay. Our results underlined the increased microbial reduction in the mature biofilm in the presence of the combination Formulation and CPX, even at a lower concentration of CPX. Formulation increased the percentage of biofilm biomass reduction, inducing a disruption of the biofilm structure itself. Our present findings confirm that MIC CPX combined with Formulation also induced an antimicrobial effect in the G. mellonella assay. Formulation facilitated the perturbation of the biofilm polymeric matrix, enhancing the antibiotic penetration and its antimicrobial action on bacteria, underlining Formulation's role as an enhancer of ciprofloxacin antibacterial action.},
}

Biofilms/drug effects
*Urinary Tract Infections/drug therapy/microbiology
Ciprofloxacin/pharmacology
Animals
Microbial Sensitivity Tests
Escherichia coli/drug effects
*Anti-Bacterial Agents/pharmacology/chemistry
*Acetylcysteine/pharmacology/chemistry
*Bromelains/chemistry/pharmacology
Moths/microbiology
Humans

@article {pmid40427046,
year = {2025},
author = {Hwang, I and Kang, CG and Lim, SJ and Kim, HJ and Kang, R and Jeon, SH and Lee, SH and Kim, JW and Kang, JS},
title = {Human Placenta Hydrolysate Protects Against Acetaminophen-Induced Liver Injury in Mice.},
journal = {Biomedicines},
volume = {13},
number = {5},
pages = {},
pmid = {40427046},
issn = {2227-9059},
support = {N/A//Green Cross Wellbeing/ ; },
abstract = {Background/Objectives: Acetaminophen (APAP) is a widely used analgesic and antipyretic, but overdose can lead to APAP-induced liver injury (AILI), a major cause of acute liver failure. While N-acetylcysteine (NAC) is the current standard of care, its efficacy is significantly reduced when administered after the peak time of liver injury, highlighting the need for alternative therapeutic strategies. Human placenta hydrolysate (HPH) has shown potential as a therapeutic agent for various liver diseases due to its rich content of bioactive compounds. This study aimed to investigate the hepatoprotective effects of HPH in a mouse model of AILI. Methods: HPH was administered to mice for three days prior to APAP treatment. The effects of HPH on liver morphology, necrosis, liver enzymes, phase I/II detoxification enzymes, oxidative stress markers, and inflammatory cytokines were evaluated. Results: HPH pretreatment attenuated APAP-induced liver necrosis and congestion, reduced serum levels of liver enzymes. In addition, HPH showed a concentration-dependent attenuation of APAP-induced decrease in human hepatocyte viability. HPH modulated phase I/II enzyme expression by downregulating CYP2E1 and upregulating SULT1A1, UGT1A6, GSTP1, and TPMT. HPH also exhibited antioxidant effects by increasing SOD and GPx activities, reducing MDA levels, and restoring the GSH/GSSG ratio. Furthermore, HPH attenuated the APAP-induced increase in the inflammatory cytokines TNF-α and IL-6. These findings suggest that HPH protects against AILI through multiple mechanisms, including the modulation of phase I/II detoxification, activation of antioxidants, and inhibition of inflammation. Conclusions: HPH could be a potential therapeutic option for APAP overdose and related liver injuries.},
}

@article {pmid40425069,
year = {2025},
author = {Morales, EN and Malecki, CC and Maruri, A and Sánchez, VR and Portu, A and Goldman, A and Chiaramoni, NS and Fenoy, IM},
title = {Preclinical evaluation of N-acetyl-cysteine in association with liposomes of lung surfactant's lipids for the treatment of pulmonary fibrosis and asthma.},
journal = {Toxicology and applied pharmacology},
volume = {},
number = {},
pages = {117412},
doi = {10.1016/j.taap.2025.117412},
pmid = {40425069},
issn = {1096-0333},
abstract = {PURPOSE: There is a need to generate new treatments against pulmonary diseases such as idiopathic fibrosis and asthma. N-acetylcysteine (NAC) has multiple clinical applications, but its unstable nature and route of administration limits its effectiveness. New pulmonary delivery strategies, such as liposomes made of lung surfactant lipids, could overcome NAC's limitations. This work aims to evaluate the efficacy of NAC combined with liposomes as a treatment for asthma and in preventing fibrotic development.

METHODS: Unilamellar vesicles were obtained through the dehydration-rehydration method followed by multiple membrane extrusion and characterized by Dynamic Light Scattering and Transmission electron microscopy. Lung fibrosis was induced by bleomycin administration, and liposomal formulation of NAC (LipoNAC) was evaluated as a preventive treatment. LipoNAC formulation was also evaluated in a therapeutic regimen for asthma using the classic ovalbumin model. For both models, the administration of the treatment was via the intranasal route.

RESULTS: NAC treatments (free NAC and LipoNAC) improved lung histopathology and decreased collagen deposition when tested in the lung fibrosis model. Only LipoNAC decreased serum levels of lactate dehydrogenase, myeloperoxidase activity in lung fluid and lung TGF-β. Although both treatments decreased Th2 cytokine and histopathological inflammation in the asthma model, only LipoNAC treatment significantly decreased mucus in asthmatic mice.

CONCLUSIONS: These results indicate that surfactant liposomal delivery of NAC potentiates its anti-inflammatory, mucolytic, and antioxidant activity, rendering it a promising therapy for respiratory diseases.},
}

@article {pmid40421021,
year = {2025},
author = {Rastgoo, S and Pourvali, K and Raeissadat, SA and Eslamian, G and Zand, H},
title = {Co-administration of vitamin D and N-acetylcysteine to modulate immunosenescence in older adults with vitamin D deficiency: a randomized clinical trial.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1570441},
pmid = {40421021},
issn = {1664-3224},
mesh = {Humans ; *Acetylcysteine/administration & dosage ; Aged ; Male ; Female ; *Vitamin D/administration & dosage ; *Immunosenescence/drug effects ; *Vitamin D Deficiency/drug therapy/immunology/blood ; Leukocytes, Mononuclear/immunology/drug effects/metabolism ; Middle Aged ; Cellular Senescence/drug effects ; Dietary Supplements ; Aged, 80 and over ; },
abstract = {BACKGROUND: Immunosenescence is an important factor in the impaired immune response in older adults and plays a significant role in the development of biological aging. Targeting immunosenescence could present a novel pharmacological approach to mitigating aging and age-related diseases. We aimed to investigate the effect of N-acetylcysteine (NAC) and vitamin D (Vit-D) on the senescence of peripheral blood mononuclear cells (PBMCs).

METHOD: This randomized clinical trial was conducted on older adults with Vit-D deficiency. Eligible participants were randomly assigned to one of four groups to receive either (A) 1000 IU of Vit-D daily (D1) (B), 1000 IU of Vit-D plus 600 mg of NAC daily (D1N) (C), 5000 IU of Vit-D daily (D5), or (D) 5000 IU of Vit-D plus 600 mg of NAC daily (D5N) for 8 weeks. Senescence-associated beta-galactosidase (SA-β-gal) staining, expression of senescence-related genes, and serum inflammatory factors were measured at baseline and after 8 weeks.

RESULTS: After the intervention, supplementation with D5N and D5 significantly downregulated p16, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) expression and decreased SA-β-gal activity compared to the D1 group. Additionally, co-administration of NAC with 1000 IU of Vit-D significantly downregulated p16 transcripts in PBMCs compared to Vit-D 1000 IU alone. No significant differences were observed between the groups in serum IL-6, C-reactive protein (CRP), or the neutrophil-to-lymphocyte ratio (NLR) after the intervention.

CONCLUSIONS: The loading dose of Vit-D significantly attenuates senescence in PBMCs of older adults. However, co-administration of NAC with both the standard and loading doses of Vit-D further enhances these beneficial effects.

CLINICAL TRIAL REGISTRATION: https://irct.behdasht.gov.ir, identifier IRCT20230508058120N1.},
}

Humans
*Acetylcysteine/administration & dosage
Aged
Male
Female
*Vitamin D/administration & dosage
*Immunosenescence/drug effects
*Vitamin D Deficiency/drug therapy/immunology/blood
Leukocytes, Mononuclear/immunology/drug effects/metabolism
Middle Aged
Cellular Senescence/drug effects
Dietary Supplements
Aged, 80 and over

@article {pmid40420092,
year = {2025},
author = {Li, L and Lu, J and Fu, S and Li, W and Wang, Y and Wang, K and Tao, Y and Liu, S},
title = {Evodiamine induces ferroptosis in prostate cancer cells by inhibiting TRIM26-mediated stabilization of GPX4.},
journal = {Chinese medicine},
volume = {20},
number = {1},
pages = {71},
pmid = {40420092},
issn = {1749-8546},
support = {82203167//National Natural Science Foundation of China/ ; 82460722//National Natural Science Foundation of China/ ; GSWSQNPY2024-12//gansu provincial health industry science and technology innovation project/ ; CY2022-MS-A09//cuiying scientific and technological innovation program of lanzhou university second hospital/ ; CY2023-MS-A05//cuiying scientific and technological innovation program of lanzhou university second hospital/ ; GZKP2023-36//traditional chinese medicine scientific research project of gansu province, china/ ; CYXZ2024-11//cuiying scientific training program for undergraduates of lanzhou university/ ; },
abstract = {BACKGROUND: Prostate cancer is a major global health challenge, characterized by high morbidity and mortality rates. Traditional treatment options, including androgen deprivation therapy and chemotherapy, often lead to drug resistance. In recent years, natural compounds have garnered attention for their potential therapeutic effects. Evodiamine, a bioactive alkaloid from Evodia rutaecarpa, has demonstrated promising anti-cancer properties in various malignancies, including oral squamous cell carcinoma, breast, colorectal, and ovarian cancers. This study explores the efficacy of evodiamine in prostate cancer cells and investigates the mechanisms underlying evodiamine-induced cell death.

METHODS: To investigate the effects of evodiamine on prostate cancer cells, various cell lines, including both castration-sensitive and castration-resistant variants, were treated with different concentrations of evodiamine for various durations. Cell viability, proliferation, invasion ability, and colony formation were assessed using the CCK8 assay, EdU assay, 3D matrigel drop invasion assay, and colony formation assay, respectively. The effects of evodiamine on apoptosis were analyzed using FACS, Hoechst staining, and Western blot. To evaluate its effects on ferroptosis, malondialdehyde (MDA) and glutathione (GSH) assay kits, as well as DCFH-DA and the lipid peroxidation sensor BODIPY[™] 581/501 C11 fluorescent probes, were employed. The molecular mechanisms through which evodiamine regulates GPX4 protein instability were investigated using Western blot and TRIM26 ectopic expression. Additionally, a mouse xenograft model derived from DU145 cells was established to evaluate the in vivo effects of evodiamine and its molecular mechanisms, utilizing hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and Western blot analysis.

RESULTS: Evodiamine significantly suppressed cell viability, proliferation, invasion, and colony formation in prostate cancer cells. Importantly, evodiamine-induced cell death in the PC3 and DU145 cell lines was independent of apoptosis pathway. Instead, evodiamine increased reactive oxygen species (ROS) production, lipid ROS levels and MDA levels, while decreasing GSH levels, indicating the induction of ferroptosis. The key role of ROS in evodiamine-induced ferroptosis was further confirmed by the partial reversal of cell death upon treatment with the ROS scavenger N-acetylcysteine (NAC). Mechanistically, evodiamine induced ferroptosis by destabilizing GPX4 protein in a TRIM26-dependent manner. Moreover, in vivo studies demonstrated that evodiamine significantly inhibited tumor growth and induced ferroptosis in tumor cells, highlighting its therapeutic potential.

CONCLUSION: This study demonstrates that evodiamine exerts potent antitumor effects against prostate cancer through inhibiting TRIM26-mediated stabilization of GPX4 protein and triggering ferroptosis. These findings suggest that evodiamine, a natural product derived from traditional Chinese medicine, could be a promising therapeutic agent for prostate cancer.},
}

@article {pmid40418638,
year = {2025},
author = {Maxwell, MN and Murphy, BT and McDonald, FB and O'Halloran, KD},
title = {Exploring the respiratory efficacy of combined chronic glucocorticoid and antioxidant interventions in the mdx mouse: The PREDNAC trial.},
journal = {Experimental physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/EP092491},
pmid = {40418638},
issn = {1469-445X},
support = {SFI 19/FFP/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; //Department of Physiology, UCC/ ; },
abstract = {Duchenne muscular dystrophy (DMD) is characterized by respiratory muscle injury and weakness, ultimately leading to respiratory failure. Impaired respiratory muscle performance, fibrosis and inflammation in early disease are evident in the dystrophin-deficient mdx mouse model of DMD. Prednisone or similar treatment is the current standard of care for DMD and exerts its benefits via an anti-inflammatory action, but chronic treatment is associated with side-effects. A recent study demonstrated improved function in mdx limb muscle with weekly glucocorticoid treatment compared with daily treatment. Herein, we investigated the effect of weekly α-methylprednisolone (PRED) treatment alone and the effect of PRED in combination with daily intake of the antioxidant N-acetyl cysteine, NAC (PREDNAC) on respiratory performance. One-month-old male mdx mice received PRED (0.8 mg/kg methylprednisolone i.p. weekly) or PREDNAC (0.8 mg/kg methylprednisolone i.p. weekly and 1% NAC in drinking water daily) for 3 months. At 4 months of age, conscious breathing was measured in vivo by whole-body plethysmography. Under urethane general anaesthesia, respiratory EMG and inspiratory pressure were measured at baseline and during maximal activity. The intrinsic force-generating capacity of the diaphragm was determined ex vivo. Neither PRED nor PREDNAC influenced breathing or diaphragm force-generating capacity in mdx mice. There was a significant increase in diaphragm and parasternal EMG activity, but inspiratory pressure was unchanged with treatment. We conclude that neither PRED nor PREDNAC has a major beneficial effect on respiratory system performance in the mdx mouse model of DMD. Weekly administration of glucocorticoids is inadequate to protect respiratory performance in mdx mice, which might reflect the higher duty cycle of respiratory muscles compared with limb muscles.},
}

@article {pmid40418545,
year = {2025},
author = {Varikasuvu, SR and Manne, M and Kumar, S and Mudgal, SK and Raj, V and Varshney, S and Gupta, P and Grover, A and Goyal, C and Lal, V and Singh, H and Lisa, M and Saransh Workshop Members, },
title = {COVID-19 clinical outcomes and N-acetylcysteine (CoViNAC study): a GRADE compliant meta-analysis of randomized controlled trials with molecular docking and dynamics simulation studies with Mpro of SARS-CoV-2.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {71},
number = {5},
pages = {95-102},
doi = {10.14715/cmb/2025.71.5.13},
pmid = {40418545},
issn = {1165-158X},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Molecular Docking Simulation ; *SARS-CoV-2/enzymology/drug effects ; Randomized Controlled Trials as Topic ; *Coronavirus 3C Proteases/metabolism/chemistry ; *COVID-19 Drug Treatment ; Molecular Dynamics Simulation ; COVID-19/mortality/virology ; Treatment Outcome ; Antiviral Agents/therapeutic use ; },
abstract = {N-acetylcysteine (NAC) has been proposed as an adjuvant therapy for COVID-19, but evidence from randomized controlled trials (RCTs) remains inconclusive. This systematic review and meta-analysis evaluated NAC's efficacy in improving mortality and recovery/discharge rates. Additionally, molecular docking and molecular dynamics simulation (MDMS) studies were conducted to assess NAC's interaction with the SARS-CoV-2 main protease (Mpro), a key enzyme for viral replication. A systematic search identified 12 RCTs, with 11 trials (1125 patients) included in the mortality analysis. NAC significantly reduced mortality (RR=0.59, 95% CI 0.39-0.88, p=0.01; I[2]=62%), indicating a 41% decreased risk of death. Six RCTs (656 patients) showed improved recovery/discharge rates (RR=1.09, 95% CI 1.03-1.14, p=0.003; I[2]=0%). MDMS studies demonstrated stable NAC binding at the Mpro catalytic site, interacting with His41 and Cys145, crucial for enzymatic activity. These findings suggest NAC significantly improves clinical outcomes in COVID-19 and may inhibit viral replication by targeting Mpro. This integrated evidence substantiates NAC's potential as a critical adjuvant therapy.},
}

Humans
*Acetylcysteine/therapeutic use
Molecular Docking Simulation
*SARS-CoV-2/enzymology/drug effects
Randomized Controlled Trials as Topic
*Coronavirus 3C Proteases/metabolism/chemistry
*COVID-19 Drug Treatment
Molecular Dynamics Simulation
COVID-19/mortality/virology
Treatment Outcome
Antiviral Agents/therapeutic use

@article {pmid40414419,
year = {2025},
author = {Chakraborty, S and Rao, S and Tripathi, SJ},
title = {The neuroprotective effects of N-acetylcysteine in psychiatric and neurodegenerative disorders: From modulation of glutamatergic transmission to restoration of synaptic plasticity.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110527},
doi = {10.1016/j.neuropharm.2025.110527},
pmid = {40414419},
issn = {1873-7064},
abstract = {N-acetylcysteine (NAC) is an effective pleiotropic drug with a strong safety profile. It is predominantly used as a mucolytic agent and in the treatment of paracetamol overdose. However, extensive research in the last decade has shown the prominent efficacy of NAC in many neuropsychiatric and neurodegenerative disorders. NAC acts through multiple mechanisms; primarily, it releases cysteine and modulates glutamatergic and monoaminergic transmission. Further, it restores glutathione levels, promotes oxidative balance, reverses decreased synaptic plasticity, reduces neuroinflammation and mitochondrial dysfunction, and provides neurotrophic support. Additionally, it regulates one-carbon metabolism pathways, leading to the production of key metabolites. In this review, we will be discussing in-depth mechanisms of action of NAC and its promising ability to reverse neuropathological changes, particularly cognitive deficits, and associated plasticity changes in various psychiatric and neurodegenerative diseases, including depression, bipolar disorders, schizophrenia, Alzheimer's disease, Huntington's disease, traumatic brain injury, aging. Overall, several preclinical studies and clinical trials have demonstrated the efficacy of NAC in reversing regressive plasticity, cognitive deficits, and associated changes in the brain. NAC remains among the strongest candidates with a high safety profile for managing several types of neurological disorders.},
}

@article {pmid40411876,
year = {2025},
author = {Chen, Y and Jiang, G and Huang, Y and Song, S and Fu, H and Du, B and Xiao, Y and Li, P and Shi, K and Huang, Y and Song, Q and Gao, X and Xie, Q},
title = {Lipoprotein-Based Nanocatalyst Enables Targeted Treatment of APAP-Induced Liver Injury via Enhanced Macropinocytosis.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e2500507},
doi = {10.1002/adhm.202500507},
pmid = {40411876},
issn = {2192-2659},
support = {82270618//National Natural Science Foundation of China/ ; 82070604//National Natural Science Foundation of China/ ; 82171358//National Natural Science Foundation of China/ ; 23S41900100//Shanghai Science and Technology Development Foundation/ ; 22QA1405000//Shanghai Rising-Star Program/ ; 2023ZKZD21//Shanghai Municipal Education Commission/ ; 2022YFC2502800//Key Technologies Research and Development Program/ ; 2018CR005//Ruijin Hospital/ ; shslczdzk01103//Shanghai Municipal Health Commission/ ; },
abstract = {Drug-induced liver injury (DILI), predominantly caused by acetaminophen (APAP) overdose, is characterized by excessive reactive oxygen species (ROS) production and subsequent hepatocyte necrosis. Although N-acetylcysteine (NAC) remains the only approved treatment, its effectiveness is limited by a narrow therapeutic time window and reduced efficacy in advanced cases. To address these limitations, an innovative therapeutic approach is developed utilizing ceria's antioxidant properties. In this study, a reconstituted high-density lipoprotein-encapsulated ceria nanocatalyst (CeO2-rHDL) is engineered to overcome the aggregation tendency and targeting limitation of naked ceria nanoparticles. These findings revealed that CeO2-rHDL enters hepatocytes through macropinocytosis, a process synergistically enhanced by both APAP and NAC, facilitating efficient liver targeting. The nanocatalyst demonstrated remarkable therapeutic efficacy by restoring mitochondrial function through ROS reduction. When combined with NAC, CeO2-rHDL significantly improved survival outcomes in DILI mice. This lipoprotein-based nanocatalyst system represents a promising therapeutic strategy for DILI treatment, offering enhanced targeting capabilities and improved therapeutic efficacy.},
}

@article {pmid40409732,
year = {2025},
author = {Kuttikrishnan, S and Suleman, M and Ahmad, F and Mariyam, Z and Habeeba, U and Prabhu, KS and Buddenkotte, J and Steinhoff, M and Uddin, S},
title = {Curcumin induces apoptosis via downregulation of SKP2 and induction of GADD45A/CDKN1A expression through generation of ROS in cutaneous T-cell lymphoma cells.},
journal = {Toxicology and applied pharmacology},
volume = {},
number = {},
pages = {117403},
doi = {10.1016/j.taap.2025.117403},
pmid = {40409732},
issn = {1096-0333},
abstract = {Curcumin, a plant derived natural product isolated from Curcuma longa. The aim of this study is to investigate the anti-proliferative effects and the underlying mechanisms of curcumin in Cutaneous T cell lymphoma (CTCL), a type of non-Hodgkin lymphoma that primarily affects the skin. The study found that curcumin induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases leading to growth inhibition. Furthermore, Curcumin treatment downregulated the expression of S-phase kinase protein (SKP2) with concomitant upregulation of GADD45A, CDKN1A and CDKN1B. Curcumin also suppresses the expression of anti-apoptotic molecules including XIAP and cIAPs. Curcumin treatment of CTCL cells generates reactive oxygen species (ROS) and depletion of glutathione. Pretreatment of CTCL with N-acetyl cysteine prevented curcumin-mediated generation of ROS and prevention caspase activity. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Molecular docking studies revealed a strong binding affinity of curcumin to the active site of SKP2, primarily involving key residues crucial for its activity. Altogether, our results suggest that targeting SKP2 and GADD45A signaling by curcumin could be an attractive strategy for the treatment of CTCL.},
}

@article {pmid40409588,
year = {2025},
author = {Medisah, ME and Badiee, MS and Mahdavinia, M and Motamed, H and Rahmani, AH},
title = {Lactate is a prognostic marker of acute liver failure in early identification of patients susceptible to liver transplantation following acute acetaminophen poisoning.},
journal = {Annales pharmaceutiques francaises},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pharma.2025.05.007},
pmid = {40409588},
issn = {0003-4509},
abstract = {BACKGROUND: Acetaminophen (APAP) is the most commonly used analgesic and antipyretic drug, and its intentional or accidental overdose can lead to acute liver failure (ALF). Rapid prognosis and the selection of appropriate patients for transplantation in ALF are crucial. Lactate is the end product of anaerobic glycolysis and an indicator for determining the oxygen status in cells. The aim of this study was to investigate the relationship between serum lactate level and the prognosis of ALF due to acute APAP poisoning in patients referred to Razi Hospital, Ahvaz.

METHODS: This cross-sectional and prospective study was conducted on 34 healthy individuals (as controls) and 34 patients diagnosed with acute APAP poisoning. Serum levels of APAP, lactate, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T.bil), direct bilirubin (D.bil), and gamma-glutamyl transferase (GGT) were measured in healthy individuals and patients with acute APAP poisoning within 24 hours of admission. The relationship between the dose of APAP consumed, the amount of N-acetylcysteine (NAC) received, and the age and gender of the patients with lactate level was also evaluated.

RESULTS: The mean dose of APAP in the patients was 10.75 gr. A total of 85% of the patients received NAC. The mean volume of NAC injection was 4.4 mmol/L. The number of women with APAP overdose was higher than men. Lactate level increased with increasing APAP doses. The mean serum lactate level significantly reduced after 24 hours compared to the initial admission, and the levels of liver markers increased significantly after 24 hours.

CONCLUSION: In order to accept lactate as an international criterion in early identification of liver transplant candidate patients and reduce their mortality, clinical validity studies including definition and validation of clinical conditions related to lactate level and reliability tests are necessary. Therefore, early and periodic determination of serum lactate level seems to be essential as a promising biomarker for the prognosis of ALF caused by acute APAP poisoning.},
}

@article {pmid40404947,
year = {2025},
author = {Bai, H and Du, S and Qiu, D and Li, S and Gao, R and Zhang, Z},
title = {GPX4 Inhibition Contributes to NLRP3-Mediated Pyroptosis and Cognitive Impairment in Ketamine-Exposed Neonatal Rats.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40404947},
issn = {1559-1182},
support = {NDYB2022-4//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; NDYB2022-7//Initial Scientific Research Foundation of Inner Mongolia Agricultural University/ ; 31572580//National Natural Science Foundation of China/ ; 31572580//National Natural Science Foundation of China/ ; SYKJYB202301//Discipline Project of College of Veterinary Medicine/ ; },
abstract = {Increasing evidence reveals that multiple or prolonged exposure to ketamine causes hippocampal damage and cognitive dysfunction. However, the critical mechanisms underlying ketamine-induced neurotoxicity in the developing brain remain elusive. The present study was designed to investigate the role of GPX4 in ketamine-induced pyroptosis and cognitive dysfunction in the developing rat hippocampus. To achieve this goal, we conducted Western blotting, ELISA tests, histopathological analysis, Morris water maze tests, cell viability assays, and biochemical analyses on PC12 cells, HAPI cells, and 7-day-old rats. Additionally, N-acetylcysteine (NAC) and RSL3 were administered prior to continuous ketamine exposure. Our findings indicate that GPX4 inhibition by RSL3 enhances lipid peroxidation and mitochondrial damage, activates NLRP3/caspase-1 axis-dependent pyroptosis, and exacerbates hippocampal damage and cognitive dysfunction following ketamine exposure, while NAC effectively mitigates the effects of RSL3. Collectively, our in vivo and in vitro results support the notion that GPX4 may serve as a negative regulator of pyroptosis in ketamine-induced hippocampal damage and cognitive dysfunction. Our study proposes a novel strategy for treating ketamine-induced neurotoxicity through upregulating GPX4 expression.},
}

@article {pmid40401298,
year = {2024},
author = {Thomas, MC and Edwards, CJ and Dunlap, A},
title = {Practice Patterns for N-acetylcysteine Dosing for Acetaminophen Toxicity in the United States.},
journal = {Innovations in pharmacy},
volume = {15},
number = {4},
pages = {},
pmid = {40401298},
issn = {2155-0417},
abstract = {Background: Although the FDA approved acetaminophen toxicity dosing regimen for intravenous n-acetylcysteine (NAC) is a three-bag regimen, alternate regimens have been published which are generally simpler, and decrease errors and adverse effects. It is not clear how pervasive alternative regimens are used in hospitals in the US and reasons for a change from the FDA regimen. Objective: Characterize practice patterns for treating acetaminophen toxicity. Methods: A pilot-tested, electronic survey containing demographic and practice pattern questions for acetaminophen toxicity management was sent to residency program directors. The survey was open for 4 weeks with several reminder e-mails sent to non-responders. Descriptive statistics were used to summarize the data. Results: There were 119 responses (9.2% response rate). Responses were representative of all geographic areas in the US and were most commonly from community hospitals (67.2%) and those with 300 or more beds (72.2%). Nearly two-thirds used the FDA approved NAC regimen, whereas others used an alternate regimen. Reasons for making the change were for simplicity, to decrease errors or adverse events, or based on local poison center recommendations. More than one-third of respondents reported not using a maximum dosing weight. Conclusions: N-acetylcysteine is usually administered intravenously using the FDA approved regimen for acetaminophen toxicity. The weight for dosing was commonly capped at 100 kg, but some institutions did not use a maximum. Alternative intravenous regimens have been implemented at some institutions with the impetus for change being safety and simplicity.},
}

@article {pmid40400197,
year = {2025},
author = {Naseem, S and Xuan, MF and Hua, H and Park, S and Manzoor, A and Teng, H and Jin, H and Li, X and Li, Q},
title = {Vitamin C and N-acetylcysteine promotes bovine AD-MSCs proliferation and differentiation via Akt/mTOR/P70S6K signaling pathway for cultured meat production.},
journal = {Animal bioscience},
volume = {},
number = {},
pages = {},
doi = {10.5713/ab.24.0776},
pmid = {40400197},
issn = {2765-0189},
abstract = {OBJECTIVE: Traditional meat production is insufficient to meet the increasing protein requirements; necessitating cultured meat, which is safe, worthwhile, and scalable. Fat is crucial for making cultured meat more acceptable to consumers by enhancing flavour and providing a natural appearance. Mesenchymal stem cells from adipose tissue are a promising source for this purpose, but in vitro expansion of cells decreases their proliferation ability and increases cellular senescence. The objective of this study was to improve the proliferation and differentiation abilities of adipose-derived mesenchymal stem cells (AD-MSCs).

METHODS: In this study, vitamin C (VC) and N-acetylcysteine (NAC) antioxidants were used to treat AD-MSCs from Yanbian cattle testicles. CCK8, EdU staining, RT-qPCR, and western blot were used to test the cell viability and proliferation ability of AD-MSCs, ORO staining, triglycerides assay, and adipogenic specific markers expression were determined to analyse the adipogenic differentiation ability. Furthermore, oxidative stress parameters and activation of the Akt/mTOR/P70S6K signalling pathway were also studied.

RESULTS: Results showed that VC and NAC both increased proliferation and differentiation ability of AD-MSCs by increasing the expression of cell cycle regulatory and differentiation genes and proteins expression, and decreasing the expression of cell cycle inhibitory factors, and up-regulating stemness markers expression, while co-treatment showed enhanced effect. Oxidative stress was reduced by decreased ROS production, malondialdehyde content, and enhanced glutathione activity, as well as declined cellular senescence. Subsequently, the Akt/mTOR/P70S6K signalling pathway was activated by VC and VC+NAC treatment in AD-MSCs, while NAC only activates Akt expression, indicating its role in controlled cell growth.

CONCLUSION: This research concludes that NAC (2 mM) and VC (200 μM) improved the proliferation, differentiation potential, and stemness by decreasing oxidative stress and senescence, parallelly activating Akt/mTOR/P70S6K signalling pathway, while combined treatment (NAC+VC) enhanced these effects, providing bases for their utilisation to culture fat in cultivated meat production.},
}

@article {pmid40398509,
year = {2025},
author = {Chen, SJ and Wu, CL and Lin, LY and Horng, JL},
title = {Evaluating N-acetylcysteine for mitigating cisplatin-induced oxidative stress and ionocyte damage in a zebrafish model.},
journal = {Toxicology and applied pharmacology},
volume = {},
number = {},
pages = {117401},
doi = {10.1016/j.taap.2025.117401},
pmid = {40398509},
issn = {1096-0333},
abstract = {In this study, we examined the protective effects of N-acetylcysteine (NAC) against cisplatin-induced toxicity in zebrafish embryos. Cisplatin (cis-diamminedichloroplatinum II), a widely used anticancer drug, is associated with significant cytotoxic effects toward non-target tissues, including renal and ototoxic damage. Using zebrafish embryos exposed to cisplatin, we evaluated survival rates, hatching rates, ionocyte densities, oxidative stress, and platinum accumulation. NAC co-treatment significantly enhanced survival and hatching rates, preserved ionocyte density, mitigated oxidative stress, and reduced platinum accumulation. These findings highlight ionocytes as an effective model for assessing non-renal toxicity due to their high metabolic activity and mitochondrial abundance. The results suggest that NAC might serve as a co-therapeutic agent to alleviate cisplatin-induced toxicity during chemotherapy.},
}

@article {pmid40398422,
year = {2025},
author = {Sonar, SA and Bhat, R and Thompson, HL and Coplen, CP and Uhrlaub, JL and Jergovic, M and Nikolich, JŽ},
title = {Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70100},
doi = {10.1111/acel.70100},
pmid = {40398422},
issn = {1474-9726},
support = {P01 AG052359/AG/NIA NIH HHS/United States ; //Bowman Professorship in Medical Sciences/ ; },
abstract = {Lymph nodes (LN) are the key organs in charge of long-term maintenance of naïve lymphocytes and their initial, primary activation upon infection. Accumulating evidence indicates that LN stromal cells undergo degenerative changes with aging that critically impair LN function, including the generation of protective primary immune responses. The nature of these defects remains incompletely understood. We here demonstrate that age-related LN stromal changes manifest themselves in mitochondrial dysfunction and oxidative stress. Ex vivo, all three major stromal cell subsets, fibroblastic reticular cells (FRC), lymphatic endothelial cells (LEC), and blood endothelial cells (BEC) exhibit elevated mitochondrial reactive oxygen species (ROS) stress, reduced mitochondrial potential, and elevated mitochondrial mass with aging. Old FRC also exhibited elevated cytoplasmic ROS production. This was accompanied by the reduced ability of old LN stromal cells to support Tn survival in vitro, a defect alleviated by pretreating old LN stroma with the general antioxidant N-acetyl cysteine (NAC) as well as by mitochondrial ROS-reducing (mitoquinone) and mitophagy-inducing (urolithin A) compounds. Mitochondrial dysfunction and, in particular, reduced mitochondrial potential in old FRC were also seen upon vaccination or infection in vivo. Consistent with these results, in vivo antioxidant treatment of old mice with NAC restored to adult levels the numbers of antigen-specific CD8[+] effector T cells and their production of granzyme B in response to antigenic challenge.},
}

@article {pmid40397293,
year = {2025},
author = {Zheng, Y and Zou, X and Li, Q and Jiang, D and Zhu, F and Wu, Y},
title = {Exosomes derived from umbilical cord blood NK cells inhibit the progression of pancreatic cancer by targeting ROS-mediated mitochondrial dysfunction.},
journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society},
volume = {33},
number = {1-2},
pages = {8},
pmid = {40397293},
issn = {1319-0164},
support = {JYHL2022MS20//TaiShan Industrial Experts Programme/ ; 2023TSGC0549//Small and Medium Sized Enterprise Innovation Capability Enhancement Project of Shandong Province/ ; 2023ZDYF010144//Key Research and Development Program of Rizhao City/ ; JYSJ2022B04//the Practical Teaching Education Research Project Plan of Jining Medical University/ ; 202410443016//College Students' Innovative Entrepreneurial Training Plan Program/ ; },
abstract = {Emerging research indicates that natural killer (NK) cell-derived exosomes (NK-exo) play a significant role in cancer development. However, their regulatory mechanisms, particularly in pancreatic cancer, remain poorly elucidated. This study employed an in vitro co-culture system and an in vivo subcutaneous tumor model to evaluate the anti-tumor effect of NK-exo on pancreatic cancer. Umbilical cord blood (UCB)-derived NK-exo displayed characteristic exosomal morphology, size, and marker expression and was internalized by PANC- 1 cells. NK-exo significantly and dose-dependently reduce cell proliferation, migration, and invasion (P < 0.01). Further analysis demonstrated that NK-exo induced mitochondrial apoptosis in PANC- 1 cells by altering reactive oxygen species (ROS, P < 0.0001) and mitochondrial membrane potential (MPP) levels (P < 0.0001), effects that were significantly diminished with N-acetylcysteine (NAC) treatment (P < 0.0001). Furthermore, NK-exo treated PANC- 1 cells showed upregulation of the apoptotic markers Caspase3 (P < 0.0001) and Caspase9 (P = 0.0086) and reduced the release of PGC- 1α (P = 0.0064), TFAM (P < 0.0001), and SOD2 (P = 0.0021) as demonstrated by qRT-PCR. Western blot analyses revealed a dose dependent significant elevation of total Caspase3, Caspase9, Bax, and cytochrome c level and depression in the anti-apoptotic Bcl- 2. Animal experiments further confirmed that NK-exo treatment significantly reduced tumor volume and weight and increased Bax protein expression relative to the tumor model group. These findings indicate that NK-exo can enter PANC- 1 cells via endocytosis, induce mitochondrial oxidative damage, and suppress PANC- 1 cell progression, thereby demonstrating a robust anti-pancreatic cancer effect.},
}

@article {pmid40394754,
year = {2025},
author = {Sun, Y and Zhou, Y and Huang, D and Zhao, Z and Shao, Q and Li, J and Zhao, X and Liu, X},
title = {Erk1/2 Orchestrates SSPH I-Induced Oxidative Stress, Mitochondrial Dysfunction and Ferroptosis in Hepatocellular Carcinoma.},
journal = {Journal of cellular and molecular medicine},
volume = {29},
number = {10},
pages = {e70609},
pmid = {40394754},
issn = {1582-4934},
support = {82060793//National Natural Science Foundation of China/ ; 2021JJB140005//Natural Science Foundation of Guangxi Province/ ; 2022C043//Young talents in Gui Pai Xing lin of Guangxi University of Chinese Medicine/ ; 2021007//Qihuang Project Team of Guangxi University of Chinese Medicine/ ; },
mesh = {*Ferroptosis/drug effects ; *Carcinoma, Hepatocellular/metabolism/pathology/drug therapy ; Humans ; *Liver Neoplasms/metabolism/pathology/drug therapy ; *Oxidative Stress/drug effects ; Animals ; *Mitochondria/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Mice ; *MAP Kinase Signaling System/drug effects ; *Saponins/pharmacology ; Cell Line, Tumor ; Mice, Nude ; Iron/metabolism ; Cell Survival/drug effects ; Xenograft Model Antitumor Assays ; Butadienes ; Nitriles ; },
abstract = {Although Erk1/2 has been linked to oxidative stress regulation in hepatocellular carcinoma (HCC), the interplay among Erk1/2, reactive oxygen species (ROS), and iron metabolism remains poorly characterised. The steroidal saponin SSPH I, a recognised ferroptosis inducer, exerts dual pharmacological effects via Erk1/2 and ROS-dependent pathways. This study aimed to investigate the regulatory mechanisms of Erk1/2 in ferroptosis and oxidative stress and analyse their feedback regulatory effects on Erk1/2 in HCC using SSPH I as a pharmacological probe, and further elucidate the anti-HCC effects and mechanisms of SSPH I in vitro and in vivo. Mechanistic studies utilised three inhibitors: U0126 (Erk1/2 phosphorylation inhibitor), Ferrostatin-1 (ferroptosis inhibitor), and N-acetyl cysteine (ROS scavenger), combined with SSPH I to delineate its effects on cell viability, mitochondrial dynamics, ferroptosis induction and oxidative stress. Mechanistically, SSPH I disrupted mitochondrial function and suppressed HCC cell survival through iron accumulation and ROS generation, while concurrently activating Erk1/2 signalling. Pharmacological inhibition of ROS or iron pathways partially attenuated SSPH I-induced ferroptosis and ROS generation, but failed to abrogate these effects. Erk1/2 inhibition completely abolished SSPH I-mediated regulation of the Nrf1/2-HO-1 axis and ferroptosis-related protein expression in cellular and animal models, identifying Erk1/2 as the upstream regulatory node. Notably, while both SSPH I and U0126 monotherapies inhibited xenograft growth, their combined use resulted in antagonistic effects. These findings establish Erk1/2 activation as the central molecular mechanism orchestrating SSPH I-driven oxidative stress amplification, mitochondrial dysfunction and ferroptosis execution in HCC.},
}

*Ferroptosis/drug effects
*Carcinoma, Hepatocellular/metabolism/pathology/drug therapy
Humans
*Liver Neoplasms/metabolism/pathology/drug therapy
*Oxidative Stress/drug effects
Animals
*Mitochondria/drug effects/metabolism/pathology
Reactive Oxygen Species/metabolism
Mice
*MAP Kinase Signaling System/drug effects
*Saponins/pharmacology
Cell Line, Tumor
Mice, Nude
Iron/metabolism
Cell Survival/drug effects
Xenograft Model Antitumor Assays
Butadienes
Nitriles

@article {pmid40395300,
year = {2023},
author = {Campos-Blázquez, JP and Flores-Maldonado, C and Gallardo, JM and Bonilla-Delgado, J and Pedraza-Ramírez, AA and López-Méndez, O and Cortés-Malagón, EM and Contreras, RG},
title = {Ouabain promotes claudin-1, -2, and -4 autophagic degradation through oxidative stress and AMPK activation in MDCK cells.},
journal = {Autophagy reports},
volume = {2},
number = {1},
pages = {2256146},
pmid = {40395300},
issn = {2769-4127},
abstract = {Epithelial cells transport substances through the cellular and paracellular pathways. The last one depends on tight junctions, particularly on claudins, the family of integral membrane proteins responsible for the permeability and selectivity of these junctions. 300 nM ouabain (OUA) induces endocytosis and lysosomal degradation of claudin-2 and -4 in an Src and ERK1/2 kinases-dependent manner. Here we investigate whether OUA-induced lysosomal degradation of claudins implicates autophagy in renal epithelial Madin-Darby canine kidney cells. During autophagy, LC3 protein binds phosphatidylethanolamine and incorporates, together with protein p62, into the phagophore. Subsequently, the autolysosome degrades both LC3 and p62 proteins. OUA's occupancy of its site in the Na[+]/K[+]ATPase (300 nM, 10 h) increases autophagic flux because of degradation of LC3 and p62 and an increase in the number of autophagosomes, as detected by fluorescent LC3 and p62 puncta and the rise in autolysosomes seen by the GFP-LC3-RFP probe. Finally, OUA increases the colocalisation of claudin-1, -2, or -4 with p62 in these puncta. OUA induces autophagy increasing reactive oxygen species generation that activates AMP-activated protein kinase, phosphorylating ULK1 at S555. The autophagy inducer rapamycin causes a degradation of the studied claudins comparable to the one generated by OUA. Furthermore, the autophagy inhibitor dorsomorphin blocks OUA-induced autophagy and claudin-1, -2, and -4 degradation. These results demonstrated that OUA induces claudin-1, -2, and -4 autophagy through oxidative stress. Abbreviations: AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: Adenosine triphosphate; DM: dorsomorphin; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LC3: microtubule-associated protein 1A/1B-light chain 3; MDCK: Madin-Darby canine kidney; mTOR: mammalian target of rapamycin; NAC: N-acetylcysteine; OUA: ouabain; PCC: Pearson's correlation coefficient; PE: phosphatidylethanolamine, Rapa: rapamycin; ROS: reactive oxygen species; SNK: Student-Newman-Keuls; TER: transepithelial electrical resistance; TJs: tight junctions; ULK1: Unc-51-like kinase 1.},
}

@article {pmid40394693,
year = {2025},
author = {Chen, Y and Nan, Y and Xu, L and Dai, A and Orteg, RMM and Ma, M and Zeng, Y and Li, J},
title = {Polystyrene nanoplastics exposure induces cognitive impairment in mice via induction of oxidative stress and ERK/MAPK-mediated neuronal cuproptosis.},
journal = {Particle and fibre toxicology},
volume = {22},
number = {1},
pages = {13},
pmid = {40394693},
issn = {1743-8977},
support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; Male ; Mice, Inbred C57BL ; *Polystyrenes/toxicity ; *Copper/metabolism/toxicity ; *Neurons/drug effects/pathology ; *Cognitive Dysfunction/chemically induced ; MAP Kinase Signaling System/drug effects ; Humans ; Mice ; *Nanoparticles/toxicity ; *Microplastics/toxicity ; Cell Line, Tumor ; },
abstract = {BACKGROUND: Recent studies emphasize the significance of copper dyshomeostasis in neurodegenerative diseases, such as Alzheimer's and Parkinson's, thereby highlighting the role of copper in neurotoxicity. Cuproptosis, a novel mechanism of copper-dependent cell death, remains underexplored, particularly concerning environmental pollutants like polystyrene nanoplastics (PS-NPs). While PS-NPs are recognized for inducing neurotoxicity through various forms of cell death, including apoptosis and ferroptosis, their potential to trigger neuronal cuproptosis has not yet been investigated. This study aims to determine whether exposure to PS-NPs induces neurotoxicity via cuproptosis and to explore the preliminary molecular mechanisms involved, thereby addressing this significant knowledge gap.

METHODS: Seven-week-old male C57BL/6 mice were exposed to PS-NPs at dose of 12.5 mg/kg, and were co-treated with the antioxidant N-acetylcysteine (NAC). Complementary in vitro experiments were conducted using SH-SY5Y neuronal cells exposed to PS-NPs at a concentration of 0.75 mg/mL, with interventions that included the copper chelator tetrathiomolybdate (TTM), NAC, and the MAPK inhibitor PD98059.

RESULTS: Exposure to PS-NPs significantly increased cerebral copper accumulation (P < 0.05) and induced cuproptosis, characterized by lipid-acylated DLAT oligomerization, dysregulation of cuproptosis regulators (FDX1, LIAS, HSP70), and mitochondrial damage. In murine models, PS-NPs elicited neurotoxicity, as evidenced by neuronal loss, decreased Nissl body density, impaired synaptic plasticity, and suppressed oxidative stress markers (GSH, SOD, Nrf2), alongside activation of the ERK-MAPK pathway, ultimately resulting in deficits in learning and memory. Treatment with NAC alleviated these adverse effects. In SH-SY5Y cells, exposure to PS-NPs resulted in reduced cell viability (p < 0.01), an effect that was mitigated by TTM. Furthermore, NAC and PD98059 were found to reverse elevated copper levels, cuproptosis markers, and mitochondrial anomalies (p < 0.05).

CONCLUSION: This study presents preliminary evidence indicating that PS-NPs may induce neuronal cuproptosis, potentially through the oxidative stress-mediated activation of the ERK-MAPK pathway, which contributes to cognitive dysfunction in mice. These findings provide insights into the potential mechanisms underlying PS-NPs neurotoxicity and highlight possible therapeutic targets, such as copper chelation or MAPK inhibition, for mitigating the neurological risks associated with nanoplastic exposure, pending further validation in human-relevant models.},
}

Animals
*Oxidative Stress/drug effects
Male
Mice, Inbred C57BL
*Polystyrenes/toxicity
*Copper/metabolism/toxicity
*Neurons/drug effects/pathology
*Cognitive Dysfunction/chemically induced
MAP Kinase Signaling System/drug effects
Humans
Mice
*Nanoparticles/toxicity
*Microplastics/toxicity
Cell Line, Tumor

@article {pmid40389439,
year = {2025},
author = {Zhang, YH and Dai, CS and Wang, YJ and Wang, WY and Qi, TT and Xia, MC and Zhou, G and Cui, YM},
title = {Intestinal permeability of N-acetylcysteine is driven by gut microbiota-dependent cysteine palmitoylation.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {4623},
pmid = {40389439},
issn = {2041-1723},
support = {82204515//National Natural Science Foundation of China (National Science Foundation of China)/ ; 7232262//Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)/ ; },
mesh = {*Gastrointestinal Microbiome/physiology ; *Acetylcysteine/metabolism/pharmacokinetics ; Animals ; Humans ; Rats ; Male ; Permeability ; *Cysteine/metabolism ; Lipoylation ; *Intestinal Mucosa/metabolism ; Rats, Sprague-Dawley ; Female ; Specific Pathogen-Free Organisms ; Germ-Free Life ; Intestinal Barrier Function ; },
abstract = {Trillions of intestinal microbiota are essential to the permeability of orally administered drugs. However, identifying microbial-drug interactions remains challenging due to the highly variable composition of intestinal flora among individuals. Using single-pass intestinal perfusion (SPIP) platform, we establish the microbiota-based permeability screening framework involving germ-free (GF) and specific-pathogen-free (SPF) rats to compare in-situ Peff-values and metabolomic profiles of 32 orally administered drugs with disputable classifications of permeability, prior to the verifications of bioorthogonal chemistry and LC-MS/MS. In contrast with SPF controls, N-Acetylcysteine (NAC) exhibits significantly increased permeability in GF rats, which is inversely related to reduced cysteine-3-ketosphinganine by Bacteroides. To further validate these microbiome features, we integrate clinical descriptors from a prospective cohort of 319 participants to optimize a 15-feature eXtreme Gradient Boosting (XGB) model, which reveal that cysteine palmitoylation by intestinal microbiota has significantly affected NAC permeability. By comparison of net reclassification improvement (NRI) index, this machine learning (ML) model of clinical prediction model encompassing intestinal microbial features outperforms other three commercial models in predicting NAC permeability. Here we have developed an intestinal microbiota-based strategy to evaluate uncharacterized NAC permeability, thus accounting for its discordant biopharmaceutics classification.},
}

*Gastrointestinal Microbiome/physiology
*Acetylcysteine/metabolism/pharmacokinetics
Animals
Humans
Rats
Male
Permeability
*Cysteine/metabolism
Lipoylation
*Intestinal Mucosa/metabolism
Rats, Sprague-Dawley
Female
Specific Pathogen-Free Organisms
Germ-Free Life
Intestinal Barrier Function

@article {pmid40387057,
year = {2025},
author = {Zhang, Y and Chen, M and Niu, R and Guo, D and Sun, Z},
title = {Mechanistic Insights into T-2 Toxin-Induced Thymic Epithelial Cell Injury and Immunotoxicity via the ROS-NF-κB-NLRP3 Signaling Axis.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c00355},
pmid = {40387057},
issn = {1520-5118},
abstract = {Thymic epithelial cells (TECs) are critical for thymic structure and function, yet the impact of T-2 toxin (T-2) on TECs and related molecular pathways remains unclear. This study sheds light on the mechanisms of T-2-induced TEC damage, focusing on the ROS-NF-κB-NLRP3 signaling axis. The in vivo and in vitro analyses suggest that T-2 induces TEC injury through ROS-driven NLRP3 inflammasome activation, NF-κB signaling, inflammation, and apoptosis. Molecular docking analysis verified the binding of T-2 to critical components involved in oxidative stress, inflammatory signaling pathways, and apoptosis. These findings were further supported by therapeutic interventions targeting ROS and NLRP3. N-acetylcysteine (NAC) effectively reduced ROS levels, suppressed NF-κB signaling, inhibited NLRP3 activation, and mitigated inflammation and apoptosis, effects mirrored by the NLRP3 inhibitor MCC950, emphasizing the critical role of ROS-mediated NLRP3 inflammasome activation through NF-κB signaling in T-2-induced TEC damage. Concurrently, inhibition of the NF-κB signaling further suppressed ROS levels, NLRP3 inflammasome activation, and apoptosis in MTEC1 cells, emphasizing the pivotal function of the ROS-NF-κB-NLRP3 axis in the pathogenesis of T-2-induced thymic injury. Our study offers an in-depth insight into the mechanisms driving T-2-induced immunotoxicity and identifies potential therapeutic strategies targeting these pathways to mitigate thymic injury and preserve immune function.},
}

@article {pmid40384860,
year = {2025},
author = {Gallego-Rentero, M and Botella, LM and Mascaraque, M and Nicolás-Morala, J and Albiñana, V and Abarca-Lachen, E and Gilaberte, Y and González, S and Juarranz, Á and Carrasco, E},
title = {N-acetylcysteine and raloxifene boost photodynamic therapy against cutaneous squamous cell carcinoma by decreasing TGFβ1 secreted by cancer-associated fibroblasts.},
journal = {International journal of biological sciences},
volume = {21},
number = {7},
pages = {3164-3182},
pmid = {40384860},
issn = {1449-2288},
mesh = {*Photochemotherapy/methods ; *Raloxifene Hydrochloride/therapeutic use/pharmacology ; Animals ; *Carcinoma, Squamous Cell/drug therapy/metabolism ; *Acetylcysteine/therapeutic use/pharmacology ; Mice ; *Transforming Growth Factor beta1/metabolism ; *Skin Neoplasms/drug therapy/metabolism ; Humans ; Cell Line, Tumor ; *Cancer-Associated Fibroblasts/metabolism/drug effects ; },
abstract = {Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent skin cancer. While surgery remains the gold standard treatment, non-invasive methods like photodynamic therapy (PDT) stand out for their high efficacy and minimal cosmetic impact. However, resistance to PDT is still a challenge. Numerous cellular processes involved in cancer biology and therapy resistance are regulated by the TGFβ1/SMAD pathway. Using in vitro bidimensional and tridimensional cultures of cSCC cell lines, we studied the development of resistance to PDT in response to TGFβ1 secreted by cancer associated fibroblasts. Our results highlight the TGFβ1 co-receptor endoglin as a key molecular player in the process. Importantly, targeting endoglin expression with N-acetylcysteine (NAC) or raloxifene significantly reduced TGFβ1 levels and effectively prevented resistance. In addition, the combination of PDT with NAC resulted in an improved therapeutic outcome in vivo in SKH-1 mice with cSCC photogenerated by chronic exposition to ultraviolet light. In conclusion, the combination of PDT with NAC or raloxifene enhances PDT efficacy by mitigating resistance mechanisms, which can open new avenues for the treatment of cSCC.},
}

*Photochemotherapy/methods
*Raloxifene Hydrochloride/therapeutic use/pharmacology
Animals
*Carcinoma, Squamous Cell/drug therapy/metabolism
*Acetylcysteine/therapeutic use/pharmacology
Mice
*Transforming Growth Factor beta1/metabolism
*Skin Neoplasms/drug therapy/metabolism
Humans
Cell Line, Tumor
*Cancer-Associated Fibroblasts/metabolism/drug effects

@article {pmid40381462,
year = {2025},
author = {Liu, M and Ding, C and Yi, Q and Quan, H and Li, W and Wang, Y and Lin, X and Wang, M and Wang, J},
title = {Carboxylesterase-activated hepatocyte-targeting fluorescent probe for drug-induced liver injury diagnosis.},
journal = {Bioorganic chemistry},
volume = {162},
number = {},
pages = {108587},
doi = {10.1016/j.bioorg.2025.108587},
pmid = {40381462},
issn = {1090-2120},
abstract = {In this study, a novel fluorescent probe DCI-Gal-Bz toward CEs was developed. DCI-Gal-Bz exhibits excellent sensitivity and selectivity toward CEs, which is not disturbed by physiologically relevant interferences. DCI-Gal-Bz could specifically distinguish hepatocytes from A549, HeLa, and SGC-7901 cells, showing good hepatocyte-targeting potential, which is because the terminal galactose of DCI-Gal-Bz can be selectively recognized by HepG2 cells overexpressing ASGPR. DCI-Gal-Bz could effectively monitor CEs activity in APAP-induced liver injury (DILI), and reveal the upregulation of CEs during N-acetylcysteine (NAC) hepatoprotective therapy. In other words, DCI-Gal-Bz can clearly distinguish between healthy, injured and repaired states, being a powerful tool for exploring liver CEs-related diseases.},
}

@article {pmid40381010,
year = {2025},
author = {Li, J and Zheng, Q and Wang, F},
title = {Fabrication of N-acetylcysteine-loaded chitosan-cloaked polyphenol nanoparticles for treatment of pediatric pneumonia and acute lung injury.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {40381010},
issn = {1432-1912},
abstract = {Bacterial infectious acute pneumonia has long presented a significant barrier to human health and the fast elimination of antibacterial in lung tissue. Engineering nanoformulations that are easily prepared and possess mucoadhesive characteristics for administering antibacterial drugs are crucial for addressing pneumonia and lung injury. This investigation utilized FDA-approved tannic acid (TA) to develop a nanocomplex by cloaking chitosan (CH) to attain prolonged anti-infection efficacy against acute pneumonia. The flash nanocomplexation (FNC) process was employed for developing chitosan-cloaked poly(vinyl alcohol)/TA/N-acetylcysteine (NAC) nanoparticles (CPTN NPs) using NAC as the model drug, relying on non-covalent interactions between the components. The investigation of pneumonia revealed that the robust electrostatic interaction between negatively charged mucin and positively charged chitosan in the trachea facilitated the retention of NAC in the lungs for a minimum of 24 h post-inhalation of CPTN NPs, effectively constraining pneumonia within 3 days. The DPPH values of 97.42 ± 5.1 for CPTN NPs reveal excellent antioxidant ability. The cell viability of NCI-H441 and A549 cells remained above 90% of 100 μg/mL for NAC and CPTN NPs. The antibacterial efficacy of CPTN NPs exhibited a 99.9% reduction compared to the untreated group. The mucoadhesive CPTN NPs, characterized by excellent biocompatibility and produced using a simple and reproducible method, may offer a novel approach to administering CPTN NPs to address acute pediatric pneumonia and lung injury.},
}

@article {pmid40380998,
year = {2025},
author = {Sun, S and Wang, Y and Shen, Y and Li, W and Hu, Z and Peng, Y and Zheng, J},
title = {Metabolic activation and cytotoxicity of carvedilol mediated by cytochrome P450s in vitro and in vivo.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {40380998},
issn = {1432-0738},
abstract = {Carvedilol (CAR) is commonly administered in the treatment of essential hypertension. Current reports suggest that CAR therapy may elevate the risk of hepatotoxicity, occasionally progressing to liver injury. However, the underlying mechanisms of the toxicity remain poor understood. This study investigated CAR-associated hepatotoxicity through reactive metabolites formation. In the microsomal incubation mixture containing CAR (50 μM), four phase I metabolites (M1-M4) were detected. Upon the addition of glutathione (GSH), N-acetylcysteine (NAC), or cysteine as trapping agents, four GSH conjugates (M5-M8), four NAC conjugates (M9-M12), and four cysteine conjugates (M13-M16) were also detected. Chemical synthesis of 8-hydroxy CAR identified M1 as the primary oxidative metabolite of CAR. Following the administration of CAR (25 mg/kg), we detected GSH conjugate (M5) in bile, NAC conjugate (M9) in urine, and cysteine adduct (M13) in proteolytic mixture of liver tissues of rat. Furthermore, it was found that CYP3A4 dominated the metabolic activation of CAR. Additionally, CAR exhibited time-course changes and dose-dependent (0, 25, 50, and 100 mg/kg) protein adduction in rat liver tissues, as well as time- and concentration-dependent (0, 10, 25, 50 and 100 μM) inhibition of hepatocyte viability. Ketoconazole (KTZ) significantly decreased the susceptibility of hepatocytes to CAR-induced cytotoxicity. Collectively, these findings offer new insight into the hepatotoxicity mechanism associated with the metabolic activation of CAR.},
}

@article {pmid40375363,
year = {2025},
author = {Edzeamey, FJ and Ramchunder, Z and Valle Gómez, A and Ge, H and Marobbio, CMT and Pourzand, C and Virmouni, SA},
title = {Therapeutic combination of L-ascorbic acid, N-acetylcysteine, and dimethyl fumarate in Friedreich's ataxia: insights from in vitro models.},
journal = {Redox report : communications in free radical research},
volume = {30},
number = {1},
pages = {2505303},
pmid = {40375363},
issn = {1743-2928},
mesh = {*Acetylcysteine/pharmacology/therapeutic use ; *Dimethyl Fumarate/pharmacology/therapeutic use ; *Friedreich Ataxia/drug therapy/metabolism ; *Ascorbic Acid/pharmacology/therapeutic use ; Humans ; Reactive Oxygen Species/metabolism ; Mitochondria/drug effects/metabolism ; Fibroblasts/metabolism/drug effects ; Frataxin ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Membrane Potential, Mitochondrial/drug effects ; Iron-Binding Proteins/metabolism/genetics ; NF-E2-Related Factor 2/metabolism ; Cell Survival/drug effects ; },
abstract = {Friedreich's Ataxia (FRDA) is a rare neurological disorder caused by an abnormal expansion of Guanine-Adenine-Adenine (GAA) repeat in intron 1 of the FXN gene, which encodes frataxin, leading to reduced expression of frataxin, a mitochondrial protein essential for cellular homeostasis. Frataxin deficiency results in oxidative stress and mitochondrial dysfunction and impaired redox balance. Currently, there is no cure for FRDA. This study aimed to evaluate the therapeutic potential of antioxidants dimethyl fumarate (DMF), N-acetylcysteine (NAC), and L-ascorbic acid (LAA) in restoring mitochondrial redox homeostasis and frataxin levels in FRDA patient-derived fibroblasts and 2D sensory neurons. We assessed cell viability, mitochondrial and cellular reactive oxygen species (ROS) levels, mitochondrial DNA copy number, mitochondrial membrane potential, and frataxin and NRF2 expression at both mRNA and protein levels following antioxidant treatment, either individually or in combination. Treatment with LAA, NAC, and DMF resulted in significant reductions in mitochondrial and cellular ROS, along with increased FXN and NRF2 expression, and enhanced NRF2 nuclear translocation. Furthermore, these compounds improved aconitase/citrate synthase activity, GSH/GSSG ratios, and mitochondrial membrane potential. Notably, the combination of LAA and NAC consistently alleviated multiple disease-associated defects in FRDA cells, suggesting its potential as a promising therapeutic approach.},
}

*Acetylcysteine/pharmacology/therapeutic use
*Dimethyl Fumarate/pharmacology/therapeutic use
*Friedreich Ataxia/drug therapy/metabolism
*Ascorbic Acid/pharmacology/therapeutic use
Humans
Reactive Oxygen Species/metabolism
Mitochondria/drug effects/metabolism
Fibroblasts/metabolism/drug effects
Frataxin
Oxidative Stress/drug effects
Antioxidants/pharmacology/therapeutic use
Membrane Potential, Mitochondrial/drug effects
Iron-Binding Proteins/metabolism/genetics
NF-E2-Related Factor 2/metabolism
Cell Survival/drug effects

@article {pmid40374378,
year = {2025},
author = {Li, K and Wang, YJ and Wei, K and Li, WL and Liu, YB and Hu, JN and Chang, WG and Zhang, WX and Chen, L and Li, W},
title = {Ginsenoside Rg2 Alleviates HFD/STZ-Induced Diabetic Nephropathy by Inhibiting Pyroptosis via NF-κB/NLRP3 Signaling Pathways.},
journal = {The American journal of Chinese medicine},
volume = {53},
number = {3},
pages = {909-930},
doi = {10.1142/S0192415X2550034X},
pmid = {40374378},
issn = {1793-6853},
mesh = {*Ginsenosides/pharmacology/therapeutic use/administration & dosage ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Diabetic Nephropathies/drug therapy/etiology/genetics/metabolism ; *Pyroptosis/drug effects/genetics ; *Signal Transduction/drug effects/genetics ; *NF-kappa B/metabolism ; Diet, High-Fat/adverse effects ; Male ; Mice, Inbred C57BL ; Humans ; *Diabetes Mellitus, Experimental/drug therapy ; *Phytotherapy ; Streptozocin/adverse effects ; Mice ; Inflammasomes/metabolism ; Cell Line ; Panax/chemistry ; },
abstract = {Diabetes mellitus (DM) is considered to be the most widespread epidemic worldwide, and diabetic nephropathy (DN) is one of the most serious diabetic complications. Its complex pathogenesis makes treatment of DN an ongoing medical challenge. Ginseng (Panax ginseng. C. A Meyer) is a valuable medicinal herb with a long medicinal and culinary history. Ginsenoside Rg2 (Rg2), an important active component in ginseng, has effective inhibitory effects on lipogenesis and hepatic glucose production. However, the potential effect and mechanism of Rg2 on DN remain unclear. In this study, we investigated the effect of Rg2 on DN in high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice and high glucose (HG)-induced human kidney 2 (HK-2) cells. The results demonstrated that Rg2 significantly improved the levels of FBG, dyslipidemia and impaired kidney function in DN mice. Additionally, Rg2 decreased the phosphorylation levels of IKKβ, IκBα, and NF-κB p65, inhibited the activation of NLRP3 inflammasomes (NLRP3, ASC, and Caspase 1), and restrained release of inflammatory factors (IL-18 and IL-1[Formula: see text]. In HG-induced HK-2 cells, Rg2 showed similar inhibitory effects on pyroptosis via NF-κB/NLRP3 signaling pathways. Moreover, the effect of Rg2 on inhibiting the activation of NF-κB/NLRP3 signaling pathways may have a relationship to reducing the overproduction of reactive oxygen species (ROS), which is further supported by the ROS inhibitor N-acetylcysteine (NAC). In conclusion, our findings clearly indicated that Rg2 could prevent the progress of DN by inhibiting the activation of pyroptosis-related NF-κB/NLRP3 signaling pathways in vivo and in vitro, suggesting that Rg2 may be a novel and promising therapeutic agent in the treatment of DN.},
}

*Ginsenosides/pharmacology/therapeutic use/administration & dosage
Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Diabetic Nephropathies/drug therapy/etiology/genetics/metabolism
*Pyroptosis/drug effects/genetics
*Signal Transduction/drug effects/genetics
*NF-kappa B/metabolism
Diet, High-Fat/adverse effects
Male
Mice, Inbred C57BL
Humans
*Diabetes Mellitus, Experimental/drug therapy
*Phytotherapy
Streptozocin/adverse effects
Mice
Inflammasomes/metabolism
Cell Line
Panax/chemistry

@article {pmid40362589,
year = {2025},
author = {Ontawong, A and Nehra, G and Maloney, BJ and Vaddhanaphuti, CS and Bauer, B and Hartz, AMS},
title = {N-Acetylcysteine Attenuates Aβ-Mediated Oxidative Stress, Blood-Brain Barrier Leakage, and Renal Dysfunction in 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {9},
pages = {},
pmid = {40362589},
issn = {1422-0067},
support = {1R01NS133250-24A1/NH/NIH HHS/United States ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Blood-Brain Barrier/drug effects/metabolism ; *Acetylcysteine/pharmacology ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/metabolism/drug therapy ; Mice, Transgenic ; Disease Models, Animal ; Aldehydes/metabolism ; Male ; Antioxidants/pharmacology ; Brain/metabolism/drug effects ; Kidney/drug effects/metabolism ; S100 Calcium Binding Protein beta Subunit/blood ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) pathology and is closely linked to oxidative stress, which contributes to blood-brain barrier leakage, renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine (NAC), an FDA-approved antioxidant, on oxidative stress, brain Aβ levels, barrier leakage, renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a rodent diet supplemented with 600 mg/kgDiet NAC for 4 weeks; wild-type (WT) mice and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma S100β levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared to WT. NAC treatment of 5xFAD mice reduced brain Aβ40 levels, normalized 4-HNE levels to control levels, improved creatinine clearance, decreased capillary leakage, and lowered S100β plasma levels. NAC improved cognitive performance in 5xFAD mice, as shown by Y-maze. Our findings indicate that Aβ-induced oxidative stress contributes to barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and other Aβ-related pathologies by reducing oxidative stress.},
}

Animals
*Oxidative Stress/drug effects
*Blood-Brain Barrier/drug effects/metabolism
*Acetylcysteine/pharmacology
*Amyloid beta-Peptides/metabolism
Mice
*Alzheimer Disease/metabolism/drug therapy
Mice, Transgenic
Disease Models, Animal
Aldehydes/metabolism
Male
Antioxidants/pharmacology
Brain/metabolism/drug effects
Kidney/drug effects/metabolism
S100 Calcium Binding Protein beta Subunit/blood

@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