@article {pmid40728675,
year = {2025},
author = {Kow, CS and Ramachandram, DS and Hasan, SS and Thiruchelvam, K},
title = {Effect of N-Acetylcysteine on mortality in COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {40728675},
issn = {1568-5608},
abstract = {INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has prompted global interest in potential adjunctive therapies. N-acetylcysteine (NAC), a mucolytic agent that enhances intracellular glutathione synthesis, has antioxidant properties and may indirectly modulate inflammation through redox regulation. While preclinical and observational data suggest potential mortality benefits, findings from randomized controlled trials (RCTs) have been inconsistent.

OBJECTIVE: To systematically review and synthesize the evidence from RCTs evaluating the effect of NAC on mortality in patients with COVID-19.

METHODS: This systematic review and meta-analysis was conducted according to PRISMA guidelines. Six databases were searched from inception to March 21, 2025. Eligible studies were RCTs comparing NAC to placebo or standard care in adult COVID-19 patients, with mortality as a reported outcome. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane RoB 2 tool. Statistical analyses were performed with a random-effects model to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs).

RESULTS: Ten RCTs comprising 1,424 patients were included. NAC regimens varied by dose and route. The pooled OR for mortality was 0.49 (95% CI: 0.25-0.94; I[2] = 67%), indicating a 51% reduction in the odds of death among patients receiving NAC. Seven studies had low risk of bias; three had some concerns, primarily due to open-label designs.

CONCLUSION: NAC may reduce mortality in COVID-19 patients, particularly when administered at higher doses or via non-oral routes. Further large-scale RCTs are needed to confirm these findings and establish optimal dosing and administration strategies.},
}

@article {pmid40726828,
year = {2025},
author = {Manoharan, A and Whiteley, G and Kuppusamy, R and Jensen, S and Glasbey, T and Chen, Z and Moshkanbaryans, L and Moore, KH and Das, T and Manos, J},
title = {Combating biofilm formation and bacterial killing: N-acetylcysteine's efficacy against Pseudomonas aeruginosa in urinary catheters.},
journal = {Biofilm},
volume = {10},
number = {},
pages = {100296},
pmid = {40726828},
issn = {2590-2075},
abstract = {Uropathogenic Pseudomonas aeruginosa is a significant contributor to catheter-associated urinary tract infections (CA-UTIs), distinguished by its unique biofilm-forming properties compared to other strains. Despite its clinical significance, optimized strategies for biofilm eradication in the bladder and on catheters remain limited. Thus, the aim of this study was to highlight the potent antibacterial and biofilm-inhibitory effects of N-acetyl cysteine (NAC) against uropathogenic P. aeruginosa. Additionally, we sought to investigate its effect against catheter obstruction caused by P. aeruginosa in a patient, and whether this phenomenon can be replicated in vitro to underscore the urgency of addressing this critical challenge. We demonstrated that uropathogenic P. aeruginosa form thick, mucoid biofilms in vitro that can heavily occlude catheters, with bacterial titres of between 10[8] and 10[11] CFU/cm, thus impairing catheter functionality. Furthermore, treatment with NAC significantly reduced viable bacteria by > 4log10 (p < 0.01), and inhibited biofilm formation and associated obstruction till experiment endpoint (96h). NAC also displayed significant bactericidal activity (p < 0.001) against P. aeruginosa and significantly impeded bacterial attachment and aggregation through modulation of colloidal forces and change in the structure of the bacterial cell surface, thus impairing the bacterium's ability to initiate biofilm development. Mechanistically, NAC alters the bacterial surface structure, disrupting biofilm-associated virulence. Hence our study found that NAC treatment physically disrupts uropathogenic P. aeruginosa biofilms and significantly alters its virulence. Our novel findings highlight the dual bactericidal and anti-biofilm properties of NAC in vitro, offering valuable insights into its potential application for preventing P. aeruginosa biofilm formation and catheter blockage in CA-UTI management.},
}

@article {pmid40724969,
year = {2025},
author = {Hsieh, CY and Lin, JN and Chou, YF and Hsu, CJ and Chen, PR and Wen, YH and Wu, CC and Sun, CH},
title = {Molecular Mechanisms of Aminoglycoside-Induced Ototoxicity in Murine Auditory Cells: Implications for Otoprotective Drug Development.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
pmid = {40724969},
issn = {1422-0067},
support = {TTCRD 113-04//Buddhist Tzu Chi Medical Foundation/ ; NSTC-113-2314-B-303-005//Minister of Science and Technology in Taiwan/ ; },
mesh = {Animals ; Mice ; *Ototoxicity/metabolism/etiology/prevention & control/pathology ; *Aminoglycosides/adverse effects/toxicity ; Proto-Oncogene Proteins c-akt/metabolism ; Endoplasmic Reticulum Chaperone BiP ; *Hair Cells, Auditory/drug effects/metabolism/pathology ; Gentamicins/toxicity ; Cell Line ; Signal Transduction/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Endoplasmic Reticulum Stress/drug effects ; *Anti-Bacterial Agents/adverse effects ; *Protective Agents/pharmacology ; },
abstract = {Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology-comprising cell-model selection, transcriptomic analysis, and a gentamicin-Texas Red (GTTR) uptake assay-to guide the development of otoprotective strategies. We first utilized two murine auditory cell lines-UB/OC-2 and HEI-OC1. We focused on TMC1 and OCT2 and further explored the underlying mechanisms of ototoxicity. UB/OC-2 exhibited a higher sensitivity to gentamicin, which correlated with elevated OCT2 expression confirmed via RT-PCR and Western blot. Transcriptomic analysis revealed upregulation of PI3K-Akt, calcium, and GPCR-related stress pathways in gentamicin-treated HEI-OC1 cells. Protein-level analysis further confirmed that gentamicin suppressed phosphorylated Akt while upregulating ER stress markers (GRP78, CHOP) and apoptotic proteins (cleaved caspase 3, PARP). Co-treatment with PI3K inhibitors (LY294002, wortmannin) further suppressed Akt phosphorylation, supporting the role of PI3K-Akt signaling in auditory cells. To visualize drug entry, we used GTTR to evaluate its applicability as a fluorescence-based uptake assay in these cell lines, which were previously employed mainly in cochlear explants. Sodium thiosulfate (STS) and N-acetylcysteine (NAC) significantly decreased GTTR uptake, suggesting a protective effect against gentamicin-induced hair cell damage. In conclusion, our findings showed a complex ototoxic cascade involving OCT2- and TMC1-mediated drug uptake, calcium imbalance, ER stress, and disruption of PI3K-Akt survival signaling. We believe that UB/OC-2 cells serve as a practical in vitro model for mechanistic investigations and screening of otoprotective compounds. Additionally, GTTR may be a simple, effective method for evaluating protective interventions in auditory cell lines. Overall, this study provides molecular-level insights into aminoglycoside-induced ototoxicity and introduces a platform for protective strategies.},
}

Animals
Mice
*Ototoxicity/metabolism/etiology/prevention & control/pathology
*Aminoglycosides/adverse effects/toxicity
Proto-Oncogene Proteins c-akt/metabolism
Endoplasmic Reticulum Chaperone BiP
*Hair Cells, Auditory/drug effects/metabolism/pathology
Gentamicins/toxicity
Cell Line
Signal Transduction/drug effects
Phosphatidylinositol 3-Kinases/metabolism
Endoplasmic Reticulum Stress/drug effects
*Anti-Bacterial Agents/adverse effects
*Protective Agents/pharmacology

@article {pmid40724874,
year = {2025},
author = {Duensing, HM and Dixon, JM and Hunter, OR and Graves, NC and Smith, NC and Tomes, AJ and Fahrenholtz, CD},
title = {Preclinical Evaluation of Repurposed Antimalarial Artemisinins for the Treatment of Malignant Peripheral Nerve Sheath Tumors.},
journal = {International journal of molecular sciences},
volume = {26},
number = {14},
pages = {},
pmid = {40724874},
issn = {1422-0067},
support = {2024-FLG-0073//North Carolina Biotechnology Center/ ; n/a//High Point University Natural Science Fellows Supply Grant/ ; },
mesh = {*Artemisinins/pharmacology/therapeutic use ; *Antimalarials/pharmacology/therapeutic use ; Humans ; Oxidative Stress/drug effects ; Cell Line, Tumor ; *Drug Repositioning ; Artesunate/pharmacology ; Schwann Cells/drug effects/metabolism ; Animals ; *Nerve Sheath Neoplasms/drug therapy/metabolism/pathology ; Lipid Peroxidation/drug effects ; },
abstract = {Malignant peripheral nerve sheath tumors (MPNSTs) are a rare type of soft tissue sarcoma associated with poor prognoses. The standard of care for non-resectable tumors consists of surgical excision followed by radiation and chemotherapy. MPNSTs are most common in patients with neurofibromatosis type 1 but can also occur sporadically. Regardless of origin, MPNSTs most often rely on signaling pathways that increase basal oxidative stress. This provides the basis for developing therapeutics with mechanisms that can potentiate oxidative stress to selectively eradicate tumor cells at doses that are tolerable for normal cells. Artemisinin derivatives are a mainstay of malaria therapy worldwide, with a well-established safety profile. Artemisinin's antimalarial effects are due to an endoperoxide bridge in its chemical structure that induces oxidative stress. We found that artesunate (ARS) and metabolite dihydroartemisinin (DHA) are selectively cytotoxic to MPNST cells relative to normal Schwann cells with the endoperoxide bridge required for activity. Mechanistically, DHA induced oxidative stress, lipid peroxidation, and DHA-mediated cytotoxicity could be prevented with co-administration of the antioxidant N-acetyl-cysteine. Furthermore, we found that DHA was able to selectively remove MPNST from co-culture with normal Schwann cells. These data supports the further development of artemisinins for the clinical management of MPNST.},
}

*Artemisinins/pharmacology/therapeutic use
*Antimalarials/pharmacology/therapeutic use
Humans
Oxidative Stress/drug effects
Cell Line, Tumor
*Drug Repositioning
Artesunate/pharmacology
Schwann Cells/drug effects/metabolism
Animals
*Nerve Sheath Neoplasms/drug therapy/metabolism/pathology
Lipid Peroxidation/drug effects

@article {pmid40723450,
year = {2025},
author = {Deshetty, UM and Oladapo, A and Mohankumar, Y and Horanieh, E and Buch, S and Periyasamy, P},
title = {Protective Effects of N-Acetylcysteine in Alleviating Cocaine-Mediated Microglial Activation and Neuroinflammation.},
journal = {Biology},
volume = {14},
number = {7},
pages = {},
pmid = {40723450},
issn = {2079-7737},
support = {P20GM130461 (Pilot)/GM/NIGMS NIH HHS/United States ; },
abstract = {Cocaine misuse induces microglial activation and neuroinflammation, contributing to neurodegeneration and behavioral impairments. Prior studies have shown that cocaine induces mitochondrial dysfunction, dysregulated mitophagy, and lysosomal impairment in microglia. Here, we investigated the therapeutic potential of N-acetylcysteine (NAC) in mitigating cocaine-induced microglial activation and neuroinflammation. Mouse primary microglial cells (MPMs) were pretreated with NAC (5 mM) for 1 h prior to cocaine exposure (10 µM, 24 h) and analyzed for markers of microglial activation, mitophagy, and lysosomal integrity using Western blot, Seahorse assays, lysosomal pH, and membrane potential measurements. In vivo, C57BL/6N mice received NAC (200 mg/kg, i.p.) 1 h before daily cocaine injections (20 mg/kg, i.p.) for 7 days. Behavioral assays (open field, novel object recognition) and brain biomarker analyses (frontal cortex, hippocampus) were performed. Cocaine exposure elevated CD11b, mitophagy markers (PINK1, PARK, and DLP1), and autophagy proteins (Beclin1, and p62), while impairing mitochondrial and lysosomal functions. NAC pretreatment restored mitochondrial and lysosomal function, reduced reactive oxygen species, and normalized protein expression. In vivo, NAC also alleviated cocaine-induced microglial activation and behavioral deficits. These findings highlight NAC as a promising therapeutic agent to counteract cocaine-mediated neuroinflammation and neurotoxicity.},
}

@article {pmid40722964,
year = {2025},
author = {Zhao, J and Zhao, Y and Song, S and Zhang, S and Yang, G and Qiu, Y and Tian, W},
title = {Gallic Acid Alleviates Acetaminophen-Induced Acute Liver Injury by Regulating Inflammatory and Oxidative Stress Signaling Proteins.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {7},
pages = {},
doi = {10.3390/antiox14070860},
pmid = {40722964},
issn = {2076-3921},
support = {24A230003//Key R&D Projects of Henan Provincial Colleges and Universities/ ; 252300420175//Natural Science Foundation of Henan Province/ ; 252102111024//Henan Provincial Key R&D and Promotion Program/ ; },
abstract = {Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury (DILI) globally, which necessitates effective therapies. Gallic acid (GA), a naturally abundant polyphenol, possesses potent antioxidant and anti-inflammatory properties that may overcome the limitations of N-acetylcysteine (NAC), such as its narrow therapeutic window. This study systematically investigated the hepatoprotective effects and underlying molecular mechanisms of GA against APAP-induced acute liver injury (ALI). Mice received an intraperitoneal injection of APAP (300 mg/kg), followed by an oral administration of GA (50 or 100 mg/kg) or NAC (150 mg/kg) 1 h post-intoxication. Both GA and NAC significantly ameliorated hypertrophy and histopathological damage, as evidenced by reduced serum ALT/AST levels and inflammatory cytokines. TUNEL staining revealed a marked suppression of apoptotic and necrotic cell death, further supported by the downregulation of pro-apoptotic Bax and the upregulation of anti-apoptotic Bcl-2 mRNA expression. GA and NAC treatment restored hepatic glutathione (GSH) content, enhanced antioxidant enzyme gene expression, and reduced malondialdehyde (MDA) accumulation. Mechanistically, GA and NAC inhibited MAPK phosphorylation while activating AMPK signaling. Taken together, these findings demonstrate that GA mitigates APAP-induced ALI by modulating oxidative stress and inflammation through the regulation of MAPK/AMPK signaling proteins.},
}

@article {pmid40722832,
year = {2025},
author = {Rarinca, V and Gurzu, IL and Nicoara, MN and Ciobica, A and Visternicu, M and Ionescu, C and Balmus, IM and Plavan, GI and Todirascu-Ciornea, E and Gurzu, B},
title = {Neurobehavioral and Oxidative Stress Effects of SiO2 Nanoparticles in Zebrafish and the Protective Role of N-Acetylcysteine.},
journal = {Biomedicines},
volume = {13},
number = {7},
pages = {},
doi = {10.3390/biomedicines13071762},
pmid = {40722832},
issn = {2227-9059},
abstract = {Background/Objectives: Silicon dioxide nanoparticles (SiO2NPs) do not exist in isolation in the environment but can interact with other substances, thus influencing their toxic effects on aquatic organisms. We assessed the combined impact of SiO2NPs and N-acetylcysteine (NAC), an antioxidant with the potential to counteract nanoparticle-induced oxidative stress (OS). Methods: Behavioral assessments, including the social interaction test and color preference test, were performed to evaluate neurobehavioral changes. OS biomarkers, including malondialdehyde (MDA) levels for lipid peroxidation and the activity of key antioxidant enzymes such as glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), were assessed to evaluate the extent of cellular damage. Results: The results indicate that prolonged exposure to SiO2NPs induces significant behavioral disruptions, including reduced exploratory behavior and increased anxiety-like responses. Furthermore, biochemical analysis revealed increased OS, suggesting nanoparticle-induced cellular toxicity. NAC co-treatment partially reversed these effects, particularly improving locomotor outcomes and antioxidant response, but was less effective on social behavior. Conclusions: These findings highlight the ecological and health risks posed by SiO2NPs and point toward the need for further toxicological studies on their long-term biological effects.},
}

@article {pmid40716720,
year = {2025},
author = {Gao, J and Liu, X and Wang, B and Huang, Y and Chen, R and Yuan, W and Luo, Q and Lu, H and Tian, G},
title = {Acute toxicity effects of rice paddy bactericide bismerthiazol on zebrafish (Danio rerio) embryos.},
journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP},
volume = {},
number = {},
pages = {110303},
doi = {10.1016/j.cbpc.2025.110303},
pmid = {40716720},
issn = {1532-0456},
abstract = {Bismerthiazol is an extensively utilized agricultural bactericide in paddy fields. However, its toxicity to aquatic animals remains poorly understood. Through acute exposure of zebrafish (Danio rerio) embryos, we determined that the 72-h half-lethal concentration (LC50) of bismerthiazol was 7.38 mg/L, and 3 mg/L bismerthiazol induced systemic developmental abnormalities. Further studies showed that low concentrations (25 ng/L, 50 ng/L) of bismerthiazol selectively impaired notochord and muscle development in embryos and reduced their motility. Additionally, bismerthiazol exposure upregulated the Sonic hedgehog (SHH) signaling pathway and myogenic gene expression. It also increased reactive oxygen species (ROS) levels while decreasing the enzymatic activity of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD). Notably, the antioxidant N-acetylcysteine (NAC) rescued the bismerthiazol-induced notochord and muscle defects. In summary, our findings demonstrate that acute bismerthiazol exposure causes developmental toxicity in aquatic organisms by inducing oxidative stress, highlighting its potential ecological risk.},
}

@article {pmid40715197,
year = {2025},
author = {Ben Ali, C and Morel, A and Morvan, M and Moktefi, A and Nguyen-Peyre, KA and Van Wynsberghe, M and Sakhi, H and Bartolucci, P and Audard, V and Hénique, C},
title = {Podocyte dysfunction driven by heme in sickle-cell nephropathy.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {27136},
pmid = {40715197},
issn = {2045-2322},
mesh = {Humans ; *Podocytes/metabolism/pathology/drug effects ; *Anemia, Sickle Cell/complications/metabolism/pathology ; *Heme/metabolism ; Oxidative Stress/drug effects ; Heme Oxygenase-1/metabolism ; Apoptosis/drug effects ; Glomerulosclerosis, Focal Segmental/pathology/metabolism/etiology ; Male ; NF-kappa B/metabolism ; Female ; Cell Line ; Hemin/pharmacology ; DNA Damage ; Adult ; },
abstract = {Sickle-cell disease (SCD) is characterized by vaso-occlusive crises and chronic hemolytic anemia, leading to tissue damage affecting various organs, including the kidneys. Hemolysis contributes to sickle-cell nephropathy (SCN) but the molecular mechanisms underlying the intravascular hemolysis and heme release involved in podocyte damage leading to proteinuria and chronic kidney disease remain uncertain. This study explored the impact of heme on podocyte function by exposing human podocytes cell line to hemin (5 μM hemin for 4 and 24 h), with or without the antioxidant N-acetyl cysteine (NAC). We then assessed the relevance of in vitro studies on renal biopsy specimens from controls with primary and secondary forms of focal segmental glomerulosclerosis (FSGS) and patients with SCD-related FSGS. After 4 h of hemin exposure, podocyte cytoskeleton alterations and increased apoptosis were observed. At 24 h, heme oxygenase-1 (HO-1) expression increased, alongside oxidative stress, DNA damage, and mitochondrial and endoplasmic reticulum dysfunctions. NF-κB pathway activation suggested an adaptive response. NAC partially reduced these effects, indicating oxidative stress's central role while implicating additional mechanisms in apoptosis induction. Renal biopsies from patients with focal segmental glomerulosclerosis (FSGS), including SCD-related cases, showed elevated HO-1 and BiP in podocytes compared to normal glomeruli, along with reduced synaptopodin, indicating damage. In conclusion, this study highlights the molecular mechanisms underlying heme-induced podocyte damage in SCN. Oxidative stress appears to play a key role, but other pathological pathways are also involved. These results open up new perspectives for understanding and treating SCN.},
}

Humans
*Podocytes/metabolism/pathology/drug effects
*Anemia, Sickle Cell/complications/metabolism/pathology
*Heme/metabolism
Oxidative Stress/drug effects
Heme Oxygenase-1/metabolism
Apoptosis/drug effects
Glomerulosclerosis, Focal Segmental/pathology/metabolism/etiology
Male
NF-kappa B/metabolism
Female
Cell Line
Hemin/pharmacology
DNA Damage
Adult

@article {pmid40712831,
year = {2025},
author = {Mavraganis, G and Sakelliou, A and Georgiopoulos, G and Delialis, D and Papaioannou, M and Maneta, E and Angelidakis, L and Zervas, G and Poulios, A and Papanikolaou, K and Draganidis, D and Chatzinikolaou, A and Jamurtas, AZ and Stamatelopoulos, K and Fatouros, IG and Mitrakou, A},
title = {Evidence of a redox-dependent control of vascular function following muscle-damaging exercise in young adults: A randomized placebo-controlled trial.},
journal = {Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.hjc.2025.07.007},
pmid = {40712831},
issn = {2241-5955},
abstract = {BACKGROUND: High intensity resistance exercise may temporarily induce vascular dysfunction mediated by pro-oxidant and pro-inflammatory pathways. In the present study we aimed to evaluate the possible protective effect of the antioxidant N-acetyl cysteine (NAC) on vascular function after a bout of high-intensity resistance exercise.

METHODS: In this randomized, cross-over, placebo-controlled study, ten healthy male volunteers (mean age 24.2±2.1 years) who exercised regularly were randomized to a daily oral administration of NAC or placebo during an 8-day recovery after an acute intense eccentric exercise protocol. Pulse wave velocity (PWV) and flow-mediated dilation (FMD) measurements were performed pre- and post-exercise in both study arms.

RESULTS: Muscle exercise induced a significant decrease in FMD in the placebo arm (p=0.017) during the first 48 hours after exercise recovering thereafter. In contrast, in the NAC arm, FMD did not decrease significantly. By linear mixed model analysis, a higher increase in CD4 cells levels correlated with preserved FMD (p=0.046) only in the placebo arm (p=0.811 in the NAC arm). PWV did not present significant fluctuations before and after exercise in either arm (p>0.05).

CONCLUSIONS: A bout of eccentric exercise induced endothelial dysfunction which was attenuated by NAC, indicating that oxidative stress may be implicated in vivo in this setting.},
}

@article {pmid40712548,
year = {2025},
author = {Liu, JR and Wu, FN and Lin, S and Chen, C and Liu, Y and Fan, JW and Hong, Q and Chen, YH},
title = {Gestational zearalenone causes fetal intrauterine growth restriction partially through deriving ROS-Drp1 mediated placental PANoptosis.},
journal = {Ecotoxicology and environmental safety},
volume = {302},
number = {},
pages = {118636},
doi = {10.1016/j.ecoenv.2025.118636},
pmid = {40712548},
issn = {1090-2414},
abstract = {The ubiquity of zearalenone (ZEA) in cereal-based products and the aquatic environment raises growing concerns about health problems to humans and animals. Here, we explored the mechanism by which ZEA exposure during pregnancy induced fetal growth restriction (FGR). Interestingly, both fetal weights and crown-rump length were significant decreases when dams were administrated with ZEA. Consistently, the incidence of FGR is significantly increased in ZEA group in a dose-dependent manner. Moreover, mean placental weight and diameter was significantly reduced in ZEA group, suggesting that poor placental development may be involved in ZEA-induced FGR. The genome-wide expression profiles of mouse placentas were significantly different between two groups by RNA-sequencing. GO and KEGG analysis indicated significant enrichment of these differentially expressed genes in mitochondrial apoptotic signaling pathway, inflammatory cell apoptotic process, necroptosis, and regulation of mitochondrial membrane potential. Further study showed that mitochondrial quality control disorder and PANoptosis plays an important role in ZEA-induced poor placental development. Mdivi-1, an inhibitor of Drp-1, attenuated ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. N-acetylcysteine (NAC), an antioxidant, abolished ZEA-induced mitochondrial quality control disorder and PANoptosis in mouse placentas and human placental trophoblasts. Importantly, Mdivi-1 and NAC rescued gestational ZEA exposure-induced poor placental development and FGR in mice. Our results indicate that ZEA exposure during pregnancy caused poor placental development and subsequently FGR may be via deriving ROS-Drp1 mediated placental PANoptosis.},
}

@article {pmid40710512,
year = {2025},
author = {Wu, L and Lv, L and Xiang, Y and Yi, D and Liang, Q and Ji, M and Deng, Z and Qin, L and Ren, L and Liang, Z and He, J},
title = {Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2/HO-1 Activation in Mice.},
journal = {Marine drugs},
volume = {23},
number = {7},
pages = {},
pmid = {40710512},
issn = {1660-3397},
support = {No. YCBZ2021007//the Innovation Project of Guangxi Graduate Education/ ; No. 31960717//the National Natural Science Foundation of China/ ; No. ABDC-b202305//Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention/ ; },
mesh = {Animals ; Rosmarinic Acid ; *Acetaminophen/toxicity/adverse effects ; NF-E2-Related Factor 2/metabolism ; *Chemical and Drug Induced Liver Injury/prevention & control/drug therapy/metabolism/etiology ; *Depsides/pharmacology ; Mice ; *Oxidative Stress/drug effects ; *Cinnamates/pharmacology ; *Ferroptosis/drug effects ; Male ; Antioxidants/pharmacology ; Liver/drug effects/pathology ; Disease Models, Animal ; Heme Oxygenase-1/metabolism ; Signal Transduction/drug effects ; Protective Agents/pharmacology ; Membrane Proteins ; },
abstract = {Liver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N-acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepatotoxicity. Therefore, exploring novel liver-protecting drugs and elucidating their mechanisms of action is of great scientific significance and clinical value. Rosmarinic acid (RA), as a natural polyphenolic compound, has been proven to have significant antioxidant activity. Previous studies have shown that it has a protective effect against drug-induced liver injury. Nevertheless, the precise protective mechanism of RA in APAP-induced acute liver injury (AILI) has not been fully defined. This study was based on an AILI mouse model to systematically explore the liver-protecting effect of RA and its underlying molecular mechanisms. The research results showed that pretreatment with RA could notably mitigate liver pathological injury. It could decrease the activities of ALT and AST in the serum, suppress the liver inflammatory reaction, and reverse the decline in the levels of CAT, T-AOC, SOD, and GSH caused by APAP. Meanwhile, RA could enhance antioxidant defense capabilities by activating the Keap1/Nrf2/HO-1 signaling pathway, regulate the xCT/GPX4 axis to inhibit lipid peroxidation, and thus block the process of ferroptosis. In conclusion, this study confirmed that RA exerts a protective effect against AILI by regulating the Keap1/Nrf2/HO-1 axis to enhance antioxidant capacity and inhibit ferroptosis through the xCT/GPX4 pathway. Our research provides a theoretical basis for RA as a potential therapeutic agent for APAP-induced liver injury.},
}

Animals
Rosmarinic Acid
*Acetaminophen/toxicity/adverse effects
NF-E2-Related Factor 2/metabolism
*Chemical and Drug Induced Liver Injury/prevention & control/drug therapy/metabolism/etiology
*Depsides/pharmacology
Mice
*Oxidative Stress/drug effects
*Cinnamates/pharmacology
*Ferroptosis/drug effects
Male
Antioxidants/pharmacology
Liver/drug effects/pathology
Disease Models, Animal
Heme Oxygenase-1/metabolism
Signal Transduction/drug effects
Protective Agents/pharmacology
Membrane Proteins

@article {pmid40706520,
year = {2025},
author = {Zhang, SF and Li, N and Liu, DL and Li, YH and Yang, Y and Ma, Y and Wang, YQ and Ma, Y and Luan, ZJ},
title = {Yttrium nitrate activates the oxidative stress-mediated NF-κB pathway to induce testicular inflammatory response and reduce sperm quality in mice.},
journal = {Ecotoxicology and environmental safety},
volume = {302},
number = {},
pages = {118720},
doi = {10.1016/j.ecoenv.2025.118720},
pmid = {40706520},
issn = {1090-2414},
abstract = {The rising environmental levels of yttrium have sparked concerns regarding its possible health hazards. Nevertheless, limited toxicological data are available to determine yttrium's toxicity and potential mechanisms on sperm. In our research, the action of oxidative stress and the NF-κB pathway on decreased sperm quality and testicular inflammatory reaction induced by yttrium exposure was analyzed. Yttrium nitrate (YN), N-Acetyl Cysteine (NAC), and JSH-23 were used to intervene in mice and cells in vivo and in vitro experiments. Eosin-nigrosine staining, in vitro fertilization, Annexin V-FITC/PI staining, ICP-MS, Hematoxylin-eosin staining, RT-qPCR, DCFH-DA staining, biochemical methods, ELISA, and western blot were applied to detect sperm motility, fertilizing capacity, apoptosis, Y[3+] accumulation, testicular structure, testicular function, and NF-κB gene expression, ROS, MDA, GSH, pro-inflammatory cytokines, and NF-κB protein expression, respectively. The results revealed that YN exposure reduced sperm motility, increased sperm apoptosis, disrupted testicular tissue structure and function in mice. Exposure to YN increased ROS content and NF-κB pathway activation in testicular tissue and cells, resulting in upregulation of pro-inflammatory cytokines in the testis. When NAC scavenged ROS, the YN-induced sperm damage and inflammatory reaction, and NF-κB pathway abnormal activation in the testis of mice were alleviated. In addition, sperm damage and testicular inflammatory reaction caused by YN were alleviated after blocking the NF-κB pathway with JSH-23 treatment. Our present study elucidated that YN could damage sperm quality and induce testicular inflammatory reaction, establishing YN's toxicological impact on the male reproductive system.},
}

@article {pmid40703903,
year = {2025},
author = {Mehta, PP and Annam, RS and Hadiyel, IN},
title = {Catastrophic Outcomes: Rapid Multi-Organ Failure from Paraquat Poisoning- A Case Report.},
journal = {Nigerian medical journal : journal of the Nigeria Medical Association},
volume = {66},
number = {2},
pages = {811-817},
pmid = {40703903},
issn = {0300-1652},
abstract = {Paraquat dichloride, a potent herbicide widely used in agriculture, poses a severe health risk due to its high toxicity. Ingesting even small amounts can cause fatal multi-organ failure. We report a case of a 19-year-old male who ingested approximately 5 ml of 24% paraquat dichloride. He presented with stable vital signs, but initial laboratory results showed elevated urea (26mg/dL), creatinine (0.97 mg/dL), and hypokalemia (3.2 mEq/L). Despite interventions including gastric lavage, N-Acetyl cysteine, methylprednisolone, and supportive care, he developed severe metabolic acidosis (HCO[3]- 22.8 to 16.3 mEq/L), acute renal failure (creatinine 0.97 to 4.62 mg/dL, urea 26 to 99 mg/dL, serum potassium 3.2 to 2.62 mEq/L), and multi-organ dysfunction. The unavailability of hemoperfusion has impacted the outcome. The patient's rapid deterioration highlights paraquat's aggressive nature and underscores the necessity for better therapeutic strategies and regulatory measures to prevent such poisoning.},
}

@article {pmid40690881,
year = {2025},
author = {Philips, TJ and N'guessan, BB and Dotse, E and Abankwah, JK and Appiah-Opong, R},
title = {Riboceine and N-acetylcysteine protect normal prostate cells from chemotherapy-induced oxidative stress while selectively modulating the cytotoxicity of methotrexate and docetaxel in prostate (PC-3) and breast cancer (MCF-7) cells.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {190},
number = {},
pages = {118355},
doi = {10.1016/j.biopha.2025.118355},
pmid = {40690881},
issn = {1950-6007},
abstract = {BACKGROUND: Cancer chemotherapy often results in severe side effects due to its non-selective cytotoxicity toward rapidly dividing normal cells. These adverse effects are largely driven by oxidative stress resulting from elevated reactive oxygen species (ROS) production. Riboceine (RIB), a synthetic precursor of glutathione (GSH), and N-acetylcysteine (NAC), a clinically used antioxidant, hold promise in mitigating oxidative damage; however, their impact on chemotherapy efficacy and the molecular mechanisms involved remain incompletely understood.

AIM: This study aimed to evaluate the cytoprotective potential of RIB and NAC against methotrexate (MET)- and docetaxel (DOC)-induced toxicity in normal and cancer cells, and to explore mechanistic pathways using integrative network pharmacology and molecular docking approaches.

METHODOLOGY: Cytotoxic effects of MET and DOC, alone or in combination with RIB or NAC, were assessed in normal prostate epithelial (PNT-2), prostate cancer (PC3), and breast cancer (MCF-7) cell lines using the Resazurin assay. Intracellular ROS and GSH levels were quantified using DCF and OPA fluorescence assays, respectively. Network pharmacology, protein-protein interaction (PPI) analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and molecular docking were conducted using SwissTargetPrediction, STRING, ShinyGO, Cytoscape, and AutoDock Vina platforms.

RESULTS: MET and DOC showed dose-dependent cytotoxicity in PNT-2 and PC3 cells, but limited efficacy in chemoresistant MCF-7 cells. RIB and NAC significantly reduced ROS and restored GSH levels in PNT-2 cells, protecting them against oxidative injury. These antioxidants preserved anticancer effects in PC3 cells but reduced chemotherapy efficacy in MCF-7 cells, likely due to elevated redox buffering and transporter expression. Network analyses identified BCL-2, MAPK8, and SOD among key antioxidant and apoptotic targets. However, no direct experimental validation of these mechanisms was performed, and apoptotic markers such as Annexin V or caspase-3 were not assessed.

CONCLUSION: RIB and NAC provide selective cytoprotection to normal prostate cells during chemotherapy while maintaining anticancer effects in sensitive prostate cancer cells. However, their concurrent use in resistant cancers like MCF-7 may reduce drug efficacy, warranting cautious clinical application. Time-shifted antioxidant administration (e.g., post-chemotherapy) could be explored as a strategy to balance protection and efficacy. Future studies should include in vivo validation, apoptosis profiling, and protein-level mechanistic assays to confirm the predicted pathways.},
}

@article {pmid40689471,
year = {2025},
author = {Zhu, L and Li, X and Yu, S and Huang, L and Chen, S and Zheng, Z and Su, L},
title = {Dual role of reactive oxygen species in the effects of cadmium on microglial survival and phagocytosis.},
journal = {Environmental science. Processes & impacts},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5em00299k},
pmid = {40689471},
issn = {2050-7895},
abstract = {Cadmium (Cd), a significant occupational and environmental pollutant, poses significant health risks due to its bioaccumulation and long biological half-life. Although Cd exposure has been identified as a risk factor for neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, its specific effects on microglia-the resident immune cells of the central nervous system (CNS)-remain poorly understood. Here, we demonstrate that Cd exerts dual, dose-dependent effects on primary microglia. High doses (1-2 μM) triggered oxidative stress, apoptosis, and viability loss, whereas subtoxic doses (0.125-0.5 μM) enhanced phagocytic activity and ATP production. Notably, low-dose Cd elevated glutathione (GSH) levels, suggesting adaptive redox activation. Pretreatment with N-acetylcysteine (NAC) prevented high-dose Cd-induced cytotoxicity but suppressed the stimulatory effects of low-dose Cd on phagocytic activity and ATP production. Interestingly, NAC pretreatment paradoxically amplified phagocytosis at 1 μM Cd, despite partial ROS reduction. Collectively, our findings reveal that mild oxidative stress from low-dose Cd exposure promotes microglial phagocytosis via antioxidant responses, offering new insights into Cd's neurotoxic mechanisms.},
}

@article {pmid40684828,
year = {2025},
author = {Yoon, B and Suresh, RN and Shivakumara, CS and Harsha, KB and Mohan, CD and Sethi, G and Rangappa, KS and Ahn, KS},
title = {Triazolyl-indolo-quinoxaline triggers differential cell death pathways in pancreatic cancer via ROS/p38 axis.},
journal = {Chemico-biological interactions},
volume = {420},
number = {},
pages = {111668},
doi = {10.1016/j.cbi.2025.111668},
pmid = {40684828},
issn = {1872-7786},
abstract = {Pancreatic cancer is characterized by aggressive progression, rapid metastasis, and resistance to conventional therapies, resulting in poor survival outcomes. Despite significant advances in research, effective treatment options for pancreatic cancer remain limited. In this study, we investigated the mechanisms of SRN-19-induced cell death in pancreatic cancer cells. Our findings demonstrated that SRN-19 promotes both apoptosis and paraptosis. Molecular analyses confirmed the upregulation of apoptotic markers, including cleaved PARP, Bax, and caspase-9/3, along with the downregulation of anti-apoptotic proteins Bcl-2 and Bcl-xL in both MIA PaCa-2 and AsPC-1 cells. Additionally, SRN-19 treatment led to reduced Alix expression and elevated levels of ATF4 and CHOP, markers associated with paraptosis, accompanied by alterations in mitochondrial membrane potential (MMP) in BxPC-3 cells. SRN-19 also induced a dose-dependent increase in reactive oxygen species (ROS) production and a corresponding decrease in the GSH/GSSG ratio. Pretreatment with N-acetylcysteine (NAC) attenuated ROS accumulation, restored Alix expression, and reduced cleaved PARP levels, confirming the involvement of ROS in apoptosis induction. Furthermore, SRN-19 activated the p38 MAPK pathway, and inhibition of p38 by SB203580 diminished ROS levels, reduced cleaved PARP expression, and restored MMP. Collectively, these results suggest that SRN-19 promotes ROS generation, activates the p38 MAPK pathway, and induces cell death in pancreatic cancer cells through both apoptotic and paraptotic mechanisms.},
}

@article {pmid40684388,
year = {2025},
author = {Zhu, Y and Wang, G and Feng, D and Li, S and Zhang, X and Yao, J and Deng, L and Lei, X},
title = {NEFA Induces Ferroptosis in Transition Dairy Cattle Liver by Increasing Lipid Reactive Oxygen Species and Downregulating SLC7A11.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c00935},
pmid = {40684388},
issn = {1520-5118},
abstract = {Excessive lipid mobilization in transition dairy cattle leads to elevated levels of nonesterified fatty acids (NEFA), causing liver injury. Ferroptosis, a novel cell death mechanism, has significant roles in liver disease progression. However, its potential role in NEFA-induced liver injury remains unclear. In this study, we demonstrated ferroptosis occurrence in the transition cattle liver through histopathological damage, increased lipid peroxidation, and iron accumulation. In vitro, using ferroptosis inducer RAS-selective lethal 3 (RSL3), NEFA significantly enhanced ferroptosis in bovine hepatocytes. Subsequent experiments with ferroptosis inhibitor ferrostatin-1 (Fer-1) showed Fer-1 markedly reduced NEFA-enhanced ferroptosis, confirming ferroptosis' critical role. Mechanistic studies revealed that NEFA promoted ferroptosis by inducing lipid ROS production effectively inhibited by N-acetylcysteine (NAC) and by downregulating SLC7A11 expression. In conclusion, ferroptosis critically mediates NEFA-induced liver injury in transition dairy cattle, indicating that targeting this pathway may offer potential therapeutic strategies to mitigate liver damage associated with excessive lipid mobilization.},
}

@article {pmid40683237,
year = {2025},
author = {Sarangi, P and Pradhan, LK and Bhoi, S and Sahoo, BS and Chauhan, NR and Raut, S and Das, SK},
title = {N-acetyl cysteine mediated inhibition of glucose regulated protein-78 abrogates activating transcription factor-4 dependent endoplasmic reticulum stress and neurodegeneration following exposure to di-2-ethylhexyl phthalate in zebrafish brain.},
journal = {The Science of the total environment},
volume = {995},
number = {},
pages = {180068},
doi = {10.1016/j.scitotenv.2025.180068},
pmid = {40683237},
issn = {1879-1026},
abstract = {Recent findings have highlighted the neurological consequences of exposure to the plasticizer di-2-ethylhexyl phthalate (DEHP), including neurobehavioral transformation, cognitive dysfunction, and neurodegeneration. Endoplasmic reticulum (ER) stress plays a distinct role in altering cellular responses by inducing cell death. Based on existing literature, we were primarily interested in understanding whether the gross biochemical and neuromorphological outcomes of DEHP are associated with augmented ER stress in the neuronal microenvironment. Furthermore, we aimed to establish the neuroprotective efficacy of N-acetyl cysteine (NAC) against DEHP-induced ER stress in the zebrafish brain. Our core findings strongly support the argument that DEHP, being a global neurotoxicant, induces heightened oxidative stress and dysregulated calcium homeostasis, which contribute to ER stress mediated neurodegeneration via ATF4-dependent upregulation of GRP78 in the zebrafish brain. However, NAC reversed DEHP-induced calcium dysregulation (F4,20 = 11.97, p < 0.05; n = 6/group) and ATF4-mediated (F4,8 = 11.05; p < 0.05; n = 6/group) ER stress by inhibiting GRP78 (F4,8 = 31.83; p < 0.05; n = 6/group) in the zebrafish brain. NAC also promoted neuroprotection through upregulation of endogenous BDNF (F4,8 = 13.93, p < 0.05; n = 6/group) and NeuN (F4,8 = 56.95, p < 0.05; n = 6/group) expression and inhibition of CC3-mediated (F4,8 = 22.03, p < 0.05; n = 6/group) neurodegeneration in the periventricular grey zone (PGZ) of the zebrafish brain. To summarize these observations, our study establishes a strong correlation between NAC co-supplementation and restoration of DEHP-induced ER stress and neuropathology in zebrafish, but the study needs further validation to warrant the NAC-mediated potential therapeutic development against DEHP.},
}

@article {pmid40679610,
year = {2025},
author = {Özocak, AB and Şen, LS and Arıtürk, LA and Özkeçeci, N and Yüksel, M and Eyüboğlu, İP and Erzik, C and Yenal, NÖ and Ercan, F and Atıcı, AE and Yeğen, BÇ},
title = {Elabela alleviates ischemia/reperfusion-induced hepatic and remote organ injury by inhibiting oxidative stress in rats.},
journal = {Pflugers Archiv : European journal of physiology},
volume = {},
number = {},
pages = {},
pmid = {40679610},
issn = {1432-2013},
support = {TTU-2022-10530//Marmara University Scientific Research Projects Unit/ ; TTU-2022-10530//Marmara University Scientific Research Projects Unit/ ; },
abstract = {Hepatic injury is one of the most critical problems in major liver surgeries, trauma, sepsis or shock. The novel Elabela (ELA) peptide was shown to exert protective effects against cardiac and renal injury. We hypothesized that ELA could also have protective effects in hepatic ischemia-reperfusion (HI/R) injury and associated remote organ injury. Male (n = 37) and female (n = 37) Sprague-Dawley rats were used. Rats were divided into short-term and long-term HI/R injury groups. Each group was then divided into saline-treated, N-acetylcysteine-treated (NAC, 150 mg/kg) and ELA-treated (40 μg/kg) subgroups. Immediately before hepatic ischemia and during reperfusion, rats were subcutaneously injected with saline, NAC or ELA, while injections in long-term groups were continued twice a day for four days. Short-term and long-term sham-operation groups received saline injections. Hepatic blood flow was measured via laser Doppler flowmetry. Intracardiac blood was obtained for analyses of aminotransferase, alanine aminotransferase, bilirubin, urea, creatinine and interleukin (IL)-6. Caspase-3 and 8-hydroxy-2'-deoxyguanosine levels were determined and histopathological analyses (hematoxylin-eosin and alpha-smooth muscle actin (SMA) immunohistochemical staining) were performed in hepatic tissues. Levels of malondialdehyde, antioxidant glutathione, myeloperoxidase activity, luminol and lucigenin-enhanced chemiluminescence were measured in liver, lung, and kidney. Significant improvement in hepatic blood flow was observed in both short- and long-term ELA-treated groups. HI/R-induced elevations in reactive oxygen species in all the studied tissues were decreased by ELA, indicating its efficient radical scavenging function similar to NAC treatment. ELA treatment improved hepatic function tests and alleviated liver fibrosis, as detected by increased alpha-SMA-immunoreactivity. Serum IL-6 levels were increased by ELA treatment, suggesting its role in the activation of IL-6-dependent intracellular pathways which may contribute to hepatocyte proliferation and liver regeneration. Similar to the common use of NAC in hepatic surgery, Elabela appears to have a therapeutic potential in alleviating the consequences of hepatic postreperfusion injury.},
}

@article {pmid40679014,
year = {2025},
author = {Liu, D and Yang, Z and Lu, Y and Yang, W},
title = {Construction and characterization of thiolated chitosan coated TPGSylated nanodiamonds for oral delivery of curcumin.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {38},
number = {3},
pages = {1095-1105},
pmid = {40679014},
issn = {1011-601X},
mesh = {*Curcumin/administration & dosage/chemistry ; *Chitosan/chemistry ; Administration, Oral ; *Nanodiamonds/chemistry ; *Vitamin E/chemistry/analogs & derivatives ; Particle Size ; Drug Liberation ; *Drug Carriers/chemistry ; *Sulfhydryl Compounds/chemistry ; Solubility ; Drug Delivery Systems ; Humans ; },
abstract = {Low water solubility and poor intestinal permeability hinder the oral absorption of curcumin (CUR). To address this, we designed a core-shell structured nanoparticle based on nanodiamonds (NDs) and thiolated chitosan (TCS). First, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) covalently modified NDs were prepared and loaded with CUR (CUR@NDs-TPGS). N-acetylcysteine (NAC) was then coupled to chitosan (CS) to obtain positively charged CS-NAC, which electrostatically coated the negatively charged NDs-TPGS/CUR. Particle size (PS), zeta potential (ZP) and drug loading efficiency (DLE) were selected as screening indices to optimize the formulation and preparation process of CUR@NDs-TPGS/CS-NAC via single-factor experiments. The results showed that after coating with CS-NAC, the PS of optimized CUR@NDs-TPGS/CS-NAC increased from 183.63±5.24 nm to 245.24±3.95 nm, the ZP value flipped from -25.47±1.36 to +25.81±1.06 and the DLE value decreased slightly. Moreover, the nanoparticles adopted a spherical morphology and the cumulative release percentage of the nanocomplexes within 24 h decreased from 35.69% to 25.54% after coating. CUR@NDs-TPGS/CS-NAC remained stable within 48 h in simulated intestinal fluid. Mucin adsorption, GI retention and oral absorption of CUR@NDs-TPGS/CS-NAC were further enhanced compared to CUR@NDs-TPGS. These findings suggest that CUR@NDs-TPGS/CS-NAC is a promising carrier for oral delivery of CUR.},
}

*Curcumin/administration & dosage/chemistry
*Chitosan/chemistry
Administration, Oral
*Nanodiamonds/chemistry
*Vitamin E/chemistry/analogs & derivatives
Particle Size
Drug Liberation
*Drug Carriers/chemistry
*Sulfhydryl Compounds/chemistry
Solubility
Drug Delivery Systems
Humans

@article {pmid40677760,
year = {2025},
author = {Kim, M and Lee, HK and Lee, H and Lee, HS},
title = {Prdx6 regulates in vivo myeloid cell development via redox control during Xenopus embryogenesis.},
journal = {Animal cells and systems},
volume = {29},
number = {1},
pages = {438-445},
pmid = {40677760},
issn = {1976-8354},
abstract = {Peroxiredoxin6 (Prdx6) is a bifunctional antioxidant enzyme with both peroxidase and phospholipase A2 activities. Although its molecular roles are well established, the developmental role of Prdx6 remains poorly understood. To address this gap in the literature, this study aimed to examine the in vivo function of Prdx6 in primitive myelopoiesis using Xenopus laevis embryos. We found that prdx6 is specifically expressed in myeloid progenitors originating from the anterior ventral blood island during early embryogenesis. Knockdown of prdx6 significantly reduced the number of myeloid cells, without affecting their migration ability. Embryos depleted of prdx6 exhibited elevated levels of reactive oxygen species (ROS) and decreased cellular proliferation. Co-injection of morpholino (MO)-resistant prdx6 mRNA or treatment with N-acetylcysteine (NAC) successfully restored both ROS levels and myeloid cell numbers, suggesting that Prdx6 supports primitive myeloid cell development by maintaining redox homeostasis. These findings reveal a novel role of Prdx6 in ROS-dependent proliferation of myeloid progenitors during early vertebrate development.},
}

@article {pmid40675338,
year = {2025},
author = {Shtilbans, A},
title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tjnut.2025.07.004},
pmid = {40675338},
issn = {1541-6100},
abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10 (CoQ10), creatine, and N-acetylcysteine (NAC) in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of such conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.},
}

@article {pmid40672024,
year = {2025},
author = {Mavridis, C and Zisis, IE and Docea, AO and Buga, AM and Tsatsakis, A and Mamoulakis, C},
title = {Reducing Contrast-Induced Nephropathy Risk in a Murine Model: Role of Avanafil and Vardenafil in Modulating Oxidant/Antioxidant Balance.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e86136},
pmid = {40672024},
issn = {2168-8184},
abstract = {INTRODUCTION: Contrast-induced nephropathy (CIN) is a major clinical problem, particularly under conditions of preexisting renal insufficiency and comorbidities. The present study evaluates the potential of phosphodiesterase type 5 inhibitors (PDE5is), avanafil (AVA), and vardenafil (VAR) to prevent CIN by modulating oxidative stress in a murine model.

METHODS: Two sets of 25 male Wistar rats were allocated into five groups: control, CIN, N-acetylcysteine (NAC), VAR, and AVA. Indomethacin, L-NG-Nitro arginine methyl ester (L-NAME), and iopromide were used to induce CIN. Oxidative stress markers were evaluated, i.e., total antioxidant capacity (TAC), protein carbonyl (PROTC), thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and catalase (CAT) activity.

RESULTS: In comparison with the control group, TAC, GSH, and CAT activity were reduced, while TBARS and PROTC levels were elevated in the CIN group. Variations in treatment by VAR, AVA, and NAC induced a notable rise in TAC and blood levels of GSH while lowering TBARS in tissue.

CONCLUSION: The treatment groups with VAR, AVA, and NAC were noted with higher values of TAC, CAT, and GSH, while lower values of TBARS and PROTC indicated a protective effect against oxidative injury. The findings indicate that VAR and AVA effectively control the oxidant/antioxidant status, preventing oxidative stress and the incidence of CIN. Further research would be required to replicate these findings and identify the therapeutic potential of VAR and AVA in clinical conditions.},
}

@article {pmid40671632,
year = {2025},
author = {Hunt, RL and Oh, J and Jain, A and Kuo, TH and Berardi, D and Jian, W and Song, D and Wu, Q and Goodman, AL and Palm, NW and Zimmermann, M and Johnson, CH and Crawford, JM},
title = {Discovery of a Widespread Polyamine-Low-Molecular-Weight Thiol Hybrid Pathway in Clostridioides difficile.},
journal = {ACS infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsinfecdis.5c00286},
pmid = {40671632},
issn = {2373-8227},
abstract = {Clostridioides difficile infection can cause severe inflammation in the gastrointestinal (GI) tract, leading to diarrhea, colitis, and an increased risk of colorectal cancer. Colonization of C. difficile is associated with microbial community-level changes in the expression of polyamine and polyamine precursor biosynthesis genes. Polyamines are abundant cationic metabolites that serve indispensable functions for all kingdoms, particularly in gut homeostasis. Catabolism of the polyamine precursors arginine and ornithine offers C. difficile supplemental nutrition while subverting host immunity, yet existing models of C. difficile metabolism are incomplete regarding polyamines with comparable importance in the gut (e.g., spermidine). In this study, we conducted feeding studies with isotope-labeled polyamines and discovered a network of low-molecular-weight thiol (LMWT) molecules termed clostridithiols (CSHs) constructed from polyamines conjugated with N-acetylcysteine (NAC) moieties. NAC is clinically used as a mucolytic agent and is a well-established redox molecule. Through the analysis of a human microbiota diversity collection, we established that these previously uncharacterized hybrid metabolites are widely detected in Firmicutes and Bacteroidetes. A genetic screen using DNA from an alternative CSH producerBacteroides uniformis enabled the identification and validation of a two-gene operon, including a gene encoding a domain of unknown function, that was conserved in both producing organisms and other members of the microbiome. CSH abundance in GI mucosal biopsies positively correlated with colorectal cancer compared with matched healthy control samples. These studies indicate that human microbial metabolism broadly unites polyamine and LMWT functionalities to generate metabolites that may be associated with disease.},
}

@article {pmid40661819,
year = {2025},
author = {Ramezaninejad, S and Zaboli, E and Eslamijouybari, M and Mirzakhani, L and Shaki, F and Moosazadeh, M and Namvar, HR and Shabani, AM and Salehifar, E},
title = {Evaluation of the Safety and Efficacy of N-acetylcysteine in the Prevention of Paclitaxel-induced Peripheral Neuropathy: A Randomized, Double-blind, and Placebo-controlled Trial.},
journal = {Journal of research in pharmacy practice},
volume = {14},
number = {1},
pages = {18-26},
pmid = {40661819},
issn = {2319-9644},
abstract = {OBJECTIVE: Paclitaxel-induced peripheral neuropathy (PIPN) is a disabling condition that leads to discontinuation or dose reduction of chemotherapy and reduces the patient's quality of life (QOL). We investigated the effect of N-acetylcysteine (NAC) in preventing PIPN.

METHODS: This study was a randomized, double-blind, and placebo-controlled clinical trial conducted at a chemotherapy center of Mazandaran University of Medical Sciences. Breast cancer patients receiving the Adriamycin/Cyclophosphamide-Taxol regimen were enrolled. All patients received 1200 mg NAC or placebo in two doses before each cycle of paclitaxel. Response to treatment was assessed based on improvements in the Numeric Pain Rating Scale (NRS), NCI-CTCAE, NPS, FACT/GOG-Ntx, and EORTC-QLQ. Two blood samples were taken at baseline and last cycle to determine the oxidative factors.

FINDINGS: Sixty patients were enrolled. At the last cycle, changes in NRS were decreasing in the NAC group but increasing in the placebo group. Thirteen patients (44.8%) in the NAC group and only one patient (3.4%) in the placebo group still reported no neuropathy in the end. A significant difference was observed between the two groups in the Ntx subscale and the Fact-G total score at the last cycle (P < 0.001). The QOL increased in the NAC and decreased in the placebo group. Glutathione levels, MDA, and TAC differed significantly between the two groups (P < 0.001, <0.001, and 0.04, respectively), but no significant difference in NO levels (P = 0.5).

CONCLUSION: Oral NAC at a dose of 1200 mg daily for two doses can reduce the incidence and severity of PIPN and improve patients' QOL.},
}

@article {pmid40659140,
year = {2025},
author = {Yan, L and Zeng, Q and Wang, W and Liang, Y and Lang, R and Zhan, J and Yang, J and Yu, R and Wang, X},
title = {Jianpi Qushi Heluo Formula ameliorates podocytes injury related with ROS-mediated NLRP3 inflammasome activation in membranous nephropathy by promoting PINK1-dependent mitophagy.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120291},
doi = {10.1016/j.jep.2025.120291},
pmid = {40659140},
issn = {1872-7573},
abstract = {Jianpi Qushi Heluo formula (JQHF) is an evidence-based herbal formula based on "Fangji Huangqi Decoction" in the classic of traditional Chinese medicine (TCM) synopsis of the Golden Chamber. Its effectiveness in reducing idiopathic membranous nephropathy (IMN) proteinuria, edema and other clinical symptoms and improving kidney injury has been confirmed by clinical trials and animal experiments. These results demonstrate the critical significance of reducing podocyte injury by regulating mitophagy through integrating ethnopharmacology.

AIM OF THE STUDY: This study aimed to explore the protective effects of JQHF on podocyte injury in IMN, focusing on its role in promoting PINK1-dependent mitophagy to inhibit reactive oxygen species (ROS) mediated activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome.

MATERIALS AND METHODS: The main components of JQHF were identified by ultra-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MSE). Passive Heymann nephritis (PHN) was induced in rats using anti-Fx1A antiserum, while podocyte injury in vitro was stimulated with sublytic complement C5b-9 (sC5b-9). The PHN rats were treated with JQHF, and autophagy inhibitor 3-methyladenine (3-MA) combined with JQHF was used for pathway verification, and Benazepril served as a positive control. In vitro, podocytes were exposed to palmitic acid (PA, a ROS inducer) and N-acetylcysteine (NAC, a ROS scavenger). Further, we silenced the expression of PINK1 in podocytes model and intervened with JQHF-containing serum. Renal function was assessed through biochemical analyses and histopathology. Mitochondrial function was measured by detecting mitochondrial membrane potential (MMP), ROS levels as well as mitochondrial ultrastructure. The expression of podocyte structural proteins (desmin, nephrin, podocin) and inflammasome-related markers (NLRP3, caspase-1, IL-1β, IL-6) was analyzed to assess podocyte injury and inflammasome activation.

RESULTS: (1) In vitro, in contrast to the control group, PA intervention caused increased ROS accumulation, reduced MMP, upregulated NLRP3 and caspase-1 expression, as well as elevated expression of inflammatory factors IL-1β and IL-6. The expression of nephrin and podocin was notably reduced. By contrast, NAC reversed these effects. (2) In vivo, JQHF effectively ameliorated mitochondrial damage, reduced NLRP3 expression and mitigated podocyte injury in PHN rats. The protective effects of JQHF were diminished by 3-MA, confirming the involvement of autophagy. (3) In vitro, JQHF-containing serum attenuated C5b-9-induced podocyte injury, improved mitochondrial dysfunction, and inhibited ROS-mediated activation of NLRP3 inflammasome. Silencing PINK1 significantly reversed these protective effects.

CONCLUSION: JQHF can alleviate podocyte damage, that through inhibiting ROS-mediated NLRP3 inflammasome activation by improving PINK1-mediated mitophagy.},
}

@article {pmid40656400,
year = {2025},
author = {Maalbi, O and Elachhab, N and Elkabbaj, A and Arfaoui, M and Hindi, S and Lahbabi, S and Oudghiri, N and Tachinante, R},
title = {Management of Acute Fatty Liver of Pregnancy: A Retrospective Study of 12 Cases Compared With Data in the Literature.},
journal = {Cureus},
volume = {17},
number = {6},
pages = {e85753},
pmid = {40656400},
issn = {2168-8184},
abstract = {Introduction Acute fatty liver of pregnancy (AFLP) is a rare and potentially life-threatening obstetric condition marked by hepatic dysfunction due to fat accumulation in liver cells. It generally arises in the later stages of pregnancy or shortly after delivery. Clinical presentation is often nonspecific, with symptoms such as gastrointestinal discomfort, nausea, and increased thirst or urination. In more severe cases, signs of liver failure may develop, including jaundice, altered mental status, and coagulation abnormalities. Laboratory tests typically reveal elevated liver enzymes, impaired coagulation, and abnormalities in blood counts. The condition poses significant risks for both mother and fetus, and timely diagnosis and appropriate multidisciplinary management are essential for favorable outcomes. Methods The objective of our study was to analyze the management of this pathology in our intensive care unit and compare it with the literature. This is a retrospective, descriptive, and analytical study conducted in the intensive care unit of Souissi Maternity Hospital, including 12 cases admitted from January 1, 2023, to December 31, 2024. We used a data extraction sheet covering demographic, diagnostic criteria, complications, and maternal and obstetric management, to analyze the data collected from medical records of pregnant women. Results Our retrospective study of 12 AFLP cases revealed a mean patient age of 29.8 ± 5.24 years and an average gestational age of 34.8 weeks. Gravidity and parity medians were 2 and 2.5, respectively. Gestational hypertension was present in five of the patients (41.7%), with some complicated by preeclampsia or eclampsia. All 12 patients met the Swansea diagnostic criteria (more than six criteria for each patient), with jaundice in 11 patients (91.7%), nausea/vomiting in nine of them (75%), and epigastric pain in seven parturients (58.3%) being the most common clinical presentations. Laboratory findings showed elevated transaminases in 10 patients (83% >3x normal, mean aspartate aminotransferase (AST) of 683.36 IU/L, mean alanine aminotransferase (ALT) of 428 IU/L), and total bilirubin was elevated >14 µmol/L in all patients, mean 169 µmol/L). Coagulopathy was common, with eight patients (66%) having a prothrombin time (PT) < 70%. Maternal complications were frequent in 11 patients (95%), including renal failure in eight of them (72%), hemorrhagic complications in five patients (45%), often necessitating blood transfusions, altered consciousness, and sepsis. Fetal complications included four intrauterine fetal death (33%) and three acute fetal distress (25%). Management was multidisciplinary, focusing on prompt uterine evacuation, hemostasis correction, and management of renal, infectious, neurological, and respiratory complications. No patients in our cohort received plasmapheresis due to equipment unavailability. Conclusion Both the existing literature and our service's protocol prioritize immediate fetal delivery as the definitive intervention to halt disease progression. While the literature explores adjunctive therapies such as N-acetylcysteine (NAC) and plasmapheresis, the core focus remains on meticulous supportive care to address the numerous complications arising from liver failure.},
}

@article {pmid40651645,
year = {2025},
author = {Yao, L and Xiang, F and Peng, S and Wang, L and Li, H and Chen, X and Hu, L and Mo, H},
title = {Ferrous gluconate-loaded sodium alginate hydrogel facilitates ferroptosis in Streptococcus hemolyticus and cures Streptococcal infections.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {145900},
doi = {10.1016/j.ijbiomac.2025.145900},
pmid = {40651645},
issn = {1879-0003},
abstract = {Streptococcus hemolyticus has recently regained public attention as "man-eating bacteria" and raised significant public health concerns due to the ever-increasing incidence of infections and severe toxic shock syndrome resulting from inadequate treatment. The growing challenge of antimicrobial resistance further emphasizes the urgent need for the development of novel wound dressings to prevent infections. This study demonstrated that ferrous gluconate (FeGlu) facilitated ferroptosis in S. hemolyticus accompanied with hallmarks of iron dependence, reactive oxygen species (ROS) burst, and lipid peroxidation. Moreover, the addition of inhibitors, including liproxstatin-1 (LIP-1), N-Acetylcysteine (NAC) and glutathione (GSH) hindered the happening of ferroptosis. In light of this, an antibacterial hydrogel was formulated by cross-linking FeGlu with sodium alginate (SA). This hydrogel exhibited excellent fluidity, self-healing properties, biocompatibility, and exceptional bactericidal efficacy. Furthermore, it displayed a superior therapeutic effect while posing no toxic risk in human skin fibroblast (HSF) cells. Proteomic analysis revealed that the FeGlu-hydrogel induced cell death by disrupting various pathways, including transmembrane transport, biomacromolecule synthesis, and cellular metabolism. Additionally, the FeGlu-hydrogel displayed a broad bactericidal spectrum against Streptococcus species, including Streptococcus pneumoniae and Streptococcus mutans. Collectively, these results proved that the FeGlu-hydrogel is a promising biomaterial for the treatment of Streptococcus-related infections.},
}

@article {pmid40649839,
year = {2025},
author = {Orea, W and Carrillo, ED and Hernández, A and Moreno, R and García, MC and Sánchez, JA},
title = {Pharmacological Preconditioning with Diazoxide Upregulates HCN4 Channels in the Sinoatrial Node of Adult Rat Cardiomyocytes.},
journal = {International journal of molecular sciences},
volume = {26},
number = {13},
pages = {},
pmid = {40649839},
issn = {1422-0067},
mesh = {Animals ; *Diazoxide/pharmacology ; *Sinoatrial Node/metabolism/drug effects/cytology ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism/genetics ; Rats ; *Myocytes, Cardiac/metabolism/drug effects ; Reactive Oxygen Species/metabolism ; Male ; *Up-Regulation/drug effects ; Rats, Sprague-Dawley ; Heart Rate/drug effects ; Decanoic Acids ; Hydroxy Acids ; Potassium Channels ; },
abstract = {Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K[+] (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC's effects on other channels remain largely unexplored. In this study, we hypothesized that DZX regulates the expression of hyperpolarization-activated cyclic nucleotide potassium channel 4 (HCN4) channels in sinoatrial node cells (SANCs), the specialized cardiomyocytes that generate the heartbeat. DZX increased the heart rate in intact adult rats. Patch-clamp experiments revealed an increase in the magnitude of ionic currents through HCN4 channels, which was abolished by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the selective mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assays showed that DZX increased HCN4 channel expression at the mRNA and protein levels. Immunofluorescence analyses revealed that PPC increased HCN4 fluorescence, which was abolished by NAC. DZX increased nuclear translocation of c-Fos and decreased protein abundance of RE1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), suggesting the involvement of these factors. Our results suggest that PPC increases the heart rate by upregulating HCN4 channel expression through a mechanism involving c-Fos, REST, and ROS.},
}

Animals
*Diazoxide/pharmacology
*Sinoatrial Node/metabolism/drug effects/cytology
*Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism/genetics
Rats
*Myocytes, Cardiac/metabolism/drug effects
Reactive Oxygen Species/metabolism
Male
*Up-Regulation/drug effects
Rats, Sprague-Dawley
Heart Rate/drug effects
Decanoic Acids
Hydroxy Acids
Potassium Channels

@article {pmid40642398,
year = {2025},
author = {Kindlon, EA and Pidgeon, GP},
title = {N-Acetyl Cysteine as a promising therapeutic approach in ovarian cancer: potential and perspectives.},
journal = {Academia oncology},
volume = {2},
number = {2},
pages = {},
pmid = {40642398},
issn = {2998-7741},
support = {R01 CA114051/CA/NCI NIH HHS/United States ; },
abstract = {Ovarian cancer is the seventh most common cancer in women and the eighth most common cause of cancer death worldwide. It is an aggressive disease with five-year survival rates below 45% and many patients relapse within 2 years. Further treatments become more intense, resulting in chemotherapy drug resistance and increased toxicity. This has created the need to develop new therapeutic strategies to improve the quality of life and treatment options for ovarian cancer patients. Studies have reported the role of cysteine in ovarian cancer, primarily as a precursor of glutathione (GSH), contributing to the endogenous antioxidant mechanism. The membrane-permeable cysteine precursor N-acetylcysteine (NAC) can enhance the intracellular cysteine pool and thus results in decreased oxidative stress. This characteristic provides NAC with a rationale as a potentially effective chemo-protectant in ovarian cancer treatment. In this review, we summarize the effects of NAC supplementation in ovarian cancer from recent preclinical studies. The role of NAC in chemotherapy response, and mechanisms to overcome chemo resistance in ovarian cancer (including targeting the Mirk/dyrk1B kinase pathway) are also explored. While NAC holds therapeutic promise in alleviating treatment-associated toxicities, its application in ovarian cancer requires careful consideration based on tumour subtype, redox context, and treatment timing. Future research incorporating subtype-specific models and clinical trials will be essential to delineate the precise role of NAC and optimize its integration into ovarian cancer treatment regimens.},
}

@article {pmid40640645,
year = {2025},
author = {Chaudhary, KR and Viegas, C and Pirela, P and Atalaia, M and Ruivinho, B and Arora, S and Singh, A and Brandão, P and Singh, C and Fonte, P},
title = {Inhalable N-Acetylcysteine-loaded Lactose-coated PLGA Nanoparticles for Tuberculosis Treatment.},
journal = {Pharmaceutical research},
volume = {},
number = {},
pages = {},
pmid = {40640645},
issn = {1573-904X},
support = {2020.08839. BD//Fundação para a Ciência e a Tecnologia/ ; UIDB/04326/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04326/2020//Fundação para a Ciência e a Tecnologia/ ; LA/P/0101/2020//Fundação para a Ciência e a Tecnologia/ ; UIDB/04565/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04565/2020//Fundação para a Ciência e a Tecnologia/ ; LA/P/0140/2020//Fundação para a Ciência e a Tecnologia/ ; UIDB/04585/2020//Fundação para a Ciência e a Tecnologia/ ; },
abstract = {OBJECTIVE: Glutathione (GSH), known for having mucolytic, anti-inflammatory, and antioxidant activities, is used in clinical practice in several pathologies, including tuberculosis (TB). N-acetylcysteine (NAC) has been primarily used to treat lung conditions and paracetamol-induced liver toxicity. However, NAC exhibits potential antimycobacterial activity through several mechanisms including immunomodulation, enhancement of GSH levels, and direct antimycobacterial effect. In this work, we aim to develop an effective drug delivery system for NAC for inhalable formulations.

METHODS: Herein, we report the development of lactose-coated NAC-loaded Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NAC-PLGA NPs) obtained by double emulsion methodology. Lactose has a double role, as a cryoprotectant agent and dispersant for inhalable formulations. The physicochemical properties of lactose-coated NAC-PLGA NPs were examined in terms of particle size, polydispersity index (PdI), zeta potential (ZP), encapsulation efficiency, and morphology. The in vitro release and lung deposition studies were assessed.

RESULTS: The physicochemical characterization studies revealed the compatibility of the drug with the selected excipients. Moreover, lactose-coated NAC-PLGA NPs showed particle size of 310 ± 3 nm, PdI of 0.15 ± 0.01, and of -11.5 ± 0.4 mV. The in vitro release study suggested a biphasic release profile. Likewise, in vitro lung deposition studies revealed desirable lung deposition parameters, indicating effective particle size for efficient pulmonary delivery. Additionally, in vitro studies for antimycobacterial activity exhibited superior antibacterial activity against Mycobacterium Tuberculosis (MTB) H37Rv.

CONCLUSIONS: These preliminary findings suggest that lactose-coated NAC-PLGA NPs can open the door to new therapeutic options against one of the most drug-refractory and drug-resistant infectious diseases, TB.},
}

@article {pmid40640553,
year = {2025},
author = {Musillo, C and Ajmone-Cat, MA and De Simone, R and Tassinari, R and Maranghi, F and Tait, S and Samà, M and Giona, L and Pieroni, EM and Alessi, R and Henning, T and Weber, D and Lippert, RN and Pisanu, ME and Chirico, M and Iorio, E and Fratini, F and Berry, A and Cirulli, F},
title = {Maternal stressors disrupt mouse placental proteome and fetal brain development in a sex-specific fashion through inflammation and oxidative stress.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {40640553},
issn = {1476-5578},
abstract = {Adverse maternal conditions during pregnancy result in an increased risk for neuropsychiatric disorders in the offspring, although the underlying mechanisms are poorly understood. We have recently shown that two distinct insults, prenatal stress (PNS) or maternal high-fat diet (mHFD), increase inflammation and oxidative stress in the brain of adolescent female mice. Here, we sought to investigate the early mechanisms underlying such effects, focusing on the placenta and fetal brain, as well as the protective effects of the antioxidant N-acetyl-cysteine (NAC), in C57Bl6/N mice. We used a multi-disciplinary approach combining proteomic, metabolomic, lipidomic and histological analysis to characterize the structural and functional changes of the placenta; moreover, a targeted gene expression analysis was carried out in the brains of male and female fetuses to evaluate oxidative stress and inflammatory-related changes. Our data highlight comparable, but sex-specific, responses to the two maternal stressors, which target placenta and fetal brain, and are buffered by NAC administration. Placental function was specifically disrupted in males, with signaling pathways of cardio-metabolic risk emerging in this sex. By contrast, fetal brain was affected in females, with an increased expression of genes related to inflammation and oxidative stress. In conclusion, we provide evidence for an early origin of sex-dependent embedding of prenatal adverse experiences in different organs which might explain differential susceptibility to later disease trajectories.},
}

@article {pmid40637414,
year = {2025},
author = {Han, GZ and Li, S and Cui, YY and Shao, B and Song, Y and Jiang, SL and Zhang, ZQ},
title = {ROS-Dependent Endoplasmic Reticulum Stress Is Involved in Silica-Induced Pulmonary Fibrosis through the GRP78/CHOP/TXNIP/NLRP3 Signaling Pathway in Rats.},
journal = {Chemical research in toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.chemrestox.5c00135},
pmid = {40637414},
issn = {1520-5010},
abstract = {Several studies have suggested that silica-induced reactive oxygen species (ROS) stimulate the endoplasmic reticulum to undergo endoplasmic reticulum stress (ERS), which eventually leads to pulmonary fibrosis. However, the mechanisms by which ROS-dependent ERS leads to silicosis and fibrosis remain unclear. In this study, male rats were intratracheally instilled with a single dose of crystalline silica (SiO2) suspension (100 mg/mL, 1 mL) to establish silicosis and then were injected intravenously with 1 mL of N-Acetylcysteine (NAC) (at the dose of 20, 40, or 80 mg/kg, respectively) daily to inhibit ROS-dependent ERS. Rats given a single intratracheal dose of SiO2 suspension and subsequently receiving daily intravenous injections of phosphate buffer solution (PBS) served as models, while those given a single intratracheal dose of PBS and subsequently receiving daily intravenous injections of PBS served as controls. After 40 days, lung samples were taken for pathological observation, and the levels of glucose-regulated protein 78(GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), thioredoxin-interacting protein (TXNIP), and nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 inflammasome (NLRP3 inflammasome) were assessed. The results showed that compared with the control group, the lung tissues of the model rats exhibited obvious fibrosis and ERS, accompanied by the elevated levels of GRP78, CHOP, TXNIP, and NLRP3 inflammasome. After ROS were inhibited with NAC, the degree of lung fibrosis and ERS was significantly alleviated, and the levels of the aforementioned cytokines were also reduced. Moreover, the higher the dose of NAC intervention, the more pronounced the effects. The results demonstrated that ROS-dependent ERS is deeply involved in silica-induced pulmonary fibrosis through the GRP78/CHOP/TXNIP/NLRP3 signaling pathway in rats.},
}

@article {pmid40636588,
year = {2025},
author = {Roy, D and Sarkar, S and Biswas, SC},
title = {N-acetyl L-cysteine and Growth Factors Impede Endoplasmic Reticulum Stress and Inflammatory Responses in Astrocytes to Amyloid-β in Serum-free Culture.},
journal = {Annals of neurosciences},
volume = {},
number = {},
pages = {09727531251340150},
pmid = {40636588},
issn = {0972-7531},
abstract = {BACKGROUND: Astrocytes play an integral role in Alzheimer's disease (AD) pathology, where they may act as a double-edged sword. The existing serum-supplemented in vitro astrocyte culture models are not suitable to study certain stress response mechanisms that occur in AD.

PURPOSE: Here, we tried to develop a serum-free murine primary cortical astrocyte culture model to study endoplasmic reticulum (ER) stress and inflammation to investigate the effect of amyloid-beta (Aβ1-42).

METHODS: Astrocytes were cultured in a controlled serum-free environment to minimise interference from serum components. Serum-free astrocytes were exposed to oligomeric Aβ and subjected to imaging, immunocytochemistry, real-time PCR and western blot analysis.

RESULTS: Using an established protocol, no significant activation of eIF2α, a key marker of ER stress, was observed under serum-free conditions, but with the removal of N-acetyl cysteine (NAC), ER stress response was enhanced after 24 hours of Aβ exposure. Subsequently, the Aβ-induced inflammatory response, assessed through TNF-α expression, which was minimal in the presence of growth factors, became pronounced when these factors were withdrawn. Concomitantly, a significant increase in astrocytes reactivity, assessed by GFAP expression upon 24 hours of Aβ exposure, was observed. Transcript analysis revealed a time-dependent shift in the expression of inflammatory molecules, with early time points showing an increase in anti-inflammatory markers, while late exposure promoting pro-inflammatory responses.

CONCLUSION: This study identifies that NAC and growth factors impede ER stress and inflammatory responses in astrocytes upon Aβ exposure in serum-free culture. These findings also highlight the potential of a serum-free culture system for studying ER stress and inflammation in astrocytes to understand the complex role of these cells in AD pathophysiology.},
}

@article {pmid40633428,
year = {2025},
author = {Zhang, M and Lin, X and He, J and Zuo, Y and Fan, Q and Agida, I and Tan, H and Zhu, C and Cheng, J and Wang, T},
title = {SENP1-Sirt3 axis regulates type II alveolar epithelial cell activity to confer resistance against oxidative damage in lung tissue.},
journal = {Redox biology},
volume = {85},
number = {},
pages = {103752},
doi = {10.1016/j.redox.2025.103752},
pmid = {40633428},
issn = {2213-2317},
abstract = {Oxidative damage exacerbates pulmonary fibrosis by impairing alveolar type II epithelial (AT2) cell function. This study demonstrates that the SUMO-specific protease 1 (SENP1)-Sirtuin 3 (Sirt3) axis, critical for mitochondrial redox regulation, is suppressed in AT2 cells during lung injury. In bleomycin-induced pulmonary fibrosis models, activating the SENP1-Sirt3 axis via Sirt3 SUMOylation site mutation (Sirt3 K223R) reduced Superoxide Dismutase 2 (SOD2) acetylation, thereby lowering mitochondrial reactive oxygen species (mtROS) accumulation and apoptosis. This intervention increased AT2 cell proliferation and differentiation into alveolar type I cells while reducing Keratin 8 (KRT8)[+] transitional cell number, a profibrotic population. Additionally, SENP1-Sirt3 activation attenuated inflammation and fibrosis in lung tissue. Transcriptomic analysis linked the axis to enhanced Wnt signaling and lipid metabolism pathways, promoting AT2 stemness. Antioxidant N-acetylcysteine (NAC) supplementation mirrored these benefits, reinforcing ROS clearance as a therapeutic mechanism. These findings highlight SENP1-Sirt3 as a pivotal regulator of AT2 resilience, offering a potential strategy to mitigate fibrosis by targeting mitochondrial oxidative stress and cellular plasticity.},
}

@article {pmid40631939,
year = {2025},
author = {Masini, S and Bruschi, M and Menotta, M and Canonico, B and Montanari, M and Ligi, D and Monittola, F and Mannello, F and Piersanti, G and Crinelli, R and Magnani, M and Fraternale, A},
title = {Redox modulation by a synthetic thiol compound reduces LPS-induced pro-inflammatory cytokine expression in macrophages via AP-1/NLRP3 axis and influences the crosstalk with endothelial cells.},
journal = {Free radical research},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/10715762.2025.2529914},
pmid = {40631939},
issn = {1029-2470},
abstract = {Perturbation in redox status elicits multiple cellular pathways, including those involved in the inflammatory response. A thiol-based molecule (I-152), releasing N-acetyl-cysteine (NAC) and β-mercaptoethylamine (MEA), was exploited as a redox-modulating agent, and its effects on pro-inflammatory cytokine expression and secretion in lipopolysaccharide (LPS)-stimulated macrophages (MΦ) were investigated. I-152 inhibited cytokine gene expression as well as protein secretion of the most important inflammatory cytokines in three different MΦ models in vitro and ex vivo. It alleviated inflammation via the c-Jun/AP-1 and NF-κB signaling pathways, depending on the dose, and regulated NLRP3 inflammasome expression, leading to decreased IL-1β and IL-18 release and reduced pyroptotic cell death. Consequently, the influence of redox-modulated MΦ secretome on the crosstalk with endothelial cells was evaluated. Co-culture experiments between THP-1 MΦ, that had been pretreated with I-152 before LPS stimulation, and Human Vascular Endothelial Cells (HUVECs) showed reduced VCAM/ICAM expression in these cells in concomitance with a less oxidized and inflamed MΦ proteomic portrait. Overall, our findings suggest that I-152 redox modulation could target the AP-1/NLRP3 axis, affecting LPS-induced inflammation in MΦ and influencing HUVEC responses, revealing a complex and bidirectional interchange.},
}

@article {pmid40626337,
year = {2025},
author = {Roque-Torres, JL and Woolcock, AD and Santos, A and Serpa, PBDS and Mukhopadhyay, A and Moore, GE},
title = {Effect of N-Acetylcysteine, Ascorbic Acid, and a Vitamin E Analog on Oxidative and Storage Lesions in Canine Packed Red Blood Cells.},
journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)},
volume = {},
number = {},
pages = {e70002},
doi = {10.1111/vec.70002},
pmid = {40626337},
issn = {1476-4431},
abstract = {OBJECTIVE: To describe storage and oxidative lesions in canine packed red blood cells (pRBCs) during routine storage with additives, including saline, N-acetylcysteine (NAC), ascorbic acid (AA), and vitamin E analog (VE).

DESIGN: Prospective, comparative study of canine pRBCs with or without antioxidant additives during routine 42-day storage.

SETTING: University teaching hospital.

ANIMALS: Nine leukoreduced units of canine pRBCs were aseptically separated into three aliquots (Groups 1, 2, and 3) on the same day as collection (day 0). All aliquots were shipped overnight and received by the investigators on day 1.

INTERVENTIONS: Antioxidants (or control solution) were added on day 1, with three treatment groups that included saline (control, Group 1), NAC and AA (Group 2), and AA and a VE (Group 3).

MEASUREMENTS AND MAIN RESULTS: Blood was collected from each aliquot on day 1, before the addition of antioxidants for baseline measurement of glutathione and intraerythrocytic reactive oxygen species (ROS). Additional samples were collected from each aliquot on days 7, 28, and 42. Type 3 fixed-effects tests were used to compare the impact of group and time on each measurement. All groups showed storage lesions and glutathione depletion by day 42 compared with baseline, regardless of the antioxidant additive. Intraerythrocytic ROS accumulation was lower in Group 3 (AA and a VE) compared with other groups at all time points after baseline (p < 0.0001).

CONCLUSIONS: The addition of AA and a VE to canine pRBCs reduced ROS accumulation but did not prevent glutathione depletion during routine storage. Further studies using antioxidants as additives in canine pRBCs are warranted.},
}

@article {pmid40623627,
year = {2025},
author = {Kim, JE and Wang, SH and Kang, TC},
title = {Reciprocal c-Abl-GPx1 regulation controls CA1 neuronal viability to oxidative stress via ERK1/2-DRP1-mediated mitochondrial dynamics.},
journal = {Neuropharmacology},
volume = {278},
number = {},
pages = {110586},
doi = {10.1016/j.neuropharm.2025.110586},
pmid = {40623627},
issn = {1873-7064},
abstract = {Abelson murine leukemia viral oncogene homolog 1 (c-Abl, also known as ABL1) is a potent selenium-independent regulator of expression and activity of glutathione peroxidase-1 (GPx1) and extracellular signal-regulated kinase 1/2 (ERK1/2). Since GPx1-ERK1/2 pathway modulates dynamin-related protein 1 (DRP1) serine (S) 616 phosphorylation, we investigated whether c-Abl participates in GPx1-ERK1/2 interaction and DRP1-mediated mitochondrial dynamics in CA1 neurons in response to oxidative stress induced by L-buthionine sulfoximine (BSO, an oxidative stress inducer) and status epilepticus (SE). In the present study, BSO enhanced c-Abl tyrosine (Y) 245 phosphorylation, ERK1/2 activity and GPx1 upregulation in the CA1 region under physiological condition. Imatinib (a c-Abl inhibitor) ameliorated BSO-induced c-Abl Y245, but elicited further ERK1/2 phosphorylation without affecting GPx1 expression. GPx1 knockdown enhanced BSO-induced c-Abl Y245 phosphorylation, but decreased ERK1/2 activity. BSO also facilitated mitochondrial fission in CA1 neurons by augmenting DRP1 expression and its S616 phosphorylation in the CA1 region, which were diminished by GPx1 knockdown and U0126 (an ERK1/2 inhibitor), but reinforced by imatinib. SE increased c-Abl Y245 phosphorylation and mitochondrial length in CA1 neurons, accompanied by reduced GPx1 expression and ERK1/2 phosphorylation. Imatinib and N-acetylcysteine (NAC, an antioxidant) attenuated these post-SE events and CA1 neuronal death. However, GPx1 knockdown deteriorated SE-induced CA1 neuronal degeneration accompanied by augmenting c-Abl Y245 phosphorylation and mitochondrial elongation in CA1 neurons. These findings indicate that the impaired reciprocal regulation between c-Abl and GPx1 may cause CA1 neuronal degeneration in response to oxidative stress by abrogating ERK1/2-DRP1-mediated mitochondrial fission.},
}

@article {pmid40618512,
year = {2025},
author = {Renaldi, R and Persico, AM and Wiguna, T and Tanra, AJ},
title = {Breaking the cycle of oxidative stress for better behavioral health in autism spectrum disorder: A scoping review.},
journal = {Asian journal of psychiatry},
volume = {110},
number = {},
pages = {104575},
doi = {10.1016/j.ajp.2025.104575},
pmid = {40618512},
issn = {1876-2026},
abstract = {Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by socio-communicative and behavioral challenges. ASD is increasingly linked to oxidative stress, which stems from a destructive imbalance state whereby excessive reactive oxygen species (ROS) overwhelm antioxidant defenses. This redox imbalance triggers a cascade of cellular dysfunctions, which in neurons include synaptic inefficiency, altered receptor function, excitotoxicity, and chronic neuroinflammation. All these dysfunctions add an additional burden to the genetic and epigenetic contributions underlying autism pathophysiology in each single individual, ultimately exacerbating ASD core symptoms. Strikingly, children with ASD exhibit diminished antioxidant capacity, correlated with heightened behavioral severity and impaired quality of life. This scoping review explores the intricate relationship between oxidative stress and ASD, evaluating current therapeutic strategies aimed at restoring redox balance while identifying critical research gaps. Interventions such as N-acetylcysteine (NAC), vitamin and mineral supplementation, and dietary antioxidants have shown promise in mitigating oxidative damage and improving social responsiveness. Other strategies, in particular hyperbaric oxygen therapy (HBOT) and cleanroom environments, are highly controversial. Well-designed randomized placebo-controlled trials (RCTs) integrating clinical and psychodiagnostic measures with precision medicine frameworks, are crucial for developing targeted therapies that, restoring redox homeostasis, may optimize neurodevelopmental outcomes. By summarizing current evidence and addressing these gaps, this review underscores the therapeutic potential of oxidative stress correction in improving the quality of life of individuals with ASD.},
}

@article {pmid40617496,
year = {2025},
author = {Hu, H and Liu, Y and Xu, C and Chen, J and Xu, S and Tang, Y and Ren, Y and Lian, Z and Wang, R and Chen, S and Sun, Y},
title = {Mitochondria-Targeted ROS-Scavenging Polymer Protects the Hepatocytes and Macrophages against Hepatic Ischemia-Reperfusion Injury.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2025.07.004},
pmid = {40617496},
issn = {1878-7568},
abstract = {While liver transplantation (LT) is the most effective therapeutic intervention for end-stage liver diseases, hepatic ischemia-reperfusion injury (HIRI) remains a major determinant of adverse clinical outcomes. Mitochondrial reactive oxygen species (ROS) have been implicated in HIRI pathogenesis. In this study, we conjugated the small molecule, antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) with a neutral, long-circulating, and mitochondria-targeting polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), to obtain a conjugate containing 10% TEMPO (OPT10). OPT10 exhibited reliable biocompatibility and efficiently mitigated mitochondrial ROS in hepatocytes; it was also readily internalized into hepatic macrophages, promoting polarization to the anti-inflammatory M2 phenotype for over 24 h. Through these effects, together with reducing oxidative stress and decreasing activation of the MAPK pathway, OPT10 could attenuate innate immune-driven inflammation and alleviate HIRI. Compared with clinically used antioxidants such as N-acetylcysteine (NAC) and glutathione (GSH), OPT10 exhibited superior efficacy in ameliorating HIRI in a mouse model and can be considered a promising candidate for clinical translation. STATEMENT OF SIGNIFICANCE: Liver transplantation remains an effective therapeutic intervention for end-stage liver diseases. Alleviating hepatic ischemia-reperfusion injury (HIRI) is crucial for enhancing graft viability and improving long-term patient outcomes. Excessive production of mitochondrial reactive oxygen species (mtROS) during HIRI not only exacerbates hepatocellular damage but also promotes macrophage M1 polarization, thereby driving hepatic inflammation and injury. In this study, we synthesized a mitochondria-targeted ROS-scavenging polymer that enabled precise delivery to both hepatocytes and macrophages, effectively alleviating liver injury and offering novel insights into therapeutic strategies for HIRI.},
}

@article {pmid40614987,
year = {2025},
author = {Ghosh, M and Viswaroopan, N and Kshirsagar, SM and Khan, J and Mohiuddin, S and Srivastava, RK and Athar, M and Banga, AK},
title = {Sustained delivery of 4-phenylbutyric acid via chitosan nanoparticles in foam for decontamination and treatment of lewisite-mediated skin injury.},
journal = {International journal of pharmaceutics},
volume = {682},
number = {},
pages = {125928},
doi = {10.1016/j.ijpharm.2025.125928},
pmid = {40614987},
issn = {1873-3476},
abstract = {Lewisite, a chemical warfare agent, induces severe skin injury by oxidative stress and endoplasmic reticulum (ER) dysfunction, necessitating innovative antidote strategies. This study developed chitosan nanoparticle-loaded foam formulations for rapid skin decontamination and sustained topical delivery of 4-phenylbutyric acid (4-PBA), an ER stress-reducing chaperone. Nanoparticles were synthesized via ionic gelation using low (LMW) and medium molecular weight (MMW) chitosan. The optimized formulations, N31 (LMW) and N35 (MMW), achieved drug loadings of 5.04 % and 10.09 % w/w, particle sizes of 141.88 ± 26.31 nm and 176.10 ± 36.97 nm, monodisperse distributions (PDI < 0.3), high entrapment efficiency (>93 %) and good stability with zeta potential of -16.67 mV and -19.37 mV, respectively. Incorporation into foam enabled both effective decontamination (>70 % efficiency) and sustained 4-PBA delivery. In vitro release studies demonstrated sustained drug release over 24 h. Permeation studies using dermatomed human skin revealed that nanoparticle formulations significantly reduced 4-PBA delivery: N35 decreased permeation by 38.4 % (214.35 ± 16.6 µg/cm[2] vs. 348.10 ± 5.37 µg/cm[2] for free 4-PBA), while N31 reduced it by 81.35 % (64.90 ± 6.89 µg/cm[2]). Both formulations retained efficacy in PAO challenged skin, with N35 delivering 158.54 ± 53.93 µg/cm[2] and N31 138.25 ± 14.72 µg/cm[2] over 24 h. Furthermore, in vivo studies showed that the optimized formulation with N35 chitosan (4-PBA N35 + N-acetyl cysteine (NAC)) significantly protects against PAO-induced skin injury and inflammatory cytokine production in Ptch1+/-/SKH-1 hairless mice. Thus, the translational feasibility and effective treatment by the foam formulated 4-PBA N35 + NAC against arsenical-induced skin injury is demonstrated.},
}

@article {pmid40610674,
year = {2025},
author = {Chen, X and Zhang, F and Zhou, Z and Jiang, D and Wen, L},
title = {Xuebijing inhibits alveolar macrophage M1 polarization by regulating ROS-mediated NLRP3 inflammasome signaling.},
journal = {In vitro cellular & developmental biology. Animal},
volume = {},
number = {},
pages = {},
pmid = {40610674},
issn = {1543-706X},
support = {2023JJ60067//Natural Science Foundation of Hunan Province/ ; kq2208449//Natural Science Foundation of Changsha/ ; 202103020580//Hunan Provincial Health and Family Planning Commission/ ; },
abstract = {BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating acute pulmonary conditions with high mortality rates and limited effective treatment options. This study aimed to investigate the therapeutic potential of XBJ on ALI and its potential mechanism.

METHODS: We developed an in vitro model of lipopolysaccharide (LPS)-induced ALI and evaluated the effects of XBJ pre-treatment on oxidative stress, inflammatory responses, and the polarization state of alveolar macrophages.

RESULTS: LPS exposure significantly elevated the levels of reactive oxygen species (ROS) and oxidants 8-hydroxy-2'-deoxyguanosine (8-OHDG) and malondialdehyde (MDA) in alveolar macrophages. It also elevated the concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-23. XBJ and quercetin significantly mitigated the increase in these indicators. Moreover, XBJ and quercetin both downregulated the expression of key proteins in the NLRP3 inflammasome pathway in the ALI model. Similar to the ROS inhibitor N-acetylcysteine (NAC), XBJ and quercetin significantly decreased M1 polarization markers like CD86 and inducible nitric oxide synthase (iNOS), while increasing M2 polarization markers such as CD206 and arginase-1 (Arg-1). Notably, the overexpression of NLRP3 was able to reverse the inhibitory effect of XBJ on macrophage M1 polarization.

CONCLUSION: XBJ inhibits the M1 polarization of alveolar macrophages by targeting ROS-mediated NLRP3 inflammasome signaling, thereby reducing the inflammatory response. These results indicate that XBJ may offer a novel therapeutic strategy for ALI/ARDS by modulating macrophage polarization and inflammation.},
}

@article {pmid40609922,
year = {2025},
author = {Ye, T and Tang, C and Yang, D and Zhang, Q and Liao, Y and Dai, J and Tang, H and Ke, C and Peng, Y and Ye, Y and Li, W and Zheng, J},
title = {Metabolic activation and cytotoxicity of bavachin mediated by CYP3A in mice.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111630},
doi = {10.1016/j.cbi.2025.111630},
pmid = {40609922},
issn = {1872-7786},
abstract = {Bavachin (BVC), a flavonoid, is found in Psoraleae fructus (PF) which has been reported to induce various adverse effects, particularly hepatotoxicity, such as increases of serum alanine transaminase and aspartate transaminase in mice given BVC. However, the mechanisms underlying its hepatotoxicity remain unclear. During the incubation of mouse microsomes with BVC in the presence of glutathione (GSH) or N-acetylcysteine (NAC), one oxidative metabolite (M1), one GSH conjugate (M2), and one NAC conjugate (M3) were observed. M1 was successfully synthesized by selective oxidation of BVC. Similar microsomal incubations of synthetic M1 offered M2 and M3. Following oral administration of BVC, the presence of biliary M2 and urinary M3 was observed in mice given BVC. CYP3A identified as the major enzyme was involved in the metabolic activation of BVC. The metabolic activation of BVC involved hydroxylation of BVC and sequential oxidation of the hydroxylation product to the corresponding o-quinone derivative. BVC treatment resulted in significant cytotoxicity in cultured mouse primary hepatocytes, and pretreatment with 1-aminobenzotriazole and ketoconazole decreased the susceptibility of hepatocytes to the cytotoxicity of BVC. Oral administration of PF extract resulted in a quick decline in hepatic GSH, along with the detection of GSH conjugate M2, in mice. BVC, a principal component of PF, was also found to deplete hepatic GSH in mice over a brief period. This evidence suggests that metabolic activation of BVC leads to depletion of GSH in vivo and that BVC contributes to the depletion of hepatic GSH caused by PF extract.},
}

@article {pmid40605647,
year = {2025},
author = {Gok, O and Sharma, A and Kambhampati, SP and Smith Khoury, E and Kannan, S and Kannan, RM},
title = {Sustained and Step-Wise Drug Release by a Novel Double Responsive Dendrimer-N-Acetylcysteine Conjugate.},
journal = {Biomacromolecules},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biomac.5c00283},
pmid = {40605647},
issn = {1526-4602},
abstract = {Polyamidoamine (PAMAM) dendrimers have emerged as promising vehicles for targeting the brain due to their intrinsic ability to penetrate through the injured blood-brain barrier. Herein, we present a novel drug delivery system based on a fourth generation PAMAM dendrimer as a brain targeting nanomedicine for the delivery of an anti-inflammatory drug N-acetyl cysteine with a sustained drug release profile. This D"ester"(NAC"ss"NAC) design enables NACs conjugated to the periphery of PAMAM dendrimers in the dimer form with ester and disulfide bonds to be sequentially released in a stepwise manner, responding to environmental pH and redox potential. Moreover, in vitro studies were conducted with a fluorescently labeled conjugate to confirm its nontoxic behavior and time-dependent cellular uptake, together with improved anti-inflammatory and antioxidative effects over endotoxin-activated microglia. These findings demonstrate that the DNACNAC conjugate has a high potential to be utilized as a promising dendrimer-based nanomedicine platform for prolonged treatment of neuroinflammation-related CNS disorders.},
}

@article {pmid40603753,
year = {2025},
author = {Tang, Y and Luo, J and Jiang, B and Deng, J and Li, J and Qin, L},
title = {Overexpression of MEOX2 inhibits breast cancer cell metastasis by targeting oxidative stress-induced RGS5.},
journal = {In vitro cellular & developmental biology. Animal},
volume = {},
number = {},
pages = {},
pmid = {40603753},
issn = {1543-706X},
abstract = {This study aimed to investigate the role of mesenchymal homeobox 2 (MEOX2) on breast cancer cell metastasis and its underlying mechanism. Overexpression of MEOX2 in human lymphatic endothelial cell (HLEC) lines was established to assess the adhesion and transendothelial migration of MCF7 and MDA-MB-231 cells to the HLEC cells. After being treated with the oxidative stress inducer H2O2 and the antioxidant N-acetylcysteine (NAC), cell viability, reactive oxygen species (ROS) levels, adhesion, and transendothelial migration of MCF7 and MDA-MB-231 cells to HLEC cells were detected. Tumor volume changes were observed in the xenograft model. The expression of C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 7 (CCR7), MEOX2, and G protein signal transduction regulator 5 (RGS5) in tumor tissues and ROS levels were detected. MEOX2 was lowly expressed in breast cancer tissues. Upregulated MEOX2 inhibited the proliferation of lymphatic endothelial cells and the adhesion and transendothelial migration of MCF7 and MDA-MB-231 cells to HLEC cells. After MCF7 and MDA-MB-231 cells were treated with oxidative stress inducer H2O2, ROS levels increased, and cell viability and MEOX2 expression decreased. After NAC or overexpressed MEOX2 treatment, MEOX2 expression increased, ROS and RGS5 levels, adhesion, and transendothelial migration ability decreased in HLEC cells. Overexpression of MEOX2 resulted in smaller tumor volume, lower ROS levels, and lower CXCR4 and CCR7 expression levels. MEOX2 and RGS5 are pivotal in regulating breast cancer metastasis, offering valuable insights into potential therapeutic strategies for breast cancer metastasis.},
}

@article {pmid40603325,
year = {2025},
author = {Asgharzadeh, J and Derakhshan, L and Asgharzadeh, N and Mardani, M and Shahrani, D and Shahrani, M and Shahrani Korrani, M},
title = {N-acetylcysteine reduces the hepatic complications of social isolation stress through modulation of interleukin 1 and 6 gene expression and liver enzymes in mice.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23166},
pmid = {40603325},
issn = {2045-2322},
support = {IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; IR.IAU.AHVAZ.REC.1403.444//javad asgharzadeh/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Social Isolation/psychology ; Mice ; Male ; *Liver/drug effects/enzymology/metabolism ; Female ; *Interleukin-6/genetics/metabolism ; *Stress, Psychological/complications/drug therapy ; *Interleukin-1beta/genetics/metabolism ; Oxidative Stress/drug effects ; Catalase/metabolism ; Antioxidants/pharmacology/metabolism ; Malondialdehyde/metabolism/blood ; *Liver Diseases/etiology/drug therapy ; },
abstract = {Social isolation stress can alter liver function. This study examined the effects of N-acetylcysteine (NAC) on biochemical and genetic liver changes in mice under social isolation stress. Ten male and ten female mice were individually placed in Plexiglas cages for mating. Their pups were divided into six groups of eight (three male and three female): a control group receiving normal saline, a social isolation stress group (SIS + NS) also receiving saline, and a social isolation stress group treated with intraperitoneal NAC (SIS + NAC). Behavioral tests, including Resident Intruder, Sociability Index, and Social Novelty Preference Index, were conducted. Liver catalase, serum antioxidant capacity, malondialdehyde, and gene expression of interleukin 1 beta and interleukin 6 in the liver were assessed. NAC reduced violent behaviors while increasing interaction duration and frequency in the Sociability test. It enhanced liver catalase and serum antioxidant capacity while reducing serum malondialdehyde and liver interleukin 1 beta and interleukin 6 expression. The results of this study showed that N-acetylcysteine exerts its effects by reducing oxidative stress and reducing genes involved in inflammation. These findings suggest that NAC, with its antioxidant and anti-inflammatory properties, mitigates liver damage caused by social isolation stress.},
}

Animals
*Acetylcysteine/pharmacology
*Social Isolation/psychology
Mice
Male
*Liver/drug effects/enzymology/metabolism
Female
*Interleukin-6/genetics/metabolism
*Stress, Psychological/complications/drug therapy
*Interleukin-1beta/genetics/metabolism
Oxidative Stress/drug effects
Catalase/metabolism
Antioxidants/pharmacology/metabolism
Malondialdehyde/metabolism/blood
*Liver Diseases/etiology/drug therapy

@article {pmid40601178,
year = {2025},
author = {Azarmehr, Z and Poshtareh, F and Shafiei, N and Shirinsokhan, A and Rahmati, F},
title = {The neuroprotective effect of N-acetylcysteine by regulating inflammation and expression ‎of TNF-α and ERK gene expression in the rats exposed to different doses of cadmium.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {666},
pmid = {40601178},
issn = {1573-4978},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Rats ; *Cadmium/toxicity ; *Tumor Necrosis Factor-alpha/genetics/metabolism ; Rats, Wistar ; *Inflammation/metabolism/drug therapy/genetics ; Male ; *Neuroprotective Agents/pharmacology ; Gene Expression Regulation/drug effects ; MAP Kinase Signaling System/drug effects ; Brain/drug effects/metabolism/pathology ; Gene Expression/drug effects ; Interleukin-1beta/metabolism ; },
abstract = {BACKGROUND: Cadmium is known to disrupt cellular proliferation through unregulated cell division. This process leads to activation of TNF-α cytokines, resulting in cellular damage and increased inflammation in cells, including brain cells. This study investigates the regulation of TNF-α and ERK gene expression patterns mediated by N-acetylcysteine in response to cadmium exposure in Wistar rats.‎.

METHODS AND RESULTS: Wistar rats (n = 37) were divided into five groups: control (G1), acute cadmium exposure (G2), chronic cadmium exposure (G3), acute cadmium with N-acetylcysteine (G4), and chronic cadmium with N-acetylcysteine (G5). Brain tissue sections were prepared and stained with H&E. Then, the G-FAP was measured ‎using immunohistochemistry. ELISA was employed to detect IL-1β and IL-10 levels. TNF and ERK gene expression ‎was assessed using RT-PCR. Histopathological examination revealed increased glial inflammatory cells in groups G2 and G3. N-acetylcysteine reduced inflammatory cell infiltration, and G-FAP staining confirmed decreased astrocytic accumulation in G5. IL-1β levels significantly decreased in G5 after N-acetylcysteine therapy, while IL-10 levels increased after treatment but subsequently declined due to chronic cadmium exposure. TNF gene expression increased in G2 and G3 but decreased significantly in G5, demonstrating N-acetylcysteine's suppressive effect. Furthermore, ERK gene expression significantly increased in G2 and ‎G3. However, there were notable decreases in both G4 and G5 compared to cadmium-exposed controls.

CONCLUSION: This study demonstrated that N-acetylcysteine mitigates oxidative stress-induced tissue damage, prevents apoptosis, and exhibits anti-inflammatory properties by downregulating TNF-α and upregulating ERK gene expression.},
}

Animals
*Acetylcysteine/pharmacology
Rats
*Cadmium/toxicity
*Tumor Necrosis Factor-alpha/genetics/metabolism
Rats, Wistar
*Inflammation/metabolism/drug therapy/genetics
Male
*Neuroprotective Agents/pharmacology
Gene Expression Regulation/drug effects
MAP Kinase Signaling System/drug effects
Brain/drug effects/metabolism/pathology
Gene Expression/drug effects
Interleukin-1beta/metabolism

@article {pmid40600170,
year = {2025},
author = {Soleimani, P and Nekoonam, S and Zafari, F and Sabbaghziarani, F},
title = {Effects of the combination of melatonin and N-acetylcysteine on the inflammatory response in a rat model of cerebral ischemia.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {83-90},
pmid = {40600170},
issn = {2667-2421},
abstract = {Stroke is the second leading cause of death and long-term damage globally. Inflammation is a significant factor in the onset of ischemic stroke. This study investigated the simultaneous administration of melatonin and N-acetylcysteine (NAC) on inflammation in rat cerebral ischemia. First, 30 male Wistar rats were randomly divided into five groups (n = 6), including the sham group without ischemia, the ischemic group, and the ischemic groups treated with NAC, melatonin, and NAC + melatonin, respectively. To induce ischemia, a silicone-coated monofilament was placed from the common carotid artery towards the middle cerebral artery and stained for 60 min. The rats were treated by administering NAC (50 mg/kg), melatonin (5 mg/kg) and the combination of NAC + melatonin by intraperitoneal injection after ischemia induction. The animals were assessed for sensory-motor activity at 24 and 72 h. Following sacrifice, the rats' brain was dissected to estimate infarct volume after triphenyltetrazolium chloride (TTC) staining. Inflammatory parameters were then analyzed through gene expression analysis using reverse transcription quantitative polymerase chain reaction (RT-qPCR) for nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and nucleotide oligomerization domain (NOD)-like receptor family with pyrin domain 1 and 3 (NLRP1 and NLRP3). The results showed a significant decrease in mRNA expression of the target genes in the rats treated with NAC + melatonin compared to the ischemic group (p < 0.05). The group that received the combined treatment exhibited enhanced sensory-motor function and a reduced brain infarct volume compared to the other groups (p < 0.05). In summary, the combined use of NAC and melatonin has shown promise in enhancing neurobehavioral function and decreasing the volume of cerebral infarction by regulating the inflammatory signaling pathway.},
}

@article {pmid40599576,
year = {2025},
author = {Zertuche-Arias, T and Alatorre-Meda, M and Rivero, IA and Juárez, P and Castro-Ceseña, AB},
title = {N-Acetylcysteine and pro-adrenomedullin dual-crosslinked gelatin-chitosan hydrogels with enhanced mechanical and mineralization performance.},
journal = {RSC advances},
volume = {15},
number = {28},
pages = {22524-22533},
pmid = {40599576},
issn = {2046-2069},
abstract = {Bone regeneration requires coordination between bone formation, vascularization, and inflammatory regulation. However, current biomaterials often fail to provide mechanical stability and sustained bioactivity while supporting cell viability. This study presents the development and characterization of hydrogels composed of methacrylated gelatin (GelMA) and chitosan methacrylate (ChMA), crosslinked by photopolymerization (GC hydrogels). These were evaluated for their mineralization potential in vitro and ex vivo when loaded with N-acetylcysteine (NAC), a bioactive antioxidant (GCN); a pro-angiogenic peptide derived from adrenomedullin (PAMP, GCP); or both compounds (GCNP). FT-IR spectroscopy confirmed successful polymer methacrylation and the interaction of NAC with the polymer network. Scanning electron microscopy revealed that NAC increased the pore size from 24.49 ± 14.19 μm (GC) to 200.49 ± 80.42 μm (GCN). NAC also enhanced mechanical performance, with GCN exhibiting the highest compressive strength (151.79 ± 44.81 kPa) and GCNP the highest stiffness (Young's modulus: 55.26 ± 5.79 kPa). NAC-containing hydrogels degraded faster than GC, enabling biphasic release over 14 days. In vitro and ex vivo assays using pre-osteoblastic cells and a calvarial defect model demonstrated that GCNP hydrogels significantly enhanced cell viability and mineralization, increasing calcium deposition by 2.5-fold compared to GC (p < 0.01). These findings suggest that NAC not only reinforces the mechanical strength of hydrogel scaffolds designed for temporary support in non-load-bearing bone defects, but also acts as a bioactive agent upon release. Its combination with the pro-adrenomedullin peptide (PAMP) results in synergistic effects on mineralization. GCNP hydrogels are therefore promising candidates for drug delivery and bone tissue regeneration.},
}

@article {pmid40599236,
year = {2025},
author = {Tan, J and Bao, Z and Qin, K and Zhu, L and Zheng, C and Jin, J and Zhang, L and Xu, H},
title = {Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E-Dependent Pyroptosis in Pancreatic Cancer Cells.},
journal = {MedComm},
volume = {6},
number = {7},
pages = {e70250},
pmid = {40599236},
issn = {2688-2663},
abstract = {Mutations in mitogen-activated protein kinase kinase (MEK) are prevalent in pancreatic ductal adenocarcinoma (PDAC), but many MEK inhibitors inadvertently activate protein kinase B (AKT). We propose a promising PDAC treatment strategy by combining the MEK inhibitor trametinib with neobractatin (NBT), a natural compound from Garcinia bracteata. Our results demonstrated that this combination significantly impeded cell growth by inducing gasdermin E (GSDME)-mediated pyroptosis and apoptosis. GSDME, overexpressed in PDAC tissues and correlated with histological differentiation, underscores the role of pyroptosis in PDAC. RNA-seq results indicated that the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was the primary target of the combination treatment. Mechanistic studies revealed the combination effectively reduced both total and phosphorylated AKT levels, thereby inhibiting protein kinase B/IκB kinase (AKT/IKK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathways. Additionally, the combination disrupted mTOR complex 2 (mTORC2), preventing the trametinib-induced AKT activation. MicroRNA sequencing analysis indicated that the combination reduced AKT levels by upregulated miR-149-5p. Further research demonstrated that the combination increased intracellular reactive oxygen species (ROS), while N-acetylcysteine (NAC, a ROS scavenger) reversed the cell growth inhibition and AKT suppression. In vivo, the combination significantly inhibited tumor growth by inducing pyroptosis and apoptosis, outperforming gemcitabine. Our findings provide novel insights into the potential of combining NBT and trametinib to induce pyroptosis and apoptosis through the ROS/AKT/GSDME axis, offering a theoretical basis for future PDAC treatment.},
}

@article {pmid40598772,
year = {2025},
author = {Wang, Y and Liu, J and Zhu, S and Hu, S and Chen, X and Mandon, E and Tran, NT and Zhang, S and Qi, Y and Ma, H and He, R and Cao, Y and Su, Q and Gallagher, TL and Ii, Z and Zhou, C and Tai, PWL and Gao, G and Xie, J},
title = {miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2025.06.038},
pmid = {40598772},
issn = {1525-0024},
abstract = {Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the FDA-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated virus serotype 8 (AAV8) and demonstrated its potent protection in a murine model of APAP overdose-induced ALF. Slc16a2, Cyb5b, and Acsl5 were identified as critical targets acting synergistically to mitigate toxicity. Liver transcriptome revealed that miR-375 overexpression or silencing of the targets of miR-375 increased Gstm3 expression in mice. AAV8-mediated Gstm3 expression protects against APAP-ALF, and the protection was further enhanced by disrupting the expression of Cyp2e1. Additionally, CYP2E1 and GSS, which contribute to APAP detoxification, were down- and upregulated by miR-375, respectively. These findings suggest that miR-375 prevents APAP-ALF by orchestrating the expression of pharmacogenes and enhancing glutathione synthesis. We conclude that miR-375 and its targets are promising therapeutic targets for APAP-ALF.},
}

@article {pmid40596939,
year = {2025},
author = {Shiau, JP and Yang, CW and Liu, W and Yu, SY and Yen, CH and Chang, FR and Sheu, JH and Chang, HW},
title = {Excavatolide C has oxidative-stress-dependent antiproliferative and apoptotic effects against breast cancer cells.},
journal = {BMC cancer},
volume = {25},
number = {1},
pages = {1023},
pmid = {40596939},
issn = {1471-2407},
support = {KMUH108-8M37, KMUH109-9M35, and KMUH111-1M32//Kaohsiung Medical University Hospital/ ; MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 112-P06//National Sun Yat-sen University-KMU Joint Research Project/ ; KMU-TC113A04//Kaohsiung Medical University Research Center/ ; KMU-DK(A)113003 and KMU-TB114009//Kaohsiung Medical University/ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Cell Proliferation/drug effects ; Female ; Cell Line, Tumor ; *Triple Negative Breast Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; DNA Damage/drug effects ; Membrane Potential, Mitochondrial/drug effects ; *Antineoplastic Agents/pharmacology ; Anthozoa/chemistry ; *Macrolides/pharmacology ; Animals ; MCF-7 Cells ; *Breast Neoplasms/drug therapy ; },
abstract = {BACKGROUND: Triple negative breast cancer (TNBC) shows a poor response to targeted therapy drugs for non-triple-negative breast cancer (non-TNBC). Developing anticancer drugs that are effective for both TNBC and non-TNBC cells is necessary. The marine coral Briareum excavatum-derived excavatolide C (EXCC) exhibits anti-bladder cancer cell proliferation. However, the anti-breast cancer properties and drug safety of are unclear.

METHODS: This study aimed to evaluate the antiproliferative effect and mechanisms (oxidative stress, DNA damage, and apoptosis) caused by EXCC on TNBC and non-TNBC cells in parallel with normal cells.

RESULTS: EXCC demonstrated higher antiproliferative effects in various breast cancer cell lines (MDA-MB-231, Hs578t, MDA-MB-468, and MCF7) than in normal breast cell lines (H184B5F5/M10; M10) as detected in a 48 h ATP assay. MDA-MB-231 and MCF7 were chosen as representative TNBC and non-TNBC cells, respectively, to clarify the underlying molecular mechanisms. EXCC highly upregulated reactive oxygen species and mitochondrial superoxide, reduced the mitochondrial membrane potential, and downregulated glutathione in breast cancer compared with normal cells. These EXCC-triggered antiproliferative and oxidative stress changes were attenuated by the ROS inhibitor N-acetylcysteine (NAC). Consistently, in breast cancer cells, EXCC triggered subG1 accumulation, apoptosis, caspase activation, and DNA damage (γH2AX and 8-hydroxy-2'-deoxyguanosine), all of which were alleviated by NAC.

CONCLUSION: Overall, the antiproliferative effects and molecular mechanisms caused by EXCC in breast cancer treatment depend on oxidative stress. Without cytotoxicity to normal cells, EXCC is a potential antiproliferative marine natural product for TNBC and non-TNBC cells.},
}

Humans
*Oxidative Stress/drug effects
*Apoptosis/drug effects
Cell Proliferation/drug effects
Female
Cell Line, Tumor
*Triple Negative Breast Neoplasms/drug therapy/metabolism/pathology
Reactive Oxygen Species/metabolism
DNA Damage/drug effects
Membrane Potential, Mitochondrial/drug effects
*Antineoplastic Agents/pharmacology
Anthozoa/chemistry
*Macrolides/pharmacology
Animals
MCF-7 Cells
*Breast Neoplasms/drug therapy

@article {pmid40596396,
year = {2025},
author = {Bozdemir, N and Cakir, C and Cinar, O and Cinar, FU},
title = {Antioxidant-supplemented media modulates ROS by regulating complex I during mouse oocyte maturation.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {23029},
pmid = {40596396},
issn = {2045-2322},
support = {1919B012303439//The Scientific and Technological Research Council of Turkey/ ; 1919B012303439//The Scientific and Technological Research Council of Turkey/ ; },
mesh = {Animals ; *Reactive Oxygen Species/metabolism ; Mice ; *Oocytes/metabolism/drug effects/cytology ; *Antioxidants/pharmacology ; Female ; Oogenesis/drug effects ; *In Vitro Oocyte Maturation Techniques/methods ; *Electron Transport Complex I/metabolism ; *Culture Media/pharmacology/chemistry ; Ubiquinone/analogs & derivatives/pharmacology ; Acetylcysteine/pharmacology ; },
abstract = {In Vitro Oocyte Maturation (IVM) is a technique used to mature oocytes in laboratory setting. However, IVM can lead to an imbalance of reactive oxygen species (ROS), which can damage the oocytes. To prevent this, antioxidants are added to the culture medium. How these antioxidants affect Complex I, a crucial ROS-producing protein within the mitochondrial membrane, remains uncertain. To address this gap, our study aimed to achieve two key objectives. First, we investigated, for the first time, the Complex I expression during mouse oogenesis. Second, we examined the influence of an antioxidant-containing medium on Complex I and ROS levels. Germinal vesicle (GV)-stage oocytes were incubated in culture media containing acetyl-l-carnitine (ALC), α-lipoic acid (ALA), MitoQ, N-acetyl-l-cysteine (NAC) until the metaphase I (MI) and metaphase II (MII) stages. Complex I and ROS levels increased in MI and MII oocytes. Additionally, ALA and NAC increased Complex I and ROS levels, while MitoQ decreased these levels in MI and MII oocytes. Interestingly, ALC did not affect MI oocytes, but decreased the Complex I and ROS levels in MII oocytes. By elucidating the interplay between antioxidants, Complex I, and ROS during oogenesis, we pave the way for future research to improve female fertility.},
}

Animals
*Reactive Oxygen Species/metabolism
Mice
*Oocytes/metabolism/drug effects/cytology
*Antioxidants/pharmacology
Female
Oogenesis/drug effects
*In Vitro Oocyte Maturation Techniques/methods
*Electron Transport Complex I/metabolism
*Culture Media/pharmacology/chemistry
Ubiquinone/analogs & derivatives/pharmacology
Acetylcysteine/pharmacology

@article {pmid40590290,
year = {2025},
author = {Nikoosokhan, P and Ghezelayagh, Z and Hajiaghalou, S and Alizadeh Moghadam Masouleh, A and Ebrahimi, B},
title = {In Vitro Culture of Vitrified Immature Mouse Testicular Tissue in The Presence of N-acetylcysteine Antioxidant.},
journal = {International journal of fertility & sterility},
volume = {19},
number = {3},
pages = {296-304},
pmid = {40590290},
issn = {2008-076X},
abstract = {BACKGROUND: Cryopreservation of immature testicular tissue is a suitable method for spermatogonial stem cell (SSC) preservation in prepubertal boys, who are at risk of infertility due to cancer treatments. Viable spermatozoa can be obtained by transplantation or in vitro culture of cryopreserved testicular tissue. Optimizing the culture conditions is essential for reducing tissue damage caused by oxidative stress produced during cryopreservation and culture. Our objective was to improve the culture conditions of vitrified immature mouse testicular tissue by using N-acetylcysteine (NAC) antioxidant.

MATERIALS AND METHODS: In this experimental study, testicular tissues of 6-day-old immature NMRI mice were isolated, vitrified, and distributed into three groups: control, culture I (cultured without NAC), and culture II (cultured in the presence of 125 mM NAC). After seven days of culture, histological analysis, cell viability, apoptotic-related gene expression, promyelocytic leukaemia zinc finger (Plzf) gene expression, and Caspase-3 protein expression were assessed. Moreover, the malondialdehyde (MDA) level was measured in the culture media.

RESULTS: Tissue integrity and higher viability level were observed in the culture II group compared to the other two groups. Furthermore, the Bax/Bcl-2 ratio and MDA level were decreased significantly in the culture ӀӀ group, whereas Caspase-3 and Plzf gene expression were significantly increased.

CONCLUSION: Our data revealed that the presence of 125 mM NAC improves the developmental process of vitrifiedwarmed immature mouse testicular fragments during in vitro culture, thus it may have potential implications for in vitro culturing of human prepubertal testicular tissues.},
}

@article {pmid40584623,
year = {2025},
author = {Lounici, A},
title = {Guarding minds: a narrative review on how n-acetylcyteine and ketones could shield sensitive patients from antibiotic neurotoxicity.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1613152},
pmid = {40584623},
issn = {1663-9812},
abstract = {BACKGROUND: Antibiotics, indispensable in combating infectious diseases and extending life expectancy, are among the most commonly prescribed medications globally. However, neurotoxicity, encompassing neurological and psychiatric adverse effects, is an underrecognized phenomenon associated with all major classes of antibiotics. Certain antibiotics, such as fluoroquinolones, carry risks of permanent damage, including central and peripheral nervous system injury and mitochondrial dysfunction. Sensitive populations, such as the elderly and individuals with compromised organ function or genetic predispositions, are particularly vulnerable.

AIMS: To review evidence on the neurological and psychiatric side effects of antibiotics and evaluate potential neuroprotective strategies like N-acetylcysteine (NAC) and ketone bodies.

METHOD: Narrative review of preclinical and clinical studies, clnical case reports and epidemiological data.

RESULTS: Neurological and psychiatric side effects are rare, but they can be devastating. NAC shows promise in preclinical studies for mitigating oxidative stress and cellular damage. Ketones, through ketogenic diets or exogenous supplementation, may provide neuroprotection via enhanced mitochondrial function and anti-oxidative and anti-inflammatory effects.

CONCLUSION: While initial findings are promising, further research is required to validate the clinical efficacy of these protective agents. Improved understanding of antibiotic neurotoxicity and potential mitigation strategies could lead to safer prescribing practices, particularly for vulnerable populations, balancing risk mitigation with the essential benefits of antibiotics.},
}

@article {pmid40583489,
year = {2025},
author = {Niu, C and Li, RT and Hao, XS and Qi, X and Wang, FZ and Fei, HR},
title = {Scutebarbatine B Exerts Anti-Breast Cancer Activity by Inducing Cell Cycle Arrest and Apoptosis Through Multiple Pathways.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70007},
pmid = {40583489},
issn = {1099-1573},
support = {ZR2022MH178//Shandong Provincial Natural Science Foundation, China/ ; },
abstract = {Breast cancer is the most commonly occurring cancer among women with high mortality. Identifying effective anticancer compounds to improve the overall survival is imperative. The present study was designed to evaluate the effects and underlying mechanisms of Scutebarbatine B (SBT-B), a diterpenoid alkaloid extracted from Scutellaria barbata D. Don (S. barbata), on breast cancer. Cell viability assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, immunofluorescence, flow cytometry analysis, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, Western blot analysis, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and dihydroethidium (DHE) staining were performed to elucidate the anticancer mechanisms of SBT-B in vitro. Mice xenograft models were used to assess the anticancer properties in vivo. We demonstrated that SBT-B suppressed the proliferation of breast cancer cells in a dose-dependent manner. SBT-B treatment induced DNA damage response, G2/M phase arrest and downregulated the expression of cyclinB1, cyclinD1, Cdc2, and p-Cdc2. SBT-B could trigger apoptosis through increasing the cleavage of caspase-8, caspase-9 and PARP in breast cancer cells. Additionally, SBT-B elevated the generation of intracellular reactive oxygen species (ROS). Treatment with a ROS scavenger N-acetyl cysteine (NAC) partially blocked viability reduction and cleavage of caspase-8 and PARP induced by SBT-B. Moreover, SBT-B blocked pRB/E2F1 and Akt/mTOR pathways. Incubation with SBT-B increased the expression of IRE1 and phospho-JNK. In vivo, SBT-B exhibited significant suppression of tumor growth in xenograft models. We demonstrate firstly that SBT-B induces DNA damage, cell cycle arrest and apoptosis in breast cancer cells. ROS generation, suppression of oncogenic signaling and activation of IRE1/JNK pathway play an essential role in the anticancer activity of SBT-B. Our study highlights the potential of SBT-B as an alternative candidate to treat human breast cancer.},
}

@article {pmid40582321,
year = {2025},
author = {Ziari, HA and Shaki, F and Seyedabadi, M and Safarzade, A and Amiri, FT and Talebi-Garakani, E and Sayyad, MS},
title = {Protective effects of benfotiamine supplementation and aerobic training against noise-induced cardiovascular damage: A focus on oxidative stress and inflammatory pathways.},
journal = {Biochemical and biophysical research communications},
volume = {777},
number = {},
pages = {152235},
doi = {10.1016/j.bbrc.2025.152235},
pmid = {40582321},
issn = {1090-2104},
abstract = {BACKGROUND: Environmental pollution, particularly noise exposure, may contribute to the development and progression of cardiovascular disorders by triggering oxidative stress and inflammatory pathways. This study evaluated the protective effects of benfotiamine (BFT) supplementation and moderate-intensity continuous training (MICT), alone or in combination, against noise-induced cardiac damage in male mice.

METHODS AND RESULTS: Eight-week-old mice (n = 8/group) were divided into six groups: control, noise-exposed (Noise) subjected to 100 dB (dB), noise + moderate-intensity continuous exercise training (MICT), noise + BFT group (200 mg/kg/day), noise + MICT + BFT, and noise + N-acetylcysteine (NAC) groups. Noise exposure and other treatments were administered over four weeks. Histopathological changes, oxidative stress parameters, and the gene expression of inflammatory markers were evaluated. Noise exposure markedly increased cardiac ROS, NO, MDA, and protein carbonyl content, while significantly decreasing GSH and FRAP levels (all p < 0.001 vs. control). Treatment with BFT or MICT partially restored redox balance, whereas combined BFT + MICT treatment produced more pronounced improvements (e.g.

, MDA: 9.91 ± 4.45; GSH: 101.2 ± 20.1 μM). Inflammatory markers IL-6, TNF-α, IL-1β, and NF-κB were upregulated by noise and significantly attenuated by all interventions, with the greatest reduction observed in the combined group. Histological analysis confirmed that the combined therapy more effectively preserved myocardial architecture compared to monotherapies.

CONCLUSION: Our findings suggest that BFT's antioxidant and anti-inflammatory properties, in combination with MICT as a non-pharmacological approach, may protect against noise-induced cardiovascular problems. BFT and MICT mitigate noise-induced cardiac injury via antioxidant and anti-inflammatory mechanisms, with additive benefits evident in the combined treatment group.},
}

@article {pmid40579121,
year = {2025},
author = {Ma, H and Cao, T and Zhang, F and Sun, D and Chen, L and Lin, Y and Lai, S and Jiang, B and Zhou, Y and You, J and Liu, X and Wang, Y and Lin, F and Liu, Y and Wang, J and He, W and Li, Q},
title = {Nuclear Pirin promotes HCC by acting as a key inflammation-facilitating factor.},
journal = {Gut},
volume = {},
number = {},
pages = {},
doi = {10.1136/gutjnl-2024-334087},
pmid = {40579121},
issn = {1468-3288},
abstract = {BACKGROUND: Chronic inflammation and elevated reactive oxygen species are key contributors to hepatocellular carcinoma (HCC) progression.

OBJECTIVE: This study aims to investigate the role of the oxidative stress sensor protein Pirin (PIR) as a critical mediator of inflammation in HCC progression.

DESIGN: We investigated PIR's role in HCC tumourigenesis through RNA interference, genetic knockout and pharmaceutical inhibition in HCC cell lines and various mouse models. Furthermore, we used transcriptomics, quantitative reverse transcription PCR, western blot, immunofluorescence staining and immunohistochemistry analysis to elucidate the molecular details.

RESULTS: This study reveals a novel redox-dependent mechanism governing PIR's nuclear shuttling, contributing to liver inflammation and HCC progression. We identified a positive feedback axis where nuclear PIR amplifies inflammatory responses, leading to hepatitis and HCC advancement. Cytokines in this loop are regulated by PIR-enhanced v-rel reticuloendotheliosis viral oncogene homolog A (RELA) transcription, promoting PIR's nuclear translocation, increasing proinflammatory cytokine levels, and disrupting redox balance. We confirmed that liver parenchymal cells produce autocrine cytokines supporting their growth and malignancy. Notably, PIR's redox-mediated nuclear shift can be inhibited by N-acetyl cysteine or PIR inhibitors, reducing HCC promotion in mice.

CONCLUSION: We elucidate a novel redox-dependent regulatory mechanism governing the nuclear localisation of PIR and its role in promoting liver inflammation and HCC progression. Our findings underscore the significance of cellular redox status in regulating PIR's activity and highlight the potential of targeting this pathway with antioxidants to mitigate HCC progression.},
}

@article {pmid40566670,
year = {2025},
author = {Dorodian, P and Shahverdi, A and Alizadeh, A and Rashki Ghaleno, L and Abbasihormozi, S and Esmaeili, V and Akbarinejad, V and Sharafi, M},
title = {Effects of N-Acetyl Cysteine on Human Post-Thaw Sperm Quality and Mitochondrial Uncoupling Protein 2 Relative Quantity.},
journal = {Biopreservation and biobanking},
volume = {},
number = {},
pages = {},
doi = {10.1089/bio.2024.0007},
pmid = {40566670},
issn = {1947-5543},
abstract = {Reactive oxygen species (ROS) during cryopreservation causes mechanical, biochemical, and structural damage to the sperm, which leads to reduced sperm motility and fertility. N-acetyl cysteine is a cysteine-derived amino acid antioxidant that functions as a scavenger of ROS and regulates mitochondrial activity. Mitochondrial uncoupling protein 2 (UCP2) plays a leading role in this process and is one of the major regulators of human spermatozoa motility and metabolism. The purpose of the study was to examine the changes in UCP2 in frozen-thawed human sperm when exposed to N-acetyl cysteine, an effective antioxidant commonly used in human semen freezing. Semen samples were collected from 20 normozoospermia men and were divided into four experimental groups: fresh, frozen control, frozen N-Acetylcysteine (NAC, 100 μM), and frozen negative control with Genipin (25 μM). Subsequently, post-thaw sperm quality parameters, as well as UCP2 relative quantity, ROS, mitochondrial membrane potential (MMP), and malondialdehyde, were assessed. Semen treated with NAC exhibited significantly higher total and progressive motility, as well as viability, when compared to the control and genipin groups (p < 0.05). Moreover, UCP2 relative quantity was significantly lower in all frozen groups compared to the fresh group (p < 0.0001). The UCP2 relative quantity was not significantly different between NAC and control groups (p ≥ 0.05). Also, there were no significant differences in MMP, ROS, and malondialdehyde levels among the frozen groups (p ≥ 0.05). It can be concluded that UCP2 undergoes a modification during cryopreservation, and it could be an explanation of the reduction in post-thaw motility of sperm. Additionally, NAC supplementation in freezing media enhances post-thaw sperm motility and viability.},
}

@article {pmid40566456,
year = {2025},
author = {Moldovan, M and Muntean, M and Schauer, SA and Moldovan, R and Mitrea, DR},
title = {Oxidative Stress and Ultrastructural Analysis in Heart, Aorta, Skeletal Muscle and Lung of Rats Treated with N-Acetylcysteine or Rutin After Sprint Running.},
journal = {Journal of functional morphology and kinesiology},
volume = {10},
number = {2},
pages = {},
pmid = {40566456},
issn = {2411-5142},
abstract = {Background: Sprinting, a high-intensity, short-duration exercise, induces oxidative stress. This causes molecular and ultrastructural alterations. Antioxidant supplementation may mitigate side effects of near or complete exhaustion. Methods: Twenty-eight healthy male adult rats received orally normal saline, carboxymethylcellulose (vehicle), artificial, N-acetylcysteine or a natural antioxidant, Rutin. Rats were subjected to treadmill sprinting at increasing speeds for 5 days/week. After 26 days, samples were collected to measure oxidative stress (malondialdehyde, MDA; the ratio of reduced-to-oxidized glutathione, GSH/GSSG), inflammation markers (enzymatic level of inducible nitric oxide synthase, iNOS; cytokine level of tumor necrosis factor alpha, TNFα) and for transmission electron microscopy (TEM) analysis. Results: Rutin attenuated MDA levels and increased antioxidant protection in all tissues, while NAC decreased the lipid peroxidation in all tissues except the lungs. NAC increased aortic inflammation, with higher TNF-α and iNOS. Sprinting caused intimal detachment in the heart and aorta. Rutin and NAC minimized endocardium alterations. Additionally, Rutin prevented myocardial disorganization. Conclusions: Rutin mitigated the oxidative stress damage of sprinting in the heart, aorta, skeletal muscle and lung. NAC protected against oxidative injury caused by sprinting in the heart, aorta and muscle but not the lung, and it induced aortic inflammation.},
}

@article {pmid40564126,
year = {2025},
author = {Armeli Grigio, L and Boci, D and Di Vieste, G and Cassanelli, G and Epis, OM and Viadana, A and Bertuzzi, F and Pintaudi, B},
title = {Real-World Effectiveness of Different Nutraceutical Formulations on Pain Intensity of Subjects with Diabetic Peripheral Neuropathy: An Observational, Retrospective, Case-Control Study.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
pmid = {40564126},
issn = {2227-9059},
abstract = {Background/Objectives. Diabetic peripheral neuropathy is a debilitating disease-related complication with a significant impact on quality of life. Its management represents a therapeutic challenge. Antioxidant agents such as α-lipoic acid, N-acetyl cysteine, and glutatione may be useful treatment strategies. Methods. A real-world, observational, retrospective, case-control study involving consecutive subjects with type 2 diabetes with diabetic peripheral neuropathy was performed. Participants who were supplemented with three different formulations for 12 weeks (high-dose α-lipoic acid (800 mg); low-dose α-lipoic acid (100 mg) plus glutathione (200 mg) plus Vitamin D (800 IU); N-acetyl cysteine (600 mg) plus glutathione (200 mg) plus Vitamin D (800 IU)) were compared with a non-treated control group. Questionnaires aimed at investigating the degree of disability and quality of life were administered. The primary endpoint was the change in neuropathic pain intensity measured by the Numerical Rating Scale (NRS). Results. Among 750 consecutive screened subjects with type 2 diabetes, 98 (13%) had diabetic neuropathy (mean age 66.7 ± 7.6 years, diabetes duration 11.3 ± 6.7 years, HbA1c 8.1 ± 1.5%, 43.8% insulin-treated). When comparing the differences between treatment groups in the changes in individual questionnaire scores between baseline and follow-up, all three supplements showed significant reductions compared to the control group in the NRS scale scores. No side effects have been reported during the study. Conclusions. As well as lipoic acid, other substances with specific activity on the genesis of neuropathic pain, such as N-acetyl cysteine and glutathione, have proved effective in reducing the intensity of pain.},
}

@article {pmid40563994,
year = {2025},
author = {Elkalla, N and Elhamammsy, MH and Bedair, NI and Elazazy, O and El Kholy, AA},
title = {A Promising Approach to Psoriasis Vulgaris Management with N-Acetylcysteine and Vitamin E: Targeting the Interplay of Inflammatory and Oxidative Stress.},
journal = {Biomedicines},
volume = {13},
number = {6},
pages = {},
pmid = {40563994},
issn = {2227-9059},
abstract = {Background: Psoriasis is a persistent, inflammatory skin disease with autoimmune characteristics. Beyond the obvious signs of skin lesions, it has negative systemic repercussions that impair the patient's quality of life. This study aimed to determine the effectiveness of N-acetylcysteine (NAC) alone or in combination with Vitamin E in the treatment of mild to moderate active psoriasis vulgaris. Methods: This study was an open-label, prospective, randomized, controlled interventional clinical trial conducted at Cairo Hospital for Dermatology and Venereology (Al-Haud Al-Marsoud). In total, 45 patients with mild to moderate symptoms were randomly assigned to three groups, with fifteen patients each, as follows: the control group received the standard psoriatic treatment of topical steroids and salicylic acid; the acetylcysteine group received standard psoriatic treatment in addition to NAC 600 mg per day 30 min prior to breakfast for 8 weeks; and the acetylcysteine and Vitamin E group received standard psoriatic treatment in addition to NAC 600 mg per day, in a similar way of dosing like the previous group, and Vitamin E 1000 mg per day. All participants performed a comprehensive assessment including hematological parameters, the Psoriasis Area and Severity Index (PASI), the Dermatology Life Quality Index (DLQI), malondialdehyde (MDA), and interleukin-36 gamma (IL-36γ). Results: The treatment strategy involving the use of NAC alone and in combination with Vitamin E showed significant improvement in the assessed parameters compared to the control group receiving conventional therapy. The acetylcysteine group showed improvements of 41% in PASI and 49.4% in DLQI, a decrease of 34.3% in MDA, and a decrease of 31% in IL-36γ. Similarly, the acetylcysteine and Vitamin E group showed improvements of 52% in PASI and 42% in DLQI, a decrease of 37% in MDA, and a decrease of 35% in IL-36γ. There were no significant differences found between the N-acetylcysteine and N-acetylcysteine and Vitamin E groups. Moreover, significant positive correlations were found between MDA, IL-36γ, and PASI at baseline and after the third follow-up. Conclusions: This study found promising therapeutic benefits in the addition of NAC to the conventional therapy in psoriatic patients with mild to moderate symptoms, as it significantly improved psoriasis disease outcomes and improved the patient's quality of life. However, the addition of Vitamin E to the NAC regimen did not show additional benefits.},
}

@article {pmid40559816,
year = {2025},
author = {Cui, L and Duan, J and Mao, P and Zhong, J and He, S and Dong, J and Liu, K and Guo, L and Li, J and Wang, H},
title = {Meloxicam Alleviates Oxidative Stress Through Nrf2/HO-1 Activation in Bovine Endometrial Epithelial Cells.},
journal = {Veterinary sciences},
volume = {12},
number = {6},
pages = {},
pmid = {40559816},
issn = {2306-7381},
support = {32072937//National Natural Science Foundation of China/ ; 32102735//National Natural Science Foundation of China/ ; 8//International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions/ ; JATS[2023]456//the earmarked fund for Jiangsu Agricultural Industry Technology System/ ; 2023YFD1801100//the National Key R&D Program of China/ ; BK20210808//Natural Science Foundation of Jiangsu Province/ ; D18007//the 111 Project/ ; N/A//the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)/ ; },
abstract = {Meloxicam has been identified as an adjuvant therapeutic component in the management of bovine uterine diseases, exhibiting anti-inflammatory and antioxidant effects. However, the mechanisms underlying its antioxidant actions in the context of bovine uterine diseases remain incompletely understood. The objective of this research was to determine whether meloxicam exerts its antioxidant effects through the Nrf2/HO-1 signaling pathway. By employing N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), along with inhibitors directed against heme oxygenase-1 (HO-1) or nuclear factor erythroid 2-related factor 2 (Nrf2), we investigated the dynamic changes in oxidative stress markers (ROS and malondialdehyde) and antioxidant indices (comprising catalase, superoxide dismutase, and glutathione), as well as the expression profiles of Nrf2 and inflammation-associated genes and proteins in bovine endometrial epithelial cells (BEECs) subjected to lipopolysaccharide (LPS) stimulation. As a result, meloxicam alleviated the LPS-induced elevation of oxidative stress marker levels and the reduction in antioxidant enzyme activities and antioxidant substance contents in BEECs. Compared to NAC, meloxicam demonstrated superior efficacy in activating the Nrf2 pathway, with the promotion of NRF2 expression (~1.6-fold) and nuclear translocation. The pretreatment of cells with HO-1 or Nrf2 inhibitors markedly attenuated the antioxidant activity of meloxicam. In summary, meloxicam primarily alleviates LPS-induced oxidative stress through the activation of the Nrf2/HO-1 pathway in BEECs.},
}

@article {pmid40557447,
year = {2025},
author = {Heun, F and Meißner, J and Schieder, AK and Ohnesorge, B and Busse, C},
title = {Pantoea agglomerans in Equine Ulcerative Keratitis: Prevalence and Comparative Efficacy of Four Topical Antiseptics.},
journal = {Veterinary ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1111/vop.70044},
pmid = {40557447},
issn = {1463-5224},
abstract = {OBJECTIVE: To determine the minimal bactericidal concentration (MBC) and effective contact time of four topical antiseptics-polyhexanide, povidone-iodine (PVP-I), hypochlorous acid (HOCl), and N-acetylcysteine (NAC)-against Pantoea agglomerans, a pathogen frequently isolated in equine ulcerative keratitis.

ANIMALS STUDIED: Over a 17-month sampling period, clinical isolates were collected from horses with ulcerative keratitis. The most frequently isolated strain (Pantoea agglomerans, n = 14) was selected for in vitro analysis.

PROCEDURE(S): All isolates were used to determine the MBCs of the four antiseptics. Each was tested in triplicate at serial dilutions per isolate. Additionally, the requisite contact time for a bactericidal effect was evaluated at a supratherapeutic dilution for each substance with each isolate at defined time points ranging from 15 s to 5 min.

RESULTS: The MBCs of polyhexanide, PVP-I, HOCL, and NAC were 3.2 ppm (0.00032%), 16 ppm (0.0016%), 0.8 ppm (0.00008%), and 3200 ppm (0.32%), respectively. Polyhexanide (6.4 ppm), PVP-I (64 ppm), and HOCL (6.4 ppm) were effective within 15 s. NAC (6400 ppm) required 1-2 min to achieve bactericidal effects.

CONCLUSIONS: All antiseptics tested demonstrated efficacy against P. agglomerans. Polyhexanide, PVP-I, and HOCl achieved rapid bactericidal activity, while NAC required higher concentrations and longer exposure. These results support the use of these agents-particularly the faster-acting three-as potential alternatives to antibiotics in treating equine ulcerative keratitis. They may aid the reduction of antibiotic use in line with the One Health approach.},
}

@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.},
}