@article {pmid41452016,
year = {2025},
author = {Kang, Y and Gallagher, D and Herrmann, N and Black, SE and Kiss, A and Oh, PI and Ramirez, J and Swardfager, W and Lanctôt, KL},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107036},
doi = {10.1002/alz70859_107036},
pmid = {41452016},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/drug therapy ; *Executive Function/drug effects ; Aged ; *Acetylcysteine/therapeutic use ; Neuropsychological Tests ; Middle Aged ; *Antioxidants/therapeutic use ; Oxidative Stress/drug effects ; Treatment Outcome ; },
abstract = {BACKGROUND: Oxidative stress (OS) plays a significant role in vascular mild cognitive impairment (vMCI), and the antioxidant N-acetylcysteine (NAC) was proposed to mitigate cognitive decline. However, our randomized clinical trial (NCT03306979) found no significant effects of NAC on executive function in vMCI patients. Despite this, heterogeneity in response to NAC was observed, leading to post-hoc analyses aimed at identifying clinical predictors of NAC response.

METHOD: A 24-week, randomized clinical trial included participants with vMCI (<1SD population norms in executive function, memory, working memory, or processing speed with cardiovascular disease). Baseline clinical variables were selected a priori and assessed for their effects on changes in executive function z-scores between NAC and placebo using univariate analyses. Variables with at least a 0.37 difference between their levels (cut-off based on observed improvements in executive function across all participants: β[95%CI]=0.37[0.18-0.56], p<0.001) were considered potential predictors of NAC response. A multivariate regression model with selected variables was used to estimate NAC's effects under both treatments' scenarios. An index score was calculated as the difference in predicted changes in executive function between the NAC and placebo models. Participants were grouped into quartiles according to their index scores. The treatment effect of each quartile was determined by calculating the mean difference in the empirical change in executive function between NAC and placebo groups. A 95%CI was estimated using bootstrapping with 1000 iterations.

RESULT: A total of 53 participants (mean[SD] Age=67.7[7.9], %male=66%, BMI=27.2[5.5], MoCA=22.6[3.2]) completed the trial. Analysis found that younger age, higher BMI, non-APOE4 carrier status, lower Apathy Evaluation Scale-self scores, elevated homocysteine levels, and ACE inhibitor use were associated with greater improvements in executive function with NAC. Mean treatment effect [95%CI] for each quartile were: Q1=-0.68[-1.18,-0.15], Q2=-0.16[-0.62,0.34], Q3=0.08[-0.57,0.72], Q4=1.01[0.28,1.86]. A likelihood ratio test showed that the treatment effect significantly varied across quartiles (p<0.001). Percent responders (improvement >0.37 in executive function z-scores) among participants who received NAC were: Q1=0%, Q2=25%, Q3=62.5%, Q4=100% (χ²(3)=10.4, p=0.02).

CONCLUSION: These findings show significant variability in response to NAC among vMCI patients, with certain subgroups showing more pronounced benefits. This highlights the need for personalized therapeutic strategies targeting OS in vMCI.},
}

Humans
Male
Female
*Cognitive Dysfunction/drug therapy
*Executive Function/drug effects
Aged
*Acetylcysteine/therapeutic use
Neuropsychological Tests
Middle Aged
*Antioxidants/therapeutic use
Oxidative Stress/drug effects
Treatment Outcome

@article {pmid41451781,
year = {2025},
author = {Kang, Y and Herrmann, N and Gallagher, D and Chen, JJ and Mah, E and Survilla, K and Vieira, D and Black, SE and Andreazza, AC and Kiss, A and Oh, PI and Ramirez, J and Swardfager, W and Marzolini, S and Lanctôt, KL},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106789},
doi = {10.1002/alz70859_106789},
pmid = {41451781},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/drug therapy ; Aged ; Neuropsychological Tests ; *Acetylcysteine/therapeutic use ; Executive Function/drug effects ; Middle Aged ; *Antioxidants/therapeutic use ; Cardiac Rehabilitation ; Oxidative Stress/drug effects ; },
abstract = {BACKGROUND: Oxidative stress (OS) is implicated in the etiology of vascular mild cognitive impairment (vMCI), a form of cognitive decline originating from cerebrovascular pathology. vMCI is characterized by early deficits in executive function and memory, with OS suspected to contribute to its development. Although aerobic exercise has been shown to improve cognitive function and oxidative balance, it can also lead to an increase in OS. We hypothesized that the antioxidant N-acetylcysteine (NAC) may help mitigate this damage by replenishing glutathione levels, particularly in those undergoing exercise interventions. This study evaluated the efficacy and safety of oral NAC for improving cognitive function in vMCI patients participating in a cardiac rehabilitation program.

METHOD: In this 24-week randomized clinical trial, patients with vMCI (1SD below the norm in executive function, memory, processing speed or working memory, with significant cardiovascular disease) were randomized to receive either NAC (2400mg/day) or placebo. Participants were recruited from the Toronto Rehab Institute-Cardiac rehabilitation program. Cognitive function was assessed using a 60-minute neuropsychological battery, with executive function as the primary outcome. Phonemic fluency, semantic fluency, and the Trail Making Test B were administered as part of the executive function. Z-scores for each task were computed based on published age-matched norms, and a composite z-score was calculated for overall executive function. Data were analyzed using mixed-effects models adjusting for relevant covariates. Adverse events (AEs) were monitored throughout the study period.

RESULT: A total of 59 participants [mean(SD) age = 67.6(7.7), male(%) = 69.5%, mean(SD) MoCA= 22.5(3.2)] were randomized. Executive function improved over time (β=0.36, 95%CI=[0.20, 0.53], p<0.001), with no significant differences between NAC (n=29) and placebo (n=30) (β= -0.04, 95%CI= [-0.28, 0.20], p=0.7) while controlling for sex, years of education, BMI, homocysteine levels, and VO2. NAC was well-tolerated, with no significant differences in the frequency or severity of AEs between groups. Common AEs included dyspepsia, nausea, and headache. Most AEs resolved post-treatment.

CONCLUSION: NAC supplementation did not provide additional cognitive benefits beyond that of cardiac rehabilitation in patients with vMCI.},
}

Humans
Male
Female
*Cognitive Dysfunction/drug therapy
Aged
Neuropsychological Tests
*Acetylcysteine/therapeutic use
Executive Function/drug effects
Middle Aged
*Antioxidants/therapeutic use
Cardiac Rehabilitation
Oxidative Stress/drug effects

@article {pmid41446880,
year = {2025},
author = {van Brummelen, R and van Brummelen, AC},
title = {The role of neuro-supportive substances of natural origin in neurological conditions-A literature-based formulators' perspective.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1647092},
pmid = {41446880},
issn = {1664-2295},
abstract = {Products of natural origin are seldom tested up to a point of full acceptance, mainly due to a lack of financial viability for commercialization. Yet many come with a rich history of use and proof of concept testing. We investigated literature regarding the possible role and function of the best known of these nutraceuticals in relationship to three neurological conditions i.e. stroke, Alzheimer's - (AD) and Parkinson's disease (PD), and their potential as supportive therapies. Current studies suggest that citicoline has a neuroprotective effect in ischemic conditions, playing a role in the restoration of the barrier function of endothelial cells, activating repair mechanisms and possibly decreasing ischemic lesion size in stroke, as well as increasing dopamine availability in PD. Citicoline was also demonstrated to increase the levels of sirtuin 1 (SIRT1), thus reducing inflammation-leading to improved cognitive status and a better quality of life in cognitive impairment. N-Acetylcysteine (NAC) shows pro-cognitive effects, increasing glutathione (GSH) levels that are decreased in AD and PD patients, possibly decreasing neuroinflammation. Mechanistic studies indicate the potential neuroprotective and neurorestorative effects of resveratrol by its anti-inflammatory and anti-apoptotic activity, also increasing SIRT1 levels and promoting the outgrowth of neurite protrusions and synaptogenesis. Curcumin's anti-inflammatory effects via inhibition of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can potentially delay progression of PD. Some nutraceuticals, e.g., citicoline, show synergism in combination with current therapies. We propose a renewed, risk-benefit approach for inclusion of the investigated nutraceuticals with limited indications in certain neurological treatment regimens.},
}

@article {pmid41445121,
year = {2025},
author = {Mehrpour, O and Soltani, M and Karami-Mohajeri, S and Khanamani Falahatipour, S},
title = {Acetaminophen poisoning: contemporary intravenous acetylcysteine regimens and early discharge pathways.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14656566.2025.2610370},
pmid = {41445121},
issn = {1744-7666},
abstract = {INTRODUCTION: Acetaminophen (paracetamol, APAP) overdose remains a leading cause of drug-induced acute liver failure, yet N-acetylcysteine (NAC) prevents hepatic injury.

AREAS COVERED: We conducted a narrative search of PubMed/MEDLINE, Embase, and Google Scholar (January 2000-August 2025) and reviewed NAC regimens, including the 3-bag protocol (21 h), the U.S. FDA-labeled 2-bag regimen (20 h), and the 12-h Scottish and Newcastle Acetylcysteine Protocol (SNAP), as well as early-stop pathways. Across regimens, efficacy is broadly similar, but simplified protocols reduce non non-immunoglobulin E reactions and dosing errors. SNAP delivers 300 mg/kg over 12 h and is extended only when stopping criteria are not met, whereas early-stop pathways (NACSTOP/SARPO) are restricted to selected low-risk patients. In most acute overdoses, NAC can be stopped when APAP is < 10 mg/L, ALT/AST are stable or falling, and INR is acceptable.

EXPERT OPINION: A protocolized NAC pathway with clear stop/extend rules is the most impactful way to improve care. Escalation (higher or prolonged dosing, early hepatology/transplant referral, and consideration of ECTR) should be reserved for high-risk cases. In low- and middle-income countries (LMICs), dose and timing history can guide empiric NAC when levels are delayed. Biomarkers and artificial intelligence remain useful adjuncts, not substitutes, for laboratory-based decisions.},
}

@article {pmid41444149,
year = {2025},
author = {Peng, AJC and Kang, Y and Gallagher, D and Herrmann, N and Ismail, Z and Black, SE and Kiss, A and Oh, PI and Ramirez, J and Swardfager, W and Survilla, K and Mah, E and Vieira, D and Lanctôt, KL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e106844},
doi = {10.1002/alz70857_106844},
pmid = {41444149},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/drug therapy/psychology ; Aged ; Double-Blind Method ; *Acetylcysteine/therapeutic use ; *Apathy/drug effects ; Neuropsychological Tests ; *Antioxidants/therapeutic use ; Middle Aged ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) are non-cognitive changes that often co-occur with mild cognitive impairment (MCI) and independently increase the risk of progression to dementia. Of the NPS, apathy is a particularly strong risk factor. Oxidative stress and vascular risk factors of dementia have been implicated together to contribute to neurodegeneration. We previously found that oxidative stress biomarkers in individuals with vascular MCI (vMCI) were associated with apathy, suggesting antioxidants may be potential treatments. Here, we explored the efficacy of antioxidant N-acetylcysteine (NAC) as a treatment for NPS in individuals with vMCI.

METHOD: This is a secondary analysis from a double-blind, RCT ("MOVE-IT") that was conducted on exercising older adults with vMCI (cardiovascular diseases and ≥1 SD below the norm in executive function, processing speed, memory, or working memory). Participants were recruited from a cardiac rehabilitation program. Over 24 weeks, participants received either 2400mg of NAC or placebo as treatment. Neuropsychiatric assessments were taken at weeks 0, 12, and 24. The Mild Behavioural Impairment Checklist (MBI-C) was used to capture five main domains of pre-dementia NPS: apathy, emotional dysregulation (ED), impulse control, social inappropriateness, and psychosis.

RESULT: All 59 participants (n = 29 NAC, n = 30 Placebo, 69% male, mean[SD]: age=67.6[7.7], BMI=27.4[5.5], MoCA=22.5[3.2]) provided MBI-C data for this analysis. Zero-inflated Poisson mixed models with subject as random effect were used to address the high proportion of participants without NPS and to fit the incremental severity scores in each MBI-C domain. Covariates included age, sex, and number of cardiovascular risk factors (hypertension, coronary artery disease, hypercholesterolemia, dyslipidemia, type-2 diabetes, > 5-year smoking history, obesity). Significant treatment effects over time were observed for apathy (Baseline: 56% apathy+, β[SD] = -1.35[.415], z = -3.26, p = .001) and ED (Baseline: 54% ED+, β[SD] = -.731[.306], z = -2.03, p = .043) scores at week 12. On average, scores decreased more in the NAC group (mean[SD]: apathy = -1.56[3.27], ED = -2.04[4.20]) than in the placebo group (mean[SD]: apathy = -0.296[1.66], ED = -0.481[1.67]) after 12 weeks. No treatment effects were observed for the other domains.

CONCLUSION: The findings support NAC as a potential treatment for apathy and emotional dysregulation in individuals with vMCI and at risk of dementia, thereby reducing associated burdens.},
}

Humans
Male
Female
*Cognitive Dysfunction/drug therapy/psychology
Aged
Double-Blind Method
*Acetylcysteine/therapeutic use
*Apathy/drug effects
Neuropsychological Tests
*Antioxidants/therapeutic use
Middle Aged

@article {pmid41441921,
year = {2025},
author = {Yavuz, M and Acer, S and Celik, O and Argun, M and Ozmen, O and Tok, L},
title = {Assessment of neuroprotective efficacy of N-acetylcysteine compared with brimonidine in an experimental glaucoma model.},
journal = {International ophthalmology},
volume = {46},
number = {1},
pages = {53},
pmid = {41441921},
issn = {1573-2630},
mesh = {Animals ; *Brimonidine Tartrate/therapeutic use ; Female ; Rats ; Disease Models, Animal ; Rats, Wistar ; *Glaucoma/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use ; *Acetylcysteine/therapeutic use/pharmacology ; Retinal Ganglion Cells/pathology/drug effects ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Intraocular Pressure/drug effects ; Adrenergic alpha-2 Receptor Agonists ; },
abstract = {PURPOSE: To investigate the neuroprotective effects of N-acetylcysteine (NAC) in comparison with brimonidine in an experimental glaucoma model.

METHODS: Thirty-two adult female Wistar albino rats were randomly assigned to five groups: Control, Sham, NAC, Brimonidine, and Combination (NAC + Brimonidine). Glaucoma was induced in the right eye by optic nerve crush in all groups except Control. Treatments were administered intraperitoneally every 72 h for 30 days. Neuroprotection was assessed histopathologically by measuring ganglion cell layer (GCL) thickness and total retinal thickness. Apoptotic activity and glial activation were evaluated by quantifying B-cell lymphoma/leukemia-2 (BCL-2), BCL-2-associated X protein (BAX) and glial fibrillary acidic protein (GFAP) expression. Oxidative stress and antioxidant capacity were assessed using malondialdehyde (MDA), total oxidant status (TOS), glutathione (GSH) and total antioxidant capacity (TAC) levels.

RESULTS: NAC significantly preserved GCL and total retinal thickness compared with the Sham group (P < 0.001), with neuroprotective efficacy comparable to brimonidine (P > 0.05). The combination therapy group demonstrated the most pronounced neuroprotective effects. NAC treatment increased antiapoptotic BCL-2 and GSH levels while reducing BAX, GFAP, MDA, and TOS levels (P < 0.001).

CONCLUSIONS: NAC exhibited substantial neuroprotective effects in an intraocular pressure-independent glaucoma model, likely mediated through its antioxidant properties and modulation of apoptotic pathways. These findings suggest that NAC may serve as a promising adjunctive therapy for glaucomatous optic neuropathy and other retinal neurodegenerative disorders characterized by oxidative stress and apoptosis.},
}

Animals
*Brimonidine Tartrate/therapeutic use
Female
Rats
Disease Models, Animal
Rats, Wistar
*Glaucoma/drug therapy/metabolism/pathology
*Neuroprotective Agents/therapeutic use
*Acetylcysteine/therapeutic use/pharmacology
Retinal Ganglion Cells/pathology/drug effects
Oxidative Stress/drug effects
Apoptosis/drug effects
Intraocular Pressure/drug effects
Adrenergic alpha-2 Receptor Agonists

@article {pmid41440725,
year = {2025},
author = {Hong, M and Kedeshian, K and Hoffman, L and Kita, A},
title = {Preliminary Evaluation of an Injectable Therapeutic for Cisplatin Ototoxicity Using Neuronal SH-SY5Y Cells.},
journal = {Medicines (Basel, Switzerland)},
volume = {12},
number = {4},
pages = {},
doi = {10.3390/medicines12040030},
pmid = {41440725},
issn = {2305-6320},
support = {1K08DC019957-01/NH/NIH HHS/United States ; Not applicable//American Neurotology Society/ ; },
abstract = {BACKGROUND/OBJECTIVES: Though ototoxic, cisplatin is a mainstay of chemotherapy for a variety of cancers. One suggested mechanism of cisplatin ototoxicity involves damage to the spiral ganglion afferent neurons in the inner ear. There is a need for a high-throughput model to screen medications for efficacy against cisplatin and to develop a local therapeutic to mitigate cisplatin's debilitating side effects. Microparticles encapsulating a therapeutic medication are an injectable and tunable method of sustained drug delivery, and thus a promising treatment.

METHODS: SH-SY5y human neuroblastoma cells were used as a cell line model for the spiral ganglion neurons. The cells were dosed with cisplatin and four potential therapeutics (melatonin, metformin, cyclosporine, and N-acetylcysteine), with cell viability measured by CCK-8 assay. The most promising therapeutic, N-acetylcysteine (NAC), was then encapsulated into multiple poly(lactic-co-glycolic acid) (PLGA) microparticle subtypes of varied lactide-glycolide (L:G) ratios and NAC amounts. The elution profile of each microparticle subtype was determined over two months.

RESULTS: Of the therapeutics screened, only cells dosed with 1 or 10 mM NAC prior to cisplatin injury demonstrated an improvement in cell viability (73.8%, p < 1 × 10[-8]) when compared to cells dosed with cisplatin alone. The 75:25 L:G microparticles demonstrated an increase in the amount of NAC released compared to the 50:50 L:G microparticles.

CONCLUSIONS: NAC is a potential therapeutic agent for cisplatin toxicity when tested in a neuronal cell line model. NAC was encapsulated into PLGA microparticles and eluted detectable concentrations of NAC for 6 days, which is a first step towards otoprotection for the weeks long duration of chemotherapy treatment. This work describes a method of screening potential therapeutics and a strategy to develop local drug eluting treatments to protect against cisplatin ototoxicity.},
}

@article {pmid41440550,
year = {2025},
author = {Parpoudi, S and Mantzoros, I and Ioannidis, O and Zapsalis, K and Gamali, T and Kyziridis, D and Gekas, C and Anestiadou, E and Symeonidis, S and Bitsianis, S and Kotidis, E and Pramateftakis, MG and Miliaras, D and Bikouli, A and Iosifidis, G and Angelopoulos, S},
title = {Effect of N-Acetyl-L-Cysteine (NAC) on Inflammation After Intraperitoneal Mesh Placement in an Escherichia coli Septic Rat Model: A Randomized Experimental Study.},
journal = {Medical sciences (Basel, Switzerland)},
volume = {13},
number = {4},
pages = {},
doi = {10.3390/medsci13040318},
pmid = {41440550},
issn = {2076-3271},
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Escherichia coli/drug effects ; *Surgical Mesh/adverse effects ; Rats ; *Escherichia coli Infections/drug therapy ; Disease Models, Animal ; *Inflammation/drug therapy/etiology ; *Sepsis/drug therapy/microbiology ; Male ; Tissue Adhesions ; Cytokines/blood ; },
abstract = {Background/Objectives: The safety of intraperitoneal mesh placement in contaminated fields remains controversial because of the increased risk of inflammation and adhesion formation. N-acetyl-L-cysteine (NAC) has antioxidant, pro-fibrinolytic and antibiofilm actions that could attenuate this response. The aim of this study is to determine whether NAC reduces mesh-related inflammation in a septic model created by intraperitoneal Escherichia coli (E.coli) inoculation. The primary comparison was prospectively defined between E. coli-inoculated animals treated with NAC (D) and those without NAC (B). Groups without E. coli (A,C,E) are presented for context and were compared previously. Methods: In this randomized, double-blind experimental model (five groups, n = 20 per group), all rats underwent midline laparotomy with intraperitoneal placement of a composite mesh, followed by standardized ciprofloxacin administration. The septic groups received intraperitoneal E. coli, while the NAC-treated groups additionally received intraperitoneal NAC (150 mg/kg). Serum levels of IL-1α, IL-6, and TNF-α were measured on postoperative days 7, 14, and 21. On day 21, adhesions were graded using the Modified Diamond system, histology (inflammatory infiltration, fibrosis, neovascularization) was scored, and mesh cultures were obtained. Cytokine data were analyzed with repeated-measures ANOVA, while categorical or ordinal outcomes were assessed using χ[2] or Fisher's exact tests with Bonferroni-adjusted pairwise comparisons. Results: E. coli inoculation significantly increased adhesion burden and worsened histologic scores compared with controls (both p < 0.001). NAC administration in the septic model significantly reduced adhesions and improved all histologic domains relative to E. coli alone (all p ≤ 0.003), with values comparable to controls (non-significant across domains). For cytokines, there was a significant overall group effect for IL-1α, IL-6, and TNF-α (all p < 0.001), without a main effect of time or time × group interaction. Pairwise contrasts showed lower IL-1α (p = 0.024), IL-6 (p < 0.001), and TNF-α (p < 0.001) levels in group D versus B, and lower IL-6 and TNF-α in group D versus A (both p < 0.001). Mesh culture positivity rate was higher in group B than A (p < 0.001) and showed a non-significant reduction in group D versus B (p = 0.10). No perioperative deaths occurred. Conclusions: NAC attenuated septic, mesh-associated inflammation-normalizing adhesions and histology and reducing IL-6 and TNF-α- supporting its role as a host-directed adjunct alongside antibiotics. Further translational studies are warranted to define the optimal dose, timing, and clinical indications.},
}

Animals
*Acetylcysteine/pharmacology/therapeutic use
*Escherichia coli/drug effects
*Surgical Mesh/adverse effects
Rats
*Escherichia coli Infections/drug therapy
Disease Models, Animal
*Inflammation/drug therapy/etiology
*Sepsis/drug therapy/microbiology
Male
Tissue Adhesions
Cytokines/blood

@article {pmid41440263,
year = {2025},
author = {Liu, Z and Li, X and Liu, S and Cai, Y and Xu, X and Gao, S and Yao, C and Wang, L and Xie, X and Cai, Y and Jiang, L and Liu, J and Li, M and Li, Y and Huang, X and Chen, H},
title = {Transcriptomic Evaluation of Hollow Microneedles-Mediated Drug Delivery for Rheumatoid Arthritis Therapy.},
journal = {Biosensors},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/bios15120782},
pmid = {41440263},
issn = {2079-6374},
support = {32171456, 82100430//National Natural Science Foundation of China/ ; 2024YFB3211600//National Key R&D Program of China/ ; 2023A1515111139, 2025A1515010608, 2020A1515111139//Guangdong Basic and Applied Basic Research Foundation/ ; 2024B03J0121, 2024B03J1284//Science and Technology Program of Guangzhou, China/ ; 2023A03J1008//Science and Technology Projects in Guangzhou/ ; 24xkjc011//Fundamental Research Funds for the Central Universities, Sun Yat-sen University/ ; 2024-skllmd-11//Open Fund of the State Key Laboratory of Luminescent Materials and Devices (South China University of Technology)/ ; JCYJ20220818102201003//Shenzhen Science and Technology Program/ ; },
mesh = {*Arthritis, Rheumatoid/drug therapy ; *Drug Delivery Systems/methods ; Animals ; Needles ; *Transcriptome ; Pyrimidines/administration & dosage/therapeutic use ; Piperidines/administration & dosage/therapeutic use ; Acetylcysteine/administration & dosage ; Humans ; Pyrroles/administration & dosage ; Gene Expression Profiling ; },
abstract = {Microneedle array-based drug delivery offers a minimally invasive and safe approach for breaching the skin barrier, enabling localized and targeted treatment-an advantage particularly valuable in chronic condition management, such as rheumatoid arthritis (RA). RA presents a multifaceted pathophysiology, often necessitating long-term pharmacological management. However, conventional oral administration may lead to systemic drug distribution, increasing the likelihood of adverse effects, and ultimately undermining therapeutic efficacy. In this study, a hollow microneedle array was employed for effective delivery of Tofacitinib and the antioxidant N-acetylcysteine (NAC). A comprehensive evaluation was conducted across multiple levels, in which inflammation and cartilage degradation were assessed histologically using hematoxylin-eosin (H&E) and Safranin O-Fast Green staining. Radiologically, micro-computed tomography (micro-CT) was employed to visualize bone structure alterations. On the molecular level, enzyme-linked immunosorbent assay (ELISA) was used to quantify inflammatory cytokines and oxidative stress markers. Furthermore, differentially expressed genes and enriched signaling pathways were identified through transcriptomic profiling pre- and post-treatment. And the potential regulatory targets and mechanistic insights into the therapeutic response were elucidated through correlation analyses between gene expression profiles and pathological indicators. This study provides a mechanistic and computational basis for precision targeted therapy, validates the efficacy and safety of microneedle delivery in a rheumatoid arthritis (RA) model, and demonstrates its potential application in local drug delivery strategies.},
}

*Arthritis, Rheumatoid/drug therapy
*Drug Delivery Systems/methods
Animals
Needles
*Transcriptome
Pyrimidines/administration & dosage/therapeutic use
Piperidines/administration & dosage/therapeutic use
Acetylcysteine/administration & dosage
Humans
Pyrroles/administration & dosage
Gene Expression Profiling

@article {pmid41440136,
year = {2025},
author = {Mulè, S and Parini, F and Galla, R and Uberti, F},
title = {Neuroinflammation-Modulating Properties Combining Glutathione, N-Acetylcysteine, and Uridine Monophosphate in a Formulation Supplement: An In Vitro Study.},
journal = {Brain sciences},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/brainsci15121340},
pmid = {41440136},
issn = {2076-3425},
abstract = {Background: Neuropathic pain is a complex condition often resistant to current therapies due to limited efficacy and adverse effects. Nutraceuticals offer promising alternatives, combining antioxidant and anti-inflammatory properties with good tolerability. This study aimed to compare the effects of a commercial nutraceutical formulation, SUPERALA CARNITINE[®] (Pharma Suisse Laboratories SpA, Milan, Italy), containing Alpha-Lipoic Acid (ALA), with a novel formulation, called SUPERALA CARNITINE[®] Forte, where ALA and vitamin B6 were replaced by N-acetylcysteine (NAC), Glutathione (GSH), and Uridine monophosphate (UMP). Methods: An indirect gut-peripheral nerve axis was employed to simulate oral absorption, metabolism, and effect on nervous tissues using 3D in vitro models. Both formulations and their individual components were assessed for cytotoxicity and permeability in the gut model (Caco-2 cells in Transwell[®]) and, after gut metabolism, for antioxidant capacity, anti-inflammatory activity, and neuroprotective potential in the peripheral nerve model. Results: SUPERALA CARNITINE[®] Forte improved cell viability and favoured the maintenance of intestinal integrity, showing enhanced permeability, and significantly reduced oxidative stress (OS) and pro-inflammatory cytokines (TNF-α, IL-2) at the peripheral nervous system. In addition, it increased levels of neuronal markers (p75, MPZ, NRG1, ERβ) and decreased NaV1.7 and NaV1.8 activity, indicating greater neuroprotection and analgesic modulation than the ALA-based formula. Conclusions: The replacement of ALA and vitamin B6 with NAC, GSH, and UMP produced favorable responses in vitro on neuronal cells, supporting a hypothetical potential interest in this nutraceutical combination and justifying further future in vivo investigations.},
}

@article {pmid41431629,
year = {2025},
author = {Sinaeinejad, M and Karimi, M and Razavizadeh, M and Arj, A and Tabatabaei, SH and Mortezazadeh, M and Shirsalimi, N and Pirzad, S and Mofidi, A and Kashani, M},
title = {Efficacy of N-Acetylcysteine on Liver Function and Metabolic Profiles in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Double-Blind, Randomized Controlled Trial.},
journal = {Addiction & health},
volume = {17},
number = {},
pages = {1667},
pmid = {41431629},
issn = {2008-4633},
abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is a common liver disorder associated with metabolic abnormalities. This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) in improving liver function and metabolic profile in patients with MASLD.

METHODS: In this randomized controlled trial (RCT), 69 patients with MASLD were randomly assigned to either the NAC group (600 mg, administered three times daily, n=34) or the placebo group (n=35) for eight weeks. The severity of hepatic steatosis, liver enzymes, and metabolic profile were measured at baseline and the final trial. Data were analyzed using SPSS.

FINDINGS: Following eight weeks of NAC administration in patients with MASLD, no significant changes were observed compared to the placebo in hepatic steatosis grade (P=0.215), serum aspartate aminotransferase (AST) (P=0.21), alanine transaminase (ALT) (P=0.28), malondialdehyde (MDA) (P=0.79), total antioxidant capacity (TAC) (P=0.56), triglycerides (P=0.15), total cholesterol (P=0.28), low-density lipoprotein cholesterol (P=0.32), and high-density lipoprotein cholesterol (P=0.16). However, NAC administration resulted in significant reductions in fasting blood glucose (FBG) (P=0.01), fasting insulin levels (P<0.001), homeostatic model assessment for insulin resistance (HOMA-IR) (P<0.001), and C-reactive protein (CRP) (P<0.001), along with a significant increase in total glutathione levels (P=0.003), compared to the placebo group.

CONCLUSION: NAC administration in patients with MASLD does not significantly impact hepatic steatosis, liver enzymes, or lipid profiles; however, it improves oxidative, glycemic, and inflammatory markers. Therefore, NAC may be a beneficial adjunct therapy for managing metabolic parameters and reducing inflammation and oxidative stress in MASLD patients.

TRIAL REGISTRATION: The trial was registered with the Iranian Registry of Clinical Trials (IRCT20201220049772N1) on February 20, 2021.},
}

@article {pmid41428714,
year = {2025},
author = {Rocha, MBM and Assis, EIT and Azevedo, VAN and Lima Neto, MF and Silva, AWB and Godinho, AN and Freire, JMO and Félix, EDS and Ribeiro, RP and Gomes, GA and Silva, JRV},
title = {Piperine protects ovarian follicles and stromal cells against doxorubicin-induced adverse effects in mouse ovaries.},
journal = {JBRA assisted reproduction},
volume = {},
number = {},
pages = {},
doi = {10.5935/1518-0557.20250187},
pmid = {41428714},
issn = {1518-0557},
abstract = {OBJECTIVE: This study investigates the effects of Piperine (PIP) on doxorubicin (DOX)-induced changes in mouse ovarian follicles, stromal cells, collagen fibers, and mRNA expression of nuclear factor erythroid 2-related factor (NRF2), superoxide dismutase (SOD), and catalase (CAT).

METHODS: The mice were randomly divided into seven groups. In the first three groups, they received saline (1), both DOX and N-acetylcysteine (2), or DOX only (3). In groups 4 and 5, mice were treated with DOX in combination with 0.1 or 10.0mg/kg PIP. In groups 6 and 7, mice received 0.1 or 10.0mg/kg PIP alone. After 10 days, ovaries were collected and used to evaluate follicular morphology and growth, collagen fibers, stromal cells, and mRNA for NRF2, SOD, and CAT.

RESULTS: Mice treated with DOX showed reduced percentage of normal follicles, but the combination of DOX with PIP or NAC prevented this effect, maintaining follicle integrity similar to untreated animals. Ovaries of mice treated with PIP alone had similar percentage of normal follicles compared to control group. Additionally, the association of DOX and PIP preserved collagen levels similar to control, while PIP or NAC alone did not influence collagen distribution. Ovaries of mice treated with both DOX and NAC showed a reduction in stromal cells, but those treated with both DOX and PIP maintained the levels of collagens similar to control.

CONCLUSIONS: The DOX and PIP preserved the integrity of follicles and collagen fibers in mouse ovaries, which opens a new possibility to protect primordial follicles during chemotherapy.},
}

@article {pmid41165773,
year = {2025},
author = {Schuurman, M and Wilson, RB and Borradaile, N and Wang, R},
title = {The antioxidant, N-acetyl-L-cysteine, affects beta cell oxidative stress, insulin secretion, and intracellular signaling pathways in MIN6 cells.},
journal = {Cell and tissue research},
volume = {402},
number = {3},
pages = {267-281},
pmid = {41165773},
issn = {1432-0878},
support = {152944)/CAPMC/CIHR/Canada ; 152944)/CAPMC/CIHR/Canada ; },
mesh = {*Acetylcysteine/pharmacology ; *Oxidative Stress/drug effects ; *Insulin-Secreting Cells/drug effects/metabolism/cytology ; *Insulin/metabolism ; *Signal Transduction/drug effects ; *Antioxidants/pharmacology ; Insulin Secretion ; Animals ; Mice ; Cell Line ; Adenosine Triphosphate/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Glucose/pharmacology ; Phosphorylation/drug effects ; },
abstract = {There is intense public interest in the potential of antioxidant supplements as a preventative treatment for conditions associated with increased oxidative stress, such as type 2 diabetes mellitus. However, there is limited evidence regarding the effects of antioxidants on beta cells during physiological and pathological conditions. We examined the direct effects of N-acetyl-L-cysteine (NAC) supplementation on the MIN6 beta cell line under physiological and fatty acid stress conditions. MIN6 cells were cultured in growth medium with or without NAC (physiological conditions) or growth medium plus palmitate with or without NAC (fatty acid stress conditions). We observed that MIN6 cells receiving NAC, under physiological or fatty acid stress conditions, displayed significantly reduced cellular ATP content and oxidative stress without changes to markers of cell proliferation or apoptosis. Regardless of the treatment conditions, NAC lowered basal insulin release with no change to cellular insulin content, yet improved high glucose-stimulated insulin secretion (GSIS) was only observed under physiological conditions. Importantly, phosphorylated AKT was significantly reduced with NAC supplementation under physiological and fatty acid stress conditions, which was inversely proportional to ERK1/2[Thr202/Tyr204] phosphorylation during fatty acid stress. Our findings provided evidence that NAC directly impacts ATP production and insulin signaling pathways in MIN6 cells. This study highlights the importance of investigating ROS balance in pancreatic beta cells under physiological and pathological conditions to determine if antioxidant therapies can improve functionality without interfering with essential signaling processes.},
}

*Acetylcysteine/pharmacology
*Oxidative Stress/drug effects
*Insulin-Secreting Cells/drug effects/metabolism/cytology
*Insulin/metabolism
*Signal Transduction/drug effects
*Antioxidants/pharmacology
Insulin Secretion
Animals
Mice
Cell Line
Adenosine Triphosphate/metabolism
Proto-Oncogene Proteins c-akt/metabolism
Glucose/pharmacology
Phosphorylation/drug effects

@article {pmid41424200,
year = {2025},
author = {Sadri, H and Shahrokhi, N and Ebrahimi-Rad, M and Mardani, M and Sadeghi, S and Pooya, M},
title = {Synergistic Antiba cterial and Antibiofilm Activity of N-acetylcysteine Combined with Niosomal Recombinant Lysostaphin against MRSA Staphylococcus aureus.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/1061186X.2025.2607397},
pmid = {41424200},
issn = {1029-2330},
abstract = {Wound infections significantly impair healing and often result in chronic wounds, burdening healthcare systems substantially. The principal pathogen in such infections is Staphylococcus aureus (S. aureus), which forms biofilms that resist host defenses and conventional therapies. To overcome these challenges, recombinant lysostaphin (rLyso) was encapsulated in niosomes using thin-film hydration and evaluated with N-acetylcysteine (NAC) against standard and clinical S. aureus strains. In this study, we assessed antibacterial and antibiofilm activities by determining the minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC). The measurements were complemented using fluorescence and confocal microscopy. Cytotoxicity was assessed in L929 fibroblasts, and in vivo efficacy was histologically investigated in BALB/c mouse wound models. The NAC/niosomal rLyso formulation exhibited the most potent antibacterial and antibiofilm effects, significantly lowering the MIC values (standard: 1250/5.9 μg/ml; clinical: 1250/2 μg/ml) and achieving notable biofilm eradication (MBEC: standard: 5000/23.6 μg/ml; clinical: 1250/2 μg/ml).Cytotoxicity assays confirmed high biocompatibility, with nearly 100% cell viability at MIC, while NAC alone was highly toxic. The combination of two agents achieved full bacterial clearance in vivo and accelerated wound healing. As a result, these findings suggest that NAC combined with niosomal rLyso synergistically disrupts S. aureus biofilms, enhances antimicrobial activity, and promotes wound repair. Such features make it a promising therapeutic strategy against resistant staphylococcal infections.},
}

@article {pmid41422903,
year = {2025},
author = {Chaabani, H and Ayed, I and Rjiba, K and Abid, S and Eyer, J and Arnoult, D},
title = {Trifloxystrobin induces oxidative stress-dependent activation of the OMA1-DELE1-HRI integrated stress response leading to apoptosis in human neuroblastoma cells.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {127562},
doi = {10.1016/j.envpol.2025.127562},
pmid = {41422903},
issn = {1873-6424},
abstract = {Trifloxystrobin (TFX), a potent inhibitor of complex III in the mitochondrial respiratory chain, is a widely used strobilurin fungicide whose neurotoxic mechanisms remain poorly defined. This study investigated the molecular pathways underlying TFX-induced toxicity in human SH-SY5Y neuronal-like neuroblastoma cells, with particular emphasis on oxidative stress, mitochondrial dysfunction, and activation of the Integrated Stress Response (ISR). TFX exposure (24 h) exhibited an IC50 of approximately 100 μM, induced G0/G1 cell cycle arrest, and triggered mitochondria-mediated apoptosis, as evidenced by loss of mitochondrial membrane potential (ΔΨm), Bax activation, cytochrome c release, DNA fragmentation, phosphatidylserine exposure, and caspase-3 activation. These effects were accompanied by increased mitochondrial superoxide levels and decreased ATP production, indicating profound mitochondrial impairment. Pretreatment with N-acetylcysteine (NAC) markedly restored cell viability, reduced ROS accumulation, prevented ΔΨm dissipation, and diminished apoptotic damage. Mechanistically, TFX activated the ISR through the OMA1-DELE1-HRI mitochondrial stress signaling axis, as confirmed by loss-of-function experiments targeting these proteins. Importantly, both NAC and the ISR inhibitor ISRIB (Integrated Stress Response InhiBitor) significantly attenuated ISR activation and the resulting apoptosis, demonstrating that oxidative stress serves as an upstream trigger for ISR engagement and cell death. Collectively, these findings reveal that TFX induces oxidative stress-dependent activation of the OMA1-DELE1-HRI ISR pathway, linking mitochondrial dysfunction to apoptosis in human neuroblastoma cells. To our knowledge, this is the first report identifying ISR activation as a mechanistic component of strobilurin fungicide-induced neurotoxicity.},
}

@article {pmid41422364,
year = {2025},
author = {Xing, HB and Li, HY and Zheng, GZ and Zhang, QH and Zhai, L and Wu, X and Du, SX and Li, XD},
title = {Resveratrol synergizes with cisplatin to suppress osteosarcoma U2-OS cells via up-regulating Cx43 and inducing ROS-dependent apoptosis.},
journal = {Discover oncology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12672-025-04313-1},
pmid = {41422364},
issn = {2730-6011},
support = {JCYJ20190812171411416//Science and Technology Research and Development Foundation of Shenzhen/ ; JCYJ20210324131405016//Science and Technology Research and Development Foundation of Shenzhen/ ; JCYJ20230807142814031//Science and Technology Research and Development Foundation of Shenzhen/ ; A2018523//Medical Science and Technology Research Foundation of Guangdong Province/ ; },
abstract = {BACKGROUND: Resveratrol (Res), a plant-derived polyphenol, exerts synergistic effects when combined with various chemotherapeutic drugs, enhancing the antitumor activity of traditional chemotherapy. However, whether Res combined with cisplatin (CDDP) produces a synergistic inhibitory effect on osteosarcoma cell growth and its underlying mechanisms remain unclear.

METHODS: We investigated the responses of U2-OS cells to Res, CDDP, or their combination using Cell Counting Kit-8 (CCK-8) for proliferation, flow cytometry for apoptosis, wound healing assays for migration, and Transwell assays for invasion. The effects of the two drugs on Wnt/β-catenin signaling were analyzed via quantitative real-time PCR (qRT-PCR) and western blotting. Additionally, the relationship between Cx43 and Wnt/Wnt/β-catenin signaling was explored by knocking down Cx43 using lentiviral infection.

RESULTS: The combination of Res and CDDP exhibited greater cytotoxicity against osteosarcoma U2-OS cells than either drug alone, and this effect was synergistic as determined by the Chou-Talalay equation. Cx43 knockdown attenuated the strong antitumor effect of the Res + CDDP combination and restored Wnt/β-catenin signaling activity. Furthermore, the Res + CDDP combination generated more reactive oxygen species (ROS) than individual treatments, inducing ROS-dependent apoptosis, which was blocked by N-acetylcysteine (NAC).

CONCLUSIONS: Res combined with CDDP exerts a synergistic inhibitory effect on osteosarcoma by upregulating Cx43 and inducing ROS-dependent apoptosis. This study may provide a novel therapeutic strategy and potential clinical applications for osteosarcoma treatment.},
}

@article {pmid41421415,
year = {2025},
author = {Sun, R and Fan, H and Ma, Q and Li, X and Liu, J and Xu, C and Liu, C and Zhang, D and Ma, W},
title = {LL37-induced mitochondrial stress activates the mtDNA/cGAS/STING pathway to promote mast cell-mediated rosacea inflammation.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.12.026},
pmid = {41421415},
issn = {1873-4596},
abstract = {BACKGROUND: Rosacea is a chronic inflammatory skin disease characterized by persistent facial erythema and telangiectasia. The antimicrobial peptide LL37 is a key initiator in rosacea, with mast cells serving as critical inflammatory mediators. However, the precise mechanism underlying LL37-induced mast cell degranulation remains unclear.

METHODS: The rosacea RNA-seq dataset GSE65914 was downloaded from the Gene Expression Omnibus (GEO) database and subjected to transcriptome analysis. DCFH-DA staining was performed to detect oxidative stress. Mitochondrial function was evaluated using MitoSOX and JC-1 staining. Calcein AM/Co[2+] quencher staining was employed to assess mitochondrial permeability transition pore (mPTP) opening. Transmission electron microscopy was utilized to observe mitochondrial ultrastructure. Cytosolic mitochondrial DNA (mtDNA) was evaluated via immunofluorescence and qPCR. Western blotting and CUT&RUN assays were conducted to detect activation of the cGAS/STING/NF-κB axis. Mast cell degranulation was assessed using ELISA. N-acetylcysteine (NAC) was administered to scavenge reactive oxygen species (ROS). Cyclosporin A (CsA) was used to inhibit mPTP opening. SP23 was applied for chemical degradation of STING. A LL37-induced rosacea-like dermatitis mouse model was established and topically treated with applied CsA/SP23 cream.

RESULTS: Transcriptomic profiling reveals significant enrichment of the cGAS/STING signaling pathway in rosacea lesions. LL37 induces oxidative stress-driven mitochondrial damage in mast cells, resulting in the leakage of mtDNA. Cytosolic mtDNA activates the cGAS/STING/NF-κB signaling pathway, inducing mast cell degranulation. ROS scavenging, blockade of mPTP or targeted degradation of STING significantly reduced mast cell activation. Animal experiments demonstrated that topical administration of CsA or SP23 suppressed cGAS/STING/NF-κB signaling in dermal mast cells and alleviated rosacea-like dermatitis.

CONCLUSION: LL37 promotes mast cell-driven inflammation through mitochondrial stress and innate immune activation and suggest that targeting the mtDNA/cGAS/STING pathway may offer a promising therapeutic strategy for rosacea.},
}

@article {pmid41419903,
year = {2025},
author = {Tekdemir, A and Ekici, MA and Çelikten, B and Helvacıoğlu Kıvanç, B},
title = {Comparison of calcium hydroxide removal efficiency of ethylenediaminetetraacetic acid, phytic acid and N-acetylcysteine using sonic activation: a micro-CT study.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-025-07455-4},
pmid = {41419903},
issn = {1472-6831},
abstract = {BACKGROUND: The aim of this study was to compare the efficacy of ethylenediaminetetraacetic acid (EDTA), phytic acid (IP6), and N-acetylcysteine (NAC) with sonic activation on the removal efficiency of calcium hydroxide (Ca(OH)2) from root canals with micro-computed tomography (micro-CT) analysis.

METHODS: Thirty-two extracted human mandibular first premolars were used in this study. The teeth were randomly divided into 4 groups based on the chelating agents to be used to remove Ca(OH)2 from the root canals (n=8). The root canals were prepared with the ProTaper rotary system up to X5. The specimens were scanned using micro-CT after preparation. Calcium hydroxide paste was delivered into root canals using a syringe system (SURE-Paste) combined with a lentulo spiral. All teeth were scanned using micro-CT to determine the filling volume. After 7 days, Ca(OH)2 was removed from the root canals. EDTA was used with syringe irrigation for the first group while, EDTA, IP6, and NAC were used with sonic activation at other groups, respectively, to remove Ca(OH)2. Teeth were scanned using micro-CT to calculate the volume and the percentage of Ca(OH)2 remnants. Data were analyzed statistically by one-way ANOVA and Duncan's tests (α=0.05).

RESULTS: None of the chelating agents and irrigation techniques completely removed Ca(OH)2. The percentage of the remnant volume of the Ca(OH)2 was significantly different between the groups (p < 0.05). The EDTA with syringe irrigation group had higher Ca(OH)2 remnant volume values compared to other groups (p < 0.05). The use of the EDTA, IP6, and NAC with sonic activation did not significantly affect the percentage of remaining Ca(OH)2 (p > 0.05).

CONCLUSIONS: The calcium hydroxide removal efficiencies of all three chelating agents were similar. IP6 and NAC can be used as alternatives to EDTA for Ca(OH)2 removal from the root canals with sonic activation.},
}

@article {pmid41418387,
year = {2025},
author = {Zhao, XY and Yan, M and Zheng, L and Gou, CL and Huang, Q and Li, LG and Yu, XR and Lu, JY and Hu, C and Zhang, SH and Kong, C and Leng, F and Li, TF},
title = {Curcumin-mediated photodynamic action disturbs TOM70-depedent MIC60 import to damage mitonchondria against breast cancer.},
journal = {Journal of photochemistry and photobiology. B, Biology},
volume = {274},
number = {},
pages = {113339},
doi = {10.1016/j.jphotobiol.2025.113339},
pmid = {41418387},
issn = {1873-2682},
abstract = {The regulation of mitochondrial membrane proteins is of crucial significance for breast cancer therapy. TOM70, which located in mitochondria outer membrane, could import MIC family molecules to preserve mitochondrial homeostasis. However, there are few agents targeting TOM70. Therein, the effects of curcumin and it's mediated photodynamic therapy (PDT) on the TOM70 and mitochondrial function for breast cancer treatment were investigated. The 4 T1 and MDA-MB-231 cells were utilized as the breast cancer cells. The 4 T1 cell-bearing mice were constructed as the breast cancer animal model. The anti-cancer efficacy was validated using the CCK-8, Annexin-V/PI staining, colony formation. The associated molecules were detected by Western blots (WB), RT-qPCR, and Immunohistochemistry (IHC). The target was verified by molecular docking, CETSA, and DARTS. The mitochondrial proteins and DNA were extracted for the MIC60 and mtDNA damage detection. Curcumin treatment showed poor efficacy in the breast cancer model, as characterized by cell viability, apoptosis, proliferation of breast cancer cells, and the growth of tumor grafts in mice. However, curcumin-mediated PDT inhibited breast cancer in vitro and in vivo. Further exploration identified curcumin bond to TOM70, which is highly expressed in breast cancer, thereby activating it. But curcumin-induced PDT inactivated TOM70 through generated reactive oxygen species (ROS), which in turn interfered with the binding of MIC60 and its translocation into mitochondria. Curcumin-triggered PDT led to severe mitochondrial damage compared with the curcumin treatment, which could be blocked by the N-Acetylcysteine (NAC). Additional TOM70 rescue dampened curcumin PDT-mediated mitochondrial damage and anti-breast cancer efficacy. To summarize, the present research identifies curcumin-induced PDT inactivated TOM70, thereby attenuating MIC60 import, leading to mitochondrial damage against breast cancer. We propose a novel approach to tumor treatment through the regulation of mitochondrial membrane proteins using the phytomedicine-driven PDT.},
}

@article {pmid41415424,
year = {2025},
author = {Rukh, S and Meechan, DW and Roberts, A and Siggins, C and Erwin, ZD and Maynard, TM and LaMantia, AS},
title = {Distinct cellular and transcriptional mechanisms mediate an antioxidant therapeutic response in 22q11-deleted upper layer cortical projection neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.03.692138},
pmid = {41415424},
issn = {2692-8205},
abstract = {We characterized cellular and molecular mechanisms underlying the therapeutic response in vitro and in vivo to the antioxidant N-acetyl cysteine (NAC), which in the LgDel 22q11.2 Deletion Syndrome mouse model restores growth and connectivity of upper layer cortical projection neurons (L ayer 2/3 PNs) and improves cognitive performance. NAC treatment of primary cultured LgDel L 2/3 PNs does not restore these neurons to a wild type (WT) state. Rather than returning to the bimodal dendrite and axon size distribution seen in WT, LgDel L 2/3 PN dendrite and axon growth in vitro increases unimodally in response to NAC. In parallel, altered expression of 22q11-deleted genes and presumed downstream targets are unchanged. Instead, novel antioxidant defense and neuronal growth genes are differentially expressed: some generally NAC-regulated, others responsive only in the context of 22q11 deletion. Apparently, NAC ameliorates L 2/3 PN developmental pathology without restoring WT cell states or typical expression of mutant genes or their downstream targets. NAC also elicits differential expression of antioxidant defense genes in 22q11-deleted L 2/3 PNs-but not L 5/6 counterparts-in the developing postnatal LgDel mouse cortex, rather than modulating 22q11 genes or downstream targets. These NAC-dependent, L 2/3 PN-selective in vivo cellular and transcriptional changes differ substantially from those in primary culture. Thus, despite some in vitro and in vivo parallels, the NAC therapeutic response that diminishes oxidative stress-related L 2/3 PN circuit and behavioral pathology due to 22q11 deletion has a unique in vivo signature.},
}

@article {pmid41415037,
year = {2025},
author = {Qi, J and Yin, Z and Peng, Y and Zhang, F and Li, Y and Xia, X and Jia, X},
title = {Evaluation of antioxidant co-therapy for polymyxin B-associated nephrotoxicity and mortality: a real-World retrospective cohort study.},
journal = {Journal of pharmaceutical policy and practice},
volume = {18},
number = {1},
pages = {2568673},
pmid = {41415037},
issn = {2052-3211},
abstract = {BACKGROUND: Polymyxin B is increasingly used to treat infections caused by multidrug-resistant gram-negative bacteria; however, its widespread clinical use is hindered by the high incidence of nephrotoxicity. Antioxidants, such as vitamin C, N-acetylcysteine (NAC), and methionine, have demonstrated renoprotective effects in preclinical models, although clinical evidence remains limited. This study aimed to investigate the potential protective effects of these antioxidants against polymyxin B-associated acute kidney injury (AKI) in real-world clinical practice.

METHODS: This retrospective cohort study included adult in patients who received intravenous polymyxin B for ≥ 3 days between August 2018 and August 2020. The patients were classified into an antioxidant group (co-administered vitamin C, NAC, or methionine for ≥ 3 days) or a control group. Propensity score weighting was applied to balance the baseline covariates. The primary outcome was the incidence of polymyxin B-associated AKI and the secondary outcome was discharge mortality.

RESULTS: A total of 321 patients were included, with 77 and 244 patients in the antioxidant and control groups, respectively. After propensity score adjustment, there were no statistically significant differences in AKI incidence (26.9% vs. 19.2%, P = 0.352) or discharge mortality (7.7% vs. 15.4%, P = 0.220) between the groups. Subgroup analyses of individual antioxidants also showed no significant differences in AKI or mortality, except for a lower unadjusted mortality in the methionine group (0% vs. 13.9%, P = 0.042), which lost significance after adjustment.

CONCLUSION: This exploratory study did not provide conclusive evidence that vitamin C, NAC, or methionine reduced the risk of polymyxin B-associated AKI. The potential association between antioxidant use and reduced mortality warrants further investigation. Large-scale prospective studies are required to confirm the clinical utility of antioxidant cotherapy in patients receiving polymyxin B.},
}

@article {pmid41412528,
year = {2025},
author = {Wu, Z and Kuang, Z and Liang, L and Liu, J and Wang, G and Zou, F},
title = {TGF-β/LAMB3 axis drives ROS-dependent renal fibrosis under hypoxic conditions.},
journal = {Free radical biology & medicine},
volume = {244},
number = {},
pages = {395-409},
doi = {10.1016/j.freeradbiomed.2025.12.024},
pmid = {41412528},
issn = {1873-4596},
abstract = {Hypoxia is a well-established driver of renal fibrosis, but the underlying mechanisms remain unclear. In this study, we demonstrate that hypoxia-induced excessive reactive oxygen species (ROS) drive renal fibrosis, while the antioxidant N-acetylcysteine (NAC) ameliorates this pathological process. Hypoxia-induced ROS overproduction in renal tubular epithelial cells acts as the central regulator driving concurrent partial epithelial-mesenchymal transition (pEMT) and TGF-β secretion. Integrated ATAC-seq and RNA-seq analysis demonstrates that TGF-β treatment induces LAMB3 upregulation in fibroblasts through enhanced chromatin accessibility at its promoter region. Mouse model of hypoxic renal fibrosis shows marked upregulation of both TGF-β and LAMB3, implicating their involvement in fibrogenesis under hypoxic conditions. Kidney-targeted knockdown of LAMB3 significantly ameliorates hypoxia-induced renal fibrosis. TGF-β secreted by hypoxic renal tubular epithelial cells activates canonical Smad signaling in fibroblasts, which in turn upregulates LAMB3 to initiate PI3K/AKT-dependent myofibroblast differentiation. Pharmacological ROS scavenging by NAC potently disrupts this TGF-β/LAMB3 axis, improving kidney fibrosis under hypoxic conditions. Our findings reveal that TGF-β/LAMB3 axis drives ROS-dependent renal fibrosis under hypoxic conditions, identifying LAMB3 and ROS as potential therapeutic targets for fibrotic kidney diseases.},
}

@article {pmid41412471,
year = {2025},
author = {Chang, YC and Lin, WH and Ko, HH and Lo, YC and Chang, HS and Lin, HC and Chen, YF},
title = {Formononetin protects against oxaliplatin-induced peripheral neurotoxicity via Nrf2/HO-1 antioxidant pathway without impairing anticancer efficacy.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103368},
doi = {10.1016/j.neuro.2025.103368},
pmid = {41412471},
issn = {1872-9711},
abstract = {Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intolerable adverse effect of oxaliplatin and paclitaxel. The intolerance to CIPN symptoms often leads to poor compliance and treatment discontinuation, jeopardizing survival outcomes. However, no Food and Drug Administration (FDA)-approved interventions exist for preventing or treating CIPN. A major challenge has been that neuroprotective candidates often diminish the effectiveness of chemotherapy, limiting their translational development. Here, we aimed to identify neuroprotective agents that maintain anticancer activity. Using ND7/23 dorsal root ganglion neurons treated with oxaliplatin and paclitaxel, we screened our compound library and identified formononetin, a natural isoflavone, as a promising candidate. Formononetin significantly protected ND7/23 DRG neurons against oxaliplatin-induced neurotoxicity by reducing oxidative stress and apoptosis via activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and modulating protein expressions of pro-apoptotic B-cell lymphoma 2-associated X (Bax) and anti-apoptotic B-cell lymphoma 2 (BCL-2). Formononetin showed limited protection against paclitaxel-induced structural neurite damage. Importantly, unlike the ROS scavenger N-acetylcysteine (NAC), which decreased the anticancer effectiveness of both oxaliplatin and paclitaxel, formononetin maintained their anticancer effects in colorectal cancer HT29 cells and cervical cancer SiHa cells. Taken together, formononetin holds potential as a neuroprotectant to prevent oxaliplatin-induced neurotoxicity without compromising anticancer efficacy.},
}

@article {pmid41401723,
year = {2025},
author = {Lin, CH and Lane, HY},
title = {Sodium benzoate treatment linked to increased glutathione levels and improved positive and negative symptoms, global function, and quality of life in patients with clozapine-resistant schizophrenia: secondary analysis of a randomized clinical trial.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {103},
number = {},
pages = {112733},
doi = {10.1016/j.euroneuro.2025.11.010},
pmid = {41401723},
issn = {1873-7862},
abstract = {Oxidative stress is implicated in schizophrenia. Glutathione (GSH), a crucial endogenous antioxidant, is usually reduced in individuals with schizophrenia. GSH and its precursor, N-acetyl cysteine, have demonstrated potential as adjunctive treatment for schizophrenia; however, their effectiveness appears inconsistent, possibly because of their limited ability to penetrate the blood-brain barrier (BBB). Administration of sodium benzoate, capable of crossing BBB, enhanced GSH capacity and antipsychotic-like activity in animals. Further, adjunctive benzoate therapy improved clinical and functional outcomes in patients with schizophrenia, including clozapine-resistant schizophrenia (CRS). Whether sodium benzoate can also boost GSH to exert its therapeutic efficacy for schizophrenia deserves elucidation. This secondary analysis used data from a double-blind trial, in which 60 patients with CRS were randomized to receive addon treatment of sodium benzoate (n = 40) or placebo (n = 20) for 6 weeks. Clinical and functional assessments were conducted bi-weekly. Plasma levels of GSH were assayed at baseline and endpoint. As a result, six-week treatment of sodium benzoate was linked to increased GSH levels than placebo. Among the 40 benzoate receivers, the changes in GSH levels were correlated with the improvements in positive symptoms, negative symptoms, quality of life, and global function. In comparison, among placebo recipients, GSH changes were not associated with any changes in clinical or functional variables. The findings suggest that benzoate treatment may be related with elevation in GSH levels in CRS patients and improvement in functional outcomes as well as positive and negative symptoms. Longer-term studies in other populations are necessary in the future.},
}

@article {pmid41399893,
year = {2025},
author = {Aly, S and Ali, M and Sayed, A and Hamadneh, BN and Yousef, M and Khalil, M and Rizk, A and El-Messery, TM and Kamel, RM and Mohammed, BM and Abdelkarim, DO and Younis, M},
title = {Enhanced color and antioxidant properties of sunflower protein concentrates extracted under alkaline conditions using anti-greening reagents.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70389},
pmid = {41399893},
issn = {1097-0010},
abstract = {BACKGROUND: Sunflower protein concentrates (SPCs) are valuable plant-derived ingredients. However, their application is limited by greening during alkaline extraction, caused by chlorogenic acid (CGA) oxidation. This study systematically developed and characterized SPCs extracted under alkaline conditions with two anti-greening reagents, N-acetylcysteine (NAC) and ascorbic acid (ASC), each applied at 12 mg g[-1] meal. The findings provide novel insights into how these reagents modulate the amino acid composition, structural conformation, and antioxidant potential, and improve color in SPCs obtained from completely hulled (SPC-CH) and unhulled (SPC-UH) sunflower seeds.

RESULTS: The addition of ASC during extraction increased the total phenolic content to 130.51 g kg[-1] CGA in SPC-CH and 119.08 g kg[-1] CGA in SPC-UH. The antioxidant capacity, measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, reached 1084.38 mmol kg[-1] Trolox equivalent (TE) in ASC-treated SPC-CH, compared with 891.08 and 937.58 mmol kg[-1] TE in the distilled water (DW) and NAC treatments. Both ASC and NAC inhibited greening, producing SPCs with a more acceptable yellowish color. Structural analysis showed only minor alterations in protein secondary structure across all extraction methods, indicating that protein integrity was maintained. Thermal stability and amino acid composition evaluations further supported the suitability of these SPCs for food applications.

CONCLUSION: The use of ASC and NAC as anti-greening reagents improved the color and antioxidant potential of sunflower protein concentrates while maintaining structural stability. This approach enables the sustainable production of high-quality SPCs, suitable for functional food formulations. © 2025 Society of Chemical Industry.},
}

@article {pmid41389180,
year = {2025},
author = {Naik, S and Boopathy, R and Das, T and Mishra, M},
title = {Unravelling the Mechanism of N-Acetylcysteine in Alleviating Smoke-Induced Hypoxia-Driven Ocular Defects in Drosophila melanogaster.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {291},
pmid = {41389180},
issn = {1559-1182},
mesh = {Animals ; *Drosophila melanogaster/drug effects ; *Acetylcysteine/pharmacology/therapeutic use ; *Hypoxia/complications/drug therapy ; *Smoke/adverse effects ; *Eye/drug effects/pathology ; Drosophila Proteins/metabolism/genetics ; Particulate Matter ; },
abstract = {Smoke that includes particulate matter (PM), carbon monoxide (CO), sulfur dioxide (SO2), and nitrogen dioxide (NO2) has a substantial negative impact on human health. PM, which can vary from tiny dust to coarse particles, enters the respiratory system and reduces the amount of oxygen taken in by the lungs, leading to hypoxia. Drosophila was employed as the model organism to study the effects of smoke-induced hypoxia on eye development and to evaluate N-Acetylcysteine (NAC) as a potential protective agent. In this study, Drosophila eggs were exposed to 0.1 g of coconut husk smoke . Furthermore, different size fractions of particulate matter (PM) (10, 2.5, and 1.0 µm) and concentrations of different gases were monitored to correlate the inference of PM and gases on the tracheal terminal tube. To determine whether CO and PM (10, 2.5, and 1 µm) contribute to hypoxia, quantitative PCR analysis of sima and tango was performed, revealing a significant upregulation of sima expression. Impairment of the tracheal terminal branches results in reduced oxygen delivery to tissues, which affects the development of photoreceptor cells. Biochemical estimation disclosed the presence of reactive oxygen species, which led to cellular injury and DNA damage. The marked downregulation of NinaE (Rh1), Rh3, and Rh6 causes internal defect in the eye. Treatment with NAC restored all these abnormalities to normal levels. This research provides insight into how smoke-induced hypoxia disrupts eye development, while NAC shows potential as an effective therapeutic agent in counteracting its harmful effects.},
}

Animals
*Drosophila melanogaster/drug effects
*Acetylcysteine/pharmacology/therapeutic use
*Hypoxia/complications/drug therapy
*Smoke/adverse effects
*Eye/drug effects/pathology
Drosophila Proteins/metabolism/genetics
Particulate Matter

@article {pmid41385627,
year = {2025},
author = {Li, Y and Yu, T and Wang, Z and Wang, J and Tang, Y and Zhang, Y and Li, H and Zhou, H and Yin, P and Yao, S},
title = {A fluorescent probe for concurrent detection of cysteine, homocysteine, and superoxide anion.},
journal = {Science advances},
volume = {11},
number = {50},
pages = {eadx6659},
pmid = {41385627},
issn = {2375-2548},
mesh = {*Cysteine/analysis/metabolism ; *Superoxides/analysis/metabolism ; *Homocysteine/analysis/metabolism ; Animals ; *Fluorescent Dyes/chemistry ; Zebrafish ; Humans ; Oxidation-Reduction ; Oxidative Stress ; Mice ; },
abstract = {Redox imbalance is a key factor in the pathogenesis of diseases such as epilepsy and liver injury. Superoxide anion (O2[•-]), cysteine (Cys), and homocysteine (Hcy) play central roles in maintaining redox homeostasis, and their dysregulation drives oxidative stress and disease progression. Here, we report a multifunctional fluorescent probe, BPC, capable of simultaneously and selectively detecting Cys, Hcy, and O2[•-] in complex biological environments. BPC shows high sensitivity, selectivity, and biocompatibility, enabling real-time visualization of redox fluctuations in living cells and zebrafish with minimal cytotoxicity. In pentylenetetrazole (PTZ)- and acetaminophen (APAP)-induced models of epilepsy and liver injury, BPC revealed notable alterations in Cys, Hcy, and O2[•-] levels, providing mechanistic insights into redox dysregulation. Moreover, BPC successfully tracked redox restoration following N-acetylcysteine (NAC) treatment. These findings establish BPC as a versatile tool for redox biology and highlight its promise for diagnostic and therapeutic applications.},
}

*Cysteine/analysis/metabolism
*Superoxides/analysis/metabolism
*Homocysteine/analysis/metabolism
Animals
*Fluorescent Dyes/chemistry
Zebrafish
Humans
Oxidation-Reduction
Oxidative Stress
Mice

@article {pmid41383104,
year = {2025},
author = {Kim, HB and Kim, YJ and Lim, HM and Suh, SW and Lee, JH and Lee, CJ and Woo, RS},
title = {N-acetylcysteine Restores Impaired Dentate Gyrus Neurogenesis in a Neonatal Maternal Separation Rat Model.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en25041},
pmid = {41383104},
issn = {1226-2560},
abstract = {Early-life stress (ELS) is a major contributor to neurodevelopmental vulnerability, particularly within the dentate gyrus (DG), where oxidative burden and microglial activation disrupt adult neurogenesis. Here, we examined whether N-acetylcysteine (NAC), a cysteine prodrug and glutathione precursor, could counteract impaired neurogenesis induced by neonatal maternal separation (NMS). Adolescent NAC administration restored the number of Ki67[+] proliferating progenitors and DCX[+] immature neurons in the DG of NMS rats, accompanied by reduced reactive oxygen species, suppressed iNOS induction, and attenuated microglial activation. NAC also normalized EAAC1 expression, indicating enhanced neuronal antioxidant capacity. Notably, NAC rescued diminished neurogenesis in EAAC1 knockout mice, demonstrating its efficacy under both stress-induced and transporter-deficient redox imbalance. These findings identify NAC as a potent modulator of hippocampal neuroplasticity, acting through the restoration of redox and inflammatory homeostasis, and support its potential as an early therapeutic strategy to mitigate long-lasting neurodevelopmental consequences of ELS.},
}

@article {pmid41381010,
year = {2025},
author = {Xu, R and Liang, XW and Cai, QH and Cai, YW and Sun, N and Li, YP and Shi, ZJ and Hu, B and He, XH and Zha, QB and Ouyang, DY},
title = {Hyperthermia induces reductive stress in murine macrophages.},
journal = {Biochimica et biophysica acta. Molecular basis of disease},
volume = {},
number = {},
pages = {168133},
doi = {10.1016/j.bbadis.2025.168133},
pmid = {41381010},
issn = {1879-260X},
abstract = {Hyperthermia induces heat stress (HS) and injuries in various human organs, or even leads to mortality, yet the underlying mechanism is incompletely uncovered. Our study revealed that HS in macrophages induced concurrent activation of pyroptotic, apoptotic, and necroptotic pathways, and the formation of PANoptosome-like complexes. However, these processes proceeded independently of ROS, as the ROS scavengers N-acetyl cysteine and mito-TEMPO failed to prevent the cell death (PANoptosis) despite effectively suppressing oxidative stress. Instead, HS caused reductive stress marked by NADPH accumulation and thioredoxin (Trx) system dysfunction. Trx1 aggregation impaired redox regulation, leading to aberrant disulfide bonding in mitochondrial proteins (e.g., Drp1, Bcl-2). The Trx reductase exogenous substrate DTNB partially rescued cell viability by restoring redox balance, confirming Trx failure as a key driver of cytotoxicity. Notably, such reductive stress was accompanied by DNA damage and mitochondrial injury during HS. Pharmacologic intervention revealed that pan-caspase inhibition by IDN-6556 abrogated the reductive stress and its consequences (ROS production, DNA damage, and mitochondrial injury), and suppressed the pyroptotic/apoptotic signaling and lytic cell death. However, the caspase inhibition alone triggered compensatory receptor-interaction protein 3 (RIPK3) activation, necessitating dual inhibition with GSK'872 (RIPK3 inhibitor) to fully block PANoptotic cell death. In vivo validation showed protection of the IDN-6556/GSK'872 combination against HS-induced injury on the intestines through reduced DNA damage and PANoptosis suppression. Our study reveals that reductive stress-mediated Trx dysfunction, not oxidative stress, underlies HS-induced PANoptosis. Dual targeting of caspases and RIPK3 provides a novel therapeutic avenue against heat shock-associated diseases.},
}

@article {pmid41380831,
year = {2025},
author = {Etemadi, Y and Akakpo, JY and Fields, TA and Ramachandran, A and Jaeschke, H},
title = {Differential Effects on Acetaminophen-induced Nephrotoxicity and Liver Injury Following Modulation of Glutathione Resynthesis.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {115896},
doi = {10.1016/j.fct.2025.115896},
pmid = {41380831},
issn = {1873-6351},
abstract = {Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), with acute kidney injury (AKI) increasing morbidity and mortality. N-acetylcysteine (NAC) prevents APAP-induced liver damage, but not AKI, highlighting the need to address differential inter-organ responses to APAP toxicity. We investigated the relationship between hepatic glutathione (GSH) depletion, liver injury, and subsequent kidney damage following APAP overdose. Male C57BL/6J mice received either moderate (300 mg/kg) or severe (600 mg/kg) overdoses of APAP, with or without buthionine sulfoximine (BSO, 50 mg/kg) to deplete GSH, or NAC (500 mg/kg) to replenish GSH. A moderate APAP overdose elevated liver injury markers (alanine aminotransferase, ALT) without significantly affecting blood urea nitrogen (BUN) levels, though kidney injury molecule-1 (KIM-1) expression increased. A severe overdose significantly increased ALT activities, and BUN and creatine levels, together with marked upregulation of renal KIM-1 and histological evidence of cortical damage. BSO exacerbated APAP-induced kidney but not liver injury, where GSH remained depleted at 24 hours. In contrast, NAC protected against APAP hepatotoxicity but not AKI. Thus, these findings demonstrate critical organ-specific responses to APAP toxicity and underscore the need for targeted therapeutic strategies specifically addressing APAP-induced kidney injury.},
}

@article {pmid41378547,
year = {2024},
author = {Kotze, C and Swanepoel, J and Kruger, EC and Decloedt, E},
title = {The management and clinical outcome of paracetamol poisoning in South African adults: A single-centre retrospective review.},
journal = {South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde},
volume = {114},
number = {12},
pages = {e1986},
doi = {10.7196/SAMJ.2024.v114i12.1986},
pmid = {41378547},
issn = {2078-5135},
mesh = {Humans ; *Acetaminophen/poisoning ; Female ; Retrospective Studies ; South Africa/epidemiology ; Adult ; Male ; *Chemical and Drug Induced Liver Injury/mortality/etiology/therapy/epidemiology ; *Drug Overdose/mortality ; *Analgesics, Non-Narcotic/poisoning ; Young Adult ; Acetylcysteine/therapeutic use ; Antidotes/therapeutic use ; Treatment Outcome ; },
abstract = {BACKGROUND: Paracetamol is a commonly prescribed drug, and often implicated in pharmaceutical overdoses. Paracetamol-induced hepatotoxicity is a common cause of acute liver failure in many high-income countries, but little is known about the factors associated with severity of liver injury and poor clinical outcomes among those treated in sub-Saharan African settings.

OBJECTIVE: To describe the characteristics of patients presenting with paracetamol poisoning, and to identify factors associated with severity of liver injury and poor outcomes in adults with biochemical evidence of paracetamol-induced liver damage treated at a South African (SA) tertiary hospital.

METHODS: A retrospective medical record review was conducted of all adult patients (≥18 years old) admitted between August 2013 and August 2018 to a tertiary referral centre in Cape Town, SA, with paracetamol poisoning and biochemical evidence of liver impairment. Demographics, clinical and laboratory data were obtained. Management practices and clinical outcomes were assessed.

RESULTS: The records of 91 patients were included in the analysis. The median (interquartile range (IQR)) age was 29 (23 - 39) years, and 63% were female. The majority of paracetamol poisonings followed an intentional overdose (91%). Acute single ingestions were the most common (81%) type of toxic ingestion, compared with staggered overdose and repeated supratherapeutic ingestion, and the median (IQR) number of tablets ingested was 22 (20 - 39). Two-thirds of patients developed mild liver injury and 12% developed acute kidney injury. The overall mortality rate was 12%. Mortality was lower in those who received intravenous N-acetylcysteine (NAC) before serum paracetamol concentrations were known compared with those who only received NAC after concentrations were known (8.8% v. 36%, p=0.03). A significant proportion of deaths occurred in those with accidental overdose compared with those with intentional overdosing (57% v. 7.2%; p=0.004). People living with HIV (p=0.04), a history of chronic alcoholism (p=0.04), chronic liver disease (p=0.01) and severity of acute kidney stage (p<0.001) were all associated with increased mortality.

CONCLUSION: A high case fatality rate was observed in the studied population. Early identification of at-risk individuals and prompt initiation of NAC can reduce poor outcomes. Larger multicentre studies are needed to identify independent predictors of paracetamol-induced hepatoxicity and mortality in Africa.},
}

Humans
*Acetaminophen/poisoning
Female
Retrospective Studies
South Africa/epidemiology
Adult
Male
*Chemical and Drug Induced Liver Injury/mortality/etiology/therapy/epidemiology
*Drug Overdose/mortality
*Analgesics, Non-Narcotic/poisoning
Young Adult
Acetylcysteine/therapeutic use
Antidotes/therapeutic use
Treatment Outcome

@article {pmid41377542,
year = {2025},
author = {Thoppil, J and Farrar, JD and Sharma, D and Kirby, S and Mobley, A and Courtney, DM},
title = {Reactive oxygen species elevations in human immune cell subsets during sepsis are mitigated by norepinephrine and N-acetylcysteine.},
journal = {World journal of critical care medicine},
volume = {14},
number = {4},
pages = {108638},
pmid = {41377542},
issn = {2220-3141},
abstract = {BACKGROUND: Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Peripheral blood mononuclear cells (PBMCs) are critical mediators of the immune response and may exhibit redox imbalance during sepsis. Reactive oxygen species (ROS) are known to influence immune cell signaling, and excessive ROS accumulation may contribute to sepsis-associated immune alterations.

AIM: To assess intracellular ROS levels in PBMC subsets from septic patients and determine whether norepinephrine (NE) or N-acetylcysteine (NAC) modulate ROS levels following inflammatory stimulation in vitro.

METHODS: PBMCs were isolated from Department of Emergency patients meeting SEP-1/SEP-2 sepsis criteria and from healthy controls without signs of infection. Intracellular ROS levels were measured using a total ROS detection assay and analyzed by flow cytometry. PBMCs were also stimulated in vitro with lipopolysaccharide (LPS) or hydrogen peroxide (H2O2), with or without co-treatment with NE or NAC.

RESULTS: ROS levels were significantly elevated in CD3+ and CD14+ cells from septic patients compared to controls. In vitro stimulation of control PBMCs with LPS or H2O2 increased ROS in CD3+ and CD14+ cells, which was attenuated by co-treatment with NE or NAC.

CONCLUSION: ROS levels are elevated in specific PBMC subsets in sepsis, particularly CD3+ T cells and CD14+ monocytes. NE and NAC reduced ROS accumulation in vitro, supporting their potential role as redox modulators. These findings warrant further mechanistic investigation into immune redox regulation in sepsis.},
}

@article {pmid41373660,
year = {2025},
author = {Izquierdo-Bermejo, S and Chioua, M and Hadjipavlou-Litina, D and López-Muñoz, F and Marco-Contelles, J and Oset-Gasque, MJ},
title = {Neuroprotective and Antioxidant Properties of Different Novel Steroid-Derived Nitrones and Oximes on Cerebral Ischemia In Vitro.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
doi = {10.3390/ijms262311506},
pmid = {41373660},
issn = {1422-0067},
support = {UCJC-NENs, UCJC-CHONICEN,UCJC- HDACi-ICTUS//Universidad Camilo José Cela (UCJC)/ ; SAF2015-65586-R//Spanish Ministry of Economy and Competitiveness/ ; },
mesh = {*Oximes/pharmacology/chemistry ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Nitrogen Oxides/pharmacology/chemistry ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; *Brain Ischemia/drug therapy/metabolism/pathology ; Animals ; *Steroids/chemistry/pharmacology ; Cell Survival/drug effects ; Humans ; Rats ; },
abstract = {Despite the substantial global impact of ischemic stroke, current therapeutic options remain limited and only partially effective. To advance neuroprotective strategies that could improve the safety and efficacy of existing treatments while preserving brain tissue, we synthesized and evaluated seven new nitrones (MC3, MC5, MC7) and oximes (MC1, MC2, MC4, MC6) derived from different neuroactive steroids-ethisterone (MC1-3), mifepristone (MC4-5) and stanolone (MC6-7)-in an in vitro model of cerebral ischemia. Overall, these derivatives exhibited neuroprotective and antioxidant effects superior to those of the reference compounds cholesteronitrone ChN2, α-tert-butyl nitrone (PBN) and N-acetylcysteine (NAC). Notably, nitrones showed greater neuroprotective, anti-necrotic, and antioxidant potency than their corresponding oximes, regardless of the degree of molecular conjugation. Among them, the stanolone-derived nitrone MC7, which lacks conjugated double bonds, displayed the most balanced and robust profile, consistently enhancing cell viability, reducing necrotic cell death, and suppressing superoxide anion production. Consequently, MC7 has been selected as a promising lead compound for further in vivo studies of cerebral ischemia.},
}

*Oximes/pharmacology/chemistry
*Neuroprotective Agents/pharmacology/chemistry/chemical synthesis
*Nitrogen Oxides/pharmacology/chemistry
*Antioxidants/pharmacology/chemistry/chemical synthesis
*Brain Ischemia/drug therapy/metabolism/pathology
Animals
*Steroids/chemistry/pharmacology
Cell Survival/drug effects
Humans
Rats

@article {pmid41373526,
year = {2025},
author = {Pachhapure, S and Shin, YM and Kim, DG and Choi, DR and Yun, JI and Kim, JH and Jang, BC},
title = {The Mitigating Effect and Mechanism of Polydeoxyribonucleotide Against Zoledronic Acid-Induced Growth Suppression of Human Gingival Fibroblasts.},
journal = {International journal of molecular sciences},
volume = {26},
number = {23},
pages = {},
doi = {10.3390/ijms262311367},
pmid = {41373526},
issn = {1422-0067},
support = {B20220018//This work was supported by a grant (No. B20220018) from Zerone Cellvane Inc./ ; },
mesh = {Humans ; *Zoledronic Acid/pharmacology/adverse effects ; *Gingiva/cytology/drug effects/metabolism ; *Polydeoxyribonucleotides/pharmacology ; *Fibroblasts/drug effects/metabolism/cytology ; Cell Proliferation/drug effects ; STAT3 Transcription Factor/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/metabolism ; },
abstract = {Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is widely used to treat osteoporosis and bone metastases. However, its clinical application is limited by adverse effects, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is associated with cytotoxicity in oral mucosal cells. Polydeoxyribonucleotide (PDRN), a salmon sperm-derived DNA polymer with regenerative and anti-inflammatory properties, has shown therapeutic potential in tissue repair; however, its ability to mitigate ZA-induced cytotoxicity remains poorly understood. Here, we investigated the molecular mechanisms of ZA-induced toxicity in HGF-1 cells, a human gingival fibroblast line, and evaluated the protective effects of PDRN. ZA treatment (50 µM, 48 h) significantly inhibited HGF-1 cell growth, accompanied by reduced phosphorylation of protein kinase B (PKB) and signal transducer and activator of transcription 3 (STAT-3), along with increased phosphorylation of TANK-binding kinase 1 (TBK1). TBK1 silencing restored cell growth under ZA exposure, whereas silencing PKB or STAT-3 further suppressed cell growth even without ZA. Co-treatment with PDRN (100 µg/mL) effectively prevented and reversed ZA-induced HGF-1 cytotoxicity. Mechanistically, PDRN inhibited ZA-induced TBK1 phosphorylation and partially restored PKB phosphorylation, though it did not reverse the reduction in p-STAT-3. Additionally, ZA significantly elevated intracellular reactive oxygen species (ROS) levels at 8 h, which were attenuated by PDRN. The antioxidant N-acetylcysteine (NAC) similarly reduced ZA-induced ROS and p-TBK1 levels and improved cell growth, although it had limited effects on p-PKB at 8 h. Importantly, delayed PDRN treatment following ZA exposure reversed ZA-induced cell growth inhibition and TBK1 activation in a dose- and time-dependent manner. In summary, these findings demonstrate that ZA suppresses HGF-1 cell growth through ROS production, TBK1 activation, and inhibition of PKB and STAT-3, whereas PDRN counteracts these effects primarily by suppressing TBK1 activation and oxidative stress.},
}

Humans
*Zoledronic Acid/pharmacology/adverse effects
*Gingiva/cytology/drug effects/metabolism
*Polydeoxyribonucleotides/pharmacology
*Fibroblasts/drug effects/metabolism/cytology
Cell Proliferation/drug effects
STAT3 Transcription Factor/metabolism
Reactive Oxygen Species/metabolism
Cell Line
Phosphorylation/drug effects
Protein Serine-Threonine Kinases/metabolism

@article {pmid41371424,
year = {2025},
author = {Liu, W and Liu, Y and Shi, J and Li, J and Li, G and Quan, J and Zhao, W},
title = {Prepuberty exposure to polystyrene nanoplastics induces cardiac inflammation through calcium overload-mediated ROS/JAK1/STAT3 signaling cascade.},
journal = {Free radical biology & medicine},
volume = {244},
number = {},
pages = {133-146},
doi = {10.1016/j.freeradbiomed.2025.12.006},
pmid = {41371424},
issn = {1873-4596},
abstract = {Polystyrene nanoparticles (PS-NPs) pose a significant threat to human health. In the present study, we aimed to investigate the toxicological effects of low-dose of PS-NPs on cardiac development and function following prepubertal exposure. Postpartum dams and their offspring were exposed to PS-NPs at concentrations of 0, 50 mg/L, and 100 mg/L via their daily drinking water, commencing from gestational day 1 and continuing until postnatal day (PND) 35. The results demonstrated that PS-NPs induced cardiac developmental toxicity in offspring. Proteomic analysis indicated that PS-NP exposure led to differentially expressed proteins, which were mainly enriched in JAK/STAT3 signaling pathway, inflammatory response pathway and antioxidant response signaling pathway. We subsequently found that exposure to PS-NPs in HL-1 cells increased the levels of reactive oxygen species (ROS), IL-6, IL-17, and TNF-α, as well as upregulated the expression of pJAK1 and pSTAT3. Treatment of HL-1 cells with N-Acetylcysteine (NAC) normalized the activity of the JAK1/STAT3 pathway and the levels of inflammatory cytokines. Furthermore, either inhibition of JAK1 with upadacitinib or knockdown of STAT3 in PS-NP-exposed HL-1 cells led to proinflammatory cytokine levels comparable to those in control cells. Given the well-established link between oxidative stress and mitochondrial calcium dysregulation, we demonstrated that PS-NP exposure impaired mitochondrial function by promoting calcium influx, which is mediated by the increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). This process facilitated calcium transfer through the IP3R3-GRP75-VDAC1 complex. Notably, pharmacological inhibition of calcium flux attenuated PS-NP-induced mitochondrial dysfunction, oxidative stress, and inflammatory responses in HL-1 cardiomyocytes. Collectively, our findings indicate that prepubertal PS-NP exposure triggers cardiac inflammation, which is likely mediated by MAM-dependent mitochondrial calcium overload and subsequent activation of the ROS/JAK1/STAT3 signaling axis.},
}

@article {pmid41360758,
year = {2025},
author = {Ma, X and Si, F and Ma, J and Feng, C and Wang, Y and Wang, L and Yu, J},
title = {Endoplasmic Reticulum Stress: A Novel Target for the Prevention and Treatment of Hypertension and Its Related Diseases.},
journal = {Journal of cellular and molecular medicine},
volume = {29},
number = {23},
pages = {e70977},
pmid = {41360758},
issn = {1582-4934},
support = {81960086//National Natural Science Foundation of China/ ; 82160089//National Natural Science Foundation of China/ ; 82460086//National Natural Science Foundation of China/ ; CY2021-MS-A13//Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital/ ; YJS-BD-24//Special Fund Project for Doctoral Training of the Lanzhou University Second Hospital/ ; PR0124002//International science and technology cooperation base/ ; },
mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Hypertension/prevention & control/drug therapy/metabolism/pathology ; Animals ; Oxidative Stress/drug effects ; Taurochenodeoxycholic Acid/therapeutic use/pharmacology ; Renin-Angiotensin System/drug effects ; Antihypertensive Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Molecular Targeted Therapy ; Phenylbutyrates/therapeutic use/pharmacology ; },
abstract = {Endoplasmic reticulum stress (ERS) emerges as a critical pathophysiological nexus in hypertension and related cardiovascular diseases. Chronic ERS activation via the IRE1α-XBP1, ATF6, and PERK pathways drives vascular endothelial dysfunction (reduced NO bioavailability, increased ET-1), renin-angiotensin system (RAS) hyperactivation, sympathetic overactivation, and vascular smooth muscle cell (VSMC) maladaptive proliferation/apoptosis, collectively promoting hypertension progression and end-organ damage. Pharmacological targeting of ERS demonstrates therapeutic promise: chemical chaperones 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA) stabilise proteostasis, reduce oxidative stress, and inhibit apoptosis; antioxidants N-acetylcysteine (NAC) and melatonin attenuate ERS-oxidative stress crosstalk. Notably, conventional antihypertensives-ACE inhibitors and angiotensin receptor blockers (ARBs)-exert ancillary benefits by suppressing ERS beyond their primary RAS blockade. Preclinical evidence supports the efficacy of these strategies in reversing hypertensive pathophysiology. Future research must prioritise isoform-selective ERS modulator development, validation in human trials, biomarker discovery, and elucidating ERS roles in therapy-induced hypertension. Targeting ERS represents a transformative mechanotherapeutic paradigm for precision hypertension management.},
}

Humans
*Endoplasmic Reticulum Stress/drug effects
*Hypertension/prevention & control/drug therapy/metabolism/pathology
Animals
Oxidative Stress/drug effects
Taurochenodeoxycholic Acid/therapeutic use/pharmacology
Renin-Angiotensin System/drug effects
Antihypertensive Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Molecular Targeted Therapy
Phenylbutyrates/therapeutic use/pharmacology

@article {pmid41360103,
year = {2025},
author = {Yang, CW and Chen, CY and Yen, CH and Shu, CW and Lee, HY and Chang, HW},
title = {Threo-2,3-bis-(4-hydroxy-3-methoxyphenyl)-3-methoxypropanol (THMP) Inhibits Bladder Cancer Cell Proliferation via Oxidative Stress-dependent Apoptosis and DNA Damage.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2752-9897},
pmid = {41360103},
issn = {1439-0221},
support = {KMUH-111-1R55//Kaohsiung Medical University Hospital/ ; KMUH-112-2R57//Kaohsiung Medical University Hospital/ ; KMUH-113-3R49//Kaohsiung Medical University Hospital/ ; MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology/ ; NSTC 113-2324-B-037-027//National Science and Technology Council/ ; TB114009//Kaohsiung Medical University/ ; TC114A04//Kaohsiung Medical University/ ; NSYSU-KMU-114-P15//National Sun Yat-sen University-KMU Joint Research Project/ ; KMU-TC114A04//Kaohsiung Medical University Research Center/ ; },
abstract = {Many lignans exhibit antiproliferative effects against cancer cells, but it is rarely reported for threo-2,3-bis-(4-hydroxy-3-methoxyphenyl)-3-methoxypropanol (THMP), an edible red-pepper-derived lignan. This study evaluates the antiproliferative effects and mechanism of THMP against bladder cancer cells (BFTC905 and T24) regarding ATP content and flow cytometry assays in parallel with the presence and absence of N-acetylcysteine (NAC), an oxidative stress inhibitor. THMP suppressed bladder cancer cell viability in the ATP assay, which was reverted by NAC. Regarding flow cytometry, THMP triggered subG1 arrest and enhanced annexin V-affinity intensity. This apoptotic response was further supported by the finding that THMP upregulated the activation of caspases 3, 8, and 9, which is apoptotic signaling. Moreover, oxidative stress was induced by THMP regarding the upregulation of reactive oxygen species (ROS) and mitochondrial superoxide and the exhaustion of glutathione and mitochondrial membrane potential. Regarding γH2AX and 8-hydroxy-2-deoxyguanosine detection, THMP was confirmed to have DNA damage ability. These mechanisms were alleviated by NAC. Overall, THMP is the first report demonstrating the antiproliferative effect against bladder cancer cells and clarifying its oxidative stress-dependent mechanisms.},
}

@article {pmid41358602,
year = {2025},
author = {Wang, H and Wang, H and Yang, Y and Wang, T and Wang, C and Wu, D and Zheng, C and Wei, W},
title = {Berberine Suppresses Pathogenic Fungus Aspergillus fumigatus Hyphal Growth via Mitochondrial Fragmentation-Induced ROS Elevation and Hog1-MAPK Activation.},
journal = {ACS infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsinfecdis.5c00749},
pmid = {41358602},
issn = {2373-8227},
abstract = {Berberine (BER), a natural isoquinoline alkaloid, exhibits broad-spectrum antifungal activity, yet its mechanism against Aspergillus fumigatus─a leading cause of invasive fungal infections─remains poorly understood. Here, we aim to unveil the mechanism of BER against the pathogenicity of A. fumigatus through mitochondrial dynamics and related pathways. In vitro assays revealed that berberine treatment triggered mitochondrial fragmentation, resulting in reactive oxygen species (ROS) overaccumulation. Subsequent proteomic analyses identified Hog1-MAPK as the central signaling hub activated by ROS stress. Upon activation, Hog1 localizes to the nucleus. ROS scavenging (N-acetylcysteine (NAC) treatment) abolished BER's antifungal effects, confirming the ROS-Hog1-cell cycle axis. Crucially, in a murine invasive aspergillosis model, BER reduced the fungal burden in lungs and improved survival rates. Thus, we demonstrate that berberine suppresses A. fumigatus growth by disrupting mitochondrial dynamics, elevating reactive ROS, and activating the Hog1-MAPK signaling cascade, ultimately inducing cell cycle arrest. Our findings unveil a previously unrecognized mechanism linking mitochondrial morphology dysregulation to cell cycle control in fungi and establish BER as a promising therapeutic agent targeting mitochondrial-ROS-Hog1 signaling in A. fumigatus infections.},
}

@article {pmid41353446,
year = {2025},
author = {Kusuma, B and Rawat, S and Saha, O and Nimesh, S and Sadhu, S and Awasthi, A and Maiti, TK and Banerjee, A},
title = {Depletion of myeloid cells in AG129 mice reduces the infection-mediated oxidative stress and restrains dengue virus-induced thymic atrophy.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-025-02572-7},
pmid = {41353446},
issn = {1478-811X},
support = {CRG/2023/003638//Science and Engineering Research Board/ ; },
abstract = {BACKGROUND: Infection-associated thymic atrophy is common and results in T-cell imbalance and immune dysfunction. Severe dengue, caused by infection with the dengue virus (DV), is associated with perturbation of T cell functions. However, it is unclear whether perturbation of T cell functions is linked to changes in thymic function during dengue infection.

METHODS: Herein, we employed a dengue virus serotype 2 (DV-2)-infected mouse model and Neonatal Thymic Organ Culture (NTOC) to study the impact of DV-2 infection on thymic function. Further, the contribution of infiltrating immune cells, especially myeloid cells, and reactive oxygen species (ROS) in the thymus on DV-2-induced thymic atrophy was studied by depleting Gr-1 + myeloid cells and quenching ROS in mice.

RESULTS: We have demonstrated that DV-2 infection caused a massive thymic atrophy, dominated by a loss of CD4[+] CD8[+] double-positive (DP) thymocytes, reduction in naïve T cells in blood and spleen, a significant increase in the infiltration of myeloid cells, and a reactive oxygen species (ROS) burst in the thymus. Using Neonatal Thymic Organ Culture (NTOC), we confirmed that DV-2 infection alone cannot induce thymic atrophy. Further, we documented that depletion of Gr-1 + myeloid cells, or quenching of ROS using N-acetylcysteine (NAC) during DV-2 infection, partially protected thymic architecture. This protection of thymus function is also reflected in the thymic interstitial fluid proteome profile, where myeloid cells depletion or NAC treatment in DV-2-infected mice confirmed the reversal of protein expression associated with oxidative stress and neutrophil degranulation pathways within the thymus. Further, managing oxidative stress also influenced cytokine production by T cells in the spleen of infected mice.

CONCLUSIONS: Thus, our study confirms that thymic atrophy does not depend on viremia level but on the interaction between immune cells and the virus, highlighting the contribution of infiltrating myeloid cells and, thus, ROS in DV-2-associated thymic atrophy.},
}

@article {pmid41352626,
year = {2025},
author = {Chen, X and Wang, S and Ding, B and Nie, Y and Liu, F and Zhang, X and Yu, B and Li, X and Dou, J and Sun, W and Zhou, X},
title = {Dibutyl Phthalate (DBP) Induces Cervical Injury and Promotes Malignant Transformation of Cervical Epithelial Cells.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {115885},
doi = {10.1016/j.fct.2025.115885},
pmid = {41352626},
issn = {1873-6351},
abstract = {Dibutyl phthalate (DBP), a widespread phthalate with reproductive toxicity and potential carcinogenicity, its cervical effects remain unclear. This study explored DBP's cervical toxicity and mechanisms via epidemiological analysis, network toxicology, and in vivo/in vitro models. Urinary 6 phthalate metabolites in 104 cervical cancer (CC) patients and 104 controls (detected by UPLC-MS/MS) showed elevated levels of MBP, MEHP, MEOHP, MEHHP, MECPP, and ΣDEHP in CC patients; MBP had the strongest CC risk association (adjusted OR=2.54, P < 0.001). Network toxicology identified 9 core targets of DBP (e.g., CASP3, MAPK8/14, ESR1) and key pathways involved (TNF, MAPK, apoptosis, oxidative stress, etc.). Short-term DBP exposure (mice: 10-50 mg/kg/day; HcerEpic cells: 100-400 μM) induced cervical injury/oxidative stress, suppressed NRF2, and activated MAPK/NF-κB; N-acetylcysteine (NAC) supplementation mitigated damages. Long-term exposure to environmentally relevant DBP concentrations (10[-7] M) promoted HcerEpic cell malignant transformation (e.g., enhanced proliferation, migration, invasion, epithelial-mesenchymal transition) via activation of the TGF-β/Smad2/3 and MAPK pathways, with in vivo tumorigenicity validated in nude mice. In conclusion, our findings not only elucidate the molecular mechanisms underlying DBP-induced cervical injury and malignant transformation, but also provide theoretical evidence for evaluating the health risks of phthalates (PAEs) and guiding prevention strategies for environmental pollutant-related female reproductive malignancies.},
}

@article {pmid41349802,
year = {2025},
author = {Jiang, Y and Chen, C and Huang, D and Qian, P and Zhu, S},
title = {Interactive effects of H2O2 and NO on mitochondrial function and oxidative mtDNA damage in cold-stored peach fruit.},
journal = {Plant science : an international journal of experimental plant biology},
volume = {364},
number = {},
pages = {112923},
doi = {10.1016/j.plantsci.2025.112923},
pmid = {41349802},
issn = {1873-2259},
abstract = {Hydrogen peroxide (H2O2) and nitric oxide (NO), as bioactive species, play critical regulatory roles in plants and correlate with each other under physiological and stressful conditions. The protective effect of NO has been demonstrated through the enhancement of the antioxidative system and the alleviation of oxidative mitochondrial DNA (mtDNA) damage in mitochondria under cold stress. To investigate the effect of H2O2 on mitochondrial function and mtDNA damage in cold-stored peaches and elucidate the interactive effects of H2O2 and NO, sodium nitroprusside (SNP, an NO donor) -pretreated peaches were further treated with H2O2 and the scavenger of reactive oxygen species (N-acetyl cysteine, NAC). Treatment with H2O2 significantly increased endogenous ROS content, raised levels of 8-hydroxyguanosine (8-OHdG) and apurinic/apyrimidinic (AP) sites, and decreased the activities of key enzymes in the BER pathway and superoxide dismutase (SOD), thereby escalating mtDNA damage. Meanwhile, H2O2 negatively regulated mitochondrial function by enlarging the openness of mitochondrial permeability transition pore, aggravating the consumption of oxygen, and reducing the respiratory control ratio of mitochondria and membrane potential. In contrast, NAC, working in conjunction with NO, substantially up-regulated gene expression of the BER pathway. It indicated that H2O2 treatment counteracted the NO-induced protection of mitochondria in cold-stored peaches. This study provides new insight for understanding the crosstalk of different signal molecules in plants.},
}

@article {pmid41341490,
year = {2025},
author = {Hossain, KR and Alghalayini, A and Turkewitz, DR and Valenzuela, SM},
title = {CLIC1 and CLIC4 demonstrate cell protective antioxidant activity against UV exposure.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1674374},
pmid = {41341490},
issn = {2296-634X},
abstract = {BACKGROUND: Redox homeostasis is critical for maintaining healthy biological systems. Under physiological conditions, the human antioxidant defence system relies on enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Recent studies have shown that members of the Chloride Intracellular Ion Channel (CLIC) protein family, particularly CLIC1 and CLIC4, also exhibit antioxidant and cytoprotective activities. Overexpression of these proteins confers cellular protection, whereas their knockdown increases susceptibility to oxidative stress.

METHODS: This in vitro study investigated the antioxidant and cellular protective effects of CLIC1 and CLIC4 against UV-induced damage in human skin cells. Comparative analyses were performed using known endogenous antioxidant proteins, glutaredoxin (Grx) and Glutathione S-transferase-Omega (GST-Ω), as well as the antioxidant drug N-acetylcysteine (NAC). Recombinant purified CLIC proteins (rCLIC1 and rCLIC4) were added exogenously to skin cells, while CLIC knockdown models were used to assess loss-of-function effects.

RESULTS AND DISCUSSION: Exogenous addition of rCLIC1 and rCLIC4 provided significant cellular protection against UV-induced oxidative damage, reducing reactive oxygen species (ROS) production. In contrast, knockdown of CLIC1 or CLIC4 increased cellular vulnerability to oxidative stress. The protective and antioxidant activities of rCLIC1 and rCLIC4 were comparable to those of Grx, GST-Ω, and NAC. These findings highlight the potent antioxidant and cytoprotective roles of CLIC1 and CLIC4 in maintaining cellular redox balance. The ability of exogenously added recombinant CLIC proteins to mitigate oxidative and UV-induced damage suggests potential therapeutic applications for this protein family in oxidative stress-related conditions.},
}

@article {pmid41340591,
year = {2026},
author = {Demirtas, N and Mazlumoglu, BS and Celep, NA and Cadirci, E and Halici, Z and Palabiyik-Yucelik, SS},
title = {Epigallocatechin-3-Gallate Provides Hepatoprotection Through Endoplasmic Reticulum Stress/TXNIP/NLRP3 Axis in Paracetamol-Induced Acute Liver Injury.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {138},
number = {1},
pages = {e70155},
doi = {10.1111/bcpt.70155},
pmid = {41340591},
issn = {1742-7843},
mesh = {Animals ; *Catechin/analogs & derivatives/pharmacology ; *Endoplasmic Reticulum Stress/drug effects ; *Chemical and Drug Induced Liver Injury/prevention & control/pathology/drug therapy/metabolism/etiology ; *Acetaminophen/toxicity ; Male ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; *Antioxidants/pharmacology ; Liver/drug effects/pathology/metabolism ; Signal Transduction/drug effects ; Inflammasomes/metabolism/drug effects ; Disease Models, Animal ; Rats, Wistar ; },
abstract = {Epigallocatechin-3-gallate (EGCG) is a polyphenolic compound with strong antioxidant properties and is abundantly found in green tea. We investigated how EGCG affects the liver injury of high-dose paracetamol in this study. In our study, 56 rats were divided into seven groups (n = 8): healthy control, EGCG (100 mg/kg), paracetamol (2 g/kg), paracetamol + EGCG 25 (2 g/kg + 25 mg/kg), paracetamol + EGCG 50 (2 g/kg + 50 mg/kg), paracetamol + EGCG 100 (2 g/kg + 100 mg/kg) and paracetamol + N-acetyl cysteine (NAC, 2 g/kg + 140 mg/kg). Our findings suggest that high-dose paracetamol induces liver injury through endoplasmic reticulum (ER) stress and that EGCG alleviates liver injury by attenuating ER stress-induced inflammasome signalling.},
}

Animals
*Catechin/analogs & derivatives/pharmacology
*Endoplasmic Reticulum Stress/drug effects
*Chemical and Drug Induced Liver Injury/prevention & control/pathology/drug therapy/metabolism/etiology
*Acetaminophen/toxicity
Male
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Rats
*Antioxidants/pharmacology
Liver/drug effects/pathology/metabolism
Signal Transduction/drug effects
Inflammasomes/metabolism/drug effects
Disease Models, Animal
Rats, Wistar

@article {pmid41340222,
year = {2025},
author = {Shi, Q and Wu, M and Zhong, J and Chen, C and Huang, Z and Peng, J and Yang, D and Zan, X and Wang, Z},
title = {Procyanidin Capsules Combat ALF by Restoring Mitochondrial Homeostasis and Inhibiting Necroptosis via the PGAM5/DRP1/PINK1 Pathway.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e08742},
doi = {10.1002/advs.202508742},
pmid = {41340222},
issn = {2198-3844},
support = {G2023003//Natural Science Foundation of Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province/ ; Y202457244//General Research Project of Zhejiang Provincial Education Department/ ; },
abstract = {Acute liver failure (ALF) is a life-threatening, multifactorial condition characterized by rapid progression, extensive hepatocellular necrosis, and high mortality rates. Current therapeutic options, including artificial liver support systems (ALSS) and liver transplantation, are limited by high costs, donor shortages, and insufficient efficacy. Mitochondrial dysfunction and necrotic cell death play central roles in both acute and chronic liver injury; however, their contribution to ALF remains poorly understood. In this study, self-assembled procyanidin capsules (PC-Ca) are developed with sustained antioxidant and anti-inflammatory properties that selectively accumulate in the liver of an ALF model. These findings demonstrate that PC-Ca significantly improves survival rates and more effectively mitigates liver injury, inflammation, and necrosis in thioacetamide (TAA)-induced ALF in mice and rabbits than the standard clinical agent, N-acetylcysteine (NAC). This protective effect is mediated through enhanced oxidative stress defense via activation of the KEAP1-NRF2 axis and inhibition of necroptosis via the RIPK1/RIPK3/MLKL pathway. In addition, PC-Ca preserves mitochondrial morphology and function via the PGAM5/DRP1/PINK1 pathway, offering hepatoprotection. These findings suggest that PC-Ca represents a promising therapeutic strategy for ALF, with the modulation of mitochondrial homeostasis offering valuable insights for the development of next-generation pharmacological interventions.},
}

@article {pmid41339973,
year = {2025},
author = {Shokoohi, M and Nasr Esfahani, MH and Khaki, AA and Ghazi Soltani, G and Alihemmati, A and Mohammadzadeh Boukani, L},
title = {N-acetylcysteine Improved Expression of FSHR, LHCGR, Catsper-1, Catsper-2, and SF-1 Genes in Testis of Rats with Varicocele.},
journal = {Reproductive sciences (Thousand Oaks, Calif.)},
volume = {},
number = {},
pages = {},
pmid = {41339973},
issn = {1933-7205},
abstract = {Varicocele, a condition of insufficient oxygen supply to testicular tissue leading to hypoxia, is a major factor contributing to male infertility. This study investigated the potential protective effects of N-acetylcysteine (NAC), a potent antioxidant, on sperm characteristics and hormonal receptor expression in a rat model of varicocele-induced testicular injury. Thirty-two adults male Wistar rats were randomly assigned to four groups: Sham, varicocele, varicocele with NAC treatment (varicocele + NAC), and NAC treatment only (NAC). Serum testosterone, LH, and FSH levels were measured, and sperm characteristics, testicular histology, and expression of some genes involved in sperm motility (Catsper-1 and Catsper-2), germ cell development (FSHR), and steroidogenesis (SF-1 and LHCGR) were evaluated in each group. Results revealed that varicocele significantly decreased serum testosterone levels, while simultaneously decreasing sperm quality, germ cell count, and expression of all the mentioned genes (P < 0.05). Also, the level of LH and FSH was significantly increased (P < 0.05). Notably, NAC treatment significantly improved sperm quality and protected testicular tissue against varicocele, suggesting its potential as a therapeutic agent for male infertility. This study demonstrates that NAC may offer a promising strategy for mitigating testicular damage induced by Varicocele.},
}

@article {pmid41339444,
year = {2025},
author = {Da, X and Guo, Q and Lu, Y and Huang, J and Mo, J and Lu, L and Fan, M and Zhao, X and Guo, T and Qi, Z and Haoshang, and Lu, H},
title = {Bile metabolite palmitic acid augments the migration of gallbladder cancer cells through the ROS/NF-кB signaling pathway.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-31035-9},
pmid = {41339444},
issn = {2045-2322},
support = {2023-YBSF-549//Shaanxi key research and development program Project/ ; },
abstract = {Bile reflux, resulting from pancreaticobiliary reflux (PBR), not only alters the chemical of bile but also constitutes a significant risk factor for the occurrence and development of gallbladder cancer. In previous studies, the authors identified a marked elevation of palmitic acid (PA) levels in the bile of patients with PBR. This study seeks to elucidate the mechanisms of promoting the migration of gallbladder cancer cells, with the objective of contributing novel strategies and theoretical foundations for the treatment of gallbladder cancer. We performed a cytotoxicity screening on the NOZ and GBC-SD human gallbladder cancer cell line using varying concentrations of palmitic acid. These following methodologies were employed to investigate the mechanism of PA in NOZ and GBC-SD cells. Intracellular lipid droplet accumulation was assessed using Oil red O staining, while cell migration capability was evaluated through the Transwell migration assay. Reactive oxygen species (ROS) levels were quantified using the superoxide anion fluorescent probe, Dihydroethidium (DHE), in conjunction with a ROS detection kit. The expression levels of relevant genes and proteins were analyzed using Western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence (IF) techniques. In NOZ and GBC-SD cells, it was observed that palmitic acid facilitates the accumulation of intracellular lipid droplets and diminishes cellular activity while augmenting the cells' migratory capacity. Furthermore, elevated concentrations of PA have been shown to increase ROS levels in NOZ and GBC-SD cells. This elevation also activates the Nuclear factor-kappa B (NF-κB) and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Antioxidant Response Element (ARE) signaling pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) to NOZ and GBC-SD cells treated with high concentrations of PA effectively inhibits the enhancement of cell migration and epithelial-mesenchymal transition (EMT) induced by PA. PA promotes EMT in human gallbladder cancer cells by overproducing ROS and activating the NF-κB and NRF2/ARE signaling pathways, thereby facilitating increased migration.},
}

@article {pmid41333762,
year = {2025},
author = {Prabu, OG and Islami, NN and Mellenia, J and Nugroho, P and Rajabto, W and Shatri, H},
title = {N-Acetylcysteine Role in Maintaining Renal Function in Cancer Patients with Cisplatin-Based Chemotherapy.},
journal = {International journal of nephrology and renovascular disease},
volume = {18},
number = {},
pages = {337-348},
pmid = {41333762},
issn = {1178-7058},
abstract = {BACKGROUND: Cisplatin is a cornerstone chemotherapeutic agent used widely to treat various solid malignancies. Despite its efficacy, the usage of cisplatin is limited by its dose-dependent nephrotoxicity causing cisplatin-induced acute kidney injury (AKI) in up to 45% of treated patients. Current preventive strategies are limited to supportive measurement resulting in questionable clinical outcomes. N-acetylcysteine (NAC), a thiol-containing compound with antioxidant and anti-inflammatory properties, is already known for its safety.

PURPOSE: This review aims to explore the mechanisms of cisplatin-induced AKI, the role of NAC in its prevention, and the current evidence.

METHODS: A narrative review has been conducted of several literature, including preclinical and clinical studies evaluating NAC's efficacy in preventing cisplatin-induced AKI.

RESULTS: Cisplatin has cytotoxic effect via DNA structures disruption, leading to impairment of cell repair mechanism, triggering apoptosis that works effectively against cancer cells. However, cisplatin also accumulates in renal proximal tubular epithelial cells, disrupting DNA structures, increasing reactive oxygen species (ROS), inducing mitochondrial dysfunction and inflammation, all leading to apoptosis. NAC can counteract these mechanisms by scavenging ROS directly via its thiol group and indirectly by replenishing glutathione. Preclinical studies have demonstrated consistent NAC nephroprotective effects. However, findings from clinical studies remain inconsistent due to limited sample sizes, varied dosing regimens, and differences in administration routes, making comparison between studies difficult to conduct.

CONCLUSION: NAC exhibits strong nephroprotective properties through antioxidant, anti-inflammatory, and cytoprotective mechanisms as consistently shown in preclinical studies. Despite the limited current clinical evidence supporting these findings, NAC remains a promising agent for cisplatin-induced AKI prevention. Future research should focus on large-scale, well-designed, standardized clinical trials with optimized dosing strategies to validate NAC's efficacy and establish its clinical role.},
}

@article {pmid41333684,
year = {2025},
author = {Freitas, ÍS and Guimarães, FS and Gomes, FV},
title = {Protective Effects of N-Acetylcysteine Against Schizophrenia-Related Behavioral and Parvalbumin Interneuron Deficits Induced by Adolescent Stress.},
journal = {Schizophrenia bulletin open},
volume = {6},
number = {1},
pages = {sgaf029},
pmid = {41333684},
issn = {2632-7899},
abstract = {BACKGROUND AND HYPOTHESIS: Adolescent stress has been linked to an increased risk of developing psychiatric disorders, including schizophrenia. Previous findings from our group suggest that adolescent stress causes redox imbalance and functional impairments in parvalbumin (PV) interneurons and their associated perineuronal nets (PNNs) in the ventral hippocampus (vHip). These changes are associated with behavioral abnormalities, vHip hyperactivity, and dopamine system overdrive, mirroring observations in people with schizophrenia. Thus, we hypothesized that the antioxidant N-acetylcysteine (NAC) could mitigate schizophrenia-related alterations induced by adolescent stress in adult rats.

STUDY DESIGN: Male Sprague-Dawley rats were subjected to a combination of daily footshock and restraint stress during adolescence [postnatal days (PD) 31-40]. NAC (900 mg/L) was administered through the drinking water either during (PD31-40) or after the adolescent stress (PD51-60). In adulthood (PD63), rats underwent behavioral tests to assess anxiety-like behaviors, social interaction, and cognition. From PD70, in vivo recordings of dopamine neurons in the ventral tegmental area (VTA) and immunostaining of PV, PNNs, and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-Oxo-dG) in the vHip were performed.

STUDY RESULTS: Adolescent stress causes, in adulthood, anxiety-like responses, deficits in sociability and cognitive function, increased VTA dopamine neuron population activity, reduced PV[+] cells in the vHip, including those surrounded by PNNs, and enhanced expression of 8-Oxo-dG, particularly in PV[+] cells. NAC treatment, whether administered during or after adolescent stress, significantly attenuated these alterations.

CONCLUSIONS: NAC effectively mitigates schizophrenia-related changes induced by adolescent stress and may serve as a pharmacological intervention for prevention and treatment strategies.},
}

@article {pmid41332654,
year = {2025},
author = {Feng, J and Carreño, M and Jung, H and Naidu, SD and Arroyo-Diaz, N and Ang, AD and Kulkarni, B and Kisielewski, D and Suzuki, T and Yamamoto, M and Hayes, JD and Honda, T and Leon-Ruiz, B and Eggler, AL and Vitturi, DA and Dinkova-Kostova, AT},
title = {The electrophilic metabolite of kynurenine, kynurenine-CKA, targets C151 in Keap1 to derepress Nrf2.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.18.689077},
pmid = {41332654},
issn = {2692-8205},
abstract = {The Kelch-like ECH-associated protein 1 / Nuclear factor-erythroid 2 p45-related factor 2 (Keap1/Nrf2) system responds to a wide array of structurally diverse small molecules, of both exogenous and endogenous origin, by inducing a robust cytoprotective program that allows adaptation during oxidative, metabolic and inflammatory stress. Here, we report that exposure to the tryptophan metabolite kynurenine and its electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA) leads to an increase in the abundance of transcription factor Nrf2 and induction of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), in murine and human cells. Additionally, both kynurenine and Kyn-CKA activate the aryl hydrocarbon receptor (AhR). Using cellular thermal shift assays, we found that Kyn-CKA increases the thermal stability of Keap1-mCherry fusion protein, but not free mCherry, indicating target engagement of Keap1, the principal repressor of Nrf2. The use of purified recombinant BTB domain of Keap1 and its C151S mutant counterpart revealed that Kyn-CKA reacts with wild-type, but not C151S mutant, Keap1-BTB, and at a much faster rate than with the small molecule thiol N -acetyl cysteine, demonstrating Kyn-CKA is targeted to react with C151 by the surrounding protein environment. In close agreement, Kyn-CKA increased the abundance of Nrf2 and expression of NQO1 in mouse embryonic fibroblast (MEF) cells expressing wild-type Keap1, but its inducer potency was greatly diminished in C151S-Keap1 mutant MEFs. Experiments in WT, AhR-knockout, and Nrf2-knockout primary murine bone marrow-derived macrophages showed that Nrf2 is required for the acute anti-inflammatory activity of Kyn-CKA, whereas AhR is dispensable. Together, these findings demonstrate that Kyn-CKA targets C151 in Keap1 to derepress Nrf2 and reveal that Nrf2, but not AhR, is a main contributor to the anti-inflammatory activity of Kyn-CKA in macrophages.},
}

@article {pmid41332367,
year = {2025},
author = {Meng, Q and Chen, B and Zhang, C and Jia, L and Yao, X and Liu, G},
title = {1,25-Dihydroxyvitamin D3 mitigates high glucose-induced oxidative stress, inflammation, and extracellular matrix accumulation in glomerular mesangial cells via the ROS/TXNIP/NLRP3 pathway.},
journal = {Histology and histopathology},
volume = {},
number = {},
pages = {25021},
doi = {10.14670/HH-25-021},
pmid = {41332367},
issn = {1699-5848},
support = {2024ZD047//Bingtuan Science and Technology Program/ ; },
abstract = {BACKGROUND: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a physiologically active form of vitamin D. Our study investigated the renoprotective functions of 1,25(OH)2D3 in diabetic nephropathy (DN) progression and its underlying mechanism targeting the ROS/TXNIP/NLRP3 inflammasome pathway.

METHODS: DN was induced in Wistar rats via high-fat diet (4 weeks) and streptozotocin injection (30 mg/kg, i.p.); hyperglycemic rats were randomized into DN and DN + 1,25(OH)2D3 (16 μg/kg, 12 weeks) groups. Rat mesangial HBZY-1 cells were maintained under normal glucose (5.5 mM), high glucose (25 mM), high glucose plus 1,25(OH)2D3 (1-50 nM), or high glucose plus N-acetylcysteine (NAC, 10 mM). Cell viability was assessed by the CCK-8 assay. Oxidative stress parameters (ROS via DCFH-DA fluorescence, MDA content, SOD activity) and pyroptosis markers (LDH release, PI/Hoechst 33342 nuclear staining) were quantified. Renal histopathology was performed using PAS and Masson trichrome staining. Biochemical analyses included serum creatinine, urea nitrogen, and 24-h urinary protein quantification. Molecular profiling encompassed ELISA (IL-1β, IL-6, TNF-α, IL-18, fibronectin, collagen IV), RT-qPCR (NOX2, NOX4, NLRP3, ASC), western blotting (TXNIP, NLRP3, ASC, caspase-1, IL-1β, IL-18, collagen IV, fibronectin, laminin), and TXNIP immunofluorescence.

RESULTS: 1,25(OH)2D3 significantly attenuated high glucose-induced pathological alterations in HBZY-1 cells, including ROS overproduction, TXNIP upregulation, NLRP3 inflammasome activation, oxidative stress, inflammation, extracellular matrix (ECM) deposition, and pyroptotic cell death. Consistently, 1,25(OH)2D3 suppressed ROS/TXNIP/NLRP3/caspase-1 signaling, ameliorated renal dysfunction, and mitigated histopathological damage in DN rats.

CONCLUSION: 1,25(OH)2D3 confers renoprotection in DN by inhibiting the ROS/TXNIP/NLRP3 inflammasome axis, thereby suppressing oxidative stress, inflammatory cytokine production, ECM accumulation, and pyroptotic cell death in glomerular mesangial cells and renal tissues.},
}

@article {pmid41326062,
year = {2026},
author = {Li, XY and Liu, YJ and Meng, XH and Gong, C and Yang, JL and Qiang, Y and Wang, J and Hou, XD},
title = {Ginsenoside Rk1 inhibits postharvest fruit anthracnose by disrupting reactive oxygen species (ROS) homeostasis and activating the autophagic mechanism in Colletotrichum gloeosporioides.},
journal = {Pesticide biochemistry and physiology},
volume = {216},
number = {Pt 1},
pages = {106727},
doi = {10.1016/j.pestbp.2025.106727},
pmid = {41326062},
issn = {1095-9939},
mesh = {*Colletotrichum/drug effects/metabolism ; *Reactive Oxygen Species/metabolism ; *Autophagy/drug effects ; Homeostasis/drug effects ; Fruit/microbiology ; *Plant Diseases/microbiology/prevention & control ; *Ginsenosides/pharmacology ; Fungal Proteins/metabolism ; },
abstract = {Anthracnose is a highly contagious and destructive plant disease caused by Colletotrichum gloeosporioides. The objective of this study was to investigate the antifungal activity and mechanism of ginsenoside Rk1 (GRk1) against C. gloeosporioides. In vitro experiments demonstrated that GRk1 exhibited substantial antifungal activity, with EC50 values of 64.58 mg L[-1], surpassing the plant-derived pesticide d-limonene. Additionally, GRk1 could effectively suppress the dissemination of anthracnose spots in postharvest fruit. By observing the microstructure of C. gloeosporioides, it was observed that the mycelium structure underwent notable changes, and autophagosomes engulfed the organelles in the experimental groups. Fluorescent staining revealed specific signals in mycelial autophagosomes, and Western Blot analysis confirmed the upregulation of the autophagy-related protein Atg8. These findings indicate that GRk1 may activate the autophagy process by promoting Atg8 expression. Proteomic analysis revealed that the expression of Sec20 and Mpv17 proteins was significantly downregulated, whose dysregulated expression is associated with the crosstalk between SNAREs and peroxisomes during vesicle trafficking and metabolic processes. Assessment of catalase (CAT) activity, hydrogen peroxide (H2O2) content, and superoxide anion (O2[-]) levels further demonstrated that GRk1 could disrupt intracellular reactive oxygen species (ROS) homeostasis in mycelia. Moreover, the introduction of the ROS scavenger N-acetylcysteine (NAC) markedly inhibited autophagy, indicating that GRk1 promotes autophagy by inducing oxidative stress. Collectively, GRk1 inhibits pathogens via the ROS-autophagy axis. These findings suggested that GRk1 holds potential as a promising alternative to fungicides for the biological control of anthracnose.},
}

*Colletotrichum/drug effects/metabolism
*Reactive Oxygen Species/metabolism
*Autophagy/drug effects
Homeostasis/drug effects
Fruit/microbiology
*Plant Diseases/microbiology/prevention & control
*Ginsenosides/pharmacology
Fungal Proteins/metabolism

@article {pmid41324913,
year = {2025},
author = {Tao, S and Tao, H and Liu, Y and Wang, S and Li, M and Wang, J and Lu, G and Zhang, L and Gu, H},
title = {Intragastric administration of Vitamin C and N-acetylcysteine mitigates computed tomography radiation-induced biological damage in rats.},
journal = {International journal of radiation biology},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/09553002.2025.2591790},
pmid = {41324913},
issn = {1362-3095},
abstract = {PURPOSE: To assess the protective effects of intragastric Vitamin C and N-acetylcysteine (NAC) against DNA damage from CT scan radiation in rats.

MATERIALS AND METHODS: The male Sprague Dawley rats (n = 8 per group) were allocated into four distinct groups: control (no CT radiation), IR (CT radiation only), Vitamin C (200 mg/kg with CT radiation), and NAC (200 mg/kg with CT radiation). Antioxidants were administered intragastrically 3 hours before scanning. Non-control groups underwent CT radiation at 120 kVp and 110 mA for 3 scans. Surface absorbed dose was measured with thermoluminescent dosimeter chips. Serum total antioxidant capacity (TAC) was measured pre- and post-scanning. γ-H2AX foci in peripheral blood lymphocytes were assessed at baseline, 1 hour, and 24 hours post-scan. Bone marrow smears were prepared 24 hours post-scan, stained with Giemsa, and micronucleus (MN) frequency in polychromatic erythrocytes was evaluated.

RESULTS: TAC levels increased by 68.2% in the Vitamin C group and 152.3% in the NAC group compared to the IR group. γ-H2AX foci rates decreased by 10.3% in the Vitamin C group and 14.3% in the NAC group compared to the IR group. MN frequency decreased by 28.6% in the Vitamin C group and 34.9% in the NAC group compared to the IR group. No significant difference was found between Vitamin C and NAC.

CONCLUSION: Oral Vitamin C and NAC significantly mitigate radiation exposure from CT imaging in rats. Both antioxidants effectively reduce γ-H2AX foci and micronucleus formation, offering substantial protection against radiation-induced DNA damage.},
}

@article {pmid41318115,
year = {2025},
author = {Mongkon, I and Kariya, R and Pearngam, P and Settha, N and Saisuwan, K and Boonnate, P and Sittithumcharee, G and Vaeteewoottacharn, K and Saeeng, R and Okada, S},
title = {Andrographolide Induces ROS-dependent Apoptosis and Suppresses STAT3 Phosphorylation in Primary Effusion Lymphoma Cells.},
journal = {Anticancer research},
volume = {45},
number = {12},
pages = {5299-5311},
doi = {10.21873/anticanres.17869},
pmid = {41318115},
issn = {1791-7530},
mesh = {*Diterpenes/pharmacology ; *Reactive Oxygen Species/metabolism ; *STAT3 Transcription Factor/metabolism ; *Apoptosis/drug effects ; Animals ; Humans ; *Lymphoma, Primary Effusion/drug therapy/metabolism/pathology ; Phosphorylation/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Caspases/metabolism ; },
abstract = {BACKGROUND/AIM: Primary effusion lymphoma (PEL) is a rare and aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis due to resistance to conventional chemotherapy. Andrographolide (AG), a diterpenoid lactone extracted from Andrographis paniculata, has shown anti-tumor activity in several malignancies, but its effects on PEL are unknown.

MATERIALS AND METHODS: PEL cell viability was assessed by MTT assay. Apoptosis was evaluated via Annexin V/PI staining and caspase activation. ROS generation was measured by DCFH-DA staining. Protein expression changes were analyzed by Western blotting. To determine the roles of ROS and caspases, cells were co-treated with a reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) or the pan-caspase inhibitor Q-VD-OPh. AG's in vivo effects were tested in a xenograft mouse model.

RESULTS: AG inhibited PEL cell proliferation in a dose- and time-dependent manner. Apoptosis was mediated via ROS production and caspase activation. STAT3 phosphorylation was suppressed in a ROS-dependent manner. In vivo, AG (500 mg/kg/day, oral gavage) significantly reduced tumor burden without observable toxicity.

CONCLUSION: AG exerts anti-tumor effects against PEL by inducing ROS-dependent apoptosis and suppressing STAT3 signaling. These findings suggest that AG may serve as a promising therapeutic agent for PEL.},
}

*Diterpenes/pharmacology
*Reactive Oxygen Species/metabolism
*STAT3 Transcription Factor/metabolism
*Apoptosis/drug effects
Animals
Humans
*Lymphoma, Primary Effusion/drug therapy/metabolism/pathology
Phosphorylation/drug effects
Mice
Xenograft Model Antitumor Assays
Cell Line, Tumor
Cell Proliferation/drug effects
Cell Survival/drug effects
Caspases/metabolism

@article {pmid41314277,
year = {2025},
author = {Kim, NY and Gowda, SV and Harsha, KB and Kumar, DCV and Mohan, CD and Shivakumara, CS and Rangappa, KS and Ahn, KS},
title = {Multimodal cell death induced by indirubin-3'-oxime through inhibition of Akt/mTOR axis in lung cancer cells.},
journal = {Chemico-biological interactions},
volume = {423},
number = {},
pages = {111851},
doi = {10.1016/j.cbi.2025.111851},
pmid = {41314277},
issn = {1872-7786},
abstract = {Lung cancer is a major type of malignancy that has contributed to a high mortality rate for many years. Discovering new small molecules with strong cytotoxic effects on lung cancer is crucial for developing new therapies. In this study, we describe the synthesis of a novel triazole-indirubin-3'-oxime derivative (designated as CRM1) and examine its ability to induce distinct forms of cell death, as well as elucidate the cytotoxicity-associated molecular mechanisms in lung cancer cells. CRM1 selectively reduced cell viability in lung cancer cell lines (A549, PC9, and H1299) without significantly affecting the viability of normal lung cells (HEL299). Mechanistic investigations have demonstrated that CRM1 induces paraptosis through the downregulation of Alix and the upregulation of ATF4 and CHOP. This process is associated with disruption of mitochondrial membrane potential, induction of endoplasmic reticulum stress, and accumulation of reactive oxygen species (ROS). CRM1 was observed to induce apoptosis, as indicated by DNA fragmentation, an increase in Sub-G1 cell population, as well as elevated caspase-3 cleavage and Bax expression. CRM1 also promoted autophagy, as evidenced by increased expression of Atg7, phosphorylated Beclin-1, and LC3-II, as well as enhanced autophagosome formation. Pharmacological inhibition studies confirmed the independent induction of apoptosis, paraptosis, and autophagy. Pre-exposure of cancer cells to N-acetyl cysteine abrogated CRM1-induced cytotoxicity. Mechanistic studies demonstrated that CRM1 suppresses the activation of Akt, mTOR, and p70S6K, while the overexpression of Akt counteracts the CRM1-driven cytotoxic effects. CRM1 also synergistically potentiated the cytotoxic efficacy of paclitaxel by co-targeting multiple cell death processes. Collectively, these results suggest CRM1 as a promising cytotoxic candidate with a multimodal mechanism of action in lung cancer cells.},
}

@article {pmid41312470,
year = {2025},
author = {Lin, IC and Tsai, WW and Wu, VC and Pan, HC and Chuang, MH and Chen, JY},
title = {Saline and N-acetylcysteine-based strategies and other approaches to prevent the risk of CA-AKI: a meta-analysis.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1608626},
pmid = {41312470},
issn = {2296-858X},
abstract = {BACKGROUND: While hydration is currently the most evidence-supported strategy for preventing contrast-associated acute kidney injury (CA-AKI) in patients undergoing cardiovascular angiography, the potential benefits of combining a saline and N-acetylcysteine (NAC) based strategy with additional pharmacologic interventions remain uncertain.

METHODS: We conducted a search for randomized controlled trials (RCTs) in PubMed, Embase, and the Cochrane library from the inception to 26th January 2024. RCTs involving adults undergoing cardiovascular angiography were analyzed, comparing the effects of saline and NAC-based strategies combined with additional agents compared to saline. The primary outcome was the risk of CA-AKI. The comparative effectiveness was visually represented through a network diagram and forest plot, with the treatments ranked by P-score in a league table.

RESULTS: We included 72 trials with 14,671 patients, 1,843 AKI events, comparing 12 different interventions based on hydration and NAC. The incidence of CA-AKI was 11.74% in the hydration with oral NAC group versus 15.49% in the hydration with saline alone group (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.62-0.97). Compared to individuals with saline alone, the incidence of CA-AKI in the hydration with intravenous NAC group was 10.62% (OR 0.71, 95% CI 0.52-0.99); In hydration with oral NAC and statin group, the incidence of CA-AKI was 8.28% (OR 0.47, 95% CI 0.29-0.77).

CONCLUSION: This network meta-analysis highlights that the combination of hydration with oral or intravenous NAC is more effective than hydration alone in preventing CA-AKI. Additionally, hydration with oral NAC and a statin significantly outperforms hydration with oral NAC alone in preventing CA-AKI.

CRD42024502497.},
}

@article {pmid41312188,
year = {2025},
author = {Benedetti, F and Santus, P},
title = {N-acetylcysteine in paediatrics: a review of efficacy, safety and dosing strategies in respiratory care.},
journal = {Drugs in context},
volume = {14},
number = {},
pages = {},
pmid = {41312188},
issn = {1745-1981},
abstract = {N-acetylcysteine (NAC) is widely used for its mucolytic, antioxidant, anti-inflammatory and synergistic antibacterial properties in the treatment of respiratory diseases. NAC and other mucolytics and mucoactive medications are frequently employed in the adult population and in paediatric settings to improve mucus clearance in conditions such as cystic fibrosis, bronchiolitis, pneumonia, and both chronic and acute bronchitis, with varying degrees of success. This narrative review evaluates the efficacy and safety of NAC in paediatric acute and chronic respiratory diseases, synthesizing data from clinical trials, observational studies and real-world evidence, with a particular focus on optimizing dosing based on patient-specific characteristics. Numerous studies indicate that oral NAC doses of 20 mg/kg/day for acute conditions and 200 mg three times daily for chronic conditions are generally effective and well tolerated in children. However, most participants in these studies were older than 9 years, resulting in a lack of literature-based evidence for the optimal dosing in younger children over 2 years of age. Given the significant weight variations within this age group, weight-based dosing is recommended to ensure appropriate drug exposure and optimize treatment benefits. Weight-based dosing adjustments and patient monitoring may help optimize treatment outcomes and reinforce the overall positive safety and tolerability profile in paediatric settings. NAC is a valuable therapeutic agent for paediatric respiratory diseases, particularly in older children. In younger patients, weight-adjusted dosing and careful monitoring for potential adverse effects may help maximize efficacy and maintain its favourable tolerability profile.},
}

@article {pmid41304539,
year = {2025},
author = {Zhang, Y and Xiao, Z and Mao, P and Yang, F and Ma, Y and Xian, B and Fu, M and Li, G},
title = {Effects of Decabromodiphenyl Ether (BDE209) Exposure on Toxicity and Oxidative Stress of Beas-2B Cells.},
journal = {Toxics},
volume = {13},
number = {11},
pages = {},
pmid = {41304539},
issn = {2305-6304},
support = {42207498//National Natural Science Foundation of China/ ; GKLECHRC-03//Open Fund Project of Guangdong Provincial Key Laboratory of Environmental Catalysis and Health Risk Control/ ; Guike Neng 2101Z017//Guangxi Key Laboratory of environmental pollution control theory and technology/ ; Guike Neng 2101Z014//Guangxi Key Laboratory of environmental pollution control theory and technology/ ; },
abstract = {Decabromodiphenyl ether (BDE209) has been widely used because of its excellent flame-retardant properties and ability. On the one hand, many studies have shown that the presence of BDE209 can potentially threaten human health and the environment. The production and processing of products containing BDE209 is prohibited except for special applications in China. On the other hand, the study of BDE209 on respiratory cells is not yet fully understood. Consequently, this study aims to investigate the mechanisms of toxic damage and oxidative stress induced by BDE209 exposure in lung epithelial Beas-2B cells. The proliferation of Beas-2B cells under BDE209 exposure was first analyzed by using a real-time label-free cell analyzer (RTCA). Then the cells' morphological changes were observed using laser confocal microscopy. Subsequently, the effects of BDE209 exposure alone, combined exposure to N-acetylcysteine (NAC) and BDE209, on reactive oxygen species (ROS) levels and antioxidant defense-related factors in Beas-2B cells were analyzed separately. The results show that BDE209 exposure induces the proliferation of Beas-2B cells with a dose-dependent increase in inhibition. Microscopic observation of Beas-2B cells reveals significant damage and death. The levels of ROS are significantly increased (p < 0.01), the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) are increased, the contents of catalase (CAT) are decreased, and the activities of glutathione peroxidase (GPX) are first decreased and then increased. However, under the co-exposure of NAC and BDE209, ROS levels are significantly reduced (p < 0.01), MDA contents decrease, and SOD activities increase. In summary, BDE209 exposure leads to inhibition of Beas-2B cell proliferation, cellular morphology damage, increased ROS levels, and disturbances in antioxidant defense-related factors. The cells showed toxic damage and oxidative stress. In contrast, NAC can suppress ROS levels, enhance SOD activity, and inhibit GPX activity, thereby alleviating BDE209-induced cellular damage.},
}

@article {pmid41303345,
year = {2025},
author = {Mulè, S and Ferrari, S and Galla, R and Uberti, F},
title = {Neuroprotective Pathway Modulation by a Novel Coriandrum sativum, N-Acetylcysteine and Glutathione-Based Formulation: Insights from In Vitro 3D Models.},
journal = {International journal of molecular sciences},
volume = {26},
number = {22},
pages = {},
doi = {10.3390/ijms262210857},
pmid = {41303345},
issn = {1422-0067},
mesh = {*Acetylcysteine/pharmacology/chemistry ; *Glutathione/pharmacology/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; *Coriandrum/chemistry ; *Plant Extracts/pharmacology/chemistry ; Blood-Brain Barrier/drug effects/metabolism ; Humans ; Oxidative Stress/drug effects ; Animals ; Cell Survival/drug effects ; Palmitic Acids/pharmacology ; },
abstract = {Pain remains a major clinical challenge due to its complex physiopathology and limited treatment options. In this context, several supplements based on palmitoylethanolamide (PEA) and alpha-lipoic acid (ALA) are known for their neuroprotective properties. ALA-based supplements have shown potential, but concerns about adverse effects persist. This study examines the formulations of two commercial products based on ALA and PEA, IperALA[®] and IperALA[®] Forte, in which ALA and vitamin D3 are replaced with Coriandrum sativum extract (C. sativum e.s.), N-acetylcysteine (NAC) and glutathione (GSH), assessing improvement of neuroprotective, anti-inflammatory and analgesic properties of the new formulation. Intestinal, blood-brain barrier (BBB), and central nervous system (CNS) models were sequentially stimulated with the test compounds. Both formulations were assessed for cytotoxicity, barrier integrity, permeability, oxidative stress, inflammation, and neuroprotection-related biomarkers. IperALA[®] Forte demonstrated superior performance compared to IperALA[®] and individual agents. It enhanced cell viability, preserved intestinal and BBB integrity, and improved compound permeability. Notably, it reduced ROS and pro-inflammatory cytokines (TNFα, IL-1), while increasing analgesic markers (CB2R, GABA) in the central system. The replacement of ALA and vitamin D3 with C. sativum, NAC, and GSH in IperALA[®] Forte significantly improved the neuroprotective, antioxidant, and anti-inflammatory profile of the supplement. These results indicate a possible connection between the observed neuroprotective properties and the pathways involved in nociception and pain regulation, stating the hypothetical potential relevance of this approach for the treatment of pain-related conditions.},
}

*Acetylcysteine/pharmacology/chemistry
*Glutathione/pharmacology/chemistry
*Neuroprotective Agents/pharmacology/chemistry
*Coriandrum/chemistry
*Plant Extracts/pharmacology/chemistry
Blood-Brain Barrier/drug effects/metabolism
Humans
Oxidative Stress/drug effects
Animals
Cell Survival/drug effects
Palmitic Acids/pharmacology

@article {pmid41300501,
year = {2025},
author = {Aremu, TD and Blanco Ayala, T and Meza-Sosa, KF and Ramírez Ortega, D and González Esquivel, DF and Vázquez Cervantes, GI and Flores, I and González Alfonso, WL and Custodio Ramírez, V and Salazar, A and Pineda, B and Pérez de la Cruz, G and Gómez Manzo, S and Roldan Roldan, G and Carrillo Mora, P and Pérez de la Cruz, V},
title = {N-Acetylcysteine Prevents Skeletal Muscle Cisplatin-Induced Atrophy by Inducing Myogenic microRNAs and Maintaining the Redox Balance.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111344},
pmid = {41300501},
issn = {2076-3921},
support = {IA101224//UNAM-PAPIIT/ ; IN207025//DGAPA-UNAM/ ; },
abstract = {Cisplatin (CIS) is a widely used chemotherapeutic agent known for its efficacy; however, it induces several adverse effects, most notably cachexia, which is characterized by progressive loss of skeletal muscle mass, weakness, and reduced body weight. N-acetylcysteine (NAC) a compound with antioxidants properties, has been shown to mitigate CIS-induced neurotoxicity in experimental models. This study aimed to investigate the myoprotective effects of NAC during CIS treatment and explore the redox and molecular mechanisms involved in this response. For this, female Wistar rats were divided into four experimental groups: Control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p for 5 days), and NAC + CIS (NAC for 8 days, with CIS administered from day 4 onward). After treatment, muscle strength, redox status, mitochondrial biogenesis, expression of myogenic microRNAs and morphological changes were evaluated. CIS treatment caused muscle atrophy, decreased GSH/GSSG ratio, impaired cellular function, increased lipid peroxidation and altered antioxidant enzymes activity. These effects were mitigated by NAC coadministration. CIS also reduced the mtDNA/nDNA ratio; however, NAC treatment tended to increase TFAM and PGC-1α expression levels. Furthermore, CIS suppressed the expression of muscular miR-1-3p, miR-133a-3p and miR-206-3p, while NAC restored their levels when co-administered with CIS. These findings suggest that NAC may serve as a promising adjuvant therapeutic strategy to counteract CIS-induced myotoxicity through redox regulation and modulation of molecular pathways related to muscle integrity and regeneration.},
}

@article {pmid41300472,
year = {2025},
author = {Zhao, P and Yan, H and Wang, R and Zhao, J and Zheng, X and Li, D and Guo, X and Ji, F and Long, C and Shen, L and Wei, G and Wu, S},
title = {Parthenolide Restores Testosterone Biosynthesis After Nanoplastic Exposure by Blocking ROS-Driven NF-κB Nuclear Translocation.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111315},
pmid = {41300472},
issn = {2076-3921},
support = {CSTB2024NSCQ-LZX0054//the Project of Sponsored by Natural Science Foundation of Chongqing/ ; },
abstract = {Nanoplastics are pervasive contaminants that adversely affect male reproductive function, yet the molecular basis of polystyrene nanoplastic (PS-NP) toxicity in immature testes and effective preventive strategies remain unclear. Here, male mice (postnatal days 22-35, PND 22-35) and TM3 Leydig cells were exposed to graded PS-NPs, followed by transcriptomic profiling to identify differentially expressed genes (DEGs). Candidate therapeutics were prioritized using Connectivity Map (CMap) analysis and molecular docking, and protein interactions were examined by co-immunoprecipitation (Co-IP). PS-NPs accumulated in immature testes, eliciting excessive reactive oxygen species (ROS) and activation of NF-κB. These events coincided with the downregulation of steroidogenic enzymes (CYP11A1 and StAR) and disruption of testicular microarchitecture. In TM3 cells, PS-NPs suppressed testosterone synthesis in a concentration-dependent manner; this effect was fully reversed by pretreatment with N-acetylcysteine (NAC) or Bay 11-7082. Co-IP demonstrated p65-steroidogenic factor-1 (SF-1) binding consistent with formation of a transcriptional repressor complex targeting steroidogenic genes. CMap and docking analyses nominated parthenolide (PTL) as a candidate inhibitor of NF-κB nuclear translocation (predicted binding affinity, -6.585 kcal/mol), and PTL mitigated PS-NP-induced impairment of testosterone synthesis in vitro. Collectively, these data indicate that PS-NPs disrupt testosterone biosynthesis in immature testes through the ROS/NF-κB/p65-SF-1 axis, while PTL emerges as a candidate small molecule to counter nanoplastic-associated reproductive toxicity. These findings underscore translational relevance and support future evaluation under chronic low-dose exposure conditions, including in vivo validation of PTL efficacy, pharmacokinetics, and safety.},
}

@article {pmid41300463,
year = {2025},
author = {Han, M and Zhao, M and Bai, F and Wang, M and Zhang, B and Shi, J and Liu, Z},
title = {Reactive Oxygen Species (ROS) Drive Osteocyte Dysfunction in Diabetic Osteoporosis by Impairing Autophagy and Triggering Apoptosis.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
doi = {10.3390/antiox14111306},
pmid = {41300463},
issn = {2076-3921},
support = {32071246//National Natural Science Foundation of China/ ; 23YXYJ0127//Research Program of Science and Technology in Xi'an City/ ; xzy022023079//Basic Scientific Research Funds of Xi 'an Jiaotong University/ ; },
abstract = {This study investigates the mechanisms underlying osteocyte injury in a high glucose (HG) environment and explores potential therapeutic targets and diagnostic markers for diabetic osteoporosis, a common complication of type 2 diabetes mellitus (T2DM). Hyperglycemia induces oxidative stress through the reactive oxygen species (ROS) production, which impair osteocytes and accelerate bone loss. To examine these effects, MLO-Y4 cells and primary mouse osteocytes were cultured under normal glucose and HG conditions, with additional treatments using N-acetylcysteine (NAC, ROS scavenger) and rapamycin (autophagy promoter and mTOR inhibitor). Cell viability, ROS levels, and the autophagy and apoptosis markers expression (Beclin1, LC3, p62, Bax, Bcl2, cytochrome C, and caspase3) were assessed using CCK8/ATP level assay, flow cytometry, Western blot, qRT-PCR, immunofluorescence, and TUNEL staining. The results showed that HG inhibits cell proliferation, induces insulin resistance, generates ROS, alters antioxidant enzymes, and promotes oxidative stress, leading to mTOR activation, subsequent autophagy inhibition, and osteocyte apoptosis. NAC mitigated these effects, while rapamycin prevented HG-induced apoptosis by inhibiting mTOR activation and promoting autophagy. This suggests that ROS-induced mTOR activation impairs autophagy and hinders the clearance of damaged osteocytes, triggering apoptosis. This research provides foundational evidence and novel insights into diabetic osteoporosis pathogenesis and potential therapies.},
}

@article {pmid41295319,
year = {2025},
author = {Yu, MS and Chiu, CY and Lo, FS and Lin, WC and Wu, LJ and Yen, CY and Yu, MC},
title = {Dynamics of Urine Metabolomics and Tubular Inflammatory Cytokines in Type 1 Diabetes Across Disease Durations.},
journal = {Metabolites},
volume = {15},
number = {11},
pages = {},
pmid = {41295319},
issn = {2218-1989},
support = {CMRPG3F2261, CMRPG3F2262, CMRPG3F2263//Linkou Chang Gung Memorial Hospital/ ; },
abstract = {Background/Objectives: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by sustained inflammation, leading to diabetic kidney disease (DKD). This study investigated urinary tubular injury biomarkers and metabolomic profiles in relation to albuminuria and renal function across varying durations of T1D. Methods: A cross-sectional analysis was conducted in 247 youth-onset T1D patients categorized by disease duration: short ≤ 5 years (T1D-S, n = 62), medium 6-10 years (T1D-M, n = 67), and long > 10 years (T1D-L, n = 118). Urinary cytokines (MCP-1, KIM-1, NGAL) were measured by ELISA. Metabolomic profiling was performed using [1]H-NMR spectroscopy. Results: Urinary MCP-1/Cr, KIM-1/Cr, and NGAL/Cr levels were significantly elevated in T1D patients compared with non-diabetic controls, but did not correlate with disease duration. Metabolomic profiling identified distinct urinary signatures across T1D duration. Specifically, N-acetylcysteine (NAC) and N-delta-acetylornithine (NAO) increased progressively, while N-acetylaspartate (NAA) and pyruvic acid decreased with longer disease duration. These four metabolites remained statistically significant after both based on Mann-Whitney tests with false discovery rate (FDR) correction (q < 0.05) and application of a conservative alpha threshold (p < 0.01), suggesting potential disruptions in amino acid and carbohydrate metabolism. Conclusions: Urinary biomarkers (MCP-1/Cr, NGAL/Cr, and KIM-1/Cr) are sensitive indicators of subclinical kidney dysfunction in T1D patients, often preceding albuminuria. Alterations in amino acid-related metabolites (NAC, NAA, and NAO) and pyruvate highlight possible metabolic disturbances associated with T1D duration and oxidative stress. However, given the cross-sectional design, longitudinal studies are needed to confirm causality and clarify their predictive value in DKD progression.},
}

@article {pmid41282901,
year = {2025},
author = {Kong, X and Ibukun, F and Khan, MJ and Hafiz, G and Wehling, D and Dreger, K and Singh, M and Birch, D and Jaffe, G and Naufal, F and Traboulsi, EI and Duncan, J and Hufnagel, R and Carroll, J and Lu, Y and Matsui, R and Moulton, LH and Hawkins, B and Campochiaro, PA and , },
title = {Protocol for NAC Attack, a phase-3, multicenter randomized, parallel, double masked, placebo controlled trial evaluating the efficacy and safety of oral N-acetylcysteine (NAC) in patients with retinitis pigmentosa.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.05.25339486},
pmid = {41282901},
abstract = {BACKGROUND: Retinitis pigmentosa (RP) is the most common inherited retinal disease. Genetic mutations of many genes have been linked to RP. The mutations cause rod photoreceptor degeneration while sparing cone photoreceptors. However, loss of rod photoreceptors results in oxidative stress leading to cone photoreceptors degeneration, causing constriction of visual fields. In animal models of RP, treatments that reduce oxidative stress, including N-acetylcysteine (NAC), promote cone survival and maintenance of function.

METHODS: NAC Attack, funded by the US National Institutes of Health, is a multicenter, randomized, double-masked, parallel and placebo-controlled clinical trial testing whether oral NAC can delay disease progression in RP. A total of about 483 RP patients aged 18-65 are recruited from 31 sites in America and Europe, and randomized 2:1 to take NAC 1800 mg bid or placebo for 45 months. Eligible eyes have best-corrected visual acuity (BCVA) of 20/63 or better and the ellipsoid zone (EZ) width on the horizontal fovea optical coherence tomography (OCT) scan between 1500 µm and 8000 µm. The primary outcome is the cumulative loss of EZ, calculated as the area above the curve using EZ width measured every 9 months over 45 months. Secondary outcomes are change in mean macular sensitivity (MMS) measured by microperimetry and change in BCVA best-corrected visual acuity (BCVA) from baseline to M45. The long-term safety and tolerability of oral NAC 1800 mg bid will be assessed based upon the incidence and severity of ocular and systemic adverse events.

DISCUSSION: Data from NAC Attack will provide clinical evidence (or lack of) on the role of oxidative stress in human RP. Findings from NAC Attack have the potential to change clinical management of a blinding disease and will lead to a better understanding of basic mechanisms in RP. Moreover, data from NAC Attack will advance our knowledge on safety and drug interaction of NAC, informing studies in other medical areas where NAC is of interest for its potential in treating many medical conditions. Therefore, the trial is of high public health, clinical, and scientific significances.

TRIAL REGISTRATION: The ClinicalTrials.gov ID for NAC Attack is NCT05537220 .},
}

@article {pmid41282011,
year = {2025},
author = {Yu, C and Zhang, M and Xia, W},
title = {Asymmetric dimethylarginine mediates oxidative stress and atrial remodeling in HL-1 cells.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1696845},
pmid = {41282011},
issn = {2296-858X},
abstract = {INTRODUCTION: Atrial fibrillation (AF) is a common cardiac arrhythmia, and endothelial dysfunction and oxidative stress (OS) are key mechanisms promoting atrial remodeling. Asymmetric dimethylarginine (ADMA) inhibits nitric oxide synthase (NOS) but its role in AF-related atrial remodeling remains unclear.

METHODS: Mouse atrial myocyte HL-1 cells were treated with ADMA, H2O2, N-acetylcysteine (NAC), or their combinations. Cell viability, reactive oxygen species (ROS) levels, and TGF-β1 expression were detected using CCK-8, flow cytometry, fluorescence microscopy, and Western blot. A clinical cohort study included 60 AF patients and 30 controls to measure serum ADMA, TGF-β1, and NO levels.

RESULTS: ADMA (30 μM) significantly increased ROS generation and upregulated p47phox and TGF-β1 expression in HL-1 cells, which was reversed by NAC. AF patients had higher serum ADMA and TGF-β1 levels and lower NO levels than controls (P<0.01).

DISCUSSION: ADMA may induce TGF-β1 expression by enhancing NOX-ROS levels, leading to myocardial oxidative damage and atrial remodeling, which provides new insights into AF pathophysiology.},
}

@article {pmid41281764,
year = {2025},
author = {Hu, P and Fu, S and Li, B and Zhu, X and Tu, B and Han, C and Wang, J and Xu, W and Liu, X and Zhu, S and Wang, C and Deng, Z and Deng, Y and Xin, S and Song, J and Liu, J and Cui, K},
title = {N-Homocysteinylation of HMGB1/2 Promotes Corpus Cavernosum Endothelial Senescence in Erectile Dysfunction.},
journal = {International journal of biological sciences},
volume = {21},
number = {15},
pages = {6723-6744},
pmid = {41281764},
issn = {1449-2288},
mesh = {Male ; Humans ; *Homocysteine/metabolism/analogs & derivatives ; *Erectile Dysfunction/metabolism ; *HMGB1 Protein/metabolism ; Cellular Senescence/physiology ; Hyperhomocysteinemia/metabolism ; Middle Aged ; Endothelial Cells/metabolism ; *Penis/metabolism ; Animals ; },
abstract = {Homocysteine (Hcy) is an age-related risk factor for erectile dysfunction (ED), with enhanced vascular toxicity in middle-aged and elderly individuals. However, folate-based Hcy-lowering therapies have shown limited efficacy, necessitating a reevaluation of its age-dependent pathogenic mechanism. Here, we demonstrate that senescent endothelial cells exhibit heightened responsiveness of methionyl-tRNA synthetase 1 (MARS1) to Hcy, promoting the production of homocysteine thiolactone (HTL) and widespread N-homocysteinylation (K-Hcy) of proteins. K-Hcy, rather than acetylation, drives cytoplasmic translocation and extracellular release of high mobility group box proteins 1 and 2 (HMGB1/2), amplifying the senescence-associated secretory phenotype (SASP). Competitive inhibition of MARS1 with N-acetylcysteine (NAC) attenuates endothelial senescence and improves erectile function in middle-aged individuals with hyperhomocysteinemia by reducing HTL, rather than Hcy itself, while synergizing with tadalafil. Collectively, our findings highlight the pivotal role of the age-dependent MARS1-HTL axis in the pathogenesis of homocysteine-induced ED, offering a promising therapeutic strategy for ED in the aging population.},
}

Male
Humans
*Homocysteine/metabolism/analogs & derivatives
*Erectile Dysfunction/metabolism
*HMGB1 Protein/metabolism
Cellular Senescence/physiology
Hyperhomocysteinemia/metabolism
Middle Aged
Endothelial Cells/metabolism
*Penis/metabolism
Animals

@article {pmid41276507,
year = {2025},
author = {Liu, X and Hu, W and Sun, J and Wu, B},
title = {Fructose intake driven glycolysis-ROS-EGFR axis specifically promotes the generation and pathogenicity of Th17 cells.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-025-66064-5},
pmid = {41276507},
issn = {2041-1723},
support = {32170886//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32470939//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Th17 cells are quite heterogeneous. Treating Th17-related inflammatory disorders requires understanding the functionally diverse subtypes in the context of tissue homeostasis, which is shaped by nutrient availability among other factors. Here, we show that increased consumption of fructose exacerbates colitis and experimental autoimmune encephalomyelitis (EAE), via pathogenic Th17 cells. Fructose selectively enhances the differentiation and function of this pathogenic subtype of Th17 cells, which are induced by a combination of IL1β, IL-6 and IL-23 (pTh17). In contrast, TGFβ1and IL-6-induced homeostatic, non-pathogenic Th17 cells remain unaffected. Notably, fructose enhances metabolic activity in pTh17 cells, leading to increased ROS production and subsequently promoting pathogenic-Th17 cell differentiation. N-acetyl cysteine (NAC), a ROS scavenger, specifically impaired pathogenic-Th17 cell immunity and mitigated high-fructose regulated colitis and EAE disease. Mechanistically, ROS accumulation results in elevated EGFR expression and phosphorylation, which leads to increased nuclear translocation. Nuclear EGFR binds to STAT3, enhancing its transcriptional activity at the CNS6 and CNS9 regions of Rorc. In summary, our work describes here a mechanism through which high fructose intake specifically exacerbates pathogenic Th17-cell-related pathologies and provides potential therapeutic targets for pTh17-mediated diseases.},
}

@article {pmid41274519,
year = {2025},
author = {Burke, G and Ebrahimi, F and Fehrenbach, G and Buckley, C and Murphy, E and Devine, D and Major, I},
title = {Controlled-release hybrid hydrogels delivering synergistic N-acetyl cysteine, ibuprofen, and progesterone combinations for enhanced peripheral nerve regeneration.},
journal = {International journal of pharmaceutics},
volume = {687},
number = {},
pages = {126423},
doi = {10.1016/j.ijpharm.2025.126423},
pmid = {41274519},
issn = {1873-3476},
abstract = {Peripheral nerve injuries (PNI) remain a major clinical challenge, particularly for defects exceeding 3 cm. Autografts are the current gold standard for small gaps, but their use is limited by donor site morbidity, infection risk, and poor outcomes in larger defects. Synthetic grafts and allografts have achieved only modest clinical success, underscoring the need for therapeutic systems that actively support regeneration. This study investigated three FDA-approved drugs - N-acetyl cysteine (NAC), ibuprofen (Ibu), and progesterone (Prog) - for their synergistic potential to enhance Schwann cell (SC) and PC-12 cell proliferation as a strategy for peripheral nerve repair. High-throughput screening using Alamar Blue assays assessed viability and proliferation at 24, 48, and 72 h across dual- and triple-drug combinations. The optimised formulation of 75 µM NAC, 16.25 µM Ibu, and 30 µM Prog significantly increased proliferation compared with untreated controls without inducing cytotoxicity. A validated high-performance liquid chromatography (HPLC) method was developed to quantify simultaneous release of all three drugs from polyethylene glycol dimethacrylate-dipentaerythritol hexa(3-mercaptopropionate) (PEGDMA-DiPETMP) hydrogels. Controlled, sequential release was achieved, with complete elution of NAC within 24 h, Ibu within 72 h, and Prog over 21 days. These timelines correspond to the early antioxidative, anti-inflammatory, and neurotrophic phases of peripheral nerve repair. Although proliferation assays were conducted using directly applied drug combinations, the established release behaviour provides a mechanistic rationale for future validation of hydrogel-mediated delivery. The synergistic combination of NAC, Ibu, and Prog delivered from PEGDMA-DiPETMP hybrid hydrogels provides a reproducible and temporally coordinated release platform that promotes cellular proliferation and supports peripheral nerve regeneration.},
}

@article {pmid41274204,
year = {2025},
author = {Zhu, Y and Wu, J and Zhao, S and Yang, J and Huang, M and Liu, N and Yang, B and Che, Z and Ju, J},
title = {Environmentally relevant concentrations of polystyrene nanoplastics induce Parkinson's-like neurotoxicity in C. elegans via oxidative stress.},
journal = {Environment international},
volume = {206},
number = {},
pages = {109926},
doi = {10.1016/j.envint.2025.109926},
pmid = {41274204},
issn = {1873-6750},
abstract = {This study reveals that environmentally relevant polystyrene nanoplastics (PS-NPs) induces Parkinson's disease (PD)-like pathology in Caenorhabditis elegans (C. elegans) through oxidative stress. Wild-type and transgenic strains were exposed to PS-NPs at concentrations of 0.1-100 μg/L to assess behavioral toxicity, neuronal damage, and molecular mechanisms. Locomotor deficits (reduction in body bends and head thrashes) and disrupted PD-associated behaviors (impairment of food-induced basal slowing response; increased swimming paralysis rate) were observed at all concentrations, while developmental parameters remained unaffected. Although some behavioral endpoints didn't exhibit a strictly monotonic dose-response, Jonckheere-Terpstra trend analyses confirmed significant overall trends for multiple key parameters, underscoring the pervasive impact of PS-NP exposure. Selective degeneration of dopaminergic neurons and exacerbated α-synuclein aggregation confirmed neuropathological specificity. Transcriptomic analysis linked these phenotypes to oxidative stress, showing elevated reactive oxygen species (ROS) and upregulation of antioxidant enzymes (SOD-3, GST-4), alongside paradoxical suppression of the redox regulator skn-1. Genetic validation using trx-1 mutants prevented PS-NP-induced paralysis, whereas trx-4 deficiencies exacerbated toxicity, highlighting their distinct roles in redox defense. Co-treatment with N-acetylcysteine (NAC) attenuated PS-NP-induced paralysis, lowering the rate from 51.33 % to 29.47 %, though rescue failure in trx-4 mutants indicated mechanistic complexity and the indispensable role of endogenous defense systems. Critically, neurotoxicity occurred even at 0.1 μg/L PS-NPs, a level relevant to environmental contamination. These findings establish PS-NPs as potent inducers of PD-like neurodegeneration via complex oxidative stress cascades, validated by genetic and antioxidant interventions at environmentally realistic exposure levels, and highlight the urgency of monitoring nanoplastic pollution and developing antioxidant-based interventions.},
}

@article {pmid41270839,
year = {2025},
author = {Gunes, M and Öcal, GK and Kılıclı, B and Ozturk, AM and Armagan, G and Karavana, SY},
title = {N-acetylcysteine loaded electrospun core/shell nanofibers: a promising system for ferroptosis in spinal cord injury.},
journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V},
volume = {},
number = {},
pages = {114938},
doi = {10.1016/j.ejpb.2025.114938},
pmid = {41270839},
issn = {1873-3441},
abstract = {Spinal cord injury (SCI) induces a cascade of secondary damage mechanisms, including oxidative stress, inflammation, and cell death, which severely impair neuronal recovery. In this study, N-acetylcysteine (NAC), a thiol-based antioxidant with limited CNS bioavailability, was encapsulated in polycaprolactone (PCL) nanofibers using emulsion electrospinning. This approach allows localized and sustained drug delivery. Span 80 and Poloxamer 407 were used as surfactants to stabilize the emulsion and increase the hydrophilicity of the fibers. The resulting core/shell nanofibers (NAC-CSN) exhibited uniform morphology, improved wettability, and favorable mechanical properties, while supporting cell viability and migration in vitro. Sustained NAC release over several days was achieved, indicating diffusion-controlled delivery. In a rat model of SCI, NAC-CSN treatment attenuated oxidative and ferroptotic damage and promoted early neuroregeneration, which enabled measurable locomotor recovery. These findings suggest that NAC-CSN scaffolds offer an effective neuroprotective strategy against secondary SCI damage and, by enabling localized antioxidant delivery at the lesion site, represent a clinically applicable platform for future tissue engineering and translational therapies.},
}

@article {pmid41268347,
year = {2025},
author = {Chen, Q and Xiao, Z and Ying, X and Yang, Y and Chen, J and Wu, Z and Zeng, W and Miao, C and Nan, Y and Huang, Q and Ai, K},
title = {Molybdenum-bridged endo-exogenous antioxidant synergy reverses acute kidney injury via mitochondrial homeostasis reconstruction.},
journal = {Bioactive materials},
volume = {54},
number = {},
pages = {777-796},
pmid = {41268347},
issn = {2452-199X},
abstract = {Acute kidney injury (AKI) progression is driven by mitochondrial redox collapse in proximal tubular epithelial cells (PTECs), where reactive oxygen species (ROS) surge and molybdenum (Mo) metabolic dysregulation create an "oxidative storm-defense collapse" cycle. Conventional antioxidant therapies fail to halt AKI chronicity due to their inability to restore Mo-dependent detoxification enzymes (e.g., Mo-containing Amidoxime Reducing Component, mARC). To address this dual pathology, we developed N-acetylcysteine (NAC)-modified molybdenum disulfide quantum dots (NMDs) that implement an endo-exogenous antioxidant collaborative strategy, synergizing exogenous ROS elimination with endogenous Mo enzyme restoration. NMDs achieve triple-tiered targeting: 1) Organ-selective accumulation leveraging NMDs' hydrophilicity and ultrasmall size; 2) Cell-specific internalization through Organic Anion Transporter 1 (OAT1)-mediated active uptake into PTECs; 3) Mitochondrial precision delivery guided by NAC's intrinsic mitochondrial affinity. Within pathological microenvironments, NMDs exhibit multidimensional therapeutic superiority: exposed Mo(Ⅳ) directly quenches mitochondrial ROS via electron transfer (external clearance), while released Mo ions reactivate mARC and NAC supplies glutathione precursors, synergistically rebuilding endogenous antioxidant defenses (internal reinforcement). In vivo validation demonstrated NMDs' superior therapeutic efficacy, outperforming clinical antioxidant NAC. This work pioneers a "scavenging-fortification" strategy through Mo-centric metabolic regulation and nanotechnology integration, validating Mo-based materials' therapeutic potential and establishing a paradigm for mitochondrial-targeted AKI treatment.},
}

@article {pmid41267214,
year = {2025},
author = {Minchenberg, SB and Ribera, MO and Hionides Gutierrez, A and Datta, A and Brezani, V and Santos, B and Hong, SM and Kulkarni, S and Nagesh, PT and Szabo, G},
title = {Unraveling the gastrointestinal tract's response to alcohol binges: Neutrophil recruitment, neutrophil extracellular traps, and intestinal injury.},
journal = {Alcohol, clinical & experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1111/acer.70196},
pmid = {41267214},
issn = {2993-7175},
support = {R01AA011576/NH/NIH HHS/United States ; R56AA017729/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Excessive alcohol consumption results in gastrointestinal (GI) tract dysfunction, including disruption of the intestinal barrier and exposure of the liver to microbes and gut-derived pathogen-associated molecular patterns (PAMPs). The upper GI tract is exposed to the highest amount of alcohol, but little is known about alcohol's impact on GI inflammation. This study aimed to evaluate the initial effects of alcohol binges on GI inflammation.

METHODS: A murine model of binge drinking was established with daily oral gavages of alcohol (3.5 g/kg) for 3 days in C57BL/6J female mice. The proximal small intestine (PSI), distal small intestine (DSI), and colon were evaluated for inflammation at 3 and 24 h after the last binge. To determine whether reactive oxygen species (ROS) contribute to intestinal inflammation, a subset of mice were given 500 mg/kg N-acetyl-cysteine (NAC) with alcohol via gavage. To assess the role of neutrophil extracellular traps (NETs), mice were treated 1 h before the alcohol binges with 5 mg/kg of DNase, a nonspecific inhibitor of NETs.

RESULTS: Alcohol binges induced a PSI enteropathy with neutrophil recruitment, activation, NETs, and increased serum endotoxin without significant changes in PSI pro-inflammatory cytokines. Neutrophil recruitment and serum endotoxin normalized 24 h after the last binge with persistent PSI villous blunting. While alcohol generated ROS, administration of the antioxidant, NAC, failed to prevent the PSI enteropathy, neutrophil activation, or increased serum endotoxin. DNase treatment improved the PSI enteropathy and reduced serum endotoxin, neutrophil recruitment, and neutrophil activation. We found robust upregulation of Gal-3 and CXCL10 in the PSI after alcohol binges is associated with neutrophil recruitment and activation.

CONCLUSION: Alcohol binges result in a PSI enteropathy, transient infiltration of neutrophils, and NETs that are independent of ROS production. Treatment with DNase, a nonspecific inhibitor of NETs, mitigates alcohol-induced PSI enteropathy, neutrophil recruitment and bacterial translocation.},
}

@article {pmid41260340,
year = {2025},
author = {Zmuda, AJ and Toensing, AJ and Wissbroecker, KB and Niehaus, TD},
title = {Bacillus subtilis encodes three N-acetylcysteine deacetylase enzymes that can catalyze the final step in S-(2-succino)cysteine breakdown.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110954},
doi = {10.1016/j.jbc.2025.110954},
pmid = {41260340},
issn = {1083-351X},
abstract = {Succination occurs when the TCA cycle intermediate fumarate reacts with cellular thiols, such as cysteine, yielding the damaged metabolite S-(2-succino)cysteine (2SC). Increased fumarate levels result in global succination of thiol-containing macromolecule and metabolites, which has been implicated in many human diseases. 2SC is a chemically stable molecule, however, enzymatic breakdown pathways have been identified in prokaryotes that involve N-acetylation of 2SC followed by a breakdown step that results in release of the succino- moiety and N-acetylcysteine (NAC). NAC must be metabolized to cysteine to be assimilated, but enzymes catalyzing NAC deacetylation had hitherto not been thoroughly characterized. Here, we describe three enzymes in Bacillus subtilis, ScmP, YhaA, and YtnL, that all possess high NAC deacetylase activity in vitro. All three enzymes are metal-dependent hydrolases that are most active with cobalt and show remarkable specificity to NAC compared to structurally related acetylated small molecules. Growth assays demonstrated that these genes are functionally redundant in B. subtilis, and growth on NAC is only severely compromised when all three genes are knocked out of the genome. Together, our biochemical and genetic studies complete the functional characterization of the three step 2SC degradation pathway in B. subtilis.},
}

@article {pmid41248871,
year = {2025},
author = {Wang, L and Wang, C and Ding, H and Feng, S and Wang, X and Wu, J and Liu, D},
title = {Soybean glycinin and β-conglycinin disrupted the interaction bwteen mitochondria and endoplasmic reticulum in porcine intestinal epithelial cells through oxidative stress cascades.},
journal = {Developmental and comparative immunology},
volume = {},
number = {},
pages = {105523},
doi = {10.1016/j.dci.2025.105523},
pmid = {41248871},
issn = {1879-0089},
abstract = {Soybean glycinin (11S) and β-conglycinin (7S) are major contributors to allergic diarrhea and intestinal barrier damage in young animals. This study investigated the molecular mechanisms underlying the 7S- and 11S-induced dysfunction of mitochondrial and endoplasmic reticulum (ER) interactions in porcine intestinal epithelial (IPEC-J2) cells via the oxidative stress pathway. The results showed that 7S- and 11S-induced oxidative stress, as evidenced by reduced manganese superoxide dismutase (Mn-SOD) activity and elevated 8-Hydroxy-2'-deoxyguanosine (8-OHdG) levels, with excessive reactive oxygen species (ROS) accumulation and elevated Ca[2+] levels; decreased mitochondrial membrane potential (MMP), damaged mitochondria-associated endoplasmic reticulum membranes (MAM) structure; up-regulated the protein expression of glucose-regulated protein 75 (GRP75) and mitochondrial Rho-GTPase 1 (Miro1), while inositol 1,4,5 -trisphosphate receptor (IP3R), voltage-dependent anion channel 1 (VDAC1), mitofusin2 (MFN2) and phosphofurin acidic cluster sorting protein 2 (PACS2) were down-regulated. N-acetylcysteine (NAC)pre-treatment alleviated ROS accumulation and mitigated Ca[2+] overload and MAM dysfunction, thereby ameliorating IPEC-J2 cell injury. In conclusion, 7S- and 11S-induced ROS burst to disrupt mitochondria-ER interaction homeostasis, leading to MAM structural damage and calcium dysregulation in IPEC-J2 cells, NAC effectively mitigated this process by scavenging ROS. These findings elucidate the critical involvement of subcellular organelle interaction disorders in food allergy pathogenesis and provide novel insights for targeted intervention strategies.},
}

@article {pmid41245027,
year = {2025},
author = {Kamal, S and Akhavan, S and Warolin, J and Baig, A},
title = {A case of lactobezoar: Outpatient management in a neonate.},
journal = {JPGN reports},
volume = {6},
number = {4},
pages = {427-429},
doi = {10.1002/jpr3.70061},
pmid = {41245027},
issn = {2691-171X},
abstract = {A lactobezoar is a conglomerate of undigested and partially digested milk components and is the most common form of bezoar in infants. Described treatments include hospitalization for intravenous fluids and cessation of feeds, endoscopy with administration of N-acetyl cysteine, and surgical or endoscopic removal. We report a case of a 5-month-old infant with a history of prematurity of 28 weeks, with poor feeding and emesis, found to have a gastric lactobezoar on imaging without signs of obstruction that was managed without surgical intervention. This case presentation describes the successful treatment of a patient with 100% whey formula for the treatment of lactobezoar, avoiding invasive treatment and hospitalization.},
}

@article {pmid41243318,
year = {2025},
author = {Ikegaki, Y and Terachi, A and Yamao, S and Nagano, T and Iwasaki, T and Kamada, S},
title = {Epsin 3 Promotes Cellular Senescence Through Reactive Oxygen Species-Mediated Induction of DNA Damage.},
journal = {Genes to cells : devoted to molecular & cellular mechanisms},
volume = {30},
number = {6},
pages = {e70067},
doi = {10.1111/gtc.70067},
pmid = {41243318},
issn = {1365-2443},
support = {25640063//Japan Society for the Promotion of Science/ ; 17K15595//Japan Society for the Promotion of Science/ ; 20K07591//Japan Society for the Promotion of Science/ ; 20K15791//Japan Society for the Promotion of Science/ ; 21K05308//Japan Society for the Promotion of Science/ ; 24K10360//Japan Society for the Promotion of Science/ ; JPMJSP2148//Japan Science and Technology Agency/ ; //Uehara Memorial Foundation/ ; //Japan Science Society/ ; #4067//Hyogo Science and Technology Association/ ; },
mesh = {*Reactive Oxygen Species/metabolism ; *Cellular Senescence/genetics ; *DNA Damage ; Humans ; rac1 GTP-Binding Protein/metabolism/antagonists & inhibitors ; Oxidative Stress ; Acetylcysteine/pharmacology ; },
abstract = {Cellular senescence is caused by various stresses, including DNA damage, oxidative stress, oncogene activation, and telomere shortening. However, the detailed molecular mechanisms of cellular senescence have yet to be elucidated. Recently, using comparative transcriptomics and quantitative PCR, we identified several genes that are specifically upregulated in senescent cells in a p53-dependent manner, including Epsin 3 (EPN3). However, the functional relevance of EPN3 to senescence has not yet been defined. Here, we performed functional analyses to investigate the relationship between EPN3 and the senescence program. We found that EPN3 knockdown suppressed senescent phenotypes induced by DNA damage. Furthermore, ectopic expression of EPN3 induced senescence accompanied by increased reactive oxygen species (ROS) and accumulation of DNA damage. Furthermore, EPN3-induced DNA damage was suppressed by genetic and pharmacological inhibition of Rac1. Finally, treatment with ROS scavengers, N-acetyl-l-cysteine (NAC) and l-Ascorbic Acid (LAA), prevented EPN3-induced DNA damage, and a Rac1 inhibitor reduced ROS levels in EPN3-expressing stable clones. These results indicate that EPN3 induces DNA damage and promotes senescence via Rac1 activity and ROS generation.},
}

*Reactive Oxygen Species/metabolism
*Cellular Senescence/genetics
*DNA Damage
Humans
rac1 GTP-Binding Protein/metabolism/antagonists & inhibitors
Oxidative Stress
Acetylcysteine/pharmacology

@article {pmid41242433,
year = {2025},
author = {Shiozawa, A and Kajiwara, C and Ishii, Y and Tateda, K},
title = {N-acetylcysteine is associated with restoration of autophagy-related signaling and reduced intracellular Mycobacterium avium in alveolar type 1 epithelial cells.},
journal = {Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy},
volume = {},
number = {},
pages = {102864},
doi = {10.1016/j.jiac.2025.102864},
pmid = {41242433},
issn = {1437-7780},
abstract = {PURPOSE: In patients with pulmonary Mycobacterium avium complex disease, the barrier function of the airway epithelium is reduced. In this study, we focused on the host defense responses of alveolar epithelial cells to M. avium.

METHODS AND RESULTS: Clinical isolates of M. avium were used to infect murine alveolar type 1 epithelial cells (AT1s). Administration of N-acetylcysteine suppressed bacterial growth in the infected cells. Expression of the autophagosome marker microtubule-associated protein 1 light chain 3 was decreased in M. avium-infected cells and appeared to be restored by N-acetylcysteine administration. M. avium infection negatively affected the autophagic pathway, specifically mTORC1 signaling and its upstream factor, SLC37A4, which was partially restored by N-acetylcysteine administration. Autophagy inhibition by bafilomycin attenuated the NAC-associated reduction in bacterial load, suggesting involvement of autophagy-related pathways.

CONCLUSIONS: Our results suggest that M. avium infection is associated with suppressed autophagy-related responses in AT1s. NAC may function as an immunomodulatory agent by modulating autophagy-associated pathways and reducing intracellular bacterial burden.},
}

@article {pmid41242411,
year = {2025},
author = {Dai, J and Du, Y and Wang, Y and Yang, G},
title = {N-Acetylcysteine suppresses proteasome pathway activation and muscular damage induced by microplastics and chromium nanoparticles.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {127387},
doi = {10.1016/j.envpol.2025.127387},
pmid = {41242411},
issn = {1873-6424},
abstract = {Under global plastic proliferation, microplastics (MPs) have become significant environmental pollutants. Annually, over one million patients undergo orthopedic surgeries involving chromium alloy implants, which release chromium nanoparticles (Cr NPs) during long-term intraosseous residence. These particles migrate to adjacent muscle tissues, potentially inducing adverse effects. This study aimed to investigate the combined impact of Cr NPs and MPs co-exposure on muscle systems and underlying mechanisms. Human tissue analysis confirmed concurrent Cr NPs and MPs accumulation in peri-implant regions. In vitro experiments showed elevated reactive oxygen species (ROS) levels and pro-inflammatory cytokine expression in C2C12 cells exposed to Cr NPs/MPs individually or combined, with synergistic enhancement under co-exposure conditions. Zebrafish models exhibited spinal deformities, reduced motility, and histopathological muscle damage following pollutant exposure. Mechanistic studies revealed proteasome pathway activation as a key mediator, evidenced by PSMD2 overexpression, Notably, N-acetylcysteine (NAC) pretreatment ameliorated co-exposure-induced muscle injury, reduced ROS accumulation, and inhibited proteasome activation. This research provides new perspectives on Cr NP/MP synergistic toxicity and identifies NAC as a potential therapeutic strategy against pollution-related muscle damage.},
}

@article {pmid41242401,
year = {2025},
author = {Mohammadpour-Asl, S and Shirpoor, A and Alipour, S and Naderi, R},
title = {Nandrolone decanoate induces liver damage via TGF-β/Smad3/miR-29 and regulation of FAT/CD36, PTP1B, HNF4A expression in male rats: Rescue Effect of N-acetylcysteine.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {},
number = {},
pages = {106902},
doi = {10.1016/j.jsbmb.2025.106902},
pmid = {41242401},
issn = {1879-1220},
abstract = {Anabolic-androgenic steroid (AAS) abuse is associated with damage to various organs, including the liver. However, the underlying molecular mechanisms remain unclear. This study was conducted to elucidate the effect of nandrolone decanoate on liver injury, both alone and in combination with N-acetylcysteine (NAC), and its related mechanisms. Twenty-four male Wistar rats were randomly subdivided into three groups: Control (Con), Nandrolone (10mg/kg) (ND), and Nandrolone + NAC (ND+NAC: 150mg/kg daily). After 6 weeks, nandrolone treatment led to increased levels of triglycerides, cholesterol, LDL, AST, ALT, and ALP, along with a decreased HDL level compared to the control group. ND administration also elevated the expression of PTP1B, HNF4A, and FAT/CD36 genes, as well as protein levels of MMP-2, MMP-9, TGF-β1, SMAD-3, and SREBP-1. miRNA-29b levels decreased in liver tissue following nandrolone exposure, as determined by RT-PCR. Moreover, histopathological examination showed increased fibrosis after ND treatment. Consumption of NAC along with ND partially ameliorated gene and protein expression alterations and fibrotic changes, and improved the undesirable lipid profile and liver enzyme levels compared to the ND group. These findings indicate that ND-induced liver abnormalities may be partly associated with lipid homeostasis changes mediated by overexpression of the aforementioned genes and proteins. They also demonstrate that these effects can be reduced by using NAC as an antioxidant and anti-inflammatory agent.},
}

@article {pmid41241719,
year = {2025},
author = {El Far, MS and Kassem, MA and Edward, EA and Evans, BA and Baker, DJ and Zakaria, AS},
title = {Genomic insights into ST85 and ST158 belonging to recently emerged global clones of multidrug-resistant Acinetobacter baumannii isolates from Egypt: in vitro assessment of repurposed drug-antibiotic combinations.},
journal = {Annals of clinical microbiology and antimicrobials},
volume = {24},
number = {1},
pages = {63},
pmid = {41241719},
issn = {1476-0711},
mesh = {*Acinetobacter baumannii/genetics/drug effects/isolation & purification/classification ; Egypt/epidemiology ; *Drug Resistance, Multiple, Bacterial/genetics ; *Anti-Bacterial Agents/pharmacology ; Humans ; *Acinetobacter Infections/microbiology/epidemiology/drug therapy ; Microbial Sensitivity Tests ; beta-Lactamases/genetics/metabolism ; Phylogeny ; Multilocus Sequence Typing ; Whole Genome Sequencing ; Genome, Bacterial ; Bacterial Proteins/genetics/metabolism ; Drug Repositioning ; Genotype ; Virulence ; },
abstract = {BACKGROUND: The strikingly rapid increase in multidrug-resistant Acinetobacter baumannii (MDRAB) incidence rates represents a major challenge in healthcare settings. This is due to the limitation of the currently available treatment options to combat tenacious A. baumannii infections. MDRAB isolates belonging to recently emerged global clones GC9 and GC10 are on the rise, especially in the Middle East and Africa, which warrants a thorough investigation of these global clones.

METHODS: Thirteen A. baumannii isolates belonging to less well-studied global clones were selected from 46 isolates collected in Alexandria, Egypt, after determining their clone using MLST. Susceptibility to multiple antibiotic classes was determined by the Kirby-Bauer disk diffusion method. Testing of carbapenemase activity and selected virulence phenotypes was done. Whole genome sequencing, phylogenetic analysis, and molecular characterization of the resistance and virulence genotypes were performed. Checkerboard assay was employed for testing the combination of each of ciclopirox and N-acetylcysteine (NAC), as potential repurposed drugs, with each of meropenem and levofloxacin antibiotics against MDRAB isolates.

RESULTS: All the isolates displayed multidrug resistance and were carbapenemase-positive. One isolate showed strong biofilm formation, whereas 4 and 8 isolates were moderate and weak biofilm formers, respectively. Twelve out of thirteen isolates were positive twitchers. The isolates showed moderate phospholipase and strong protease activities. However, low phospholipase production was detected in one isolate. The genomic analysis revealed that 3 and 10 isolates belonged to ST85 (GC9) and ST158 (GC10), respectively. All 13 isolates harbored multiple resistance genes including oxa23 and carried an RP-T1 rep type plasmid. Phylogenetic analysis demonstrated that the isolates were clustered together forming subclades with others from Alexandria/Egypt. The AbGRI3-2 resistance island (RI) was detected in ST158 isolates carrying R3-T60 rep type and 9 antibiotic resistance genes. The combination of NAC with each of meropenem or levofloxacin showed a synergistic action against 3 and one isolate(s), respectively, using the checkerboard assay.

CONCLUSION: The current study provides an in-depth characterization of the collected MDRAB isolates from the global clones GC9 and GC10. The endemicity of these clones necessitates strategies to mitigate ongoing MDRAB outbreaks in countries like Egypt. Combination of NAC with meropenem or levofloxacin represents a promising treatment option against the newly emerged global clones that needs further in vivo testing.},
}

*Acinetobacter baumannii/genetics/drug effects/isolation & purification/classification
Egypt/epidemiology
*Drug Resistance, Multiple, Bacterial/genetics
*Anti-Bacterial Agents/pharmacology
Humans
*Acinetobacter Infections/microbiology/epidemiology/drug therapy
Microbial Sensitivity Tests
beta-Lactamases/genetics/metabolism
Phylogeny
Multilocus Sequence Typing
Whole Genome Sequencing
Genome, Bacterial
Bacterial Proteins/genetics/metabolism
Drug Repositioning
Genotype
Virulence

@article {pmid41240208,
year = {2025},
author = {Qi, X and Hu, Y and Yang, J and Jiang, M and Zhang, J and Du, Y and Hu, C},
title = {Selenium alleviates Staphylococcus aureus-induced mastitis by modulating mitochondrial dynamics and inhibiting the ROS/NLRP3/Pyroptosis pathway.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {82},
pmid = {41240208},
issn = {1573-4978},
mesh = {Animals ; *Selenium/pharmacology/metabolism ; *Pyroptosis/drug effects ; Female ; Reactive Oxygen Species/metabolism ; Staphylococcus aureus/drug effects/pathogenicity ; Cattle ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Mastitis, Bovine/drug therapy/microbiology/metabolism ; *Mitochondrial Dynamics/drug effects ; *Staphylococcal Infections/drug therapy ; Mitochondria/metabolism/drug effects ; Signal Transduction/drug effects ; *Mastitis/drug therapy/microbiology ; Membrane Potential, Mitochondrial/drug effects ; Disease Models, Animal ; },
abstract = {BACKGROUND: The pathogenesis of bovine mastitis involves inflammation and cell death, with pyroptosis being a key factor in its development. Currently, antibiotics remain the primary therapeutic option for bovine mastitis, however, the increasing prevalence of antibiotic resistance constitutes a major public health threat. Selenium (Se) has been reported to alleviate inflammation primarily through its antioxidant properties, but the mechanism by which Se regulates pyroptosis in bovine mastitis remains unclear.

METHODS AND RESULTS: In this study, an in vitro mastitis model was established by infecting MAC-T cells with inactivated Staphylococcus aureus (S. aureus) (MOI = 10, 12 h). The results revealed that the mitochondrial membrane potential of the MAC-T cells in the infection group decreased significantly. Moreover, the accumulation of Reactive oxygen species (ROS) was accompanied by the activation of NOD-like receptor family containing pyrin domain 3 (NLRP3), the expression of the pyroptosis-related genes gasdermin D amino terminal fragment (GSDMD-N), and cysteine ​​aspartate specific protease 1 (cleaved-caspase 1). Pretreatment with Se, the NLRP3 inhibitor MCC950 and the antioxidant N-acetylcysteine ​​(NAC) attenuated mitochondrial damage, ROS accumulation, and the inhibition of pyroptosis. An in vivo mastitis model was established in mice fed a high-selenium diet (containing 1.5 mg/kg Se) and intramammarily injected with inactivated S. aureus (1 × 10[8] CFU/mL). Histological analysis revealed intact alveolar structure and reduced inflammatory cell infiltration in mice fed the high-selenium diet. The expression of the inflammasome NLRP3 downregulated, and the expression of GSDMD-N, a direct executor of pyroptosis, upregulated.

CONCLUSION: Our in vitro and in vivo results confirmed that Se alleviate mitochondrial damage and pyroptosis by inhibiting the NLRP3 pathway, ultimately alleviating mastitis.},
}

Animals
*Selenium/pharmacology/metabolism
*Pyroptosis/drug effects
Female
Reactive Oxygen Species/metabolism
Staphylococcus aureus/drug effects/pathogenicity
Cattle
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Mastitis, Bovine/drug therapy/microbiology/metabolism
*Mitochondrial Dynamics/drug effects
*Staphylococcal Infections/drug therapy
Mitochondria/metabolism/drug effects
Signal Transduction/drug effects
*Mastitis/drug therapy/microbiology
Membrane Potential, Mitochondrial/drug effects
Disease Models, Animal

@article {pmid41239787,
year = {2025},
author = {Li, J and Li, W and Xue, Y and Zhu, H and Zhang, D and Ren, Y and Wu, C and Liu, Y and Peng, L and Yang, Z and Li, H and Liu, C and Li, Z and Jin, Z and Huang, H},
title = {Oral Ingestion of Polystyrene Microplastics Aggravates Chronic Pancreatitis Through ROS Induced NF-κb/TGF-β Signaling Pathway and Alteration of Gut Microbiota.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {22},
pages = {e71223},
doi = {10.1096/fj.202501205RR},
pmid = {41239787},
issn = {1530-6860},
support = {82020108005//MOST | NSFC | Major International Joint Research Programme/ ; 82370655//MOST | National Natural Science Foundation of China (NSFC)/ ; 82370658//MOST | National Natural Science Foundation of China (NSFC)/ ; //Wuxi Taihu Lake Talent Plan, Supports for Leading Talents inMedical and Health Profession/ ; },
mesh = {Animals ; Mice ; *NF-kappa B/metabolism ; *Microplastics/toxicity ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; *Polystyrenes/toxicity/administration & dosage ; *Transforming Growth Factor beta/metabolism ; *Pancreatitis, Chronic/metabolism/chemically induced/pathology/microbiology ; *Gastrointestinal Microbiome/drug effects ; Male ; Mice, Inbred C57BL ; Fibrosis ; Pancreatic Stellate Cells/metabolism/drug effects ; Administration, Oral ; },
abstract = {Microplastics (MPs), as a kind of emerging pollutant, have attracted widespread attention. The effects of MPs of different diameter sizes on chronic pancreatitis and their underlying mechanisms remain to be explored. Therefore, we established a mouse chronic pancreatitis model exposed to two-diameter polystyrene particles (2 or 0.5 μm) for 6 weeks. We found that MPs exposure resulted in severe pancreatic fibrosis in mice, which was negatively correlated with particle size. In-depth mechanistic exploration revealed that after exposure to MPs, MPs can enter pancreatic stellate cells through the cell membrane, stimulate the activation of cellular ROS, further activate the NF-κB and TGF-β signaling pathways, and increase the levels of fibrotic proteins and collagen. The pancreatic fibrosis can be reversed by the ROS inhibitor N-acetyl cysteine (NAC). Meanwhile, oral intake of polystyrene particles in chronic pancreatic mice also affected the diversity of intestinal bacteria, downregulating the bacteria in the Bacteroidota phylum and upregulating the bacteria in the Verrucomicrobiota phylum, which could be another potential mechanism underlying the pathogenic effect of pancreatic fibrosis. Our findings reveal the adverse effects of MPs on chronic pancreatitis through inducing cellular ROS, activating pancreatic stellate cells and altering gut microbes.},
}

Animals
Mice
*NF-kappa B/metabolism
*Microplastics/toxicity
*Reactive Oxygen Species/metabolism
*Signal Transduction/drug effects
*Polystyrenes/toxicity/administration & dosage
*Transforming Growth Factor beta/metabolism
*Pancreatitis, Chronic/metabolism/chemically induced/pathology/microbiology
*Gastrointestinal Microbiome/drug effects
Male
Mice, Inbred C57BL
Fibrosis
Pancreatic Stellate Cells/metabolism/drug effects
Administration, Oral

@article {pmid41234378,
year = {2025},
author = {Sadeghzadeh-Bazargan, A and Farahani, S and Goodarzi, A and Zeinali, R and Gheisari, M and Atefi, N and Ghassemi, M and Roohaninasab, M and Dehghani, A},
title = {The Effectiveness and Safety of Oral N-Acetylcysteine in Combination With Narrow-Band Ultraviolet B (NB-UVB) Phototherapy Compared With NB-UVB Phototherapy Alone in the Treatment of Vitiligo: A Pilot Study.},
journal = {Health science reports},
volume = {8},
number = {11},
pages = {e71467},
pmid = {41234378},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Vitiligo is an autoimmune skin disease, characterized by depigmented patches over skin. Numerous studies have been conducted to identify the most effective treatment for this condition. Based on high rate of oxidative stress in pathogenesis of vitiligo, antioxidant treatments like N-acetylcysteine (NAC) is suggested. This study aimed to evaluate the efficacy and safety of oral NAC in combination with narrow-band UVB (NB-UVB) phototherapy, comparing it to NB-UVB therapy alone in treating patients with generalized vitiligo.

METHODS: This single-blind, randomized controlled Phase 1 trial conducted over a period of 4 months, involving 16 participants. The patients were split into two, with one group receiving 600 mg of oral NAC twice daily, alongside NB-UVB, while the control group received only phototherapy. The patients were reassessed after 2 and 4 months, with evaluations based on the Vitiligo Extent Tensity Index (VETI), overall patient satisfaction, treatment tolerability, and side effects.

RESULTS: Among the 16 patients, 68.8% were male, with an average age of 40.7 ± 9.9 years. Both treatment groups showed a significant reduction in VETI scores during the second and third assessments (p < 0.05). However, the difference between the two groups was not statistically significant (p > 0.05). Patient satisfaction was notably higher in the NAC + NB-UVB group during the second visit (p = 0.01), and by the third visit, 75% of patients in the NAC + NB-UVB group reported excellent satisfaction, compared to 25% in the control group (p = 0.07). Treatment tolerability was similar across both groups, though one patient in the NAC + NB-UVB group experienced dizziness, which was resolved after adjusting the dose.

CONCLUSION: Oral NAC appears to be a safe adjuvant therapy in the treatment of generalized vitiligo patients in combination with NB-UVB phototherapy.

TRIAL REGISTER NAME: "Evaluation of the efficacy of NB-UVB phototherapy with oral N- acetylcysteine compared with NB-UVB phototherapy alone in the treatment of vitiligo patients: a randomized controlled clinical trial".Clinical trial registration number: IRCT20210729052013N1.},
}

@article {pmid41230648,
year = {2025},
author = {Nair, AS and Thimmappa, PY and Jasti, DB and Rodrigues, JA and Gangadharan, G and Sivakumar, G and Nagareddy, PR and Shivashankar, KN and Umakanth, S and Joshi, MB},
title = {Biochemical Modifications of Homocysteine Drive Neutrophil Extracellular Trap Formation in Ischemic Stroke.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {39},
number = {22},
pages = {e71221},
doi = {10.1096/fj.202500844RR},
pmid = {41230648},
issn = {1530-6860},
support = {EMR/2017/001680//DST | Science and Engineering Research Board (SERB)/ ; },
mesh = {*Extracellular Traps/metabolism ; Animals ; Mice ; *Ischemic Stroke/metabolism/pathology ; *Homocysteine/metabolism ; Male ; Humans ; *Neutrophils/metabolism ; Hyperhomocysteinemia/metabolism ; Mice, Inbred C57BL ; Female ; Platelet Activation ; },
abstract = {Excessive production of neutrophil extracellular traps (NETs) contributes to immunothrombosis activation in ischemic stroke pathogenesis. The metabolic and mechanistic regulators of NET formation in relation to platelet activation during ischemic stroke remain poorly understood. In the present study, using multiple animal and clinical models of stroke, we examined the role of homocysteine and its biochemical modifications on NET formation and concomitant neuronal damage, platelet aggregation, motor and gait functions. Phosphoproteomics analysis of neutrophils in response to homocysteine revealed an enrichment of kinases and phosphoproteins associated with thrombosis. Homocysteinylated albumin induced significant NET formation via Erk1/2, Akt, ATM, and PAD4-dependent pathways, independent of reactive oxygen species. Hyperhomocysteinemic mice fed a methionine-rich diet exhibited elevated NETs components (neutrophil elastase, citrullinated histones, cell-free DNA (cfDNA)), platelet activation, neuronal damage, and impaired motor, balance, and learning functions. UCCAO-induced ischemia exacerbated neuronal damage, motor dysfunction, and platelet activation in hyperhomocysteinemic mice, which were reversed by disrupting NETs with N-acetyl cysteine and DNase. In stroke patients, homocysteine, neutrophil elastase, and cfDNA levels were significantly elevated, independent of comorbidities (e.g., hypertension, type 2 diabetes), etiology (TOAST classification), or stroke severity. Additionally, stroke patients generated autoantibodies against homocysteinylated albumin, which positively correlated with neutrophil elastase levels. This study identifies homocysteine and its modifications as key metabolic regulators of NETosis in stroke, linking NETs formation to platelet activation and neuronal damage. These findings highlight potential therapeutic targets for mitigating stroke pathogenesis through the modulation of NETs.},
}

*Extracellular Traps/metabolism
Animals
Mice
*Ischemic Stroke/metabolism/pathology
*Homocysteine/metabolism
Male
Humans
*Neutrophils/metabolism
Hyperhomocysteinemia/metabolism
Mice, Inbred C57BL
Female
Platelet Activation

@article {pmid41229849,
year = {2025},
author = {Oscullo, G and Méndez, R and Olveira, C and Girón, R and García-Clemente, M and Máiz, L and Sibila, O and Golpe, R and Rodríguez-Hermosa, JL and Barreiro, E and Prados, C and Rodríguez-Lopez, J and de la Rosa, D and Martinez-García, MÁ},
title = {What is the optimal dose of N-acetylcysteine in adult patients with bronchiectasis?-data from the RIBRON registry.},
journal = {Journal of thoracic disease},
volume = {17},
number = {10},
pages = {9003-9012},
pmid = {41229849},
issn = {2072-1439},
abstract = {BACKGROUND: Bronchiectasis is characterized by excessive respiratory secretions, the management of which is clinically significant. Among the available pharmacological treatments, mucolytics play a pivotal role. N-acetylcysteine (N-AC) is the most commonly used mucolytic; however, the optimal dosing regimen remains inadequately defined. The primary aim of the present study is to specifically evaluate the efficacy of 1,200 mg/day of N-AC compared to 600 mg/day in patients with bronchiectasis.

METHODS: This was a retrospective, longitudinal, observational, multi-center study conducted across 43 centers, involving a cohort of 2,461 adult patients diagnosed with bronchiectasis based on a stable clinical state receiving either 600 mg/day of N-AC (n=252) or 1,200 mg/day (n=116), and provided follow-up data were available for 2 years. Propensity score matching (PSM) was employed to balance baseline characteristics between groups. Final outcomes were further adjusted for additional clinically relevant variables. Intergroup differences in intra-group changes were analyzed using a Poisson test.

RESULTS: Following PSM, the 1,200 mg/day N-AC group (n=104) demonstrated a statistically significant, fully adjusted reduction in exacerbations (-48.6%, P=0.01), hospitalizations (-29.9%, P=0.038), and total exacerbation rates (-54.1%, P=0.002), compared to the 600 mg/day group (n=219). Furthermore, the proportion of patients with more than 20 cc/day of sputum volume and those with mucopurulent sputum decreased by 24.3% (P=0.001) and 8.5% (P=0.041), respectively, in the 1,200 mg/day group versus the 600 mg/day group. No statistically significant difference was observed in the rate of Pseudomonas aeruginosa isolation (-0.9%; P=0.35).

CONCLUSIONS: N-AC at a dose of 1,200 mg/day is more effective than 600 mg/day in reducing exacerbations, hospitalizations, and daily sputum volume in patients with bronchiectasis.},
}

@article {pmid41226610,
year = {2025},
author = {Kadlecsik, C and Bognár, G and Kenari, F and Pintér, Z and Ribeiro, JCO and Envall, MG and Carvalho-Silva, VH and Napolitano, HB and Perjési, P},
title = {(E)-2-Benzylidenecyclanones: Part XXI-Reaction of Cyclic Chalcone Analogs with Cellular Thiols: Comparison of Reactivity of (E)-2-Arylidene-1-Indanone with -1-Tetralone and -1-Benzosuberone Analogs in Thia-Michael Reactions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110573},
pmid = {41226610},
issn = {1422-0067},
support = {EFOP-3.6.1.-16-2016-00004//European Social Fund/ ; },
mesh = {Humans ; Animals ; Mice ; *Sulfhydryl Compounds/chemistry ; *Tetralones/chemistry ; Cell Line, Tumor ; *Chalcones/chemistry ; *Indans/chemistry/pharmacology ; Glutathione/chemistry/metabolism ; Antineoplastic Agents/pharmacology/chemistry ; },
abstract = {In vitro cytotoxicity of three (E)-3-(4'-X-benzylidene)-1-indanones (2a-c) displayed lower cytotoxicity towards murine P388 and L1210 leukemic cells as well as human Molt 4/C8 and CEM T-lymphocytes than the respective six- (3a-c) and seven-membered (4a-c) analogs. To study whether thiol reactivity-as a possible basis of their mechanism of action-correlates with the observed cytotoxicities, kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of 2a-c were investigated. Furthermore, it was also the aim of the work to compare the thiol reactivity of the open-chain chalcones (1) and their carbocyclic analogs (2-4) with different ring sizes (n = 5-7). The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the high initial rate and low conversion of the 2a indanone in comparison with those of the carbocyclic analog tetralone (3a) and benzosuberone (4a). Thiol reactivity and cancer cell cytotoxicity showed a dependence on both the ring size and the nature of aromatic substituents.},
}

Humans
Animals
Mice
*Sulfhydryl Compounds/chemistry
*Tetralones/chemistry
Cell Line, Tumor
*Chalcones/chemistry
*Indans/chemistry/pharmacology
Glutathione/chemistry/metabolism
Antineoplastic Agents/pharmacology/chemistry

@article {pmid41226401,
year = {2025},
author = {Sasaninia, K and Era, IH and Newman, N and Melendez, J and Akif, W and Sharma, E and Nikjeh, O and Glassman, I and Jiménez, C and Sharma, N and Xu, A and Lambros, M and Zhou, M and Tiwari, R and Venketaraman, V},
title = {Additive Effects of N-Acetylcysteine and [R4W4] Combination Treatment on Mycobacterium avium.},
journal = {International journal of molecular sciences},
volume = {26},
number = {21},
pages = {},
doi = {10.3390/ijms262110361},
pmid = {41226401},
issn = {1422-0067},
mesh = {*Acetylcysteine/pharmacology ; *Mycobacterium avium/drug effects ; Humans ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; Macrophages/microbiology/drug effects ; Drug Synergism ; *Peptides, Cyclic/pharmacology ; THP-1 Cells ; Drug Therapy, Combination ; Membrane Potentials/drug effects ; },
abstract = {Mycobacterium avium is an opportunistic pathogen and a leading contributor to nontuberculous mycobacterial infections in immunocompromised individuals. However, treatment duration, antibiotic toxicity, and resistance present challenges in the management of mycobacterium infections, prompting the need for novel treatment. N-acetylcysteine (NAC) has demonstrated potent antimycobacterial activity, while antimicrobial peptides such as the cyclic [R4W4] have shown additive effects when combined with first-line antibiotics. This study aimed to investigate the mechanism and efficacy of NAC and [R4W4] combination therapy against M. avium. A membrane depolarization assay was used to evaluate the effects of NAC and [R4W4] on M. avium cell membrane integrity. Antimycobacterial activity was assessed by treating cultures with varying concentrations of NAC, [R4W4], a combination, or a sham treatment. The same regimens were applied to M. avium-infected THP-1-derived macrophages to assess intracellular efficacy. NAC and [R4W4] each disrupted the M. avium membrane potential, with enhanced effects in combination. The combination treatment significantly reduced M. avium survival in both the culture and infected macrophages compared with NAC alone and untreated controls. [R4W4] and NAC also demonstrated potent antibacterial activity, while the lowest MIC and the combination of [R4W4] and NAC displayed additive effects, indicating an improved bacterial inhibition compared to individual treatments. These findings demonstrate the additive activity of NAC and [R4W4] against M. avium in vitro and suggest that combining antioxidant compounds with antimicrobial peptides may represent a promising strategy for treating mycobacterial infections.},
}

*Acetylcysteine/pharmacology
*Mycobacterium avium/drug effects
Humans
*Anti-Bacterial Agents/pharmacology
Microbial Sensitivity Tests
Macrophages/microbiology/drug effects
Drug Synergism
*Peptides, Cyclic/pharmacology
THP-1 Cells
Drug Therapy, Combination
Membrane Potentials/drug effects

@article {pmid41223462,
year = {2025},
author = {Mumcu, T and Oncuoglu, S and Mumcu, A and Yılmaz, Ü and Ertekin, K},
title = {Emission based sensing of N-acetyl cysteine via silver equipped anthraquinone derivatives.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {348},
number = {Pt 1},
pages = {127152},
doi = {10.1016/j.saa.2025.127152},
pmid = {41223462},
issn = {1873-3557},
abstract = {In this work we investigated emission-based response of silver complexes of two newly synthesized anthraquinone derivatives for N-acetylcysteine (NAC) and thioglycolic acid. The interaction of the probes, DHA-dibenzonitrile and DHA-dibutanenitrile with silver nanoparticles resulted in metal chelation and following quenching of the fluorescence. To determine whether the emission intensity of the complexes was re-stored again, thiol compounds; NAC and thioglycolic acid were used. The released dyes re-emitted light, allowing the system to exhibit an intensity-based turn-on type sensor behavior for the NAC and thioglycolic acid, respectively. The re-stored fluorescence was monitored as a strong emission based analytical signal at 560 nm. The complex stoichiometries were investigated using several approaches, including Job's plot, density functional theory (DFT) and FT-IR measurements. The findings relying on HOMO-LUMO and energy gap calculations highlight that Ag coordination and following acetylcysteine adduction significantly re-shape both local nucleophilic and electrophilic regions, modulating the global electronic structure and reactivity of anthraquinone derivatives. N-acetylcysteine exhibited an exceptional spectral response at pH 9.0 in a buffered solution exhibiting 13.6 and 14.4-fold enhancement in the emission intensity, respectively. The reported linear responses for a concentration range of; 1.0 × 10[-5] M -1.0 × 10[-2] M, can easily be adopted to determination of the NAC levels in drugs, in vitro studies or in serum samples. Limit of detection (LOD) and limit of quantification (LOQ) values of the DHA-dibutanenitrile derivative for the NAC molecule were found to be 1.28 × 10[-6] and 1.21 × 10[-5] mol × L[-1], respectively. Similarly, the DHA-dibenzonitrile exhibited 1.11 × 10[-6] and 1.28 × 10[-5] mol × L[-1] of LOD and LOQ values, respectively.},
}

@article {pmid41220916,
year = {2025},
author = {Pinho, SA and Barosa, C and Deus, CM and Jones, JG and Oliveira, PJ and Cunha-Oliveira, T},
title = {Metabolic priming alters the morphology and metabolism of human dermal fibroblasts.},
journal = {EXCLI journal},
volume = {24},
number = {},
pages = {1419-1437},
pmid = {41220916},
issn = {1611-2156},
abstract = {The metabolic environment provided by the culture medium plays a critical role in shaping cellular function and mitochondrial activity in vitro. In this study, we investigated the effects of metabolic priming on the metabolism and morphology of Normal Human Dermal Fibroblasts (NHDFs) by manipulating glucose availability in the culture medium. Our strategy involved transitioning NHDFs from traditional high-glucose medium (HGm) to either a medium with physiological glucose levels (LGm) or a glucose-free, galactose-containing medium (OXm). Prior to cellular characterization, we confirmed the absence of glucose in the culture media and fetal bovine serum using [1]H nuclear magnetic resonance (NMR) spectroscopy. Given previous observations of elevated reactive species under glucose-free conditions, we explored the cellular adaptations associated with a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS). Cells cultured in OXm exhibited increased metabolic activity, elevated protein content, and substantial metabolic remodeling. Morphological analysis revealed enlargement of the cell body, cytoplasm, mitochondria, and nuclei, indicative of extensive structural adaptation. Notably, oxygen consumption rate (OCR) nearly doubled within 24 h of exposure to OXm, reflecting a rapid mitochondrial response to metabolic stress. The presence of the antioxidant N-acetyl cysteine (NAC) attenuated this increase, suggesting that redox signaling plays a key role in mitochondrial bioenergetic adaptation. These findings underscore the complex interplay between metabolic context, oxidative stress, and cellular morphology, and highlight the importance of appropriate normalization strategies in metabolic studies. See also the graphical abstract(Fig. 1).},
}

@article {pmid41215814,
year = {2025},
author = {Lang, SH and Salgado, AC and Snyder, MT and Rawls-Castillo, B and Williams, A and Gijavanekar, C and Elsea, SH and Wang, X and Tessier, MEM and Soler-Alfonso, C and Scaglia, F},
title = {Biochemical and clinical response to a sulfur-restricted diet in ethylmalonic encephalopathy.},
journal = {Molecular genetics and metabolism reports},
volume = {45},
number = {},
pages = {101270},
pmid = {41215814},
issn = {2214-4269},
abstract = {INTRODUCTION: Ethylmalonic encephalopathy (EE) is an often-severe inborn error of metabolism caused by biallelic variants in the ETHE1 gene leading to impaired detoxification of hydrogen sulfide (H2S). H2S is produced both exogenously by anerobic intestinal bacteria as well as by the endogenous catabolism of the sulfur-containing amino acids methionine and cysteine. Existing therapies including metronidazole, N-acetylcysteine (NAC), and orthotopic liver transplantation (OLT) have been pursued with the objective of reducing or detoxifying exogenously produced H2S. However, strategies to reduce endogenously produced H2S using a methionine and cysteine restricted diet are an understudied therapeutic avenue.

METHODS: We performed an open-label, single-arm study to evaluate the effects of dietary intervention with a methionine and cysteine restricted diet (20-30 mg/kg/day) on biochemical parameters and overall clinical trajectory in three patients with molecularly confirmed ethylmalonic encephalopathy (two with attenuated phenotypes, one classically affected). All three patients were receiving a combination of medical therapy with metronidazole and NAC and were status-post OLT at the time of diet initiation. Plasma butyrylcarnitine (C4) levels were measured at diagnosis, serially following initiation of medical therapy and OLT, and at regular follow-up visits in a metabolic clinic after diet initiation. Additionally, we obtained untargeted metabolomics studies and directly evaluated ethylmalonate, butyrylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine, glutarylcarnitine, and methylsuccinate levels in the pre- OLT/medical therapy, post- OLT/medical therapy, and post- sulfur-restricted diet states.

RESULTS: We observed a 20-38 % reduction in plasma C4 levels in all three patients following OLT and combination medical therapy with NAC and metronidazole. An 8-10 % reduction in C4 was observed following the introduction of dietary therapy in the two patients with attenuated phenotypes and an 82 % increase in C4 was seen in the patient with the classical phenotype. The metabolic profile as assessed by untargeted metabolomics analysis was largely unchanged in the pre-OLT/medical therapy, post-OLT/medical therapy, and post-diet states.

CONCLUSIONS: The modest biochemical response to a sulfur-restricted diet observed in our cohort likely reflects the relatively minor contribution of endogenous sulfur-containing amino acid catabolism to overall H2S production. Further work is needed to study the impact of dietary intervention on the natural history of EE including diet only trials in the animal model as well as in the pre-OLT period in human participants.},
}

@article {pmid41212275,
year = {2025},
author = {Raza, W and Meena, A and Luqman, S},
title = {Antitumor effects of diosmetin in Ehrlich ascites carcinoma mouse model: insights into ROS-mediated mechanisms.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41212275},
issn = {1432-1912},
support = {HCP-007//Central Institute of Medicinal and Aromatic Plants/ ; },
abstract = {Cancer remains one of the leading global health challenges, highlighting the continuous need for innovative therapeutic approaches. In this context, medicinal plants have been recognized as potential candidates for developing bioactive compounds, including flavonoids, which have demonstrated good anticancer properties. Diosmetin, a flavonoid aglycone predominantly found in citrus fruits, has shown potent anticancer properties due to its ability to induce cell cycle arrest, induce apoptosis, and inhibit tumor progression. This study evaluates the anticancer potential of diosmetin across various cancer cell lines such as prostate, skin, liver, lung, and in a murine Ehrlich ascites carcinoma (EAC) model. The cytotoxic effects of diosmetin were assessed by using three independent assays like SRB, MTT, and NRU. Diosmetin exhibited potent antiproliferative effects, with the lung and hepatic cancer cell lines showing the highest sensitivity. Furthermore, in the EAC mouse model, diosmetin significantly reduced tumor growth and promoted cell death. Mechanistic investigations revealed that diosmetin increases reactive oxygen species (ROS) generation in tumor cells. This is further confirmed by co-treatment with N-acetyl cysteine (NAC), a ROS inhibitor. Additionally, diosmetin demonstrated favorable pharmacokinetic and drug-likeness properties, including high gastrointestinal absorption and non-toxicity towards human erythrocytes. These findings suggest that diosmetin holds considerable promise as a potential anticancer agent, warranting further investigation for its therapeutic development.},
}

@article {pmid41211476,
year = {2025},
author = {Fesharaki-Zadeh, A and Belliveau, T and Pietrzak, RH and Arnsten, A},
title = {A novel multimodal pharmacologic approach using guanfacine, N-acetylcysteine, and donepezil in severe TBI: a case series.},
journal = {Frontiers in rehabilitation sciences},
volume = {6},
number = {},
pages = {1648002},
pmid = {41211476},
issn = {2673-6861},
abstract = {Traumatic brain injury (TBI) remains a leading cause of long-term morbidity and disability worldwide. Individuals with moderate to severe TBI often experience persistent neurocognitive deficits, including short-term memory loss, executive dysfunction, and slowed cognitive processing for which there are currently no FDA-approved treatments. This case series investigates the synergistic use of guanfacine, N-acetylcysteine (NAC), and donepezil (GND) administered alongside ongoing cognitive rehabilitation, with treatment effects evaluated through pre- and post-intervention Montreal Cognitive Assessment (MoCA) scores. The guanfacine/NAC combination has previously been reported to improve working memory and executive function in individuals with mild TBI, suggesting its potential applicability to more severe TBI cases. Guanfacine, an alpha-2A agonist approved for ADHD, enhances prefrontal cortical function; Donepezil, a cholinesterase inhibitor, is widely used to treat cognitive symptoms in mild cognitive impairment and early dementia; and NAC, a potent antioxidant and glutamate modulator, has demonstrated neuroprotective effects across a range of clinical contexts, including TBI. Each of these agents has a well-established safety profile. The encouraging outcomes observed in this case series underscore the potential of the GND regimen as a multimodal pharmacologic approach to target the complex neurochemical disruptions following TBI. These preliminary findings warrant further investigation in larger, placebo-controlled trials in order to more rigorously assess the safety, efficacy, and translational potential of this intervention for mitigating chronic cognitive sequelae in individuals with moderate to severe TBI.},
}

@article {pmid41210458,
year = {2025},
author = {Abdullah, WHAABW and Mohamad, MIBK and Baharuddin, MNAB},
title = {Beyond the dose: unmasking 'therapeutic' paracetamol toxicity in a chronic alcohol user with severe acidosis-a case report.},
journal = {AME case reports},
volume = {9},
number = {},
pages = {114},
pmid = {41210458},
issn = {2523-1995},
abstract = {BACKGROUND: Paracetamol (PCM), widely used for its analgesic and antipyretic properties, is generally considered safe at recommended doses. However, its metabolism can be significantly altered in chronic alcohol users due to enzyme induction and glutathione (GSH) depletion. While some clinicians maintain that "therapeutic" doses remain harmless in alcoholics, others argue there is no safe threshold. This case report bridges these opposing views by highlighting an atypical presentation of PCM-induced toxicity in a chronic alcoholic. It adds to existing literature by illustrating how severe lactic acidosis may overshadow more typical hepatic symptoms, thereby delaying diagnosis and treatment.

CASE DESCRIPTION: A 53-year-old male with a 20-year history of alcohol use presented to the emergency department (ED) with sudden-onset dyspnea and profound metabolic acidosis. Initially misdiagnosed as mesenteric ischemia, subsequent investigations revealed strikingly elevated aminotransferases, coagulopathy, and a PCM level above the normal therapeutic range-despite the patient's claim of following standard dosing. Intravenous N-acetylcysteine (NAC) was started, but the patient deteriorated rapidly and succumbed on day 2. Autopsy or long-term follow-up data were unavailable due to the acute course and lack of liver transplantation options. Although previous guidelines have debated whether PCM dosing must be reduced in chronic alcoholics, this case underscores the potential dangers, even within seemingly acceptable intake levels.

CONCLUSIONS: Clinicians must maintain a high index of suspicion for PCM toxicity in chronic alcoholics, recognising that atypical presentations-such as isolated lactic acidosis and respiratory distress-can conceal the true aetiology. This case reinforces the need for routine PCM-level checks in unexplained acute liver failure, prompt NAC administration, and a balanced perspective regarding "therapeutic" dosing in alcoholics. The findings underscore the call for more nuanced guidelines and further research to determine appropriate dose thresholds and monitoring strategies for alcohol-dependent individuals. By harmonising these divergent clinical stances, patient safety can be enhanced through tailored, vigilant practice.},
}

@article {pmid41208834,
year = {2025},
author = {Yaqubi, S and Seyedalipour, B and Karimian, M},
title = {Modulation of lncRNAs and oxidative stress related genes by N-acetylcysteine and S-methylcysteine in rotenone-induced Parkinson's disease.},
journal = {Biochemistry and biophysics reports},
volume = {44},
number = {},
pages = {102328},
pmid = {41208834},
issn = {2405-5808},
abstract = {Oxidative stress and changes in lncRNA expression are key factors in the pathophysiology of Parkinson's disease. This study investigated the protective effects of N-acetylcysteine and S-methylcysteine on the expression of long non-coding RNAs and oxidative stress-related genes in the brain, as well as the activity of antioxidant enzymes in the brain and serum of mice with rotenone-induced Parkinson's disease. In this experimental study, 56 male BALB/c mice were utilized and treated continuously for 10 days. Gene expression of superoxide dismutase, glutathione peroxidase, catalase, Nrf2, Ho-1, and long non-coding RNAs Malat1, Neat1, and Gas5 in the brain was analyzed using real-time PCR. Biochemical assays measured antioxidant enzyme activities, malondialdehyde levels, and total antioxidant capacity in brain tissue and serum. A bioinformatics approach, including molecular docking and the construction of a gene interaction network, was also performed. Our data showed decreased expression of antioxidant genes and Nrf2 and Ho-1 regulatory factors in the Parkinson's group, which were significantly restored by N-acetylcysteine and S-methylcysteine treatments. Long non-coding RNAs were elevated in the Parkinson's disease model and reduced by interventions. Antioxidant enzyme activity and oxidative stress markers were significantly improved by N-acetylcysteine, S-methylcysteine, and their combination. Molecular docking suggested stable interactions of these compounds with antioxidant enzymes. The interaction network highlights Nrf2 as a central regulator of antioxidant genes, modulated by specific lncRNAs. Findings support the neuroprotective role of N-acetylcysteine, S-methylcysteine through activation of the Nrf2/Ho-1 pathway, modulation of long non-coding RNAs, and oxidative stress improvement in Parkinson's disease.},
}

@article {pmid41208439,
year = {2025},
author = {Wang, H and Zhang, Y and Zhao, L and Wang, C and He, C and Duan, C},
title = {NADH Mimic-Decorated Coordination Capsules for Biomimetic Capture of NO and Electrocatalytic Reduction to NH3.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e19123},
doi = {10.1002/anie.202519123},
pmid = {41208439},
issn = {1521-3773},
support = {22171034//National Natural Science Foundation of China/ ; 2024YFA1510301//National Key Research and Development Program of China/ ; DUT22LAB606//Fundamental Research Funds for the Central Universities/ ; },
abstract = {Sustainable conversion of NO offers a promising technology for artificial nitrogen cycle, but faces challenges in integrating electrocatalysis with NO capture. Herein, a biomimetic NO capture-activation-conversion strategy was firstly formulated by encapsulating N-acetylcysteine (NAC) within a nicotinamide adenine dinucleotide (NADH) mimic-containing coordination capsule, enabling efficiently NH3 electrosynthesis. The installed NADH mimics onto the capsule interacted with the highly reactive NO-adduct generated from NAC within the microenvironment akin to the pocket of enzyme, facilitating intramolecular hydride transfer of the substrate-involving clathrate, accompanied by the formation of oxidated NAD[+] mimics. Subsequently, the cobalt-based coordination capsule consecutively reserved e[-] from cathode while donating 2e[-] to the NAD[+] mimic simultaneously for active cofactor recovered and recycle. This coordination capsule-mediated biomimetic system exhibited enzymatic kinetics following the Michaelis-Menten mechanism in the electrochemical NO reduction and realized almost 100% Faraday efficiency at potentials below -0.2 VRHE with a substantial NH3 yield rate of 121.6 µmol·h[-1]·cm[-2] at -0.3 VRHE, ranking among the optimal electrocatalytic NO performance ever achieved, offering an attractive avenue toward renewable electricity-driven nitrogen fixation exploiting bioinspired artificial catalyst.},
}

@article {pmid41207540,
year = {2025},
author = {Kamimura, N and Iuchi, K and Igarashi, T and Ohsawa, I and Nito, C and Usuda, J and Ohta, S},
title = {Molecular hydrogen mitigates acetaminophen-induced liver injury and enhances the effects of N-acetylcysteine in diabetic mice.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110176},
doi = {10.1016/j.jnutbio.2025.110176},
pmid = {41207540},
issn = {1873-4847},
abstract = {Acetaminophen (APAP) overdose induces severe liver injury, especially in diabetic patients. N-acetylcysteine (NAC) is commonly used as an approved antidote for APAP toxicity; however, its narrow therapeutic window limits its clinical utility. This study investigated the protective effects of molecular hydrogen (H2) against APAP-induced hepatotoxicity in diabetic mice. Diabetic db/db mice were provided with hydrogen-dissolved water (H2-water) for two weeks prior to APAP administration. Consumption of H2-water significantly attenuated APAP-induced liver injury, as evidenced by improved histological findings and decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Using transgenic mice expressing redox-sensitive green fluorescent protein, H2 was shown to reduce both cytosolic and mitochondrial oxidative stress caused by APAP overdose. We observed that H2 modulated c-Jun N-terminal kinase (JNK) activation, inhibited mitochondrial translocation of Bax, and suppressed the release of mitochondrial endonucleases. Additionally, H2 enhanced the expression of the hepatoprotective hormone fibroblast growth factor 21 (FGF21). These findings suggest that H2 protects against APAP-induced liver injury in diabetic mice by attenuating oxidative stress and upregulating FGF21 expression. Although NAC acts as an antioxidant, H2 was more effective in reducing mitochondrial oxidative stress. Importantly, co-treatment with H2 and NAC provided greater protection against APAP-induced hepatotoxicity than NAC alone. This synergistic effect may result from differences in the mechanisms by which NAC and H2 influence FGF21 expression and mitochondrial oxidative stress. The combination of H2 and NAC may offer an improved therapeutic strategy for treating APAP-induced liver injury in diabetic patients.},
}

@article {pmid41206153,
year = {2025},
author = {Nasr, A},
title = {Retraction notice to .ÇÿEffect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study.ÇÖ.},
journal = {Reproductive biomedicine online},
volume = {51},
number = {5},
pages = {105286},
doi = {10.1016/j.rbmo.2025.105286},
pmid = {41206153},
issn = {1472-6491},
}

@article {pmid41205773,
year = {2025},
author = {Wang, Y and Zhang, X and Yang, W and Liu, X and Xie, S and Zhang, L and Xiao, X and Xie, F and Zhu, J and Lin, H and Liu, X and Xiong, L},
title = {Caveolin-1 Drives Ferroptosis in MDSCs via PKA-DRP1-Mediated ER‒mitochondria Crosstalk to Shape Breast Cancer Immunosuppression.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.11.001},
pmid = {41205773},
issn = {1873-4596},
abstract = {BACKGROUND: Caveolin-1 (Cav-1) has been implicated in breast cancer progression and tumor-microenvironment remodeling. We investigated whether and how tumor-derived Cav-1 regulates myeloid-derived suppressor cell (MDSC) fate and function to shape the immunosuppressive tumor immune microenvironment (TIME).

METHODS: Using murine 4T1 breast cancer models and complementary cell culture systems, Cav-1 was manipulated by overexpression and CRISPR/Cas9 knockout. MDSCs were isolated from tumors or bone marrow and analyzed by flow cytometry, Western blotting, immunofluorescence, transmission electron microscopy and ELISA. Ferroptosis is modulated pharmacologically (RSL3, ferrostatin-1), and reactive oxygen species (ROS) are inhibited by N-acetylcysteine. ER stress (ERS), endoplasmic reticulum-mitochondrial contacts and PKA-DRP1 signaling were investigated via biochemical assays, immunoprecipitation and transcriptome/bioinformatic analyses. Statistical comparisons were performed via Student's t test and ANOVA.

RESULTS: High Cav-1 expression is correlated with immune checkpoint markers; enhanced recruitment of MDSCs with an immunosuppressive phenotype; and increased secretion of IL-6, IL-10 and CXCL1. Cav-1 promoted ER stress (increased p-PERK, IRE1α, and GRP78), strengthened ER-mitochondrial contacts and upregulated MAM proteins (GRP75, IP3R, and VDAC1) via PKA-dependent DRP1 phosphorylation. These changes increased intracellular ROS, iron accumulation and lipid peroxidation; downregulated SLC7A11 and GPX4; and increased HMOX1 and oxidized phosphatidylcholine (OxPC) release, which is consistent with ferroptosis in MDSCs. Ferroptosis or ROS inhibition (ferrostatin-1, NAC) attenuated OxPC release, restored T-cell proliferation and function in coculture and limited tumor growth in vivo.

CONCLUSIONS: Tumor-derived Cav-1 promotes ROS-dependent ferroptosis in MDSCs via PKA-DRP1-mediated ER-mitochondrial crosstalk, causing the release of oxidized phosphatidylcholines that suppress T-cell function and promote an immunosuppressive TME. Targeting this axis may improve the response of breast cancer patients to immunotherapy.},
}

@article {pmid41202965,
year = {2025},
author = {Kuttikrishnan, S and Mariyam, Z and Ahmad, F and Suleman, M and Habeeba, U and Panicker, AJ and Prabhu, KS and Merhi, M and Dermime, S and Al Shabeeb Akil, AS and Bhat, AA and Ansari, AW and Uddin, S},
title = {Selective induction of apoptosis in T-cell acute lymphoblastic leukemia by pristimerin through dual PI3K/AKT pathway inhibition and ROS generation.},
journal = {European journal of pharmacology},
volume = {1008},
number = {},
pages = {178329},
doi = {10.1016/j.ejphar.2025.178329},
pmid = {41202965},
issn = {1879-0712},
abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by the aberrant activation of survival pathways, particularly the PI3K/AKT axis. Pristimerin (Prist), a naturally occurring quinonemethide triterpenoid, has recently gained attention for its anti-cancer potential. In this study, we demonstrate that Prist effectively inhibits the proliferation of T-ALL cell lines (Jurkat and Molt 4) by inducing G0/G1 cell cycle arrest and triggering intrinsic and extrinsic caspase-dependent apoptosis. Prist significantly increases reactive oxygen species (ROS) levels and depletes glutathione (GSH), leading to mitochondrial dysfunction and cytochrome c release. Notably, ROS scavenging with N-acetylcysteine (NAC) abrogated Prist-induced apoptosis, highlighting ROS as a critical mediator of its cytotoxicity. Network pharmacology and molecular docking revealed AKT as a key target of Prist, with strong binding affinity confirmed through docking analysis. Prist downregulated phosphorylated AKT and inhibitor of apoptosis proteins (XIAP, cIAP1/2), supporting its pro-apoptotic mechanism. Importantly, Prist inhibited the proliferation and AKT phosphorylation in activated primary human T cells but spared resting T cells, indicating selective cytotoxicity. These findings establish Prist as a promising therapeutic candidate for T-ALL through the selective targeting of PI3K/AKT-driven survival signaling.},
}

@article {pmid41200300,
year = {2025},
author = {Tareq, HM and Mashi, SK},
title = {Investigation of augmentin-induced hepatobiliary damage and its modulation by N-acetylcysteine in male rats.},
journal = {Open veterinary journal},
volume = {15},
number = {9},
pages = {4276-4285},
pmid = {41200300},
issn = {2218-6050},
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use/administration & dosage ; Male ; Rats ; *Chemical and Drug Induced Liver Injury/drug therapy ; Oxidative Stress/drug effects ; *Anti-Bacterial Agents/adverse effects ; *Antioxidants/pharmacology ; Liver/drug effects/pathology ; Tumor Necrosis Factor-alpha/blood ; Rats, Sprague-Dawley ; Malondialdehyde/blood ; },
abstract = {BACKGROUND: Augmentin is a common antibiotic used to treat infections. However, it may cause liver damage. Toxicity often involves oxidative stress and inflammation. N-acetylcysteine (NAC) is known for its antioxidant and anti-inflammatory effects and may help protect the liver.

AIM: This study aimed to assess whether NAC could reduce Augmentin-induced liver and bile duct injury.

METHODS: Forty adult male rats were divided into four groups (T1, T2, T3, and T4). Group 1 was the control group. Group 2 received Augmentin (30 mg/kg/day). Group 3 received 150 mg/kg/day NAC. Group 4 received both NAC and Augmentin. Treatments lasted for 35 days. Serum levels of tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), glutathione (GSH), and CYP7A1 were measured. Histopathology was also performed.

RESULTS: Augmentin alone caused a significant (p < 0.05) increase in TNF-α (13.82 ± 0.31), MDA (407.25 ± 10.65), and CYP7A1 (7.69 ± 0.48). GSH dropped to (9.10 ± 0.43). Liver tissues showed inflammation, sinusoidal venostasis, and bile duct damage. NAC-treated rats had significantly (p < 0.05) lower TNF-α (4.88-4.97), MDA (253.05-258.15), and CYP7A1 (4.30-4.38). GSH levels significantly (p < 0.05) increased to (15.58-17.02). Histology improved with NAC. Livers exhibited fewer cell injuries and a more normal architecture.

CONCLUSION: NAC reduced the oxidative stress and inflammation caused by Augmentin. It also protected the liver structure. These findings suggest that NAC is a useful supplement for preventing drug-induced liver injury.},
}

Animals
*Acetylcysteine/pharmacology/therapeutic use/administration & dosage
Male
Rats
*Chemical and Drug Induced Liver Injury/drug therapy
Oxidative Stress/drug effects
*Anti-Bacterial Agents/adverse effects
*Antioxidants/pharmacology
Liver/drug effects/pathology
Tumor Necrosis Factor-alpha/blood
Rats, Sprague-Dawley
Malondialdehyde/blood

@article {pmid41197729,
year = {2025},
author = {Wang, Y and Hekimi, S},
title = {Elevated cellular accumulation of endogenous and exogenous CoQ by altered intracellular trafficking.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110878},
doi = {10.1016/j.jbc.2025.110878},
pmid = {41197729},
issn = {1083-351X},
abstract = {Coenzyme Q (CoQ) is produced in the inner membrane of mitochondria, from where it is transported to other cellular membranes. Cellular CoQ levels drop when its synthesis is interrupted, indicating that it can be degraded or eliminated in some way by currently still uncharacterized mechanisms. Low cellular iron availability has been found to lower CoQ levels, at least in part by inhibiting the action of the CoQ biosynthetic enzyme COQ7. These findings prompted us to test the effect of elevated intracellular iron content on CoQ levels. In the mouse macrophage cell line RAW264.7, we found that supplementation with ferrous ions (Fe[2+]) boosts CoQ levels rapidly and reversibly. Iron loading also increases the cellular accumulation of exogenous CoQ10 provided in the media. N-acetyl cysteine significantly attenuates the elevation of CoQ levels by iron, suggesting that the effect of iron is mediated by a redox mechanism, although overall cellular reactive oxygen species (ROS) levels were not affected. Treating RAW264.7 cells with the ROS-generator paraquat also dramatically increases CoQ, further pointing to a redox mechanism. No effect on the abundance of several COQ proteins was observed after iron or paraquat treatment, indicating that their effect on CoQ levels is unlikely to arise from altered mitochondrial CoQ synthesis. In contrast, we observed that targeting lysosome function also affects CoQ levels, suggesting that the effects we observe relate to degradation and/or recycling. Our study suggests that targeting these mechanisms could allow for new therapeutic options to boost cellular CoQ levels in patients.},
}