@article {pmid41897092,
year = {2026},
author = {Villani, C and Di Clemente, A and Invernizzi, RW and Rezzonico, R},
title = {N-Acetylcysteine Reduces Tissue Injury Induced by Oxygen-Glucose Deprivation in an Organotypic Culture of Mouse Cerebral Cortex Slices.},
journal = {Children (Basel, Switzerland)},
volume = {13},
number = {3},
pages = {},
doi = {10.3390/children13030379},
pmid = {41897092},
issn = {2227-9067},
support = {A009114//Zambon (Italy)/ ; },
abstract = {BACKGROUND/OBJECTIVES: Hypoxic-ischemic encephalopathy is the leading cause of infant mortality and disability. Hypothermic therapy is effective in hypoxic-ischemic encephalopathy, albeit in a limited number of cases. Hypothermia requires advanced technologies and significant financial resources, which are difficult to sustain in low-income countries, with devastating consequences. Valid alternatives to hypothermia therapy are therefore needed.

METHODS: In vitro organotypic cultures of mouse cerebral cortex slices were used to demonstrate the direct protective effect of N-acetylcysteine (NAC) against brain tissue damage induced by oxygen-glucose deprivation (OGD), and to identify the concentrations and time window that maximize the drug's effectiveness. NAC's effectiveness was measured by the incorporation of propidium iodide (PI), a marker of cell membrane integrity.

RESULTS: Adding 0.1 and 1 mM NAC to the incubation medium before OGD strongly reduced OGD-induced PI incorporation, by 80% (p < 0.0002) and 89% (p < 0.0001), respectively. Administration of 1 mM NAC 1 h after OGD maintained a high degree of protection against OGD-induced damage (80% reduction in PI incorporation; p < 0.0001), while at 0.1 mM, the efficacy of NAC dropped to 44% (p < 0.005). Administration of NAC 4 h after OGD reduced PI incorporation to 52% (p < 0.005) at 1 mM, while at 0.1 mM, the effect was not significant (17%; p > 0.05). Exposure of slices to 0.1 and 1 mM NAC reduced PI incorporation in female cerebral cortex slices (p < 0.006), while only the higher concentration was effective in male slices (p < 0.05). Exposure to 0.1 mM NAC increased tissue levels of total glutathione (p = 0.0185), while no significant effect was observed with 1 mM NAC.

CONCLUSIONS: This work highlights the direct effect of NAC in protecting cerebral cortex cells from OGD-induced damage and identifies the concentrations and time window that maximize the drug's effect. The results underscore the need for further studies to verify the in vivo efficacy of NAC at concentrations found to be active in vitro, and for clinical trials to evaluate whether NAC can reduce hypoxia-induced brain damage in newborns.},
}

@article {pmid41897452,
year = {2026},
author = {Stranieri, C and Di Leo, EG and Danese, E and Poffe, R and Barbieri, A and Pighi, L and Randon, A and Cominacini, L and Fratta Pasini, AM},
title = {Decreased Plasma Concentration of Hydrogen Sulfide in Hospitalized COVID-19 Patients: A Novel Determinant of Mortality?.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030307},
pmid = {41897452},
issn = {2076-3921},
support = {NO GRANT NUMBER//University of Verona, Italy, School of Medicine and Zambon Italia SRL./ ; },
abstract = {In this study, we first focused on measuring H2S and oxidative stress as indicators of in-hospital mortality observed within 24 h from admission in hospitalized non-survivor and survivor patients affected by COVID-19. Then, we analyzed whether N-acetylcysteine (NAC) can increase H2S and GSH concentrations in different cell lines. H2S levels were significantly increased in all COVID-19 patients (both survivors and non-survivors) compared to non-COVID-19 subjects (p = 0.0016), but non-survivors showed significantly lower H2S plasma levels than survivors (p = 0.008). Oxidative stress measured as circulating malondialdehyde (MDA) resulted in lower levels in non-COVID-19 subjects than in the two COVID-19 patient groups (p = 0.03). However, non-survivors had significantly higher plasma MDA than survivors (p = 0.0001). A Kaplan-Meier curve for H2S indicates a markedly reduced survival probability in COVID-19 patients with lower H2S levels (log-rank p = 0.004). NAC activity significantly reduced reactive oxygen species and lipid peroxidation induced by tert-butyl hydroperoxide in cultured cells (p from <0.01 to <0.001). Furthermore, NAC increased the cellular production of H2S (p < 0.01) and GSH (p < 0.01). These findings indicate the important prognostic role of H2S in COVID-19 patients at hospital admission and that NAC might be helpful in all clinical situations characterized by low levels of H2S.},
}

@article {pmid41897494,
year = {2026},
author = {Babiloni-Chust, I and Donato, L and Sartori, S and Carl, M and Zerti, D and Rinaldi, C and Flati, V and Feligioni, M and D'Angelo, R and Maccarone, R and Poggi, L},
title = {Oxidative Stress Signaling and Regenerative Responses in a Larval Zebrafish Model of Retinal Light Damage.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {3},
pages = {},
doi = {10.3390/antiox15030348},
pmid = {41897494},
issn = {2076-3921},
abstract = {The zebrafish (Danio rerio) is a widely used model for studying retinal regeneration. In adults, light-induced retinal damage (LIRD) serves as an environmental phototoxic stressor that induces photoreceptor degeneration and regenerative responses, whereas larval models remain comparatively underexplored. In this study, we validate a larval LIRD paradigm as a versatile system for studying acute phototoxic injury and early regeneration-associated transcriptomic responses. Using high-throughput RNA sequencing, we profiled retinal transcriptional changes 48 h post-LIRD and complemented these findings with targeted pharmacological modulation of redox signaling. Larval LIRD induced robust activation of canonical apoptotic and regeneration-associated pathways, recapitulating key features of adult LIRD models while engaging previously underexplored gene-regulatory networks. Among these, pathways related to oxidative stress responses, antioxidant enzymes, and oxygen metabolism were prominently regulated. Functional attenuation of oxidative stress using the N-acetylcysteine reduced phototoxic injury-induced apoptosis and proliferation, while inflammatory markers remained largely unaffected. Conversely, subtoxic intra-retinal hydrogen peroxide exposure was sufficient to induce proliferative markers without eliciting apoptosis response. At the signaling level, modulation of oxidative stress influenced components of growth-associated signaling pathways activated during early injury response. Together, these findings support a role for oxidative stress as a key component of early injury-associated signaling in larval retinal regeneration. This study integrates histological, transcriptomic, and pharmacological analyses to interrogate early regenerative programs and provides a comprehensive transcriptomic resource for exploring redox-associated mechanisms in retinal injury and repair.},
}

@article {pmid41898249,
year = {2026},
author = {Duman, E and Maçin, A and Özdemir, İ and Öztürk, Ş and Tuncer, MC},
title = {Synergistic Antitumor Effects of Rosmarinic Acid and Cisplatin in Retinoblastoma: Evidence from 2D and 3D Tumor Models.},
journal = {Biomedicines},
volume = {14},
number = {3},
pages = {},
doi = {10.3390/biomedicines14030602},
pmid = {41898249},
issn = {2227-9059},
abstract = {Background/Objectives: Retinoblastoma (RB) is the most common primary intraocular malignancy in children, with treatment limited by chemoresistance and therapy-related toxicity. Enhancing the efficacy of conventional chemotherapeutics while reducing dose-related adverse effects is crucial. This study investigates the chemosensitizing potential of rosmarinic acid (RA), a natural polyphenolic compound, in combination with cisplatin (Cis) in RB models. Methods: The antiproliferative and synergistic effects of RA and Cis were evaluated in Y79 and WERI-Rb1 RB cell lines using MTT assays and Combination Index (CI) analysis. Apoptosis and oxidative stress were assessed by Annexin V-FITC/PI flow cytometry and intracellular reactive oxygen species (ROS) measurements, respectively. Three-dimensional (3D) tumor spheroids were generated from Y79 cells for in vitro validation using spheroid size analysis, ATP-based viability assays, and live/dead fluorescence staining. The ROS dependency of cytotoxicity was further examined using N-acetylcysteine (NAC) pretreatment. Cytokine secretion was analyzed by ELISA, and apoptosis-related gene expression was assessed by qRT-PCR. Results: RA and Cis reduced cell viability in a dose- and time-dependent manner, while their combination induced significantly enhanced cytotoxicity, confirmed by CI values < 1. Combined treatment increased apoptotic populations, elevated intracellular ROS, and upregulated Caspase-3 and Caspase-9. These effects were maintained in 3D spheroids, with reduced spheroid size and impaired integrity. NAC pretreatment attenuated ROS generation and partially rescued cell viability, indicating a ROS-dependent, but not exclusive, contribution to cytotoxicity. Conclusions: RA synergistically enhances cisplatin-induced anticancer effects in RB through oxidative stress, engagement of intrinsic (mitochondria-associated) apoptotic signaling, and reduction of tumor cell-derived inflammatory and angiogenic mediators. These findings highlight the potential of RA and Cis combination as a chemosensitizing strategy for RB therapy, warranting further in vivo evaluation.},
}

@article {pmid41898408,
year = {2026},
author = {Muriel, P and Vargas-Pozada, EE and Márquez-Quiroga, LV and Ramos-Tovar, E},
title = {Potential Therapeutic Strategies for Steatosis, Oxidative Stress, Inflammation, and Fibrosis in Liver Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {6},
pages = {},
doi = {10.3390/ijms27062546},
pmid = {41898408},
issn = {1422-0067},
mesh = {Humans ; *Oxidative Stress/drug effects ; *Liver Cirrhosis/drug therapy/metabolism ; *Inflammation/drug therapy/metabolism ; Ursodeoxycholic Acid/therapeutic use/pharmacology ; Animals ; *Fatty Liver/drug therapy/metabolism ; *Liver Diseases/drug therapy/metabolism ; Antioxidants/therapeutic use/pharmacology ; Pyridones/therapeutic use/pharmacology ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; },
abstract = {Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA to treat primary biliary cholangitis (PBC). In addition, UDCA has been demonstrated to protect against metabolic dysfunction-associated steatohepatitis, fibrosis, and drug-induced liver injury (DILI). The mechanism of action of UDCA has been attributed not only to decreasing the effects of toxic bile acids but also to protecting mitochondrial integrity and function, as well as to antioxidant, anti-inflammatory, and anti-apoptotic activities. UDCA can scavenge reactive oxygen species (ROS) and activate the nuclear factor-E2-related factor-2 (Nrf2) pathway, thereby exerting antioxidant activity. The anti-inflammatory activity of UDCA is associated with its ability to inhibit the nuclear factor-κB pathway. Pirfenidone is a well-recognized antifibrotic drug for the treatment of idiopathic pulmonary fibrosis; its effects on liver fibrosis have also been demonstrated. Pirfenidone exerts anti-inflammatory effects by attenuating the nucleotide-binding oligomerization domain-like receptor 3 inflammasome signaling pathway. The antioxidant actions of pirfenidone are associated with its ability to upregulate the Nrf2 pathway. Both the anti-inflammatory and antioxidant properties of pirfenidone act together to attenuate lung and liver fibrosis, decreasing transforming growth factor-β levels, inhibiting profibrogenic hepatic stellate cell activation, and increasing extracellular matrix degradation. Methyltransferases utilize S-adenosyl-L-methionine (SAM) as a methyl donor for most transmethylation reactions in the body. SAM increases reduced glutathione (GSH) levels, exerting important antioxidant effects. Evidence indicates that SAM prevents fibrosis and attenuates hepatocellular carcinoma development, improving patient survival. N-acetylcysteine (NAC) is a precursor to L-cysteine and GSH and is used in clinical settings to treat cancer, nephropathy, heart disease, pulmonary fibrosis, polycystic ovary syndrome, and influenza. Regarding the liver, NAC is the most accepted treatment for DILI, especially after paracetamol overdose. Owing to its antioxidant and anti-inflammatory actions, NAC has been successfully used to treat chronic liver injuries, including hepatosteatosis and fibrosis. Therefore, ursodeoxycholic acid, pirfenidone, S-adenosyl-L-methionine, and N-acetylcysteine could represent therapeutic strategies for the treatment of liver pathologies.},
}

Humans
*Oxidative Stress/drug effects
*Liver Cirrhosis/drug therapy/metabolism
*Inflammation/drug therapy/metabolism
Ursodeoxycholic Acid/therapeutic use/pharmacology
Animals
*Fatty Liver/drug therapy/metabolism
*Liver Diseases/drug therapy/metabolism
Antioxidants/therapeutic use/pharmacology
Pyridones/therapeutic use/pharmacology
Anti-Inflammatory Agents/therapeutic use/pharmacology

@article {pmid41888118,
year = {2026},
author = {Angioli, C and Ferriero, A and Eleonora, P and Tesoriere, G and Agostini, B and Tramonti, A and Contestabile, R and Vernì, F},
title = {Tumor suppressor function of SHMT in a Drosophila Ras[V12]Dlg[RNAi] model: DNA damage and synergistic gene-nutrient interaction with PLP.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08602-7},
pmid = {41888118},
issn = {2041-4889},
support = {AR1231889041EBDD//Sapienza Università di Roma (Sapienza University of Rome)/ ; AR1241905DD95C63//Sapienza Università di Roma (Sapienza University of Rome)/ ; },
abstract = {Serine hydroxymethyltransferase (SHMT) is a key enzyme in one-carbon (1 C) metabolism, essential for nucleotide synthesis and epigenetic maintenance. In mammals, there are two distinct SHMT isozymes: the cytosolic SHMT1 and the mitochondrial SHMT2. Several studies report that high SHMT levels in cancer contribute to metabolic reprogramming. Conversely, a limited number of studies have linked decreased SHMT1 expression to the progression and poor prognosis of hepatocellular carcinoma and renal cell carcinoma, suggesting that SHMT may play dual roles as an oncogene or tumor suppressor, depending on the cellular context. However, the molecular mechanisms underlying SHMT tumor suppressor role remain unknown. In this work, we used the Drosophila Ras[V12]Dlg[RNAi] cancer model to investigate the effects of SHMT depletion on cancer progression and the associated mechanisms. We found that RNAi-mediated SHMT silencing promotes the progression of Ras[V12]Dlg[RNAi] cancers by impairing thymidylate biosynthesis in the folate pathway. SHMT depletion in Ras[V12]Dlg[RNAi] cells causes DNA and chromosome damage and renders these cells sensitive to genotoxic stressors such as X-rays or hydroxyurea. Genome instability is correlated with cancer progression, and it is largely due to the generation of reactive oxygen species (ROS) and, to a lesser degree, to replicative stress and compromised DNA repair mechanisms, all arising from SHMT depletion. Antioxidant treatment with N-acetyl cysteine (NAC) significantly reduces both DNA damage and tumor progression. Intriguingly, the combined depletion of SHMT and its cofactor pyridoxal 5'-phosphate (PLP) further increases oxidative stress, leading to extensive DNA damage that induces apoptosis in Ras[V12]Dlg[RNAi] cells, thereby limiting the tumor growth. Taken together, our data suggest that a diminished SHMT activity may drive the progression of Ras[V12]Dlg[RNAi] cancers through ROS-induced genome instability. Additionally, our study points to a novel gene-nutrient interaction, SHMT-PLP, that impacts cancer growth with potential therapeutic implications.},
}

@article {pmid41889224,
year = {2026},
author = {Badroo, IA and Nandurkar, HP and Nagale, VK and Khan, SK and Khanday, AH and Wani, ZA and Lone, MA},
title = {Paraquat Dichloride Induced Cytotoxicity in Primary Hepatocytes via an Antioxidative and Mitochondrial-Dependent Pathway.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70162},
pmid = {41889224},
issn = {1099-1263},
abstract = {The liver serves as the primary detoxification organ, playing a crucial role in protecting against environmental toxicants. Paraquat (PQ), a widely used herbicide in agricultural and domestic applications, has been extensively documented to induce severe toxicity in various tissues and disrupt multiple cellular signaling pathways. This study investigates the cytotoxic and genotoxic effects of PQ on isolated primary rat hepatocytes, obtained via the collagenase perfusion method. A comprehensive toxicity assessment was conducted, including cell viability at different PQ concentrations, reactive oxygen species (ROS) generation, reduced (GSH) and oxidized glutathione (GSSG) levels, mitochondrial membrane potential (MMP) collapse, lysosomal integrity, and lipid peroxidation (MDA) content. A significant increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) leakage indicated hepatocellular membrane disruption. PQ exposure resulted in excessive ROS generation, mitochondrial dysfunction, oxidative stress, and apoptosis activation through the caspase-9/-3 signaling cascade. Notably, coincubation with the ROS scavenger N-acetylcysteine (NAC) significantly attenuated ROS generation, apoptosis, and hepatocyte damage, underscoring the role of oxidative stress in PQ-induced hepatotoxicity. These findings provide mechanistic insights into PQ-induced cytotoxicity, demonstrating that ROS overproduction and mitochondrial impairment are the primary drivers of hepatocyte injury. Given the extensive use of PQ and its potential environmental and human health risks, these findings are critical for understanding its toxicological impact and exploring antioxidant-based therapeutic strategies to mitigate liver damage.},
}

@article {pmid41887487,
year = {2026},
author = {Zhang, B and Liu, Z and Li, Q and Tian, M and Gao, Y and Kishi, H and Xu, D},
title = {Endoplasmic reticulum stress mediates oxidative stress-driven endothelial impairment and atherogenesis induced by sodium perfluorononenoxybenzene sulfonate exposure.},
journal = {Environmental research},
volume = {},
number = {},
pages = {124344},
doi = {10.1016/j.envres.2026.124344},
pmid = {41887487},
issn = {1096-0953},
abstract = {Sodium perfluorononenoxybenzene sulfonate (OBS), a substitute for perfluorooctane sulfonate (PFOS), has been frequently detected in the environment and human blood. Although OBS exposure has been identified as a novel risk factor for atherosclerosis associated with endothelial dysfunction, the underlying molecular mechanisms remain unclear. In this study, in vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that OBS exposure induced oxidative stress, activated the PERK-eIF2α-ATF4 axis of endoplasmic reticulum stress (ERS) and triggered NF-κB signaling. Pharmacological inhibition with N-acetylcysteine (NAC, an antioxidant), 4-phenylbutyric acid (4-PBA, an ERS inhibitor), and BAY 11-7082 (an inhibitor for NF-κB signaling pathway) revealed a sequential pathogenic cascade, in which oxidative stress acts upstream to initiate ERS and compromise endothelial barrier function, leading to NF-κB activation, which drives inflammatory responses, monocyte adhesion, and impaired endothelial migration. Consistent with these findings, in vivo experiments in ApoE[-]/[-] mice showed that OBS exposure caused endothelial impairment, collagen deposition, and oxidative stress in aortic tissues, accompanied by upregulating the expression of ERS and inflammation-related markers. These findings suggest that ERS serves as a key mediator linking oxidative stress to inflammation in OBS-induced endothelial dysfunction, highlighting the potential cardiovascular hazards of OBS as an emerging PFOS alternative.},
}

@article {pmid41878339,
year = {2026},
author = {Valenzuela-Valderrama, M and Varas, A and Rubilar, M and Lorca, M and Mella, J and Espinosa-Bustos, C and Mellado, M and Echeverría, J},
title = {3D-QSAR study for the development of chalcone-based inhibitors targeting ovarian cancer cells with experimental validation.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1746658},
pmid = {41878339},
issn = {1663-9812},
abstract = {BACKGROUND: Ovarian cancer remains one of the most lethal gynecological malignancies, mainly due to late-stage diagnosis and frequent chemoresistance.

PURPOSE: This study sought to develop 3D-QSAR models-Comparative Molecular Field and Similarity Index Analysis (CoMFA and CoMSIA)-to predict the antiproliferative activity of synthetic chalcone derivatives against A2780 ovarian cancer cells and to explore potential mechanisms of action through antioxidant response biomarkers.

MATERIALS AND METHODS: CoMFA and CoMSIA models were developed using a dataset of 64 chalcone derivatives and validated using q[2], r[2] ncv, and other statistical metrics. Twelve chalcones predicted as active were synthesized and characterized by FT-IR and NMR spectroscopy. Their antiproliferative effects were evaluated using MTT assays, complemented by clonogenic testing, intracellular glutathione quantification, and analysis of biomarkers, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO1). The most active compounds were further assessed in a cisplatin-resistant A2780 subline, with N-acetylcysteine (NAC) used to probe reactive oxygen species (ROS)-dependent mechanisms.

RESULTS AND DISCUSSION: The CoMFA and CoMSIA models demonstrated strong predictive performance (q[2] = 0.763/0.789; r[2] ncv = 0.963/0.920). Contour maps highlighted steric and electrostatic features linked to enhanced antiproliferative activity. The twelve synthesized chalcones exhibited experimental pIC50 values that strongly correlated with model predictions. Compounds 065, 066, and 072 showed the highest potency, with compound 072 also reducing clonogenic survival. Active derivatives increased intracellular glutathione and upregulated HO-1 without activating canonical Nrf2 signaling. In cisplatin-resistant A2780 cells, compounds 072 and 074 displayed markedly higher potency (IC50 = 6.50 and 10.22 μM) than cisplatin (93.4 μM). Their cytotoxicity was abrogated by NAC, indicating a ROS-dependent mode of action.

CONCLUSION: CoMFA and CoMSIA models accurately predicted the activity of synthetic chalcones, and the biological findings identify these derivatives as promising candidates for the treatment of ovarian cancer, including chemoresistant forms.},
}

@article {pmid41874704,
year = {2026},
author = {Mohammed, I and Nankya, Y and Hong, UT and Kan, A and Abdelhafid, AM and Latunde-Dada, GO},
title = {The role of N-acetylcysteine and glutathione in the management of Parkinson's disease: a systematic review of oxidative biomarkers and clinical outcomes.},
journal = {Amino acids},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00726-026-03513-5},
pmid = {41874704},
issn = {1438-2199},
abstract = {Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons, leading to both motor and non-motor symptoms. Oxidative stress is a significant contributor to the pathophysiology of PD, and glutathione (GSH) depletion contributes to neuronal damage. N-acetylcysteine (NAC), a bioavailable cysteine donor, can support endogenous GSH synthesis and may also exert antioxidant effects independent of GSH replenishment. NAC and GSH are proposed neuroprotective interventions due to their antioxidant properties. This systematic review evaluated the effects of NAC and GSH on oxidative stress and PD symptoms, comparing them with healthy controls or a placebo. A systematic search was conducted in Cochrane Library, PubMed, Web of Science, Ovid (Embase and MEDLINE), Scopus, and ProQuest for studies published between January 2003 and December 2024, including randomised controlled trials (RCTs) and non-randomised studies. Two reviewers assessed the study quality and extracted data. The primary outcome was the change in motor and non-motor symptoms as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) and were interpreted using minimal clinically important difference (MCID) thresholds. Secondary outcomes included biochemical redox markers such as blood GSH, cerebrospinal fluid (CSF) GSH, GSSG, and GSH/GSSG ratio and imaging-based functional outcomes, particularly DAT binding assessed by DaTscan SPECT. The GSH/GSSG ratio reflects redox status (reduced vs. oxidised glutathione), CSF outcomes primarily reported NAC concentrations, and brain GSH was quantified using magnetic resonance spectroscopy (MRS). Exclusion criteria included studies on conditions other than PD, those that did not use NAC or GSH as the primary intervention, and those without a comparator group. Nine studies, conducted between 2009 and 2019, met the inclusion criteria and involved 196 participants. NAC improved both motor and non-motor symptoms and significantly increased GSH/GSSG ratios, GSH levels in the CSF, and DAT binding. In contrast, intranasal GSH showed only modest increases in brain levels without significant improvements in symptoms or oxidative stress markers. The studies had limitations, including small sample sizes, short intervention durations, and inconsistencies in dosage and administration routes. These factors constrain the strength of the conclusions, and evidence for both NAC and GSH remains preliminary. Furthermore, while NAC shows promise as a neuroprotective intervention, findings for GSH are inconclusive. More large-scale, long-term randomised controlled trials are needed to validate these results and explore NAC and GSH's long-term therapeutic potential in managing PD.},
}

@article {pmid41868894,
year = {2026},
author = {Zhang, Y and Han, X and Jiao, F and Huang, G and Liang, Y},
title = {Association of vitamin D and N-acetylcysteine supplementation with anxiety, cognition, and biomarkers in generalized anxiety disorder: a retrospective cohort study.},
journal = {American journal of translational research},
volume = {18},
number = {2},
pages = {1517-1527},
pmid = {41868894},
issn = {1943-8141},
abstract = {OBJECTIVE: To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD).

METHODS: This retrospective cohort study included 88 propensity-score-matched patients with GAD from Beidahuang Group Neuropsychiatric Hospital. Based on clinical records, patients were classified into an observation group (vitamin D3 + NAC + usual care) and a control group (usual care only). Anxiety symptoms and cognitive function were assessed using the Beck Anxiety Inventory (BAI), Automatic Thought Questionnaire (ATQ), and Dysfunctional Attitudes Scale (DAS). Serum levels of 25-hydroxyvitamin D [25(OH)D], inflammatory markers [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)], oxidative stress parameters [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD)], and neurochemical markers [brain-derived neurotrophic factor (BDNF), dopamine (DA), Serotonin (5-HT), norepinephrine (NE)] were measured at baseline and week 8.

RESULTS: After 8 weeks, both groups showed significant improvements in BAI, ATQ, and DAS scores, with greater reductions in the observation group (all P < 0.05). The observation group also exhibited more favorable changes in biomarkers: greater increases in 25(OH)D, GSH, SOD, BDNF, DA, 5-HT, and NE, and greater decreases in MDA, IL-6, and hs-CRP compared to the control group (all P < 0.05). Adverse event incidence was low and similar between groups.

CONCLUSION: In this retrospective cohort, combined vitamin D and NAC supplementation was associated with significantly greater improvements in anxiety symptoms, cognitive patterns, and relevant metabolic biomarkers in patients with GAD compared to usual care alone, supporting its potential as an adjunctive therapy.},
}

@article {pmid41870350,
year = {2026},
author = {Cardoso, JMDF and Ferreira, RV and Rasslan, R and Otsuki, DA and Utiyama, EM and Montero, EFS and , },
title = {Combined N-acetylcysteine and tranexamic acid attenuate acidosis and fibrinolysis in a swine polytrauma model.},
journal = {The journal of trauma and acute care surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/TA.0000000000004965},
pmid = {41870350},
issn = {2163-0763},
abstract = {BACKGROUND: Traumatic coagulopathy is a major contributor to mortality after severe hemorrhage. Tranexamic acid (TXA) reduces fibrinolysis, and N-acetylcysteine (NAC) has antioxidant and anti-inflammatory properties. Both agents have shown benefit individually, but their combined effect has not been previously investigated in trauma. We hypothesized that early administration of NAC with TXA during resuscitation could attenuate acidosis and fibrinolysis in an experimental study with a hemorrhagic shock and polytrauma swine model.

METHODS: Thirty-six male Landrace pigs (28.3 ± 3.0 kg) were randomized into five groups: Sham (n = 5), Ringer lactate (n = 5), NAC (n = 6), TXA (n = 6), and NAC+TXA (n = 6). Animals underwent experimental standardized polytrauma (femur fracture, controlled hemorrhage of 60% blood volume), followed by immediate resuscitation and a grade IV liver injury. Standard physiological parameters, blood gases, lactate, coagulation tests, fibrinogen, and thromboelastometry (ROTEM parameters) were assessed at baseline, post-shock, post-resuscitation, post-liver injury, and final.

RESULTS: All trauma groups developed profound shock physiology compared with Sham. The NAC+TXA group demonstrated the most complete correction of acid-base status, achieving the highest final pH (7.5 ± 0.03), significantly greater than Ringer lactate (7.3 ± 0.09), NAC (7.3 ± 0.06), and TXA (7.3±0.11) (P = 0.001). Lactate and base deficit showed directionally similar improvements.Thromboelastometry showed attenuated fibrinolysis with combined therapy. The NAC+TXA group exhibited lower maximum lysis after liver injury compared with NAC (10 ± 3% vs 16 ± 4%, P = .008). Other ROTEM parameters displayed directionally similar trends toward improved clot formation.

CONCLUSIONS: In this swine polytrauma model, the combined administration of NAC and TXA was associated with improved in acid-base status and attenuation of fibrinolysis. While these physiological effects are preliminary, they support additional experimental investigations to clarify mechanisms, reproducibility, and potential translational relevance of NAC+TXA as an adjunct in damage control resuscitation. (J Trauma Acute Care Surg. 2026;00:00-00. Copyright © 2026 Wolters Kluwer Health, Inc. All rights reserved.

LEVEL OF EVIDENCE: Experimental animal study.},
}

@article {pmid41862922,
year = {2026},
author = {Essam, A and Domiaty, SE and Attia, N and Helal, H and Meheissen, M},
title = {N-acetylcysteine nano-spray versus conventional treatment in the management of radiotherapy-induced oral mucositis in oral cancer patients: a randomized clinical trial.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-026-07959-7},
pmid = {41862922},
issn = {1472-6831},
abstract = {BACKGROUND: Radiation-induced oral mucositis (RIOM) is a common and debilitating complication of radiotherapy in oral cancer patients, significantly impairing quality of life and potentially interrupting treatment. This study evaluated the therapeutic efficacy of N-acetylcysteine (NAC) nano-spray in managing RIOM, with particular emphasis on mucositis severity, quality of life, and serum gastrin-17 levels.

MATERIALS AND METHODS: In this randomized clinical study, 40 oral cancer patients undergoing radiotherapy were allocated in a 1:1 ratio to receive either NAC nano-spray (n = 20) or conventional therapy (n = 20) for six weeks. Mucositis severity was assessed using the World Health Organization (WHO) Oral Mucositis Severity Scale, and quality of life was evaluated using the Oral Health Impact Profile (OHIP-14). Serum gastrin-17 levels were measured before and after treatment.

RESULTS: Patients treated with NAC nano-spray demonstrated a significant reduction in WHO mucositis grades and significantly improved OHIP-14 scores compared with the control group (p < 0.05). Additionally, a significant increase in serum gastrin-17 levels was observed in the NAC group relative to conventional therapy (p < 0.05). These effects were evident during radiotherapy and at the end of treatment.

CONCLUSIONS: N-acetylcysteine nano-spray appears to be an effective therapeutic option for the management of RIOM, reducing mucositis severity and improving quality of life in oral cancer patients.

TRIAL REGISTRATION: The trial was registered at Clinical Trials .gov on 24/7/2025, registration number: (NCT07082621).},
}

@article {pmid41863011,
year = {2026},
author = {Tola, HT and Kılıç, S},
title = {Experimental evaluation of N-acetylcysteine against doxorubicin cardiotoxicity in rats.},
journal = {BMC pharmacology & toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40360-025-01073-0},
pmid = {41863011},
issn = {2050-6511},
abstract = {BACKGROUND: Doxorubicin (DOX) is a widely used anthracycline antibiotic in the treatment of pediatric malignancies. However, its clinical application is significantly limited by its well-documented cardiotoxic side effects. The hypothesis of this study is that N-acetylcysteine (NAC), as an antioxidant agent, may reverse DOX-induced cardiotoxicity. Therefore, we aimed to evaluate the potential protective role of NAC against DOX-induced cardiotoxicity in rat heart tissue in this experimental study.

METHODS: Thirty rats were randomly divided into three groups (n = 10 each): control, DOX, and DOX + NAC. The control group received physiological saline via oral gavage at 0 and 24 h, followed by intraperitoneal saline at 48 h. The DOX group received saline at the same intervals, but received 20 mg/kg DOX intraperitoneally at 48 h. The treatment group received 140 mg/kg NAC orally at 0 and 24 h, followed by 20 mg/kg DOX intraperitoneally at 48 h.

RESULTS: Compared to controls, the DOX group showed significantly increased malondialdehyde levels and decreased levels of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase (p < 0.05). In the NAC-treated group, these values were comparable to controls. Histologically, the DOX group exhibited edema, inflammation, vacuolization, hemorrhage, necrosis, and myofibrillar disorganization, while these alterations were largely absent in the NAC group (p < 0.005).

CONCLUSION: In our study, NAC did not produce significant biochemical improvement in DOX-damaged heart tissue but provided substantial histological protection against DOX toxicity. These findings highlight NAC as a promising agent for reducing DOX-induced cardiac toxicity.},
}

@article {pmid41856984,
year = {2026},
author = {Huang, S and Song, Z and Shi, C and Tao, D and Wen, J and Chen, Y and Luo, Y},
title = {A single extinction-based treatment with N-Acetylcysteine produces long-term reduction in cocaine relapse.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03954-2},
pmid = {41856984},
issn = {2158-3188},
abstract = {Cocaine addiction is characterized by high relapse rates associated with glutamate dysregulation, presenting significant challenges for long-term treatment. N-acetylcysteine (NAC) has shown promise in preventing drug relapse by normalizing glutamate function, potentially mediated by glutamate 2/3 (mGlu2/3) receptor activation. This study investigated the therapeutic potential of NAC in reducing cocaine-seeking behavior using the self-administration model. After establishing stable cocaine self-administration and a 7-day abstinence period, rats received a single dose of NAC (100 mg/kg, i.p.) 30 min before the first extinction training session. NAC significantly reduced cocaine-seeking behavior on the first day of extinction but not in subsequent extinction sessions. Following extinction, tests for cue-induced reinstatement and spontaneous recovery were conducted. Results showed that NAC administration on the first day of extinction effectively reduced cocaine-seeking during the reinstatement test, with effects lasting at least 28 days. The mGlu2/3 antagonist LY341495 (1 mg/kg) fully blocked this enduring suppression of reinstatement without altering the immediate decrease in drug-seeking observed on the first day of extinction. Additionally, NAC administration on the initial extinction day also reduced context-induced reinstatement of cocaine-seeking behavior. These results indicate that NAC exerts its anti-relapse effects via mGlu2/3 receptors. A single NAC treatment combined with extinction training can produce lasting suppression of relapse, highlighting its therapeutic promise for addiction treatment.},
}

@article {pmid41861379,
year = {2026},
author = {Barthelemy, N and Lee, W and Gregori, NZ and Lam, BL and Sengillo, JD},
title = {Nutritional supplements: current evidence for retinitis pigmentosa and Stargardt disease.},
journal = {Current opinion in ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1097/ICU.0000000000001213},
pmid = {41861379},
issn = {1531-7021},
abstract = {PURPOSE OF REVIEW: Inherited retinal diseases (IRDs) are genetically and phenotypically heterogeneous disorders that cause progressive vision loss and lack broadly effective disease-modifying therapies. Increasing evidence implicates metabolic stress, oxidative injury, and photoreceptor-retinal pigment epithelium (RPE) dysfunction in IRD pathophysiology. This review evaluates the evidence and limitations surrounding nutritional and metabolic interventions for retinitis pigmentosa and Stargardt disease.A narrative review of preclinical studies, randomized controlled trials, and contemporary genetic re-analyses was performed. Nutritional interventions reviewed include vitamin A, vitamin E, N-acetylcysteine (NAC), omega-3 fatty acids (docosahexaenoic acid), carotenoids and apocarotenoids, and the deuterated vitamin A analog C20-D3-retinyl acetate (ALK-001).

RECENT FINDINGS: Initial studies suggesting a protective effect of vitamin A in retinitis pigmentosa were not confirmed in subsequent trials or genetic re-analyses, which identified baseline differences between groups as a possible contributor to the original findings. In contrast, supplemental vitamin E may accelerate disease progression. NAC demonstrated acceptable tolerability and modest short-term improvements in visual function in early-phase trials, with a phase 3 study ongoing. Omega-3 fatty acids, carotenoids, and apocarotenoids have not shown consistent clinically meaningful benefit in retinitis pigmentosa or Stargardt disease despite strong mechanistic rationale. In Stargardt disease, ALK-001 reduces lipofuscin accumulation in animal models and clinical trials are ongoing to assess efficacy in patients.

SUMMARY: Most nutritional supplements studied to date have not demonstrated durable or clinically meaningful benefit in IRDs. Vitamin A supplementation in retinitis pigmentosa is no longer supported by current evidence, while NAC remains a promising metabolic therapy under investigation. High-quality, genotype-informed clinical trials with clinically relevant endpoints are needed before nutritional interventions can be incorporated into IRD management guidelines.},
}

@article {pmid41862110,
year = {2026},
author = {Liu, Y and Xiao, Z and Zhang, Y and Chen, Q and Luo, S and Wang, Y and Miao, Z and Tao, Z and Gong, D},
title = {Polypyrrole nanozymes with cell-free DNA scavenging and ferroptosis inhibition capabilities for the treatment of acetaminophen-induced acute liver injury.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.03.030},
pmid = {41862110},
issn = {1878-7568},
abstract = {Acute liver failure (ALF) can result from the progressive development of acute liver injury triggered by acetaminophen (APAP) overdose. The core mechanisms involve an imbalance in the antioxidant system and upregulation of the inflammatory response, which collectively induce ferroptosis/apoptosis. Herein, nanozymes (PPy-Mg NPs) were synthesized through coordination reaction between polypyrrole nanoparticles (PPy NPs) and magnesium ions. The enriched PPy-Mg NPs were explored as active anti-inflammatory nanozymes for effective acute liver injury treatment. Enriched cationic PPy-Mg NPs in the liver effectively scavenged excess reactive oxygen and nitrogen species (RONS) and cell-free DNA. It is worth emphasizing that in the delayed AILI mouse models, bioactive PPy-Mg NPs not only reduced oxidative stress levels but also modulated multiple biological signaling pathways, such as NF-κB, Nrf2-Keap1, ferroptosis/apoptosis. The research indicates the possible medical application of PPy-Mg NPs nanozymes in efficient enrichment treatment for acute liver injury. STATEMENT OF SIGNIFICANCE: APAP-induced liver injury (AILI) can progress to acute liver failure (ALF), presenting a significant clinical challenge. Currently, N-acetylcysteine (NAC) is the only medication approved treatment; however, its efficacy in patients with advanced AILI remains unsatisfactory. Therefore, the development of new therapeutics for the treatment of AILI are crucial. This work developed a PPy-Mg NPs nanozyme for the efficient AILI treatment. PPy-Mg NPs provide constructive applications of polypyrrole-based nanozymes for AILI treatment, which covers upstream metabolic rescue (RONS scavenging), necrotic debris clearance (cfDNA removal), and residual cell protection (ferroptosis inhibition) across temporal and spatial dimensions, holds potential for extending therapeutic windows and enhancing protection rates in high-risk/complex cases.},
}

@article {pmid41862408,
year = {2026},
author = {Hareedy, MS and Abdelrahem, MH and Hassan, SS and Elkaliny, HH},
title = {Effects of Lithium and Verapamil on Thyroid and Kidney Function in Mice: A Preclinical Study.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70172},
pmid = {41862408},
issn = {1099-1263},
abstract = {Lithium (Li) salts are still one of the basic therapies for manic-depressive illness, which has a double-edged nature where the good efficacy is threatened by possible toxicity if Li levels are elevated. The effects of verapamil and N-acetylcysteine (NAC) on Li levels and Li-related toxicity in the thyroid gland and kidneys were studied. Five groups of mice (normal control, Li, verapamil, Li + verapamil, and Li + NAC) were evaluated for levels of urea, creatinine, thyroid hormones (T3 and T4), thyroid-stimulating hormone (TSH), sodium, and potassium after 6 weeks. Li levels were measured in all groups that received Li. Renal and thyroid tissues were assessed histologically. T4 and T3 were significantly elevated in the Li, Li + verapamil, and Li + NAC groups compared to the normal control (p < 0.0001), while TSH was significantly decreased (p < 0.001). Levels of Li, potassium, and urea were elevated by the co-administration of verapamil or NAC, while serum creatinine was significantly decreased compared to the Li-treated group. Verapamil and NAC elevated the serum levels of Li and augmented the effects of Li on the thyroid gland, urea, and potassium levels.},
}

@article {pmid41852760,
year = {2026},
author = {Elsheshtawy, NE and Risha, EF and Abdelhamid, FM and Rajab, BS and Bagadood, R and Bokhari, B and Sindi, G and Ateya, AI and Rezk, S and El-Boshy, ME},
title = {Protective effects of Lagerstroemia speciosa against paracetamol-induced renal and testicular toxicity in rats via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.},
journal = {Frontiers in toxicology},
volume = {8},
number = {},
pages = {1751678},
pmid = {41852760},
issn = {2673-3080},
abstract = {INTRODUCTION: Paracetamol (PCM) is widely used as an analgesic; however, at high doses, it is well recognized for its hepatotoxic effects and is increasingly associated with renal and reproductive damage.

METHODS: In the present study, the protective potential of ethanolic Lagerstroemia speciosa leaf extract (EELS; 500 mg/kg/day, orally for 24 days) was investigated against PCM-induced kidney and testicular injury in male rats, using N-acetyl cysteine (NAC) as a reference treatment.

RESULTS: PCM administration led to pronounced impairment in sperm quality and significant disturbances in serum biochemical parameters, reflected by elevated renal function markers, sodium, and phosphorus levels, together with reduced calcium, potassium, and testosterone. These changes were accompanied by clear evidence of oxidative stress, as indicated by increased malondialdehyde and decreased reduced glutathione. Moreover, inflammatory and apoptotic responses were markedly intensified, whereas antioxidant and steroidogenic regulators were suppressed. Histopathological findings further confirmed extensive structural damage in renal and testicular tissues. Notably, treatment with EELS or NAC substantially mitigated these alterations, restoring most parameters toward normal values.

CONCLUSION: Collectively, these findings demonstrate that EELS exerts notable nephroprotective and gonadoprotective effects comparable to NAC, largely through the attenuation of oxidative stress, inflammation, and apoptosis.},
}

@article {pmid41854407,
year = {2026},
author = {Qi, L and Kou, H and Chernatynskaya, A and Huang, D and Mani, VJ and Karacal, H and Ercal, N and Yang, H},
title = {Dendrimer Nanogels with Built-in Free Radical Scavenging Enable Efficient Topical Delivery of a Hydrophilic Antioxidant to Restore Lens Redox Balance for Cataract Treatment.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.5c24072},
pmid = {41854407},
issn = {1944-8252},
abstract = {Cataract is a leading cause of vision impairment worldwide and are primarily caused by oxidative stress that damages and aggregates lens proteins, leading to lens opacification. However, the eye's anatomical barriers limit the penetration and bioavailability of antioxidant therapies. To address this challenge, a dendrimer-based nanogel with a built-in reactive oxygen species (ROS)-scavenging capability developed by us was employed to deliver the antioxidant N-acetylcysteine (NAC) to the lens. NAC was loaded into a generation-5 PEGylated poly(amidoamine) dendrimer (G5-PEG-TK, termed the GPT) nanogel. The resulting NAC-GPT was characterized for its ROS-scavenging activity, bioavailability, and corneal permeability. The efficacy of NAC-GPT was evaluated ex vivo and in vivo using a sodium selenite (Na2SeO3)-induced cataract model. Both ex vivo and in vivo results demonstrated that NAC-GPT significantly increased the level of NAC accumulation in the lens. Furthermore, the in vivo study shows that NAC-GPT significantly increased the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), an indicator of redox balance restoration. In particular, the GSH/GSSG ratio in NAC-GPT-treated lenses was nearly 2-fold higher than that of the untreated cataract control. These findings indicate that the GPT nanogel platform can effectively deliver antioxidants to the eye and is a promising noninvasive antioxidant delivery strategy with the ability to restore redox balance in cataract.},
}

@article {pmid41845136,
year = {2026},
author = {Meadows, JW and Hendrickson, RG and Stolbach, AI},
title = {ACMT Practice Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose (2026 Update).},
journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology},
volume = {},
number = {},
pages = {},
pmid = {41845136},
issn = {1937-6995},
}

@article {pmid41847871,
year = {2026},
author = {Singh, LK and Singh, SP and Sharma, P},
title = {Oxidative-stress-responsive polymeric nanocarriers for Alzheimer's disease: emerging antioxidant strategies using NAC and curcumin.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-37},
doi = {10.1080/09205063.2026.2644503},
pmid = {41847871},
issn = {1568-5624},
abstract = {A complex combination of oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein aggregation initiates Alzheimer disease (AD), and redox imbalance becomes an initial and lead pathological process. Traditional antioxidants like N-acetylcysteine (NAC) and curcumin demonstrate high mechanistic capacity but have poor stability, are rapidly metabolicized and have low blood-brain barrier (BBB) penetration. Polymeric nanocarriers can be a solution to these drawbacks, as they offer controlled delivery, better targeting to the brain, and dynamic delivery in response to microenvironmental changes. This review is a synthesis of recent developments in oxidative-stress-responsive polymeric systems (PLGA-, chitosan-, and hybrid polymer-based nanoparticles) designed to be used in precise redox modulation. We emphasize the therapeutic synergies of co-delivery of dual NAC-curcumin that is backed with in-vitro and in-vivo results of enhanced antioxidant activity, mitochondrial integrity, and cognitive improvements in AD models. The most important translational obstacles such as nanoparticle scalability, regulatory obstacles, and interpatient heterogeneity are acutely addressed, as well as new developments such as AI-driven formulation design and personalized oxidative biomarker profiling. All these innovations put redox-targeted nanomedicine as a prospective next-generation therapy of AD.},
}

@article {pmid41840883,
year = {2026},
author = {Tian, Y and Zhang, L and Zhao, P and Liu, X and Jin, F and Liu, Y and Li, J},
title = {Electroacupuncture mitigates lung injury, increases endogenous antioxidant levels and modulates Nrf2 signaling in a rat model of chronic obstructive pulmonary disease.},
journal = {Acupuncture in medicine : journal of the British Medical Acupuncture Society},
volume = {},
number = {},
pages = {9645284261424261},
doi = {10.1177/09645284261424261},
pmid = {41840883},
issn = {1759-9873},
abstract = {BACKGROUND: Electroacupuncture (EA) has shown efficacy in the treatment of chronic obstructive pulmonary disease (COPD), but the underlying mechanism of action remains unclear. Oxidative stress is a main pathological process in COPD. This aim of this study was to explore the anti-oxidant effect of EA in a COPD rat model.

METHODS: Rats were divided into control, model, EA, sham acupuncture (SA) and N-acetylcysteine (NAC) groups. All rats except those in the control group were exposed to cigarette smoke combined with repeated bacterial infection to induce a COPD rat model. Rats in the EA group received EA at GV14 and bilateral BL13/BL23 for a further 8 weeks, while rats in SA group were given manual acupuncture at sites 5 mm from the traditional acupuncture point locations (without electrical stimulation) as a negative control. NAC (54 mg/kg/d) was used in the NAC group as a positive control. Lung function was assessed by whole body plethysmography, and tissue structure was assessed by histology. mRNA and protein levels of oxidative indicators and nuclear factor E2-related factor (Nrf2) signaling were measured by qPCR and immunohistochemistry or Western blotting, respectively.

RESULTS: After EA treatment, lung function and pathological features were improved. Total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) in serum, as well as SOD1 and heme oxygenase (HO)-1 in lung tissue, were increased, while markers of oxidative stress-lipid peroxidation (LPO) and malonaldehyde activity (MDA)-were decreased. Nrf2 protein in the nucleus of lung tissue, as well as HO-1 and γ-glutamylcysteine synthetase (γ-GCS) mRNA and protein, were improved. NAC, as an antioxidant, was better than EA at increasing the expression of HO-1 protein and γ-GCS mRNA.

CONCLUSIONS: EA was beneficial for the treatment of COPD in this rat model and exerted antioxidant effects via mechanisms potentially related to Nrf2 signaling.},
}

@article {pmid41841373,
year = {2026},
author = {Walls, AC and Vaughan, AS and Balachandran, K},
title = {Development of a nasal airway-on-chip co-culture model to study particulate matter exposure.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5lc00978b},
pmid = {41841373},
issn = {1473-0189},
abstract = {Particulate matter (PM) is a major component of urban air pollution and is strongly associated with respiratory diseases. However, the mechanisms of PM-induced inflammation remain poorly understood due to a lack of physiologically-relevant airway models which can incorporate PM exposure. To address this, we used our nasal airway-on-chip platform to establish a co-culture model of human nasal epithelial cells and human pulmonary microvascular endothelial cells and used this model to investigate the effects of PM exposure on the nasal airway. In particular, we sought to understand the PM-induced reactive oxygen species (ROS)-mediated inflammatory response of the co-culture. Upon PM exposure, we observed a significant increase in ROS production consistent with oxidative stress-mediated injury. Additionally, treatment with the ROS scavenger N-acetyl-cysteine attenuated ROS levels and showed a trend toward reduced inflammation, suggesting a protective effect. These findings support the utility of our model for studying PM-induced airway inflammation in a more physiologically-relevant environment.},
}

@article {pmid41832950,
year = {2026},
author = {de Oliveira, AP and Pacheco, G and Lopes, ALF and da Silva Araujo, AK and de Sousa Chaves, L and de Araújo, S and de Sousa Lima, EB and Alves, EHP and Queiroz-Junior, CM and Teixeira, MM and Costa, VV and Souza, JMT and Barros, AB and de Araujo Sousa, PS and Rocha, JA and Araújo, AJ and Filho, JDBM and Véras, LMC and Vasconcelos, DFP and Medeiros, JVR},
title = {Imidazole Alkaloids Epiisopilosine and Epiisopiloturine Attenuate Acetaminophen-Induced Liver Toxicity in Mice via Autophagy Modulation and Anti-Inflammatory Effects.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {3},
pages = {e70782},
doi = {10.1002/jbt.70782},
pmid = {41832950},
issn = {1099-0461},
support = {308981/2023-5//Conselho Nacional de Desenvolvimento CientÍfico e TecnolÓgico/ ; //CoordenaÇÃo de AperfeiÇoamento de Pessoal de NÍvel Superior/ ; 308981/2023-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Animals ; *Autophagy/drug effects ; Male ; Mice ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism/prevention & control ; *Acetaminophen/adverse effects/toxicity ; Mice, Inbred BALB C ; *Anti-Inflammatory Agents/pharmacology ; *Imidazoles/pharmacology/chemistry ; *Alkaloids/pharmacology/chemistry ; *Liver/drug effects/metabolism/pathology ; 4-Butyrolactone/analogs & derivatives ; },
abstract = {There is increasing interest in natural metabolites, such as alkaloids, due to their potential in treating liver diseases, including acetaminophen (APAP)-induced hepatotoxicity. Alkaloids are known to modulate autophagy, a mechanism associated with liver protection. Epiisopilosine (EPIIS) and epiisopiloturine (EPI), imidazole alkaloids derived from Pilocarpus microphyllus (Jaborandi), exhibit anti-inflammatory and hepatic immunomodulatory effects. Therefore, this study aimed to compare the hepatoprotective and autophagy-modulating effects of EPI and EPIIS in a murine model of APAP-induced hepatotoxicity. In the experimental design, male BALB/c mice received APAP (750 mg/kg, i.p.) to induce hepatotoxicity, followed by phosphate-buffered saline (PBS), N-acetylcysteine (NAC-318 mg/kg, i.p.), or alkaloids (0.3, 1, or 3 mg/kg, i.p.) 30 min later. To assess the involvement of autophagy, hydroxychloroquine (HCQ; 80 mg/kg, i.p.), an autophagy inhibitor, was administered 2 h before APAP. Treatment with EPI, EPIIS, or NAC significantly reduced liver toxicity (p < 0.05). APAP-treated mice exhibited marked centrilobular necrosis, which was markedly reduced following the treatment with Jaborandi alkaloids. Furthermore, EPIIS and EPI significantly reduced the inflammatory and oxidative markers. Administration of HCQ 2 h before APAP abolished these effects. Western blotting analysis revealed increased LC3B expression, a marker of autophagy, in the hepatic tissues of the treated mice, indicating that EPIIS and EPI modulate autophagy. Molecular docking analysis suggested potential interactions between the alkaloids and CXCL10, a chemokine linked to inflammation and autophagy inhibition. These findings demonstrate that EPIIS and EPI protect against APAP-induced hepatotoxicity in mice, potentially by modulating autophagy and reducing inflammation.},
}

Animals
*Autophagy/drug effects
Male
Mice
*Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism/prevention & control
*Acetaminophen/adverse effects/toxicity
Mice, Inbred BALB C
*Anti-Inflammatory Agents/pharmacology
*Imidazoles/pharmacology/chemistry
*Alkaloids/pharmacology/chemistry
*Liver/drug effects/metabolism/pathology
4-Butyrolactone/analogs & derivatives

@article {pmid41812834,
year = {2026},
author = {Rathor, P and Tiwari, AK and Patel, RP and Verma, A and Singh, SP and Ch, R},
title = {Brain lipidomics identifies mitochondrial redox dysfunction and metabolic trade-offs associated with Parkinson's disease-like pathology induced by Nanoplastics exposure.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2026.03.023},
pmid = {41812834},
issn = {1873-4596},
abstract = {Growing nanoplastics exposure raises concern for neurotoxicity, particularly given recent evidence of plastic accumulation within human brain tissue a highly lipid enriched organ, yet effects on brain lipid metabolism remain poorly understood. Here, we employed high-resolution untargeted lipidomics to map brain lipid perturbations in Drosophila melanogaster chronically exposed to environmentally relevant levels of polystyrene nanoplastics (PS- NPs). PS-NPs accumulated in fly brains and induced dose-dependent remodeling of mitochondrial membrane lipids, notably cardiolipins and phosphatidylethanolamines, accompanied by increased diacylglycerols/triacylglycerols and monounsaturated fatty acids and by lipid droplet expansion. Guided by these lipidomic signatures, targeted biochemical assays demonstrated depolarized mitochondrial membrane potential, elevated mitochondrial reactive-oxygen species, inhibition of respiratory-chain complexes I and IV, and a shift in NAD(H) and NADP(H) redox couples toward a reduced state and increasing lipid peroxidation. This redox imbalance was accompanied by decreased tyrosine-hydroxylase expression, dopamine depletion, and impaired locomotor behavior, hallmarks of Parkinson's disease (PD)-like neurodegeneration. Dopaminergic neurochemistry was impaired (tyrosine hydroxylase and dopamine decreased), with concomitant reduction of GABA, and locomotor and circadian deficits emerged. Remarkably, co-treatment with the antioxidant N-acetylcysteine (NAC) restored mitochondrial membrane potential, reduced mitochondrial ROS and lipid peroxidation, normalized neutral lipid and MUFA accumulation, and rescued neurotransmitter levels and behavior. Stable-isotope tracing confirmed disrupted TCA cycle flux after NPs exposure that was rescued by NAC. Collectively, these findings reveal lipidomic remodeling as a critical link between environmental NPs exposure and PD-like pathology, highlighting mitochondrial redox-lipid interactions as early determinants and support redox-directed interventions to mitigate risk.},
}

@article {pmid41809881,
year = {2026},
author = {Huang, NF and Ling, P and Xu, YJ and Feng, XF and Zheng, Y and Sun, T},
title = {Xing-Pi-Qing-Gan decoction alleviates alcoholic liver disease by down-regulating DDIT3 and restoring Nrf2/HO-1 antioxidant signaling: Multi-omics and experimental evidence.},
journal = {World journal of gastroenterology},
volume = {32},
number = {8},
pages = {115077},
pmid = {41809881},
issn = {2219-2840},
mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Liver Diseases, Alcoholic/drug therapy/pathology/metabolism ; NF-E2-Related Factor 2/metabolism ; Signal Transduction/drug effects ; Humans ; Mice ; Disease Models, Animal ; Ethanol/toxicity ; Oxidative Stress/drug effects ; Liver/pathology/drug effects ; Male ; Heme Oxygenase-1/metabolism ; Down-Regulation/drug effects ; Antioxidants/metabolism/pharmacology ; Mice, Inbred C57BL ; Hep G2 Cells ; Network Pharmacology ; Membrane Proteins/metabolism ; Multiomics ; },
abstract = {BACKGROUND: Alcoholic liver disease (ALD) is driven by oxidative stress, lipid metabolism, inflammation, and apoptosis. Current therapies lack efficacy in targeting multi-pathway mechanisms. Xing-Pi-Qing-Gan decoction (XPQG) is an improved traditional Chinese medicine designed to alleviate ALD, but its molecular mechanism remains unknown.

AIM: To illustrate the therapeutic targets and molecular pathways of XPQG for the treatment of ALD by integrating chemical profiling, network pharmacology, transcriptomics, and experimental verification in vivo and in vitro.

METHODS: The components of XPQG were analyzed using ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry. Then, the protective effect of XPQG on ethanol-induced liver injury, especially its regulatory effect on DDIT3 expression and associated Nrf2/HO-1 antioxidant signaling, was investigated through in vivo animal experiments and in vitro cell experiments. A mouse model of ALD was developed, and the mechanism of XPQG was validated through hematoxylin and eosin (H&E) staining, Western blot, and quantitative RT-PCR. In addition, the key role of DDIT3 in XPQG-mediated protection was further verified by siDDIT3 cell transfection technology. Animal experiments with the reactive oxygen species inhibitor N-acetylcysteine (NAC) further validated the mechanism of XPQG to alleviate liver injury by regulating oxidative stress.

RESULTS: In ethanol-treated HepG2 cells, XPQG dose-dependently reduced the formation of lipid droplets, inhibited the expression of tumor necrosis factor-α, interleukin-6, interleukin-1β, and alleviated oxidative stress. In mice, XPQG (15.2 g/kg) lowered the liver/body weight ratio, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase; H&E and Oil Red O demonstrated a reduction in steatosis. Network pharmacology and RNA-seq converged on MAPK signaling, suggesting DDIT3 as a likely key effector in XPQG-mediated protection. DDIT3 knockdown in HepG2 cells attenuated the benefits of XPQG, supporting DDIT3 as a critical effector mechanism in XPQG-mediated protection. The use of NAC further illustrates the correlation of drugs to oxidative stress in disease effects.

CONCLUSION: In summary, the results of the study suggest that XPQG is effective in improving ethanol-induced acute liver injury (ALD). Its mechanism involves the suppression of DDIT3 and the enhancement of Nrf2/HO-1 pathway activity.},
}

Animals
*Drugs, Chinese Herbal/pharmacology/therapeutic use
*Liver Diseases, Alcoholic/drug therapy/pathology/metabolism
NF-E2-Related Factor 2/metabolism
Signal Transduction/drug effects
Humans
Mice
Disease Models, Animal
Ethanol/toxicity
Oxidative Stress/drug effects
Liver/pathology/drug effects
Male
Heme Oxygenase-1/metabolism
Down-Regulation/drug effects
Antioxidants/metabolism/pharmacology
Mice, Inbred C57BL
Hep G2 Cells
Network Pharmacology
Membrane Proteins/metabolism
Multiomics

@article {pmid41808863,
year = {2026},
author = {Yin, Y and Wu, X and Liu, Z and Luo, Y and Jing, M and Jing, K and Li, Q and Wang, F and Huang, J},
title = {Network meta-analysis of pharmacological treatments for idiopathic pulmonary fibrosis: evaluating effects on lung function.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1761899},
pmid = {41808863},
issn = {1663-9812},
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic interstitial lung disease of unknown cause. Its main feature is a steady decline in lung function, which is also the primary target for treatment. Existing research has investigated various drugs to slow IPF progression, but their effectiveness and how they affect key pulmonary function indicators need to be systematically evaluated and analysed.

METHODS: This systematic review and network meta-analysis searched eight databases to identify randomised controlled trials assessing the effects of various pharmacological treatments on lung function in patients with IPF. The risk of bias in the included studies was evaluated using tools from the Cochrane Handbook. Network meta-analysis was conducted using Stata 19.0 and R 4.5.1 software. The study protocol was registered in PROSPERO (CRD420251148658).

RESULTS: This study included 121 publications comprising 162 studies, covering 16,525 IPF patients across nine countries. The overall risk of bias assessment showed that while most studies had a low risk of bias in random sequence generation, concerns regarding allocation concealment and blinding were identified in a substantial proportion of the included studies. Network meta-analysis revealed that Nerandomilast was the most effective intervention for improving Forced Vital Capacity (FVC) (SUCRA: 98.85%). N-acetylcysteine (NAC) combined with Roxithromycin (RXM) was the most effective intervention for improving Vital Capacity (VC) (SUCRA: 88.8%) and Forced Expiratory Volume in 1 s/Forced Vital Capacity (FEV1/FVC) (SUCRA: 97.45%). Ambroxol was the most effective intervention for improving Total Lung Capacity (TLC) (SUCRA: 82.52%), while Thalidomide was the most effective intervention for improving Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) (SUCRA: 90.93%).

CONCLUSION: The results suggest that drugs targeting different pulmonary function parameters have corresponding mechanisms of action. Nerandomilast shows potential for improving FVC, while NAC combined with RXM may enhance VC and FEV1/FVC. Ambroxol appears effective in increasing TLC, and Thalidomide may boost DLCO. Nonetheless, these findings need validation through higher-quality studies in the future. Additionally, future research should examine the long-term effectiveness of new drugs like Nerandomilast and Pamrevlumab, while also improving comprehensive assessments of synergistic changes across various pulmonary function indicators.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251148658.},
}

@article {pmid41807727,
year = {2026},
author = {Tan, LX and Zhang, YY and Liu, ZJ and Cao, Y and Liu, JJ and Mo, MH and Liu, T},
title = {The fungistatic mechanism of benzaldehyde against the nematophagous fungus Arthrobotrys oligospora suggests a method for manipulating soil fungistasis.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-09836-z},
pmid = {41807727},
issn = {2399-3642},
support = {32160022//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Germination and growth of biocontrol microorganisms in soil are often inhibited by soil fungistasis (SF), resulting in unsatisfactory control efficacy. Therefore, exploring mechanisms underlying SF is important for developing efficient biocontrol agents. Benzaldehyde has a strong fungistatic effect against the nematophagous fungus Arthrobotrys oligospora. Our transcriptome analysis suggested a fungistatic model by which benzaldehyde induces reactive oxygen species (ROS), leading to energy deficiency and in turn activating the AMPK-mTOR pathway. The ROS-inducing compound retinol enhanced benzaldehyde fungistasis (BF), whereas the antioxidant substance N-acetyl cysteine reduced ROS production and enhanced BF resistance in A. oligospora. Inhibiting the glutathione antioxidant system by blocking the supply of NADPH decreased BF resistance in A. oligospora. Furthermore, the AMPK activator acadesine bolstered BF resistance in A. oligospora, while the AMPK inhibitor dorsomorphin dihydrochloride or knocking out the AMPK gene had the opposite effect. These results strongly support a fungistatic mechanism of action for benzaldehyde. Finally, we found that the fungistatic mechanism of benzaldehyde similarly underlies SF, with the AMPK activators acadesine or metformin effectively increasing the SF resistance of A. oligospora. This study suggests a mechanism by which soil inhibits fungi and offers a potential method for improving SF resistance of fungal biocontrol agents.},
}

@article {pmid41801306,
year = {2026},
author = {Xie, M and Weng, J and Li, C and Liu, Q and Feng, Y and Zhang, H and Chang, Q and Chung, KF and Adcock, IM and Li, F and Fan, X},
title = {Mechanisms of Anti-Oxidants, N-Acetylcysteine and Elamipretide (SS-31), on Ozone-Induced Airway Hyperresponsiveness and Mucus Hypersecretion.},
journal = {Lung},
volume = {204},
number = {1},
pages = {},
pmid = {41801306},
issn = {1432-1750},
support = {81870031//National Natural Science Foundation of China/ ; U1803126//National Natural Science Foundation of China/ ; YG2019ZDA24//Shanghai Jiao Tong University/ ; 202304295107020044//Anhui Provincial Institute of Translational Medicine/ ; },
mesh = {Animals ; Ozone ; *Acetylcysteine/pharmacology ; Mice, Inbred C57BL ; *Antioxidants/pharmacology ; *Mucus/metabolism ; Oxidative Stress/drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein ; *Oligopeptides/pharmacology ; Reactive Oxygen Species/metabolism ; Mice ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Cell Line ; Carrier Proteins/metabolism ; *Bronchial Hyperreactivity/chemically induced/metabolism/prevention & control/physiopathology ; Phosphatidylinositol 3-Kinases/metabolism ; *Lung/drug effects/metabolism/physiopathology ; Humans ; Mitochondria/metabolism/drug effects ; Caspase 1/metabolism ; Bronchoalveolar Lavage Fluid/cytology ; Inflammation Mediators/metabolism ; },
abstract = {BACKGROUND: Ozone (O3) exposure induces acute airway injury characterized by airway hyperresponsiveness (AHR) and airway mucus hypersecretion (AMH). Oxidative stress and mitochondria-derived reactive oxygen species (mtROS) are key contributors. We investigated and compared the protective mechanisms of N-acetylcysteine (NAC) and the mitochondria-targeted antioxidant Elamipretide (SS-31) in O3-induced airway inflammation, AHR and AMH.

METHODS: Wild-type C57BL/6J mice received intraperitoneal NAC or SS-31 1 h before a single O₃ exposure. AHR, bronchoalveolar lavage (BAL) inflammatory cells, mucus production and mucin expression, inflammatory mediators, oxidative stress indices, and PI3K/AKT and NLRP3/caspase-1/GSDMD pathway activation were assessed in vivo. BEAS-2B cells were pretreated with NAC, SS-31, or the PI3K/AKT inhibitor LY294002 before O₃ exposure, and pathway activation was evaluate d in vitro.

RESULTS: NAC and SS-31 comparably attenuated O₃-induced AHR, reduced BAL inflammatory cell influx, and decreased AMH and MUC5B expression. Both treatments improved redox balance by reducing ROS/mtROS, lowering malondialdehyde (MDA), increasing superoxide dismutase (SOD) activity, and improving GSH/GSSG. NAC and SS-31 also suppressed O₃-induced inflammatory gene expression and inhibited activation of PI3K/AKT and NLRP3/caspase-1/GSDMD signaling in mouse lungs and BEAS-2B cells. PI3K inhibition recapitulated these protective effects in vitro, supporting a mechanistic role for PI3K/AKT signaling during acute O₃ exposure.

CONCLUSIONS: NAC and SS-31 protect against acute O₃-induced AHR and AMH by alleviating oxidative stress and suppressing PI3K/AKT-driven inflammatory and pyroptotic pathways. Targeting oxidative stress, including mitochondrial ROS, may represent a viable strategy to mitigate airway damage caused by acute O₃ exposure.},
}

Animals
Ozone
*Acetylcysteine/pharmacology
Mice, Inbred C57BL
*Antioxidants/pharmacology
*Mucus/metabolism
Oxidative Stress/drug effects
NLR Family, Pyrin Domain-Containing 3 Protein
*Oligopeptides/pharmacology
Reactive Oxygen Species/metabolism
Mice
Proto-Oncogene Proteins c-akt/metabolism
Signal Transduction/drug effects
Disease Models, Animal
Male
Cell Line
Carrier Proteins/metabolism
*Bronchial Hyperreactivity/chemically induced/metabolism/prevention & control/physiopathology
Phosphatidylinositol 3-Kinases/metabolism
*Lung/drug effects/metabolism/physiopathology
Humans
Mitochondria/metabolism/drug effects
Caspase 1/metabolism
Bronchoalveolar Lavage Fluid/cytology
Inflammation Mediators/metabolism

@article {pmid40398422,
year = {2025},
author = {Sonar, SA and Bhat, R and Thompson, HL and Coplen, CP and Uhrlaub, JL and Jergovic, M and Nikolich, JŽ},
title = {Age-Related Oxidative Stress and Mitochondrial Dysfunction in Lymph Node Stromal Cells Limit the Peripheral T Cell Homeostatic Maintenance and Function.},
journal = {Aging cell},
volume = {24},
number = {8},
pages = {e70100},
pmid = {40398422},
issn = {1474-9726},
support = {P01 AG052359/AG/NIA NIH HHS/United States ; P30 CA023074/CA/NCI NIH HHS/United States ; //Bowman Professorship in Medical Sciences/ ; },
mesh = {*Oxidative Stress ; Animals ; *Mitochondria/metabolism/drug effects/pathology ; *Stromal Cells/metabolism ; *Lymph Nodes/metabolism/cytology/pathology/immunology ; Mice ; Reactive Oxygen Species/metabolism ; *Homeostasis ; *Aging ; *T-Lymphocytes/metabolism/immunology ; Mice, Inbred C57BL ; },
abstract = {Lymph nodes (LN) are the key organs in charge of long-term maintenance of naïve lymphocytes and their initial, primary activation upon infection. Accumulating evidence indicates that LN stromal cells undergo degenerative changes with aging that critically impair LN function, including the generation of protective primary immune responses. The nature of these defects remains incompletely understood. We here demonstrate that age-related LN stromal changes manifest themselves in mitochondrial dysfunction and oxidative stress. Ex vivo, all three major stromal cell subsets, fibroblastic reticular cells (FRC), lymphatic endothelial cells (LEC), and blood endothelial cells (BEC) exhibit elevated mitochondrial reactive oxygen species (ROS) stress, reduced mitochondrial potential, and elevated mitochondrial mass with aging. Old FRC also exhibited elevated cytoplasmic ROS production. This was accompanied by the reduced ability of old LN stromal cells to support Tn survival in vitro, a defect alleviated by pretreating old LN stroma with the general antioxidant N-acetyl cysteine (NAC) as well as by mitochondrial ROS-reducing (mitoquinone) and mitophagy-inducing (urolithin A) compounds. Mitochondrial dysfunction and, in particular, reduced mitochondrial potential in old FRC were also seen upon vaccination or infection in vivo. Consistent with these results, in vivo antioxidant treatment of old mice with NAC restored to adult levels the numbers of antigen-specific CD8[+] effector T cells and their production of granzyme B in response to antigenic challenge.},
}

*Oxidative Stress
Animals
*Mitochondria/metabolism/drug effects/pathology
*Stromal Cells/metabolism
*Lymph Nodes/metabolism/cytology/pathology/immunology
Mice
Reactive Oxygen Species/metabolism
*Homeostasis
*Aging
*T-Lymphocytes/metabolism/immunology
Mice, Inbred C57BL

@article {pmid41663723,
year = {2026},
author = {Zhang, XD and Atalla, N and Rodriguez, E and Teng, C and Bai, X and Teng, JMC},
title = {Development of a controlled ex vivo human skin platform for quantitative evaluation of age-related functional biomarkers following application of topical treatments.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41663723},
issn = {2045-2322},
mesh = {Humans ; *Biomarkers/metabolism ; *Skin Aging/drug effects/radiation effects ; *Zinc Oxide/pharmacology/administration & dosage ; *Skin/drug effects/metabolism/radiation effects/pathology ; Adult ; Middle Aged ; Female ; Male ; Aged ; Cellular Senescence/drug effects ; Ultraviolet Rays/adverse effects ; Administration, Topical ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Tumor Suppressor Protein p53/metabolism ; Acetylcysteine/pharmacology/administration & dosage ; Interleukin-1beta/metabolism ; },
abstract = {Targeting cellular senescence presents a promising approach to slow visible skin aging and promote tissue repair. However, most preclinical models fail to capture the full architecture of human skin or accommodate diverse skin types, limiting their translational relevance. To address this gap, we developed a controlled ex vivo human skin explant platform using freshly acquired tissues from donors of varying ages and Fitzpatrick skin types. This model applies standardized UVA and UVB doses to induce reproducible photodamage, enabling the assessment of both preventative and reparative effects of topical treatments. The results showed that ND-ZnO and NAC reduced levels of p16^INK4a and p53, which are key biomarkers measuring cellular senescence; ND-ZnO and exosomes lowered IL-1β expression, which is a biomarker measuring inflammation. Histological analysis confirmed these findings, with ND-ZnO-treated skins preserved epidermal structure, reduced inflammatory features, and maintained dermal collagen organization. We then conducted a four-week single-patient case study using the same ND-ZnO formulation. Visible improvements in redness, pigmentation, and texture were observed, aligned with the molecular and histological changes seen ex vivo. These findings suggested that the ex vivo platform has the potential to be used as a more inclusive, human-relavent model for evaluating and quantifying the anti-aging efficacies of topical treatments across diverse skin types and age groups.},
}

Humans
*Biomarkers/metabolism
*Skin Aging/drug effects/radiation effects
*Zinc Oxide/pharmacology/administration & dosage
*Skin/drug effects/metabolism/radiation effects/pathology
Adult
Middle Aged
Female
Male
Aged
Cellular Senescence/drug effects
Ultraviolet Rays/adverse effects
Administration, Topical
Cyclin-Dependent Kinase Inhibitor p16/metabolism
Tumor Suppressor Protein p53/metabolism
Acetylcysteine/pharmacology/administration & dosage
Interleukin-1beta/metabolism

@article {pmid41661511,
year = {2026},
author = {Appell, MB and Kanan, Y and Malmberg, K and Appidi, T and Khan, M and Campochiaro, PA and Ensign, LM},
title = {A gel-forming antioxidant eye drop for photoreceptor protection in retinitis pigmentosa.},
journal = {Drug delivery and translational research},
volume = {16},
number = {4},
pages = {1052-1063},
pmid = {41661511},
issn = {2190-3948},
support = {R01EY031041/EY/NEI NIH HHS/United States ; P30EY001765/EY/NEI NIH HHS/United States ; T32EY007143/EY/NEI NIH HHS/United States ; R01EY031041/EY/NEI NIH HHS/United States ; P30EY001765/EY/NEI NIH HHS/United States ; T32EY007143/EY/NEI NIH HHS/United States ; },
mesh = {Animals ; *Retinitis Pigmentosa/drug therapy/pathology ; *Antioxidants/administration & dosage/chemistry ; Ophthalmic Solutions/administration & dosage ; *Acetylcysteine/administration & dosage/analogs & derivatives/chemistry ; Mice ; Gels ; Disease Models, Animal ; Rats ; Male ; *Photoreceptor Cells, Vertebrate/drug effects ; Mice, Inbred C57BL ; },
abstract = {Retinitis pigmentosa (RP) is a chronic genetic condition that leads to progressive loss of photoreceptor cells and vision. While gene therapy is available for a small subset of patients with specific mutations, developing a therapeutic that broadly targets the cellular stresses that lead to cell death could address a major unmet need. One such option would be utilizing antioxidant therapies to neutralize reaction oxygen species (ROS) in the retina that underlie RP progression. Here, we describe an approach for delivering the antioxidants N-acetyl cysteine (NAC) or N-acetyl cysteine ethyl ester (NACET) with a gel-forming eye drop previously demonstrated to provide therapeutic drug delivery in the posterior segment in animals. We demonstrated therapeutic protection of photoreceptor structure and function in a chemically-induced rat model of RP (48% increase in photopic b-wave amplitude), as well as some limited protection in an aggressive genetic mouse model (rd10) of retinal degeneration (~ 31% increase in photopic b-wave amplitude) with once daily application. However, antioxidants have inherent stability issues when stored in solution, so we investigated the use of additional excipients to improve stability and retain potency. While a promising approach, future work to address product stability and efficacy in larger eyes is needed for further development.},
}

Animals
*Retinitis Pigmentosa/drug therapy/pathology
*Antioxidants/administration & dosage/chemistry
Ophthalmic Solutions/administration & dosage
*Acetylcysteine/administration & dosage/analogs & derivatives/chemistry
Mice
Gels
Disease Models, Animal
Rats
Male
*Photoreceptor Cells, Vertebrate/drug effects
Mice, Inbred C57BL

@article {pmid41790529,
year = {2026},
author = {Ommi, NB and Mattocks, DAL and Horowitz, MC and Nichenametla, SN},
title = {D, L-Buthionine-(S, R)-sulfoximine recapitulates the anti-obesity effects of sulfur amino acid restriction without the associated deleterious effects on bone in male mice.},
journal = {Aging},
volume = {18},
number = {1},
pages = {82-99},
doi = {10.18632/aging.206358},
pmid = {41790529},
issn = {1945-4589},
abstract = {Sulfur amino acid restriction (SAAR), a diet low in methionine and lacking cysteine, reduces obesity but also lowers bone mineral density (BMD) and increases marrow adipose tissue. Because the SAAR diet lacks cysteine, it exerts cysteine restriction (CysR), in addition to methionine restriction (MetR). We previously reported that the anti-obesity effect of the SAAR diet was exclusively due to CysR. Follow-up studies revealed that CysR decreases obesity by lowering glutathione (GSH), and that D, L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH biosynthesis, recapitulates the SAAR-induced lean phenotype on a methionine-replete diet. Here, we investigated whether the detrimental effects of the SAAR diet on bone are mediated solely by CysR and whether BSO, similar to the SAAR diet, exerts deleterious effects. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (control diet, CD), 0.12% methionine (SAAR diet), SAAR diet supplemented with a GSH precursor, N-acetylcysteine (NAC) in water, and CD supplemented with BSO in water. Femurs and tibiae of SAAR mice had lower trabecular and cortical BMD, fewer osteoblasts, reduced biomechanical strength, and more marrow adipocytes than in CD mice. NAC reversed all these effects, suggesting that CysR mediates the detrimental effects of the SAAR diet on bone. Despite its anti-obesity effects, BSO did not exert any detrimental effects on bones. Future studies should investigate mechanisms, age-at-onset, tissue-specific, and gender-specific effects of BSO on bone health. Long-term studies to establish the therapeutic efficacy and off-target effects of BSO are critical for developing it as an anti-obesity drug in humans.},
}

@article {pmid41780686,
year = {2026},
author = {Sun, W and Xie, L and Jiang, X and Zhu, Q and Feng, H and Cun, D and Wu, L and Yang, M},
title = {A functional lyoprotectant platform enables storage-stable, mucus-penetrating siRNA delivery to the lung.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114749},
doi = {10.1016/j.jconrel.2026.114749},
pmid = {41780686},
issn = {1873-4995},
abstract = {Respiratory diseases remain a major global health concern, where pathological mucus accumulation and chronic inflammation severely compromise lung function. RNA therapeutics have emerged as a transformative modality to address underlying molecular pathologies beyond the capabilities of small-molecule drugs. However, effective delivery of RNA therapeutics to the lungs remains hindered by significant challenges. The instability of lipid nanoparticles (LNPs) in liquid formulations compromises their storage and cold-chain transport, while the pathological mucus hypersecretion characteristic of chronic airway diseases impedes nanoparticle penetration and delivery efficacy. Herein, we propose a functional lyoprotectant strategy that bridges formulation stability and biological functionality within a single design. Specifically, N-acetylcysteine (NAC), a clinically used mucolytic, was incorporated into a sucrose-based lyoprotectant matrix as a functional additive, enabling lyophilization while introducing mucus-modulating capability. The lyophilized LNPs preserved physicochemical integrity, maintained siRNA encapsulation, and achieved efficient mucus penetration and gene silencing in vitro and in vivo. In murine models of mucus-hypersecretory lung disease, a single-dose administration achieved enhanced therapeutic outcomes through a sequential and dual-action complementary mechanism, including extracellular NAC-mediated mucolysis and intracellular RNAi-mediated inflammation suppression. This work pioneers the concept of a functional lyoprotectant, offering a generalizable platform for storage-stable and biologically active inhaled RNA therapeutics.},
}

@article {pmid41780678,
year = {2026},
author = {Cai, YY and Yang, LJ and Pan, MM and Nurtay, N and Yu, YP and Xie, M and Jiang, M and Wang, Y and Yu, X and Xu, L},
title = {PtCu-bimetallic modified MOF nanozyme composites for alleviating acute liver injury via reactive oxygen species elimination and inflammation regulation.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114774},
doi = {10.1016/j.jconrel.2026.114774},
pmid = {41780678},
issn = {1873-4995},
abstract = {Excessive reactive oxygen species (ROS) accumulation and dysregulated inflammation drive acetaminophen (APAP)-induced acute liver injury (ALI), yet the therapeutic effect of the commonly used clinical drug N-acetylcysteine (NAC) still has certain limitations at present. Here, we engineered a multifunctional nanozyme nanocomposite, MPCNH, by in situ deposition of bimetallic PtCu nanoparticles onto UiO-66 metal-organic frameworks (MOFs), loading NAC, and coating with hyaluronic acid (HA) to enhance biocompatibility. MPCNH exhibited cascade superoxide dismutase (SOD)-like and catalase (CAT)-like catalytic activities, enabling rapid ROS clearance and mitochondrial protection in APAP-challenged hepatocytes. Meanwhile, the delivery of the therapeutic drug NAC was achieved. In vivo, MPCNH lowered serum transaminases, activated the Keap1-Nrf2 antioxidant pathway, shifted macrophages polarization toward an anti-inflammatory M2 phenotype and restored metabolic balance. By integrating catalytic and pharmacological functions, MPCNH offers a synergistic strategy to simultaneously eliminate oxidative stress and regulate inflammation, providing a promising therapeutic platform for oxidative stress-driven liver injury.},
}

@article {pmid41780618,
year = {2026},
author = {Ge, Y and Luo, N and Zhang, M and Shi, J and Xu, X and Wang, Y},
title = {Advances on botanicals targeting programmed cell death in acetaminophen-induced liver injury.},
journal = {Journal of ethnopharmacology},
volume = {363},
number = {},
pages = {121466},
doi = {10.1016/j.jep.2026.121466},
pmid = {41780618},
issn = {1872-7573},
abstract = {Acetaminophen (APAP), a widely used analgesic and antipyretic drug, poses a significant clinical challenge worldwide due to its potential to induce hepatotoxicity following overdose. At present, limited therapeutic options exist for APAP overdose. Moreover, N-acetylcysteine (NAC), the first-line clinical agent in routine use, suffers from a narrow therapeutic window and numerous adverse effects, which limits its clinical utility. Plants constitute a rich reservoir of phytochemicals that engage in multiple pharmacological processes, positioning them as a cornerstone in pharmaceutical innovation. The therapeutic use of herbs for liver conditions is historically recognized in classical works such as the "Treatise on Febrile Diseases," "Compendium of Materia Medica," and "Thousand Golden Prescriptions."

AIM OF THE REVIEW: Chinese herbal medicines and their extracts have garnered significant attention for the prevention and treatment of acetaminophen (APAP)-induced liver injury (AILI), largely due to their therapeutic efficacy and favorable safety profile. The programmed cell death (PCD) induced by APAP, and the impact and potential mechanism on the pathogenesis of AILI are discussed in this review. Furthermore, various botanicals that can be used to prevent AILI, as well as the structure-activity relationships and potential mechanisms, are discussed.

METHODS: Articles published over the past decade were retrieved from databases including Web of Science, PubMed, and CNKI, using the keywords APAP, AILI, natural products, and traditional Chinese medicine. Studies that failed to clearly characterize the components of plant extracts were excluded. Subsequently, a preliminary classification was performed based on the chemical structures of the included natural products, with priority given to relatively novel agents supported by robust research data or notable research advances. Following a systematic review and synthesis of key study details, including experimental design, phenotypic alterations, and mechanism elucidation, the decision was made to conduct further in-depth analysis focusing on the type of PCD. Ultimately, more than 160 papers were selected and discussed in this review.

RESULTS: A systematic review of the literature identified plant extracts with anti-AILI properties, which can be categorized into nine distinct classes based on their bioactive structures. By comparing the experimental research evidence from 44 natural compounds, not only were several more promising compounds such as sinomenine, dihydromyricetin, tannic acid and pterostilbene obtained, but it also helped to clarify the protective mechanisms of these extracts. Studies have found that numerous derivatives of natural products are capable of concurrently modulating multiple signaling pathways, such as Nrf2-HO1, NF-κB, and RIPK/MLKL, to alleviate PCD caused by APAP, thereby offering potential strategies for the prevention or treatment of AILI.

CONCLUSION: This review systematically elucidates the mechanisms by which structurally diverse phytochemicals alleviate APAP-induced hepatotoxicity, with a specific focus on their modulatory roles in programmed cell death pathways implicated in AILI. These findings provide valuable insights for the development of novel hepatoprotective therapeutics.},
}

@article {pmid41779942,
year = {2026},
author = {Lucas, D and Munoz, C and Muller, CR and Gu, X and Wolfe, SR and Cuddington, CT and Palmer, AF and Cabrales, P},
title = {Acellular Hemoglobin Impairs Cardiomyocyte Excitation-Contraction Coupling.},
journal = {ASAIO journal (American Society for Artificial Internal Organs : 1992)},
volume = {},
number = {},
pages = {},
doi = {10.1097/MAT.0000000000002668},
pmid = {41779942},
issn = {1538-943X},
abstract = {Heart failure is a significant complication of chronic intravascular hemolysis, a condition characterized by red blood cells (RBCs) breakdown, leading to the release of acellular hemoglobin (Hb) and its oxidized form, methemoglobin (MetHb), into the bloodstream. Acellular Hb promotes nitric oxide (NO) scavenging, oxidative stress, inflammation, iron overload, and functional tissue impairment. This study investigates the direct impact of Hb and MetHb on cardiomyocyte function by assessing calcium transients, fractional shortening, and reactive oxygen species (ROS) formation. The study also evaluated the effects of polymerized Hb, NO scavenging, and antioxidant therapy using N-acetylcysteine (NAC) on cardiomyocyte contractility. Our results show that acellular Hb and MetHb impair cardiomyocyte function by prolonging calcium transient half-life, reducing contractility, and increasing ROS production. Polymerization of Hb and antioxidant supplementation offered partial protection but did not fully mitigate these effects. Inhibiting NO synthase did not increase Hb toxicity, indicating that NO scavenging is not the sole toxicity pathway. These findings demonstrate that Hb-induced cardiomyocyte dysfunction involves a multifactorial mechanism, including NO scavenging, oxidative stress, and disrupted calcium dynamics. Although Hb polymerization and antioxidants offer limited protection, novel multi-target strategies are essential to address Hb toxicity in hemolytic disorders and the use of Hb-based oxygen carriers.},
}

@article {pmid41771427,
year = {2026},
author = {Lu, Y and Cheng, S and Zhang, Y and Li, Y and Liu, L},
title = {Novel 1,2,3-triazole-based compound triggers apoptosis through DNA damage response involving ATM/ATR signaling in liver cancer cells.},
journal = {Biochemical pharmacology},
volume = {248},
number = {},
pages = {117856},
doi = {10.1016/j.bcp.2026.117856},
pmid = {41771427},
issn = {1873-2968},
abstract = {1,2,3-Triazole-substituted cabotegravir analogues, i.e., KJ-9, have been developed as lead structures to explore their potential as antitumor agents. The new analogue exhibited significant anti-proliferative activity against various human cancer cell lines, with particularly strong effects on the HepG2 and HCCLM3 liver cancer lines, as it induced a marked loss of colony-forming ability and triggered apoptosis upon KJ-9 exposure. Furthermore, treatment with KJ-9 increased the Bax-to-Bcl-2 protein ratio and activated cleaved caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP). Meanwhile, KJ-9 treatment induced a blockage in the cell cycle (G2/M), increased DNA damage levels, and induced the accumulation of histone variant H2AX (γ-H2AX) protein. Furthermore, there was strong induction of p-ATM and p-ATR proteins, along with their downstream effectors p-CHK1 and p-CHK2. Additionally, KJ-9 treatment increased phosphorylation levels of the tumor suppressor protein p53 and inhibited components of the PI3K/AKT pathway. Although it did not significantly affect AKT phosphorylation, the ATM/ATR inhibitor CGK733 significantly reversed KJ-9-induced upregulation of p-ATM, p-ATR, p-p53, γ-H2AX, and activated caspase-3. Moreover, reactive oxygen species (ROS) were generated in greater quantities by KJ-9 treatment. After KJ-9 treatment, ROS were suppressed by the addition of the antioxidant N-Acetylcysteine (NAC), leading to increased levels of p-AKT and reduced levels of p-ATM, p-ATR, p-p53, cleaved caspase-3, and γ-H2AX. These findings suggest that KJ-9 promotes oxidative stress, which further inhibits AKT activation while activating the ATM/ATR pathway, leading to p53 accumulation, sustained DNA damage responses, G2/M-phase cell cycle arrest, and apoptosis in both HepG2 cells and HCCLM3 cells.},
}

@article {pmid41761803,
year = {2026},
author = {Nasir, W and Ul Hassan, S and Aslam, B and Majeed, W},
title = {Unfolding protection: Terminalia arjuna targets UPR pathways to counteract ER stress in hepatotoxicity.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {4},
pages = {1073-1082},
doi = {10.36721/PJPS.2026.39.4.REG.14749.1},
pmid = {41761803},
issn = {1011-601X},
mesh = {Animals ; *Terminalia/chemistry ; *Endoplasmic Reticulum Stress/drug effects ; Rats, Wistar ; *Plant Extracts/pharmacology/isolation & purification ; Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/metabolism/prevention & control/pathology ; Oxidative Stress/drug effects ; Rats ; Male ; *Liver/drug effects/pathology/metabolism ; *Unfolded Protein Response/drug effects ; Apoptosis/drug effects ; Signal Transduction/drug effects ; Plant Bark/chemistry ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; },
abstract = {BACKGROUND: Drug-induced liver injury (DILI) from acetaminophen (APAP) overdose involves ER stress, oxidative damage, apoptosis, and inflammation.

OBJECTIVE: This study assesses Terminalia arjuna bark extract (TAE) against APAP-induced toxicity in rats, comparing its efficacy with N-acetylcysteine (NAC) through key signaling and inflammatory markers.

METHODS: Twenty-four Wistar rats were equally divided into four groups: Control Negative (CN, no treatment), Control Positive (CP, acetaminophen 350 mg/kg), N-acetylcysteine (NAC, 150 mg/kg), and Terminalia arjuna bark extract (TAE, ethanolic, 80 mg/kg). Over 14 days, liver injury was induced in the CP group via acetaminophen, while the NAC and TAE groups received their respective treatments. Animals were decapitated on day 15, and biological samples were collected for analysis. Biochemical assessments included liver function markers (ALT, AST) and oxidative stress parameters (SOD, TAC, TBARS, TOS). Gene expression studies were performed for oxidative stress regulators (Keap1, Nrf2) and ER stress signaling molecules (ERK, JNK, PPAR-α, AKT). Histopathological examination evaluated liver architecture and cellular integrity.

RESULTS: Acetaminophen induced significant hepatotoxicity, as reflected by elevated liver enzymes, increased oxidative stress, altered gene expression, and disrupted liver histology. APAP toxicity resulted in elevated oxidative stress, apoptosis, inflammation, and ER stress, leading to significant hepatic damage (p < 0.0001 vs CN). NAC and TAE treatments mitigated these effects, with TAE demonstrating superior improvement in oxidative stress markers (p < 0.0001 vs CP). Gene expression analysis revealed a protective shift in the Keap1-Nrf2 pathways in the treated groups. Histopathology confirmed reduced necrosis and preserved hepatic architecture in the NAC and TAE groups.

CONCLUSION: T. arjuna exhibits potent hepatoprotective effects, comparable to NAC, through modulation of oxidative stress, apoptosis, and ER stress pathways. Further studies are needed to explore its clinical applicability in acute liver injury management.},
}

Animals
*Terminalia/chemistry
*Endoplasmic Reticulum Stress/drug effects
Rats, Wistar
*Plant Extracts/pharmacology/isolation & purification
Acetaminophen/toxicity
*Chemical and Drug Induced Liver Injury/metabolism/prevention & control/pathology
Oxidative Stress/drug effects
Rats
Male
*Liver/drug effects/pathology/metabolism
*Unfolded Protein Response/drug effects
Apoptosis/drug effects
Signal Transduction/drug effects
Plant Bark/chemistry
Acetylcysteine/pharmacology
Antioxidants/pharmacology

@article {pmid41754714,
year = {2026},
author = {Xie, Y and Ruan, B and Yin, Y and Fan, L and Tang, H and Dai, H and You, S and Yao, S and Wang, G and Xu, Y},
title = {A Biomimetic NAC-Loaded PCL/Modified Chitosan/dECM Fibrous Scaffold for Accelerating Diabetic Wound Healing and Minimizing Scarring.},
journal = {Polymers},
volume = {18},
number = {4},
pages = {},
pmid = {41754714},
issn = {2073-4360},
support = {ZDYF2025GXJS148//2025 Provincial Key R&D Sanya Yazhou Bay Science and Technology City Joint Innovation Project/ ; ZDYF2024GXJS016//2024 Key R & D projects in Hainan Province/ ; ZR202306010004//Natural Science Foundation of Shandong Province/ ; BZLX2023004//Research projects of the University Institute in the construction period of Shangyu District, Shaoxing City/ ; N/A//The 2024 Chu Tian Talent Plan Science and Technology Innovation Team Project/ ; },
abstract = {The development of innovative wound dressings capable of accelerating diabetic wound healing while simultaneously reducing scar formation is a significant clinical challenge. In this study, we designed and fabricated a multifunctional nanofibrous scaffold PCL/Az-CS/dECM/NAC by incorporating decellularized extracellular matrix (dECM) and N-acetylcysteine (NAC) into a composite backbone of polycaprolactone (PCL) and azidobenzoic acid-modified chitosan (AZCS). The scaffold exhibited ideal hydrophilicity and swelling capacity, and demonstrated excellent biocompatibility. In vitro studies demonstrated that the scaffold effectively scavenged reactive oxygen species (ROS) and promoted the polarization of macrophages from the M1 phenotype to the M2 phenotype; in vivo studies confirmed that the PCL/AZ-CS/dECM/NAC scaffold significantly accelerated wound closure, promoted mature angiogenesis, and facilitated orderly collagen deposition. The PCL/AZ-CS/dECM/NAC scaffold mitigated scar formation by increasing the proportion of regenerative type III collagen, optimizing the collagen I/III ratio. Our findings suggest that the PCL/AZ-CS/dECM/NAC scaffold is a highly promising candidate for a multifunctional dressing designed to treat recalcitrant diabetic wounds and prevent excessive scarring.},
}

@article {pmid41754089,
year = {2026},
author = {Dawi, J and Affa, S and Au, S and Misakyan, Y and Gonzalez, E and Chorbajian, A and Hammi, M and Dave, P and Qumsieh, K and Venketaraman, V},
title = {Efficacy and Safety of Glutathione Supplementation in Patients with HIV Infection and HIV-Tuberculosis Co-Infection.},
journal = {Nutrients},
volume = {18},
number = {4},
pages = {},
pmid = {41754089},
issn = {2072-6643},
abstract = {Glutathione (GSH), the most abundant intracellular non-protein thiol, is a central regulator F redox homeostasis, immune function, and mitochondrial integrity. In human immunodeficiency virus (HIV) infection, persistent oxidative stress and impaired precursor availability result in sustained glutathione deficiency, contributing to immune dysfunction, inflammation, and disease progression despite effective antiretroviral therapy. This redox imbalance is further exacerbated in HIV-tuberculosis co-infection, where compounded inflammatory and metabolic stress increases susceptibility to opportunistic infections and treatment-related complications. This review examines the efficacy and safety of glutathione supplementation and precursor-based strategies in HIV infection and HIV-tuberculosis co-infection. Evidence from mechanistic studies, clinical trials, and translational research suggests that glutathione repletion, achieved through direct supplementation or precursor approaches such as N-acetylcysteine, Glycine and N-acetylcysteine (GlyNAC), and cysteine-rich dietary interventions, can restore intracellular thiol balance, improve immune cell function, enhance mitochondrial performance, and reduce systemic oxidative stress. These interventions have shown consistent safety and tolerability across diverse populations, including individuals receiving complex antiretroviral and antitubercular regimens, with gastrointestinal discomfort being the most commonly reported adverse effect and serious toxicities remaining rare. Despite encouraging findings, translation into routine clinical practice remains limited by methodological heterogeneity, short study durations, and lack of standardized biomarkers and long-term outcome data. Future research should prioritize rigorously designed trials incorporating mechanistic endpoints, standardized redox measurements, and clinically meaningful outcomes. Collectively, the available evidence supports glutathione-centered strategies as promising adjuncts to existing HIV and tuberculosis treatment paradigms, warranting further investigation to define their role in improving immune resilience and long-term clinical outcomes.},
}

@article {pmid41753798,
year = {2026},
author = {Wang, F and Wang, W and Gu, H},
title = {Intrinsic Acidity of N-Acetylcysteine Mediates Enhanced Inhibition of Klebsiella pneumoniae and Its Biofilms by Polymyxin B.},
journal = {Microorganisms},
volume = {14},
number = {2},
pages = {},
pmid = {41753798},
issn = {2076-2607},
abstract = {This study investigated the combined antibacterial and anti-biofilm activity of polymyxin B (PB) with intrinsically acidic N-acetylcysteine (NAC) against Klebsiella pneumoniae. The minimum inhibitory concentrations (MICs) of PB, acidic NAC, and neutralized NAC against 34 K. pneumoniae strains were determined using the broth microdilution. Drug interactions were assessed by checkerboard assays and the fractional inhibitory concentration index (FICI), while biofilm inhibition was quantified using crystal violet staining. Polymyxin B resistance was identified in the reference multidrug-resistant strain K. pneumoniae ATCC BAA-1705. The PB-NAC combination showed an additive effect (FICI 0.53-0.63) against PB-resistant and PB-intermediately susceptible strains, whereas indifferent interactions were observed in PB-susceptible strains. Furthermore, sub-inhibitory concentrations of the combination produced significantly stronger biofilm inhibition than either agent alone. Neutralization of NAC markedly reduced its antibacterial and anti-biofilm activities, with substantial inhibition observed only at concentrations ≥ 32 mg/mL. These findings demonstrate that the combination of PB and acidic NAC exerts additive antibacterial effects, particularly against resistant K. pneumoniae strains, and enhances biofilm inhibition. Notably, the intrinsic acidity of NAC is essential for its antimicrobial and anti-biofilm activity.},
}

@article {pmid41752465,
year = {2026},
author = {Hu, C and Xu, P and Hu, J and Fang, B and Meng, J and Tang, Y},
title = {A Novel Pyrazole Pyrimidine Derivative MBP346 Induces Cell Death via ROS-Mediated Mitochondrial Damage in Human Head and Neck Squamous Cell Carcinoma.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {4},
pages = {},
pmid = {41752465},
issn = {1420-3049},
mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Pyrazoles/pharmacology/chemistry ; *Pyrimidines/pharmacology/chemistry ; Cell Line, Tumor ; *Mitochondria/drug effects/metabolism/pathology ; Cell Proliferation/drug effects ; *Squamous Cell Carcinoma of Head and Neck/metabolism/drug therapy/pathology ; *Head and Neck Neoplasms/metabolism/drug therapy/pathology ; Apoptosis/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; *Antineoplastic Agents/pharmacology/chemistry ; Cell Death/drug effects ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; },
abstract = {Background: Head and neck squamous cell carcinoma (HNSCC) represents almost 95% of head and neck cancer cases and ranks as the sixth most prevalent malignant tumor globally. Several treatment strategies, such as surgery, radiation, and chemotherapy, are implemented to boost the outcomes for patients with HNSCC. However, the overall survival rate for patients with HNSCC has remained poor. MBP346 is a novel pyrazole pyrimidine compound that is cytotoxic to HNSCC cells. Therefore, this study aims to investigate its effect on HNSCC and to explore its possible molecular mechanism. Methods: Cell viability of HNSCC (Cal33 and Scc15) cells and normal NOK cells treated with MBP346 was determined by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Colony formation assay and Edu assay were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was used for detecting cell cycle-related and cell apoptotic-related proteins. Immunofluorescence assay was performed to analyze the effect of MBP346 on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Results: MBP346 significantly inhibited the proliferation of Cal33 and Scc15 cells, with half inhibitory concentrations of 1.56 ± 0.13 μmol·L[-1] and 4.41 ± 0.28 μmol·L[-1], respectively. The cell cycle-related proteins CyclinD1, CyclinA2, and CDK2 were downregulated, and P21 was upregulated in Cal33 and Scc15 cells treated with MBP346, which blocked the cell cycle in the S phase. MBP346 induced cell apoptosis in Cal33 and Scc15 cells by inducing ROS production. In addition, the elevated ROS decreased MMP to accelerate apoptosis. N-acetylcysteine (NAC), an ROS inhibitor, suppressed MBP346-induced cell apoptosis. Conclusions: MBP346 may serve as a therapeutic agent in HNSCC by inducing cell death. It achieves this by halting cell proliferation through cell cycle arrest and enhancing apoptosis due to increased ROS, which results in mitochondrial dysfunction.},
}

Humans
*Reactive Oxygen Species/metabolism
*Pyrazoles/pharmacology/chemistry
*Pyrimidines/pharmacology/chemistry
Cell Line, Tumor
*Mitochondria/drug effects/metabolism/pathology
Cell Proliferation/drug effects
*Squamous Cell Carcinoma of Head and Neck/metabolism/drug therapy/pathology
*Head and Neck Neoplasms/metabolism/drug therapy/pathology
Apoptosis/drug effects
Membrane Potential, Mitochondrial/drug effects
Cell Survival/drug effects
*Antineoplastic Agents/pharmacology/chemistry
Cell Death/drug effects
Cell Cycle/drug effects
Cell Cycle Checkpoints/drug effects

@article {pmid41750648,
year = {2026},
author = {Han, JS and Park, K and Kim, YL and Lim, JH and Park, SY and Park, SN},
title = {Evaluation of Intratympanic Alpha-Lipoic Acid and Diltiazem as Alternatives to Dexamethasone in Noise-Induced Hearing Loss in a Murine Model.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750648},
issn = {2076-3921},
support = {RS-2022-NR075243 and RS-2024-00340841//National Research Foundation of Korea/ ; },
abstract = {This study evaluates the protective effects of alpha-lipoic acid (ALA), diltiazem (DIL), and N-acetylcysteine (NAC) as potential adjunctive agents to enhance intratympanic dexamethasone (IT-DEX) therapy in noise-induced hearing loss. A two-phase experiment using C57BL/6J mice was conducted. In phase 1, candidate drugs were screened by perilymph concentration analysis using ultra-high-performance liquid chromatography, auditory brainstem response (ABR) threshold, and organ of Corti (OC) morphology. Western blot analysis evaluated inflammatory markers. Phase 2 investigated the synergistic effects of co-administration of the most promising candidates with DEX. All drugs successfully penetrated the inner ear via IT injection. In the noise-induced hearing loss model, ALA and DIL individually demonstrated significant improvements in ABR thresholds and OC morphology compared to DEX alone, while NAC showed no therapeutic benefit. Western blot analysis revealed that ALA and DIL suppressed inflammatory markers through distinct antioxidant-mediated mechanisms, contrasting with DEX's anti-inflammatory pathway. However, combination therapy with DEX + ALA or DEX + DIL increased middle ear inflammation and failed to produce synergistic therapeutic effects. While ALA and DIL showed individual therapeutic promise through complementary mechanisms, combination with DEX did not enhance efficacy, suggesting that simple drug combinations may not translate to improved IT therapy outcomes.},
}

@article {pmid41750596,
year = {2026},
author = {Sun, M and Feng, Z and Wang, Z and Wu, R and Du, K and Zhu, J and Liu, K and Zhang, L and Zhang, M and Qiu, Z},
title = {BACH1-CHAC1-Glutathione Axis Aggravates Myocardial Ischemia-Reperfusion Injury by Enhancing Ferroptosis and Oxidative Stress.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
pmid = {41750596},
issn = {2076-3921},
support = {82370282//National Natural Science Foundation of China/ ; },
abstract = {Myocardial ischemia-reperfusion injury (MIRI) is a pathological process in which reperfusion-induced oxidative stress and metabolic derangement further aggravate myocardial damage and blunt the benefit of reperfusion. Ferroptosis is increasingly implicated in MIRI, with the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis constituting a key antioxidant barrier. Although GSH depletion is recognized as a critical event, its upstream regulation in MIRI remains unclear. Against this background, we investigate the BACH1-CHAC1-GSH pathway as a putative upstream regulatory axis of ferroptosis in MIRI and a potential molecular target. Here, using an oxygen-glucose deprivation/reoxygenation (OGD/R) model in AC16 and the reversibility conferred by the ferrostatin-1, RNA sequencing identified the GSH-degrading enzyme CHAC1 as a modulator that is induced by stress and promotes ferroptosis. Experiments showed that CHAC1 overexpression aggravated OGD/R-induced injury, depleted GSH, suppressed GPX4 and enhanced lipid peroxidation, whereas CHAC1 knockdown was partially protective. N-acetylcysteine (NAC) replenished GSH, restored GPX4 activity and partially rescued CHAC1-driven injury. In a mouse myocardial I/R model, cardiotropic adeno-associated virus-mediated CHAC1 overexpression worsened cardiac dysfunction, enlarged infarct and fibrosis areas, and increased myocardial iron deposition. Dual-luciferase assays revealed that the transcription factor BACH1 activates the CHAC1 promoter, and BACH1 silencing attenuated ferroptosis by suppressing CHAC1 and restoring the GSH-GPX4 axis. Collectively, our data identify the BACH1-CHAC1-GSH axis as an upstream amplifier of ferroptosis in MIRI through glutathione depletion and impairment of GPX4-dependent antioxidant defense. These findings refine the mechanistic link between reperfusion-phase redox imbalance and ferroptosis and highlight BACH1/CHAC1 inhibition or augmentation of GSH precursors as potential cardioprotective strategies in ischemic heart disease.},
}

@article {pmid41749341,
year = {2026},
author = {Mudzengi, D and Mashatole, S and Xiang, Q and Adrion, C and Glover, N and Ngwanto, T and Mdluli, J and Boniface, S and Rassool, M and Matome, B and Paramo, L and Svensson, E and Fasanmi, A and Angelo, S and Moyo, M and Marx, C and Khosa, C and Mokaba, L and Mofokeng, N and Lalashowi, J and Nacy, C and Charalambous, S and Fumane, E and Maphossa, V and Beattie, T and Brumskine, W and Venter, C and Mapamba, D and Heinrich, N and Rajaram, S and Kooverjee, S and Botha, L and Nell, M and Easton, A and Foraida, S and Warren, RM and Sabi, I and Ntinginya, N and Wallis, RS and , },
title = {panTB-HM: a multi-arm clinical trial of a pan-TB regimen targeting both host and microbe.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-026-09568-9},
pmid = {41749341},
issn = {1745-6215},
support = {RIA2019AMR-2647//EDCTP/ ; },
abstract = {BACKGROUND: Newer oxazolidinones will be required to advance regimens in pan-TB indications. The addition of host-directed agents may help promote the recovery of lung function during TB treatment and prevent post-TB lung disease.

METHODS: The panTB-HM trial assesses the capacity of three novel regimens containing the oxazolidinone sutezolid and the antioxidant N-acetylcysteine (NAC) to meet the target criteria proposed by WHO for pan-TB indications (including use without rifamycin susceptibility testing and of 4 months or less duration) in a phase 2C trial.

DISCUSSION: This trial is ground-breaking in its objectives and design for a 4-month pan-TB indication (in a non-inferiority comparison to standard treatment) and its evaluation of lung function recovery (in a superiority comparison).

TRIAL REGISTRATION: ClinicalTrials.gov NCT05686356. Registered on 13 Jan 2023.},
}

@article {pmid41740408,
year = {2026},
author = {Wang, HZ and Xiong, YM and Song, SL and Zhao, QC and Chen, XY and Gao, JR and Li, YY and Qin, ZF},
title = {Low doses of chlorothalonil cause testicular impairment in mammals through the antimicrobial-like mechanism.},
journal = {Journal of hazardous materials},
volume = {506},
number = {},
pages = {141563},
doi = {10.1016/j.jhazmat.2026.141563},
pmid = {41740408},
issn = {1873-3336},
abstract = {Chlorothalonil is a widely used fungicide that exerts activity through interacting with glutathione (GSH) and thiol-containing proteins or other nucleophilic molecules due to its electrophilicity. However, it remains little known whether chlorothalonil exerts similar actions in mammals and causes male reproductive damage. Here, we detected reduced cell viability and glycolytic impairment coupled with the redox imbalance including ROS accumulation in GC-1 cells (testicular germ cell line) treated with chlorothalonil; however, the nucleophilic antioxidant N-acetylcysteine (NAC) rescued chlorothalonil-caused cell damage. In animal experiments, exposure to chlorothalonil (30, 300, and 3000 μg/kg/d) from gestational day 10 to postnatal day (PND) 10 caused slight effects on testicular development in suckling male mice. However, extended exposure to postnatal week (PNW) 15 resulted in testicular impairment in male offspring, including germ cell apoptosis, reduced sperm count, and increased sperm tail malformation, along with reduced GSH content and altered expression of redox-related genes, and certain significant alterations even occurred in the low-dose group. Furthermore, we also observed reduced motility and redox disturbance in mouse sperm in vitro, and NAC exerted significant rescue effects. Moreover, surface plasmon resonance (SPR) analysis revealed the binding of chlorothalonil to β-actin, a sensitive target of electrophilic substances. Taken together, all data indicate that low dose of chlorothalonil caused testicular impairment in mice possibly through interacting with nucleophilic molecules. This study challenges the acceptable daily intake (20 or 30 μg/kg/d) of chlorothalonil established previously, and calls for great attention on male reproductive hazards of more electrophilic pollutants.},
}

@article {pmid41737465,
year = {2026},
author = {Jiang, M and Lu, W and Zhuang, J and Song, J and Zhao, Y and Zhou, C and Zhou, Y and Shu, W and Zhu, Z and Jiang, L and Wu, P and Wu, A and Sheng, S and Zhu, S and Wang, Z},
title = {A bioinspired anisotropic anti-inflammatory scaffold enhances spinal nerve regeneration and neural circuit reconstruction via FGF13/Ca[2+]/CaMK2A/CREB pathway.},
journal = {Materials today. Bio},
volume = {37},
number = {},
pages = {102929},
pmid = {41737465},
issn = {2590-0064},
abstract = {Spinal cord injury (SCI) induces severe neurological impairment, exacerbated by secondary inflammation and disrupted neural circuitry. Inspired by the spinal cord's electromechanical microenvironment, we developed a biomimetic conductive nerve scaffold via directional freeze-casting of gelatin methacryloyl (GelMA) hydrogel incorporated with N-acetylcysteine-modified silver nanowires (NAC-AgNWs). The scaffold exhibits axially aligned microchannels, tunable mechanical strength, and conductivity akin to native spinal tissue. In a rat model of complete spinal cord transection (2 mm), the scaffold exhibited dual therapeutic effects: (1) early-stage anti-inflammatory modulation (mediated by the synergistic interplay between AgNWs and NAC), and (2) sustained neural reconstruction, evidenced by robust axonal bridging across the lesion, synapse reformation, and significant functional recovery. Integrated transcriptomic analyses revealed the FGF13/Ca[2+]/CaMK2A/CREB axis as the activated pathway driving neurite outgrowth and neural circuit reconstruction. This biomaterial design establishes a novel therapeutic paradigm for SCI repair, integrating structural guidance, immunomodulation, and activation of pro-regenerative signaling.},
}

@article {pmid41722831,
year = {2026},
author = {Perera, KDC and Vasta, AK and Menon, JU},
title = {Mucopenetrative Lipid-Polymer nanoparticles show Potent Anti-Inflammatory activity in a human Lung-on-Chip model.},
journal = {International journal of pharmaceutics},
volume = {693},
number = {},
pages = {126688},
doi = {10.1016/j.ijpharm.2026.126688},
pmid = {41722831},
issn = {1873-3476},
abstract = {Airway mucus presents a significant barrier to inhaled drug delivery, particularly for nanoparticle-based interventions, with this barrier exacerbated in chronic respiratory diseases (CRDs) due to hyperviscous secretions and persistent inflammation. In this study, a dual-functional lipid-polymer hybrid nanoparticle was developed to combine rapid mucolysis with sustained anti-inflammatory activity, and its performance was evaluated using both conventional in vitro assays and a physiologically relevant lung-on-a-chip model. Dipalmitoylphosphatidylcholine (DPPC)-coated PLGA nanoparticles (hydrodynamic diameter 378.1 ± 23.0 nm; 58-61 wt% lipid; ζ ≈ +3 mV) encapsulated N-acetylcysteine (NAC) within the lipid shell for rapid release and all-trans retinoic acid (ATRA) within the core for sustained delivery. NAC exhibited a burst release of 44.2-52.5% within 6 h and significantly reduced the viscosity of cystic fibrosis-mimetic mucus, enabling a 26.5-fold higher penetration across a ∼ 0.6 mm mucus plug compared to NAC-free controls. The formulation was well tolerated by pulmonary epithelial and fibroblast cells and demonstrated high cellular uptake driven by the DPPC coating. To assess efficacy under physiologically relevant airway conditions, a human lung-on-a-chip model incorporating air-liquid interface, flow, and cyclic stretch was employed. In this model, repeated dosing of NAC + ATRA nanoparticles resulted in a 2.6-fold reduction in IL-6 and a 2.3-fold reduction in IL-8 levels compared to diseased controls at 72 h, outperforming NAC-free nanoparticles at early timepoints and maintaining suppression over 9 days. These findings demonstrate the therapeutic promise of dual-functional mucopenetrative nanoparticles and establish the utility of lung disease-on-chip platforms for evaluating inhaled nanotherapeutics under physiologically relevant conditions.},
}

@article {pmid41720502,
year = {2026},
author = {Afşar, E and Öz, M and Eranıl, I},
title = {Hepato-Cardiac Axis in Epirubicin Toxicity: Role of Kynurenine Pathway and N-Acetylcysteine Antioxidant Intervention.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.70118},
pmid = {41720502},
issn = {1099-1263},
abstract = {Epirubicin (EPI) is a widely used chemotherapeutic agent; however, its clinical utility is limited by severe side effects, particularly the production of reactive oxygen species (ROS). Among these, cardiotoxicity is one of the most critical issues, and it is worsened by impaired hepatic clearance resulting from liver dysfunction. This study aimed to investigate molecular changes induced by EPI in the liver within the kynurenine pathway (KP), their possible contribution to cardiotoxicity, and the protective effects of N-acetylcysteine (NAC). Rats received intraperitoneal injections of 50 or 300 mg/kg NAC, followed 1 h later by 9.6 mg/kg EPI. Tryptophan (Trp), kynurenine (Kyn), kynurenic acid (KYNA), quinolinic acid (QA), kynureninase, and kynurenine 3-monooxygenase (KMO) levels in the liver and cleaved caspase-3 levels in the liver and heart tissue were measured using ELISA. Hepatic and cardiac total antioxidant status (TAS) and total oxidant status (TOS) were determined using a colorimetric method. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), creatine kinase-MB isoenzyme (CK-MB), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (T-chol), and triglyceride (TG) were analyzed with a clinical biochemistry analyzer. Cardiac morphology was examined using hematoxylin-eosin staining. EPI administration was associated with increases in plasma CK-MB, the AST/ALT ratio, LDL, T-chol, and TG, with these increases partially attenuated by NAC treatment. Hepatic levels of Trp, QA, and KMO were positively correlated with plasma CK-MB and the AST/ALT ratio. Additionally, EPI appeared to increase oxidative stress in heart tissue and induce morphological changes. At the same time, NAC treatment was associated with partial improvement in these parameters, suggesting that alterations in the hepatic KP may be linked to possible cardiac involvement. Our findings suggest that EPI-induced alterations in hepatic KP may impair hepatic clearance, and NAC administration may provide partial protection, warranting further investigation of a possible hepato-cardiac interaction.},
}

@article {pmid41713986,
year = {2026},
author = {Li, S and Xia, L and Wang, S and Ju, R and Han, Z and Lv, X and Han, B and Chi, J},
title = {N-acetylcysteine-functionalized biodegradable polysaccharide hydrogel patches for the repair of acute liver injury.},
journal = {Carbohydrate polymers},
volume = {379},
number = {},
pages = {124983},
doi = {10.1016/j.carbpol.2026.124983},
pmid = {41713986},
issn = {1879-1344},
mesh = {Animals ; *Hydrogels/chemistry/pharmacology ; *Acetylcysteine/chemistry/pharmacology ; Mice ; Humans ; Acetaminophen ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism ; Male ; Human Umbilical Vein Endothelial Cells/drug effects ; Liver/drug effects/pathology ; Cell Proliferation/drug effects ; Hepatocytes/drug effects ; Chondroitin Sulfates/chemistry ; Apoptosis/drug effects ; Mice, Inbred C57BL ; Biocompatible Materials/chemistry/pharmacology ; *Polysaccharides/chemistry ; },
abstract = {Acute liver injury (ALI) caused by acetaminophen (APAP) has a high incidence rate worldwide, and severe cases may cause liver failure or even death. N-acetylcysteine (NAC), as an effective treatment drug approved for clinical application in ALI, has limitations such as a short half-life and the requirement for high-dose injections. Consequently, it is imperative to optimize new administration method of NAC and promote alternative therapeutic strategies for ALI. Herein, hydrogel patches ONC composed of oxidized chondroitin sulfate (OCS) and NAC-grafted CMCS were developed, and their reparative effects on APAP-induced ALI were investigated. ONC hydrogels exhibited excellent biocompatibility and appropriate biodegradability, and favorable hemostatic effects in the liver. In vitro experiments demonstrated that ONC could promote the proliferation and migration of hepatocytes, as well as the angiogenesis of HUVECs. By establishing an APAP-induced ALI model in mice, liver enzymes after ONC hydrogel patches treatment recovered to near-normal levels. Moreover, histological examination, RT-qPCR, and transcriptome sequencing results demonstrated that ONC patches could reduce the expression of inflammatory factors and apoptosis in the liver, while simultaneously activating antioxidant-related signaling pathways, thereby promoting the regeneration and functional repair of damaged tissues. Therefore, ONC hydrogel patches may be a promising alternative strategy for treating ALI.},
}

Animals
*Hydrogels/chemistry/pharmacology
*Acetylcysteine/chemistry/pharmacology
Mice
Humans
Acetaminophen
*Chemical and Drug Induced Liver Injury/drug therapy/pathology/metabolism
Male
Human Umbilical Vein Endothelial Cells/drug effects
Liver/drug effects/pathology
Cell Proliferation/drug effects
Hepatocytes/drug effects
Chondroitin Sulfates/chemistry
Apoptosis/drug effects
Mice, Inbred C57BL
Biocompatible Materials/chemistry/pharmacology
*Polysaccharides/chemistry

@article {pmid41708253,
year = {2026},
author = {Wang, P and Zhong, Y and Liu, J and Gao, L and Long, T and Li, Z},
title = {Dietary titanium dioxide particles (E171) promote colitis-associated colorectal cancer development in mice through macrophage-derived S100A8/S100A9secretion mediated by NLRP3/Caspase 1/GSDMD pathway.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {2},
pages = {215-226},
doi = {10.1016/S1875-5364(26)61092-8},
pmid = {41708253},
issn = {1875-5364},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Calgranulin A/metabolism/genetics ; Mice ; *Titanium/adverse effects/administration & dosage ; *Calgranulin B/metabolism/genetics ; *Macrophages/metabolism/drug effects ; *Caspase 1/metabolism/genetics ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Male ; *Colitis-Associated Neoplasms/chemically induced/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *Colorectal Neoplasms/genetics/etiology/chemically induced/metabolism ; },
abstract = {Colitis-associated colorectal cancer (CAC) is a major contributor to cancer-related mortality worldwide. Titanium dioxide (TiO2, E171), a widely used food additive, has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development. In this study, CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo, while lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro. We found that dietary E171 intake accelerated CAC development, exacerbated inflammatory responses and oxidative stress, and upregulated CAC-associated genes, including S100a8, S100a9, Lcn2, S100a11, Cxcl2, and interleukin-1α (Il-1α). E171 also increased the expression of S100A8, S100A9, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and gasdermin-D N-terminal (GSDMD-N) in macrophages within colon tumors. In inflammatory macrophages, E171 exposure enhanced cell viability, increased reactive oxygen species (ROS) levels, and elevated the expression and secretion of S100A8 and S100A9, consistent with in vivo histological observations. Furthermore, E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors, including N-acetylcysteine (NAC, ROS inhibitor), MCC950 (NLRP3 inhibitor), Z-YVAD-FMK (caspase 1 inhibitor), disulfiram (GSDMD inhibitor), and transfection of NLRP3 small interfering ribonucleic acid (siRNA). These results indicate that dietary E171 promotes CAC development by activating macrophages, with S100A8 and S100A9 serving as key mediators, and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Calgranulin A/metabolism/genetics
Mice
*Titanium/adverse effects/administration & dosage
*Calgranulin B/metabolism/genetics
*Macrophages/metabolism/drug effects
*Caspase 1/metabolism/genetics
Mice, Inbred C57BL
RAW 264.7 Cells
Male
*Colitis-Associated Neoplasms/chemically induced/genetics/metabolism
Humans
Signal Transduction/drug effects
*Colorectal Neoplasms/genetics/etiology/chemically induced/metabolism

@article {pmid41704764,
year = {2026},
author = {Huang, X and Meng, Y and Song, J and Zhu, Y and Li, J and Xi, Y and Peng, X and Xiong, Y},
title = {KNSTRN knockdown impairs autophagy flux to inhibit bladder cancer progression.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114734},
pmid = {41704764},
issn = {2589-0042},
abstract = {Bladder cancer (BLCA) is a common malignant tumor of the urinary system. Kinetochore-localized astrin-binding protein (KNSTRN) has been implicated in the initiation and progression of multiple cancers. Furthermore, abnormal autophagy levels have been shown to significantly impact tumor development. However, the mechanism by which KNSTRN regulates autophagy in BLCA remains unclear. This study reveals that KNSTRN knockdown inhibits autophagy flux in BLCA. The mechanism involves ROS-dependent disruption of lysosomal function upon KNSTRN knockdown, thereby impeding autophagosome-lysosome fusion. Clioquinol restores lysosomal activity by regulating lysosomal pH, subsequently reestablishing autophagy flux. The ROS scavenger N-acetylcysteine (NAC) reverses lysosomal dysfunction and reactivates the autophagic flux. Furthermore, the autophagy activator rapamycin (Rapa) effectively counteracts KNSTRN knockdown-induced cell death in both in vitro and in vivo experiments. Collectively, we demonstrate that KNSTRN knockdown induces intracellular ROS accumulation and lysosomal dysfunction, thereby disrupting autophagic flux and inhibiting BLCA progression.},
}

@article {pmid41701447,
year = {2026},
author = {Sabry, S and Ammar, MK and Taeima, M and Nassar, N and ElFiky, A and Saleh, A},
title = {Preventing Contrast-Induced Acute Kidney Injury in Egyptian Patients Undergoing Coronary Angiography: A Randomized Controlled Trial.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {41701447},
issn = {1179-1918},
abstract = {BACKGROUND AND OBJECTIVES: Contrast-induced acute kidney injury (CI-AKI) observed after coronary angiography (CAG) requires preventive strategies guided by clinical judgment. Evidence is still lacking regarding the prevention of CI-AKI in patients undergoing coronary angiography. This study aimed to compare the effect of a high dose of N-acetylcysteine (NAC) plus preprocedural hydration, a high dose of atorvastatin (HDS) plus preprocedural hydration, or preprocedural hydration alone on the prevention of CI-AKI in patients undergoing elective coronary angiography.

METHODS: A prospective multi-armed randomized comparative study was conducted on elective patients undergoing CAG. Patients were randomly assigned to either control group [n = 40], who received hydration with 0.9% saline started just before contrast media injection and continued for 12 h at a rate 1.0 mL/kg/min after angiography; NAC group [n = 40], who received oral NAC 1200 mg daily started 5 days before angiography and good hydration; or HDS group [n = 40], receiving one oral dose of atorvastatin 80 mg 24 h before angiography and good hydration. CI-AKI was defined as an increase in serum creatinine of > 25% of baseline or an absolute increase of 0.5 mg/dL above baseline after 48 h. Incidence of CI-AKI and incidence of complications were assessed for all groups.

RESULTS: The study included 120 patients. The incidence of CI-AKI was [32.5%] in the control group, [20%] in the NAC group, and [12.5%] in the HDS group. The incidence of CI-AKI was significantly lower in the high-dose statin group compared with the control group (risk ratio = 1.658; 95% CI 1.050-2.433). In-hospital clinical outcomes showed no statistical significance among the three groups.

CONCLUSIONS: Both NAC and high-dose statins may reduce CI-AKI incidence in patients undergoing CAG, with statins showing more promising results. These findings support prophylactic strategies for CI-AKI prevention in high-risk patients undergoing CAG. In-hospital outcomes were comparable.

CLINICAL TRIAL REGISTRATION: Clinical-Trials.gov (ID; NCT06139952, Date; December 2023).},
}

@article {pmid41700562,
year = {2026},
author = {Gregory, E and Wilkinson, EP and Leyngold, I},
title = {N-acetylcysteine and Vitamin C oral antioxidant therapy for teprotumumab-related hearing dysfunction: case series and review of literature.},
journal = {Orbit (Amsterdam, Netherlands)},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/01676830.2025.2608253},
pmid = {41700562},
issn = {1744-5108},
abstract = {We report three cases of successful treatment of teprotumumab-related hearing dysfunction with N-acetylcysteine (NAC) and ascorbic acid (Vitamin C). To investigate NACs effectiveness in the treatment of other types of auditory symptoms through a review of available literature. Three patients with thyroid eye disease (TED) developed symptoms of ear fullness and hearing loss during infusions of teprotumumab. Audiogram revealed above-normal pure tone average hearing threshold frequencies. They were treated with once-daily oral administration of 600 mg N-acetyl cysteine and 500 mg ascorbic acid (Vitamin C). All patients experienced nearly complete resolution of their ear symptoms prior to completing their teprotumumab therapy. They continued to remain symptom-free throughout the remaining teprotumumab infusions and onwards. This study showcases that antioxidant therapy with N-acetylcysteine and Vitamin C appears to be a promising, safe, and inexpensive potential treatment option for teprotumumab-related hearing dysfunction in our patient group.},
}

@article {pmid41686281,
year = {2026},
author = {Moon, UY and Kim, YE and Nguyen, HD and Choi, HJ},
title = {CREB2 Functions as a Central Mediator of Oxidative Neuronal Death Triggered by Microglial Glutamate Release Under Neuroinflammatory Conditions.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01695-w},
pmid = {41686281},
issn = {1573-6830},
support = {2710086662/RS-2025-02213662//Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare/ ; RS-2023-00246655 and RS-2024-00356135//National Research Foundation of Korea/ ; },
abstract = {Glutamate-induced oxidative cytotoxicity is a major driver of neuronal loss in neurodegenerative diseases, yet the upstream transcriptional regulators linking oxidative stress to neuronal death remain unclear despite the known involvement of the p53-GADD45α pathway. CREB2 (ATF4) is a stress-responsive transcription factor, but its role in microglia-mediated oxidative neurotoxicity has not been fully defined. Here, we investigated CREB2 function in oxidative glutamate toxicity using HT22 hippocampal neurons, primary mouse hippocampal cells, and a kainic acid (KA)-injected rat model. Oxidative stress was induced by glutamate, intracellular ROS levels were quantified with DCFDA, and the antioxidant N-acetylcysteine (NAC) was used to confirm oxidative dependency. Microglia-derived glutamate was assessed by stimulating BV2 cells with lipopolysaccharide (LPS) and applying glutamate-containing conditioned medium (LPS-CM) to HT22 cells. Exogenous glutamate robustly increased CREB2 expression in HT22 and primary neurons, accompanied by ROS accumulation and cell death, whereas NAC suppressed these effects. Inhibition of p53 by siRNA or pifithrin-α (PFT-α) attenuated glutamate-induced CREB2 upregulation, and CREB2 knockdown blocked GADD45α induction and protected neurons. In Vivo, KA injection caused robust CREB2 upregulation in the damaged CA3 region. Importantly, conditioned medium from LPS-activated BV2 microglia increased CREB2 expression and ROS levels in HT22 cells in an NAC-sensitive manner, supporting a glutamate-associated oxidative mechanism rather than receptor-mediated excitotoxicity. Collectively, these results suggest that CREB2 functions between upstream p53 signaling and downstream GADD45α activation as a redox-sensitive mediator of oxidative neuronal death, and may represent a potential therapeutic target in neurodegenerative diseases associated with oxidative stress and neuroinflammation.},
}

@article {pmid41683511,
year = {2026},
author = {Hikisz, P and Adamus-Grabicka, AA and Budzisz, E},
title = {Multifaceted Anticancer Activity of Flavanone/Chromanone Intermediates for Five-Membered Heterocyclic Derivatives: Targeting Oxidative Stress, Apoptosis, and MAPK Signaling in Colorectal Cancer.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {3},
pages = {},
pmid = {41683511},
issn = {1420-3049},
support = {503/3-066-02/503-31-001//Medical University of Lodz/ ; 2024/08/X/NZ7/01232//National Science Center/ ; 2023/07/X/NZ3/01404//National Science Center/ ; },
mesh = {Humans ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; *Flavanones/pharmacology/chemistry ; *Colorectal Neoplasms/metabolism/drug therapy/pathology ; *Antineoplastic Agents/pharmacology/chemistry ; Cell Line, Tumor ; *MAP Kinase Signaling System/drug effects ; Reactive Oxygen Species/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; *Heterocyclic Compounds/pharmacology/chemistry ; },
abstract = {This study explores the multifaceted anticancer mechanisms of flavanone analogues and spiropyrazoline condensed with flavanone ring against colorectal cancer (CRC) cell lines. Five-membered heteroaromatic scaffolds, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. Building upon previous findings, we investigated three lead derivatives (1, 3, and 5) with potent antiproliferative activity (IC50 < 35 μM). The compounds induced pronounced oxidative stress, evidenced by increased lipid peroxidation and reduced membrane fluidity, primarily within the hydrophobic layers of cell membranes. Preincubation with the antioxidant N-acetylcysteine (NAC) significantly attenuated these effects, confirming the pivotal role of reactive oxygen species (ROS) in their cytotoxicity. Mechanistic studies revealed that the derivatives triggered intrinsic apoptosis, characterized by the cleavage of PARP and the activation of caspase-9 and caspase-3. Furthermore, the compounds modulated key signaling pathways involved in cell survival and proliferation. Specifically, they inhibited the pro-oncogenic ERK1/2 MAPK pathway while inducing cell line-dependent alterations in p38 and JNK activity. Concurrently, all derivatives reduced the level of the transcription factor Nrf2, a master regulator of antioxidant defense and a mediator of chemoresistance in CRC. Collectively, these findings indicate that flavanone/chromanone derivatives exert their anticancer activity through a synergistic mechanism involving ROS generation, disruption of redox homeostasis, inhibition of Nrf2 signaling, and modulation of MAPK-dependent apoptotic pathways. These results highlight the therapeutic potential of flavanone-based compounds and their spiropyrazoline analogues as multifunctional anticancer agents targeting oxidative stress and survival signaling in colorectal cancer.},
}

Humans
*Apoptosis/drug effects
*Oxidative Stress/drug effects
*Flavanones/pharmacology/chemistry
*Colorectal Neoplasms/metabolism/drug therapy/pathology
*Antineoplastic Agents/pharmacology/chemistry
Cell Line, Tumor
*MAP Kinase Signaling System/drug effects
Reactive Oxygen Species/metabolism
Cell Proliferation/drug effects
Cell Survival/drug effects
*Heterocyclic Compounds/pharmacology/chemistry

@article {pmid41681844,
year = {2026},
author = {Rodriguez, V and Villani, A and Sénica, M and Panebianco, C and Pazienza, V and Preto, A},
title = {Harnessing Postbiotics to Boost Chemotherapy: N-Acetylcysteine and Tetrahydro β-Carboline Carboxylic Acid as Potentiators in Pancreatic and Colorectal Cancer.},
journal = {Cancers},
volume = {18},
number = {3},
pages = {},
pmid = {41681844},
issn = {2072-6694},
support = {ID. 23006 project//Associazione Italiana Ricerca sul Cancro (AIRC) under IG 2019/ ; UIDB/04050/2020//Fundação para a Ciência e Tecnologia/ ; UID/04050//Centro de Biologia Molecular e Ambiental/ ; },
abstract = {BACKGROUND: Pancreatic cancer (PC) and colorectal cancer (CRC) are among the most lethal malignancies, with growing evidence pointing to the gut microbiota's role in their progression. This study aimed to explore the anticancer potential of two microbiota-derived postbiotics, N-acetylcysteine (NAC) and tetrahydro β-carboline carboxylic acid (THC), in targeting some hallmark traits of PC and CRC, both as standalone agents and in combination with standard chemotherapeutics (gemcitabine for PC and 5-fluorouracil (5-FU) for CRC).

METHODS: Cell viability assays and IC50 determination was assessed using either the Muse™ Count & Viability Kit or the Sulforhodamine B assay; cell death was determined by Annexin V/Propidium Iodide and cell cycle assessed by Propidium Iodide was analyzed by flow cytometry.

RESULTS: Here, we found that NAC selectively reduced the viability of PC cells BxPC-3 without triggering apoptosis, while effectively inducing apoptosis in PC cells Panc-1 and in CRC cell lines. THC exhibited stronger anticancer activity, inhibiting proliferation and promoting apoptosis in all tested PC and CRC cells, even at lower concentrations. Combination treatments yielded promising enhancement effects. NAC enhanced the cytotoxicity of gemcitabine in Panc-1 cells through increased apoptosis. NAC, when combined with 5-FU, also increased apoptosis of CRC cells. THC further potentiated gemcitabine's impact on Panc-1 cells by increasing apoptosis and by inducing cell cycle changes in BxPC-3. In the CRC model, THC co-treatment with 5-FU reduced cell viability and increased apoptosis in all cells.

CONCLUSIONS: These findings provide preliminary in vitro evidence supporting the potential of integrating microbiota-derived postbiotics with conventional chemotherapy both in PC and CRC.},
}

@article {pmid41678124,
year = {2026},
author = {Batsaikhan, T and Lee, HS and Yang, H and Ferdushi, R and Key, J and Seo, YJ},
title = {Therapeutic Effects of N-Acetylcysteine-Primed, Iron Oxide Nanoparticle-Enhanced Mesenchymal Stem Cell Exosomes in Ototoxicity Hearing Loss.},
journal = {Tissue engineering and regenerative medicine},
volume = {},
number = {},
pages = {},
pmid = {41678124},
issn = {2212-5469},
abstract = {BACKGROUND: Sensorineural hearing loss caused by ototoxic agents remains irreversible due to the limited regenerative capacity of cochlear hair cells. Exosome-based therapies derived from mesenchymal stem cells (MSCs) offer a promising, cell-free alternative to protect auditory structures by modulating oxidative stress and inflammation. In this study, we evaluated the therapeutic potential of exosomes isolated from nanoparticle (NP) labeled, N-acetylcysteine primed tonsil-derived mesenchymal stem cells (T-MSCs), hereafter referred to as SPISOME-NAC, in kanamycin-induced ototoxicity models.

METHODS: T-MSCs were labeled with positively charged PLGA-PEI clustered SPIONs, with or without NAC pretreatment. Antioxidant enzyme activity (SOD, CAT, GSH), ROS levels, and PRDX1 expression were assessed in vitro. Exosomes were isolated and analyzed via nanoparticle tracking analysis. Their therapeutic efficacy was evaluated in both ex vivo cochlear explants and mouse model of kanamycin-induced ototoxicity. Hair cell survival was quantified via Myosin VIIa immunostaining, and auditory function was assessed using auditory brainstem responses (ABR). Pro-inflammatory cytokines (TNF-α, IL-1, IL-6) were measured via qRT-PCR.

RESULTS: NAC pretreatment significantly enhanced cell viability, increased GSH activity, and reduced intracellular ROS and PRDX1 levels in NP-labeled T-MSCs. Exosomes derived from NAC-pretreated cells (SPISOME-NAC) conferred superior protection to cochlear hair cells, particularly in the basal turn, and significantly improved hearing thresholds in vivo. Furthermore, SPISOME-NAC treatment downregulated inflammatory cytokines in cochlear tissue.

CONCLUSION: SPISOME-NAC exhibit enhanced antioxidant and anti-inflammatory properties, providing functional protection in an ototoxicity-induced hearing loss model. By preventing ROS-mediated mitochondrial damage and apoptosis in cochlear hair cells, NAC interrupts a key pathogenic mechanism in ototoxicity, preserving auditory structure and function. These findings support NAC-primed exosomes as a novel therapeutic strategy for sensorineural hearing loss.},
}

@article {pmid41677644,
year = {2026},
author = {Khamineh, Y and Panahi-Alanagh, S and Zolghadri, S and Mavaddatiyan, L and Ryszkiel, I and Stanek, A and Talkhabi, M},
title = {Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation.},
journal = {Cells},
volume = {15},
number = {3},
pages = {},
pmid = {41677644},
issn = {2073-4409},
mesh = {Humans ; Female ; *Acetylcysteine/pharmacology ; *Ovarian Neoplasms/pathology/genetics/drug therapy ; *Ketoglutaric Acids/pharmacology ; Cell Line, Tumor ; *Computational Biology/methods ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; Protein Interaction Maps/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; },
abstract = {Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; however, their combined effects in ovarian cancer are not well characterized. In this study, we applied an integrative approach combining network pharmacology analysis with in vitro experiments to investigate the effects of NAC and AKG on OVCAR3 ovarian cancer cells. Common molecular targets of NAC and AKG were identified by intersecting predicted compound targets with ovarian cancer-associated genes, followed by protein-protein interaction network construction and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Experimental validation assessed the effects of NAC and AKG, alone and in combination, on cell viability, apoptosis, migration, and clonogenic capacity. Network analysis identified 70 shared target genes enriched in pathways related to apoptosis, cellular stress responses, and cell migration. In vitro experiments demonstrated that combined treatment with NAC (10 mM) and AKG (100 µM) significantly reduced cell viability, increased apoptotic cell death, and markedly suppressed cell migration and colony formation compared with single-agent treatments. Overall, these findings indicate that the combination of NAC and AKG exerts enhanced inhibitory effects on ovarian cancer cell growth and motility in vitro.},
}

Humans
Female
*Acetylcysteine/pharmacology
*Ovarian Neoplasms/pathology/genetics/drug therapy
*Ketoglutaric Acids/pharmacology
Cell Line, Tumor
*Computational Biology/methods
Apoptosis/drug effects
Cell Movement/drug effects
Cell Survival/drug effects
Cell Proliferation/drug effects
Protein Interaction Maps/drug effects
Gene Expression Regulation, Neoplastic/drug effects

@article {pmid41677304,
year = {2026},
author = {Higazy, D and Vergauwe, F and Coenye, T and Ciofu, O},
title = {Evolutionary adaptations of Pseudomonas aeruginosa biofilms to ciprofloxacin and antioxidant co-treatment in synthetic sputum medium.},
journal = {Microbiology spectrum},
volume = {14},
number = {3},
pages = {e0314925},
pmid = {41677304},
issn = {2165-0497},
support = {//Egyptian Ministry of Higher Education/ ; BOF20/GOA/002//Ghent University Special Research Fund/ ; },
mesh = {*Ciprofloxacin/pharmacology ; *Biofilms/drug effects/growth & development ; *Pseudomonas aeruginosa/drug effects/genetics/physiology ; *Antioxidants/pharmacology ; *Sputum/microbiology ; *Anti-Bacterial Agents/pharmacology ; Microbial Sensitivity Tests ; Humans ; Cystic Fibrosis/microbiology ; Pseudomonas Infections/microbiology ; Drug Resistance, Bacterial/drug effects/genetics ; Bacterial Proteins/genetics ; Culture Media/chemistry ; Mutation ; Acetylcysteine/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {UNLABELLED: Antimicrobial resistance (AMR) is a growing public health concern, particularly in biofilm-related infections, where microbial aggregates display high levels of tolerance. Oxidative stress has been hypothesized to accelerate the development of resistance, whereas antioxidants (AOs) may mitigate this process. In this study, we investigated the impact of AOs on the evolution of ciprofloxacin (CIP) resistance in Pseudomonas aeruginosa PAO1 using synthetic cystic fibrosis sputum medium (SCFM2), which mimics the physiochemical conditions of cystic fibrosis (CF) respiratory infections. Experimental evolution was performed over six passages with CIP alone or in combination with edaravone (ED), N-acetyl-cysteine (NAC), or thiourea (THU). Population analysis profiles and minimum inhibitory concentration (MIC) assays demonstrated that CIP treatment produced high-level resistance (MIC 8-32 mg/L), whereas CIP + AO treatments markedly suppressed resistance development (MIC 0.75-2 mg/L). Whole-genome sequencing revealed distinct mutational patterns. CIP-treated isolates carried mutations in mexR and nalC (efflux pump regulators), and gyrA (fluoroquinolone target), consistent with elevated resistance, along with additional mutations in rocR and dnaX. In contrast, evolved isolates in the presence of CIP + AO harbored nfxB mutations associated with lower resistance, while CIP + ED uniquely produced a mutation in parS. These findings support the role of reactive oxygen species (ROS) in driving resistance evolution under CF-like conditions and suggest that antioxidants can suppress this process, providing a potential strategy for limiting antimicrobial resistance in biofilm-associated infections.

IMPORTANCE: Fighting antimicrobial resistance (AMR) is one of the greatest health challenges of our time. To find new ways to stop it, we need to better understand how resistance develops. Our study suggests that antioxidants may help slow down the process that allows bacteria to become resistant. We also show that resistance develops more quickly, and in a different way, when bacteria grow in conditions that resemble the human body rather than in standard laboratory media. In particular, the synthetic sputum medium promoted the formation of aggregated biofilms-sticky communities of cells that often occur in chronic and hard-to-treat infections.},
}

*Ciprofloxacin/pharmacology
*Biofilms/drug effects/growth & development
*Pseudomonas aeruginosa/drug effects/genetics/physiology
*Antioxidants/pharmacology
*Sputum/microbiology
*Anti-Bacterial Agents/pharmacology
Microbial Sensitivity Tests
Humans
Cystic Fibrosis/microbiology
Pseudomonas Infections/microbiology
Drug Resistance, Bacterial/drug effects/genetics
Bacterial Proteins/genetics
Culture Media/chemistry
Mutation
Acetylcysteine/pharmacology
Oxidative Stress/drug effects

@article {pmid41666086,
year = {2026},
author = {Babayigit, Z and Yiğider, AP and Yiğit, O and Algün Gedik, A and Dumur, S and Uzun, H},
title = {Effect of intratympanic N-acetylcystein (NAC) on vestibulotoxicity model formed with intratympanic gentamicin in Guinea pigs.},
journal = {Acta oto-laryngologica},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/00016489.2025.2600090},
pmid = {41666086},
issn = {1651-2251},
abstract = {BACKGROUND: N-acetylcysteine (NAC) can protect against this damage.

AIM: To evaluate the effect of intratympanic NAC on the vestibulotoxicity model formed with intratympanic gentamicine in guinea pigs.

DESIGN: Experimental Animal Study.

METHODS: Guinea pigs were randomly divided into three groups. Group1 (control), group2 was treated with intratympanic(IT) gentamicin and group3 was treated with IT gentamicin + NAC. A single dose of NAC was applied on the 1st,3rd, and5th days. Cervical-vestibular evoked myogenic potentials (c-VEMP) measurements and blood samples were taken from the guinea pigs on the day 0,10,30.

RESULTS: In group2 on day 10 c-VEMP latency was prolonged and on day 30 c-VEMP responses were lost in half of animals. A partial loss of c-VEMP values was observed in the group3. Serum total antioxidant capacity (TAC) and superoxide dismutase (SOD) activity in group3 (on the 7th and 30th day) were significantly higher than those in the group2. Tissue SOD and glutathione (GSH) were lower, while the malondialdehyde (MDA) and lipid hydroperoxide (LOOH) were the higher in group2.

CONCLUSION: Gentamicin induced loss in c-VEMP responses and NAC played an effective role in reducing this loss which were confirmed by oxidative capacity at tissue and serum level.},
}

@article {pmid41663453,
year = {2026},
author = {Heshmati, ZS and Amiri-Yekta, A and Khosravifar, M and Akbarian, F and Moini, A and Eftekhari-Yazdi, P and Hafezi, M and Afsharian, P},
title = {Administration of N-acetylcysteine influence the expression of apoptotic genes in the granulosa cells of infertile women diagnosed with endometriosis.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41663453},
issn = {2045-2322},
support = {401000042//Royan Institute for Reproductive Biomedicine, ACECR, Iran/ ; 2447/1400/D//Royan Lotus Charity Foundation, Iran/ ; },
mesh = {Humans ; Female ; *Acetylcysteine/administration & dosage/pharmacology ; *Endometriosis/complications/drug therapy/genetics ; *Granulosa Cells/metabolism/drug effects ; Adult ; *Apoptosis/drug effects/genetics ; *Infertility, Female/drug therapy/genetics/etiology ; Superoxide Dismutase/blood ; Antioxidants ; Caspase 3/genetics/metabolism ; Oxidative Stress/drug effects ; Gene Expression Regulation/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; },
abstract = {Endometriosis is a chronic, multifactorial disorder. Reactive oxygen species (ROS) and oxidative stress (OS) contribute to the development of endometriosis by affecting apoptosis-related genes in granulosa cells. N-acetylcysteine (NAC) is an antioxidant that reduces OS. This randomized controlled trial aimed to investigate the effects of NAC on serum levels of superoxide dismutase (SOD) and total antioxidant capacity (TAC), as well as the expression of apoptotic genes in granulosa cells. Infertile women with endometriosis were enrolled and administered either NAC (1200 mg/day; n = 11) or placebo (n = 14). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum SOD and TAC levels. The expression of Bcl-2, Bax, and Caspase-3 genes in granulosa cells was evaluated by Real-Time Polymerase Chain Reaction. NAC treatment increased serum SOD and TAC levels. Additionally, the expression of pro-apoptotic genes Bax and Caspase-3 in granulosa cells decreased compared to the placebo group, while the expression of the anti-apoptotic gene Bcl-2 increased. We conclude that administration of N-acetylcysteine (NAC) can reduce apoptosis in granulosa cells of women with infertility due to endometriosis.},
}

Humans
Female
*Acetylcysteine/administration & dosage/pharmacology
*Endometriosis/complications/drug therapy/genetics
*Granulosa Cells/metabolism/drug effects
Adult
*Apoptosis/drug effects/genetics
*Infertility, Female/drug therapy/genetics/etiology
Superoxide Dismutase/blood
Antioxidants
Caspase 3/genetics/metabolism
Oxidative Stress/drug effects
Gene Expression Regulation/drug effects
Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
bcl-2-Associated X Protein/genetics/metabolism

@article {pmid41659018,
year = {2025},
author = {Spurrier-Best, L and Butcher, D and Blackham-Hayward, E and Kertesz, Z and Chichger, H},
title = {Nicotine-free electronic vape fluid stimulates angiogenic processes in vitro through ARF6-mediated oxidative stress.},
journal = {Frontiers in toxicology},
volume = {7},
number = {},
pages = {1699112},
pmid = {41659018},
issn = {2673-3080},
abstract = {INTRODUCTION: The increase in e-cigarette use in the population has led to substantial interest in the health impacts associated with e-cigarette smoking. E-cigarette smoking represents a key external environmental cell stressor. Whilst there have been several studies to investigate the effect of nicotine-containing e-cigarette fluid, there is still a significant lack of understanding of how nicotine-free e-cigarette smoking can impact individuals. However, preliminary studies indicate that nicotine-free e-cigarette smoking can cause impaired endothelial function in humans.

MATERIALS AND METHODS: In the present study, we therefore used a common brand of nicotine-free e-cigarette and human umbilical vein endothelial cells to assess angiogenic processes in vitro.

RESULTS: We observed a significant upregulation in endothelial cell adhesion, migration and new tube formation with exposure to nicotine-free e-cigarette condensate (eVape) which was abrogated with exposure to the antioxidant, N-acetyl cysteine. Proteome analysis demonstrated that eVape exposure increased expression of the pro-angiogenic factors, angiogpoeitin-2, endoglin (CD105), PIGF and VEGF, as well as the ADP ribosylation factor, ARF6, and ARF6-GEF, ARNO. Chemical inhibition of ARNO reduced eVape-induced oxidative stress, angiogenic processes, and release of angiogpoeitin-2, endoglin (CD105) and VEGF.

DISCUSSION: These findings demonstrate that nicotine-free eVape causes aberrant upregulated angiogenesis in an in vitro model of the human endothelium through ARNO-dependent signalling. This study is the first to demonstrate the molecular mechanisms in response to the cellular stressor, nicotine-free eVape which underlie impaired vascular function.},
}

@article {pmid41657721,
year = {2026},
author = {Peerapen, P and Putpeerawit, P and Boonmark, W and Thongboonkerd, V},
title = {Systematic evaluation and comparison of the in vitro inhibitory activities of dietary supplements against calcium oxalate crystal formation, growth and aggregation: Implications for kidney stone prevention.},
journal = {Current research in food science},
volume = {12},
number = {},
pages = {101326},
pmid = {41657721},
issn = {2665-9271},
abstract = {Kidney stone disease (KSD), particularly calcium oxalate (CaOx) type, remains a global health problem. Many efforts have been made to prevent KSD, including the use of some dietary supplements. However, mechanisms underlying their anti-KSD properties have remained poorly understood, and their relative anti-KSD properties have previously been unknown. Herein, we systematically evaluated and compared the inhibitory effects of five well-known dietary supplements on CaOx crystals. Caffeine (CAF), epigallocatechin-3-gallate (EGCG), N-acetylcysteine (NAC), resveratrol (RES) and trigonelline (TRIG) (at 1, 10 and 100 μM, which are within their physiologic levels in the urine) were subjected to CaOx crystallization, growth and aggregation assays. Degrees of their CaOx crystal-inhibitory activities were then compared. CAF inhibited crystal formation, EGCG inhibited crystal formation and growth, NAC inhibited crystal aggregation, RES inhibited crystal growth, and TRIG inhibited crystal formation and growth. However, RES promoted crystal aggregation and thus served as a dual modulator (acting as an inhibitor and promoter at different steps of stone formation). Almost all of these inhibitory effects were concentration-dependent. Comparing the CaOx-inhibitory activities of these compounds revealed that EGCG was the most potent inhibitor against CaOx crystal formation (with the crystal abundance-inhibitory activity of 85.61 ± 5.12 %), whereas RES was the most potent inhibitor against CaOx crystal growth (with the crystal growth-inhibitory activity of 92.99 ± 1.67 %). NAC was the only inhibitor against CaOx crystal aggregation (with the crystal aggregation-inhibitory activity of 22.97 ± 0.75 %). These data indicate the direct inhibitory effects of various dietary supplements against CaOx crystal formation, growth and aggregation, supporting their roles in KSD prevention.},
}

@article {pmid41654163,
year = {2026},
author = {Thakur, M and Mutyala, D and Amoliga, AA and Kondati, R and Batra, S},
title = {ROS-Driven Rewiring of Hippo-Inflammation-Polycomb Axis by PFOA in 2D and 3D Lung Epithelial Models.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154426},
doi = {10.1016/j.tox.2026.154426},
pmid = {41654163},
issn = {1879-3185},
abstract = {Perfluorooctanoic acid (PFOA), a persistent organic pollutant and prominent member of the per- and polyfluoroalkyl substances (PFAS) family, continues to raise global concern due to its bioaccumulation and potential for chronic human exposure. While hepatic and systemic toxicities of PFOA are well documented, its effects on lung epithelial integrity, particularly at environmentally relevant concentrations, remain incompletely understood. In this study, we investigated the cellular and molecular responses to PFOA in human alveolar lung epithelial cells (A549) cultured under both 2D submerged monolayer and 3D air-liquid interface (ALI) conditions, representing systemic and barrier-relevant exposure models. Cells were exposed to 10-1000nM PFOA for 24h to assess changes in pro-inflammatory mediators, including transcription factors-NF-κB and STAT3, pattern recognition receptors (TLR4 and RAGE), cytokine/chemokine production (IL-6, IL-8, CCL2, CCL5), and damage-associated molecular patterns (HSP70, HMGB1). PFOA also appeared to trigger translational stress responses, including stress granule and P-body formation, along with alterations in Hippo signaling via YAP/TAZ overactivation. PFOA-challenged cells exhibited activation of Polycomb Repressive Complexes and associated silencing histone marks (H3K27me3, H2AK119Ub), along with HDACs and SIRT family members, indicative of a redox-driven Polycomb-mediated gene silencing program. Oxidative stress was identified as the central driver of epigenetic and Hippo pathway disruptions, as observed in cells pre-exposed to 1 mM N-acetylcysteine (NAC). Despite these molecular alterations, epithelial cell migration capacity remains unaffected under acute exposure. Our results provide key mechanistic insights into PFOA-mediated disruption of redox homeostasis, immune signaling, and epigenetic plasticity in A549 cells, as well as identifying biomarkers for future biomonitoring efforts and studying regulatory frameworks.},
}

@article {pmid41654007,
year = {2026},
author = {Dutta, D and Behera, A and Roy, D and Sukla, S and Banerjee, S},
title = {Mechanistic exploration of methylglyoxal-induced hepatotoxicity involving oxidative stress, apoptosis, and gluconeogenic modulation.},
journal = {Chemico-biological interactions},
volume = {428},
number = {},
pages = {111954},
doi = {10.1016/j.cbi.2026.111954},
pmid = {41654007},
issn = {1872-7786},
mesh = {*Pyruvaldehyde/toxicity ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Humans ; Animals ; *Gluconeogenesis/drug effects ; Hep G2 Cells ; Reactive Oxygen Species/metabolism ; Mice, Inbred BALB C ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Liver/drug effects/metabolism/pathology ; Male ; Sirtuin 1/metabolism ; Acetylcysteine/pharmacology ; Chemical and Drug Induced Liver Injury/pathology/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Cell Survival/drug effects ; },
abstract = {Methylglyoxal (MG) is a precursor of advanced glycation end-products produced during glycolysis. MG accumulation is linked to various pathophysiological conditions through the production of reactive oxygen species (ROS). This investigation uncovers the mechanism of MG-induced hepatotoxicity in vitro and in vivo. We assessed MG's dose- and time-dependent cytotoxicity (0.001-10 μM) in HepG2 cells using the cell viability assay. We examined the protective effects of N-acetylcysteine (NAC) against MG toxicity using MTT reagent, monitoring ROS generation, apoptosis (via flow cytometry), and mitochondrial membrane potential (with JC1 dye staining). For the in vivo study, BALB/c mice received MG (290 mg/kg and 400 mg/kg) at 6 h and 14 h intervals to induce hepatotoxicity. We conducted liver histopathology and protein expression analysis for apoptotic markers (Bax, Bcl-2, and caspase-3) and gluconeogenesis regulators (SIRT1, PGC1α, and glucose 6-phosphatase or G6Pase) in both cell lines and liver tissues. MG caused significant dose- and time-dependent toxicity in HepG2 cells by promoting cell death, increasing ROS and apoptosis, and altering the mitochondrial membrane potential at 5 μM. NAC (5 and 10 mM) protected against MG-induced toxicity. In mice, MG led to elevated spleen and liver weight, aspartate transferase (AST), alanine transaminase (ALT), glucose, malondialdehyde, and decreased superoxide dismutase levels. MG upregulated pro-apoptotic and gluconeogenic proteins in HepG2 cells, while NAC significantly reduced their levels. MG also increased the expression of proteins involved in apoptosis and gluconeogenesis. MG-induced caspase-dependent hepatotoxicity was mediated by the production of ROS and the activation of gluconeogenesis via SIRT1-dependent PGC1α activation.},
}

*Pyruvaldehyde/toxicity
*Apoptosis/drug effects
*Oxidative Stress/drug effects
Humans
Animals
*Gluconeogenesis/drug effects
Hep G2 Cells
Reactive Oxygen Species/metabolism
Mice, Inbred BALB C
Membrane Potential, Mitochondrial/drug effects
Mice
Liver/drug effects/metabolism/pathology
Male
Sirtuin 1/metabolism
Acetylcysteine/pharmacology
Chemical and Drug Induced Liver Injury/pathology/metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Cell Survival/drug effects

@article {pmid41653207,
year = {2026},
author = {Zhang, M and Guan, C and Sheng, G and Ding, Z and Zhao, Y and Zhao, G and Li, W and Hu, Z and Peng, Y and Zheng, J},
title = {Pyrazinamide-induced hepatotoxicity mediated by aldehyde oxidase and xanthine oxidase.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {41653207},
issn = {1432-0738},
support = {ZK[2023]319//Guizhou Provincial Science and Technology Department/ ; },
abstract = {Pyrazinamide (PZA) has been approved for the treatment of tuberculosis in clinical practice. However, its adverse effects, particularly hepatotoxicity, have raised concerns. The present study aimed at exploring the potential relationship between PZA-induced hepatotoxicity and its metabolites resulting from metabolic activation. Glutathione (GSH) conjugates with confirmed structures were detected in mouse cytosol incubations containing PZA or pyrazinoic acid (POA, a major metabolite of PZA) supplemented with glutathione (GSH). Such GSH metabolites were also observed in both liver homogenates from mice administered with PZA and mouse primary hepatocytes exposed to PZA. Aldehyde oxidase (AO) and xanthine oxidase (XOD) were identified as key enzymes in the metabolic activation of PZA and POA. Both vitamin C (VC) and N-acetylcysteine (NAC) were found to reduce the generation of GSH conjugates derived from PZA and POA in incubation systems. Additionally, VC alleviated the susceptibility of hepatocytes to PZA-induced cytotoxicity. Consecutive administration of PZA for 7 days resulted in a marked elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice, and PZA-derived hepatic protein adduction was detected. Allopurinol administration attenuated the elevated serum ALT and AST in company with a reduction in the formation of GSH conjugates. This work provides solid evidence for the correlation between the metabolic activation of PZA and PZA-induced hepatotoxicity, enhancing the understanding of the underlying mechanisms of PZA toxicity in terms of molecular chemical structure.},
}

@article {pmid41642676,
year = {2026},
author = {Anandakrishnan, A and O'Halloran, A and Diamond, T},
title = {Successful Heat Stroke-Induced Pediatric Acute Liver Failure Treatment With N-Acetylcysteine Case Report.},
journal = {Critical care explorations},
volume = {8},
number = {2},
pages = {e1371},
pmid = {41642676},
issn = {2639-8028},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Heat Stroke/complications ; Male ; Child ; *Liver Failure, Acute/drug therapy/etiology ; *Free Radical Scavengers/therapeutic use ; },
abstract = {BACKGROUND: Previously healthy children are at risk of developing exertional heat stroke when experiencing extreme heat. Pediatric clinicians in primary care, emergency department, and critical care settings should be versed in the management of complications of exertional heat stroke. Pediatric acute liver failure (PALF) in the setting of heat stroke is rarely reported in published literature.

CASE SUMMARY: A 9-year-old male presented with heat stroke-induced PALF. He initially presented to an emergency department for altered mental status. During his clinical course, despite appropriate identification and initial treatment of exertional heat stroke, his symptoms progressed, including ongoing agitation, hepatic encephalopathy, coagulopathy, and severe transaminase elevation meeting clinical criteria for PALF.

CONCLUSIONS: He was treated with N-acetylcysteine (NAC) with resolution of his PALF without complications. In this article, we review the patient's clinical course, the rationale for treatment with NAC, and the management of heat stroke-induced PALF.},
}

Humans
*Acetylcysteine/therapeutic use
*Heat Stroke/complications
Male
Child
*Liver Failure, Acute/drug therapy/etiology
*Free Radical Scavengers/therapeutic use

@article {pmid41642111,
year = {2026},
author = {Dos Santos, IWR and Souza-Monteiro, D and Frazão, DR and da Silva, ZAL and de Moura, JDM and Cruz, JN and Collares, FM and de Souza-Rodrigues, RD and Cintra, LTÂ and Lima, RR},
title = {N-Acetylcysteine Reduces Alveolar Bone Loss and Mitigates Systemic Oxidative Damage in Rats With Apical Periodontitis.},
journal = {International endodontic journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/iej.70108},
pmid = {41642111},
issn = {1365-2591},
support = {307747/2025-5//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 408329/2022-0//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 404431/2024-0//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 400706/2024-5//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 409576/2025-5//Científico e Tecnológico (CNPq, Brazil) of the Brazilian Ministry of Science, Technology and Innovation/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), Ministry of Education/ ; 406436/2022-3//National Institute of Science and Technology in 3D Printing and Advanced Materials Applied to Human and Veterinary Health/ ; },
abstract = {AIM: This study aimed to evaluate the effects of N-acetylcysteine (NAC) supplementation in apical periodontitis (AP) induced in rats.

METHODOLOGY: Eighteen male Wistar rats were randomly assigned to three groups: control, AP, and AP plus NAC. NAC was administered by oral gavage (100 mg/kg/day), beginning 1 day after lesion induction and continued daily until the day preceding euthanasia. AP induction was performed by exposing the dental pulp of the lower first molars bilaterally, maintaining this condition for 28 days. After this period, the animals were euthanized, and the following biological materials were collected: blood (for systemic oxidative stress analysis) and hemimandibles for histopathological and histochemical, and micro-computed tomography analyses, aiming to measure bone quality parameters and periapical volume. Statistical analyses were performed using one-way ANOVA and Tukey's post hoc test. In addition, correlation analyses and multivariate analyses of variance (MANOVA) were performed on the biochemical parameters.

RESULTS: The study results showed that animals supplemented with NAC had greater preservation of bone quality parameters and a reduction in periapical volume progression when compared to the only apical periodontitis group. Additionally, in the analysis of systemic oxidative stress, supplemented animals showed higher antioxidant parameter levels and lower oxidant levels compared to non-supplemented animals, which also showed reduced preservation of bone collagen content.

CONCLUSIONS: The study findings suggest that NAC supplementation promoted greater preservation of bone quality, reduced periapical volume development, and modulation of endogenous antioxidant and oxidant aspects. This indicates that NAC can decrease local and systemic damage caused by AP, highlighting its potential as an adjunctive agent in processes involving systemic oxidative stress and the preservation of biological structures.},
}

@article {pmid41637640,
year = {2026},
author = {Pandey, AM and Zhou, R and Singh, D and Li, F and He, M and Le, A and Herdrich, J and Chen, Y and Shah, R and Adusei-Poku, S and Rohlwing, NJ and Koo, J and Ong, ZY and Oldfield, E},
title = {Antifungal Activity of Lipophilic Bisphosphonates.},
journal = {ACS infectious diseases},
volume = {12},
number = {2},
pages = {766-780},
doi = {10.1021/acsinfecdis.5c00838},
pmid = {41637640},
issn = {2373-8227},
mesh = {*Antifungal Agents/pharmacology/chemistry ; *Diphosphonates/pharmacology/chemistry ; Humans ; Microbial Sensitivity Tests ; *Candida glabrata/drug effects/growth & development ; Drug Resistance, Fungal ; Drug Synergism ; },
abstract = {We investigated the activity of a series of 75 lipophilic bisphosphonates against Candida glabrata. Thirty-six compounds had MIC < 1 μg/mL, 18 had MIC < 0.5 μg/mL, and 2 had MIC = 0.13 μg/mL, comparable to amphotericin B and caspofungin. The lipophilic bisphosphonates were ∼20-fold more potent against C. glabrata than the most potent hydrophilic bisphosphonate, zoledronate. The most active compounds were pyridinium bisphosphonates followed by imidazolium bisphosphonates, while aryl bisphosphonates were less active. Several compounds had selectivity index values against a human cell line in the 1000-3600 range, the most selective compounds being para-substituted pyridinium bisphosphonates. We also found similar activity against a caspofungin-resistant FKS2 (F659S) mutant. Some combinations of lipophilic bisphosphonates had synergistic activity with FICI values in the ∼0.3-0.5 range, and similar synergies were observed with fluconazole, implicating ergosterol biosynthesis inhibition leading to compromised membrane structure and function. Cell growth inhibition was rescued by ascorbic acid, glutathione, and N-acetyl cysteine, indicating a ROS-based killing mechanism. There was also synergy with other antifungals but very strong antagonism with verapamil (FICI ∼4), which blocks calcium channels. Unlike hydrophilic bisphosphonates, which target farnesyl diphosphate synthase, lipophilic bisphosphonates also target squalene synthase, suggesting that the combination of multitargeting bisphosphonates is one origin of the synergistic interactions observed. Given that one of the lipophilic bisphosphonates studied here (BPH-1237) has been shown to have activity against many other human fungal pathogens, combinations with the compounds described here may be of interest as antifungal leads.},
}

*Antifungal Agents/pharmacology/chemistry
*Diphosphonates/pharmacology/chemistry
Humans
Microbial Sensitivity Tests
*Candida glabrata/drug effects/growth & development
Drug Resistance, Fungal
Drug Synergism

@article {pmid41632564,
year = {2026},
author = {Zhang, J and Yan, M and Tang, Y and Liu, M and Yao, W and Zhang, Q and Chen, H},
title = {A First-Aid Nanomedicine Endowed with Microenvironment Self-Adaptive Regulation Ability to Facilitate Acute Liver Failure Prophylaxis and Therapy.},
journal = {ACS nano},
volume = {20},
number = {6},
pages = {4989-5006},
doi = {10.1021/acsnano.5c18314},
pmid = {41632564},
issn = {1936-086X},
mesh = {Animals ; *Liver Failure, Acute/prevention & control/drug therapy/metabolism/pathology ; *Nanomedicine ; Mice ; *Copper/chemistry/pharmacology/therapeutic use ; Macrophages/drug effects/metabolism ; Humans ; Oxidative Stress/drug effects ; *Sulfides/chemistry/pharmacology/therapeutic use ; *Nanoparticles/chemistry ; Male ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; },
abstract = {Acute liver failure (ALF) represents a life-threatening medical emergency with high mortality, yet limited treatment is available clinically. Here, we report albumin-biomineralized nonstoichiometric copper sulfide nanoparticles serving as first-aid nanomedicine to combat ALF, conceptualized as NanoAID. The NanoAID exhibits an electron-donor nanoantioxidant property to scavenge reactive oxygen species and concurrent anti-inflammatory capacity to reprogram pro-inflammatory M1 macrophages into anti-inflammatory M2-phenotype, thereby mitigating excessive oxidative and inflammatory stress in ALF lesions. More interestingly, we found Cu ions release under an in situ oxidative stress switch and the resulting H2S gas generation by NanoAID degradation, which further enhance the biosynthesis of intrahepatic antioxidant enzyme SOD1 and the repolarization of M1-to-M2 macrophages, respectively, thereby self-reinforcing ALF therapy. Such microenvironment self-adaptive regulation confers NanoAID with effective prophylactic efficacy and significant ALF survival advantages over the FDA-approved N-acetyl cysteine in multiple animal models, extending the first-aid window to 6 h post APAP intoxication. Transcriptomics results reveal the molecular mechanisms of NanoAID by promoting antioxidative and inhibiting inflammatory pathways, underscoring its great potential as a next-generation first-aid nanomedicine for ALF management.},
}

Animals
*Liver Failure, Acute/prevention & control/drug therapy/metabolism/pathology
*Nanomedicine
Mice
*Copper/chemistry/pharmacology/therapeutic use
Macrophages/drug effects/metabolism
Humans
Oxidative Stress/drug effects
*Sulfides/chemistry/pharmacology/therapeutic use
*Nanoparticles/chemistry
Male
Mice, Inbred C57BL
RAW 264.7 Cells
Reactive Oxygen Species/metabolism

@article {pmid41630014,
year = {2026},
author = {Ali̇hossei̇ni̇, H and Çolakoğlu, EÇ and Haydardedeoğlu, AE and Özen, D},
title = {N-acetylcysteine reduces serum creatinine, blood urea nitrogen, symmetric dimethylarginine and urine protein to creatinine ratio in cats with chronic kidney disease: a double-blind, placebo-controlled clinical trial.},
journal = {BMC veterinary research},
volume = {22},
number = {1},
pages = {},
pmid = {41630014},
issn = {1746-6148},
abstract = {BACKGROUND: Oxidative stress is considered a significant contributing factor of chronic kidney disease (CKD). To date, there is a paucity of clinical data in the literature regarding the effect of N-Acetylcysteine (NAC) in cats with naturally developing CKD. The aim of the study is to evaluate whether the addition of NAC in the treatment of cats with acute exacerbations of CKD could improve kidney function biomarkers over the use of intravenous fluid therapy alone.

METHODS: A total of 50 client-owned cats were included in the study. The inclusion criteria comprised cats previously diagnosed with azotemic CKD (IRIS stage 2-4) in addition to ultrasonographic evidence of bilaterally decreased renal mass, rough surface contours, and alteration of renal cortical echogenicity. All cats were examined using standard clinical procedures, including clinical examination, blood analyses, abdominal ultrasonography, dipstick urinalysis and urine culture. Computer-generated randomisation was utilised to assign the cats into the following groups: NAC (n:40): N-acetylcysteine (70 mg/kg, diluted in 50 ml 0.9% saline solution, administered intravenously over a period of seven days, and a placebo group (n:10) 50 ml 0.9% saline solution, IV for 7 days. Blood analyses and dipstick urinalysis were repeated on the eighth day of treatment. Between-group differences in baseline age and weight were assessed using the Student's t-test, while sex distribution was evaluated with the Fisher's exact test. Treatment effects across time were analysed using a two-way mixed-design ANOVA, with "Group" and "Time" entered as fixed factors and their interaction term included in the model.

RESULTS: SDMA and creatinine concentrations decreased significantly in both groups, but the concentrations of both were significantly lower in the NAC group after treatment (Day 8 values: SDMA NAC 16.5 ± 1.21 µg/dl versus placebo 27 ± 3.89 µg/dl; P = 0.04 and Creatinine NAC 4.01 ± 0.25 mg/dl versus placebo 6.44 ± 0.9 mg/dl; P < 0.001). UPC and BUN decreased significantly in the NAC group, but no change was observed in the placebo group.

CONCLUSION: The incorporation of NAC into treatment regimens demonstrates potential as a treatment strategy for cats with acute-on-chronic kidney disease.},
}

@article {pmid41624281,
year = {2025},
author = {Pas, D and Oltmanns, H and Meißner, J},
title = {In vitro characterization of antimicrobial efficacy and cytotoxicity of polyvinylpyrrolidone-iodine, N-acetylcysteine, methylglyoxal, and N-chlorotaurine as alternative antimicrobials in treating bovine clinical endometritis.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1699857},
pmid = {41624281},
issn = {2297-1769},
abstract = {Bovine clinical endometritis (CE) is a common indication for antibiotic use in dairy cows. The increase in bacterial resistance and the aspired decrease in antibiotic use under the One Health concept call for alternatives in treatment. Polyvinylpyrrolidone-iodine (PVP), N-acetylcysteine (NAC), methylglyoxal (MGO), and N-chlorotaurine (NCT) are known substances with antibacterial properties that could potentially serve as those alternatives. In a broth microdilution assay, their efficacy against the common cause of endometritis, Trueperella pyogenes, was investigated. By cytotoxicity testing on a primary bovine endometrial epithelial cell culture, potential adverse effects on cell proliferation, viability, and immune response (IL-6) were examined. While all four substances had an antibacterial effect on T. pyogenes, PVP, MGO, and NCT also showed cytotoxic effects. In contrast, NAC was tolerated well by the cells. In sum, the four tested substances can be considered potential alternatives to antibiotic treatments. Further research is, however, necessary to investigate their toxic effects in ex vivo or in vivo models and to identify effective dosages in animals.},
}

@article {pmid41620910,
year = {2026},
author = {Bai, X and Luo, Y and Huang, J and Liu, G},
title = {Effect of linezolid combined with N-acetylcysteine on lung function, blood gas and inflammation in patients with severe pneumonia.},
journal = {Pakistan journal of pharmaceutical sciences},
volume = {39},
number = {3},
pages = {803-808},
doi = {10.36721/PJPS.2026.39.3.REG.13264.1},
pmid = {41620910},
issn = {1011-601X},
mesh = {Humans ; *Linezolid/therapeutic use/adverse effects ; *Acetylcysteine/therapeutic use/adverse effects ; Male ; Female ; Middle Aged ; *Pneumonia/drug therapy/physiopathology/blood ; Blood Gas Analysis ; *Anti-Bacterial Agents/therapeutic use/adverse effects ; Aged ; Drug Therapy, Combination ; *Lung/drug effects/physiopathology ; Adult ; Treatment Outcome ; Respiratory Function Tests ; Inflammation/drug therapy ; C-Reactive Protein/metabolism ; },
abstract = {BACKGROUND: Severe pneumonia is a serious lung disease. The continuous and regular administration of antibiotics is currently used for severe pneumonia. However, the single antibiotic may enhance the drug resistance and the overall efficacy is not ideal.

OBJECTIVES: This study aimed to investigate the efficacy and safety of linezolid combined with N-acetylcysteine (NAC) on lung function, blood gas and inflammation in patients with severe pneumonia.

METHODS: Eighty-four severe pneumonia patients were divided into linezolid group and linezolid +NAC group, which received the treatment using linezolid and linezolid combined with NAC for ten days, respectively. The total treatment efficacy was assessed. Before and after treatment, the pulmonary function indexes, blood gas indexes inflammatory response indexes were determined.

RESULTS: Compared with linezolid group, in linezolid +NAC group the disappearance time of cough, sputum and lung rales were shortened, the total effective rate, peak expiratory flow, forced expiratory volume in one second/forced vital capacity, arterial oxygen partial pressure and blood oxygen saturation were increased, the arterial carbon dioxide partial pressure and serum tumor necrosis factor α, interleukin 6 and hypersensitive C-reactive protein levels were decreased (all P < 0.05).

CONCLUSION: In treating severe pneumonia, linezolid combined with NAC can significantly improve the lung function of patients, improve the blood gas indicators and reduce the inflammatory response, thus alleviating the clinical symptoms.},
}

Humans
*Linezolid/therapeutic use/adverse effects
*Acetylcysteine/therapeutic use/adverse effects
Male
Female
Middle Aged
*Pneumonia/drug therapy/physiopathology/blood
Blood Gas Analysis
*Anti-Bacterial Agents/therapeutic use/adverse effects
Aged
Drug Therapy, Combination
*Lung/drug effects/physiopathology
Adult
Treatment Outcome
Respiratory Function Tests
Inflammation/drug therapy
C-Reactive Protein/metabolism

@article {pmid41619526,
year = {2026},
author = {Monti, DA and Zabrecky, G and Kremens, D and Liang, TW and Wintering, NA and Vedaei, F and Navarreto, E and Gupta, M and Steinmetz, A and Bazzan, AJ and Mohammed, F and Newberg, AB},
title = {N-Acetylcysteine is associated with changes in functional connectivity in patients with Parkinson's disease.},
journal = {Parkinsonism & related disorders},
volume = {144},
number = {},
pages = {108216},
doi = {10.1016/j.parkreldis.2026.108216},
pmid = {41619526},
issn = {1873-5126},
abstract = {INTRODUCTION: This study assessed the changes in functional connectivity from resting functional magnetic resonance imaging (fMRI) in patients with Parkinson's disease (PD) given N-Acetylcysteine (NAC), the prodrug to L-cysteine and a precursor to the natural biological antioxidant glutathione (GSH). The aim of this study was to determine whether NAC is associated with changes in functional connectivity, particularly in the basal ganglia, and improvements in Parkinson's symptoms.

METHODS: Forty-four patients with PD were randomized to either weekly intravenous infusions of NAC (50 mg/kg) plus oral doses (500 mg twice per day) for six months plus standard of care, or standard of care only. Participants received pre and post brain imaging with resting Blood Oxygen Level Dependent (BOLD) MRI to measure functional connectivity between key brain regions involved with PD. These findings were compared to changes in PD symptoms as measured by the Unified Parkinson's Disease Rating Scale (UPDRS).

RESULTS: There were significant differences in the NAC group compared to the control group in functional connectivity measures after NAC. Specifically, there was significantly different functional connectivity between basal ganglia structures and the precuneus, precentral gyrus, postcentral gyrus, and particularly the Rolandic operculum. Changes in the precuneus also correlated with changes in UPDRS scores.

CONCLUSION: The results suggest that NAC may positively affect brain functional connectivity in PD patients, with corresponding positive clinical effects. Larger scale studies are warranted.},
}

@article {pmid41617440,
year = {2026},
author = {Choi, SH and Seo, J and Jeong, SM},
title = {Splicing Factor SF3B4 Suppresses Pancreatic Cancer Growth and Migration by Inhibiting Autophagy.},
journal = {Anticancer research},
volume = {46},
number = {2},
pages = {737-747},
doi = {10.21873/anticanres.17983},
pmid = {41617440},
issn = {1791-7530},
mesh = {Humans ; *Autophagy/drug effects ; *RNA Splicing Factors/metabolism/genetics ; Cell Movement/drug effects ; *Pancreatic Neoplasms/pathology/genetics/metabolism/drug therapy ; Cell Proliferation/drug effects ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Fluorouracil/pharmacology ; *Carcinoma, Pancreatic Ductal/pathology/genetics/metabolism/drug therapy ; Apoptosis/drug effects ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; },
abstract = {BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, characterized by aggressive progression, profound chemoresistance and unique metabolic adaptations such as elevated autophagy. Although the splicing factor SF3B4 has been reported to function as an oncogene in other malignancies, its role in PDAC remains unclear. This study aimed to elucidate the functional and mechanistic significance of SF3B4 in PDAC.

MATERIALS AND METHODS: SF3B4 expression in PDAC was analyzed using patient datasets and experimental models. Functional assays including cell proliferation, colony formation, migration, and autophagy analyses were performed in PDAC cells. Reactive oxygen species (ROS) levels were evaluated. Sensitivity to 5-fluorouracil (5-FU) and apoptotic responses were also evaluated.

RESULTS: SF3B4 acts as a tumor suppressor in PDAC by inhibiting autophagy, a process that this cancer uniquely depends on for survival. SF3B4 overexpression inhibited proliferation, colony formation and migration of PDAC cells. Mechanistically, SF3B4 suppressed autophagic flux, resulting in increased ROS accumulation and subsequent inhibition of tumorigenic phenotypes. Treatment with the antioxidant N-acetylcysteine (NAC) rescued the tumor suppressive effects of SF3B4 overexpression. Moreover, SF3B4 overexpression sensitized PDAC cells to 5-FU, accompanied by enhanced apoptotic responses.

CONCLUSION: SF3B4 is a context-dependent splicing factor that functions as a tumor suppressor in PDAC by regulating autophagy and redox homeostasis. Targeting the SF3B4-autophagy-ROS axis may represent a promising strategy to suppress PDAC progression and overcome chemoresistance.},
}

Humans
*Autophagy/drug effects
*RNA Splicing Factors/metabolism/genetics
Cell Movement/drug effects
*Pancreatic Neoplasms/pathology/genetics/metabolism/drug therapy
Cell Proliferation/drug effects
Cell Line, Tumor
Reactive Oxygen Species/metabolism
Fluorouracil/pharmacology
*Carcinoma, Pancreatic Ductal/pathology/genetics/metabolism/drug therapy
Apoptosis/drug effects
Gene Expression Regulation, Neoplastic
Animals
Mice

@article {pmid41616897,
year = {2026},
author = {Shirpoor, A and Zarrini, Z and Naderi, R},
title = {N-acetyl-cysteine alleviates nandrolone decanoate-induced hippocampal cell apoptosis in rats via reversing protein expressions of S1P1, Akt and FOXO3a signaling pathway.},
journal = {Steroids},
volume = {228},
number = {},
pages = {109759},
doi = {10.1016/j.steroids.2026.109759},
pmid = {41616897},
issn = {1878-5867},
mesh = {Animals ; *Hippocampus/drug effects/cytology/metabolism ; *Apoptosis/drug effects ; Male ; *Forkhead Box Protein O3/metabolism ; Rats, Wistar ; *Signal Transduction/drug effects ; Rats ; *Proto-Oncogene Proteins c-akt/metabolism ; Nandrolone Decanoate ; *Acetylcysteine/pharmacology ; *Nandrolone/analogs & derivatives/pharmacology ; },
abstract = {Illicit use of nandrolone can result in apoptosis in the hippocampus tissue but the underlying mechanism is unknown. The present study evaluated the role of S1P1/Akt/FOXO3a pathway in hippocampus cell apoptosis following exposure to nandrolone decanoate either alone or in combination with N-acetyl-cysteine. Twenty-four male Wistar rats were randomly divided into three groups (n = 8): control, nandrolone (10 mg/kg; intramuscularly; three times per week), and nandrolone + N-acetyl-cysteine (150 mg/kg; intraperitoneally). After six weeks of treatment, the number of apoptotic cells was significantly increased in the nandrolone treated group compared with the control group. Compared to control group, nandrolone group showed significant upregulation of NOX2, iNOS, 8-OHdG, P-FOXO3a/FOXO3a and lactate dehydrogenase (LDH) protein expression in rat hippocampus cells. Conversely, the protein expressions of P-Akt/Akt and S1P1 were significantly downregulated in hippocampus tissue of rats treated with nandrolone compared with control rats. Co-administration of N-acetyl-cysteine with nandrolone significantly reduced the apoptotic index and reversed the expressions of S1P1, P-Akt/Akt and P-FOXO3a/FOXO3a in the hippocampus neurons compared with the nandrolone group. These findings suggest that S1P1/Akt/FOXO3a signaling pathway may at least in part play an important role in the progression of apoptosis induced by nandrolone exposure, providing new insights into the pathogenesis and potential treatment of nandrolone-induced hippocampal damage.},
}

Animals
*Hippocampus/drug effects/cytology/metabolism
*Apoptosis/drug effects
Male
*Forkhead Box Protein O3/metabolism
Rats, Wistar
*Signal Transduction/drug effects
Rats
*Proto-Oncogene Proteins c-akt/metabolism
Nandrolone Decanoate
*Acetylcysteine/pharmacology
*Nandrolone/analogs & derivatives/pharmacology

@article {pmid41613139,
year = {2025},
author = {Gao, W and Lin, Z and Bao, Y and Liu, M and Ma, G and Chen, X and Yu, S and Zeng, Y},
title = {A stage specific NETs-related signature in alcoholic steatohepatitis: from molecular subtyping to therapeutic vulnerabilities.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1711388},
pmid = {41613139},
issn = {1664-3224},
mesh = {Humans ; *Fatty Liver, Alcoholic/genetics/immunology/diagnosis/metabolism/drug therapy ; Animals ; Mice ; Matrix Metalloproteinase 7/genetics/metabolism ; *Neutrophils/immunology/metabolism ; Gene Expression Profiling ; Proto-Oncogene Proteins c-fos/genetics/metabolism ; Male ; Transcriptome ; Gene Regulatory Networks ; Molecular Docking Simulation ; },
abstract = {BACKGROUND: Alcohol-associated steatohepatitis (ASH) is a globally prevalent liver disease, with robust evidence implicating neutrophil extracellular traps (NETs) as a central pathological phenomenon driving inflammation and progression. However, the core genomic signatures that govern NETs and underlying molecular mechanisms within the ASH microenvironment remain poorly defined.

METHODS: Building on the prominent NETs formation phenomenon in ASH, we established a core pool of NETs-related hub genes through intersection of ASH-derived differentially expressed genes (DEGs), key WGCNA modules, and a curated NETs gene set. From this NET-focused pool, a consensus of three machine learning algorithms (LASSO, SVM, RF) distilled a final diagnostic signature, which was rigorously validated in training and external cohorts via ROC analysis and neural networks. Patient heterogeneity was then investigated using consensus clustering with this signature, followed by immune profiling and functional validation in human and mouse ASH models. Therapeutic potential was explored through drug database enrichment and molecular docking.

RESULTS: A NETs-focused three-gene signature (FOS, MMP7, CXCL6) achieved exceptional diagnostic accuracy for ASH (AUC = 1.00 in training; 0.983 in validation). It stratified ASH into a Metabolic-dominant (C1) subtype and a Pro-inflammatory (C2) subtype, the latter exhibiting higher MMP7/CXCL6, lower FOS, and enriched cytotoxic infiltration. In vivo, FOS rose in acute injury but declined in chronic models and human ASH, whereas MMP7/CXCL6 remained elevated, suggesting a temporal shift from acute FOS-dominant response to sustained MMP7/CXCL6-mediated inflammation. Finally, drug-gene interaction analysis identified several potential therapeutic modulators, including N-acetylcysteine (NAC), with predicted high binding affinities to FOS and MMP7.

CONCLUSION: FOS, MMP7, and CXCL6 constitute a clinically actionable signature capturing the stage-specific dynamics of NETs-driven inflammation in ASH. Beyond its diagnostic and stratifying utility, this signature highlights potential therapeutic avenues for clinical intervention.},
}

Humans
*Fatty Liver, Alcoholic/genetics/immunology/diagnosis/metabolism/drug therapy
Animals
Mice
Matrix Metalloproteinase 7/genetics/metabolism
*Neutrophils/immunology/metabolism
Gene Expression Profiling
Proto-Oncogene Proteins c-fos/genetics/metabolism
Male
Transcriptome
Gene Regulatory Networks
Molecular Docking Simulation

@article {pmid41607252,
year = {2026},
author = {Huang, R and Wu, Y and Liu, X and Zou, L and Li, J and He, J and Yang, L and Yang, X},
title = {Sulfur-Fumigation Engineered Ceria Nanoparticles With Augmented Oxygen Vacancies for Enhanced Therapy of Drug-Induced Liver Injury.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e13609},
doi = {10.1002/smll.202513609},
pmid = {41607252},
issn = {1613-6829},
support = {CSTB2024NSCQ-MSX0554//Natural Science Foundation of Chongqing/ ; },
abstract = {The excessive generation of reactive oxygen species (ROS) and its synergistic interplay with inflammation and apoptosis play a critical role in the progression of drug-induced liver injury (DILI). Ceria nanoparticles are potential DILI therapy candidates due to their self-renewable ROS scavenging activity. However, the clinical translation of ceria nanoparticles for DILI therapy is challenged by enhanced ROS scavenging activity and prolonged hepatic retention. Herein, the sulfur-fumigation approach is used to modulate the ROS scavenging activity of ceria nanoparticles through the surface microstructure reconfiguration mechanism. The sulfur-fumigation induces nanoparticle contraction and crystalline fusion. Crucially, sulfur-fumigation decreases (111) plane exposure but increases (200) and (220) plane exposure. These changes cause the generation of abundant oxygen vacancies, which significantly enhances the ROS scavenging activity of ceria nanoparticles, even when the surface area is decreased. Together with an appropriate hydrodynamic diameter (135.9 nm) for liver targeting, the sulfur-fumigated ceria nanoparticles can easily accumulate in the liver and alleviate ROS, inflammation, and apoptosis in DILI mice. Compared to the clinical standard N-acetylcysteine (NAC), the sulfur-fumigated ceria nanoparticles show better therapeutic efficacy across most of the detected parameters. These findings suggest that sulfur-fumigation is a potent surface reconfiguration strategy to engineer highly active ceria nanoparticles for DILI therapy.},
}

@article {pmid41606955,
year = {2026},
author = {Wang, C and Zhang, H and Guan, C and Li, Y and Yang, S and Huang, L},
title = {Glutamine transporter SLC1A5 inhibits autophagy-mediated CD276 degradation to promote esophageal cancer progression.},
journal = {Cancer biology & therapy},
volume = {27},
number = {1},
pages = {2621606},
pmid = {41606955},
issn = {1555-8576},
mesh = {Humans ; Animals ; *Amino Acid Transport System ASC/metabolism/genetics/antagonists & inhibitors ; Mice ; *Esophageal Neoplasms/pathology/metabolism/genetics ; *Autophagy ; *Minor Histocompatibility Antigens/metabolism/genetics ; Cell Proliferation ; Disease Progression ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Female ; Xenograft Model Antitumor Assays ; Male ; Glutamine/metabolism ; Mice, SCID ; Mice, Inbred NOD ; Proteolysis ; },
abstract = {BACKGROUND: CD276/B7-H3 is an immune checkpoint molecule often overexpressed in cancers, representing a potential therapeutic target. The underlying mechanisms for CD276 upregulation remain unclear. This study investigates how glutamine metabolism affects CD276 protein stability and esophageal squamous cell carcinoma (ESCC) progression.

METHODS: CD276 and SLC1A5 expression were analyzed in 90 ESCC clinical tissues and TCGA/GEO datasets. CCK-8, colony formation, wound healing and transwell assays were performed in KYSE150 and KYSE450 cells. Autophagy was quantified by immunofluorescence and western blot. Mitochondrial reactive oxygen species (ROS) levels measured by flow cytometry. Rescue experiments used N-acetylcysteine (NAC) and chloroquine (CQ). Finally, antitumor effects of SLC1A5 inhibitor V9302 in the presence or absence of CD276 were evaluated in NOD/SCID mice (n = 5 per group) bearing KYSE150 xenografts.

RESULTS: CD276 and SLC1A5 upregulated in ESCC tissues (P < 0.05). CD276 overexpression enhanced ESCC cell proliferation and migration by 42.3% and 58.7%, respectively (P < 0.01). CQ but not MG-132 increased CD276 expression in ESCC cells. SLC1A5 stabilized CD276 protein without altering CD276 mRNA levels, by suppressing ROS-dependent autophagic degradation. NAC reversed ROS-induced CD276 degradation, while CQ abrogated CD276 downregulation upon glutamine metabolism inhibition. Inhibiting glutamine metabolism could reverse ESCC cell proliferation induced by CD276 overexpression. Moreover, combination of V9302 and CD276 knockout significantly reduced KYSE150 cell-derived xenograft tumor volume by 65.2% (95% CI 58.3-72.1%, P < 0.001) in NOD/SCID mice, without affecting mouse body weight (P > 0.05).

CONCLUSION: SLC1A5 enhances CD276 stability by suppressing ROS-autophagy signaling, promoting ESCC progression. Targeting glutamine metabolism to enhance CD276 degradation might be a novel therapeutic strategy for ESCC.},
}

Humans
Animals
*Amino Acid Transport System ASC/metabolism/genetics/antagonists & inhibitors
Mice
*Esophageal Neoplasms/pathology/metabolism/genetics
*Autophagy
*Minor Histocompatibility Antigens/metabolism/genetics
Cell Proliferation
Disease Progression
Reactive Oxygen Species/metabolism
Cell Line, Tumor
Female
Xenograft Model Antitumor Assays
Male
Glutamine/metabolism
Mice, SCID
Mice, Inbred NOD
Proteolysis

@article {pmid41603285,
year = {2026},
author = {Karimi-Dehkordi, M and Saghaei, F and Saberian, M and Nejad, HS and Sohrabi, F and Zabihi, N},
title = {Feselol Ameliorates Acetaminophen-Induced Hepatotoxicity Through Multi-Pathway Modulation of Oxidative Stress, Inflammation, and Apoptosis in Mice.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {2},
pages = {e70710},
doi = {10.1002/jbt.70710},
pmid = {41603285},
issn = {1099-0461},
mesh = {Animals ; *Acetaminophen/adverse effects/toxicity ; *Oxidative Stress/drug effects ; Mice ; *Apoptosis/drug effects ; *Chemical and Drug Induced Liver Injury/metabolism/pathology/drug therapy/prevention & control ; Male ; *Inflammation/drug therapy/metabolism/chemically induced/pathology ; Liver/metabolism/pathology/drug effects ; },
abstract = {BACKGROUND AND AIM: Acetaminophen (APAP) overdose is a major cause of drug-related acute liver failure around the world. The limited treatment options beyond N-acetylcysteine (NAC) show a clear need for new liver-protective agents. Feselol, a natural compound known for its strong antioxidant effects, has become a potential candidate. This research aimed to evaluate feselol's anti-inflammatory, anti-apoptotic, and protective qualities against APAP-induced acute liver damage in a mouse model.

MATERIAL AND METHOD: The experiment included 42 mice divided into 7 groups, with some being administered a toxic dose of APAP only and others being given APAP in combination with 25 or 50 mg/kg of feselol. Serum levels of AST (serum aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), and GGT (gamma-glutamyl transferase) were examined. SOD (superoxide dismutase), CAT (catalase), GPx (glutathione peroxidase) activities and MDA (malondialdehyde) levels were measured by colorimetric method. The liver tissue was analyzed through H&E staining. The expression of IL-1β, TNF-α, Bax, Caspase 3, and Bcl-2 genes was also examined by Real-time PCR.

RESULTS: The results showed that treatment of feselol at different doses with APAP led to a decrease in MDA levels to 23.25 nmol/mg (p < 0.05). Also, the activities of SOD, CAT and GPx enzymes in the group treated with a dose of 50 mg/kg of feselol with APAP were 33.09, 109.86, and 109.80, respectively, which was significant compared to the APAP group (p < 0.05). The results showed that simultaneous treatment with feselol and APAP resulted in a decrease in IL-1β and TNF-α gene expression by 1.67 and 1.015 fold, respectively (p < 0.05). Also, the expression of Bax (3.22-fold) and Caspase 3 (1.26-fold) genes decreased in the feselol-treated group and the expression of Bcl-2 (0.59-fold) gene increased. In the group that received APAP and feselol, the liver tissue was close to that of the control group. Feselol (50 mg/kg) coadministered with APAP significantly reduced ALT, AST, ALP, and GGP enzyme activity compared to the APAP-treated group (p < 0.05).

CONCLUSION: This study is notable for the discovery of feselol's pharmacological effects as a preventive drug against oxidative stress-associated hepatic impairment.},
}

Animals
*Acetaminophen/adverse effects/toxicity
*Oxidative Stress/drug effects
Mice
*Apoptosis/drug effects
*Chemical and Drug Induced Liver Injury/metabolism/pathology/drug therapy/prevention & control
Male
*Inflammation/drug therapy/metabolism/chemically induced/pathology
Liver/metabolism/pathology/drug effects

@article {pmid41602262,
year = {2025},
author = {Zacharia, GS and Ravte, V and Jyala, A and Shehi, E},
title = {Complementary and Alternative Medicine-Induced Combined Hepatorenal Toxicity: A Case Report.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e100197},
pmid = {41602262},
issn = {2168-8184},
abstract = {Drug-induced liver injury (DILI) is a leading cause of liver disease globally, with complementary and alternative medicine (CAM) representing a significant contributor due to its widespread use and limited regulation. CAM encompasses diverse practices and products, with regional and ethnic diversity, many of which are used to treat liver disease. Even though a few natural remedies have been utilized for centuries, most lack scientific evidence for their safety and efficacy. This report describes a 42-year-old male who self-treated his fatty liver with CAM, culminating in severe concomitant hepatic and renal dysfunctions. Comprehensive evaluation excluded viral, autoimmune, metabolic liver diseases, and obstructive biliary diseases. The Roussel Uclaf Causality Assessment Method (RUCAM) score indicated a probable causal link between CAM and DILI of hepatocellular pattern. The constituents of the CAM, extracts of Carica papaya, Alstonia boonei, and Tetrapleura tetraptera, have been implicated in hepatotoxicity in animal models. Discontinuing the supplements and supportive care, including N-acetyl cysteine, led to symptomatic and biochemical improvement. This case highlights the importance of clinicians' awareness of CAM-related DILI, emphasizing the need for vigilance and patient education about the potential risks associated with herbal products.},
}

@article {pmid41602127,
year = {2025},
author = {Zeng, Q and Sun, Y and Lei, M and Liu, Z and Yan, X and Li, R and Zheng, J and Zha, J and Zhang, L and Guan, X and Yao, J},
title = {Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis.},
journal = {Liver research (Beijing, China)},
volume = {9},
number = {4},
pages = {324-337},
pmid = {41602127},
issn = {2542-5684},
abstract = {BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (HIRI) is a major contributor to liver dysfunction and failure, particularly in the context of liver transplantation. Its pathogenesis is primarily driven by ferroptosis, oxidative stress, and mitochondrial dysfunction. Given the interplay among these mechanisms through redox imbalance and disrupted energy metabolism, nicotinic acid (NA)-recognized for its antioxidative and metabolic regulatory properties-emerges as a promising therapeutic candidate. This study aims to investigate the protective effects of NA on HIRI and elucidate its underlying mechanisms.

METHODS: An HIRI model in mice and a hypoxia/reoxygenation (H/R) model in primary hepatocytes were established to evaluate the effects of NA treatment on oxidative stress. NA was administered prior to model induction. N-acetylcysteine (NAC) was used as a comparator. Comprehensive assessments of ferroptosis, oxidative stress, mitophagy, and mitochondrial biogenesis markers were conducted using Western blotting, immunohistochemistry, immunofluorescence, and biochemical assays.

RESULTS: NA pretreatment reduced serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH) levels, suppressed inflammation by decreasing neutrophil infiltration and macrophage activation, and mitigated oxidative stress by lowering reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It enhanced antioxidant defenses, inhibited ferroptosis, and improved mitochondrial health through increased mitophagy, mitochondrial biogenesis, and mitochondrial permeability transition pore (mPTP) stabilization, leading to enhanced ATP production and mitochondrial function in HIRI.

CONCLUSIONS: NA improves mitochondrial function by promoting mitophagy and mitochondrial biogenesis, which reduces ferroptosis and oxidative stress, thereby alleviating HIRI.},
}

@article {pmid41601049,
year = {2026},
author = {Firouzjaei, Y and Hajizadeh Moghaddam, A and Sohabatzadeh, F and Khanjani Jelodar, S and Farhadi, M},
title = {Neuroprotective effects of plasma-activated N-acetylcysteine against streptozotocin-induced behavioral deficits in rats: Attenuation of oxidative stress and cholinergic dysfunction.},
journal = {Ecotoxicology and environmental safety},
volume = {309},
number = {},
pages = {119619},
doi = {10.1016/j.ecoenv.2025.119619},
pmid = {41601049},
issn = {1090-2414},
mesh = {Animals ; *Acetylcysteine/pharmacology ; Male ; *Oxidative Stress/drug effects ; Rats ; *Neuroprotective Agents/pharmacology ; Streptozocin/toxicity ; Behavior, Animal/drug effects ; *Cognitive Dysfunction/chemically induced/drug therapy ; Plasma Gases ; },
abstract = {N-Acetylcysteine (NAC), a thiol-containing antioxidant, has demonstrated neuroprotective potential in various neurological disorders. Recently, cold atmospheric plasma (CAP) technology has emerged as a promising approach for modifying the physicochemical properties of biomolecules. This study investigated the neuroprotective effects of plasma-activated N-acetylcysteine (PAN) in a rat model of intracerebroventricular streptozotocin (icv-STZ)-induced cognitive impairment, with particular emphasis on redox homeostasis and cholinergic function. The physicochemical properties of PAN were characterized using FTIR, LC-MS/MS, and DPPH assay. Male rats received a single icv-STZ injection (3 mg/kg) on day 0, followed by oral administration of NAC or PAN (50 mg/kg) every other day for three weeks. Cognitive performance and anxiety-like behaviors were assessed using the shuttle box, novel object recognition, and elevated plus maze tests. Subsequently, oxidative stress indices (TAC, GSH, SOD, CAT, MDA, NO), cholinergic markers (AChE activity, ACh levels), and the expression of AChE, α7 nAChR, Nrf2, Keap1 and BDNF genes were quantified in the hippocampus and cerebral cortex. FTIR and LC-MS/MS analyses revealed plasma-induced chemical modifications in NAC, resulting in the generation of novel compounds. The DPPH assay further demonstrated superior radical scavenging activity of PAN compared with NAC. Behaviorally, PAN administration significantly alleviated STZ-induced cognitive deficits and anxiety-like behaviors. Biochemically, PAN normalized TAC, GSH, MDA, NO, and ACh levels, increased CAT and SOD activities, and reduced AChE activity. At the transcriptional level, PAN upregulated α7 nAChR, Nrf2 and BDNF expression while downregulating AChE and Keap1. Collectively, these findings suggest that PAN mitigates behavioral impairments in the icv-STZ rat model of Alzheimer's disease, potentially through attenuation of oxidative stress and restoration of cholinergic neurotransmission.},
}

Animals
*Acetylcysteine/pharmacology
Male
*Oxidative Stress/drug effects
Rats
*Neuroprotective Agents/pharmacology
Streptozocin/toxicity
Behavior, Animal/drug effects
*Cognitive Dysfunction/chemically induced/drug therapy
Plasma Gases

@article {pmid41597285,
year = {2026},
author = {Chung, YY and Kim, B and Lee, J and Kwak, S and Jung, M and Kim, YS and Baek, SK},
title = {Establishing a Non-Surgical Mouse Model of Laryngopharyngeal Reflux Disease: Acid-Induced Epithelial Disruption and Protective Role of N-Acetylcysteine.},
journal = {Cells},
volume = {15},
number = {2},
pages = {},
pmid = {41597285},
issn = {2073-4409},
support = {2021R1F1A1056645 (RS-2021-NR063002)//National Research Foundation of Korea/ ; 2023R1A2C1004538 (RS-2023-NR076554)//National Research Foundation of Korea/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Female ; Disease Models, Animal ; Mice, Inbred C57BL ; *Laryngopharyngeal Reflux/pathology/drug therapy/metabolism ; Mice ; Cadherins/metabolism ; Matrix Metalloproteinase 7/metabolism ; *Acids ; Epithelial Cells/drug effects/pathology/metabolism ; *Protective Agents/pharmacology ; },
abstract = {Laryngopharyngeal reflux disease (LPRD) results from the retrograde flow of gastric contents into the upper aerodigestive tract, causing epithelial injury. Progress in its management has been limited by the lack of objective biomarkers and reproducible in vivo models. This study aimed to establish a chronic, non-surgical mouse model of LPRD and to investigate the protective effect of N-acetylcysteine (NAC). Female C57BL/6 mice were randomly assigned to three groups: control (standard drinking water), study (acidified water, pH 3.0, for 12 weeks), and treatment (acidified water for 12 weeks plus NAC supplementation during the final 4 weeks). Body weight, food intake, and water consumption were monitored weekly. Pharyngeal tissues were analyzed by immunohistochemistry and Western blotting. Chronic acid exposure resulted in loss of membrane-localized E-cadherin, cytoplasmic redistribution, and upregulation of matrix metalloproteinase-7 (MMP-7). These molecular alterations were accompanied by enhanced phosphorylation of ERK and c-Jun, consistent with activation of the ROS-ERK-c-Jun signaling pathway. NAC supplementation was associated with partial restoration of E-cadherin, reduced MMP-7 expression, and attenuation of ERK/c-Jun phosphorylation. No systemic toxicity or weight loss was observed, indicating good tolerability of the model. This non-surgical ingestion-based model faithfully recapitulates key epithelial features of LPRD and provides a feasible platform for mechanistic investigation and exploratory therapeutic studies. NAC may exert protective effects against acid-induced epithelial injury in this model.},
}

Animals
*Acetylcysteine/pharmacology/therapeutic use
Female
Disease Models, Animal
Mice, Inbred C57BL
*Laryngopharyngeal Reflux/pathology/drug therapy/metabolism
Mice
Cadherins/metabolism
Matrix Metalloproteinase 7/metabolism
*Acids
Epithelial Cells/drug effects/pathology/metabolism
*Protective Agents/pharmacology

@article {pmid41596085,
year = {2025},
author = {Chen, X and Gao, D and Wang, M and Wang, L and Hu, H and Wen, C and Tang, Y},
title = {Neutrophil Extracellular Traps in Systemic Lupus Erythematosus: Pathogenic Mechanisms, Crosstalk with Oxidative Stress, and Antioxidant Therapeutic Potential.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {1},
pages = {},
pmid = {41596085},
issn = {2076-3921},
support = {82305145//National Natural Science Foundation of China/ ; LQ23H270006//Zhejiang Provincial Natural Science Foundation of China/ ; },
abstract = {Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and the formation of immune complexes (ICs), which lead to widespread inflammation and tissue damage. Neutrophil extracellular traps (NETs), web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, play a crucial role in innate immunity by defending against pathogens. However, excessive NET formation and ineffective clearance of these structures contribute to the development of SLE. This review explores the mechanisms behind NET formation in SLE, their relationship with oxidative stress, and the potential role of antioxidants in treatment. Research indicates that SLE patients exhibit two key abnormalities: excessive NET formation and impaired NET clearance. Excessive NET formation is driven by proinflammatory low-density granulocytes (LDGs) and immune complexes (ICs). Impaired NET clearance stems from reduced DNase1/DNase1L3 activity or anti-nuclease autoantibodies. These two abnormalities lead to elevated circulating NETs. These NETs act as autoantigen reservoirs, forming pathogenic NET-ICs that amplify autoimmune responses. Oxidative stress drives NET formation by activating NADPH oxidase. In contrast, various antioxidants, including enzymatic and non-enzymatic types, can inhibit NET formation via scavenging reactive oxygen species (ROS) and blocking NADPH oxidase activation. Preclinical studies show that antioxidants such as curcumin, resveratrol, and mitochondrial-targeted MitoQ reduce NET formation and ameliorate lupus nephritis; clinical trials confirm that curcumin and N-acetylcysteine (NAC) lower SLE disease activity and reduce proteinuria, supporting their role as safe adjuvant therapies. However, high-dose vitamin E may exacerbate autoimmunity, highlighting the need for dose optimization. Future research should aim to clarify the mechanisms underlying NET formation in SLE and to optimize new antioxidant therapies, including assessments of their long-term efficacy and safety.},
}

@article {pmid41595622,
year = {2025},
author = {Dinç, M and Bayrak, HÇ and Karasu, R and Aykaç, B and Soydemir, ÖC and Saricetin, A},
title = {Intra-Articular N-Acetylcysteine Reduces Synovitis Without Preventing Cartilage Degeneration in Experimental Osteoarthritis.},
journal = {Biomedicines},
volume = {14},
number = {1},
pages = {},
pmid = {41595622},
issn = {2227-9059},
abstract = {Background/Objectives: Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by synovial inflammation, oxidative stress, and progressive cartilage degeneration. This study investigated whether intra-articular N-acetylcysteine (NAC) attenuates synovial inflammation and oxidative stress and whether these effects translate into structural cartilage protection. Methods: OA was induced in rats by anterior cruciate ligament transection (ACLT). NAC (5 mg/50 µL) was administered intra-articularly once weekly for three weeks post-ACLT. Inflammatory cytokines (IL-1β, IL-6, TNF-α), oxidative stress markers (iNOS, TAS, TOS, OSI), and cartilage degradation markers (MMP-13, COMP, CTX-II) were quantified in synovial fluid and cartilage homogenates using ELISA. Cartilage integrity was evaluated histologically using the modified Mankin scoring system. Results: Compared with controls, NAC significantly reduced synovial IL-1β, IL-6, TNF-α, MMP-13, and iNOS levels and improved the synovial redox profile by increasing TAS and reducing TOS and OSI (all p < 0.05). In contrast, NAC did not significantly alter cartilage homogenate levels of inflammatory cytokines, oxidative stress indices, or degradation markers (COMP, CTX-II, MMP-13). Histological analysis demonstrated persistent cartilage fissuring, hypocellularity, and proteoglycan loss in both groups (p > 0.05). Conclusions: Intra-articular NAC exerts potent anti-inflammatory and antioxidative effects within the synovial compartment but fails to prevent cartilage degeneration in the ACLT model. These findings indicate a compartment-specific therapeutic profile, suggesting that NAC may function as a symptom-modifying agent in synovitis-dominant OA rather than a structure-modifying therapy. Future studies should focus on optimized delivery systems or combination strategies targeting cartilage and subchondral bone to achieve disease modification.},
}

@article {pmid41593603,
year = {2026},
author = {Jiang, Y and Ma, P and Yang, Y and Shi, X and Liu, X and Sun, M},
title = {The Achilles' heel of hepatocellular carcinoma: ginsenoside compound K as a novel GPX4 degrader promotes ferroptosis in hepatocellular carcinoma.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {277},
pmid = {41593603},
issn = {1479-5876},
support = {20DZ2272200//Key Laboratory of Chronic Deficiency Liver Disease of the State Administration of Traditional Chinese Medicine of the People's Republic of China/ ; shslczdzk01201//Shanghai Key Specialty of Traditional Chinese Clinical Medicine/ ; zyyzdxk-2023060//National Administration of Traditional Chinese Medicine/ ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) remains a major therapeutic challenge, highlighting the need for agents that engage non-apoptotic regulated cell death pathways. Ginsenoside compound K (CK), a bioactive metabolite derived from ginseng saponins, has demonstrated antitumor activity, however, its efficacy and underlying mechanisms in HCC are not well defined. Given the emerging role of ferroptosis in HCC, we investigated whether CK suppresses HCC by inducing this iron-dependent form of cell death.

METHODS: The antitumor effects of CK were evaluated in HepG2 and Hep3B cells and in a xenograft mouse model. Ferroptotic cell death was assessed by measuring reactive oxygen species (ROS), ferrous iron (Fe²⁺), malondialdehyde (MDA), and glutathione (GSH) levels, and by rescue experiments using ferroptosis inhibitors (N-acetylcysteine, NAC; Trolox) or GPX4 overexpression. Mechanistic studies were performed using RNA sequencing, ubiquitination assays, and genetic manipulation of OTUB2 expression.

RESULTS: CK inhibited HCC cell proliferation in a dose-dependent manner and robustly induced ferroptosis hallmarks, including ROS accumulation, enhanced lipid peroxidation, and GSH depletion. These cytotoxic effects were largely abrogated by ferroptosis inhibitors or GPX4 overexpression, confirming a ferroptosis-dependent mechanism. In vivo, CK significantly reduced tumor growth in xenograft models and recapitulated key ferroptosis features. Mechanistically, CK was identified as a functional inhibitor of the deubiquitinase OTUB2. Suppression of OTUB2 promoted ubiquitin-dependent degradation of GPX4, a central negative regulator of ferroptosis, thereby sensitizing HCC cells to ferroptosis.

CONCLUSIONS: Our findings identify CK as a novel OTUB2 inhibitor that induces ferroptosis in HCC by destabilizing GPX4. This work delineates a previously unrecognized OTUB2/GPX4 regulatory axis in ferroptosis and supports CK as a promising candidate for further translational development for HCC therapy.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07587-9.},
}

@article {pmid41593161,
year = {2026},
author = {Ozhan, O and Ekici, C and Ates, B and Yildiz, A and Balcioglu, S and Vardi, N and Parlakpinar, H},
title = {N-acetyl cysteine amide mitigates oxidative stress and apoptosis in a rat model of renal ischemia-reperfusion injury.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {6323},
pmid = {41593161},
issn = {2045-2322},
support = {2209a//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
abstract = {Renal ischemia–reperfusion (IR) injury is a major cause of acute kidney injury, in which oxidative stress (OS) and apoptosis play central roles. N-acetyl cysteine amide (NACA), a lipophilic derivative of N-acetylcysteine, exhibits improved cellular penetration and antioxidant activity. This study investigated the renoprotective effects of NACA in a rat model of renal IR injury. Twenty-eight female Wistar albino rats were randomized into four groups (n = 7): Control, IR, NACA + IR (100 mg/kg i.p., 30 min before ischemia), and IR + NACA (100 mg/kg i.p., immediately after ischemia). Following right nephrectomy, the left renal pedicle was clamped for 60 min and reperfused for 24 h. Serum renal function markers, kidney OS parameters, histopathological injury, and caspase-3 immunoreactivity were evaluated. Renal IR injury significantly increased serum blood urea nitrogen and creatinine levels and induced histopathological damage characterized by tubular dilatation, cast formation, and degeneration. Catalase (CAT) and superoxide dismutase (SOD) activities were significantly altered; malondialdehyde increased after IR and was reduced by NACA pretreatment, whereas myeloperoxidase and total glutathione did not differ significantly among groups. NACA pretreatment attenuated inflammatory cell infiltration, tubular dilatation, and caspase-3 immunoreactivity, while partially restoring CAT and SOD activity. Post-ischemic NACA administration was less effective, particularly in reducing apoptosis and inflammatory infiltration. NACA confers partial renoprotection against renal IR injury, with pretreatment providing superior efficacy. These findings highlight the importance of antioxidant timing and suggest NACA as a potential prophylactic strategy when renal ischemia is predictable.},
}

@article {pmid41593024,
year = {2026},
author = {Chen, Z and Zhang, X and Li, J and Feng, C and Xiong, Y and Yan, L},
title = {Facile Synthesis of Thioketal-Functionalized Poly(amino acid) Nanocarriers for ROS-Triggered Drug Release in Cancer Therapy.},
journal = {ACS macro letters},
volume = {15},
number = {2},
pages = {259-266},
doi = {10.1021/acsmacrolett.5c00731},
pmid = {41593024},
issn = {2161-1653},
mesh = {*Reactive Oxygen Species/metabolism ; Animals ; *Doxorubicin/chemistry/pharmacology/administration & dosage/therapeutic use ; *Drug Carriers/chemistry/chemical synthesis ; Mice ; Drug Liberation ; Humans ; *Amino Acids/chemistry ; *Nanoparticles/chemistry ; *Polymers/chemistry/chemical synthesis ; Cell Line, Tumor ; *Antineoplastic Agents/chemistry ; Micelles ; Female ; Mice, Inbred BALB C ; Antibiotics, Antineoplastic/chemistry ; },
abstract = {Polymer nanocarriers offer significant advantages in antitumor drug delivery; however, achieving a balance between minimizing nonspecific drug release in blood circulation and maximizing specific intracellular drug release remains a critical challenge. To address this, this study developed a cross-linked poly(amino acid) nanocarrier sensitive to intracellular reactive oxygen species (ROS). A novel thioketal-functionalized, ROS-sensitive bicyclic amino acid N-carboxyanhydride (NCA) monomer was designed and synthesized, and ROS-responsive poly(amino acid)s were prepared via ring-opening polymerization. Polymeric nanomicelles loaded with doxorubicin (DOX) were successfully fabricated using a microemulsion method, and their ROS-responsive properties were systematically evaluated. In vitro release experiments demonstrated that the nanocarrier exhibited H2O2 concentration-dependent, ROS-triggered drug release characteristics. The oxidative response behavior of the drug-loaded nanomicelles was further validated in cellular and animal models by introducing the ROS scavenger N-acetylcysteine (NAC). In a 4T1 tumor-bearing mouse model, these drug-loaded nanomicelles showed enhanced tumor retention and superior tumor suppression compared to free DOX. This study demonstrates that thioketal-functionalized poly(amino acid) nanocarriers hold promise in balancing blood circulation stability and intracellular specific drug release, providing a novel design strategy for developing efficient and safe poly(amino acid)-based anticancer nanomedicines.},
}

*Reactive Oxygen Species/metabolism
Animals
*Doxorubicin/chemistry/pharmacology/administration & dosage/therapeutic use
*Drug Carriers/chemistry/chemical synthesis
Mice
Drug Liberation
Humans
*Amino Acids/chemistry
*Nanoparticles/chemistry
*Polymers/chemistry/chemical synthesis
Cell Line, Tumor
*Antineoplastic Agents/chemistry
Micelles
Female
Mice, Inbred BALB C
Antibiotics, Antineoplastic/chemistry

@article {pmid41586115,
year = {2025},
author = {Jafarzadeh, E and Pashaei-Asl, R and Hakimi, P and Pashaiasl, M},
title = {The Effect of Letrozole and N-Acetylcysteine on the Expression Levels of Genes Involved in Glucose Metabolism in Patients with Polycystic Ovary Syndrome: A Clinical Trial Study.},
journal = {Journal of reproduction & infertility},
volume = {26},
number = {2},
pages = {81-89},
pmid = {41586115},
issn = {2228-5482},
abstract = {BACKGROUND: N-acetylcysteine (NAC) is a supplement commonly used in patients with polycystic ovary syndrome (PCOS). The expansion of oocyte-associated cumulus cells (CCs) and the quality of the oocyte are critical factors influencing fertilization rates and clinical pregnancy outcomes in assisted reproductive techniques (ARTs). Genes such as phosphofructokinase (PFKP) and pyruvate kinase isoform M2 (PKM2) are involved in glucose metabolism and are crucial in the regulation of oocyte competence and developmental potential. The purpose of the current study was to evaluate the effects of letrozole and NAC on the expression of PFKP and PKM2 in CCs of PCOS patients undergoing ART.

METHODS: The study evaluated 20 PCOS women undergoing ART to assess the effect of letrozole and NAC on the expression levels of PKM2 and PFKP genes in cumulus cells. Women were randomly assigned using a simple randomization method into four groups: control, NAC, letrozole, and NAC plus letrozole, with five women in each group. Gene expression levels of PKM2 and PFKP were measured using real-time PCR.

RESULTS: The expression level of PKM2 was significantly higher in the letrozole plus NAC group compared to the control group (p<0.05). In NAC group, PFKP was significantly expressed compared to the control group (p<0.05). There were no significant differences among the other groups compared to the control group.

CONCLUSION: NAC can improve the quality of oocytes by increasing the expression level of genes involved in the glucose metabolism (PKM2, PFKP) of CCs, thereby potentially improving ART success rate in PCOS patients. Therefore, administering NAC along with letrozole can have a synergistic effect on increasing the expression level of genes associated with blastocyst quality in PCOS patients.},
}

@article {pmid41582130,
year = {2026},
author = {Li, C and Yuan, Y and Bao, Y and Ni, Y and Chen, N and Piao, J and Wang, L and Zhu, Z},
title = {Synergistic regulation of TGF-β1/Smad2/3 signaling and inflammatory pathways via SA/NAC-based nanoplatforms: a novel strategy to enhance anti-fibrotic therapeutic outcomes in idiopathic pulmonary fibrosis.},
journal = {Journal of nanobiotechnology},
volume = {24},
number = {1},
pages = {173},
pmid = {41582130},
issn = {1477-3155},
support = {LQ20H270014//National Natural Science Foundation of Zhejiang Province/ ; LY23H280010//Zhejiang Provincial Natural Science Foundation of China/ ; 2023JKZKTS23//Research Project of Zhejiang Chinese Medical University/ ; },
mesh = {Animals ; *Transforming Growth Factor beta1/metabolism ; *Idiopathic Pulmonary Fibrosis/drug therapy/metabolism ; Mice ; Signal Transduction/drug effects ; *Smad2 Protein/metabolism ; Smad3 Protein/metabolism ; *Acetylcysteine/pharmacology/chemistry ; Humans ; Mice, Inbred C57BL ; Inflammation/drug therapy/metabolism ; Macrophages/metabolism ; Male ; Disease Models, Animal ; Bleomycin ; Nanoparticles/chemistry ; Fibroblasts/drug effects ; RAW 264.7 Cells ; },
abstract = {Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by progressive fibrosis and poor prognosis, with no current therapies capable of reversing the fibrotic changes. The aberrant repair driven by fibroblast activation and an inflammatory microenvironment results in irreversible IPF. In this work, a macrophage-derived apoptotic body delivery system (SA + NAC@AB) co-loaded with sodium arsenite (SA) and N-acetylcysteine (NAC) was developed to exert synergistic antifibrotic activity against IPF via coordinated regulation of TGF-β1 signaling and inflammation. Apoptotic bodies derived from macrophages inherit inflammation-homing capability, enabling targeted delivery to fibrotic lesions. In vivo evaluation in a bleomycin-induced IPF mouse model demonstrated that SA + NAC@AB effectively targeted the lungs, significantly improved body weight and survival, and alleviated pulmonary fibrosis. Immunofluorescence and Western blot analyzes revealed that SA + NAC@AB reduced Smad2/3 phosphorylation and M2 macrophage polarization, indicating regulation of the TGF-β1/Smad2/3 pathway and inflammation as part of its mechanism of action. Furthermore, in vitro studies validated the enhanced efficacy of SA + NAC@AB, which significantly promoted fibroblast uptake, thereby potentiating its inhibitory effects on fibroblast viability, as well as TGF-β1-induced migration and differentiation. In conclusion, our study demonstrates that SA + NAC@AB represents an effective therapeutic strategy for IPF, offering a promising novel approach by modulating both the TGF-β1/Smad2/3 signaling pathway and the inflammatory response.},
}

Animals
*Transforming Growth Factor beta1/metabolism
*Idiopathic Pulmonary Fibrosis/drug therapy/metabolism
Mice
Signal Transduction/drug effects
*Smad2 Protein/metabolism
Smad3 Protein/metabolism
*Acetylcysteine/pharmacology/chemistry
Humans
Mice, Inbred C57BL
Inflammation/drug therapy/metabolism
Macrophages/metabolism
Male
Disease Models, Animal
Bleomycin
Nanoparticles/chemistry
Fibroblasts/drug effects
RAW 264.7 Cells

@article {pmid41579736,
year = {2026},
author = {Mah, E and Gallagher, D and Gao, F and Ramirez, J and Rabin, JS and Survilla, K and Vieira, D and Chen, JJ and Kang, Y and Andreazza, A and Herrmann, N and Kiss, A and Marzolini, S and Oh, P and Swardfager, W and Black, SE and Lanctôt, KL},
title = {Frontal white matter hyperintensity burden predicts cognitive response to N-acetylcysteine and exercise in vascular mild cognitive impairment.},
journal = {Neurobiology of aging},
volume = {161},
number = {},
pages = {39-46},
doi = {10.1016/j.neurobiolaging.2026.01.005},
pmid = {41579736},
issn = {1558-1497},
mesh = {Humans ; *Cognitive Dysfunction/therapy/pathology/psychology/diagnostic imaging/etiology ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; Aged ; *Acetylcysteine/therapeutic use/administration & dosage ; *Cognition/drug effects ; Magnetic Resonance Imaging ; Executive Function ; *Exercise Therapy ; Treatment Outcome ; Middle Aged ; Aged, 80 and over ; *Frontal Lobe/pathology/diagnostic imaging ; },
abstract = {Vascular mild cognitive impairment (vaMCI) is a prodromal stage of dementia defined by cognitive deficits due to cerebrovascular disease. Increased white matter hyperintensity (WMH) volume has been associated with reduced executive function (EF). We explored whether lower baseline frontal and global WMH volume predicted an improvement in EF in vaMCI participants treated with N-acetylcysteine (NAC) and exercise as compared to placebo and exercise. Fifty-eight individuals with vaMCI received exercise therapy and were randomized to NAC or placebo. EF was assessed using the Trail Making Test Part B (TMT-B), Digit Symbol-Coding Test (DSCT), and a test of phonemic fluency, at baseline, 3 months, and 6 months. WMH volumes were measured from baseline magnetic resonance imaging scans. Linear mixed models were used. All participants improved on TMT-B (β = -0.185, SE = 0.046, p < 0.001) and phonemic fluency (β = 4.440, SE = 0.911, p < 0.001) over 6 months. A significant three-way interaction between baseline frontal WMH volume, treatment group, and timepoint predicted TMT-B performance at 3 months (β = 0.160, SE = 0.076, p = 0.039), but not at 6 months. No significant interactions were found for DSCT or phonemic fluency. Global WMH did not predict treatment response. Participants demonstrated improvement in EF regardless of treatment group and WMH volume. Lower frontal WMH volume predicted a greater improvement in TMT-B performance at 3 months in those treated with NAC versus placebo. These findings underscore the importance of considering participant heterogeneity in trials for vaMCI.},
}

Humans
*Cognitive Dysfunction/therapy/pathology/psychology/diagnostic imaging/etiology
*White Matter/pathology/diagnostic imaging
Male
Female
Aged
*Acetylcysteine/therapeutic use/administration & dosage
*Cognition/drug effects
Magnetic Resonance Imaging
Executive Function
*Exercise Therapy
Treatment Outcome
Middle Aged
Aged, 80 and over
*Frontal Lobe/pathology/diagnostic imaging

@article {pmid41579706,
year = {2026},
author = {Madhavan, A and Schiano-Visconte, M and Dutton, L and Cantalupo, M and Balasco, L and Mavillonio, A and Chelini, G and Bozzi, Y and Pangrazzi, L},
title = {Astaxanthin improves behavioural and immune dysfunction in the Shank3b mouse model of autism spectrum disorder.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119051},
doi = {10.1016/j.biopha.2026.119051},
pmid = {41579706},
issn = {1950-6007},
mesh = {Animals ; *Autism Spectrum Disorder/drug therapy/immunology/psychology/genetics/metabolism ; *Nerve Tissue Proteins/genetics ; Disease Models, Animal ; Mice ; *Behavior, Animal/drug effects ; Mice, Knockout ; Cytokines/metabolism ; Male ; Oxidative Stress/drug effects ; Xanthophylls/pharmacology/therapeutic use ; *Antioxidants/pharmacology ; Mice, Inbred C57BL ; *Anti-Inflammatory Agents/pharmacology ; Social Interaction/drug effects ; Microfilament Proteins ; },
abstract = {Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviours. Numerous studies have associated ASD with immune dysregulation and inflammation, with neuroinflammatory processes reported in ASD individuals and mouse models. Altered immune cell profiles and cytokine levels have been observed in the peripheral blood (PB), supporting systemic immune dysfunction. Recently we showed that the administration of antioxidant molecule N-acetylcysteine (NAC) reduced oxidative stress and inflammation and counteracted behavioural deficits in two mouse models of ASD, providing a rationale for exploring other redox-active compounds. Here, we investigated the effects of astaxanthin (AST), potent antioxidant and anti-inflammatory molecule, in the Shank3b model (Shank3b[-/-] mice). AST treatment significantly improved core ASD-like behaviours, including social interaction deficits, motor incoordination, and repetitive grooming. In the cerebellum, AST reduced pro-inflammatory cytokines and counteracted microglial hyperactivation. In peripheral immune compartments, AST modulated cytokine expression. Pro-inflammatory markers were downregulated in Shank3b[-/-] mice in the bone marrow and spleen while they were elevated in Shank3b controls, suggesting immune rebalancing (i.e. adaptive modulation suppressing harmful inflammation while supporting protective immunity). As a limitation, oxidative stress assays were not performed here. Receiver operating characteristic (ROC) analysis suggests that TNF and IFNγ expression in peripheral immune cells may be promising biomarkers of treatment response. Notably, unlike NAC, AST did not induce pro-inflammatory effects in Shank3b[+/+] animals. These findings show that AST administration may counteract behavioural deficits and immune dysfunction in Shank3b[-/-] mice, therefore suggesting its potential as a safe immunomodulatory therapy for ASD.},
}

Animals
*Autism Spectrum Disorder/drug therapy/immunology/psychology/genetics/metabolism
*Nerve Tissue Proteins/genetics
Disease Models, Animal
Mice
*Behavior, Animal/drug effects
Mice, Knockout
Cytokines/metabolism
Male
Oxidative Stress/drug effects
Xanthophylls/pharmacology/therapeutic use
*Antioxidants/pharmacology
Mice, Inbred C57BL
*Anti-Inflammatory Agents/pharmacology
Social Interaction/drug effects
Microfilament Proteins

@article {pmid41577060,
year = {2026},
author = {Abdeltawab, M and Ebid, AH and Ahmed, O and Mobarez, MA and Ibrahim, M},
title = {N-acetylcysteine reduces incidence and duration of linezolid-associated thrombocytopenia in critically ill patients: A randomized controlled trial.},
journal = {Environmental toxicology and pharmacology},
volume = {122},
number = {},
pages = {104944},
doi = {10.1016/j.etap.2026.104944},
pmid = {41577060},
issn = {1872-7077},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration & dosage ; *Thrombocytopenia/chemically induced/prevention & control/epidemiology/drug therapy ; Male ; Critical Illness ; Middle Aged ; Female ; *Linezolid/adverse effects ; Aged ; Double-Blind Method ; Incidence ; Adult ; *Anti-Bacterial Agents/adverse effects ; Aged, 80 and over ; },
abstract = {Linezolid-associated thrombocytopenia (LAT) limits its use in critically ill patients. This double-blind, randomized, placebo-controlled trial evaluated intravenous N-acetylcysteine (IV NAC) for LAT prevention in 250 critically ill adults receiving linezolid for ≥ 48 h. Patients received IV NAC (600 mg every 12 h) or placebo. The primary endpoint was LAT incidence (platelet count <150 × 10 [3]/mm[3] or >50 % reduction from baseline). NAC significantly reduced LAT incidence (16.8 % vs. 41.6 %; p < 0.001), platelet transfusions (1.6 % vs. 11.2 %; p = 0.003), and linezolid discontinuations (6.4 % vs. 32.0 %; p < 0.001). NAC delayed LAT onset (adjusted hazard ratio 0.24; p < 0.001) and accelerated platelet recovery (adjusted hazard ratio 3.88; p = 0.011), with greatest benefit in moderate-severity cases. These findings suggest IV NAC may offer a preventive benefit against LAT in critically ill patients, though multicenter validation is needed to confirm generalizability across diverse clinical settings. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05944458. Registered on July 6, 2023.},
}

Humans
*Acetylcysteine/therapeutic use/administration & dosage
*Thrombocytopenia/chemically induced/prevention & control/epidemiology/drug therapy
Male
Critical Illness
Middle Aged
Female
*Linezolid/adverse effects
Aged
Double-Blind Method
Incidence
Adult
*Anti-Bacterial Agents/adverse effects
Aged, 80 and over

@article {pmid41575655,
year = {2026},
author = {Li, B and Liu, P and Yang, X and Li, M and Lei, L and Meng, Z and Song, Y and Lan, J and Ouyang, C and Ma, J and Liu, Q},
title = {NAC and DNase I synergistically reduce NETs to attenuate severe acute pancreatitis via suppressing the NETs/NF-κB/CXCL3 pathway.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {2},
pages = {58},
pmid = {41575655},
issn = {1573-675X},
mesh = {*Deoxyribonuclease I/pharmacology/therapeutic use ; *Extracellular Traps/drug effects/metabolism ; *NF-kappa B/metabolism/genetics ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Pancreatitis/drug therapy/metabolism/pathology ; Mice ; Signal Transduction/drug effects ; Male ; Humans ; Neutrophils/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Neutrophil extracellular traps (NETs) drive severe acute pancreatitis (SAP) progression by promoting pancreatic injury, duct obstruction, and systemic inflammation. Reactive oxygen species (ROS) are critical for NETs formation, while NETs degradation remains therapeutically challenging. This study investigates whether combined N-acetylcysteine (NAC) and deoxyribonuclease I (DNase I) therapy mitigates SAP and associated lung injury by suppressing NETs formation and degradation, respectively, and explores the underlying molecular mechanisms. NETs were elevated in SAP pancreatic tissue. In vitro, NAC reduced NETs formation by inhibiting oxidative stress, while DNase I degraded preformed NETs. Combined therapy surpassed monotherapy efficacy, synergistically attenuating NETs burden. In vivo, Early dual intervention degraded NETs, reduced neutrophil infiltration and apoptosis, and lowered inflammatory cytokines, thereby alleviating pancreatitis and lung injury. Mechanistically, dual therapy suppressed NF-κB activation in pancreatic tissue, decreasing CXCL3 release and subsequent CXCR2-positive neutrophil recruitment, ultimately ameliorating SAP. NAC and DNase I synergistically target NETs generation and clearance, offering a promising redox-based therapeutic strategy for SAP.},
}

*Deoxyribonuclease I/pharmacology/therapeutic use
*Extracellular Traps/drug effects/metabolism
*NF-kappa B/metabolism/genetics
Animals
*Acetylcysteine/pharmacology/therapeutic use
*Pancreatitis/drug therapy/metabolism/pathology
Mice
Signal Transduction/drug effects
Male
Humans
Neutrophils/drug effects/metabolism
Reactive Oxygen Species/metabolism
Mice, Inbred C57BL
Apoptosis/drug effects
Oxidative Stress/drug effects

@article {pmid41574386,
year = {2026},
author = {Yadav, N and Singh, R and Mondal, SK and Mandal, AK},
title = {Molecular insights of p-benzoquinone-induced red blood cell dysfunction: probable implications to cigarette smoke-associated pathologies.},
journal = {Free radical research},
volume = {60},
number = {1},
pages = {67-90},
doi = {10.1080/10715762.2026.2620638},
pmid = {41574386},
issn = {1029-2470},
mesh = {Humans ; *Erythrocytes/drug effects/metabolism/pathology ; *Benzoquinones/adverse effects/toxicity ; Oxidation-Reduction ; *Cigarette Smoking/adverse effects ; },
abstract = {Cigarette smoke (CS) is a complex mixture of numerous chemicals, including p-benzosemiquinone (pBSQ), which oxidizes to p-benzoquinone (pBQ) in the lungs of smokers and enters circulation. Despite its high reactivity, the direct impact of pBQ on human red blood cells (RBC) remains underexplored. Herein, we investigated the molecular insights into how pBQ compromises human RBC physiology and its role in mediating CS-associated pathologies by integrating redox biochemistry, membrane integrity, and omics-based approaches. Our findings reveal that pBQ disrupted redox homeostasis, evidenced by glutathione depletion, elevated reactive oxygen species, lipid peroxidation, and reduced antioxidant enzyme activity. pBQ also triggered methemoglobin formation, hemoglobin aggregation, and reduced oxygen-binding capacity. Biophysical analysis of RBCs revealed reduced membrane fluidity, alterations in membrane proteins and lipids, disrupted zeta potential, and sedimentation dynamics, suggesting altered deformability, an indication of impaired microvascular transit. Untargeted metabolomics and lipidomics profiling revealed metabolic reprogramming and remodeling of the membrane lipids. Depletion of polyunsaturated fatty acids alongside accumulation of saturated species in the membrane points toward membrane stiffening. Pathway analysis highlighted perturbations in fatty acid biosynthesis and redox homeostasis. Disease enrichment analysis linked these changes to hypertension and other pathologies that are previously linked to redox imbalance and CS exposure. Notably, NAC co-treatment mitigated these effects, preserving RBC integrity and redox homeostasis. These findings underscore that pBQ is a critical mediator of CS-induced RBC dysfunction and establish a mechanistic link to its contribution to smoking-associated complications.},
}

Humans
*Erythrocytes/drug effects/metabolism/pathology
*Benzoquinones/adverse effects/toxicity
Oxidation-Reduction
*Cigarette Smoking/adverse effects

@article {pmid41563857,
year = {2026},
author = {Race, NS and Uchida, K and Burcham, PC and Shi, R},
title = {Multimodal Toxicity of Acrolein and Associated Therapeutic Strategies in Central Nervous System Trauma and Disease.},
journal = {Annual review of biomedical engineering},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-bioeng-103023-035352},
pmid = {41563857},
issn = {1545-4274},
abstract = {Acrolein is a highly reactive α,β-unsaturated aldehyde produced endogenously through lipid peroxidation and enzymatic metabolism and exogenously via environmental exposures. Acrolein covalently adducts to DNA and proteins, leading to oxidative stress, mitochondrial dysfunction, and inflammation, including innate immune response activation via natural antibodies. Acrolein is difficult to measure in biological systems, but acrolein-bound covalent products can be measured reliably. Therapeutically, nucleophilic small molecules that scavenge acrolein such as hydralazine, phenelzine, dimercaprol, carnosine, and N-acetylcysteine (NAC) have shown neuroprotective effects in animal models of multiple sclerosis, Parkinson's disease, spinal cord injury, and traumatic brain injury. These effects include preserved membrane and mitochondrial integrity, reduced inflammation, reduced pain, and improved motor, sensory, and cognitive outcomes. Alternative strategies that enhance clearance or inhibit production of acrolein show promise but face limitations. Acrolein is a key pathophysiological mediator and a viable therapeutic target in central nervous system trauma and neurodegenerative diseases.},
}