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

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

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

SETTING: University teaching hospital.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CLINICALTRIALS: gov identifier: NCT06105060.},
}

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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