@article {pmid41184618,
year = {2025},
author = {Zhang, YM and Lu, H and Xiao, BJ and Xu, CC and Zhou, FF and Li, T and Zhan, ZJ and Lu, JJ},
title = {Sino-C, a novel sinomenine derivative, induces cell death by disrupting cholesterol homeostasis in colorectal cancer cells.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41184618},
issn = {1745-7254},
abstract = {Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, necessitating the discovery of novel therapeutic agents. Sinomenine (Sin), a natural product derived from traditional Chinese medicine, has been extensively modified to enhance its therapeutic potential. Here, we synthesized Sino-C, a novel Sin derivative, and evaluated its anti-CRC activity. Sino-C exhibited significant anticancer effects both in vitro and in vivo. Mechanistically, Sino-C upregulated cholesterol homeostasis-related genes and increased intracellular cholesterol levels in CRC cells. Cholesterol depletion with methyl-β-cyclodextrin (MβCD) alleviated Sino-C-induced cholesterol accumulation, reduced cell death, and reversed cleaved PARP expression, indicating cholesterol imbalance as a critical mediator of Sino-C's activity. Furthermore, Sino-C-induced cholesterol imbalance promoted lipid peroxidation and endoplasmic reticulum (ER) stress, contributing to cell death. The antioxidant vitamin E (Ve), N-acetylcysteine (NAC), or PERK inhibitor GSK2656157 could reverse these effects of Sino-C. Clinical correlation analysis further revealed that high expression of Sino-C-upregulated cholesterol homeostasis genes was linked to better survival outcomes in CRC cohorts. In conclusion, this study highlights the therapeutic potential of Sino-C in CRC. In vitro mechanistic findings suggest that Sino-C exerts its anticancer effects through modulation of cholesterol metabolism, positioning natural product derivatives as valuable candidates for further development.},
}

@article {pmid41184380,
year = {2025},
author = {Kim, JE and Wang, SH and Kang, TC},
title = {PARP1-TRPM2-PKC cascade distinctly regulates reactive astrogliosis and clasmatodendrosis through NF-κB and AKT pathways in the hippocampus of chronic epilepsy rats.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38371},
pmid = {41184380},
issn = {2045-2322},
support = {HRFN-202410-002//Hallym University/ ; },
mesh = {Animals ; *TRPM Cation Channels/metabolism/genetics ; Rats ; *Hippocampus/metabolism/pathology ; *Proto-Oncogene Proteins c-akt/metabolism ; *NF-kappa B/metabolism ; *Poly (ADP-Ribose) Polymerase-1/metabolism ; Signal Transduction ; *Epilepsy/metabolism/pathology ; Astrocytes/metabolism/pathology ; *Gliosis/metabolism/pathology ; Male ; Rats, Sprague-Dawley ; Chronic Disease ; Disease Models, Animal ; },
abstract = {The epileptic hippocampi of rodent models show reactive astrogliosis and autophagic astroglial death (clasmatodendrosis) in the CA1 region, which contributes to spontaneous seizures. Oxidative stress upregulates transient receptor potential melastatin 2 (TRPM2, a non-selective Ca[2+] permeable cation channel) in astrocytes. However, the roles of TRPM2 in reactive astrogliosis and clasmatodendrosis in the epileptic hippocampus are largely unknown. In the present study, we found that TRPM2 was upregulated in astrocytes within the CA1 region of chronic epilepsy rats. N-acetylcysteine (NAC, an antioxidant) and PJ34, a poly-(ADP-ribose) polymerase-1 (PARP1) inhibitor, downregulated TRPM2 expression in reactive astrocytes and attenuated clasmatodendritic degeneration in this region, accompanied by reduced nuclear factor-κB (NF-κB) p65 serine (S) 311 phosphorylation. Both NAC and PJ34 increased pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1, a phosphatase for AKT) expression concomitant with reduced AKT S473 phosphorylation and microtubule-associated protein 1 A/1B-light chain 3 (LC3)-II/LC-I ratio. However, TRPM2 knockdown deteriorated clasmatodendritic degeneration and elevated AKT S473 phosphorylation and LC3-II/LC-I ratio without altering PHLPP1 expression. Bisindolylmaleimide (BIM, a protein kinase C inhibitor) exacerbated clasmatodendrosis accompanied by reduced p65 S311 phosphorylation and elevated AKT S473 phosphorylation in reactive astrocytes without affecting TRPM2 expression. Therefore, our findings suggest that PARP1-TRPM2-PKC-NF-κB signaling pathway may inhibit clasmatodendrosis, but facilitate reactive astrogliosis. In addition, NAC and PJ34 may attenuate clasmatodendrosis by activating PHLPP1-AKT-mediated pathway.},
}

Animals
*TRPM Cation Channels/metabolism/genetics
Rats
*Hippocampus/metabolism/pathology
*Proto-Oncogene Proteins c-akt/metabolism
*NF-kappa B/metabolism
*Poly (ADP-Ribose) Polymerase-1/metabolism
Signal Transduction
*Epilepsy/metabolism/pathology
Astrocytes/metabolism/pathology
*Gliosis/metabolism/pathology
Male
Rats, Sprague-Dawley
Chronic Disease
Disease Models, Animal

@article {pmid41181138,
year = {2025},
author = {Kang, LP and Xie, H and Huang, HJ and Xu, P and Xu, C and Huang, DH and Jiang, ZB},
title = {Pterostilbene inhibits non-small cell lung cancer progression by activating the STING pathway and enhancing antitumor immune response.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1622284},
pmid = {41181138},
issn = {1664-3224},
mesh = {Animals ; *Carcinoma, Non-Small-Cell Lung/drug therapy/immunology/pathology/metabolism ; Humans ; *Lung Neoplasms/drug therapy/immunology/pathology/metabolism ; Mice ; Signal Transduction/drug effects ; *Membrane Proteins/metabolism ; *Stilbenes/pharmacology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Tumor Microenvironment/drug effects/immunology ; Xenograft Model Antitumor Assays ; Cell Survival/drug effects ; *Antineoplastic Agents/pharmacology ; Disease Progression ; A549 Cells ; },
abstract = {INTRODUCTION: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, and current therapies often yield limited efficacy. This study investigated the antitumor potential and mechanisms of Pterostilbene (PTE), a natural stilbenoid with superior bioavailability.

METHODS: The antitumor effects of PTE were assessed in A549 and H358 NSCLC cell lines to determine its impact on cell viability, cell cycle, apoptosis, and reactive oxygen species (ROS) generation, using N-acetylcysteine (NAC) to confirm the role of ROS. Key molecular mechanisms were probed via Western blot, siRNA knockdown, and pharmacological inhibition (H-151). The in vivo efficacy of PTE and its effect on the tumor immune microenvironment were evaluated in H358 xenograft and immunocompetent LLC1 murine models.

RESULTS: PTE suppressed cell viability in a concentration- and time-dependent manner, inducing G2/M phase arrest and mitochondrial apoptosis driven by ROS. It triggered DNA damage and activated the STING pathway, leading to TBK1/IRF3 phosphorylation and the secretion of T-cell chemoattractants (CXCL10, CXCL9, CCL5). STING inhibition markedly attenuated PTE's effects. In vivo, PTE suppressed tumor growth and remodeled the tumor microenvironment by increasing granzyme B[+], TNF-α[+], and IFN-γ[+] CD8[+] T cells while reducing myeloid-derived suppressor cells and regulatory T cells.

DISCUSSION: Our findings elucidate a dual mechanism whereby PTE directly kills NSCLC cells via ROS-mediated apoptosis and simultaneously reinvigorates antitumor immunity through STING pathway activation. This positions PTE as a promising candidate for combination immunotherapy in NSCLC.},
}

Animals
*Carcinoma, Non-Small-Cell Lung/drug therapy/immunology/pathology/metabolism
Humans
*Lung Neoplasms/drug therapy/immunology/pathology/metabolism
Mice
Signal Transduction/drug effects
*Membrane Proteins/metabolism
*Stilbenes/pharmacology
Cell Line, Tumor
Reactive Oxygen Species/metabolism
Apoptosis/drug effects
Tumor Microenvironment/drug effects/immunology
Xenograft Model Antitumor Assays
Cell Survival/drug effects
*Antineoplastic Agents/pharmacology
Disease Progression
A549 Cells

@article {pmid41178763,
year = {2025},
author = {Koprowska, K and Fischer-Durand, N and Michlewska, S and Gapińska, M and Grodzicka, M and Makal, A and Krzeszczakowska, J and Wrona-Piotrowicz, A and Lignières, L and Salmain, M and Rudolf, B},
title = {Metallocarbonyl bromomaleimide derivatives for thiol bioconjugation and disulfide bridging: spectroscopic and biological properties.},
journal = {Dalton transactions (Cambridge, England : 2003)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5dt02375k},
pmid = {41178763},
issn = {1477-9234},
abstract = {Mono- and dibromomaleimides have been introduced as useful reagents for the modification of cysteine residues, disulfide rebridging and peptide stapling. Herein, we investigate the reaction of the organometallic compounds CpFe(CO)2(η[1]-2-bromomaleimidato) and CpFe(CO)2(η[1]-2,3-dibromomaleimidato) and their organic analogs 2-bromomaleimide and 2,3-dibromomaleimide with the bioactive thiols N-acetyl cysteine methyl ester and 1-thio-β-D-glucose tetraacetate, along with the disulfide-containing protein bovine insulin. Substitution and/or addition products were isolated and characterized by NMR, IR and MS and the molecular structure of two reaction products was confirmed by X-ray diffraction. In the case of the organic derivatives, formation of the dithiomaleimide adducts was also assessed by the emission of fluorescence in the green region. Visible light irradiation of the metallocarbonyl dithiomaleimides resulted in the decomposition of the organometallic fragment and generation of fluorescent products. This feature greatly helped to delineate the transformations operated by the metallocarbonyl compounds within cancer cells and provided clues to their molecular mechanism of action.},
}

@article {pmid41174747,
year = {2025},
author = {Sharma, AR and Chatterjee, S and Lee, YH and Sharma, G and Kim, JG and Kim, JC and Lee, SS},
title = {Nano-size tantalum particles suppress the osteogenic activity of osteoblasts and stimulate osteoclasts.},
journal = {Journal of biological engineering},
volume = {19},
number = {1},
pages = {95},
pmid = {41174747},
issn = {1754-1611},
support = {NRF-2020R1C1C1008694//National Research Foundation of Korea/ ; NRF-2020R1I1A3074575//National Research Foundation of Korea/ ; 2022RIS-005//Ministry of Education/ ; },
abstract = {BACKGROUND: Tantalum (Ta) and its derivatives are inert, possess mechanical qualities such as corrosion resistance, and are biocompatible. They also offer structural support during surgical correction, such as bone grafts during surgery, in instances of dental or skeletal disabilities. However, various sizes of Ta particles could be expelled from the implant's surface due to mechanical stress and load-induced wear caused by micromotion between loose implant surfaces during usage. Therefore, the study examined the effects of nano (25 nm) and micro-sized Ta particles (10 μm and 40-50 μm) on osteoblasts and osteoclasts.

RESULTS: Osteoblasts efficiently phagocytosed 25 nm sized Ta particles compared to micro-sized particles and triggered significant biological effects. Only 25 nm Ta particles suppressed ALP activity, downregulated osteogenic regulators and markers, and inhibited collagen synthesis and mineralization. Moreover, 25 nm sized Ta particles induced inflammatory responses in osteoblasts by increasing Cox-2 expression and activating the NFkB signaling pathway. Nano-sized Ta particles induced intracellular ROS generation in osteoblasts and osteoclasts. Compared to micro-sized Ta particles, 25 nm sized Ta particles stimulated osteoclast formation, but ROS scavenging by N-acetyl cysteine (NAC) inhibited Ta particle-mediated osteoclastogenesis. Likewise, ALP activity of osteoblasts was partially restored after NAC treatment. 25 nm Ta particles suppressed Axin-2 reporter activity and protein levels of pGSK3β and β-catenin stability, implicating suppressed WNT signaling in treated osteoblasts. Expression levels of several families of antagonists like DKK, sFRP, and SOST of the WNT signaling pathway were found elevated several-fold in 25 nm-sized Ta particles treated osteoblasts, explaining suppressed WNT signaling pathway in exposed osteoblasts.

CONCLUSION: Ta supports osseointegration and biocompatibility, but micromotion-induced nanoscale wear particles may disrupt osteoprogenitor function and enhance osteoclast activity, risking implant loosening. Thus, vigilant post-operative monitoring for nano-sized Ta particles is advisable and critical in detecting early osteolysis and ensuring implant longevity.},
}

@article {pmid41172065,
year = {2025},
author = {Piazza, FRG and Schuch, JB and Ferreira, DNSDS and Gabiatti, MP and Kessler, FHP and von Diemen, L and Hansen, F},
title = {Serum 25-Hydroxyvitamin D Levels did not improve with N-Acetylcysteine administration nor with abstinence in Adults Treated for Alcohol Use Disorder: A Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.},
journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)},
volume = {},
number = {},
pages = {},
doi = {10.47626/1516-4446-2025-4304},
pmid = {41172065},
issn = {1809-452X},
support = {08129.011787/2015-95/Senad/Secretaria Nacional de Políticas Sobre Drogas/Brazil ; 2015-0488/FIPE/HCPA/Fundo de Incentivo à Pesquisa e Eventos/Hospital de Clínicas de Porto Alegre/Brazil ; 001/Capes/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/Brazil ; },
abstract = {OBJECTIVE: N-acetylcysteine (NAC) is a medication known for its hepatoprotective properties and potential to reduce cravings and psychoactive substance use. Vitamin D is metabolized in the liver, and individuals with alcohol abuse often have lower levels. This study aims to evaluate the effect of NAC administration on vitamin D levels (25(OH)D) in adults with alcohol use disorder (AUD) undergoing treatment.

METHODS: This is a secondary analysis of a randomized, double-blind, placebo-controlled study with 47 male AUD patients who received either NAC (600mg twice daily, n=22) or placebo (n=25) for eight weeks. Blood samples were analyzed to assess 25(OH)D, liver and renal functions, and glutathione metabolism. The effects of time, intervention, and their interaction on 25(OH)D were evaluated using Generalized Estimating Equations.

RESULTS: At hospitalization, 45.0% of patients had 25(OH)D deficiency and 21.7% insufficiency. After eight weeks, 43.3% of patients had deficiency, and 40.0% had insufficiency. Intervention (NAC vs. placebo) (p = 0.130), study time (p = 0.429), and their interaction (p = 0.834) showed no significant effect on 25(OH)D levels.

CONCLUSION: There is a high prevalence of 25(OH)D deficiency and insufficiency in AUD patients. 25(OH)D levels did not improve spontaneously with abstinence, and NAC intervention did not significantly affect 25(OH)D concentrations.},
}

@article {pmid41168006,
year = {2025},
author = {Wang, D and Zhou, S and Tang, Y and Liang, Z and Yu, X and Huang, G and Huang, C and Wang, S and Liu, H},
title = {S-nitrosylation of paired-related homeobox 1 promotes cardiac remodeling following myocardial infarction.},
journal = {Redox biology},
volume = {},
number = {},
pages = {103887},
doi = {10.1016/j.redox.2025.103887},
pmid = {41168006},
issn = {2213-2317},
abstract = {BACKGROUNDS: Cardiac remodeling, mediated by fibroblast-to-myofibroblast differentiation, is a key pathophysiologic step to determine the prognosis of patients following myocardial infarction (MI). Paired-related homeobox 1 (Prrx1) is a master transcription factor of fibroblasts for myofibroblastic lineage progression. Protein S-nitrosylation by nitric oxide (NO) is highly related to regulate cellular functions. This study is to investigate whether and how Prrx1 S-nitrosylation plays a key role in postischemic remodeling of heart.

METHODS: The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac fibrosis was assessed using Masson staining. Heart function was measured by echocardiography.

RESULTS: MI induced cardiac remodeling as cardiac fibrosis and heart dysfunction in mice, accompanied with increased Prrx1 transcriptional activity, but inhibited by N-acetyl-cysteine administration. In recombinant human protein, NO donors increased Prrx1 S-nitrosylation at cysteine 207 (C207). In human cardiac fibroblasts, oxygen-glucose deprivation or transforming growth factor beta upregulated NO productions, Prrx1 S-nitrosylation, Prrx1 transcriptional activity, Wnt5a gene expression, and fibroblast-to-myofibroblast differentiation, which were abolished by Prrx1-C207R mutant. In vivo, exogenous expression of Prrx1-C209R alleviated MI-induced cardiac fibrosis and promoted the recovery of heart functions in mice. Fibroblast-specific Prrx1 gene knockout prevented cardiac fibrosis and heart dysfunctions in mice fowling MI. In human patients with post-MI, Prrx1 S-nitrosylation was increased.

CONCLUSION: Upregulation of Prrx1 by S-nitrosylation increases Wnt5a gene expression to induce fibroblast-to-myofibroblast differentiation, which contributes to cardiac remodeling after MI. In perspective, targeting Prrx1 S-nitrosylation should be considered to improve the outcome of patients with MI.},
}

@article {pmid41158731,
year = {2025},
author = {Solga, I and Şahin, A and Yogathasan, V and Hofer, L and Celik, FG and El Rai, A and Hosen, MR and Wischmann, P and Becher, S and Polzin, A and Gerdes, N and Jung, C and Kelm, M and Chennupati, R},
title = {Acute blood loss anemia aggravates endothelial dysfunction after acute myocardial infarction.},
journal = {Frontiers in cardiovascular medicine},
volume = {12},
number = {},
pages = {1635293},
pmid = {41158731},
issn = {2297-055X},
abstract = {BACKGROUND: Anemia is frequently observed in patients with acute myocardial infarction (AMI) and is known to be associated with poor prognosis. We recently demonstrated that acute blood loss anemia is associated with a compensatory increase in endothelial nitric oxide (NO)-dependent flow-mediated dilation (FMD) responses. However, the effects of acute anemia on systemic endothelial function after AMI remain unclear. In this study, we evaluated systemic endothelial function following AMI in an established murine model of acute blood loss anemia. We hypothesize that acute anemia aggravates systemic endothelial dysfunction (ED) after AMI.

METHODS AND RESULTS: Acute anemia was induced in male C57BL/6J mice by repeated blood withdrawal for three consecutive days. Separate groups of anemic and non-anemic mice underwent AMI via left anterior descending artery (LAD) ligation (45 min), followed by reperfusion. Endothelial function was assessed using both in vivo and in vitro methods 24 h post-AMI. Impaired FMD (in vivo) and endothelium-dependent relaxation (EDR) responses were observed in the aorta, femoral, and saphenous arteries of AA mice compared to their respective control groups 24 h post-AMI. Analysis of oxidative products of NO in plasma revealed reduced nitrite and nitrate levels in acute anemia compared to controls 24 h post-AMI. Immunohistochemistry of aortic tissues from both anemic groups showed increased reactive oxygen species (ROS) product 4-Hydroxynonenal (4-HNE). Co-incubation of RBCs from anemic mice or anemic acute coronary syndrome (ACS) patients with aortic rings from wild-type mice demonstrated attenuated EDR responses. Supplementation with the ROS scavenger N-acetyl cysteine (NAC) for four weeks improved both in vivo and ex vivo EDR in acute anemic mice 24 h post-AMI.

CONCLUSION: After AMI, acute anemia is associated with ROS-mediated severe endothelial dysfunction, which is partly mediated by RBCs. Antioxidant supplementation with NAC is a potential therapeutic option to reverse the severe ED in anemia following AMI.},
}

@article {pmid41156848,
year = {2025},
author = {Huang, J and Di, Y and Song, Q and Cheng, Z and Wu, H and Wu, M and He, M and Zhang, G and Wang, F and Tong, L},
title = {ROS-Mediated Necroptosis Promotes Coxsackievirus B3 Replication and Myocardial Injury.},
journal = {Microorganisms},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/microorganisms13102389},
pmid = {41156848},
issn = {2076-2607},
support = {2022J01311//Natural Science Foundation of Fujian Province/ ; 81860354//National Natural Science Foundation of China/ ; 605-50Y18058//High-Level Talent Innovation and Entrepreneurship Program of Huaqiao University/ ; 2024QZC002YR//QuanZhou High Level Talent Innovation and Entrepreneurship Project/ ; },
abstract = {Coxsackievirus B3 (CVB3) is a primary causative agent of viral myocarditis (VMC), which can lead to both acute and chronic cardiac inflammation accompanied by progressive heart failure and arrhythmias. Although CVB3 has been implicated in various forms of programmed cell death, whether it triggers necroptosis and the underlying mechanisms remains unclear. This study aimed to investigate the role and mechanism of CVB3-induced necroptosis and its effect on viral replication. Using both in vitro and in vivo models, we demonstrated that CVB3 infection significantly upregulates the expression of key necroptotic markers RIP1 and RIP3 in HeLa cells and mouse myocardial tissues. This upregulation was accompanied by elevated intracellular reactive oxygen species (ROS) levels and suppression of the Nrf2/HO-1 antioxidant pathway. Intervention with the necroptosis inhibitor Necrostatin-1 (Nec-1) or the ROS scavenger N-acetylcysteine (NAC) markedly attenuated cell death, suppressed viral replication, and ameliorated myocardial injury and inflammatory responses in infected mice. Mechanistically, CVB3 inhibits the Nrf2/HO-1 pathway, thereby inducing substantial ROS accumulation that promotes necroptosis. This effect can be reversed by NAC treatment. Our study reveals a novel mechanism through which CVB3 induces ROS-dependent necroptosis via the suppression of the Nrf2/HO-1 pathway, providing new insights into the pathogenesis of viral myocarditis and suggesting potential therapeutic strategies.},
}

@article {pmid41154783,
year = {2025},
author = {Moyano, P and Flores, A and Sanjuan, J and Plaza, JC and Guerra-Menéndez, L and Abascal, L and Mateo, O and Del Pino, J},
title = {Cholinergic Transmission Dysregulation and Neurodegeneration Induced by Thyroid Signaling Disruption Following Butylparaben Single and Repeated Treatment.},
journal = {Biology},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/biology14101380},
pmid = {41154783},
issn = {2079-7737},
support = {172C126PMA//Fundación Alborada/Luunt Medicina Amabiental/Catedra Extraordinaria de Patologia y Medioambiente/ ; },
abstract = {Butylparaben (BP), a widely used preservative, was implicated in cognitive impairment, though its neurotoxic mechanisms remain elusive. Basal forebrain cholinergic neurons (BFCN) are selectively lost in dementias, contributing to cognitive decline. To explore different mechanisms related with BFCN loss, we employed BF SN56 cholinergic wild-type or silenced cells for Tau, amyloid-beta precursor protein (βApp), acetylcholinesterase (AChE), or glycogen synthase kinase-3 beta (GSK3β) genes, exposing them to BP (0.1-80 µM) for 1 or 14 days alongside triiodothyronine (T3; 15 nM), N-acetylcysteine (NAC; 1 mM), or recombinant heat shock protein 70 (rHSP70; 30 µM). BP disrupted cholinergic transmission by AChE inhibition and provoked cell death through thyroid hormones (THs) pathway disruption, Aβ/p-Tau protein accumulation, AChE-S overexpression, and oxidative stress (OS). Aβ/p-Tau accumulation was correlated with HSP70 downregulation, OS exacerbation, and GSK3β hyperactivation (for p-Tau). BP-induced OS was mediated by reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (NRF2) pathway disruption. All observed effects were contingent upon TH signaling impairment. These findings uncover novel mechanistic links between BP exposure and BFCN neurodegeneration, providing a framework for therapeutic strategies.},
}

@article {pmid41154722,
year = {2025},
author = {Gopal, T and John Kathiravan, AD and Kabanov, AV and Casey, CA and Saraswathi, V},
title = {The Pathophysiology of Alcohol-Associated Liver Disease: Focusing on Superoxide Dismutase 1 as a Therapeutic Target.},
journal = {Biology},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/biology14101319},
pmid = {41154722},
issn = {2079-7737},
support = {1R01AA030793-24/NH/NIH HHS/United States ; 1P50AA030407-24/NH/NIH HHS/United States ; },
abstract = {Alcohol-associated liver disease (ALD) is a major health problem of global importance, caused by chronic alcohol consumption, leading to the accumulation of reactive oxygen species (ROS) and subsequent oxidative stress-a central mechanism in liver injury. Superoxide dismutase 1 (SOD1), a Cu-Zn containing antioxidant enzyme, plays a crucial role in attenuating ALD-induced oxidative stress triggered by ethanol metabolism. However, alcohol exposure, whether chronic, acute or binge, differentially affects SOD1 levels, either diminishing its expression or temporarily compensating for alcohol-induced oxidative damage. Regardless, overexpression of SOD1 reverses early stages of ethanol-induced liver inflammation and injury in animal models, highlighting the protective role of SOD1. Current therapies, including alcohol abstinence, corticosteroids, and pentoxifylline, have limited long-term efficacy. Antioxidant-based treatments, such as N-acetylcysteine (NAC) and S-adenosyl-L-methionine (SAM), have demonstrated moderate benefits. While combination therapies like NAC with prednisolone yield more promising outcomes, these benefits are often limited in duration. The use of natural compounds including nutraceuticals and probiotics provide liver protection by enhancing antioxidant defenses, reducing inflammation, and mitigating alcohol-induced liver damage. In particular, these compounds upregulate antioxidant enzymes like SOD1. Recent research suggests that enhancing the activity of SOD1, particularly through nanoformulated SOD1 (NanoSOD1), which had direct effect on the oxidative stress at the cellular level, could offer a promising therapeutic option for ALD. NanoSOD1 aims to improve the bioavailability and stability of SOD1, offering a targeted approach to reduce oxidative stress and protect against liver damage. The effectiveness of NanoSOD1 to improve antioxidant defenses suggests a valuable therapeutic arsenal in ALD treatment. Taken together, given the limited treatment options for ALD, increasing SOD1 activity is essential for managing the progression of the disease.},
}

@article {pmid41154576,
year = {2025},
author = {Hsu, FT and Kuo, YY and Chao, CY},
title = {High-Frequency, Low-Intensity Pulsed Electric Field and N-Acetylcysteine Synergistically Protect SH-SY5Y Cells Against Hydrogen Peroxide-Induced Cell Damage In Vitro.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101267},
pmid = {41154576},
issn = {2076-3921},
support = {NSTC 113-2112-M-002-024//National Science and Technology Council/ ; NSTC 112-2112-M-002-033//National Science and Technology Council/ ; MOST 110-2112-M-002-004//Ministry of Science and Technology/ ; },
abstract = {Oxidative stress plays an important role in the progression of neurodegenerative diseases (NDDs), and N-acetylcysteine (NAC) has gained attention as a potential agent due to its antioxidant capabilities. This study investigated the synergistic neuroprotective effects of combining NAC with non-contact, high-frequency, low-intensity pulsed electric field (H-LIPEF) stimulation on SH-SY5Y human neuronal cells subjected to hydrogen peroxide (H2O2)-induced oxidative damage. It was found that after SH-SY5Y cells were pretreated with NAC and exposed to H-LIPEF stimulation, the oxidative stress of cells was reduced in the subsequent treatment with H2O2. The results showed that the combined NAC and H-LIPEF treatment significantly improved cell viability and more effectively reduced mitochondrial apoptosis. Mechanistic analyses revealed that the combination substantially decreased levels of superoxide and intracellular H2O2, which was associated with enhanced activation of the phosphorylated Akt (p-Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2)/superoxide dismutase type 2 (SOD2) signaling pathway. Furthermore, the treatment reduced the accumulation of 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dG) accumulation and elevated MutT homolog 1 (MTH1) expression, indicating a protective effect against oxidative DNA damage. These results suggest that H-LIPEF enhances the neuroprotective efficacy of low-dose NAC, highlighting the potential of this combination approach as a new therapeutic strategy for the treatment of NDDs.},
}

@article {pmid41154550,
year = {2025},
author = {Peralta-Buendía, K and Cuevas-López, B and García-Arroyo, FE and Díaz-Rojas, M and León-Contreras, JC and Silva-Palacios, A and Gonzaga, G and Tapia, E and Saavedra, E and Hernández-Pando, R and Pedraza-Chaverri, J and Sánchez-Lozada, LG and Aparicio-Trejo, OE},
title = {Early Administration of N-Acetylcysteine Provides Renal and Cardiac Mitochondrial and Redox Protection, Preventing the Development of Cardio-Renal Syndrome Type IV Induced by 5/6NX.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101241},
pmid = {41154550},
issn = {2076-3921},
support = {IN202725//Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT)/ ; 21-1252//Fondos de Gasto Directo Autorizados a la Subdirección de Investigación Básica del Instituto Nacional de Cardiología Ignacio Chávez/ ; CBF2023-2024-190//Consejo Nacional de Humanidades, Ciencia y Tecnología (CONAHCyT)/ ; },
abstract = {Chronic kidney disease (CKD) cardiac impairment is manifested as cardio-renal syndrome type 4 (CRS-IV). The kidneys and heart are highly dependent on mitochondria; thus, bioenergetics and redox and biogenesis alterations are critical in CKD and heart damage. Most previous studies have focused on the advanced stage of CRS-IV, but mitochondrial impairment onset in the early stages and its pathological pathways are poorly understood. In this work, we characterized mitochondrial bioenergetics, biogenesis and redox impairment in both tissues in the early stages after CKD and analyzed their relationship with CRS-IV in a CKD model with 5/6 nephrectomy (NX). We found the first cardiac mitochondrial alterations 10 days after surgery, together with an increase in plasma cardio-renal connectors, derived from renal mitochondrial damage. Oxidative phosphorylation capacity decreased and uncoupling led to oxidative stress, inflammation, cardiac hypertrophy and ejection fraction reduction, triggering CRS-IV. N-acetylcysteine (NAC) administration prevented mitochondrial alterations in both organs and heart damage. Interestingly, the protective effects of NAC correlated with SIRT1/3-PGC-1α pathway overactivation. These results suggest that mitochondrial biogenesis induction and redox regulation protection in the early stages after renal damage serve as a strategy to prevent bioenergetic alterations in the kidneys and heart, preventing inflammation and CRS-IV development.},
}

@article {pmid41154544,
year = {2025},
author = {Zhao, B and Fan, L and Liu, M and Wu, H and Zhang, Y and Shen, Q and Kang, J},
title = {Androgen-Induced Lactic Acid Accumulation Contributes to the Apoptosis of Ovarian Granulosa Cells in Polycystic Ovary Syndrome Mice.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101235},
pmid = {41154544},
issn = {2076-3921},
support = {82171634//the National Natural Science Foundation of China/ ; 31971068//the National Natural Science Foundation of China/ ; 7242085//Beijing Natural Science Foundation/ ; },
abstract = {BACKGROUND: Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The apoptosis of granulosa cells (GCs) is strongly associated with the impaired follicular development in PCOS. The underlying mechanisms, however, remain incompletely elucidated. A significant increase in circulating lactic acid, an anaerobic respiration product, has been detected in PCOS patients. Yet, alterations in local ovarian lactic acid levels and their impact on GCs remain unknown.

METHODS: PCOS mouse models were established via 20-day daily subcutaneous dehydroepiandrosterone (DHEA) injections. In vitro experiments utilized DHEA-treated KGN cells to mimic hyperandrogenic conditions. Circulating, ovarian, and cellular lactic acid concentrations were quantified. Intracellular and extracellular pH values were measured using BCECF-AM fluorescent probe and a blood gas analyzer, respectively. Apoptosis was assessed through both flow cytometry and TUNEL assay. The antioxidant N-acetylcysteine (NAC) was used to investigate its effects on lactic acid levels and the subsequent GC apoptosis.

RESULTS: High androgen levels caused mitochondrial damage, promoted anaerobic glycolysis and led to lactic acid accumulation, inducing decreased intracellular pH and thus apoptosis of GCs. The antioxidant NAC effectively alleviated oxidative stress, mitigated mitochondrial damage, and decreased lactic acid levels and apoptosis in KGN cells. In PCOS mice, NAC improved ovarian morphology, but it did not affect the estrous cycle of the mice.

CONCLUSIONS: Hyperandrogenemia-induced mitochondrial dysfunction caused the accumulation of lactic acid and thus apoptosis of ovarian GCs in PCOS mice. NAC enhanced mitochondrial function, consequently decreasing lactic acid concentrations. These findings suggest novel therapeutic targets for PCOS.},
}

@article {pmid41153879,
year = {2025},
author = {Arena, R and Manuguerra, S and Gonzalez, MM and Petrosillo, E and Lanzoni, D and Poulain, C and Debeaufort, F and Giromini, C and Francesca, N and Messina, CM and Santulli, A},
title = {Valorization of Blue Crab (Callinectes sapidus) By-Products into Antioxidant Protein Hydrolysates for Nutraceutical Applications.},
journal = {Animals : an open access journal from MDPI},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/ani15202952},
pmid = {41153879},
issn = {2076-2615},
support = {Project Code (CUP): G53D23003940006, Grant Assignment No. 1048//Project CELLtoFOOD, Italian Ministry of University and Research (MUR) funded by the European Union/ ; grant code CN_00000033, CUP B73C22000790001//NextGenerationEU. NBFC-National Biodiversity Future Center-Node 6 Biodiversity and human wellbeing/ ; },
abstract = {The Atlantic blue crab (Callinectes sapidus) is an opportunistic invasive species in the Mediterranean that is negatively affecting biodiversity, fisheries, and tourism. In Italy, it is appreciated for its good meat quality, but the processing yield is low (21.87 ± 2.38%), generating a significant amount of by-products (72.45 ± 4.08%), which are underutilized. Valorizing this biomass is in line with circular economy principles and can improve both environmental and economic sustainability. This study aimed to valorize Atlantic blue crab by-products (BCBP), producing protein hydrolysates and assessing their in vitro bioactivities, in order to plan applications in animal food and related sectors. BCBP hydrolysates were obtained by enzymatic hydrolysis using Alcalase and Protamex enzymes. The treatment with Alcalase resulted in a higher degree of hydrolysis (DH = 23% in 205 min) compared to Protamex (DH = 14% in 175 min). Antioxidant activity of the hydrolisates was evaluated through DPPH, ABTS, reducing power and FRAP assays, as well as in vitro test in fibroblasts (HS-68). At 10 mg/mL, hydrolysates from both enzymes exhibited the maximum radical scavenging activity in DPPH and ABTS assays. In HS-68 cells, 0.5 mg/mL hydrolysates protected against H2O2-induced oxidative stress, showing a cell viability comparable to cells treated with 0.5 mM N-acetyl cysteine (NAC), as an antioxidant. Statistical analyses were performed using one-way ANOVA followed by Student-Newman-Keuls (SNK) or Games-Howell post hoc tests, with significance set at p < 0.05. Overall, both enzymes efficiently hydrolyzed BCBP proteins, generating hydrolysates with significant antioxidant activity and cytoprotective effects. These results demonstrate the potential to produce high-quality bioactive compounds from BCBPs, suitable for food, nutraceutical, and health applications. Scaling up this valorization process represents a viable strategy to improve sustainability and add economic value to the management of this invasive species, turning a problem in a resource.},
}

@article {pmid41151839,
year = {2025},
author = {El Nsouli, D and Chung, C and Wilkins, H and Alqeisi, T and Maqsood, M and Sandhu, R and Bate-Jones, PE and Johnson, GD and Jameel, A},
title = {Quality improvement project to enhance adherence to RCEM standards for patients with paracetamol overdose.},
journal = {BMJ open quality},
volume = {14},
number = {4},
pages = {},
doi = {10.1136/bmjoq-2025-003518},
pmid = {41151839},
issn = {2399-6641},
mesh = {Humans ; *Acetaminophen/adverse effects/therapeutic use/poisoning ; *Quality Improvement ; *Drug Overdose/drug therapy ; Female ; Male ; Acetylcysteine/therapeutic use ; Emergency Service, Hospital/organization & administration/statistics & numerical data ; Adult ; Middle Aged ; *Guideline Adherence/statistics & numerical data/standards ; Analgesics, Non-Narcotic ; Scotland ; },
abstract = {BACKGROUND: Delayed or inconsistent administration of N-acetylcysteine (NAC) for paracetamol overdose in the emergency department (ED) poses a risk to patient safety, with current Royal College of Emergency Medicine (RCEM) standards often not being met. The traditional 21-hour NAC regimen is associated with adverse drug reactions, medication errors and prolonged admissions. The Scottish and Newcastle Acetylcysteine Protocol (SNAP) was introduced as a simpler alternative with comparable efficacy. This quality improvement project (QIP) aimed to improve compliance with RCEM standards by implementing targeted interventions while also reducing the length of inpatient stay and maintaining patient safety.

METHOD: This QIP was conducted at Royal Derby Hospital using a multidisciplinary, systematic approach based on Plan-Do-Study-Act cycles. Baseline data were collected from 100 randomly selected patients (November 2021-May 2022) and compared with outcomes during a 52-week intervention period (September 2023-August 2024). Interventions included educational sessions, quick reference materials and enhanced prescribing tools. Data were analysed for compliance with RCEM standards, adverse events (liver function derangement and anaphylactoid reactions) and system-level measures, such as length of inpatient stay and timing of paracetamol plasma levels.

RESULTS: A total of 214 patients were included. Compliance with RCEM standard 1 improved from 36% to 43%. No change was noted for standards 2 and 3. Median inpatient stay decreased from 35 hours to 30.5 hours. No significant differences were found in adverse events. Special cause variation was identified in paracetamol plasma level timing, attributed to early sampling in some cases.

CONCLUSION: This QIP addressed problems of delayed or inconsistent NAC administration in the ED by improving compliance with RCEM standard 1 and reducing inpatient stay while maintaining patient safety. Although standards 2 and 3 did not improve, the interventions proved cost-effective, feasible and scalable. Future work should focus on sustaining improvements and exploring patient-centred outcomes across diverse healthcare settings.},
}

Humans
*Acetaminophen/adverse effects/therapeutic use/poisoning
*Quality Improvement
*Drug Overdose/drug therapy
Female
Male
Acetylcysteine/therapeutic use
Emergency Service, Hospital/organization & administration/statistics & numerical data
Adult
Middle Aged
*Guideline Adherence/statistics & numerical data/standards
Analgesics, Non-Narcotic
Scotland

@article {pmid41150214,
year = {2025},
author = {de-Luna-López, MC and Valdivia-Flores, AG and Quezada-Tristán, T and Ortiz-Martínez, R and Rangel-Muñoz, EJ and Hernández-Valdivia, E and Albarrán-Rodríguez, E and de Santiago-Díaz, E},
title = {Protective Effect of Ethoxyquin and N-acetylcysteine on Biochemical and Pathological Changes Induced by Chronic Exposure to Aflatoxins in Laying Hens.},
journal = {Toxins},
volume = {17},
number = {10},
pages = {},
doi = {10.3390/toxins17100514},
pmid = {41150214},
issn = {2072-6651},
support = {PIP/SA 25-1//Autonomous University of Aguascalientes/ ; 227916/209250//CONAHCYT/ ; },
mesh = {Animals ; Chickens ; *Acetylcysteine/pharmacology/therapeutic use ; *Aflatoxins/toxicity ; Female ; Liver/drug effects/pathology/metabolism ; Kidney/drug effects/pathology/metabolism ; *Ethoxyquin/pharmacology ; *Antioxidants/pharmacology ; *Protective Agents/pharmacology ; Glutathione/metabolism ; Poultry Diseases/chemically induced/prevention & control ; Glutathione Transferase/metabolism ; },
abstract = {Aflatoxins (AFs) represent a major threat to poultry health and food safety due to their hepatotoxic, immunosuppressive, and carcinogenic effects. This study evaluated the chemoprotective potential of ethoxyquin (EQ) and N-acetylcysteine (NAC) in laying hens (80.8 and 33.3 mg/kg BW/d) exposed to chronic dietary AFs contamination (0.0-1.5 mg/kg). A total of 360 Hy-Line W36 Leghorn hens were monitored over 72 weeks using biochemical and histopathological analyses of liver and kidney tissues. NAC significantly (p < 0.01) increased hepatic and renal levels of reduced glutathione (GSH) and stimulated glutathione S-transferases (GST) and gamma-glutamyl transferase (GGT) activity, enhancing detoxification. Both agents significantly (p < 0.05) reduced plasma ALT and AST levels, preserved total protein concentrations, and attenuated liver and kidney hypertrophy. EQ demonstrated antioxidant effects, stabilizing enzymatic responses and limiting tissue damage. Histopathological analysis revealed fewer structural alterations and cellular degeneration, especially in the NAC-treated group (p < 0.01). These results suggest that NAC and EQ activate endogenous detoxification mechanisms, both enzymatic and non-enzymatic, effectively mitigating chronic aflatoxin toxicity. Their dietary supplementation offers a safe and sustainable chemoprotection strategy to support poultry health and productivity, particularly in regions facing high mycotoxin exposure.},
}

Animals
Chickens
*Acetylcysteine/pharmacology/therapeutic use
*Aflatoxins/toxicity
Female
Liver/drug effects/pathology/metabolism
Kidney/drug effects/pathology/metabolism
*Ethoxyquin/pharmacology
*Antioxidants/pharmacology
*Protective Agents/pharmacology
Glutathione/metabolism
Poultry Diseases/chemically induced/prevention & control
Glutathione Transferase/metabolism

@article {pmid41149623,
year = {2025},
author = {Radomska-Leśniewska, DM and Niderla-Bielińska, J and Kujawa, M and Jankowska-Steifer, E},
title = {Targeting Metabolic Dysregulation in Obesity and Metabolic Syndrome: The Emerging Role of N-Acetylcysteine.},
journal = {Metabolites},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/metabo15100645},
pmid = {41149623},
issn = {2218-1989},
abstract = {Obesity and metabolic syndrome (MetS), growing global health concerns, are closely linked to the development of insulin resistance, type 2 diabetes, steatotic liver disease, and cardiovascular diseases (CVDs). An increase in visceral adipose tissue, the main symptom of MetS, contributes to systemic metabolic dysfunction, resulting in disturbances in glucose and lipid metabolism, mitochondrial dysfunction, and redox imbalance, which creates a vicious cycle of inflammation and oxidative stress, accelerating comorbidities. N-acetylcysteine (NAC), a precursor to glutathione, with antioxidant and anti-inflammatory properties, is described as a potent metabolic modulator that restores metabolic homeostasis. NAC's ability to modulate oxidative stress and inflammation may be particularly valuable in preventing or mitigating cardiovascular complications of MetS. The aim of this narrative review is to summarize current evidence from cellular, animal, and human studies on NAC's impact on metabolic health. MetS affects nearly one-third of the global population; therefore, there is a pressing need for accessible therapeutic strategies. NAC appears to offer potential benefits as an adjunctive agent for individuals with metabolic disturbances, but further research is needed to confirm its efficacy and establish its role in clinical practice.},
}

@article {pmid41145378,
year = {2025},
author = {Gad, FA and Emam, MA and Abdelhameed, AA and Khalil, DM and Elgebaly, EA and Bakhuraysah, MM and Albattal, SB and Alotaibi, KS and Soliman, MM},
title = {N-acetyl cysteine and vitamin E attenuate acrylamide-induced hepatotoxicity via regulation of miRNA-34a and P53/Nrf2/SIRT 1 signaling pathways.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/01480545.2025.2574393},
pmid = {41145378},
issn = {1525-6014},
abstract = {The present study is aimed to evaluate the hepatoprotective role of N-acetyl cysteine (NAC) and vitamin E (VE), as potent antioxidants, against acrylamide (ACR)-induced hepatotoxicity via investigation of alterations in miRNA-34a, P53, Nrf2, and SIRT 1 hepatic expressions in addition to, changes in liver function tests, oxidative stress/antioxidant parameters, cytokines, histopathological analysis and immunohistochemical expressions of caspase 3. For this study, thirty-five male rats were randomly assigned into seven equal groups: group I (control), group II received ACR at dose 20 mg/kg b.wt., group III received NAC at dose 150 mg/kg b.wt., group IV received VE at a dose of 100 mg/kg b.wt., group V received NAC+ACR, group VI received VE+ACR and finally group VII received NAC+VE+ACR, for 28 days. ACR induced marked hepatic tissue damage as evident by severe alterations in hepatic biomarkers, in addition to histological and immunohistochemical pictures. This was accompanied by a significant elevation of hepatic MDA and apoptotic genes expressions, alteration in miRNA-34a and P53/Nrf2/SIRT1 pathway as well as cytokines. In contrast, marked depletion for antioxidant parameters was detected. These findings were confirmed with marked histological changes. Co-administration of NAC and VE significantly attenuated the hepatotoxic effects of ACR where liver parameters, oxidative status, genetic expressions, and liver histo-architecture were improved in comparison to ACR, NAC+ACR, and VE+ACR groups. NAC and/or VE had powerful antioxidants and could be used as an applicable hepatoprotective agent against oxidative damage mediated by ACR via regulation of miRNA-34a and P53/Nrf2/SIRT 1 signaling pathways.},
}

@article {pmid41139132,
year = {2025},
author = {Sonwani, A and Pathak, A and Jain, K},
title = {Development and characterization of multifunctional dendrimeric nanoconjugates for delivery of rutin: in vitro characterization for potential neuroprotective application.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17435889.2025.2576463},
pmid = {41139132},
issn = {1748-6963},
abstract = {AIM: In the present research work, multifunctional dendrimeric nanoconjugates were developed, where poly(amidoamine) dendrimer generation 4.0 (G4.0) was conjugated with folic acid and N-acetyl cysteine simultaneously to deliver rutin for potential neuroprotective applications.

METHODS: G4.0 was functionalized with folic acid and N-acetyl cysteine by carbodiimide coupling chemistry, and the conjugation was confirmed using [1]H NMR and FTIR spectroscopy. Further, rutin was incorporated within the conjugate, and the rutin-loaded dendrimeric conjugate was evaluated for size, drug release, cytotoxicity, cellular uptake, and antioxidant activity.

RESULTS: The results of FTIR and [1]H NMR confirmed the conjugation of folic acid and N-acetyl cysteine over the dendrimeric surface. The particle size of NAC-FA-G4.0 was 163.4 ± 16.63 nm, which was increased to 229.76 ± 14.05 nm following the rutin incorporation. The in vitro drug release study showed an initial burst release of rutin, i.e. 44.27 ± 6.4% from dendrimeric conjugate within 4 h, followed by sustained release up to 72 h. The safety and biocompatibility of the developed nanoconjugate were confirmed by the hemolytic toxicity and cytotoxicity studies.

CONCLUSION: The developed rutin-loaded dendrimeric conjugate showed improved antioxidant activity and acetylcholinesterase inhibition, suggesting promising neuroprotection properties and hence may be further explored for the treatment of neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41138574,
year = {2025},
author = {Teng, C and Chen, JW and Shen, LS and Lin, Z and Lin, YS and He, WY and Yuan, ZH and Yang, ZX and Liu, YX and Lei, YB and Zhang, H and Chen, S and Chen, GQ},
title = {Arnicolide C induces ROS-mediated modulation of PI3K/Akt and MAPK pathways to suppress MYC in hepatocellular carcinoma.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {148},
number = {},
pages = {157423},
doi = {10.1016/j.phymed.2025.157423},
pmid = {41138574},
issn = {1618-095X},
abstract = {BACKGROUND: The urgent need for more effective therapies for hepatocellular carcinoma (HCC), an aggressive and lethal liver cancer, has prompted the search for novel compounds with distinct mechanisms of action. Targeting reactive oxygen species (ROS) has emerged as a promising anticancer strategy, particularly for natural products that modulate redox homeostasis. Arnicolide C (AC), a sesquiterpene lactone from Centipeda minima, has demonstrated potential anticancer activity, but its efficacy against HCC and the underlying mechanisms remain unclear.

METHODS: We assessed the effects of AC on HCC cell proliferation, apoptosis, and metastasis through a series of in vitro assays. Its antitumor efficacy was further validated in a xenograft mouse model. RNA-seq-based bioinformatics analysis was conducted to explore potential molecular targets and pathways. ROS generation by AC was evaluated using both chemical and cellular assays. The role of ROS in mediating AC's effects was investigated in vitro and in vivo using the ROS scavenger N-acetylcysteine (NAC).

RESULTS: AC markedly inhibited HCC cell proliferation, triggered apoptosis, and suppressed metastatic behaviors. Notably, AC reduced tumor growth without overt toxicity in vivo. Mechanistically, AC downregulated the oncogene MYC by modulating the PI3K/Akt and MAPK pathways. Importantly, AC induced ROS accumulation in HCC cells, and NAC abrogated its antitumor effects and reversed the suppression of MYC and related signaling pathways.

CONCLUSION: AC exerts potent anti-HCC activity via ROS-mediated modulation of PI3K/Akt and MAPK signaling, resulting in MYC downregulation. These findings support AC as a promising redox-targeting therapeutic agent for HCC.},
}

@article {pmid41138059,
year = {2025},
author = {Yin, X and Xia, R and Song, H and Zhang, Y and Guo, D and Gan, F},
title = {Pharmacokinetics and bioequivalence of two N-acetylcysteine tablets in healthy Chinese volunteers under fasting and fed conditions.},
journal = {Clinical pharmacology in drug development},
volume = {},
number = {},
pages = {},
doi = {10.1002/cpdd.1619},
pmid = {41138059},
issn = {2160-7648},
support = {//Guangdong Tailai Runzhi Pharmaceutical Technology Co., Ltd/ ; },
abstract = {N-acetylcysteine (NAC) is a derivative of cysteine with potent mucolytic and antioxidant properties. However, the pharmacokinetics of NAC tablets remain unclear in healthy Chinese subjects. This study aimed to assess the pharmacokinetics, bioequivalence, and safety of a domestically manufactured NAC tablet (600 mg) compared with the reference formulation in healthy Chinese volunteers under both fasting and fed conditions. A single-dose, randomized, open-label, two-formulation, crossover bioequivalence study was conducted, using a two-period, two-sequence design under fasting conditions and a four-period, fully replicated crossover design under fed conditions. Blood samples were collected at predetermined time points and analyzed using a validated liquid chromatography-tandem mass spectrometry method. The 90% confidence intervals for the geometric mean ratios (test/reference) of the maximum plasma concentration, the area under the concentration-time curve from time zero to the last measurable concentration, and from time zero to infinity were all within the accepted bioequivalence range of 80%-125%. Furthermore, both the test and reference formulations were well tolerated, and no serious adverse events were reported. These results demonstrate that the test and reference NAC tablets are bioequivalent and exhibit similar pharmacokinetic profiles and safety in healthy Chinese subjects under both fasting and fed conditions.},
}

@article {pmid41136359,
year = {2025},
author = {Pan, X and Su, Z and Huang, Z and Chen, Y and Li, X and Zheng, X},
title = {N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {435},
pmid = {41136359},
issn = {2158-3188},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/adverse effects ; Mice ; *Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/chemically induced/drug therapy ; Mice, Transgenic ; Male ; Microglia/drug effects ; *Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; Disks Large Homolog 4 Protein/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder that predominantly affects the elderly, leading to a progressive decline in cognitive function. Accumulating evidence suggests that many environmental and dietary factors, especially chronic ethanol exposure, aggravate the risk of this disease. However, its precise influence on AD has not yet been clarified. Here, we show that ethanol exposure caused earlier and severer cognitive behavioral impairments, more beta amyloid (Aβ) depositions, microglia activation, decreased total antioxidant capacity (T-AOC). Moreover, inflammatory mediators, such as Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and Tumor necrosis factor-alpha (TNF-α) increased, while pivotal proteins involved in dendritic and synaptic development, such as Synaptophysin (SYP), postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) decreased in APP/PS1 mice. N-acetylcysteine (NAC), a well-known antioxidant, could attenuate cognitive behavioral impairments and neuroinflammatory damage by restoring inflammatory and neurodevelopmental mediators. In general, our study uncovered that chronic ethanol exposure may exacerbate AD progress at the pathological and molecular levels and NAC may act as a potential drug for the treatment of AD patients with chronic ethanol exposure.},
}

Animals
*Acetylcysteine/pharmacology
*Ethanol/toxicity/adverse effects
Mice
*Oxidative Stress/drug effects
Disease Models, Animal
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Neuroinflammatory Diseases/chemically induced/drug therapy
Mice, Transgenic
Male
Microglia/drug effects
*Antioxidants/pharmacology
Brain-Derived Neurotrophic Factor/metabolism/drug effects
Amyloid beta-Peptides/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects
Disks Large Homolog 4 Protein/metabolism/drug effects
Amyloid beta-Protein Precursor/genetics

@article {pmid41135647,
year = {2025},
author = {Lei, Y and Forest, A and Daneault, C and Liu, Y and Pantopoulos, K and Tantiworawit, A and Phrommintikul, A and Chattipakorn, S and Chattipakorn, N and Rosiers, CD and Sweeney, G},
title = {Correlation of plasma lipidomic profiles with cardiometabolic disease in transfusion-dependent thalassemia patients with six-month N-acetylcysteine intervention: A prospective cohort study.},
journal = {Clinical biochemistry},
volume = {},
number = {},
pages = {111030},
doi = {10.1016/j.clinbiochem.2025.111030},
pmid = {41135647},
issn = {1873-2933},
abstract = {OBJECTIVES: Oxidative stress, driven by iron imbalance from recurrent blood transfusions, is a major contributor to cardiometabolic complications in transfusion-dependent thalassemia (TDT). N-acetylcysteine (NAC), a glutathione precursor, is a well-known antioxidant with cardioprotective effects achieved by mitigating the impact of oxidative stress on cell metabolism. Current study aimed to evaluate the effect of a six-month NAC intervention by focusing on previously reported changes in the plasma lipidome in TDT patients. Design & Methods A randomized cohort of 62 Thai TDT patients was divided into two groups: both received six months of cocktail therapy involving standardized blood transfusions and iron chelator therapy, with the intervention group additionally receiving 600 mg oral NAC daily and the control group receiving a placebo. Plasma lipidomic profiling was performed using mass spectrometry to assess 339 previously annotated lipid features significantly altered in TDT patients. Clinical parameters, including heart rate variability (HRV), were measured before and after the intervention.

RESULTS: NAC treatment significantly altered 152 plasma lipid features (P < 0.03), 78 of which were also altered in the placebo group. Importantly, 29 lipid features (26 unique lipids) were restored toward healthy control levels following NAC treatment. Within this subset, circulating diacylglycerophosphocholines PC(14:0_20:4) and cholesteryl ester CE 18:3 positively correlated with HRV, a clinical marker markedly improved in NAC-treated patients.

CONCLUSIONS: Six-month oral NAC intervention modified the plasma lipidomic profile in TDT patients, partially restoring lipid species likely disrupted by chronic oxidative stress. The observed correlation between NAC-responsive lipids and improved HRV suggests a potential cardioprotective effect. These findings highlight the potential of NAC as an adjunctive therapy to mitigate cardiometabolic complications in TDT.},
}

@article {pmid41133840,
year = {2025},
author = {Asgharzadeh, N and Noori, A and Amini-Khoei, H and Yazdanpanahi, N and Korrani, MS},
title = {N-acetyl Cysteine Reduces Behavioral Disorders of the First and Second-generation Weaned Mice through the Modulation of TAC and the DNMT1 Gene Expression in the Hippocampus.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128372635250927103524},
pmid = {41133840},
issn = {1873-4286},
abstract = {INTRODUCTION: This research aimed to reveal the role of antioxidants and DNMT1 gene expression in behavioral disorders after exposure to stress.

METHODS: Forty-eight male and female mice (weight 25-35 grams) were used. Their pups (weight 18-22 grams) were divided into 6 groups (n=20), Control, Social isolation stress (SIS), and SIS + N-acetylcysteine (NAC) 150 mg/kg intraperitoneally for male and 3 similar groups for female subjects, eight mice from each group were used for the first-generation experiments and another for mating and producing the second generation. The second-generation pups were designated into 9 groups A to I. After conducting behavioral tests of the Morris water maze (MWM) and shuttle box, they were anesthetized, decapitated, and their brains were removed. The neuronal counts of CA1 and CA3 were performed. DNMT1 gene expression, total antioxidant capacity (TAC), and malondialdehyde (MDA) of the brain were measured.

RESULTS: Spatial memory, passive avoidance, and TAC decreased in the SIS groups. MDA and DNMT1 gene expression of the SIS groups increased (p<0.001). Dead neurons in the CA1 and CA3 regions increased in the SIS group (p<0.001).

DISCUSSION: According to the results of this study, N-acetylcysteine enhanced learning and memory while reducing neuronal death by decreasing oxidative stress. Additionally, it lowered the expression of the DNMT1 gene, which plays a crucial role in DNA methylation.

CONCLUSION: After studying the human population, N-acetylcysteine may be introduced as an adjunct therapy to help mitigate the effects of stress.},
}

@article {pmid41128676,
year = {2025},
author = {Dunbar, KY and Dali, G and DeMayo, MM and Logge, W and Hurzeler, T and Kelly, C and Watt, J and Squeglia, LM and Kirkland, AE and Haber, PS and Morley, KC},
title = {The Effect of N-Acetylcysteine (NAC) on Neurometabolites and Cognitive Function in Adults With Alcohol Use Disorder: A Preliminary Randomized Controlled Trial.},
journal = {Neuropsychopharmacology reports},
volume = {45},
number = {4},
pages = {e70066},
pmid = {41128676},
issn = {2574-173X},
support = {2021/GNT200985//National Health and Medical Research Council/ ; //University of Sydney/ ; },
mesh = {Humans ; *Acetylcysteine/pharmacology/administration & dosage/therapeutic use ; Male ; Female ; Middle Aged ; Adult ; *Cognition/drug effects ; *Alcoholism/drug therapy/metabolism/diagnostic imaging/psychology ; Glutamic Acid/metabolism ; Glutathione/metabolism ; Aspartic Acid/metabolism/analogs & derivatives ; Double-Blind Method ; *Gyrus Cinguli/metabolism/drug effects/diagnostic imaging ; Proton Magnetic Resonance Spectroscopy ; },
abstract = {BACKGROUND AND AIMS: Preclinical studies have demonstrated that N-acetylcysteine stabilizes levels of glutamate and glutathione and reduces alcohol-seeking behaviors, indicating it as a potential pharmacotherapy for the management of alcohol use disorder. In this preliminary study, we examined brain metabolite levels and cognitive functioning in individuals with alcohol use disorder enrolled in a randomized controlled trial of N-acetylcysteine versus placebo.

METHODS: In this preliminary trial, 23 participants (average age = 49; 70% male) with moderate to severe alcohol use disorder (DSM-5) were randomized to receive 2400 mg/day of N-acetylcysteine (N = 9) or placebo (N = 14). At baseline and follow-up (M = 19 days; SD = 3.73 days post-baseline), participants underwent proton magnetic resonance spectroscopy ([1]H-MRS) to assess levels of glutamate (Glu), glutathione (GSH) and total N-acetylaspartate (tNAA) in the anterior cingulate cortex (ACC) and completed the Stroop Color and Word Test (SCWT; a measure of distractor interference and cognitive control) and the Trail Making Test (TMT; a measure of set shifting ability).

RESULTS: There were no significant differences between the N-acetylcysteine or placebo groups in neurometabolite concentrations (GSH/Cr: p = 0.75, CI; -0.12-0.09, tNAAG/Cr: p = 0.797, CI; -0.10-0.13, Glu/Cr: p = 0.60, CI; -0.19-0.32), or cognitive scores (Stroop: p = 0.57, CI; -306.93-172.78, TMT: p = 0.166, CI; -6.62-36.77).

CONCLUSION: These preliminary findings indicate that N-acetylcysteine may not alter brain neurometabolite levels within the ACC or show improvements in certain domains of cognitive functioning measured by the SCWT and TMT, specifically resistance to distractor interference and set-shifting ability respectively, in individuals with alcohol use disorder.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03879759.},
}

Humans
*Acetylcysteine/pharmacology/administration & dosage/therapeutic use
Male
Female
Middle Aged
Adult
*Cognition/drug effects
*Alcoholism/drug therapy/metabolism/diagnostic imaging/psychology
Glutamic Acid/metabolism
Glutathione/metabolism
Aspartic Acid/metabolism/analogs & derivatives
Double-Blind Method
*Gyrus Cinguli/metabolism/drug effects/diagnostic imaging
Proton Magnetic Resonance Spectroscopy

@article {pmid41127960,
year = {2025},
author = {Martínez-Gili, L and Fucho, R and Caballero, F and Núñez, S and Jaara, HS and Alarcón-Vila, C and Rico, N and Nagasawa, HT and García-Ruiz, C and Fernández-Checa, JC and Torres, S},
title = {l-Cysteine-Glutathione Mixed Disulfide, a Novel Bioavailable Sulfhydryl-Modified Glutathione Precursor, Protects against Early Liver Injury Induced by Short-Term Hypercholesterolemia.},
journal = {Chemical research in toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.chemrestox.5c00272},
pmid = {41127960},
issn = {1520-5010},
abstract = {Oxidative stress contributes to the damage of biological molecules and is linked to the development of multiple diseases, including liver disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD). In mammals, reduced glutathione (GSH) is a pivotal antioxidant that regulates cellular responses to redox imbalances caused by reactive oxygen and nitrogen species. The presence of reduced GSH within mitochondria is especially crucial for preserving the organelle's routine performance by eliminating hydrogen peroxide generated under both physiological and pathological conditions. Cumulative evidence indicates that MASLD is associated with a diminished mitochondrial GSH (mGSH) pool, attributed to alterations in mitochondrial membrane fluidity due to cholesterol accumulation. Therefore, strategies aimed at boosting mGSH may offer therapeutic benefits against MASLD-associated liver injury. This study aims to investigate whether l-cysteine-glutathione disulfide (l-CySSG), a proposed GSH donor and precursor, can effectively restore total and mGSH in vitro and in vivo in mice fed cholesterol-enriched (HC) or methionine-choline-deficient (MCD) diets. Additionally, S-adenosylmethionine (SAM), a compound that serves as both a GSH precursor and a membrane fluidizer, along with N-acetylcysteine (NAC), a GSH precursor by providing cysteine, was used as the control molecules in the study. Our findings show that l-CySSG has great potential as a liver protector, especially due to its good oral bioavailability. Although it does not restore GSH levels in the mitochondria as efficiently as SAM does, l-CySSG can still offer protection against liver damage, possibly through mechanisms that are not yet fully understood. Overall, l-CySSG emerges as a promising alternative for treating conditions related to oxidative stress and mitochondrial dysfunction, paving the way for future research and therapeutic development.},
}

@article {pmid41126973,
year = {2025},
author = {Yudhawati, R and Husodo, S and Aini, FN},
title = {N-Acetylcysteine as a Potential Immunomodulator in Tuberculosis: Evidence of IL-2 Elevation in a Pilot Study.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {14381-14390},
pmid = {41126973},
issn = {1178-7031},
abstract = {PURPOSE: Aimed to investigate the potential of N-acetylcysteine (NAC) as an adjunctive immunomodulatory therapy to support the host immune response against Mycobacterium tuberculosis by enhancing interleukin-2 (IL-2) production.

PATIENTS AND METHODS: A quasi-experimental study was conducted on the effect of NAC administration on IL-2 levels in patients newly diagnosed with pulmonary tuberculosis at Universitas Airlangga Teaching Hospital, Indonesia. Participants who met the inclusion criteria were subsequently divided into two groups: treatment group (received 600 mg every 12 hours of NAC therapy, n = 15) and control group (did not receive NAC therapy, n = 15). Enzyme-linked immunosorbent assay (ELISA) was used to analyze IL-2 levels in both groups, which were subsequently compared using statistical analysis.

RESULTS: Analysis of IL-2 levels before treatment with NAC revealed no significant difference between the treatment and control groups. The treatment group exhibited a significant increase in IL-2 levels after NAC administration (p=0.023). The median IL-2 level in the treatment group increased from 243.7 to 386.62 ng/L after two weeks of NAC administration, whereas in the control group, it decreased from 303.6 to 285.89 ng/L. The comparison test analysis of delta IL-2 levels also showed a significant difference between the treatment and control group (p = 0.025), with the median value of delta IL-2 levels in the treatment group being 147.0 ng/L and -24.7 ng/L in the control group.

CONCLUSION: This preliminary study demonstrated that IL-2 levels significantly increased with NAC supplementation, suggesting an enhanced immune response and its potential as an adjunct to standard tuberculosis therapy.},
}

@article {pmid41125047,
year = {2025},
author = {Zheng, Z and Lin, X and Ma, F and Shi, Q and Li, X and Wang, Y and Li, H and Ge, RS and Pan, P},
title = {Zearalenone impairs trophoblast function via ROS-mediated apoptosis and autophagy: A mechanistic insight into unexplained recurrent spontaneous abortion.},
journal = {Ecotoxicology and environmental safety},
volume = {305},
number = {},
pages = {119259},
doi = {10.1016/j.ecoenv.2025.119259},
pmid = {41125047},
issn = {1090-2414},
abstract = {The impact of zearalenone (ZEN) on miscarriage, especially unexplained recurrent spontaneous abortion (URSA), remains unclear. We collected follicular fluid from URSA patients and found significantly elevated ZEN levels. This study further investigated ZEN's cytotoxic effects on human (HTR-8) and primary rat trophoblast cells. In HTR-8 cells, ZEN exposure (0.05-50 μM) induced time-dose-dependent suppression of cell viability, with concomitant reductions in human chorionic gonadotrophin (hCG) levels. ZEN (0.05-50 μM) downregulated the expression of antioxidants (SOD1, SOD2, CAT1 and GPX1) and anti-apoptotic gene (BCL2), and upregulated apoptotic genes (P53 and CASP9). ZEN affected the expression of nutrient transporters, including CD36 (at ≥ 50 μM), LDLR (at ≥50 μM), and SLC38A2 (at ≥ 5 μM). Flow cytometry analysis demonstrated that ZEN, at concentrations of ≥ 10 μM, induced reactive oxygen species (ROS) production, reduced mitochondrial membrane potential (MMP), and promoted apoptosis in HTR-8 cells. These effects were attenuated by acetylcysteine (NAC). In primary rat trophoblast cells, ZEN at ≥ 50 μM similarly triggered ROS generation, decreased MMP, and enhanced apoptosis, which were partially reversed by NAC. Western blot analysis further revealed that ZEN at concentrations as low as 5 μM induced autophagy in HTR-8 cells, as evidenced by increased levels of BECLIN1, LC3B, and p62. Notably, the ZEN-induced upregulation of LC3B protein was attenuated by NAC. ZEN remarkably reduced the phosphorylation of AKT1, AKT2, ERK1/2, and mTOR. These findings suggest that ZEN may harm pregnancy health through ROS-mediated apoptosis and autophagy in trophoblast cells.},
}

@article {pmid41124265,
year = {2025},
author = {Li, N and Liu, Z and Chen, C and Jiang, H and Liu, Y and Ni, D},
title = {Activatable fluorescent ratiometric probes for early diagnosis and prognostic assessment of acute kidney injury.},
journal = {Science advances},
volume = {11},
number = {43},
pages = {eaea1654},
doi = {10.1126/sciadv.aea1654},
pmid = {41124265},
issn = {2375-2548},
mesh = {*Acute Kidney Injury/diagnosis/metabolism ; Animals ; Mice ; *Fluorescent Dyes/chemistry ; Early Diagnosis ; Prognosis ; Hydrogen Peroxide/metabolism ; Humans ; Hepatitis A Virus Cellular Receptor 1/metabolism ; Male ; Disease Models, Animal ; Kidney/metabolism ; },
abstract = {Early and accurate diagnosis of acute kidney injury (AKI) is crucial for clinical treatment. However, most existing fluorescent probes are prone to background interference and limited renal targeting. We developed a ratiometric nanoprobe (RP-SC) that synergistically responded to H2O2 and targeted kidney injury molecule-1 (KIM-1). In AKI kidneys, RP-SC was hydrolyzed and slowly released encapsulated Hcy-BOH and Cy-Dopa. The H2O2 level was semi-quantitatively analyzed by fluorescence ratio (FHcy-BOH/FCy-Dopa). RP-SC exhibited prominent renal fluorescence in AKI mice, making it possible to accurately diagnose AKI and dynamically monitor renal function for up to 60 hours. RP-SC could monitor the process of AKI in vivo and provide an earlier warning of AKI than traditional strategies, subsequently evaluating the recovery of renal function after N-acetyl cysteine (NAC) treatment. Our study confirmed the ability of RP-SC for longitudinal monitoring of renal function in vivo by dual-targeting capacity, providing an effective tool for accurate diagnosis of early AKI while tracking the dynamic process of AKI treatment.},
}

*Acute Kidney Injury/diagnosis/metabolism
Animals
Mice
*Fluorescent Dyes/chemistry
Early Diagnosis
Prognosis
Hydrogen Peroxide/metabolism
Humans
Hepatitis A Virus Cellular Receptor 1/metabolism
Male
Disease Models, Animal
Kidney/metabolism

@article {pmid41114544,
year = {2025},
author = {Altowijri, MA and Abdelmageed, ME and El-Gamal, R and El-Agamy, DS},
title = {The protective effects of neferine against paracetamol-induced liver injury are associated with the activation of SIRT1/Nrf2/HO-1 signaling pathway and inhibition of NF-kappa B/TNF-alpha/iNOS/COX-II cascade.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/01480545.2025.2559844},
pmid = {41114544},
issn = {1525-6014},
abstract = {Drug-induced hepatotoxicity is a significant public health issue that influences the development of novel pharmaceutical therapies and the retraction of numerous promising medications from the market.Therefore, the current study investigated the potential hepato-protective benefits of NEF against hepatotoxicity caused by paracetamol (APAP) in mice and assessed its underlying mechanisms. Mice were divided randomly into six groups; control (received normal saline), NEF control, APAP, N-acetylcysteine (NAC; served as a standard treatment) + APAP, NEF (10 mg/kg) + APAP, and NEF (20 mg/kg) + APAP. The serum and hepatic tissues were collected for different biochemical, genetic, and histological assessments. APAP induced profound hepatic damage that was evident through all biochemical, histological, and molecular assessments. NEF pretreatment opposed the elevation of liver injury biomarkers and attenuated hepatic histological disruption. At the molecular level, NEF increased the hepatic level and protein expression of SIRT-1. NEF increased the hepatic mRNA and protein expression of Nrf2 and HO-1. NEF also decreased hepatic level of oxidative stress biomarker, MDA and increased the hepatic levels of antioxidants: GSH, GR, GST, TAC, and SOD, NEF also counteracted the activation of NF-κB and inhibited the upregulation of different inflammatory cytokines as TNF-α and interleukins- (IL-1β and IL-6). Furthermore, NEF pretreatment decreased the hepatic level and mRNA expression of COX-II and iNOS. NEF ameliorated APAP-induced liver injury in mice where the higher dose of NEF (20 mg/kg) was more effective than the lower (10 mg/kg) compared to NAC. This effect is association with upregulation of SIRT-1/Nrf2/HO-1 and interruption of NF-κB/cytokines/iNOS/COX-II signaling cascades.},
}

@article {pmid41114213,
year = {2025},
author = {Liška, TJ and Janovec, L and Michalková, R and Potočňák, I and Samolova, E and Tvrdoňová, M and Bekešová, S and Gramblička, M and Kudličková, Z and Trizna, L and Sabolová, D and Mojžiš, J and Vilková, M},
title = {Conformational Dynamics, Isomerization, and Biological Activity of Acridine-Thiazolidinone Hybrids: A Combined Experimental and Theoretical Study.},
journal = {ACS omega},
volume = {10},
number = {40},
pages = {47007-47021},
pmid = {41114213},
issn = {2470-1343},
abstract = {A new series of acridin-4-yl-based thiazolidinone derivatives was synthesized and structurally characterized using NMR, IR, HRMS, and single-crystal X-ray diffraction. NMR analysis in solution revealed signal multiplicity suggestive of isomeric or conformational heterogeneity. To investigate this behavior, we employed GFN2-xTB, DFT (PBE0-D4 and revDSD-PBEP86-D4), and ab initio molecular dynamics simulations. Theoretical results indicated a preference for nonplanar conformers due to steric hindrance and internal rotations, in agreement with experimental NMR and crystallographic data. Conformational searches and NMR prediction further supported the predominance of E C1N2 Z N3C4 Z C7C8 and Z C1N2 E N3C4 Z C7C8 isomers in solutions. Biological evaluation revealed selective cytotoxicity of compound 4e against HeLa and A549 cell lines (IC50 = 14.75 and 17.75 μM, respectively). Mechanistic studies in HeLa cells demonstrated dose-dependent apoptosis induction, mitochondrial membrane hyperpolarization, cytochrome c release, S-phase cell cycle arrest, and elevated intracellular ROS. Co-treatment with the antioxidant N-acetylcysteine (NAC) significantly mitigated these effects, suggesting a ROS-mediated mitochondrial apoptotic pathway. This integrated experimental-theoretical study highlights the importance of conformational dynamics in modulating biological activity and provides valuable insights into the structure-activity relationship of acridine-thiazolidinone hybrids. The results support their potential as modular scaffolds for further development of anticancer agents.},
}

@article {pmid41113963,
year = {2025},
author = {Bai, LY and Chiu, CF and Wu, CY and Weng, JR},
title = {Hydrogen peroxide and cisplatin regulate the ROS/PKM2 pathway to affect the growth of cancer.},
journal = {American journal of cancer research},
volume = {15},
number = {9},
pages = {4082-4091},
pmid = {41113963},
issn = {2156-6976},
abstract = {Aberrant production of reactive oxygen species (ROS) cause DNA damage which led to the chronic diseases and cancer. During glycolysis, the enzyme pyruvate kinase M2 (PKM2) is responsible for energy metabolism and its overexpression can be found in various malignancies. To investigate the impact of PKM2 and ROS, hydrogen peroxide (H2O2) and cisplatin were used. This study showed that H2O2 and cisplatin induced ROS production and apoptosis in these four tumor cells: pancreatic cancer, oral cancer, gastric cancer, and hepatocellular carcinoma. In addition, H2O2- and cisplatin-increased apoptosis was partially reduced by pre-treatment with an antioxidant N-acetylcysteine (NAC) in SC-M1 gastric cancer and HSC-3 oral cancer cells. Interestingly, the levels of p-PKM2 in the nucleus were downregulated after treatment with H2O2 and cisplatin. This phenomenon was reversed with the combination of NAC. These findings provide PKM2 may be a potential target for anticancer therapy.},
}

@article {pmid41110517,
year = {2025},
author = {Hu, Y and Gong, Q and Jia, X and Zhu, Q and Zheng, C and Ali, T and Li, S and Liang, R and Feng, J},
title = {P2Y6 Receptor Blockade Promotes Depression-like Symptoms Through Oxidative Stress and Impaired Autophagy.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.10.268},
pmid = {41110517},
issn = {1873-4596},
abstract = {The P2Y6 receptor (P2Y6R) is implicated in neuroinflammation and synaptic plasticity, but its role in depression remains unclear. This study reveals a crucial role for the P2Y6 receptor (P2Y6R) in depression. Using a chronic restraint stress (CRS) mouse model, we found reduced hippocampal P2Y6R expression. Pharmacological inhibition of P2Y6R with MRS2578 (MRS) induced robust depressive-like behaviors in mice, including anhedonia and behavioral despair, accompanied by decreased hippocampal serotonin and norepinephrine. At the molecular level, MRS disrupted synaptic integrity, evidenced by reduced expression of key synaptic proteins (PSD95, synaptophysin, SNAP25, mature BDNF) and impaired associated signaling pathways. Our multi-omics analysis further showed that P2Y6R inhibition profoundly disrupted neuronal autophagic flux and metabolic homeostasis. Importantly, the late-stage autophagy inhibitor chloroquine, but not the early-stage inhibitor 3-methyladenine, attenuated MRS-induced depressive symptoms and restored synaptic protein expression, suggesting lysosomal dysfunction is a key contributor. We identified that MRS disrupts neuronal autophagy primarily through the P2Y6-Oxidative stress axis, as evidenced by dysregulated antioxidant defences and increased oxidative damage markers, including protein carbonyls (PC), 3-nitrotyrosine (3-NT), and the lipid peroxidation product 4-hydroxynonenal (4-HNE). Crucially, antioxidant intervention with N-acetylcysteine (NAC) rescued MRS-induced depressive behaviors, synaptic deficits, and normalized oxidative stress and autophagy dynamics. Validation with P2Y6R agonists confirmed that the observed effects were specific to P2Y6R inhibition. These findings establish the P2Y6- Oxidative stress-autophagy axis as a novel and promising therapeutic target for Major Depressive Disorder, offering new avenues for more effective treatments.},
}

@article {pmid41025906,
year = {2025},
author = {Laxmanan, K and Shin, H and Jo, J and Bose, S and Ranganathan, P and Nam, SY and Kang, HW},
title = {Theranostic Polyaniline-Integrated N-Acetyl-l-Cysteine Hydrogel for Synergistic Photothermal Antibacterial Therapy and Enhanced Cell Migration.},
journal = {ACS applied bio materials},
volume = {8},
number = {10},
pages = {8751-8766},
doi = {10.1021/acsabm.5c00829},
pmid = {41025906},
issn = {2576-6422},
mesh = {*Anti-Bacterial Agents/pharmacology/chemistry/chemical synthesis ; *Hydrogels/chemistry/pharmacology ; Escherichia coli/drug effects ; Cell Movement/drug effects ; Staphylococcus aureus/drug effects ; *Aniline Compounds/chemistry/pharmacology ; *Acetylcysteine/chemistry/pharmacology ; Microbial Sensitivity Tests ; Humans ; *Biocompatible Materials/pharmacology/chemistry/chemical synthesis ; Photothermal Therapy ; Theranostic Nanomedicine ; Materials Testing ; Particle Size ; },
abstract = {Bacterial infections continue to pose a significant global health challenge, highlighting the urgent need for innovative therapeutic approaches that combine antibacterial efficacy with photothermal treatment modalities. In this study, we report a theranostic multifunctional hydrogel (APQ@NH), comprising Asiatic acid (AA)-doped polyaniline (PANi) loaded with quercetin (Q), and incorporated into an N-acetyl-l-cysteine (NAC)-based hydrogel matrix, for in vitro antibacterial and photothermal applications. The APQ@NH hydrogel exhibits excellent rheological stability and controlled, sustained drug release behavior, ensuring prolonged antibacterial activity. Upon near-infrared 808 nm laser irradiation, the APQ@NH hydrogel effectively generates localized hyperthermia, facilitating membrane disruption and enhancing the intracellular delivery of antibacterial agents. The photothermal conversion efficiency (PCE) of APQ@NH was calculated to be 21.7% under 808 nm laser irradiation, confirming its effective photothermal capability. This synergistic system exhibited potent antibacterial activity against both Escherichia coli (E.coli) and Staphylococcus aureus (S. aureus) , resulting in substantial bacterial eradication. Additionally, in vitro studies confirmed the hydrogel's ability to promote cell migration, further supporting its potential for wound healing applications.},
}

*Anti-Bacterial Agents/pharmacology/chemistry/chemical synthesis
*Hydrogels/chemistry/pharmacology
Escherichia coli/drug effects
Cell Movement/drug effects
Staphylococcus aureus/drug effects
*Aniline Compounds/chemistry/pharmacology
*Acetylcysteine/chemistry/pharmacology
Microbial Sensitivity Tests
Humans
*Biocompatible Materials/pharmacology/chemistry/chemical synthesis
Photothermal Therapy
Theranostic Nanomedicine
Materials Testing
Particle Size

@article {pmid41109361,
year = {2025},
author = {Chentunarayan Singh, N and Yadav, N and Sharma, RK and Gupta, P and Sarkar, J and Mitra, K},
title = {Oxidative stress-mediated DNA damage promotes selective degradation of nuclear components via noncanonical autophagy in Triple-negative breast cancer cells.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.10.264},
pmid = {41109361},
issn = {1873-4596},
abstract = {SK (SK), a secondary plant metabolite from Lithospermum erythrorhizon, is an inducer of oxidative stress and a DNA Topoisomerase inhibitor with promising anticancer properties. However, the underlying mechanisms, especially the involvement of autophagy in cancer cell death, are poorly understood. Here, we report a novel mechanism of action that activates a noncanonical, Beclin1-independent but ATG5-dependent autophagy pathway triggered by oxidative stress in two distinct subtypes of triple-negative breast cancer (TNBC) cell lines: mesenchymal stem cell-like MDA-MB-231 and basal-like-1 MDA-MB-468. We observed that this noncanonical autophagy pathway specifically targets and degrades nuclear material by nucleophagy. Electron microscopy analysis of both cell lines revealed distinct nuclear alterations, including envelope-limited chromatin sheets (ELCS), nuclear buds, and micronuclei after SK treatment. Furthermore, numerous autophagosomes and lysosomes were found in close proximity to the nuclear membrane, suggesting the occurrence of nucleophagy. The localization of γ-H2AX in nuclear buds and micronuclei observed by confocal microscopy indicated cytosolic leakage of damaged DNA. Additionally, western blot analysis confirmed the role of the cGAS-STING pathway, which is essential for detecting damaged DNA in the cytosol. Inner nuclear membrane protein Lamin B1 was found to interact with LC3II and was subsequently degraded through the nucleophagy pathway. Knockout of ATG5 using CRISPR-Cas9 reduced autophagy, while Beclin1 knockdown did not reduce LC3II conversion, indicating that the process follows a noncanonical autophagy pathway that is dependent on ATG5 and independent of Beclin1. SK induces oxidative stress, leading to mitochondrial depolarization and DNA damage accumulation, which subsequently triggers autophagy and ultimately causes apoptotic cell death. Treatment with the ROS scavenger N-acetylcysteine (NAC) reduced nuclear stress, mitochondrial dysfunction, autophagy, and cell death, emphasizing the role of oxidative stress in SK-induced cell death. MDA-MB-468 cells exhibited greater sensitivity to SK-induced nuclear stress and cell death compared to MDA-MB-231 cells. Taken together, we demonstrate that SK exerts its anticancer effects in TNBC cells through the generation of oxidative stress and noncanonical autophagy, thus highlighting SK's potential for targeted anticancer therapeutics.},
}

@article {pmid41099880,
year = {2025},
author = {Lee, MY and Tseng, WL and Yang, ZY and Chien, TM and Chiu, CC and Lo, YH and Chen, CY and Chang, HW},
title = {Ginger-derived 1-(4'-hydroxy-3'-methoxyphenyl)-5-methoxydecan-3-one (HMPM) induces apoptosis and DNA damage against triple-negative breast cancer cells in vitro.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {1036},
pmid = {41099880},
issn = {1573-4978},
support = {ZYAFGH_A_114013//Zuoying Armed Forces General Hospital/ ; ZYAFGH_A_114013//Zuoying Armed Forces General Hospital/ ; ZYAFGH_A_114013//Zuoying Armed Forces General Hospital/ ; NSTC 114-2314-B-037-032//National Science and Technology Council/ ; NSTC 114-2320-B-037-015//National Science and Technology Council/ ; KMU-TB114009//Kaohsiung Medical University/ ; KMU-TC114A04//Kaohsiung Medical University Research Center/ ; },
mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy/metabolism/genetics/pathology ; *Apoptosis/drug effects ; *DNA Damage/drug effects ; Cell Line, Tumor ; *Zingiber officinale/chemistry/metabolism ; Cell Proliferation/drug effects ; Oxidative Stress/drug effects ; Female ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; },
abstract = {BACKGROUND: Ginger contains many biocompounds, but the antiproliferative effects of its phenylalkanoids (such as 1-(4'-hydroxy-3'-methoxyphenyl)-5-methoxydecan-3-one (HMPM)) on cancer cells are rarely reported. This study aims to explore the antiproliferative effects and mechanisms of HMPM on triple-negative breast cancer (TNBC) cells.

METHODS: ATP-based viability, flow cytometry, and Western blotting were conducted to explore the anti-TNBC in vitro effects and mechanisms.

RESULTS: HMPM inhibits the proliferation of several breast cancer cell lines. Two TNBC cell lines (Hs578T and MDA-MB-231), showing the highest sensitivity to HMPM, exhibited oxidative stress-dependent antiproliferation, as validated by N-acetylcysteine (NAC). Regarding flow cytometry, HMPM changes cell cycle distribution; upregulates apoptosis (annexin V), reactive oxygen species, and mitochondrial oxidative stress; and downregulates mitochondrial membrane potential and glutathione to a greater extent in TNBC cells than in normal breast cells (H184B5F5/M10), attenuated by NAC. Regarding flow cytometry and Western blotting, HMPM notably triggers oxidative stress-mediated caspase 3 and 8 activation in TNBC cells compared to M10 cells. Finally, HMPM causes oxidative DNA damage, as indicated by γH2AX and 8-hydroxy-2-deoxyguanosine flow cytometry.

CONCLUSION: Taken together, the ginger-derived HMPM offers antiproliferative activity against TNBC cells via oxidative stress-dependent changes with limited cytotoxicity to normal cells.},
}

Humans
*Triple Negative Breast Neoplasms/drug therapy/metabolism/genetics/pathology
*Apoptosis/drug effects
*DNA Damage/drug effects
Cell Line, Tumor
*Zingiber officinale/chemistry/metabolism
Cell Proliferation/drug effects
Oxidative Stress/drug effects
Female
Membrane Potential, Mitochondrial/drug effects
Reactive Oxygen Species/metabolism
Cell Survival/drug effects

@article {pmid41098416,
year = {2025},
author = {Kuo, WT and Lai, IH},
title = {Medication, Nutrition, and Hygiene in COVID-19 Prevention and Treatment: A Comprehensive Narrative Review.},
journal = {Global challenges (Hoboken, NJ)},
volume = {9},
number = {10},
pages = {e00223},
pmid = {41098416},
issn = {2056-6646},
abstract = {Despite advances in Coronavirus Disease 2019 (COVID-19) prevention and treatment, emerging variants and persistent challenges continue to affect global health. Studies are retrieved from PubMed using title-based searches for COVID-19, SARS-CoV-2, and related therapies from 2020 to 2025, focusing on randomized controlled trials, systematic reviews, and clinical guidelines. This review explores treatments, nutrients, and adjuvant therapies that support the immune system in fighting COVID-19. It highlights the role of antiviral medications such as remdesivir, nirmatrelvir/ritonavir, and molnupiravir in reducing mortality and hospitalizations. Additionally, adjunctive therapies like corticosteroids, interleukin-6 (IL-6) inhibitors, Janus kinase (JAK) inhibitors, and N-acetylcysteine (NAC) are discussed for their potential to modulate inflammation. Nutritional support, including omega-3 fatty acids, vitamins D, C, and A, zinc, selenium, and probiotics, enhances immune function. Preventive measures, such as hygiene practices, wearing masks, and physical distancing, reduce transmission. An integrated approach that combines antiviral treatments with adjunctive therapies, prevention, and nutrition is crucial for improving outcomes.},
}

@article {pmid41085263,
year = {2025},
author = {Shi, M and Li, X and Fan, Z and Wang, Y and Li, C and Ning, Y and Ma, Y and Sun, M and Xia, X and Du, J and Zheng, JC},
title = {N-Acetylcysteine-Capped TLQP21-Containing Au Nanocages Alleviate Depression in Mice.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c11681},
pmid = {41085263},
issn = {1936-086X},
abstract = {Major depressive disorder (MDD) is the most prevalent neuropsychiatric disorder globally. Promising therapies for MDD are urgently needed due to the limited effectiveness, delayed efficacy, and non-negligible side effects of current treatments. Oxidative stress and neuroinflammation have been recognized as key contributors to MDD. Here, we developed an antioxidant N-acetylcysteine (NAC)-capped Au nanocage (TNNC) that entrapped VGF-derived peptide TLQP21 with neuro-immunomodulatory effects. Once internalized by cells suffering from oxidative stress, NAC was consumed, and TLQP21 was released from TNNC. TNNC administration alleviated MDD-like behaviors of the chronic unpredictable mild stress (CUMS)-exposed mice and effectively relieved oxidative stress in the brains. Moreover, TLQP21 in TNNC inhibits the activation, excessive synaptic pruning, and inflammatory responses of microglia through targeting the complement C1q receptor (C1qR) and complement C3a receptor 1 (C3aR1). This work provides a bioinspired strategy to target multiple pathogenic factors in one nanoparticle for the intervention of MDD and other diseases.},
}

@article {pmid41083115,
year = {2025},
author = {Hu, H and Chen, J and Wang, X and Gong, M and Li, W and Liu, Y and Li, H and Huang, M and Liu, A and Liu, Z},
title = {Resveratrol attenuates trimethyltin chloride-induced cardiac defects via the ROS/Wnt/β-catenin pathway.},
journal = {Comparative biochemistry and physiology. Toxicology & pharmacology : CBP},
volume = {},
number = {},
pages = {110373},
doi = {10.1016/j.cbpc.2025.110373},
pmid = {41083115},
issn = {1532-0456},
abstract = {Trimethyltin chloride (TMT), a toxic byproduct of organotin manufacturing, is an emerging environmental contaminant linked to developmental cardiotoxicity. However, its pathogenic mechanism remains undefined. Here, using zebrafish embryos, we show that TMT exposure induced dose-dependent cardiac malformations, increasing pericardial area by 44.9 % and decreasing heart rate by 16.8 % at 5 μM (both P < 0.001), accompanied by excessive ROS (+48.5 %, P < 0.001) and mitochondrial ROS (+82.8 %, P < 0.001) generation. Co-treatment with resveratrol (RSV) or the ROS inhibitor N-acetylcysteine (NAC) reduced TMT-induced cardiac defects and suppressed ROS and mitochondrial ROS overproduction (all P < 0.05). RSV or NAC also mitigated DNA damage, mitochondrial injury, and apoptosis in the heart. Mechanistically, TMT inhibited the Wnt/β-catenin signaling pathway (-61.7 % β-catenin, P < 0.001), an effect attenuated by RSV or NAC. Inhibition of apoptosis with Ac-DEVD-CHO or activation of Wnt/β-catenin signaling with CHIR likewise alleviated TMT-induced cardiac malformations. These results indicate that TMT disrupts heart development through ROS-mediated suppression of Wnt/β-catenin signaling, leading to mitochondrial damage, DNA damage, and apoptosis. Furthermore, RSV, a dietary antioxidant, provides significant protection against TMT-induced cardiac developmental toxicity. This study identifies potential molecular targets for preventing and treating embryonic heart injury caused by environmental toxicants.},
}

@article {pmid41081839,
year = {2025},
author = {Prisciandaro, JJ and Jarnecke, AM and Joseph, JE and Gray, KM and Santa Ana, EJ and Back, SE},
title = {Effects of N-acetylcysteine treatment on frontal glutamate and GABA levels and associations with drinking quantity in people with co-occurring posttraumatic stress disorder and alcohol use disorder.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41081839},
issn = {1432-2072},
abstract = {RATIONALE: Though half of people with posttraumatic stress disorder (PTSD) develop alcohol use disorder (AUD), co-occurring PTSD and AUD (PTSD + AUD) is associated with more severe clinical outcomes relative to either alone and little remains known about the pathophysiology of PTSD + AUD. PTSD and AUD have each been associated with marked dysfunction in brain glutamate and GABA systems, making these systems promising targets for pharmacological intervention, including N-acetylcysteine (NAC), which restores extracellular glutamate concentrations via GLT-1 and System Xc-.

OBJECTIVES AND METHODS: Based on promising results from our pilot study of NAC, we recently completed a 12-week, randomized, double-blind, placebo-controlled clinical trial of NAC for PTSD + AUD. As part of this trial, we acquired proton MR spectroscopy ([1]H-MRS) data at pretreatment and ~ 8-weeks posttreatment in a subsample of (n = 44) participants to evaluate whether NAC significantly affects frontal glutamate levels (i.e., represented by Glx, glutamate + glutamine), with exploratory evaluation of GABA and glutathione levels, and whether NAC-related changes in neurometabolite levels correspond to decreased drinking and/or PTSD symptoms, in people with PTSD + AUD.

RESULTS: We found that NAC was associated with significantly higher frontal Glx (t = 2.45, p = 0.017), and significantly lower GABA (t = -2.82, p = 0.007) but equivalent glutathione (t = -1.00, p = 0.321), levels relative to placebo. Finally, lower NAC-related GABA, but not Glx or glutathione, levels were significantly associated with decreased drinks per drinking day (t = 2.57, p = 0.014), but not percent drinking days or PTSD symptoms (ps > 0.10).

CONCLUSIONS: Though preliminary, these findings are consistent with the mechanistic hypothesis that NAC reduces drinking quantity through its effects on excitatory and inhibitory neurotransmission in people with PTSD + AUD.},
}

@article {pmid41073871,
year = {2025},
author = {Mandler, WK and Knepp, AK and Leonard, SS and McKinney, W and Keeley, S and Qian, Y},
title = {Characterization of engineered stone dust-induced reactive oxygen species generation and cytotoxicity in vitro.},
journal = {Journal of toxicology and environmental health. Part A},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/15287394.2025.2562482},
pmid = {41073871},
issn = {1528-7394},
abstract = {Engineered stone (ES) fabrication generates respirable dust containing crystalline silica (CS), linked to accelerated silicosis outbreaks. Mechanisms underlying this toxicity, particularly the role of particle aging, remain unclear. In the occupational setting, workers are exposed to engineered stone dust (ESD) upon generation by cutting and grinding ES; however, ESD-initiated toxicity is frequently studied in labs using aged particles. This study aimed to compare radical generation and in vitro cytotoxicity of fresh versus aged ESD. Three different respirable ES types (ES A: 60% CS; B: 20%; C: 0%), granite (30%), and Min-u-Sil 5 (MS5, 99.5%) were generated using an automated cutting system and analyzed either freshly stored under N2 at -80°C or after aging in air at room temperature for 2 weeks. RAW 264.7 macrophages were exposed to particles (10 µg/well, 100 µg/ml, 31.25 µg/cm[2], 24 hr), and viability, apoptosis, necrosis, and intracellular reactive oxygen species (ROS) were measured. Fresh ESD/granite exhibited significantly higher electron paramagnetic resonance (EPR) radical signals than aged counterparts and MS5. Fresh ES/granite reduced macrophage viability, while aged materials/MS5 did not. Apoptosis increased with all particles where fresh/aged difference occurred only in ES B. Necrosis rose markedly with fresh ES A. Intracellular ROS was elevated by some materials, but N-acetylcysteine (NAC) antioxidant failed to prevent cytotoxicity induced by fresh particles. In conclusion, freshly generated ESD displayed greater radical-generating capacity and distinct cytotoxic effects compared to aged ESD, influenced by factors beyond CS content. ROS-independent mechanisms appear crucial for acute cytotoxicity. These findings indicate particle aging as a critical factor in ESD toxicological assessment.},
}

@article {pmid41072831,
year = {2025},
author = {Hösch, NG and Reis, RAF and Novaes, RD and Nascimento, CGO and Ventura, RR and Ruginsk, SG and Amin-Naves, J},
title = {N-acetylcysteine prevents ethanol-induced neuropathic pain by downregulating nociceptive activation of supraspinal brain areas.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.alcohol.2025.10.003},
pmid = {41072831},
issn = {1873-6823},
abstract = {Considering the important clinical applications of N-acetylcysteine (NAC), the present study investigated the effects of NAC treatment on ethanol-induced neuropathic alterations. For this purpose, a total number of eighty-one male adult Wistar rats were used. Alcoholic neuropathy was induced by administration of 38 % (v/v) ethanol (10 g/kg/day, oral gavage) for 10 weeks. NAC solution (1.4 g/kg/day, oral gavage) was administered immediately after ethanol treatment, also for 10 weeks. The electronic von Frey, Randall Selitto and tail flick tests were used to characterize the nociceptive thresholds to mechanical and thermal stimulations. The Rota-rod test was used to evaluate motor coordination, whereas the open field test was employed to assess general locomotor activity. The present study also determined the integrity of the sciatic nerve and the number of c-Fos immunoreactive neurons in key brain structures. As expected, long-term exposure to ethanol reduced the thickness of myelin sheath in the peripheral nerve, as well as induced allodynia, mechanical and thermal hypernociception, as well as motor incoordination. Although ethanol treatment did not alter general locomotor activity, it increased the number of rearing events, indicating enhanced exploratory behavior. In the brain, chronic ethanol consumption was associated with higher levels of c-Fos expression in the dorsal raphe nucleus, parvocellular and magnocellular groups of the hypothalamic paraventricular nucleus, and also in the periaqueductal gray. Consistent with its protective effects, NAC treatment prevented the development of all ethanol-induced alterations, including at central level. Taken together, these results suggest that NAC consistently prevents ethanol-induced neuropathy.},
}

@article {pmid41071453,
year = {2025},
author = {Ma, G and Yin, G and Wu, X and Yang, Z},
title = {FAM72A Promotes Colorectal Cancer Progression by Regulating Reactive Oxygen Species and Inhibiting Cellular Pyroptosis.},
journal = {Digestive diseases and sciences},
volume = {},
number = {},
pages = {},
pmid = {41071453},
issn = {1573-2568},
abstract = {BACKGROUND AND AIMS: Colorectal cancer (CRC) is a common malignant tumor worldwide with a complex pathogenesis and an urgent need for new molecular targets. The aim of this study was to investigate the expression of FAM72A in CRC and its potential mechanism to affect cancer cell proliferation and invasion through regulating cellular pyroptosis.

METHODS: The expression of FAM72A in various cancers was analyzed by TIMER2.0 and GEPIA2 databases, and its relationship with the prognosis of CRC patients was evaluated. FAM72A was knocked down and overexpressed in CRC cell lines HCT116 and DLD1, respectively, and changes in cell proliferation and invasion ability were assessed by CCK-8, EdU, Transwell, and scratch assays. Meanwhile, the regulatory effects of FAM72A on cellular pyroptosis-associated proteins and inflammatory factors were detected by Western blotting and ELISA, and the role of ROS in FAM72A-regulated cellular pyroptosis and cancer cell behaviors was further explored by N-Acetylcysteine (NAC) intervention assay. Finally, the effect of FAM72A on tumor growth was verified by in vivo nude mouse experiments.

RESULTS: High levels of FAM72A expression were observed in CRC, linking it to poor prognosis in patients. Knockdown of FAM72A significantly inhibited the proliferation, migration, and invasion of CRC cells and activated cellular pyroptosis, accompanied by the upregulation of NLRP3, Caspase-1, and GSDMD expression and the increased secretion of IL-1β and IL-18. In contrast, overexpression of FAM72A inhibited cell pyroptosis and enhanced cancer cell proliferation and invasion. NAC intervention experiments demonstrated that ROS played a critical role in FAM72A-regulated cell pyroptosis and CRC progression. Furthermore, in vivo experiments showed that knockdown of FAM72A significantly inhibited the growth of subcutaneous transplanted tumors in nude mice.

CONCLUSION: FAM72A inhibits cellular pyroptosis by decreasing ROS levels, which in turn promotes the proliferation and invasion of CRC cells, and it is expected to be a potential therapeutic target for CRC.},
}

@article {pmid41067161,
year = {2025},
author = {Ogawa, H and Uchida, Y and Enjuto, LE},
title = {N-acetylcysteine inhalation improved sputum rheology in chronic productive cough: Clinical application in two cases.},
journal = {Respiratory investigation},
volume = {63},
number = {6},
pages = {1246-1249},
doi = {10.1016/j.resinv.2025.08.009},
pmid = {41067161},
issn = {2212-5353},
abstract = {This pilot study evaluated the effects of inhaled N-acetylcysteine (NAC) on sputum rheology in patients with chronic productive cough (CPC). Rheological measurements before and 30 min after inhalation were compared retrospectively in 16 outpatients receiving either NAC (n = 9) or bromhexine hydrochloride (BXH) (n = 7). NAC inhalation significantly reduced critical strain (γC), an indicator of sputum stringiness, from 2370 [1310-4390] % to 643 [389-700] % (median and interquartile range), with a significantly greater effect than BXH. This reduction was observed regardless of airway fungal colonization. In addition, two case reports, a 67-year-old man with bronchorrhea and a 79-year-old woman with refractory asthma, demonstrated improved quality-of-life scores evaluated with the Cough and Sputum Assessment Questionnaire (CASA-Q) and rheological improvement following 1-2 weeks of twice-daily NAC inhalation. These findings suggest that nebulized NAC may be a promising add-on therapy for refractory airway diseases characterized by high sputum stringiness (γC).},
}

@article {pmid41065101,
year = {2025},
author = {Kang, LP and Li, NN and Chen, PS and Chen, HH and Huang, DH and Jiang, ZB},
title = {Plumbagin Triggers STING Pathway Activation to Suppress Non-Small Cell Lung Cancer Progression.},
journal = {Chemical biology & drug design},
volume = {106},
number = {4},
pages = {e70176},
doi = {10.1111/cbdd.70176},
pmid = {41065101},
issn = {1747-0285},
support = {2022A1515110790//Guangdong Basic and Applied Basic Research Foundation of China/ ; 2024A1515012478//Guangdong Basic and Applied Basic Research Foundation of China/ ; 20251345//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20221361//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 20241285//Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 2320004000290//Zhuhai Science and Technology Innovation Bureau/ ; 2420004000007//Zhuhai Science and Technology Innovation Bureau/ ; 2420004000006//Zhuhai Science and Technology Innovation Bureau/ ; 242//Zhuhai Science and Technology Innovation Bureau/ ; 202303//Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine/ ; B2025352//Medical Science and Technology Research Fund of Guangdong Province/ ; [2023] 108//Guangdong Province-Provincial Chinese Medicine construction special fund named Traditional Chinese Medicine Inheritance Studio construction project Guangdong Chinese Medicine Office Letter/ ; },
mesh = {*Naphthoquinones/pharmacology/chemistry ; Humans ; *Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/metabolism ; *Lung Neoplasms/pathology/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; *Membrane Proteins/metabolism/antagonists & inhibitors/genetics ; Apoptosis/drug effects ; Signal Transduction/drug effects ; Cell Proliferation/drug effects ; Cell Line, Tumor ; *Antineoplastic Agents, Phytogenic/pharmacology/chemistry ; Cell Survival/drug effects ; },
abstract = {Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Plumbagin (PLBG), a naturally occurring active naphthoquinone derived from Chinese herbal plants, exhibits anti-cancer effects across multiple cancer types. However, the mechanisms underlying PLBG-induced anti-tumor activity in NSCLC remain incompletely understood. Our study demonstrated that PLBG significantly inhibited NSCLC cell proliferation and induced apoptosis by elevating intracellular and mitochondrial reactive oxygen species (ROS), leading to mitochondrial dysfunction. The ROS scavenger N-acetylcysteine (NAC) abrogated PLBG-induced apoptosis and restored cell viability. Notably, RNA sequencing analysis revealed that differentially expressed genes in PLBG-treated cells were enriched in the cytosolic DNA-sensing pathway and STING pathway. Mechanistically, PLBG treatment activated the STING pathway and upregulated key chemokines (CXCL10, CXCL9, CCL5) in NSCLC cells. Critically, STING inhibition by H151 attenuated PLBG-induced apoptosis, confirming the essential role of STING. These results suggest that PLBG exerts potent anti-NSCLC effects through ROS-mediated apoptosis, STING pathway activation, and chemokine induction, while concurrently inhibiting pro-survival signaling. These findings position PLBG as a promising therapeutic candidate for NSCLC treatment.},
}

*Naphthoquinones/pharmacology/chemistry
Humans
*Carcinoma, Non-Small-Cell Lung/pathology/drug therapy/metabolism
*Lung Neoplasms/pathology/drug therapy/metabolism
Reactive Oxygen Species/metabolism
*Membrane Proteins/metabolism/antagonists & inhibitors/genetics
Apoptosis/drug effects
Signal Transduction/drug effects
Cell Proliferation/drug effects
Cell Line, Tumor
*Antineoplastic Agents, Phytogenic/pharmacology/chemistry
Cell Survival/drug effects

@article {pmid41063445,
year = {2025},
author = {Kim, TW and Ko, SG},
title = {Jujuboside B Induces Ferroptosis and Overcomes Radioresistance Through the PPARγ-ATF3-Gpx4 Signaling Pathway in Non-Small Cell Lung Cancer.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70111},
pmid = {41063445},
issn = {1099-1573},
support = {2018R1D1A1B07048556//National Research Foundation of Korea/ ; 2020R1A5A2019413//National Research Foundation of Korea/ ; },
abstract = {Jujuboside B (JJB) is a saponin extracted from the Ziziphus jujuba var. spinose and has been reported to have anticancer effects. However, the detailed mechanism of its anti-cancer effect in non-small cell lung cancer (NSCLC) remains unclear. New combination therapies may be able to overcome TRAIL resistance. In this study, we found that JJB regulates the activity of PPARγ and investigated whether the combination of JJB and TRAIL had synergistic anti-cancer effects against NSCLC cells. Experimental procedure: We assessed cell death induced by the combination of TRAIL and JJB in NSCLC cells using ATPlite Luminescence, LDH, and caspase activity assays. We also examined endoplasmic reticulum (ER) stress-mediated cell death using the intracellular calcium assay and western blot analysis. The combination of JJB and TRAIL significantly reduced cell viability and increased apoptotic cell death by binding CHOP to the DR4/5 promoter in NSCLC cells. JJB induced ferroptosis by increasing the expression of Nox4 and ATF3 and the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as by reducing the expression of SLC7A11 and Gpx4 and the level of glutathione (GSH) through the activation of ER stress. Consistent with this, N-acetylcysteine (NAC) suppressed ER stress-mediated ferroptosis by reducing the expression of Nox4, ATF3, and cleaved caspase-3 and by increasing the expression of SLC7A11 and Gpx4 in JJB-treated NSCLC cells. In radioresistant NSCLC models, combined treatment with JJB and radiation induced ferroptosis and overcame radioresistance by regulating the epithelial-mesenchymal transition (EMT) phenomenon. Therefore, JJB could be a potential therapeutic strategy in NSCLC.},
}

@article {pmid41061823,
year = {2025},
author = {Tsai, HR and Chang, WC and Lee, YC},
title = {Oral acetylcysteine and the risk of age-related macular degeneration: A retrospective cohort study.},
journal = {Ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ophtha.2025.09.025},
pmid = {41061823},
issn = {1549-4713},
abstract = {PURPOSE: N-acetylcysteine (NAC) functions as both a direct antioxidant agent and precursor for glutathione synthesis, both of which are implicated in the pathogenesis of age-related macular degeneration (AMD). However, whether NAC use confers protective effects against AMD remains unclear. This study aimed to investigate potential associations between NAC use and the risks of AMD development in a large cohort of the Taiwanese population.

DESIGN: Retrospective cohort study PARTICIPANTS AND CONTROLS: The study included 22,498 NAC users and 138,607 non-NAC users between 2003 and 2017 before propensity score matching (PSM).

METHODS: This nationwide, population-based study leveraged data from the Taiwan National Health Insurance Research Database. PSM was applied to ensure comparability of baseline demographics and comorbidities between NAC users and non-users. Stratified analyses by age and sex were conducted, and a cumulative defined daily dose was calculated to evaluate dose-response relationships among NAC users. Cox proportional hazards regression models were employed post-PSM to estimate the hazard ratio (HR) for each outcome.

MAIN OUTCOME MEASURES: Outcome measures included the HR of overall, dry, and wet AMDs RESULTS: After PSM, 5234 patients were included in each cohort: NAC users and non-NAC users. NAC users exhibited a significantly lower risk of AMD than non-users did (HR 0.19; 95% CI: 0.14-0.26; p < 0.001). This protective effect was observed for both dry (HR 0.19; 95% CI: 0.14-0.26) and wet (HR 0.31; 95% CI: 0.12-0.81) AMDs. Stratified analyses demonstrated a reduced risk of AMD among NAC users, consistent across different age and sex groups. A dose-response relationship was identified, with higher cumulative doses of NAC associated with greater reductions in the risk of AMD and dry AMD. Sensitivity analyses for patients aged ≥ 60 and ≥ 70 years further supported the association between NAC use and reduced AMD risk, particularly for dry AMD.

CONCLUSIONS: NAC use was associated with a significantly reduced risk of AMD, especially dry AMD. These findings support the need for further investigation into the effectiveness of NAC as a preventive treatment for AMD.},
}

@article {pmid41061299,
year = {2025},
author = {Park, A and Son, YG and Lee, KW and Kim, JY and Kim, KD},
title = {Rotenone-mediated mitochondrial ROS generation inhibits melanogenesis in B16F10 cells by inducing the ERK activation-MITF degradation pathway.},
journal = {Biochemical and biophysical research communications},
volume = {786},
number = {},
pages = {152762},
doi = {10.1016/j.bbrc.2025.152762},
pmid = {41061299},
issn = {1090-2104},
abstract = {Pachyrhizus erosus seeds have been reported to have various biological activities, including antifungal, antisecretory, insecticidal, antibacterial, and antispasmodic properties. In this study, we evaluated the hypopigmentation effects of the ethanol extract of Pachyrhizus erosus seeds (PESE), identified rotenone as a representative active metabolite, and proposed a mechanism for inhibiting α-MSH-mediated melanogenesis in B16F10 cells. PESE treatment effectively inhibited melanin synthesis in B16F10 cells stimulated with α-MSH or forskolin. Among the three major metabolites characterized from PESE, pachyrrhizine, neotenone, and rotenone, only rotenone exhibited a strong inhibitory effect on melanin synthesis at a concentration of 8 nM, with minimal cytotoxicity. Rotenone suppressed transcriptional expression of melanosomal genes, TRP-1 and TYR, in B16F10 cells stimulated by α-MSH, primarily due to a reduction in the protein level of microphthalmia-associated transcription factor (MITF). Rotenone, an inhibitor of mitochondrial electron transport chain complex I, induced mitochondrial reactive oxygen species (ROS) production, and the increased ROS activated ERK. Treatment with N-acetylcystein (NAC), a ROS scavenger, or PD98059, an ERK inhibitor, suppressed the decrease in MITF protein induced by rotenone, thereby eliminating the hypopigmentation effect of rotenone. These findings provide novel insights into the whitening activity mechanism of rotenone and suggest that mitochondrial damage may affect melanogenesis.},
}

@article {pmid41052996,
year = {2025},
author = {Szkudlarek, HJ and Singh Mann, R and Wieczerzak, K and Sarikahya, MH and Uzuneser, TC and De Felice, M and Rodríguez-Ruiz, M and Galindo, JP and Pusparajah, M and Whitehead, SN and Rushlow, WJ and Hardy, DB and Schmid, S and Yeung, KK and Laviolette, SR},
title = {The antioxidant N-acetylcysteine prevents cortical neuropathological phenotypes caused by adolescent Δ-9-tetrahydrocannabinol exposure in male rats.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {374},
pmid = {41052996},
issn = {2158-3188},
support = {MOP-123378//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
mesh = {Animals ; *Dronabinol/toxicity/adverse effects ; *Acetylcysteine/pharmacology ; Male ; *Antioxidants/pharmacology ; Rats ; *Oxidative Stress/drug effects ; *Prefrontal Cortex/drug effects/pathology ; Rats, Sprague-Dawley ; Phenotype ; Disease Models, Animal ; },
abstract = {Clinical and pre-clinical evidence demonstrates that adolescent Δ-9-tetrahydrocannabinol (THC) exposure, the primary psychoactive component of cannabis, increases the risk of developing neuropsychiatric symptoms in later life. The medial prefrontal cortex (mPFC) serves as a pathophysiological nexus point underlying many cannabis-related pathophysiological outcomes. Nevertheless, the molecular mechanisms underlying these risk factors are poorly understood. THC increases oxidative stress, which is a well-established causal factor for increased neuropsychiatric risk, including schizophrenia. N-acetylcysteine (NAC) is an antioxidant glutathione precursor that normalizes glutamate and GABA activity in neuropathological states. We examined if NAC may prevent the pathophysiological impacts of THC using a rodent model of adolescent brain development and chronic THC exposure. We report that NAC treatment prevents cognitive, synaptic, neuronal and neurochemical deficits induced by adolescent THC. These findings highlight the critical role of THC-induced oxidative stress as a contributing factor to cannabinoid-mediated neuropsychiatric risk and identifies a novel antioxidant treatment candidate for the prevention and/or reversal of these pathophysiological outcomes.},
}

Animals
*Dronabinol/toxicity/adverse effects
*Acetylcysteine/pharmacology
Male
*Antioxidants/pharmacology
Rats
*Oxidative Stress/drug effects
*Prefrontal Cortex/drug effects/pathology
Rats, Sprague-Dawley
Phenotype
Disease Models, Animal

@article {pmid41049074,
year = {2025},
author = {Sun, X and Shen, L and Zheng, R and Tao, M and Chen, S},
title = {MRPL35 Attenuates Neonatal Parenteral Nutrition-Associated Cholestasis by Modulating the ROS/JNK/NF-κB Pathway.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {13489-13502},
pmid = {41049074},
issn = {1178-7031},
abstract = {OBJECTIVE: This study aimed to elucidate the role of the MRPL35/ROS/JNK/NF-κB signaling pathway in the pathogenesis of neonatal parenteral nutrition-associated cholestasis (PNAC) to identify underlying mechanisms and potential therapeutic targets.

METHODS: The study employed both human and animal models. Neonates receiving parenteral nutrition for at least 2 weeks were divided into PNAC (n=10) and control groups (n=13). A PNAC model was established in male Sprague-Dawley rats (parenteral nutrition for 14 days, n=6/group), with interventions including adenovirus-mediated MRPL35 overexpression and N-acetylcysteine (NAC) treatment. Inflammatory markers, oxidative stress indicators, and signaling pathway activation were assessed using ELISA, immunohistochemistry, qRT-PCR, and Western blotting.

RESULTS: Clinically, neonates with PNAC exhibited elevated serum levels of AST, DBil, TBA, TNF-α, and IL-1β, along with reduced levels of anti-inflammatory cytokines (IL-4, IL-10), increased ROS, and higher apoptosis in peripheral blood mononuclear cells (PBMCs). MRPL35 expression was significantly downregulated and JNK and NF-κB pathways were activated. In the animal model, PNAC rats showed severe liver injury, elevated TNF-α, IL-1β and ROS in hepatocytes, and higher hepatocyte apoptosis; the expression of MRPL35 mRNA was significantly downregulated. Overexpression of MRPL35 reduced JNK/NF-κB activation, inflammatory cytokines, oxidative stress and liver injury, effects that were enhanced by co-treatment with N-acetylcysteine (NAC).

CONCLUSION: The MRPL35/ROS/JNK/NF-κB signaling pathway plays a critical role in the pathogenesis of PNAC. Targeting MRPL35 is expected to alleviate liver injury by blocking mitochondrial ROS signaling, offering a novel precision treatment model targeting the mitochondrial-inflammation axis for PNAC.},
}

@article {pmid41045636,
year = {2025},
author = {Sreevaram, HH and Kishore, A and Sivanesan, S and Prabhakaran, M and Karunakaran, B and Kasirajan, SP and Jyothi, AK and Maria Francis, Y},
title = {Comparative neuroprotective efficacy of N-acetylcysteine and naringin in lead-induced neurotoxicity: Restoration of BDNF, neurotransmitters, and cognitive function.},
journal = {Morphologie : bulletin de l'Association des anatomistes},
volume = {109},
number = {367},
pages = {101075},
doi = {10.1016/j.morpho.2025.101075},
pmid = {41045636},
issn = {1286-0115},
abstract = {BACKGROUND: Exposure to lead acetate is reported to induce neurotoxicity associated with cognitive dysfunction, neurotransmitter dysfunction, oxidative stress, neuroinflammation, and neuronal damage in the hippocampus. Flavonoids and other natural compounds possessing antioxidant and neuroprotective properties can be of therapeutic interest. In the current study, naringin's protective property as a flavonoid was compared with that of N-acetylcysteine (NAC) against lead-induced neurotoxicity in rats.

METHODS: Adult rats were randomly distributed into control, lead acetate-treated, lead+NAC-treated, lead+low-dose naringin, and lead+high-dose naringin groups, each group containing 6 animals. The Novel Object Recognition (NOR) test was used for the evaluation of cognitive function. Biochemical analysis of hippocampal glutamate, acetylcholine, Brain-Derived Neurotrophic Factor (BDNF), Nuclear factor erythroid 2-related factor 2 (Nrf2), pro-inflammatory markers (IL-6, GFAP), and serum lead levels was done. Histopathological analysis of hippocampal sections by crystal violet staining was done.

RESULTS: Exposure to lead acetate-induced severe neurotoxicity in the guise of compromised recognition memory, reduced glutamate and acetylcholine content, reduced BDNF and Nrf2 expression, increased IL-6 and GFAP content, and severe hippocampal neuronal damage. NAC treatment effectively reversed cognitive function, neurotransmitter content, neurotrophic factors, and diminished neuroinflammation. Dose-dependent neuroprotection was afforded by naringin, where the high-dose group had better recovery in all the parameters than the low-dose group. Interestingly, high-dose naringin was similar to or even larger than that of NAC's neuroprotection, normalization of hippocampal histoarchitecture, enhancement of antioxidant defense, and decrease in pro-inflammatory markers and serum lead levels.

CONCLUSION: Lead acetate causes profound neurotoxicity on cognition, neurotransmission, oxidative stress, and inflammation. Naringin, especially at high doses, exhibits highly potent neuroprotective effects, such as NAC, preventing lead-induced cognitive dysfunction and hippocampal pathology by displaying antioxidant, anti-inflammatory, and neurotrophic effects. The results propose naringin as a potential natural drug candidate for preventing and/or treating lead-induced neurotoxicity.},
}

@article {pmid41044637,
year = {2025},
author = {Havaldar, AA},
title = {Successful management of paraquat poisoning: a case report.},
journal = {Journal of medical case reports},
volume = {19},
number = {1},
pages = {479},
pmid = {41044637},
issn = {1752-1947},
mesh = {Humans ; *Paraquat/poisoning ; Adult ; Male ; Female ; *Herbicides/poisoning ; *Immunosuppressive Agents/therapeutic use/administration & dosage ; *Cyclophosphamide/therapeutic use/administration & dosage ; Acetylcysteine/therapeutic use ; Treatment Outcome ; Renal Replacement Therapy/methods ; India ; },
abstract = {BACKGROUND: Paraquat is a herbicide used for weed control and is one of the lethal poisons associated with high mortality. Exposure to this compound could be accidental or as a deliberate self-harm. Clinical manifestations can range from mild symptoms initially to multiorgan failure. Owing to high case fatality (50-90%) and no specific antidote is available; different treatment regimens are proposed with variable success rates. Here, we present two patients with paraquat poisoning, their initial presentation, clinical progress, and successful management.

CASE PRESENTATION: Two young adults, one 29-year-old male and one 32-year-old female patient from South India, presented with gastrointestinal symptoms and worsening renal and Liver failure. Patients had already received gastric lavage at the local hospital and later transferred to our hospital. We initiated immunosuppressive therapy with cyclophosphamide at 15 mg/kg/day for 3 days and steroids. Both patients received renal replacement therapy and N-acetyl cysteine infusion. We observed improvement in clinical and biochemical parameters over a week. There were no respiratory symptoms throughout the hospitalization. At the time of discharge, both patients were off renal replacement therapy. On long-term follow-up after 2.5 years, both patients had recovered well without any renal dysfunction.

CONCLUSION: This case report highlights the successful management of paraquat poisoning with high-dose cyclophosphamide with steroids. The timely initiation of immunosuppression prevented disease progression and facilitated prompt recovery.},
}

Humans
*Paraquat/poisoning
Adult
Male
Female
*Herbicides/poisoning
*Immunosuppressive Agents/therapeutic use/administration & dosage
*Cyclophosphamide/therapeutic use/administration & dosage
Acetylcysteine/therapeutic use
Treatment Outcome
Renal Replacement Therapy/methods
India

@article {pmid41038427,
year = {2025},
author = {Silva, SANM and Machado, FDS and Santos, LS and de Castro, MVL and Nogueira, ML and Soares, MBP and Alves Serafim Rocha, S and Araújo, RM and Dias, RB and Bezerra, DP and Araújo, AJ and Marinho Filho, JDB},
title = {CORDIAQUINONE B INDUCES CYTOTOXICITY AND OXIDATIVE STRESS-MEDIATED APOPTOSIS IN HUMAN COLORECTAL CANCER CELLS IN VITRO AND IN VIVO.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111764},
doi = {10.1016/j.cbi.2025.111764},
pmid = {41038427},
issn = {1872-7786},
abstract = {Cordiaquinones are natural molecules derived from the Varronia and Cordia genera with diverse biological potential. In this work, the effects of Cordiaquinone B were initially evaluated in a panel of cancer cell lines. Subsequently, it was first-hand investigated both in vitro and in vivo in human colorectal adenocarcinoma (HCT-116) cells. Experiments were conducted using two-dimensional (2D) and three-dimensional (3D) cell cultures and in the HCT-116 xenograft model in immunodeficient CB17-SCID mice. Cordiaquinone B inhibited the viability of both adherent and non-adherent cancer cell lines without inducing hemolysis in human erythrocytes. In Cordiaquinone B-treated HCT-116 cells, morphological changes and alterations in apoptosis-related protein levels were observed, indicating an apoptotic mechanism associated with mitochondrial oxidative stress. This was supported by an increased mitochondrial superoxide content and prevention of observed cytotoxic and apoptotic effects by N-acetylcysteine (NAC) pretreatment. In the 3D tumor model of HCT-116 spheroids, Cordiaquinone B treatment led to a spheroid size reduction. Additionally, in CB17-SCID mice, a dose of 3 mg/kg/day inhibited HCT-116 tumor growth by 42.6% without causing severe organ toxicity or alterations in hematological parameters, except for mild to moderate hepatic and pulmonary alterations. These results demonstrate the efficacy of Cordiaquinone B and highlight its potential as a promising candidate for colorectal cancer therapy.},
}

@article {pmid41032464,
year = {2025},
author = {Li, H and Wei, X and Sun, H},
title = {Molecular Insights into Bismuth's New Applications against Antimicrobial Resistance and Coronaviruses.},
journal = {Accounts of chemical research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.accounts.5c00471},
pmid = {41032464},
issn = {1520-4898},
abstract = {ConspectusBismuth, a heavy metal distinguished by its low toxicity, compared to lead or mercury, has long been associated with medicine for the treatment of various conditions, notably as a key component in triple and quadruple therapies for eradicating Helicobacter pylori, including antibiotic-resistant strains. Compounds such as bismuth subsalicylate (BSS) and colloidal bismuth subcitrate (CBS) enhance the efficacy of antibiotics, e.g., metronidazole and tetracycline. Over the past two decades, the knowledge on the molecular mechanism of action of bismuth drugs has been significantly advanced, in particular with the aid of the metallomics/metalloproteomics, facilitating the discovery of novel therapeutic applications beyond H. pylori eradication.This Account describes how the molecular mechanism of action of bismuth drugs was unveiled at a system level by multiple-metalloproteomics approaches, which enable the comprehensive identification of bismuth-binding proteins with diverse affinities in bacteria. By integration with other techniques such as proteomics, bioinformatics and molecular biology, the sustained efficacy of bismuth drugs was attributable to their capacities to disrupt multiple biological pathways through binding and functional perturbation of key enzymes, in particular, those enzymes bearing CXnC (n = 2, 7), CXnH (n = 5, 6) and HXnH (n = 0-2, 8) motifs, in consistence with the thiophilic nature and high acidic property of bismuth.The generated knowledge on the mode of action of bismuth drugs lays a solid foundation for further exploration of their novel therapeutic applications. Our extensive studies have revealed that bismuth drugs and compounds hold great potential as versatile agents in combating antimicrobial resistance (AMR) crisis through co-therapies with clinically used antibiotics. This includes bismuth drugs as broad-spectrum inhibitors of metallo-β-lactamases (MBLs), enzymes responsible for resistance to β-lactam antibiotics, to fight against MBLs-positive bacterial infection together with β-lactams; bismuth drugs serve as adjuvants of Cefiderocol (Fetroja), the only clinically approved sideromycin, against infections caused by multidrug-resistant Pseudomonas aeruginosa and Burkholderia cepacia; bismuth drugs (and relevant compounds) in combination with clinically used antibiotics could combat Pseudomonas aeruginosa infections by disrupting iron homeostasis and functionally impairing Fe-S cluster-containing enzymes in multidrug-resistant Pseudomonas aeruginosa; newly developed bismuth compounds serve as novel metalloantibiotics to combat AMR. Moreover, the ability of bismuth to disrupt key zinc finger proteins for the transcription and replication in coronavirus rendered its new potential in treating coronavirus infections, particularly SARS-CoV-1 and SARS-CoV-2. Combining clinically used bismuth drugs with N-acetyl cysteine (NAC), a thiol-containing drug, increases bismuth uptake in blood plasma to therapeutic levels for SARS-CoV-2 without apparent toxicity. Bismuth drugs, therefore, hold great potential for the treatment of viral infections.We anticipate that our mechanism-guided discoveries of bismuth's new therapeutic applications are poised to inspire researchers in relevant fields to rationally design drugs (and metallodrugs) and repurpose FDA-approved drugs, ultimately leading to the development of new effective therapeutics for combating emerging infectious diseases, which will positively impact human health and well-being.},
}

@article {pmid41031098,
year = {2025},
author = {Leavy, OC and Goemans, AF and Hernandez-Beeftink, T and Stockwell, AD and Allen, RJ and Guillen-Guio, B and Adegunsoye, A and Booth, HL and Fahy, WA and Fingerlin, TE and Virk, HS and Hall, IP and Hart, SP and Hill, MR and Hirani, N and Kaminski, N and Ma, SF and McAnulty, RJ and Sheng, XR and Millar, AB and Molina-Molina, M and Navaratnam, V and Neighbors, M and Parfrey, H and Saini, G and Sayers, I and Strek, ME and Tobin, MD and Whyte, MKB and Zhang, Y and Maher, TM and Molyneaux, PL and Oldham, JM and Yaspan, BL and Flores, C and Martinez, F and Reynolds, CJ and Schwartz, DA and Noth, I and Jenkins, RG and Wain, LV},
title = {Sex-specific genetic effects on susceptibility to idiopathic pulmonary fibrosis.},
journal = {ERJ open research},
volume = {11},
number = {5},
pages = {},
pmid = {41031098},
issn = {2312-0541},
abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood; differing environmental exposures due to historically sex-biased occupations and diagnostic bias are possible explanations. To date, over 20 independent genetic association signals have been reported for IPF susceptibility, but these have been discovered when combining males and females. The objectives of the present study were to assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF and to test for sex-specific associations with IPF susceptibility.

METHODS: We performed a genome-wide single nucleotide polymorphism (SNP)-by-sex interaction study meta-analysis of IPF risk in six independent case-control studies comprising 4561 cases (1280 females, 3281 males) and 22 888 controls (8360 females, 14 528 males) of European genetic ancestry. We used polygenic risk scores (PRSs) comprising common (minor allele frequency >1%) autosomal variants to assess differences in genetic risk prediction between males and females.

RESULTS: The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific association results. Three new independent genetic association signals were identified (p<1×10[-6]).

CONCLUSIONS: The predictive accuracy of common autosomal SNP-based PRSs did not vary significantly between males and females. We prioritised three genetic variants whose effect on IPF risk may be modified by sex. These findings would not account for the differences in prevalence between males and females. Future studies should ensure adequate representation of both sexes.},
}

@article {pmid41030491,
year = {2025},
author = {Iguh, C and Bakhsh, I and Grujic, S},
title = {Acute Hepatitis in a Patient Treated With Ribociclib for Metastatic Breast Carcinoma.},
journal = {Journal of medical cases},
volume = {16},
number = {9},
pages = {372-380},
pmid = {41030491},
issn = {1923-4163},
abstract = {Ribociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, is widely used in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Although hepatotoxicity is a recognized adverse effect, severe cases of ribociclib-induced liver injury with histologic confirmation of submassive hepatic necrosis remain rare. We describe a case of a postmenopausal woman with newly diagnosed stage IV HR+/HER2-negative invasive lobular carcinoma who developed acute hepatocellular injury 8 weeks after initiating ribociclib and anastrozole. The patient presented with fatigue, jaundice, and dark urine, and was found to have markedly elevated transaminases (alanine aminotransferase 1,825 U/L; aspartate aminotransferase 1,536 U/L) and hyperbilirubinemia. A thorough workup excluded viral, autoimmune, and obstructive hepatobiliary causes. Liver biopsy demonstrated confluent centrilobular necrosis without fibrosis or significant inflammation. Causality assessments yielded an R-factor of 20.73, a Roussel Uclaf Causality Assessment Method score of 10 (highly probable), and a Naranjo score of 7 (probable). Ribociclib was discontinued and intravenous N-acetylcysteine (NAC) initiated, leading to gradual normalization of liver enzymes. The patient was maintained on anastrozole alone, with no recurrence of liver injury and stable disease at 13-month follow-up. This case highlights the potential for ribociclib to induce severe hepatocellular injury with histologic evidence of submassive necrosis. Early recognition and structured causality assessment ensures patient safety. In patients with significant hepatotoxicity, discontinuation of ribociclib and non-rechallenge may be prudent. Furthermore, consideration of NAC in management is important in cases demonstrating persistent transaminitis despite ribociclib discontinuation.},
}

@article {pmid41023622,
year = {2025},
author = {Diako, K and Rahimi, S and Mirbagheri Saghaleksari, SA and Mousavi Eshkelani, SM and Keshavarz Taramsari, N and Beigi Harchegani, A and Mohsenifar, Z and Shahriarinour, M and Ranji, N},
title = {N-Acetylcysteine as an anti-oxidant and anti-inflammatory agent in decreasing histopathological damages and oxidative stress after mercury exposure in lung tissue of rats.},
journal = {BMC biotechnology},
volume = {25},
number = {1},
pages = {108},
pmid = {41023622},
issn = {1472-6750},
abstract = {BACKGROUND: Mercury (Hg) is a naturally occurring heavy metal with high toxicitythat affects various organs. This study aimed to evaluate the protective effects of N-acetylcysteine (NAC) on the lung tissue of Wistar rats exposed to mercury.

METHODS: Rats were divided into five groups: H1 (control), H2 (single dose of Hg), H3 (continuous dose of Hg), H4 (single dose of Hg+ single dose of NAC), and H5 (continuous dose of Hg+ continuous dose of NAC). The expression levels of SOD1, NOS, TIMP1, Fibronectin1, HIF1, MPO, MMP2 and TIMP2 were analyzed using qRT-PCR.

RESULTS: Mercury levels in the blood and lung tissues significantly increased in the H2 and H3 groups compared to the H4 and H5 groups, respectively. Hg exposure in H3 group significantly (P < 0.001) led to the upregulation of MPO (4.55-fold), HIF1(4.31-fold), MMP2 (4.20-fold), TIMP1(3.18-fold), TIMP2 (4.83-fold), NOS (3.52-fold), and FN1 (3.52-fold), along with the downregulation of SOD1 (0.51-fold) compare to control group (H1). In contrast, rats treated with NAC after Hg exposure in H5 group significantly (p < 0.01–0.001) showed downregulation of MPO (2.49-fold), HIF1(2.12-fold), MMP2 (1.94-fold), TIMP1(1.92-fold), TIMP2 (1.96-fold), NOS (2.00-fold), and FN1 (1.90-fold), and upregulation of SOD1 (0.76-fold) compare to H3 group. A significant reduction in mercury levels was also observed in the blood and lung tissue of rats treated with NAC compared to those exposed Hg alone.

CONCLUSION: NAC exerts a protective effect against mercury-induced cytotoxicity and genotoxicity in rat lungs by scavenging mercury and modulating the expression of oxidative stress-related genes.},
}

@article {pmid41020832,
year = {2025},
author = {Cherneva, DI and Kehayova, G and Dimitrova, S and Dragomanova, S},
title = {The Central Nervous System Modulatory Activities of N-Acetylcysteine: A Synthesis of Two Decades of Evidence.},
journal = {Current issues in molecular biology},
volume = {47},
number = {9},
pages = {},
pmid = {41020832},
issn = {1467-3045},
abstract = {N-acetylcysteine (NAC) has garnered increasing interest for its neurotherapeutic capabilities beyond its recognized functions as a mucolytic agent and an antidote for acetaminophen toxicity. This review consolidates findings from both preclinical and clinical studies to investigate NAC's diverse modulatory effects on the central nervous system (CNS). NAC primarily functions as an antioxidant by replenishing glutathione and mitigating oxidative stress; however, it produces glutathione-independent effects through the modulation of mitochondrial redox systems, ferroptosis, and the Nrf2-ARE signaling pathway. It plays a significant role in neuroinflammatory processes by inhibiting the production of cytokines, the expression of iNOS, and the activation of microglia. Furthermore, NAC affects various neurotransmitter systems-including glutamatergic, dopaminergic, GABAergic, serotonergic, cholinergic, and adrenergic pathways-by modulating synaptic transmission, receptor activity, and transporter functionality. It promotes neuroprotection through the enhancement of neurotrophic factors, the preservation of mitochondrial integrity, and the upregulation of survival signaling pathways. Recent evidence also emphasizes NAC's role in gene expression and the regulation of cortisol levels. The extensive range of NAC's neurobiological effects highlights its therapeutic potential in treating neurodegenerative and neuropsychiatric disorders. Nevertheless, the variability in clinical outcomes indicates a pressing need for more focused, mechanism-based research.},
}

@article {pmid41019354,
year = {2025},
author = {Aziz, ND and Azeez, DD and Mosa, AU and Al-Kareem, ZA and Majeed, SA and Ghafil, FA},
title = {Hepatoprotective potential of N-acetyl cysteine in rats with phenytoin induced liver injury.},
journal = {F1000Research},
volume = {14},
number = {},
pages = {593},
pmid = {41019354},
issn = {2046-1402},
mesh = {Animals ; *Phenytoin/adverse effects/toxicity ; *Acetylcysteine/pharmacology/therapeutic use ; Male ; *Chemical and Drug Induced Liver Injury/prevention & control/pathology/drug therapy/blood ; Rats, Wistar ; Rats ; *Liver/drug effects/pathology ; Anticonvulsants/toxicity ; Aspartate Aminotransferases/blood ; Alanine Transaminase/blood ; Bilirubin/blood ; *Protective Agents/pharmacology ; },
abstract = {BACKGROUND: Phenytoin is an anticonvulsant medication that is effective in treating various seizure disorders. It is mostly metabolized by the liver, which increases the risk of PHT-induced hepatotoxicity.

AIMS: This study aimed to assess the effectiveness of N-acetylcysteine (NAC) in protecting the liver from phenytoin-induced hepatotoxicity in rats.

MATERIALS AND METHODS: Four sets of five rats male Wistar albino rats (Rattus norvegicus) used for this study was based on their availability, well-established physiology, and long history of use in pharmacological and toxicological studies each were used for analysis. Each of the four groups received different treatments: the control group received normal saline, one group received 200 mg/kg/day of NAC, another group received 5 mg/kg/day of phenytoin, and the fourth group received 200 mg/kg/day of both phenytoin and NAC. The treatments were administered orally by gavage for 45 days. Biochemical indicators (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total serum bilirubin (TSB)) were measured in serum after the animals were anaesthetized and the experiment ended. Histological analysis was performed on liver specimens.

RESULTS: Our investigation showed that phenytoin significantly elevated liver enzymes and total serum bilirubin compared to the control and NAC groups. The concurrent administration of NAC and phenytoin led to a notable reduction in these biomarkers, excluding ALP levels. Moreover, the group that received NAC alone did not exhibit a significant increase in the levels of these biomarkers compared with the control group. The histopathological results were in agreement with the biochemical tests.

CONCLUSION: This study concluded that Concomitant administration of NAC and phenytoin lowered the risk of phenytoin-induced hepatotoxicity. Moreover, this study confirmed that NAC is relatively safe when administered for a relatively prolonged period.},
}

Animals
*Phenytoin/adverse effects/toxicity
*Acetylcysteine/pharmacology/therapeutic use
Male
*Chemical and Drug Induced Liver Injury/prevention & control/pathology/drug therapy/blood
Rats, Wistar
Rats
*Liver/drug effects/pathology
Anticonvulsants/toxicity
Aspartate Aminotransferases/blood
Alanine Transaminase/blood
Bilirubin/blood
*Protective Agents/pharmacology

@article {pmid41018992,
year = {2025},
author = {Miller, TJ and Qiu, L and Nevin, A and Williams, R and Beachy, W},
title = {"Too Much of a Good Thing": Inadvertent Acetaminophen Overdose in a Low-Weight Elderly Patient.},
journal = {Clinical case reports},
volume = {13},
number = {10},
pages = {e71031},
pmid = {41018992},
issn = {2050-0904},
abstract = {Commonly used for its analgesic and anti-pyretic properties, acetaminophen ("Tylenol") is effective in managing generalized pain. Complications arise with supratherapeutic dosing of acetaminophen, especially in elderly and frail individuals with diminished glutathione production and reduced metabolic drug clearance potential. Limited cases outline this danger and offer alternative dosing considerations to avoid drug-induced liver injury from acetaminophen (DILI). We present a unique case of an 89-year-old woman without prior liver disease who developed acute liver failure (ALF) while taking recommended dosing of acetaminophen. Physical exam was revealing for generalized abdominal pain, lethargy, and vomiting without ascites, jaundice, or asterixis upon admission. She progressed to ALF with encephalopathy and worsening transaminitis along with evidence of synthetic liver failure. With an elevated acetaminophen level and no prior history of liver disease with Tylenol dosing of 30 mg/kg/dose, DILI due to acetaminophen toxicity was suspected. N-acetylcysteine (NAC) and albumin infusions were initiated with improvement in transaminitis and acute tubular necrosis (ATN). The patient was discharged after 12 days to a rehabilitation facility for strength recovery without long-term sequelae or transplant. While 4000 mg/day dosing regimen is generally safe, it can be dangerous for certain patients. Using the typical pediatric, weight-based regimen of 15 mg/kg as a framework, this patient represents a 66% higher dose than recommended. Considering her frailty and age, this case emphasizes the importance of patient-specific risk factors in acetaminophen dosing and prioritizing an individualized, weight-based approach to analgesic management.},
}

@article {pmid41016202,
year = {2025},
author = {Zhang, Y and Huang, C and Qiu, Y and Li, R and Liu, J and Du, Y and Li, D},
title = {Synergistic elimination of bacillus Calmette-Guérin biofilm and tissue restoration facilitated by ultrasound-mediated nanoparticles and antioxidants.},
journal = {International immunopharmacology},
volume = {166},
number = {},
pages = {115582},
doi = {10.1016/j.intimp.2025.115582},
pmid = {41016202},
issn = {1878-1705},
abstract = {Biofilm formation in Mycobacterium tuberculosis (MTB) enhances antibiotic resistance by impeding drug penetration and evading host immunity. This poses a significant challenge to conventional drug therapies, highlighting the urgent need for novel treatment strategies to overcome MTB's biofilm-mediated resistance. This study introduces the development of low-intensity ultrasound-mediated levofloxacin (LEV) and catalase (CAT) -loaded PEG-PLGA nanoparticles (LEV@CAT-NPs) for antimicrobial sonodynamic therapy (aSDT), offering an innovative strategy to combat BCG biofilm infection, by utilizing BCG as a model for MTB. N-acetylcysteine (NAC) was supplemented during the latter stages of the treatment process of anti-infection therapy to facilitate the transformation of macrophages to the M2 phenotype and to promote tissue repair. Ultrasound-mediated LEV@CAT-NPs, along with the subsequent addition of NAC not only enhanced repair at the infection site but also led to a progressive resolution of the inflammatory response in tissues. The treatment regimen induced a shift in macrophage polarization towards the M2 phenotype and modulated cytokine expression, decreasing pro-inflammatory while increasing anti-inflammatory cytokines, which contributed to the restoration of redox balance in the infected tissues. This study proposes a novel therapeutic strategy that not only targets drug-resistant MTB but also promotes tissue repair, highlighting its dual role in infection management.},
}

@article {pmid40944367,
year = {2025},
author = {Roussos, A and Kitopoulou, K and Borbolis, F and Ploumi, C and Gianniou, DD and Li, Z and He, H and Tsakiri, E and Borland, H and Kostakis, IK and Samiotaki, M and Trougakos, IP and Bohr, VA and Palikaras, K},
title = {Urolithin Α modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/15548627.2025.2561073},
pmid = {40944367},
issn = {1554-8635},
abstract = {Mitochondrial dysfunction and impaired mitophagy are hallmarks of ageing and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, Urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analysis reveals that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In Caenorhabditis elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.Abbreviations: Ca[2+]: calcium ions; BJ: human foreskin fibroblasts; BNIP3: BCL2 interacting protein 3; BP: bipyridyl; CAMK2D: calcium/calmodulin dependent protein kinase II delta; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DEGs: differentially expressed genes; DEPs : differentially expressed peptides; DFP: deferiprone; DNM1L/DRP1: dynamin 1 like; EGTA: ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid; EMC: endoplasmic reticulum membrane protein complex; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone; GO: gene ontology; GSVA: Gene Set Variation Analysis; HUVECs: human umbilical vein endothelial cells; IMM: inner mitochondrial membrane; ITPR/InsP3R: inositol 1,4,5-triphosphate receptor; MAM: mitochondria-associated ER membrane; MAPK: mitogen-activated protein kinase; MCU: mitochondrial calcium uniporter; MEFs: mouse embryonic fibroblasts; NAC : N-acetylcysteine; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; NMN: nicotinamide mononucleotide; NR: nicotinamide riboside; OMM: outer mitochondrial membrane; PCA: principal-component analysis; PPARGC1A/PGC1α: PPARG coactivator 1 alpha; PQ: paraquat; TMCO: transmembrane and coiled-coil domains 1; TMRE: tetramethylrhodamine ethyl ester perchlorate; UA: urolithin A; VDAC: voltage dependent anion channel.},
}

@article {pmid41012520,
year = {2025},
author = {Josef, M and Abdellatif, MM and Abdelmonem, R and El-Nabarawi, MA and Teaima, M and Bedair, HM and Attia, A},
title = {Invasomes and Nanostructured Lipid Carriers for Targeted Delivery of Ceftazidime Combined with N-Acetylcysteine: A Novel Approach to Treat Pseudomonas aeruginosa-Induced Keratitis.},
journal = {Pharmaceutics},
volume = {17},
number = {9},
pages = {},
pmid = {41012520},
issn = {1999-4923},
abstract = {Objectives: This study was designed to optimize a ceftazidime (CTZ)-loaded nanocarrier that could efficiently permeate across corneal tissues. Moreover, N-acetylcysteine (NAC) was combined with an optimized CTZ-loaded formula to augment the antimicrobial activity and facilitate the efficient healing of Pseudomonas aeruginosa-induced keratitis. Methods: Different CTZ-loaded invasomes (INVs) and CTZ-loaded nanostructured lipid carriers (NLC) were fabricated and fully characterized via the determination of the entrapment efficiency (EE%), particle size (PS), surface charge, and percentage of CTZ release. Next, NAC was added to the optimized formulae from each nanocarrier, which were further assessed through ex vivo corneal permeation and in vitro antimicrobial activity studies. Finally, an in vivo evaluation of the optimal nanocarrier in the presence of NAC was performed. Results: Both nanocarriers showed nanoscale PS with sufficient surface charges. CTZ-loaded NLC formulae showed a higher EE% range with a sustained drug release profile. Both optimized formulae showed a spherical shape and excellent stability. Moreover, the antibacterial activity and biofilm inhibition assessments confirmed the synergistic effects of NAC when combined with different CTZ-loaded nanocarriers. However, the optimized CTZ-loaded INV formula achieved higher corneal permeation and deposition compared to the optimized CTZ-loaded NLC formula. Finally, the in vivo assessment confirmed the dominance of the optimized CTZ-loaded INV formula combined with NAC, where the microbiological, histopathological, and immunohistopathological examinations showed the rapid eradication of keratitis. Conclusions: Recent strategies for the incorporation of antibiotics into nanocarriers, combined with mucolytic agents, can offer a promising platform to boost the therapeutic efficiency of antibiotics and prevent antimicrobial resistance.},
}

@article {pmid41011426,
year = {2025},
author = {Shen, J and Li, Y and Miao, H},
title = {The PP2A Catalytic Subunit PPH21 Regulates Biofilm Formation and Drug Resistance of Candida albicans.},
journal = {Microorganisms},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/microorganisms13092093},
pmid = {41011426},
issn = {2076-2607},
abstract = {Candida albicans (C. albicans) biofilms exhibit enhanced resistance to conventional antifungal agents; however, the underlying pathogenic mechanisms warrant deeper exploration. Protein phosphatase 2A (PP2A), especially its catalytic activity, is crucial for maintaining physiological balance. This study focused on the role of the PP2A catalytic subunit coding gene PPH21 in biofilm formation and drug resistance of C. albicans. The mutant strain (pph21Δ/Δ) was generated and identified. The oxidative stress was detected by the reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). The autophagic activity was evaluated, and the autophagosomes were observed by transmission electron microscopy (TEM). The biofilm formation was measured by XTT reduction assay, crystal violet (CV) staining, and scanning electron microscopy (SEM). The susceptibility to antifungal agents was examined by XTT reduction assay and spot assay. Additionally, the antioxidant N-acetylcysteine (NAC) was applied to clarify the regulatory effect of C. albicans autophagy on oxidative stress. The pathogenicity of PPH21 in oral C. albicans infection was evaluated through in vivo experiments. We found that PPH21 deletion led to increased oxidative stress and autophagic activities, but it can be reversed by the application of NAC. Moreover, PPH21 deletion also impaired the biofilm formation ability and reduced resistance to antifungal agents. Our findings revealed that PPH21 is involved in both virulence and stress adaptation of C. albicans.},
}

@article {pmid41011382,
year = {2025},
author = {Jotic, A and Cirkovic, I and Bozic, D and Savic Vujovic, K and Milovanovic, J and Folic, M and Trivic, A and Cvorovic, L and Radivojevic, N},
title = {Antibiofilm Effects of N-Acetyl Cysteine on Staphylococcal Biofilm in Patients with Chronic Rhinosinusitis.},
journal = {Microorganisms},
volume = {13},
number = {9},
pages = {},
doi = {10.3390/microorganisms13092050},
pmid = {41011382},
issn = {2076-2607},
support = {451-03-65/2024-03/200110//Ministry of Science, Technological Development and Innovation, the Republic of Serbia/ ; },
abstract = {Staphylococcal bacterial biofilm plays an important role in the pathogenesis and bacterial persistence of chronic rhinosinusitis. N-acetyl cysteine (NAC) has an inhibitory role in biofilm formation, suppressing adhesion and matrix production or favoring dispersal of preformed biofilm. The aim of this study was to examine the in vitro effect of NAC on Staphylococcal biofilm formation by bacterial strains isolated from tissue samples of patients with chronic rhinosinusitis with or without nasal polyps (CRSwNP and CRSsNP). Prospective study included 75 patients with CRS. The biofilm-forming capacity of isolated strains was detected by microtiter-plate method and the effects of sub-inhibitory (1/2x, 1/4x, and 1/8x minimal inhibitory concentration, MIC) and supra-inhibitory minimal concentrations (2x, 4x, and 8xMIC) of NAC on biofilm production were investigated. Staphylococcal bacterial strains were isolated in 54 (72%) patients, and the most frequently isolated species were Staphylococcus aureus (40.7%). Coagulase-negative Staphylococci species were weak producers of biofilm, while S. aureus was a strong biofilm producer. Concentration of 3.1 mg/mL (1/2 MIC) was sufficient to completely prevent biofilm formation in 77.8% of the isolates, where 49.6 mg/mL (8xMIC) led to the complete eradication of formed biofilm in 81.5% of the isolates. The subinhibitory and eradication effects were dose- and strain-dependent. There were no significant differences in MIC values between isolates from patients with CRSwNP and CRSsNP isolates. NAC proved to be effective in inhibiting biofilm formation and reducing formed biofilm by Staphylococcal isolates from patients with CRS. A comparable antibiofilm effect was exhibited in both phenotypes of CRS, indicating that NAC's antibiofilm activity was independent of the underlying clinical phenotype, and more targeted on biofilm matrix components.},
}

@article {pmid41005550,
year = {2025},
author = {Sawyer, TW and Song, Y},
title = {Protective Effects of N-Acetylcysteine and its Amide Derivative Against Toxic Metals In Vitro: Potential Alternatives/Adjuncts to Traditional Chelators.},
journal = {Environmental toxicology and pharmacology},
volume = {},
number = {},
pages = {104825},
doi = {10.1016/j.etap.2025.104825},
pmid = {41005550},
issn = {1872-7077},
abstract = {The protective efficacies of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) against the toxicity of compounds containing arsenic, cadmium, cobalt, chromium and mercury, were compared to those of dimercaprol, dimercaptosuccinic acid, 2,3-dimercaptopropanesulphonate, D-penicillamine, and derivatives of ethylenediamine tetraacetic acid and diethylenetriaminepentaacetic in CHO-K1 cells. Both NAC and NACA were found to confer protection against these metals, with comparable or better efficacy than many of the test chelators. Results from studies using the glutathione synthesis inhibitor buthionine sulphoximine were consistent with NAC/NACA protection being mediated through both GSH up-regulation and chelation. Given NAC's activity against metal toxicity, widespread clinical use, parenteral or oral routes of administration, high clinical safety, low cost and ease of accessibility, it should be given consideration as a broad-spectrum protectant against toxic metal poisoning as a treatment or adjunct/combination treatment. Its more lipophilic derivative NACA, also warrants attention, especially in those cases where brain toxicity is a concern.},
}

@article {pmid41001250,
year = {2025},
author = {Rankin, TJ and Mayer, S and Laird, JG and Lobeck, B and Kalmanek, E and Drack, AV},
title = {N-Acetylcysteine Ameliorates Loss of the Electroretinogram b-wave in a Bardet-Biedl Syndrome Type 10 Mouse Model.},
journal = {Journal of experimental neurology},
volume = {6},
number = {1},
pages = {49-63},
pmid = {41001250},
issn = {2692-2819},
abstract = {Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder characterized by retinal degeneration leading to blindness. This study investigates the therapeutic efficacy of N-Acetylcysteine (NAC), an oxygen free radical scavenger, in ameliorating retinal degeneration associated with BBS using a murine model of BBS10. BBS is caused by mutations in BBS genes, the protein products of which are involved in ciliary function; mutant or absent BBS10 protein disrupts the assembly of the BBSome protein complex, disturbing ciliary trafficking and leading to photoreceptor cell dysfunction and death. Photoreceptor function can be assessed using the electroretinogram (ERG), and anatomy can be assessed using optical coherence tomography (OCT) and histology to demonstrate progressive degeneration over time. This study utilizes Bbs10 [-/-] mice to assess the effect of NAC supplementation on retinal degeneration. Results reveal that NAC supplementation ameliorates the progressive degeneration of the retinal outer nuclear layer (ONL) on OCT and mitigates the loss-of-b-wave ERG phenotype observed in Bbs10 [-/-] mice. The ERG b-wave is generated by retinal bipolar cells after synapsing with photoreceptors which have been hyperpolarized by light exposure. Reducing the loss-of-b-wave phenotype may indicate improved synaptic function. Synaptic staining demonstrates a correlation between the absence of an electropositive b-wave and mislocalized presynaptic terminals, highlighting the significance of synaptic integrity for retinal function. These findings suggest NAC as a promising therapeutic intervention for managing BBS10-related retinal degeneration.},
}

@article {pmid40998099,
year = {2025},
author = {Lawless, SC and Kelley, C and Nikulina, E and Tahir, U and Kaur, A and Alarcon, JM and Bergold, PJ},
title = {Chronic functional deficits following a single closed head injury in mice are prevented by minocycline and N-acetyl cysteine.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104049},
doi = {10.1016/j.mcn.2025.104049},
pmid = {40998099},
issn = {1095-9327},
abstract = {Traumatic brain injury (TBI) can produce chronic limb coordination and gait deficits that are associated with ongoing white matter damage. In rodent TBI models, chronic motor deficits may be obscured by aging or motor compensation. In addition, there are no treatments for TBI. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases total CAP amplitudes that recover by 90 DPI and increase further at 180 DPI. Total CAP amplitude changes are blocked by dosing of minocycline and N-acetylcysteine beginning 12 h post-injury (MN12). Injured or sham mice have similar times to traverse or number of foot faults on beam walk. DeepLabCut™ markerless limb tracking provides limb positions used to develop novel assays to assess beam walk and simple/complex wheel. Absition analysis integrates the duration and extent of foot faults during beam walk. Injured mice develop absition deficits at 90 DPI that worsen at 180 DPI suggesting a chronic and progressive decline. Chronic absition deficits are blocked by MN12 treatment. Speed typically assesses performance on simple/complex wheel. Novel limb coordination assays show that at 180 DPI, injured mice decrease coordination that significantly correlates with increased total CAP amplitude. MN12 alleviates chronic corpus callosum dysfunction and motor deficits suggesting a strong efficacy to treat TBI. DeepLabCut™ limb tracking reveals chronic deficits and motor compensation not seen with standard outcomes.},
}

@article {pmid40995338,
year = {2025},
author = {Semnic, I and Rački, V and Perković, O and Vuletić, V},
title = {Mercury exposure leading to functional vitamin B12 deficiency and subacute combined degeneration: a case report and literature review.},
journal = {Frontiers in toxicology},
volume = {7},
number = {},
pages = {1580275},
pmid = {40995338},
issn = {2673-3080},
abstract = {INTRODUCTION: The association between neurological symptomatology and heavy metal exposure has been reported in the literature. A few cases of extrapyramidal symptomatology and subacute combined degeneration have been described as manifestations of mercury intoxication. We highlight a case of a patient presenting with Parkinsonian features (tremor, rigidity, and bradykinesia), pyramidal deficits, dysarthria, paresthesia, mild cognitive decline, and emotional lability, with proven elevated mercury levels in blood and hair and elevated arsenic in urine.

CASE: A 60-year-old man, with history of mercury exposure while working at the Centre for Waste Management and Environmental Protection presented to a neurologist after 10 months of persistent tremors, muscle spasms, paresthesia, and irritability, followed by the onset of bradykinesia, slurred speech, rigidity, insomnia, and subtle cognitive decline. Laboratory investigations revealed functional vitamin B12 and vitamin D deficiencies, while toxicological quantitative analysis showed elevated blood mercury levels (15.2 μg/L) and hair root levels (3 μg/g). MRI of the brain was normal, whereas MRI of the posterior cervical spine detected signs of myelopathy. Florodeoxyglucose (FDG) Positron Emission Tomography (PET) of the brain revealed bilateral temporal and parietal glucose hypometabolism, most pronounced in the left inferior parietal and left superior temporal regions. Single-Photon Emission Computed Tomography (SPECT) imaging of dopaminergic neurons in the striatum was negative, and the patient was unresponsive to levodopa. Multivitamin therapy (vitamins B, E, and D) with selenium, in combination with symptomatic therapy (benzodiazepines, muscle relaxants, and antidepressants) provided minimal relief, leading to the introduction of N-acetyl cysteine, which resulted in moderate improvement of symptoms. Physical and speech therapy were of great importance in this case.

DISCUSSION: This case is unique because it represents the development of therapy-resistant extrapyramidal symptoms over 3 years of mercury exposure, likely leading to subacute combined degeneration due to functional vitamin B12 deficiency. Epidemiological data describe methylmercury poisoning, known as Minamata disease, which presents with -somatosensory deficits, ataxia, parkinsonism, dysarthria, and visual and hearing impairments.

CONCLUSION: Toxicological screening for heavy metals in blood and urine should be considered in patients presenting with unexplained, levodopa-resistant extrapyramidal symptoms, behavioral and sleep disturbances, cognitive decline, and other non-specific neurological signs.},
}

@article {pmid40993955,
year = {2025},
author = {Marazziti, D and Caruso, V and Cappellato, G and Chiarantini, I and Gurrieri, R and Perrone, P and Violi, M and Crivelli, NSB and Weiss, F and Perugi, G},
title = {The Emerging Role of N-Acetylcysteine in Psychiatry: A Narrative Review of Available Data.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673365458250901115725},
pmid = {40993955},
issn = {1875-533X},
abstract = {N-acetylcysteine (NAC), a cysteine derivative with a reactive thiol group, possesses antioxidant and anti-inflammatory properties. Its redox activity plays a central role in scavenging reactive oxygen and nitrogen species and modulating cellular signaling pathways. Recent research highlights its potential role in psychiatric disorders through the modulation of oxidative stress and inflammatory pathways. This narrative review examines the efficacy of NAC in treating psychiatric conditions, including mood disorders, schizophrenia, anxiety disorders, post-traumatic stress disorder (PTSD), obsessive- compulsive disorder (OCD), substance use disorders (SUDs), and neurodevelopmental disorders. A comprehensive search of PubMed, Scopus, Embase, PsycINFO, and Google Scholar databases was conducted for studies published between March 1, 2007, and December 30, 2024. The search utilized keywords related to NAC and psychiatric disorders. Data were critically analyzed to evaluate NAC's therapeutic potential. Preclinical studies demonstrate NAC's benefits in reducing oxidative stress, inflammation, and modulating neurotransmitter systems. Animal models of depression, schizophrenia, and OCD show symptom reduction through glutamatergic and antioxidant mechanisms. Clinical trials reveal NAC's efficacy as an adjunct in treating major depressive disorder, bipolar disorder, and schizophrenia, particularly for negative and cognitive symptoms. Evidence for anxiety disorders, PTSD, and OCD is limited but suggests anxiolytic and anti-obsessive effects. In SUDs, NAC shows promise in reducing cravings and substance- seeking behavior, while preliminary findings in autism suggest improvements in irritability and hyperactivity. NAC exhibits potential as an adjunctive treatment for various psychiatric disorders due to its safety profile, low cost, and broad mechanisms of action. However, clinical results are mixed, highlighting the need for larger, well-designed trials to confirm its efficacy and define optimal dosing strategies.},
}

@article {pmid40990566,
year = {2025},
author = {Morrow, LM and Barr, EA and Grossi, E and Pillai, VK and Kight, KA and Wright, EB and Turner, RP and Swatzyna, RJ},
title = {Identifying Neuroinflammation: The Diagnostic Potential of Spindling Excessive Beta in the EEG.},
journal = {Clinical EEG and neuroscience},
volume = {},
number = {},
pages = {15500594251376475},
doi = {10.1177/15500594251376475},
pmid = {40990566},
issn = {2169-5202},
abstract = {This manuscript examines the pivotal role of neuroinflammation in the central nervous system (CNS), particularly considering the impact of the COVID-19 pandemic. Neuroinflammation serves as a defense mechanism against various insults, including toxins, infections, and trauma. However, if left untreated, neuroinflammation can become chronic, leading to significant symptomatic and structural brain damage. Notably, neuroinflammation can mimic psychological disorders, complicating diagnosis and treatment. Current diagnostic methods for neuroinflammation-such as lumbar punctures, MRIs, brain biopsies, blood tests, and PET scans-are often hindered by inaccuracy, invasiveness, and cost. This study posits that electroencephalography (EEG), particularly identifying spindling excessive beta (SEB) activity, offers a promising, non-invasive, and cost-effective alternative for detecting neuroinflammation. This study investigates the relationship between SEB activity and neuroinflammation, focusing on traumatic brain injury (TBI). Through statistical analysis of EEG data from 1,233 psychiatric patients, we identified and compared two groups: 75 non-benzodiazepine-using adults without TBI and 79 non-benzodiazepine using adults with TBI exhibiting SEB activity. We identified a significant prevalence of SEB in individuals with refractory psychiatric conditions, underscoring the significance of this biomarker for neuroinflammation. Furthermore, we examine the therapeutic implications of reducing SEB through interventions such as guanfacine combined with N-Acetyl Cysteine (NAC), photobiomodulation, and hyperbaric oxygen therapy, all of which have demonstrated efficacy in mitigating neuroinflammation. These findings suggest that EEG could play a transformative role in the early detection and management of neuroinflammatory conditions, paving the way for more personalized and effective treatments for mental health disorders.},
}

@article {pmid40988585,
year = {2025},
author = {Mohammad, A and Ibrahim, M and Akram, M and Mohsin, H and Imran, MT and Khan Alizai, HN},
title = {N-acetylcysteine for Parkinson's disease: a translational systematic review of mechanistic and early clinical data.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2025.2563489},
pmid = {40988585},
issn = {1758-2032},
abstract = {BACKGROUND: Parkinson's disease (PD) involves progressive motor and non-motor decline, linked to oxidative stress and glutathione depletion. N-acetylcysteine (NAC), a glutathione precursor and antioxidant, is a potential disease-modifying therapy.

OBJECTIVE: To evaluate preclinical and clinical evidence on NAC in PD, focusing on motor and non-motor outcomes, dopaminergic function, and oxidative stress biomarkers.

METHODS: A PRISMA-compliant review of MEDLINE and Embase (May 2025) identified prospective studies in animal models or adults with PD. Outcomes included Unified Parkinson's Disease Rating Scale (UPDRS), dopamine transporter (DAT) imaging, glutathione levels, and safety.

RESULTS: Twelve studies met criteria. Preclinical models showed consistent neuroprotection. Intravenous NAC raised brain glutathione levels; high-dose oral NAC reached CSF. Two open-label trials (n = 65), reported ~ 13% improvement in UPDRS scores and 4-9% dopamine transporter signal increases over three months. No serious adverse events were attributed to NAC.

CONCLUSIONS: Larger randomized controlled trials are needed to test efficacy and disease-modifying potential.},
}

@article {pmid40987193,
year = {2025},
author = {Tang, J and Chen, B and Yu, F and Xu, L and Yu, M and Wang, C and Zhang, F and Zhang, L and Yang, Y and Hou, J and Li, X and Xu, W and Zhang, N},
title = {BPA exposure activated estrogen receptor α (ER-α) and ROS to induce pyroptosis in cochlear hair cells.},
journal = {Ecotoxicology and environmental safety},
volume = {304},
number = {},
pages = {119094},
doi = {10.1016/j.ecoenv.2025.119094},
pmid = {40987193},
issn = {1090-2414},
abstract = {Increasing evidence links hearing loss to environmental pollutant exposure, with cochlear hair cell being a key target. Bisphenol A (BPA) has been suggested to cause ototoxicity, but its mechanism is not fully understood. In this study, cell viability was assessed by varying concentrations of BPA (0-150 μM) exposed to mouse cochlear hair cells (HEI-OC1), followed by RNA transcriptome sequencing to identify the possible molecular mechanisms. Results showed that BPA above 50 μM reduced cell viability in a dose-dependent manner. RNA sequencing identified 1764 differentially-expressed genes, comprised of 1152 up-regulated and 612 down-regulated genes. Notably, estrogen receptor-related genes were enriched, with a marked up-regulation of estrogen receptor α (ER-α) at both mRNA and protein levels. GO and KEGG analyses revealed the main pathway involvement for oxidative damage, lipid metabolism, protein phosphorylation, and DNA damage. STRING analyses constructed gene networks to identify functionally interacting genes correlated with pyroptotic pathways. BPA exposure induced pyroptosis-like morphological changes characterized by cell swelling, rounding, and membrane blebbing. Increased intracellular ROS and mitochondrial superoxide (MitoSOX) levels, reduced mitochondrial membrane potential (ΔΨm), and elevated intracellular calcium (Ca[2+]) levels were observed. Flow cytometry showed an increased proportion of apoptotic and necrotic cells. Pyroptosis-related genes, including caspase-3, caspase-8, caspase-9, and GSDME, were down-regulated, while IL-1β and IL-18 were up-regulated. Protein expressions of caspase-3, caspase-8, caspase-9, and GSDME were decreased, while cleaved caspase-3 and N-terminal GSDME (GSDME-NT) were increased. Furthermore, ROS inhibitor N-acetylcysteine (NAC) and the ER-α antagonist fulvestrant alleviated BPA-induced cell death, and suppressed the protein expressions of the pyroptotic pathway. These results demonstrate that BPA exposure induces ototoxicity possibly through activating ER-α and triggering mitochondrial ROS that contributes to pyroptosis.},
}

@article {pmid40977385,
year = {2025},
author = {Papke, V and Klimes-Dougan, B and Sahasrabudhe, SA and Mueller, BA and Park, YW and Öz, G and Eberly, LE and DiMaggio-Potter, ME and Kartha, RV and Cloyd, J and Coles, L and Cullen, KR},
title = {Examination of oxidative stress and glutamate as potential mechanisms of N-acetylcysteine in the treatment of non-suicidal self-injury in young people assigned female at birth: randomised trial.},
journal = {BJPsych open},
volume = {11},
number = {5},
pages = {e221},
doi = {10.1192/bjo.2025.10839},
pmid = {40977385},
issn = {2056-4724},
abstract = {BACKGROUND: Non-suicidal self-injury (NSSI) often emerges during adolescence and young adulthood. A prior open-label pilot study suggested that N-acetylcysteine (NAC) may reduce NSSI frequency in young individuals.

AIMS: This study investigated potential NSSI-related biological markers for NAC in young adults with a history of NSSI using a placebo-controlled, randomised clinical trial of two NAC dosage regimens.

METHOD: Forty-three individuals (assigned female at birth) aged 16-24 years and with a history of NSSI were randomly assigned to either low-dose NAC (3600 mg/day), high-dose NAC (5400 mg/day) or placebo treatment for 4 weeks. Participants underwent blood draws, magnetic resonance imaging with spectroscopy and clinical assessments before and after treatment. Primary outcomes included brain glutathione (GSH), blood reduced to oxidised GSH ratio and brain glutamate. Secondary outcomes included antioxidant protein levels, brain gamma-aminobutyric acid concentrations, functional connectivity (between amygdala and insula) and clinical outcomes. Pharmacokinetics, tolerability and correlations among measures were also explored.

RESULTS: For 39 participants who completed study assessments at follow-up, weekly NSSI and depression symptoms improved similarly across both treatment and placebo groups, with no significant group differences in primary or secondary outcomes at follow-up. Some significant correlations emerged.

CONCLUSIONS: The study did not support the proposed biological signatures of NAC in young adults with NSSI, although exploratory findings suggested potential biological correlates of clinical improvement. Further research is necessary to explore neurobiologically based treatments for young adults with NSSI.},
}

@article {pmid40619022,
year = {2025},
author = {Fang, L and Zuo, L and Xing, F and Wang, Y and Chen, R and Zhang, F and Zuo, D},
title = {Repositioning miconazole: a novel drug for inducing cell death and differentiation in myeloid leukemia.},
journal = {Biochemical pharmacology},
volume = {241},
number = {},
pages = {117126},
doi = {10.1016/j.bcp.2025.117126},
pmid = {40619022},
issn = {1873-2968},
mesh = {Humans ; Acetylcysteine/pharmacology ; Adenine/pharmacology/analogs & derivatives ; Amino Acid Chloromethyl Ketones/pharmacology ; *Antifungal Agents/pharmacology/therapeutic use ; *Apoptosis/drug effects ; Caspase Inhibitors/pharmacology ; Cell Differentiation/drug effects ; *Drug Repositioning ; HL-60 Cells ; K562 Cells ; *Leukemia, Myeloid, Acute/drug therapy ; *Miconazole/pharmacology/therapeutic use ; *Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Male ; Animals ; Mice ; Mice, Nude ; Xenograft Model Antitumor Assays ; },
abstract = {Myeloid leukemia is a common form of blood cancer worldwide. Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family, is frequently overexpressed in various solid tumors and hematological cancers. Miconazole, a broad-spectrum anti-fungal agent, has exhibited anti-tumor properties against multiple cancer types, but its specific effects on leukemia remain unknown. The purpose of our research is to investigate whether miconazole targets MCL-1 to exert an anti-leukemic effect. Our research has demonstrated that miconazole directly binds to MCL-1 in HL60 and K562 cells, significantly inhibiting cell growth and decreasing MCL-1 protein levels, presumably by promoting MCL-1 degradation. Miconazole induces apoptosis, autophagy, and the production of reactive oxygen species (ROS). However, these effects can be attenuated by Z-VAD-FMK, 3-methyladenine (3-MA), and N-acetyl-L-cysteine (NAC). Meanwhile, miconazole-induced reduction of MCL-1 protein is reversed. Animal studies confirm the anti-myelocytic leukemia efficacy of miconazole in vivo. Unexpectedly, at low concentrations and with prolonged exposure, miconazole also promotes cell differentiation. This differentiation effect is positively associated with autophagy and ROS accumulation induced by miconazole, without altering MCL-1 expression. In conclusion, miconazole, identified through a drug repositioning (DR) approach, might be a potential therapeutic candidate for myeloid leukemia by either facilitating cell death or promoting cell differentiation.},
}

Humans
Acetylcysteine/pharmacology
Adenine/pharmacology/analogs & derivatives
Amino Acid Chloromethyl Ketones/pharmacology
*Antifungal Agents/pharmacology/therapeutic use
*Apoptosis/drug effects
Caspase Inhibitors/pharmacology
Cell Differentiation/drug effects
*Drug Repositioning
HL-60 Cells
K562 Cells
*Leukemia, Myeloid, Acute/drug therapy
*Miconazole/pharmacology/therapeutic use
*Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors
Male
Animals
Mice
Mice, Nude
Xenograft Model Antitumor Assays

@article {pmid40975184,
year = {2025},
author = {An, Z and Hu, H and Wang, Q and Qiu, Y and Chu, J and Xia, Y and Li, S},
title = {Dietary Selenium deficiency activates the NLRP3 inflammasome to induce gallbladder pyroptosis by regulating glycolysis and histone lactylation through ROS/HIF-1α pathway.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110118},
doi = {10.1016/j.jnutbio.2025.110118},
pmid = {40975184},
issn = {1873-4847},
abstract = {Selenium (Se) is an essential micronutrient, and inadequate intake can disrupt redox balance in digestive organs, promoting inflammation. Enhanced glycolysis leads to lactate accumulation, exacerbating the inflammatory response through inflammation-related pathways. Histone lysine lactylation plays a key role in epigenetic regulation. The effect of Se deficiency on the gallbladder remains unclear. To explore the mechanism of Se deficiency on gallbladder injury and the regulatory role of histone lactylation, we established Se-deficient swine models and in vitro cell models. Histopathological observation of the gallbladder found that Se deficiency led to inflammatory damage to the gallbladder. Metabolomics and proteomics results showed that Se deficiency led to significant enrichment of "glycolytic flux", "oxidative stress", and "hypoxia-inducible factor-1 α (HIF-1α) signaling pathway". Further studies have found that Se deficiency led to oxidative stress in gallbladder tissue, abnormal expression of HIF-1α factor, increased glycolysis levels, excessive lactate production, increased histone lactylation, and pyroptosis. HIF-1α knockdown suppressed Se deficiency-induced glycolysis and reduced lactate accumulation. In vitro studies using N-acetylcysteine (NAC), 2-deoxyglucose (2-DG), Oxamate and A-485 showed that Reactive oxygen species (ROS) regulated increased glycolysis through HIF-1α and increased H3K18 lactylation (H3K18la) levels through substrate-dependent modifications. Furthermore, H3K18la activated NLRP3 inflammasome, triggering pyroptosis and inflammatory cascades. In conclusion, the results of this study showed that dietary Se deficiency promotes glycolysis-dependent histone lactylation via the ROS/HIF-1α pathway, activating NLRP3 inflammasome, leading to pyroptosis and inflammation in gallbladder. These findings provide insights into targeted therapies for Se deficiency-related metabolic disorders and pathological changes in organs.},
}

@article {pmid40969002,
year = {2025},
author = {Wei, M and Xue, H and Gu, X and Zhang, K and Huang, Z and Lu, B and Ji, L},
title = {Chlorogenic acid promotes liver regeneration and repair after acetaminophen-induced liver injury via alleviating oxidative stress and enhancing fatty acid β-oxidation by activating Nrf2.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo01485a},
pmid = {40969002},
issn = {2042-650X},
abstract = {Acetaminophen (ACM)-induced hepatotoxicity involves an acute injury phase followed by a recovery phase. Although N-acetylcysteine (NAC) is widely used clinically to mitigate ACM-caused hepatotoxicity during the initial injury phase, effective therapeutic strategies to promote liver regeneration (LR) during the recovery phase remain unavailable. Chlorogenic acid (CGA), abundantly present in dietary sources, has been shown to exert significant hepatoprotective effects. This study reported that CGA not only promoted LR in mice following ACM (300 mg kg[-1]) intoxication (p < 0.05) but also significantly elevated the survival rate of mice treated with a lethal dose (500 mg kg[-1]) of ACM, increasing survival from approximately 9% to 45%. Mechanistically, CGA alleviated oxidative liver damage by activating nuclear factor erythroid 2-related factor 2 (Nrf2) and facilitated energy supply for LR via enhancing fatty acid β-oxidation mediated by peroxisome proliferator-activated receptor α (PPARα). Genetic Nrf2 knockout (Nrf2[-/-]) and pharmacological inhibition of PPARα (using GW6471) confirmed the critical roles of both Nrf2 and PPARα in this process. Further analysis revealed that the CGA-induced Nrf2 activation upregulated the expression of peroxisome proliferator-activated receptor gamma, coactivator 1-alpha (PGC-1α), a key coactivator of PPARα. Collectively, CGA promoted LR following ACM intoxication by alleviating hepatic oxidative stress via activating Nrf2. Additionally, Nrf2 activation triggered the expression of PGC-1α, which further strengthened PPARα-mediated fatty acid β-oxidation, thereby supplying sufficient energy for CGA-promoted LR following ACM intoxication. These findings highlight CGA's hepatoprotective effects and suggest it as a promising dietary supplement for promoting LR following toxic injury.},
}

@article {pmid40961779,
year = {2025},
author = {Chen, S and Han, Q and Zhou, Z and Gao, M and Song, J and Zhang, B and Guo, Y and Lv, Z},
title = {Dietary N-acetylcysteine supplementation improves antioxidant capacity and production performance of breeder hens and offspring.},
journal = {Poultry science},
volume = {104},
number = {11},
pages = {105745},
doi = {10.1016/j.psj.2025.105745},
pmid = {40961779},
issn = {1525-3171},
abstract = {This study investigated the effects of dietary N-acetylcysteine (NAC) supplementation on the antioxidant capacity and production performance of broiler breeder hens and their offspring. The breeder hens were randomly assigned to two groups: one received a corn-soybean meal-based control diet, while the other was supplemented with 1 g/kg NAC. Eggs from each group were randomly selected for incubation, and the offspring broilers were fed a basal diet. Dietary NAC treatment not only increased the albumen height and Haugh unit values of eggs but also improved fertilization rates (P < 0.05). Additionally, broiler chicks from the NAC-treated hens demonstrated higher eviscerated weight, full evisceration rate, and semi-eviscerated weight (P < 0.05). Dietary supplementation with NAC in breeder hens enhanced antioxidant capacity, as evidenced by increased total antioxidant capacity and catalase (CAT) activity in egg yolk, elevated CAT and glutathione peroxidase activities in breeder hen serum, and higher superoxide dismutase activity in chick serum. In particular, the NAC-treated group showed significantly higher glutathione levels and lower malondialdehyde levels throughout the transition from breeder hens to offspring (P < 0.05). Furthermore, maternal NAC treatment decreased the relative mRNA expression levels of pro-inflammatory cytokines interferon-γ, interleukin 18, and interleukin 6 in the ileum of the offspring broilers (P < 0.05). In conclusion, maternal dietary supplementation with NAC can continuously enhance the antioxidant capability and intestinal barrier function of chicken offspring, while also improving egg quality, growth performance and slaughter performance.},
}

@article {pmid40954254,
year = {2025},
author = {El-Alamin, MMA and Elkhalek, OA and Azab, MM},
title = {An environmental green factorial design/assisted spectrofluorimetric technique for quantitation of citicoline in pharmaceutical dosage form and wastewater.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {32547},
pmid = {40954254},
issn = {2045-2322},
mesh = {*Wastewater/chemistry/analysis ; Spectrometry, Fluorescence/methods ; Limit of Detection ; Reproducibility of Results ; *Water Pollutants, Chemical/analysis ; o-Phthalaldehyde/chemistry ; Pharmaceutical Preparations/chemistry ; Green Chemistry Technology/methods ; },
abstract = {A novel, sensitive, and straightforward spectrofluorimetric method was developed for the quantitative determination of citicoline in pharmaceutical formulations and wastewater. The technique depends on the efficient derivatisation of the primary amino group of citicoline with O-phthalaldehyde (OPA) and N-acetylcysteine (NAC) in borate buffer (pH 11), yielding a highly fluorescent derivative. The fluorescence intensity was measured at 425 nm with an excitation wavelength of 341 nm. Experimental parameters affecting the derivatisation reaction were thoroughly optimised. Under optimal conditions, the method exhibited a linear response over the concentration range of 50.0-300.0 ng/mL, with an excellent correlation coefficient (R[2] = 0.9942). The limits of detection (LOD) and quantification (LOQ) were 6.4 ng/mL and 19.5 ng/mL, respectively. The approach demonstrated high accuracy and precision, with per cent recovery values close to 100% and a relative standard deviation (RSD) of 0.512%, confirming its reliability. Validation was done in agreement with ICH Q2(R1) guidelines, and statistical comparison with previously reported approaches indicated no significant difference in performance. The sustainability of the method was studied using the analytical greenness tools confirms the method's eco-friendly profile. Collectively, these contributions advance drug bioavailability while promoting a more efficient and sustainable analytical framework.},
}

*Wastewater/chemistry/analysis
Spectrometry, Fluorescence/methods
Limit of Detection
Reproducibility of Results
*Water Pollutants, Chemical/analysis
o-Phthalaldehyde/chemistry
Pharmaceutical Preparations/chemistry
Green Chemistry Technology/methods

@article {pmid40950264,
year = {2025},
author = {Long, S and Qin, H and Guo, J and Liu, L},
title = {Therapeutic outcomes and inflammatory modulation of inhaled N-acetylcysteine bronchoalveolar lavage in severe pneumonia.},
journal = {American journal of translational research},
volume = {17},
number = {8},
pages = {6630-6638},
pmid = {40950264},
issn = {1943-8141},
abstract = {OBJECTIVE: To evaluate the therapeutic efficacy of inhaled N-acetylcysteine (NAC) bronchoalveolar lavage (iNAC-BAL) in severe pneumonia (SP) and explore its effects on inflammatory cytokines modulation.

METHODS: A total of 146 SP cases were assigned to two groups: the control group received bronchoalveolar lavage with isotonic saline (0.9% NaCl) alone, while the observation group received additional NAC aerosol inhalation. Clinical efficacy, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, intensive care unit (ICU) stay, duration of ventilator dependence, adverse reactions, symptom resolution times, respiratory mechanics, pulmonary function, inflammatory cytokines, and humoral immunity were assessed and compared between the two groups.

RESULTS: The observation group achieved better therapeutic effects (P=0.007), with significantly lower APACHE II scores, shorter ICU stays, reduced ventilator dependence, faster symptom resolution, and fewer adverse events (all P<0.05). Additionally, respiratory dynamics, lung function, inflammatory cytokines, and humoral immunity improved markedly in the observation group compared with the control group (all P<0.05).

CONCLUSION: iNAC-BAL demonstrates significant clinical efficacy and potent anti-inflammatory effects in the management of SP.},
}

@article {pmid40948959,
year = {2025},
author = {Bohn, MC and Oltmanns, H and Harting, H and Meißner, J},
title = {N-acetyl cysteine as an additive to bone cement against pathogens involved in periprosthetic joint infections.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1595821},
pmid = {40948959},
issn = {2296-4185},
abstract = {Periprosthetic joint infections (PJIs) and septic loosening of implants are common complications following surgical replacement of destructive joints in both human and veterinary medicine. Increasing occurrence of multi-resistant bacteria and failure to manage periprosthetic joint infections make it necessary to identify new antibacterial substances for the treatment and prevention of these infections. N-acetyl cysteine (NAC), a derivative of the amino acid cysteine, has been chosen as a candidate substance due to its shown antibacterial activity. The aim of the study was to evaluate the suitability of NAC for the use together with polymethylmethacrylate bone cement in the context of PJIs. Antibacterial activity of pure NAC and NAC-containing bone cement against clinical isolates of Staphylococcus (S.) pseudintermedius was tested by determining minimal inhibitory concentrations, analyzing growth of bacteria on bone cement, and examining the influence on infection of human osteosarcoma (HOS) cells. Cytotoxicity of pure NAC and bone cement with NAC against HOS cells was analyzed with viability and proliferation assays, Live/Dead staining of cells on bone cement, measurement of Interleukin-6 (IL-6) release, and visualizing activation of p38 MAP kinase with Western blotting. NAC inhibited growth of Staphylococcus pseudintermedius at 2.5 mg/mL and reduced bacterial growth on bone cement but could not inhibit infection of cells at 1.5 mg/mL. The IC50 of pure NAC for viability was 3.6 mg/mL. Bone cement with NAC reduced viability and proliferation at some concentrations but did not provoke IL-6 release. Western blots indicated that p38 could be activated following treatment with NAC. Taken together, antibacterial effectiveness could be shown but cytocompatibility of NAC in bone cement was limited, so that NAC cannot currently be used as a bone cement additive. Further research is necessary to balance antibacterial activity and cytotoxicity.},
}

@article {pmid40947894,
year = {2025},
author = {Li, C and Zhang, Y and Pan, Y and Wu, H and Zhang, C and Wu, Y and Meng, R and Su, J},
title = {N-Acetylcysteine Promotes the Maturation of Sheep Oocytes and Embryo Development In Vitro.},
journal = {Reproduction in domestic animals = Zuchthygiene},
volume = {60},
number = {9},
pages = {e70084},
doi = {10.1111/rda.70084},
pmid = {40947894},
issn = {1439-0531},
abstract = {During the in vitro maturation process of oocytes, oxidative stress is commonly present, and excessive oxidative stress can affect oocyte maturation. Thus, adding antioxidants during maturation is an effective strategy for reducing oxidative stress. N-acetylcysteine (NAC), a derivative of cysteine, participates in glutathione (GSH) metabolism and stimulates glutathione synthesis. However, a clear understanding of the effect of NAC on sheep oocytes remains unknown. In this study, we investigated NAC's impact on the maturation of sheep oocytes, and the results revealed that the maturation rate, and subsequently the cleavage and blastocyst formation, were significantly enhanced by incubation with 1 mM NAC. The GSH and Ca[2+] levels increased, and the cortical granules were significantly elevated, whereas the reactive oxygen species levels were significantly reduced in the 1 mM NAC-treated group. Additionally, the number of inner cell masses was significantly increased. The findings of this study support the hypothesis that NAC increases oocyte maturation rate by protecting them from oxidative stress damage. These discoveries provide a new approach for improving the efficiency of in vitro production of sheep embryos.},
}

@article {pmid40945056,
year = {2025},
author = {Harvey, HJ and Szepe, KJ and Hendry, AC and Archer, DB and Avery, SV},
title = {Sorbic acid resistance and metabolism of Brettanomyces bruxellensis in the spoilage of low sugar soft drinks.},
journal = {International journal of food microbiology},
volume = {443},
number = {},
pages = {111439},
doi = {10.1016/j.ijfoodmicro.2025.111439},
pmid = {40945056},
issn = {1879-3460},
abstract = {Brettanomyces bruxellensis is an emerging spoilage yeast of low-sugar ethanol fermentation processes and alcoholic beverages. As soft (non-alcoholic) drinks manufacturers transition towards low sugar formulations, this study investigated the ability of B. bruxellensis to grow in different soft-drink and preservative conditions. Multiple B. bruxellensis isolates grew comparably to the common spoilage yeast Z. bailii in a variety of soft drink formulations, including zero sugar lemonades, low-sugar fruit juices, and carbonated beverages. Growth assays with B. bruxellensis in laboratory minimal-medium supplemented with low (0.1 %) glucose were characterised by turbid biomass accumulation (a spoilage indicator) and resistance to the major food preservative sorbic acid (SA), known to cause oxidative stress and to inhibit respiration. Analysis of respiro-fermentative metabolism revealed that B. bruxellensis favoured respiration over fermentation regardless of glucose concentration, with oxygen limitation significantly reducing its growth. Cell-to-cell heterogeneity was used as a tool to test whether cellular levels of respiratory reactive oxygen species (ROS) influence the organism's SA resistance phenotype. At low glucose, sorted cell-subpopulations with high background ROS were more SA resistant than low ROS cells. Furthermore, the antioxidant N-acetyl cysteine (NAC) hyper-sensitized these cell subpopulations to SA. Therefore, one explanation for SA resistance despite the organism's primarily respiratory metabolism could be that respiratory ROS builds cells' resilience to (subsequent) SA-induced oxidative stress. The work shows that B. bruxellensis is capable of growth in zero- or low-sugar media and drinks formulations, and in the presence of relatively high sorbic acid levels.},
}

@article {pmid40943427,
year = {2025},
author = {Albahri, G and Badran, A and Hellany, H and Baydoun, S and Abdallah, R and Alame, M and Hijazi, A and Maresca, M and Baydoun, E},
title = {Mandragora autumnalis: Phytochemical Composition, Antioxidant and Anti-Cancerous Bioactivities on Triple-Negative Breast Cancer Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {17},
pages = {},
doi = {10.3390/ijms26178506},
pmid = {40943427},
issn = {1422-0067},
abstract = {Breast cancer is a common and chronic condition, and despite improvements in diagnosis, treatment, and prevention, the number of cases of breast cancer is rising annually. New therapeutic drugs that target specific checkpoints should be created to fight breast cancer. Mandragora autumnalis possesses substantial cultural value as a herb and is regarded as one of the most significant medicinal plants; however, little is known about its anticancerous biological activity and chemopreventive molecular pathways against the triple-negative breast cancer (MDA-MB-231) cell line. In this study, the antioxidant, anticancer, and underlying molecular mechanisms of the Mandragora autumnalis ethanolic leaves extract (MAE) were evaluated, and its phytochemical composition was determined. Results indicated that MAE diminished the viability of MDA-MB-231 cells in a concentration- and time-dependent manner. Although MAE exhibited 55% radical scavenging activity at higher concentrations in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the attenuation of its cytotoxic effects in MDA-MB-231 cells with N-acetylcysteine (NAC) co-treatment suggests a potential role of oxidative stress. Additionally, MAE caused an increase in the tumor suppressor p53. Moreover, this extract caused a significant decrease in the expression of Ki-67 (a cellular proliferation marker), MMP-9 (matrix metalloproteinase-9, an enzyme involved in extracellular matrix degradation and metastasis), and STAT-3 (a transcription factor regulating cell growth and survival). Also, MAE altered cell cycle, cell migration, angiogenesis, invasion, aggregation, and adhesion to suppress cellular processes linked to metastasis. All of our research points to MAE's potential to function as an anticancer agent and opens up new possibilities for the development of innovative triple-negative breast cancer treatments.},
}

@article {pmid40939324,
year = {2025},
author = {Zhang, Y and Chen, J and Lin, W and Qin, Z and Zhou, D and Li, P and Xiong, W},
title = {Quantitative LC-MS/MS profiling of N-Acetylcysteine in chicken plasma: Method validation and pharmacokinetic characterization.},
journal = {Poultry science},
volume = {104},
number = {11},
pages = {105777},
doi = {10.1016/j.psj.2025.105777},
pmid = {40939324},
issn = {1525-3171},
abstract = {N-Acetylcysteine (NAC), an essential precursor in glutathione synthesis, exhibits broad therapeutic potential but remains pharmacokinetically (PK) poorly characterized in poultry. To address this gap, we developed and validated a novel LC-MS/MS method that incorporates an isotope-labeled internal standard (d[3]-NAC) and a surrogate matrix (5 mg/mL bovine serum albumin). This approach effectively overcame interference from endogenous thiols through one-step methanol protein precipitation followed by DTT reduction, with chromatographic separation on a C18 column using 0.1 % formic acid-acetonitrile gradient elution (0.3 mL/min). Method validation demonstrated excellent linearity (0.01-4 μg/mL, R[2] > 0.99), sensitivity (LOD: 0.005 μg/mL; LLOQ: 0.01 μg/mL), accuracy (84.9-114.77 %), and precision (RSD < 10.61 %). Pharmacokinetic studies in broilers revealed distinct profiles under intravenous (IV, 10 mg/kg) and oral administration (10, 20, 40 mg/kg): (1) IV injection achieved rapid high exposure (AUC0-t: 14.573 ± 2.2 h·μg/mL) with prolonged elimination (t1/2: 3.59 ± 2.59 h). (2) Oral dosing showed dose-proportional absorption (tmax: 0.65-0.81 h) but low bioavailability (F: 17.04-22.56 %), though higher doses accelerated absorption (t1/2 increased from 1.31 ± 0.19 h at 10 mg/kg to 3.40 ± 2.29 h at 40 mg/kg). These findings establish two clinical application paradigms: (1) IV administration is optimal for acute respiratory crises due to its immediate high plasma concentration. (2) Oral delivery suits chronic supplementation, with dose escalation enhancing absorption efficiency. The validated LC-MS/MS platform provides a robust solution for veterinary drug analysis in biologically complex matrices, while the PK insights directly inform rational NAC regimens in poultry respiratory disease management.},
}

@article {pmid40935016,
year = {2025},
author = {Zuo, H and Huang, L and Huang, M and Ma, X and Zheng, C and Holman, BWB and Zhang, Y and Luo, X and Mao, Y},
title = {Peroxiredoxin 6 (Prdx6) and oxidative stress in post-mortem beef tenderization: A proteomic perspective.},
journal = {Journal of proteomics},
volume = {},
number = {},
pages = {105527},
doi = {10.1016/j.jprot.2025.105527},
pmid = {40935016},
issn = {1876-7737},
abstract = {This research explored the role of peroxiredoxin 6 (Prdx6)-mediated non‑selenium glutathione peroxidase (NSGPx) activity in modulating the tenderization process of beef during post-mortem aging, extending up to 168 h. Shear force, NSGPx activity, differential protein abundance, heat shock proteins (HSP70, HSP27), and troponin-T levels were analyzed in beef longissimus lumborum muscles treated with hydrogen peroxide (H2O2), N-acetylcysteine (NAC), mercaptosuccinic acid (MA), or saline (Control). MA treatment inhibited NSGPx activity and accelerated tenderization compared to NAC. Proteomics revealed that proteins differentially abundant between 0 and 24 h post-mortem were linked to cytoskeleton, extracellular matrix, amino acid metabolism, and apoptosis pathways.MA upregulated HSP70 abundance, oxidative stress, and troponin-T breakdown. H2O2 upregulated HSP70 and HSP27 abundance only within 6-12 h post-mortem. These results demonstrate that oxidative stress treatments modulate protein dynamics during aging, offering insights into strategies to enhance beef tenderness. SIGNIFICANCE: This study highlights peroxiredoxin 6 (Prdx6) as a crucial regulatory element that affects oxidative stress-associated pathways involved in the meat tenderization process during post-mortem beef aging. We demonstrate that inhibiting Prdx6's on‑selenium glutathione peroxidase (NSGPx) enzymatic activity with mercaptosuccinic acid (MA) increases HSP70 abundance and accelerates troponin-T proteolysis through enhanced oxidative stress and calcium signaling pathways. Conversely, antioxidant N-acetylcysteine (NAC) delays tenderization by preserving cytoskeletal integrity. Our TMT-based proteomics further identifies 35 core proteins linking extracellular matrix remodeling, amino acid metabolism, and apoptosis to tenderness modulation. These findings provide the first mechanistic evidence that targeted manipulation of Prdx6 activity can optimize beef aging efficiency. For the meat industry, MA treatment offers a science-driven strategy to reduce tenderization time by >20 % within 24-72 h post-mortem, lowering processing costs while maintaining quality. This work also establishes HSP70 and troponin-T degradation as novel biomarkers for real-time monitoring of oxidative stress in meat processing systems.},
}

@article {pmid40931599,
year = {2025},
author = {Osman, AG and Avula, B and Khan, IA and Chittiboyina, AG},
title = {Unraveling Origins of N-Acetylcysteine (NAC): A Critical Review.},
journal = {Journal of dietary supplements},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/19390211.2025.2555015},
pmid = {40931599},
issn = {1939-022X},
abstract = {The controversial status of N-acetylcysteine (NAC) as a dietary supplement ingredient has renewed interest in its origin. This opinion article critically examines the scientific literature to investigate whether NAC is a naturally occurring compound, with a particular focus on its potential presence in plants. The primary objective of this opinion is to determine the natural occurrence of NAC, specifically within herbal matter. The classification of NAC as a dietary ingredient falls outside the scope of this analysis. We will rigorously evaluate the methodologies implemented in establishing NAC's presence in plant or herbal sources, specifically in Allium species which are often touted to contain NAC. By analyzing the strengths and weaknesses of prior research, we aim to clarify the evidence supporting the origin of NAC.},
}

@article {pmid40921646,
year = {2025},
author = {Morley, K and Arunogiri, S and Connor, JP and Clark, PJ and Chatterton, ML and Baillie, A and Slade, T and Berk, M and Lubman, D and Haber, PS},
title = {N-acetyl cysteine for the treatment of alcohol use disorder: study protocol for a multi-site, double-blind randomised controlled trial (NAC-AUD study).},
journal = {BMJ open},
volume = {15},
number = {9},
pages = {e091631},
doi = {10.1136/bmjopen-2024-091631},
pmid = {40921646},
issn = {2044-6055},
mesh = {Humans ; *Acetylcysteine/therapeutic use ; Double-Blind Method ; *Alcoholism/drug therapy ; Randomized Controlled Trials as Topic ; Cost-Benefit Analysis ; Adult ; Male ; Treatment Outcome ; Multicenter Studies as Topic ; Female ; Alcohol Drinking ; Cognition/drug effects ; },
abstract = {INTRODUCTION: Current treatments for alcohol use disorders (AUD) have limited efficacy. A previous 28-day pilot trial of N-acetyl cysteine (NAC) vs placebo found NAC to be feasible and safe, with evidence of improvement on some measures of alcohol consumption. Thus, the primary aim of the NAC-AUD study is to examine the therapeutic and cost-effectiveness of NAC vs placebo in improving treatment outcomes for AUD. We will also examine the (i) effect of NAC vs placebo on mood, markers of liver injury, cognition and hangover symptoms; and (ii) predictors of any response.

METHODS AND ANALYSIS: This double-blind trial will randomise participants with AUD to a 12-week regimen of either NAC (2400 mg/day) or placebo. All participants will receive medical management. The primary drinking outcome will be the number of heavy drinking days (HDDs) per week, validated by phosphatidylethanol (PEth). Secondary alcohol-related outcomes will include standard drinks per drinking day (SDDD) per week and absence of any HDDs. Other secondary outcomes will include markers of liver injury, depression, anxiety, craving, hangover symptoms, cognition and blood oxidative stress markers. We will also examine the cost-efficacy of NAC vs placebo.

ETHICS AND DISSEMINATION: Ethics approval for the study has been granted by The Sydney Local Health District Ethics Review Committee (X21-0342& HREC2021/ETH11614). There are no restrictions on publication from the sponsor or other parties.

TRIAL REGISTRATION NUMBER: NCT05408247.},
}

Humans
*Acetylcysteine/therapeutic use
Double-Blind Method
*Alcoholism/drug therapy
Randomized Controlled Trials as Topic
Cost-Benefit Analysis
Adult
Male
Treatment Outcome
Multicenter Studies as Topic
Female
Alcohol Drinking
Cognition/drug effects

@article {pmid40919813,
year = {2025},
author = {Ishii, K and Kurihara, Y and Yoshimura, M and Walenna, NF and Shimizu, A and Ozuru, R and Hiromatsu, K},
title = {FABP4-dependent fatty acid oxidation-fueled mitochondrial ROS induces the mobilization of cellular iron and facilitates Trypanosoma cruzi proliferation in murine adipocytes.},
journal = {mBio},
volume = {},
number = {},
pages = {e0218025},
doi = {10.1128/mbio.02180-25},
pmid = {40919813},
issn = {2150-7511},
abstract = {Fatty acid-binding protein 4 (FABP4) is a cytosolic lipid chaperone predominantly expressed in adipocytes. It has been shown that Trypanosoma cruzi targets adipose tissues and resides in adipocytes. However, how T. cruzi manipulates adipocytes to redirect nutrients for its benefit remains unknown. Here, we uncover the role of FABP4 in facilitating T. cruzi infection in murine 3T3-L1 adipocytes. We demonstrate that pharmacological or genetic inhibition of FABP4, carnitine palmitoyltransferase I (CPT-1), or fatty acid oxidation (FAO) abrogates the intracellular growth of T. cruzi in adipocytes. We also found that inhibiting FABP4, CPT-1, or FAO eliminates the infection-induced elevation of mitochondrial and cellular reactive oxygen species (ROS) in adipocytes. Furthermore, T. cruzi infection-induced elevation of ROS in adipocytes increased the cytosolic Fe[2+], which fueled T. cruzi proliferation. The treatment with antioxidants such as ROS scavenger N-acetyl cysteine (NAC) or mitochondrial ROS inhibitors MitoQ increased the expression level of mRNA for Ferroportin and Ferritin, leading to the decrease in cytosolic Fe[2+] and the intracellular growth inhibition of T. cruzi in adipocytes. The addition of ferrous sulfate reversed the FABP4 inhibitor or antioxidant-induced decrease in adipocyte parasite burden. Our results demonstrate that T. cruzi exploits host FABP4 to facilitate fatty acid oxidation and elevate cellular ROS, increasing the labile iron pool for the intracellular replication of T. cruzi in adipocytes. These results highlight the therapeutic possibility of host FABP4 as a drug target for T. cruzi infection.IMPORTANCEPersistent infection with a protozoan parasite, Trypanosoma cruzi, causes Chagas disease. While it has been appreciated that adipose tissues are one of the sites of persistent infection, the mechanism of how the parasite survives in adipocytes remains to be established. Our study highlights FABP4, a key regulator of metabolic dysfunction and inflammation, as a therapeutic host target controlling T. cruzi infection in adipocytes. We uncover the importance of FABP4 for T. cruzi replication in mouse adipocytes through engagement with lipid droplet degradation and trafficking of liberated free fatty acids to the host cell's mitochondria, which are utilized for fatty acid oxidation (FAO). T. cruzi infection-induced FAO fuels reactive oxygen species, and the subsequent iron mobilization accelerates parasite replication. These results shed light on the mechanisms of T. cruzi persistent infection in adipocytes, raising the possibility of host FABP4 as a drug target for T. cruzi infection.},
}

@article {pmid40917936,
year = {2025},
author = {Ma, Z and Xu, Q and Xu, X},
title = {The Pathophysiological Role of Mitochondrial Oxidative Stress in Rheumatic Diseases.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {12021-12044},
pmid = {40917936},
issn = {1178-7031},
abstract = {Mitochondria play a crucial role in reactive oxygen species (ROS)-dependent rheumatic diseases, including ankylosing spondylitis, osteoarthritis (OA), systemic lupus erythematosus (SLE) and scleroderma. Mitochondrial DNA (mtDNA), which encodes mitochondrial proteins, is more vulnerable to oxidants compared to nuclear DNA. When mtDNA gets damaged, it leads to mitochondrial dysfunction, such as electron transport chain impairment and loss of mitochondrial membrane potential. Moreover, the damaged mtDNA functions as a damage-associated molecular pattern (DAMP), triggering inflammatory and immune responses. In this review, ROS-related transcription factors and downstream cell signaling pathways are investigated. It also explains the mechanism of mitochondrial dysfunction and the clinical significance of major rheumatic diseases, as well as the clinical transformation status of key antioxidants, the risks/reasons for promoting mitochondrial ROS research in rheumatic diseases, and antioxidant therapy. We conclude that targeting oxidative stress with antioxidant agents,such as polyphenols, garlic, pomegranate, Coenzyme Q10, probiotic, α-lipoic acid, N-acetylcysteine (NAC), selenium, microalgae, fucoidan, resveratrol, quercetin, and curcumin should be considered as promising new strategies for treating rheumatic diseases lacking effective treatments.},
}

@article {pmid40700980,
year = {2026},
author = {Li, Y and Li, Y and Chen, H and Chen, Y and Ni, Y and Ji, J and Wang, K and Jin, Q},
title = {Self-assembled copper-amino acid nanoleaves for targeted treatment of deep-seated bacterial infections via chemodynamic therapy and cuproptosis-like death.},
journal = {Biomaterials},
volume = {325},
number = {},
pages = {123566},
doi = {10.1016/j.biomaterials.2025.123566},
pmid = {40700980},
issn = {1878-5905},
mesh = {*Copper/chemistry/therapeutic use/pharmacology ; Animals ; *Anti-Bacterial Agents/pharmacology/therapeutic use/chemistry ; Mice ; Biofilms/drug effects ; Reactive Oxygen Species/metabolism ; Humans ; Hyaluronic Acid/chemistry ; *Bacterial Infections/drug therapy ; *Amino Acids/chemistry ; Acetylcysteine/chemistry ; Female ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; },
abstract = {Transition metal ions such as Cu[2+] are promising broad-spectrum bactericidal agents. However, transition metal ions are not used to treat deep-seated bacterial infections in clinic owing to easy deactivation by proteins and lack of targeting ability. Herein, hyaluronic acid (HA)-modified copper-N-acetyl-l-cysteine (NAC) nanoleaves (CNH NLs) are developed to treat deep-seated bacterial infections by targeted delivery of Cu[2+] to infection sites. Cu-NAC nanoleaves (CN NLs) can be synthesized by coordinate assembly of Cu[2+] and NAC, which are further coated with HA to obtained CNH NLs with targeting ability. CNH NLs are stable in neutral physiological environment, while can be easily decomposed in acidic infection sites, leading to rapid release of Cu[2+]. The released Cu[2+] disrupts bacterial membranes, depletes glutathione, generates reactive oxygen species (ROS), and induces cuproptosis-like bacterial death, exhibiting potent activity against both planktonic bacteria and biofilms. The targeted accumulation and excellent therapeutic efficacy of CNH NLs is further confirmed on murine bacterial keratitis and pneumonia models, highlighting their therapeutic potential for deep-seated infections.},
}

*Copper/chemistry/therapeutic use/pharmacology
Animals
*Anti-Bacterial Agents/pharmacology/therapeutic use/chemistry
Mice
Biofilms/drug effects
Reactive Oxygen Species/metabolism
Humans
Hyaluronic Acid/chemistry
*Bacterial Infections/drug therapy
*Amino Acids/chemistry
Acetylcysteine/chemistry
Female
Mice, Inbred BALB C
Microbial Sensitivity Tests

@article {pmid40901687,
year = {2025},
author = {Koonsiripaiboon, P and Ruamtawee, W and Simasingha, N and Tanasoontrarat, W and Claimon, T and Sethasine, S},
title = {Efficacy of N-acetylcysteine vs dexamethasone in preventing postembolization syndrome post-transarterial chemoembolization in hepatocellular carcinoma: A randomized controlled trial.},
journal = {World journal of gastroenterology},
volume = {31},
number = {31},
pages = {109630},
doi = {10.3748/wjg.v31.i31.109630},
pmid = {40901687},
issn = {2219-2840},
mesh = {Humans ; *Carcinoma, Hepatocellular/therapy/pathology ; *Liver Neoplasms/therapy/pathology ; *Acetylcysteine/therapeutic use/administration & dosage ; Middle Aged ; Male ; *Chemoembolization, Therapeutic/adverse effects/methods ; Female ; Adult ; Double-Blind Method ; *Dexamethasone/therapeutic use/administration & dosage ; Aged ; Treatment Outcome ; Incidence ; Thailand/epidemiology ; Syndrome ; Young Adult ; Adolescent ; },
abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a major health concern in Thailand, with most patients diagnosed at the intermediate stage. Transarterial chemoembolization (TACE) is the standard treatment; however, postembolization syndrome (PES) remains a common complication. Although both dexamethasone (DEXA) and N-acetylcysteine (NAC) have shown efficacy in reducing PES, no study has directly compared their effects.

AIM: To compare the incidence of PES between DEXA and NAC in intermediate-stage HCC patients undergoing conventional TACE (cTACE).

METHODS: A randomized, double-blind, controlled trial was conducted at two tertiary hospitals in Thailand from November 2024 to April 2025. Eligible HCC patients (aged 18-70 years) were randomized (1:1) to receive either NAC (150 mg/kg/hour loading dose, followed by 50 mg/kg over 4 hours, then 6.25 mg/kg/ hour for 48 hours post-cTACE) or DEXA (8 mg IV 1 hour before cTACE). cTACE was performed by blinded interventional radiologists. The primary outcome was PES occurrence within 48 hours, assessed using South West Oncology Group toxicity coding and the Common Terminology Criteria for Adverse Events. The secondary outcomes were post-cTACE liver decompensation and the dynamic changes in the albumin-bilirubin (ALBI) score.

RESULTS: A total of 56 intermediate-stage HCC patients were included (DEXA, n = 28; NAC, n = 28). Most had preserved liver function, with 92.9% classified as Child-Pugh A. The maximum tumor size was 6.2 cm, and 85.7% had multiple lesions. Additionally, 39 patients (69.6%) met the beyond up-to-7 criteria. Overall, 27 patients (48.2%) developed PES. After adjusting for confounding factors, the NAC group had a significantly lower incidence of PES than the DEXA group (32.1% vs 64.3%; adjusted odds ratio = 0.17, 95% confidence interval: 0.03-0.87, P = 0.033). Only two patients (3.6%) developed post-cTACE liver decompensation. Furthermore, 51.8% patients experienced worsening ALBI scores within 48 hours post-procedure; however, the rate of ALBI score worsening did not significantly differ between the groups.

CONCLUSION: Compared with DEXA, NAC significantly reduces the incidence of PES, regardless of its impact on liver function recovery. Therefore, NAC is a preferable option for reducing PES in Barcelona Clinic Liver Cancer-B stage HCC patients with preserved liver function.},
}

Humans
*Carcinoma, Hepatocellular/therapy/pathology
*Liver Neoplasms/therapy/pathology
*Acetylcysteine/therapeutic use/administration & dosage
Middle Aged
Male
*Chemoembolization, Therapeutic/adverse effects/methods
Female
Adult
Double-Blind Method
*Dexamethasone/therapeutic use/administration & dosage
Aged
Treatment Outcome
Incidence
Thailand/epidemiology
Syndrome
Young Adult
Adolescent

@article {pmid40900813,
year = {2025},
author = {Kumar, S and Agrawal, P and Mendhey, P and Dhatwalia, SK and Sitasawad, SL},
title = {Antioxidants ameliorates glucose/glucose oxidase-induced myocardial damage through mitochondrial and MAPK pathway.},
journal = {3 Biotech},
volume = {15},
number = {9},
pages = {323},
doi = {10.1007/s13205-025-04441-z},
pmid = {40900813},
issn = {2190-572X},
abstract = {Diabetes is characterized by high blood glucose concentration that leads to the generation of elevated levels of free radicals (oxidative stress) via auto-oxidation. Oxidative stress plays a key role in diabetes-associated progressive pathologies including myocardial complications. The aim of the present study is to investigate the protective effects of antioxidants in glucose/glucose oxidase (G/GO)-dependent oxidative stress-induced cardiac cell damage. We found that exposure of G (33mM)/GO (1.6 milliunits) to cardiac muscle H9c2 cells resulted in a significant increase in apoptosis as indicated by accumulation of membrane phospholipid phosphatidylserine, DNA damage, and intracellular esterase activity. Confocal microscopy and FACS analysis further showed that G/GO induced the production of reactive oxygen and reactive nitrogen species which led to the loss of mitochondrial membrane potential and release of cytochrome c in H9c2 cells. Treatment of H9c2 cells with antioxidants like N-Acetyl Cysteine, catalase or glutathione abolished the G/GO-induced free radicals, perturbed the mitochondrial membrane potential, and induced cytochrome c release. These antioxidants also inhibited G/GO-induced cell death, caspases, and cleavage of PARP. In addition, antioxidants restored G/GO-induced suppression of antiapoptotic proteins, Bcl-2, Bcl-xL, cFLIP, XIAP, and survivin. Furthermore, G/GO impacted the MAPK pathway via activation of Raf1, MEK1 and ERK1/2 in oxidative stress-dependent manner. Pharmacologic inhibition of Raf1 also abolished G/GO-induced apoptosis. Thus, our data suggest that antioxidants have a strong protective efficacy against G/GO-induced oxidative stress through inhibition of mitochondrial and MAPK-mediated pathways in cardiac cells.},
}

@article {pmid40891511,
year = {2025},
author = {Narayanasamy, B and Helmueller, S and Zhang, Y and Lee, YJ},
title = {Current Advances in Anticancer Properties of Heptamethine Carbocyanine DZ-1 Conjugated to Artesunate: Generation of Reactive Oxygen Species.},
journal = {Journal of cellular biochemistry},
volume = {126},
number = {9},
pages = {e70062},
doi = {10.1002/jcb.70062},
pmid = {40891511},
issn = {1097-4644},
support = {//This study was supported by the following grants: National Institutes of Health R21CA259243 (Yong J. Lee), R01CA265827 (Yong J. Lee), R21CA256419 (Yi Zhang), and Department of Defense W81XWH-22-1-1095 RA210084 (Yong J. Lee)./ ; },
mesh = {Humans ; Artesunate ; *Reactive Oxygen Species/metabolism ; *Antineoplastic Agents/pharmacology/chemistry ; Apoptosis/drug effects ; *Artemisinins/pharmacology/chemistry ; Cell Line, Tumor ; *Carbocyanines/pharmacology/chemistry ; Membrane Potential, Mitochondrial/drug effects ; HCT116 Cells ; Cell Survival/drug effects ; Mitochondria/metabolism/drug effects ; },
abstract = {Heptamethine cyanine dyes and anticancer agents based conjugates are being developed for enhanced targeting and killing of cancer cells. DZ-1 dye conjugated agents induced cytotoxicity and mechanism of action have been shown in previous studies. In this study, a conjugated form of DZ-1 and artesunate (DZ-1-ART) was used to evaluate its cytotoxicity and elucidate the mechanism of actions in various cancer cell lines. Cells survival assays indicated dose-dependent cytotoxic activities of DZ-1-ART in HCT116, BxPC-3, and OVCAR-3 cell lines. Immunoblotting and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay confirmed involvement of apoptosis in DZ-1-ART-induced cytotoxicity. To elucidate the anticancer mechanism of the action of DZ-1-ART, MitoTracker and JC-1 assay were used. The results showed that translocation of DZ-1-ART in the mitochondria was followed by disruption of mitochondrial outer membrane potential. Dichlorofluorescin diacetate assay confirmed the generation of reactive oxygen species (ROS) in DZ-1-ART treated cancer cells. An antioxidant, N-acetyl cysteine treatment with DZ-1-ART showed reduction in cell death as well as suppression of ROS generation. When compared to HCT116 wild-type cells, Bak and Bax-deficient HCT116 cells also showed similar levels of cytotoxicity of DZ-1-ART. Taken together, this study's results reported that DZ-1-ART could induce mitochondria-mediated, ROS-generated, and Bak and Bax-independent apoptosis in cancer cells.},
}

Humans
Artesunate
*Reactive Oxygen Species/metabolism
*Antineoplastic Agents/pharmacology/chemistry
Apoptosis/drug effects
*Artemisinins/pharmacology/chemistry
Cell Line, Tumor
*Carbocyanines/pharmacology/chemistry
Membrane Potential, Mitochondrial/drug effects
HCT116 Cells
Cell Survival/drug effects
Mitochondria/metabolism/drug effects

@article {pmid40884714,
year = {2025},
author = {Sun, Y and Liu, C and Liang, Y and Lv, A and Nie, W and Bao, S and Li, X and Zhou, J and Tong, W and Tao, Y and Wang, X and Dong, T},
title = {Mitophagy Activation by N-Acetylcysteine Protects against Mic60 Deficiency-Induced Auditory Neuropathy.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {40884714},
issn = {1995-8218},
abstract = {Auditory neuropathy (AN) is a sensorineural hearing loss that impairs speech perception, but its mechanisms and treatments remain limited. Mic60, essential for the mitochondrial contact site and cristae organizing system, is linked to neurological disorders, yet its role in the auditory system remains unclear. We demonstrate that Mic60[+/-] mice develop progressive hearing loss from 6 months of age, with reduced auditory brainstem response amplitudes despite preserved outer hair cell function, consistent with AN. Mitochondrial abnormalities in spiral ganglion neurons (SGNs) emerge by 3 months, followed by mitochondrial loss and SGN degeneration, indicating progressive auditory neuron dysfunction. In vitro, Mic60 deficiency disrupts mitochondrial respiration, reversible by N-acetylcysteine (NAC). NAC treatment preserves mitochondrial integrity and rescues hearing by enhancing mitophagy. Our findings establish Mic60[+/-] mice as an AN animal model, highlight the role of Mic60 in the mitochondria of primary auditory neurons, and identify NAC as a potential AN treatment.},
}

@article {pmid40881937,
year = {2025},
author = {Moody, TW and Ramos-Alvarez, I and Mantey, SA and Jensen, RT},
title = {Bombesin Receptor Subtype-3 Regulates Tumor Growth by HER2 Tyrosine Phosphorylation in a Reactive Oxygen Species-Dependent Manner in Lung Cancer Cells.},
journal = {Targets (Basel)},
volume = {3},
number = {1},
pages = {},
doi = {10.3390/targets3010007},
pmid = {40881937},
issn = {2813-3137},
abstract = {Bombesin receptor subtype-3 (BRS-3) is a type 1 G-protein-coupled receptor. BRS-3 is an orphan GPCR which is structurally related to the neuromedin B and gastrin-releasing peptide receptors. When activated, BRS-3 causes phosphatidylinositol turnover in lung cancer cells. BRS-3 stimulates tyrosine phosphorylation of the epidermal growth-factor receptor (ErbB1), however it is unknown if it transactivates ErbB2/HER2. Adding the nonpeptide BRS-3 allosteric-agonist, MK-5046 or the peptide agonist, BA1 to the lung cancer cell line, NCI-H727 or BRS-3-transfected NCI-H1299 lung cancer cells, increased tyrosine phosphorylation of HER2/ERK2. This increase was antagonized by the BRS-3 peptide antagonist, Bantag-1 and the small molecule BRS-3 antagonist, ML-18. The increase in HER2/ERK phosphorylation caused by MK-5046 was inhibited by ROS inhibitors, N-acetylcysteine and Tiron (superoxide-scavenger). Adding MK-5046 to lung cancer cells increased reactive-oxygen species which was inhibited by NAC or Tiron. MK-5024 and BA1 increased NSCLC colony formation whereas, Bantag-1/ML-18 inhibited proliferation. These results indicate that in lung cancer cells activation of BRS-3 regulates HER2-transactivation in ROS-dependent manner which can mediate tumor growth. These results raise the possibility that the use of HER2-inhibiting compounds alone or in combination with other agents, could be a novel approach in the treatment of these tumors.},
}

@article {pmid40879897,
year = {2025},
author = {Stoddart, K and Davies, M and Oughton, J and Malcolm, E and AlSharari, SD and Shoaib, M},
title = {Selective Effects of Acutely Administered N-Acetyl-Cysteine in Rodent Models of Nicotine-Conditioned Behaviours.},
journal = {Addiction biology},
volume = {30},
number = {9},
pages = {e70051},
doi = {10.1111/adb.70051},
pmid = {40879897},
issn = {1369-1600},
support = {ORF-2025-829//King Saud University, Riyadh, Saudi Arabia: Ongoing Research Funding program/ ; //Faculty of Medical Sciences, Newcastle University/ ; },
mesh = {Animals ; *Acetylcysteine/pharmacology/administration & dosage ; *Nicotine/pharmacology/administration & dosage ; Rats ; Male ; Motor Activity/drug effects ; Dose-Response Relationship, Drug ; Disease Models, Animal ; *Tobacco Use Disorder/drug therapy ; *Nicotinic Agonists/pharmacology/administration & dosage ; Discrimination Learning/drug effects ; Conditioning, Operant/drug effects ; Rats, Sprague-Dawley ; Behavior, Animal/drug effects ; },
abstract = {Chronic nicotine administration leads to neuroadaptations, an important process in nicotine and tobacco dependence for which treatments are limited. The cysteine pro-drug, N-acetyl-cysteine (NAC), is a promising glutamatergic agent that has shown some clinical efficacy in reducing nicotine use in humans. The purpose of this study was to examine NAC in two rodent models of nicotine dependence. NAC (0, 5, 20, 50 and 100 mg/kg) was examined on locomotor activity in groups of rats previously exposed to nicotine or saline. In the second experiment, NAC (0, 50 and 100 mg/kg i.p.) was evaluated against the discriminative stimulus effects of nicotine (0.2 mg/kg) using a two-lever procedure under a tandem schedule (VI10"-FR10) of food reinforcement. Pre-treatment with NAC in doses greater than 20 mg/kg attenuated the expression of conditioned hyperactivity when rats were placed in locomotor boxes previously paired with chronic nicotine administration. The same doses of NAC had modest effects in attenuating nicotine-stimulated hyperactivity in nicotine-treated or saline-treated rats tested in the same locomotor boxes. In the discrimination task, NAC did not generalise to the nicotine stimulus and nor did it modify the dose-response curve to nicotine, suggesting that NAC may not modify the subjective effects of nicotine. These results suggest NAC selectively attenuates conditioned responses to nicotine-paired stimuli without modifying nicotine-induced hyperactivity or the discriminative stimulus effects of nicotine. Thus, the study proposes that if NAC was to act in a similar selective manner in humans, the specific action of NAC to attenuate conditioned responses may limit its potential as a treatment to manage nicotine dependence.},
}

Animals
*Acetylcysteine/pharmacology/administration & dosage
*Nicotine/pharmacology/administration & dosage
Rats
Male
Motor Activity/drug effects
Dose-Response Relationship, Drug
Disease Models, Animal
*Tobacco Use Disorder/drug therapy
*Nicotinic Agonists/pharmacology/administration & dosage
Discrimination Learning/drug effects
Conditioning, Operant/drug effects
Rats, Sprague-Dawley
Behavior, Animal/drug effects

@article {pmid40875537,
year = {2025},
author = {Back, SE and Gray, K and Jarnecke, AM and Saraiya, TC and Santa Ana, EJ and Killeen, T and Joseph, JE and Prisciandaro, JJ and Brown, DG and Nietert, PJ and Stecker, T and Rothbaum, A and Jones, JL and Flanagan, JC and Brady, KT},
title = {N-Acetylcysteine for the Treatment of Co-Occurring Posttraumatic Stress Disorder and Alcohol Use Disorder: A Double-Blind, Randomized Controlled Trial.},
journal = {The Journal of clinical psychiatry},
volume = {86},
number = {4},
pages = {},
doi = {10.4088/JCP.25m15803},
pmid = {40875537},
issn = {1555-2101},
mesh = {Humans ; *Acetylcysteine/therapeutic use/administration & dosage/adverse effects/pharmacology ; *Stress Disorders, Post-Traumatic/drug therapy/complications/therapy ; Adult ; Male ; Female ; Double-Blind Method ; Middle Aged ; *Alcoholism/drug therapy/complications/therapy ; Cognitive Behavioral Therapy/methods ; Aged ; Treatment Outcome ; Young Adult ; },
abstract = {Objective: Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are common co-occurring conditions associated with a more severe clinical profile and poorer treatment outcomes than either disorder alone. To date, no medications have proven efficacious in the treatment of co-occurring PTSD/AUD. Methods: This randomized, double-blind, placebo-controlled trial examined the efficacy of N-acetylcysteine (NAC; 2,400 mg/day) among individuals (N=182, aged 21-65 years) who met DSM-5 criteria for current PTSD/AUD. Participants were randomized 1:1 to receive 12 weeks of NAC (n=93) or placebo (n=89). All participants received weekly, individual, cognitive behavioral therapy (CBT) for AUD. Follow-up visits occurred at 3-, 6-, and 12-months posttreatment. Primary outcomes included the Clinician Administered PTSD Scale for DSM-5 (CAPS-5), PTSD Checklist for DSM-5 (PCL-5), Timeline Follow-Back (TLFB), and the Obsessive Compulsive Drinking Scale at 12 weeks. The TLFB evaluated the frequency and amount of alcohol consumption. A secondary measure evaluated depression symptoms. Results: Intent-to-treat analyses showed that participants in both the NAC and placebo groups evidenced significant reductions in the CAPS-5 (B=-0.19, P<.001) and PCL-5 (B=-0.20, P<.001) during treatment, with no significant group differences. Both groups also showed significant reductions in alcohol use (drinks per drinking day [B=-0.02, P<.001], percent heavy drinking days [B=-0.14, P<.001], percent days abstinent [B=0.29, P=.022]) and craving (B=-0.12, P<.001) during treatment, but with no significant group differences. There were no group differences in retention or adverse events. Conclusions: Although NAC was well tolerated, it was not more effective than placebo in improving symptoms of PTSD or AUD when added to individual CBT for AUD. Trial Registration: ClinicalTrials.gov identifier: NCT02966873.},
}

Humans
*Acetylcysteine/therapeutic use/administration & dosage/adverse effects/pharmacology
*Stress Disorders, Post-Traumatic/drug therapy/complications/therapy
Adult
Male
Female
Double-Blind Method
Middle Aged
*Alcoholism/drug therapy/complications/therapy
Cognitive Behavioral Therapy/methods
Aged
Treatment Outcome
Young Adult

@article {pmid40873781,
year = {2025},
author = {Guan, H and Huang, L and Liu, Y and Zhu, E and Chen, L and Li, W and Wu, H and Zhang, X and Qin, R and Zheng, J and Mo, Y and Zhong, M and Xu, B and Dai, X and Wei, Q and Chen, Y and Wang, Q and Zheng, Z and Ma, K and Tang, C},
title = {Anti-PS IgG Immune Complexes Impair Macrophage Phagocytosis in SLE via LOX-Dependent Oxidative Stress.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {11521-11538},
pmid = {40873781},
issn = {1178-7031},
abstract = {PURPOSE: Systemic lupus erythematosus (SLE) is a severe autoimmune disease with systemic complications mediated by immune-complex formation. The elevated level of anti-phosphatidylserine (PS) IgG has been implicated in SLE pathogenesis. In this study, we aimed to explore the effector mechanisms of PS immune-complex during lupus development.

PATIENTS AND METHODS: Serological profiles of immune-complexes in SLE patients were analyzed. Immunofluorescence staining showed PS-IgG immune-complex deposition in kidney biopsies of lupus nephritis patients. C57BL/6J mice were immunized with PS for immune-complex and renal function assessment. The roles of PS-IgG immune-complex and lysyl oxidase (LOX) were validated from SLE PBMCs, THP-1 cell line and PS-immunized lupus mice. The intracellular reactive oxygen species (ROS) levels, and phagocytosis function were examined by flow cytometry in SLE PBMCs, THP-1 cell line and PS-immunized lupus mice. For in vitro treatment, the effects of antioxidant N-acetylcysteine (NAC) and LOX inhibitor β-Aminopropionitrile (BAPN) were verified in THP-1 cell line and cells from PS-immunized lupus mice.

RESULTS: SLE and lupus nephritis (LN) patients showed significant elevated circulating and glomerular PS-IgG immune-complex levels. ROC analysis indicated PS-IgG immune-complex as a strong biomarker in SLE and LN. Mechanistically, induced macrophages from SLE patients treated with PS-IgG immune-complex significantly increased cytoplasmic ROS levels, elevated LOX expression and exhibited dampened phagocytotic function. In mice, PS immunization triggered PS-IgG immune complex formation, increased LOX expression, immune-complex deposited glomerular nephritis, and impaired phagocytotic function of macrophages. NAC and BAPN treatment restored the phagocytotic function of human and murine macrophages.

CONCLUSION: Our results indicate that PS-IgG immune-complex can directly impair macrophage phagocytotic functions via LOX mediated-oxidative stress and may serve as a novel biomarker for SLE.},
}