Toxicology Mechanisms and Methods最新文献

{"title":"Metformin partially modulates cisplatin-induced neuronal senescence but does not prevent rat peripheral sensory hypersensitivity.","authors":"Tareq Saleh, Fairouz Nairat, Raghda Barham, Randa Naffa, Noor A Barakat, Mohammad A Ismail, Razan Aldiqs, Homood M As Sobeai, Moureq R Alotaibi, Sofian Al Shboul, Mohammad Alsalem, Nidaa A Ababneh","doi":"10.1080/15376516.2026.2748395","DOIUrl":"10.1080/15376516.2026.2748395","url":null,"abstract":"<p><p>Therapy-induced senescence (TIS) is recognized as a contributor to chemotherapy-associated adverse effects, including neurotoxicity. While senolytics have shown promise in alleviating chemotherapy-induced peripheral neuropathy (CIPN), their clinical translation might be hindered by unfavorable safety profiles, shifting interest toward less toxic senomorphics. We investigated the senomorphic potential of metformin (Met) in counteracting cisplatin (Cis)-induced senescence using both an <i>in vitro</i> model of human induced pluripotent stem cell-derived motor neurons (iPSC-MNs) and an <i>in vivo</i> rat model of CIPN. Exposure of iPSC-MNs to Cis induced hallmark features of senescence, including increased senescence-associated β-galactosidase (SA-β-gal) activity and upregulation of senescence-associated markers, as confirmed by immunofluorescence (increased p16^INK4a and decreased Lamin B1) and qPCR (<i>CDKN2A</i>, <i>CDKN1A</i>, <i>CXCL8</i> upregulation) analyses. While Met did not significantly reduce SA-β-gal activity or restore cell viability, it attenuated the expression of key senescence-associated transcripts, including <i>CDKN2A</i> and components of the senescence-associated secretory phenotype (SASP) such as <i>CXCL8</i>, indicating partial senomorphic activity. <i>In vivo</i>, Cis administered in two cycles (cumulative dose: 23 mg/kg) elicited mechanical allodynia and thermal hyperalgesia in Sprague-Dawley rats. Analysis of dorsal root ganglia (DRG) on day 8 post-treatment revealed strong SA-β-gal staining and increased expression of <i>cdkn1a</i>, <i>cdkn2a</i>, and SASP mediators (<i>Il6</i>). Met pretreatment reversed the upregulation of <i>cdkn1a</i>, <i>cdkn2a</i>, and <i>Il6</i>, but did not alleviate the sensory deficits induced by Cis. Our findings support a partial senomorphic activity of Met both <i>in vitro</i> and <i>in vivo</i> yet demonstrate its limited efficacy in functionally mitigating CIPN.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-16"},"PeriodicalIF":2.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol alleviates coal dust-induced pulmonary fibrosis by inhibiting the transformation of lung epithelial cells and fibroblasts.","authors":"Ge Zhou, Amin Li, Ruikai Wang","doi":"10.1080/15376516.2026.2749667","DOIUrl":"https://doi.org/10.1080/15376516.2026.2749667","url":null,"abstract":"<p><strong>Objective: </strong>To observe the inhibition of resveratrol on coal dust-induced pulmonary fibrosis and explore the possible mechanism.</p><p><strong>Methods: </strong>A mouse model of pneumoconiosis was established by coal dust inhalation, and resveratrol was administered as treatment. Lung inflammation and fibrosis were observed using hematoxylin/eosin (HE) and Masson staining, and hydroxyproline content was measured by colorimetric assay. In vitro, lung epithelial cells were exposed with coal dust alone or in combination with resveratrol. Cell migration and invasion abilities were assessed using wound healing assay and Transwell assay. The key molecules of epithelial-mesenchymal transition (EMT) were detected by western blotting and ELISA. Additionally, the effects of resveratrol on proliferation and collagen production in TGF-β1-stimulated fibroblasts were examined using EDU, CCK-8, and western blotting. Results: The coal dust group showed marked inflammatory cell infiltration, collagen deposition, and elevated hydroxyproline levels in lung tissue, all of which were significantly improved in the resveratrol-treated group. In vitro, coal dust increased the migration rate, invasive ability, downregulated E-cadherin, and upregulated N-cadherin, vimentin, and Snail of lung epithelial cells, whereas these cellular changes were markedly attenuated in the resveratrol-treated group. Moreover, the levels of TGF-β1 and TNF-α were significantly lower in the resveratrol-treated group than in the coal dust group. In fibroblasts, the cell proliferation rate and collagen (COL-1, COL-3, α-SMA) were lower in the resveratrol-treated group than in the TGF-β1-stimulated group.</p><p><strong>Conclusion: </strong>Resveratrol inhibited EMT in lung epithelial cells, reduced TGF-β1 and TNF-α release, suppressed fibroblast-to-myofibroblast transformation (FMT), and alleviated coal dust-induced pulmonary fibrosis.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-15"},"PeriodicalIF":2.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperbaric oxygen therapy ameliorates cyclophosphamide-induced spermatogenic impairment by suppressing the RhoA/ROCK signaling pathway in mice.","authors":"Lin Ma, Tong Yang, Lei Wang, Shiya Liu, Xuemei Qiu, Zhongjian Bao, Yong Sun","doi":"10.1080/15376516.2026.2750253","DOIUrl":"https://doi.org/10.1080/15376516.2026.2750253","url":null,"abstract":"<p><p>Hyperbaric oxygen (HBO) therapy has shown potential to improve sperm quality and reproductive outcomes, but the mechanisms underlying its protective effects remain unclear. This study investigated whether HBO ameliorates cyclophosphamide (CYP)-induced spermatogenic impairmentand whether Rhoa/Rock signaling is involved. Male BALB/c mice were assigned to control, CYP, and CYP + HBO groups. CYP was administered intraperitoneally for five consecutive days, followed by HBO treatment at 2.5 ATA for 60 min/day, 5 days/week for 2 weeks. Sperm parameters, serum sex hormones, testicular histopathology, oxidative stress indices, and Rhoa/Rock-related proteins were assessed. Rhoa knockout (KO) mice were additionally used for mechanistic evaluation. Compared with CYP treatment alone, HBO treatment increased sperm count by 80.95% (P < 0.0001) and progressive motility by 160.96% (P < 0.0001), while decreasing the sperm abnormality rate by 38.88% (P < 0.0001). HBO also reduced testicular MDA levels by 40.90% (P < 0.0001) and increased SOD activity by 69.53% (P = 0.0005). These changes were accompanied by reduced Rhoa and Rock1 protein expression and increased Nrf2 and Ho-1 expression. In Rhoa KO mice, the beneficial effects of HBO on serum hormone levels, sperm parameters, testicular indices, oxidative stress markers, and Nrf2/Ho-1 expression were largely abolished. These findings indicate that HBO therapy alleviates CYP-induced testicular oxidative stress injury and spermatogenic impairment, with Rhoa/Rock signaling contributing to the protective response.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-15"},"PeriodicalIF":2.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastics as Microbiota Modulators: Rewiring the Gut Metabolism Immune Axis.","authors":"Sermin Algul, Yunus Emre Beyhan, Oguz Ozcelik","doi":"10.1080/15376516.2026.2749674","DOIUrl":"https://doi.org/10.1080/15376516.2026.2749674","url":null,"abstract":"<p><p>Microplastics (MPs) have emerged as pervasive environmental contaminants with increasing relevance to human health. Beyond their role as inert particulate pollutants, accumulating evidence suggests that MPs may act as biologically active modulators of the gastrointestinal ecosystem. The gut represents a major interface for MP exposure, where ingested particles interact with intestinal epithelial cells, mucus layers, immune components, and resident microbial communities. This review summarizes current evidence on MPs' capacity to alter gut microbiota composition, impair intestinal barrier integrity, disrupt microbial metabolite production, and promote inflammatory and metabolic disturbances.Experimental studies indicate that MP exposure may reduce microbial diversity, shift the abundance of key bacterial taxa, impair tight junction proteins, and increase intestinal permeability. These changes may facilitate the translocation of bacterial products such as lipopolysaccharide, thereby activating inflammatory pathways including TLR4/NF-κB signaling. In parallel, MP-associated dysbiosis may alter short-chain fatty acids, bile acid metabolism, and tryptophan-derived metabolites, suggesting plausible biological pathways relevant to insulin resistance, hepatic lipid dysregulation, cardiometabolic risk, and gut-brain axis disruption. However, most available evidence is derived from animal and in vitro models, and causal relationships in humans remain insufficiently established. Major limitations include heterogeneous exposure protocols, non-standardized particle characterization, limited human longitudinal data, and difficulty separating particle-specific effects from those of associated chemical contaminants.Future studies integrating environmentally realistic exposure models, standardized microbiome analyses, multi-omics approaches, and human cohort designs are needed. Overall, the gut microbiota may represent a critical biological interface through which MPs interact with host physiology; however, further evidence is required before definitive conclusions can be drawn regarding their role in human chronic disease susceptibility.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-49"},"PeriodicalIF":2.7,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol as a Modulator of Reproductive Toxicity: Evidence and Mechanistic Perspectives.","authors":"Pandi Anandakumar, Nabendu Sen","doi":"10.1080/15376516.2026.2751576","DOIUrl":"https://doi.org/10.1080/15376516.2026.2751576","url":null,"abstract":"<p><p>Resveratrol (RSV) is a naturally occurring polyphenolic stilbene that has attracted considerable interest for its biological effects on reproductive health. Drug and chemical-induced reproductive toxicity encompass diverse disturbances that can impair cellular homeostasis, endocrine function, gametogenesis, and reproductive tissue integrity. Available studies indicate that RSV treatment is associated with improved redox balance, reduced inflammatory responses, preservation of cellular and mitochondrial integrity, attenuation of apoptotic signaling, and modulation of steroidogenic and reproductive functions. Nrf2-associated antioxidant responses and SIRT1-related signaling have been reported across several experimental models, while additional findings implicate PI3K/Akt and NF-κB/JNK-c-Jun-associated responses. Ferroptosis, autophagy, and AhR-associated signaling have also emerged as potential contributors in selected models. This review highlights the experimental evidence for RSV in drug- and chemical-induced reproductive toxicity and examines the molecular responses associated with its reported protective effects across diverse experimental models of reproductive injury.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-32"},"PeriodicalIF":2.7,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NRF2-KEAP1 Signaling in Chromium-Induced Lung Carcinogenesis: Mechanistic Insights and Evidence Gaps.","authors":"Bhavani Manoj Varma, Abilash Valsala Gopalakrishnan","doi":"10.1080/15376516.2026.2750969","DOIUrl":"https://doi.org/10.1080/15376516.2026.2750969","url":null,"abstract":"<p><p>Hexavalent chromium [Cr(VI)] is a recognized environmental and occupational carcinogen associated with an increased risk of lung cancer. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) pathway regulates cellular responses to oxidative and electrophilic stress and may influence cell survival following Cr(VI) exposure. Under basal conditions, KEAP1 promotes NRF2 ubiquitination and proteasomal degradation. Oxidative or electrophilic stress can impair this process, allowing NRF2 to accumulate and activate genes involved in antioxidant defense, detoxification, and cellular redox regulation, including HMOX1, NQO1, and GCLC. Although these responses can protect normal cells from acute stress, persistent NRF2 activity has also been associated with metabolic adaptation, resistance to apoptosis, and tumor-promoting phenotypes in several cancer models.However, the extent to which NRF2-KEAP1 signaling directly contributes to Cr(VI)-induced lung carcinogenesis remains incompletely established. Many studies on Cr(VI) have investigated oxidative stress, inflammation, genotoxicity, and cellular transformation. In contrast, relatively few have directly tested whether NRF2 activation is causally involved in tumor initiation or progression in chromium-exposed lung models. This review examines the relationship among Cr(VI) exposure, redox imbalance, and NRF2-KEAP1 signaling, distinguishing findings from chromium-specific experimental systems from mechanisms inferred from broader lung cancer research. It also discusses downstream processes relevant to carcinogenesis, occupational exposure, and risk assessment, as well as potential preventive or therapeutic strategies. The available evidence supports NRF2-KEAP1 signaling as an important component of the cellular response to Cr(VI)-associated stress, but further mechanistic studies are needed to establish its specific causal contribution to chromium-induced lung carcinogenesis.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-32"},"PeriodicalIF":2.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Toxicological Mechanisms of Pharmaceutical Nitrosamines: DNA Damage, Metabolic Activation, Carcinogenesis, and Advanced Analytical Detection Strategies.","authors":"Pradip Karale, Vishal Chabukswar, Ishvari Avachar, Nilesh Chaudhari, Raosaheb Shendge","doi":"10.1080/15376516.2026.2749670","DOIUrl":"https://doi.org/10.1080/15376516.2026.2749670","url":null,"abstract":"<p><p>In light of the valsartan recalls in 2018, nitrosamine impurities have become some of the most important pharmaceutical quality concerns to be seen in recent years, as NDMA and other nitrosamines have been discovered in angiotensin receptor blockers, metformin, ranitidine, and many other medicines. Nitrosamine impurities fall under the IARC classification of probable human carcinogens (Group 2A), and although present in very small amounts, these have prompted stricter standards for their presence, as set by the FDA, EMA, MHRA, PMDA, and Health Canada. The present review provides an overview of the current mechanistic knowledge within four interrelated areas. The first aspect to be discussed is that of the chemistry of nitrosamine generation. Second, the mechanisms underlying the metabolic activation via cytochrome P450 are explained in detail with emphasis on the key role played by α-hydroxylation, isoform specificities (with CYP2E1 and CYP2A6 enzymes being the most important players) and the mechanistic fork leading to either toxication through dealkylation or detoxification through denitrosation and hence determining the genotoxicity potential of the chemical. Third, the DNA adduct formation and mutagenicity associated with the nitrosamine compound is connected to the structure-based risk assessment systems like the Carcinogenic Potency Categorization Approach (CPCA). Fourth, analytical detection methods such as high resolution mass spectrometry, which can operate with sub-part per billion sensitivity levels, and computational prediction techniques are discussed as indispensable supplements to the mechanism-based risk assessment.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-48"},"PeriodicalIF":2.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splenic Toxicity and Gene Expression Alterations Induced by Perfluorobutanesulfonic Acid (PFBS) Ingestion in Sprague Dawley Rats.","authors":"Janelene R Sanders, Senia O Moore, Hannah F Olofintuyi, Worlanyo Eric Gato","doi":"10.1080/15376516.2026.2745930","DOIUrl":"https://doi.org/10.1080/15376516.2026.2745930","url":null,"abstract":"<p><p>Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are synthetic chemicals widely used in industrial and consumer products. Chronic exposure to PFAS has been associated with adverse health outcomes, including kidney cancer, thyroid dysfunction, pregnancy complications, and liver damage. This study investigates the splenic toxicity of Perfluorobutanesulfonic acid (PFBS), a short-chain PFAS compound composed of a four-carbon backbone bonded to fluorine atoms and a sulfonic acid functional group. PFBS is commonly found in wastewater, household dust, and cleaning agents. To assess its biological impact, Sprague Dawley rats were fed diets containing varying concentrations of PFBS. Histological analysis of the spleen revealed no overt structural damage and molecular profiling indicated significant alterations in gene expression. SYK, a spleen tyrosine kinase protein increased in PFBS exposed groups. A significant increase in the rat weight of exposed groups and marginally inflamed spleens may suggest some effects of PFBS ingestion on the treated animals. Transcripts associated with T-cell regulation and protein phosphorylation were upregulated, while inflammatory and immune-related genes were downregulated. Serum LDH levels showed slight elevation in PFBS-exposed groups, and animals receiving higher doses exhibited increased body weight compared to controls. These findings suggest that dietary ingestion of PFBS induces subtle but measurable toxicological effects on splenic function and immune regulation, probably indicating further research into its long-term health implications.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-11"},"PeriodicalIF":2.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotoxic effects of mercury: <i>in vitro</i> and <i>in vivo</i> studies.","authors":"Kajal Gaur, Yasir Hasan Siddique","doi":"10.1080/15376516.2026.2747093","DOIUrl":"https://doi.org/10.1080/15376516.2026.2747093","url":null,"abstract":"<p><p>Pollution remains a major global public health challenge, with mercury recognized as a highly hazardous environmental toxicant because of its persistence, bioaccumulation, and pronounced neurotoxicity. Mercury occurs in elemental, inorganic, and organic forms, particularly methylmercury (MeHg), which readily accumulates in biological systems and adversely affects the central nervous system. This narrative review summarizes current evidence on mercury-induced neurotoxicity, focusing on oxidative stress, neuroinflammation, mitochondrial dysfunction, altered energy metabolism, excitotoxicity, neurodevelopmental toxicity, epigenetic alterations, and disruption of neuronal signaling. The effects of mercury exposure on neural cell populations, including neurons, astrocytes, and oligodendrocytes, are also discussed, with particular emphasis on vulnerable populations such as pregnant women, fetuses, and children. Despite substantial progress, important gaps remain regarding long-term neurological outcomes, molecular mechanisms, dose-response relationships, sex-dependent susceptibility, and effective therapeutic interventions.A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar during January-February 2026 for studies published up to February 2026. The search combined terms related to mercury exposure and neurotoxicity, including \"mercury,\" \"methylmercury,\" \"mercury exposure,\" \"neurotoxicity,\" \"oxidative stress,\" \"neuroinflammation,\" \"mitochondrial dysfunction,\" \"neurodevelopment,\" and \"epigenetic alterations,\". Original research and relevant English-language reviews were included, while editorials, conference abstracts, duplicates, and studies unrelated to mercury-induced neurological effects were excluded. Titles and abstracts were screened, followed by full-text assessment of potentially relevant studies. As this was a narrative review, no formal risk-of-bias or quality-of-evidence assessment was performed.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-29"},"PeriodicalIF":2.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remogliflozin attenuates cyclophosphamide-associated peripheral neurotoxicity in rats: concomitant changes in redox, inflammatory, neurotrophic, and apoptosis-related markers.","authors":"Daniyah A Almarghalani, Marwa Qadri, Abdulaziz Alarifi, Hany M Fayed, Aya A Shokry","doi":"10.1080/15376516.2026.2740665","DOIUrl":"10.1080/15376516.2026.2740665","url":null,"abstract":"<p><p>Peripheral neurotoxicity represents a debilitating complication of cancer chemotherapy. Although cyclophosphamide (CP) is an alkylating agent with lower clinical propensity for classic peripheral neuropathy than platinum compounds or taxanes, its reactive metabolites provoke significant neurotoxic injury in experimental settings. This study investigated whether remogliflozin (Remo), a sodium-glucose cotransporter-2 inhibitor (SGLT2) with pleiotropic antioxidant and anti-inflammatory properties, attenuates CP-associated peripheral neurotoxicity in an experimental rat model. Twenty-four male Wistar rats were divided into four groups: control, CP alone (100 mg/kg intraperitoneally once weekly), CP plus Remo 25 mg/kg/day orally, and CP plus Remo 50 mg/kg/day orally, all for one month. Behavioral assessments revealed that CP treatment was associated with altered motor coordination and nociceptive responses, which showed dose-related numerical improvements with Remo treatment. Biochemically, Remo treatment was associated with a favorable shift in redox markers, evidenced by higher Nrf2, glutathione, and superoxide dismutase levels, alongside reduced malondialdehyde. Remo treatment was associated with lower concentrations of inflammatory markers, including NF-κB, MCP-1, TNF-α, IL-6, and IL-1β. Furthermore, Remo treatment was associated with increased BDNF and CREB concentrations, PI3K, and total/phosphorylated Akt (with an improved p-Akt/total Akt ratio), along with lower concentrations of caspase-3 and BAX, and higher BCL-2. Histopathological and immunohistochemical analyses demonstrated that Remo was associated with preserved nerve structural integrity, attenuated myelin loss, and elevated Nrf2 and p-Akt immunoreactivity. These findings suggest that Remo is associated with attenuation of CP-induced peripheral neurotoxicity in rats, presenting a phenotypically consistent biomarker profile that warrants further causal and mechanistic evaluation.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-22"},"PeriodicalIF":2.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}