Toxicology Mechanisms and Methods最新文献

{"title":"Nephroprotective role of edaravone against polystyrene nanoplastic-induced endoplasmic reticulum stress in Wistar rats.","authors":"Rachna Yadav, Ashok Jangra, Dinesh Dhingra, Sapana Kushwaha, Itishree Dubey, Dinesh Kumar","doi":"10.1080/15376516.2026.2664035","DOIUrl":"10.1080/15376516.2026.2664035","url":null,"abstract":"<p><strong>Background: </strong>Plastics in particular nanoplastics pose the major environmental threat worldwide. Nanoplastics refers to smaller plastic components with size less than 100 nm. Previous studies indicated that plastics could accumulate in blood and various other tissues, leading to hepatotoxicity, nephrotoxicity, neurotoxicity, and reproductive toxicity. Endoplasmic Reticulum (ER) stress disrupts the functionality of ER due to various factors, leading to the accumulation of unfolded and misfolded proteins inside the ER. The current study aimed to investigate the protective effect of edaravone against nephrotoxicity induced by Polystyrene Nanoplastics (PSNPs) through ER-Stress pathway. In this study, we examined the role of ER Stress in PSNPs induced renal damage for the first time.</p><p><strong>Methods: </strong>A total of thirty-two female Wistar rats were used (<i>n</i> = 8), where the first group served as vehicle-control. The second group was administered with PSNPs (10-mg/kg, orally) over a duration of five weeks. The third and fourth groups received PSNPs combined with edaravone at dosages of 5-mg/kg and 10-mg/kg respectively during the period (Day 22^nd-35^th). After five weeks, animals were euthanized and samples were collected.</p><p><strong>Results: </strong>Compared to vehicle-control rats, PSNPs exposed rats demonstrated a significant elevation in creatinine, MDA and nitrite alongside a decrease in body weight, kidney weight and GSH concentration. PSNPs administered group showed significant abnormalities in kidney histopathology and increased protein expression levels of GRP78, CHOP and caspase-12, whereas edaravone treatment decreased renal oxidative stress, histopathological abnormalities and protein expression of GRP78, CHOP and caspase-12.</p><p><strong>Conclusion: </strong>Edaravone may serve as a therapeutic intervention for PSNPs induced nephrotoxicity.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1130-1144"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781977","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":"Investigation of perfluorooctanoic acid exposure induced renal dysfunction associated with oxidative stress, fibrosis, and impaired angiogenic signaling in male Wistar rats.","authors":"Lavanya Hongal, M David","doi":"10.1080/15376516.2026.2673546","DOIUrl":"10.1080/15376516.2026.2673546","url":null,"abstract":"<p><p>Perfluorooctanoic acid (PFOA), a persistent per- and polyfluoroalkyl substance, is widely detected in environmental and biological systems and has been associated with renal toxicity. However, the integrated relationship between oxidative stress, erythropoietic regulation, angiogenic signaling and fibrotic remodeling remains insufficiently defined. This study evaluated dose- and duration-dependent nephrotoxic effects of sub-chronic PFOA exposure in male Wistar albino rats. Animals received oral administration of PFOA at 48 or 96 mg/kg body weight over exposure periods of 30, 60 and 90 days. Renal toxicity was assessed using serum biochemical markers, hematological parameters, electrolyte levels and erythropoietin concentration. Oxidative stress was evaluated through lipid peroxidation and antioxidant enzyme activities. Histopathological changes were examined using hematoxylin-eosin, Masson's trichrome, Periodic Acid-Schiff and Alcian blue staining, while immunohistochemistry was performed for Vimentin and vascular endothelial growth factor (VEGF). PFOA exposure resulted in significant renal dysfunction, including increased serum urea, uric acid and blood urea nitrogen levels, accompanied by enhanced lipid peroxidation and reduced antioxidant defenses (<i>p</i> < 0.05). Histological examination revealed glomerular atrophy, tubular degeneration, inflammatory infiltration and collagen deposition. Increased Vimentin expression and reduced VEGF immunoreactivity indicated epithelial-mesenchymal transition and impaired angiogenic signaling. Collectively, the findings demonstrate that PFOA-induced nephrotoxicity involves coordinated disruption of redox balance, hypoxia-responsive signaling and angiogenic pathways rather than isolated oxidative injury. This integrative framework provides mechanistic insight into PFAS-associated renal disease and identifies the erythropoietin-VEGF axis as a potential target for early intervention.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1243-1265"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964732","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 and metabolic effects of chronic aspartame consumption in rodent models: a systematic review and meta-analysis.","authors":"Arbind Kumar Choudhary, Nishant Singh","doi":"10.1080/15376516.2026.2662931","DOIUrl":"10.1080/15376516.2026.2662931","url":null,"abstract":"<p><p>Aspartame (ASP), a widely used artificial sweetener, remains the subject of scientific scrutiny regarding its long-term safety. While regulatory agencies assert safety at established acceptable daily intake (ADI) levels, accumulating preclinical rodent data suggests potential adverse effects under chronic exposure conditions. This systematic review and meta-analysis synthesized evidence from 13 rodent studies investigating neurotoxic and metabolic endpoints. Our quantitative meta-analysis of the oxidative stress domain (<i>k</i> = 8) demonstrated a very large and statistically significant increase in oxidative damage (pooled Hedges' g = +4.44; 95% CI: 2.94 to 5.94), suggesting oxidative stress as a major hypothesized mechanism of aspartame-induced injury. Qualitatively, chronic exposure was associated with neurobehavioural deficits, including spatial learning and memory impairments, alongside metabolic dysfunction such as glucose intolerance and dyslipidaemia. Notably, these effects were observed in several studies utilizing doses equivalent to the human ADI. However, the interpretation of these findings is constrained by high statistical heterogeneity (I² = 85.4%) and a lack of detailed reporting in primary studies, resulting in uncertain internal validity across several risk-of-bias domains. While these results provide a critical signal regarding the neurotoxic and metabolic potential of aspartame, they underscore the urgent need for improved reporting standards in preclinical toxicology and long-term human epidemiological studies to fully clarify its safety profile.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1045-1058"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730138","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":"Characterization of unusual immunoassay cross-reactive cannabinoid metabolites in canine urine via gas chromatography-mass spectrometry.","authors":"Chris Pickard, John P Buchweitz, Andreas F Lehner","doi":"10.1080/15376516.2026.2665315","DOIUrl":"10.1080/15376516.2026.2665315","url":null,"abstract":"<p><p>Recent increases in cannabis use and dog ownership have elevated the risk of canine cannabis intoxication, prompting a need for efficient diagnostic tools. Enzyme immunoassays (EIAs) that employ monoclonal antibodies specific to 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THC-COOH) are commonly employed for preliminary screening and frequently return positive results in canine urine, yet these are not corroborated by gas chromatography-mass spectrometry (GC-MS), suggesting immunoassay cross-reactivity that raises concerns about false positives. The present study incorporated confirmatory GC-MS and GC-MS/MS analyses with mass spectral deconvolution to investigate EIA-positive, GC-MS-negative samples. Two novel compounds with molecular weights of 446 and 460 were identified following trimethylsilylation in the corresponding urine samples. Structural analysis suggests these compounds may be metabolic derivatives of tetrahydrocannabivarin (THCV), a cannabinoid with growing presence in consumer products. These compounds are structurally distinct from Δ⁹-THC-COOH yet exhibit EIA-reactivity. Ion fragmentation patterns, derivatization behavior, and comparison to established mass spectral libraries support the possibility of 11-hydroxylated and 9-carboxylated THCV analogs. The findings point to THCV metabolism as a plausible source of EIA-cross-reactivity in canines, raising important implications for veterinary toxicology and drug screening protocols. This study contributes crucial insights into canine cannabinoid metabolism and highlights limitations of existing immunoassays when influenced by structurally similar analytes.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1162-1182"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821177","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":"Copper-based nanoparticles-associated neurotoxicity: ions or particles?","authors":"Zehra Keskin, Can Özgür Yalçın, Engin Yenilmez, Ezgi Öztaş, Mahmoud Abudayyak","doi":"10.1080/15376516.2026.2664036","DOIUrl":"10.1080/15376516.2026.2664036","url":null,"abstract":"<p><p>The widespread use of engineered nanomaterials raises concerns regarding their potential toxicity to human health and the environment. Among metal oxide nanoparticles, copper-based nanoparticles (Cu-based NPs) are extensively produced and utilized due to their unique physicochemical properties. The dissolution of NPs leads to the release of ionic species, and still, there is no clear consensus on whether metal-based NPs' toxicity arises primarily from the nanoparticles themselves or from the ionic species generated through metal ion dissolution. This study systematically evaluated the cellular uptake and toxicological profiles of various Cu-based NPs (Cu, CuO, Cu₂O, and CuFe₂O₄) in comparison to ionic copper (CuCl₂) using the PC12 neuronal model. ICP-MS analysis demonstrated that cellular uptake was both dose- and particle-dependent; notably, CuO NPs yielded the highest intracellular copper accumulation. Cytotoxicity assays (MTT and NRU) revealed that all Cu-based NPs showed significantly higher toxicity than CuCl₂. Furthermore, Cu-based NP exposure, particularly with Cu₂O, triggered a robust oxidative stress response characterized by significant alterations in GSH, CAT, and MDA levels. This oxidative imbalance was closely associated with a marked increase in apoptosis and necrosis and substantial DNA damage. Our findings elucidate that the oxidation state and chemical formulation of copper nanoparticles significantly dictate their neurotoxic potential, with Cu₂O NPs exhibiting the most pronounced geno- and cytotoxicity. These results highlight the necessity of considering nanoparticle-specific effects beyond simple ion dissolution in the safety assessment of engineered nanomaterials.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1145-1161"},"PeriodicalIF":2.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843239","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":"Protective effect of Dapagliflozin on hepatic encephalopathy induced by thioacetamide in rats: involvement of ERK, JNK, and Nrf2/HO-1 pathways.","authors":"Hadir Farouk, Salma A El-Marasy, Marwa S Khattab, Yasmin M Abd El-Aziz, Rasha E Mostafa","doi":"10.1080/15376516.2026.2725745","DOIUrl":"https://doi.org/10.1080/15376516.2026.2725745","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with oxidative stress, neuroinflammation, and hyperammonaemia secondary to hepatic dysfunction. This study aimed to investigate dapagliflozin's effects (DAPA) against HE induced by thioacetamide (TAA) in rats and to elucidate the roles of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling pathways. HE was induced by injection of TAA (200 mg/kg) intraperitoneally 2 times every other day. Two groups were pretreated with DAPA at 5 and 10 mg/kg for 15 days; on the 13th day, rats were given TAA (200 mg/kg, i.p.) twice, 2 days apart. Behavioral assessments, including object recognition and rotarod tests, were conducted, and serum and tissue samples were collected for biochemical and molecular analyses. DAPA pretreatment ameliorated TAA effects, improved recognition memory, enhanced muscular tone and motor coordination. DAPA also reduced ALT (alanine aminotransferase), AST (aspartate aminotransferase), and ammonia serum levels. Additionally, it restored antioxidant balance, decreased malonaldehyde (MDA) and increased reduced glutathione (GSH). Moreover, it reduced tissue inflammation and inhibited apoptosis; where tumor necrosis factor-alpha (TNF-α) and caspase-3 expression were suppressed. DAPA was associated with increased Nrf2/HO-1 pathway-related protein expression while decreasing pERK/total ERK and pJNK/total JNK ratios, along with nuclear factor kappa-light-chain-enhancer of activated B cells, p65 subunit (NF-κB-p65) protein expression. Histopathologically, DAPA improved hepatic and brain architecture. Collectively, DAPA exhibits hepatoprotective and neuroprotective effects against TAA-induced HE accompanied by modulation in oxidative-, inflammatory-, and apoptotic-related protein expression, highlighting its therapeutic potential in hepatic encephalopathy.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-18"},"PeriodicalIF":2.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148832367","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":"A Dose-Unit-Aware Predictive Toxicology Framework for Literature-Derived In Vitro Carbon Nanotube Cytotoxicity.","authors":"Deniz Özkan Vardar, Necati Vardar","doi":"10.1080/15376516.2026.2725744","DOIUrl":"https://doi.org/10.1080/15376516.2026.2725744","url":null,"abstract":"<p><p>Carbon nanotubes (CNTs) are increasingly used as engineered nanomaterials, but their in vitro cytotoxicity remains difficult to synthesize because reported viability outcomes vary across dose metrics, exposure durations, CNT types, functionalization states, cell models, and assay systems. This study developed an exploratory, literature-derived, dose-unit-aware predictive toxicology framework for binary classification of CNT-induced cytotoxicity using standardized cell viability data. Experimental-condition-level records were extracted from eligible in vitro CNT studies and harmonized according to dose, dose unit, exposure duration, CNT type, functionalization, cell line, assay type, and viability outcome. Cytotoxicity was defined as cell viability below 70%. A primary-core dataset, including 146 µg/mL records from 11 articles, was used for nominal concentration-based modeling, whereas a secondary unit-aware dataset, including 212 records from 13 articles, incorporated both µg/mL and µg/cm² observations while retaining dose-unit identity as an explicit predictor. Logistic Regression and Random Forest classifiers were trained using log-transformed dose-related variables and experimental-context predictors. Performance was assessed using stratified cross-validation, article-grouped cross-validation, leave-one-article-out validation, and leave-one-family-out validation with fold-level variability considered to reflect uncertainty and to mitigate overoptimistic estimates arising from within-study similarity. Random Forest showed higher point estimates under conventional stratified validation, whereas Logistic Regression provided comparatively stable discrimination under stricter grouped-validation settings. Ablation-based stress testing identified high-dose non-toxic A549/MTT observations as a major source of false-positive toxicity predictions, particularly for Random Forest. A dose × dose-unit interaction sensitivity analysis did not consistently improve grouped or leave-one-out validation; therefore, the additive unit-aware model was retained as the primary unit-aware analysis. The unit-aware analysis demonstrated that surface-dose records can be incorporated without assuming equivalence between nominal mass concentration and surface-area-normalized exposure. The framework provides a transparent strategy for curating, validating, stress-testing, and cautiously modeling heterogeneous literature-derived CNT viability data in nanosafety research.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-22"},"PeriodicalIF":2.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148832413","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":"Unveiling the neurodevelopmental toxicity of PFOA and PFOS: evidence from integration of <i>in silico</i> and <i>in vitro</i> study.","authors":"Lili Xin, Rui Guo, Jiawei Sun, Yue Su, Jiahang Cai, Wanzhen Li, Zhongxiao Wan, Jianshu Wang","doi":"10.1080/15376516.2026.2723920","DOIUrl":"https://doi.org/10.1080/15376516.2026.2723920","url":null,"abstract":"<p><p>Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are well-known neurodevelopmental toxicants, but the potential molecular mechanism needs to be further clarified. This study aimed to investigate the underlying mechanism of PFOA and PFOS-induced neurodevelopmental toxicity by integrating network toxicology, transcriptomic data from autism spectrum disorder patients and <i>in vitro</i> study. Network toxicology identified 42 core targets that enriched in a total of 105 significant GO entries and 142 KEGG pathways. With the disease-context comparison from the transcriptomic, 10 hub targets and 22 common KEGG pathways were identified. Cellular senescence-associated responses including cellular senescence and cell cycle were proposed as one of the potential mechanisms underlying PFOA and PFOS co-exposure-induced neurodevelopmental toxicity. Molecular docking analysis showed that PFOA and PFOS elicits potential binding capacities with hub targets, with TP53 and MAPK 13 exhibiting lower binding affinities with both PFASs, further predicting the potential role of these targets in PFASs-induced neurodevelopmental toxicity. After PFOA and PFOS co-treatment, reduced cell viability, a senescence-like phenotype characterized by cell cycle arrest and increased positive senescence β-galactosidase, upregulation of senescence-associated biomarkers including TP53, p53, p21 and IL-6 as well as the significant up-regulation of <i>MAPK1</i>, <i>MAPK3</i>, <i>MAPK13</i> and <i>MAPK14</i> genes were observed in human neuroblastoma SH-SY5Y cells. Thereafter, these findings suggested the multi-target and multi-pathway characteristic of PFOA and PFOS co-exposure-induced neurodevelopmental toxicity with cellular senescence-associated responses as one of the potential molecular mechanisms.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-18"},"PeriodicalIF":2.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809077","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":"Advances in artificial intelligence and machine learning for toxicity prediction in computational toxicology: a comprehensive review.","authors":"Gerald Shija","doi":"10.1080/15376516.2026.2712550","DOIUrl":"10.1080/15376516.2026.2712550","url":null,"abstract":"<p><p>Over the past three decades, artificial intelligence (AI) and machine learning (ML) have revolutionized computational toxicology, providing powerful tools for predicting chemical toxicity and supporting safer assessments for human health and the environment. This review offers a critical 30-year synthesis (1995-2025) that distinguishes itself from narrower prior works through its interdisciplinary integration of historical evolution, multi-omics data fusion, nanotoxicity challenges, regulatory frameworks, multi-stakeholder perspectives, and emerging hybrid and generative models. Key findings reveal a clear progression from early artificial neural networks capturing non-linear patterns in the 1990s to modern deep learning architectures such as convolutional neural networks and graph neural networks that have achieved over 85% accuracy, primarily in retrospective benchmarks on ToxCast and Tox21 datasets for endpoints including hepatotoxicity, cardiotoxicity, and nanotoxicity. However, prospective validation on novel compounds remains limited, representing a critical translational gap. Traditional machine learning methods (random forests and support vector machines) effectively handle imbalanced high-throughput screening data, facilitating multi-omics integration and applications across pharmaceuticals, pesticides, cosmetics, and nanoparticles. These approaches strengthen read-across strategies, Integrated Approaches to Testing and Assessment (IATA), and Threshold of Toxicological Concern (TTC) frameworks. Regulatory acceptance, guided by OECD principles, increasingly emphasizes explainable AI to ensure transparency and validation. In conclusion, AI/ML approaches can substantially reduce animal testing, accelerate safety evaluations, and address data gaps, yet require ongoing attention to biases, model opacity, and limited prospective performance. Hybrid mechanistic-AI models, federated learning, and strengthened cross-sector collaboration represent the most promising path forward.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-19"},"PeriodicalIF":2.7,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148621482","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 thioacetamide-induced nephrotoxicity: association with Nrf2/HO-1, SIRT1/AMPK, and TLR4/NF-κB pathway modulation.","authors":"Marwa Qadri, Daniyah A Almarghalani, Abdulaziz Alarifi, Bassim M S A Mohamed, Hany M Fayed","doi":"10.1080/15376516.2026.2718918","DOIUrl":"10.1080/15376516.2026.2718918","url":null,"abstract":"<p><p>Thioacetamide (TAA) induces renal injury <i>via</i> oxidative stress and inflammation. Remogliflozin (Remo), an SGLT2 inhibitor, was evaluated for potential renoprotection. Twenty-four male Wistar rats were assigned to control, TAA (100 mg/kg IP twice weekly), TAA + Remo 25 mg/kg, or TAA + Remo 50 mg/kg (oral daily). Outcomes included renal function, oxidative stress (GSH, SOD, MDA), antioxidant biomarkers (Nrf2, HO-1), inflammatory mediators (TLR4/NF-κB, TNF-α, IL-1β), metabolic/kinase biomarkers (SIRT1, AMPK, PI3K, AKT), and histopathology/immunohistochemistry (mTOR, MYD88, Nrf2). Remogliflozin was associated with lower serum creatinine, urea, and uric acid, with endpoint-specific differences between doses. Remo was associated with higher renal Nrf2, HO-1, SIRT1, and p-AMPK, and lower MDA, TLR4, NF-κB, TNF-α, IL-1β, PI3K, and AKT. Histopathology and IHC showed associations with reduced tissue injury, lower mTOR and MYD88 immunoreactivity, and increased Nrf2 staining. While the 50 mg/kg group showed changes in more markers, this does not establish uniform dose superiority or a formal dose-response relationship; at 25 mg/kg, effects differed among AMPK-related endpoints. Direct 25-versus-50 mg/kg comparisons were included in the Tukey-Kramer analysis for each endpoint. No pharmacokinetic measurements or formal dose-response analyses were performed. In this exploratory model, remogliflozin was associated with attenuation of TAA-induced renal injury and modulation of related biomarkers. Causal mechanisms remain to be confirmed by targeted intervention studies. Findings are limited to young male Wistar rats and should not be generalized to other populations or clinical settings. Remogliflozin warrants further preclinical investigation in TAA-associated renal injury.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-22"},"PeriodicalIF":2.7,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724265","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}