Toxicology Mechanisms and Methods最新文献_第8页

New mechanistic approach of TiCN film-coated NiTi substrate toxicity: impairment in mitochondrial electron transfer in diabetic rat tooth gum cells. TiCN膜包覆NiTi底物毒性的新机制研究：糖尿病大鼠牙牙龈细胞线粒体电子转移损伤。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-04-28 DOI: 10.1080/15376516.2025.2479000

Abbas Razmi, Enayatollah Seydi, Behnaz Ashtari, Ali Neshasteh-Riz, Parvaneh Naserzadeh

{"title":"New mechanistic approach of TiCN film-coated NiTi substrate toxicity: impairment in mitochondrial electron transfer in diabetic rat tooth gum cells.","authors":"Abbas Razmi, Enayatollah Seydi, Behnaz Ashtari, Ali Neshasteh-Riz, Parvaneh Naserzadeh","doi":"10.1080/15376516.2025.2479000","DOIUrl":"10.1080/15376516.2025.2479000","url":null,"abstract":"In recent years, researchers have focused on using new materials for screws in bone jaw tissue replacement. However, concerns regarding the cytotoxicity and biocompatibility of these materials for cells remain a subject of ongoing discussion. In this study, a novel implant for bone jaw tissue regeneration was fabricated by depositing the titanium carbo-nitride (TiCN) film on NiTi shape memory alloy substrate using the Cathodic Arc Physical Vapor Deposition (CAPVD) technique. Our study emphasized positive cellular responses of TiCN-coated NiTi substrate on diabetic rat tooth gum cells for 1, 15, and 30 days. Initially, the evaluation focused on the characterization and distribution of NiTi alloy in tissues. Then, the levels of factors such as components of White Blood Cells (WBC), ATP, oxidative stress parameters, cytochrome c release and damage to the lysosomal membrane were evaluated in all groups. The results indicated that in the group of diabetic rats with TiCN-coated NiTi substrate, the level of oxidative stress parameters decreased. In addition, the cell viability, glutathione (GSH) intracellular and ATP increased and the rate of cytochrome c release, and damage to the lysosome membrane decreased. It can be concluded that the TiCN-coated NiTi screw is a promising material for bone jaw tissue replacement in diabetic patients due to its low cytotoxicity.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"633-643"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626117","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}

引用次数: 0

Cytotoxic potential of an indole-conjugated Oleanolic acid analogue: suppression of NSCLC proliferation through modulation of mitochondrial apoptotic dynamics. 吲哚共轭齐墩果酸类似物的细胞毒性潜力：通过调节线粒体凋亡动力学抑制非小细胞肺癌增殖。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-03-25 DOI: 10.1080/15376516.2025.2481915

Srividya Subramanian, Sankar Pajaniradje, Suhail Ahmad Bhat, Sathyapriya Chandramohan, Parthiban Anaikutti, Rukkumani Rajagopalan

{"title":"Cytotoxic potential of an indole-conjugated Oleanolic acid analogue: suppression of NSCLC proliferation through modulation of mitochondrial apoptotic dynamics.","authors":"Srividya Subramanian, Sankar Pajaniradje, Suhail Ahmad Bhat, Sathyapriya Chandramohan, Parthiban Anaikutti, Rukkumani Rajagopalan","doi":"10.1080/15376516.2025.2481915","DOIUrl":"10.1080/15376516.2025.2481915","url":null,"abstract":"Pre-clinical toxicological investigations are pivotal in the development of safer and more efficacious chemotherapeutic agents. Oleanolic acid (OA), a naturally occurring pentacyclic triterpenoid, has demonstrated anticancer potential but is often limited by the toxic side effects of its derivatives. In the current study, we carried out the facile synthesis of a modified OA analogue, OD2, and studied its cytotoxicity and efficacy analysis across several cell lines. Mechanistic toxicology was explored through fluorescence-based assays. Annexin-V/Propidium Iodide (A-V/PI) staining and TUNEL assays were used to confirm apoptosis. OD2 exhibited dose-dependent cytotoxicity, with a pronounced effect on A549 lung cancer cells compared to other cancerous and non-cancerous cell lines. Apoptosis was found to be the predominant mode of cell death, evidenced by Fluorescence imaging analysis of chromatin condensation and mitochondrial dysfunction. This was further validated by an increase in Annexin-V-positive and TUNEL-positive cells in treated groups. OD2 activated the intrinsic mitochondrial apoptotic pathway as evidenced by increased Bax and decreased Bcl-2 protein abundance levels. While the current study showcases the therapeutic potential of the selective toxicological activity of OD2, future studies will focus on the deconvolution of its potential polypharmacological mode of action and decoding the basis of its selective action, so as to glean important lessons that can be applied in the development of chemotherapeutic agents with favorable toxicological profiles.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"668-681"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658727","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}

引用次数: 0

Exploring the impact of ambient air PM_2.5 on multiple sclerosis: an experimental dive into neuroinflammation. 探索环境空气PM2.5对多发性硬化症的影响：神经炎症的实验研究。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-03-11 DOI: 10.1080/15376516.2025.2468726

Shilan Mozaffari, Mohammad Sadegh Hassanvand, Maryam Baeeri, Mahdi Gholami, Zahra Bayrami, Masud Yunesian, Mohammad Ali Sahraian, Shekoufeh Nikfar, Mohammad Abdollahi

{"title":"Exploring the impact of ambient air PM2.5 on multiple sclerosis: an experimental dive into neuroinflammation.","authors":"Shilan Mozaffari, Mohammad Sadegh Hassanvand, Maryam Baeeri, Mahdi Gholami, Zahra Bayrami, Masud Yunesian, Mohammad Ali Sahraian, Shekoufeh Nikfar, Mohammad Abdollahi","doi":"10.1080/15376516.2025.2468726","DOIUrl":"10.1080/15376516.2025.2468726","url":null,"abstract":"There is mounting evidence about the connection between particulate matter (PM) and neuroinflammation. This study aimed to evaluate the toxicological effects of PM2.5 associated with inflammatory factors in a mouse's multiple sclerosis (MS) model. Thirty C57BL/6 male mice were categorized into five groups: a group of healthy mice, a control cuprizone-induced MS group, and three MS-induced groups, intranasally exposed to three concentrations of ambient air PM2.5 (5, 10, and 20 mg/mL) from Tehran in a phosphate-buffered saline (PBS) solution. All mice were investigated by motor function, molecular, and histopathological assays. Moreover, the chemical content of the collected PM2.5 was assessed and reported. The cumulative exposure doses were equal to 0.025, 0.05, and 0.1 mg per gram of body weight of mice, which were approximately 3.52, 7.04, and 14.08 times higher than the human daily dose in Tehran. The PM2.5-exposed groups showed a high inflammatory response characterized by a significant increase in the mRNA expression of tumor necrosis alpha (TNF-α), NLRP3, and interleukin 18 (IL-18). In addition, the PM2.5-exposed groups exhibited a notably lower velocity level, total traveled distance (TD), and duration traveled in the central zone (DC) than the control group. The histopathological assays revealed significant pathological alterations and demyelination in the PM2.5-exposed groups compared to the control group. Identifying the risks and reducing the likelihood of exposure through preventive measures and regulations can result in financial savings and improve the quality of life for MS patients.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"581-591"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606481","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}

引用次数: 0

Leveraging AlphaFold models to predict androgenic effects of endocrine-disrupting chemicals through zebrafish androgen receptor analysis. 利用AlphaFold模型通过斑马鱼雄激素受体分析预测内分泌干扰化学物质的雄激素效应。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-03-12 DOI: 10.1080/15376516.2025.2477036

Md Adnan Karim, Chang Gyun Park, Hyunki Cho, Annmariya Elayanithottathil Sebastian, Chang Seon Ryu, Juyong Yoon, Young Jun Kim

{"title":"Leveraging AlphaFold models to predict androgenic effects of endocrine-disrupting chemicals through zebrafish androgen receptor analysis.","authors":"Md Adnan Karim, Chang Gyun Park, Hyunki Cho, Annmariya Elayanithottathil Sebastian, Chang Seon Ryu, Juyong Yoon, Young Jun Kim","doi":"10.1080/15376516.2025.2477036","DOIUrl":"10.1080/15376516.2025.2477036","url":null,"abstract":"The androgen receptor (AR) activation by androgens is vital for tissue development, sexual differentiation, and reproductive attributes in zebrafish (Danio rerio). However, our understanding of the molecular mechanisms behind their activation remains limited. In this study, we employed both ab initio (AlphaFold) and homology (SWISS-MODEL) structure models of zebrafish androgen receptor ligand-binding domain (zAR-LBD) to explore the binding specificity, binding affinity, and molecular interactions of endogenous hormones (testosterone (T), 11-ketotestosterone (11-KT), and dihydrotestosterone (DHT)) in a computational simulation. Molecular docking analysis showed that both structures formed the same interactions and similar patterns of binding energy with androgens. Molecular Dynamics (MD) simulation analysis revealed that hydrogen bond occupancy aligned with in vitro findings related to androgenic effect. When comparing complexes modeled by SWISS-MODEL and AlphaFold, significant differences were observed in root mean square deviation (RMSD) and root mean square fluctuations (RMSF). The AlphaFold structures also exhibited a clear separation between ligands in principal component analysis. Further correlation analysis between in silico features and in vitro EC50 values identified MMPBSA energies as the most significant contributors to ligand-specific variance in the in silico complexes (p < 0.05). Overall, this integrative approach offers significant insights into the molecular mechanisms underlying zebrafish AR activity.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"620-632"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587148","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}

引用次数: 0

Cellular mechanisms of medium-chain chlorinated paraffins toxicity: the effect of cellular lipid content. 中链氯化石蜡毒性的细胞机制：细胞脂质含量的影响。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-03-31 DOI: 10.1080/15376516.2025.2481909

Nikola Vrzáčková, Petr Svoboda, Jana Dudová, Vojtěch Škop, Magdalena Melčová, Jaroslav Zelenka, Jana Pulkrabová, Tomáš Ruml

{"title":"Cellular mechanisms of medium-chain chlorinated paraffins toxicity: the effect of cellular lipid content.","authors":"Nikola Vrzáčková, Petr Svoboda, Jana Dudová, Vojtěch Škop, Magdalena Melčová, Jaroslav Zelenka, Jana Pulkrabová, Tomáš Ruml","doi":"10.1080/15376516.2025.2481909","DOIUrl":"10.1080/15376516.2025.2481909","url":null,"abstract":"Research on chlorinated paraffins (CPs) is growing, with accumulating evidence of CPs being present in biological matrices and animal tissues. However, their cellular-level impacts remain underexplored. This study investigates the effects of medium-chain CPs on adipose and liver cell models. The results show that CPs are more toxic at lower concentrations in 3T3-L1 preadipocytes than in adipocytes, suggesting that intracellular lipids may offer protection against these contaminants. However, neither simulated lipolysis in adipocytes nor lipogenesis in HepG2 hepatocytes revealed any lipid-dependent effects of CPs. CP exposure reduced heme oxygenase 1 expression, indicating a biological response to these contaminants. In a coculture model of adipocytes and macrophages, CP exposure influenced cell signaling, with lipid-rich adipocytes modulating macrophage immune responses. Our results demonstrate that medium-chain CPs accumulation in lipid-rich tissues does not significantly affect their toxic effects. However, it may influence cell signaling within adipose tissue.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"655-667"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754750","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}

引用次数: 0

Investigating the genomic and biochemical effects of dalapon on antioxidant systems in zebrafish, Danio rerio. 研究达拉蓬对斑马鱼抗氧化系统的基因组和生化影响。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-03-12 DOI: 10.1080/15376516.2025.2473525

Mehtap Bayır, Abdulkadir Bayır, Burcu Naz Uzun, Serpil Turhan

{"title":"Investigating the genomic and biochemical effects of dalapon on antioxidant systems in zebrafish, Danio rerio.","authors":"Mehtap Bayır, Abdulkadir Bayır, Burcu Naz Uzun, Serpil Turhan","doi":"10.1080/15376516.2025.2473525","DOIUrl":"10.1080/15376516.2025.2473525","url":null,"abstract":"This research explored the effects of dalapon exposure on the expression of various genes, including cat, sod1, sod2, sod3a, sod3b, gpx1a, gpx3, gpx4a, gpx4b, gpx7, gpx8, gpx9, gstr, g6pd, and gsr, along with the activities of related antioxidant enzymes (AEs), such as CAT, SOD, GPX, G6PD, GST, and GR in zebrafish. Kidney and liver tissues were analyzed to assess oxidative stress levels. Results indicated that both the concentration of dalapon (25 and 50 ppm) and the duration of exposure had a significant effect on AE activities and gene expression. RT-PCR analysis suggested that changes in gene expression among dalapon-exposed zebrafish might indicate a rapid response to pesticide-induced stress. Moreover, the activities of CAT, G6PD, and GST increased in response to dalapon exposure at the specified concentrations. In contrast, prolonged exposure exceeding 72 h led to significantly higher malondialdehyde levels in liver and kidney tissues compared to the control group. These findings enhance our understanding of the role of antioxidant enzymes in oxidative stress and provide important insights for developing aquaculture breeding programs focused on improving fish stress tolerance. Furthermore, phylogenetic analysis and conserved gene synteny analysis confirmed that the antioxidant enzyme genes in zebrafish are orthologous to those found in other model organisms, such as medaka and stickleback. Consequently, these results could be beneficial for other vertebrate species.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"604-619"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606484","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}

引用次数: 0

Mitochondrial toxic prediction of marine alga toxins using a predictive model based on feature coupling and ensemble learning algorithms. 基于特征耦合和集成学习算法的预测模型对海洋藻类毒素的线粒体毒性预测。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-04-11 DOI: 10.1080/15376516.2025.2484318

Guangyin Jia, Ruiji Zhang, Xinyi Zheng, Liujun Guo, Yan Zhao, Tingting Yan

{"title":"Mitochondrial toxic prediction of marine alga toxins using a predictive model based on feature coupling and ensemble learning algorithms.","authors":"Guangyin Jia, Ruiji Zhang, Xinyi Zheng, Liujun Guo, Yan Zhao, Tingting Yan","doi":"10.1080/15376516.2025.2484318","DOIUrl":"10.1080/15376516.2025.2484318","url":null,"abstract":"Alga toxins have recently emerged as environmental risk factors to multiple human health issues. Mitochondrial toxicity is an essential element in the field of ecotoxicology, it is necessary to screen and manage mitochondrial toxicants from common alga toxins. To overcome the limitations of traditional animal and cell experiments, computational toxicology is increasingly emphasized. In this study, all the publicly available datasets were compiled to create the largest mitochondrial toxicity dataset to date, establishing a robust and high-performance QSAR screening model. The model couples and filters 12 molecular fingerprints and 318 descriptors as features, capturing more information about molecular structure and properties. By comparing 8 machine learning algorithms and using a weighted soft voting method to integrate the two optimal algorithms, we established 108 prediction models and identified the best ensemble learning model MACCS_LK for screening and defining its application domain. Additionally, the efficacy of MACCS fingerprints in representing mitochondrial toxicants was established, and a mechanistic analysis of the identified model based on the SHAP method and 11 structural alerts uncovered in this study was conducted, enhancing the interpretability of this model. This study highlights the key roles of lipophilic structures such as aromatic rings and long hydrocarbon chains and their related physicochemical properties in predicting toxicity outcomes. The mitochondrial toxicity of six algal toxins was predicted by employing this model, and the results indicating that two of them possess mitochondrial toxic effects. This model has high reliability and accuracy, making it applicable for predicting mitochondrial toxicity of more marine biotoxins.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"682-700"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701247","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}

引用次数: 0

Propofol alleviates traumatic brain injury through regulating Th17/Treg balance by activation of the AMPK/SIRT1 pathway. 异丙酚通过激活AMPK/SIRT1通路调节Th17/Treg平衡，减轻创伤性脑损伤。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-04-02 DOI: 10.1080/15376516.2025.2481893

Dan Wang, Hui Sun, Kerong Hai, Ningkang Li, Yang Gu, Zengrui Ma

{"title":"Propofol alleviates traumatic brain injury through regulating Th17/Treg balance by activation of the AMPK/SIRT1 pathway.","authors":"Dan Wang, Hui Sun, Kerong Hai, Ningkang Li, Yang Gu, Zengrui Ma","doi":"10.1080/15376516.2025.2481893","DOIUrl":"10.1080/15376516.2025.2481893","url":null,"abstract":"Traumatic brain injury (TBI), a prevalent neurological disorder in clinical practice, is primarily induced by external trauma. Propofol has been reported to alleviate the symptoms associated with TBI. In this study, a TBI model was established in mice using the controlled cortical impact (CCI) method. After treatment with propofol and BML-275, neuronal damage in the TBI model was assessed through the modified Neurological Severity Score (mNSS), Hematoxylin and Eosin (HE) staining, and Nissl staining. To investigate the role of the AMPK/SIRT1 pathway in propofol-regulated TBI, AMPKα-silenced vectors and overexpressed SIRT1 vectors were transfected. Western blot was performed to evaluate the expression of proteins involved in the AMPK/SIRT1 pathway and pyroptosis markers. The regulatory impact of Th17/Treg balance was examined by detecting the key transcription factors RORγt and FOXP3 through immunofluorescent staining and RT-qPCR. Enzyme-linked immunosorbent assay (ELISA) was used to measure IL-17 and IL-10 concentrations. Results showed that propofol significantly reduced neuronal injury in the TBI model, an effect that was reversed by BML-275. Moreover, propofol mitigated pyroptosis by downregulating Caspase-1 and GSDMD-N expression post-TBI. Propofol inhibited Th17 differentiation while promoting Treg differentiation by modulating RORγt/FOXP3 and IL-17/IL-10 levels. Silencing AMPKα markedly diminished propofol's effects on Th17 and Treg differentiation, with these effects being reversed upon SIRT1 overexpression. Propofol suppressed neuronal pyroptosis through the regulation of Th17/Treg balance via activation of the AMPK/SIRT1 pathway. These findings suggest propofol exerts a protective effect against neuronal damage following TBI, potentially through the modulation of the Th17/Treg balance and AMPK/SIRT1 signaling pathway.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"644-654"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765051","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}

引用次数: 0

Mechanisms involved in the valproic acid-induced hepatotoxicity: a comprehensive review. 丙戊酸引起肝毒性的机制：综述。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-07-01 Epub Date: 2025-02-06 DOI: 10.1080/15376516.2025.2459176

Rohan Kadam, Mahesh Palkar, Ravindra Babu Pingili

{"title":"Mechanisms involved in the valproic acid-induced hepatotoxicity: a comprehensive review.","authors":"Rohan Kadam, Mahesh Palkar, Ravindra Babu Pingili","doi":"10.1080/15376516.2025.2459176","DOIUrl":"10.1080/15376516.2025.2459176","url":null,"abstract":"Adverse drug reactions (ADR) remain a challenge in modern healthcare, particularly given the increasing complexity of therapeutics. An anticonvulsant medicine which is frequently used in treatment of epilepsy and other neurological conditions is valproic acid (VPA), is frequently associated with hepatotoxicity, a severe ADR that complicates its clinical use, which can take two different forms: Type I, which is defined by dose-dependent and reversible liver damage, and Type II, an idiosyncratic reaction that can result in severe liver failure, frequently complicates its clinical application. Oxidative stress, the creation of reactive metabolites, mitochondrial dysfunction, carnitine shortage, immune-mediated reactions, glutathione depletion, and blockage of the bile salt export pump (BSEP) are some of the numerous underlying mechanisms of VA-induced hepatic damage. The production of reactive oxygen species and the liver's antioxidant protection are out of balance as a cause of oxidative stress, which is a significant factor in VPA intoxication. VPA can also accelerate the build-up of fatty acids, which increases the risk of steatosis, due to its interaction with the metabolism of carnitine. Immune-mediated processes have been shown to increase liver injury, implying that the immunity system may possibly be involved in VPA hepatotoxicity. Hepatocyte injury and cholestasis are caused by BSEP inhibition, which impairs bile flow. The complex interaction between biochemical and cellular mechanisms that underlie valproic acid's hepatotoxic potential calls for additional research to clarify the precise pathways implicated and create mitigation techniques for this ADR.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"565-580"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053779","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}

引用次数: 0

Application of the threshold of toxicological concern (TTC) in the evaluation of drinking water contact chemicals. 毒性关注阈值在饮用水接触化学品评价中的应用。

IF 3.2 4区医学

Toxicology Mechanisms and Methods Pub Date : 2025-06-01 Epub Date: 2023-11-29 DOI: 10.1080/15376516.2023.2279041

Kelly A Magurany, J Caroline English, Kevin D Cox

{"title":"Application of the threshold of toxicological concern (TTC) in the evaluation of drinking water contact chemicals.","authors":"Kelly A Magurany, J Caroline English, Kevin D Cox","doi":"10.1080/15376516.2023.2279041","DOIUrl":"10.1080/15376516.2023.2279041","url":null,"abstract":"The Threshold of Toxicological Concern (TTC) is an approach for assessing the safety of chemicals with low levels of exposure for which limited toxicology data are available. The original TTC criteria were derived for oral exposures from a distributional analysis of a dataset of 613 chemicals that identified 5th percentile no observed effect level (NOEL) values grouped within three tiers of compounds having specific structural functional groups and/or toxic potencies known as Cramer I, II and III classifications. Subsequent assessments of the TTC approach have established current thresholds to be scientifically robust. While the TTC has gained acknowledgment and acceptance by many regulatory agencies and organizations, use of the TTC approach in evaluating drinking water chemicals has been limited. To apply the TTC concept to drinking water chemicals, an exposure-based approach that incorporates the current weight of evidence for the target chemical is presented. Such an approach provides a comparative point of departure to the 5th percentile TTC NOEL using existing data, while conserving the allocation of toxicological resources for quantitative risk assessment to chemicals with greater exposure or toxicity. This approach will be considered for incorporation into NSF/ANSI/CAN 600, a health effects standard used in the safety evaluation of chemicals present in drinking water from drinking water contact additives and materials certified to NSF/ANSI/CAN 60 and 61, respectively.","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"450-466"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462831","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}

引用次数: 0