Journal of Applied Toxicology最新文献

{"title":"Oxidative DNA damage contributes to usnic acid-induced toxicity in human induced pluripotent stem cell-derived hepatocytes","authors":"Xiugong Gao,&nbsp;Kayla Campasino,&nbsp;Miranda R. Yourick,&nbsp;Yu Cao,&nbsp;Jeffrey J. Yourick,&nbsp;Robert L. Sprando","doi":"10.1002/jat.4620","DOIUrl":"10.1002/jat.4620","url":null,"abstract":"<p>Dietary supplements containing usnic acid have been increasingly marketed for weight loss over the past decades, even though incidences of severe hepatotoxicity and acute liver failure due to their overuse have been reported. To date, the toxic mechanism of usnic acid-induced liver injury at the molecular level still remains to be fully elucidated. Here, we conducted a transcriptomic study on usnic acid using a novel in vitro hepatotoxicity model employing human induced pluripotent stem cell (iPSC)-derived hepatocytes. Treatment with 20 μM usnic acid for 24 h caused 4272 differentially expressed genes (DEGs) in the cells. Ingenuity Pathway Analysis (IPA) based on the DEGs and gene set enrichment analysis (GSEA) using the whole transcriptome expression data concordantly revealed several signaling pathways and biological processes that, when taken together, suggest that usnic acid caused oxidative stress and DNA damage in the cells, which further led to cell cycle arrest and eventually resulted in cell death through apoptosis. These transcriptomic findings were subsequently corroborated by a variety of cellular assays, including reactive oxygen species (ROS) generation and glutathione (GSH) depletion, DNA damage (pH2AX detection and 8-hydroxy-2′-deoxyguanosine [8-OH-dg] assay), cell cycle analysis, and caspase 3/7 activity. Collectively, the results of the current study accord with previous in vivo and in vitro findings, provide further evidence that oxidative stress-caused DNA damage contributes to usnic acid-induced hepatotoxicity, shed new light on molecular mechanisms of usnic acid-induced hepatotoxicity, and demonstrate the usefulness of iPSC-derived hepatocytes as an in vitro model for hepatotoxicity testing and prediction.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1329-1346"},"PeriodicalIF":2.7,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4620","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure of cinnamyl alcohol in co-culture of BEAS-2B and dendritic cells: Interaction between CYP450 and cytokines","authors":"Kelly Yoshizaki,&nbsp;Daniela Perroni Frias,&nbsp;Kevin Maier,&nbsp;Juliana Smelan,&nbsp;Aristides Tadeu Correia,&nbsp;Luanda Mara da Silva Oliveira,&nbsp;Luís Fernando Amato-Lourenço,&nbsp;Bruna Tereso Santillo,&nbsp;Carla Máximo Prado,&nbsp;Telma Miyuki Oshiro,&nbsp;Jose Alexandre M. Barbuto,&nbsp;Thais Mauad,&nbsp;Mariangela Macchione","doi":"10.1002/jat.4623","DOIUrl":"10.1002/jat.4623","url":null,"abstract":"<p>The prevalence of fragrances in various hygiene products contributes to their sensorial allure. However, fragrances can induce sensitization in the skin or respiratory system, and the mechanisms involved in this process are incompletely understood. This study investigated the intricate mechanisms underlying the fragrance's effects on sensitization response, focusing on the interplay between CYP450 enzymes, a class of drug-metabolizing enzymes, and the adaptive immune system. Specifically, we assessed the expression of CYP450 enzymes and cytokine profiles in culture of BEAS-2B and mature dendritic cells (mDC) alone or in co-culture stimulated with 2 mM of a common fragrance, cinnamyl alcohol (CA) for 20 h. <i>CYP1A1</i>, <i>CYP1A2</i>, <i>CYP1B1</i>, <i>CYP2A6</i>, and <i>CYP2A13</i> were analyzed by RT-PCR and IL-10, IL-12p70, IL-18, IL-33, and thymic stromal lymphopoietin (TSLP) by Cytometric Bead Array (CBA). Through RT–PCR analysis, we observed that CA increased <i>CYP1A2</i> and <i>CYP1B1</i> expression in BEAS-2B, with a further increased in BEAS-2B-mDC co-culture. Additionally, exposure to CA increased IL-12p70 levels in mDC rather than in BEAS-2B-mDC co-culture. In regards to IL-18, level was higher in BEAS-2B than in BEAS-2B-mDC co-culture. A positive correlation between the levels of IL-10 and <i>CYP1B1</i> was found in mDC-CA-exposed and between IL-12p70 and <i>CYP1A1</i> was found in BEAS-2B after CA exposure. However, IL-12p70 and <i>CYP1A2</i> as well as IL-18, IL-33, and <i>CYP1A1</i> levels were negative, correlated mainly in co-culture control. These correlations highlight potential immunomodulatory interactions and complex regulatory relationships. Overall, exposure to CA enhances CYP450 expression, suggesting that CA can influence immune responses by degrading ligands on xenosensitive transcription factors.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1317-1328"},"PeriodicalIF":2.7,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876459","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":"Impact of bisphenol A and analogues eluted from resin-based dental materials on cellular and molecular processes: An insight on underlying toxicity mechanisms.","authors":"Divya Sangeetha Rajkumar, Rajashree Padmanaban","doi":"10.1002/jat.4605","DOIUrl":"https://doi.org/10.1002/jat.4605","url":null,"abstract":"<p><p>Dental resin systems, used for artificial replacement of teeth and their surrounding structures, have gained popularity due to the Food and Drug Administration's (FDA) recommendation to reduce dental amalgam use in high-risk populations and medical circumstances. Bisphenol A (BPA), an endocrine-disrupting chemical, is an essential monomer within dental resin in the form of various analogues and derivatives. Leaching of monomers from resins results in toxicity, affecting hormone metabolism and causing long-term health risks. Understanding cellular-level toxicity profiles of bisphenol derivatives is crucial for conducting toxicity studies in in vivo models. This review provides insights into the unique expression patterns of BPA and its analogues among different cell types and their underlying toxicity mechanisms. Lack of a consistent cell line for toxic effects necessitates exploring various cell lines. Among the individual monomers, BisGMA was found to be the most toxic; however, BisDMA and BADGE generates BPA endogenously and found to elicit severe adverse reactions. In correlating in vitro data with in vivo findings, further research is necessary to classify the elutes as human carcinogens or xenoestrogens. Though the basic mechanisms underlying toxicity were believed to be the production of intracellular reactive oxygen species and a corresponding decline in glutathione levels, several underlying mechanisms were identified to stimulate cellular responses at low concentrations. The review calls for further research to assess the synergistic interactions of co-monomers and other components in dental resins. The review emphasizes the clinical relevance of these findings, highlighting the necessity for safer dental materials and underscoring the potential health risks associated with current dental resin systems.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863913","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":"Research progress in the development of 3D skin models and their application to in vitro skin irritation testing","authors":"Hongxia Lu,&nbsp;Xulei Zuo,&nbsp;Jiayu Yuan,&nbsp;Zhuoying Xie,&nbsp;Lihong Yin,&nbsp;Yuepu Pu,&nbsp;Zaozao Chen,&nbsp;Juan Zhang","doi":"10.1002/jat.4618","DOIUrl":"10.1002/jat.4618","url":null,"abstract":"<p>Toxicological assessment of chemicals is crucial for safeguarding human health and the environment. However, traditional animal experiments are associated with ethical, technical, and predictive limitations in assessing the toxicity of chemicals to the skin. With the recent development of bioengineering and tissue engineering, three-dimensional (3D) skin models have been commonly used as an alternative for toxicological studies. The skin consists of the subcutaneous, dermis, and epidermis. All these layers have crucial functions such as physical and biological protection and thermoregulation. The epidermis is the shallowest layer protecting against external substances and media. Because the skin is the first contact point for many substances, this organ is very significant for assessing local toxicity following skin exposure. According to the classification of the United Nations Global Harmonized System, skin irritation is a major potentially hazardous characteristic of chemicals, and this characteristic must be accurately assessed and classified for enhancing chemical safety management and preventing and reducing chemical accidents. This review discusses the research progress of 3D skin models and introduces their application in assessing chemical skin irritation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1302-1316"},"PeriodicalIF":2.7,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855102","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":"In vitro toxicity evaluation in A549 cells of diesel particulate matter from two different particle sampling systems and several resuspension media","authors":"Oskari J. Uski,&nbsp;Gregory D. Rankin,&nbsp;Håkan Wingfors,&nbsp;Roger Magnusson,&nbsp;Christoffer Boman,&nbsp;Ala Muala,&nbsp;Anders Blomberg,&nbsp;Jenny Bosson,&nbsp;Thomas Sandström","doi":"10.1002/jat.4616","DOIUrl":"10.1002/jat.4616","url":null,"abstract":"<p>In urban areas, inhalation of fine particles from combustion sources such as diesel engines causes adverse health effects. For toxicity testing, a substantial amount of particulate matter (PM) is needed. Conventional sampling involves collection of PM onto substrates by filtration or inertial impaction. A major drawback to those methodologies is that the extraction process can modify the collected particles and alter their chemical composition. Moreover, prior to toxicity testing, PM samples need to be resuspended, which can alter the PM sample even further. Lastly, the choice of the resuspension medium may also impact the detected toxicological responses. In this study, we compared the toxicity profile of PM obtained from two alternative sampling systems, using in vitro toxicity assays. One system makes use of condensational growth before collection in water in an impinger – BioSampler (CG-BioSampler), and the other, a Dekati® Gravimetric Impactor (DGI), is based on inertial impaction. In addition, various methods for resuspension of DGI collected PM were compared. Tested endpoints included cytotoxicity, formation of cellular reactive oxygen species, and genotoxicity. The alternative collection and suspension methods affected different toxicological endpoints. The water/dimethyl sulfoxide mixture and cell culture medium resuspended particles, along with the CG-BioSampler sample, produced the strongest responses. The water resuspended sample from the DGI appeared least toxic. CG-BioSampler collected PM caused a clear increased response in apoptotic cell death. We conclude that the CG-BioSampler PM sampler is a promising alternative to inertial impaction sampling.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 8","pages":"1269-1278"},"PeriodicalIF":2.7,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4616","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140849031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bafi A1 inhibits nano-copper oxide-induced mitochondrial damage by reducing the release of copper from lysosomes","authors":"Zhi Huang,&nbsp;Mo Lin,&nbsp;Lei Wang,&nbsp;Liangding Dou,&nbsp;Xin Hou,&nbsp;Jinwen Zhang,&nbsp;Yongchao Huang,&nbsp;Lifang Wei,&nbsp;Ran An,&nbsp;Dai Wang,&nbsp;Youliang Yao,&nbsp;Dongbei Guo,&nbsp;Zhibo Li,&nbsp;Yongxing Zhang","doi":"10.1002/jat.4624","DOIUrl":"10.1002/jat.4624","url":null,"abstract":"<p>This study demonstrated that both copper oxide nanoparticles (CuO-NPs) and copper nanoparticles (Cu-NPs) can cause swelling, inflammation, and cause damage to the mitochondria of alveolar type II epithelial cells in mice. Cellular examinations indicated that both CuO-NPs and Cu-NPs can reduce cell viability and harm the mitochondria of human bronchial epithelial cells, particularly Beas-2B cells. However, it is clear that CuO-NPs exhibit a more pronounced detrimental effect compared with Cu-NPs. Using bafilomycin A1 (Bafi A1), an inhibitor of lysosomal acidification, was found to enhance cell viability and alleviate mitochondrial damage caused by CuO-NPs. Additionally, Bafi A1 also reduces the accumulation of dihydrolipoamide S-acetyltransferase (DLAT), a marker for mitochondrial protein toxicity, induced by CuO-NPs. This observation suggests that the toxicity of CuO-NPs depends on the distribution of copper particles within cells, a process facilitated by the acidic environment of lysosomes. The release of copper ions is thought to be triggered by the acidic conditions within lysosomes, which aligns with the lysosomal Trojan horse mechanism. However, this association does not seem to be evident with Cu-NPs.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 8","pages":"1257-1268"},"PeriodicalIF":2.7,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828043","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 proposed in vitro cytotoxicity test battery to detect and predict hepatotoxicity via multiple mechanisms and pathways: a minireview","authors":"Saura C. Sahu","doi":"10.1002/jat.4619","DOIUrl":"10.1002/jat.4619","url":null,"abstract":"<p>The 21st-century toxicity testing program recommends the use of cytotoxicity data from human cells in culture for rapid in vitro screening focusing on biological pathways of potential toxicants to predict in vivo toxicity. Liver is the major organ for both endogenous and exogenous chemical metabolism of xenobiotics. Therefore, this review was undertaken to evaluate side by side five different currently used commercial cytotoxicity assay kits for purpose of rapid predictive screening of potential hepatotoxicants. The test compounds for this review were selected from the NIH LiverTox and FDA Liver Toxicity Knowledge Base (LTKB) databases. Human liver HepG2, HepaRG, and rat liver Clone 9 cell cultures were used as the in vitro liver models. Five commercial assay kits representing different biomarkers or pathways were selected for this review. These kits are Vita-Orange Cell Viability Assay Kit (Sigma-Aldrich), CellTiter-Glo Cell Viability Assay Kit (Promega), CytoTox-ONE Homogeneous Membrane Integrity Assay Kit (Promega), DNA Quantitation Fluorescence Assay Kit (Sigma-Aldrich), and Neutral Red Based In Vitro Toxicology Assay Kit (Sigma-Aldrich). This review found that these kits can all be used for rapid predictive cytotoxicity screening of potential hepatotoxicants in human liver HepG2 and rat liver Clone 9 cells in culture as in vitro liver models without compromising quality and accuracy of endpoint measurements as well as the length of toxicity screening time. Unraveling the structure–activity relationship of potential hepatotoxins would help to classify their hepatotoxic effects. Therefore, in addition to the current regulatory hepatotoxicity testing strategies, development and regulatory approval of hepatotoxins need to be discussed in order to identify potential gaps in the safety assessment. The overall results of our study support the hypothesis that a battery of rapid, simple, and reliable assays is an excellent tool for predicting in vivo effects of suspected liver toxins. The human liver HepaRG cells do not appear to be an ideal in vitro liver model for this purpose.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1868-1873"},"PeriodicalIF":2.7,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828332","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":"Voacangine protects hippocampal neuronal cells against oxygen–glucose deprivation/reoxygenation-caused oxidative stress and ferroptosis by activating the PI3K-Akt-FoxO signaling","authors":"Ying Li,&nbsp;Yan Sun,&nbsp;Jianghong Wang,&nbsp;Xiaolong Wang,&nbsp;Wenjie Yang","doi":"10.1002/jat.4615","DOIUrl":"10.1002/jat.4615","url":null,"abstract":"<p>Voacangine, a naturally occurring alkaloid, has been testified to display beneficial effects on a variety of human diseases, but its role in ischemic stroke is unclear. The impacts of voacangine on oxygen–glucose deprivation/reoxygenation (OGD/R)-tempted hippocampal neuronal cells are investigated. The bioinformatics analysis found that voacangine is a bioactive ingredient that may have good effects on ischemic stroke. KEGG pathways analysis found that voacangine may regulate ischemic stroke through modulating the PI3K-Akt-FoxO signaling pathway. Voacangine could mitigate OGD/R-tempted cytotoxicity in HT22 cells. Voacangine mitigated OGD/R-tempted oxidative stress in HT22 cells by diminishing reactive oxygen species level and enhancing superoxide dismutase level. Voacangine mitigated OGD/R-tempted ferroptosis in HT22 cells. Voacangine promoted activation of the PI3K-Akt-FoxO signaling in OGD/R-induced HT22 cells. Inactivation of the PI3K-Akt-FoxO signaling pathway reversed the protective effects of voacangine against OGD/R-tempted oxidative stress, cytotoxicity, and ferroptosis in HT22 cells. In conclusion, voacangine protects hippocampal neuronal cells against OGD/R-caused oxidative stress and ferroptosis by activating the PI3K-Akt-FoxO signaling.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 8","pages":"1246-1256"},"PeriodicalIF":2.7,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140652394","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":"Prediction of physicochemical and pharmacokinetic properties of botanical constituents by computational models","authors":"Yitong Liu,&nbsp;Michael Lawless,&nbsp;Miao Li,&nbsp;Kiara Fairman,&nbsp;Michelle R. Embry,&nbsp;Constance A. Mitchell","doi":"10.1002/jat.4617","DOIUrl":"10.1002/jat.4617","url":null,"abstract":"<p>Botanicals contain complex mixtures of chemicals most of which lack pharmacokinetic data in humans. Since physicochemical and pharmacokinetic properties dictate the in vivo exposure of botanical constituents, these parameters greatly impact the pharmacological and toxicological effects of botanicals in consumer products. This study sought to use computational (i.e., in silico) models, including quantitative structure–activity relationships (QSAR) and physiologically based pharmacokinetic (PBPK) modeling, to predict properties of botanical constituents. One hundred and three major constituents (e.g., withanolides, mitragynine, and yohimbine) in 13 botanicals (e.g., ashwagandha, kratom, and yohimbe) were investigated. The predicted properties included biopharmaceutical classification system (BCS) classes based on aqueous solubility and permeability, oral absorption, liver microsomal clearance, oral bioavailability, and others. Over half of these constituents fell into BCS classes I and II at dose levels no greater than 100 mg per day, indicating high permeability and absorption (%F_a &gt; 75%) in the gastrointestinal tract. However, some constituents such as glycosides in ashwagandha and Asian ginseng showed low bioavailability after oral administration due to poor absorption (BCS classes III and IV, %F_a &lt; 40%). These in silico results fill data gaps for botanical constituents and could guide future safety studies. For example, the predicted human plasma concentrations may help select concentrations for in vitro toxicity testing. Additionally, the in silico data could be used in tiered or batteries of assays to assess the safety of botanical products. For example, highly absorbed botanical constituents indicate potential high exposure in the body, which could lead to toxic effects.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 8","pages":"1236-1245"},"PeriodicalIF":2.7,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4617","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140663751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human-derived cardiomyocytes","authors":"Abdullah Al Sultan,&nbsp;Zahra Rattray,&nbsp;Nicholas J. W. Rattray","doi":"10.1002/jat.4613","DOIUrl":"10.1002/jat.4613","url":null,"abstract":"<p>Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus on their association with increased heart failure risk, limiting TZD use in diabetes management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive in vitro investigation utilising a novel toxicoproteomics pipeline coupled with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into TZD cardiotoxicity. The cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production upon exposure to either TZD agents, which may underpin TZD cardiotoxicity. Our toxicoproteomics analysis revealed that mitochondrial dysfunction primarily stems from oxidative phosphorylation impairment, with distinct signalling mechanisms observed for both agents. The type of cell death differed strikingly between the two agents, with rosiglitazone exhibiting features of caspase-dependent apoptosis and pioglitazone implicating mitochondrial-mediated necroptosis, as evidenced by the protein upregulation in the phosphoglycerate mutase family 5–dynamin-related protein 1 axis. Furthermore, our analysis revealed additional mechanistic aspects of cardiotoxicity, showcasing drug specificity. The downregulation of various proteins involved in protein machinery and protein processing in the endoplasmic reticulum was observed in rosiglitazone-treated cells, implicating proteostasis in the rosiglitazone cardiotoxicity. Regarding pioglitazone, the findings suggested the potential activation of the interplay between the complement and coagulation systems and the disruption of the cytoskeletal architecture, which was primarily mediated through the integrin-signalling pathways responsible for pioglitazone-induced myocardial contractile failure. Collectively, this study unlocks substantial mechanistic insight into TZD cardiotoxicity, providing the rationale for future optimisation of antidiabetic therapies.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 8","pages":"1214-1235"},"PeriodicalIF":2.7,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4613","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140668238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}