Toxicology and applied pharmacology最新文献

{"title":"Cell morphology and gene expression: tracking changes and complementarity across time and cell lines","authors":"Vanille Lejal ,&nbsp;David Rouquié ,&nbsp;Olivier Taboureau","doi":"10.1016/j.taap.2025.117530","DOIUrl":"10.1016/j.taap.2025.117530","url":null,"abstract":"<div><div>Effective drug discovery relies on combining target knowledge with functional assays and multi-omics data to understand chemicals' molecular actions. However, the relationship between changes in cell morphology and gene expression deregulation over the duration of exposure and across cell lines following chemical exposition remains unclear. To explore this, we analyzed Cell Painting and L1000 data for 106 compounds across three cell lines from osteoblast, lung, and breast tumors (U2OS, A549, and MCF7) at three time points (6 h, 24 h, 48 h) using a 10 μM concentration. Following chemical exposure, we observed significant and specific differences in the spatial organization of cellular structures and components over time and across cell lines in the Cell Painting data, whereas transcriptomic responses showed less pronounced variability. Using Weighted Gene Co-expression Network Analysis (WGCNA) and enrichment analysis, we identified connections between cell morphology and gene deregulation for chemicals with similar biological effects (<em>e.g.</em>, HDAC and CDK inhibitors). These findings suggest that while Cell Painting shows distinct patterns, both technologies offer complementary insights into compound-induced cellular changes, enhancing drug discovery and chemical risk assessment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117530"},"PeriodicalIF":3.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peroxynitrite is key to Cylindrospermopsin-mediated MASLD to MASH progression via triggering TXNIP binding to NLRP3 and subsequent inflammasome activation","authors":"Punnag Saha ,&nbsp;Dipro Bose ,&nbsp;Subhajit Roy ,&nbsp;Madhura More ,&nbsp;Ayushi Trivedi ,&nbsp;Bryan W. Brooks ,&nbsp;Shuo Xiao ,&nbsp;Wing-Kin Syn ,&nbsp;Anna Mae Diehl ,&nbsp;Saurabh Chatterjee","doi":"10.1016/j.taap.2025.117527","DOIUrl":"10.1016/j.taap.2025.117527","url":null,"abstract":"<div><div>Harmful algal bloom (HAB) toxins are shown to be associated with Metabolic dysfunction-associated steatohepatitis (MASH) progression. Several studies link the HAB toxin microcystin to hepatic inflammasome activation, but the role of cylindrospermopsin (CYN) in Metabolic dysfunction-associated steatotic liver disease (MASLD) pathology remains unknown. Using a mouse model of MASLD, we show that CYN exposure served as a second hit for MASLD to MASH progression, as shown by histopathology and NAS scoring. The pathology was attenuated by the use of NADPH oxidase 2 (NOX2) inhibitor apocynin and peroxynitrite inhibitor phenylboronic acid. Inhibition of peroxynitrite and other redox signaling processes decreased stellate cell activation and fibronectin protein in the hepatic lobules, thus confirming the involvement of the above nitrosative moiety in early fibrotic remodeling, crucial for MASH progression. Redox inhibitors also decreased the endothelial Nitric Oxide Synthase (eNOS)/inducible Nitric Oxide Synthase (iNOS) protein ratio, thus raising the yield of inducible nitric oxide and facilitating the uncoupling of eNOS. Mechanistically, peroxynitrite inhibitors coupled with attenuation of redox processes prevented Thioredoxin-interacting protein (TXNIP) colocalization with NLRP3 and resulted in the inhibition of NLRP3 inflammasome activation, a crucial mediator of hepatic inflammation in MASH. Hepatocyte-hepatic macrophage crosstalk, crucial for MASH progression, was shown to induce NOX2 activation, the generation of 3-nitrotyrosine in close proximity to iNOS, a predictive nitric oxide source, thus confirming the role of these cells in activating the inflammation cascade. The results show a crucial role of peroxynitrite in TXNIP-NLRP3 induced inflammasome activation and can be a crucial therapeutic target in treating MASH etiology from environmental exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117527"},"PeriodicalIF":3.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro confirmation of estrogenic and antiandrogenic pesticide bioactivity using schild regression analysis","authors":"Christina Boxberger ,&nbsp;Leon Earl Gray Jr ,&nbsp;Nicola Evans ,&nbsp;Justin M. Conley ,&nbsp;Elizabeth Medlock Kakaley","doi":"10.1016/j.taap.2025.117523","DOIUrl":"10.1016/j.taap.2025.117523","url":null,"abstract":"<div><div>A broad range of anthropogenic chemicals have been reported to display estrogenic (ER) or antiandrogenic bioactivity using high throughput screening (HTS) <em>in vitro</em> assays. Some regulatory agencies have developed tiered <em>in vitro – in vivo</em> endocrine screening batteries in which positive <em>in vitro</em> results automatically “trigger” studies with laboratory animals. Since <em>in vitro</em> assays can produce a number of false positive and false negative results, automatically triggering <em>in vivo</em> testing could result in the unnecessary use of animals and other resources. The <em>in vitro</em> false positive rate may be particularly high with reported AR antagonists, because many nonspecific mechanisms can disrupt competitive AR dose-response assays such that chemicals falsely appear to be competitive AR ligands. In the current investigation, we illustrated the utility of <em>in vitro</em> Schild regression to interrogate the <em>in vitro</em> ER and/or anti-AR bioactivity of pesticides which were positive in HTS ER or AR models. Schild regression discriminates chemicals that act as true competitive receptor ligands from those that disrupt signaling <em>via</em> noncompetitive mechanisms. The chemicals studied included seven pesticides listed by EPA as high priority for <em>in vivo</em> ER or anti-AR testing and two pesticides listed as low priority, as well as 17β-estradiol (E2) and hydroxyflutamide (OHF) as ER and anti-AR reference ligands. Two out of four pesticides tested for ER agonist activity were cytotoxic, and four out of seven pesticides tested for AR antagonist activity, plus OHF, were true competitive AR antagonists (two true positives and two false negatives). Herein, we propose a tiered strategy that includes a more in-depth analysis of <em>in vitro</em> bioactivity using Schild regression to determine if HTS or other <em>in vitro</em> bioactivity data results from true competitive receptor antagonism or some nonspecific mechanism. This strategy could reduce unnecessary <em>in vivo</em> testing for chemicals that are not AR antagonists <em>in vitro.</em></div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117523"},"PeriodicalIF":3.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction-associated cellular senescence is partially involved in bleomycin-induced pulmonary fibrosis in mice","authors":"Ya-Xin Yao ,&nbsp;Xue Lu ,&nbsp;Zhao Li ,&nbsp;Hao-Yu Liao ,&nbsp;Zhi-Bing Liu ,&nbsp;Hui Zhao ,&nbsp;Hua Wang ,&nbsp;De-Xiang Xu ,&nbsp;Zhu-Xia Tan","doi":"10.1016/j.taap.2025.117524","DOIUrl":"10.1016/j.taap.2025.117524","url":null,"abstract":"<div><div>Accumulating data demonstrate that bleomycin (BLM), a clinically used antineoplastic drug, induces pulmonary interstitial fibrosis. However, the specific mechanism remains unclear. This study was carried out for the purpose of evaluating the effect of mitochondrial dysfunction-associated senescence on BLM-induced pulmonary fibrosis. Adult C57BL/6 J mice were intratracheally instilled with BLM (2.5 mg/kg). Pulmonary α-SMA and Vimentin, two indicators of epithelial-mesenchymal transition (EMT), were increased, and pulmonary collagen deposition was shown in BLM-treated mice. Pulmonary p16 and p21, two biomarkers of cell cycle arrest, were elevated, and pulmonary SASP indicators were up-regulated in BLM-treated mice. The reduction of mitochondrial area in BLM-treated mouse lungs was revealed by transmission electron microscopy. ATP content was reduced in BLM-treated mouse lungs. Pulmonary SOD2 and IDH2, two enzymes located in mitochondria, were decreased in BLM-treated mice. Sirtuin3 (SIRT3), an NAD⁺-dependent deacetylase located in mitochondria, was down-regulated in BLM-treated mouse lungs. Interestingly, <em>Sirt3</em> gene knockout aggravated BLM-evoked mitochondrial dysfunction-associated senescence in mouse lungs. <em>Sirt3</em> gene knockout exacerbated BLM-induced lung fibrosis. Conversely, nicotinamide mononucleotide (NMN), an NAD⁺ precursor, weakened BLM-induced down-regulation of mitochondrial SIRT3 activity in mouse lungs. NMN pretreatment attenuated BLM-induced mitochondrial dysfunction-associated senescence in mouse lungs. Finally, NMN pretreatment alleviated BLM-induced EMT and lung fibrosis. These results indicate that mitochondrial dysfunction-associated senescence partially contributed to BLM-induced pulmonary fibrosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117524"},"PeriodicalIF":3.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of human pharmacokinetics of procymidone and its major phase I and II metabolites using a PBPK model with enterohepatic circulation","authors":"Kota Hirasawa ,&nbsp;Takeshi Adachi ,&nbsp;Hayato Takeuchi ,&nbsp;Tomohiro Kuroda ,&nbsp;Jun Abe ,&nbsp;Miki Nakajima","doi":"10.1016/j.taap.2025.117525","DOIUrl":"10.1016/j.taap.2025.117525","url":null,"abstract":"<div><div>Physiologically based pharmacokinetic (PBPK) modeling is a valuable approach for addressing the scarcity of human toxicokinetic data, particularly in the risk assessment of agrochemicals. While numerous PBPK models have been developed to describe various pharmacokinetics processes, modeling the complex kinetics of enterohepatic circulation remains challenging. Procymidone, a widely used fungicide, undergoes initial metabolism to hydroxylated-procymidone, an active metabolite with antiandrogenic properties, followed by glucuronidation. In rabbits, monkeys, and chimeric mice with humanized liver, the glucuronic acid conjugate is rapidly excreted in urine. However, in rats, it is primarily excreted into bile, deconjugated in the gastrointestinal tract, and subsequently reabsorbed, leading to enterohepatic circulation. This species difference in biliary excretion is considered a key factor contributing to the elevated plasma levels of hydroxylated-procymidone in rats, which are associated with rat-specific developmental toxicity. To estimate human internal exposure to hydroxylated-procymidone, a PBPK model was developed incorporating quantitative prediction of complex pharmacokinetics. This model was constructed without relying on human <em>in vivo</em> data, instead integrating advanced <em>in vitro</em> systems, such as bile canalicular membrane transporter assays using sandwich-cultured human hepatocytes and <em>in vitro</em>-to-<em>in vivo</em> extrapolation. By comparing the predicted plasma concentration of hydroxylated-procymidone in humans with measured values in rats, significant interspecies differences were observed, suggesting that the risk of developmental toxicity associated with procymidone exposure is lower in humans than in rats.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117525"},"PeriodicalIF":3.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a complex 3D in vitro alternative model to evaluate the safety of advanced materials","authors":"Melissa Anne Tutty ,&nbsp;Tecla Simone ,&nbsp;Adriele Prina-Mello","doi":"10.1016/j.taap.2025.117520","DOIUrl":"10.1016/j.taap.2025.117520","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Drug-induced liver injury (DILI) &lt;em&gt;i.e.&lt;/em&gt;, liver damage caused by pharmaceutical and other chemical substances, represents a significant clinical challenge in both its diagnosis and treatment, with DILI remaining a major factor in drug attrition and market withdrawal, accounting for approximately 50 % of reported cases of acute liver failure. For decades, conventional &lt;em&gt;in vitro&lt;/em&gt; two-dimensional (2D) monolayer cultures and &lt;em&gt;in vivo&lt;/em&gt; animal models have been the gold standard in preclinical studies of DILI. However, these models exhibit critical limitations in the accurate replication of metabolic functionality and complexity of human hepatic tissue, a particular disadvantage in the context of drug testing. Rooted in the 3Rs principle of Replacement, Reduction and Refinement, and driven by regulatory frameworks such as REACH (Regulation (EC) No 1907/2006) and Directive 2010/63/EU, which promote ethical alternatives in toxicological studies, one strategy for overcoming issues prevalent when assessing DILI has been the development and adoption of NAMs, or New Approach Methodologies. The use of these innovative and alternative advanced non-animal &lt;em&gt;in vitro&lt;/em&gt; systems, which can include 3D cell spheroids, organoids and organ-on-chip (OoC) technology, have shown promising results in recapitulating tissue-mimetic and biologically relevant aspects of target tissue and organs, specifically regarding the liver. Supported by European Union (EU) initiatives like Horizon Europe, and the Joint Research Centres EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), a core aim of NAMs is to bridge the pre-clinical knowledge gap when evaluating the safety of both drugs and advanced materials (AMs) by developing more predictive and mechanistic safety assessments. Challenges remain however regarding regulatory acceptance, model standardisation and integration into the existing risk assessment frameworks. In spite of these hurdles, NAMs have the potential to transform toxicology, by providing more human-relevant, efficient and ethical alternatives to conventional testing methods.&lt;/div&gt;&lt;div&gt;With this in mind, this work deals with the development of a state-of-the-art complex 3D hepatic spheroid model, cultured from both parenchymal (human hepatocellular carcinoma; HepG2) and non-parenchymal (a mixed population of Kupffer cells (KCs), hepatic stellate cells (HSCs) and liver sinusoidal endothelial (LSEC)) cells. This promising NAM not only reconstructs the intrinsic architecture of the human liver, but also facilitates chronic and repeated viability testing over 30 days. The models ability to assess both safety and efficacy to a panel of common hepatotoxins and two representative advanced materials was assessed by ATP quantification, with this study demonstrating the reliability of using NAMs-based systems for &lt;em&gt;in vitro&lt;/em&gt; DILI assessment and their revolutionary potential for pre-clinical safety screening as a nove","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117520"},"PeriodicalIF":3.4,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empagliflozin attenuates sorafenib-promoted renal ferroptosis and inflammation by targeting cyclooxygenase-2/prostaglandin E2 axis","authors":"Ming-Kai Tsai ,&nbsp;Wen-Chin Lee ,&nbsp;Shih-Chung Huang ,&nbsp;Chao-Cheng Huang ,&nbsp;Yi-Chen Wang ,&nbsp;Chien-Han Yuan ,&nbsp;Chih-Chiang Wang ,&nbsp;Ching-Han Liu ,&nbsp;Nan-Chieh Huang ,&nbsp;Yi-Chen Chang ,&nbsp;Cheng-Chieh Fang ,&nbsp;Bi-Wen Yeh ,&nbsp;Jen-Hao Yang ,&nbsp;Yu-Cheng Ho ,&nbsp;Yung-Kuo Lee ,&nbsp;Cheng-Chun Wu ,&nbsp;Kun-Yuan Hsiao ,&nbsp;Wei-Lun Liu ,&nbsp;Shih-Ming Yang ,&nbsp;Cheng-Yi Huang ,&nbsp;Tian-Huei Chu","doi":"10.1016/j.taap.2025.117512","DOIUrl":"10.1016/j.taap.2025.117512","url":null,"abstract":"<div><div>The increased risk of nephrotoxicity may impact the life quality and survival outcome in cancer patients receiving sorafenib therapy. Therefore, the development of novel strategy against sorafenib nephrotoxicity is an urgent work. Sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin have been approved for renal failure treatment. So far, the potential of empagliflozin against sorafenib nephrotoxicity has not yet been reported. The SGLT2 and apoptotic marker expressions in the sorafenib-treated renal proximal tubular cells (HK-2 cells) was investigated using immunoblot analysis. The cell viability was evaluated in HK-2 cells after sorafenib ± empagliflozin treatment using Alamar blue assay. The immunoblot analysis was applied to study the effect of sorafenib ± empagliflozin treatment on ferroptotic and proinflammatory stresses in HK-2 cells. The cell death, ferroptosis, lipid peroxidation, cytokine storm, and immune cells recruitments of kidneys was investigated in mice receiving a 28-day sorafenib ± empagliflozin administration using histopathological analyses. Sorafenib exposure dose-dependently upregulated SGLT2 in HK-2 cells, and empagliflozin significantly attenuated the sorafenib-induced cell death in HK-2 cells and mouse kidneys. Moreover, the sorafenib-stimulated iron deposition, oxidative DNA damage, lipid peroxidation, and glutathione peroxidase 4 (GPX4)/ SLC7A11 (xCT)-dependent ferroptosis were significantly alleviated by empagliflozin in mouse kidneys. The sorafenib-promoted cyclooxygenase-2 (COX-2)/prostaglandin E₂ (PGE₂) signaling as a ferroptosis driver was significantly blocked by empagliflozin in HK-2 cells and mouse kidneys. Empagliflozin also attenuated the sorafenib-stimulated-HMGB1/IL-1β proinflammatory signaling <em>in vitro</em> and <em>in vivo</em>. Furthermore, the sorafenib-promoted macrophage and neutrophil infiltrations were significantly reduced by empagliflozin in mouse kidneys. Collectively, empagliflozin may serve as a potent anti-ferroptotic and anti-inflammatory agent against sorafenib nephrotoxicity by targeting COX-2/PGE₂ axis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117512"},"PeriodicalIF":3.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arctigenin relieves inflammation and remodels the nasal epithelial barrier function in allergic rhinitis via the KLF5/BIRC3/NFκB axis","authors":"Lili Xu ,&nbsp;Yujuan An ,&nbsp;Ting Liu ,&nbsp;Yanan Zhang ,&nbsp;Xiaoyu Chen ,&nbsp;Xing Liu ,&nbsp;Gang Wei ,&nbsp;Hongzhou Ge","doi":"10.1016/j.taap.2025.117510","DOIUrl":"10.1016/j.taap.2025.117510","url":null,"abstract":"<div><div>Allergic rhinitis (AR) is a significant global health issue that necessitates effective treatments. This paper investigates the mechanism of arctigenin (ATG) in alleviating AR. An AR mouse model was constructed and administered with different doses of ATG or positive control dexamethasone. Human nasal epithelial cells (HNEpCs) were stimulated with IL-4 and IL-13 to mimic AR-induced epithelial cell damage. Bioinformatic analysis was performed to predict target proteins of ATG and downstream factors of KLF5. AR mice and HNEpCs were treated with KLF5 overexpression lentivirus and BIRC3 knockdown lentivirus. HNEpCs were treated with NF-κB pathway agonist TWEAK. Our results revealed that ATG remodeled the nasal epithelial barrier function and alleviated inflammation in AR mice and inhibited IL-4/IL-13-induced inflammatory injury in HNEpCs. Mechanistically, ATG inhibited the expression of KLF5 protein. KLF5 transcriptionally activated BIRC3 and the NF-κB pathway. KLF5 overexpression exacerbated inflammatory injury in AR mice and HNEpCs, which was reversed by BIRC3 knockdown. NF-κB pathway agonist exacerbated inflammatory injury in HNEpCs. In conclusion, ATG remodels the nasal epithelial barrier function and alleviates AR in mice by inhibiting KLF5 protein expression and BIRC3 transcription and impairing the NF-κB pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117510"},"PeriodicalIF":3.4,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myocardial ischemia/reperfusion-induced glycolysis enhances damage through TRPM7 histone lactylation","authors":"Shan Hu ,&nbsp;Guiqing Liu ,&nbsp;Haiyan Xiang ,&nbsp;Jun Shao ,&nbsp;Wanqi Lan ,&nbsp;Chao Luo ,&nbsp;Yonggang Shi ,&nbsp;Wu Liu ,&nbsp;Congcong Li ,&nbsp;Yanhua Tang ,&nbsp;Juesheng Yang","doi":"10.1016/j.taap.2025.117508","DOIUrl":"10.1016/j.taap.2025.117508","url":null,"abstract":"<div><h3>Background</h3><div>Myocardial ischemia-reperfusion (I/R) is pivotal in myocardial infarction. Transient receptor potential melastatin 7 (TRPM7) plays an instrumental role in sustaining intracellular ion concentration and osmotic pressure. This study aimed to explore the function and mechanism of TRPM7 in the myocardial I/R model.</div></div><div><h3>Methods</h3><div>AC16 cardiomyocytes were exposed to hypoxia for 4 h and reoxygenated for 2, 4, 6, 8, and 12 h (H/R1 to H/R5). Cellular functions were evaluated using the MTT assay and flow cytometry. Protein expression was assessed by western blotting. Metabolic variations were detected with pyruvate and lactate kits. Chromatin Immunoprecipitation assays elucidated transcriptional regulation. A myocardial I/R model was constructed, and a TRPM7 inhibitor was administered in the corresponding group; immunohistochemistry, HE staining, and TUNEL assays were conducted for tissue-level detection.</div></div><div><h3>Results</h3><div>The findings revealed a significant decline in cell survival rates, and an increase in apoptosis and TRPM7 expression of AC16 cardiomyocytes under hypoxia/reoxygenation (H/R) conditions, with peak effects in the H/R3 condition. Silencing TRPM7 significantly reversed H/R-induced Ca²⁺ influx, cell survival rates, and apoptosis. Metabolic analyses indicated an upregulation of glycolysis in AC16 cardiomyocytes under the early stage of H/R, evidenced by elevated glycolysis-related proteins, pyruvate, and lactate levels, and the glycolytic inhibitor 2-Deoxy-<span>d</span>-glucose (2-DG) inhibited the expression of TRPM7. Subsequent assays showed that H/R-induced glycolysis promoted TRPM7 transcription through histone lactylation, a finding corroborated by the in vivo I/R model.</div></div><div><h3>Conclusions</h3><div>This study highlighted that histone lactylation could be a potential therapeutic target for modulating TRPM7 expression and mitigating I/R injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117508"},"PeriodicalIF":3.4,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the cGAS-STING pathway in monocytes exacerbates pulmonary fibrosis induced by paraquat poisoning","authors":"Yangyang Sun ,&nbsp;Zheming Yuan ,&nbsp;Weidong Li ,&nbsp;Xueyang Lin ,&nbsp;Chen Yang ,&nbsp;Yufeng Yang ,&nbsp;Hui Miao ,&nbsp;Shengran Wang ,&nbsp;Ziqi Cui ,&nbsp;Zhenghao Bao ,&nbsp;Simin Lang ,&nbsp;Weiqiang Sun ,&nbsp;Hongpeng Huang ,&nbsp;Xin Sui ,&nbsp;Xianli Du ,&nbsp;Wenya Feng ,&nbsp;Jun Yang ,&nbsp;Yongan Wang ,&nbsp;Yuan Luo","doi":"10.1016/j.taap.2025.117502","DOIUrl":"10.1016/j.taap.2025.117502","url":null,"abstract":"<div><div>Paraquat (PQ), a total contact herbicide, triggers progressive pulmonary fibrosis and multiorgan failure. This toxicity occurs <em>via</em> DNA damage-induced mitochondrial dysfunction and dysregulated extracellular matrix (ECM) remodeling, highlighting the urgent need for novel therapeutic strategies. This study systematically investigated monocytic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling in PQ-associated fibrotic lung pathology, focusing on its mechanistic involvement in innate immune regulation. Analysis of the single-cell dataset derived from lung tissue of PQ-poisoned patient revealed significant activation of the TGF-β signaling pathway in fibroblasts and marked hyperactivation of the cGAS-STING pathway in monocytes. Cell co-culture assays confirmed that PQ treatment activated the cGAS-STING pathway in monocytes co-cultured with fibroblasts. Consequently, transforming growth factor-β1 (TGF-β1) expression was upregulated, which stimulated fibroblast activation. The pharmacological cGAS antagonist G150 demonstrated significant attenuation of PQ-triggered cGAS-STING pathway in monocytes and downregulated TGF-β1 expression, thereby preventing fibroblast activation in co-culture systems. Similarly, the mouse-specific cGAS inhibitor RU.521 effectively reduced collagen deposition and fibrosis severity while also improving survival rates in PQ-treated mice. Additionally, RU.521 suppressed pulmonary cGAS activity and reduced levels of downstream cGAS-STING pathway proteins. In conclusion, pharmacological targeting of monocyte-driven cGAS-STING pathway emerges as a promising strategy against PQ-associated fibrotic lung disease.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117502"},"PeriodicalIF":3.4,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}