Toxicology and applied pharmacology最新文献

{"title":"Tryptanthrin alleviate lung fibrosis via suppression of MAPK/NF-κB and TGF-β1/SMAD signaling pathways in vitro and in vivo","authors":"Min Niu ,&nbsp;Yong-Zhi Wang ,&nbsp;Xiang-min Deng ,&nbsp;Xin Wu ,&nbsp;Zheng-Ying Hua ,&nbsp;Ting-Ting Lv","doi":"10.1016/j.taap.2025.117285","DOIUrl":"10.1016/j.taap.2025.117285","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease of unknown etiology, remains a therapeutic challenge with limited treatment options. This study investigates the therapeutic potential and molecular mechanisms of Tryptanthrin, a bioactive indole quinazoline alkaloid derived from <em>Isatis tinctoria</em> L., in pulmonary fibrosis. In a bleomycin-induced murine IPF model, Tryptanthrin administration (5 and 10 mg/kg/day for 28 days) significantly improved pulmonary function parameters and attenuated histological evidence of fibrosis. Mechanistic analysis revealed dual pathway modulation: Tryptanthrin suppressed MAPK/NF-κB signaling through inhibition of phosphorylation events, subsequently reducing pulmonary levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Concurrently, it attenuated TGF-β1/Smad pathway activation by decreasing TGF-β1 expression and Smad2/3 phosphorylation, thereby downregulating fibrotic markers including COL1A1, α-smooth muscle actin (α-SMA), and fibronectin in lung tissues. Complementary in vitro studies using Lipopolysaccharide (<em>LPS</em>) or TGF-β1-stimulated NIH3T3 fibroblasts confirmed these anti-inflammatory and anti-fibrotic effects through analogous pathway inhibition. Our findings demonstrate that Tryptanthrin exerts therapeutic effects against pulmonary fibrosis via coordinated modulation of both inflammatory (MAPK/NF-κB) and fibrotic (TGF-β1/Smad) signaling cascades, suggesting its potential as a novel multi-target therapeutic agent for IPF management.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117285"},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634676","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":"Behavioral and endocrine effects of early-life exposure to etonogestrel in zebrafish","authors":"Amanda Carolina Cole Varela ,&nbsp;Lisiane Siqueira ,&nbsp;Milena Fortuna ,&nbsp;Suelen Mendonça Soares ,&nbsp;Natália Freddo ,&nbsp;Ísis Piasson Barletto ,&nbsp;Maíra Souza Ariotti ,&nbsp;Milena Zanoello Bertuol ,&nbsp;Gabriéla Witkowski Rutikoski ,&nbsp;Cecília Mazutti Andrade ,&nbsp;Leonardo José Gil Barcellos","doi":"10.1016/j.taap.2025.117300","DOIUrl":"10.1016/j.taap.2025.117300","url":null,"abstract":"<div><div>Progestin use as a contraceptive has increased exponentially in the last few decades, as has its disposal in the environment. These synthetic hormones can impair the physiology and behavior of non-target organisms, such as fish. In this study, we evaluated the effects of exposure to an environmentally relevant concentration of etonogestrel (ETO, 3.2 ng L⁻¹) on the behavior and endocrine system of zebrafish (<em>Danio rerio</em>) larvae. We found that ETO caused anxiogenic-like behavior in larvae, as demonstrated by the open-field and light-dark tests. The exposed larvae also presented an increase in whole-body cortisol levels. These changes may lead to an ecological imbalance, emphasizing the risk of early exposure to progestins in the environment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117300"},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629086","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":"Proline betaine facilitates angiogenesis in bronchopulmonary dysplasia","authors":"Wangdui Cili,&nbsp;Zhiye Qi,&nbsp;Qinghua Zhong,&nbsp;Yin Li,&nbsp;Xia Huang,&nbsp;Ruoting Yang,&nbsp;Si Tang,&nbsp;Qingyuan Li,&nbsp;Li Yang,&nbsp;Yue Ning,&nbsp;Yunbo Xie,&nbsp;Yanli Feng,&nbsp;Jiang Duan","doi":"10.1016/j.taap.2025.117301","DOIUrl":"10.1016/j.taap.2025.117301","url":null,"abstract":"<div><h3>Background</h3><div>Bronchopulmonary dysplasia (BPD) is prevalent and severe diseases in preterm infants, characterized by abnormal lung development. This study aims to investigate the therapeutic potential of proline betaine, a natural alkaloid recognized for its vasculo-protective and anti-inflammatory properties, in BPD model.</div></div><div><h3>Methods</h3><div>Network pharmacology was utilized to predict the targets of proline betaine and BPD-related genes (BPD-RGs). In vitro, HUVECs were treated with proline betaine to evaluate its effects on proliferation and angiogenesis. In vivo, a hyperoxia-induced BPD rat model (85 % oxygen, first day to 14th day) was used to evaluate the effects of proline betaine on pulmonary injury, angiogenesis and fibrosis.</div></div><div><h3>Results</h3><div>We identified a total of 100 proline-betaine targets and 825 BPD-RGs, with 20 shared targets between them. These shared targets modulated inflammation, immune response, hypoxia, and vascular homeostasis, especially the vascular phenotype. In vitro<em>,</em> proline betaine significantly enhanced the activity, number of tubes, and capillary length of HUVECs. The pro-angiogenic effect of proline betaine on HUVECs was dose-dependent. The hyperoxia-induced BPD rat model corroborated these findings. In vivo, proline betaine increased the radial alveolar count and reduced the mean linear intercept and collagen content in the lung. Mechanistically, proline betaine upregulated VEGF and VEGFR2 expression as well as MEK/ERK pathway activity. Notably, blocking the VEGFR2 and MEK/ERK pathways made proline betaine less effective as a medicine.</div></div><div><h3>Conclusion</h3><div>Proline betaine enhances angiogenesis and mitigates pulmonary injury through the MEK/ERK pathway. These findings suggest that proline betaine could serve as a novel therapeutic strategy for managing BPD in neonates.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117301"},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634666","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":"Involvement of GSK-3β, NF-κB, PPARγ, and apoptosis in amlodipine's anticancer effect in BALB/c mice","authors":"El-Shaimaa A. Arafa ,&nbsp;Maha M. Abdel-Fattah ,&nbsp;Emad H.M. Hassanein ,&nbsp;Manal A. Buabeid ,&nbsp;Wafaa R. Mohamed","doi":"10.1016/j.taap.2025.117298","DOIUrl":"10.1016/j.taap.2025.117298","url":null,"abstract":"<div><div>Lung cancer is the primary cause of death due to cancer all over the world despite the decrease in the mortality rates from cancer in general. While chemotherapy is a commonly employed treatment for lung cancer, its efficacy is limited due to poor tissue selectivity, inadequate delivery to tumor sites, and associated side effects. The present work aims to assess the potential anti-cancer effectiveness of amlodipine, a calcium channel blocker, on murine lung cancer via modulating GSK-3β, NF-κB, PPARγ, and apoptosis. Lung cancer was induced in BALB/c mice by intraperitoneal injection of 1.5 g/kg in two doses of urethane: once on the 1st and the second on the 60th day of the experiment. Amlodipine was administered orally at a dose of 10 mg/kg/day for the last 28 days of experiment. Relative to urethane group, amlodipine mitigated urethane-induced histopathological abnormalities. It restored oxidant/antioxidant balance by normalizing MDA, GSH, and SOD. Furthermore, it exerted a marked anti-inflammatory effect through downregulating lung MPO, ICAM-1, IL-6, TNF-α, and NF-қB expressions. Amlodipine enhanced apoptosis of cancer cells as evidenced by increasing Bax and decreasing Bcl-2 expression. The anticancer effect of amlodipine was suggested to be mediated through increasing PPARγ and reducing GSK3β and <em>p</em>-GSK3β signaling. Collectively, these results suggest that amlodipine could exert a promising anticancer effect against lung cancer through modulating GSK-3β, NF-κB, PPARγ, and apoptosis. Our findings could be highly significant in clinical settings, offering a valuable adjuvant option for managing lung carcinoma, particularly in patients with cardiovascular disorders.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117298"},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634659","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":"Arsenic and metabolic diseases: New insights from mesenchymal stem cells","authors":"Yuxin Hu ,&nbsp;Jialin He ,&nbsp;Yue Ma ,&nbsp;Lili Ge ,&nbsp;Bin Lou ,&nbsp;Xin Fang ,&nbsp;Huihui Wang ,&nbsp;Yuanyuan Xu","doi":"10.1016/j.taap.2025.117299","DOIUrl":"10.1016/j.taap.2025.117299","url":null,"abstract":"<div><div>Arsenic is a common toxic metal contaminant in the environment. Humans are exposed to arsenic through drinking water, air, food, and medical treatment. Chronic exposure to arsenic is a well-documented risk factor of type 2 diabetes and a potential risk factor of osteoporosis and obesity. Mesenchymal stem cells (MSCs) are adult stem cells with multiple differentiation potential and immunomodulatory capacity. These cells have shown therapeutic potential in experimental studies of metabolic diseases by differentiating into parenchymal cells of damaged tissues, such as islet-like cells and osteoblasts, and resisting chronic inflammation. Meanwhile, when key functional genes were suppressed in MSCs, experimental animals showed metabolic disease-related changes, such as insulin resistance and obesity. Arsenic exposure inhibits the differentiation capacity of MSCs, leads to changes in the synthesis and secretion of immunomodulatory factors, and induces cellular senescence and apoptosis. Therefore, dysfunction and death of MSCs may be important pathogenesis of arsenic-related metabolic diseases. Future studies on the functional changes of MSCs in arsenic-related metabolic diseases and the role of MSCs in arsenic pathogenesis are worthwhile. In addition, the mechanism of arsenic-induced dysfunction in MSCs needs to be explored in depth.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117299"},"PeriodicalIF":3.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626115","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":"Exploring the mechanism of baicalein on breast cancer based on network pharmacology, molecular docking and in vivo experiments","authors":"Gaotao Zhang ,&nbsp;Zhiqin Liu ,&nbsp;Yuanzhuang Xu ,&nbsp;Fei Cao ,&nbsp;Xiaowei Huo ,&nbsp;Queting Chen ,&nbsp;Duqiang Luo","doi":"10.1016/j.taap.2025.117297","DOIUrl":"10.1016/j.taap.2025.117297","url":null,"abstract":"<div><div>Abstract</div><div>Breast cancer ranks among the most deadly gynecological cancers and presents a significant risk to women's health. Baicalein, a flavonoid extracted from <em>Radix Scutellariae</em>, has garnered significant interest due to its potential anti-cancer properties. However, further research is required to determine the precise anti-cancer mechanisms of baicalein. Hence, we investigated the anti-tumor properties and underlying mechanisms of baicalein in breast cancer, utilizing both network pharmacology and experimental approaches. The effects of baicalein on cellular proliferation, the cell cycle, and apoptosis were assessed through MTT assays, plate cloning, and flow cytometry techniques. Furthermore, network pharmacology was employed to identify the primary target and pathway associated with baicalein in the context of breast cancer. The validation of these target and the elucidation of baicalein anti-breast cancer mechanisms were carried out using Western blotting, qRT-PCR, molecular docking, CETSA assays, and IHC. Behavioral experiments were conducted to assess the physical changes and toxicity of baicalein in model mice. Our findings demonstrated that baicalein significantly reduced the growth of both MCF-7 and MDA-MB-231 cell lines in a dose-dependent manner, inhibited cell proliferation, induced G0/G1 phase arrest, and triggered apoptosis. Notably, SRC serves as a therapeutic target for baicalein, with the Hippo pathway identified as a crucial mechanism of action in this context. Intraperitoneal injection of baicalein has been demonstrated to effectively inhibit tumor growth, while concurrently ameliorating splenomegaly and enhancing the fatigue resistance of the model mice. The findings confirm that baicalein was a potential drug for the treatment of breast cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117297"},"PeriodicalIF":3.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620361","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":"Carvacrol attenuated myocardial infarction through NLRP3-mediated pyroptosis and mTOR/Nrf2/PPARγ-dependent autophagic signaling","authors":"Hina Aslam ,&nbsp;Faisal Albaqami ,&nbsp;Najeeb Ur Rehman ,&nbsp;Fawad Ali Shah","doi":"10.1016/j.taap.2025.117281","DOIUrl":"10.1016/j.taap.2025.117281","url":null,"abstract":"<div><div>Myocardial ischemia, also known as myocardial infarction or heart attack, is a significant global health issue and a leading cause of mortality worldwide. The present study focuses on investigating the cardioprotective role of carvacrol on three specific pathways: nuclear factor E2-related factor (Nrf2) / peroxisome proliferator-activated receptor factor (PPARγ)-coupled anti-inflammatory response, inflammasome (NLRP3)-mediated pyroptosis, and mammalian target of rapamycin (mTOR)-dependent autophagic signaling. Male Sprague Dawley rats were divided into three experimental cohorts to determine the best dose for carvacrol (20 mg / kg, 50 mg / kg, and 80 mg/ kg) and the optimum treatment strategy. Our findings showed that isoproterenol raised the production of ROS, induced NLRP3-mediated pyroptosis, and modulated the mTOR-linked signaling cascade. Treatment with carvacrol activated the Nrf2 / HO-1 and PI3K / AKT signaling pathways that led to the reversal of NLRP3 inflammasome. Moreover, the Nrf2 inhibitor all-trans-retinoic acid (ATRA) antagonizes the protective effects of carvacrol and exacerbates myocardial infarction by inducing inflammatory mediators. Taken together, our findings suggest that carvacrol mitigated isoproterenol-induced myocardial ischemia, partially through the activation of Nrf2 and PPARγ and downregulation of NLRP3.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117281"},"PeriodicalIF":3.3,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597835","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":"Evaluation of several farnesyloxycarbostyril derivatives as potential 15-LOX-1 inhibitors for prostate cancer treatment","authors":"Mehrdad Aghasizadeh ,&nbsp;Tayebe Moghaddam ,&nbsp;Ahmad Reza Bahrami ,&nbsp;Hamid Sadeghian ,&nbsp;Seyed Jamal Alavi ,&nbsp;Tahmineh Kazemi ,&nbsp;Maryam M. Matin","doi":"10.1016/j.taap.2025.117293","DOIUrl":"10.1016/j.taap.2025.117293","url":null,"abstract":"<div><div>The impact of 15-lipoxygenase-1 (15-LOX-1) in the progression of prostate cancer (PCa) is noteworthy, as it correlates with the Gleason score of the disease. Thus, development of specific 15-LOX-1 inhibitors would be desirable for targeted therapy of PCa. This study focused on evaluating the anti-prostate cancer potency of three farnesyloxycarbostyril derivatives, 6-, 7- and 8-farnesyloxycarbostyril (6-, 7- and 8-FQ), as potential inhibitors of 15-LOX-1 on PCa cells. To this end, the enzymatic activity of 15-LOX was first assessed in PCa and human dermal fibroblast (HDF) cells. Subsequently, the cytotoxic effects and apoptosis-inducing capabilities of the compounds were assessed through MTT assay and FITC-annexin V/PI staining, respectively. Among the compounds, 8-FQ was selected for further assessment in a mouse model bearing xenograft human PCa tumor. The results demonstrated that the most effective compound, 8-FQ, caused an 84-fold and 15.7-fold reduction in 15-LOX activity in PC-3 cells at 30 and 14 μM concentrations, respectively. The MTT assay revealed a dose- and time-dependent toxicity of the compounds on PCa cells, and flow cytometry results indicated that apoptosis served as the dominant mechanism of cell death. Given the upregulation of 15-LOX-1 in human PCa cells, the study concludes that the heightened sensitivity to 8-FQ is likely associated with elevated levels of 15-LOX-1. <em>In vivo</em> experiments using immunosuppressed C57BL/6 mice bearing human PC-3 tumors revealed that 8-FQ, at a dosage of 10 mg/kg, exhibited strong antitumor effects with minimal side effects, indicating its potential as a promising therapeutic agent for PCa following further optimization.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117293"},"PeriodicalIF":3.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587146","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":"Corrigendum to “Shikonin modulates activated fibroblast apoptosis in silicosis fibrosis via the PI3K/Akt signaling pathway: A network pharmacology approach” [Toxicology and Applied Pharmacology. 2025 Feb, 495, 117236]","authors":"Shengpeng Wen ,&nbsp;Sirong Chang ,&nbsp;Huning Zhang ,&nbsp;Wenyue Zhang ,&nbsp;Yi Guo ,&nbsp;Na Zhang ,&nbsp;Anning Yang ,&nbsp;Yue Sun ,&nbsp;Zhihong Liu","doi":"10.1016/j.taap.2025.117294","DOIUrl":"10.1016/j.taap.2025.117294","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117294"},"PeriodicalIF":3.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The resveratrol attenuates reactive oxygen species mediated DNA damage in cardiac malformations caused by 4-tert-octylphenol","authors":"Xin Wang ,&nbsp;Jin Chen ,&nbsp;Hanwen Hu ,&nbsp;Mingxue Gong ,&nbsp;Mengqin Wu ,&nbsp;Bofu Ye ,&nbsp;Han Hu ,&nbsp;Zuo Du ,&nbsp;Anfei Liu ,&nbsp;Shaoxin Huang ,&nbsp;Tao Jing ,&nbsp;Zhenzhong Liu","doi":"10.1016/j.taap.2025.117284","DOIUrl":"10.1016/j.taap.2025.117284","url":null,"abstract":"<div><div>4-tert-octylphenol (4-t-OP) is an alkylphenolic environmental endocrine disruptor extensively distributed in the environment, posing potential hazards to living organisms. Research has demonstrated that 4-t-OP induces cardiac injury and abnormalities in embryonic development, which can adversely affect heart development. The excessive production of reactive oxygen species (ROS) triggered by 4-t-OP may result in DNA damage. Hence, we hypothesized that ROS-mediated DNA damage plays a crucial role in abnormal cardiac development in zebrafish embryos exposed to 4-t-OP, while resveratrol (RSV), a common antioxidant found in natural foods, may provide protection. In this study, we exposed zebrafish embryos at 2 h post-fertilization (hpf) to various doses of 4-t-OP in combination with relevant inhibitor/agonist therapies. Using microscopy, we observed morphological alterations in the cardiac structure of zebrafish embryos at 72 hpf. The underlying molecular mechanisms were assessed through immunofluorescence, DCFH-DA probe, MitoSOX™ staining, Quantitative polymerase chain reaction, and other methods. Our findings revealed that 4-t-OP caused dose-dependent cardiac defects in zebrafish embryos. The overexpression of ROS/mitochondrial ROS (mtROS) induced by 4-t-OP was significantly reduced by the addition of RSV or the ROS inhibitor <em>N</em>-acetyl-L-cysteine (NAC). Furthermore, the inclusion of RSV or NAC significantly mitigated cardiac deformities, cardiac apoptosis, and DNA damage. Additionally, the apoptosis inhibitor Ac-DEVD-CHO and the Wnt/β-catenin agonist CHIR99021 decreased 4-t-OP-induced cardiac abnormalities. Moreover, the naturally occurring small molecule chemical RSV provided protection against 4-t-OP-induced heart developmental injury. This study elucidates the molecular mechanisms by which 4-t-OP induces oxidative stress, DNA damage, and cardiac defects in the heart of zebrafish larvae through the ROS/Wnt/β-catenin signaling pathway. These findings present novel molecular targets for the prevention and therapy of congenital heart disease, as well as enhance our understanding of the cardiotoxic effects of 4-t-OP.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117284"},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537599","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}