Toxicology and applied pharmacology最新文献

{"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":"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":"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":"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}

{"title":"Toxicokinetic insights into distinct mechanisms of action of two thyroid toxicants: Propylthiouracil and pregnenolone 16α‑carbonitrile","authors":"Naïs Clavel Rolland ,&nbsp;Bénédicte Kiehr ,&nbsp;Meiling Zhu ,&nbsp;Chun Chen ,&nbsp;Peng Gao ,&nbsp;Thierry Pourcher ,&nbsp;Olivier Blanck","doi":"10.1016/j.taap.2025.117282","DOIUrl":"10.1016/j.taap.2025.117282","url":null,"abstract":"<div><div>Thyroid hormones (THs) are critical for metabolic regulation and brain development. Disruptions in TH homeostasis, especially during fetal development, can lead to irreversible neurodevelopmental impairments. Thyroid hormone system-disrupting chemicals (THSDCs), are of growing concern for human health due to their potential to interfere with TH signaling. This study investigates the toxicokinetic properties of two THSDCs: propylthiouracil (PTU), which inhibits TH synthesis, and pregnenolone-16α‑carbonitrile (PCN), which enhances the TH hepatic metabolism. Using <em>in vitro</em> approaches and <em>in vivo</em> models involving pregnant, fetal, and neonatal rats, we aimed to characterize the absorption, distribution, metabolism, and excretion (ADME) profiles of these compounds. Liver metabolism, fraction unbound, plasma concentrations, and tissue distribution of PTU and PCN were assessed. Our investigation demonstrated that PCN underwent quick liver metabolism, resulting in undetectable PCN levels in adult and newborn rat tissues as well as in maternal milk. In contrast, PTU exhibited high permeability through the intestinal barrier and was slowly metabolized by the liver, leading to high PTU concentrations in the maternal milk, thyroid gland, and the brain of fetuses and newborns. These latter results raise concerns regarding the potential direct effect of PTU on neonatal brain development. Especially, the hypothesis that PTU can interact with brain peroxidases involved in detoxification processes warrants further investigation. These findings highlight the intricate relationship between THSDC exposure, altered TH synthesis and metabolism, and subsequent impacts on neurodevelopment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117282"},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537649","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":"Mitochondrial iron deficiency mediated inhibition of ecdysone synthesis underlies lead (Pb) induced developmental toxicity in Drosophila melanogaster","authors":"Zhi-Hua Liu ,&nbsp;YuYin Zhai ,&nbsp;Jiakai Zhang ,&nbsp;Wei Huang ,&nbsp;Wanrong Li ,&nbsp;Wenting Qin","doi":"10.1016/j.taap.2025.117283","DOIUrl":"10.1016/j.taap.2025.117283","url":null,"abstract":"<div><div>Lead (Pb) is a pervasive heavy metal possessing developmental toxicity, at least in part, by disrupting iron homeostasis. In this study, we aimed to elucidate the underlying mechanism of iron deficiency mediated developmental defects in Pb exposed <em>Drosophila melanogaster</em>, mainly focusing on iron-dependent synthesis of ecdysone signaling, which plays a key role in the development of insects. Herein, we found Pb exposure resulted in iron deficiency in mitochondria by inhibiting expression of mitoferrin (evidenced by qPCR assay), the mitochondrial iron importer. Further study demonstrated that biosynthesis of ecdysone, a hormone synthesized with the help of iron-containing cytochrome P450s in mitochondria, was inhibited following Pb exposure. Ecdysone supplementation, to some extent, rescued Pb induced developmental delay and reproductive defects in <em>Drosophila melanogaster.</em> Furthermore, we found that disruption of mitoferrin and ecdysone synthesis was restored by NAC (N-Acetylcysteine, a well-known ROS scavenger), suggesting that oxidative stress plays a key role in Pb mediated mitochondrial iron dys-homeostasis and developmental toxicity. This study therefore revealed that mitochondrial iron deficiency mediated inhibition of ecdysone synthesis is a key event associated with iron dys-homeostasis mediated developmental defects caused by Pb exposure. Meanwhile, our study indicated that mitochondria may act as an important target of Pb, thus providing potential protective strategies against Pb toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117283"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512441","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":"Role of activating transcription factor 3 as a mediator of the protective effects of berberine against lipopolysaccharide-stimulated SW982 cells and in rheumatoid arthritis animal models","authors":"Kwan Yong Yeon ,&nbsp;Seongmi Ji ,&nbsp;Hyae Gyeong Cheon","doi":"10.1016/j.taap.2025.117279","DOIUrl":"10.1016/j.taap.2025.117279","url":null,"abstract":"<div><div>This study aimed to explore the protective effects of berberine against rheumatoid arthritis (RA) and clarify the role of activating transcription factor 3 (ATF3) in the mechanism of action of berberine, using a lipopolysaccharide (LPS)-stimulated SW982 human synovial cell line. Berberine treatment resulted in a concentration-dependent reduction in LPS-induced proinflammatory cytokines and matrix metalloproteinases (MMPs) in SW982 cells. These inhibitory effects were associated with increased ATF3 expression, reduced nuclear translocation of nuclear factor-κB (NF-κB), and diminished phosphorylation of mitogen-activated protein kinase (MAPK). In contrast, ATF3 knockdown reversed the suppressive effects of berberine on proinflammatory cytokines and MMP production, leading to enhanced MAPK phosphorylation; however, it had minimal impact on adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Furthermore, AMPK knockdown negated the protective effects of berberine and reduced ATF3 levels, whereas treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, replicated the beneficial effects of berberine. In an in vivo collagen-induced arthritis (CIA) mouse model, intraperitoneal administration of berberine significantly reduced paw edema and arthritis severity, accompanied by ATF3 induction and increased AMPK phosphorylation in the synovial tissue. These findings highlighted the pivotal role of ATF3 in mediating the protective effects of berberine in RA- and LPS-activated synoviocytes, suggesting its potential as a therapeutic agent for RA management.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117279"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511194","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":"EGFR tyrosine kinase inhibitor ZZC4 overcomes acquired resistance to gefitinib","authors":"Mawusse K.I. Attiogbe ,&nbsp;Ting-ting Huang ,&nbsp;Hong-yi Zhao ,&nbsp;Hong-ying Wang ,&nbsp;Lei Cao ,&nbsp;Ping-ping Yan ,&nbsp;San-qi Zhang ,&nbsp;Yong-xiao Cao","doi":"10.1016/j.taap.2025.117280","DOIUrl":"10.1016/j.taap.2025.117280","url":null,"abstract":"<div><div>Despite the tremendous progress of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) development, acquired resistance mechanisms have limited their efficacy in treating non-small cell lung cancer (NSCLC). To overcome these limitations, novel EGFR-TKIs are needed. In our previous study, we presented ZZC4 as a potent EGFR-TKI. In this study, we developed NSCLC cells resistant to EGFR-TKI gefitinib and osimertinib and assessed the effect and mechanism of action of ZZC4 on those cells. HCC827 cells were cultured with gefitinib in a concentration-escalation manner to achieve HCC827 gefitinib-resistant (HCC827-GR) cells after 6 months of treatment. Then, the effect of ZZC4 was assessed at the cellular and animal levels. To understand ZZC4's mechanism of action, the proteome alteration induced by ZZC4 on the resistant cell line was compared to the parental HCC827 cells using comparative proteomics. The result showed that gefitinib's IC₅₀ on HCC827 was 533 nM, approximately 80 times its IC₅₀ on normal cells (7.6 nM), confirming its resistance to HCC827 cells. The obtained resistant cells were treated with ZZC4, which potently suppressed the resistant cells' proliferation with an IC₅₀ of 0.1 nM. In tumor-bearing mice, ZZC4 also suppressed the growth of HCC827-GR cell tumors with an inhibition ratio of 82 % at ZZC4 4 mg/kg. Further, the proteomic analysis revealed that ZZC4 inhibited HCC827-GR cell growth by upregulating CDKN1B and downregulating CCNA2 and CHEK1. In conclusion, ZZC4 overcomes resistance to gefitinib by altering the cell cycle pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117280"},"PeriodicalIF":3.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143504330","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":"Misrepresentation of mouse genotypes: A call for precision","authors":"Wei Li","doi":"10.1016/j.taap.2025.117276","DOIUrl":"10.1016/j.taap.2025.117276","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117276"},"PeriodicalIF":3.3,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479843","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":"Analysis of accumulation of DNA double-strand breaks in mouse tissues by pulsed-field gel electrophoresis","authors":"Takeshi Terabayashi ,&nbsp;Takako Sasaki ,&nbsp;Toshimasa Ishizaki ,&nbsp;Tadashi Tomo ,&nbsp;Yoshihiro Nishida ,&nbsp;Katsuhiro Hanada","doi":"10.1016/j.taap.2025.117278","DOIUrl":"10.1016/j.taap.2025.117278","url":null,"abstract":"<div><div>Double-strand DNA breaks (DSBs) are among the most cytotoxic DNA lesions, which can lead to chromosomal instability and eventually cell death. The substances that can potentially induce DSB formation are thus regarded as genotoxic. To date, many genotoxicity tests for detecting DNA breaks have been designed. However, there are limited options available for measuring the accumulation of DSBs in vivo. In this study, we aimed to evaluate a method of detecting the DSBs formed by the direct action of genotoxic substances using pulsed-field gel electrophoresis (PFGE). This approach has the advantage of making it easier to distinguish between DSBs and single-strand DNA breaks (SSBs) induced by the direct action of genotoxic substances. To confirm the detection of DSBs using PFGE, we investigated their accumulation after treatment with <em>cis</em>-diamminedichloroplatinum(II) (cisplatin) or γ-rays in mouse organs. The results revealed the successful detection of cisplatin-induced DSB formation in mouse kidney and thymus and γ-ray-induced DSB formation in all organs. We also discuss the advantages of PFGE-based detection of DSBs in vivo.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117278"},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473909","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}