Toxicology and applied pharmacology最新文献_第8页

Corrigendum to “Rat-to-human PBPK model of U-47700: Unveiling pharmacokinetic risks of a synthetic opioid through interspecies extrapolation” [Toxicology and Applied Pharmacology, 499 (2025) 117352] “U-47700的鼠对人PBPK模型：通过物种间外推揭示合成阿片类药物的药代动力学风险”的勘误表[毒理学和应用药理学，499(2025)117352]。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-05-03 DOI: 10.1016/j.taap.2025.117370

Lina Zhong , Longjie Li , Qingfeng He , Xiao Zhu , Ping Xiang , Xiaoqiang Xiang , Hui Yan

引用次数: 0

Interactions between cadmium and 17β-estradiol at physiologically relevant levels evoke unsynchronized events in MCF-7 breast cancer cells: Impaired cell growth and activation of estrogen receptor α-related pathways 镉和17β-雌二醇在生理相关水平上的相互作用在MCF-7乳腺癌细胞中引起不同步的事件：细胞生长受损和雌激素受体α相关途径的激活

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-05-02 DOI: 10.1016/j.taap.2025.117360

Koki Kanameda , Azumi Honda , Masayo Hirao-Suzuki , Narumi Sugihara , Masufumi Takiguchi , Shuso Takeda

{"title":"Interactions between cadmium and 17β-estradiol at physiologically relevant levels evoke unsynchronized events in MCF-7 breast cancer cells: Impaired cell growth and activation of estrogen receptor α-related pathways","authors":"Koki Kanameda , Azumi Honda , Masayo Hirao-Suzuki , Narumi Sugihara , Masufumi Takiguchi , Shuso Takeda","doi":"10.1016/j.taap.2025.117360","DOIUrl":"10.1016/j.taap.2025.117360","url":null,"abstract":"<div><div>Cadmium (Cd), a heavy metal, is implicated in the development of estrogen receptor α (ERα)-positive breast cancers (BCs). However, controversy surrounds whether Cd is estrogenic or anti-estrogenic for the malignancy of <em>in vivo</em> animal models and human observational/epidemiological studies, a debate also presents in <em>in vitro</em> experiments. The development of ERα-positive BCs is stimulated by circulating 17β-estradiol (E2). Thus, potential biological interactions between E2 and Cd in the progression of ERα-positive BCs exist. Although the interactions between Cd and E2 at physiologically relevant levels (1 nM each) may not have been confirmed <em>in vitro</em><em>,</em> it is likely to occur. Therefore, this study aims to investigate the interactions of chemicals in human BC MCF-7 cells (ERα-positive) using a sequential exposure system in which chemicals are added to cells every 24–48 h. Pretreatment with Cd, but not secondary treatment, interfered with E2-mediated oncogenic actions by inducing cell cycle arrest at the S phase. This was accompanied by changes in the expression of genes regulating the cell cycle checkpoint and upregulation of the tumor suppressor <em>metallothionein 1F</em> gene, which E2 suppressed. Paradoxically, ERα-mediated estrogenic pathways were upregulated. In conclusion, this study is the first to show that physiologically relevant levels of Cd may dampen E2-induced oncogenic events independent of the E2/ERα-mediated pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117360"},"PeriodicalIF":3.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912015","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}

引用次数: 0

Polycyclic aromatic hydrocarbon-aryl hydrocarbon receptor signaling regulates chronic inflammation in lung-gut axis 多环芳烃-芳烃受体信号通路调控肺肠轴慢性炎症

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-05-02 DOI: 10.1016/j.taap.2025.117359

Tzu-Yu Cheng , Ching-Shan Luo , Po-Hao Feng , Kuan-Yuan Chen , Chih-Cheng Chang , Nguyen Van Hiep , Yueh-His Chen , Yun-Kai Yeh , Sheng-Ming Wu

{"title":"Polycyclic aromatic hydrocarbon-aryl hydrocarbon receptor signaling regulates chronic inflammation in lung-gut axis","authors":"Tzu-Yu Cheng , Ching-Shan Luo , Po-Hao Feng , Kuan-Yuan Chen , Chih-Cheng Chang , Nguyen Van Hiep , Yueh-His Chen , Yun-Kai Yeh , Sheng-Ming Wu","doi":"10.1016/j.taap.2025.117359","DOIUrl":"10.1016/j.taap.2025.117359","url":null,"abstract":"<div><div>Polycyclic aromatic hydrocarbons (PAHs) are broadly identified in environmental pollutants and also formed during the heat processing of meat, including grilling, roasting, smoking, and frying, particularly at high temperatures. Besides, the PAHs influence inflammatory response through activation of aryl hydrocarbon receptor (AhR) signaling. Recently, the role of the PAHs/AhR axis in inflammatory diseases has attracted major attention in the regulation of lung function, gut barrier function, and systemic inflammation. Many experiments have been conducted to determine the role of the PAHs/AhR/cytochrome P450 1A1 signaling activation on elevation of inflammation in the lung–gut axis. In contrast, several dietary AhR ligands can improve inflammatory function by modulating the AhR signaling, thereby strengthening the intestinal barrier. This review includes the pivotal roles of xenobiotic and diet-derived AhR ligands in the regulation of chronic lung diseases and systemic inflammation and their relevance in the lung–gut axis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117359"},"PeriodicalIF":3.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921164","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}

引用次数: 0

Zebrafish larvae as a model for investigating dual effects of fluoride on bone development 斑马鱼幼体作为研究氟化物对骨骼发育双重影响的模型

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-05-01 DOI: 10.1016/j.taap.2025.117357

Xin Wang , Junjun Li , Yumei Fan , Xiaodi Zhang , Yanmei Yang , Yanhui Gao

{"title":"Zebrafish larvae as a model for investigating dual effects of fluoride on bone development","authors":"Xin Wang , Junjun Li , Yumei Fan , Xiaodi Zhang , Yanmei Yang , Yanhui Gao","doi":"10.1016/j.taap.2025.117357","DOIUrl":"10.1016/j.taap.2025.117357","url":null,"abstract":"<div><div>Long-term excessive ingestion of fluoride is a severe public health threat globally. Skeletal fluorosis, a significant manifestation of prolonged fluoride exposure, is characterized by aberrant bone structure and alterations in bone function. However, there is currently a shortage of an efficient, fast, and easy-to-operate biological model for application in the field of fluorosis research. Zebrafish larvae, with human - like skeletal traits, high reproduction, rapid development, and transparency, are commonly used in bone disease studies. This study evaluates the potential of zebrafish larvae as a novel model for fluoride-induced bone impairment. Results showed dose-dependent differences in cranial and spinal bone mineralization in zebrafish larvae exposed to sodium fluoride (NaF). The detection results of bone formation-related indicators indicated a considerable increase in alkaline phosphatase (ALP) activity in zebrafish larvae at doses of 0.5 and 1 mg/L. Simultaneously, the expression of critical bone formation proteins (BMP2, and β-catenin) was elevated in the 1 and 4 mg/L groups, which is largely consistent with the results of cranial bone mineralization. Fluoride - exposed zebrafish also showed abnormal bone metabolism markers. The total phosphorus (TP) content in the zebrafish larvae of the 100 mg/L group was markedly reduced. The total calcium (TCa) content in the zebrafish of the NaF group zebrafish was slightly decreased, although the tartrate-resistant acid phosphatase (StrACP) activity increased. In conclusion, different fluoride doses cause osteoporosis and osteosclerosis in zebrafish larvae, linked to enhanced osteogenic and osteoclastic activities and abnormal key bone - forming protein expression.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117357"},"PeriodicalIF":3.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918081","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}

引用次数: 0

Corrigendum to “Protective effect of hydrogen-rich water on spermatogenesis in high-fat diet obese rats” [Toxicology and Applied Pharmacology Volume 499, June 2025, 117334] “富氢水对高脂饮食肥胖大鼠精子发生的保护作用”的勘误表[毒理学和应用药理学卷499，June 2025, 117334]。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-29 DOI: 10.1016/j.taap.2025.117356

Mohammad Hossein Rigi , Seyyedeh Zahra Asghari , Elaheh Eshtad , Seyedeh Elnaz Nazari , Akram Aminian , Khatereh Kharazmi , Fereshteh Asgharzadeh , Amir Avan , Seyed Mahdi Hassanian , Tyler W. LeBaron , Majid Khazaei

引用次数: 0

Mouse nephron formation is impaired by moderate dose arsenical exposure 中等剂量砷暴露可损害小鼠肾元形成

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-29 DOI: 10.1016/j.taap.2025.117355

Carlos Agustin Isidro Alonso , Jenna Haverfield , Gabriela Regalado , Sihem Sellami , Natascha Gagnon , Ajay Rajaram , Pierre Olivier Fiset , Tomoko Takano , Aimee K. Ryan , Koren K. Mann , Indra R. Gupta

{"title":"Mouse nephron formation is impaired by moderate dose arsenical exposure","authors":"Carlos Agustin Isidro Alonso , Jenna Haverfield , Gabriela Regalado , Sihem Sellami , Natascha Gagnon , Ajay Rajaram , Pierre Olivier Fiset , Tomoko Takano , Aimee K. Ryan , Koren K. Mann , Indra R. Gupta","doi":"10.1016/j.taap.2025.117355","DOIUrl":"10.1016/j.taap.2025.117355","url":null,"abstract":"<div><div>Millions of people are exposed to concentrations of arsenic that exceed the World Health Organization's limit of 10 μg/L. Inorganic arsenic (iAsIII) is metabolized by arsenic 3 methyltransferase (As3mt) that converts it to methylated arsenicals, mono and dimethyl arsonous acid (MMA and DMA). Chronic arsenic exposure is linked to an increased risk of chronic kidney disease (CKD), however, the effects of arsenic exposure on kidney development remain unclear. We hypothesized that exposure to arsenicals impairs nephron formation during mouse kidney development. Mouse embryonic kidney explants were treated with iAsIII and MMAIII (1.5 μM or 200 μg/L). iAsIII inhibited growth of kidney explants and ureteric bud branching morphogenesis at embryonic day 11.5 (E11.5) and E12.5, but not at E13.5. Similar effects were observed when kidney explants were treated with MMAIII. Additionally, iAsIII exposure increased apoptosis in the metanephric mesenchyme of E11.5 explants and decreased <em>Gdnf</em> transcription. To assess the impact of iAS exposure <em>in utero</em> and early postnatal life, female mice harboring a humanized version of <em>AS3MT</em> and wild-type mice with murine <em>As3mt</em> were exposed to iAsIII throughout gestation and weaning and their offspring were analyzed for kidney defects. Pups with human <em>AS3MT</em> exposed to 1.5 μM iAsIII <em>in utero,</em> showed a 20 % reduction in kidney weight normalized to body weight and a 28 % reduction in nephron number, compared to kidneys of wild-type mice.</div><div>In conclusion, exposure to arsenicals during embryonic development impairs ureteric bud branching morphogenesis and decreases nephron endowment, which may predispose to CKD in adulthood.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117355"},"PeriodicalIF":3.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899369","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}

引用次数: 0

Triptophenolide aggravates triptolide-induced liver injury through disrupting the biological function of intestine 雷公藤酚内酯通过破坏肠道生物功能加重雷公藤甲素引起的肝损伤

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-24 DOI: 10.1016/j.taap.2025.117354

Binbin Zhang , Qiuxia Lin , Manyun Dai , Zhanxuan Wu , Liqiong Chen , Fei Li

{"title":"Triptophenolide aggravates triptolide-induced liver injury through disrupting the biological function of intestine","authors":"Binbin Zhang , Qiuxia Lin , Manyun Dai , Zhanxuan Wu , Liqiong Chen , Fei Li","doi":"10.1016/j.taap.2025.117354","DOIUrl":"10.1016/j.taap.2025.117354","url":null,"abstract":"<div><div><em>Tripterygium wilfordii</em>, Hook f. (TW) has been traditionally used in Chinese medicine to treat conditions like rheumatoid arthritis, nephritis, and lupus erythematosus. However, the toxic reactions to the liver pose a huge obstacle to TW's clinical applications. The toxicological mechanisms of TW remain unclear. Male C57BL/6 mice were administered with TW ingredient triptolide (TP) and triptophenolide (TPH) alone or in combination to investigate their individual and synergistic effects on the liver. Elisa tested for LPS in the plasma correlated with liver injury. Metabolomics and 16S rRNA analysis were used to investigate pathological markers associated with intestine function disorder which may contribute to liver injury. The correlation analysis between the differential metabolites and the changing flora was carried out to find the fundamental metabolic molecules, and the results of the correlation analysis were verified by the addition of metabolites in vivo. The concurrent use of TPH and TP cause intestinal bleeding and microbial dysbiosis, then augment level of LPS in the plasma to prompting more severe liver damage induced by TP. Metabolomic analysis and changes in microflora composition proved that the toxic metabolite PCS was significantly related to intestinal barrier damage, and the addition of PCS promoted hepatotoxicity in combination administration. By augmenting PCS, TPH compromises the gut barrier, escalates circulating LPS, and activates the hepatic TLR4/MyD88 pathway, thereby exacerbating TP-induced hepatic injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117354"},"PeriodicalIF":3.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921699","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}

引用次数: 0

Effect of ponatinib on the metabolism of cariprazine in vitro and in vivo and the underlying mechanism 波纳替尼对卡吡嗪体内外代谢的影响及其机制

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-24 DOI: 10.1016/j.taap.2025.117353

Hualu Wu , Haoxin Fu , Fangyuan Xia , Jun Wu , Peiqi Wang , Lu Cao , Ren-ai Xu , Lu Shi

{"title":"Effect of ponatinib on the metabolism of cariprazine in vitro and in vivo and the underlying mechanism","authors":"Hualu Wu , Haoxin Fu , Fangyuan Xia , Jun Wu , Peiqi Wang , Lu Cao , Ren-ai Xu , Lu Shi","doi":"10.1016/j.taap.2025.117353","DOIUrl":"10.1016/j.taap.2025.117353","url":null,"abstract":"<div><div>Cariprazine is an antipsychotic medication that has been approved for the treatment of schizophrenia and manic or mixed episodes. Patients with tumors frequently develop psychiatric disorders, necessitating the combination of antitumor and antipsychotic drugs. The objective of the present study was to examine the inhibitory impacts of three antitumor drugs (olmutinib, napabucasin and ponatinib) on the metabolism of cariprazine, and the molecular docking of cariprazine and ponatinib in relation to CYP3A4 was also evaluated. As the results, the half-maximal inhibitory concentration (IC<sub>50</sub>) values of ponatinib and olmutinib <em>in vitro</em> were < 10 μM, whereas napabucasin was >20 μM. Among these, ponatinib exhibited the smallest IC<sub>50</sub> value. The metabolic stability of cariprazine was observed in the presence or absence of ponatinib in rat liver microsomes (RLM). The IC<sub>50</sub> shift experiments demonstrated that the inhibition of cariprazine by ponatinib was non-time-dependent. In addition, ponatinib was shown to inhibit cariprazine in a mixed manner (RLM) and a competitive manner (HLM), respectively. In the <em>in vivo</em> study, the co-administration of ponatinib resulted in a significant 0.35-fold increase in both AUC<sub>(0-t)</sub> and AUC<sub>(0-∞)</sub> for cariprazine, accompanied by a significant 0.25-fold decrease in the CL<sub>z/F</sub>. Furthermore, the metabolites desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR) exhibited disparate increases in both AUC<sub>(0-t)</sub> and AUC<sub>(0-∞)</sub>. Molecular docking studies had demonstrated that both cariprazine and ponatinib could engage in hydrophobic interactions with residue PHE-304 on CYP3A4. Consequently, when ponatinib is employed in conjunction with cariprazine in a clinical setting, it is imperative to assess the efficacy and adverse effects, and adjust the dosage to attain the optimal efficacy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117353"},"PeriodicalIF":3.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882757","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}

引用次数: 0

Rat-to-human PBPK model of U-47700: Unveiling pharmacokinetic risks of a synthetic opioid through interspecies extrapolation U-47700大鼠对人PBPK模型：通过种间外推揭示合成阿片类药物的药代动力学风险

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-22 DOI: 10.1016/j.taap.2025.117352

Lina Zhong , Longjie Li , Qingfeng He , Xiao Zhu , Ping Xiang , Xiaoqiang Xiang , Hui Yan

{"title":"Rat-to-human PBPK model of U-47700: Unveiling pharmacokinetic risks of a synthetic opioid through interspecies extrapolation","authors":"Lina Zhong , Longjie Li , Qingfeng He , Xiao Zhu , Ping Xiang , Xiaoqiang Xiang , Hui Yan","doi":"10.1016/j.taap.2025.117352","DOIUrl":"10.1016/j.taap.2025.117352","url":null,"abstract":"<div><div>U-47700, a synthetic μ-opioid receptor agonist and emerging new psychoactive substance, poses critical public health risks due to its high abuse liability and fatal overdose potential. Ethical barriers prohibit clinical pharmacokinetic studies of such controlled substances, necessitating alternative approaches. Here, we developed the first physiologically based pharmacokinetic (PBPK) model for U-47700 by integrating <em>in vitro</em> experiments—including Caco-2 permeability, tissue-plasma partitioning, plasma protein binding, and human liver microsomal clearance. The rat PBPK model accurately predicted plasma concentration-time profiles across doses, and the metabolite's PBPK model was further established and validated to describe the kinetics of <em>N</em>-desmethyl-U-47700 and <em>N</em>,<em>N</em>-didesmethyl-U-47700. Human extrapolation <em>via</em> IVIVE (<em>in vitro-in vivo</em> extrapolation) and allometric scaling revealed rapid systemic clearance (0.944–1.371 L/h/kg). For illicit drugs like U-47700, where clinical trials are unfeasible, this PBPK framework bridges computational modeling, preclinical insights, and real-world evidence, offering a critical tool to decode pharmacokinetic curves, estimate administration timelines from postmortem samples, and assess polydrug interaction risks. By enabling mechanistic insights into synthetic opioid toxicity, this work informs overdose prevention strategies and mitigates the societal impact of high-risk designer drugs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117352"},"PeriodicalIF":3.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873461","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}

引用次数: 0

Solasodine inhibits the Th2 immune response and airway remodeling in asthmatic mice through the Runx3/NLRP3 pathway 索拉索定通过Runx3/NLRP3通路抑制哮喘小鼠Th2免疫反应和气道重塑

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-21 DOI: 10.1016/j.taap.2025.117351

Zhen Guo , Cuixiang Zhao , Yanni Fang , Xiuxuan Yue , Qiuxia Wang , Changhua Qu , Jinpeng Cui

{"title":"Solasodine inhibits the Th2 immune response and airway remodeling in asthmatic mice through the Runx3/NLRP3 pathway","authors":"Zhen Guo , Cuixiang Zhao , Yanni Fang , Xiuxuan Yue , Qiuxia Wang , Changhua Qu , Jinpeng Cui","doi":"10.1016/j.taap.2025.117351","DOIUrl":"10.1016/j.taap.2025.117351","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore the therapeutic effects of Solasodine on Th2 immune responses and airway remodeling, and to assess whether its mechanism involves NLRP3 inflammasome inactivation mediated by Runx3.</div></div><div><h3>Methods</h3><div>We created an asthma model with wild-type and Runx3 knockout mice using ovalbumin (OVA). After oral administration of Solasodine, we assessed inflammatory and Th2 immune responses using HE staining, ELISA, and flow cytometry. Airway remodeling was assessed with Masson's trichrome staining and α-SMA and TGF-β immunohistochemistry. Mucus secretion was analyzed through MUC5AC immunohistochemistry, and expectoration assays. We studied NLRP3 inflammasome activation using immunohistochemistry and Western blot. We used western blotting and flow cytometry to evaluate how Solasodine regulates Runx3 protein levels.</div></div><div><h3>Results</h3><div>Solasodine effectively inhibited the inflammatory response in OVA-induced asthmatic mice, evidenced by reducing inflammatory cell infiltration and lower IL-4, IL-5, and IL-13 levels, decreasing airway remodeling and mucus secretion. Solasodine reduced airway hyperresponsiveness, shown by a lower Penh value. Solasodine boosts Runx3 expression and suppresses NLRP3 inflammasome activation in asthmatic mice. We created an asthma model in Runx3 knockout mice and administered Solasodine at a consistent dose. Following OVA induction, Runx3 knockout mice showed greater inflammation, a Th2 immune response, airway remodeling, and mucus secretion than wild-type mice. Solasodine is less effective in Runx3 knockout asthmatic mice than in wild-type mice.</div></div><div><h3>Conclusion</h3><div>The anti-asthmatic effects of Solasodine are shown through the inhibition in the Th2 immune response, airway remodeling, hyperresponsiveness, and mucus secretion. The effectiveness may be linked to Runx3-mediated the NLRP3 inflammasomes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117351"},"PeriodicalIF":3.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882758","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}

引用次数: 0