Toxicology and applied pharmacology最新文献

{"title":"Repurposing of bithionol as a potential anxiolytic agent through NF-κB suppression: Insights from behavioural, biochemical, and molecular modelling studies","authors":"Kiran Satao ,&nbsp;Maheshkumar Borkar ,&nbsp;Angel Godad ,&nbsp;Gaurav Doshi","doi":"10.1016/j.taap.2025.117700","DOIUrl":"10.1016/j.taap.2025.117700","url":null,"abstract":"<div><div>Chronic stress activates neuroinflammatory responses through the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, rendering anxiety disorders the leading psychological disease. For the current investigation, an anxiety-related mouse model of restraint stress was adopted to analyse the potential anxiolytic activities of bithionol, a Food and Drug Administration (FDA) an approved anthelmintic drug. It is expected that bithionol should act through inhibiting the process of NF-κB activation, which reduces pro-inflammatory cytokines production. Three dosages of bithionol (25, 50, 100 mg/kg) were administered in male Swiss albino mice subjected to chronic restraint stress, of which diazepam served as the comparator anxiolytic. The behavioural tests, like the Marble Burying Test, Open Field Test (OFT), Elevated Plus Maze (EPM), Light and Dark Transition Screening test, were used for determining anxiety-like behaviours. Therapy with bithionol significantly reduced NF-κB, Tumor necrosis factor- alpha (TNF-α), as well as (Interleukin-1beta) IL-1β, while enhancing serotonin levels primarily at the highest dose of 100 mg/kg, as revealed through biochemical analysis of brain homogenates. These observations suggest that bithionol exhibits dose-dependent anxiolytic activity, possibly through suppression of the NF-κB pathway as well as neuroinflammatory reductions. Molecular modelling study has been performed to gain the insights of molecular level interactions between bithionol and NF-κB, TNF-α and IL-1β. Thus, the repurposing of bithionol for anxiety disorders is investigated.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117700"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878937","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":"Ghrelin-disrupting activity of arsenic and its relation to cardiometabolic diseases","authors":"Kamrun Nahar Rossi ,&nbsp;Faysal Abedin ,&nbsp;Nayan Chandra Mohanto ,&nbsp;Biplob Ahmed ,&nbsp;Sobuj Mia ,&nbsp;Nesar Uddin ,&nbsp;Rajoana Karim Rimi ,&nbsp;Osman Goni ,&nbsp;Sharon Jahan Sarder ,&nbsp;Sajib Hossain ,&nbsp;Mainul Islam ,&nbsp;Ahsanul Mahbub Jubayar ,&nbsp;Md Shofikul Islam ,&nbsp;Shakhawoat Hossain ,&nbsp;Md Ashraful Hoque ,&nbsp;Daigo Sumi ,&nbsp;Zahangir Alam Saud ,&nbsp;Seiichiro Himeno ,&nbsp;Khaled Hossain","doi":"10.1016/j.taap.2025.117676","DOIUrl":"10.1016/j.taap.2025.117676","url":null,"abstract":"<div><div>Arsenic (As) exposure is linked to a special type of obesity without increasing body mass index. This obesity is accompanied by the reduction of skeletal muscle mass and elevation of insulin resistance (IR). Obesity and IR are the key risk factors for cardiometabolic diseases (CMDs). Ghrelin, a small peptide hormone, is linked to CMDs through multiple mechanisms. However, the ghrelin-disrupting activity of As and its implication in the promotion of CMDs has not yet been documented. Therefore, this study was designed to explore the association of As exposure with serum ghrelin levels and its relation to the risk of CMDs, particularly obesity, skeletal muscle mass reduction, and IR in the participants (<em>n</em>=421) selected from low- and high-As exposure rural areas in Bangladesh. The participants in high-exposure areas had a significantly lower median interquartile range of serum ghrelin levels than those in low-exposure area. Serum ghrelin levels of the participants were decreased with increasing concentrations of As in drinking water, hair, and nails. Ghrelin levels were inversely linked to obesity measures related to As exposure, including waist circumference, triceps skinfold thickness, and serum leptin levels. Decreased ghrelin levels were associated with the reduction of muscle mass measures, serum creatinine levels, and lean body mass. Ghrelin levels were decreased with increasing levels of insulin and IR as assessed by HOMA-IR. Furthermore, As-related HOMA-IR was significantly mediated by lowering the ghrelin levels. These findings collectively indicated that the ghrelin-disrupting activity of As might be involved in the pathophysiology of As-promoted CMDs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117676"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696415","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":"Dapagliflozin regulates kynurenine metabolism and microglial activation to alleviate diabetes-associated cognitive impairment","authors":"Yanhong Jia ,&nbsp;Jiangxia Pang ,&nbsp;Chen Sun ,&nbsp;Puyun Wang ,&nbsp;Qianqian Huang ,&nbsp;Xueyun Zhao ,&nbsp;Dongming Zhang","doi":"10.1016/j.taap.2025.117696","DOIUrl":"10.1016/j.taap.2025.117696","url":null,"abstract":"<div><div>Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown significant therapeutic potential in alleviating Diabetes-associated cognitive dysfunction (DACD). However, its specific effects on microglia remain to be further explored. In this study, a type 2 diabetes mellitus (T2DM) mouse model induced by a high-fat diet/streptozotocin (HFD/STZ) was used. It was found that dapagliflozin could significantly reduce fasting blood glucose levels, alleviate weight loss, and improve cognitive function performance in behavioral tests (Y-maze, Morris water maze, and novel object recognition). Histological and biochemical analyses indicated that dapagliflozin could reduce hippocampal neuronal damage, enhance antioxidant capacity (manifested as increased levels of superoxide dismutase and catalase, and decreased malondialdehyde content), and effectively inhibit neuroinflammation (significantly reduced levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6). Transcriptomic and metabolomic analyses revealed that dapagliflozin rebalanced the kynurenine pathway by down-regulating indoleamine 2,3-dioxygenase (IDO1) and kynurenine monooxygenase (KMO), while up-regulating kynurenic acid transaminase 1 (KYAT1), promoting the transformation of metabolic products from neurotoxic substances (such as 3-hydroxykynurenine and kynurenic acid) to neuroprotective substances (kynurenic acid). Additionally, in vitro experiments in high glucose (HG)-stimulated BV-2 microglia further verified that dapagliflozin exerted anti-inflammatory effects by inhibiting the Toll-like receptor/myeloid differentiation factor 88 (TLR/MyD88) signaling pathway and regulating kynurenine metabolic reprogramming. At the same time, overexpression of KMO reversed these effects. In conclusion, these results reveal the multi-dimensional neuroprotective mechanisms of dapagliflozin in DACD, providing substantial evidence for its potential as a therapeutic agent for diabetes-related cognitive dysfunction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117696"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844312","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":"Akkermansia muciniphila enhances the antitumour efficacy of αPD-1 therapy in gastric cancer by remodelling the tumour immune microenvironment","authors":"Ziyi Yang ,&nbsp;Lanfan Liang ,&nbsp;Xin Li ,&nbsp;Xizhen Peng ,&nbsp;Xinyi Qian ,&nbsp;Zehua Huang ,&nbsp;Xi Wang ,&nbsp;Qing Hu ,&nbsp;Xiangsheng Fu","doi":"10.1016/j.taap.2026.117711","DOIUrl":"10.1016/j.taap.2026.117711","url":null,"abstract":"<div><div>There is growing advocacy for employing probiotics as adjuncts to potentiate immune checkpoint blockade (ICB) in cancer therapy. In this study, we investigated whether the probiotic <em>Akkermansia muciniphila</em> (<em>A. muciniphila</em>) could enhance the antitumour responses to anti-PD-1 (αPD-1) in gastric cancer (GC) by reshaping the tumour microenvironment (TME). A subcutaneous GC model was established in male strain 615 mice by inoculating 1 × 10⁶ Mouse Forestomach Carcinoma (MFC) cells on Day 10. <em>A. muciniphila</em> was given by daily oral gavage (1 × 10⁹ CFU per mouse) from Day 0 to Day 31, and the αPD-1 antibody was administered intraperitoneally (100 μg per mouse) every 3 days from Day 16 to Day 31. Tumour volume was recorded every 3 days, and tumours were collected on Day 31 for histology, flow cytometry, enzyme-linked immunosorbent assay (ELISA), 16S rRNA sequencing and statistical analyses. Combined treatment with <em>A. muciniphila</em> and αPD-1 significantly inhibited subcutaneous tumour growth (<em>P</em> &lt; 0.0001) and promoted tumour cell apoptosis (<em>P</em> &lt; 0.0001). <em>A. muciniphila</em> increased the therapeutic effectiveness of αPD-1 treatment by driving CD8⁺ T-cell accumulation within the TME (<em>P</em> &lt; 0.0001). Supplementation with <em>A. muciniphila</em> reshaped the leading constituents of the gut microbiota and was associated with a significant fall in the relative abundance of <em>Escherichia coli</em> (<em>E. coli</em>) (<em>P</em> = 0.0170). By driving CD8⁺ T-cell infiltration and activation and reshaping the intestinal microbiota, <em>A. muciniphila</em> augmented the efficacy of αPD-1 therapy against gastric tumours.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117711"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948828","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":"Norcantharidin inhibits the EZH2-mediated JAK2/STAT3 signaling pathway to inhibit the proliferation of non-small cell lung cancer","authors":"Shuang Wu ,&nbsp;Wei Zhang","doi":"10.1016/j.taap.2026.117714","DOIUrl":"10.1016/j.taap.2026.117714","url":null,"abstract":"<div><h3>Objective</h3><div>The purpose of this study was firstly to investigate the anti-tumor effects of NCTD on NSCLC cell proliferation, apoptosis, migration, and invasion. Secondly, it aimed to explore whether these effects were associated with the modulation of the EZH2/JAK2/STAT3 signaling axis.</div></div><div><h3>Methods</h3><div>This study employed a series of in vitro experiments, including CCK-8, Edu staining, colony formation, flow cytometry, and Transwell assays, to evaluate the effects of NCTD on the proliferation, apoptosis, migration, and invasion of NSCLC cells. The in vivo anti-tumor efficacy was evaluated using an A549 xenograft mouse model. Underlying mechanisms were explored via western blot and genetic perturbation (knockdown and overexpression) of EZH2.</div></div><div><h3>Results</h3><div>The results of the in vitro experiments demonstrated that NCTD significantly inhibited NSCLC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Furthermore, NCTD effectively suppressed tumor growth in the xenograft mouse model. The molecular mechanism study revealed that NCTD treatment was associated with downregulation of EZH2 and concomitant suppression of JAK2/STAT3 phosphorylation and activation of the JAK2/STAT3 signaling pathway. Genetic knockdown of EZH2 mimicked the anti-tumor effects of NCTD, whereas overexpression of EZH2 partially reversed its efficacy.</div></div><div><h3>Conclusion</h3><div>The anti-tumor activity of NCTD is associated with the downregulation of EZH2 protein expression and concomitant inhibition of the JAK2/STAT3 signaling pathway. These findings provide novel insights into the molecular mechanisms underlying NCTD's anti-tumor activity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117714"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953076","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":"Targeting sonic hedgehog (shh) signaling pathways by the concentration–dependent topical resveratrol for protection from cyclophosphamide-induced alopecia in a mouse model","authors":"Aml A. El-Din,&nbsp;Dina M. Tahoon,&nbsp;Maaly A. Abd Elmaaboud,&nbsp;Fleur F. Abd Elmoniem,&nbsp;Amany A. Abdin","doi":"10.1016/j.taap.2025.117681","DOIUrl":"10.1016/j.taap.2025.117681","url":null,"abstract":"<div><h3>Background</h3><div>Chemotherapy-induced alopecia (CIA) is a common and inevitable side effect of systemic cancer treatment. There is an urgent need for novel therapies for cancer patients suffering from hair loss to improve their quality of life. This study aimed to investigate the potential protective effect of concentration-dependent topical resveratrol on hair follicles via targeting sonic hedgehog (Shh) signaling and its related downstream regulatory (Sirt-1), proliferative (Ki-67), and apoptotic status (caspase-3 and Bcl-2) pathways in cyclophosphamide-induced alopecia in female C57BL/6 mice model. Methods: All animals were subjected to depilation at the start of the experiment, then mice were divided into 5 equal groups as follows: Control group, cyclophosphamide (CPA)-untreated alopecia group, minoxidil (MXL) + CPA-alopecia, Resveratrol low concentration (RSV L10) + CPA-alopecia, Resveratrol high concentration (RSV H80) + CPA-alopecia. The effects of these drugs on hair coverage score, Shh signaling, Sirt-1, proliferation, and apoptosis were assessed. Results: Low concentration of topical RSV showed a significant increase in hair coverage score. Shh, Sirt-1, immunohistochemical expression levels of Ki-67, and Bcl-2 were significantly elevated, significantly decreasing caspase-3 expression in skin tissue. Moreover, the superiority extended to include histopathological findings and dermatoscopic skin monitoring compared to the groups that received either topical minoxidil 2 % or RSV at high concentration. Conclusion: Topical low-dose resveratrol protects against CIA by activating Shh signaling and modulating follicular proliferative and apoptotic pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117681"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726284","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":"Shionone ameliorates pulmonary fibrosis by activating mitophagy via PINK1-Parkin pathway","authors":"Yijia Su ,&nbsp;Qiang Fu ,&nbsp;Xilin Wu ,&nbsp;Xianhua Che ,&nbsp;Zhe Jiang ,&nbsp;Xuezheng Li","doi":"10.1016/j.taap.2025.117693","DOIUrl":"10.1016/j.taap.2025.117693","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited clinical treatment options. Shionone (SHI), a major active compound derived from <em>Ligularia fischeri</em> Turcz (LF), has shown pharmacological potential; however, its mechanism of action against PF remains unclear. This study investigates the anti-fibrotic effects and underlying pathways of SHI using a bleomycin (BLM)-induced PF mouse model and a Transforming Growth Factor-β (TGF-β)-stimulated A549 cell model. The results demonstrate that SHI treatment markedly alleviates BLM-induced alveolar damage, collagen accumulation, and inflammatory responses, while significantly improving survival rates in mice. At the molecular level, SHI activates the PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy pathway, leading to increased expression of autophagy-related proteins such as LC3II/LC3I and Beclin1, decreased levels of p62 and pro-fibrotic markers, enhanced clearance of dysfunctional mitochondria, restoration of mitochondrial membrane potential (MMP), and reduction of reactive oxygen species (ROS) accumulation. In vitro experiments further confirm that SHI inhibits fibrosis in TGF-β-challenged A549 cells through the same mechanism. This study is the first to elucidate that SHI mitigates PF by regulating mitophagy, offering a promising therapeutic target and potential drug candidate for PF. Future research may focus on optimizing the clinical application strategies of SHI.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117693"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791017","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":"Effects of prenatal DINP exposure induced hepatic steatosis and underlying mechanism","authors":"Yahui Jin ,&nbsp;Junli Zhao ,&nbsp;Xinjing Wang ,&nbsp;Dan Li ,&nbsp;Meiqiong Wu ,&nbsp;Ben Li","doi":"10.1016/j.taap.2026.117707","DOIUrl":"10.1016/j.taap.2026.117707","url":null,"abstract":"<div><div>Prenatal exposure to diisononyl phthalate (DINP) exerts sex-specific effects on offspring liver lipid metabolism, yet the underlying mechanisms remain insufficiently defined. In this study, pregnant mice were administered DINP throughout gestation, and offspring were evaluated through growth assessment, liver histopathology, lipid profiling, hepatic gene expression, and fecal metabolomics to investigate potential gut–liver axis involvement. Maternal weight and food intake were unaffected, whereas offspring exhibited growth retardation and developmental delay. Male offspring showed elevated serum and hepatic triglycerides and total cholesterol, accompanied by marked hepatic steatosis, while females displayed milder lipid deposition.</div><div>Mechanistic analyses indicated that males exhibited impaired fatty acid oxidation, with upregulation of fatty acid binding protein (FABP) and perilipin 2 (PLIN2) and downregulation of peroxisome proliferator-activated receptor alpha (PPARα). In contrast, females maintained fatty acid β-oxidation through increased carnitine palmitoyltransferase-1a (CPT-1A) expression and lipid regulation mediated by peroxisome proliferator-activated receptor gamma (PPARγ). Fecal metabolomics revealed alterations in α-linolenic acid metabolism and ubiquinone biosynthesis in males, suggesting disrupted fatty acid utilization and mitochondrial function contributing to hepatic lipid accumulation. Female offspring primarily showed alterations in glycerophospholipid metabolism, which may facilitate membrane remodeling and lipid redistribution, thereby mitigating steatosis.</div><div>In summary, prenatal DINPexposure induces hepatic steatosis through sex-specific disruptions of the gut–liver metabolic axis. Males are more susceptible to lipid accumulation, whereas females exhibit compensatory adaptations that preserve metabolic balance. These findings provide mechanistic insight into the sex-dependent metabolic consequences of early-life DINP exposure and support a more comprehensive evaluation of its safety profile.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117707"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906713","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":"CYP genetic polymorphism, and CYP3A inducers and inhibitors regulate apatinib metabolism: Consequences for drug exposure and toxicity risks","authors":"Zhe Wang ,&nbsp;Le-hao Jin ,&nbsp;Ni-hong Pang ,&nbsp;Jun-er Xu ,&nbsp;Xiao-yu Xu ,&nbsp;Wei Sun ,&nbsp;Xiao-dan Zhang ,&nbsp;Jian-chang Qian","doi":"10.1016/j.taap.2025.117692","DOIUrl":"10.1016/j.taap.2025.117692","url":null,"abstract":"<div><div>Apatinib is a tyrosine kinase inhibitor metabolized by hepatic cytochromes P450 (CYPs). This study investigated how CYP genetic variations affect apatinib metabolism and response. We employed a multi-scale approach including enzyme kinetic studies with recombinant human CYP variants (<em>n</em> = 3), cellular proliferation assays in CYP3A4-overexpressing A549 cells (n = 3), and pharmacokinetic studies in rats treated with CYP3A modulators (<em>n</em> = 6 per group). CYP3A4*18, CYP2D6*10, and CYP2C9*3 variants showed markedly reduced metabolic activity. CYP3A4*18 overexpression enhanced apatinib's anti-proliferative effect in A549 cells. In rats, dexamethasone decreased apatinib exposure by inducing CYP3A expression, while ketoconazole increased exposure without altering CYP3A levels. Both CYP genetic polymorphisms and drug interactions significantly influence apatinib metabolism, highlighting the importance of personalized dosing strategies for optimizing therapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117692"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775941","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":"miR-207 mitigates silica-induced pulmonary fibrosis by suppressing fibroblast-to-Myofibroblast transition via multi-target modulation of the TGF-β1/SMADs signaling pathways in mice","authors":"Shu-ling Du ,&nbsp;Yuan-yuan Cui ,&nbsp;Xuan Zhou ,&nbsp;Wei-Lei Gong ,&nbsp;Zhao-qiang Zhang ,&nbsp;Gui-zhi Han","doi":"10.1016/j.taap.2025.117661","DOIUrl":"10.1016/j.taap.2025.117661","url":null,"abstract":"<div><div>TGF-β1/SMADs signaling pathway plays a vital role in development of silicosis, with SMADs serving as the core transducers. Accordingly, any fluctuation in SMAD abundance can decisively steer the disease trajectory. Our previous research revealed miR-207 suppresses the progression of silicosis fibrosis by targeting Smad3. Further bioinformatic analysis suggested that miR-207 could also bind to the sequences of genes of Smad2 and Smad7, raising the possibility that miR-207 functions as a coordinated rheostat of multiple SMADs. However, the specific regulatory mechanisms of miR-207 in silicosis remains unexplored. In this study, a mouse model of silicosis was established by administering a silica suspension (20 μg/μL, 80 μL) via nasal drip daily for 16 days. On day 17, the silica–dusted mice were transfected with either miR-207 mimics or inhibitors. Lungs samples were harvested on day 45 for histological assessment of injury. Then, the expression levels of miR-207, Smad2, and Smad7 were determined using RT-qPCR, and the levels of SMAD2 and 7, Collagen I and III, and indicators of fibroblast-to-myofibroblast transdifferentiation (FMT) (α-SMA, FAP-1, and Vimentin) were determined using Western blot. The results showed that miR-207 coordinately downregulated SMAD2 and upregulated SMAD7 at both the mRNA and protein levels in silica-exposed mice, with concomitant reductions in FMT indicators (α-SMA, FAP-1 and Vimentin) and collagen levels. Therefore, we concluded that miR-207 suppresses silicosis progression in mice by inhibiting FMT via modulation of the TGF-β1/SMADs signaling pathway by targeting SMADs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117661"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145639846","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}