Toxicology and applied pharmacology最新文献

{"title":"Systematic evaluation of Tox21 compounds that target β-adrenergic receptors and their role in cardiotoxicity","authors":"Xi Luo ,&nbsp;Li Zhang ,&nbsp;Srilatha Sakamuru ,&nbsp;Precious A. Adesina ,&nbsp;Jinghua Zhao ,&nbsp;Menghang Xia ,&nbsp;Tuan Xu ,&nbsp;Deborah K. Ngan ,&nbsp;Jameson Travers ,&nbsp;Savannah Wood ,&nbsp;Ray Sukhawanit ,&nbsp;Anthony Garrison ,&nbsp;Carleen Klumpp-Thomas ,&nbsp;Stephen S. Ferguson ,&nbsp;Hu Zhu ,&nbsp;Matthew D. Hall ,&nbsp;David M. Reif ,&nbsp;Ruili Huang","doi":"10.1016/j.taap.2025.117567","DOIUrl":"10.1016/j.taap.2025.117567","url":null,"abstract":"<div><div>β-adrenergic receptors play important roles in heart failure and drug-induced cardiotoxicity (DICT). The Tox21 10 K library of drugs and environmental chemicals have been tested for their activity against β-adrenergic receptor subtypes 1 and 2 (ADRB1 and ADRB2), as well as inhibition of the human ether-à-go-go-related gene (hERG) in a quantitative high-throughput screening (qHTS) format. In this study, the Tox21 compound activity profiles in the ADRB1/2 and hERG assays were compared in relation to their DICT potential. The results showed that compounds that acted as ADRB1 agonists, ADRB2 antagonists, or hERG inhibitors were more likely to exhibit DICT. The ADRB1 and ADRB2 assays shared similar compound activity profiles, while the hERG inhibition assay identified a distinct set of active compounds. In addition, we identified structural features that may differentiate the cardiotoxic and non-toxic ADRB1 agonists. Finally, machine learning models were developed for ADRB1 activity prediction based on chemical structure. The models were used to virtually screen a collection of approximately 360 K diverse compounds, with the highest-ranked compounds selected for experimental validation. This work represents the first systematic study of drugs and environmental chemicals against ADRB1/2, providing important insights into β-adrenergic receptor-related cardiotoxicity mechanisms. By clarifying how specific pharmacological interactions contribute to cardiac risk, it provides a framework for early cardiotoxicity prediction and the design of safer therapeutics through integrated profiling and modeling.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117567"},"PeriodicalIF":3.4,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076155","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":"Preclinical safety and toxicokinetic evaluation of TJ0113, a first-in-class mitophagy inducer for Parkinson's disease","authors":"Yanan Tian ,&nbsp;Fengqi Wang ,&nbsp;Jikai Shen ,&nbsp;Ruiqi Zhang ,&nbsp;Qianwen Chen ,&nbsp;Le Xu ,&nbsp;Dong Liu ,&nbsp;Mengyang Fan ,&nbsp;Zhen Tian ,&nbsp;Xufeng Cen ,&nbsp;Xiaoyan Xu ,&nbsp;Hongguang Xia","doi":"10.1016/j.taap.2025.117565","DOIUrl":"10.1016/j.taap.2025.117565","url":null,"abstract":"<div><div>Mitochondrial dysfunction is a key driver of neurodegeneration, highlighting mitophagy as a tractable therapeutic axis. Yet the clinical translation of mitophagy-targeting agents requires robust, GLP-compliant nonclinical safety data to support and de-risk human trials in line with international guidelines. TJ0113, a first-in-class small-molecule inducer of mitophagy, has shown disease-modifying activity in preclinical models and is being evaluated in a registered, randomized, double-blind, placebo-controlled Phase II trial in Parkinson's disease (<span><span>NCT06596005</span><svg><path></path></svg></span>). We conducted a comprehensive safety assessment of TJ0113 in Sprague–Dawley rats and Beagle dogs under GLP. Single-dose studies (up to 1500 mg/kg, oral) and repeat-dose studies (rats: 15, 30, 100 mg/kg/day for 26 weeks; dogs: 6, 20, 60 mg/kg/day for 39 weeks) evaluated systemic toxicity, toxicokinetics (TK), safety pharmacology endpoints (including ECG), and a standard genotoxicity battery (Ames, chromosomal aberration, micronucleus) consistent with ICH S2(R1). No treatment-related mortality or target-organ toxicity occurred. A modest increase in relative kidney organ coefficient in rats was observed but without biochemical or histopathological correlates and was considered non-adverse. Clinical pathology, ECG, and dog urinalysis remained within physiological limits; all genotoxicity tests were negative. TK showed rapid absorption with linear, dose-proportional exposure and no accumulation at the end of dosing. The NOAELs were 100 mg/kg/day in rats (26 weeks) and 60 mg/kg/day in dogs (39 weeks). These data establish a favorable nonclinical safety profile for TJ0113 and provide GLP evidence supporting further clinical development of this selective mitophagy-targeting agent.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117565"},"PeriodicalIF":3.4,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070553","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":"Berberine alleviates acute embolism-induced lung inflammation and injury by suppressing miR-22-5p expression and modulating the TLR4/NF-κB signaling pathway","authors":"Shimo Shen ,&nbsp;Biao Yan ,&nbsp;You Li ,&nbsp;Jingbo Jiang","doi":"10.1016/j.taap.2025.117563","DOIUrl":"10.1016/j.taap.2025.117563","url":null,"abstract":"<div><h3>Context</h3><div>Acute pulmonary embolism (APE) caused by blood clotting in pulmonary arteries triggers lung microvascular leakage and inflammation. While APE significantly affects right ventricular function, the associated lung injury and inflammation mechanisms remain understudied. Berberine has been established as an effective anti-inflammatory compound in traditional medicine.</div></div><div><h3>Objective</h3><div>To investigate whether berberine can prevent APE-associated inflammation and pulmonary hypertension, potentially facilitating thrombus resolution in pulmonary arteries.</div></div><div><h3>Materials &amp; methods</h3><div>We employed pulmonary artery smooth muscle cells (PASMCs) treated with platelet-derived growth factor (PDGF) as an in vitro pulmonary embolism model and Sprague-Dawley rats treated with blood clot suspension as an in vivo model. Berberine treatment, miR-22-5p modulation and toll-like receptor (TLR4) overexpression were performed to elucidate the underlying mechanisms.</div></div><div><h3>Results</h3><div>Berberine treatment attenuated PDGF-induced proliferation of PASMCs in a dose-dependent manner. In the APE model, berberine administration significantly reduced elevated right ventricular systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP) while alleviating lung inflammation. Berberine treatment downregulated miR-22-5p expression in lung tissue, whereas miR-22-5p overexpression in lungs exacerbated lung inflammation responses. Conversely, miR-22-5p inhibition attenuated lung inflammation and hypertension status. Moreover, miR-22-5p overexpression increased the protein levels of TLR4 and nuclear factor kappa B (NF-κB), whereas miR-22-5p inhibition reduced them. Berberine treatment decreased the levels of miR-22-5p, TLR4, and NF-κB, while TLR4 overexpression reversed the beneficial effects of berberine treatment.</div></div><div><h3>Discussion and conclusion</h3><div>Our findings suggest that berberine treatment prevents pulmonary hypertension and lung inflammation associated with APE through inhibition of the miR-22-5p/TLR4/NF-κB signaling pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117563"},"PeriodicalIF":3.4,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070508","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":"17-Methoxyl-7-hydroxy-benzene-furanchalcone improves mitochondrial biogenesis and oxidative stress following myocardial ischemia/reperfusion injury through the AMPK/SIRT1 pathway based on network pharmacology","authors":"Yuanheng Huang ,&nbsp;Yan Zhou ,&nbsp;Qiuhua Qin ,&nbsp;Sirui Mo ,&nbsp;Zudong Xu ,&nbsp;Zhiwei Tang ,&nbsp;Yaosheng Wu ,&nbsp;Feizhang Qin","doi":"10.1016/j.taap.2025.117560","DOIUrl":"10.1016/j.taap.2025.117560","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial biogenesis and oxidative stress are pivotal in myocardial ischemia/reperfusion (I/R) injury. 17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) has been shown to significantly protect mitochondria during myocardial I/R injury. However, the potential mechanisms involved remain unknown. This study aimed to investigate the impact of MHBFC on myocardial I/R injury through network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.</div></div><div><h3>Methods and results</h3><div>A rat I/R model was developed by inducing 1 h of coronary occlusion followed by 3 h of reperfusion. It was found that MHBFC significantly ameliorated cardiac function, reduced infarct size and cardiac enzymes, and increased the copy number of mitochondrial DNA and ATP production. MHBFC exposure also significantly elevated antioxidant enzyme activity and suppressed ROS production. Network pharmacology analysis identified that core targets of MHBFC associated with myocardial I/R injury were significantly enriched in the adenosine 5′-monophosphate activated protein kinase (AMPK)/silent mating type information regulation 2 homolog-1 (SIRT1) signaling pathway. Molecular docking analyses showed the strong binding of MHBFC with AMPK and SIRT1. Molecular dynamics simulation verified the stability of the docked complex. Western blot analysis confirmed that MHBFC activated the AMPK/SIRT1 pathway, and its protective effects were further validated in hypoxia/reoxygenation-.</div><div>treated H9c2 cardiomyocytes.</div></div><div><h3>Conclusion</h3><div>The study concludes that MHBFC mitigates myocardial I/R injury by improving mitochondrial biogenesis and oxidative stress through activation of the AMPK/SIRT1 pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117560"},"PeriodicalIF":3.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065532","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":"Dual activation of AhR and Nrf2 pathways by the natural stilbenoid tapinarof protects against particulate matter-induced skin barrier dysfunction","authors":"Chia-Hsuan Lin ,&nbsp;Horng-Huey Ko ,&nbsp;Jin-Ye Wu ,&nbsp;Hsun-Shuo Chang ,&nbsp;Chia-Hung Yen ,&nbsp;Chien-Chih Chiu ,&nbsp;Yih-Fung Chen","doi":"10.1016/j.taap.2025.117559","DOIUrl":"10.1016/j.taap.2025.117559","url":null,"abstract":"<div><div>Particulate matter (PM) causes skin barrier dysfunction by inducing reactive oxygen species (ROS) overproduction and oxidative stress. The aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor (Nrf2) coordinate xenobiotic metabolism and antioxidant defense, respectively, playing key roles in cytoprotection. This study aimed to investigate the therapeutic potential of tapinarof, a natural stilbenoid dually activating AhR and Nrf2 pathways, against PM-induced epidermal damage. Human keratinocyte HaCaT cells were exposed to urban dust PM (NIST® SRM® 1649b) to model PM-induced epidermal damage. An image-based analysis algorithm that eliminates PM fluorescence interference was developed, prompting the use of alternative wavelengths for specifically analyzing PM-induced cellular responses. Tapinarof potentiated PM-induced CYP1A1 and HO-1 expression, confirming AhR/Nrf2 activation. This dual pathway activation protected cells from PM-induced oxidative stress and cell death, as validated using the AhR antagonist, CH223191, and Nrf2 inhibitor, brusatol. Confocal imaging and immunoblotting suggested that tapinarof preserved PM-damaged epidermal barrier integrity by restoring the delocalization of tight junction protein ZO-1 and adherens junction complex E-cadherin/β-catenin and maintaining expressions of cornified envelope protein filaggrin. Dual activation of AhR/Nrf2 pathways effectively protects against PM-induced epidermal barrier dysfunction, highlighting the therapeutic potential of naturally derived dual AhR/Nrf2 activators like tapinarof against environmental skin damage.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117559"},"PeriodicalIF":3.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058637","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":"Differential cannabinoid-like effects, receptor affinity and physiologically based pharmacokinetics of the synthetic cannabinoids 4F-MDMB-BINACA, 4F-MDMB-BICA and 5F-MDMB-PICA in mice: A comparative study","authors":"Yawen Xu ,&nbsp;Simeng Zhang ,&nbsp;Xuesong Shi ,&nbsp;Lixin Kuai ,&nbsp;Yuanyuan Chen ,&nbsp;Kaixi Li ,&nbsp;Xiangyu Li ,&nbsp;Yanling Qiao ,&nbsp;Dan Wang ,&nbsp;Cheng Jiang ,&nbsp;Peng Xu","doi":"10.1016/j.taap.2025.117549","DOIUrl":"10.1016/j.taap.2025.117549","url":null,"abstract":"<div><div>Synthetic cannabinoid receptor agonists (SCRAs) 4F-MDMB-BINACA, 4F-MDMB-BICA, and 5F-MDMB-PICA share a “tail” group but differ in indazole/indole cores and N-fluoroalkyl chain lengths (C4 vs. C5). However, the impact of these structural variations on cannabimimetic potency and the influence of the inhalational abuse route remain unclear. This study integrated behavioural profiling, receptor binding analysis, and pharmacokinetic modelling to address these gaps. ICR mice were administered the three SCRAs via inhalation or intraperitoneal (i.p.) injection, and cannabinoid “tetrad effects” (analgesia, hypothermia, catalepsy, locomotor suppression) were quantified. Surface plasmon resonance (SPR) was used to determine CB₁/CB₂ receptor binding specificities, while physiologically based pharmacokinetic (PBPK) models predicted tissue/brain distribution. Results showed that after i.p. administration, the ED₅₀ rank for tetrad effects of four cannabinoid tetrad effects was 5F-MDMB-PICA ≈ 4F-MDMB-BINACA &lt;4F-MDMB-BICA, consistent with CB₁ affinity (K_D: 7.772 × 10⁻⁶, 8.468 × 10⁻⁵, and 7.599 × 10⁻⁵ M, respectively). Inhalation reversed the hierarchy for analgesia and hypothermia to 5F-MDMB-PICA &lt;4F-MDMB-BICA &lt;4F-MDMB-BINACA, with 4F-MDMB-BICA showing enhanced relative potency that offsets its lower CB₁ affinity. ADMET predictions indicated 5F-MDMB-PICA had the highest risk score, with greater lipophilicity, longer half-life, and extensive brain accumulation. These findings demonstrate that minimal structural changes and administration route profoundly alter SCRAs potency, refining structure-activity relationships and informing route-specific risk assessment strategies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117549"},"PeriodicalIF":3.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058672","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":"Vanadyl sulfate supplementation alters the intestinal microbiome and bile acid metabolism","authors":"Xiaojia He ,&nbsp;Kristine K. Dennis ,&nbsp;Zachery R. Jarrell ,&nbsp;ViLinh Tran Ly,&nbsp;Young-Mi Go,&nbsp;Dean P. Jones","doi":"10.1016/j.taap.2025.117548","DOIUrl":"10.1016/j.taap.2025.117548","url":null,"abstract":"<div><div>Less than 10 μg/kg body weight (BW) vanadium (V) is consumed daily by humans in their diet and drinking water. V in the form of vanadyl sulfate (V⁺⁴) is promoted as an over-the-counter supplement with anti-diabetic effects and is consumed by some individuals at up to 200 μg/kg BW per day in dietary supplements. The impact of long-term consumption of high-dose V supplements on intestinal microbial communities and intestinal metabolomics is not known. This project tested the hypothesis that long-term intake of high-dose supplemental vanadyl sulfate alters the intestinal microbiome and metabolome in mice. In this study, four-week-old C57BL/6 J female mice were fed standard mouse food and provided V⁺⁴ (0.02, 0.2, 2 mg/L in drinking water) or control drinking water (0 μg V⁺⁴/d) for 6 months. Cecal contents were analyzed with 16S rRNA microbiome sequencing and liquid chromatography-high-resolution mass spectrometry. Biostatistics, bioinformatics, community detection, and metabolic pathway enrichment analysis were used to characterize vanadyl sulfate-dependent changes to the cecal microbiome and metabolome. Pathway analysis of metabolomics data identified alterations to bile acid metabolism, likely by altering reabsorption, and inflammatory pathways including arachidonic acid and linoleate metabolism. Bile acids including cholic acid, chenodeoxycholic acid/deoxycholic acid, and lithocholic acid were decreased in V⁺⁴-treated animals. In addition, altered arachidonic acid levels associated with inflammatory pathways were observed. Integrated microbiome-metabolome analysis identified unique communities with inflammation-related metabolites as well as metabolites and microbes linked to bile acid metabolism. In summary, chronic high-dose V⁺⁴ exposure at levels similar to human dietary supplement use altered bile acid metabolism and inflammatory pathways and resulted in compositional changes to the microbiome.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117548"},"PeriodicalIF":3.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058692","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":"Cardiorespiratory failure and sudden death induced by carfentanil exposure: Involvement of central mu1 opioid receptors","authors":"Xiuping Gao,&nbsp;Jianguo Zhuang,&nbsp;Shan Shi,&nbsp;Zikuan Chen,&nbsp;Fadi Xu","doi":"10.1016/j.taap.2025.117550","DOIUrl":"10.1016/j.taap.2025.117550","url":null,"abstract":"<div><div>Inhalation of aerosolized carfentanil (CRF) could result in death, but the relevant mechanisms remain unclear. To establish a model of CRF-induced death, we recorded cardiorespiratory activities in rats placed in a double-chamber plethysmograph. CRF exposure (10.0 mg/m³ for 15 min) failed to cause death in any of the tested female rats (0/8), but induced death in 3/8 of the male rats. CRF exposure decreased ventilation (60 %) and heart rate (25 %) within the first 5 min exposure, which was maintained to the end of the experiment and dissipated on the next day in the surviving rats. In contrast, ventilatory depression and bradycardia were suddenly aggravated 45 min after the onset of CRF exposure, which led to ventilatory and cardiac arrest within the following 15 min in the dead rats. Subsequently, the cardiorespiratory responses were recorded in male rats after the following pretreatment: a) naloxone (NLX) and b) naloxone methiodide (NLM) to systemically and peripherally block opioid receptors (ORs) respectively; and c) β-funaltrexamine (β-FNA) and d) naloxonazine (NLZ) to systemically antagonize both mu1 and mu2 opioid receptors (mu1Rs and mu2Rs) and only mu1Rs respectively. NLX blocked all cardiorespiratory responses, while NLM only slightly attenuated the initial V_E depression. β-FNA and NLZ nearly blocked V_E depression with little impact on bradycardia. All antagonists, except NLM, prevented CRF-caused death. In conclusion, our results establish a rat model of CRF exposure-induced cardiorespiratory failure and sudden death and reveal a key role of central ORs, especially mu1Rs, in the genesis of the cardiorespiratory failure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117550"},"PeriodicalIF":3.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145047603","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":"Toxicological assessment of diphenyl ether using adult zebrafish and human lymphocytes: Biochemical, genotoxic, cytotoxic, histopathological and ultrastructural analysis","authors":"Shiv Kumar ,&nbsp;Pallvi Thapar ,&nbsp;Anupam Kaur ,&nbsp;Pooja Chadha","doi":"10.1016/j.taap.2025.117552","DOIUrl":"10.1016/j.taap.2025.117552","url":null,"abstract":"<div><div>In the present investigation, the toxicological impact of diphenyl ether (DE) was assessed in gills and blood of adult zebrafish through biochemical, genotoxic, histopathological and ultrastructural analysis. Moreover, in human lymphocytes, toxic effects of DE were evaluated using <em>in vitro</em> assays such as chromosomal aberration and cytokinesis-block micronucleus (CBMN) assay. The exposure concentrations of DE used for the toxicity assessment were 2.13 mg/L (¼ LC₅₀) and 4.25 mg/L (½ LC₅₀) for zebrafish as well as human lymphocytes. Significant changes in the biochemical parameters such as SOD, GST, AChE activity and MDA levels were reported after DE exposure in zebrafish gill. The olive tail moment (OTM) was found to be significantly increased in gill and blood cells of DE exposed zebrafish. The MN assay revealed significantly elevated frequency of erythrocytic cytoplasmic abnormalities (ECA), erythrocytic nuclear abnormalities (ENA) and micronuclei (MN) in the DE exposed zebrafish. Various types of histopathological alterations were reported in gill tissue of zebrafish exposed to DE which were further confirmed through SEM analysis. The SEM analysis of erythrocytes of zebrafish exposed to DE revealed the morphological alterations such as irregular shaped erythrocytes with irregular boundaries, swollen erythrocytes <em>etc.</em> Moreover, <em>In vitro</em> assay such as chromosomal aberration assay showed the different types alterations such as polyploidy, satellite association, telomeric association and chromosomal breakage in human blood cells exposed to DE. Different kinds of abnormalities such as multiple nucleated cells, late apoptotic cells, micronucleated cells <em>etc.</em> were reported after DE exposure to human lymphocytes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117552"},"PeriodicalIF":3.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145055859","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":"Paeoniflorin attenuates hyperprolactinemia by targeting the pituitary mPRα-mediated, dopamine receptor-independent signaling in vivo and in vitro","authors":"Bingqi Lin ,&nbsp;Yun Yi ,&nbsp;Xiaolan Mo ,&nbsp;Yifan Yang ,&nbsp;Yuhao Li ,&nbsp;Chunxia Wang ,&nbsp;Yuanyi Wei","doi":"10.1016/j.taap.2025.117551","DOIUrl":"10.1016/j.taap.2025.117551","url":null,"abstract":"<div><div>Although dopamine receptor agonists are the primary therapies for prolactinoma and hyperprolactinemia, a population of patients are resistant or intolerant. Our previous findings have suggested that paeoniflorin, a major active ingredient contained in some frequently-used traditional Chinese formulas for hyperprolactinemia-related disorders, inhibits prolactin secretion via both dopamine receptor-dependent and independent pathways. Here, it was found that paeoniflorin ameliorated the antipsychotic olanzapine-induced hyperprolactinemia in rats and suppressed prolactin protein expression in GH3 rat pituitary tumor cells lacking dopamine receptor. Further, paeoniflorin suppressed olanzapine-induced overexpression of prolactin and estrogen receptor (ER) α proteins, but it reversed the downregulated protein expression of membrane progesterone receptor (mPR) α both in the pituitary of the rats and in GH3 cells. Network pharmacology analysis predicted that mPRα served as a core therapeutic target of paeoniflorin in hyperprolactinemia, with the transforming growth factor (TGF) β signaling pathway potentially mediating this pharmacological interaction. Molecular docking predicted that paeoniflorin interacted with mPRα. Silencing mPRα abolished paeoniflorin-mediated suppression of prolactin expression, confirming its essential role in mediating the effects of paeoniflorin. In addition, paeoniflorin upregulated TGFβ1 and downregulated ERα in an mPRα-dependent manner. Notably, ERα overexpression reversed inhibition of paeoniflorin on prolactin, while TGFβ1 inhibition attenuated the effect of paeoniflorin on ERα, highlighting the critical contributions of TGFβ1 and ERα to this regulatory pathway. Thus, our results in vivo and in vitro suggest that paeoniflorin attenuates hyperprolactinemia by targeting the pituitary mPRα-mediated, dopamine receptor-independent signaling, in which, TGFβ1 and ERα participate.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117551"},"PeriodicalIF":3.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145055872","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}