Toxicology and applied pharmacology最新文献

OAT1/3 regulate the absorption of CP-25 in the rat synovium ooat1 /3调节大鼠滑膜对CP-25的吸收

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-05-04 DOI: 10.1016/j.taap.2025.117371

Jinzhang Gao , Wei Sun , Lei Ni , Qingqing Sun , Jiangrui Cheng , Ning Xiao , Feng Xiao , Wei Wei , Chun Wang

{"title":"OAT1/3 regulate the absorption of CP-25 in the rat synovium","authors":"Jinzhang Gao , Wei Sun , Lei Ni , Qingqing Sun , Jiangrui Cheng , Ning Xiao , Feng Xiao , Wei Wei , Chun Wang","doi":"10.1016/j.taap.2025.117371","DOIUrl":"10.1016/j.taap.2025.117371","url":null,"abstract":"<div><div>Paeoniflorin-6’-O-benzene sulfonate (CP-25) is a new ester derivative formed by esterification of paeoniflorin. We found that CP-25 inhibits the abnormal proliferation and migration of inflammatory fibroblast-like synoviocytes (FLS). However, the mechanism by which CP-25 is absorbed by FLS remains unclear. Therefore, we established a UPLC–MS/MS methodology to study the mechanism of CP-25 uptake by FLS. Our research revealed that the uptake of CP-25 by rat FLS was time- and concentration-dependent and that the concentration of CP-25 reached a dynamic equilibrium after approximately 60 min. A glucose-free environment, a low-temperature environment or the inhibition of ATP synthesis significantly reduced the absorption of CP-25 by FLS. Furthermore, we confirmed through siRNA interference and overexpression through transient transfection that organic anion transporter (OAT)1/3 play a major role in the process of active uptake of CP-25 by FLS. Additionally, we validated the absorption of CP-25 mediated by OAT1/3 in the synovia with OAT1/3 substrates and inhibitors. Moreover, the absorption of CP-25 by FLS from adjuvant arthritis rats and rheumatoid arthritis patients was significantly lower than that by FLS from normal rats and normal individuals. Taken together, our data suggested that CP-25 is absorbed by FLS through an active transport process, which is mediated primarily by OAT1/3. This study provides an experimental and theoretical basis for further exploration of the molecular mechanism involved.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117371"},"PeriodicalIF":3.3,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907154","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

The synthetic opioid isotonitazene induces locomotor activity and reward effects through modulation of the central dopaminergic system in mice 合成阿片样物质异戊二烯通过调节中枢多巴胺能系统诱导小鼠运动活动和奖励效应

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-05-03 DOI: 10.1016/j.taap.2025.117361

Ken-ichi Tomiyama , Masahiko Funada

{"title":"The synthetic opioid isotonitazene induces locomotor activity and reward effects through modulation of the central dopaminergic system in mice","authors":"Ken-ichi Tomiyama , Masahiko Funada","doi":"10.1016/j.taap.2025.117361","DOIUrl":"10.1016/j.taap.2025.117361","url":null,"abstract":"<div><div>Synthetic opioids, which differ from fentanyl, have recently emerged as new psychoactive substances and pose public health concerns. The pharmacological effects and drug dependency of these benzimidazole-based opioids, also known as nitazenes, remain unclear. In this study, we examined the selectivity of opioid receptors, effects on motor activity, and expression of reward effects for isotonitazene, which has been detected in many poisonings and fatalities since 2019. Isotonitazene was most selective for the μ-receptor and exhibited more potent agonist effects, with an EC<sub>50</sub> of 0.02 nM, than morphine (EC<sub>50</sub> = 34 nM) and fentanyl (EC<sub>50</sub> = 4.0 nM). In ICR mice, isotonitazene (up to 0.05 mg/kg) increased the locomotor activity in a dose-dependent manner. This effect was significantly suppressed by pretreatment with the opioid receptor antagonists naloxone (3 mg/kg) and β-FNA (1 mg/kg), the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg), and dopamine D2 receptor antagonist raclopride (6 mg/kg). The reward effects of isotonitazene, evaluated using conditioned place preference (CPP) in mice, showed that conditioning with isotonitazene produced significant dose-dependent CPP scores. Microdialysis analysis also confirmed that the isotonitazene dose that induced CPP (0.05 mg/kg) significantly increased dopamine levels in the nucleus accumbens of mice. These results suggest that isotonitazene, similar to fentanyl and morphine, is a compound with a high risk of forming drug dependence and reward effects via the dopaminergic nervous system. This study provides foundational data for biological evaluation of other nitazene compounds.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"500 ","pages":"Article 117361"},"PeriodicalIF":3.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904412","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

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

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

Mechanistic and metabolic exploration of neohesperidin against lung cancer cell lines through ROS-mediated mitochondrial apoptosis: An in-silico and in-vitro approach 新橙皮苷通过ros介导的线粒体凋亡对抗肺癌细胞系的机制和代谢探索：一种计算机和体外方法

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-17 DOI: 10.1016/j.taap.2025.117350

Ruchi Pandey , Khushboo Choudhary , Surendra Rajit Prasad , Pranesh Kumar , Priya Bisht , Dande Aishwarya , Pallaprolu Nikhil , Sachindra Kumar , Ramalingam Peraman , Nitesh Kumar

{"title":"Mechanistic and metabolic exploration of neohesperidin against lung cancer cell lines through ROS-mediated mitochondrial apoptosis: An in-silico and in-vitro approach","authors":"Ruchi Pandey , Khushboo Choudhary , Surendra Rajit Prasad , Pranesh Kumar , Priya Bisht , Dande Aishwarya , Pallaprolu Nikhil , Sachindra Kumar , Ramalingam Peraman , Nitesh Kumar","doi":"10.1016/j.taap.2025.117350","DOIUrl":"10.1016/j.taap.2025.117350","url":null,"abstract":"<div><div>Lung cancer is a significant contributor to global mortality rates in the human population. However, the results of current treatment options are still unsatisfactory. Thus, the study explores low-toxic natural substances that release caspases and trigger apoptosis. Neohesperidin (NHP), a flavonoid, has anticancer efficacy although its molecular mechanism is unknown. In the current work, through <em>in-silico</em> and in-vitro screening, we discovered that NHP significantly reduces the expression of x-linked inhibitor of apoptosis protein (xIAP) and ATP on its administration, leading to apoptosis in human and mice lung (A549 and LLC-1) cancerous cells. Furthermore, NHP promoted the production of second-mitochondria-derived-activator-of-caspase (SMAC) and triggers mitochondrial dysfunction which also promotes apoptosis (51.1 %) as well as necrosis (25.8 %). This mechanism is regulated by mitochondria-mediated (Bax and Bcl-2) caspases-dependent apoptotic and ROS mediated pathway which increases SMAC expression by 21.2 % along with lowering the xIAP level (by 36.5 %). Moreover, network pharmacology was utilized to delineate the interactions of the compounds within biological networks, emphasizing their potential to target multiple pathways. In addition, we investigated the alterations in metabolites within A549 cells caused by NHP using liquid-chromatography-high-resolution-mass-spectrometry (LC-HRMS)-based metabolomics. The results revealed perturbations in metabolomes that are involved in multiple pathways. Therefore, this study indicates that NHP is a potential therapeutic agent to mitigate and control the proliferation of lung cancer and also regulates the energy metabolism.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117350"},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852032","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

Impact of spinal anesthesia on myocardial damage, ultrastructure and cellular mechanisms in rats undergoing thoracic incision surgery 脊髓麻醉对胸椎切口大鼠心肌损伤、超微结构及细胞机制的影响

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-17 DOI: 10.1016/j.taap.2025.117349

Tsun-Jui Liu , Vanita Shih , Yueh-Chiao Yeh , Wen-Lieng Lee , Li-Chuan Wang , Hui-Chin Lai

{"title":"Impact of spinal anesthesia on myocardial damage, ultrastructure and cellular mechanisms in rats undergoing thoracic incision surgery","authors":"Tsun-Jui Liu , Vanita Shih , Yueh-Chiao Yeh , Wen-Lieng Lee , Li-Chuan Wang , Hui-Chin Lai","doi":"10.1016/j.taap.2025.117349","DOIUrl":"10.1016/j.taap.2025.117349","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to investigate the impact of surgery on cardiac injury and microscopic ultrastructural changes in the heart, as well as the potential protective cellular mechanisms of spinal anesthesia.</div></div><div><h3>Methods</h3><div>Male Sprague-Dawley rats were randomly assigned to four groups: Control (regular rats), Sham (received spinal saline injection), Surgery (received spinal saline followed by surgery) and Bupivacaine (received spinal bupivacaine 0.5 %, 50 μL followed by surgery), and Bupivacaine (received spinal bupivacaine 0.5 %, 50 μL followed by surgery). The serum and hearts of the rats were assessed for troponin I, NT-proBNP, electron microscopy, catecholamines, markers of oxidative stress and endoplasmic reticulum stress, as well as apoptosis and autophagy.</div></div><div><h3>Results</h3><div>After surgery, the hearts showed signs of injury, with decreased tissue troponin I and elevated NT-proBNP levels. Electron microscopy revealed mitochondrial swelling, disarrangement and cytosolic vacuoles. Serum epinephrine levels and expression of β1 and β2 adrenergic receptors were elevated. Serum nitrate and nitrite levels (markers of oxidative stress), along with the ER stress indicator GRP78 and autophagy indicators LC3 and LAMP-1, were heightened, and cardiomyocyte apoptosis increased. These effects can be mitigated with the use of spinal bupivacaine.</div></div><div><h3>Conclusions</h3><div>Surgery can cause ultrastructural and cellular damage, elevate sympathetic activity, oxidative stress, and endoplasmic reticulum stress, leading to autophagy and cardiomyocyte apoptosis. Spinal anesthesia can protect the heart from these injuries.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117349"},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850688","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

H3K9/18 lactylation regulates DNA damage due to nickel exposure in human bronchial epithelial cells H3K9/18乳酸化调节人支气管上皮细胞镍暴露引起的DNA损伤

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-16 DOI: 10.1016/j.taap.2025.117347

Xiaomin Xie , Chaowei Wen , Quekun Peng , Daimin Xiang , Xinyi Pan , Xinmei Lan , Zijian Chen , Xiaohui Hua , Guiying Wang , Chuanshu Huang

{"title":"H3K9/18 lactylation regulates DNA damage due to nickel exposure in human bronchial epithelial cells","authors":"Xiaomin Xie , Chaowei Wen , Quekun Peng , Daimin Xiang , Xinyi Pan , Xinmei Lan , Zijian Chen , Xiaohui Hua , Guiying Wang , Chuanshu Huang","doi":"10.1016/j.taap.2025.117347","DOIUrl":"10.1016/j.taap.2025.117347","url":null,"abstract":"<div><div>Nickel, a well-known heavy metal with lung carcinogenic properties, is recognized for its effects on cellular metabolism, oxidative stress, and gene expression. While these cellular alterations have prompted investigations into its potential impact on histone modifications, specific associations with histone lactylation remain under exploration. In the present study, we demonstrate that nickel exposure induces lactylation of histone H3 at lysines 9 (H3K9) and 18 (H3K18), accompanied by reactive oxygen species (ROS) accumulation and DNA damage in human bronchial epithelial Beas-2B cells. Inhibition of H3K9 and H3K18 lactylation, achieved by overexpressing mutated H3K9R and H3K18R, respectively, markedly abolishes ROS generation and DNA damage caused by nickel exposure. This highlights the novel biological effects of H3K9 and H3K18 lactylation in nickel-induced lung toxicity. Mechanistic investigations show that nickel-induced lactylation of H3K9 and H3K18 is mediated by elevated LDHA expression, leading to lactate accumulation, which results from the upregulation of <em>LDHA</em> mRNA transcription through HIF-1α/c-Jun axis and enhanced LDHA protein stability <em>via</em> TNF-α-mediated induction of HSP70, respectively. Our findings uncover a novel effect of nickel exposure on histone H3 lactylation and its biological impact on ROS accumulation and DNA damage through the HIF-1α/c-Jun/LDHA and TNF-α/HSP70/LDHA pathways. These results provide significant insights into the role of histone lactylation in heavy metal-induced lung toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117347"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854756","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

Demethylzeylasteral inhibits osteosarcoma cell proliferation by regulating METTL17-mediated mitochondrial oxidative phosphorylation 去甲基化zeylastal通过调节mettl17介导的线粒体氧化磷酸化抑制骨肉瘤细胞增殖

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-04-16 DOI: 10.1016/j.taap.2025.117348

Jingyu Cao , Haotian Zhang , Chengbo Wang , Lihua He , Ya Li , Zimeng Wang , Xianxiao Li , Faisal Aziz , Minglei Yang , Xiangzhan Zhu

{"title":"Demethylzeylasteral inhibits osteosarcoma cell proliferation by regulating METTL17-mediated mitochondrial oxidative phosphorylation","authors":"Jingyu Cao , Haotian Zhang , Chengbo Wang , Lihua He , Ya Li , Zimeng Wang , Xianxiao Li , Faisal Aziz , Minglei Yang , Xiangzhan Zhu","doi":"10.1016/j.taap.2025.117348","DOIUrl":"10.1016/j.taap.2025.117348","url":null,"abstract":"<div><h3>Abstract</h3><div>Osteosarcoma (OS) represents the most common primary bone malignancy, characterized by substantial disability and mortality, thereby underscoring the critical need for more effective therapeutic interventions to improve clinical outcomes. Demethylzeylasteral (DEM) is a bio-active compound has been reported for its anti-tumor properties through various mechanisms. Nonetheless, the specific effects of DEM on OS have yet to be fully elucidated. This study demonstrated that DEM significantly inhibited OS cell proliferation both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, DEM impairs mitochondrial OXPHOS by targeting METTL17, a known regulator of mitochondrial translation, resulting in reduced ATP production. Subsequent investigations revealed that METTL17 knockdown exerts potent anti-tumor effects in OS, significantly suppressing both <em>in vitro</em> cell proliferation and <em>in vivo</em> xenograft tumor growth. Furthermore, METL17 overexpression significantly alleviated the inhibitory effects of DEM on cell proliferation, while restoring ATP production and oxygen consumption rates. These findings suggest that DEM impedes OS growth by inducing mitochondrial dysfunction through targeting METTL17, thereby highlighting a novel therapeutic strategy and potential molecular target for OS treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"499 ","pages":"Article 117348"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852344","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}

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