Toxicology and applied pharmacology最新文献

{"title":"Comparison of alveolar macrophages senescence between cigarette smoke-exposed and naturally aged mice and the role of P2X7R in CS-induced airway inflammation.","authors":"Ping Huang, Xichen Pang, Zhe Wang, Xiaofeng Li, Tingting Zhang, Sha Huang, Lulu Zhang, Xinrui Qiao, Xiaoli Zeng, Xiaoju Liu","doi":"10.1016/j.taap.2026.118088","DOIUrl":"https://doi.org/10.1016/j.taap.2026.118088","url":null,"abstract":"<p><p>Aging is intricately linked to chronic obstructive pulmonary disease (COPD). Alveolar macrophages (AMs) senescence-induced impaired phagocytosis may contribute to persistent airway inflammation in COPD. The P2X7 receptor (P2X7R) is a crucial modulator of cellular senescence. However, its roles in AMs senescence and phagocytosis remain unclear. In this study, naturally aged mice, cigarette smoke (CS)-exposed mice, and MH-S cells stimulated by cigarette smoke extract (CSE) were used to compare the degree of AMs senescence and phagocytosis between CS-exposed and naturally aged mice, and to confirm the function and mechanism of P2X7R. Results showed that pulmonary function gradually declined, AMs senescence increased, and phagocytosis decreased with increasing age. CS-exposed mice exhibited similar levels of AMs senescence and impaired phagocytosis as aged mice, but more severe pulmonary dysfunction, histopathological damage, and airway inflammation. P2X7R was elevated in AMs from CS-exposed mice and CSE-treated MH-S cells. Mechanistically, the P2X7R antagonist A438079 reduced ROS levels and p-p38 MAPK, restored SIRT1 expression, and reduced Ac-NF-κB p65, thereby alleviating cellular senescence and impaired phagocytosis in CSE-treated MH-S cells. Tert-butyl hydroperoxide, a ROS inducer, can reverse the protective effects of A438079. In vivo, treatment with A438079 alleviates AMs senescence and impaired phagocytosis, and improves pulmonary dysfunction, histopathological damage, and airway inflammation in CS-exposed mice. In conclusion, our findings demonstrate that the degree of AMs senescence and impaired phagocytosis is similar between CS-exposed and aged mice. Furthermore, CS may induce AMs senescence and impaired phagocytosis via the P2X7R-mediated ROS/p38 MAPK/SIRT1/NF-κB pathway, thereby driving airway inflammation.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118088"},"PeriodicalIF":3.6,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228712","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":"Hyperthermia exacerbates methamphetamine cardiotoxicity by promoting neutrophil-dominant inflammation and Map3k6-associated p38/ERK signaling.","authors":"Congcong Hou, Xiang Li, Wenjing Zhang, Jiayin Wang, Zeying Guo, Pengli Sun, Miao Gao, Xin Ni, Zixu Wang, Di Wen, Chunling Ma","doi":"10.1016/j.taap.2026.118083","DOIUrl":"10.1016/j.taap.2026.118083","url":null,"abstract":"<p><p>Methamphetamine (METH) abuse is frequently accompanied by life-threatening hyperthermia, yet the contribution of hyperthermia to METH-induced cardiac injury remains poorly defined. Here, we tested whether elevated ambient temperature amplifies METH cardiotoxicity by aggravating hyperthermia. C57BL/6 mice were exposed to different ambient temperatures (18 °C, 22 °C, or 28 °C) and treated with METH. METH rapidly increased core body temperature, whereas exposure at 28 °C further intensified hyperthermia and caused 20% mortality. In surviving mice, METH at 28 °C significantly reduced cardiac function-including heart rate, cardiac output, stroke volume, ejection fraction and fractional shortening, and i induced myocardial eosinophilic degeneration, focal myofiber disruption, cardiomyocyte lysis and inflammatory cell infiltration. Cardiac transcriptomics revealed a distinct inflammatory program enriched for cytokine-cytokine receptor interaction, chemokine signaling, leukocyte chemotaxis and neutrophil migration. RT-qPCR confirmed increased cardiac expression of CCL2, CXCL1, ITGAM, ICAM-1 and MMP9, and inflammatory cytokines were also elevated. Immune-infiltration analysis identified prominent neutrophil accumulation, and gene-set enrichment analysis (GSEA) indicated activation of oxidative stress-related pathways. Among stress-related kinases, mitogen-activated protein kinase kinase kinase 6 (Map3k6, also known as ASK2) was upregulated and positively correlated with neutrophil-dominant infiltration and inflammatory markers. METH at 28 °C also increased p38 and extracellular signal-regulated kinase (ERK) phosphorylation. These findings identify elevated ambient temperature as a critical amplifier of METH-induced cardiac injury and implicate Map3k6-associated p38/ERK activation in hyperthermia-associated cardiac inflammation and functional impairment. Collectively, our results indicate that hyperthermia exacerbates METH cardiotoxicity, potentially involving Map3k6-associated p38/ERK signaling and neutrophil-dominant immune infiltration, providing new mechanistic insights into temperature-associated cardiac vulnerability following METH abuse.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118083"},"PeriodicalIF":3.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184431","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":"High Normal dietary casein attenuates bisphenol A-induced multiorgan toxicity in rats: Preservation of renal integrity, glucose homeostasis, and immune surveillance via modulation of oxidative stress, inflammation, and apoptosis.","authors":"Hend A Essa, Abeer E El-Metwally","doi":"10.1016/j.taap.2026.118085","DOIUrl":"https://doi.org/10.1016/j.taap.2026.118085","url":null,"abstract":"<p><p>Bisphenol A (BPA) causes multiorgan toxicity via oxidative stress, inflammation, and apoptosis, and the effect of nutritionally relevant elevation of casein intake is unknown. To evaluate whether a nutritionally relevant elevation of dietary casein (18% vs. 14%) attenuates BPA-induced multiorgan toxicity in rats, male Wistar rats were divided into four groups (n = 8/group) and treated for 35 days: control (14% casein), casein 18% alone, BPA (50 mg/kg/day +14% casein), and BPA + 18% casein. We measured oxidative and inflammatory markers, renal function, metabolic parameters, hematological parameters, histopathology and immunohistochemistry in kidney, spleen, and pancreas. BPA significantly increased malondialdehyde, interleukin-6, tumor necrosis factor-alpha, creatinine, kidney injury molecule-1, insulin resistance, white blood cells, neutrophils, and monocytes, and decreased reduced glutathione, glutathione S-transferase, superoxide dismutase, catalase, interleukin-4, serum soluble CD4 and CD8 protein levels, hemoglobin, red blood cells, platelets, and lymphocytes. BPA also caused renal tubular necrosis, splenic degeneration, pancreatic fibrosis, and upregulated caspase-3 and inducible nitric oxide synthase. Co-administration of 18% casein partially attenuated these effects, reducing malondialdehyde by 35-40%, creatinine by 40%, and insulin resistance by 53%, and restoring antioxidant enzymes and glucose tolerance. However, several parameters remained significantly different from controls. Nutritionally relevant elevation of casein (18%) provides significant partial protection against BPA-induced toxicity, supporting dietary protein modulation as a supportive strategy.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118085"},"PeriodicalIF":3.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184485","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":"Auriculasin induces LACTB expression to regulate colorectal cancer cell apoptosis, ferroptosis, invasion, and in vivo tumor growth.","authors":"Jia-Sheng Ke, Ling Zeng, Xiao-Jing Chen, Yi Qiu, Yu-Ze Wu, Jia-Bin Du, Zhong-Shi Hong, Chun-Xiao Wang","doi":"10.1016/j.taap.2026.118082","DOIUrl":"10.1016/j.taap.2026.118082","url":null,"abstract":"<p><p>Previous studies have found that auriculasin isolated from Flemingia philippinensis has a significant anticancer effect in colorectal cancer (CRC), but there are few studies on its mechanism. Treatment of CRC cells with auriculasin showed that auriculasin promoted LACTB expression in a dose-dependent manner, thereby enhancing reactive oxygen species (ROS) production and inhibiting cell viability. Auriculasin significantly enhanced CRC cell apoptosis and caspase-3/8/9 activities, and overexpression of LACTB also increased the caspase activities, but LACTB siRNA or N-acetyl-L-cysteine (NAC) significantly reduced the pro-apoptotic effects of auriculasin and LACTB. Auriculasin or LACTB overexpression significantly inhibited cell invasion, reducing the expression and secretion of matrix metalloproteinase (MMP)-2/9, while LACTB siRNA or NAC restored cell invasion levels. Auriculasin also significantly increased the levels of Fe²⁺ and malondialdehyde (MDA), and inhibited the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), but these effects were suppressed by LACTB siRNA; meanwhile, the inhibitory effects of auriculasin, LACTB overexpression and ferroptosis inducer erastin on cell viability could be blocked by the ferroptosis inhibitor ferrostatin-1 or LACTB siRNA, indicating that auriculasin induced ferroptosis through LACTB. Further xenograft mouse model (the most commonly used animal model for tumor research) also showed that auriculasin suppressed tumor growth, increased Fe²⁺ and MDA levels, and inhibited GPX4 and SLC7A11 expression, while LACTB knockdown restored tumor growth by reducing ferroptosis. Therefore, auriculasin enhances ROS production by inducing LACTB expression, thereby increasing apoptosis and ferroptosis, inhibiting cell invasion, and ultimately reducing tumor growth.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118082"},"PeriodicalIF":3.6,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170217","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":"Juglone induces GSDME-mediated pyroptosis by targeting HSP90α ATPase domain to promote STAT3 degradation in glioblastoma multiforme.","authors":"Hao-Di Wu, Shuai Chen, Jia-Wen Li, Liu-Tao Ma, Jia-Nan Ma, Yong-Ang Li, Ye Xiong, Yu-Jia Yang, Shi-Hao Chen, Jia-Yi Chen, Xue Wang, Peng Wang","doi":"10.1016/j.taap.2026.118070","DOIUrl":"https://doi.org/10.1016/j.taap.2026.118070","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly aggressive primary brain tumor with grim overall median survival, and its therapeutic efficacy is severely limited due to drug resistance. Therefore, developing effective and safe chemotherapy regimens is urgently required. Juglone, a natural bioactive constituent derived from traditional Chinese herbs, has emerged as a promising therapeutic agent against various human malignancies. However, the direct molecular target and the mechanisms against GBM remain poorly defined. Herein, we demonstrated that juglone exhibited anti-GBM activity both in vitro and in vivo by selectively inducing GSDME-mediated pyroptosis, but not canonical GSDMD-mediated pyroptosis. Genetic ablation of GSDME or pharmacological inhibition of caspase-3 significantly abolished juglone-elicited pyroptotic cell death. Mechanistically, juglone induced mitochondrial fission and subsequent mtROS production, which constituted a positive regulatory loop to initiate caspase-3/GSDME-mediated pyroptosis. Furthermore, combining network pharmacology, ATPase activity assay, cellular thermal shift assay (CETSA), and co-immunoprecipitation, we identified HSP90α as a direct binding target of juglone, with the binding interface localized to the ATP-binding pocket of HSP90α. Further mechanistic analysis revealed that juglone disrupted the HSP90α-STAT3 interaction, facilitating ubiquitin-proteasome-dependent STAT3 degradation and concurrently elevating oxidative stress. In summary, our study uncovered a regulatory axis linking juglone to the HSP90α/STAT3 signaling, which governs mtROS-driven pyroptosis in GBM cells. As a novel HSP90α ATPase inhibitor, juglone represents a promising natural therapeutic candidate for GBM intervention.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118070"},"PeriodicalIF":3.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to 'Low, but not high, dose triptolide controls neuroinflammation and improves behavioral deficits in toxic model of multiple sclerosis by dampening of NF-κB activation and acceleration of intrinsic myelin repair' [Toxicol. Appl. Pharmacol. 342 (2018), 86-98].","authors":"Nima Sanadgol, Fereshteh Golab, Ali Mostafaie, Mehdi Mehdizadeh, Roghayeh Khalseh, Mohammad Abdollahi, Gelareh Vakilzadeh, Ghorban Taghizadeh, Mohammad Sharifzadeh","doi":"10.1016/j.taap.2026.118078","DOIUrl":"10.1016/j.taap.2026.118078","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118078"},"PeriodicalIF":3.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148318","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":"Raloxifene suppresses chemically-induced oxidative hepatocyte injury in vitro and in vivo by targeting protein disulfide isomerase.","authors":"Xiangyu Hao, Yi-Chen Jia, Tian-Hao Xiao, Patricia Verina Pudji, Yong Xiao Yang, Bao Ting Zhu","doi":"10.1016/j.taap.2026.118074","DOIUrl":"10.1016/j.taap.2026.118074","url":null,"abstract":"<p><p>Ferroptosis, often characterized by glutathione depletion-associated oxidative stress and lipid peroxidation, contributes importantly to many pathological conditions, including drug-induced liver injury. Protein disulfide isomerase (PDI or PDIA1) has emerged as a pivotal upstream regulator of chemically-triggered ferroptosis and also an important therapeutic target. In this work, we identified raloxifene (RAL), a clinically-used selective estrogen receptor modulator, as a suppressor of chemically-induced oxidative ferroptosis and liver toxicity both in vitro and in vivo. Mechanistically, RAL can interact directly with PDI in both purified systems and cultured hepatocytes, leading to inhibition of its enzymatic activity. This inhibition decreases the dimerization (i.e., catalytic activation) of the inducible nitric oxide synthase (iNOS) and the subsequent buildup of cellular nitric oxide (NO), and these changes are associated with reduced accumulation of cellular reactive oxygen species, including lipid peroxides. RAL treatment markedly mitigates acetaminophen-evoked liver injury in vivo, as reflected by normalized serum enzyme levels, decreased lipid oxidative damage, and improved tissue morphology. Together, these results reveal that RAL can effectively limit oxidative ferroptotic injury in hepatocytes in both cellular and animal settings via its direct inhibition of PDI-mediated oxidative signaling cascade. The findings reveal a novel estrogen receptor-independent, PDI-targeted mechanism for the hepatoprotective actions of RAL, and also illustrate its promise for treating ferroptosis-associated liver injuries.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118074"},"PeriodicalIF":3.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115153","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":"Retraction notice to \"Apple polyphenol phloretin complexed with ruthenium is capable of reprogramming the breast cancer microenvironment through modulation of PI3K/Akt/mTOR/VEGF pathways\" [Toxicol. Appl. Pharmacol. 434 (2022) 115822].","authors":"Souvik Roy, Anil Kumar Mondru, Tania Chakraborty, Abhijit Das, Sandipan Dasgupta","doi":"10.1016/j.taap.2026.118051","DOIUrl":"10.1016/j.taap.2026.118051","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118051"},"PeriodicalIF":3.6,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Methcathinone disrupts glycerophospholipid metabolism and selectively activates the p38/COX-2 axis to induce anxiety-like behaviour in zebrafish\" [Toxicol. Appl. Pharmacol. 515 (2026) 117965].","authors":"Peng Gao, Yijia Zhou, Zihan Wang, Linrong Yin, Binjie Wang, Song Chian","doi":"10.1016/j.taap.2026.118048","DOIUrl":"10.1016/j.taap.2026.118048","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118048"},"PeriodicalIF":3.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026074","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":"Retraction notice to \"Paroxetine attenuates doxorubicin-induced cardiotoxicity: Integrated network pharmacology, molecular modeling, and in vivo evidence consistent with modulation of GRK2/iNOS-related pathways\" [Toxicol. Appl. Pharmacol. 513 (2026) 117864].","authors":"Mahmoud Nabil, Rasha Abdel-Ghany, Nader E Abo-Dya, Waleed Barakat, Mahmoud H Elbatreek","doi":"10.1016/j.taap.2026.118032","DOIUrl":"10.1016/j.taap.2026.118032","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"118032"},"PeriodicalIF":3.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971358","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}