Pub Date : 2025-12-29DOI: 10.1016/j.taap.2025.117698
Sangping Li, Shule Tan, Xiangsheng Tian, Yiquan Ou, Shujuan Hu, Weichao Zhao, Dingxin Long
This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin–eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe2+ levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.
{"title":"Resveratrol mitigates TOCP-induced spinal cord neurotoxicity by suppressing ferroptosis, a process mediated through the p62/Keap1/Nrf2 pathway","authors":"Sangping Li, Shule Tan, Xiangsheng Tian, Yiquan Ou, Shujuan Hu, Weichao Zhao, Dingxin Long","doi":"10.1016/j.taap.2025.117698","DOIUrl":"10.1016/j.taap.2025.117698","url":null,"abstract":"<div><div>This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin–eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe<sup>2+</sup> levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117698"},"PeriodicalIF":3.4,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878751","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}
Pub Date : 2025-12-27DOI: 10.1016/j.taap.2025.117695
Wonkyun Jung , Man S. Kim , Beom-Geon Kim , Sung-Min Hong , Sanghyeon Yu , Kanghyun Kwon , Mi-Jin Yang , Min Beom Heo , Ik Hwan Kwon , Seong-Jin Choi , Hyosun Choi , Ji Ae Lee , Eun-Jung Park
Microplastics have emerged as a major risk to human health. In this study, we dosed polystyrene nanoparticles (PS-NPs) via the pharynx for 90 days and assessed local and systemic toxicity. PS-NPs increased white blood cell counts and decreased blood potassium levels, and they were widely distributed in the lungs and hearts. The total count of pulmonary cells increased with dose, whereas the proportion of macrophages decreased. Levels of immune regulation-related cytokines increased markedly in the lungs of male and female mice exposed to PS-NPs, accompanied by infiltration of inflammatory cells and the aggregation of foamy macrophages. Collagen fiber-and lamellar body-like structures were notably observed in the lungs and hearts of PS-NP-treated mice, accompanied by elevations in both blood total cholesterol and pulmonary IL-11 levels. We also investigated cellular responses in alveolar macrophages (MH-S cells), bronchial epithelial cells (BEAS-2B), and cardiomyocytes (H9C2), which are considered primary target organs for inhaled PS-NPs. PS-NPs inhibited the proliferation of H9C2 cells but not that of BEAS-2B or MH-S cells. In addition, PS-NPs disrupted the expression of energy metabolism-related genes, including those involved in oxidative phosphorylation and respiratory electron transport, across all three cell types, inducing a proteotoxic stress response that involved both mitochondrial and endoplasmic reticulum stress. Based on these results, we propose that chronic inhalation of PS-NPs may lead to fibrotic lesions via immune dysregulation and energy metabolism dysfunction.
{"title":"Inhaled polystyrene nanoparticles may cause fibrotic lesions via immune dysregulation and energy metabolism disturbance","authors":"Wonkyun Jung , Man S. Kim , Beom-Geon Kim , Sung-Min Hong , Sanghyeon Yu , Kanghyun Kwon , Mi-Jin Yang , Min Beom Heo , Ik Hwan Kwon , Seong-Jin Choi , Hyosun Choi , Ji Ae Lee , Eun-Jung Park","doi":"10.1016/j.taap.2025.117695","DOIUrl":"10.1016/j.taap.2025.117695","url":null,"abstract":"<div><div>Microplastics have emerged as a major risk to human health. In this study, we dosed polystyrene nanoparticles (PS-NPs) via the pharynx for 90 days and assessed local and systemic toxicity. PS-NPs increased white blood cell counts and decreased blood potassium levels, and they were widely distributed in the lungs and hearts. The total count of pulmonary cells increased with dose, whereas the proportion of macrophages decreased. Levels of immune regulation-related cytokines increased markedly in the lungs of male and female mice exposed to PS-NPs, accompanied by infiltration of inflammatory cells and the aggregation of foamy macrophages. Collagen fiber-and lamellar body-like structures were notably observed in the lungs and hearts of PS-NP-treated mice, accompanied by elevations in both blood total cholesterol and pulmonary IL-11 levels. We also investigated cellular responses in alveolar macrophages (MH-S cells), bronchial epithelial cells (BEAS-2B), and cardiomyocytes (H9C2), which are considered primary target organs for inhaled PS-NPs. PS-NPs inhibited the proliferation of H9C2 cells but not that of BEAS-2B or MH-S cells. In addition, PS-NPs disrupted the expression of energy metabolism-related genes, including those involved in oxidative phosphorylation and respiratory electron transport, across all three cell types, inducing a proteotoxic stress response that involved both mitochondrial and endoplasmic reticulum stress. Based on these results, we propose that chronic inhalation of PS-NPs may lead to fibrotic lesions via immune dysregulation and energy metabolism dysfunction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117695"},"PeriodicalIF":3.4,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145858117","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}
Pub Date : 2025-12-24DOI: 10.1016/j.taap.2025.117696
Yanhong Jia , Jiangxia Pang , Chen Sun , Puyun Wang , Qianqian Huang , Xueyun Zhao , Dongming Zhang
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.
{"title":"Dapagliflozin regulates kynurenine metabolism and microglial activation to alleviate diabetes-associated cognitive impairment","authors":"Yanhong Jia , Jiangxia Pang , Chen Sun , Puyun Wang , Qianqian Huang , Xueyun Zhao , 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":"2025-12-24","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}
Pub Date : 2025-12-24DOI: 10.1016/j.taap.2025.117697
Maha M. Abdel-Fattah, Yasmeen M. Abozaid, Basim Anwar Shehata Messiha, Marwa M. Khalaf
Doxorubicin (DOX) is a powerful anthracycline utilized in the management of several malignant disorders, involving both solid and hematological tumors. Despite its effectiveness as cytotoxic agent, its therapeutic use is restricted as cardiac toxicity proportional to the drug dosage. Saxagliptin (SAXA) is a selective and potent member of the dipeptidyl peptidase (DPP)-IV inhibitor family utilized in the management of type two diabetes. It also possesses several biological actions, involving anti-inflammatory and antioxidant properties. This work sought to ascertain the underlying molecular mechanisms and determine the shielding role of SAXA against DOX-induced cardiotoxicity. Thirty-two rats were randomly assigned to four experimental groups, including a normal control group administered the vehicle only, a SAXA group receiving SAXA alone (10 mg/kg), a DOX control group receiving DOX (20 mg/kg) as a single dose, and a SAXA treatment group receiving SAXA plus DOX. Compared to DOX control group, pretreatment with SAXA (10 mg/kg) significantly reduced serum concentrations of CK-MB and CTnI by 37.11 % and 46.32 %, respectively, in addition to a marked improvement in the histopathological features of heart tissues. Moreover, SAXA significantly decreased MDA by 56.05 % and increased GSH and SOD in DOX-intoxicated rats by 493.28 % and 458.32 %, respectively. Additionally, western blot analysis revealed that SAXA pretreatment significantly down-regulated TLR-4 and NLRP3 by 34.9 % and 33.99 %, respectively. Furthermore, ELISA analysis showed that SAXA pretreatment significantly down-regulated NF-κB, caspase-1, and IL-1β by 44.04 %, 78.7 %, and 57.7 %, respectively. The findings of this study suggest that SAXA may exert a cardioprotective effect against DOX-induced toxicity, likely through its antioxidant and anti-inflammatory properties.
{"title":"Saxagliptin mitigates doxorubicin-induced cardiotoxicity by modulating NLRP3/caspase-1/IL-1β and TLR-4/NF-κB pathways","authors":"Maha M. Abdel-Fattah, Yasmeen M. Abozaid, Basim Anwar Shehata Messiha, Marwa M. Khalaf","doi":"10.1016/j.taap.2025.117697","DOIUrl":"10.1016/j.taap.2025.117697","url":null,"abstract":"<div><div>Doxorubicin (DOX) is a powerful anthracycline utilized in the management of several malignant disorders, involving both solid and hematological tumors. Despite its effectiveness as cytotoxic agent, its therapeutic use is restricted as cardiac toxicity proportional to the drug dosage. Saxagliptin (SAXA) is a selective and potent member of the dipeptidyl peptidase (DPP)-IV inhibitor family utilized in the management of type two diabetes. It also possesses several biological actions, involving anti-inflammatory and antioxidant properties. This work sought to ascertain the underlying molecular mechanisms and determine the shielding role of SAXA against DOX-induced cardiotoxicity. Thirty-two rats were randomly assigned to four experimental groups, including a normal control group administered the vehicle only, a SAXA group receiving SAXA alone (10 mg/kg), a DOX control group receiving DOX (20 mg/kg) as a single dose, and a SAXA treatment group receiving SAXA plus DOX. Compared to DOX control group, pretreatment with SAXA (10 mg/kg) significantly reduced serum concentrations of CK-MB and CTnI by 37.11 % and 46.32 %, respectively, in addition to a marked improvement in the histopathological features of heart tissues. Moreover, SAXA significantly decreased MDA by 56.05 % and increased GSH and SOD in DOX-intoxicated rats by 493.28 % and 458.32 %, respectively. Additionally, western blot analysis revealed that SAXA pretreatment significantly down-regulated TLR-4 and NLRP3 by 34.9 % and 33.99 %, respectively. Furthermore, ELISA analysis showed that SAXA pretreatment significantly down-regulated NF-κB, caspase-1, and IL-1β by 44.04 %, 78.7 %, and 57.7 %, respectively. The findings of this study suggest that SAXA may exert a cardioprotective effect against DOX-induced toxicity, likely through its antioxidant and anti-inflammatory properties.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117697"},"PeriodicalIF":3.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840717","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}
Pub Date : 2025-12-18DOI: 10.1016/j.taap.2025.117693
Yijia Su , Qiang Fu , Xilin Wu , Xianhua Che , Zhe Jiang , Xuezheng Li
Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited clinical treatment options. Shionone (SHI), a major active compound derived from Ligularia fischeri 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.
{"title":"Shionone ameliorates pulmonary fibrosis by activating mitophagy via PINK1-Parkin pathway","authors":"Yijia Su , Qiang Fu , Xilin Wu , Xianhua Che , Zhe Jiang , 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":"2025-12-18","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}
Pub Date : 2025-12-18DOI: 10.1016/j.taap.2025.117694
Sofia Jonasson, Åsa Gustafsson, Johanna Qvarnström, Marcus Carlsson, Nina Forsgren, Fredrik Ekström, Linda Elfsmark
Preclinical evaluation of oximes as antidotes for organophosphorus nerve agent (OPNAs) poisoning is predominantly based on protection ratio of the antidote against lethal doses. Developing protection indexes involves considerable animal distress and, due to the limited precision, requires large animal cohorts. This study aimed to establish an in vivo model for evaluating new therapeutic substances more aligned with the 3R principles that also enables detailed quantification of specific biological effects to better understand the impact of treatment.
Anesthetized Sprague-Dawley rats were tracheostomized and connected to a small animal ventilator allowing simultaneous registration of respiratory function. Rats were exposed to 1xLD50 VX or tabun, and progression of poisoning was monitored in real-time through measurements of respiratory resistance (RRS) over a 30-min period. Additional assessments included clinical symptoms and acetylcholine esterase (AChE) inhibition in blood. Pre-treatment with oxime (obidoxime, HI-6, RS194B) or atropine were used to validate the model.
Exposure to OPNAs resulted in rapid increases in RRS to 250–300 % above baseline. HI-6 and obidoxime were the most effective treatments, mitigating both respiratory and enzymatic effects of OPNA poisoning, while RS194B treatment delayed onset of symptoms but did not fully reverse toxicity. Tabun-inhibited AChE was generally more resistant to reactivation with oximes than VX- inhibited enzymes. The findings indicate that maintaining AChE activity above 15–20 % is sufficient to restore respiratory function and alleviate symptoms to levels comparable to unexposed controls.
This study highlights the value of high-sensitivity, real-time monitoring of physiological metrics like respiratory resistance in evaluating novel antidotes for OPNA poisoning.
{"title":"Establishment of a real-time monitored animal model to evaluate novel therapeutic strategies for organophosphorus nerve agent poisonings","authors":"Sofia Jonasson, Åsa Gustafsson, Johanna Qvarnström, Marcus Carlsson, Nina Forsgren, Fredrik Ekström, Linda Elfsmark","doi":"10.1016/j.taap.2025.117694","DOIUrl":"10.1016/j.taap.2025.117694","url":null,"abstract":"<div><div>Preclinical evaluation of oximes as antidotes for organophosphorus nerve agent (OPNAs) poisoning is predominantly based on protection ratio of the antidote against lethal doses. Developing protection indexes involves considerable animal distress and, due to the limited precision, requires large animal cohorts. This study aimed to establish an <em>in vivo</em> model for evaluating new therapeutic substances more aligned with the 3R principles that also enables detailed quantification of specific biological effects to better understand the impact of treatment.</div><div>Anesthetized Sprague-Dawley rats were tracheostomized and connected to a small animal ventilator allowing simultaneous registration of respiratory function. Rats were exposed to 1xLD<sub>50</sub> VX or tabun, and progression of poisoning was monitored in real-time through measurements of respiratory resistance (R<sub>RS</sub>) over a 30-min period. Additional assessments included clinical symptoms and acetylcholine esterase (AChE) inhibition in blood. Pre-treatment with oxime (obidoxime, HI-6, RS194B) or atropine were used to validate the model.</div><div>Exposure to OPNAs resulted in rapid increases in R<sub>RS</sub> to 250–300 % above baseline. HI-6 and obidoxime were the most effective treatments, mitigating both respiratory and enzymatic effects of OPNA poisoning, while RS194B treatment delayed onset of symptoms but did not fully reverse toxicity. Tabun-inhibited AChE was generally more resistant to reactivation with oximes than VX- inhibited enzymes. The findings indicate that maintaining AChE activity above 15–20 % is sufficient to restore respiratory function and alleviate symptoms to levels comparable to unexposed controls.</div><div>This study highlights the value of high-sensitivity, real-time monitoring of physiological metrics like respiratory resistance in evaluating novel antidotes for OPNA poisoning.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117694"},"PeriodicalIF":3.4,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800769","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}
Pub Date : 2025-12-15DOI: 10.1016/j.taap.2025.117692
Zhe Wang , Le-hao Jin , Ni-hong Pang , Jun-er Xu , Xiao-yu Xu , Wei Sun , Xiao-dan Zhang , Jian-chang Qian
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 (n = 3), cellular proliferation assays in CYP3A4-overexpressing A549 cells (n = 3), and pharmacokinetic studies in rats treated with CYP3A modulators (n = 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.
{"title":"CYP genetic polymorphism, and CYP3A inducers and inhibitors regulate apatinib metabolism: Consequences for drug exposure and toxicity risks","authors":"Zhe Wang , Le-hao Jin , Ni-hong Pang , Jun-er Xu , Xiao-yu Xu , Wei Sun , Xiao-dan Zhang , 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":"2025-12-15","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}
Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the Tripterygium wilfordii Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells in vitro and in vivo. Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.
{"title":"Celastrol delays the progression of hepatocellular carcinoma by suppressing SLC1A5-mediated glutamine dependence","authors":"Simeng Xiao , Yun Zhao , Zhiguo Chen , Yangkun Xiong , Dingmei Zhang , Gang Zhou , Cong Zhang","doi":"10.1016/j.taap.2025.117690","DOIUrl":"10.1016/j.taap.2025.117690","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the <em>Tripterygium wilfordii</em> Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells <em>in vitro</em> and <em>in vivo</em>. Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117690"},"PeriodicalIF":3.4,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769301","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}
Pub Date : 2025-12-14DOI: 10.1016/j.taap.2025.117691
Victor Enrique Sarmiento-Ortega , Diana Moroni-González , José Everardo Avelino-Cruz , Miguel Garcia-Gonzalez , Rubén Vázquez-Roque , Eduardo Brambila , Samuel Treviño
Cadmium (Cd) is an environmental pollutant increasingly linked to cardiovascular morbidity. While its toxic effects have been well documented at high doses, the impact of chronic exposure to the minimal risk level remains underexplored. This study aimed to investigate the mechanistic basis of Cadmium-induced cardiotoxicity at low doses and to evaluate the cardioprotective potential of pioglitazone, a PPARγ agonist with anti-inflammatory and antioxidant properties. Male Wistar rats were exposed chronically to Cd in drinking water (Cd, 15 mg/L) for 3 and 5 months, with or without pioglitazone co-treatment (2.5 mg/kg bw/day). Hemodynamic parameters, serum biomarkers (hs-TnI, NT-proBNP, sST2, IL-6, TNF-α), ventricular morphometry, histology, and activation of MAPK signaling (p-ERK1/2, p-JNK, p-p38) were evaluated. At 5 months, Cd exposure significantly increased systolic and diastolic blood pressure, hs-TnI, and NT-proBNP, without affecting CK-MB or hs-PCR. Structural changes included selective left ventricular hypertrophy, increased cardiomyocyte size, and elevated HW/BW and LVW/BW ratios. Cadmium also disrupted the IL-33/sST2 axis, elevating IL-6 and TNF-α, which indicates the presence of chronic inflammation. Mechanistically, Cd activated the MAPK pathway, with marked increases in p-p38 and p-JNK. Pioglitazone partially reversed these alterations by reducing inflammatory cytokines, restoring IL-33 levels, downregulating MAPK activation, and attenuating cardiac remodeling. Chronic exposure to the minimal risk of cadmium dosage induces subclinical yet progressive cardiotoxicity through inflammatory and MAPK-dependent pathways. Pioglitazone confers partial protection by modulating these mechanisms, underscoring its therapeutic potential in mitigating environmentally induced cardiovascular injury.
{"title":"Pioglitazone attenuates cardiovascular remodeling cadmium-induced through the MAPK pathway","authors":"Victor Enrique Sarmiento-Ortega , Diana Moroni-González , José Everardo Avelino-Cruz , Miguel Garcia-Gonzalez , Rubén Vázquez-Roque , Eduardo Brambila , Samuel Treviño","doi":"10.1016/j.taap.2025.117691","DOIUrl":"10.1016/j.taap.2025.117691","url":null,"abstract":"<div><div>Cadmium (Cd) is an environmental pollutant increasingly linked to cardiovascular morbidity. While its toxic effects have been well documented at high doses, the impact of chronic exposure to the minimal risk level remains underexplored. This study aimed to investigate the mechanistic basis of Cadmium-induced cardiotoxicity at low doses and to evaluate the cardioprotective potential of pioglitazone, a PPARγ agonist with anti-inflammatory and antioxidant properties. Male Wistar rats were exposed chronically to Cd in drinking water (Cd, 15 mg/L) for 3 and 5 months, with or without pioglitazone co-treatment (2.5 mg/kg bw/day). Hemodynamic parameters, serum biomarkers (hs-TnI, NT-proBNP, sST2, IL-6, TNF-α), ventricular morphometry, histology, and activation of MAPK signaling (p-ERK1/2, p-JNK, p-p38) were evaluated. At 5 months, Cd exposure significantly increased systolic and diastolic blood pressure, hs-TnI, and NT-proBNP, without affecting CK-MB or hs-PCR. Structural changes included selective left ventricular hypertrophy, increased cardiomyocyte size, and elevated HW/BW and LVW/BW ratios. Cadmium also disrupted the IL-33/sST2 axis, elevating IL-6 and TNF-α, which indicates the presence of chronic inflammation. Mechanistically, Cd activated the MAPK pathway, with marked increases in p-p38 and p-JNK. Pioglitazone partially reversed these alterations by reducing inflammatory cytokines, restoring IL-33 levels, downregulating MAPK activation, and attenuating cardiac remodeling. Chronic exposure to the minimal risk of cadmium dosage induces subclinical yet progressive cardiotoxicity through inflammatory and MAPK-dependent pathways. Pioglitazone confers partial protection by modulating these mechanisms, underscoring its therapeutic potential in mitigating environmentally induced cardiovascular injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117691"},"PeriodicalIF":3.4,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769304","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}
Pub Date : 2025-12-12DOI: 10.1016/j.taap.2025.117689
Mamata De, Ashley Fields, Guy Lagaud
{"title":"Corrigendum to \"Toxicokinetics and in vivo genotoxicity after single dose oral gavage and intravenous administration of N-Nitrosonornicotine in Sprague Dawley rats\" [Toxicology and Applied Pharmacology 505 (2025), 117572].","authors":"Mamata De, Ashley Fields, Guy Lagaud","doi":"10.1016/j.taap.2025.117689","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117689","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117689"},"PeriodicalIF":3.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757836","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号