Pub Date : 2025-11-17DOI: 10.1016/j.taap.2025.117648
Hyewon Jang , Wonhyoung Park , Hee Seung Kim , Gwonhwa Song , Whasun Lim , Sunwoo Park
Thymol, a phenolic monoterpene derivative found in the essential oil of Thymus vulgaris L., Lamiaceae, is currently under investigation for potential applications in pharmaceuticals, functional foods, and cosmetics. Despite ongoing research in these areas, the potential therapeutic effects of thymol on endometriosis remain unconfirmed. Endometriosis, characterized by the growth of endometrial tissue outside the uterus. Available treatment options, including medications and surgery, have limitations and are no curative. To address these limitations, our study aimed to explore the therapeutic potential of thymol in endometriosis, through simultaneous in vitro and in vivo investigations. Our results indicate that thymol induces antioxidant activity and regulate intracellular calcium ions. Further thymol administration reduced the size of endometriosis lesions in animal models and modulated immune responses, resulting in alterations in spleen populations of CD4+ T and CD8+ T cells and macrophages, as well as changes in the expression of cytokine-related genes. Overall, our findings suggest that thymol holds promise as a therapeutic agent for endometriosis.
{"title":"Endometriosis lesion growth inhibition and immune modulation function of thymol in vitro and in vivo","authors":"Hyewon Jang , Wonhyoung Park , Hee Seung Kim , Gwonhwa Song , Whasun Lim , Sunwoo Park","doi":"10.1016/j.taap.2025.117648","DOIUrl":"10.1016/j.taap.2025.117648","url":null,"abstract":"<div><div>Thymol, a phenolic monoterpene derivative found in the essential oil of <em>Thymus vulgaris L., Lamiaceae</em>, is currently under investigation for potential applications in pharmaceuticals, functional foods, and cosmetics. Despite ongoing research in these areas, the potential therapeutic effects of thymol on endometriosis remain unconfirmed. Endometriosis, characterized by the growth of endometrial tissue outside the uterus. Available treatment options, including medications and surgery, have limitations and are no curative. To address these limitations, our study aimed to explore the therapeutic potential of thymol in endometriosis, through simultaneous in vitro and in vivo investigations. Our results indicate that thymol induces antioxidant activity and regulate intracellular calcium ions. Further thymol administration reduced the size of endometriosis lesions in animal models and modulated immune responses, resulting in alterations in spleen populations of CD4<sup>+</sup> T and CD8<sup>+</sup> T cells and macrophages, as well as changes in the expression of cytokine-related genes. Overall, our findings suggest that thymol holds promise as a therapeutic agent for endometriosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117648"},"PeriodicalIF":3.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557939","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 : 2025-11-17DOI: 10.1016/j.taap.2025.117647
Lin Fu , Lichang Chen , Xianru Peng , Changyun Yang , Jiamin Sun , Zemin Chen , Sudan Gan , Shiyue Li , Haixiong Tang , Yidan Lin , Lihong Yao
E-cadherin is a critical adheren junctional protein for maintaining airway epithelial integrity. Downregulation of E-cadherin is commonly seen in asthma. Mammalian target of rapamycin (mTOR), a central regulator of metabolism, is implicated in asthma pathogenesis. This study was aimed to elucidate the role of mTOR signaling pathway on airway epithelial E-cadherin dysfunction in toluene diisocyanate (TDI)-induced asthma. Male BALB/c mice and in vitro cultured airway epithelial cell line BEAS-2B were exposed to TDI for modeling, and treated with rapamycin, an inhibitor of the mTOR signaling. We observed increased phosphorylation of mTOR and its downstream molecule p70s6k in TDI-exposed mice and cultured epithelia, indicating activation of mTOR signaling. In vivo, treatment with rapamycin dramatically alleviated TDI-induced airway hyperreactivity, decreased airway neutrophilia and eosinophilia, and suppressed the release of IL-4, IL-5 and IL-17 in the bronchoalveolar lavage fluid (BALF), suggesting a central role for mTOR in the development of TDI-induced asthma. Moreover, the TDI-induced downregulated E-cadherin expression in the lung was also significantly recovered by rapamycin, accompanied by less production of soluble E-cadherin (sE-cadherin), which is a marker of E-cadherin disruption and epithelial injury. Similar results were observed in cultured airway epithelial cells. Taken together, our data demonstrated that mTOR mediates airway epithelial E-cadherin disruption in TDI-induced asthma.
e -钙粘蛋白是维持气道上皮完整性的关键粘附连接蛋白。e -钙粘蛋白下调常见于哮喘。哺乳动物雷帕霉素靶蛋白（mTOR）是一种代谢中枢调节因子，与哮喘发病有关。本研究旨在阐明mTOR信号通路在甲苯二异氰酸酯（TDI）诱导哮喘气道上皮E-cadherin功能障碍中的作用。将雄性BALB/c小鼠和体外培养的气道上皮细胞系BEAS-2B暴露于TDI中进行建模，并用mTOR信号抑制剂雷帕霉素处理。我们观察到tdi暴露小鼠和培养上皮中mTOR及其下游分子p70s6k的磷酸化增加，表明mTOR信号被激活。在体内，雷帕霉素治疗可显著减轻tdi诱导的气道高反应性，降低气道嗜中性粒细胞和嗜酸性粒细胞，抑制支气管肺泡灌洗液（BALF）中IL-4、IL-5和IL-17的释放，提示mTOR在tdi诱导的哮喘发展中起核心作用。此外，tdi诱导的肺E-cadherin表达下调也被雷帕霉素显著恢复，同时可溶性E-cadherin （sE-cadherin）的产生减少，这是E-cadherin破坏和上皮损伤的标志。在培养的气道上皮细胞中也观察到类似的结果。综上所述，我们的数据表明，在tdi诱导的哮喘中，mTOR介导气道上皮e -钙粘蛋白破坏。
{"title":"mTOR mediates airway epithelial E-cadherin disruption in toluene diisocyanate-induced asthma","authors":"Lin Fu , Lichang Chen , Xianru Peng , Changyun Yang , Jiamin Sun , Zemin Chen , Sudan Gan , Shiyue Li , Haixiong Tang , Yidan Lin , Lihong Yao","doi":"10.1016/j.taap.2025.117647","DOIUrl":"10.1016/j.taap.2025.117647","url":null,"abstract":"<div><div>E-cadherin is a critical adheren junctional protein for maintaining airway epithelial integrity. Downregulation of E-cadherin is commonly seen in asthma. Mammalian target of rapamycin (mTOR), a central regulator of metabolism, is implicated in asthma pathogenesis. This study was aimed to elucidate the role of mTOR signaling pathway on airway epithelial E-cadherin dysfunction in toluene diisocyanate (TDI)-induced asthma. Male BALB/c mice and in vitro cultured airway epithelial cell line BEAS-2B were exposed to TDI for modeling, and treated with rapamycin, an inhibitor of the mTOR signaling. We observed increased phosphorylation of mTOR and its downstream molecule p70s6k in TDI-exposed mice and cultured epithelia, indicating activation of mTOR signaling. In vivo, treatment with rapamycin dramatically alleviated TDI-induced airway hyperreactivity, decreased airway neutrophilia and eosinophilia, and suppressed the release of IL-4, IL-5 and IL-17 in the bronchoalveolar lavage fluid (BALF), suggesting a central role for mTOR in the development of TDI-induced asthma. Moreover, the TDI-induced downregulated E-cadherin expression in the lung was also significantly recovered by rapamycin, accompanied by less production of soluble E-cadherin (sE-cadherin), which is a marker of E-cadherin disruption and epithelial injury. Similar results were observed in cultured airway epithelial cells. Taken together, our data demonstrated that mTOR mediates airway epithelial E-cadherin disruption in TDI-induced asthma.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117647"},"PeriodicalIF":3.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557342","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 : 2025-11-15DOI: 10.1016/j.taap.2025.117645
Zhijian Pan , Han Wu , Yancai Liu , Haoyang Yu , Jiayi Shu , Changyan Yang , Jianglong Wang , Fengxia Du , Min Shao , Hefeng Zhou
OV is a highly lethal malignancy plagued by chemoresistance, necessitating the development of novel therapeutic agents. The Wnt/β-catenin pathway, driven by its central component β-catenin (CTNNB1), is a key oncogenic axis in OV, making it an attractive therapeutic target. We employed an integrated strategy combining in vitro assays (MTT, Western blot), in silico analyses (network pharmacology, WGCNA, molecular docking, molecular dynamics simulations), and biophysical validation assays (CETSA, DARTS) to systematically investigate the anti-cancer mechanism of the natural compound AU. AU potently inhibited the viability of A2780 OV cells by inducing apoptosis. Our comprehensive bioinformatic analysis identified CTNNB1 as a high-confidence direct target of AU. Clinical data confirmed that CTNNB1 is overexpressed in OV and correlates with poor patient prognosis. Molecular docking and dynamics simulations predicted a stable AU-CTNNB1 interaction, which was then experimentally validated by both CETSA and DARTS, confirming direct target engagement in a cellular context. Mechanistically, AU treatment resulted in the dose-dependent suppression of key proteins in the Wnt/β-catenin and HIF-1 signaling pathways. AU exerts its anti-OV activity by directly binding to CTNNB1. This interaction inhibits the oncogenic Wnt/β-catenin pathway, leading to the concurrent suppression of the HIF-1 pathway and the induction of apoptosis. Our study provides a complete mechanistic rationale for the development of AU as a novel targeted therapy for ovarian cancer.
{"title":"Aucubin directly targets β-catenin to co-suppress Wnt and HIF-1 pathways in ovarian cancer: Computational and experimental validation","authors":"Zhijian Pan , Han Wu , Yancai Liu , Haoyang Yu , Jiayi Shu , Changyan Yang , Jianglong Wang , Fengxia Du , Min Shao , Hefeng Zhou","doi":"10.1016/j.taap.2025.117645","DOIUrl":"10.1016/j.taap.2025.117645","url":null,"abstract":"<div><div>OV is a highly lethal malignancy plagued by chemoresistance, necessitating the development of novel therapeutic agents. The Wnt/β-catenin pathway, driven by its central component β-catenin (CTNNB1), is a key oncogenic axis in OV, making it an attractive therapeutic target. We employed an integrated strategy combining <em>in vitro</em> assays (MTT, Western blot), <em>in silico</em> analyses (network pharmacology, WGCNA, molecular docking, molecular dynamics simulations), and biophysical validation assays (CETSA, DARTS) to systematically investigate the anti-cancer mechanism of the natural compound AU. AU potently inhibited the viability of A2780 OV cells by inducing apoptosis. Our comprehensive bioinformatic analysis identified CTNNB1 as a high-confidence direct target of AU. Clinical data confirmed that CTNNB1 is overexpressed in OV and correlates with poor patient prognosis. Molecular docking and dynamics simulations predicted a stable AU-CTNNB1 interaction, which was then experimentally validated by both CETSA and DARTS, confirming direct target engagement in a cellular context. Mechanistically, AU treatment resulted in the dose-dependent suppression of key proteins in the Wnt/β-catenin and HIF-1 signaling pathways. AU exerts its anti-OV activity by directly binding to CTNNB1. This interaction inhibits the oncogenic Wnt/β-catenin pathway, leading to the concurrent suppression of the HIF-1 pathway and the induction of apoptosis. Our study provides a complete mechanistic rationale for the development of AU as a novel targeted therapy for ovarian cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117645"},"PeriodicalIF":3.4,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534759","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 : 2025-11-14DOI: 10.1016/j.taap.2025.117633
Ivonne M.C.M. Rietjens
This is a letter to the Editor related to: Huang et al. Effect of parental perinatal exposure to L-Glutamate Monosodium Salt Monohydrate on developmental neurotoxicity in rat offspring published in 2025 in Toxicol. Appl. Pharmacol., 502; 117,450. The content provides an addition to the discussion on the safety evaluation of glutamates.
{"title":"Letter to the editor related to: Huang et al. Effect of parental perinatal exposure to L-glutamate monosodium salt monohydrate on developmental neurotoxicity in rat offspring","authors":"Ivonne M.C.M. Rietjens","doi":"10.1016/j.taap.2025.117633","DOIUrl":"10.1016/j.taap.2025.117633","url":null,"abstract":"<div><div>This is a letter to the Editor related to: Huang et al. Effect of parental perinatal exposure to L-Glutamate Monosodium Salt Monohydrate on developmental neurotoxicity in rat offspring published in 2025 in Toxicol. Appl. Pharmacol., 502; 117,450. The content provides an addition to the discussion on the safety evaluation of glutamates.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117633"},"PeriodicalIF":3.4,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534848","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 : 2025-11-14DOI: 10.1016/j.taap.2025.117641
Ailifeire Tuerxuntayi , Wenhui Shi , Tian Shi , Kudelaiti Abudukelimu , Beiyao Gao , Paziliya Abulaiti , Kailibinuer Nuermaimaiti , Najimangu Rehemutula , Shenglong Xue , Yingying Xing , Weidong Liu , Zhuoshuyi Liu , Jiangwei Liu , Feng Gao
Purpose
This study aimed to investigate whether high-altitude hypoxia exacerbates non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and to evaluate the protective effects of Paeoniflorin (PF).
Methods
Male Sprague-Dawley rats were orally administered 300 mg/kg aspirin (ASA) to induce NSAID enteropathy, followed by 3 weeks of 5500 m high-altitude hypoxia exposure. Rats were divided into normoxic control (Con), hypoxic control (Hcon), hypoxic ASA model (HAsa), and PF treatment groups (25/50/100 mg/kg/day, LPF/MPF/HPF). The body weight changes, oxidative stress markers (MPO, SOD), inflammatory factors (IL-1β, TNF-α, IL-10), intestinal histology, tight junction proteins (ZO-1, Occludin), TLR4/NF-κB pathway activation, and gut microbiota composition (16S rRNA sequencing) were evaluated.
Results
The HAsa group exhibited the most severe intestinal damage, characterized by significant villus injury and inflammatory cell infiltration (P < 0.05). Mechanistically, this damage was driven by TLR4/NF-κB pathway activation, accompanied by significantly increased pro-inflammatory cytokines (IL-1β, TNF-α) and decreased anti-inflammatory cytokine IL-10 (P < 0.05). Oxidative stress was concurrently heightened, as evidenced by significantly elevated MPO levels and reduced SOD activity (P < 0.05). Consequently, the expression of tight junction proteins (ZO-1, Occludin) was significantly downregulated (P < 0.05), indicating compromised intestinal barrier function. Furthermore, 16S rRNA sequencing revealed gut microbiota dysbiosis, characterized by a decline in beneficial bacteria like Lactobacillus and Bifidobacterium and an expansion of harmful genera like Romboutsia and Turicibacter (P < 0.05). PF intervention dose-dependently reversed these alterations by effectively suppressing the TLR4/NF-κB pathway (P < 0.05), ameliorating inflammation and oxidative stress, and restoring mucosal barrier integrity. Concurrently, PF supplementation reshaped the gut microbiota, thereby normalizing the balance between beneficial and pathogenic bacteria (P < 0.05).
Conclusion
High-altitude hypoxia synergistically exacerbates NSAID-induced intestinal injury. PF protects against this injury primarily via modulating the TLR4/NF-κB pathway, highlighting its therapeutic potential for high-altitude populations on NSAIDs.
{"title":"Paeoniflorin attenuates ASA-induced enteropathy in simulated high-altitude hypoxia in rats by regulating intestinal inflammation, intestinal barrier, and intestinal flora","authors":"Ailifeire Tuerxuntayi , Wenhui Shi , Tian Shi , Kudelaiti Abudukelimu , Beiyao Gao , Paziliya Abulaiti , Kailibinuer Nuermaimaiti , Najimangu Rehemutula , Shenglong Xue , Yingying Xing , Weidong Liu , Zhuoshuyi Liu , Jiangwei Liu , Feng Gao","doi":"10.1016/j.taap.2025.117641","DOIUrl":"10.1016/j.taap.2025.117641","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to investigate whether high-altitude hypoxia exacerbates non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and to evaluate the protective effects of Paeoniflorin (PF).</div></div><div><h3>Methods</h3><div>Male Sprague-Dawley rats were orally administered 300 mg/kg aspirin (ASA) to induce NSAID enteropathy, followed by 3 weeks of 5500 m high-altitude hypoxia exposure. Rats were divided into normoxic control (Con), hypoxic control (Hcon), hypoxic ASA model (HAsa), and PF treatment groups (25/50/100 mg/kg/day, LPF/MPF/HPF). The body weight changes, oxidative stress markers (MPO, SOD), inflammatory factors (IL-1β, TNF-α, IL-10), intestinal histology, tight junction proteins (ZO-1, Occludin), TLR4/NF-κB pathway activation, and gut microbiota composition (16S rRNA sequencing) were evaluated.</div></div><div><h3>Results</h3><div>The HAsa group exhibited the most severe intestinal damage, characterized by significant villus injury and inflammatory cell infiltration (<em>P</em> < 0.05). Mechanistically, this damage was driven by TLR4/NF-κB pathway activation, accompanied by significantly increased pro-inflammatory cytokines (IL-1β, TNF-α) and decreased anti-inflammatory cytokine IL-10 (<em>P</em> < 0.05). Oxidative stress was concurrently heightened, as evidenced by significantly elevated MPO levels and reduced SOD activity (<em>P</em> < 0.05). Consequently, the expression of tight junction proteins (ZO-1, Occludin) was significantly downregulated (<em>P</em> < 0.05), indicating compromised intestinal barrier function. Furthermore, 16S rRNA sequencing revealed gut microbiota dysbiosis, characterized by a decline in beneficial bacteria like <em>Lactobacillus</em> and <em>Bifidobacterium</em> and an expansion of harmful genera like <em>Romboutsia</em> and <em>Turicibacter</em> (<em>P</em> < 0.05). PF intervention dose-dependently reversed these alterations by effectively suppressing the TLR4/NF-κB pathway (<em>P</em> < 0.05), ameliorating inflammation and oxidative stress, and restoring mucosal barrier integrity. Concurrently, PF supplementation reshaped the gut microbiota, thereby normalizing the balance between beneficial and pathogenic bacteria (<em>P</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>High-altitude hypoxia synergistically exacerbates NSAID-induced intestinal injury. PF protects against this injury primarily via modulating the TLR4/NF-κB pathway, highlighting its therapeutic potential for high-altitude populations on NSAIDs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117641"},"PeriodicalIF":3.4,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534805","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 : 2025-11-13DOI: 10.1016/j.taap.2025.117644
Shuo Wang, Bufan Yang, Guangyao Li, Dongju Lin
Diosbulbin B (DLB) is the most abundant diterpene lactone in herbal medicine Dioscorea bulbifera L. (DB). DLB is able to cause severe liver injury. The early studies showed that CYP3A4-mediated metabolic activation of DLB to form the corresponding cis-enedial metabolite was associated with DLB-induced hepatotoxicity. Schisantherin A (SchA), the primary lignan ingredient isolated from herbal medicine Schisandra fructus (SF), can inhibit CYP3A4 activity. The objective of the study is to examine the protective effect of SchA against DLB-induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological examination demonstrated that SchA exhibited dose-dependent protection against DLB-induced hepatotoxicity. In vitro experiments showed that SchA reduced the generation of DLB-derived pyrrole-glutathione (GSH) conjugates, indicating the metabolic activation of DLB in vitro was inhibited by SchA. Toxicokinetic studies displayed that the maximal concentration (Cmax) and area under the concentration–time curve (AUC) of DLB in mouse blood and liver were significantly increased after pretreatment with SchA, leading to augmenting the accumulation of DLB in vivo. Additionally, SchA ameliorated hepatic GSH depletion induced by DLB, increased urinary excretion of DLB, and reduced excretion of DLB-GSH conjugates in urine, suggesting that the metabolic activation of DLB in vivo was inhibited by SchA. In summary, our studies manifested the protection of SchA against hepatotoxicity of DLB was correlated with inhibiting metabolic activation of DLB. Thus, our study may provide the prospects for developing SchA as a detoxification candidate for DLB intoxication and may explain the protective mechanism of SF against liver injury induced by DB.
薯蓣皂苷B （Dioscorea bulbifera L.， DB）是中药中含量最多的二萜内酯。DLB可导致严重的肝损伤。早期研究表明，cyp3a4介导的DLB代谢激活形成相应的顺式内端代谢物与DLB诱导的肝毒性有关。五味子素A （Schisantherin A, SchA）是从中药五味子（Schisandra fructus， SF）中分离得到的木脂素主要成分，具有抑制CYP3A4活性的作用。本研究旨在探讨沙棘多糖对dlb诱导的肝毒性的保护作用及其机制。生物化学和组织病理学检查表明，SchA对dlb诱导的肝毒性具有剂量依赖性的保护作用。体外实验表明，SchA减少了DLB衍生的吡咯-谷胱甘肽（GSH）偶联物的生成，表明SchA在体外抑制了DLB的代谢激活。毒动学研究表明，经SchA预处理后，DLB在小鼠血液和肝脏中的最大浓度（Cmax）和浓度-时间曲线下面积（AUC）显著增加，导致DLB在体内蓄积增加。此外，SchA改善了DLB诱导的肝脏GSH消耗，增加了DLB的尿排泄，减少了DLB-GSH偶联物在尿中的排泄，表明SchA抑制了DLB在体内的代谢激活。综上所述，我们的研究表明，SchA对DLB肝毒性的保护作用与抑制DLB代谢激活有关。因此，我们的研究可能为开发SchA作为DLB中毒的解毒候选物提供了前景，并可能解释SF对DB诱导的肝损伤的保护机制。
{"title":"Schisantherin A alleviates hepatotoxicity induced by diosbulbin B in mice via suppressing metabolic activation of diosbulbin B","authors":"Shuo Wang, Bufan Yang, Guangyao Li, Dongju Lin","doi":"10.1016/j.taap.2025.117644","DOIUrl":"10.1016/j.taap.2025.117644","url":null,"abstract":"<div><div>Diosbulbin B (DLB) is the most abundant diterpene lactone in herbal medicine <em>Dioscorea bulbifera</em> L. (DB). DLB is able to cause severe liver injury. The early studies showed that CYP3A4-mediated metabolic activation of DLB to form the corresponding <em>cis</em>-enedial metabolite was associated with DLB-induced hepatotoxicity. Schisantherin A (SchA), the primary lignan ingredient isolated from herbal medicine Schisandra fructus (SF), can inhibit CYP3A4 activity. The objective of the study is to examine the protective effect of SchA against DLB-induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological examination demonstrated that SchA exhibited dose-dependent protection against DLB-induced hepatotoxicity. <em>In vitro</em> experiments showed that SchA reduced the generation of DLB-derived pyrrole-glutathione (GSH) conjugates, indicating the metabolic activation of DLB <em>in vitro</em> was inhibited by SchA. Toxicokinetic studies displayed that the maximal concentration (C<sub>max</sub>) and area under the concentration–time curve (AUC) of DLB in mouse blood and liver were significantly increased after pretreatment with SchA, leading to augmenting the accumulation of DLB <em>in vivo</em>. Additionally, SchA ameliorated hepatic GSH depletion induced by DLB, increased urinary excretion of DLB, and reduced excretion of DLB-GSH conjugates in urine, suggesting that the metabolic activation of DLB <em>in vivo</em> was inhibited by SchA. In summary, our studies manifested the protection of SchA against hepatotoxicity of DLB was correlated with inhibiting metabolic activation of DLB. Thus, our study may provide the prospects for developing SchA as a detoxification candidate for DLB intoxication and may explain the protective mechanism of SF against liver injury induced by DB.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117644"},"PeriodicalIF":3.4,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530441","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 : 2025-11-12DOI: 10.1016/j.taap.2025.117642
Yanhong Liu , Xiaochun Feng , Xiaoxiao Dai , Di Li , Yuan Luo
Background
Sevoflurane (SEV) demonstrates cardiac protection, but its mechanism remains unclear. Long non-coding RNA CYTOR (LncRNA CYTOR) expression is altered in damaged heart cells and may promote disease, yet SEV- LncRNA CYTOR interaction studies are limited.
Objective
Investigate lncRNA CYTOR's function in cardiomyocyte H/R injury and determine if SEV acts via the lncRNA CYTOR/miR-24-3p axis.
Methods
Cardiomyocytes underwent H/R (6 h hypoxia) and 2.0 % SEV pretreatment. Cell function was assessed using qRT-PCR, CCK-8 assay, flow cytometry, and ELISA. lncRNA CYTOR-miR-24-3p binding was confirmed by dual-luciferase and RIP assays. Rescue studies employed lncRNA CYTOR overexpression (pcDNA3.1-lncRNA CYTOR) and miR-24-3p mimic transfection.
Results
H/R injury halved cell viability increased oxidative stress, inflammation, and elevated lncRNA CYTOR. SEV treatment effectively alleviated these effects. However, overexpressing lncRNA CYTOR negated SEV's protective action. The underlying mechanism involves the direct binding of lncRNA CYTOR to miR-24-3p, resulting in its suppression. SEV alleviated H/R damage by downregulating lncRNA CYTOR, thereby derepressing miR-24-3p and promoting survival while reducing stress and inflammation. Crucially, miR-24-3p mimic transfection rescued the detrimental effects of lncRNA CYTOR overexpression.
Conclusion
SEV protects against cardiomyocyte H/R injury by suppressing lncRNA CYTOR expression. This relieves lncRNA CYTOR's inhibition of miR-24-3p, activating protective pathways. The lncRNA CYTOR/miR-24-3p axis emerges as a novel regulatory mechanism and a potential therapeutic target for ischemia-reperfusion injury.
{"title":"Mechanism of lncRNA CYTOR/miR-24-3p in sevoflurane-mediated cardiomyocyte protection against hypoxia/reoxygenation injury in cardiomyocytes","authors":"Yanhong Liu , Xiaochun Feng , Xiaoxiao Dai , Di Li , Yuan Luo","doi":"10.1016/j.taap.2025.117642","DOIUrl":"10.1016/j.taap.2025.117642","url":null,"abstract":"<div><h3>Background</h3><div>Sevoflurane (SEV) demonstrates cardiac protection, but its mechanism remains unclear. Long non-coding RNA CYTOR (LncRNA CYTOR) expression is altered in damaged heart cells and may promote disease, yet SEV- LncRNA CYTOR interaction studies are limited.</div></div><div><h3>Objective</h3><div>Investigate lncRNA CYTOR's function in cardiomyocyte H/R injury and determine if SEV acts via the lncRNA CYTOR/miR-24-3p axis.</div></div><div><h3>Methods</h3><div>Cardiomyocytes underwent H/R (6 h hypoxia) and 2.0 % SEV pretreatment. Cell function was assessed using qRT-PCR, CCK-8 assay, flow cytometry, and ELISA. lncRNA CYTOR-miR-24-3p binding was confirmed by dual-luciferase and RIP assays. Rescue studies employed lncRNA CYTOR overexpression (pcDNA3.1-lncRNA CYTOR) and miR-24-3p mimic transfection.</div></div><div><h3>Results</h3><div>H/R injury halved cell viability increased oxidative stress, inflammation, and elevated lncRNA CYTOR. SEV treatment effectively alleviated these effects. However, overexpressing lncRNA CYTOR negated SEV's protective action. The underlying mechanism involves the direct binding of lncRNA CYTOR to miR-24-3p, resulting in its suppression. SEV alleviated H/R damage by downregulating lncRNA CYTOR, thereby derepressing miR-24-3p and promoting survival while reducing stress and inflammation. Crucially, miR-24-3p mimic transfection rescued the detrimental effects of lncRNA CYTOR overexpression.</div></div><div><h3>Conclusion</h3><div>SEV protects against cardiomyocyte H/R injury by suppressing lncRNA CYTOR expression. This relieves lncRNA CYTOR's inhibition of miR-24-3p, activating protective pathways. The lncRNA CYTOR/miR-24-3p axis emerges as a novel regulatory mechanism and a potential therapeutic target for ischemia-reperfusion injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117642"},"PeriodicalIF":3.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522841","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":"Response to Dr. Ivonne M.C.M. Rietjens' letter regarding \"Effect of Parental perinatal exposure to L-Glutamate monosodium salt monohydrate on developmental neurotoxicity in rat offspring\".","authors":"Zizhao Huang, Xiao Xiao, Xuan Zhang, Haijiao Jiang, Xiulan Zhao, Qinzhi Wei, Xingfen Yang, Haixia Sui, Tong Ou, Daoyuan Yang, Weichunbai Zhang, Xudong Jia, Yan Song, Ling Yong","doi":"10.1016/j.taap.2025.117643","DOIUrl":"10.1016/j.taap.2025.117643","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117643"},"PeriodicalIF":3.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522894","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 : 2025-11-11DOI: 10.1016/j.taap.2025.117639
Yangyang Yuan , Binhui Wang , Yuyu Fan , Meiling Le , Lihai Wu , Shiyi Deng , Jian Huang , Dalei Zhang
Perfluorooctanoic acid (PFOA) is a legacy perfluoroalkyl substance (PFAS) with various detrimental health effects, prompting its replacement by hexafluoropropylene oxide dimer acid (GenX). However, the female reproductive toxicity and underlying mechanism of GenX remain inadequately understood. In this study, we comparatively evaluated the impacts of PFOA and GenX on ovarian function using integrated in vivo mouse and in vitro human granulosa cell models. Our experimental findings indicated that oral exposure to PFOA significantly reduced ovarian weight, impaired follicular development, disrupted estrous cyclicity, decreased estradiol level, and induced ovarian oxidative stress and apoptosis in mice. However, GenX did not display significant toxic effects on the ovaries at the doses tested, except for reducing ovarian GPX4 expression and serum estradiol level. Notably, both PFOA and GenX at high-concentration treatment in vitro dramatically impaired the viability and proliferation, elicited ROS overproduction and mitochondrial injury, and suppressed NRF2 and HO-1 expression in cultured KGN cells. Nevertheless, at equivalent exposure doses, GenX elicited markedly decreased adverse influences on KGN cells compared to PFOA. Molecular docking simulation indicated a stronger interaction of PFOA with NRF2 than GenX. In addition, treatment with PFOA also diminished estradiol secretion and induced apoptosis in KGN cells. In summary, PFOA exposure resulted in female reproductive impairment by inducing oxidative stress and apoptosis in mouse ovaries and human granulosa cells. Although GenX exhibited comparatively low ovarian detriment relative to PFOA, its potential risk of reproductive toxicity remains a nonnegligible concern.
{"title":"Comparative assessment of female reproductive toxicity from PFOA and its alternative GenX in mice and human granulosa cells","authors":"Yangyang Yuan , Binhui Wang , Yuyu Fan , Meiling Le , Lihai Wu , Shiyi Deng , Jian Huang , Dalei Zhang","doi":"10.1016/j.taap.2025.117639","DOIUrl":"10.1016/j.taap.2025.117639","url":null,"abstract":"<div><div>Perfluorooctanoic acid (PFOA) is a legacy perfluoroalkyl substance (PFAS) with various detrimental health effects, prompting its replacement by hexafluoropropylene oxide dimer acid (GenX). However, the female reproductive toxicity and underlying mechanism of GenX remain inadequately understood. In this study, we comparatively evaluated the impacts of PFOA and GenX on ovarian function using integrated <em>in vivo</em> mouse and <em>in vitro</em> human granulosa cell models. Our experimental findings indicated that oral exposure to PFOA significantly reduced ovarian weight, impaired follicular development, disrupted estrous cyclicity, decreased estradiol level, and induced ovarian oxidative stress and apoptosis in mice. However, GenX did not display significant toxic effects on the ovaries at the doses tested, except for reducing ovarian GPX4 expression and serum estradiol level. Notably, both PFOA and GenX at high-concentration treatment <em>in vitro</em> dramatically impaired the viability and proliferation, elicited ROS overproduction and mitochondrial injury, and suppressed NRF2 and HO-1 expression in cultured KGN cells. Nevertheless, at equivalent exposure doses, GenX elicited markedly decreased adverse influences on KGN cells compared to PFOA. Molecular docking simulation indicated a stronger interaction of PFOA with NRF2 than GenX. In addition, treatment with PFOA also diminished estradiol secretion and induced apoptosis in KGN cells. In summary, PFOA exposure resulted in female reproductive impairment by inducing oxidative stress and apoptosis in mouse ovaries and human granulosa cells. Although GenX exhibited comparatively low ovarian detriment relative to PFOA, its potential risk of reproductive toxicity remains a nonnegligible concern.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117639"},"PeriodicalIF":3.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514063","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}
Bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) are widely recognized environmental neurotoxicants implicated in Alzheimer's disease (AD). However, the shared and divergent mechanisms by which BPA and DEHP induce neurotoxicity in AD remain largely unexplored. In this study, we conducted the first systematic comparative analysis of overlapping and distinct neurotoxic pathways of BPA and DEHP by integrating network toxicology and in vitro experimental validation. Five shared core targets (MMP9, PPARG, MAPK14, BCL2, and BCL2L1) were identified from multiple databases. Experimental validation confirmed that BPA and DEHP significantly upregulated MMP9, PPARG, and phosphorylated MAPK14, while downregulating BCL2 and BCL2L1 at both transcriptional and protein levels. KEGG pathway enrichment revealed both shared and divergent pathways, with the lipid and atherosclerosis pathway emerging as a common AD-relevant pathway, whereas BPA and DEHP showed compound-specific involvement in PI3K-Akt, MAPK, and other signaling cascades. Molecular docking analysis further demonstrated favorable binding of both BPA and DEHP to the shared core targets. Collectively, this study provides novel mechanistic insights into both overlapping and distinct neurotoxic effects of BPA and DEHP in AD, offering a theoretical basis for future mechanistic research and environmental risk assessment.
{"title":"Shared and divergent neurotoxic mechanisms of Bisphenol A and Di(2-ethylhexyl) phthalate with implication for Alzheimer's disease: Insights from network toxicology and in vitro validation","authors":"Qiwei Zhang, Siqi Long, Na Zhang, Guohui Sun, Lijiao Zhao, Rugang Zhong","doi":"10.1016/j.taap.2025.117637","DOIUrl":"10.1016/j.taap.2025.117637","url":null,"abstract":"<div><div>Bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) are widely recognized environmental neurotoxicants implicated in Alzheimer's disease (AD). However, the shared and divergent mechanisms by which BPA and DEHP induce neurotoxicity in AD remain largely unexplored. In this study, we conducted the first systematic comparative analysis of overlapping and distinct neurotoxic pathways of BPA and DEHP by integrating network toxicology and in vitro experimental validation. Five shared core targets (MMP9, PPARG, MAPK14, BCL2, and BCL2L1) were identified from multiple databases. Experimental validation confirmed that BPA and DEHP significantly upregulated MMP9, PPARG, and phosphorylated MAPK14, while downregulating BCL2 and BCL2L1 at both transcriptional and protein levels. KEGG pathway enrichment revealed both shared and divergent pathways, with the lipid and atherosclerosis pathway emerging as a common AD-relevant pathway, whereas BPA and DEHP showed compound-specific involvement in PI3K-Akt, MAPK, and other signaling cascades. Molecular docking analysis further demonstrated favorable binding of both BPA and DEHP to the shared core targets. Collectively, this study provides novel mechanistic insights into both overlapping and distinct neurotoxic effects of BPA and DEHP in AD, offering a theoretical basis for future mechanistic research and environmental risk assessment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117637"},"PeriodicalIF":3.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514137","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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