Toxicology and applied pharmacology最新文献_第2页

Arsenic exposure affects Pdgfrα stromal cells in the ileum of the small intestine 砷暴露会影响小肠回肠中的Pdgfrα基质细胞。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-29 DOI: 10.1016/j.taap.2025.117582

Scott W. Ventrello, Kayla A. Lea, Lisa J. Bain

{"title":"Arsenic exposure affects Pdgfrα stromal cells in the ileum of the small intestine","authors":"Scott W. Ventrello, Kayla A. Lea, Lisa J. Bain","doi":"10.1016/j.taap.2025.117582","DOIUrl":"10.1016/j.taap.2025.117582","url":null,"abstract":"<div><div>Arsenic is a contaminant in drinking water and food, and exposure induces inflammation and barrier disruption in the small intestine and colon. Further, arsenic can alter stromal cell numbers and their signaling molecules in the duodenum. Thus, the goal of this study was to investigate arsenic's effects on morphology, Pdgfrα<sup>+</sup> stromal cell numbers, localization, and signaling in the ileum. Mice were exposed to 0, 100, and 500 ppb arsenic for 13 weeks, and intestinal sections, including the ileum, dissected out. The results show that arsenic dose-responsive increases in crypt budding and macrophage numbers in the ileum. Arsenic exposure also increased transcript expression of telocyte (<em>Cd201, Tmem158, Wnt4</em>), trophocyte (<em>Ackr4</em>, <em>Grem1</em>), Igfbp5+ fibroblast (<em>Igfbp5</em>), and Fgfr2+ fibroblast (<em>Fgfr2, Igfbp3, Wnt4</em>) markers in the ileum of female mice, but not in the males. Linear regression indicated that markers of telocytes and Fgfr2+ fibroblasts significantly correlated with <em>Wnt4</em> expression. IHC revealed the numbers of telocytes within the villi of male and females were increased by 6.3- and 2.3-fold at 500 ppb, respectively. Linear regression of Grem1 versus Bmp4 protein expression revealed significant correlation, with arsenic exposed females having higher expression of both signaling molecules. Overall, the results suggest that Pdgfrα+ stromal cells in the ileum play vital roles in maintaining intestinal stem cell (ISC) and epithelial homeostasis in response to arsenic, and that sex-dependent changes in responses exist.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117582"},"PeriodicalIF":3.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulation of NF-кB/NLRP3 signaling by sitagliptin attenuates cholestatic hepatic fibrosis 西格列汀调节NF-кB/NLRP3信号可减轻胆汁淤积性肝纤维化。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-29 DOI: 10.1016/j.taap.2025.117585

Marwa A. Elkosayer, Hoda E. Kafl, Mirhan N. Makled, Dina S. El-Agamy

{"title":"Modulation of NF-кB/NLRP3 signaling by sitagliptin attenuates cholestatic hepatic fibrosis","authors":"Marwa A. Elkosayer, Hoda E. Kafl, Mirhan N. Makled, Dina S. El-Agamy","doi":"10.1016/j.taap.2025.117585","DOIUrl":"10.1016/j.taap.2025.117585","url":null,"abstract":"<div><div>Cholestatic hepatic fibrosis which ultimately may lead to cirrhosis and hepatic failure, is a serious condition that results from prolonged cholestasis. Sitagliptin (SG), a dipeptidyl peptidase IV inhibitor, has shown beneficial effects in multiple hepatic disorders. However, the effect of SG on cholestatic hepatic fibrosis remains unexplored. Thus, this investigation elucidated the protective effect of SG against cholestatic hepatic fibrosis induced by multiple doses of alpha-naphthyl isothiocyanate (ANIT). Male Sprague-Dawley rats were assigned into five groups as follows: control, SG20, ANIT, SG10 + ANIT, and SG20 + ANIT groups. SG dose dependently antagonized the development of cholestatic hepatic fibrosis as it ameliorated the levels of serum alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin. Biochemical results were further supported by histopathological examination and transmission electron microscopy. SG decreased collagen deposition and expression of transforming growth factor-β1 (TGF-β1). Additionally, SG alleviated ANIT-induced inflammation via significant suppression of the expression of nuclear factor kappa B (NF-κB), nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome, interleukin-1β (IL-1β), and caspase-1. SG reduced oxidative stress as indicated by elevation of glutathione and catalase and reduction of malondialdehyde content in hepatic tissues. These findings suggest that SG could mitigate ANIT-mediated cholestatic hepatic fibrosis via its anti-inflammatory, anti-fibrotic, and antioxidant impact through suppression of NF-κB and NLRP3–caspase-1–IL-1β axis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117585"},"PeriodicalIF":3.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Propylparaben disrupts early embryonic development by causing oxidative stress-induced organelle dysfunction and actin zipper abnormality 对羟基苯甲酸丙酯通过引起氧化应激诱导的细胞器功能障碍和肌动蛋白拉链异常来破坏早期胚胎发育。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-27 DOI: 10.1016/j.taap.2025.117581

Zhen-Nan Pan , Li-Li Zhuang , Hui-Shan Zhao , Shu-Yuan Yin , Min Chu , Xiao-Yan Liu , Hong-Chu Bao

{"title":"Propylparaben disrupts early embryonic development by causing oxidative stress-induced organelle dysfunction and actin zipper abnormality","authors":"Zhen-Nan Pan , Li-Li Zhuang , Hui-Shan Zhao , Shu-Yuan Yin , Min Chu , Xiao-Yan Liu , Hong-Chu Bao","doi":"10.1016/j.taap.2025.117581","DOIUrl":"10.1016/j.taap.2025.117581","url":null,"abstract":"<div><div>Propylparaben (PrPB) is a commonly used preservative in personal care products and food items, but studies have shown that it can disrupt various physiological processes, especially in the reproductive system. Our previous research revealed the toxic effects of PrPB on mouse oocyte maturation. However, knowledge about the toxicity of PrPB in early embryos remains limited. In the present study, we demonstrated that in vitro exposure to 600 μM PrPB increased ROS levels, inducing autophagy, mitophagy and ER stress, ultimately leading to embryonic arrest at the 4-cell stage. PrPB exposure promoted autophagy through the induction of DNA damage, reflected by enhanced lysosome, LC3 and γH2A.X fluorescence signals. PrPB exposure enhanced mitophagy, as indicated by increased colocalization of mitochondria with LAMP1 and Parkin. PrPB exposure also caused ER stress, as indicated by disordered ER distribution and abnormal Ca<sup>2+</sup> homeostasis. In addition, 600 μM PrPB exposure disrupted the formation of the actin zipper by interfering with the localization of ZO1 and E-cadherin, further affecting blastocyst formation. Although 300 μM PrPB exposure did not affect the embryo development rate, a decreased of the percentage of TE/total cell number and a increased of the percentage of ICM/total cell number was observed, indicating poor blastocyst quality. Taken together, the results of our study demonstrate that high-dose PrPB exposure causes oxidative stress-induced organelle dysfunction and abnormal actin zipper formation, whereas low-dose PrPB exposure affects early lineage specification.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117581"},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lacosamide as a chemoprotective agent beyond anticonvulsant activity: Pharmacological modulation of Notch-1/NF-κB axis to restore antioxidant defense, inhibit apoptosis, and preserve testosterone-androgen receptor signaling in cyclophosphamide-induced prostate injury 拉科沙胺作为抗惊厥活性以外的化学保护剂：Notch-1/NF-κB轴在环磷酰胺诱导的前列腺损伤中恢复抗氧化防御、抑制细胞凋亡和保护睾丸激素-雄激素受体信号的药理调节

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-27 DOI: 10.1016/j.taap.2025.117584

Mohammed R.A. Ali , Basim A.S. Messiha , Ahmed S. Abdel-Samea , Mina Ezzat Attya , Reham H. Mohyeldin

{"title":"Lacosamide as a chemoprotective agent beyond anticonvulsant activity: Pharmacological modulation of Notch-1/NF-κB axis to restore antioxidant defense, inhibit apoptosis, and preserve testosterone-androgen receptor signaling in cyclophosphamide-induced prostate injury","authors":"Mohammed R.A. Ali , Basim A.S. Messiha , Ahmed S. Abdel-Samea , Mina Ezzat Attya , Reham H. Mohyeldin","doi":"10.1016/j.taap.2025.117584","DOIUrl":"10.1016/j.taap.2025.117584","url":null,"abstract":"<div><div>Cyclophosphamide (CPX)-induced prostatic toxicity remains a clinically relevant concern, with limited strategies available to mitigate its adverse effects. This study investigates the potential protective effects of lacosamide (LCS), an FDA-approved anticonvulsant with antioxidant, anti-inflammatory, and anti-apoptotic properties, against CPX-induced prostate injury in rats. We examined LCS's effects on the Notch-1 signaling pathway and its potential interaction with nuclear factor kappa B (NF-κB). Male Wistar albino rats were divided into five groups: normal control, LCS control (40 mg/kg/day), CPX control (200 mg/kg), and two LCS treatment groups (10 and 40 mg/kg/day) co-administered with CPX. CPX exposure significantly increased oxidative stress markers (elevated malondialdehyde; reduced glutathione, superoxide dismutase, glutathione peroxidase, and catalase), upregulated proinflammatory markers (phosphorylated NF-κB p65, interleukin-6, interleukin-1β, tumor necrosis factor-α), and increased apoptotic markers (downregulation of B-cell lymphoma 2; upregulation of Bcl-2 associated X protein and cleaved caspase-3). Additionally, CPX enhanced Notch-1 receptor and Notch-1 intracellular domain expression, decreased serum testosterone levels, altered prostate-specific antigen levels, and suppressed androgen receptor expression. LCS co-administration, particularly at the higher dose, improved these parameters, suggesting modulation of oxidative stress, inflammation, and apoptotic pathways. These findings indicate that LCS treatment may provide protective effects against CPX-induced prostatic alterations and suggest its potential consideration as an adjuvant agent during CPX-based therapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117584"},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LCN2-positive alveolar type II cells promote silica-induced pulmonary fibrosis via STAT3-TGF-β1-Smad3-mediated signaling lcn2阳性肺泡II型细胞通过STAT3-TGF-β1- smad3介导的信号传导促进二氧化硅诱导的肺纤维化。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-27 DOI: 10.1016/j.taap.2025.117579

Zihao Xie , Xia Li , Mengchen Zhang , Hangbing Cao , Fei Wang , Ruiqing Yan , HuiYu Ye , Min Mu , Jianxin Wang , Fei Wang , Xinrong Tao

{"title":"LCN2-positive alveolar type II cells promote silica-induced pulmonary fibrosis via STAT3-TGF-β1-Smad3-mediated signaling","authors":"Zihao Xie , Xia Li , Mengchen Zhang , Hangbing Cao , Fei Wang , Ruiqing Yan , HuiYu Ye , Min Mu , Jianxin Wang , Fei Wang , Xinrong Tao","doi":"10.1016/j.taap.2025.117579","DOIUrl":"10.1016/j.taap.2025.117579","url":null,"abstract":"<div><div>Lipocalin-2 (LCN2), an innate immune protein, has been identified as a potential biomarker in a range of inflammatory and fibrotic lung diseases. Nevertheless, its specific role and the underlying mechanisms in silica-induced pulmonary fibrosis remain unclear. This study found a significant increase in LCN2 expression in the lung tissues of silica-exposed mice during the stage of inflammation and fibrosis. The increased LCN2 was primarily derived from alveolar type II epithelial cells (AT2 cells). We further generated LCN2-overexpressing mouse AT2 cells (LCN2-OE AT2 cells) in vitro. These LCN2-OE AT2 cells exhibited significant upregulation of TGF-β1 and activation of Smad3, promoting the epithelial-mesenchymal transition (EMT) process. Additionally, exposure to silica in vitro led to an increase in the TGF-β1-Smad3 pathway and EMT process in AT2 cells. However, this response was effectively decreased when combined with an LCN2 inhibitor. Our findings highlight the significance of LCN2 originating from AT2 cells in both EMT and silica-induced pulmonary fibrosis, indicating a potential new treatment strategy for pulmonary fibrosis targeting LCN2.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117579"},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synergistic effects of Lorestanol, an ursane-type triterpenoid from Euphorbia aleppica, in combination with cisplatin on apoptosis in cisplatin-resistant ovarian cancer cell lines 大戟属熊烷型三萜类Lorestanol联合顺铂对顺铂耐药卵巢癌细胞凋亡的协同作用

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-26 DOI: 10.1016/j.taap.2025.117583

Seyedeh Sara Ghorbanhosseini , Mojtaba Amiri , Mustafa Ghanadian , Morteza Sadeghi , Mahmoud Aghaei

{"title":"Synergistic effects of Lorestanol, an ursane-type triterpenoid from Euphorbia aleppica, in combination with cisplatin on apoptosis in cisplatin-resistant ovarian cancer cell lines","authors":"Seyedeh Sara Ghorbanhosseini , Mojtaba Amiri , Mustafa Ghanadian , Morteza Sadeghi , Mahmoud Aghaei","doi":"10.1016/j.taap.2025.117583","DOIUrl":"10.1016/j.taap.2025.117583","url":null,"abstract":"<div><div>Lorestanol, an ursane-type triterpenoid extracted from <em>Euphorbia aleppica</em>, was evaluated for its cytotoxic and apoptotic effects both alone and in combination with cisplatin on the cisplatin-sensitive A2780-WILD and cisplatin-resistant A2780-RCIS ovarian cancer cell lines. MTT assay results showed that cisplatin had IC<sub>50</sub> values of 10.71 μM in A2780-WILD and 86.49 μM in A2780-RCIS, confirming high resistance in the latter. Lorestanol alone exhibited cytotoxicity with IC<sub>50</sub> values around 45 μM in both lines. Notably, the combination of Lorestanol and cisplatin significantly enhanced cytotoxicity, reducing cell viability from 97.33 % to 7.50 % in A2780-WILD and from 60.67 % to 23.89 % in A2780-RCIS. Combination index (CI) values indicated strong synergism (0.9 for A2780-WILD and 0.65 for A2780-RCIS), while drug reduction index (DRI) values showed decreased cisplatin dosage requirements (1.25 and 3.14, respectively).</div><div>Apoptosis analysis via Annexin V/PI staining revealed up to 88.6 % apoptosis in A2780-WILD cells treated with the combination. Mechanistically, the combination induced apoptosis through endoplasmic reticulum (ER) stress, evidenced by elevated expression of Caspase-12 and CHOP, along with increased GRP78 and PERK expression. Additionally, the combination downregulated drug resistance genes such as SOD1 and MRP1, particularly in resistant cells. Molecular docking of Lorestanol with MRP1 further supported its binding within the substrate site, highlighting interactions with key amino acid residues. These findings suggest that Lorestanol significantly enhances cisplatin efficacy and may help overcome chemotherapy resistance in ovarian cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117583"},"PeriodicalIF":3.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Network toxicology and mechanistic insights reveal the oxytocin receptor (OXTR) as a key mediator of aspartame-associated atrial remodeling. 网络毒理学和机制的见解揭示了催产素受体（OXTR）作为阿斯巴甜相关心房重构的关键介质。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-25 DOI: 10.1016/j.taap.2025.117580

Ying Kong, Shuzi Li, Chuntian Wang, Junjie Ge

{"title":"Network toxicology and mechanistic insights reveal the oxytocin receptor (OXTR) as a key mediator of aspartame-associated atrial remodeling.","authors":"Ying Kong, Shuzi Li, Chuntian Wang, Junjie Ge","doi":"10.1016/j.taap.2025.117580","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117580","url":null,"abstract":"<p><p>Atrial fibrillation (AF) is a major arrhythmic disorder with incompletely understood environmental triggers. Aspartame, a widely used artificial sweetener, has been linked to cardiovascular dysfunction, yet its role in AF remains unclear. This study aimed to elucidate the mechanistic link between aspartame and AF via oxytocin receptor (OXTR) modulation. Using a network toxicology strategy, 287 putative aspartame targets were identified; Mendelian randomization analysis singled out OXTR as a potential causal factor in AF. Functional enrichment of OXTR-interacting proteins implicated hormone signaling, neuroactive ligand-receptor interaction, and electrophysiological regulation. Transcriptomic profiling revealed low overall cardiac expression of OXTR, with enrichment in ventricular cardiomyocytes and strong correlation with cardiomyocyte markers. Molecular docking and molecular dynamics simulations confirmed stable binding of aspartame to OXTR, exhibiting binding energy and hydrogen bonding comparable to the natural ligand. In AC16 human cardiomyocytes, low-dose aspartame upregulated OXTR. It also increased COL1A1 and IL-6 expression, while reducing CACNA1C expression. OXTR knockdown reversed these effects. Collectively, our multi-level evidence indicates that aspartame may promote atrial remodeling through OXTR-dependent pathways involving fibrosis, inflammation, and ion-channel remodeling. OXTR emerges as a novel therapeutic target for mitigating aspartame-associated AF.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117580"},"PeriodicalIF":3.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

7,8-Dihydroxyflavone attenuates cisplatin-induced cardiomyocyte apoptosis and mitochondrial dysfunction via the p53/Nrf2 pathway 7,8-二羟黄酮通过p53/Nrf2途径减轻顺铂诱导的心肌细胞凋亡和线粒体功能障碍。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-22 DOI: 10.1016/j.taap.2025.117578

Zhen Tian , Ting-ting Tan , Yu-wei Hu , Jia-tong Yao , Xiao-ting Kang , Jin-yu Zhou , Dong-xu Jia , Qing-liu Li , Ru-jin Liang , Li-mei Zhao , Hua Zhu , Jing Zhao , Peng-zhou Hang

{"title":"7,8-Dihydroxyflavone attenuates cisplatin-induced cardiomyocyte apoptosis and mitochondrial dysfunction via the p53/Nrf2 pathway","authors":"Zhen Tian , Ting-ting Tan , Yu-wei Hu , Jia-tong Yao , Xiao-ting Kang , Jin-yu Zhou , Dong-xu Jia , Qing-liu Li , Ru-jin Liang , Li-mei Zhao , Hua Zhu , Jing Zhao , Peng-zhou Hang","doi":"10.1016/j.taap.2025.117578","DOIUrl":"10.1016/j.taap.2025.117578","url":null,"abstract":"<div><div>Cisplatin (CDDP), while effective as a chemotherapeutic agent, poses significant cardiovascular risks that constrain its clinical utility. This study investigated the cardioprotective effects of 7,8-dihydroxyflavone (7,8-DHF) against CDDP-induced toxicity and explored the underlying molecular mechanisms in cardiomyocytes. CDDP exposure produced dose-dependent cytotoxic effects, characterized by reduced cell viability and elevated lactate dehydrogenase (LDH) release. Co-treatment with 7,8-DHF markedly attenuated CDDP-induced cellular damage by preventing cell death, minimizing LDH leakage, and preserving mitochondrial membrane potential (MMP). The compound also suppressed cardiomyocyte apoptosis, evidenced by fewer TUNEL-positive cells and restoration of the Bcl-2/Bax ratio. 7,8-DHF decreased mitochondrial reactive oxygen species (ROS) accumulation and enhanced cellular antioxidant defenses by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) signaling. Additionally, 7,8-DHF treatment decreased both 53BP1 foci formation and p53 protein expression. The specificity of these protective mechanisms was confirmed using pharmacological agents: Nutlin-3a (p53 activator) and Brusatol (Nrf2 inhibitor), both reversed the cardioprotective effects of 7,8-DHF, establishing the critical role of p53/Nrf2 pathway modulation. In summary, these findings demonstrate that 7,8-DHF protects against CDDP-induced cardiotoxicity by preserving mitochondrial function and preventing apoptosis through targeted inhibition of the p53 signaling and activation of Nrf2-mediated antioxidant responses in cardiomyocytes. Our study provides preliminary evidence for the potential of 7,8-DHF in mitigating CDDP-associated cardiac injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117578"},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protective effects of zinc oxide nanoparticles against liver and kidney toxicity induced by oxymetholone, a steroid doping agent: Modulation of oxidative stress, inflammation, and gene expression in rats 氧化锌纳米颗粒对氧甲酮（一种类固醇兴奋剂）诱导的肝肾毒性的保护作用：大鼠氧化应激、炎症和基因表达的调节

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-19 DOI: 10.1016/j.taap.2025.117574

Nehal S. Abdelghafar , Rady I. Hamed , Eiman M. El-Saied , Maha M. Rashad , Noha A.E. Yasin , Peter A. Noshy

{"title":"Protective effects of zinc oxide nanoparticles against liver and kidney toxicity induced by oxymetholone, a steroid doping agent: Modulation of oxidative stress, inflammation, and gene expression in rats","authors":"Nehal S. Abdelghafar , Rady I. Hamed , Eiman M. El-Saied , Maha M. Rashad , Noha A.E. Yasin , Peter A. Noshy","doi":"10.1016/j.taap.2025.117574","DOIUrl":"10.1016/j.taap.2025.117574","url":null,"abstract":"<div><div>Oxymetholone, a synthetic anabolic steroid, is widely used for medical and performance-enhancing purposes but is associated with significant toxicity. Zinc oxide nanoparticles (ZnO-NPs) have attracted attention for their antioxidant and anti-inflammatory properties, which may counteract such toxic effects. This study investigates the protective role of ZnO-NPs against oxymetholone-induced liver and kidney damage in rats. Twenty-four rats were randomly assigned to four groups and treated orally as follows: control, oxymetholone (10 mg/kg), ZnO-NPs (5 mg/kg), and oxymetholone + ZnO-NPs. Oxymetholone administration significantly increased serum levels of urea, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Furthermore, oxidative stress markers, such as malondialdehyde (MDA), were significantly elevated, whereas reduced glutathione (GSH) levels were decreased in both hepatic and renal tissues. Oxymetholone exposure also upregulated the expression of pro-inflammatory and stress-related genes, including tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and nibrin (NBN). In contrast, it downregulated antioxidant genes such as nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), and superoxide dismutase (SOD). Histopathological examination revealed extensive liver and kidney damage, with immunohistochemistry demonstrating marked NF-κB expression. However, concurrent administration of ZnO-NPs mitigated these toxic effects by restoring antioxidant balance, modulating inflammatory pathways, and preserving tissue integrity. These findings suggest that ZnO-NPs have a protective role against oxymetholone-induced oxidative stress, inflammation, and tissue damage in hepatic and renal tissues.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117574"},"PeriodicalIF":3.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vitro disruption of the retinoic acid signaling pathway by industrial chemicals and pharmaceuticals 工业化学品和药物对维甲酸信号通路的体外破坏。

IF 3.4 3区医学

Toxicology and applied pharmacology Pub Date : 2025-09-19 DOI: 10.1016/j.taap.2025.117577

Anna Kjerstine Rosenmai , Jisun Paik , Eva Bay Wedebye , Nichlas Davidsen , Cecillie Henriksen , Mikala Melchiors , Terje Svingen

{"title":"In vitro disruption of the retinoic acid signaling pathway by industrial chemicals and pharmaceuticals","authors":"Anna Kjerstine Rosenmai , Jisun Paik , Eva Bay Wedebye , Nichlas Davidsen , Cecillie Henriksen , Mikala Melchiors , Terje Svingen","doi":"10.1016/j.taap.2025.117577","DOIUrl":"10.1016/j.taap.2025.117577","url":null,"abstract":"<div><div>Disruption of the retinoid signaling pathway by environmental chemicals is currently not directly assessed in regulatory testing. Although in vitro and in silico methods are available to assess disruption of this modality, more data on the selectivity and in vivo predictivity of specific assays are needed. To address this, we tested twenty-one pesticides and pharmaceuticals for their ability to agonize or antagonize the retinoic acid receptor alpha (RARα) or to inhibit the activity of aldehyde dehydrogenases (ALDH1As). Experimental data was generated using a RARα reporter gene assay and a cell line stably transfected to express two isoforms of ALDH1A for enzyme inhibition assay. The measured output of the latter was synthesized retinoic acid (RA) converted from added retinal. RARα antagonism predictions were obtained from the Danish (Q)SAR Database. Several test compounds acted as RAR agonists, while only a few inhibited ALDH1As, suggesting that the two assays together provide a more comprehensive view of how compounds impact RA signaling. Some substances were active in only one of the in vitro assays, highlighting the importance of including both models to avoid false negatives. No clear pattern was seen to suggest that either endpoint was more predictive of in vivo effects. Collectively, these findings underscore the need to include more assays for detecting different mechanisms of retinoid signal disruption in future testing regimens relying less on in vivo toxicity observation and more on predictive methods.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117577"},"PeriodicalIF":3.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145114150","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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