Food and Chemical Toxicology最新文献_第9页

Molecular mechanism of the combined exposure to AFB1 and DON in promoting the functional and phenotypic remodeling of porcine alveolar macrophages AFB1和DON联合暴露促进猪肺泡巨噬细胞功能和表型重塑的分子机制

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-08-05 DOI: 10.1016/j.fct.2025.115686

Wenshuo Zhao , Qirui Yang , Shuxin Li , Yuhang Sun

{"title":"Molecular mechanism of the combined exposure to AFB1 and DON in promoting the functional and phenotypic remodeling of porcine alveolar macrophages","authors":"Wenshuo Zhao , Qirui Yang , Shuxin Li , Yuhang Sun","doi":"10.1016/j.fct.2025.115686","DOIUrl":"10.1016/j.fct.2025.115686","url":null,"abstract":"<div><div>Aflatoxin B1 (AFB1) and deoxynivalenol (DON) often coexist and exhibit immunotoxicity. Recent studies have reported that AFB1 and DON exposure alone not only promoted immunosuppression, but also induced inflammation, demonstrating as bidirectional immunotoxicity. Nevertheless, whether the combination of AFB1 and DON exhibit bidirectional immunotoxicity and their mechanism remain unclear. Here, porcine alveolar macrophages were used as an <em>in vitro</em> model, and quantitative real-time PCR (qRT-PCR), Western blotting (WB), flow cytometry, network toxicology and molecular docking were used to investigate the bidirectional immunotoxicity and mechanism of AFB1 and DON combined contamination. Our results showed that the combined exposure of low concentrations of AFB1 and DON (0.005 + 0.5 μg/mL) induced macrophages polarizing to immunostimulatory M1 by upregulating the TLR4-NF-κB, while the combined exposure of high concentrations of AFB1 and DON (0.04 + 4 μg/mL) promoted macrophages polarizing to immunosuppressive M2 by downregulating the PI3K-AKT. The results will provide new insights for the in-depth study of the pathogenic mechanism of AFB1 and DON combined contamination.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"205 ","pages":"Article 115686"},"PeriodicalIF":3.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781164","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

Relationship between simvastatin pharmacokinetics and muscle toxicity in male mice 辛伐他汀药代动力学与雄性小鼠肌肉毒性的关系。

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-08-05 DOI: 10.1016/j.fct.2025.115688

Jamal Bouitbir , Gerda M. Sanvee , Miljenko V. Panajatovic , Natasha Bärenzung Fehrenbach , Théo Fréchard , Madhuri Manivannan , Urs Duthaler , Stephan Krähenbühl

{"title":"Relationship between simvastatin pharmacokinetics and muscle toxicity in male mice","authors":"Jamal Bouitbir , Gerda M. Sanvee , Miljenko V. Panajatovic , Natasha Bärenzung Fehrenbach , Théo Fréchard , Madhuri Manivannan , Urs Duthaler , Stephan Krähenbühl","doi":"10.1016/j.fct.2025.115688","DOIUrl":"10.1016/j.fct.2025.115688","url":null,"abstract":"<div><div>Statins are highly effective in reducing plasma LDL-cholesterol but may be myotoxic. Since the relationship between statin exposure and myotoxicity is not clearly established, the current study aimed to compare blood and skeletal muscle concentrations with myotoxicity in male mice treated orally with 5, 10 and 25 mg/kg/day simvastatin for 3 weeks.</div><div>After the first dose, simvastatin blood pharmacokinetics was dose-dependent, with exposures corresponding to humans treated with 80, 160 and 400 mg/day simvastatin. Skeletal muscle concentrations 24 h after the last dose of the three weeks-treatment period were dose-dependent with concentrations in the low nanomolar range. Simvastatin inhibited activation of key components of the insulin signaling pathway starting at 5 mg/kg/day whereas effects on physical performance and muscle strength were more accentuated at 10 than at 5 or 25 mg/kg/day. Simvastatin 25 mg/kg/day increased the SOD2 muscle protein expression. Simvastatin decreased gastrocnemius muscle total and reduced glutathione.</div><div>In conclusion, oral administration of simvastatin from 5 to 25 mg/kg/day to mice showed linear pharmacokinetics and achieved blood concentrations equivalent to those obtained in humans treated with therapeutic to supratherapeutic doses. At 25 mg/kg simvastatin, myotoxicity is less accentuated than at 10 mg/kg, possibly due to induction of protective mechanisms.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"205 ","pages":"Article 115688"},"PeriodicalIF":3.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797816","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

Occurrence, migration kinetics, and health risks of alkylphenols in colored and colorless bottled water 烷基酚在有色和无色瓶装水中的发生、迁移动力学和健康风险

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-08-05 DOI: 10.1016/j.fct.2025.115685

Mina Mohammadipour , Sajedeh Karimi , Karim Ebrahimpour , Sahar Gholipour , Farzaneh Mohammadi

{"title":"Occurrence, migration kinetics, and health risks of alkylphenols in colored and colorless bottled water","authors":"Mina Mohammadipour , Sajedeh Karimi , Karim Ebrahimpour , Sahar Gholipour , Farzaneh Mohammadi","doi":"10.1016/j.fct.2025.115685","DOIUrl":"10.1016/j.fct.2025.115685","url":null,"abstract":"<div><div>The global rise in bottled water consumption raises concerns about potential health risks associated with chemical migration from polyethylene terephthalate (PET) packaging. Alkylphenols, such as 4-nonylphenol (4-NP) and 4-tert-octylphenol (4-t-OP), are used as stabilizers in PET and are known endocrine disruptors. Their migration into bottled water may pose health risks. This study aimed to detect and quantify alkylphenols in colored and colorless PET bottled water, investigate their migration kinetics during shelf-life storage, and assess potential non-carcinogenic and estrogenic risks. A total of 30 bottled water samples, equally divided between colored and colorless PET bottles, were analyzed. Detection and quantification of 4-NP and 4-t-OP were performed using gas chromatography (GC) with a mass spectrometry (MS) detector. Results showed the presence of 4-NP and 4-t-OP in all samples, with concentrations ranging from 182 to 933 ng/L and 1.5–19 ng/L, respectively. Kinetic analysis revealed that alkylphenol migration followed a first-order model, with significantly higher concentrations and migration rates observed in colored PET bottles. Despite no significant non-carcinogenic or estrogenic risks from bottled water consumption, these findings emphasize the need for concern regarding colored PET bottles as a potentially higher source of exposure to alkylphenols. Given the widespread use of similar plastics in food and beverage packaging, cumulative exposure remains a critical issue. Continued monitoring and regulatory efforts are essential to minimize human exposure to these contaminants.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"204 ","pages":"Article 115685"},"PeriodicalIF":3.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780788","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

Mercury in online skin-lightening cosmetics: A health risk assessment of products from selected Asian countries 在线美白化妆品中的汞：对部分亚洲国家产品的健康风险评估

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-08-05 DOI: 10.1016/j.fct.2025.115676

Dave Gabriel E. Cadungog , Jhon Robin D. Yee , Raymond J. Sucgang

引用次数: 0

Breast milk contamination by toxic metals in active and passive smokers: A hidden threat to infant health 主动吸烟者和被动吸烟者的母乳被有毒金属污染：对婴儿健康的潜在威胁

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-08-04 DOI: 10.1016/j.fct.2025.115677

Nayereh Rezaie Rahimi , Pejman Shahrokhi , Farshid Soleimani , Hossein Arfaeinia , Sara Dadipoor , Ehsan Ramezanian Nik , Ali Mouseli , Niloufar Borhani Yazdi

{"title":"Breast milk contamination by toxic metals in active and passive smokers: A hidden threat to infant health","authors":"Nayereh Rezaie Rahimi , Pejman Shahrokhi , Farshid Soleimani , Hossein Arfaeinia , Sara Dadipoor , Ehsan Ramezanian Nik , Ali Mouseli , Niloufar Borhani Yazdi","doi":"10.1016/j.fct.2025.115677","DOIUrl":"10.1016/j.fct.2025.115677","url":null,"abstract":"<div><div>The presence of environmental contaminants in breast milk has become a major public health issue. Smoking has been recognized as a risk factor that can raise the concentration of pollutants in breast milk. This study was aimed at comparing the metal(oid)s levels in breast milk from active and passive smoker women, and assessing the associated health risks for infants consuming their milk. Milk samples were obtained one day after delivery. Inductively coupled plasma mass spectrometry (ICP-MS) technique was used to determine the metal(oid)s concentrations in samples. The mean ± SD concentration of Cd, Pb, Co, As, Cr and Mn in the active smoker were 1.92 ± 2.17, 17.5 ± 11.26, 0.64 ± 0.51, 3.48 ± 2.7, 1.31 ± 1.65 and 18.01 ± 8.3 μg/L, respectively and were significantly higher than passive smoker and control groups. The concentration of all metal(loid)s (except Cu and Zn) were significantly different between three groups (p-value˂0.001). The total cancer risk (TCR) in all groups was more than 1 × 10<sup>−4</sup>, which indicates a significant risk of cancer development. The findings regarding the impact of smoking and environmental tobacco smoke (ETS) exposure on lactating women and their infants underscore the urgent need for increased awareness and preventive measures.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"204 ","pages":"Article 115677"},"PeriodicalIF":3.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766430","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

Mitochondrial dynamics imbalance and energy dyshomeostasis mediated developmental toxicity of ochratoxin a in zebrafish (Danio rerio) 线粒体动力学失衡和能量失衡介导的赭曲霉毒素a对斑马鱼的发育毒性

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-08-04 DOI: 10.1016/j.fct.2025.115679

Meng Li , Mengai He , Zhenfeng Liao , Chenxi Li , Yingqiu Mi , Ningning Pan , Xinyi Xie , Zhiyu Liu , Jiayin Hou , Xueli Yu , Liezhong Chen

{"title":"Mitochondrial dynamics imbalance and energy dyshomeostasis mediated developmental toxicity of ochratoxin a in zebrafish (Danio rerio)","authors":"Meng Li , Mengai He , Zhenfeng Liao , Chenxi Li , Yingqiu Mi , Ningning Pan , Xinyi Xie , Zhiyu Liu , Jiayin Hou , Xueli Yu , Liezhong Chen","doi":"10.1016/j.fct.2025.115679","DOIUrl":"10.1016/j.fct.2025.115679","url":null,"abstract":"<div><div>Ochratoxin A (OTA) has been increasingly detected in foodstuffs and human samples. However, the molecular mechanisms of developmental toxicity induced by OTA remain poorly explored. Our results demonstrated that oxidative stress induced by OTA caused mitochondrial dysfunction in larvae, characterized by malformed mitochondria, and decreased mitochondrial membrane potential and complex II, IV and V activities. Central carbon metabolism analysis indicated that exposure to OTA induced energy metabolism disturbance by decreasing ATP contents and altering energy-relevant metabolite contents. Energy metabolism disturbance was further confirmed by transcriptomics analysis, with differentially expressed genes significantly enriching in glycolysis and TCA cycle. Additionally, molecular docking simulations and surface plasmon resonance analysis demonstrated that OTA interacted with mfn1 and mfn2, verifying its interference effects on mitochondrial dynamics. The insufficient energy supply induced by OTA activated AMP-activated protein kinase signal pathways, which accelerated catabolic processes, accompanied by decreases in yolk sac size and yolk lipid. Finally, insufficient energy supply caused developmental retardation of zebrafish larvae. Collectively, this study systematically elucidated the roles of mitochondrial dynamics imbalance and energy dyshomeostasis in the developmental toxicity induced by OTA, providing critical insights for refining food safety standards and therapeutic interventions.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"204 ","pages":"Article 115679"},"PeriodicalIF":3.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766393","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

Elucidating the mechanism of dibutyl phthalate on Alzheimer's disease through network toxicology, molecular docking and validation in mouse neuroblastoma cells 通过网络毒理学、分子对接和小鼠神经母细胞瘤细胞验证阐明邻苯二甲酸二丁酯治疗阿尔茨海默病的机制

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-08-03 DOI: 10.1016/j.fct.2025.115680

Jing Zi , Xinlong Li , Qianqian Cao , Yifan Hu , Zhichang Ran , Yanliu Li , Jiayuan He , Xiaoyu Wang , Guo Cheng , Jingyuan Xiong

{"title":"Elucidating the mechanism of dibutyl phthalate on Alzheimer's disease through network toxicology, molecular docking and validation in mouse neuroblastoma cells","authors":"Jing Zi , Xinlong Li , Qianqian Cao , Yifan Hu , Zhichang Ran , Yanliu Li , Jiayuan He , Xiaoyu Wang , Guo Cheng , Jingyuan Xiong","doi":"10.1016/j.fct.2025.115680","DOIUrl":"10.1016/j.fct.2025.115680","url":null,"abstract":"<div><div>Dibutyl phthalate (DBP), a widely used plasticizer, has been suggested to be neurotoxic. We aim to explore possible molecular mechanisms of DBP on Alzheimer's disease (AD) using a combined approach of network toxicology, molecular docking and experimental validations. We retrieved targets of DBP from ChEMBL and STITCH databases, while obtaining AD-related targets from GeneCards and OMIM databases. We identified 193 overlapping targets, and highlighted 13 core targets by protein–protein interaction analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these targets are mainly enriched in neuroinflammation, synaptic signaling, and metabolic pathways. Molecular docking showed strong binding affinities for AD-related proteins, including translocator protein (TSPO), transcription factor c-Jun (JUN), estrogen receptor 1 (ESR1), cyclin-dependent kinase inhibitor 1A (CDKN1A), and prostaglandin-endoperoxide synthase 2 (PTGS2). In validation, we exposed DBP (0–200 μM) to N2a mouse neuroblastoma cells for 48 h. Western-blot demonstrated significant upregulation of TSPO, JUN, CDKN1A, and PTGS2, while ESR1 showed an upward trend without statistical significance. In conclusion, DBP may contribute to AD development by affecting AD targets expression (TSPO, JUN, CDKN1A, and PTGS2) and modulating pathways associated with neuroinflammation and synaptic function, providing mechanistic insights on how environmental toxicants may influence neurodegenerative processes.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"204 ","pages":"Article 115680"},"PeriodicalIF":3.5,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763720","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

Mechanisms of PDC-induced testicular Toxicity: Oxidative stress, steroidogenic suppression, and modulation by ZnO-NP/TEO synergy pdc诱导睾丸毒性的机制：氧化应激、类固醇抑制和ZnO-NP/TEO协同作用的调节

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-07-31 DOI: 10.1016/j.fct.2025.115675

Asmaa S. Morsi , Hager M. Ramadan , Ahmed M. Youssef , Nadia A. Taha

{"title":"Mechanisms of PDC-induced testicular Toxicity: Oxidative stress, steroidogenic suppression, and modulation by ZnO-NP/TEO synergy","authors":"Asmaa S. Morsi , Hager M. Ramadan , Ahmed M. Youssef , Nadia A. Taha","doi":"10.1016/j.fct.2025.115675","DOIUrl":"10.1016/j.fct.2025.115675","url":null,"abstract":"<div><div>Potassium dichromate (PDC), a potent industrial toxicant, induces severe testicular damage, though its precise mechanisms remain incompletely defined. This study investigated the mechanistic pathways of PDC-induced reproductive toxicity in male Sprague-Dawley rats (n = 108). Rats were allocated into 9 groups: controls (oral, intraperitoneal) <strong>(I),(II), PDC</strong>-only (10.5 mg/kg bwt, <strong>III)</strong>, Zinc Oxide Nanoparticles, <strong>ZnO-NPs</strong>-only (5 mg/kg bwt, <strong>IV</strong>), Thyme Essential Oil, <strong>TEO</strong>-only (5 mg/kg bwt, <strong>V)</strong>, <strong>ZnO-NPs + TEO (VI)</strong>, <strong>PDC + ZnO-NPs (VII)</strong>, <strong>PDC + TEO (VIII)</strong>, and <strong>PDC + ZnO-NPs + TEO (IX)</strong>, treated for 8 weeks. <strong>PDC</strong> exposure triggered significant testicular oxidative stress, evidenced by elevated malondialdehyde <strong>(MDA)</strong> and Nitric oxide <strong>(Nox)</strong> activity alongside depleted catalase, glutathione, and total antioxidants. This redox imbalance directly correlated with impaired spermatogenesis and steroidogenesis, manifesting as reduced testis weight, decreased serum free testosterone, LH, and FSH levels, compromised sperm quality (motility, count, morphology), and downregulation steroidogenic genes <strong>(<em>StAR</em>, <em>CYP11A1</em>, HSD-3β)</strong>. Histopathological analysis confirmed seminiferous tubule degeneration and germ cell apoptosis. Critically, reversal of these effects by antioxidants <strong>(TEO, ZnO-NPs;</strong> alone/combined) <strong>validated oxidative stress and steroidogenic disruption as primary drivers of PDC testicular toxicity</strong>. These findings define the mechanistic basis of <strong>PDC-</strong>induced reproductive injury, highlighting its disruption of redox balance and endocrine function.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"204 ","pages":"Article 115675"},"PeriodicalIF":3.5,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757856","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

Tri-ortho-cresyl phosphate causes glucose intolerance and insulin resistance in mice by inducing oxidative stress 三邻甲酰磷酸通过诱导氧化应激引起小鼠葡萄糖耐受不良和胰岛素抵抗

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-07-30 DOI: 10.1016/j.fct.2025.115668

Rui Wang, Jie Chen, Pan Wang

{"title":"Tri-ortho-cresyl phosphate causes glucose intolerance and insulin resistance in mice by inducing oxidative stress","authors":"Rui Wang, Jie Chen, Pan Wang","doi":"10.1016/j.fct.2025.115668","DOIUrl":"10.1016/j.fct.2025.115668","url":null,"abstract":"<div><div>As a typical organophosphorus compound, tri-ortho-cresyl phosphate (TOCP) has been widely used as an industrial additive. But the toxicity of TOCP in the maintenance of glucose homeostasis has not been fully elucidated. In this study, the mechanism of TOCP's effect in glucose homeostasis was investigated using both animal models and cellular experiments. Subchronic exposure to TOCP in ICR mice caused increase of fast glucose level in blood and insulin resistance. In addition, we found significant oxidative stress and downregulation of glucose transporter in liver after TOCP treatment. In pancreas, compensatory pancreatic β-cell hyperplasia was observed. Notably, antioxidant vitamin C cotreatment was able to ameliorate glucose metabolism disorders and reduce oxidative stress in liver <em>in vivo</em>. In the HepG-2 cells, TOCP metabolite CBDP exposure caused decrease of glucose uptake stimulated by insulin, downregulation of glucose transporter gene and accumulation of reactive oxygen species. Vc cotreatment reversed these phenomena. This study demonstrates that organophosphorus exposure can trigger insulin resistance and glucose intolerance through induction of oxidative stress, which provides new insights in the organophosphorus compounds' metabolic toxicity and potential treatment of this toxicity.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"204 ","pages":"Article 115668"},"PeriodicalIF":3.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144748583","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

Targeting the PERK/NRF2 pathway: Enhancing cisplatin efficacy in resistant ovarian cancer cells via MRP1 and ROS modulation 靶向PERK/NRF2通路：通过MRP1和ROS调节增强顺铂对耐药卵巢癌细胞的疗效

IF 3.5 3区医学

Food and Chemical Toxicology Pub Date : 2025-07-30 DOI: 10.1016/j.fct.2025.115672

Seyedeh Sara Ghorbanhosseini , Mitra Nourbakhsh , Fatemeh Mosaffa , Mahmoud Aghaei

{"title":"Targeting the PERK/NRF2 pathway: Enhancing cisplatin efficacy in resistant ovarian cancer cells via MRP1 and ROS modulation","authors":"Seyedeh Sara Ghorbanhosseini , Mitra Nourbakhsh , Fatemeh Mosaffa , Mahmoud Aghaei","doi":"10.1016/j.fct.2025.115672","DOIUrl":"10.1016/j.fct.2025.115672","url":null,"abstract":"<div><div>Overcoming chemotherapy resistance remains a pivotal challenge in ovarian cancer treatment. This study investigates the potential of combining cisplatin with GSK2606414, a PERK inhibitor, to enhance therapeutic efficacy against cisplatin-resistant ovarian cancer cells. cisplatin resistance is driven by the PERK/NRF2 pathway, which activates MRP1 upregulation and antioxidant defenses, thus promoting cell survival. By inhibiting PERK phosphorylation, GSK2606414 disrupts this pathway, downregulating MRP1 and increasing oxidative stress to sensitize cancer cells to cisplatin.</div><div>Our findings reveal that the GSK2606414-cisplatin combination significantly reduces cell viability and proliferation, particularly in resistant cell lines, allowing for dose reduction and potentially lower side effects. The combined therapy also amplifies, increasing Caspase-12 and CHOP protein levels during endoplasmic reticulum stress. By targeting the p-PERK/p-NRF2/MRP1 and p-PERK/p-NRF2/SOD pathways, GSK2606414 decreases MRP1 expression and elevates ROS levels, rendering resistant cells more susceptible to chemotherapy. Additionally, this combination boosts intracellular cisplatin accumulation in both cisplatin-sensitive and -resistant ovarian cancer cell lines, reinforcing its cytotoxic impact.</div><div>These findings underscore the promise of GSK2606414 and cisplatin co-treatment as a potent strategy to counteract ovarian cancer resistance. This combination could potentially advance therapeutic outcomes and provide a new pharmacological approach to resistant cancers.</div></div>","PeriodicalId":317,"journal":{"name":"Food and Chemical Toxicology","volume":"204 ","pages":"Article 115672"},"PeriodicalIF":3.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757855","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