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Cadmium induces ferroptosis mediated inflammation by activating Gpx4/Ager/p65 axis in pancreatic β-cells

炎症 细胞生物学 免疫系统 程序性细胞死亡 脂质过氧化 GPX4 化学 癌症研究 氧化应激 生物 免疫学 细胞凋亡 生物化学 过氧化氢酶 谷胱甘肽过氧化物酶
作者
Huihui Hong,Xiaona Lin,Yu‐Dong Xu,Tong Tong,Jingjing Zhang,Haotian He,Lingling Yang,Yuan‐Qiang Lu,Zhou Zhou
出处
期刊:Science of The Total Environment [Elsevier]
卷期号:849: 157819-157819 被引量:34
标识
DOI:10.1016/j.scitotenv.2022.157819
摘要

Cadmium (Cd) is a widely distributed endocrine disruptor and has been reported to be closely correlated to the pathogenesis of diabetes. Since pancreatic β-cells loss and dysfunction are central to pathogenesis of diabetes, studying Cd toxicity on pancreatic β-cells and its molecular mechanism is an important scientific issue. However, less attention has been payed to study how Cd induces pancreatic β-cells death and dysfunction in recent years. Thus, our study aims to explore the toxic mechanism of Cd treatment on pancreatic β-cells using both cellular and animal models. Firstly, it was confirmed that Cd induced decreased cell viability and insulin secretion in a dose-and time-dependent manner in MIN6 cells. To explore the underlying mechanism, transcriptomic analysis was employed to screen the differentially expressed genes and disturbed metabolic pathways. Go and KEGG analysis showed that Cd exposure triggered ferroptosis process in MIN6 cells. We further validated that Cd led to GSH depletion, Gpx4 reduction, lipid peroxidation, mitochondrial membrane potential loss and ultrastructural damage at mitochondrial level. Since immune system process was also perturbed based on GO analysis, we found that Cd activated Ager/Pkc/p65 inflammatory process. Moreover, ferroptosis inhibitor Fer-1 could effectively antagonized the activation of Ager-mediated immune process. It was also revealed that Cd induced iron accumulation as well as decreased Gpx4 expression in mice islets. We also uncovered that Cd led to systemic and pancreatic inflammation as early as third week after Cd exposure. Our study emphasizes the importance of ferroptotic cell death on Cd-induced systemic chronic inflammation. A novel target is provided to prevent Cd-induced pancreatic β-cells dysfunction and improve the chronic inflammatory state for prediabetes prevention.
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