氧化应激
耳毒性
PI3K/AKT/mTOR通路
线粒体通透性转换孔
细胞凋亡
蛋白激酶B
药理学
化学
活性氧
顺铂
细胞生物学
医学
生物
内科学
生物化学
程序性细胞死亡
化疗
作者
Tian-lan Huang,Wenjun Jiang,Zan Zhou,Tian-feng Shi,Miao Yu,Meng Yu,Junqiang Si,Yanping Wang,Li Li
标识
DOI:10.1016/j.cbi.2024.110939
摘要
Cisplatin (CDDP) is broadly employed to treat different cancers, whereas there are no drugs approved by the Food and Drug Administration (FDA) for preventing its side effects, including ototoxicity. Quercetin (QU) is a widely available natural flavonoid compound with anti-tumor and antioxidant properties. The research was designed to explore the protective effects of QU on CDDP-induced ototoxicity and its underlying mechanisms in male C57BL/6 J mice and primary cultured pericytes (PCs). Hearing changes, morphological changes of stria vascularis, blood labyrinth barrier (BLB) permeability and expression of apoptotic proteins were observed in vivo by using the auditory brainstem response (ABR) test, HE staining, Evans blue staining, immunohistochemistry, western blotting, etc. Oxidative stress levels, mitochondrial function and endothelial barrier changes were observed in vitro by using DCFH-DA probe detection, flow cytometry, JC-1 probe, immunofluorescence and the establishment in vitro BLB models, etc. QU pretreatment activates the PI3K/AKT signaling pathway, inhibits CDDP-induced oxidative stress, protects mitochondrial function, and reduces mitochondrial apoptosis in PCs. However, PI3K/AKT specific inhibitor (LY294002) partially reverses the protective effects of QU. In addition, in vitro BLB models were established by coculturing PCs and endothelial cells (ECs), which suggests that QU both reduces the CDDP-induced apoptosis in PCs and improves the endothelial barrier permeability. On the whole, the research findings suggest that QU can be used as a novel treatment to reduce CDDP-induced ototoxicity.
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