Inhibiting DNA methylation alleviates cisplatin-induced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway.
Inhibiting DNA methylation alleviates cisplatin-induced hearing loss by decreasing oxidative stress-induced mitochondria-dependent apoptosis via the LRP1-PI3K/AKT pathway.
复制标题
抑制 DNA 甲基化通过 LRP1-PI3K/AKT 途径减少氧化应激诱导的线粒体依赖性细胞凋亡，从而减轻顺铂引起的听力损失
DOI：
10.1016/j.apsb.2021.11.002
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发表时间：
2022-03
影响因子：
14.5
通讯作者：
Li, Huawei
中科院分区：
文献类型：
--
作者：
He, Yingzi;Zheng, Zhiwei;Liu, Chang;Li, Wen;Zhao, Liping;Nie, Guohui;Li, Huawei
顺铂相关的耳毒性是化疗的严重副作用，可导致不可逆转的听力损失。本研究旨在评价DNA甲基转移酶(DNMT)抑制剂RG108对顺铂耳毒性的影响。应用免疫组织化学、细胞凋亡分析和听性脑干反应(ABR)检测RG108对顺铂诱导的小鼠毛细胞(HCs)和螺旋神经节神经元(SGN)损伤的影响。用罗丹明123和TMRM检测线粒体膜电位。用Cellrox Green和Mitosox-red探针检测ROS含量。通过测定耗氧率(OCR)评价线粒体呼吸功能。结果表明，RG108能明显减轻顺铂对HCS和SGN的损伤，并通过阻止ROS积聚来保护线粒体功能，从而减轻细胞凋亡率。此外，RG108还上调了HEI-OC1细胞中bcl2的表达，下调了APAF1、Bax和BAD的表达，并触发了PI3K/AKT信号通路。顺铂治疗后低密度脂蛋白受体相关蛋白1(LRP1)表达降低，LRP1启动子高甲基化。RG108处理可增加LRP1的表达，降低LRP1启动子的甲基化。综上所述，RG108可能通过激活LRP1-PI3K/AKT通路来预防顺铂所致的听力损失。RG108通过维持LRP1-PI3K/AKT信号轴，减轻顺铂耳毒性中的氧化应激和细胞凋亡，有望成为治疗听力损失的候选药物。
Cisplatin-related ototoxicity is a critical side effect of chemotherapy and can lead to irreversible hearing loss. This study aimed to assess the potential effect of the DNA methyltransferase (DNMT) inhibitor RG108 on cisplatin-induced ototoxicity. Immunohistochemistry, apoptosis assay, and auditory brainstem response (ABR) were employed to determine the impacts of RG108 on cisplatin-induced injury in murine hair cells (HCs) and spiral ganglion neurons (SGNs). Rhodamine 123 and TMRM were utilized for mitochondrial membrane potential (MMP) assessment. Reactive oxygen species (ROS) amounts were evaluated by Cellrox green and Mitosox-red probes. Mitochondrial respiratory function evaluation was performed by determining oxygen consumption rates (OCRs). The results showed that RG108 can markedly reduce cisplatin induced damage in HCs and SGNs, and alleviate apoptotic rate by protecting mitochondrial function through preventing ROS accumulation. Furthermore, RG108 upregulated BCL-2 and downregulated APAF1, BAX, and BAD in HEI-OC1 cells, and triggered the PI3K/AKT pathway. Decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1) and high methylation of the LRP1 promoter were observed after cisplatin treatment. RG108 treatment can increase LRP1 expression and decrease LRP1 promoter methylation. In conclusion, RG108 might represent a new potential agent for preventing hearing loss induced by cisplatin via activating the LRP1-PI3K/AKT pathway. RG108 attenuated oxidative stress and apoptosis in cisplatin-induced ototoxicity via maintaining LRP1–PI3K/AKT signaling axis, and it might be a potential candidate agent for the treatment of hearing loss.
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影响因子：
3.7
作者：
Aburto MR;Magariños M;Leon Y;Varela-Nieto I;Sanchez-Calderon H
通讯作者：
Sanchez-Calderon H
影响因子：
5.3
作者：
Ghosh S;Sheth S;Sheehan K;Mukherjea D;Dhukhwa A;Borse V;Rybak LP;Ramkumar V
通讯作者：
Ramkumar V
影响因子：
4.8
作者：
Fernandez-Castaneda, Anthony;Arandjelovic, Sanja;Gaultier, Alban
通讯作者：
Gaultier, Alban
抑制蛋白质精氨酸甲基转移酶 6 可减少活性氧的产生并减弱氨基糖苷类和顺铂诱导的毛细胞死亡
影响因子：
12.4
作者：
He, Yingzi;Li, Wen;Li, Huawei
通讯作者：
Li, Huawei
影响因子：
11.2
作者：
Fears, CY;Grammer, JR;Gladson, CL
通讯作者：
Gladson, CL