Novel compounds protect auditory hair cells against gentamycin-induced apoptosis by maintaining the expression level of H3K4me2
Novel compounds protect auditory hair cells against gentamycin-induced apoptosis by maintaining the expression level of H3K4me2
复制标题
新型化合物通过维持 H3K4me2 的表达水平来保护听毛细胞免受庆大霉素诱导的细胞凋亡
DOI：
10.1080/10717544.2018.1461277
复制
发表时间：
2018-04-24
期刊：
影响因子：
6
通讯作者：
Li, Huawei
中科院分区：
文献类型：
--
作者：
Li, Ao;You, Dan;Li, Huawei
摘要氨基糖苷类抗生素引起的毛细胞（HC）损失是导致听力损害的主要原因，有效预防HC损失仍然是一个未得到满足的医疗需求。据报道，表观遗传机制参与保护耳蜗细胞免受耳毒性药物损伤，在这项研究中，我们开发了新的生物活性化合物，其化学结构与表观遗传相关的赖氨酸特异性脱甲基酶1（LSD 1）抑制剂相似。据报道，LSD 1抑制剂通过阻止二甲基化组蛋白H3 K4（H3 K4 me 2）的去甲基化来保护耳蜗细胞。为了确定这些新化合物是否对HC产生类似的保护作用，我们用新化合物与庆大霉素一起处理小鼠耳蜗外植体培养物。庆大霉素暴露后，Corti器官中的HC严重丢失，而与新化合物的共同治疗显着防止庆大霉素诱导的HC丢失。暴露于庆大霉素后，HC细胞核中的H3 K4 me 2水平下降，但在新化合物存在下，H3 K4 me 2水平保持不变。细胞凋亡也参与了损伤过程，新化合物通过减少caspase-3的活化来保护内耳毛细胞免受细胞凋亡。总之，我们的研究结果表明，我们的新化合物通过防止H3 K4 me 2的去甲基化和抑制细胞凋亡来防止庆大霉素诱导的HC损失，这些结果可能为听力保护新药的开发提供理论基础。
Abstract Aminoglycoside-induced hair cell (HC) loss is a major cause of hearing impairment, and the effective prevention of HC loss remains an unmet medical need. Epigenetic mechanisms have been reported to be involved in protecting cochlear cells against ototoxic drug injury, and in this study we developed new bioactive compounds that have similar chemical structures as the epigenetics-related lysine-specific demethylase 1 (LSD1) inhibitors. LSD1 inhibitors have been reported to protect cochlear cells by preventing demethylation of dimethylated histone H3K4 (H3K4me2). To determine whether these new compounds exert similar protective effects on HCs, we treated mouse cochlear explant cultures with the new compounds together with gentamycin. There was a severe loss of HCs in the organ of Corti after gentamycin exposure, while co-treatment with the new compounds significantly protected against gentamycin-induced HC loss. H3K4me2 levels in the nuclei of HCs decreased after exposure to gentamycin, but H3K4me2 levels were maintained in the presence of the new compounds. Apoptosis is also involved in the injury process, and the new compounds protected the inner ear HCs against apoptosis by reducing caspase-3 activation. Together, our findings demonstrate that our new compounds prevent gentamycin-induced HC loss by preventing the demethylation of H3K4me2 and by inhibiting apoptosis, and these results might provide the theoretical basis for novel drug development for hearing protection.