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激活转录因子6通过调节未折叠蛋白质反应,促进了西斯丁诱导的耳毒性
Yu-Chen Liu1, Xue Bai2, Bing Liao2
1Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China; Queen Mary school, Jiangxi Medical College, Nanchang University, Nanchang, China.
概括
激活转录因子6 (ATF6) 通过减少毛细胞亡,保护免受西斯普拉丁诱导的耳毒性. 药理上激活ATF6为缓解西斯普拉丁引起的听力损失提供了潜在的治疗策略.
科学领域:
- 耳毒性研究研究
- 药物诱导损害的分子机制
- 细胞内膜网膜的应激反应应激反应
背景情况:
- 西斯是一种广泛使用的抗癌药物,但引起严重的耳毒性,主要是通过耳毛细胞死亡.
- 在西斯普拉丁诱导的毛细胞亡背后的精确机制仍然在很大程度上是未知的.
- 激活转录因子6 (ATF6),一种内细胞网膜局部化的蛋白质,与细胞应激反应有关.
研究的目的:
- 调查ATF6在西斯普拉丁诱导的耳毒性中的作用.
- 探索ATF6激活的潜力,作为治疗干预对抗西斯普拉丁诱导的听力损失.
主要方法:
- 在实验室研究中,使用暴露于西斯的小鼠听觉OC-1细胞和耳培养物.
- 在体内实验中,在接受西斯丁治疗的小鼠中,进行了ATF6激动剂的皮下注射.
- 评估亡,ATF6和CHOP表达,听觉脑干响应 (ABR) 值和外皮毛细胞存活率.
主要成果:
- 西斯普拉丁诱导了OC-1细胞的亡,增加了ATF6和CHOP的表达.
- 在体外,ATF6激动剂治疗改善了西斯普拉丁诱导的细胞毒性,并在体内预防了外皮毛细胞的损失.
- ATF6激活显著缓解了西斯胺诱导的ABR值升高.
- ATF6激活抑制了亡信号调节激酶1 (ASK1) 的表达.
结论:
- 激活ATF6可显著地防止西斯普拉丁诱导的毛细胞亡,部分通过抑制ASK1.1.
- 通过ATF6介导的未折叠蛋白质反应的药理学激活是对西斯普拉丁耳毒性有前途的治疗策略.
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