siRNA-mediated knock-down of NOX3: therapy for hearing loss?
siRNA-mediated knock-down of NOX3: therapy for hearing loss?
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DOI：
10.1007/s00018-012-1016-3
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发表时间：
2012-07
期刊：
影响因子：
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通讯作者：
Ramkumar V
中科院分区：
文献类型：
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作者：
Rybak LP;Mukherjea D;Jajoo S;Kaur T;Ramkumar V
顺铂是一种广泛使用的化疗药物，会导致严重的听力损失。先前的研究表明，顺铂暴露与耳蜗中活性氧（ROS）的增加有关。内耳表达 NADPH 氧化酶的独特异构体 NOX3。这种酶可能是耳蜗中 ROS 产生的主要来源。通过 siRNA 预处理敲低 NOX3 可防止顺铂耳毒性，这一点通过听力阈值和内耳感觉细胞的保留得到证明。跨鼓室 NOX3 siRNA 降低了耳蜗组织中 NOX3 和耳蜗损伤生物标志物的表达，包括瞬时受体香草酸 1 (TRPV1) 通道和肾损伤分子 1 (KIM-1)。此外，如 TUNEL 染色所示，针对 NOX3 的 siRNA 减少了细胞凋亡，并阻止了 Bax 表达的增加，并消除了顺铂给药后 Bcl2 表达的减少。经鼓室施用针对NOX3的siRNA可能提供一种减轻顺铂耳毒性的有用方法。在本文中，我们回顾了最近发表的有关 NOX3 在耳毒性中的作用以及 siRNA 对顺铂引起的听力损失的影响的出版物。
Cisplatin is a widely used chemotherapeutic agent that causes significant hearing loss. Previous studies have shown that cisplatin exposure is associated with increase in reactive oxygen species (ROS) in the cochlea. The inner ear expresses a unique isoform of NADPH oxidase, NOX3. This enzyme may be the primary source of ROS generation in the cochlea. The knockdown of NOX3 by pretreatment with siRNA prevented cisplatin ototoxicity, as demonstrated by preservation of hearing thresholds and inner ear sensory cells. Trans-tympanic NOX3 siRNA reduced the expression of NOX3 and biomarkers of cochlear damage, including transient receptor vanilloid 1 (TRPV1) channel and kidney injury molecule-1 (KIM-1) in cochlear tissues. In addition, siRNA against NOX3 reduced apoptosis as demonstrated by TUNEL staining, and prevented the increased expression of Bax and abrogated the decrease in Bcl2 expression following cisplatin administration. Trans-tympanic administration of siRNA directed against NOX3 may provide a useful method of attenuating cisplatin ototoxicity. In this paper, we review recent publications dealing with the role of NOX3 in ototoxicity and the effects of siRNA against cisplatin-induced hearing loss.