Han Hezhou, Dong Yaodong, Ma Xiulan
Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
Front Cell Dev Biol. 2020 Jul 28;8:702. doi: 10.3389/fcell.2020.00702. eCollection 2020.
Aminoglycoside-induced ototoxicity can have a major impact on patients' quality of life and social development problems. Oxidative stress affects normal physiologic functions and has been implicated in aminoglycoside-induced inner ear injury. Excessive accumulation of reactive oxygen species (ROS) damages DNA, lipids, and proteins in cells and induces their apoptosis. Dihydromyricetin (DHM) is a natural flavonol with a wide range of health benefits including anti-inflammatory, antitumor, and antioxidant effects; however, its effects and mechanism of action in auditory hair cells are not well understood. The present study investigated the antioxidant mechanism and anti-ototoxic potential of DHM using House Ear Institute-Organ of Corti (HEI-OC)1 auditory cells and cochlear explant cultures prepared from Kunming mice. We used gentamicin to establish aminoglycoside-induced ototoxicity models. Histological and physiological analyses were carried out to determine DHM's pharmacological effects on gentamicin-induced ototoxicity. Results showed DHM contributes to protecting cells from apoptotic cell death by inhibiting ROS accumulation. Western blotting and quantitative RT-PCR analyses revealed that DHM exerted its otoprotective effects by up-regulating levels of peroxisome proliferator activated receptor γ-coactivator (PGC)-1α and Sirtuin (SIRT)3. And the role of PGC-1α and SIRT3 in the protective effects of DHM was evaluated by pharmacologic inhibition of these factors using SR-18292 and 3-(1-1,2,3-triazol-4-yl) pyridine, respectively, which indicated DHM's protective effect was dependent on activation of the PGC-1α/SIRT3 signaling. Our study is the first report to identify DHM as a potential otoprotective drug and provides a basis for the prevention and treatment of hearing loss caused by aminoglycoside antibiotic-induced oxidative damage to auditory hair cells.
氨基糖苷类药物引起的耳毒性可对患者的生活质量和社会发展问题产生重大影响。氧化应激会影响正常生理功能，并与氨基糖苷类药物引起的内耳损伤有关。活性氧（ROS）的过度积累会损害细胞中的DNA、脂质和蛋白质，并诱导其凋亡。二氢杨梅素（DHM）是一种天然黄酮醇，具有广泛的健康益处，包括抗炎、抗肿瘤和抗氧化作用；然而，其在听觉毛细胞中的作用及其作用机制尚不完全清楚。本研究使用House Ear Institute-Organ of Corti（HEI-OC）1听觉细胞和由昆明小鼠制备的耳蜗外植体培养物，研究了DHM的抗氧化机制和抗耳毒性潜力。我们使用庆大霉素建立氨基糖苷类药物引起的耳毒性模型。进行组织学和生理学分析以确定DHM对庆大霉素引起的耳毒性的药理作用。结果表明，DHM通过抑制ROS积累有助于保护细胞免于凋亡性细胞死亡。蛋白质免疫印迹和定量RT-PCR分析显示，DHM通过上调过氧化物酶体增殖物激活受体γ-辅激活因子（PGC）-1α和沉默调节蛋白（SIRT）3的水平发挥其耳保护作用。分别使用SR-18292和3-（1-1,2,3-三唑-4-基）吡啶对这些因子进行药理抑制，评估了PGC-1α和SIRT3在DHM保护作用中的作用，这表明DHM的保护作用依赖于PGC-1α/SIRT3信号通路的激活。我们的研究是首次将DHM鉴定为一种潜在耳保护药物的报告，并为预防和治疗由氨基糖苷类抗生素引起的听觉毛细胞氧化损伤导致的听力损失提供了依据。
