Sound conditioning (SC) is defined as “toughening” to lower levels of sound over time, which reduces a subsequent noise-induced threshold shift. Although the protective effect of SC in mammals is generally understood, the exact mechanisms involved have not yet been elucidated. To confirm the protective effect of SC against noise exposure (NE) and the stress-related signaling pathway of its rescue, we observed target molecule changes caused by SC of low frequency prior to NE as well as histology analysis in vivo and verified the suggested mechanisms in SGNs in vitro. Further, we investigated the potential role of Hsp70 and Bmi1 in SC by targeting SOD1 and SOD2 which are regulated by the FoxO1 signaling pathway based on mitochondrial function and reactive oxygen species (ROS) levels. Finally, we sought to identify the possible molecular mechanisms associated with the beneficial effects of SC against noise-induced trauma. Data from the rat model were evaluated by western blot, immunofluorescence, and RT-PCR. The results revealed that SC upregulated Hsp70, Bmi1, FoxO1, SOD1, and SOD2 expression in spiral ganglion neurons (SGNs). Moreover, the auditory brainstem responses (ABRs) and electron microscopy revealed that SC could protect against acute acoustic trauma (AAT) based on a significant reduction of hearing impairment and visible reduction in outer hair cell loss as well as ultrastructural changes in OHCs and SGNs. Collectively, these results suggested that the contribution of Bmi1 toward decreased sensitivity to noise-induced trauma following SC was triggered by Hsp70 induction and associated with enhancement of the antioxidant system and decreased mitochondrial superoxide accumulation. This contribution of Bmi1 was achieved by direct targeting of SOD1 and SOD2, which was regulated by FoxO1. Therefore, the Hsp70/Bmi1-FoxO1-SOD signaling pathway might contribute to the protective effect of SC against AAT in a rat model.

中文翻译：

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Hsp70/Bmi1-FoxO1-SOD 信号通路有助于声音调节对大鼠模型中急性声损伤的保护作用

声音调节 (SC) 被定义为随着时间的推移“强化”到较低的声音水平，从而减少随后的噪声引起的阈值偏移。尽管 SC 在哺乳动物中的保护作用已被普遍理解，但所涉及的确切机制尚未阐明。为了证实 SC 对噪声暴露 (NE) 的保护作用及其救援的应激相关信号通路，我们在 NE 之前观察了由低频 SC 引起的靶分子变化以及体内组织学分析，并验证了建议的机制在体外 SGN 中。此外，我们通过靶向 SOD1 和 SOD2 来研究 Hsp70 和 Bmi1 在 SC 中的潜在作用，SOD1 和 SOD2 受基于线粒体功能和活性氧 (ROS) 水平的 FoxO1 信号通路调节。最后，我们试图确定与 SC 对噪声引起的创伤的有益作用相关的可能分子机制。来自大鼠模型的数据通过蛋白质印迹、免疫荧光和 RT-PCR 进行评估。结果表明，SC 上调螺旋神经节神经元 (SGN) 中 Hsp70、Bmi1、FoxO1、SOD1 和 SOD2 的表达。此外，听觉脑干反应 (ABR) 和电子显微镜显示，SC 可以基于显着减少听力损伤和明显减少外毛细胞损失以及 OHC 和 SGN 的超微结构变化来预防急性声损伤 (AAT)。集体，这些结果表明，Bmi1 对 SC 后噪声诱导的创伤敏感性降低的贡献是由 Hsp70 诱导触发的，并且与抗氧化系统的增强和线粒体超氧化物积累的减少有关。Bmi1 的这一贡献是通过直接靶向 SOD1 和 SOD2 实现的，后者受 FoxO1 调节。因此，Hsp70/Bmi1-FoxO1-SOD 信号通路可能有助于 SC 在大鼠模型中对 AAT 的保护作用。