中存在的齐墩果酸苷衍生物通过LRP6/GSK3β轴激活自噬，进而抑制氧化应激，从而对抗顺铂诱导的耳毒性。 注：原文中“activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity.”这部分内容逻辑上有些跳跃，翻译时尽量按照原文结构呈现，但从语义连贯角度来说不太完整清晰，推测可能是在说某种植物叶子里的齐墩果酸苷衍生物有这样的作用。可补充完整植物名称等信息以让句子更通顺表意更明确。 你可检查下原文内容是否准确完整。
The chiisanoside derivatives present in the leaves of activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity.
作者信息
Zhang Wenxin, Teng Hongbo, Zhao Tianyi, Eglitis Roberts I, Wang Xv, Yu Zhengxuan, Qu Shurong, Wang Haijing, Zhao Yaru, Fan Bowen, Liu Shuangli, Zhao Yan
机构信息
College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, Jilin, China.
International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Jilin Agricultural University, Changchun, Jilin, China.
出版信息
Front Pharmacol. 2025 Jan 15;15:1518810. doi: 10.3389/fphar.2024.1518810. eCollection 2024.
INTRODUCTION
Cisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from has abundant activity against CIO.
METHODS
In this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin-induced HEI-OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.
RESULTS
It was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.
DISCUSSION
These findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.
引言
顺铂广泛应用于多种实体恶性肿瘤的治疗。然而，顺铂诱导的耳毒性（CIO）等副作用给肿瘤治疗带来了障碍。从[来源]提取的重要天然产物齐墩果酸对CIO具有丰富的活性。
方法
在本研究中，筛选了26种齐墩果酸衍生物，化合物19对CIO损伤表现出显著的保护活性。建立了顺铂诱导的HEI-OC1细胞损伤模型和小鼠耳毒性模型。通过转录组测序揭示其调节作用，并通过分子对接、酶联免疫吸附测定、蛋白质免疫印迹和免疫荧光分析蛋白质表达水平。
结果
发现化合物19抑制细胞凋亡，减轻听力异常和螺旋神经节损伤。转录组测序揭示了其调节作用。化合物19处理提高了自噬水平，从而减轻线粒体功能障碍并减少活性氧（ROS）的积累。深入研究发现，自噬抑制剂3-甲基腺嘌呤（3-MA）削弱了化合物19对自噬的调节作用，并抑制受损细胞的清除，导致氧化应激损伤、凋亡和坏死。通过敲低LRP6，发现化合物19的保护作用被消除，自噬水平显著降低，诱导氧化应激和ROS产生，并促进顺铂暴露后的细胞凋亡。最后，使用抑制剂氯化锂抑制GSK3β的表达。发现抑制GSK3β可通过激活自噬保护细胞免受顺铂诱导的损伤。
讨论
这些发现表明，化合物19能够通过LRP6/GSK3β轴激活自噬，从而抑制氧化应激，预防耳毒性，为治疗CIO和感音神经性听力损失提供了一种新方法。
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