和厚朴酚介导的顺铂耳毒性保护过程中耳蜗内Sirtuin家族上调

文献信息

中文摘要

背景/目的： 顺铂诱导的听力损失（CIHL）是化疗的主要全球健康后遗症，每年影响超过50万癌症患者。我们此前报道，和厚朴酚——一种可与顺铂兼容的多功能分子——能够预防CIHL并上调sirtuin 3。Sirtuin家族由七个高度保守但差异表达的成员组成，它们是不同细胞区室中氧化应激调节的关键酶。因此，本研究旨在进一步验证在荷瘤小鼠模型中，和厚朴酚介导的针对CIHL的听力保护过程中整个sirtuin家族的表达和上调情况。方法：使用携带小鼠乳腺肿瘤病毒多瘤病毒中间T抗原癌基因的成年雌性小鼠。这些小鼠在70.8 ± 10.3日龄时自发形成可触及的肿瘤。采用三个周期（14天/周期）低剂量（4 mg/kg/天，每周期4天，腹腔注射）顺铂治疗模拟化疗方案以诱导CIHL。和厚朴酚（5-20 mg/kg）在顺铂给药前一小时给予。通过听性脑干反应阈值偏移和突触变化评估耳蜗功能。进行免疫染色和RT-qPCR以验证这些过程中sirtuin家族成员（1、2、3、5和7）的上调。结果：在高频范围（24-32 kHz）观察到CIHL，和厚朴酚治疗减轻了该损伤。和厚朴酚发挥耳保护作用和维持动物存活的最佳剂量为10 mg/kg。和厚朴酚治疗小鼠耳蜗中sirtuin 1、2、3、5和7的荧光信号增加。RT-qPCR证实和厚朴酚治疗显著上调sirtuin 3 mRNA。结论：Sirtuin家族上调参与和厚朴酚介导的针对CIHL的听力保护。和厚朴酚的剂量-反应曲线为未来人体研究的潜在转化应用奠定了基础。

英文摘要

Background/Objectives: Cisplatin-induced hearing loss (CIHL) is a major global health sequela of chemotherapy, affecting over half a million cancer patients annually. We previously reported that honokiol, a multifunctional molecule compatible with cisplatin, protects against CIHL and upregulates sirtuin 3. The sirtuin family is composed of seven highly conserved yet differentially expressed members that are critical enzymes for oxidative stress regulation in different cellular compartments. Therefore, this study aims to further verify the expression and upregulation of the entire sirtuin family during honokiol-mediated hearing protection against CIHL in a tumor-bearing mouse model. Methods: Adult female mice carrying the mouse mammary tumor virus polyomavirus middle T agent oncogene were used. These mice developed palpable tumors spontaneously at the age of 70.8 ± 10.3 days. CIHL was induced using a three-cycle (14 days/cycle) low-dose (4 mg/kg/day for 4 days per cycle, intraperitoneal injection) cisplatin treatment mimicking chemotherapy regimens. Honokiol (5-20 mg/kg) was administered one hour before cisplatin. Cochlear function was evaluated by auditory brainstem response threshold shifts and synaptic changes. Immunostaining and RT-qPCR were performed to verify the upregulation of sirtuin family members (1, 2, 3, 5, and 7) during these processes. Results: CIHL was observed in the high-frequency range (24-32 kHz), which was mitigated by honokiol treatment. The optimal dose of honokiol for oto-protection and animal survival was 10 mg/kg. Fluorescence signals of sirtuins 1, 2, 3, 5, and 7 increased in cochleae from honokiol-treated mice. RT-qPCR confirmed a significant upregulation of sirtuin 3 mRNA with honokiol treatment. Conclusions: Sirtuin family upregulation was involved in honokiol-mediated hearing protection against CIHL. The dose-response curve of honokiol lays the foundation for potential translational applications for human studies.