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By restoring autophagic flux and improving mitochondrial function, corosolic acid protects against Dox-induced cardiotoxicity
Cell Biology and Toxicology ( IF 6.1 ) Pub Date : 2021-07-22 , DOI: 10.1007/s10565-021-09619-8
Yan Che 1, 2 , Zhaopeng Wang 1, 2 , Yuan Yuan 1, 2 , Heng Zhou 1, 2 , Haiming Wu 1, 2 , Shasha Wang 1, 2 , Qizhu Tang 1, 2
Affiliation  

Despite effective anticancer effects, the use of doxorubicin (Dox) is limited due to its side effects as cardiotoxicity. Corosolic acid (CRA) is a pentacyclic triterpene acid isolated from Lagerstroemia speciosa L. (Banaba) leaves, and it has also been shown to improve myocardial hypertrophy and myocardial infarction which expected to be used in clinical pharmaceuticals. The purpose of this study was to explore whether CRA can improve myocardial injury caused by Dox and to clarify potential mechanisms. C57 BL/6J mice and AMPKα2 knockout mice were given a single intraperitoneal (i.p.) injection of Dox (5 mg/kg) every week for 4 weeks, while normal saline (NS) was used as control. Mice were given CRA (10 mg/kg or 20 mg/kg) or equal volumes of normal saline daily after the first time i.p. injection of Dox. After 4 weeks, echocardiography, gravimetric, hemodynamic, histological, and biochemical analyses were conducted. After Dox injury, compared with the control group, CRA increased the survival rate of mice, improved the cardiac function, decreased the oxidative stress, and reduced the apoptosis. CRA may function by promoting transcription factor EB (TFEB) nuclear translocation and thus restoring autophagic flux. We also observed that CRA protected mitochondrial structure and function, which may benefit from oxidative stress reduction or TFEB activation. In vitro, the protective effect of CRA is reversed by TFEB deletion. Then, we evaluated the expression of AMPKα2/mTOR C1 signaling pathway, the main pathway of TFEB activation. In vivo and in vitro, CRA promoted TFEB nuclear translocation by activating AMPKα2/mTOR C1 signaling, while ablating AMPKα2 reversed these results and accompanied with a decrease in the ability of CRA to resist Dox-induced cardiotoxicity. Thus, we suggested that CRA activated TFEB in an AMPKα2-dependent manner to protect against Dox cardiotoxicity.

Graphical abstract



中文翻译:

通过恢复自噬通量和改善线粒体功能,科罗索酸可防止 Dox 诱导的心脏毒性

尽管有有效的抗癌作用,但由于其心脏毒性副作用,阿霉素 (Dox) 的使用受到限制。科罗索酸 (CRA) 是一种从紫薇中分离出的五环三萜酸L. (Banaba) 叶,也被证明能改善预期用于临床药物的心肌肥大和心肌梗塞。本研究的目的是探讨 CRA 是否可以改善 Dox 引起的心肌损伤并阐明潜在机制。C57 BL/6J 小鼠和 AMPKα2 敲除小鼠每周一次腹膜内 (ip) 注射 Dox (5 mg/kg),持续 4 周,同时使用生理盐水 (NS) 作为对照。在第一次 ip 注射 Dox 后,每天给小鼠给予 CRA (10 mg/kg 或 20 mg/kg) 或等体积的生理盐水。4 周后,进行了超声心动图、重量分析、血流动力学、组织学和生化分析。在 Dox 损伤后,与对照组相比,CRA 提高了小鼠的存活率,改善了心功能,减少氧化应激,减少细胞凋亡。CRA 可能通过促进转录因子 EB (TFEB) 核转位从而恢复自噬通量发挥作用。我们还观察到 CRA 保护线粒体结构和功能,这可能受益于氧化应激减少或 TFEB 激活。在体外,TFEB 缺失可逆转 CRA 的保护作用。然后,我们评估了 AMPKα2/mTOR C1 信号通路的表达,这是 TFEB 激活的主要途径。在体内和体外,CRA 通过激活 AMPKα2/mTOR C1 信号传导促进 TFEB 核转位,而消融 AMPKα2 逆转了这些结果,并伴随着 CRA 抵抗 Dox 诱导的心脏毒性的能力下降。因此,我们建议 CRA 以 AMPKα2 依赖性方式激活 TFEB 以防止 Dox 心脏毒性。

图形概要

更新日期:2021-07-22
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