Gao Liyuan, Yuan Peipei, Wei Yaxin, Fu Yang, Hou Ying, Li Panying, Chen Yi, Ruan Yuan, Zhou Ning, Zheng Xiaoke, Feng Weisheng
Department of Medicine, Henan University of Chinese Medicine, Zhengzhou, China.
Department of Medicine, Henan University of Chinese Medicine, Zhengzhou, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou, China.
Phytomedicine. 2022 Jun;100:154065. doi: 10.1016/j.phymed.2022.154065. Epub 2022 Mar 19.
Doxorubicin (DOX) is a highly effective chemotherapeutic that is effective for various tumours. However, the clinical application of DOX has been limited by adverse reactions such as cardiotoxicity and heart failure. Since DOX-induced cardiotoxicity is irreversible, drugs to prevent DOX-induced cardiotoxicity are needed.
This study aimed to investigate the effect of total flavonoids of Selaginella tamariscina (P.Beauv.) Spring (TFST) on doxorubicin-induced cardiotoxicity.
The present study established DOX-induced cardiotoxicity models in C57BL/6 mice treated with DOX (cumulative dose: 20 mg/kg body weight) and H9c2 cells incubated with DOX (1 μM/l) to explore the intervention effect and potential mechanism of TFST. Echocardiography was performed to evaluate left ventricular functions. Heart tissue samples were collected for histological evaluation. Myocardial injury markers and oxidative stress markers were examined. Mitochondrial energy metabolism pathway associated proteins PPARα/PGC-1α/Sirt3 were detected. We also explored the effects of TFST on endoplasmic reticulum (ER) stress and apoptosis. To further investigate the protective mechanism of TFST, we used the specific small interfering RNA MFN2 (siMFN2) to explore the effect of MFN2 on TFST against DOX-induced cardiotoxicity in vitro. Flow cytometry detected reactive oxygen species, mitochondrial membrane potential and apoptosis. Cell mitochondrial stress was measured by Seahorse XF analyser.
Both in vivo and in vitro studies verified that TFST observably alleviated DOX-induced mitochondrial dysfunction and ER stress. However, these effects were reversed after transfected siMFN2.
Our results indicated that TFST ameliorates DOX-induced cardiotoxicity by alleviating mitochondrial dysfunction and ER stress by activating MFN2/PERK. MFN2/PERK pathway activation may be a novel mechanism to protect against DOX-induced cardiotoxicity.
阿霉素（DOX）是一种对多种肿瘤有效的高效化疗药物。然而，DOX的临床应用受到诸如心脏毒性和心力衰竭等不良反应的限制。由于DOX诱导的心脏毒性是不可逆的，因此需要预防DOX诱导心脏毒性的药物。
本研究旨在探讨卷柏总黄酮（TFST）对阿霉素诱导的心脏毒性的影响。
本研究在用DOX（累积剂量：20mg/kg体重）处理的C57BL/6小鼠和用DOX（1μM/l）孵育的H9c2细胞中建立DOX诱导的心脏毒性模型，以探讨TFST的干预作用和潜在机制。进行超声心动图检查以评估左心室功能。收集心脏组织样本进行组织学评估。检测心肌损伤标志物和氧化应激标志物。检测线粒体能量代谢途径相关蛋白PPARα/PGC-1α/Sirt3。我们还探讨了TFST对内质网（ER）应激和细胞凋亡的影响。为了进一步研究TFST的保护机制，我们使用特异性小干扰RNA MFN2（siMFN2）来探讨MFN2对TFST体外抗DOX诱导心脏毒性的作用。流式细胞术检测活性氧、线粒体膜电位和细胞凋亡。用海马XF分析仪测量细胞线粒体应激。
体内和体外研究均证实，TFST可显著减轻DOX诱导的线粒体功能障碍和ER应激。然而，转染siMFN2后这些作用被逆转。
我们的结果表明，TFST通过激活MFN2/PERK减轻线粒体功能障碍和ER应激，从而改善DOX诱导的心脏毒性。MFN2/PERK途径激活可能是预防DOX诱导心脏毒性的新机制。
