Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
Department of Cardiology, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
Int Immunopharmacol. 2021 Jun;95:107533. doi: 10.1016/j.intimp.2021.107533. Epub 2021 Mar 19.
Doxorubicin (DOX) is a potent chemotherapeutic drug but the clinical use was limited by its dose-dependent cardiotoxicity. Pinocembrin (PCB), a flavonoid originally isolated from honeybee propolis and rhizomes of Boesenbergia pandurate displays diverse biological activities. However, the role of PCB in DOX-induced cardiac injury and its underlying molecular mechanism are not fully elucidated. The present study was designed to evaluate the protective role of PCB in a DOX-induced cardiotoxicity in vivo and in vitro. Our results revealed that PCB administration greatly improved cardiac function and reduced cardiac fibrosis manifested by LVEF, LVFS, LVIDd, LVIDs, and myocardial fibrotic area which were impaired by DOX treatment. The cardiac injury evidenced by LDH and CK-MB activities were reduced while the levels of IL-1β and IL-18 were decreased following PCB treatment compared to DOX-treated mice. Mechanically, our present results showed that PCB significantly inhibited DOX-induced cardiomyocyte pyroptosis via activating Nrf2/Sirt3 signal pathway. Furthermore, the inhibition of Nrf2 in H9c2 cells abolished the protective role of PCB against DOX-induced cell toxicity, which was at least partly via upregulation of NLRP3-mediated pyroptosis. In conclusion, our study clearly demonstrated that PCB reduced cardiomyocyte pyroptosis to protect hearts from DOX-induced cardiotoxicity through activation of Nrf2/Sirt3 signal pathway.
多柔比星（DOX）是一种有效的化疗药物，但由于其剂量依赖性的心脏毒性，其临床应用受到限制。白杨素（PCB），一种最初从蜂胶和蓬莪术根茎中分离出来的类黄酮，具有多种生物学活性。然而，PCB 在 DOX 诱导的心脏损伤中的作用及其潜在的分子机制尚未完全阐明。本研究旨在评估 PCB 在 DOX 诱导的体内和体外心脏毒性中的保护作用。我们的研究结果表明，PCB 给药可显著改善心脏功能，减少由 DOX 处理引起的 LVEF、LVFS、LVIDd、LVIDs 和心肌纤维化面积的损伤。与 DOX 处理的小鼠相比，LDH 和 CK-MB 活性降低，IL-1β 和 IL-18 水平降低，表明心脏损伤减轻。我们的研究结果表明，PCB 通过激活 Nrf2/Sirt3 信号通路显著抑制 DOX 诱导的心肌细胞细胞焦亡。此外，在 H9c2 细胞中抑制 Nrf2 消除了 PCB 对 DOX 诱导的细胞毒性的保护作用，至少部分是通过上调 NLRP3 介导的细胞焦亡。总之，本研究清楚地表明，PCB 通过激活 Nrf2/Sirt3 信号通路减少心肌细胞细胞焦亡，从而保护心脏免受 DOX 诱导的心脏毒性。
