Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
Bioengineered. 2021 Dec;12(1):7975-7984. doi: 10.1080/21655979.2021.1985299.
The anti-tumor and anti-inflammatory effects of limonin have been established, here, we aim to explore whether limonin can induce protective effects against doxorubicin (DOX)-mediated cardiotoxicity which limits its clinical application. We found that limonin attenuated DOX-mediated cytoxicology of myocardial cell line H9C2 by measuring cell viability and reactive oxygen species (ROS) level. Additionally, limonin ameliorates DOX-induced cardiac injury in rat by examining the activity of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) concentration, and histopathological changes. Mechanistically, it was shown that limonin partially abrogated the inhibition of Nuclear factor - like 2 and Sirtuin 2 signaling induced by DOX. Furthermore, limonin-mediated protective effects on DOX-mediated cytoxicology of H9C2 were rescued by a Sirt2-specific inhibitor or siRNA against Sirt2. Thus, this work reveals that limonin can suppress DOX-mediated cardiotoxicity by activating Nrf2 and Sirt2 signaling.
柠檬苦素具有抗肿瘤和抗炎作用，本研究旨在探讨柠檬苦素是否可以诱导对抗阿霉素（DOX）介导的心脏毒性的保护作用，而 DOX 介导的心脏毒性限制了其临床应用。我们发现，通过测量细胞活力和活性氧（ROS）水平，柠檬苦素可减轻 DOX 对心肌细胞系 H9C2 的细胞毒性作用。此外，通过检测乳酸脱氢酶（LDH）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GSH-Px）和丙二醛（MDA）浓度以及组织病理学变化，我们发现柠檬苦素可改善 DOX 诱导的大鼠心脏损伤。其机制表明，柠檬苦素部分阻断了 DOX 诱导的核因子样 2 和 Sirtuin 2 信号的抑制。此外，Sirt2 特异性抑制剂或针对 Sirt2 的 siRNA 可挽救柠檬苦素介导的对 DOX 诱导的 H9C2 细胞毒性的保护作用。因此，这项工作表明，柠檬苦素可以通过激活 Nrf2 和 Sirt2 信号通路来抑制 DOX 介导的心脏毒性。
