The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China.
The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China.
Phytomedicine. 2023 Dec;121:155105. doi: 10.1016/j.phymed.2023.155105. Epub 2023 Sep 27.
Doxorubicin (Dox), which is an anticancer drug, has significant cardiac toxicity and side effects. Pyroptosis occurs during Dox-induced cardiotoxicity (DIC), and drug inhibition of this process is one therapeutic approach for treating DIC. Previous studies have indicated that emodin can reduce pyroptosis. However, the role of emodin in DIC and its molecular targets remain unknown.
HYPOTHESIS/PURPOSE: We aimed to clarify the protective role of emodin in mitigating DIC, as well as the mechanisms underlying this effect.
The model of DIC was established via the intraperitoneal administration of Dox at a dosage of 5 mg/kg per week for a span of 4 weeks. Emodin at two different doses (10 and 20 mg/kg) or a vehicle was intragastrically administered to the mice once per day throughout the Dox treatment period. Cardiac function, myocardial injury markers, pathological morphology of the heart, level of pyroptosis and mitochondrial function were assessed. Protein microarray, biolayer interferometry and pull-down assays were used to confirm the target of emodin. Moreover, GSDMD-overexpressing plasmids were transfected into GSDMD mice and HL-1 cells to further verify whether emodin suppressed GSDMD activation.
Emodin therapy markedly enhanced cardiac function and reduced cardiomyocyte pyroptosis in mice induced by Dox. Mechanistically, emodin binds to GSDMD and inhibits the activation of GSDMD by targeting the Trp415 and Leu290 residues. Moreover, emodin was able to mitigate Dox-induced cardiac dysfunction and myocardial injury in GSDMD mice overexpressing GSDMD, as shown by increased EF and FS, decreased serum levels of CK-MB, LDH and IL-1β and mitigated cell death and cell morphological disorder. Additionally, emodin treatment significantly reduced GSDMD-N expression and plasma membrane disruption in HL-1 cells overexpressing GSDMD induced by Dox. In addition, emodin reduced mitochondrial damage by alleviating Dox-induced GSDMD perforation in the mitochondrial membrane.
Emodin has the potential to attenuate DIC by directly binding to GSDMD to inhibit pyroptosis. Emodin may become a promising drug for prevention and treatment of DIC.
阿霉素（Dox）是一种抗癌药物，具有显著的心脏毒性和副作用。细胞焦亡发生在阿霉素诱导的心脏毒性（DIC）中，抑制这一过程是治疗 DIC 的一种方法。先前的研究表明，大黄素可以减少细胞焦亡。然而，大黄素在 DIC 中的作用及其分子靶点尚不清楚。
假说/目的：我们旨在阐明大黄素在减轻 DIC 中的保护作用及其作用机制。
通过每周腹腔注射阿霉素 5mg/kg，连续 4 周建立 DIC 模型。大黄素以两种不同剂量（10 和 20mg/kg）或载体通过灌胃给药，每天一次，在阿霉素治疗期间给药。评估心脏功能、心肌损伤标志物、心脏病理形态、细胞焦亡水平和线粒体功能。使用蛋白质微阵列、生物层干涉测量和下拉测定来确认大黄素的靶点。此外，将 GSDMD 过表达质粒转染到 GSDMD 小鼠和 HL-1 细胞中，进一步验证大黄素是否抑制 GSDMD 激活。
大黄素治疗明显增强了阿霉素诱导的小鼠心脏功能，并减少了心肌细胞焦亡。机制上，大黄素与 GSDMD 结合，通过靶向 Trp415 和 Leu290 残基抑制 GSDMD 的激活。此外，大黄素能够减轻 GSDMD 过表达小鼠中由 Dox 诱导的心脏功能障碍和心肌损伤，表现为 EF 和 FS 增加、血清 CK-MB、LDH 和 IL-1β 水平降低以及细胞死亡和细胞形态紊乱减轻。此外，大黄素治疗显著降低了 Dox 诱导的 HL-1 细胞中 GSDMD 过表达诱导的 GSDMD-N 表达和质膜破坏。此外，大黄素通过减轻 Dox 诱导的 GSDMD 在线粒体膜中的穿孔来减轻线粒体损伤。
大黄素通过直接与 GSDMD 结合抑制细胞焦亡，具有减轻 DIC 的潜力。大黄素可能成为预防和治疗 DIC 的一种有前途的药物。
