Wencong Tian, Ping Zhang, Lei Yang, Peng Song, Jia Zhao, Hongzhi Wang, Yongjie Zhao, Lei Cao
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引用次数: 0
Abstract
Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug used to treat a wide spectrum of tumors. However, its clinical application is limited due to cardiotoxic side effects. Astragaloside IV (AS IV), one of the major compounds present in aqueous extracts of Astragalus membranaceus, possesses potent cardiovascular protective properties, but the underlying molecular mechanisms are unclear. Thus, the aim of this study was to investigate the effect of AS IV on DOX-induced cardiotoxicity (DIC). Our findings revealed that DOX induced pyroptosis through the caspase-1/gasdermin D (GSDMD) and caspase-3/gasdermin E (GSDME) pathways. AS IV treatment significantly improved the cardiac function and alleviated myocardial injury in DOX-exposed mice by regulating intestinal flora and inhibiting pyroptosis; markedly suppressed the levels of cleaved caspase-1, N-GSDMD, cleaved caspase-3, and N-GSDME; and reversed DOX-induced downregulation of silent information regulator 1 (SIRT1) and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mice. The SIRT1 inhibitor EX527 significantly blocked the protective effects of AS IV. Collectively, our results suggest that AS IV protects against DIC by inhibiting pyroptosis through the SIRT1/NLRP3 pathway.
多柔比星(DOX)是一种强效蒽环类抗肿瘤药物,可用于治疗多种肿瘤。然而,由于其心脏毒性副作用,其临床应用受到了限制。黄芪苷 IV(AS IV)是黄芪水提取物中的主要化合物之一,具有强效的心血管保护作用,但其潜在的分子机制尚不清楚。因此,本研究旨在探讨 AS IV 对 DOX 诱导的心脏毒性(DIC)的影响。我们的研究结果表明,DOX通过caspase-1/gasdermin D(GSDMD)和caspase-3/gasdermin E(GSDME)途径诱导细胞凋亡。AS IV治疗通过调节肠道菌群和抑制化脓作用,明显改善了暴露于DOX的小鼠的心功能,减轻了心肌损伤;明显抑制了裂解的caspase-1、N-GSDMD、裂解的caspase-3和N-GSDME的水平;逆转了DOX诱导的沉默信息调节因子1(SIRT1)的下调和NLR家族含吡咯啉结构域3(NLRP3)炎性体的激活。SIRT1 抑制剂 EX527 能明显阻断 AS IV 的保护作用。总之,我们的研究结果表明,AS IV通过SIRT1/NLRP3途径抑制脓毒症,从而对DIC起到保护作用。