DanShen Decoction targets miR-93-5p to provide protection against MI/RI by regulating the TXNIP/NLRP3/Caspase-1 signaling pathway.

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2024-11-08 DOI:10.1016/j.phymed.2024.156225

Mingtai Chen, Raoqiong Wang, Lishang Liao, Yuanyuan Li, Xingyu Sun, Hao Wu, Qi Lan, Ziwen Deng, Ping Liu, Tengfei Xu, Hua Zhou, Mengnan Liu

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引用次数: 0

Abstract

Background: Bone marrow mesenchymal stem cells (BMSCs) derived exosomes have demonstrated potential therapeutic efficacy on myocardial ischemia/reperfusion injury (MI/RI). This study has explored the underlying mechanisms of Danshen decoction (DSD) pretreated BMSCs-exosomes to treat MI/RI in vivo and in vitro.

Methods: Extracellular vesicles extracted from BMSCs were identified, miRNA sequencing was performed to screen the effects of DSD, and verified to target TXNIP in vivo. After MI/RI modeling, rats were treated with BMSCs-exosomes pretreated with DSD or miRNA inhibitor. BMSCs-exosomes, DSD-pretreated BMSCs-exosomes, and miRNA inhibitor/anti-miRNA-pretreated BMSCs-exosomes were used to treat H9c2 cells or MI/RI rats. CCK-8, Tunnel staining, and flow cytometry were performed to measure cell viability. LDH, CK, CK-MB were detected to evaluate cell injury. MDA, SOD, and ROS were used to confirm oxidative stress. Furthermore, IL-1β, IL-18, cleaved-caspase-1, pro-caspase-1, NLRP3, TXNIP, and GSDMD were quantified for the TXNIP/NLRP3/Caspase-1 signaling activation. In addition, echocardiography was used to observe the heart function, and H&E stain was performed to detect pathological injury.

Results: Following DSD pretreatment, there was a marked elevation in the expression levels of miR-93-5p, miR-16-5p, and miR-15b-5p, with miR-93-5p exhibiting the highest baseMean value. The administration of a miR-93-5p inhibitor yielded effects counteractive to those observed with DSD treatment, leading to reduced cell proliferation, heightened oxidative stress (as indicated by increased levels of SOD and ROS, alongside a decrease in MDA), and enhanced cell apoptosis. Furthermore, DSD effectively mitigated the miR-93-5p-induced upregulation of key inflammatory and apoptotic markers, including IL-1β, IL-18, caspase-1, NLRP3, TXNIP, and GSDMD. Notably, exosomes derived from DSD-pretreated BMSCs demonstrated a capacity to alleviate cardiac damage.

Conclusion: DSD may target miR-93-5p within BMSC-derived exosomes to confer protection against cardiac damage by inhibiting the activation of the TXNIP/NLRP3/Caspase-1 signaling pathway, thereby mitigating cardiomyocyte pyroptosis. This study provides a theoretical foundation for the application of DSD in the treatment of MI/RI.

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丹参煎剂通过调节 TXNIP/NLRP3/Caspase-1 信号通路，靶向 miR-93-5p，从而提供对 MI/RI 的保护。

背景：骨髓间充质干细胞（BMSCs）衍生的外泌体对心肌缺血/再灌注损伤（MI/RI）具有潜在的疗效。本研究探讨了丹参煎剂（DSD）预处理的BMSCs-外泌体在体内和体外治疗心肌缺血/再灌注损伤的内在机制：方法：鉴定从BMSCs中提取的胞外囊泡，进行miRNA测序以筛选DSD的作用，并验证其在体内靶向TXNIP。MI/RI建模后，用预处理过DSD或miRNA抑制剂的BMSCs-外泌体处理大鼠。用BMSCs-外泌体、DSD预处理的BMSCs-外泌体和miRNA抑制剂/抗miRNA预处理的BMSCs-外泌体处理H9c2细胞或MI/RI大鼠。采用 CCK-8、隧道染色法和流式细胞术测量细胞活力。检测 LDH、CK、CK-MB 以评估细胞损伤。MDA、SOD和ROS用于确认氧化应激。此外，还对 IL-1β、IL-18、裂解-caspase-1、原-caspase-1、NLRP3、TXNIP 和 GSDMD 进行了量化，以确定 TXNIP/NLRP3/Caspase-1 信号的激活情况。此外，还用超声心动图观察心脏功能，用H&E染色检测病理损伤：结果：DSD预处理后，miR-93-5p、miR-16-5p和miR-15b-5p的表达水平明显升高，其中miR-93-5p的基均值最高。施用 miR-93-5p 抑制剂会产生与 DSD 治疗相反的效果，导致细胞增殖减少、氧化应激增强（表现为 SOD 和 ROS 水平升高，MDA 下降）和细胞凋亡增强。此外，DSD 还能有效缓解 miR-93-5p 诱导的关键炎症和凋亡标志物的上调，包括 IL-1β、IL-18、caspase-1、NLRP3、TXNIP 和 GSDMD。值得注意的是，从DSD预处理的BMSCs中提取的外泌体显示出缓解心脏损伤的能力：结论：DSD可能会通过抑制TXNIP/NLRP3/Caspase-1信号通路的激活，从而减轻心肌细胞的脓毒症。这项研究为应用 DSD 治疗 MI/RI 提供了理论基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.