心脉龙注射液通过MDH2/OAA途径改善阿霉素诱导的心脏毒性

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-18 DOI:10.1016/j.phymed.2025.157010

Sa Liu , Suifen Xie , Taoli Sun , Yikun Wang , Wenhu Zhou , Yuanying Yang , Bikui Zhang , Wenqun Li

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引用次数: 0

摘要

作为一种广谱抗癌药物，阿霉素（Dox）的临床应用受到其副作用的阻碍，即Dox诱导的心脏毒性（DIC）。新麦龙注射液（XML）是一种从美洲蟑螂中提取的生物活性化合物配方，已被中国国家药品监督管理局批准用于治疗心力衰竭。然而，XML是否能够缓解DIC仍然不清楚。目的探讨XML对DIC的保护作用，揭示其保护作用的分子机制。方法建立H9c2细胞和C57BL/6小鼠的DIC模型。结合HPLC-MS、网络药理学、代谢组学和实验验证，确定了XML抗DIC的核心靶点和机制。结果xml可减轻dox诱导的体外和体内细胞凋亡。HPLC/MS结合swissADME在XML中鉴定出30种有效成分。网络药理学筛选了179个与XML和DIC相关的“共靶基因”。代谢组学鉴定出24种差异代谢物，主要富集于草酰乙酸（OAA）代谢和TCA循环。通过metscape和MetaboAnalyst分析，确定了MDH2、EHMT2、CAD和MIF四个交叉基因。我们选择MDH2作为核心靶点，因为它在TCA循环中调控OAA再生。Dox下调MDH2和OAA水平，而XML干预后MDH2和OAA水平上调。当LW6抑制MDH2时，XML对细胞凋亡、心功能障碍和ATP耗竭的保护作用均被逆转，表明XML通过上调MDH2缓解DIC。结论xml通过上调MDH2促进ATP生成，抑制细胞凋亡，有效缓解DIC，为DIC的防治提供了新的理论见解和策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Xinmailong injection ameliorates Doxorubicin‑induced cardiotoxicity via the MDH2/OAA pathway

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Xinmailong injection ameliorates Doxorubicin‑induced cardiotoxicity via the MDH2/OAA pathway

Background

As a broad-spectrum anticancer drug, the clinical utility of Doxorubicin (Dox) is hampered by its side effects, known as Dox-induced cardiotoxicity (DIC). Xinmailong Injection (XML), a bioactive compound formulation extracted from the American cockroach, has been approved by China’s National Medical Products Administration for the treatment of heart failure. However, whether XML could alleviate DIC still remains unclear.

Purpose

This study aims to explore the protective role of XML against DIC and unveil the molecular mechanisms underlying its cardioprotective effects.

Methods

The DIC models of H9c2 cells and C57BL/6 mice were established. HPLC-MS, network pharmacology, metabolomics and experimental verification were combined to identify the core target and mechanism of XML against DIC.

Results

XML alleviated Dox-induced apoptosis in vitro and in vivo. HPLC/MS in conjunction with swissADME identified 30 effective components within XML. Network pharmacology screened 179 “co-targeted genes” related to XML and DIC. Metabolomics identified 24 differential metabolites, mainly enriched in oxaloacetate (OAA) metabolism and the TCA cycle. Four intersecting genes, including MDH2, EHMT2, CAD and MIF, were determined through Metascape and MetaboAnalyst analysis. MDH2 was chose as the core target as it regulated OAA regeneration within the TCA cycle. The levels of MDH2 and OAA were downregulated by Dox, whereas they were upregulated following XML intervention. When MDH2 was inhibited using LW6, the protective effects of XML on cell apoptosis, cardiac dysfunction, and ATP depletion were all reversed, indicating that XML alleviated DIC by upregulating MDH2.

Conclusion

XML effectively mitigated DIC by upregulating MDH2 to promote the generation of ATP and inhibit cell apoptosis, providing new theoretical insights and strategies for the prevention and treatment of DIC.

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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.