冠心病中药配方对磷脂过氧化信号的调节。
Regulation of phospholipid peroxidation signaling by a traditional Chinese medicine formula for coronary heart disease.
机构信息
Guangdong Engineering Research Center of Chinese Medicine and Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou 510632, China; Key Laboratory of High Incidence Diseases in Xinjiang Region, Ministry of Education (MOE), Xinjiang Medical University, Urumqi 830054, China.
Guangdong Engineering Research Center of Chinese Medicine and Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou 510632, China.
出版信息
Phytomedicine. 2023 Jun;114:154749. doi: 10.1016/j.phymed.2023.154749. Epub 2023 Mar 6.
BACKGROUND
Phospholipid peroxidation signaling was recently revealed as a novel pathological mechanism of coronary heart disease (CHD), and small molecules involved in this redox-metabolic pathway are suggested as the potential anti-CHD drugs. Danlou Tablet (DLT), a famous traditional Chinese medicine (TCM) formula characterized by multi-component and multi-target regulation, is widely used in the clinical treatment of CHD by regulating lipid metabolism. However, little information is available addressing the corresponding pharmacological mechanisms and associated active components of DLT.
PURPOSE
To study whether phospholipid peroxidation involves a novel mechanism of DLT for the therapeutic effect of CHD and to explain the essential active components.
METHODS
Firstly, the HPLC fingerprint was constructed to ensure the controllability of the quality of DLT. Then, a CHD animal model with the characteristics of lipid disorder and myocardial ischemia was established by a high-fat diet (HFD) combined with left anterior descending coronary artery (LAD) ligation. The therapeutic effect of DLT was further evaluated based on the results of the rat survival rate, cardiac function, cardiac histopathology, and myocardial ischemia indicators. Correspondingly, whether DLT can regulate the key indicators (ALOX15, GPX4, MDA, GSH, and NADPH) of the phospholipid peroxidation pathway was investigated, and Alox15 mice have been applied to confirm the mechanism of DLT. Finally, the target-mediated characterization strategy based on ALOX15, including the integration of in vivo component characterization, network pharmacology, molecular docking analysis, and activity verification, has been further implemented to reveal the key bio-active components in DLT.
RESULTS
In this study, a high-fat diet (HFD) combined with left anterior descending coronary artery (LAD) ligation was utilized to generate a CHD model, and DLT significantly improved the cardiac dysfunction and reduced the myocardial cell death susceptibility. Further results revealed that DLT reversed the protein expression of ALOX15 and GPX4, the key proteins of phospholipid peroxidation pathways, which subsequently influenced the parameters of phospholipid peroxidation (MDA, GSH, and NADPH). The ALOX15 knockout transgenic animal model confirmed that Alox15 mice lost their cardioprotective effects with DLT, suggesting that DLT exerted therapeutic effects on CHD by regulating ALOX15-mediated phospholipid peroxidation. Finally, the target-mediated characterization strategy identified that daidzein is an active component in DLT against CHD by modulating ALOX15.
CONCLUSION
Innovatively, ALOX15-mediated phospholipid peroxidation was identified as one of the critical mechanisms of DLT exerting cardioprotective effects. Our findings elucidate a novel mechanism of DLT and provide some new drug evaluation targets and therapeutic strategies for CHD.
背景
磷脂过氧化信号最近被揭示为冠心病（CHD）的一种新的病理机制，并且该氧化还原代谢途径中涉及的小分子被认为是潜在的抗 CHD 药物。丹络片（DLT）是一种以多成分、多靶点调节为特征的著名中药（TCM）配方，广泛应用于 CHD 的临床治疗，通过调节脂质代谢。然而，关于 DLT 的相应药理机制和相关活性成分的信息很少。
目的
研究磷脂过氧化是否涉及 DLT 治疗 CHD 的新机制，并解释其基本的活性成分。
方法
首先，构建 HPLC 指纹图谱以确保 DLT 的质量可控性。然后，通过高脂肪饮食（HFD）联合左前降支冠状动脉（LAD）结扎建立具有脂质紊乱和心肌缺血特征的 CHD 动物模型。根据大鼠存活率、心功能、心肌组织病理学和心肌缺血指标的结果，进一步评价 DLT 的治疗效果。相应地，研究了 DLT 是否可以调节磷脂过氧化途径的关键指标（ALOX15、GPX4、MDA、GSH 和 NADPH），并应用 Alox15 小鼠证实了 DLT 的作用机制。最后，基于 ALOX15 实施了目标介导的特征描述策略，包括体内成分特征描述、网络药理学、分子对接分析和活性验证，进一步揭示了 DLT 中的关键生物活性成分。
结果
本研究采用高脂肪饮食（HFD）联合左前降支冠状动脉（LAD）结扎建立 CHD 模型，结果表明 DLT 可显著改善心脏功能障碍并降低心肌细胞死亡易感性。进一步的结果表明，DLT 逆转了磷脂过氧化途径关键蛋白 ALOX15 和 GPX4 的蛋白表达，随后影响了磷脂过氧化参数（MDA、GSH 和 NADPH）。ALOX15 基因敲除转基因动物模型证实，Alox15 小鼠丧失了 DLT 的心脏保护作用，表明 DLT 通过调节 ALOX15 介导的磷脂过氧化发挥 CHD 的治疗作用。最后，目标介导的特征描述策略确定，大豆苷元是 DLT 调节 ALOX15 对抗 CHD 的活性成分之一。
结论
创新性地，ALOX15 介导的磷脂过氧化被确定为 DLT 发挥心脏保护作用的关键机制之一。我们的研究结果阐明了 DLT 的一种新机制，并为 CHD 提供了一些新的药物评价靶点和治疗策略。
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