A stepwise integrated strategy to explore quality markers of Qishen Yiqi dripping pills against myocardial ischemia

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2024-10-28 DOI:10.1016/j.phymed.2024.156182

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引用次数: 0

Abstract

Background

Numerous experiments and clinical practices have demonstrated the effectiveness of Qishen Yiqi dripping pills (QSYQ) on myocardial ischemia (MI). However, the bioactive ingredients and mechanisms remain unclear, leading to huge gaps between quality control and biological effect of QSYQ. Discovering quality markers (Q-markers) based on effective components is crucial for ensuring stable quality and clinical effectiveness of QSYQ.

Purpose

To explore Q-markers of QSYQ against MI by a stepwise strategy integrating serum pharmacochemistry, network pharmacology, metabolomics, quantitative analysis, and cell experiments.

Methods

Firstly, liquid/gas chromatography-mass spectrometry was applied to characterize chemical profiles of QSYQ in vitro and in vivo. Based on the serum migrating constituents, a component-target-MI interaction network was constructed. Subsequently, pharmacodynamics and metabolomics were conducted to evaluate cardioprotective effect and potential mechanism of QSYQ. Next, conjoint analysis of network pharmacology and metabolomics was performed to screen candidate Q-markers. Finally, the measurability and bioactivity were validated to justify their usage as Q-markers.

Results

A total of 97 components were identified in QSYQ, 24 prototypes of which were detected in serum. The “component-target-disease” interaction network was constructed based on serum migrating constituents. Pharmacodynamic results showed that QSYQ effectively improved cardiac function, attenuated inflammatory cell infiltration, alleviated myocardial fibrosis, and reduced the levels of myocardial enzymes and oxidative stress in MI rats. Metabolomics study demonstrated that 59 metabolites were markedly altered in MI rats, 25 of which were significantly reversely regulated by QSYQ. After integrative analysis of network pharmacology and metabolomics, 12 components were selected as candidate Q-markers of QSYQ, and the contents were quantified. These candidate Q-markers displayed synergistic protective effects against H₂O₂-induced injury in H9c2 cells. Taken together, 12 components with properties of transitivity and traceability, effectiveness, measurability, and compatibility contribution were defined as representative Q-markers of QSYQ, including Astragaloside IV, Ononin, Calycosin, Formononetin, Rosmarinic acid, Cryptotanshinone, Salvianolic acid A, Tanshinol, Ginsenoside Rb1, Ginsenoside Rg1, Nerolidol, and Santalol.

Conclusion

In this study, a novel stepwise integrated strategy was presented for discovering Q-markers related to therapeutic effects of traditional Chinese medicine prescriptions. Twelve comprehensive and representative Q-markers of QSYQ were identified for the first time to improve its quality control.

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探索芪参益气滴丸抗心肌缺血质量标志物的渐进式综合策略

背景：大量实验和临床实践证明，芪参益气滴丸（QSYQ）对心肌缺血（MI）有疗效。然而，芪参益气滴丸的生物活性成分和作用机制仍不明确，导致其质量控制和生物效应之间存在巨大差距。目的：通过整合血清药理、网络药理学、代谢组学、定量分析和细胞实验，逐步探索 QSYQ 抗心肌缺血的 Q 标志物：方法：首先，采用液/气相色谱-质谱联用技术分析 QSYQ 在体外和体内的化学特征。根据血清迁移成分，构建了成分-靶标-MI相互作用网络。随后，进行了药效学和代谢组学研究，以评估 QSYQ 的心脏保护作用和潜在机制。接着，对网络药理学和代谢组学进行联合分析，筛选出候选的 Q 标记。最后，对其可测量性和生物活性进行了验证，以证明其作为 Q 标记的合理性：结果：QSYQ 共鉴定出 97 种成分，其中 24 种原型在血清中被检测到。根据血清迁移成分构建了 "成分-目标-疾病 "相互作用网络。药效学结果表明，QSYQ 能有效改善心肌梗死大鼠的心功能，减轻炎症细胞浸润，缓解心肌纤维化，降低心肌酶和氧化应激水平。代谢组学研究表明，心肌梗死大鼠体内有 59 种代谢物发生了明显变化，其中 25 种代谢物受到 QSYQ 的显著反向调节。经过网络药理学和代谢组学的综合分析，选出了 12 个成分作为 QSYQ 的候选 Q 标记，并对其含量进行了量化。这些候选Q标记物对H9c2细胞H2O2诱导的损伤具有协同保护作用。综上所述，12种具有转运性和可追溯性、有效性、可测量性和相容性贡献的成分被定义为QSYQ的代表性Q标记物，包括黄芪皂苷Ⅳ、芒柄花苷、萼甲素、福莫尼丁、迷迭香酸、隐丹参酮、丹参酚酸A、丹参酚、人参皂苷Rb1、人参皂苷Rg1、橙花醇和山檀醇：本研究提出了一种新颖的分步综合策略，用于发现与中药方剂疗效相关的 Q 标记。首次发现了 12 个具有代表性的 QSYQ Q 标记，从而提高了 QSYQ 的质量控制水平。

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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.