International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, China; Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
J Ethnopharmacol. 2023 Oct 5;314:116669. doi: 10.1016/j.jep.2023.116669. Epub 2023 May 20.
Coronary heart disease (CHD), one of the leading causes of mortality in the world among chronic non-infectious diseases, is closely associated with atherosclerosis, which ultimately leads to myocardial injury. Wendan decoction (WDD), a classical famous formula, exerted an intervention effect on CHD according to numerous reports. However, the effective components and underlying mechanisms for the treatment of CHD have not been fully elucidated.
An in-depth investigation of the effective components and mechanisms of WDD for the intervention of CHD was further explored.
Firstly, based on our previous metabolic profile results, a quantification method for absorbed components was established by ultra-performance liquid chromatography triple quadrupole-mass spectrometry (UPLC-TQ-MS) and applied to the pharmacokinetics study of WDD. Then the network pharmacology analysis for considerable exposure components in rat plasma was employed to screen key components of WDD. Gene ontology and KEGG pathway enrichment analysis were further performed to obtain putative action pathways. The effective components and mechanism of WDD were confirmed by in vitro experiments.
A rapid and sensitive quantification method was successfully applied to the pharmacokinetic study of 16 high-exposure components of WDD at three different doses. A total of 235 putative CHD targets were obtained for these 16 components. Then, 44 core targets and 10 key components with high degree values were successively screened out by the investigation of protein-protein interaction and the network of "herbal medicine-key components-core targets". Enrichment analysis suggested that the PI3K-Akt signaling pathway was closely related to this formula's therapeutic mechanism. Furthermore, pharmacological experiments demonstrated that 5 of 10 key components (liquiritigenin, narigenin, hesperetin, 3,5,6,7,8,3',4'-heptamethoxyflavone, and isoliquiritigenin) significantly enhanced DOX-induced H9c2 cell viability. The cardioprotective effects of WDD against DOX-induced cell death through the PI3K-Akt signaling pathway were verified by western blot experiments.
The integration of pharmacokinetics and network pharmacology approaches successfully clarified 5 effective components and therapeutic mechanism of WDD for the intervention of CHD.
冠心病（CHD）是世界上慢性非传染性疾病导致死亡的主要原因之一，与动脉粥样硬化密切相关，最终导致心肌损伤。温胆汤（WDD）是一种经典的著名方剂，根据大量报道，对 CHD 具有干预作用。然而，其治疗 CHD 的有效成分和作用机制尚未完全阐明。
深入探讨 WDD 干预 CHD 的有效成分和作用机制。
首先，基于我们之前的代谢谱结果，建立了一种超高效液相色谱三重四极杆质谱（UPLC-TQ-MS）定量方法，用于 WDD 的药代动力学研究。然后，采用网络药理学分析方法筛选大鼠血浆中大量暴露成分的关键成分。进一步进行基因本体和 KEGG 通路富集分析，获得可能的作用途径。通过体外实验验证 WDD 的有效成分和作用机制。
成功地将一种快速灵敏的定量方法应用于 WDD 的 16 种高暴露成分的药代动力学研究，这三种不同剂量。共获得 16 种成分的 235 个潜在 CHD 靶点。然后，通过蛋白质-蛋白质相互作用和“中药-关键成分-核心靶点”网络的研究，筛选出 44 个核心靶点和 10 个具有高度数值的关键成分。富集分析表明，PI3K-Akt 信号通路与该配方的治疗机制密切相关。此外，药理实验表明，10 种关键成分中的 5 种（甘草素、橙皮素、橙皮苷、3,5,6,7,8,3',4'-七甲氧基黄酮和异甘草素）显著增强了 DOX 诱导的 H9c2 细胞活力。通过 Western blot 实验验证了 WDD 通过 PI3K-Akt 信号通路对 DOX 诱导的细胞死亡的心脏保护作用。
药代动力学和网络药理学方法的结合成功阐明了 WDD 干预 CHD 的 5 种有效成分和治疗机制。
