Zhang Jun, Yang Zunyuan, Jia Xue, Li Xinxin, Wang Xiangyang, Rong Hua, Liang Yinan, Zeng Wen, Jia Wei, Ma Xiaohui
The State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd, Tianjin, China.
PriMed Non-Human Primate Research Center of Sichuan PriMed Shines Bio-Tech Co., Ltd., Ya'an, Sichuan, China.
Front Pharmacol. 2022 Oct 24;13:1017433. doi: 10.3389/fphar.2022.1017433. eCollection 2022.
Heart failure (HF), the final stage of cardiovascular diseases, is a clinical syndrome of cardiac structural or functional abnormalities. QiShenYiQi Dripping Pills (T101), short for QSYQ (T101), showed effectiveness and safety in the treatment of HF according to modern pharmacological research and clinical studies, but the mechanism remains unclear. This study aims to clarify the mechanism of QSYQ (T101) in treating heart failure through the analysis to critical biomarkers, targets and pathways. In this study, the efficacies of QSYQ (T101) in non-human primates and rodents were evaluated, and the mechanism was demonstrated by integrating network pharmacology and metabolomics analysis. Furthermore, the targets from network pharmacology and the metabolites from targeted metabolomics were jointly analyzed to screen the critical pathways. In rhesus monkeys with spontaneous chronic heart failure, nasogastric administration of QSYQ (T101) for 12 weeks caused profound improvement of systolic and diastolic function as evidenced by echocardiography detection. Consistently, QSYQ (T101) administration especially with higher dose lowered the blood pressure and improved the ventricular remodeling, collagen deposition and fibrosis markedly in Spontaneous Hypertension Rats (SHR) model. Computational prediction showed that QSYQ (T101) exhibited anti-HF effects possibly through HIF-1 signaling pathway, FoxO signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway and other enriched paths. Metabolomics analysis obtained 23 significantly altered metabolites, revealing that QSYQ (T101) significantly regulated the abnormal levels of fatty acids, carnitines, organic acids pyridines, nucleosides, which were mostly involved in myocardial energy metabolism related pathways. Based on serum and myocardium metabolomics and network pharmacology, the present study revealed that the actions of QSYQ (T101) in treating HF depend on multi-components, multi-targets and multi-pathways.
心力衰竭（HF）是心血管疾病的终末阶段，是一种心脏结构或功能异常的临床综合征。根据现代药理学研究和临床研究，芪参益气滴丸（T101，简称QSYQ（T101））在治疗心力衰竭方面显示出有效性和安全性，但其机制仍不清楚。本研究旨在通过分析关键生物标志物、靶点和通路来阐明QSYQ（T101）治疗心力衰竭的机制。在本研究中，评估了QSYQ（T101）在非人灵长类动物和啮齿动物中的疗效，并通过整合网络药理学和代谢组学分析来证明其机制。此外，对网络药理学的靶点和靶向代谢组学的代谢产物进行联合分析，以筛选关键通路。在自发性慢性心力衰竭的恒河猴中，通过超声心动图检测证明，经鼻胃管给予QSYQ（T101）12周可显著改善收缩和舒张功能。同样，在自发性高血压大鼠（SHR）模型中，给予QSYQ（T101），尤其是高剂量时，可降低血压，并显著改善心室重构、胶原沉积和纤维化。计算预测表明，QSYQ（T101）可能通过缺氧诱导因子-1信号通路、叉头框蛋白O信号通路、肿瘤坏死因子信号通路、磷脂酰肌醇-3激酶-蛋白激酶B信号通路和其他富集通路发挥抗心力衰竭作用。代谢组学分析获得了23种显著改变的代谢产物，表明QSYQ（T101）显著调节了脂肪酸、肉碱、有机酸吡啶、核苷的异常水平，这些物质大多参与心肌能量代谢相关通路。基于血清和心肌代谢组学以及网络药理学，本研究表明QSYQ（T101）治疗心力衰竭的作用取决于多成分、多靶点和多通路。
