Mechanistic exploration of Yiqi Liangxue Shengji prescription on restenosis after balloon injury by integrating metabolomics with network pharmacology.

CONTEXT: Yiqi Liangxue Shengji prescription (YQLXSJ) is a traditional Chinese medicine (TCM) formula that has long been used for treatment after percutaneous coronary intervention (PCI). OBJECTIVE: To investigate the putative pharmacological mechanism of YQLXSJ on restenosis through an integrated approach utilizing metabolomics and network pharmacology. MATERIALS AND METHODS: Forty male Sprague-Dawley rats were divided into sham, model, YQLXSJ, and positive groups. YQLXSJ group received the treatment of YQLXSJ (6 g/kg/d, i.g.) and the positive group was treated with atorvastatin (2 mg/kg/d, i.g.). After 4 weeks, the improvement in intimal hyperplasia was evaluated by ultrasound, H&E staining, and immunofluorescence. UPLC-MS/MS technology was utilized to screen the differential metabolites. Network pharmacology was conducted using TCMSP, GeneCards, and Metascape, etc., in combination with metabolomics. Eventually, the core targets were acquired and validated. RESULTS: Compared to models, YQLXSJ exhibited decreased intima-media thickness on ultrasound (0.23 ± 0.02 mm vs. 0.20 ± 0.01 mm, p < 0.01) and reduced intima thickness by H&E (30.12 ± 6.05 µm vs. 14.32 ± 1.37 µm, p < 0.01). We identified 18 differential metabolites and 5 core targets such as inducible nitric oxide synthase (NOS2), endothelial nitric oxide synthase (NOS3), vascular endothelial growth factor-A (VEGFA), ornithine decarboxylase-1 (ODC1) and group IIA secretory phospholipase A2 (PLA2G2A). These targets were further confirmed by molecular docking and ELISA. DISCUSSION AND CONCLUSIONS: This study confirms the effects of YQLXSJ on restenosis and reveals some biomarkers. TCM has great potential in the prevention and treatment of restenosis by improving metabolic disorders.

Integration of network pharmacology and molecular docking technology reveals the mechanism of the herbal pairing of Codonopsis Pilosula (Franch.) Nannf and Astragalus Membranaceus (Fisch.) Bge on chronic heart failure.

BACKGROUND: The herbal pairing of Dangshen (DS) [Codonopsis pilosula (Franch.) Nannf.] and Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.] (DHP) is a traditional Chinese herbal medicine that is frequently used to treat chronic heart failure (CHF) in China. However, the pharmacological mechanism of DHP has not been fully elucidated. This is the first study aimed to reveal the active mechanism of DHP in the treatment of CHF by using network pharmacology methods. METHODS: The active ingredients of DHP were obtained from the TCMSP database, and the potential targets of DHP were predicted using the SwissTargetPrediction database. CHF-related targets were searched by the DisGeNET and GeneCards databases. The common targets between the disease and herbs were obtained using a Venn diagram. The STRING database was utilized to obtain the protein-protein interaction data. Next, we used Cytoscape 3.7.2 software to construct and analyze the herb-ingredient-potential targets-disease network. Topology analysis was used to identify the key ingredients and hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Metascape database to reveal the mechanism. Furthermore, molecular docking simulation was performed using AutoDock Vina software to assess the affinity of the key ingredients and hub genes. RESULTS: Five key ingredients and six hub genes were screened. The six hub genes were closely related to PI3K /AKT or ERK1/2 pathways. The KEGG pathways mainly involved the TNF signaling pathway, calcium signaling pathway, and cancer-related pathways. The GO enrichment analysis results showed that DHP might act on biological processes including positive regulation of kinase activity and cellular response to nitrogen compound via the three above-mentioned pathways in the treatment of CHF. Finally, the molecular docking results showed that the five key ingredients exhibited strong affinities to the six hub genes. CONCLUSIONS: This study revealed the molecular mechanism that the flavonoids in DHP may alleviate endothelial dysfunction and cardiac hypertrophy via regulation of the TNF pathway and its downstream PI3K/Akt or ERK1/2 signaling pathways, or improve excitation-contraction coupling by regulating calcium signaling pathway, thereby improving CHF. These results provide insights for further experimentation on its pharmacological effects.

Effect of traditional Asian exercise on patients with chronic heart failure: a protocol for network meta-analysis of randomised controlled trials.

INTRODUCTION: Chronic heart failure (CHF) is a common disease worldwide, and imposes a substantial burden to the healthcare system. In CHF, limited exercise capacity and affected mental well-being leads to a reduced quality of life (QOL). How to improve the QOL and exercise endurance is critical for patients with CHF. Exercise therapy, such as some traditional Asian exercises (TAEs) including Taichi, Baduanjin and Yoga, plays an important role in the rehabilitation of patients with CHF. TAE is suitable for the rehabilitation of patients with CHF because of its soft movements and can relax the body and mind. Studies have shown that TAE can regulate the overall health status of the body and exercise tolerance, improve QOL and reduce rehospitalisation rate in patients with CHF. However, the difference in efficacy of TAE in patients with CHF is not yet clear. The main purpose of this study is to conduct a network meta-analysis (NMA) of randomised trials to determine the impact of TAE on patients with CHF of different types, different causes and different New York Heart Association (NYHA) heart function classifications and to provide references for different types of patients with CHF to choose appropriate exercise rehabilitation therapy. METHODS AND ANALYSIS: The literature search will be retrieved from PubMed, the Cochrane Library, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wanfang database, Chinese biomedical literature service system (SinoMed) and Chinese Scientific Journals Database (VIP) from the date of their inception until 1 August 2021. All randomised controlled trials that evaluated the effects of three different TAE therapies (Taichi, Baduanjin and Yoga) on patients with CHF will be included. The primary outcomes are peak oxygen uptake (peak VO2), exercise capacity (6-min walking distance) and QOL tested with the Minnesota Living with Heart Failure Questionnaire. Secondary outcomes include the levels of N-terminal pro brain natriuretic peptide, left ventricular ejection fraction, systolic blood pressure and diastolic blood pressure. For included articles, two reviewers will independently extract the data, and Cochrane Collaboration's tool will be used to assess risk of bias. We will perform the Bayesian NMA to pool all treatment effects. The ranking probabilities for the optimal intervention of various treatments (Taichi, Baduanjin or Yoga) will be estimated by the mean ranks and surface under the cumulative ranking curve. Subgroup analysis for different types, different causes and different NYHA heart function classifications of CHF will be performed. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence contributing to each network estimate. ETHICS AND DISSEMINATION: The results will be disseminated through peer-reviewed publications. They will provide useful information to inform clinicians on the potential functions of TAE in CHF, and to provide consolidated evidence for clinical practice and further research of TAE. PROSPERO REGISTRATION NUMBER: CRD42020179304.

Pre-clinical Evidence: Berberine as a Promising Cardioprotective Candidate for Myocardial Ischemia/Reperfusion Injury, a Systematic Review, and Meta-Analysis.

Objective: Myocardial ischemia/reperfusion (I/R) injury is one of the causes of most cardiomyocyte injuries and deaths. Berberine (BBR) has been suggested a potential to exert protective effects against myocardial I/R injury. This systematic review aims to determine the intrinsic mechanisms of BBR's protective effects in myocardial I/R injury. Methods: Seven databases were searched for studies performed from inception to July 2020. Methodological quality was assessed by SYRCLE's-RoB tool. Results: Ten studies including a total of 270 animals were included in this study. The methodology quality scores of the included studies ranged from 5 to 7 points. The meta-analysis we conducted demonstrated that BBR significantly reduced myocardial infarct size and the incidence of ventricular arrhythmia, compared to control groups (P < 0.00001). Cardiac function of animals in the BBR treatment group was also markedly increased (P < 0.00001). The index of myocardial apoptosis and the levels of biomarkers of myocardial infarction (LDH and CK) were also decreased in the BBR treatment groups compared to the control groups (P < 0.00001). Conclusions: The pre-clinical evidence, according to our study, showed that BBR is a promising therapeutic agent for myocardial I/R injury. However, this conclusion should be further investigated in clinical studies.