Based On Network Pharmacology To Analyze The Mechanism Of Chinese Medicine For Nourishing Qi, Promoting Blood Circulation And Resolving Phlegm To Improve Insulin Resistance In Coronary Heart Disease

Insulin resistance(IR),one risk factor for coronary heart disease,drives coronary atherosclerosis by inducing the differentiation of monocytes/macrophages,inducing the apoptosis of VSMCs,and reducing fibrinolytic activity.It is thereby significant to improve the insulin sensitivity in patients with coronary heart disease(CHD)for better outcomes.In recent years,there has been great progress in traditional Chinese medicine(TCM)regarding improving insulin sensitivity of coronary heart disease.However,the complex composition and unclear mechanism of TCM limit the application of TCM in improving insulin sensitivity of CHD.This study includes three aspects:(1)analysis of the medication rules of TCM in improving insulin sensitivity of CHD;(2)verification of the effectiveness of TCM on IR of coronary heart disease;(3)study on the mechanism of TCM in improving insulin sensitivity of CHD.Part 1 Analysis of the medication rules of TCM in improving insulin sensitivity of CHDObjective:Analyze the prescription and compatibility rules of Chinese medicine for improving insulin sensitivity of patients with CHD and to find out the core Chinese medicine that can improve the insulin sensitivity of patients with CHD.Methods:CNKI,Wanfang,VIP,PubMed,EMBASE and Cochrane library were searched for relevant studies reporting TCM treatment of IR in CHD patients and the data set of TCM prescription was obtained.Statistical analysis was conducted on the frequency of use,medicinal flavor and efficacy classification of herbs.TCM Inheritance Support System(V2.5)was used to assess the association rules among herbs and to find the core herbs that can improve the insulin sensitivity of CHD.Results:A total of 39 literatures were included,involving 39 prescriptions and 98 kinds of herbs.The most frequently used Chinese herbs were invigorating blood circulation and eliminating stasis herbs.The statistical results of the frequency of Chinese medicine showed that Danshen,Huangqi,Chuanxiong,Gualou,Maidong,Sanqi,Chishao were the commonly used herbs,and Danshen-Huangqi,Danshen-Chuanxiong,Danshen-Gualou were the common medical combinationsConclusion:Herbs for invigorating blood circulation and eliminating stasis,Qi tonifying and dissipating phlegm were frequently used in the treatment of improving insulin sensitivity of CHD,reflecting the treatment of qi,blood circulation and phlegm.Danshen,Huangqi,Chuanxiong and Gualou were the core herbs that can improve the insulin sensitivity of CHD.Part 2 Meta-analysis of the effect of tonifying qi,activating blood and resolving phlegm Chinese herbs on insulin sensitivity in patients with CHDObjective:Aassess the effect of tonifying qi,activating blood circulation and resolving phlegm Chinese herbs on insulin sensitivity in patients with CHD.Methods:The CNKI,Wanfang,VIP,PubMed and other domestic and foreign databases were searched to collect the randomized controlled trials(RCTs)that reported tonifying qi,activating blood circulation and resolving phlegm Chinese herbs in treatment of CHD with IR.The retrieval was completed by October 2020.Two researchers independently searched and screened the literatures according to the proposed retrieval strategy and inclusion criteria.RevMan5.3 software was used for quantitative evaluation.The primary outcomes are homeostasis model assessment of IR(HOMA-IR)and insulin sensitivity index(ISI).Secondary outcomes are fasting serum insulin(FIN),fast blood glucose(FBG),2hPG and HbAlc.Results:A total of 11 eligible studies were finally included in the quantitative analysis,involving 944 CHD patients,479 in treatment group and 465 in control group.Meta-analysis results of primary outcomes showed that compared with the control group,the insulin sensitivity in patients with CHD was significantly improved in the group of tonifying qi,activating blood circulation and resolving phlegm herbs[HOMA-IR:MD=-0.57,95%CI(-0.75,-0.39),P<0.01;ISI:MD=-0.45,95%CI(-0.57,-0.32),P<0.01].Meta-analysis results of secondary outcomes showed that tonifying qi,activating blood circulation and resolving phlegm herbs could decrease FIN[SMD=-0.85,95%CI(-1.16,-0.54),P<0.01],FBG[MD=-0.34,95%CI(-0.61,-0.07),P=0.01],2hPG[MD=-0.93,95%CI(-1.50,-0.35),P<0.01]and HbAlc[MD=-0.65,95%CI(-0.96,-0.33),P<0.01]in CHD patients.Conclusion:Tonifying qi,activating blood circulation and resolving phlegm herbs can significantly improve the insulin sensitivity of patients with CHD.Part 3 Study on the mechanism of Danshen,Huangqi,Chuanxiong and Gualou in insulin sensitivity of CHD based on Net-work PharmacologyObjectives:Explore the mechanism of Danshen,Huangqi,Chuanxiong and Gualou on insulin sensitivity in patients with CHD.Methods:TCMSP,BATMAN-TCM and TCMID were searched to select the chemical components and disease targets of Danshen,Huangqi,Chuanxiong and Gualou.The disease targets of CHD with IR were collected by searching GeneCards database and OMIM database.The "VennDiagram" package was used to obtain the intersection of drug action targets and disease targets.The network diagram of herbs-ingredients-disease targets was drawn in Cytoscape 3.8.0.The GO function and KEGG pathway enrichment analysis of the intersection targets were conducted with "BiocManager" packages,"Clusterprofiler" packages,"Pathview"packages and "Dose" packages.Results:A total of 65 ingredients of Danshen,20 ingredients of Huangqi,14 ingredients of Gualou and 7 ingredients of Chuanxiong were selected.135 targets of Danshen,209 targets of Huangqi,25 targets of Chuanxiong and 14 targets of Gualou were obtained.A total of 754 CHD with IR targets were obtained.86 intersection targets of herbs and disease were obtained.GO functional enrichment analysis of 86 intersection targets showed that core herbs improved the insulin sensitivity of CHD by participating in response to insulin,lipid transport,positive regulation of lipid metabolic process,cellular response to insulin stimulus and glucose transmembrane transport.KEGG pathway enrichment analysis of 86 intersection targets showed that core herbs improved insulin sensitivity of CHD by regulating PI3K-Akt signaling pathway,MAPK signaling pathway,FoxO signaling pathway,NF-kappa B signaling pathway and AMPK signaling pathway.Conclusions:The effective ingredients in Danshen,Huangqi,Chuanxiong and Gualou play important roles in the treatment of CHD with IR by improving insulin sensitivity through multiple targets and multiple signal pathways.