Based On Data Mining And Network Pharmacology To Explore The Medication Rule And Pharmacological Mechanism Of Traditional Chinese Medicine Prescription In The Treatment Of Bradyarrhythmia

ObjectiveIn this study,the data mining method was used to explore the medication rule of traditional Chinese medicine prescription in treating bradyarrhythmia in recent ten years,which provided some reference for clinical prescription.Screening the core drugs of traditional Chinese medicine prescription for treating bradyarrhythmia,and using network pharmacology technology,constructing a complex biological network,discussing the pharmacodynamic mechanism of the core drugs from the molecular level,laying a theoretical foundation for the next animal experimental research,and providing ideas and methods for guiding clinical medication and new drug development.MethodsThe literature of treating bradyarrhythmia with traditional Chinese medicine prescription in recent ten years was searched in CNKI database,and the prescription name,drug composition,drug flavor and classification were counted.The database of prescription of traditional Chinese medicine was established by Excel,and frequency analysis,cluster analysis and association rule analysis were carried out by SPSS software,so as to summarize the prescription rule of traditional Chinese medicine for treating bradyarrhythmia and screen out the core prescription.The chemical components of core prescription were collected by Chinese medicine system pharmacology technology platform(TCMSP)database,and the main active components of core prescription were screened out according to OB≥30%,DL≥0.18 and Caco-2≥-0.4.The action target proteins of active ingredients were predicted by Swiss Target Prediction database and compared with bradyarrhythmia related target proteins to obtain the key target proteins of core Prescription against bradyarrhythmia,and the "drug ingredients-key target protein network" was constructed by Cytoscape software.The interaction between key target proteins was analyzed by STRING database.The KEGG pathway enrichment analysis of key target proteins was carried out by DAVID database,in order to predict the possible mechanism of core prescription against bradyarrhythmia.The target proteins related to the improvement of heart rate function in core drugs were screened by DAVID database,and the possible pathway of these target proteins to improve heart rate was analyzed,and the mechanism of heart rate promotion by core drugs was discussed.Results1.A total of 1787 Chinese documents were retrieved in this study,and 102 documents were finally included according to the standard of document inclusion.2.Among the 102 included literatures,the top 3 prescriptions were Zhigancao Decoction(25 times,accounting for 24.5%);Mahuang Fuzi Xixin Decoction(17 times,16.7%);Mahuang Fuzi Xixin decoction combined with Yanghe Decoction(7 times,accounting for 6.9%).3.A total of 97 kinds of traditional Chinese medicines were involved,and the cumulative frequency of use was 1014 times.Among them,31 were used more than 10 times.The top 10 Chinese medicines in frequency are Ramulus Cinnamomi(74),Radix Glycyrrhizae Preparata(69),Radix Aconiti Lateralis(55),Radix Astragali(53),Radix Ophiopogonis(45),Radix Salviae Miltiorrhizae(45),Herba Asari(44),Herba Ephedrae(41),Ginseng(34)and Radix Rehmanniae(25).4.According to the classification results of TCM efficacy,the most frequently used drugs are tonifying deficiency drugs,relieving exterior syndrome drugs,promoting blood circulation and removing blood stasis drugs,warming internal organs drugs and clearing heat drugs.According to the classification of drug efficacy,the top five drugs in frequency are qi-tonifying drugs,wind-cold dispersing drugs,blood-activating drugs,internal warming drugs and blood-tonifying drugs.The statistical results of drug distribution showed that warm drugs were used most frequently,followed by mild and cold drugs.5.According to cluster analysis,the drugs can be divided into four categories:Category 1: invigorating qi and nourishing yin,warming yang and restoring pulse(donkey-hide gelatin,ginger,Fructus Cannabis,jujube,radix rehmanniae recen,Radix Ophiopogonis,Prepared Liquorice Root,Ramulus Cinnamomi,ginseng,Codonopsis pilosula);Category 2: enriching blood and promoting blood circulation(Ligusticum wallichii,Angelica sinensis);Category 3: tonifying fire and yang,warming meridians(rehmannia,antler gum,Herba Asari,ephedra,aconite,cinnamon,licorice);Category 4:invigorating qi and spleen,promoting blood circulation and removing blood stasis(Salvia miltiorrhiza,Schisandra chinensis,Astragalus membranaceus,Poria cocos,Red Ginseng,Carthamus tinctorius).6.Drug association rules analysis obtained 7 groups of drug combinations,including aconite,asarum,ephedra,Ramulus Cinnamomi and Astragalus.Combined with TCM etiology and pathogenesis of bradyarrhythmia and literature research,the core prescription of this study is: aconite,asarum,ephedra,Ramulus Cinnamomi and Astragalus membranaceus.7.A total of 61 core drug active ingredients and 772 target proteins were collected.Comparing the predicted target protein with 967 target proteins related to bradyarrhythmia,136 key targets were obtained.According to the topological parameter analysis of "drug ingredients-key target protein network",the top components of degree value were kaempferol,quercetin,eriodictyol,Karanjin,Jaranol,Pectolinarigenin,Diosmetin,luteolin,Caribine,etc.,which indicated that these components were the key components of the core Prescription against bradycardia.In the network,Aconitum carmichaeli has the most target protein,followed by Ephedra,Asarum and Astragalus membranaceus,and Ramulus Cinnamomi has the least,which is similar to the prescription principle of "monarch,minister and assistant" in Chinese medicine.8.Analyze the protein-protein interaction of key target proteins and construct PPI network.The top five target proteins of degree are SRC,PIK3 CA,PIK3R1,STAT3 and mapk1,which indicate that these target proteins play an important role in the network and play an important role in anti-bradyarrhythmia therapy.9.KEGG pathway analysis of key target proteins shows that core drugs may treat bradyarrhythmia by regulating PI3K-Akt signaling pathway,HIF-1 signaling pathway,Rap1 signaling pathway,c AMP signaling pathway,TNF signaling pathway and estrogen signaling pathway.10.There are 17 target proteins related to the biological process of raising heart rate:HCN4,KCNQ1,ADRB1,SCN10 A,KCNH2,TACR3,ADRA1 A,PDE4D,AVPR1 A,MDM2,KCNA5,ADA,SCN5 A,CALM1,CACNA1 G,DRD2,PRKACA.The effects of these 17 target proteins on heart rate regulation may be related to the regulation of Calcium signaling pathway,Adrenergic signaling in cardiomyocytes,c AMP signaling pathway,Salivary secretion,Vascular smooth muscle contraction,Neuroactive ligand-receptor interaction,Renin secretion,etc.ConclusionIn recent ten years,the prescription and medication ideas for treating bradyarrhythmia have basically followed the theoretical understanding of the etiology and pathogenesis of late pulse disease by doctors of past dynasties.The methods of invigorating qi and warming yang and warming meridians are the main ones,and the five drugs of aconit Ae,asarum,ephedra,Ramulus Cinnamomi and Astragalus membranaceus are the core core drugs for treating bradyarrhythmia in TCM prescriptions.Anti-bradyarrhythmia of core prescription is a multi-component,multi-target and multi-link coordinated regulation process,which may be related to regulating the growth and apoptosis of myocardial cells,restoring the balance between ion channels of myocardial cells,improving myocardial energy metabolism,inhibiting myocardial fibrosis and so on.