An Exploration Of Biological Basis Of TCM Syndrome Differentiation And Treatment Of Coronary Heart Disease Based On Network Pharmacology And Machine Learning

As a typical cardiovascular disease,coronary heart disease(CHD)has become the number one threat to human life and health.As a treasure of the Chinese nation,traditional Chinese medicine(TCM)plays an important role in the prevention and treatment of CHD.Through thousands of years of theoretical development and clinical practice,TCM has formed a clinical diagnosis and treatment system with "holistic view" and "syndrome differentiation and treatment" as the essence,emphasizing the analysis and correct diagnosis of different syndromes of diseases,and guiding the correct and accurate drug use.TCM has achieved remarkable results in treating CHD based on syndrome differentiation and classification.However,its biological basis is still unclear and systematic research is less.Therefore,this study combined network pharmacology and machine learning technology to systematically explore the potential biological basis of TCM for the classification and treatment of CHD.Firstly,the data of 197 TCM formulae and 186 medicinal materials were analyzed by using data mining techniques such as statistical analysis,complex network,and association rule mining.It was found that Danshen,Chuanxiong and Huangqi were frequently used.TCM used in the treatment of CHD was mainly composed of blood activating medicine,stasis removing medicine,blood tonifying medicine,Qi tonifying medicine,and phlegm resolving medicine,while the core drug combinations were composed of blood activating medicine,expectorant medicine,and deficiency tonifying medicine.According to the analysis of property,taste,and meridian tropism,TCM was used in combination with warm and cold medicinal materials,mainly in sweet,hot,and bitter taste.These medicinal materials belong to the liver,spleen,heart,lung,stomach,and kidney meridians,consistent with the etiology and pathogenesis of chest pain,which is deficiency in origin,excess in superficiality,and location in heart.The node degree of the TCM network obeys the power-law distribution,and the network has heterogeneity.Most of the nodes have small degrees,and a few nodes have relatively large degrees.The nodes with large degrees exactly correspond to the core medicinal materials in TCM formulae,such as Danshen,Chuanxiong,Huangqi,Danggui,Gualou and so on.Their main functions are promoting blood circulation,removing blood stasis and tonifying blood,invigorating Qi and resolving phlegm,corresponding to the core etiology and pathogenesis of CHD.Then,combined with network pharmacology and machine learning technology,the potential biological basis of TCM syndrome classification and treatment of CHD were explored.Eight typical syndromes of CHD and TCM formulae were selected through literature research,and the corresponding bioactive compounds,potential targets,and CHD-related genes were collected from TCMID,Drug Bank,Dis Ge NET and other databases.By calculating the correlation between TCM formulae's targets and CHD-related genes on the human genome-wide background network,and the network proximity between TCM formulae's targets and targets of FDA-approved molecules for the treatment of cardiovascular diseases,we found that the potential targets of each TCM formula were significantly related to CHD-related genes,and there were certain overlaps between targets of each TCM formula and nine kinds of cardiovascular drug targets,which confirmed the effectiveness of TCM formulae on CHD at the molecular level.The eight TCM formulae could be clustered into five groups at multiple levels,and the clustering results on symptoms,targets and signaling pathways were consistent.The eight TCM formulae had the common effect of relieving angina pectoris,and were enriched in seven signaling pathways closely related to CHD,namely 5-hydroxytryptaminergic synapse,c AMP signaling pathway,calcium signaling pathway,arachidonic acid metabolism,ovarian steroidogenesis,nitrogen metabolism and steroid hormone biosynthesis.In addition,the TCM formula for each syndrome corresponded to some specific biological processes: Zuoguiyin,Shenfu DecoctionYouguiyin(Formula 7 and 8)can improve renal function by regulating thyroid hormone signaling pathway and PPAR signaling pathway;Xuefu Zhuyu Decoction,Bazhen Decoction and modified Shengmai San(Formula 2,5 and 6),used for Qi stagnation and blood stasis,Qi deficiency and blood stasis and Qi-yin deficiency,can reduce inflammatory reaction and enhance immunity through specific intervention of CXCL5,CXCL8,CXCL12,CCL19 and CCL21 in TNF signaling pathway and NF-?B signaling pathway;Gualou Xiebai Banxia Decoction(Formula 3),which is used for phlegm stagnation syndrome,can regulate intestinal immune network for Ig A production and improve immunity through specifically action on CXCR4,CXCL12 and other targets;Kuanxiong Pill(Formula 4)can improve blood circulation by regulating tryptophan metabolism;Guanxin ? formula(Formula 1)for heart blood stasis syndrome can interfere with angiogenesis by regulating VEGF signal pathway.Combined with topological similarity and functional similarity,a ranking algorithm for targets of TCM formulae for CHD was designed to identify the important targets,and it was proved that the integration of topological similarity and functional similarity was superior to the algorithm only considering topological similarity.By searching Pub Med and Pub Chem databases,we used text mining to verify some identified important targets and mechanism of TCM formulae,such as the effect on renal function of Formula 7 and 8,and the anti-inflammatory effect of Formula 2,5 and 6.Finally,the potential mechanism of Xuefu Zhuyu Wan,Fufang Danshen Di Wan and Suxiao Jiuxin Wan in the treatment of CHD with Qi stagnation and blood stasis syndrome was studied by network pharmacology and molecular docking.Through the construction of TCM formula-herb-bioactive compounds-potential targets network,protein-protein interaction network of CHD-related genes,protein-protein interaction network of potential target of TCM formulae,and enrichment analysis of GO and KEGG,we found that multiple bioactive components(catechin,quercetin,naringenin,hesperidin,isoliquiritigenin,tanshinone,ligusticum,fatty acid,and so)in these TCM formulae may act on F2,P2RY12,ITGB3,TLR4,PTGS2,SLCO1B3,SLCO1B1,ABCA1,ABCC2,ABCC6,GGCX,ENPP1,MIF,PRKAA1,F13A1 and other targets,can regulate platelet activation,complement and coagulation cascade,NF-?B signaling pathway,bile secretion,oxytocin signaling pathway,then regulate vascular endothelial function,improve inflammatory response,regulate lipid metabolism and so on,and then play a significant role in the treatment of CHD with Qi stagnation and blood stasis.In conclusion,we systematically explored the potential biological basis of treatment of CHD based on TCM syndrome differentiation by integrating data mining,network pharmacology,machine learning.This study provided modern medical evidences for precise treatment and personalized intervention of CHD in the clinical practice of TCM,and provided a reference for modern research of TCM syndrome differentiation and treatment.