| Background:Coronary heart disease is a disease with high morbidity and mortality,which seriously affects people’s living standard and life health.The change of modern diet structure,eating too thick and heavy taste,the increase of work and life pressure,mood disorders lead to gallbladder block,the longer the fire and phlegm mixed to form phlegm heat,phlegm heat blocking heart arteries,heart arteries circulation is not smooth and chest pain comes out.In the zang-fu theory system of Traditional Chinese medicine,the five zang and sic fu organs are closely related to each other,especially the relationship between the heart and the gallbladder.In Huangdi Neijing,in the Qin and Han dynasties has been the understanding of gallbladder qi through heart.Li Yan,a doctor of Ming Dynasty,clearly put forward the theory of heart and gallbladder being connected.Wang Lun,a doctor in the Ming Dynasty,put forward the method of simultaneous treatment of heart and gallbladder.The heart and gallbladder coordinate the physiological functions of the viscera and organs through the meridians and the regulation of consciousness,qi and blood,thus maintaining the healthy operation of the functional mechanism of the human body.Modern medical research has found that the induction of abnormal gallbladder metabolism,abnormal blood lipid metabolism and gallbladder diseases are the main pathological factors leading to coronary heart disease.Therefore,it is of great clinical significance to choose the Traditional Chinese medicine simultaneous treatment of heart and gallbladder method to treat coronary heart disease.Professor Li Ping,founded the Lianxia Ningxin decoction,which is composed of nine Traditional Chinese herbs,to treat the syndrome of phlegm and heat disturbing the heart of coronary heart disease under simultaneous treatment of heart and gallbladder method.In the early stage,other members of the team have evaluated the efficacy of Lianxia Ningxin decoction and conducted relevant experimental studies on the two core drugs in animal experiments,but there is a lack of discussion on the mechanism prediction of Lianxia Ningxin decoction in the treatment of coronary heart disease and related TCM theories.Therefore,this study will strengthen evidence-based medicine research on relevant theories,clinical medication rules and sample size expansion,and study on prediction of network pharmacology mechanism of Lianxia Ningxin decoction for coronary heart disease,and conduct simulation verification by using molecular docking technology.Objective:By searching the records of the theory of heart and gallbladder are connected and medical cases in ancient literates,the database of special medical cases of treating heart diseases by simultaneous treatment of heart and gallbladder is constructed.To explore the law of differentiation and treatment of heart diseases by the ancient people with the method of simultaneous treatment of heart and gallbladder,and to provide a theoretical basis for Professor Li Ping’s TCM syndrome differentiation and classification of coronary heart disease with the method of simultaneous treatment of heart and gallbladder.Data mining method was used to comprehensively analyze Professor Li Ping’s clinical experience in treating coronary heart disease by using simultaneous treatment of heart and gallbladder method from the perspectives of disease,syndrome,formula and medicine,and summarize the characteristics and rules of medication of core formulas of various syndromes,laying a foundation for the inheritance of his academic thoughts and medication experience.To verify the characteristics and advantages of treating coronary heart disease with simultaneous treatment of heart and gallbladder method through the actual clinical effect.The effectiveness of different phlegm-relieving formulas combined with blood-activating and stasis-removing drugs in the treatment of coronary heart disease was studied by the method of network meta-analysis,and an objective and comprehensive evaluation and analysis were carried out.In order to provide a scientific basis for the treatment of phlegm as the main pathological factors of coronary heart disease with integrated traditional Chinese and western medicine.Through network pharmacology and molecular docking technology,the molecular biological mechanism and material basis of Lianxia Ningxin decoction,the core formula for predicting coronary heart disease with phlegm-heat disturbing heart syndrome,in the treatment of coronary heart disease were analyzed.Methods:1 Literature RetrievalThrough the Chinese Medical Classic(5th edition),the descriptions of the theory of heart and gallbladder connection in ancient documents and materials were retrieved.And based on the Medical Cases Leiju,a collection of ancient medical cases of treat heart diseases with the method of simultaneous treatment of heart and gallbladder was collected.2 Data MiningCollect and screen the outpatient medical records of professor Li Ping’s treating coronary heart disease with Traditional Chinese medicine.The ancient and modern medical case cloud platform(V2.3.5/WEB)developed by the Institute of Traditional Chinese Medicine Information of China Academy of Chinese Medical Sciences and SPSS Modeler 14.1 were used as tools to clean,build database,standardize,analyze and excavate the included medical records.The general information of medical cases,such as TCM syndromes,drug frequency,taste and meridian,etc.were counted by frequency statistics method.Cluster analysis and association rule analysis were used to explore the correlation between syndrome types and drugs,and between different Traditional Chinese medicines.Complex network analysis was used to explore the core formulas of Professor Li Ping’s simultaneous treatment of heart and gallbladder method for treating various syndromes of coronary heart disease.3 Network Meta-AnalysisRandomized controlled trials of Huanglian Wendan Decoction,Gualou Xiebai Banxia Decoction,Xiaoxianxiong Decoction and Erchen Decoction as the main decoctions and Chinese patent medicine Danlou Tablet in the treatment of coronary heart disease published in PubMed,Embase,The Cochrane Library,Web of Science,CNKI,VIP Journal,Wanfang and other database from Construction database to December 2021 were searched.Literature was screened and literature bias risk was assessed by RevMan5.4 software.Total clinical response rate,blood lipid(TC,TG,LDL-C,HDL-C)and hS-CRP expression were used as outcome indexes,and different outcome indexes under different treatment measures were evaluated and analyzed by using Stata15.1 software.Draw diagrams such as network evidence diagram and area sorting diagram under curves.Different treatments were ranked and publication bias was assessed by comparative-correction funnel plot.4 Network Pharmacology and Molecular Docking TechnologyUsing TCMSP,TCMID and Pubchem database,literature retrieval was conducted to collect the chemical components of 9 herbs of Lianxia Ningxin decoction.Swiss Target Prediction database was used to obtain the Target of chemical components of herbs.The targets of coronary heart disease were obtained by GeneCard,GEO and other databases.The potential target of Lianxia Ningxin decoction for treating coronary heart disease was obtained by intersection of the active compound target and disease target.Potential targets were imported into String database to construct protein-protein interaction(PPI)network diagrams.Using Cytoscape3.6.1,the network of compound-herb-active ingredient-target-disease was constructed to obtain the core target of Lianxia Ningxin decoction in the treatment of coronary heart disease.The core compounds of Lianxia Ningxin decoction were obtained by topological analysis.GO enrichment analysis and KEGG pathway enrichment analysis were performed for core targets using clusterProfiler package of R language.Combining the core target,core compound and enrichment analysis results of the compound,the active component-intersection target-pathway network was constructed using Cytoscape3.6.1.To predict the mechanism of Lianxia Ningxin decoction in treating coronary heart disease.Autodock-vina and other software were used to perform molecular docking on the key active ingredients and key targets of Lianxia Ningxin decoction,in order to evaluate the reliability of network pharmacology research prediction.Results:To understand the close relationship between the heart and gallbladder in physiology,pathology and the occurrence and development of coronary heart disease from the perspective of traditional Chinese and Western medicine,and explore the advantages of using the heart and gallbladder treatment method to treat coronary heart disease.According to the theory of Traditional Chinese medicine,the stasis of gallbladder qi and the obstruction of evil factors are the main pathological mechanism of coronary heart disease.Modern medical research has found that the induction of abnormal metabolism of bile,abnormal metabolism of blood lipids and biliary diseases are the main pathological factors leading to coronary heart disease.Therefore,the use of simultaneous treatment of heart and gallbladder method has become one of the most important clinical treatment methods of traditional Chinese medicine and Western medicine.Study 1By searching the theory of heart and gallbladder are connected in ancient literature and 2322 medical cases related to heart and gallbladder,the database of special medical cases of simultaneous treatment of heart and gallbladder method was constructed.Through the retrieval and screening of ancient medical records,139 medical records related to the gallbladder in the heart disease center were obtained,and the three most involved heart diseases were insomnia,palpitations and chest obstruction,indicating that the same diseases of the heart and gallbladder are common in the diseases of the heart system.Syndrome differentiation can be roughly divided into three categories:heart and gallbladder excess syndrome(gallbladder qi stagnation,phlegm and blood stasis accumulation,phlegm-heat disturbing the heart),heart and gallbladder deficiency syndrome(heart and gallbladder qi deficiency),heart and gallbladder both excess and deficiency syndrome(heart and gallbladder empty-heat with phlegm disturbing the heart).It provides a theoretical basis for Professor Li Ping to use the simultaneous treatment of heart and gallbladder method to treat coronary heart disease.Study 2Through the method of data mining,Professor Li Ping’s medication rule for coronary heart disease treated with simultaneous treatment of heart and gallbladder method was systematically analyzed.The data results showed that among the 270 medical records,male patients were higher than female patients,the average age was 67.9 years old.Hypertension,diabetes and hyperlipidemia were found to be the highest proportion among previous history and complications.In addition,there was also a close relationship between the occurrence of coronary heart disease and gallbladder diseases.The high-frequency clinical symptoms in the four diagnosis syndrome include chest pain,chest tightness,palpitations,shortness of breath,bitter mouth,upset,dry mouth,dizziness and so on.Tongue with dark tongue,red tongue,fat tongue,white,greasy,yellow coating is more common.Slippery,wiry and rapid pulse are relatively large.The top ten drugs commonly used by tutors were yujin,shichangpu,fuling,chenpi,zhiqiao,jiangbanxia,danshen,zhuru,huanglian and shouwuteng.In terms of herb properties,the herbs are mainly cool and cold,supplemented by warm and nature herbs,focusing on the compatibility of pungent,bitter and sweet.The herbs mainly involved in the distribution of the heart,liver,lung and spleen meridians.About 75%of the patients belonged to the heart and gallbladder excess syndrome,among which the syndrome of phlegm-heat disturbing the heart(33.33%)accounted for the most,followed by the syndrome of mutual accumulation of phlegm and blood stasis(27.78%),and the syndrome of gallbladder qi stagnation(15.19%).The proportion of syndromes belonging to deficiency of heart and gallbladder accounted for 14.81%.The syndromes that belong to the both excess and deficiency of heart and gallbladder are the least,accounting for 8.89%.Through cluster analysis and association rules,it was found that the commonly used combinations are yujin,changpu;gualou,xiebai;fuling,chenpi;dilong,jiangcan;danshen,sanqi;gegen,chuanxiong;hongjingtian,huangjing,jiuyurou.Through complex network analysis,Professor Li Ping was obtained 4 core formulas for treating coronary heart disease with phlegm-heat disturbing the heart syndrome,phlegm-stasis accumulation syndrome,gallbladder qi stagnation syndrome and heart-gallbladder deficiency syndrome.Among them,phlegm-related syndromes accounted for the largest proportion.Therefore,study 3 was an evidence-based medicine study with a larger sample size.Study 3In this study,the efficacy of five phlegm-relieving traditional Chinese medicine formulas combined with conventional western medicine in the treatment of coronary heart disease was compared by network Meta analysis,and the efficacy of different outcome indicators was ranked.The results showed that in improving total clinical effective rate,modified Gualou Xiebai Banxia decoction was the best,followed by modified Huanglian Wendan decoction and Danlou tablet.In improving TC,modified Huanglian Wendan decoction was the best.The modified Erchen decoction were the best in improving TG.In improving LDL-C,modified Huanglian Wendan decoction was the best.In improving HDL-C,modified Huanglian Wendan decoction was the best.In improving hs-CRP,modified Huanglian Wendan decoction was the best.In this study,through cluster analysis,it was found that modified Huanglian Wendan decoction has the best performance in improving TC and LDL-C at the same time.Huanglian Wendan Decoction has the best performance in improving blood lipid level and inflammatory response in the treatment of coronary heart disease with phlegm as the main pathological factor.Study 4Through the research of network pharmacology,a total of 78 active components of Lianxia Ningxin decoction were screened,and there were 341 potential targets,of which 80 were common targets with diseases.Through the network topology analysis of compound-herb-active ingredients-target-disease,5 core compounds were screened out,namely quercetin,naringenin,kaempferol,nobiletin,β-sitosterol.PPI network was constructed to obtain 8 core targets of Lianxis Ningxin decoction in the treatment of coronary heart disease,which were AKT1,MMP9,TNF,IL6,IL1B,VEGFA,CXCL8 and CCL2.The results of enrichment analysis showed that fluid shear stress and atherosclerosis,AGE-RAGE signaling pathway in diabetic complications,lipid and atherosclerosis pathway had high significance and enrichment numbers,all of which contained PI3K-AKT signal path.Therefore,the PI3K-AKT signaling pathway may be the key signaling pathway for the treatment of coronary heart disease with Lianxia Ningxin decoction.Molecular docking results showed that the predicted core components had good docking affinity with all the core target docking pairs and proved the reliability of network pharmacology.Conclusion:The use of simultaneous treatment of heart and gallbladder method to treat coronary heart diseases has clear clinical significance.Lianxia Ningxin Decoction,the core decoction of phlegm-heat disturbing the heart syndrome in data mining,is a decoction with remarkable clinical effect created by Professor Li Ping under the theoretical guidance of the simultaneous treatment of heart and gallbladder method.The network Meta-analysis provides a clinical and evidence-based medical basis for the relative effectiveness of integrated traditional Chinese and Western medicine in the treatment of coronary heart disease with phlegm as the main pathological factors.Modified Huanglian Wendan decoction and Gualou Xiebai Banxia decoction have certain research value in treating coronary heart disease with phlegm-heat and phlegm-stasis.The network pharmacology study further revealed the multi-component,multi-target and multi-pathway action network between Lianxia Ningxin decoction and coronary heart disease.Through active components such as quercetin,naringenin,and kaempferol act on AKT1,MMP9 and other key targets,participate in biological processes such as oxidative stress,inflammatory response,cytokine production,etc.,play a role in protein kinase binding and cytokine production,and regulate PI3K-AKT and other signaling pathways play a role in the treatment of coronary heart disease,providing theoretical basis and research ideas for the treatment of coronary heart disease with phlegm-heat disturbing the heart syndrome using simultaneous treatment of heart and gallbladder method. |
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