Using Bioinformatics Analysis Technology To Explore The Modern Biological Connotation Of The Relationship Between Chaihu Shugan San Prescription And Syndrome

The theory of "formula matched with syndromes" is not only the core proposition of prescriptions,but also the logical basis of TCM syndrome differentiation and treatment.The scientific issues related to prescriptions and syndromes are the degree of correlation between prescriptions and syndromes and its modern biological basis.The logic of"prescriptions follow the syndrome is effective" in the prescriptions and syndromes determines that it is necessary to combine the two aspects in the study of the prescriptions or syndromes of Chinese medicine to achieve the effect of killing two birds with one stone.Liver-stagnation syndrome is one of the most common syndromes in TCM.Chai Hu Shu Gan San is a representative prescription for TCM treatment of Liver-stagnation syndrome.At present,a large number of modern connotations of Liver-stagnation syndrome and the pharmacological effects of Chai Hu Shu Gan San have been studied.Some results have been achieved,but the modern biological basis of the relationship between the Liverstagnation syndrome and Shu Gan Jie Yu prescription is still unclear.Based on the theory of"formula matched with syndromes",this article attempts to explore the chemical components of Chai Hu Shu Gan San and the types of diseases involved in the modern clinical application of Chai Hu Shu Gan San,using modern bioinformatics analysis techniques to explore the modern biological connotation of Chai Hu Shu Gan San.The thesis includes three parts:literature review,clinical investigation and biological analysis.The literature review mainly focuses on the research overview of formula and syndromes in recent years,the concept of network pharmacology and its application in the field of Chinese Medicine research,the clinical application and pharmacological research of Chai Hu Shu Gan San.The first study of the main text is the literature survey of Chai Hu Shu Gan San treating modern diseases;the second is to explore the modern biological connotation of Chai Hu Shu Gan San prescriptions matched with Liver-stagnation syndrome based on bioinformatics analysis technology.Study one:Investigation of Chai Hu Shu Gan San in modern clinical treatment of diseasesMethods:Using the literature search method,search all the literature in the CNKI database from the establishment of the database to December 2020 with the keyword as Chai Hu Shu Gan San,and collect and sort the literature on the clinical application of Chai Hu Shu Gan San and statistical analysis,to determine the dominant disease of its main treatment.Results:A total of 3608 results were retrieved in this research,including 1163 clinical literatures based on TCM syndrome differentiation with names of modern diseases with clear diagnoses treated by this prescription.The analysis found that Chai Hu Shu Gan San is widely used in 98 kinds of diseases including internal medicine,external medicine,women,children,etc,involving respiratory system,digestive system,circulatory system,endocrine system,nervous system,exercise system,urinary system,etc.The analysis of the frequency of diseases shows that there are 18 main diseases,most of which are digestive system diseases.Among them,the top 10 are chronic gastritis,depression,functional dyspepsia,reflux esophagitis,bile reflux gastritis,Cholecystitis,peptic ulcer,breast hyperplasia,hepatitis B,angina pectoris.Conclusion:Chai Hu Shu Gan San mainly treats a wide range of modern diseases,involving multiple diseases of multiple systems,of which the most commonly used are digestive system diseases including chronic gastritis,depression,breast hyperplasia,hepatitis B,and angina pectoris;the five diseases can be regarded as the dominant diseases of Chai Hu Shu Gan San.Although the pathology and manifestations of these 5 diseases are different,the phenomenon that the selection of TCM syndrome differentiation and Chai Hu Shu Gan San treat multiple diseases and syndromes reflects the experience and characteristics of TCM "different diseases and same treatment",that is,"same syndrome and same treatment".At the same time,it suggests that the various diseases that the prescription treats may have a common modern biological basis related to Liver-stagnation syndrome.Study two:Exploration of modern biological connotation of disease and syndrome relations of Chai Hu Shu Gan SanMethods:(1)Select 5 dominant diseases involved in the modern clinical application of Chai Hu Shu Gan San,namely chronic gastritis,depression,breast hyperplasia,hepatitis B,and angina pectoris,and apply biological information analysis methods to retrieve multiple disease genes target database,construct the molecular biology network of the disease;(2)Investigate the chemical composition of Chai Hu Shu Gan San compound prescription,use the compound network pharmacological analysis technology to obtain the molecular action network of the prescription;(3)Further treat the disease biology network and the pharmacological network of the prescription are fitted and analyzed,and the intersection of the two is analyzed for GO function and KEGG pathway enrichment analysis.(4)By constructing the target network of Chai Hu Shu Gan San component-Liver stagnation syndrome,conduct topological analysis on it,explore the effect material basis of the association of Chai Hu Shu Gan San-Liver stagnation syndrome,and use molecular simulation docking method to simulate and verify.Results:(1)The disease gene targets of chronic gastritis,depression,breast hyperplasia,hepatitis B,and angina pectoris are 1144,3902,4478,7696,and 1418,respectively;their common pathophysiological mechanisms involve inflammation,immune response,antiviral,and anti-virus,anti-infection,oxidative stress,tumor metastasis,DNA damage,apoptosis,aging,endocrine resistance,blood circulation,gland development,allograft rejection and other mechanisms;involved in differentiation from Th17 cells,IL,12,CAMs,5-HT,methionine synthesis,arachidonic acid synthesis metabolism,hydrogen peroxide metabolism,receptor ligand activity,cytokine-cytokine receptor interaction,growth factor receptor binding and regulation of kinase,transferase,protein kinase,Akt activity,MAPK activity related to the regulation of cascade,phosphatase,kinase binding,etc.;the common pathway involves the ERK1 and ERK2 cascade,AGEs-RAGE,HIF-1,PI3K,PI3K-Akt,ErbB,fox0,NF-?B,and prolactin,T cell receptors,NOD-like receptors,BNDF,Ras,apoptosis signaling pathways and pathways in cancer;are most associated with viral infections and carcinogenesis.(2)Chai Hu Shu Gan San contains 256 active ingredients,corresponding to 313 targets;pharmacological effects involve inflammation,oxidative stress,anti-virus,anti-infection,immune regulation,apoptosis,blood vessel development,DNA replication,kinase binding,fat metabolism,neuronal apoptosis and hormone secretion such as insulin and estrogen,G protein coupling regulated by adenylate cyclase,DNA binding transcription factor activity,transcription factor binding,protein kinase activity regulation,cell Cycle,cell migration regulation,response to mechanical stimulation,radiation,drugs,muscle cell and epithelial cell proliferation,gland development,peptidylserine phosphorylation,RNA polymerase ? regulation of pri-miRNA transcription,miRNA pair participation regulation of gene-silencing miRNA production,transcription error regulation in cancer,MicroRNAs in cancer,response to glucocorticoids and steroid hormones,leukocyte differentiation,cytokine-cytokine receptor interaction and other biological functions and processes related;involving calcium ion,cAMP,fox0,VEGF,NF?B,intracellular steroid hormone receptor,prolactin,thyroid hormone,Rapl,PI3K-Akt,AGEs-RAGE,apoptosis signaling pathway and pathways in cancer,etc.Connecting with blood circulation,cognition,aging,fat metabolism,vascular development,endocrine,immune and other physiological processes;and involve in hepatitis B,hepatitis C,HTLV-1 infection,Epstein-Barr virus infection,measles,toxoplasmosis and other infection diseases,are related to tumors such as small cell lung cancer,non-small cell lung cancer,breast cancer,pancreatic cancer,prostate cancer,bladder cancer,acute myelogenous leukemia,and chronic myelogenous leukemia.(3)Among the targets of this party,there are 127,216,228,256,and 172 targets involved in the above 5 diseases,respectively.There are 96 targets in common intersection,involving 30 key genes such as STAT3,JUN,TP53,etc.The common target involves inflammatory response,cell response to chemical stimulation,lipopolysaccharide,radiation,drugs,peptides,trauma,oxygen content,reactive oxygen metabolism process,leukocyte differentiation antigen,growth factor and other extracellular stimuli,cell apoptosis and ion transport,positive regulation of cytokine production,epithelial cell proliferation,protein breakdown,platinum drug resistance,transcription errors in cancer and other biological processes;related pathways mainly involve pathways in cancer,AGEs-RAGE,IL-17,MAPK,NF-?B,VEGF,apoptosis signaling pathway;closely related to viruses and immune diseases,cancer and liver disease.(4)There are 22 key active ingredients of Chai Hu Shu Gan San,mainly from the three Chinese medicine of Chai Hu,Xiang Fu and Gan Cao.Among them,the most key active ingredients are quercetin,luteolin,puerarin and petunidin.There are 4 kinds of the most critical ingredient,which are derived from the two Chinese medicine of Chai Hu and Xiang Fu,especially Chai Hu,which basically coincides with the positioning of the prescriptions of the monarchs and ministers.There are 8 key targets for the action of the four components,which are PTGS2,AR,NOS2,GSK3B,PPARG,HSP90AA1,MAPK14,and PTGS2.Molecular simulation docking shows that these four key components have good binding activity with their key targets,and the biological mechanisms involved in their target points are consistent with the biological connotation of the prescription-syndrome correlation.Conclusion:1.The biological basis of the relationship between Chai Hu Shu Gan San and liver depression syndrome includes:1)Inflammation,involving cytokine-mediated cytokine-cytokine receptor interaction,especially the pathophysiological link related to inflammation;Among them,interleukins(including IL-6,IL-2,IL-1?,IL-4,IL-10)and VEGFA are key factors,involving IL-17 signaling pathway,NF-?B signaling pathway,VEGF signaling pathway,PI3K-Akt signaling pathway.2)Apoptosis,involving the process of apoptosis mediated by AKT1,TP53,BCL2,etc.And MAPK,NF-?B,apoptosis signaling pathways.3)Endocrine regulation,involving the synthesis and release of prostaglandin,prolactin,AR and other hormones and receptors.PTGS2,AR,and PTGS1 are key targets.4)Oxidative stress involves the regulation of NOS2 and HSP90AA1,and the AGEs-RAGE signaling pathway is its key pathway.5)Immune regulation,involving Th17 cell differentiation,allograft rejection,and pathways are key pathways.6)The regulation of the nervous system involves processes such as neuronal apoptosis and 5-HT synthesis.The BNDF signaling pathway is the key pathway.7)The mechanism of tumorigenesis and its drug resistance,involving the proteoglycan effect in cancer,transcription error regulation in cancer,platinum drug resistance and other biological processes,cancer genes such as STAT3,JUN,FOS,MYC,and TP53;pathways in cancer,MAPK,NF-?B,and VEGF signaling pathways may be key pathways.2.The material basis of Chai Hu Shu Gan San and the syndrome of stagnation of the liver:22 key components from the three traditional Chinese medicines of Chai Hu,Xiang Fu and Gan Cao may be the material basis of Chai Hu Shu Gan San and the syndrome of stagnation of the liver,the most critical active ingredients are quercetin,luteolin,puerarin and petunidin;8 key targets are involved PTGS2,AR,NOS2,GSK3B,PPARG,HSP90AA1,MAPK14,and PTGS1.The results of molecular docking show that the four key components and their respective key targets have good binding activity,and the docked targets and their pathways are consistent with the main body of the biological connotation of the prescription-syndrome association,suggesting that they are used as the characterization of the ingredient formula significance.This study provides the biological connotation related to the Chai Hu Shu Gan San,especially the known mechanism of the stagnation of liver syndrome and the role of Chai Hu Shu Gan San involving the regulation of the nerve-endocrine-immune network.The molecular understanding also provides a certain biological basis for the further expansion of the prescription for the prevention and treatment of immune disorders and cancer,as well as a reference for the research and development of new Chinese Medicines based on molecular combinations with traditional Chinese Medicine syndromes.