Research On Medication Rules Of Traditional Chinese Medicine In The Treatment Of Autoimmune Hepatitis Based On Network Pharmacology And Drug Mining

ObjectivesIn this research,data mining and network pharmacology were used to analyze and process the literature on the oral treatment of autoimmune hepatitis with traditional Chinese medicine.The purpose of this research is to explore the rules of the use of TCM formulations,to provide some documentary basis and data support for the clinical application and experimental research direction of TCM in the treatment of autoimmune hepatitis(AIH),and to provide some reference for the development of new drugs.Methods1.Data mining:By searching the literatures of oral Chinese medicine in the treatment of autoimmune hepatitis in Wanfang Database(WF),CNKI(CNKI)and WP(WP)from the establishment of the database to December 1,2020.According to the inclusion and exclusion criteria to screen the literatures,the final literatures needed to be studied were obtained.Firstly,extracting and carry out normalized processing the document information.Secondly,to collect the literature data entry Excel spreadsheets.Establishing the literature research database of TCM treatment of autoimmune hepatitis,and import it into the ancient and modern medical case cloud platform(personal version V2.2.1)developed by the Institute of Traditional Chinese Medicine Information of China Academy of Chinese Medical Sciences.Applying the methods of data mining such as TCM frequency statistical analysis,entropy clustering analysis and correlation analysis.Finally,the core drug combinations were screened by complex network analysis,and the mechanism of action was further explored by network pharmacology.2.Network pharmacology:It mainly includes the following six aspects:(1)TTD、Drugbank、DisGeNET database were used to screen the disease targets of AIH,and the final disease targets were obtained after screening and standardized processing with Uniprot protein database.(2)TCMSP database was used to retrieve the chemical components of the core drug group,and DME attribute values were set as DL≥0.18,OB≥30%,and HL≥4h.Then SwissTargetPrediction database was used to predict the action targets of the selected active ingredients.(3)The disease target was intersected with the action target of the active ingredient of the core drug combination,and the joint action target of the two was obtained.(4)Cytoscape3.7.2 was used to construct the core drug active ingredient-common target-AIH disease network.(5)Network Analyzer in Cytoscape3.7.2 is used to analyze the topology of the constructed Network to screen out the core Network.(6)Go(BP)analysis of the common targets of the predicted core drug combinations for AIH was performed using the "Cluego" plug-in in Cytoscape3.7.2 software;KEGG pathway enrichment analysis was performed using Metascape.ResultsResults of data mining:1.A total of 104 literatures and 146 TCM prescriptions were included.There were 47 clinical trials that accounting for 45.19%of the total.There were 25 famous doctors’experiences,accounting for 24.04%of the total;Besides 23 cases and trials,accounting for 22.12%of the total and 9 postgraduate and doctoral papers,accounting for 8.65%of the total.2.The "data mining" module of ancient and modern medical case cloud platform was used to conduct statistical analysis on the TCM syndrome types of AIH involved in the included literatures,and the order of frequency was ranked from high to low,which included the syndrome of dampness-heat of liver and gallbladder,the syndrome of liver stagnation and spleen deficiency,the syndrome of Yin deficiency of liver and kidney,the syndrome of blood stasis and collation obstruction,and the syndrome of qi stagnation and blood stasis.3.A total of 146 TCM prescriptions contained 208 TCM ingredients,and the cumulative frequency of usage of all TCM ingredients was 1816 times,among which 27 herbs with the frequency of usage ≥20 were Bupleuri,Paeoniae,Orientalwormwood,Rhizoma Atractylodis Macrocephalae,Angelica sinensis,Poria cocos,glycyrrhiza,curcuma aromatica,Fructus Gardeniae,etc.4.Cluster analysis of Chinese medicine prescriptions shows that they can be divided into four categories which are"Asteragalus,Radix Scutellariae,Gardenia Fruit,Rhubarb","Bupleuri,Radix Paeoniae Peony,Atractylodes Atractylodes,Poria Cocos,Licorice,Curcuma Curcuma","Astragalus membranaceus,Radix Paeoniae Peony,Peachkemel,Tangerine Peel,Coix Seed,Fructus Schisandrae"and"Angelica,Rehmannia,Lycii Fructus,Peony Bark,Yam,Alisma alisma,Fructus Ligustri,Rehmannia rehmannii,Cornus officinalis".5.Relation analysis and complex network analysis were used to screen out the core drug pairs with the best correlation as "Bupleurum,Radix Paeoniae Paeoniae,Atractylodes Atractylodes,Poria cocos,Atractylodes wormwood,Gardenia jasminoides,Angelica Angelica and Licorice Radix".Results of network pharmacology:1.A total of 203 AIH disease related targets were obtained through retrieval and screening using TTD、Drugbank and DisGeNET database.2.The active ingredients of eight core drugs were searched in the TCMSP database,and a total of 129 active ingredients and 883 potential action targets were finally screened out.3.By taking the intersection of the above two action targets,35 common targets were finally obtained.4.Cytoscape 3.7.2 software was used to construct and visualize the network of active ingredient of core drug-disease target-AIH.Using the analysis of network pharmacology on core prescription,129 effective active ingredient are filtrated among which 14 effective active ingredient may treat the autoimmune hepatitis,such as 18α-hydroxyglycyrrhetic acid,pachymic acid,Trametenolic acid,Cerevisterol and Medicarpin.Besides there are 17 taegets which could be effective to treat the autoimmune hepatitis that contain ABCB1,NOX4,HSD11B1,CYP1B1,XDH and so on.5.Though Go functional analysis and KEGG enrichment analysis,5 main biological processes and 5 main pathways were obtained which including the biological processes of icosanoid metabolic process,terpenoid metabolic process,aromatase activity,long-chain fatty acid metabolic process and unsaturated fatty acid metabolic process with the pathways of Drug metabolis-cytochrome P450,Linoleic acid metabolism,c-type lectin receptor signaling pathway,Steroid hormone biosynthesis and Th17 cell differentiation.Conclusions1.Data mining:the main disease sites of autoimmune hepatitis are liver,spleen and kidney.The main treatment methods are to relieve the liver and invigorate the spleen,nourish the kidne,clear heat and promote diuresis,and promote blood circulation to remove blood stasis.The core drug portfolio is "Bupleurum,Radix Paeoniae Paeoniae,Atractylodes Atractylodes,Poria cocos,Atractylodes wormwood,Gardenia jasminoides,Angelica Angelica and Licorice Radix".2.Network pharmacology:applying the methods of modern medical network pharmacology,it is concluded that the core drug may prevent and cure autoimmune hepatitis by reducing inflammatory response and inhibiting autoimmune response,which provides some ideas for the formulation rule of oral Chinese medicine in treating autoimmune hepatitis.