Study On The Medication Rules And Mechanism Of Action Of Traditional Chinese Medicine In The Treatment Of Acute Respiratory Distress Syndrom

ObjectiveBased on the data mining technology and the network pharmacology approach,analyzing the prescription formulation rules of traditional Chinese medicine(TCM)and the pharmacological mechanism of core traditional Chinese herbal medicine for the treatment of acute respiratory distress syndrome(ARDS).MethodsSearching China Knowledge Resource Database(CNKI),China Biomedical Literature Database(CBM),Wanfang Data(WANFANG DATA),Weipu Chinese Science and Technology Journal Database(VIP)and PubMed to collect clinical studies on the treatment of ARDS in traditional Chinese medicine(TCM),and setting the search time limit to October 2022.According to the inclusion and exclusion criteria of the literature,Using the EndNote 20.0 software to identify the literature on the treatment of ARDS in traditional Chinese medicine,extracting the literature name,author information,research object,research method,TCM compounds,efficacy evaluation index and other information,and importing the above information into Microsoft Excel 2013 software to establish the database of literature and the database of medication.Standardizing the data of medication,and using Microsoft Excel 2013 software to analyze the frequency of herbal medicines and their tastes,properties,meridian tropism and effects.On the basis of the frequency analysis of herbal medicines,using IBM SPSS Modeler 18.0 software to analyze association rules of high-frequency herbal medicines,and the data obtained from association analysis were imported into Cytoscape 3.9.1 software for complex network visualization construction,showing the correlation degree between herbal medicines.Using IBM SPSS Statistics 25.0 software to analyze systematic clustering and factor analysis of high-frequency herbal medicines.Through the above data analysis methods,the medication rules of traditional Chinese medicine for the treatment of ARDS were explored,and the core herbal medicine for the treatment of ARDS were obtained.Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)(https://tcmspw.com/tcmsp.php)was used to retrieve the active compounds of herbal medicines and their target proteins.The UniProt database(https://www.uniprot.org/)was used to convert target proteins into corresponding standard gene names,and to delete duplicate genes and remove targets that could not be retrieved.Saving the pharmaceutical active compound and its corresponding target information to Microsoft Excel 2013 software,building the active compound of herbal medicine-target information database,and using Cytoscape 3.9.1 software to build the "herbal medicine-active compound-target" network diagram.Login to the Gene Cards:The Human Gene Database(http://www.genecards.org/)and the Online Mendelian Inheritance in Man(OMIM)(https://omim.org/)to retrieve ARDS-related target genes.The target genes derived from the two databases were combined and the duplicate values were removed to obtain ARDS-related target genes.Through Venny online platform(VEENY2.1.0)(https://bioinfogp.cnb.csic.es/tools/venny/),the disease targets and the core herbal medicine targets were intersected,and the common target genes of the disease and the core herbal medicine were obtained.Cytoscape 3.9.1 software was used to construct the "herbal medicineactive compound-target-disease" network map to screen out key target genes.The common target genes were imported into the Metascape database(https://metascape.org/)to conduct the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis and Gene Ontology(GO)enrichment analysis to explore the mechanism of action of the core herbal medicine treatment ARDS.ResultsIn this study,a total of 90 clinical research articles on the treatment of ARDS in traditional Chinese medicine were included,and 90 prescriptions of traditional Chinese medicines were extracted,with a total of 120 flavors of herbal medicine.Data mining results show that the commonly used herbal medicines for the treatment of ARDS are rhubarb,licorice,peach kernel,magnolia,pepperweed seed and so on.The most frequently used in the efficacy category of herbal medicine is heat-clearing medicine,followed by tonic medicine,cough and asthma medicine,promoting blood circulation and removing blood stasis medicine,purgative medicine and so on.The medicinal properties of herbal medicine for the treatment of ARDS are mainly cold,followed by bitterness,sweetness,spicy,etc.Herbal medicines are mostly attributed to lung meridian,liver meridian,spleen meridian,and stomach meridian.The high-frequency herbal medicine association analysis showed that the herbal medicine pairs with the highest degree of support in the second-order association rule analysis were rhubarb→magnolia,the herbal medicine combination with the highest support in the third-order association rule analysis was magnolia→ citrus+rhubarb and citrus→magnolia+rhubarb,and the herbal medicine combination with the highest support in the fourth-order association rule analysis was magnolia→ glauconite+citrus+rhubarb.Systematic cluster analysis yielded a total of eight herbal medicine combinations:C1:magnolia,citrus,rhubarb,and glauconite;C2:gardenia,forsythia,skullcap;C3:bitter almond,gypsum,trichosanthis Fructus,pepperweed seed;C4:ginseng,salvia,ophiopogon japonicas;C5:cassia twig,asarum,radix paeoniae alba,schisandra chinensis,ephedra,pinellia ternata;C6:licorice,poria;C7:peach kernel,paeonia lactiflora,safflower,ligusticum,astragali radix,rehmannia glutinosa,fructus aurantii,radix bupleuri,platycodonis radix;C8:skullcap,tangerine peel.Six common factors were extracted from factor analysis:F1:citrus,magnolia,glauconite,rhubarb;F2:paeonia lactiflora,peach kernel,safflower,angelica;F3:trichosanthis Fructus,bitter almond,gypsum,skullcap;F4:skullcap,licorice;F5:pinellia ternata,salvia,astragalus;F6:pepperweed seed,astragali radix.The results of the network pharmacology study showed that there were 6 active ingredients of the herbal medicine-rhubarb in the treatment of ARDS,namely β-sitosterol,aloe-emodin,eupatin,cassia lactone,catechin,and rhein.There are 28 potential targets for the treatment of ARDS,of which 8 are key targets,namely Prostaglandin G/H synthase 2(PTGS2),Prostaglandin G/H synthase 1(PTGS1),phosphoinositol 3-kinase(Phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit,gamma isoform,PIK3CG),inducible nitric oxide synthase(NOS2),sodium channel protein type 5 subunit α alpha(SCN5A),Estrogen receptor(ESR1),Apoptosis regulator BAX(BAX),Caspase-3(CASP3).There are 93 signaling pathways in which rhubarb is involved in regulation by KEGG pathway enrichment analysis,mainly including apoptosis,mitogen-activated protein kinase(MAPK)signaling pathway,phosphatidylinositol 3-kinase and protein kinase B(Phosphatidylinositol-3-kinase-Akt,PI3KAkt)signaling pathway,etc.;GO functional enrichment analysis yielded 742 entries,mainly involving biological processes such as cellular response to organic cyclic compound,response to hypoxia,blood circulation,and response to decreased oxygen levels and so on.ConclusionsThe data mining results show that the core herbal medicine of modern Chinese medicine for the treatment of ARDS is rhubarb,which is mostly treated from the lung,liver,spleen and stomach in the process of clinical practice,and the herbal medicines are mainly heat-clearing medicine,deficiency medicines,phlegm cough and asthma medicine,promoting blood circulation and removing blood stasis medicine,purgative medicine and so on.When composing the formula,attention is paid to the use of treatment methods such as tongfu xiere method,xuanfei tongfu method,qingre jiedu method,huoxue quyu method,and wenyang huayin method,and often use classic formulas such as da-cheng-qi decoction,xuan-bai-chengqi decoction,xue-fu-zhuo-yu decoction,xiao-qing-long decoction,etc.The rules of prescription formulation reflect the pathogenesis characteristics of ARDS,and the pathological evolution is based on excess of fu-viscera,heat toxicity,phlegm-fever,blood stasis,and retained fluid.The results of network pharmacology suggest that the main active compounds of rhubarb in the treatment of ARDS are β-sitosterol,aloe emodin,eupatin,toralactone,catechin and rhein,which regulate apoptosis,PI3K-Akt,p53,MAPK and other signaling pathways by acting on key targets such as PTGS2,PTGS1 and PIK3CG,and play a role in inhibiting inflammatory response,immune regulation,and intervening in apoptosis to treat ARDS.This reflects that rhubarb has the characteristics of multi-component,multi-target and multi-pathway in the treatment of ARDS,and has potential and good clinical application value.