Study On The Anti-depression Mechanism Of Baihe Dihuang Decoction Based On Network Pharmacology And Metabolomics

Objective: The classic prescription Baihe Dihuang Decoction is derived from Zhang Zhongjing’s "Golden Chamber Synopsis".It is composed of the emperor lily and the court medicine Dihuang.The prescription has the effects of nourishing yin and clearing heat,nourishing the heart and nourishing the lungs.It was often used in the treatment of lily disease in ancient times.The symptoms of Baihe disease in sleep,diet,mentality,and behavior are similar to the clinical manifestations of modern depression.Therefore,Baihe Dihuang Decoction is commonly used in modern times to intervene and relieve depression,and the clinical effect is significant.However,due to the many components of traditional Chinese medicine compounds,the pathogenesis of depression is complicated.Therefore,the mechanism of action has not yet been elucidated.This article combines the research methods of metabolomics and network pharmacology to analyze the antidepressant macroregulatory mechanism of Baihe Dihuang Decoction from the overall level,and provides theoretical support for the clinical application of Baihe Dihuang Decoction.Methods: 1.The databases TCMSP,SYMMAP,ETCM,and TCM-MASH were searched to obtain the natural compound components of Baihe Dihuang Tang and compound small molecule library was established.Through UPLC-Q-TOF-MSE screening,the main compounds of Lily Rehmanniae were obtained.2.The natural active ingredients were selected by EDAM principles,oral absorption and utilization(OB)values > 30% and druglike properties(DL)values > 0.18,and those that conformed to the adult drug rules were selected.3.The Pubchem database,the Targetnet database to find the target corresponding to the active ingredient of the drug,and the target with a score of 1 was used as the potential target corresponding to the drug ingredient.4.by comparing the toxicogenomics database(Comparative Toxicogenomics Database)and the comprehensive human genetic database(Genecards),the human Mendelian Genetics Database(OMIM)and Drug Bank database to retrieve the targets associated with depression,combined with the targets corresponding to the active ingredients of Baihe Dihuang Tang drug and the targets corresponding to the disease.The predicted targets were converted through the Uniprot database.Then obtain the intersection targets of lily dihuang tang and disease through STRING database.5.Construct the drug active ingredient-target network topology map and PPI target protein interaction map and obtain the core targets,and then construct the drug ingredient-target interaction network through Cytoscape＿v3.6.1 for parameter analysis.6.Establish depression using long-term chronic unpredictable stimu Lation SD rats The animal model was intervened with lily dihuang tang for retraining;UPLC-Q-TOF-MS non-targeted metabolomics was used to study the mechanism of action of lily dihuang tang for depression,and the plasma metabolic profile of lily dihuang tang treated depressed rats was characterized,combined with QI platform for principal component analysis(PCA)of metabolites in the plasma of blank control group,lily dihuang group,and mod group,and OPLS-DA analysis between groups was performed to screen the differential metabolites,combined with HMDB to identify the differential metabolites,and imported into Metabo Analyst to analyze the differential metabolite involved pathways.Results: 1.64 chemical components were quickly separated and identified,mainly including saponins,iridoids,flavonoids,acids,esters,and phenethyl alcohol glycosides,including 6 lily saponins,8 iridoids,and 16 acids.7 esters,7 phenylethanol glycosides,6flavonoids,4 alkaloids and others.2.37 species in lily and 43 species in Dioscorea were selected by database search,and 19 core targets were obtained,including HSP90AA1,CYP19A1,NR3C1,ESR1,HDAC3,HDAC1,AR,etc.The pathways involved are mainly steroid hormone synthesis,C21-steroid hormone biosynthesis,etc.which play the basis of drug action components are mainly lily saponins,terpenoids,and cyclic enol ether terpenoids in Dioscorea.3.Behavioral results of animal experiments showed that the successful construction of depression models,sucrose preference experiments,open field experiments,and elevated cross experiments showed significant differences among groups,in accordance with the statistical distribution pattern.4.Non-targeted metabolomics analyzed the differential metabolites between model-blank,model-administration,and the positive model identified a total of 43 differential metabolites,involving 11 pathways,including bile acid biosynthesis,linoleic acid metabolism,phenylalanine metabolism,unsaturated fatty acid biosynthesis,sphingolipid metabolism,steroid hormone biosynthesis,glycerophospholipid metabolism,tryptophan metabolism,α-linolenic acid metabolism,arachidonic acid metabolism,and fatty acid biosynthesis.Conclusion: This experiment used network pharmacology method combined with metabolomics method to analyze the mechanism of lily dihuang tang in treating depression and the material basis of its efficacy.the analysis concluded that lily dihuang tang has the effect of treating depression.its action components are mainly lily terpenoids,saponins,and dihuang cyclic enol ether terpenoids,which may exert antidepressant effect through arachidonic acid metabolism,glycerophospholipid metabolism,hypothalamic-pituitaryadrenal axis(HPA)pathway to exert antidepressant effects.