Revisiting The Anti-cholestatic Liver Disease Drug Actions Of The Compound Yindan Decoction Through Network Medicine Analysis Methods

Given the current lack of specific therapeutic drugs for cholestatic liver disease and the difficult of the quality control of traditional Chinese medicine herb and the mechanism of drug action,this project intends to combine disease genetics and pharmacogenomics to construct a network medicine analysis method to interpret the pathological mechanism of cholestatic liver disease.To evaluate and explore the mechanism of the compound Yindan decoction and new target in the treatment of cholestatic liver disease,our research are focused on three parts as follows:We build a disease module of cholestatic liver disease based on the human interactome,and then analyze the occurrence and development mechanism of cholestatic liver disease based on the important related disease ontology and pathways in the enrichment results.Firstly,Me SH is used to search the disease keywords related to cholestatic liver disease,and cholestatic liver disease risk genes are collected in OMIM and Dis Ge NET with the disease keywords.Then the risk gene of cholestatic liver disease is located in the human interaction group network,and their topology parameters are calculated and used to verify the disease module.Finally,the disease mechanism of cholestatic liver disease is explained by the gene enrichment results in the disease module.A total of 532 cholestasis risk genes was collected,of which 465 risk genes were significantly located in the human interactome（p<0.001）,constituting the disease module for cholestatic liver disease.We also analyzed the mechanism of the disease module based on the network topology and found that the occurrence and development of cholestasis mainly involve bile secretion,inflammation,metabolism,and other pathways.Our disease module confirmed that the phenotype involved multiple targets and multiple pathways,rather than a target or a pathway.Bile secretion,inflammation,and metabolic regulation were the most significant causes of cholestasis.It provided a reliable guarantee for the subsequent network overlap and mechanism analysis of anti-cholestatic drugs.With the help of the existing clinically applied in chemical drug for anti-cholestasis,the"drug-target"and the disease modules are overlapped to construct a network medicine analytical method.We collected drug targets of ursodeoxycholic acid（UDCA）,adenosylmethionine,and cholesterylamine according to databases such as Drugbank and DGIdb,and constructed a"drug-target"network of chemicals,and then combined the chemical drug"drug-target"and disease module positioned in the human interactome,obtained the overlapping network of the chemical drug,and enriched the important targets in the overlapping network of the chemical drug（p<0.01）.17 targets of UDCA,adenosylmethionine,and cholestyramine were collected.After constructing an overlapping network and analyzing it,we found that the three drugs mainly regulate steroid hormones,metabolism,and glucuronidation to promote the secretion of bile acid to play a therapeutic role,which is consistent with the early reports of the mechanism of these three drugs in anti-cholestatic liver disease.Therefore,the network medicine analysis method constructed in this paper can be used to analyze the mechanism of anti-cholestatic liver disease,and it provides a feasible way for further application in the research of the drug mechanism of complex ingredients such as traditional Chinese medicine.The network medical analysis method is applied to the analysis of material basis and mechanism of action of the traditional Chinese medicine compound Yindan decoction against cholestatic liver disease.According to databases such as TCMSP,TCMID,Drugbank,etc.,the relevant components and targets of compound Yindan decoction were collected,and a small molecule database of compound Yindan decoction and a network of"herbs-ingredients-targets"were constructed.The"herbs-ingredients-targets"network of compound Yindan decoction and disease module are located in the human interaction group network,and the overlapping network of“compound Yindan decoction-cholestatic liver disease”is obtained,and enrichment analysis is performed based on the important nodes in the overlapping network（p<0.01）to explore the mechanism of compound Yindan decoction against cholestatic liver disease.We screened a total of 57 active ingredients of the eight medicinal materials in the compound Yindan decoction,which acted on 215 targets.From the"herbs-ingredients-targets"network,we found that the active ingredients in the prescriptions complementing with each other.In addition,the compound Yindan decoction is significantly related to the core risk genes of cholestasis(p=5.8×10^-12),and its active ingredients regulate multiple pathways through multiple targets such as a direct association of targets and indirect regulation of genes to achieve disease treatment,such as inflammation,metabolism,steroid hormones,and glucuronidation,etc.At the same time,comparing the mechanism of action of compound Yindan decoction and chemical drug,it is found that overlapping targets in the overlapping network of Chinese herbs and chemical drugs may be the key to its therapeutic effect,and non-overlapping genes may be the research object for the anti-cholesteric liver disease,such as mediating nuclear receptor activity,inflammation and bile acid secretion related to NR1H3,NR1I3,TLR2,PPARA,ESR2,ABCB1,PPARG,SULT2A1,SLCO1A2,etc.In summary,we build a disease module for the cholestatic liver based on the human interactome and analyze the interaction between disease and drug target from the overlapping network with the network medicine method constructed,which provides a new idea for complex diseases caused by genetic,immune,environmental,and other factors.It also provides a new reference for the evaluation and exploration of the drug action mechanism of traditional Chinese medicine and the screening of new drug targets in the treatment of complex diseases.