Network Pharmacology Based Approach To Investigate The Mechanism Of Huang-Lian-Jie-Du-Tang For Treatment Of Diabetes Mellitus And Hypertension

“Homotherapy for heteropathy” is one of the basic principles of Traditional Chinese Medicine(TCM)treatment,which helps people to learn about the common characteristics of disease development and to determine the treatment direction of diseases.It is helpful for people to understand and treat diseases from holistic perspectives.The rising incidence of hypertension(HP)and Type 2 diabetes mellitus(T2DM)threatens the quality of life of patients.And modern studies have shown that people with hypertension or diabetes mellitus are often accompanied by clinical symptoms such as dizziness,excessive drinking,eating,and other clinical symptoms.The development of the two diseases is closely related to unregulated diet,emotional disorders,and other factors,it is suggested that the principle of "homotherapy-for-heteropathy" is feasible in the treatment of diabetes mellitus and hypertension.At present,the research on type 2 diabetes mellitus and hypertension on “homotherapy for heteropathy” is mainly based on the combination of disease and syndromes and on the syndrome differentiation,and there are still some deficiencies in respect of the basic biological research of this theory.Huang-Lian-Jie-Du-Tang(HLJDT),a classic prescription for heat-clearing and detoxication,was first mentioned in Handbook of Prescriptions for Emergency,written by Ge Hong(284 C.E.-364 C.E.)in the Eastern Jin Dynasty of China.In this study,the Network pharmacology approach and the theory of “homotherapy for heteropathy”in traditional Chinese medicine were used to explore the molecular mechanism behind how HLJDT presents homotherapy-for-heteropathy therapeutic efficacy in both type 2 diabetes and hypertension at a molecular level,to explore the biological connotation of HLJDT’s“Homotherapy for heteropathy” from a holistic perspective,it provided the scientific basis for “the same treatment of different diseases of HLJDT”,expecting to provide some ideas and methods for reference for studies of Material basis and mechanism of action of TCM in the treatment of different diseases.The main contents of this paper include the following three parts:1.The correlation analysis between T2 DM and HP based on Bioinformatics: Firstly,the correlation analysis of T2 DM and HP by literature mining was carried out to explore the correlation between diseases from the point of view of traditional Chinese medicine and modern medical research respectively.Secondly,several databases including Dis Ge NET,Gene Card,Malacard were used to retrieve T2DM-related targets and HP-related targets.Drugbank and TTD were applied to retrieve the targets of approved drugs for the treatment of T2 DM and HP for exploring the correlation between these two diseases.Lastly,DAVID,a functional annotation tool was used to investigate the common signaling pathway.The results showed that there were multiple common pathogenesis such as phlegm and Dampness,dual deficiency of yin and yang,etc.,the shared genes of T2 DM and HP showed 545,significantly enriched signal pathway were HIF-1 signal pathway,c GMP-PKG signal pathway,and Proteoglycans in cancer.Based on the data collected from the Drugbank database and analyzed,it was found that T2 DM and HP share 132 known therapeutic drugs,and T2 DM and HP share 254 common drug targets.Searching the TTD database,it was found that there were 5 common targets of drugs that treat T2 DM or HP.The results indicated that T2 DM and HP were closely related in pathogenesis and targets,and have a good theoretical theory basis for "Homotherapy for heteropathy".2.The material base and the mechanism of HLJDT for treatment of type 2 diabetes mellitus and hypertension: Firstly,the protein-protein interaction(PPI)network and herb-components-targets network were constructed.Following the plugin of Cytoscape including Cyto NCA and MCODE were applied to calculate the topological parameters of nodes in the network to identify the key compounds-the hub targets associations.Lastly,we conducted a Kyoto Encyclopedia of Genes and Genomes pathway analysis(KEGG),Gene Ontology(GO)annotation analysis to explore the enriched GO terms including biological processes,cellular components,molecular function,and the common signal pathway.The results showed that key compounds for “Homotherapy for heteropathy”of HLJDT including quercetin,NEOBAICALEIN,rutaecarpine,MOL001490,Palmidin A,Obacunone,(S)-Canadine,berberine,magnoflorine,palmatine,(2R)-7-hydroxy-5-methoxy-2-phenylchroman-4-one,epiberberine,phellochin,and Eriodyctiol,(flavanone).Twelve hub targets including PTPN1,ESR1,AR,SRC,JAK2,MAPK8,GAPDH,EGFR,INSR,STAT3,IGF1 R and AKT1 were obtained through the network analysis.Finally the 14*12 component target correlations were predicted.The KEGG analysis showed that HLJDT may mainly mediate HIF-1 signaling pathway and exert “Homotherapy for Heteropathy” effects.The biological function analysis of the target showed that HIF-1 signal pathway may be the major signal pathway of HLJDT treats T2 DM and HP.The results indicated that HLJDT may play a role in the regulation of HIF-1 signaling pathway through 14 key components such as quercetin and berberine acting on 12 targets such as PTPN1,INSR to exert the curative effect of "Homotherapy for Heteropathy".3.Molecular docking-based approach to investigate the key component and HLJDT for treatment of T2 DM and HP: Apply literature mining and molecular docking to further verify the interaction between components and targets.Autodock Vina docking program was used to predict the binding affinities of key compounds to hub targets,and the binding modes were also explored.The results showed that most of the components had a good binding activity to the targets with binding energy less than-5kcal/mol.Notably,six targets in the HIF-1 signal pathway,including GAPDH,EGFR,INSR,STAT3,IGF1 R,AKT1 had binding energies less than-7 kcal/mol with 14 key components,which showed better binding affinity.About 16.7% of the predicted components-target associations are verified according to literature mining.The results indicated that HLJDT may act on six targets of GAPDH,EGFR,INSR,STAT3,IGF1 R,AKT1 through quercetin,NEOBAICALEIN,rutaecarpine,MOL001490,Palmidin A,Obacunone,(S)-Canadine and berberine,magnoflorine,palmatine,(2R)-7-hydroxy-5-methoxy-2-phenylchroman-4-one,epiberberine,phellochin,and Eriodyctiol,(flavanone)jointly regulate the HIF-1 signal pathway to treat T2 DM and HP.