Chemical Components And Network Pharmacology Exploration Of The Novel Chinese Herbal Formula Modified Kai-Xin-San

Objective:Kai-Xin-San(KXS),one of the most famous Traditional Chinese Herbal formulas for treating stress-related psychiatric disease with the symptoms of depression and forgetfulness in ancient China until today,is composed of Ginseng Radix et Rhizoma,Poly gal ae Radix,Acori Tatarinowii Rhizoma,and Poria.We added Salviae Miltiorrhizae Radix et Rhizoma,Chuanxiong Rhizoma,and Morindae officinalis Radix into KXS,to prepare a new formula,termed Modified Kai-Xin-San(MKXS).This study established a method for simultaneously determining the content of 24 components in MKXS.Besides,network pharmacology techniques were employed to explore the potential mechanism of MKXS.Component-target-disease network(C-T-D)and component-target-pathway network(C-T-P)were established to predict the targets of MKXS and the central nervous system diseases in which MKXS may play a therapeutic role and related pathways also predicted by network pharmacology techniques.These studies may provide a reference for the follow-up pharmacological research.Methods:High performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry(HPLC-Q-TOF-MS)was used to collect information of MKXS under positive and negative ion modes.Subsequently,A UPLC-PDA method was established for the simultaneous determination of 24 components in MKXS,and the contents of these 24 components were analyzed.Through Drugbank database,the similarity between the main components of MKXS and the listed drugs was retrieved;ADMET parameters of each compound were calculated by ADMET module of Discovery Studio;targets of each compound were predicted by PharmMapper website;diseases and pathways related to targets were analyzed by Mas3.0 website;gene ontology was analyzed by DAVID website;protein-protein interaction analysis of target were carried out with STRING website;component-target-disease(C-P-D)network and component-target-pathway(C-T-P)network were constructed using Cytoscape software,and the topological parameters of each node in the network were analyzed;the targets of compound were validated through molecular reverse docking technology.Results:A total of 125 compounds were deduced from the solution of MKXS,including 41 saponins,11 polygalactose oligosaccharides,8 polygalactose esters,12 salvianolic acids,16 tanshinones,5 ligustilides and 32 other components.The results showed that MKXS mainly contained components such as Senkyunolide A and salvianolic acid B,and their contents were 0.823-1.173 mg/g and 0.407-0.8403 mg/g,respectively.In the C-T-P network,the five components with the highest node degree were ginsenoside Rd,salvianolic acid B,Tenuifolin,ginsenoside Re and Polygalaxanthone Ⅲ.Among 20 target-related pathways(p≤0.01),the MAPK signaling pathway,Regulation of actin cytoskeleton,insulin signaling pathway,PPAR signaling pathway,and glioma pathway were the five pathways with the highest node scores.In the C-T-D network,each compound interacted with 78.7 targets on average;compounds acting on each target usually came from two or more herbs;monoamine oxidase B,monoamine oxidase A,mitogen-activated protein kinase 10,inducible nitric oxide synthase,caspase 3 were highly linked targets;the five components with the highest node degree were Ginsenoside Rd,salvianolic acid B,Tenifoliside A,ginsenoside Rg3 and ginsenoside Re;the average number of compounds linked by each candidate target was 10.7;the degree of Alzheimer’s disease was 48,which was the highest among the disease node,followed by glioblastoma,glioma,astrocytoma and schizophrenia with a nodal degree of 38,38,28 and 23,respectively.Gene ontology analysis showed that target genes mainly being involved in biological pathways such as phosphatidylinositol-mediated signaling pathway;Protein-protein interaction analysis showed that the targets interacted extensively in vivo.;further screening and molecular reverse docking showed that compounds with high Fit value had good docking effect with targets.Conclusions:MKXS mainly contains saponins,Polygala sucrose esters,Polygala oligosaccharides,salvianolic acids,tanshinone and ligustilide.The targets of the main components in MKXS were predicted to be mainly related to MAPK signaling pathway,Regulation of actin cytoskeleton,insulin signaling pathway,PPAR signaling pathway and glioma pathway.The main components of MKXS may have therapeutic effects on Alzheimer’s disease,glioblastoma,glioma,astrocytoma and schizophrenia.