| Guanxin ? formula(GX?)has the effect of promoting blood circulation for removing blood stasis,which is widely used to treat the coronary artery disease(CAD).However,the mechanism of GX? is not explained clearly In this study,the mechanism of GX? was illuminated by the network analysis approach which has the advantage of evaluating TCM's pharmacological efect as a whole unity at molecular levelIn this study,the stasis protein interaction networks(sPIN)of 19 components,5 herbs and 1 formula in GX? were constructed;then the sPIN were integrated with CAD gene expression profile from GEO to constructed the co-expression protein interaction networks(CePIN)in different conditions of component-herb-formula three levels;afterwards the CePINs were analyzed by gene ontology enrichment analysis based on the optimal algorithm;besides,the structural reliability and the content accuracy of sPIN and CePIN were investigated.Based on the network structure analysis among CePINs and sPINs,the dynamic information hidden in the sPINs was revealed;base on the hubs analysis between different conditions,the dynamic information between modules in different conditions was revealed;based on the functional modules analysis,the mechanism of GX ? was elucidated at molecular level from componentherb-formula three levels;based on the analysis of similarities and differences of modules,the synergetic efects,the inheritance and emergence properties were illustrated to reveal the compatibility rules of traditional Chinese medicine(TCM).Four major study contents are as fellows:1.Methodological studyThe eNelator was used to cut off the 5%,10%,15%and 20%nodes of sPIN and CePIN,in order to investigate the stability of network structure by evaluating the average network connectivity.The results showed that there is almost no disturbance of the average network connectivity,hence the network structure is reliable.Base on whether there is some shared targets between CAD network from OMIM and CAD CePIN of GX?,the content accuracy was investigated.The results showed that 37%CAD targets were shared,and hence the contents of constructed networks were accuracy to some extent.Meanwhile,MCODE,MCL and FAG_EC were investigated to identify modules though evaluating the F value.The results showed that FAG_EC is the optimal algorithm.2.Mechanism analysis of GX? from component-herb-formula three levelsThe targets information of main active components of GX? was obtained from two parts:pharmacophore virtual screening and the component-protein interaction database including ChEMBL(https://www.ebi.ac.uk/chemb1/#)and STITCH(http://stitch.embLde/).The PPIs information of targets was obtained from the online updated database of String 9.1(http://stringdb.org/)which has a confidence score for every protein interaction.PPIs with a confidence score>0.7 were applied to construct sPIN using Cytoscape.Then the sPIN were integrated with CAD gene expression profile from GEO to construct the co-expression protein interaction networks(CePIN)in different conditions of component-herb-formula three levels.Afterwards the CePINs were analyzed by gene ontology enrichment analysis based on the FAG_EC algorithm Based on the network structure analysis among CePINs and sPINs,the dynamic information hidden in the sPINs was revealed;base on the hubs analysis between different conditions,the dynamic information between modules in different conditions was revealed;based on the functional modules analysis,the mechanism of GX? was elucidated at molecular level from component-herb-formula three levels.3.The analysis of synergetic effects,the inheritance and emergence propertiesThe efficacy of TCM is owing to the synergetic effects of components/herbs,which also reflects the inheritance and emergence properties.The scientific interpretation of these properties is a benefit to the explanation of the compatibility rule and it is further beneficial to the action mechanism of formulae.In this study,the synergetic effects,the inheritance and emergence properties of TCM were analyzed based on functional modules.The results showed that from the view of modules,the inheritance properties are embodied in participating in the same biological processes and having the same effects based on the same functional modules;while the emergence reflects that formulae possess the biological processes which the herbs and compounds don't have based on the new functional modules,and exert different pharmacological effects.4.The analysis of the relation between "Xinwen","Kuhan" and efficacy of TCMIn this study,the efficacy modes of "Xinwen" and "Kuhan" were constructed by Bayesian Network Approach Base on the functional modules,the relation between "Xinwen","Kuhan"and efficacy of TCM was discussed.A network analysis approach based on functional modules is applied to systematically illuminate the mechanism of Guanxin?.This study aimed to provide an efficient way to elucidate the mechanism of Guanxin ? based on functional modules at the molecular leve. |
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