Research And Application Of Optimization Method Of TCM Prescription Based On Group Collaborative Algorithm

ObjectiveThis paper is aimed to construct the weighted pharmacological network of traditional Chinese medicine(TCM)prescription with using the group collaborative algorithm and introduced the theory of monarch,minister,assistant and guide,and then proposed a new optimization method of TCM prescription.Then we plan to apply this method to the prescription optimization of Tanyu Tongzhi prescription against myocardial ischemia-reperfusion injury(MI/RI),and verified by enrichment analysis and animal experiments,in order to provides the method that can be repeated,quantified and reasoned for the optimization of TCM.Methods and Contents(1)Research on network module division method based on group collaborative algorithmThis paper proposes a network module division method with group collaborative algorithm as the core.The goal is to find the relationship between groups in the network,rather than the relationship between individuals.The algorithm aims at maximizing the group collaborative modularity,combined with the Louvain optimization strategy,carries out module identification,in order to identify the component groups that closely interact with the disease target groups in the TCM compound target network.(2)Research on network weighting method based on the theory of monarch,minister,assistant and guideCombined with clinical experience and module division,this paper explores the assignment method of different drugs about monarch,minister,assistant and guide in TCM prescription.Based on theory of monarch,minister,assistant and guide,the pharmacological network of TCM prescription was weighted.While the module division results of weighted network and unweighted network were compared,the influence of weighting method on network module division was discussed.(3)Study on Prescription Optimization of Tanyu Tongzhi prescription based on group collaborative algorithmThe optimization method of TCM prescription with the group collaborative algorithm as the core is applied to optimize the Tanyu Tongzhi prescription.By constructing the "component-target-disease" pharmacological network of Tanyu Tongzhi prescription against MI/RI,the theory of monarch,minister,assistant and guide is introduced to weight the network,the group collaborative algorithm is used to divide the modules,find the core nodes in the network,and then screen the optimized recipe 1(6 medicines)and optimized recipe 2(7 medicines).(4)The optimized results were verified by gene enrichment analysis and animal experimentsThrough gene enrichment analysis,the original prescription and the optimized prescription of Tanyu Tongzhi prescription were analyzed and compared with the biological functions and enrichment pathways.Through animal experiments,we observe the effects of the original and optimized prescriptions of Tanyu Tongzhi prescriptio on myocardial enzymes(AST,ALT,LDH,CK,CK-MB,cTnI),oxidative stress kinase(MDA),inflammatory factor(IL-1β,IL-6,TNF-α),apoptosis factors(Bcl-2,Bax)and the size of myocardial infarction in the MI/RI rats.Results(1)This paper proposes a network module division method based on group collaborative algorithm,applies it to divide modules in four networks,two public high quality protein-protein interaction networks(PPI),the pharmacological network of Zuojin Pill and Tanyu Tongzhi prescription against MI/RI,while compares with four commonly used module partition algorithms,GN algorithm,CNM algorithm,LPA algorithm and LFM algorithm.The results show that the group collaboration algorithm performs best in the module division of the four networks,and compared with other module division algorithms,the module degree Q obtained by the group collaboration algorithm is higher than that of other algorithms,and the division quality is high,which fully shows the superiority of the performance of the group collaboration algorithm.(2)The traditional theory of monarch,minister,assistant and guide is introduced into the construction of the TCM pharmacological network.According to the expert opinions and the results of network module division,the one with the best quality of network module division is selected among the three weight distribution schemes,that is,the weight values of monarch,minister,assistant and guide drugs are 20-10-6-4 respectively.Comparing the module division of weighted network and unweighted network,it is found that the network weighting method based on the theory of monarch,minister,assistant and guide has a great impact on the module division of group collaborative algorithm,which can improve the quality of module division.It also confirms the influence of the theory of monarch,minister,assistant and guide to TCM pharmacological network.(3)The optimization method of TCM prescription with the group collaborative algorithm as the core is applied to optimize the Tanyu Tongzhi prescription.We construct the "component-target-disease" pharmacological network of Tanyu Tongzhi prescription against MI/RI,while weight the network according to the theory of monarch,minister,assistant and guide,and then divide the modules by group collaborative algorithm.As a results,a total of 13 group collaboration modules were identified,and the modularity was 0.5537.The identified modules are analyzed with the proposed weighted closeness centrality(WCC),combined with degree centrality(DC)and closeness centrality(CC),the core nodes in the network are found,and the optimization prescription 1 and optimization prescription 2 are screened.(4)The optimized results were verified by gene enrichment analysis.The results of go bioaccumulation analysis showed that the overlap rate of enriched biological functions between optimized prescription 1 and optimized prescription 2 and Tanyu Tongzhi prescription was more than 94%,and the the top 30 enriched biological functions in three prescriptions were basically the same.The results of KEGG pathway enrichment analysis show that the overlapping rate of enrichment pathways between optimized prescription 1 and optimized prescription 2 and Tanyu Tongzhi prescription is more than 98%,and the top 10 enrichment pathways in the three prescriptions are basically the same.From the biological level,it shows that the functions of the original prescription,optimized prescription 1 and optimized prescription 2 are basically the same,and it also shows the effectiveness and correctness of the proposed optimization method of TCM prescription.(5)The optimization results were verified by animal experiments.The results showed that the contents of serum CK,CK-MB,LDH,AST,ALT,AST/ALT,cTnI and myocardial infarction area in the original prescription.group and the optimized prescription.group 1 were significantly lower than those in the MI/RI model group,while only the content of AST/ALT and myocardial infarction area in the optimized prescription group 2 were significantly lower than those in the MI/RI model group.It shows that three drug group can effectively reduce the degree of myocardial infarction and MI/RI injury.Compared with the MI/RI model group,the MDA content of the original prescription group and the optimized prescription 1 group decreased significantly.It shows that the original and optimized prescription 1 of Tanyu Tongzhi prescription can play a certain role in myocardial protection by reducing oxidative stress.Compared with the MI/RI model group,the contents of IL-β,IL-6 and TNF-α in the optimized prescription 1 group were significantly lower,the content of IL-1β and TNF-α in the original prescription group was significantly lower,And the content of IL-6 in optimized prescription 2 group decreased significantly.It indicates that the three groups can inhibit the inflammatory injury after reperfusion by regulating the level of inflammatory factors.Compared with the MI/RI model group,the expression of Bax protein decreased significantly and the expression of Bcl-2 protein increased significantly in the original and optimized prescription 1 groups of Tanyu Tongzhi prescription.It shows that the original and optimized prescription 1 of Tanyu Tongzhi prescription can play a myocardial protective role by inhibiting the expression of Pro apoptotic cell protein and up regulating the level of anti apoptotic protein.To sum up,the three groups have anti MI/RI effects,and their mechanisms may be related to reducing the area of myocardial infarction,reducing the release of myocardial enzymes and troponin,antioxidation,reducing inflammatory response and inhibiting cardiomyocyte apoptosis.The curative effect of optimized prescription 1 is basically the same as that of the original prescription.Conclusion(1)This study proposes a new a new optimization method of TCM prescription which based on the the theory of monarch,minister,assistant and guide and taking the group collaborative algorithm as the core.It has three characteristics:①it includes the module division algorithm with the group collaborative algorithm as the core.The algorithm aims at maximizing the group collaborative modularity and combines the Louvain optimization strategy for module identification.Compared with the classical GN algorithm,CNM algorithm based on greedy algorithm,LPA algorithm based on label propagation and LFM algorithm based on local expansion,the module division quality of this algorithm is higher than that of the above algorithms,and it performs well on different types of complex networks;②A network weighting method based on the compatibility theory of monarch,minister,assistant and guide is defined.The results show that this method has a great impact on module division and can improve the quality of module division.It also proves the influence of the TCM theory of monarch,minister,assistant and guide on pharmacological network;③The weighted closeness centrality(WCC)is defined to judge the centrality of drugs from the perspective of weighted network.It fully considers the connection strength between nodes,and strengthens the judgment of important nodes such as drug components and targets in the network.(2)The proposed optimization method of TCM prescription was applied to Tanyu Tongzhi prescription(13 medicines)which definited curative effect on MI/RI by our team previous studie,and the optimized prescription 1(6 medicines)and 2(7 medicines)of Tanyu Tongzhi prescription were selected.On the basis of constructing the "component-target-disease" network of Tanyu Tongzhi prescription against MI/RI,the weight value of monarch,minister,assistant and guide is introduced to weight the network,and then the group collaborative algorithm is used to divide the network into 13 modules,with a total modularity of 0.5537.The identified group collaboration modules are analyzed.Based on the WCC value,combined with degree centrality(DC)and closeness centrality(CC),the core nodes in the network are selected and the core drug combination is deduced.Finally,optimization prescription 1 and optimization prescription 2 are drawn up.(3)Gene enrichment analysis and animal experiments are used to verify the optimization results of Tanyu Tongzhi prescription.The results show that the optimized prescription based on group collaborative algorithm has the same curative effect as the original formula,which shows that the proposed optimization method of TCM prescription is feasible and provides a new method for the optimization of TCM prescription.Gene enrichment analysis showed that the biological functions and pathway information of the original prescription,optimized prescription 1 and optimized prescription 2 were basically the same.The results of animal experiments show that the original rprescription,optimized prescription 1 and optimized prescription 2 have the effect of anti MI/RI,and its mechanism may be related to reducing the area of myocardial infarction,reducing the release of myocardial enzymes and troponin,antioxidation,reducing inflammatory response and inhibiting cardiomyocyte apoptosis.The curative effect of optimized prescription 1 is basically the same as that of the original prescription.