| BackgroundThe network pharmacology intervene the complex disease with the combined of multiple targets. Traditional Chinese medicine (TCM) is a system science, which has the characteristics of the regulation of multiple components, multiple targets and system regulation. The general characters between the network pharmacology and traditional Chinese medicine provided new concept, strategies and methods for the study on the pharmacological mechanism and research of TCM. The organism is a complex system composed of a large number of different structures and functional components. There are some complex function and behavior created by the interaction of selective and nonlinear of element. When the biological system is in a state of steady and balance, the body is healthy according to the the Le Natsu Leo Te principle of biological network equilibrium theory. When the balance (healthy state) of the biological system (biological network) is broken, it will experience a change that can lead to pathological or disease state. The therapeutic effect of drugs on diseases is the response to external disturbance information of biological systems or biological networks. The effects of the drug will change the direction of balance which can weaken itself. It is believed that the identification of the module structure is helpful to the reduction and simplification of the biological network. This is a key factor in understanding the biological system. The network is abstracted into a hierarchical module, which can not only reduce the complexity of the whole network analysis, but also show the regional characteristics of the individual nodes behaviors. Treatment of complex diseases requires modular design to affect multiple targets. The complex biological networks can be analyzed and understood based on the modular platform. It can measures and integrates the characteristics on drug interventing network and reveal the complex pharmacological mechanism effectively.More and more evidence indicates that the module is highly preservation and reconfiguration in the development process. The reconstruction module may be think that this is in order to better adapt to the environment made big adjustment or reconfiguration (such as split or merge), the module is based on the overall change. In the reconstruction process module that is retained unchanged, the original nodes and edges, while the addition of a new node, the new edge. This is show the biological reconstruction module system homeostasis invariance (symmetry) and variability (asymmetric) coexist. Therefore, reconstruction balanced for biological system or reduce the balance is destroyed in the process. The reconstruction of the network module can be seen the equilibrium conversion module and the level is an asymmetrical dynamic conversion from module level accurately and efficiently.ObjectiveThe aim of our study was to track and quantitative analysis the reconstruction module of different compound treatments. On this basis, according to the asymmetric principle, explore generating element and onservative element from effective reconstruction modules which would explore the traditional Chinese medicine mechanism from modular pharmacological levels.MethodsFirstly, we use the collinearity diagnosis to screening different topological parameters of module, and then give the weight to different parameters using hierarchical analysis method. Secondly, baseing on the Euclidean distance, we raise a multidimensional array K value model for integrating different dimensions of topological parameters. At the same time, the maximum K value from ineffective drug group (CM) was used as cut off value for excluding the random fluctuations. Then, the effective reconstruction module will be screend. GO functional enrichment analysis was performed with DAVID 6.7 software. According to the "symmetry breaking" concept, we analysis the reconstruction module in the process of of the symmetric and asymmetric. Finally, in order to verify the asymmetric reconstruction module generators as the cerebral ischemia targets, pirinixic acid form the CTD database was related as an intervention to MCAO model rats.Results1. Different dimension parameters were screened as note, edge, average number of neighbors, network density, network centralization, betweenness centrality, average weight and shortest path. The weight for these parameters were 0.03,0.01,0.03,0.01, 0.12,0.22,0.4,0.07,0.07 and 0.02 respectively.2. Under MCODE method, Vehicle, CM, BA, JA, UA, BJ and JU group was divided into 30,12,24,24,19,19 and 29 modules respectively. The reconstruction module mapping with vehicle group were 14,22,28,25,21 and 25 respectively.3. With the application of multidimensional array K value model, the maximum value of reconstruction module in Vehicle-CM group was 0.465 while the minimum one was 0.168, and the maximum and minimum values of reconstruction module pairs in other groups were:0.573 vs.0.124 in Vehicle-BA group;0.562 vs.0.160 in Vehicle-JA group; 0.584 vs.0.167 in Vehicle-UA group; 0.587 vs.0.180 in Vehicle-BJ group and 0.556 vs.0.137 in Vehicle-JU group respectively.4. We take the maximum value of CM (0.465) as the cut off value to screen the effective reconstruction module, and the final results of effective reconstruction module screening in different groups were:5 in theVehicle-BA group; 8 in Vehicle-JA group; 5 in Vehicle-UA group; both 3 in Vehicle-BJ and Vehicle-JU group.5. In the effective reconstruction modules,454,323,246,273,117,149 biology function and 15,2,10,3,12,8 KEGG pathway were enrichment of Vehicle, BA, JA, UA, BJ and JU group, respectively, they were both overlap and non-overlap.6. There were no conservative element among Vehicle, BA, JA and UA, but one modular generating element (Vegfa-Fn1-Egf) was found between BA4-JA2; 4 pairs and 8 single generating element were also found; none conservative element among Vehicle, BA, JA and BJ was found, but one modular generating element (Il10-Ifng-Socs3-Il23a) and 2 pairs and 3 single generating element were found; There were 3 conservative elements were found among Vehicle, JAand JU, but just one generating element in UA14-JU13.7. The Il10-Ifng-Socs3-Il23a modular generating element enriched 8 common chemical compounds and Vegfa-Fnl-Egf enriched 8 common chemical compounds from CTD database.8. Pirinixic acid which was enriched by Vegfa-Fnl-Egf modular generating element can significantly reduce cerebellar infarction volume in MCAO model rats (P＜0.05).Conclusion1. Multidimensional array K value model consided both the overall change and multidimensional differencesof the module, and quantitative analysis the degree of module reconstrution.2. The effectively reconstruction module could reveal the pure pharmacological mechanism of different components. The reconstruction module of BA、JA、UAand Vehicle regulate the metabolic processes. BJ has the centralized regulation strategy while JU has the divergent regulation strategy.3. The asymmetric in reconstruction module will contribute to the pharmacological mechanism of different components from generative theory. Mining the generating element of asymmetric reconstruction module will be expected to become an effective methodto find the targets of cerebral ischemianetwork. |
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