IMCC-Based Elucidation on Divergent and Convergent of Inter-Module Coordination Maps the Pharmacological Puzzle of Natural Products on Cerebral Ischemia

Detecting the strength of inter-module coordination and modular rewiring is essential to characterize the reactive bio-systematical variation of different related drugs, especially for multiple-target compounds from traditional Chinese medicine (TCM). However, the quantitative method for inter-module connections is far from perfect. Here, an evaluation approach (named as IMCC) for inter-module coordination and its transition was developed. Applying IMCC to mouse ischemia-related genes micro-array, we investigated modular map and its rewiring from disease to drugs perturbation states: transition of IMCC distribution from vehicle to negative-phenotype group (CM) was minor than that to other positive-phenotype groups (BA, JA, or UA). Furthermore, the architecture in cerebral ischemia exhibited a characteristic "core-periphery structure", highlighting "core" as nervous injury related pathways bridged by MAPK signaling pathway. Notably, this architecture was rewired by the positive-phenotype compounds heterogeneously: BA and UA converged modules into an intensively connected integrity; whereas JA diverged partial modules and widened the remaining inter-module paths. Combination of compounds with divergent directions showed a merging or fusing mode. The conclusion was validated by in vivo experiments. This strategy may lead to systematically explore detailed variation of inter-module pharmacological action mode of multiple-target drugs and combination therapies. Funding Statement: This work was supported by National Science and Technology Major Projects “Major New Drug Development Project”. [grant number 2017ZX09301-059]. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All of the animal experiments were conducted in accordance with the Prevention of Cruelty to Animals Act 1986 and NIH Guidelines for the Care and Use of Laboratory Animals for Experimental Procedures [Council, 1996], and also approved by Ethics Committee of China Academy of Chinese Medicine.