Quantitative identification of compounds-dependent on-modules and differential allosteric modules from homologous ischemic networks

Module-based methods have made much progress in deconstructing biological networks.However,it is a great challenge to quantitatively compare the topological structural variations of modules(allosteric modules,AMs)under different situations.A total of 23,42 and 15co-expression modules were identified in baicalin(BA),jasminoidin(JA)and ursodeoxycholic acid(UA)in a global anti-ischemic mice network,respectively.Then,we integrated the methods of module-based consensus ratio(MCR)and modified Z summary module statistic to validate 12 BA,22 JA and 8 UA on-modules based on comparing with vehicle.The MCRs for pairwise comparisons were 1.55%(BA vs JA),1.45%(BA vs UA),and1.27%(JA vs UA),respectively.Five conserved allosteric modules(CAMs)and 17 unique allosteric modules(UAMs)were identified among these groups.In conclusion,module-centric analysis may provide us a unique approach to understand multiple pharmacological mechanisms associated with differential phenotypes in the era of modular pharmacology.

Identifying Qingkailing(清开灵)ingredients-dependent mesenchymal-epithelial transition factor-axiation“π”structuring module with angiogenesis and neurogenesis effects

OBJECTIVE:To explore the functional role of the drugdependent mesenchymal-epithelial transition(Met)-axiation"π"structural module of neurogenesis after processing by three components of Qingkailing injection in neurogenesis and angiogenesis in cerebral ischemia.METHODS:We used a Glutathione S-transferase(GST)-pull down assay,isothermal titration calorimetry assay,and other related methods to identify the relationships among Met,inositol polyphosphate phosphatase like 1(Inppl1),and death associated protein kinase 3(Dapk3)in this allosteric module.The biological effects of the modules of neurons generation composed of Met,Inppl1,and Dapk3 were measured through Western blot,apoptosis analysis,and double immunofluorescence labeling.RESULTS:The GST-pull down assay revealed that proline-serine-threonine rich domain of Met binds to the Src homology domain of Inppl1 to form a protein-protein complex;Dapk3 with a C-terminal domain interacts weakly with the protein kinase C domain of Met in the intracellular region.Thus,we obtained a“π”structuring module considered a neural regeneration module.The biological effects of angiogenesis and neurogenesis modules composed of Met,Inppl1,and Dapk3 were also verified.CONCLUSION:The study suggested that understanding the functional modules that contribute to pharmaceutics might provide novel signatures that can be used as endpoints to define disease processes under stroke or cerebral ischemia conditions.