Rapid action of mechanism investigation of Yixin Ningshen tablet in treating depression by combinatorial use of systems biology and bioinformatics tools

Abstract

Ethnopharmacological relevanceYixin Ningshen tablet is a CFDA-approved TCM formula for treating depression clinically. However, little is known about its active compounds and related potential target proteins, so far, no researches have been performed to investigate its mechanism of action for the treatment of depression. Aim of the studyHere we develop an original bioinformatics pipeline composed of text mining tools, database querying and systems biology combinatorial analysis, which is applied to rapidly explore the mechanism of action of Yixin Ningshen tablet in treating depression. Materials and methodsText mining and database query were applied to identify active compounds in Yixin Ningshen tablet for the treatment of depression. Then SwissTargetPrediction was used to predict their potential target proteins. PubMed was retrieved to summarize known depression related systems biology results. Ingenuity Pathway Analysis (IPA) tools and STRING were applied to construct a compound-target protein-gene protein-differential protein-differential metabolite network with the integration of compound-target interaction and systems biology results, as well as enrich the target proteins related pathways. ChEMBL and CDOCKER were used to validate the compound-target interactions. Results62 active compounds and their 286 potential target proteins were identified in Yixin Ningshen tablet for the treatment of depression. The construction of compound-target protein-gene protein-differential protein-differential metabolite network shrinked the number of potential target proteins from 286 to 133. Pathway enrichment analysis of target proteins indicated that Neuroactive ligand-receptor interaction, Calcium signaling pathway, Serotonergic synapse, cAMP signaling pathway and Gap junction were the common primary pathways regulated by both Yixin Ningshen Tablet and anti-depressant drugs, and MAPK, Relaxin, AGE-RAGE, Estrogen, HIF-1, Jak-STAT signaling pathway, Endocrine resistance, Arachidonic acid metabolism and Regulation of actin cytoskeleton were the specifically main pathways regulated by Yixin Ningshen tablet for the treatment of depression. Further validations based on references and molecular docking results demonstrated that Yixin Ningshen tablet could primarily target MAPT, CHRM1 and DRD1, thus regulating serotonergic neurons, cholinergic transmission, norepinephrine and dopamine reuptake for the treatment of depression. ConclusionsThis study displays the power of extensive mining of public data and bioinformatical repositories to provide answers for a specific pharmacological question. It furthermore demonstrates how the usage of such a combinatorial approach is advantageous for the biologist in terms of experimentation time and costs.