Deciphering the synergistic network regulation of active components from SiNiSan against irritable bowel syndrome via a comprehensive strategy: Combined effects of synephrine, paeoniflorin and naringin.

BACKGROUND: SiNiSan (SNS) is an ancient Chinese herbal prescription, and the current clinical treatment of irritable bowel syndrome (IBS) is effective. In the previous study of the research team, the multi-functional co-synergism of SNS against IBS was presented. Some potential drug targets and candidate ligands were predicted. PURPOSE: This study attempts to explore the crucial ingredient combinations from SNS formula and reveal their synergistic mechanism for IBS therapy. MATERIALS AND METHODS: In present study, a comprehensive strategy was performed to reveal IBS related pathways and biological modules, and explore synergistic effects of the ingredients, including ADME (absorption, distribution, metabolism, excretion) screening, Text mining, Venn analysis, Gene ontology (GO) analysis, Pathway cluster analysis, Molecular docking, Network construction and Experimental verification in visceral hypersensitivity (VHS) rats. RESULTS: Three compressed IBS signal pathways were derived from ClueGO KEGG analysis of 63 IBS genes, including Neuroactive ligand-receptor interaction, Inflammatory mediator regulation of TRP (transient receptor potential) channels and Serotonergic synapse. A multi-module network, composed of four IBS therapeutic modules (psychological, inflammation, neuroendocrine and cross-talk modules), was revealed by Target-Pathway network. Nine kernel targets were considered closely associated with the IBS pathways, including ADRA2A, HTR2A, F2RL1, F2RL3, TRPV1, PKC, PKA, IL-1Β and NGF. In silico analysis revealed that three crucial ingredients (synephrine, paeoniflorin and naringin) were assumed to coordinate the network of those IBS therapeutic modules by acting on these kernel targets in the important pathways. In vivo experimental results showed that the crucial ingredient combinations synergistically affected the expressions of the kernel biological molecules, and improved the minimum capacity threshold of AWR in VHS rats. CONCLUSION: The study proposes the important IBS associated pathways and the network regulation mechanisms of the crucial ingredients. It reveals the multi-target synergistic effect of the crucial ingredient combinations for the novel therapy on IBS.

Deciphering the multicomponent synergy mechanisms of SiNiSan prescription on irritable bowel syndrome using a bioinformatics/network topology based strategy.

BACKGROUND: SiNiSan (SNS) is a traditional Chinese medicine (TCM) prescription that has been widely used in the clinical treatment of irritable bowel syndrome (IBS). However, the underlying active substances and molecular mechanisms remain obscure. PURPOSE: A bioinformatics/topology based strategy was proposed for identification of the drug targets, therapeutic agents and molecular mechanisms of SiNiSan against irritable bowel syndrome. MATERIALS AND METHODS: In this work, a bioinformatics/network topology based strategy was employed by integrating ADME filtering, text mining, bioinformatics, network topology, Venn analysis and molecular docking to uncover systematically the multicomponent synergy mechanisms. In vivo experimental validation was executed in a Visceral Hypersensitivity (VHS) rat model. RESULTS: 76 protein targets and 109 active components of SNS were identified. Bioinformatics analysis revealed that 116 disease pathways associated with IBS therapy could be classified into the 19 statistically enriched functional sub-groups. The multi-functional co-synergism of SNS against IBS were predicted, including inflammatory reaction regulation, oxidative-stress depression regulation and hormone and immune regulation. The multi-component synergetic effects were also revealed on the herbal combination of SNS. The hub-bottleneck genes of the protein networks including PTGS2, CALM2, NOS2, SLC6A3 and MAOB, MAOA, CREB1 could become potential drug targets and Paeoniflorin, Naringin, Glycyrrhizic acid may be candidate agents. Experimental results showed that the potential mechanisms of SiNiSan treatment involved in the suppression of activation of Dopaminergic synapse and Amphetamine addiction signaling pathways, which are congruent with the prediction by the systematic approach. CONCLUSION: The integrative investigation based on bioinformatics/network topology strategy may elaborate the multicomponent synergy mechanisms of SNS against IBS and provide the way out to develop new combination medicines for IBS.

Exploring the multicomponent synergy mechanism of Banxia Xiexin Decoction on irritable bowel syndrome by a systems pharmacology strategy.

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin Decoction (BXD) is a representative prescription to regulate spleen and stomach in "Treatise on Febrile Diseases", which has been proven effective for the clinical treatment of irritable bowel syndrome (IBS) in the past decades. However, the active principles and molecular mechanisms involved in BXD against IBS are vague yet. AIM OF THE STUDY: To unfold multicomponent synergy mechanism of BXD on irritable bowel syndrome, this work explored active principles, drug targets and crucial pathways using a systems pharmacology strategy. MATERIALS AND METHODS: In this study, a systems pharmacology based strategy was applied by the procedures integrating compound database construction, ADME evaluation, target identification, functional annotation, pathway enrichment analysis, network analysis, and molecular docking verification. The 158 compounds from BXD were selected for the screening. The Compound-Target network (C-T) and the Target-Pathway network (T-P) were constructed. The bioinformatics and network topology were employed to systematically reveal multicomponent-target interactions of BXD. The affinity between important ingredients and the kernel targets was validated using molecular mechanics simulation. RESULTS: The 35 potential important ingredients and the 16 associated kernel targets were identified. 27 crucial pathways, in which the kernel targets participated, could regulate the biological processes, such as synthesis of inflammatory mediators, smooth muscle relaxation and synaptic plasticity, closely related to pathological mechanism of IBS. The cross-talk interactions were revealed between TNF signaling pathway, Dopaminergic synapse and cGMP-PKG signaling pathway, which would exert the synergistic influences on the occurrence and treatment of the IBS. PTGS2, CALM, NOS2, SCN5A, and PRSS1 might become novel drug targets for IBS. CONCLUSIONS: The study demonstrated that the synergy molecular mechanisms of BXD mainly involved three therapeutic modules including inhibiting inflammatory reaction, maintaining intestinal function and improving psychological regulation via the multicomponent-target interaction networks. It may also provide the promising drug targets and therapeutic agents for the development of new medicines.