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Systems Pharmacology Based Study of the Molecular Mechanism of SiNiSan Formula for Application in Nervous and Mental Diseases.

ABSTRACT: Background. Mental disorder is a group of systemic diseases characterized by a variety of physical and mental discomfort, which has become the rising threat to human life. Herbal medicines were used to treat mental disorders for thousand years in China in which the molecular mechanism is not yet clear. Objective. To systematically explain the mechanisms of SiNiSan (SNS) formula on the treatment of mental disorders. Method. A systems pharmacology method, with ADME screening, targets prediction, and DAVID enrichment analysis, was employed as the principal approach in our study. Results. 60 active ingredients of SNS formula and 187 mental disorders related targets were discovered to have interactions with them. Furthermore, the enrichment analysis of drug-target network showed that SNS probably acts through "multi-ingredient, multitarget, and multisystems" holistic coordination in different organs pattern by indirectly regulating the nutritional and metabolic pathway even their serial complications. Conclusions. Our research provides a reference for the molecular mechanism of medicinal herbs in the treatment of mental disease on a systematic level. Hopefully, it will also provide a theoretical basis for the discovery of lead compounds of natural medicines for other diseases based on traditional medicine.

SUBMITTER: Shen X

PROVIDER: S-EPMC5183803 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Systems Pharmacology Based Study of the Molecular Mechanism of SiNiSan Formula for Application in Nervous and Mental Diseases.

Shen Xia X Zhao Zhenyu Z Luo Xuan X Wang Hao H Hu Benxiang B Guo Zihu Z

Evidence-based complementary and alternative medicine : eCAM 20161212

Background. Mental disorder is a group of systemic diseases characterized by a variety of physical and mental discomfort, which has become the rising threat to human life. Herbal medicines were used to treat mental disorders for thousand years in China in which the molecular mechanism is not yet clear. Objective. To systematically explain the mechanisms of SiNiSan (SNS) formula on the treatment of mental disorders. Method. A systems pharmacology method, with ADME screening, ...[more]

PMID: 28058059

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Project description:BackgroundThe incidence of depression has been increasing globally, which has brought a serious burden to society. Sinisan Formula (SNSF), a well-known formula of traditional Chinese medicine (TCM), has been found to demonstrate an antidepressant effect. However, the therapeutic mechanism of this formula remains unclear. Thus, the present study aimed to explore the mechanism of SNSF in depression through network pharmacology combined with molecular docking methods.Materials and methodsBioactive compounds, potential targets of SNSF, and related genes of depression were obtained from public databases. Essential ingredients, potential targets, and signaling pathways were identified using bioinformatics analysis, including protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, Autodock software was further performed for conducting molecular docking to verify the binding ability of active ingredients to targets.ResultsA total of 91 active compounds were successfully identified in SNSF with the use of the comprehensive network pharmacology approach, and they were found to be closely connected to 112 depression-related targets, among which CREB1, NOS3, CASP3, TP53, ESR1, and SLC6A4 might be the main potential targets for the treatment of depression. GO analysis revealed 801 biological processes, 123 molecular functions, and 67 cellular components. KEGG pathway enrichment analysis indicated that neuroactive ligand-receptor interaction, serotonergic synapse pathways, dopaminergic synapse pathways, and GABAergic synapse pathways might have played a role in treating depression. Molecular docking suggested that beta-sitosterol, nobiletin, and 7-methoxy-2-methyl isoflavone bound well to the main potential targets.ConclusionThis study comprehensively illuminated the active ingredients, potential targets, primary pharmacological effects, and relevant mechanism of the SNSF in the treatment of depression. SNSF might exert its antidepressant effects by regulating the signaling pathway of 5-hydroxytryptamine, dopamine, GABA, and neuroactive ligand receptor interactions. Still, more pharmacological experiments are needed for verification.

Project description:Cardiac dysfunction is a critical manifestation of sepsis-induced multiorgan failure and results in the high mortality of sepsis. Our previous study demonstrated that a traditional Chinese medicine formula, Qiang-Xin 1 (QX1), ameliorates cardiac tissue damage in septic mice; however, the underlying pharmacology mechanism remains to be elucidated. The present study was aimed at clarifying the protective mechanism of the QX1 formula on sepsis-induced cardiac dysfunction. The moderate sepsis model of mice was established by cecal ligation and puncture surgery. Treatment with the QX1 formula improved the 7-day survival outcome, attenuated cardiac dysfunction, and ameliorated the disruption of myocardial structure in septic mice. Subsequent systems pharmacology analysis found that 63 bioactive compounds and the related 79 candidate target proteins were screened from the QX1 formula. The network analysis showed that the QX1 active components quercetin, formononetin, kaempferol, taxifolin, cryptotanshinone, and tanshinone IIA had a good binding activity with screened targets. The integrating pathway analysis indicated the calcium, PI3K/AKT, MAPK, and Toll-like receptor signaling pathways may be involved in the protective effect of the QX1 formula on sepsis-induced cardiac dysfunction. Further, experimental validation showed that the QX1 formula inhibited the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), MAPK (P38, ERK1/2, and JNK), and TLR4/NF-κB signaling pathways but promoted the activation of the PI3K/AKT pathway. A cytokine array found that the QX1 formula attenuated sepsis-induced upregulated levels of serum IFN-γ, IL-1β, IL-3, IL-6, IL-17, IL-4, IL-10, and TNF-α. Our data suggested that QX1 may represent a novel therapeutic strategy for sepsis by suppressing the activity of calcium, MAPK, and TLR4/NF-κB pathways, but promoting the activation of AKT, thus controlling cytokine storm and regulating immune balance. The present study demonstrated the multicomponent, multitarget, and multipathway characteristics of the QX1 formula and provided a novel understanding of the QX1 formula in the clinical application on cardiac dysfunction-related diseases.

Project description:Multi-components Traditional Chinese Medicine (TCM) treats various complex diseases (multi-etiologies and multi-symptoms) via herbs interactions to exert curative efficacy with less adverse effects. However, the ancient Chinese compatibility theory of herbs formula still remains ambiguous. Presently, this combination principle is dissected through a systems pharmacology study on the mechanism of action of a representative TCM formula, Huo-xiang-zheng-qi (HXZQ) prescription, on the treatment of functional dyspepsia (FD), a chronic or recurrent clinical disorder of digestive system, as typical gastrointestinal (GI) diseases which burden human physical and mental health heavily and widely. In approach, a systems pharmacology platform which incorporates the pharmacokinetic and pharmaco-dynamics evaluation, target fishing and network pharmacological analyses is employed. As a result, 132 chemicals and 48 proteins are identified as active compounds and FD-related targets, and the mechanism of HXZQ formula for the treatment of GI diseases is based on its three function modules of anti-inflammation, immune protection and gastrointestinal motility regulation mainly through four, i.e., PIK-AKT, JAK-STAT, Toll-like as well as Calcium signaling pathways. In addition, HXZQ formula conforms to the ancient compatibility rule of "Jun-Chen-Zuo-Shi" due to the different, while cooperative roles that herbs possess, specifically, the direct FD curative effects of GHX (serving as Jun drug), the anti-bacterial efficacy and major accompanying symptoms-reliving bioactivities of ZS and BZ (as Chen), the detoxication and ADME regulation capacities of GC (as Shi), as well as the minor symptoms-treating efficacy of the rest 7 herbs (as Zuo). This work not only provides an insight of the therapeutic mechanism of TCMs on treating GI diseases from a multi-scale perspective, but also may offer an efficient way for drug discovery and development from herbal medicine as complementary drugs.

Dataset Information

Systems Pharmacology Based Study of the Molecular Mechanism of SiNiSan Formula for Application in Nervous and Mental Diseases.

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Systems Pharmacology Based Study of the Molecular Mechanism of SiNiSan Formula for Application in Nervous and Mental Diseases.

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