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A strategy for the identification of combinatorial bioactive compounds contributing to the holistic effect of herbal medicines.

ABSTRACT: It has been well claimed that herbal medicines (HMs) elicit effects via a multi-compounds and multi-targets synergistic mode. However, it lacks appropriate strategies to uncover the combinatory compounds that take effect together and contribute to a certain pharmacological effect of an herb as a whole, which represents a major bottleneck in providing sound evidence in supporting the clinic benefits of HMs. Here, we proposed a strategy to the identification of combinatory compounds contributing to the anti-inflammatory activity of Cardiotonic Pill (CP). The strategy proposed herein contains four core steps, including the identification of bioequivalent combinatorial compounds, chemical family classification-based combinatorial screen, interactive mode evaluation, and activity contribution index assay. Using this strategy, we have successfully identified six compounds in combination responsible for the anti-inflammatory effect of CP, whose anti-inflammatory activities were found comparable to that of the whole CP. Additionally, these six compounds take effect via an additive mode but little synergism. This study, together with our recent work in the identification of bioactive equivalent compounds combination, provides a widely applicable strategy to the identification of combinatory compounds responsible for a certain pharmacological activity of HMs.

SUBMITTER: Long F

PROVIDER: S-EPMC4510521 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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A strategy for the identification of combinatorial bioactive compounds contributing to the holistic effect of herbal medicines.

Long Fang F Yang Hua H Xu Yanmin Y Hao Haiping H Li Ping P

Scientific reports 20150722

It has been well claimed that herbal medicines (HMs) elicit effects via a multi-compounds and multi-targets synergistic mode. However, it lacks appropriate strategies to uncover the combinatory compounds that take effect together and contribute to a certain pharmacological effect of an herb as a whole, which represents a major bottleneck in providing sound evidence in supporting the clinic benefits of HMs. Here, we proposed a strategy to the identification of combinatory compounds contributing t ...[more]

PMID: 26198093

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Project description:Effective compound combination (ECC; i.e, 20-S-ginsenoside Rh1, astragaloside, icariin, nobiletin, and paeonol), derived from Chinese herbal medicine, significantly ameliorates chronic obstructive pulmonary disease (COPD) in rats; however, the underlying mechanisms of ECC remain largely unclear. In this study, network pharmacology analysis integrated with experimental validation was used to explore the therapeutic mechanisms of ECC against COPD. ECC targets and COPD genes and targets were identified from multiple databases, and then used for an analysis of protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and biological functioning. BisoGenet was used to comprehensively analyze the hub-network. We validated the therapeutic effect and mechanisms of ECC both in vivo and in vitro. We identified 45 ECC targets, which were mainly related to inflammatory processes, such as the NOD-like and NF-kappa B signaling pathways, hematopoietic cell lineage, Th17 cell differentiation, cellular response to lipopolysaccharide, and interleukin-8 secretion. In addition, 1180 COPD genes and 70 COPD targets were identified as being involved in the biological functions associated with COPD development, such as cytokine-cytokine receptor interaction, the TNF signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, regulation of lymphocyte proliferation, and positive regulation of leukocyte migration. Integrative analysis of COPD genes and targets and ECC target networks revealed that 54 genes were mainly involved in the inflammatory process, such as IL-17 signaling, NF-kappa B signaling, innate immune response-activating signal transduction, and macrophage cell differentiation. Six targets (AR, ESR1, HNRNPA1, PAPR1, TP53, and VCAM1) contained in the hub-network and their four related compounds were obtained and recognized as the key molecules associated with the effects of ECC. Molecular docking validation demonstrated that four compounds could bind to six targets that interact with COPD genes. Finally, in vivo and in vitro experiments verified that ECC treatment ameliorated the symptoms of COPD in rats by improving their lung function, reducing pathological changes, and suppressing oxidative responses and pro-inflammatory cytokine secretion, while inhibiting inflammation in LPS-induced macrophages, which may be associated with NF-kappa B and MAPK signaling regulation. This study demonstrates the therapeutic mechanisms and effects of ECC on COPD via regulation of the underlying inflammatory process.

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A strategy for the identification of combinatorial bioactive compounds contributing to the holistic effect of herbal medicines.

Publications

A strategy for the identification of combinatorial bioactive compounds contributing to the holistic effect of herbal medicines.

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