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      Material Basis of Chinese Herbal Formulas Explored by Combining Pharmacokinetics with Network Pharmacology

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          Abstract

          The clinical application of Traditional Chinese medicine (TCM), using several herbs in combination (called formulas), has a history of more than one thousand years. However, the bioactive compounds that account for their therapeutic effects remain unclear. We hypothesized that the material basis of a formula are those compounds with a high content in the decoction that are maintained at a certain level in the system circulation. Network pharmacology provides new methodological insights for complicated system studies. In this study, we propose combining pharmacokinetic (PK) analysis with network pharmacology to explore the material basis of TCM formulas as exemplified by the Bushen Zhuanggu formula (BZ) composed of Psoralea corylifolia L., Aconitum carmichaeli Debx., and Cnidium monnieri (L.) Cuss. A sensitive and credible liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established for the simultaneous determination of 15 compounds present in the three herbs. The concentrations of these compounds in the BZ decoction and in rat plasma after oral BZ administration were determined. Up to 12 compounds were detected in the BZ decoction, but only 5 could be analyzed using PK parameters. Combined PK results, network pharmacology analysis revealed that 4 compounds might serve as the material basis for BZ. We concluded that a sensitive, reliable, and suitable LC-MS/MS method for both the composition and pharmacokinetic study of BZ has been established. The combination of PK with network pharmacology might be a potent method for exploring the material basis of TCM formulas.

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          Most cited references37

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          Network analysis in the social sciences.

          Over the past decade, there has been an explosion of interest in network research across the physical and social sciences. For social scientists, the theory of networks has been a gold mine, yielding explanations for social phenomena in a wide variety of disciplines from psychology to economics. Here, we review the kinds of things that social scientists have tried to explain using social network analysis and provide a nutshell description of the basic assumptions, goals, and explanatory mechanisms prevalent in the field. We hope to contribute to a dialogue among researchers from across the physical and social sciences who share a common interest in understanding the antecedents and consequences of network phenomena.
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            Herb network construction and co-module analysis for uncovering the combination rule of traditional Chinese herbal formulae

            Background Traditional Chinese Medicine (TCM) is characterized by the wide use of herbal formulae, which are capable of systematically treating diseases determined by interactions among various herbs. However, the combination rule of TCM herbal formulae remains a mystery due to the lack of appropriate methods. Methods From a network perspective, we established a method called Distance-based Mutual Information Model (DMIM) to identify useful relationships among herbs in numerous herbal formulae. DMIM combines mutual information entropy and “between-herb-distance” to score herb interactions and construct herb network. To evaluate the efficacy of the DMIM-extracted herb network, we conducted in vitro assays to measure the activities of strongly connected herbs and herb pairs. Moreover, using the networked Liu-wei-di-huang (LWDH) formula as an example, we proposed a novel concept of “co-module” across herb-biomolecule-disease multilayer networks to explore the potential combination mechanism of herbal formulae. Results DMIM, when used for retrieving herb pairs, achieves a good balance among the herb’s frequency, independence, and distance in herbal formulae. A herb network constructed by DMIM from 3865 Collaterals-related herbal formulae can not only nicely recover traditionally-defined herb pairs and formulae, but also generate novel anti-angiogenic herb ingredients (e.g. Vitexicarpin with IC50=3.2 μM, and Timosaponin A-III with IC50=3.4 μM) as well as herb pairs with synergistic or antagonistic effects. Based on gene and phenotype information associated with both LWDH herbs and LWDH-treated diseases, we found that LWDH-treated diseases show high phenotype similarity and identified certain “co-modules” enriched in cancer pathways and neuro-endocrine-immune pathways, which may be responsible for the action of treating different diseases by the same LWDH formula. Conclusions DMIM is a powerful method to identify the combination rule of herbal formulae and lead to new discoveries. We also provide the first evidence that the co-module across multilayer networks may underlie the combination mechanism of herbal formulae and demonstrate the potential of network biology approaches in the studies of TCM.
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              Molecular networks for the study of TCM pharmacology.

              To target complex, multi-factorial diseases more effectively, there has been an emerging trend of multi-target drug development based on network biology, as well as an increasing interest in traditional Chinese medicine (TCM) that applies a more holistic treatment to diseases. Thousands of years' clinic practices in TCM have accumulated a considerable number of formulae that exhibit reliable in vivo efficacy and safety. However, the molecular mechanisms responsible for their therapeutic effectiveness are still unclear. The development of network-based systems biology has provided considerable support for the understanding of the holistic, complementary and synergic essence of TCM in the context of molecular networks. This review introduces available sources and methods that could be utilized for the network-based study of TCM pharmacology, proposes a workflow for network-based TCM pharmacology study, and presents two case studies on applying these sources and methods to understand the mode of action of TCM recipes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                28 February 2013
                : 8
                : 2
                : e57414
                Affiliations
                [1 ]Pharmacology Laboratory of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
                [2 ]State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
                Cleveland Clinic Lerner Research Institute, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LXP YWB XPC. Performed the experiments: LXP YWB. Analyzed the data: LXP XPC. Contributed reagents/materials/analysis tools: SL JZ. Wrote the paper: LXP XPC.

                Article
                PONE-D-12-22310
                10.1371/journal.pone.0057414
                3585395
                23468985
                37d77c58-0aac-4951-8bab-297d545eaac9
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 July 2012
                : 23 January 2013
                Page count
                Pages: 10
                Funding
                The study was supported by the Foundation of Shanghai Municipal Health Bureau (No. 20114060), the Young Teachers Program of the Higher Education Institutions of Shanghai (No. shzy019), the Major Science and Technology Project for the 12th National Five-Year Plan-Clinical Evaluation and Research Technology Platform for TCM New Drug Research (Cancer and Related Diseases; No. 2011ZX09302-006-04), and the Macao Science and Technology Development Fund (No. 045/2011/A). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Drug Discovery
                Biotechnology
                Drug Discovery
                Chemistry
                Phytochemistry
                Phytopharmacology
                Medicine
                Cardiovascular
                Cardiovascular Pharmacology
                Complementary and Alternative Medicine
                Drugs and Devices
                Drug Research and Development
                Drug Discovery
                Cardiovascular Pharmacology
                Pharmacodynamics
                Pharmacokinetics

                Uncategorized
                Uncategorized

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