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      Structure Identification and Anti-Cancer Pharmacological Prediction of Triterpenes from Ganoderma lucidum

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          Abstract

          Ganoderma triterpenes (GTs) are the major secondary metabolites of Ganoderma lucidum, which is a popularly used traditional Chinese medicine for complementary cancer therapy. In the present study, systematic isolation, and in silico pharmacological prediction are implemented to discover potential anti-cancer active GTs from G. lucidum. Nineteen GTs, three steroids, one cerebroside, and one thymidine were isolated from G. lucidum. Six GTs were first isolated from the fruiting bodies of G. lucidum, including 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester ( 1), 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid ( 2), 3β,7β,15α,28-tetrahydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid ( 3), ganotropic acid ( 4), 26-nor-11,23-dioxo-5α-lanost-8-en-3β,7β,15α,25-tetrol ( 5) and (3β,7α)-dihydroxy-lanosta-8,24-dien- 11-one ( 6). (4 E,8 E)- N- d-2′-hydroxypalmitoyl-l- O-β- d-glucopyranosyl-9-methyl-4,8-spingodienine ( 7), and stigmasta-7,22-dien-3β,5α,6α-triol ( 8) were first reported from the genus Ganodema. By using reverse pharmacophoric profiling of the six GTs, thirty potential anti-cancer therapeutic targets were identified and utilized to construct their ingredient-target interaction network. Then nineteen high frequency targets of GTs were selected from thirty potential targets to construct a protein interaction network (PIN). In order to cluster the pharmacological activity of GTs, twelve function modules were identified by molecular complex detection (MCODE) and gene ontology (GO) enrichment analysis. The results indicated that anti-cancer effect of GTs might be related to histone acetylation and interphase of mitotic cell cycle by regulating general control non-derepressible 5 (GCN5) and cyclin-dependent kinase-2 (CDK2), respectively. This research mode of extraction, isolation, pharmacological prediction, and PIN analysis might be beneficial to rapidly predict and discover pharmacological activities of novel compounds.

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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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            Triterpenes from Ganoderma Lucidum induce autophagy in colon cancer through the inhibition of p38 mitogen-activated kinase (p38 MAPK).

            Medicinal mushroom Ganoderma lucidum is one of the most esteemed natural products that have been used in the traditional Chinese medicine. In this article, we demonstrate that G. lucidum triterpene extract (GLT) suppresses proliferation of human colon cancer cells HT-29 and inhibits tumor growth in a xenograft model of colon cancer. These effects of GLT are associated with the cell cycle arrest at G0/G1 and the induction of the programmed cell death Type II-autophagy in colon cancer cells. Here, we show that GLT induces formation of autophagic vacuoles and upregulates expression of Beclin-1 (1.3-fold increase) and LC-3 (7.3-fold increase) proteins in colon cancer cells and in tumors in a xenograft model (Beclin-1, 3.9-fold increase; LC-3, 1.9-fold increase). Autophagy is mediated through the inhibition of p38 mitogen-activated protein kinase (p38 MAPK) because p38 MAPK inhibitor, SB202190, induces autophagy and expression of Beclin-1 (1.2-fold increase) and LC-3 (7.4-fold increase), and GLT suppresses phosphorylation of p38 MAPK ( approximately 60% inhibition) in colon cancer cells. Taken together, our data demonstrate a novel mechanism responsible for the inhibition of colon cancer cells by G. lucidum and suggest GLT as natural product for the treatment of colon cancer.
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              A Comprehensive Review of the Structure Elucidation and Biological Activity of Triterpenoids from Ganoderma spp.

              Ganoderma triterpenes (GTs) are the major secondary metabolites of Ganoderma lucidum, a traditional Chinese medicine, popularly used for complementary cancer therapy. GTs are lanostane-tetracyclic triterpenes. They have been reported to possess anti-tumor, anti-inflammation, antioxidant, antimicrobial and blood fat reducing effects. To date, 316 GTs have been found and their similar chemical structures have proved difficult to elucidate. This paper compiles 316 naturally occurring triterpenes from Ganoderma based on the literature published through January 2013 along with their structures, physiological activities and 13C-NMR spectral data.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                21 May 2016
                May 2016
                : 21
                : 5
                : 678
                Affiliations
                [1 ]School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China; sunshine4003@ 123456126.com (Y.S.); fanglingwu@ 123456163.com (L.W.); sunxuefei.2008@ 123456163.com (X.S.); hbbdzhudan@ 123456163.com (D.Z.); yghui1990@ 123456163.com (G.Y.); zhangxiaoxue122@ 123456163.com (X.Z.); mxmaoxin@ 123456126.com (X.M.); sdcwjing@ 123456163.com (W.C.); lwy1054289310@ 123456163.com (W.L.)
                [2 ]Beijing Key Laboratory of TCM Foundation and New Drug Research, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China; b20100222012@ 123456163.com
                Author notes
                [* ] Correspondence: collean_zhang@ 123456163.com (Y.Z.); zhanglanzhen01@ 123456126.com (L.Z.); Tel./Fax: +86-10-8473-8618 (L.Z.); +86-10-8473-8620 (Y.Z.)
                [†]

                These authors contributed equally to this work.

                Article
                molecules-21-00678
                10.3390/molecules21050678
                6273610
                27213329
                cc54574e-540c-4c53-9bd8-0109e6bf7e1c
                © 2016 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 April 2016
                : 19 May 2016
                Categories
                Article

                ganoderma lucidum,lanostanoid triterpene,pharmacophore,protein interaction network,anti-cancer,reverse target identification

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