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      A Systems-Level Analysis of Mechanisms of Platycodon grandiflorum Based on A Network Pharmacological Approach

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          Abstract

          Platycodon grandiflorum (PG) is widely used in Asia for its various beneficial effects. Although many studies were conducted to understand the molecular mechanisms of PG, it is still unclear how the combinations of multiple ingredients work together to exert its therapeutic effects. The aim of the present study was to provide a comprehensive review of the systems-level mechanisms of PG by adopting network pharmacological analysis. We constructed a compound–target–disease network for PG using experimentally validated and machine-leaning-based prediction results. Each target of the network was analyzed based on previously known pharmacological activities of PG. Gene ontology analysis revealed that the majority of targets were related to cellular and metabolic processes, responses to stimuli, and biological regulation. In pathway enrichment analyses of targets, the terms related to cancer showed the most significant enrichment and formed distinct clusters. Degree matrix analysis for target–disease associations of PG suggested the therapeutic potential of PG in various cancers including hepatocellular carcinoma, gastric cancer, prostate cancer, small-cell lung cancer, and renal cell carcinoma. We expect that network pharmacological approaches will provide an understanding of the systems-level mechanisms of medicinal herbs and further develop their therapeutic potentials.

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          Most cited references55

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          Therapeutic target database update 2016: enriched resource for bench to clinical drug target and targeted pathway information

          Extensive drug discovery efforts have yielded many approved and candidate drugs targeting various targets in different biological pathways. Several freely accessible databases provide the drug, target and drug-targeted pathway information for facilitating drug discovery efforts, but there is an insufficient coverage of the clinical trial drugs and the drug-targeted pathways. Here, we describe an update of the Therapeutic Target Database (TTD) previously featured in NAR. The updated contents include: (i) significantly increased coverage of the clinical trial targets and drugs (1.6 and 2.3 times of the previous release, respectively), (ii) cross-links of most TTD target and drug entries to the corresponding pathway entries of KEGG, MetaCyc/BioCyc, NetPath, PANTHER pathway, Pathway Interaction Database (PID), PathWhiz, Reactome and WikiPathways, (iii) the convenient access of the multiple targets and drugs cross-linked to each of these pathway entries and (iv) the recently emerged approved and investigative drugs. This update makes TTD a more useful resource to complement other databases for facilitating the drug discovery efforts. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp.
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            PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

            Prostate cancer (PCa) is the second most common malignancy among men in the world. Castration-resistant prostate cancer (CRPC) is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy (ADT). Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor (AR) signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.
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              A novel network pharmacology approach to analyse traditional herbal formulae: the Liu-Wei-Di-Huang pill as a case study.

              Understanding the mechanisms of the pharmacological effects of herbal formulae from traditional Chinese medicine (TCM) is important for their appropriate application. However, this understanding has been impeded by the complex nature of herbal formulae. A herbal formula is a mixture of hundreds of chemical ingredients with multiple potential targets. The effects produced by an entire herbal formula cannot be adequately explained by considering separately each ingredient in it. This is a recognised problem that remains in need of methods to solve it. Here we introduce a holistic analysis method to decipher the molecular mechanisms of herbal formulae. This method combines chemical and therapeutic properties with network pharmacology, using a novel approach to evaluate the importance of the targets and ingredients of herbal formulae. We used the Liu-Wei-Di-Huang (LWDH) pill, a classic herbal formula, as an example to illustrate our method and validated some results by a following experiment. We revealed the core molecular targets and bioprocess network of the pharmacological effects of LWDH and inferred its therapeutic indications. This method provides a novel strategy to understand the mechanisms of herbal formulae in a holistic way and implies new applications of classic herbal formulae.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                01 November 2018
                November 2018
                : 23
                : 11
                : 2841
                Affiliations
                [1 ]Department of Physiology, College of Korean Medicine, Gachon University, Seongnam 13120, Korea; bmusun1@ 123456gmail.com (M.P.); psy9228@ 123456gmail.com (S.-Y.P.)
                [2 ]Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam 13120, Korea
                Author notes
                [* ]Correspondence: skysea@ 123456gachon.ac.kr (H.-J.L.); eopchang@ 123456gachon.ac.kr (C.-E.K.); Tel.: +82-31-750-5968 (H.-J.L.); +82-31-750-5493 (C.-E.K.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-4058-9457
                https://orcid.org/0000-0001-8353-3619
                Article
                molecules-23-02841
                10.3390/molecules23112841
                6278259
                30388815
                23bf986b-4052-49b3-8ba4-b82c42739050
                © 2018 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
                : 27 September 2018
                : 29 October 2018
                Categories
                Review

                platycodon grandiflorum,kilkyung,systems-level mechanism,network pharmacology,traditional asian medicine

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