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      Total saponin from Korean Red Ginseng inhibits binding of adhesive proteins to glycoprotein IIb/IIIa via phosphorylation of VASP (Ser 157) and dephosphorylation of PI3K and Akt

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          Abstract

          Background

          Binding of adhesive proteins (i.e., fibrinogen, fibronectin, vitronectin) to platelet integrin glycoprotein IIb/IIIa (αIIb/β 3) by various agonists (thrombin, collagen, adenosine diphosphate) involve in strength of thrombus. This study was carried out to evaluate the antiplatelet effect of total saponin from Korean Red Ginseng (KRG-TS) by investigating whether KRG-TS inhibits thrombin-induced binding of fibrinogen and fibronectin to αIIb/β 3.

          Methods

          We investigated the effect of KRG-TS on phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and dephosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt, affecting binding of fibrinogen and fibronectin to αIIb/β 3, and clot retraction.

          Results

          KRG-TS had an antiplatelet effect by inhibiting the binding of fibrinogen and fibronectin to αIIb/β 3 via phosphorylation of VASP (Ser 157), and dephosphorylation of PI3K and Akt on thrombin-induced platelet aggregation. Moreover, A-kinase inhibitor Rp-8-Br-cyclic adenosine monophosphates (cAMPs) reduced KRG-TS-increased VASP (Ser 157) phosphorylation, and increased KRG-TS-inhibited fibrinogen-, and fibronectin-binding to αIIb/β 3. These findings indicate that KRG-TS interferes with the binding of fibrinogen and fibronectin to αIIb/β 3 via cAMP-dependent phosphorylation of VASP (Ser 157). In addition, KRG-TS decreased the rate of clot retraction, reflecting inhibition of αIIb/β 3 activation. In this study, we clarified ginsenoside Ro (G-Ro) in KRG-TS inhibited thrombin-induced platelet aggregation via both inhibition of [Ca 2+] i mobilization and increase of cAMP production.

          Conclusion

          These results strongly indicate that KRG-TS is a beneficial herbal substance inhibiting fibrinogen-, and fibronectin-binding to αIIb/β 3, and clot retraction, and may prevent platelet αIIb/β 3-mediated thrombotic disease. In addition, we demonstrate that G-Ro is a novel compound with antiplatelet characteristics of KRG-TS.

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          Most cited references53

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          Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer.

          Korean Panax ginseng C A Meyer is mainly used to maintain the homeostasis of the body, and the pharmacological efficacy of Korean ginseng identified by modern science includes improved brain function, pain-relieving effects, preventive effects against tumors as well as anti-tumor activity, enhanced immune system function, anti-diabetic effects, enhanced liver function, adjusted blood pressure, anti-fatigue and anti-stress effects, improved climacteric disorder and sexual functions, as well as anti-oxidative and anti-aging effects. Further clinical studies of these pharmacological efficacies will continue to be carried out. Korean ginseng is found to have such main properties as ginsenoside, ployacetylene, acid polysaccharide, anti-oxidative aromatic compound, and insulin-like acid peptides. The number of ginsenoside types contained in Korean ginseng (38 ginsenosides) is substantially more than that of ginsenoside types contained in American ginseng (19 ginsenosides). Furthermore, Korean ginseng has been identified to contain more main non-saponin compounds, phenol compounds, acid polysaccharides and polyethylene compounds than American ginseng and Sanchi ginseng.
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            Role of Proteins of the Ena/VASP Family in Actin-based Motility of Listeria monocytogenes

            Intracellular propulsion of Listeria monocytogenes is the best understood form of motility dependent on actin polymerization. We have used in vitro motility assays of Listeria in platelet and brain extracts to elucidate the function of the focal adhesion proteins of the Ena (Drosophila Enabled)/VASP (vasodilator-stimulated phosphoprotein) family in actin-based motility. Immunodepletion of VASP from platelet extracts and of Evl (Ena/VASP-like protein) from brain extracts of Mena knockout (−/−) mice combined with add-back of recombinant (bacterial or eukaryotic) VASP and Evl show that VASP, Mena, and Evl play interchangeable roles and are required to transform actin polymerization into active movement and propulsive force. The EVH1 (Ena/VASP homology 1) domain of VASP is in slow association–dissociation equilibrium high-affinity binding to the zyxin-homologous, proline-rich region of ActA. VASP also interacts with F-actin via its COOH-terminal EVH2 domain. Hence VASP/ Ena/Evl link the bacterium to the actin tail, which is required for movement. The affinity of VASP for F-actin is controlled by phosphorylation of serine 157 by cAMP-dependent protein kinase. Phospho-VASP binds with high affinity (0.5 × 108 M−1); dephospho-VASP binds 40-fold less tightly. We propose a molecular ratchet model for insertional polymerization of actin, within which frequent attachment–detachment of VASP to F-actin allows its sliding along the growing filament.
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              Platelet-derived growth factor in chemotactic for fibroblasts

              Chemotaxis assays in modified Boyden chambers were used to detect fibroblast chemoattractants in materials released from early-stage inflammatory cells, namely, mast cells, platelets, and neutrophils. Strong attractant activity was found in substances released from platelets. This activity was accounted for mainly by the platelet- derived growth factor (PDGF), which is released from the platelets and which was active as a chemoattractant at 0.5-1.0 mitogenic units/ml. The mitogenic activity of purified PDGF, measured by [3H]thymidine incorporation, occurs at a similar concentration range. By varying the gradient of PDGF, we demonstrated that PDGF stimulates chemotaxis rather than random motility. Preincubation of suspensions of fibroblasts in the presence of PDGF decreased the subsequent migration of cells to a gradient of PDGF as well as to a gradient of fibronectin, which is also in attractant for fibroblasts. The chemotactic response of fibroblasts to PDGF was not inhibited by hydroxyurea or azidocytidine but was inhibited by actinomycin D and cycloheximide, suggesting that synthesis of RNA and proteins but not of DNA is required for the chemotactic response to occur. Fibroblast growth factor, epidermal growth factor, nerve growth factor, and insulin were not chemotactic for human skin fibroblasts, suggesting that the chemoattractant activity of PDGF for fibroblasts is not a general property of growth factors and mitogens. These results suggest that PDGF could have two functions in wound healing: to attract fibroblasts to migrate into the clot and then to induce their proliferation.
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                Author and article information

                Contributors
                Journal
                J Ginseng Res
                J Ginseng Res
                Journal of Ginseng Research
                Elsevier
                1226-8453
                2093-4947
                21 May 2015
                January 2016
                21 May 2015
                : 40
                : 1
                : 76-85
                Affiliations
                [1 ]Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, Inje University, Gyungnam, Republic of Korea
                [2 ]Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, Daejeon, Republic of Korea
                [3 ]Laboratory of Veterinary Physiology and Signaling, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
                Author notes
                []Corresponding author. Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, Inje University, 197, Inje-ro, Gimhae, Gyungnam 621-749, Republic of Korea. mlsjpark@ 123456inje.ac.kr
                [☆]

                These two authors contributed equally to this work.

                Article
                S1226-8453(15)00047-0
                10.1016/j.jgr.2015.05.004
                4703804
                26843825
                4cd31ae8-052d-4254-996a-ba51e166720e
                Copyright © 2015, The Korean Society of Ginseng, Published by Elsevier Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 3 March 2015
                : 30 April 2015
                : 8 May 2015
                Categories
                Research Article

                adhesive protein,clot retraction,pi3k/akt,total saponin from korean red ginseng,vasp (ser157)

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