Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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DK-MGAR101, an extract of adventitious roots of mountain ginseng, improves blood circulation by inhibiting endothelial cell injury, platelet aggregation, and thrombus formation

  • Seong, Hye Rim (College of Veterinary Medicine, Chungbuk National University) ;
  • Wang, Cuicui (College of Veterinary Medicine, Chungbuk National University) ;
  • Irfan, Muhammad (College of Veterinary Medicine, Kyungpook National University) ;
  • Kim, Young Eun (Pharmaceutical Technology Institute, Dongkook Pharmaceutical Co., Ltd.) ;
  • Jung, Gooyoung (Pharmaceutical Technology Institute, Dongkook Pharmaceutical Co., Ltd.) ;
  • Park, Sung Kyeong (Department of Beauty Care, Daejeon Health Institute of Technology) ;
  • Kim, Tae Myoung (College of Veterinary Medicine, Chungbuk National University) ;
  • Choi, Ehn-Kyoung (College of Veterinary Medicine, Chungbuk National University) ;
  • Rhee, Man Hee (College of Veterinary Medicine, Kyungpook National University) ;
  • Kim, Yun-Bae (College of Veterinary Medicine, Chungbuk National University)
  • Received : 2021.09.07
  • Accepted : 2022.01.03
  • Published : 2022.09.01
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Abstract

Background: Since ginsenosides exert an anti-thrombotic activity, blood flow-improving effects of DK-MGAR101, an extract of mountain ginseng adventitious roots (MGAR) containing various ginsenosides, were investigated in comparison with an extract of Korean Red Ginseng (ERG). Methods: In Sprague-Dawley rats orally administered with DK-MGAR101 or ERG, oxidative carotid arterial thrombosis was induced with FeCl3 (35%), and their blood flow and occlusion time were measured. To elucidate underlying mechanisms, the cytoprotective activities on rat aortic endothelial cells (RAOECs) exposed to hydrogen peroxide (H2O2) were confirmed. In addition, the inhibitory activities of DK-MGAR101 and ERG on agonist-induced platelet aggregation, thromboxane B2 production, and ATP granule release from stimulated platelets as well as blood coagulation were analyzed. Results: DK-MGAR101 containing high concentrations of Rb1, Rg1, Rg3, Rg5, and Rk1 ginsenosides (55.07 mg/g) was more effective than ERG (ginsenosides 8.45 mg/g) in protecting RAOECs against H2O2 cytotoxicity. DK-MGAR101 was superior to ERG not only in suppressing platelet aggregation, thromboxane B2 production, and granule release, but also in delaying blood coagulation, FeCl3-induced arterial occlusion, and thrombus formation. Conclusions: The results indicate that DK-MGAR101 prevents blood vessel occlusion by suppressing platelet aggregation, thrombosis, and blood coagulation, in addition to endothelial cell injury.

Keywords

Acknowledgement

This work was supported in part by Dongkook Pharmaceutical Co., Ltd.

References

  1. Ramos KS, Melchert RB, Chacon E, Acosta Jr D. Toxic responses of the heart and vascular systems. In: Klaaassen CD, editor. Casarett & Doull's toxicology. The basic science of poisons. New York: McGraw-Hill; 2001. p. 597-651.
  2. Jackson SP, Nesbitt WS, Kulkarni S. Signalling events underlying thrombus formation. J Thromb Haemostasis 2003;1:1602-12. https://doi.org/10.1046/j.1538-7836.2003.00267.x
  3. Majid A, Delanty N, Kantor J. Antiplatelet agents for secondary prevention of ischemic stroke. Ann Pharmacother 2001;35:1241-7. https://doi.org/10.1345/aph.10381
  4. Cowan DH. Platelet adherence to collagen: role of prostaglandin-thromboxane synthesis. Br J Haematol 1981;49:425-34. https://doi.org/10.1111/j.1365-2141.1981.tb07245.x
  5. Dogne JM, Hanson J, de Leval X, et al. From the design to the clinical application of thromboxane modulators. Curr Pharmaceut Des 2006;12:903-23. https://doi.org/10.2174/138161206776055921
  6. Arita H, Nakano T, Hanasaki K. Thromboxane A2: its generation and role in platelet activation. Prog Lipid Res 1989;28:273-301. https://doi.org/10.1016/0163-7827(89)90002-7
  7. Gilmer JF, Murphy MA, Shannon JA, Breen CG, Ryder SA, Clancy JM. Single oral dose study of two isosorbide-based aspirin prodrugs in the dog. J Pharm Pharmacol 2003;55:1351-7.
  8. Peter FW, Franken RJ, Wang WZ, et al. Effect of low dose aspirin on thrombus formation at arterial and venous microanastomoses and on the tissue microcirculation. Plast Reconstr Surg 1997;99:1112-21. https://doi.org/10.1097/00006534-199704000-00030
  9. Pavlidis P, Bjarnason I. Aspirin induced adverse effects on the small and large intestine. Curr Pharmaceut Des 2015;21:5089-93. https://doi.org/10.2174/1381612821666150915110058
  10. Cortellini G, Carusob C, Romano A. Aspirin challenge and desensitization: how, when and why. Curr Opin Allergy Clin Immunol 2017;17:247-54. https://doi.org/10.1097/ACI.0000000000000374
  11. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008;451:914-8. https://doi.org/10.1038/nature06797
  12. Ernst E. Panax ginseng: an overview of the clinical evidence. J Ginseng Res 2010;34:259-63. https://doi.org/10.5142/jgr.2010.34.4.259
  13. Nam KY. The comparative understanding between red ginseng and white ginsengs, processed ginsengs (Panax ginseng Meyer). J Ginseng Res 2005;29: 1-18. https://doi.org/10.5142/JGR.2005.29.1.001
  14. Shin K, Guo H, Cha Y, Ban YH, Seo DW, Choi Y, et al. CereboostTM, an American ginseng extract, improves cognitive function via up-regulation of choline acetyltransferase expression and neuroprotection. Regul Toxicol Pharmacol 2016;78:53-8. https://doi.org/10.1016/j.yrtph.2016.04.006
  15. Shah ZA, Gilani RA, Sharma P, Vohora SB. Cerebroprotective effect of Korean ginseng tea against global and focal models of ischemia in rats. J Ethnopharmacol 2005;101:299-307. https://doi.org/10.1016/j.jep.2005.05.002
  16. Han K, Shin IC, Choi KJ, Yun YP, Hong JT, Oh KW. Korea red ginseng water extract increases nitric oxide concentrations in exhaled breath. Nitric Oxide 2005;12:159-62. https://doi.org/10.1016/j.niox.2005.02.001
  17. Lee E, Zhao H, Li D, Jeong C, Kim J, Kim Y. Effect of the MeOH extract of adventitious root culture of Panax ginseng on hyperlipidemic rat induced by high fat-rich diet. Korean J Pharmacogn 2003;34:179-84.
  18. Lim H, Kim Y, Lee D, Cho S, Cho M. The antifibrotic and antioxidant activities of hot water extract of adventitious root culture of Panax ginseng (ARCP). J Appl Biol Chem 2007;50:78-84.
  19. Seog H, Jung C, Kim Y, Park H. Phenolic acids and antioxidant activities of wild ginseng (Panax ginseng C.A. Meyer) leaves. Food Sci Biotechnol 2005;14: 371-4.
  20. Yamaguchi H, Matsuura H, Kasai R, et al. Analysis of saponins of wild Panax ginseng. Chem Pharm Bull (Tokyo) 1988;36:4177-81. https://doi.org/10.1248/cpb.36.4177
  21. Paek K, Murthy HN, Hahn EJ, Zhong JJ. Large scale culture of ginseng adventitious roots for production of ginsenosides. Adv Biochem Eng Biotechnol 2009;113:51-176.
  22. Sivakumar G. Bioreactor technology: a novel industrial tool for high-tech production of bioactive molecules and biopharmaceuticals from plant roots. Biotechnol J 2006;1:19-1427. https://doi.org/10.1002/biot.200600117
  23. Sivakumar G, Yu K, Paek K. Production of biomass and ginsenosides from adventitious roots of Panax ginseng in bioreactor cultures. Eng Life Sci 2005;5: 33-342.
  24. Murthy HN, Dandin VS, Park SY, Paek KY. Quality, safety and efficacy profiling of ginseng adventitious roots produced in vitro. Appl Microbiol Biotechnol 2018;102:7309-17. https://doi.org/10.1007/s00253-018-9188-x
  25. Jin YR, Cho MR, Ryu CK, et al. Antiplatelet activity of J78 (2-chloro-3-[2'- bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), an antithrombotic agent, is mediated by thromboxane (TX) A2 receptor blockade with TXA2 synthase inhibition and suppression of cytosolic Ca2+ mobilization. J Pharmcol Exp Ther 2005;312:214-9. https://doi.org/10.1124/jpet.104.073718
  26. Lee JJ, Yang H, Yoo YM, et al. Morusinol extracted from Morus alba inhibits arterial thrombosis and modulates platelet activation for the treatment of cardiovascular disease. J Atherosclerosis Thromb 2012;19:516-22. https://doi.org/10.5551/jat.10058
  27. Jang JY, Kim TS, Cai J, et al. Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation. Lab Anim Res 2013;29:221-5. https://doi.org/10.5625/lar.2013.29.4.221
  28. Jang JY, Kim TS, Cai J, et al. Perilla oil improves blood flow through inhibition of platelet aggregation and thrombus formation. Lab Anim Res 2014;30:21-7. https://doi.org/10.5625/lar.2014.30.1.21
  29. Lee SR, Park JH, Kim ND, Choi KJ. Inhibitory effects of ginsenoside Rg3 on platelet aggregation and its mechanism of action. Korean J Ginseng Sci 1997;21:132-40.
  30. Jin YR, Yu JY, Lee JJ, et al. Antithrombotic and antiplatelet activities of Korean red ginseng extract. Basic Clin Pharmacol Toxicol 2007;100:170-5. https://doi.org/10.1111/j.1742-7843.2006.00033.x
  31. Shin JH, Kwon HW, Irfan M, Rhee MH, Lee DH. Ginsenoside Rk1 suppresses platelet mediated thrombus formation by downregulation of granule release and αIIbβ3 activation. J Ginseng Res 2021;45:490-7. https://doi.org/10.1016/j.jgr.2020.11.001
  32. Elshafay A, Tinh NX, Salman S, et al. Ginsenoside Rk1 bioactivity: a systematic review. PeerJ 2017;5:e3993. https://doi.org/10.7717/peerj.3993
  33. Ying A, Yu QT, Guo L, et al. Structural-activity relationship of ginsenosides from steamed ginseng in the treatment of erectile dysfunction. Am J Chin Med 2018;46:137-55. https://doi.org/10.1142/S0192415X18500088
  34. Zheng Z, Wang M, Cheng C, et al. Ginsenoside Rb1 reduces H2O2-induced HUVEC dysfunction by stimulating the sirtuin-1/AMP-activated protein kinase pathway. Mol Med Rep 2020;22:247-56. https://doi.org/10.3892/mmr.2020.11096
  35. Morton LF, Peachey AR, Barnes MJ. Platelet-reactive sites in collagens type I and type III. Evidence for separate adhesion and aggregatory sites. Biochem J 1989;258:157-63. https://doi.org/10.1042/bj2580157
  36. Poole AW, Watson SP. Regulation of cytosolic calcium by collagen in single human platelets. Br J Pharmacol 1995;115:101-6. https://doi.org/10.1111/j.1476-5381.1995.tb16326.x
  37. Cowan DH, Robertson AL, Shook P, Giroski P. Platelet adherence to collagen: role of plasma, ADP, and divalent cations. Br J Haematol 1981;47:257-67. https://doi.org/10.1111/j.1365-2141.1981.tb02787.x
  38. Roberts DE, McNicol A, Bose R. Mechanism of collagen activation in human platelets. J Biol Chem 2004;279:19421-30. https://doi.org/10.1074/jbc.M308864200
  39. Jeon WK, Yoo BK, Kim YE, et al. Anti-platelet activity of tissue-cultured mountain ginseng adventitious roots in human whole blood. Food Sci Biotechnol 2008;17:1197-202.
  40. Rittenhouse SE, Allen CL. Synergistic activation by collagen and 15-hydroxy-9 α,11α-peroxidoprosta-5,13-dienoic acid (PGH2) of phosphatidylinositol metabolism and arachidonic acid release in human platelets. J Clin Invest 1982;70:1216-24. https://doi.org/10.1172/JCI110720
  41. McNicol A, Nickolaychuk BR. Inhibition of collagen-induced platelet activation by arachidonyl trifluoromethyl ketone. Biochem Pharmacol 1995;50: 1795-802. https://doi.org/10.1016/0006-2952(95)02048-9
  42. Feijge MA, Van Pampus EC, Lacabaratz-Porret C, et al. Inter-individual variability in Ca2+ signalling in platelets from healthy volunteers: effects of aspirin and relationship with expression of endomembrane Ca2+-ATPases. Br J Haematol 1988;102:850-9.
  43. Lockyer S, Kambayashi J. Demonstration of flow and platelet dependency in a ferric chloride-induced model of thrombosis. J Cardiovasc Pharmacol 1999;33:718-25. https://doi.org/10.1097/00005344-199905000-00007
  44. Shin JH, Park YJ, Kim W, et al. Change of ginsenoside profiles in processed ginseng by drying, steaming, and puffing. J Microbiol Biotechnol 2019;29: 222-9. https://doi.org/10.4014/jmb.1809.09056
  45. Yu KW, Gao W, Hahn EJ, Paek KY. Jasmonic acid improves ginsenoside accumulation in adventitious root culture of Panax ginseng C.A. Meyer. Biochem Eng J 2002;11:211-5. https://doi.org/10.1016/S1369-703X(02)00029-3
  46. Kim YS, Hahn EJ, Murthy HN, Paek KY. Adventitious root growth and ginsenoside accumulation in Panax ginseng cultures as affected by methyl jasmonate. Biotechnol Lett 2004;26:1619-22. https://doi.org/10.1007/s10529-004-3183-2
  47. Ban YH, Cha Y, Choi J, et al. Blood flow-improving activity of methyl jasmonate-treated adventitious roots of mountain ginseng. Lab Anim Res 2017;33:105-13. https://doi.org/10.5625/lar.2017.33.2.105