Journal of Applied Biological Chemistry

  • Volume 66
  • /
  • Pages.171-178
  • /
  • 2023
  • /
  • 1976-0442(pISSN)
  • /
  • 2234-7941(eISSN)
The Korean Society for Applied Biological Chemistry (한국응용생명화학회)
권호 표지
DOI QR코드

DOI QR Code

Pharmacological actions of morusinol on modulation of platelet functions via integrin αIIb/β3 signaling

  • Hyuk-Woo Kwon (Department of Biomedical Laboratory Science and Microbiological Resource Research Institute, Far East University)
  • Received : 2023.02.24
  • Accepted : 2023.04.17
  • Published : 2023.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Morus alba, a popular medicinal plant belonging to the family Moraceae, has long been used commonly in traditional medicine and has various physiological activities, including antidiabetic, anti-microbial, diuretic, anti-oxidant, and anti-cancer activities. Morusinol was isolated from the root bark of M. alba; however, its biological effects have not yet been reported. Therefore, we examined the inhibitory effects of morusinol on human platelet aggregation, Ca2+ mobilization, and αIIb/β3 activity. Our data showed that collagen-induced human platelet aggregation was inhibited by morusinol without cytotoxicity. In this study, we examined whether morusinol inhibits platelet aggregation through the regulation of integrin αIIb/β3 and its associated signaling molecules. We observed that morusinol inhibited αIIb/β3 activation by regulating vasodilator-stimulated phosphoprotein, phosphatidylinositol-3 kinase, Akt (protein kinase B), and glycogen synthase kinase-3α/β. These results show that morusinol inhibited fibronectin adhesion, fibrinogen binding, and clot retraction. Taken together, morusinol shows strong antiplatelet and anti-clot retraction effects and is a potential therapeutic drug candidate to prevent platelet-related thrombosis and cardiovascular disease.

Keywords

Acknowledgement

This work was supported by a 2022 Far East University Research Grant (FEU2022S04).

References

  1. Devi B, Sharma N, Kumar D, Jeet K (2013) Morus alba Linn: A phytopharmacological review. Int J Pharm Pharm Sci 5: 14-18 
  2. Zhang H, Ma ZF, Luo X, Li X (2018) Effects of mulberry fruit (Morus alba L.) consumption on health outcomes: A mini-review. Antioxidants 7(5): 69. doi: 10.3390/antiox7050069 
  3. Butt MS, Nazir A, Sultan MT, Schroen K (2018) Morus alba L. nature's functional tonic. Trends Food Sci Technol 19: 505-512. doi: 10.1016/j.tifs.2008.06.002 
  4. Andrews RK, Berndt MC (2004) Platelet physiology and thrombosis. Thromb Res 114: 447-453. doi: 10.1016/j.thromres.2004.07.020 
  5. Kim DS, Ji HD, Rhee MH, Sung YY, Yang WK, Kim SH, Kim HK (2014) Antiplatelet activity of Morus alba leaves extract, mediated via inhibiting granule secretion and blocking the phosphorylation of extracellular-signal-regulated kinase and akt. Evid Based Complement Alternat Med 2014: 639548. doi: 10.1155/2014/639548 
  6. Kim DS, Irfan M, Sung YY, Kim SH, Park SH, Choi YH, Kim HK (2017) Schisandra chinensis and Morus alba synergistically inhibit in vivo thrombus formation and platelet aggregation by impairing the glycoprotein VI pathway. Evid Based Complement Alternat Med 2017: 639548. doi: 10.1155/2017/78396587 
  7. Varga-Szabo D, Braun A, Nieswandt B (2009) Calcium signaling in platelets. J Thromb Haemost 7: 1057-1066. doi: 10.1111/j.1538-7836.2009.03455.x 
  8. Payrastre B, Missy K, Trumel C, Bodin S, Plantavid M, Chap H (2000) The integrin αIIb/α3 in human platelet signal transduction. Biochem Pharmacol 60(8): 1069-1074. doi: 10.1016/S0006-2952(00)00417-2 
  9. Kwon HW, Kim SD, Rhee MH, Shin JH (2022) Pharmacological Actions of 5-Hydroxyindolin-2 on Modulation of Platelet Functions and Thrombus Formation via Thromboxane A2 Inhibition and cAMP Production. Int J Mol Sci 23: 14545. doi: 10.3390/ijms232314545 
  10. Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260: 3440-3450. doi: 10.1016/S0021-9258(19)83641-4 
  11. Valet C, Severin S, Chicanne G, Laurent PA, Gaits-Iacovoni F, Gratacap MP, Payrastre B (2016) The role of class I, II and III PI 3-kinases in platelet production and activation and their implication in thrombosis. Adv Biol Regul 61: 33-41. doi: 10.1016/j.jbior.2015.11.008 
  12. Chen J, De S, Damron DS, Chen WS, Hay N, Byzova TV (2004) Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice. Blood 104: 1703-1710. doi: 10.1182/blood-2003-10-3428 
  13. Sudo T, Ito H, Kimura Y (2003) Phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) by the anti-platelet drug, cilostazol, in platelets. Platelets 6: 381-390, 2003. doi: 10.1080/09537100310001598819 
  14. Patel P, Naik UP (2020) Platelet MAPKs-a 20+ year history: What do we really know?. J Thromb Haemost 18: 2087-2102. doi: 10.1111/jth.14967 
  15. Kwon HW (2018) Inhibitory Effects of PD98059, SB203580, and SP600125 on α-and δ-granule Release and Intracellular Ca2+ Levels in Human Platelets. Biomed Sci Lett 24: 253-262. doi: 10.15616/BSL.2018.24.3.253 
  16. Smolenski A (2012) Novel roles of cAMP/cGMP-dependent signaling in platelets. J Thromb Haemost 10: 167-176. doi: 10.1111/j.1538-7836.2011.04576.x 
  17. Schwarz UR, Walter U, Eigenthaler M (2001) Taming platelets with cyclic nucleotides. Biochem Pharmacol 62: 1153-1161. doi: 10.1016/S0006-2952(01)00760-2 
  18. Kwon HW, Lee DH, Rhee MH, Shin JH (2021) In vitro antiplatelet activity of mulberroside C through the up-regulation of cyclic nucleotide signaling pathways and down-regulation of phosphoproteins. Genes12: 1024. doi: 10.3390/genes12071024 
  19. Guidetti GF, Canobbio I, Torti M (2015) PI3K/Akt in platelet integrin signaling and implications in thrombosis. Adv Biol Regul59: 36-52. doi: 10.1016/j.jbior.2015.06.001 
  20. Moore SF, Agbani EO, Wersall A, Poole AW, Williams CM, Zhao X, Hers I (2021) Opposing Roles of GSK3α and GSK3β Phosphorylation in Platelet Function and Thrombosis. Int J Mol Sci 22: 10656. doi: 10.3390/ijms221910656 
  21. Moroi AJ, Watson SP (2015) Akt and mitogen-activated protein kinase enhance C-type lectin-like receptor 2-mediated platelet activation by inhibition of glycogen synthase kinase 3α/β. J Thromb Haemost 13: 1139-1150. doi: 10.1111/jth.12954 
  22. Kwon HW, Shin JH, Cho HJ, Rhee MH, Park HJ (2016) Total saponin from Korean Red Ginseng inhibits binding of adhesive proteins to glycoprotein IIb/IIIa via phosphorylation of VASP (Ser157) and dephosphorylation of PI3K and Akt. J Ginseng Res 40: 76-85. doi: 10.1016/j.jgr.2015.05.004 
  23. Kwon HW (2018) Inhibitory effect of 20(S)-Ginsenoside Rg3 on human platelet aggregation and intracellular Ca2+ levels via cyclic adenosine monophosphate dependent manner. Prev Nutr Food Sci 23: 317-325. doi: 10.3746/pnf.2018.23.4.317 
  24. Gresele P, Momi S, Falcinelli E (2011) Anti-platelet therapy: phosphodiesterase inhibitors. Br J Clin Pharmacol 72: 634-646  https://doi.org/10.1111/j.1365-2125.2011.04034.x
  25. 2Lee YY, Kim SD, Park SC, Rhee MH (2022) Panax ginseng: inflammation, platelet aggregation, thrombus formation, and atherosclerosis crosstalk. J Ginseng Res 46: 54-61. doi: 10.1016/j.jgr.2021.09.003