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Antiplatelet Effect of Nobiletin is Mediated by Activation of A2A Adenosine Receptor

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Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

Nobiletin is a polymethoxylated flavone derived from citrus peels that possesses a wide range of beneficial effects. Specifically, nobiletin exhibits anti-inflammatory, antibacterial, and antioxidant effects. Recent research showed that nobiletin is able to diminish platelet adhesion and aggregation, indicating this compound as a potential therapeutic drug in thrombosis therapy. However, the exact mechanism of nobiletin action on platelets is unclear. Hence, the main goal of our study was to investigate the molecular mechanism of nobiletin-induced platelet inhibition. We demonstrated that nobiletin blocks induced platelet activation and does not cause platelet apoptosis. Inhibition effect of nobiletin on platelets is at least partly mediated by activation of A2A adenosine receptor and consequent AC/cAMP/PKA signaling pathway activation.

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REFERENCES

  1. Kaul S., Padgett R.C., Heistad D.D. 1994. Role of platelets and leukocytes in modulation of vascular tone. Ann. N.Y. Acad. Sci. 714, 122–135.

    Article  CAS  PubMed  Google Scholar 

  2. Hamzeh-Cognasse H., Damien P., Chabert A., Pozzetto B., Cognasse F., Garraud O. 2015. Platelets and infections–complex interactions with bacteria. Front. Immunol. 6, 82.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Assinger A. 2014. Platelets and infection–an emerging role of platelets in viral infection. Front. Immunol. 5, 649.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jurk K., Kehrel B.E. 2005. Platelets: Physiology and biochemistry. Semin. Thromb. Hemost. 31 (4), 381–392.

    Article  CAS  PubMed  Google Scholar 

  5. Makhoul S., Walter E., Pagel O., Walter U., Sickmann A., Gambaryan S., Smolenski A., Zahedi R.P., Jurk K. 2018. Effects of the NO/soluble guanylate cyclase/cGMP system on the functions of human platelets. Nitric Oxide. 76, 71–80.

    Article  CAS  PubMed  Google Scholar 

  6. Bye A.P., Unsworth A.J., Gibbins J.M. 2016. Platelet signaling: A complex interplay between inhibitory and activatory networks. J. Thromb. Haemost. 14 (5), 918–930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gambaryan S., Tsikas D. 2015. A review and discussion of platelet nitric oxide and nitric oxide synthase: Do blood platelets produce nitric oxide from L-arginine or nitrite? Amino Acids. 47 (9), 1779–1793.

    Article  CAS  PubMed  Google Scholar 

  8. Papapanagiotou A., Daskalakis G., Siasos G., Gargalionis A., Papavassiliou A.G. 2016. The role of platelets in cardiovascular disease: Molecular mechanisms. Curr. Pharm. Des. 22 (29), 4493–4505.

    Article  CAS  PubMed  Google Scholar 

  9. Koupenova M., Kehrel B.E., Corkrey H.A., Freedman J.E. 2017. Thrombosis and platelets: An update. Eur. Heart J. 38 (11), 785–791.

    CAS  PubMed  Google Scholar 

  10. Wendelboe A.M., Raskob G.E. 2016. Global burden of thrombosis: Epidemiologic aspects. Circ. Res. 118 (9), 1340–1347.

    Article  CAS  PubMed  Google Scholar 

  11. Thachil J. 2016. Antiplatelet therapy – a summary for the general physicians. Clin. Med. (Lond). 16 (2), 152–160.

    Article  Google Scholar 

  12. Panche A.N., Diwan A.D., Chandra S.R. 2016. Flavonoids: An overview. J. Nutr. Sci. 5, e47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang G., Lin C.C., Yang Y., Yuan L., Wang P., Wen X., Pan M.H., Zhao H., Ho C.T., Li S. 2019. Nobiletin prevents trimethylamine oxide-induced vascular inflammation via inhibition of the NF-kappaB/MAPK pathways. J. Agric. Food Chem. 67 (22), 6169–6176.

    Article  CAS  PubMed  Google Scholar 

  14. Nakajima A., Ohizumi Y. 2019. Potential benefits of nobiletin, a citrus flavonoid, against Alzheimer’s disease and Parkinson’s disease. Int. J. Mol. Sci. 20 (14). 3380.

    Article  CAS  PubMed Central  Google Scholar 

  15. Huang H., Li L., Shi W., Liu H., Yang J., Yuan X., Wu L. 2016. The multifunctional effects of nobiletin and its metabolites in vivo and in vitro. Evid. Based Complement Alternat. Med. 2016, 2918796.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hsiao P.C., Lee W.J., Yang S.F., Tan P., Chen H.Y., Lee L.M., Chang J.L., Lai G.M., Chow J.M., Chien M.H. 2014. Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells. Tumour Biol. 35 (12), 11903–11911.

    Article  CAS  PubMed  Google Scholar 

  17. Sousa D.P., Pojo M., Pinto A.T., Leite V., Serra A.T., Cavaco B.M. 2020. Nobiletin alone or in combination with cisplatin decreases the viability of anaplastic thyroid cancer cell lines. Nutr. Cancer. 72 (2), 352–363.

    Article  CAS  PubMed  Google Scholar 

  18. Cho H.W., Jung S.Y., Lee G.H., Cho J.H., Choi I.Y. 2015. Neuroprotective effect of citrus unshiu immature peel and nobiletin inhibiting hydrogen peroxide-induced oxidative stress in HT22 murine hippocampal neuronal cells. Pharmacogn. Mag. 11 (Suppl 2), S284–S289.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu B., Huang J., Zhang B. 2016. Nobiletin protects against murine l-arginine-induced acute pancreatitis in association with downregulating p38MAPK and AKT. Biomed. Pharmacother. 81, 104–110.

    Article  CAS  PubMed  Google Scholar 

  20. Ikemura M., Sasaki Y., Giddings J.C., Yamamoto J. 2012. Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother. Res. 26 (9), 1272–1277.

    Article  CAS  PubMed  Google Scholar 

  21. Jayakumar T., Lin K.C., Lu W.J., Lin C.Y., Pitchairaj G., Li J.Y., Sheu J.R. 2017. Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms. Int. J. Mol. Med. 39 (1), 174–182.

    Article  CAS  PubMed  Google Scholar 

  22. Sodergren A.L., Ramstrom S. 2018. Platelet subpopulations remain despite strong dual agonist stimulation and can be characterised using a novel six-colour flow cytometry protocol. Sci. Rep. 8 (1), 1441.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Goh J.X.H., Tan L.T., Goh J.K., Chan K.G., Pusparajah P., Lee L.H., Goh B.H. 2019. Nobiletin and derivatives: Functional compounds from citrus fruit peel for colon cancer chemoprevention. Cancers (Basel). 11 (6). 867.

    Article  CAS  Google Scholar 

  24. Rukoyatkina N., Butt E., Subramanian H., Nikolaev V.O., Mindukshev I., Walter U., Gambaryan S., Benz P.M. 2017. Protein kinase A activation by the anti-cancer drugs ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition and apoptosis. Cell. Death Dis. 8 (6), e2898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nagy Z., Smolenski A. 2018. Cyclic nucleotide-dependent inhibitory signaling interweaves with activating pathways to determine platelet responses. Res. Pract. Thromb. Haemost. 2 (3), 558–571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Smolenski A., Bachmann C., Reinhard K., Honig-Liedl P., Jarchau T., Hoschuetzky H., Walter U. 1998. Analysis and regulation of vasodilator-stimulated phosphoprotein serine 239 phosphorylation in vitro and in intact cells using a phosphospecific monoclonal antibody. J. Biol. Chem. 273 (32), 20029–20035.

    Article  CAS  PubMed  Google Scholar 

  27. Braune S., Kupper J.H., Jung F. 2020. Effect of prostanoids on human platelet function: An overview. Int. J. Mol. Sci. 21 (23). 9020.

    Article  CAS  PubMed Central  Google Scholar 

  28. Noe L., Peeters K., Izzi B., Van Geet C., Freson K. 2010. Regulators of platelet cAMP levels: Clinical and therapeutic implications. Curr. Med. Chem. 17 (26), 2897–2905.

    Article  CAS  PubMed  Google Scholar 

  29. Vaiyapuri S., Roweth H., Ali M.S., Unsworth A.J., Stainer A.R., Flora G.D., Crescente M., Jones C.I., Moraes L.A., Gibbins J.M. 2015. Pharmacological actions of nobiletin in the modulation of platelet function. Br. J. Pharmacol. 172 (16), 4133–4145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lu W.J., Lin K.C., Liu C.P., Lin C.Y., Wu H.C., Chou D.S., Geraldine P., Huang S.Y., Hsieh C.Y., Sheu J.R. 2016. Prevention of arterial thrombosis by nobiletin: In vitro and in vivo studies. J. Nutr. Biochem. 28, 1–8.

    Article  CAS  PubMed  Google Scholar 

  31. Holinstat M., Preininger A.M., Milne S.B., Hudson W.J., Brown H.A., Hamm H.E. 2009. Irreversible platelet activation requires protease-activated receptor 1-mediated signaling to phosphatidylinositol phosphates. Mol. Pharmacol. 76 (2), 301–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Keshtkar S., Kaviani M., Jabbarpour Z., Geramizadeh B., Motevaseli E., Nikeghbalian S., Shamsaeefar A., Motazedian N., Al-Abdullah I.H., Ghahremani M.H., Azarpira N. 2019. Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis. Sci. Rep. 9 (1), 11701.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Abdol Razak N.B., Jones G., Bhandari M., Berndt M.C., Metharom P. 2018. Cancer-Associated thrombosis: An overview of mechanisms, risk factors, and treatment. Cancers (Basel). 10 (10). 380.

    Article  CAS  Google Scholar 

  34. Wojtukiewicz M.Z., Hempel D., Sierko E., Tucker S.C., Honn K.V. 2017. Antiplatelet agents for cancer treatment: A real perspective or just an echo from the past? Cancer Metastasis Rev. 36 (2), 305–329.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gambaryan S., Shpakova V. 2019. NO/cGMP sygnalling pathway in platelets. Russkii Fiziologicheskii zhurnal im. I.M. Sechenova (Rus.). 105 (8), 933–953.

    Google Scholar 

  36. Davies S.P., Reddy H., Caivano M., Cohen P. 2000. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351 (Pt 1), 95–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bain J., McLauchlan H., Elliott M., Cohen P. 2003. The specificities of protein kinase inhibitors: An update. Biochem. J. 371 (Pt 1), 199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rukoyatkina N., Walter U., Friebe A., Gambaryan S. 2011. Differentiation of cGMP-dependent and -independent nitric oxide effects on platelet apoptosis and reactive oxygen species production using platelets lacking soluble guanylyl cyclase. Thromb. Haemost. 106 (5), 922–933.

    Article  CAS  PubMed  Google Scholar 

  39. Emery A.C., Eiden M.V., Eiden L.E. 2013. A new site and mechanism of action for the widely used adenylate cyclase inhibitor SQ22,536. Mol. Pharmacol. 83 (1), 95–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lies B., Groneberg D., Gambaryan S., Friebe A. 2013. Lack of effect of ODQ does not exclude cGMP signalling via NO-sensitive guanylyl cyclase. Br. J. Pharmacol. 170 (2), 317–327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu E.Y.L., Xu M.L., Xia Y., Kong X., Wu Q., Dong T.T.X., Tsim K.W.K. 2019. Activation of G protein-coupled receptor 30 by flavonoids leads to expression of acetylcholinesterase in cultured PC12cells. Chem. Biol. Interact. 306, 147–151.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS

The work was supported by the Russian Foundation for Basic Research (project no. 19-315-90102).

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223, St. Petersburg, Russia

    V. S. Shpakova, S. P. Gambaryan & N. I. Rukoyatkina

  2. St. Petersburg State University, 199034, St. Petersburg, Russia

    A. V. Avdeeva, N. Al. Arawe, A. M. Prilepskaya & E. S. Alekseeva

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  1. V. S. Shpakova
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  2. A. V. Avdeeva
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Correspondence to V. S. Shpakova.

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The authors declare that they have no conflict of interest.

All experimental protocols were approved by the Ethics Committee of the Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences (Protocol no. 3-03 of 02.03.2020) and correspond to the 1964 Helsinki Declaration. Informed consent was obtained from all individual participants involved in the study.

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Translated by A. Prilepskaya

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Shpakova, V.S., Avdeeva, A.V., Al. Arawe, N. et al. Antiplatelet Effect of Nobiletin is Mediated by Activation of A2A Adenosine Receptor. Biochem. Moscow Suppl. Ser. A 15, 387–394 (2021). https://doi.org/10.1134/S1990747821060106

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  • DOI: https://doi.org/10.1134/S1990747821060106

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