Abstract
Cudratricusxanthone A (CTXA), a natural bioactive compound extracted from the roots of Cudrania tricuspidata Bureau, is known to possess hepatoprotective, antiproliferative and anti-inflammatory activities. However, antiplatelet, anticoagulant, and profibrinolytic properties have not been studied. The anticoagulant activities of CTXA were measured by monitoring activated partial thromboplastin-time (aPTT), prothrombin time (PT), and the activities of cell-based thrombin and activated factor X (FXa). The effects of CTXA on the expressions of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were also tested in tumor necrosis factor-α (TNF-α) activated human umbilical vein endothelial cells. Our data showed that CTXA inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation, prolonged aPTT and PT significantly and inhibited the activities and production of thrombin and FXa. CTXA prolonged in vivo bleeding time and inhibited TNF-α induced PAI-1 production. Furthermore, PAI-1/t-PA ratio was significantly decreased by CTXA. Collectively, these results indicate that CTXA possesses antithrombotic activities and suggest that the current study could provide bases for the development of new anticoagulant agents.
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Chung, M.I., J.R. Weng, J.P. Wang, C.M. Teng, and C.N. Lin. 2002. Antiplatelet and anti-inflammatory constituents and new oxygenated xanthones from Hypericum geminiflorum. Planta Medica 68: 25–29.
Correia-Da-Silva, M., E. Sousa, B. Duarte, F. Marques, F. Carvalho, L.M. Cunha-Ribeiro, and M.M. Pinto. 2011. Polysulfated xanthones: multipathway development of a new generation of dual anticoagulant/antiplatelet agents. Journal of Medicinal Chemistry 54: 5373–5384.
Dahlback, B. 2000. Blood coagulation. Lancet 355: 1627–1632.
Davie, E.W. 1995. Biochemical and molecular aspects of the coagulation cascade. Thrombosis Haemostasis 74: 1–6.
Davie, E.W., K. Fujikawa, and W. Kisiel. 1991. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30: 10363–10370.
Dejana, E., A. Callioni, A. Quintana, and G. De Gaetano. 1979. Bleeding time in laboratory animals. II—A comparison of different assay conditions in rats. Thrombosis Research 15: 191–197.
Ghosh, S., M. Ezban, E. Persson, U. Pendurthi, U. Hedner, and L.V. Rao. 2007. Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface. Journal of Thrombosis and Haemostasis 5: 336–346.
Hamaguchi, E., T. Takamura, A. Shimizu, and Y. Nagai. 2003. Tumor necrosis factor-alpha and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-kappaB-dependent pathways in cultured human umbilical vein endothelial cells. Journal of Pharmacology and Experimental Therapeutics 307: 987–994.
Hwang, J.H., S.S. Hong, X.H. Han, J.S. Hwang, D. Lee, H. Lee, Y.P. Yun, Y. Kim, J.S. Ro, and B.Y. Hwang. 2007. Prenylated xanthones from the root bark of Cudrania tricuspidata. Journal of Natural Products 70: 1207–1209.
Jeong, G.S., D.S. Lee, and Y.C. Kim. 2009. Cudratricusxanthone A from Cudrania tricuspidata suppresses pro-inflammatory mediators through expression of anti-inflammatory heme oxygenase-1 in RAW264.7 macrophages. International Immunopharmacology 9: 241–246.
Kim, D.C., S.K. Ku, and J.S. Bae. 2012a. Anticoagulant activities of curcumin and its derivative. BMB Rep 45: 221–226.
Kim, S.Y., S. Kim, J.M. Kim, E.H. Jho, S. Park, D. Oh, and H.S. Yun-Choi. 2011. PKC inhibitors RO 31-8220 and Go 6983 enhance epinephrine-induced platelet aggregation in catecholamine hypo-responsive platelets by enhancing Akt phosphorylation. BMB Reports 44: 140–145.
Kim, T.H., S.K. Ku, and J.S. Bae. 2012b. Antithrombotic and profibrinolytic activities of eckol and dieckol. Journal of Cellular Biochemistry 113: 2877–2883.
Kim, T.J., H.J. Han, S.S. Hong, J.H. Hwang, B.Y. Hwang, H.S. Yoo, Y.R. Jin, J.J. Lee, J.Y. Yu, K.H. Lee, B.W. Kang, and Y.P. Yun. 2007. Cudratricusxanthone A isolated from the root bark of Cudrania tricuspidata inhibits the proliferation of vascular smooth muscle cells through the suppression of PDGF-receptor beta tyrosine kinase. Biological and Pharmaceutical Bulletin 30: 805–809.
Lee, K.H. 2000. Research and future trends in the pharmaceutical development of medicinal herbs from Chinese medicine. Public Health Nutrition 3: 515–522.
Lee, W., E.J. Yang, S.K. Ku, K.S. Song, and J.S. Bae. 2012. Anticoagulant activities of oleanolic acid via inhibition of tissue factor expressions. BMB Reports 45: 390–395.
Li, Y., Z.J. Qian, B. Ryu, S.H. Lee, M.M. Kim, and S.K. Kim. 2009. Chemical components and its antioxidant properties in vitro: an edible marine brown alga Ecklonia cava. Bioorganic and Medicinal Chemistry 17: 1963–1973.
Lin, C.N., H.K. Hsieh, S.J. Liou, H.H. Ko, H.C. Lin, M.I. Chung, F.N. Ko, H.W. Liu, and C.M. Teng. 1996. Synthesis and antithrombotic effect of xanthone derivatives. Journal of Pharmacy and Pharmacology 48: 887–890.
Lopez, S., F. Peiretti, B. Bonardo, I. Juhan-Vague, and G. Nalbone. 2000. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis 152: 359–366.
Nowak, P., H.M. Zbikowska, M. Ponczek, J. Kolodziejczyk, and B. Wachowicz. 2007. Different vulnerability of fibrinogen subunits to oxidative/nitrative modifications induced by peroxynitrite: functional consequences. Thrombosis Research 121: 163–174.
Philip-Joet, F., M.C. Alessi, C. Philip-Joet, M. Aillaud, J.R. Barriere, A. Arnaud, and I. Juhan-Vague. 1995. Fibrinolytic and inflammatory processes in pleural effusions. European Respiratory Journal 8: 1352–1356.
Quinn, C., J. Hill, and H. Hassouna. 2000. A guide for diagnosis of patients with arterial and venous thrombosis. Clinical and Laboratory Science 13: 229–238.
Qureshi, S.H., C. Manithody, J.S. Bae, L. Yang, and A.R. Rezaie. 2008. Autolysis loop restricts the specificity of activated protein C: analysis by FRET and functional assays. Biophysical Chemistry 134: 239–245.
Rajtar, G., D. Zolkowska, Z. Kleinrok, and H. Marona. 1999. Antiplatelets activity of some xanthone derivatives. Acta Poloniae Pharmaceutica 56: 319–324.
Rao, L.V., S.I. Rapaport, and M. Lorenzi. 1988. Enhancement by human umbilical vein endothelial cells of factor Xa-catalyzed activation of factor VII. Blood 71: 791–796.
Schleef, R.R., M.P. Bevilacqua, M. Sawdey, M.A. Gimbrone Jr, and D.J. Loskutoff. 1988. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. Journal of Biological Chemistry 263: 5797–5803.
Sugo, T., C. Nakamikawa, S. Tanabe, and M. Matsuda. 1995. Activation of prothrombin by factor Xa bound to the membrane surface of human umbilical vein endothelial cells: its catalytic efficiency is similar to that of prothrombinase complex on platelets. Journal of Biochemistry 117: 244–250.
Tian, Y.H., H.C. Kim, J.M. Cui, and Y.C. Kim. 2005. Hepatoprotective constituents of Cudrania tricuspidata. Archives of Pharmacal Research 28: 44–48.
Zou, Y.S., A.J. Hou, G.F. Zhu, Y.F. Chen, H.D. Sun, and Q.S. Zhao. 2004. Cytotoxic isoprenylated xanthones from Cudrania tricuspidata. Bioorganic and Medicinal Chemistry 12: 1947–1953.
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This study was supported by the National Research Foundation of Korea (NRF) funded by the Korea government (MSIP) (Grant No. 2013-067053).
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The authors have no conflict of interest to declare.
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Hayoung Yoo and Sae-Kwang Ku contributed equally to this work.
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Yoo, H., Ku, SK., Lee, W. et al. Antiplatelet, anticoagulant, and profibrinolytic activities of cudratricusxanthone A. Arch. Pharm. Res. 37, 1069–1078 (2014). https://doi.org/10.1007/s12272-013-0290-4
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DOI: https://doi.org/10.1007/s12272-013-0290-4