Xanthohumol抑制血小板凝集作用之機轉探討

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題名:	Xanthohumol抑制血小板凝集作用之機轉探討 Mechanisms involved in the antiplatelet activity of xanthohumol
作者:	張瓊分 Chiung-fen Chang
貢獻者:	醫學科學研究所
關鍵詞:	黃腐醇啤酒花血小板凝集作用 xanthohumol hop platelet aggregation
日期:	2009
上傳時間:	2009-08-27 17:19:41 (UTC+8)
摘要:	黃腐醇(xanthohumol)是啤酒花(Humulus lupulus)的類黃酮類成分之一，由目前的研究指出xanthohumol有神經鎮定、抗癌、抗氧化、抗菌以及腸胃道反應等藥理作用；而xanthohumol可以有效抑制細胞啟始(initiation)和增生(proliferation)，目前的研究都集中在其抗癌和抗氧化方面的活性，然而xanthohumol在血小板上的藥理學功效尚未明確，因此我們有意探討xanthohumol在血小板活化過程中，對於訊息傳遞方面的抑制作用。研究結果顯示，xanthohumol隨著濃度的增加(0.5-10 ?嵱)，能有效抑制collagen (1 g/ml)、arachidonic acid (60 ?嵱)所引發的血小板凝集反應；xanthohumol (1.5和3 ?嵱)可顯著抑制collagen (1 ?慊/ml)引起的細胞內鈣離子移動和ATP釋放反應。Xanthohumol (1.5和3 ?嵱)會抑制collagen (1 ?慊/ml)誘發的PLC??2蛋白磷酸化反應。Collagen (1 ?慊/ml)和PDBu (150 nM)可以誘發細胞內protein kinase C的活化，並且將47 kDa位置的蛋白磷酸化，實驗發現xanthohumol (1.5和3 ?嵱)只可抑制collagen (1 ?慊/ml)引起的p47 protein的磷酸化，對於PDBu (150 nM)所引起的p47 protein磷酸化則沒有抑制作用。另外xanthohumol (1.5和3 ?嵱)可抑制collagen (1 ?慊/ml)引起的mitogen-activated protein kinases，如p38、ERK與JNK protein的磷酸化以及Akt的蛋白磷酸化。Xanthohumol (1.5和3 ?嵱)可抑制collagen (1 ?慊/ml)所引起的自由基產生。此外，xanthohumol (1.5和3 ?嵱)並不會增加細胞內nitric oxide產生量，也不會透過vasodilator-stimulated phosphoprotein(VASP)磷酸化反應而抑制血小板凝集反應。實驗結果證實，xanthohumol抑制血小板活化的作用可能涉及以下路徑：xanthohumol會抑制PLC??2與protein kinase C的活性及47 kDa protein的磷酸化。Xanthohumol會抑制mitogen-activated protein kinases，如p38、ERK與JNK protein的磷酸化；xanthohumol會抑制Akt的蛋白磷酸化。同時，xanthohumol可有效抑制血小板活化時產生的hydroxyl radical。以上這些結果會導致xanthohumol抑制血小板細胞內鈣離子的移動以及濃度的增加，最後抑制血小板的凝集反應。此研究意味著xanthohumol的研究可應用在治療與血小板過度活化相關之疾病。 Xanthohumol is one of the major constituents of Humulus lupulus. Xanthohumol has been reported to have sedative property, estrogenic activity, cancer-related bioactivities, antioxidant activity, stomachic effect, antibacterial and antifungal effects in recent studies. However, the pharmacological functions of xanthohumol on platelets were not yet understood, we are interested in investigating the inhibitory effects of xanthohumol on cellular signal transduction during the process of platelet activation. In this study, xanthohumol concentration-dependently (0.5-10 ?嵱) inhibited collagen (1 ?慊/ml)- and arachidonic acid (60 ?嵱)-induce platelet aggregation in washed human platelets. In addition, xanthohumol (1.5 and 3 ?嵱) markedly inhibited collagen (1 ?慊/ml)-induce intracellular Ca2+ mobilization and ATP release. Phosphorylation of p47, a marker of protein kinase C activation, was triggered by collagen (1 ?慊/ml) and PDBu (150 nM). In our experiments, xanthohumol (1.5 and 3 ?嵱) significantly inhibited phosphorylation of p47 stimulated by collagen (1 ?慊/ml) but not by PDBu (150nM). In addition, xanthohumol (1.5 and 3 ?嵱) reduced phosphorylation of MAPK and Akt stimulated by collagen (1 ?慊/ml) in human platelets. On the other hand, xanthohumol (1.5 and 3 ?嵱) also inhibited collagen (1 ?慊/ml)-induced hydroxy radicals in human platelets. Neither nitric oxide formation nor vasodilator-stimulated phosphoprotein was induced by xanthohumol in platelets. In conclusion, our study suggested that the possible pathways of anti-platelet activity of xanthohumol may involve in the following：xanthohumol may regulate the PLC??2-PKC pathway and inhibit the MAPK and Akt protein phosphorylation. Xanthohumol may inhibit hydroxyl radicals induced by collagen (1 ?慊/mL). Taken together, xanthohumol regulated these pathways to inhibit the intracellular Ca2+ mobilization and platelet aggregation. Therefore, xanthohumol may be used as an effective tool in treating pathological disorder associated with platelet hyperaggregability.
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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