臺灣博碩士論文加值系統

Caffeic acid phenethyl ester (CAPE)是由蜜蜂收集眾多植物所得的樹酯產物，為蜂膠的主要成分之ㄧ。此ㄧ物質已被證實具有抗癌、抗發炎、免疫調節的特性。然而在血小板上的藥理學功效尚未明確，因此我們有意探討CAPE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，CAPE隨著濃度的增加 (6-25 M)，能有效地抑制collagen (1 g/ml)所引起的人類血小板、人類富含血小板血漿凝集反應以及ATP釋放反應，但不影響由thrombin (0.01 U/ml)、arachidonic acid (60 M)、U46619 (1 M)、ADP (20 M)和epinephrine (10 M)所引起的反應。Collagen所引起血小板凝集反應的劑量反應曲線可以因為CAPE (15-100 M)的加入而有右移的現象，由Schild plot 分析可得pA2為4.28，斜率為0.826。Convulxin是從C. durissus terrificus蛇毒中所純化出來的，是collagen受體GPVI的致效劑 ; 而強力血小板活化物質aggretin是從Calloselasma rhodostoma蛇毒中所純化，可以活化integrin 21。CAPE也可以抑制convulxin (100 ng/ml)和aggretin (3.6 g/ml)所引起的血小板凝集反應。FITC-collagen的螢光量可以因為CAPE (25 M)的加入而減少，意味著CAPE可以可以和collagen競爭受體。在CAPE的存在下，血小板吸附到collagen上會成濃度相關的減少。CAPE (15和25 M)可以抑制由collagen所刺激細胞內鈣離子的流動、phosphoinositide的增加和thromboxane A2的形成，除此之外，CAPE (15和25 M)可以增加nitrate、cyclic GMP和cyclic GMP相關vasodilator-stimulated phosphoprotein (VASP) Ser157的磷酸化。Phorbol-12,13-dibutyrate (150 nM)和collagen (1 g/ml)可以活化血小板protein kinase C活化指標 Mr 47,000 (P47)，CAPE (15和25 M)可以明顯的抑制由這兩個活化劑所引起的磷酸化反應。另外，CAPE (15和25 M)可以減少由collagen (1 g/ml)刺激血小板所導致的ESR訊息和由collagen (10 g/ml)所引起Akt以及MAPKs家族包括ERK2、JNK1和p38 MAPK的磷酸化反應。
由結果證實，CAPE抑制血小板活性的作用可能牽涉下列路徑：(一) CAPE可以抑制collagen相關的血小板反應。(二) CAPE會增加血小板細胞內cyclic GMP的含量，並且誘發VASP磷酸化、抑制protein kinase C的活性以及47 kDa proteins磷酸化反應。綜合以上結果，導致CAPE抑制血小板細胞內鈣離子的移動以及濃度的增加，最後因而抑制血小板的凝集反應。此項作用意味著CAPE可有效地應用在治療與血小板過度活化相關之疾病。

Caffeic acid phenethyl ester (CAPE) is an active component of
propolis, which is a resinous hive product collected by honeybees from various plant sources. It has been shown to exhibit anticancer, anti-inflammatory and immunomodulatory activities in a broad spectrum of systems. However, the pharmacological affects of CAPE on platelet function are not yet understood, we are interested in investigating the inhibitory effects of CAPE on cellular signal transduction during the process of platelet activation. In this study, CAPE concentration-dependently (6-25 M) inhibited collagen (1 g/ml) induced human platelets aggregation, human platelet-rich plasma and ATP-release reaction without affecting those induced by thrombin (0.01 U/ml), AA (60 M), U46619 (1 M), ADP (20M) and epinephrine (10M). The concentration-response curve of collagen induced platelet aggregation was shifted to the right by CAPE (15-100 M) in a concentration dependent manner, the Schild plot showed the pA2 was 4.28, with a slope of -0.826. Convulxin, an agonist of the collagen receptor glycoprotein VI (GPVI), purified from C. durissus terrificus venom and aggretin, a potent platelet activator, was isolated from Calloselasma rhodostoma venom activate platelets by binding to platelet intergrin 21. CAPE also inhibited convulxin (100 ng/ml) and aggretin (3.6 g/ml) induced aggregation. Fluorescence from FITC-collagen was attenuated after incubation with CAPE (25 M), indicating that CAPE can compete receptor with collagen. In the presence of CAPE, adhesion of platelets to collagen was diminished in a dose-dependent manner. CAPE (15 and 25 M) inhibited intracellular Ca2+ mobilization, phosphoinositide breakdown, and thromboxane A2 formation stimulated by collagen (1 g/mL) in human platelets. In addition, CAPE (15 and 25 M) markedly increased levels of nitrate、 cyclic GMP and cyclic GMP-induced vasodilator-stimulated phosphoprotein (VASP), Ser157 phosphorylation. Rapid phosphorylation of a platelet protein of Mr 47, 000 (P47), a marker of protein kinase C activation, was triggered by phorbol-12,13-dibutyrate (150 nM) and collagen (1 g/mL). This phosphorylation was markedly inhibited by CAPE (15 and 25 M). Moreover, CAPE (15 and 25 M) reduced the electron spin resonance (ESR) signal intensity of hydroxyl radicals in collagen (1 g/ml)-activated platelets and MAPKs family phosophorylation including ERK2、JNK1 and p38 MAPK stimulated by collagen (10 g/ml) in human platelets.
In conclusion, our study suggested that the possible pathways of anti-platelet activity of CAPE (15 and 25 M) may involve the following pathway: (1) CAPE blocks collagen-mediated platelet functions such as: adhesion and ATP release reaction. (2) CAPE stimulated nitrate formation, followed by increasing the amount of cyclic GMP and then induced VASP phosphorylation, inhibited protein kinase C activation and 47 kDa protein phosphorylation. (3) CAPE significantly inhibited thromboxane A2 formation through reducing the hydroxyl radicals and phosphorylation of MAPK family to inhibit phospholipase A2-cyclooxygenase pathway, and intracellular Ca2+ mobilization. Taken together, CAPE may be used as an effective tool in treating pathological disorder associated with platelet hyperaggregability.

摘要……………………………………………….1
縮寫……………………………………………….6
一. 緒論………………….……………………….9
蜂膠……………………………………………………...9
CAPE….…………………………………....…...……... 11
血小板………………………………………………… .12
二. 實驗材料與方法……………………...…….33
(1)實驗材料……………………………….…………….33
(2)實驗方法……………………………………………..38
三. 結果……………………………………….52
四. 討論…………………………………………62
五. 結論………………………………………....72
六. 參考文獻……………………………………73
表……………………………………………….112
圖……………………………………………….116

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