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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 黃德富(Tur-Fu Huang) | |
dc.contributor.author | Yu-Ta Cheng | en |
dc.contributor.author | 鄭又達 | zh_TW |
dc.date.accessioned | 2021-06-13T15:19:02Z | - |
dc.date.available | 2011-08-14 | |
dc.date.copyright | 2008-08-14 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-07-24 | |
dc.identifier.citation | Barnes, M. J. (1985). 'Collagens in atherosclerosis.' Coll Relat Res 5(1): 65-97.
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(1998). 'Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not.' Blood 91(2): 491-9. Kimura, Y., T. Tani, Kanbe, T., Watanabe, K. (1985). 'Effect of cilostazol on platelet aggregation and experimental thrombosis.' Arzneimittelforschung 35(7A): 1144-9. Kornecki, E., Y. H. Ehrlich, De Mars, D. D., Lenox, R. H. (1986). 'Exposure of fibrinogen receptors in human platelets by surface proteolysis with elastase.' J Clin Invest 77(3): 750-6. Li, G., Y. J. Kim, Mantel, C., Broxmeyer, H. E. (2003). 'P-selectin enhances generation of CD14+CD16+ dendritic-like cells and inhibits macrophage maturation from human peripheral blood monocytes.' J Immunol 171(2): 669-77. Martin, E., Y. C. Lee, Murad, F. (2001). 'YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components.' Proc Natl Acad Sci U S A 98(23): 12938-42. Maurice, D. H. and R. J. Haslam (1990). 'Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP.' Mol Pharmacol 37(5): 671-81. Maurice, D. H., D. Palmer, Tilley, D. G., Dunkerley, H. A., Netherton, S. J., Raymond, D. R., Elbatarny, H. S., Jimmo, S. L. (2003). 'Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system.' Mol Pharmacol 64(3): 533-46. Merten, M. and P. Thiagarajan (2004). 'P-selectin in arterial thrombosis.' Z Kardiol 93(11): 855-63. Nicholson, C. D., R. A. Challiss, Shahid, M. (1991). 'Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes.' Trends Pharmacol Sci 12(1): 19-27. Omori, K. and J. Kotera (2007). 'Overview of PDEs and their regulation.' Circ Res 100(3): 309-27. Pollock, W. K. and T. J. Rink (1986). 'Thrombin and ionomycin can raise platelet cytosolic Ca2+ to micromolar levels by discharge of internal Ca2+ stores: studies using fura-2.' Biochem Biophys Res Commun 139(1): 308-14. Rauterberg, J., E. Jaeger, Althaus, M. (1993). 'Collagens in atherosclerotic vessel wall lesions.' Curr Top Pathol 87: 163-92. Sixma, J. J. and J. Wester (1977). 'The hemostatic plug.' Semin Hematol 14(3): 265-99. Stasch, J. P., E. M. Becker, Alonso-Alija, C., Apeler, H., Dembowsky, K., Feurer, A., Gerzer, R., Minuth, T., Perzborn, E., Pleiss, U., Schroder, H., Schroeder, W., Stahl, E., Steinke, W., Straub, A., Schramm, M.(2001). 'NO-independent regulatory site on soluble guanylate cyclase.' Nature 410(6825): 212-5. Stasch, J. P., P. Schmidt, Alonso-Alija, C., Apeler, H., Dembowsky, K., Haerter, M., Heil, M., Minuth, T., Perzborn, E., Pleiss, U., Schramm, M., Schroeder, W., Schroder, H., Stahl, E., Steinke, W.,Wunder, F. (2002). 'NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle.' Br J Pharmacol 136(5): 773-83. Straub, A., J. P. Stasch, Alonso-Alija, C., Benet-Buchholz, J., Ducke, B., Feurer, A., Furstner, C. (2001). 'NO-independent stimulators of soluble guanylate cyclase.' Bioorg Med Chem Lett 11(6): 781-4. Varga-Szabo, D., I. Pleines, Nieswandt, B. (2008). 'Cell adhesion mechanisms in platelets.' Arterioscler Thromb Vasc Biol 28(3): 403-12. Wu, C. C., F. N. Ko, Kuo, S. C., Lee, F. Y., Teng, C. M. (1995). 'YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase.' Br J Pharmacol 116(3): 1973-8. Wu, C. C., F. N. Ko, Teng, C. M. (1997). 'Inhibition of platelet adhesion to collagen by cGMP-elevating agents.' Biochem Biophys Res Commun 231(2): 412-6. Zhao, Y., P. E. Brandish, DiValentin, M., Schelvis, J. P., Babcock, G. T., Marletta, M. A. (2000). 'Inhibition of soluble guanylate cyclase by ODQ.' Biochemistry 39(35): 10848-54. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37090 | - |
dc.description.abstract | 本篇論文主要探討化合物p95wu33a 抑制人類血小板凝集的作用
機轉。在人類血小板懸浮液中,p95wu33a 呈濃度相關性的抑制由 collagen ( 10μg/ml ), AA ( 200μM ), U46619 ( 1μM ) 和thrombin(0.1U/ml) 引起的血小板凝集,其IC50 分別為0.23±0.02, 0.41±0.05,13.38±0.28 and 285.12±3.39 μM。p95wu33a 也會抑制由collagen 引起的P-selectin 表現量及thomboxane B2 生成,對於蛋白質tyrosine phosphorylation 訊息傳遞方面,在PLCγ2、PI3K、Syk、Src、LAT 這些位置都有抑制磷酸化的情形。Fibrinogen 結合到活化的醣蛋白受體GPIIb-IIIa 是血小板凝集的最終反應路徑。然而p95wu33a 並不影響fibrinogen 結合到活化態的GPIIb-IIIa。除此之外,p95wu33a 能夠顯著的加強sodium nitroprusside ( SNP )的抑制血小板凝集能力。同時也證 實了p95wu33a 能獨自顯著提升血小板內的cGMP 含量,同時加強SNP 提升胞內cGMP 的能力。在ODQ 的存在下,p95wu33a 對collagen 引 起的血小板凝集抑制作用有加強的現象。p95wu33a 能抑制由AA 和 collagen 引起的thromboxan B2 生成,對cPLA2 活性沒有直接的影響。顯示其作用非來自對內生性c P L A 2 的活性抑制, 但有可能對arachidonate-thromboxane A2 生合成路徑上的enzyme 有抑制的能力。在血小板內鈣離子濃度變化的實驗中,我們發現p95wu33a 呈濃度相關性抑制collagen 引起的Ca2+ mobilization。除此之外,在血小板附著實驗中,p95wu33a 也能以濃度相關性的抑制血小板附著到collagen 上。在動物實驗中,p95wu33a 在以10μg/g 尾靜脈注射時,能顯著的降低ICR小鼠的血小板凝集能力。此外在相同劑量下, 對於尾巴出血程度只有些微增加。综合上述結果,p95wu33a 這種具有PDE5 抑制劑和sGC 活化劑之化合物可做為抗血栓藥物之優勢化設計和研發。 | zh_TW |
dc.description.abstract | In the present study, the mechanism of antiplatelet activity of p95wu33a, a synthetic 1-( 5-methyl-2furyl )-3-phenyl-2-propen-1-one, was investigated. p95wu33a concentration-dependently inhibited platelet aggregation stimulated by collagen ( 10μg/ml ), AA ( 200μM ), U46619( 1μM ) and thrombin (0.1U/ml) with IC50 values of 0.23±0.02, 0.41±0.05,13.38±0.28 and 285.12±3.39 μM in washed human platelets, respectively. p95wu33a also inhibited collagen-induced P-selectin expression and thromboxane B2 formation. In addition, p95wu33a attenuated tyrosine phosphorylation of a number of signal proteins including PLCγ2、PI3K、Syk、Src、and LAT. Fibrinogen binding to activated glycoprotein GPIIb-IIIa
is the final common pathway of platelet aggregation. However, p95wu33a did not affect fibrinogen binding to activated GPIIb-IIIa. This suggests that the inhibitory effect of p95wu33a is not through acting as a direct antagonist of GPIIb-IIIa. Sodium nitroprusside (SNP) markedly potentiated the platelet-inhibitory effect of p95wu33a. It was demonstrated that p95wu33a itself markedly increased guanosine 3’,5’-cyclic monophosphate (cGMP) level and Sodium nitroprusside potentiated the elevated cGMP by p95wu33a. The inhibitory effect of p95wu33a on collagen-induced platelet aggregation and cGMP content was markly enhanced in the presence of ODQ, an inhibitor of sGC. p95wu33a inhibited the biosynthesis of thromboxan B2 induced by arachidonic acid and collagen. However, it had no inhibitory on cytosolic phospholipase A2, suggesting that it dose not affect the endogenous cPLA2 activity, but impairs arachidonate - thromboxane A2 biosynthesis pathway. In Fura-2 loaded platelets, p95wu33a inhibited intracellular calcium mobilization triggered by collagen. Similar to other nucleotide-elevating agent, p95wu33a dose-dependently inhibited platelet adhesion to collagen. p95wu33a significantly reduced the ex vivo platelet aggregation of PRP in ICR mice, as it was intravenously administered at a dose of 10μg/g, whereas p95wu33a at the same dose cause a slight prolongation of tailing bleeding time. In conclusion, the promising antithrombotic profile of p95wu33a, PDE5 inhibitor and sGC activator, suggests that it is an attractive lead compound for developing antiplatelet agents. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T15:19:02Z (GMT). No. of bitstreams: 1 ntu-97-R95443011-1.pdf: 1952267 bytes, checksum: df8937cdda4ed5f5a9ec4accb62a5620 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 縮寫表....................................................................................................... ii
中文摘要.................................................................................................. iv Abstract.................................................................................................... vii 第一章 緒論.............................................................................................. 1 前言.................................................................................................... 1 第一節 血小板與血管壁的交互作用................................................ 1 第二節 PDE 抑制劑........................................................................... 3 第三節 NO-sGC-cGMP pathway ....................................................... 4 第四節 p95wu33a- YC-1 衍生物....................................................... 6 第二章 研究材料與方法........................................................................ 11 第一節 材料與動物......................................................................... 11 第二節 實驗方法............................................................................. 12 第三章 實驗結果.................................................................................... 22 第四章 討論............................................................................................ 51 第五章 結論與未來展望........................................................................ 59 參考文獻................................................................................................. 61 | |
dc.language.iso | zh-TW | |
dc.title | 1-(5-Methyl-2-furyl)-3-phenyl-2-propen-1-one
抑制血小板凝集作用機轉之探討 | zh_TW |
dc.title | Antiplatelet mechanism of p95wu33a, a synthetic
1-(5-methyl-2-furyl)-3-phenyl-2-propen-1-one | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 鄧哲明(Che-Ming Teng),顏茂雄(Mao-Hsiung Yen),楊春茂(Chuen-Mao Yang) | |
dc.subject.keyword | 抗血小板藥物,PDE5抑制劑,sGC活化劑,ODQ,BAY41-2272, | zh_TW |
dc.subject.keyword | antiplatelet drug,PDE5 inhibitor,sGC activator,ODQ,BAY41-2272, | en |
dc.relation.page | 64 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-07-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
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