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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃德富(Tur-Fu Huang) | |
| dc.contributor.author | Chia-Hao Lin | en |
| dc.contributor.author | 林家豪 | zh_TW |
| dc.date.accessioned | 2021-06-07T23:59:07Z | - |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-16 | |
| dc.identifier.citation | Banno, A. and M. H. Ginsberg (2008). 'Integrin activation.' Biochem Soc Trans 36(Pt 2):
229-234. Bergmeier, W. and L. Stefanini (2009). 'Novel molecules in calcium signaling in platelets.' J Thromb Haemost 7 Suppl 1: 187-190. Bhatt, D. L. and E. J. Topol (2003). 'Scientific and therapeutic advances in antiplatelet therapy.' Nat Rev Drug Discov 2(1): 15-28. Bugaud, F., F. Nadal-Wollbold, S. Levy-Toledano, J. P. Rosa and M. Bryckaert (1999). 'Regulation of c-jun-NH2 terminal kinase and extracellular-signal regulated kinase in human platelets.' Blood 94(11): 3800-3805. Cantley, L. C. (2002). 'The phosphoinositide 3-kinase pathway.' Science 296(5573): 1655-1657. Chari, R., T. Getz, B. Nagy, Jr., K. Bhavaraju, Y. Mao, Y. S. Bynagari, S. Murugappan, K. Nakayama and S. P. Kunapuli (2009). 'Protein kinase C[delta] differentially regulates platelet functional responses.' Arterioscler Thromb Vasc Biol 29(5): 699-705. Chrzanowska-Wodnicka, M., S. S. Smyth, S. M. Schoenwaelder, T. H. Fischer and G. C. White, 2nd (2005). 'Rap1b is required for normal platelet function and hemostasis in mice.' J Clin Invest 115(3): 680-687. Chung, C. H., H. C. Peng and T. F. Huang (2001). 'Aggretin, a C-type lectin protein, induces platelet aggregation via integrin alpha(2)beta(1) and GPIb in a phosphatidylinositol 3-kinase independent pathway.' Biochem Biophys Res Commun 285(3): 689-695 79 Clemetson, K. J. and J. M. Clemetson (2001). 'Platelet collagen receptors.' Thromb Haemost 86(1): 189-197. Coughlin, S. R. (1999). 'How the protease thrombin talks to cells.' Proc Natl Acad Sci U S A 96(20): 11023-11027. Coughlin, S. R. (2000). 'Thrombin signalling and protease-activated receptors.' Nature 407(6801): 258-264. Crittenden, J. R., W. Bergmeier, Y. Zhang, C. L. Piffath, Y. Liang, D. D. Wagner, D. E. Housman and A. M. Graybiel (2004). 'CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation.' Nat Med 10(9): 982-986. Djellas, Y., J. M. Manganello, K. Antonakis and G. C. Le Breton (1999). 'Identification of Galpha13 as one of the G-proteins that couple to human platelet thromboxane A2 receptors.' J Biol Chem 274(20): 14325-14330. Elvers, M., D. Stegner, I. Hagedorn, C. Kleinschnitz, A. Braun, M. E. Kuijpers, M. Boesl, Q. Chen, J. W. Heemskerk, G. Stoll, M. A. Frohman and B. Nieswandt (2010). 'Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1.' Sci Signal 3(103): ra1. Fields, A. P. and W. C. Gustafson (2003). 'Protein kinase C in disease: cancer.' Methods Mol Biol 233: 519-537. Flevaris, P., Z. Li, G. Zhang, Y. Zheng, J. Liu and X. Du (2009). 'Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway.' Blood 113(4): 893-901. Fox, J. E., L. P. Aggerbeck and M. C. Berndt (1988). 'Structure of the glycoprotein Ib.IX complex from platelet membranes.' J Biol Chem 263(10): 4882-4890. 80 Garcia, A., H. Shankar, S. Murugappan, S. Kim and S. P. Kunapuli (2007). 'Regulation and functional consequences of ADP receptor-mediated ERK2 activation in platelets.' Biochem J 404(2): 299-308. Gong, H., B. Shen, P. Flevaris, C. Chow, S. C. Lam, T. A. Voyno-Yasenetskaya, T. Kozasa and X. Du (2010). 'G protein subunit Galpha13 binds to integrin alphaIIbbeta3 and mediates integrin 'outside-in' signaling.' Science 327(5963): 340-343. Hassock, S. R., M. X. Zhu, C. Trost, V. Flockerzi and K. S. Authi (2002). 'Expression and role of TRPC proteins in human platelets: evidence that TRPC6 forms the store-independent calcium entry channel.' Blood 100(8): 2801-2811. Hassock, S. R., M. X. Zhu, C. Trost, V. Flockerzi and K. S. Authi (2006). 'Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3.' Curr Biol 16(18): 1796-1806. Henn, V., J. R. Slupsky, M. Grafe, I. Anagnostopoulos, R. Forster, G. Muller-Berghaus and R. A. Kroczek (1998). 'CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.' Nature 391(6667): 591-594. Hitchcock, I. S., N. E. Fox, N. Prevost, K. Sear, S. J. Shattil and K. Kaushansky (2008). 'Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function: studies using a megakaryocyte lineage specific FAK knockout.' Blood 111(2): 596-604. Hofmann, T., A. G. Obukhov, M. Schaefer, C. Harteneck, T. Gudermann and G. Schultz (1999). 'Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.' Nature 397(6716): 259-263. Huang, J. S., S. K. Ramamurthy, X. Lin and G. C. Le Breton (2004). 'Cell signalling through thromboxane A2 receptors.' Cell Signal 16(5): 521-533. 81 Huang, S. K. and M. Peters-Golden (2008). 'Eicosanoid lipid mediators in fibrotic lung diseases: ready for prime time?' Chest 133(6): 1442-1450. Hughes, P. E. and M. Pfaff (1998). 'Integrin affinity modulation.' Trends Cell Biol 8(9): 359-364. Italiano, J. E., Jr., J. L. Richardson, S. Patel-Hett, E. Battinelli, A. Zaslavsky, S. Short, S. Ryeom, J. Folkman and G. L. Klement (2008). 'Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released.' Blood 111(3): 1227-1233. Jin, Y. R., K. A. Hwang, M. R. Cho, S. Y. Kim, J. H. Kim, C. K. Ryu, D. J. Son, Y. H. Park and Y. P. Yun (2004). 'Antiplatelet and antithrombotic activities of CP201, a newly synthesized 1,4-naphthoquinone derivative.' Vascul Pharmacol 41(1): 35-41. Klages, B., U. Brandt, M. I. Simon, G. Schultz and S. Offermanns (1999). 'Activation of G12/G13 results in shape change and Rho/Rho-kinase-mediated myosin light chain phosphorylation in mouse platelets.' J Cell Biol 144(4): 745-754. Knezevic, I., C. Borg and G. C. Le Breton (1993). 'Identification of Gq as one of the G-proteins which copurify with human platelet thromboxane A2/prostaglandin H2 receptors.' J Biol Chem 268(34): 26011-26017. Kozasa, T., X. Jiang, M. J. Hart, P. M. Sternweis, W. D. Singer, A. G. Gilman, G. Bollag and P. C. Sternweis (1998). 'p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13.' Science 280(5372): 2109-2111. Kramer, R. M., E. F. Roberts, B. A. Strifler and E. M. Johnstone (1995). 'Thrombin induces activation of p38 MAP kinase in human platelets.' J Biol Chem 270(46): 27395-27398. 82 Kuo, H. L., J. C. Lien, C. H. Chang, C. H. Chung, S. C. Kuo, C. C. Hsu, H. C. Peng and T. F. Huang (2011). 'NP-313, 2-acetylamino-3-chloro-1,4-naphthoquinone, a novel antithrombotic agent with dual inhibition of thromboxane A(2) synthesis and calcium entry.' Br J Pharmacol 162(8): 1871-1883. Labelle, M., S. Begum and R. O. Hynes (2011). 'Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis.' Cancer Cell 20(5): 576-590. Lafuente, E. M. (2004). 'RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion.' Dev Cell 7(4): 585-595. Leisner, T. M. (2007). 'Tickling the tails: cytoplasmic domain proteins that regulate integrin alphaIIbbeta3 activation.' Curr Opin Hematol 14(3): 255-261. Leslie, M. (2010). 'Cell biology. Beyond clotting: the powers of platelets.' Science 328(5978): 562-564. Li, Z., M. K. Delaney, K. A. O'Brien and X. Du (2006). 'Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3.' Blood 107(3): 965-972. Li, Z., M. K. Delaney, K. A. O'Brien and X. Du (2010). 'Signaling during platelet adhesion and activation.' Arterioscler Thromb Vasc Biol 30(12): 2341-2349. Lian, L., Y. Wang, M. Flick, J. Choi, E. W. Scott, J. Degen, M. A. Lemmon and C. S. Abrams (2009). 'Loss of pleckstrin defines a novel pathway for PKC-mediated exocytosis.' Blood 113(15): 3577-3584. Lova, P., S. Paganini, E. Hirsch, L. Barberis, M. Wymann, F. Sinigaglia, C. Balduini and M. Torti (2003). 'A selective role for phosphatidylinositol 3,4,5-trisphosphate in the 83 Gi-dependent activation of platelet Rap1B.' J Biol Chem 278(1): 131-138. Ma, Y. Q., J. Qin, C. Wu and E. F. Plow (2008). 'Kindlin-2 (Mig-2): a co-activator of beta3 integrins.' J Cell Biol 181(3): 439-446. Merten, M. and P. Thiagarajan (2000). 'P-selectin expression on platelets determines size and stability of platelet aggregates.' Circulation 102(16): 1931-1936. Michelson, A. D. (2010). 'Antiplatelet therapies for the treatment of cardiovascular disease.' Nat Rev Drug Discov 9(2): 154-169. Mustard, J. F., D. W. Perry, N. G. Ardlie and M. A. Packham (1972). 'Preparation of suspensions of washed platelets from humans.' Br J Haematol 22(2): 193-204. Murphy, J. W., M. R. Hidore and N. Nabavi (2003). 'G13 is an essential mediator of platelet activation in hemostasis and thrombosis.' Nat Med 9(11): 1418-1422. Murugappan, S., F. Tuluc, R. T. Dorsam, H. Shankar and S. P. Kunapuli (2004). 'Differential role of protein kinase C delta isoform in agonist-induced dense granule secretion in human platelets.' J Biol Chem 279(4): 2360-2367. Nagy, B., Jr., K. Bhavaraju, T. Getz, Y. S. Bynagari, S. Kim and S. P. Kunapuli (2009). 'Impaired activation of platelets lacking protein kinase C-theta isoform.' Blood 113(11): 2557-2567. Nieswandt, B., I. Pleines and M. Bender (2011). 'Platelet adhesion and activation mechanisms in arterial thrombosis and ischaemic stroke.' J Thromb Haemost 9 Suppl 1: 92-104. Nurden, A. T., P. Nurden, M. Sanchez, I. Andia and E. Anitua (2008). 'Platelets and wound healing.' Front Biosci 13: 3532-3548. Offermanns, S., C. F. Toombs, Y. H. Hu and M. I. Simon (1997). 'Defective platelet 84 activation in G alpha(q)-deficient mice.' Nature 389(6647): 183-186. Offermanns, S., C. F. Toombs, Y. H. Hu and M. I. Simon (2006). 'Activation of platelet function through G protein-coupled receptors.' Circ Res 99(12): 1293-1304. Ohlmann, P., K. L. Laugwitz, B. Nurnberg, K. Spicher, G. Schultz, J. P. Cazenave and C. Gachet (1995). 'The human platelet ADP receptor activates Gi2 proteins.' Biochem J 312 ( Pt 3): 775-779. Okada, T., S. Shimizu, M. Wakamori, A. Maeda, T. Kurosaki, N. Takada, K. Imoto and Y. Mori (1998). 'Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain.' J Biol Chem 273(17): 10279-10287. Parekh, A. B. (2010). 'Store-operated CRAC channels: function in health and disease.' Nat Rev Drug Discov 9(5): 399-410. Paul, B. Z., J. Jin and S. P. Kunapuli (1999). 'Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors.' J Biol Chem 274(41): 29108-29114. Pratico, D. (2008). 'Prostanoid and isoprostanoid pathways in atherogenesis.' Atherosclerosis 201(1): 8-16. Putney, J. W., Jr., L. M. Broad, F. J. Braun, J. P. Lievremont and G. S. Bird (2001). 'Mechanisms of capacitative calcium entry.' J Cell Sci 114(Pt 12): 2223-2229. Quek, L. S., J. M. Pasquet, I. Hers, R. Cornall, G. Knight, M. Barnes, M. L. Hibbs, A. R. Dunn, C. A. Lowell and S. P. Watson (2000). 'Fyn and Lyn phosphorylate the Fc receptor gamma chain downstream of glycoprotein VI in murine platelets, and Lyn regulates a novel feedback pathway.' Blood 96(13): 4246-4253. 85 Rhee, S. G. (2001). 'Regulation of phosphoinositide-specific phospholipase C.' Annu Rev Biochem 70: 281-312. Rosse, C., M. Linch, S. Kermorgant, A. J. Cameron, K. Boeckeler and P. J. Parker (2010). 'PKC and the control of localized signal dynamics.' Nat Rev Mol Cell Biol 11(2): 103-112. Saklatvala, J., L. Rawlinson, R. J. Waller, S. Sarsfield, J. C. Lee, L. F. Morton, M. J. Barnes and R. W. Farndale (1996). 'Role for p38 mitogen-activated protein kinase in platelet aggregation caused by collagen or a thromboxane analogue.' J Biol Chem 271(12): 6586-6589. Savage, B., F. Almus-Jacobs and Z. M. Ruggeri (1998). 'Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow.' Cell 94(5): 657-666. Smrcka, A. V. (2008). 'G protein betagamma subunits: central mediators of G protein-coupled receptor signaling.' Cell Mol Life Sci 65(14): 2191-2214. Steg, P. G., D. L. Bhatt, P. W. Wilson, R. D'Agostino, Sr., E. M. Ohman, J. Rother, C. S. Liau, A. T. Hirsch, J. L. Mas, Y. Ikeda, M. J. Pencina, S. Goto and R. R. Investigators (2007). 'One-year cardiovascular event rates in outpatients with atherothrombosis.' JAMA 297(11): 1197-1206. Steg, P. G., S. H. Dorman and P. Amarenco (2011). 'Atherothrombosis and the role of antiplatelet therapy.' J Thromb Haemost 9 Suppl 1: 325-332. Stenberg, P. E., R. P. McEver, M. A. Shuman, Y. V. Jacques and D. F. Bainton (1985). 'A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation.' J Cell Biol 101(3): 880-886. 86 Stephens, L. R., A. Eguinoa, H. Erdjument-Bromage, M. Lui, F. Cooke, J. Coadwell, A. S. Smrcka, M. Thelen, K. Cadwallader, P. Tempst and P. T. Hawkins (1997). 'The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101.' Cell 89(1): 105-114. Tandon, V. K., D. B. Yadav, R. V. Singh, M. Vaish, A. K. Chaturvedi and P. K. Shukla (2005). 'Synthesis and biological evaluation of novel 1,4-naphthoquinone derivatives as antibacterial and antiviral agents.' Bioorg Med Chem Lett 15(14): 3463-3466. Taylor, S. J., H. Z. Chae, S. G. Rhee and J. H. Exton (1991). 'Activation of the beta 1 isozyme of phospholipase C by alpha subunits of the Gq class of G proteins.' Nature 350(6318): 516-518. Tsuji, M., Y. Ezumi, M. Arai and H. Takayama (1997). 'A novel association of Fc receptor gamma-chain with glycoprotein VI and their co-expression as a collagen receptor in human platelets.' J Biol Chem 272(38): 23528-23531. Verma, R. P. (2006). 'Anti-cancer activities of 1,4-naphthoquinones: a QSAR study.' Anticancer Agents Med Chem 6(5): 489-499. Vinogradova, O., A. Velyvis, A. Velyviene, B. Hu, T. Haas, E. Plow and J. Qin (2002). 'A structural mechanism of integrin alpha(IIb)beta(3) 'inside-out' activation as regulated by its cytoplasmic face.' Cell 110(5): 587-597. Vu, T. K., D. T. Hung, V. I. Wheaton and S. R. Coughlin (1991). 'Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation.' Cell 64(6): 1057-1068. 87 Ware, J. A., M. Saitoh, M. Smith, P. C. Johnson and E. W. Salzman (1989). 'Response of aequorin-loaded platelets to activators of protein kinase C.' Am J Physiol 256(1 Pt 1): C35-43. White, J. G. (2004). 'Electron microscopy methods for studying platelet structure and function.' Methods Mol Biol 272: 47-63. Wu, Y., K. Suzuki-Inoue, K. Satoh, N. Asazuma, Y. Yatomi, M. C. Berndt and Y. Ozaki (2001). 'Role of Fc receptor gamma-chain in platelet glycoprotein Ib-mediated signaling.' Blood 97(12): 3836-3845. Xiang, B., G. Zhang, J. Liu, A. J. Morris, S. S. Smyth, T. K. Gartner and Z. Li (2010). 'A G(i) -independent mechanism mediating Akt phosphorylation in platelets.' J Thromb Haemost 8(9): 2032-2041. Ye, F., G. Hu, D. Taylor, B. Ratnikov, A. A. Bobkov, M. A. McLean, S. G. Sligar, K. A. Taylor and M. H. Ginsberg (2010). 'Recreation of the terminal events in physiological integrin activation.' J Cell Biol 188(1): 157-173. Zhang, Y. H., K. H. Chung, C. K. Ryu, Y. H. Lee, T. J. Kim, Y. S. Song, K. A. Hwang and Y. P. Yun (2001). 'Antiplatelet mechanism of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent.' Pharmacol Toxicol 88(4): 181-186. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17163 | - |
| dc.description.abstract | 動脈粥狀硬化栓塞(Atherothrombosis)是一種血管系統慢性發展之疾病，在臨床上
其表現不明顯，也不容易被發現，然而當其發展到一定的複雜程度時，會變成有 危害生命危險的疾病如急性冠狀動脈疾病，中風和暫時性腦缺血發作。其中不正 常的血小板活化是形成栓塞的重要原因之一。在經過一系列化合物NP-313 衍生 物的篩選，在人類血小板懸浮液( washed human platelet suspension )，我們發現化 合物PPA45 呈現濃度相關性抑制由U46619；collagen；arachidonic acid；thrombin 和thapsigargin 所引發之血小板凝集，其IC50 分別為1.37 ± 0.13，1.72 ± 0.11， 1.59 ± 0.16，3.21 ± 0.37 和21.41 ± 1.93 μM，PPA45 也呈濃度相關性抑制由上述 活化劑所誘導人類血小板之P-selectin 表現。雖然PPA45 會抑制collagen 刺激人 類血小板TXA2 的產生，但卻不會影響由thrombin 和arachidonic acid 刺激所產生 之TXA2。在鈣離子的訊息傳遞方面，PPA45 可以抑制collagen 和thrombin 所刺 激人類血小板而引發的鈣離子的濃度上升的作用，但卻不影響thapsigargin 所引起的游離鈣離子之濃度。在EGTA 存在下，我們也發現PPA45 不會影響collagen和thrombin 刺激而導致血小板內儲存鈣離子之釋放，然而PPA45 可以抑制由PMA 和OAG 所導致的人類血小板凝集，和抑制OAG 刺激所增加的人類血小板鈣離子濃度作用。這些結果顯現PPA45 可能透過DAG 路徑的訊息分子如PKC來抑制血小板的凝集，而藉由和SOCC 不相關的鈣離子通道如TRPC6 來抑制鈣離子的入流。至於PPA45 在訊息傳遞方面的作用，PPA45 會抑制collagen 所導 致的FAK，Akt，PKC，Fyn，Syk，PLCγ2，p38 和ERK 訊息分子活化，但是卻不影響c-Src 和JNK 活化情形。此外，PPA45 也會抑制thrombin 刺激的FAK, Fyn, p38 and ERK 的磷酸化表現情況，但一樣不影響c-Src 和JNK 的磷酸化表現。然而PPA45 在動物體內試驗卻沒有表現明顯的抗血栓活性，這可能與PPA45 在體內的藥效學和藥物動力學有關。綜之，我們證明PPA45 可透過抑制PKC 和多種kinases 所引起的訊息傳遞作用，而抑制血小板凝集的作用，若經過適當的結 構修飾將可成為潛力抗血小板的化合物。 | zh_TW |
| dc.description.abstract | Atherothrombosis is a progressive chronic disease in vascular system, and is always
clinically silent, whereas it becomes complicated by thrombous formation causing life-threatening events including acute coronary syndrome, stroke, and transient ischaemic attack. The abnormality of platelet activation has a crucial role in thrombosis. After screening several derivatives of NP-313, PPA45 displays the inhibitory effect on U46619-, collagen-, arachidonic acid-, thrombin- and thapsigargin-induced platelet aggregation in a concentraction-dependent manner, with the IC50 values : 1.37 ± 0.13, 1.72 ± 0.11, 1.59 ± 0.16, 3.21 ± 0.37, and 21.41 ± 1.93 μM, respectively. PP45 concentration-dependently inhibited P-selectin expression of platelet activated by these agonists. PPA45 inhibited the formation of TXA2 induced by collagen, but not by thrombin and arachidonic acid. Regarding Ca+2 signaling,PPA45 inhibited Ca+2 mobilization caused by collagen and thrombin, but not that by thapsigargin. We also found that PPA45 did not influence collagen- and thrombin-induced Ca+2 release from internal stores of platelets in the presence of EGTA. However, PPA45 shows inhibitory effect on PMA- and OAG-induced platelet aggregation, and OAG-induced Ca+2 mobilization. This implies that PPA45 inhibited platelet aggregation via downstream target of diacylglycerol ( DAG ) like PKC and affected Ca+2 mobilization through a SOCC-independent channel, TRPC6. Regarding the signaling molecules involved in its mechanism of action, PPA45 inhibited activation of FAK, Akt, PKCα, Fyn, Syk, PLCγ2, p38 and ERK but not c-Src and JNK by collagen. Similarly, PPA45 also inhibited thrombin-induced p-FAK, p-Fyn, p38 and p-ERK expression, except p-JNK and p-c-Src. However, PPA45 does not exhibit marked effect ex vivo and in vivo, and this may be caused by pharmcodynamics and pharmocokinetic factors. In addition, we demonstrated that PPA45 possesses inhibitory effect on the signaling target PKC and the upstream molecules such as Fyn, Syk, MAPKs and PLCγ2, leading to inhibition of platelet aggregation.Taken together, PPA45 has potential as an antithrombotic agent under further optimization of its structure through structure-activity relationship study. | en |
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| dc.description.tableofcontents | 中文摘要.........................................................................................................................i
Abstract........................................................................................................................iii Abbreviation table..........................................................................................................v Chapter 1 Introduction...................................................................................................1 1.1 Characterization and role of platelets..................................................1 1.2 The mechanism of platelet activation, thrombous formation and hemostasis..............................................................................................1 1.3 Atherothrombosis and antiplatelet agents.........................................2 1.4 Adhesion receptor-mediated platelet activation and signaling transduction.............................................................................................3 1.4.1 GPVI/collagen-mediated platelet activation...................................3 1.4.2 GPIb-IX/von Willebrand Factor-mediated platelet activation.......4 1.4.3 Integrin-mediated platelet activation..............................................5 1.5 Thrombin signaling and protease-activated receptors..............................7 1.6 G-protein-coupled receptors ( GPCR )-mediated platelet activation and signaling transduction............................................................................8 1.7 Calcium signaling in platelets activation.........................................10 1.8 The role of protein kinase C in platelet activation........................11 1.9 The involvement of MAPKs in platelet activation..................12 1.10 Prostanoids formation and its function in platelets.............................12 1.11 The mechanisms and limitations of current antiplatelet treatments.....13 1.12 Background of PPA45 .......................................................................14 1.13 Aim of the research..............................................................................15 Chapter 2 Materials and methods.................................................................................28 2.1 Reagents and Animals.......................................................................28 2.2 Preparation of washed human platelets and platelet-rich plasma..29 2.3 Measurements of platelet aggregation................................................30 2.4 LDH assay.................................................................................30 2.5 Flow cytometric analysis of P-selectin expression.............31 2.6 Measurement of thromboxane B2 ( TXB2 ) formation.................31 2.7 Measurement of intracellular Ca+2 mobilization...........................31 2.8 Western blotting..................................................................32 2.9 In vit r o mous e pl a t e l e t a ggr e ga t ion . . . . . . . . . . . . . . . . . . . . . . ...33 2.10 Ex vivo mouse platelet aggregation....................................................33 2.11 Pulmonary embolism..........................................................................33 2.12 Tail bleeding time in mice.................................................................34 2.13 Statistic analysis...............................................................................34 Chapter 3 Results.........................................................................................................35 3.1 PPA45 was selected f rom NP313 der ivat ives. . . .............35 3.2 Effect of PPA45 on the platelet aggregat ion . . . . . . . . . . . . . . . . .36 3.3 Effect of PPA45 on platelet LDH release . . . . . . . . . . . . . . . . . . . .36 3.4 Effect of PPA45 on U46619-, col lagen-, arachidonic acidan d t hr ombin - i ndu c ed pl a t e l e t α - gr a nul e s e c r e t ion . . . 37 3 . 5 Ef f e c t o f PPA4 5 o n c o l l a ge n - , a r a c h i d o n i c a c i d - a n d thrombin-induce TXB2 formation in platelets....................37 3.6 Ef f e c t o f PPA4 5 o n PMA- a n d OAG- i n d u c e d p l a t e l e t aggregation................................................................................38 3.7 Effect of PPA45 on collagen-, thrombin-, and thapsigargin-induced intracellular Ca+2 mobilization...........................................................39 3.8 Effect of PPA45 on OAG-induced intracellular Ca+2 mobilization....39 3.9 Effect of PPA45 on collagen mediated platelet activation signaling t ransduct ion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 0 3.10 Effect of PPA45 on thrombin mediated platelet activation signaling t ransduct ion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............41 3.11 Effect of PPA45 on in vitro platelet aggregation of mouse PRP...41 3.12 Effect of PPA45 on ex vivo platelet aggregation of mouse PRP...41 3.13 Effect of PPA45 on pulmonary thromboembolism......................42 3.14 Effect of PPA45 on bleeding time and platelet counts in mouse model................................................ ......................................42 Chapter 4 Discussion....................................................................................................67 Chapter 5 Conclusion and perspective.........................................................................74 References....................................................................................................................78 | |
| dc.language.iso | en | |
| dc.title | 化合物PPA45之拮抗血小板凝集作用及機轉之探討 | zh_TW |
| dc.title | The Antiplatelet Effects and Mechanisms of Action of Compound PPA45 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 顏茂雄(Mao-hsiung Yen),楊春茂(Chuen-Mao Yang),鄧哲明(Che-Ming Teng),吳文彬(Wen-Bin Wu) | |
| dc.subject.keyword | 血小板,抑制血小板凝集作用, | zh_TW |
| dc.subject.keyword | platelet,inhibitory effect on platelet aggregation, | en |
| dc.relation.page | 87 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-08-16 | |
| 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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