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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 符文美(Wen-Mei Fu) | |
dc.contributor.author | Kai-Hsiang Kang | en |
dc.contributor.author | 康凱翔 | zh_TW |
dc.date.accessioned | 2021-06-16T08:24:24Z | - |
dc.date.available | 2019-02-25 | |
dc.date.copyright | 2014-02-25 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-01-22 | |
dc.identifier.citation | Abramovitz, M., Wong, E., Cox, M. E., Richardson, C. D., Li, C., Vickers, P. J., 1993. 5-lipoxygenase-activating protein stimulates the utilization of arachidonic acid by 5-lipoxygenase. Eur J Biochem 215, 105-111.
Bajpai, A. K., Blaskova, E., Pakala, S. B., Zhao, T., Glasgow, W. C., Penn, J. S., Johnson, D. A., Rao, G. N., 2007. 15(S)-HETE production in human retinal microvascular endothelial cells by hypoxia: Novel role for MEK1 in 15(S)-HETE induced angiogenesis. Invest Ophthalmol Vis Sci 48, 4930-4938. Bedard, K., Lardy, B., Krause, K. H., 2007. NOX family NADPH oxidases: not just in mammals. Biochimie 89, 1107-1112. Belayev, L., Alonso, O. F., Busto, R., Zhao, W., Ginsberg, M. D., 1996. Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27, 1616-1622. Betz, A. L., 1996. Alterations in cerebral endothelial cell function in ischemia. Adv Neurol 71, 301-311. Bogenrieder, T., Herlyn, M., 2003. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene 22, 6524-6536. Brandes, R. P., 2003. Role of NADPH oxidases in the control of vascular gene expression. Antioxid Redox Signal 5, 803-811. Brash, A. R., 1999. Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem 274, 23679-23682. Brash, A. R., Jisaka, M., Boeglin, W. E., Chang, M. S., 1999. Molecular cloning of a second human 15S-lipoxygenase and its murine homologue, an 8S-lipoxygenase. Their relationship to other mammalian lipoxygenases. Adv Exp Med Biol 447, 29-36. Brunton, V. G., Frame, M. C., 2008. Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol 8, 427-432. California Acute Stroke Pilot Registry, I., 2005. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology 64, 654-659. Campbell, P. J., Yachida, S., Mudie, L. J., Stephens, P. J., Pleasance, E. D., Stebbings, L. A., Morsberger, L. A., Latimer, C., McLaren, S., Lin, M. L., McBride, D. J., Varela, I., Nik-Zainal, S. A., Leroy, C., Jia, M., Menzies, A., Butler, A. P., Teague, J. W., Griffin, C. A., Burton, J., Swerdlow, H., Quail, M. A., Stratton, M. R., Iacobuzio-Donahue, C., Futreal, P. A., 2010. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109-1113. Canals, S., Casarejos, M. J., de Bernardo, S., Rodriguez-Martin, E., Mena, M. A., 2003. Nitric oxide triggers the toxicity due to glutathione depletion in midbrain cultures through 12-lipoxygenase. J Biol Chem 278, 21542-21549. Chen, H., Song, Y. S., Chan, P. H., 2009. Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J Cereb Blood Flow Metab 29, 1262-1272. Chen, J., Li, Y., Chopp, M., 2000. Intracerebral transplantation of bone marrow with BDNF after MCAo in rat. Neuropharmacology 39, 711-716. Chen, J., Li, Y., Wang, L., Zhang, Z., Lu, D., Lu, M., Chopp, M., 2001. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32, 1005-1011. Cheranov, S. Y., Karpurapu, M., Wang, D., Zhang, B., Venema, R. C., Rao, G. N., 2008. An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis. Blood 111, 5581-5591. Chiang, A. C., Massague, J., 2008. Molecular basis of metastasis. N Engl J Med 359, 2814-2823. Chinnici, C. M., Yao, Y., Ding, T., Funk, C. D., Pratico, D., 2005. Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice. Am J Pathol 167, 1371-1377. Chiueh, C. C., 2001. Iron overload, oxidative stress, and axonal dystrophy in brain disorders. Pediatr Neurol 25, 138-147. Chiueh, C. C., Andoh, T., Chock, P. B., 2005. Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin. Toxicol Appl Pharmacol 207, 96-102. Chiueh, C. C., Wu, R. M., Mohanakumar, K. P., Sternberger, L. M., Krishna, G., Obata, T., Murphy, D. L., 1994. In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. Ann N Y Acad Sci 738, 25-36. Choi, D. W., 1985. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58, 293-297. Choi, D. W., 1988. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623-634. Choi, J. A., Kim, E. Y., Song, H., Kim, C., Kim, J. H., 2008. Reactive oxygen species are generated through a BLT2-linked cascade in Ras-transformed cells. Free Radic Biol Med 44, 624-634. Chopra, H., Timar, J., Chen, Y. Q., Rong, X. H., Grossi, I. M., Fitzgerald, L. A., Taylor, J. D., Honn, K. V., 1991. The lipoxygenase metabolite 12(S)-HETE induces a cytoskeleton-dependent increase in surface expression of integrin alpha IIb beta 3 on melanoma cells. Int J Cancer 49, 774-786. Chou, V. P., Holman, T. R., Manning-Bog, A. B., 2013. Differential contribution of lipoxygenase isozymes to nigrostriatal vulnerability. Neuroscience 228, 73-82. Chu, J., Giannopoulos, P. F., Ceballos-Diaz, C., Golde, T. E., Pratico, D., 2012. 5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease. Ann Neurol 72, 442-454. Chu, J., Pratico, D., 2012. Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer's disease mouse model. J Neuroinflammation 9, 127. Chu, L. S., Fang, S. H., Zhou, Y., Yu, G. L., Wang, M. L., Zhang, W. P., Wei, E. Q., 2007. Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats. Acta Pharmacol Sin 28, 763-772. Cimen, I., Tuncay, S., Banerjee, S., 2009. 15-Lipoxygenase-1 expression suppresses the invasive properties of colorectal carcinoma cell lines HCT-116 and HT-29. Cancer Sci 100, 2283-2291. Clark, W. M., Albers, G. W., Madden, K. P., Hamilton, S., 2000. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke 31, 811-816. Comba, A., Pasqualini, M. E., 2009. Primers on molecular pathways - lipoxygenases: their role as an oncogenic pathway in pancreatic cancer. Pancreatology 9, 724-728. Coyle, J. T., Puttfarcken, P., 1993. Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689-695. Crooks, S. W., Stockley, R. A., 1998. Leukotriene B4. Int J Biochem Cell Biol 30, 173-178. Cui, L., Zhang, X., Yang, R., Liu, L., Wang, L., Li, M., Du, W., 2010. Baicalein is neuroprotective in rat MCAO model: role of 12/15-lipoxygenase, mitogen-activated protein kinase and cytosolic phospholipase A2. Pharmacol Biochem Behav 96, 469-475. D'Autreaux, B., Toledano, M. B., 2007. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8, 813-824. Datta, K., Biswal, S. S., Xu, J., Towndrow, K. M., Feng, X., Kehrer, J. P., 1998. A relationship between 5-lipoxygenase-activating protein and bcl-xL expression in murine pro-B lymphocytic FL5.12 cells. J Biol Chem 273, 28163-28169. Daurkin, I., Eruslanov, E., Stoffs, T., Perrin, G. Q., Algood, C., Gilbert, S. M., Rosser, C. J., Su, L. M., Vieweg, J., Kusmartsev, S., 2011. Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway. Cancer Res 71, 6400-6409. Davies, P., Bailey, P. J., Goldenberg, M. M., Ford-Hutchinson, A. W., 1984. The role of arachidonic acid oxygenation products in pain and inflammation. Annu Rev Immunol 2, 335-357. Desgrosellier, J. S., Cheresh, D. A., 2010. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10, 9-22. Devchand, P. R., Keller, H., Peters, J. M., Vazquez, M., Gonzalez, F. J., Wahli, W., 1996. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384, 39-43. Donnan, G. A., Fisher, M., Macleod, M., Davis, S. M., 2008. Stroke. Lancet 371, 1612-1623. Duh, E., Aiello, L. P., 1999. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 48, 1899-1906. Ell, B., Kang, Y., 2012. SnapShot: Bone Metastasis. Cell 151, 690-690 e691. Engblom, D., Saha, S., Engstrom, L., Westman, M., Audoly, L. P., Jakobsson, P. J., Blomqvist, A., 2003. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat Neurosci 6, 1137-1138. Fagan, S. C., Hess, D. C., Hohnadel, E. J., Pollock, D. M., Ergul, A., 2004. Targets for vascular protection after acute ischemic stroke. Stroke 35, 2220-2225. Fanning, A. S., Jameson, B. J., Jesaitis, L. A., Anderson, J. M., 1998. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273, 29745-29753. Fidler, I. J., 2002. The organ microenvironment and cancer metastasis. Differentiation 70, 498-505. Fidler, I. J., 2003. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3, 453-458. Ford-Hutchinson, A. W., Gresser, M., Young, R. N., 1994. 5-Lipoxygenase. Annu Rev Biochem 63, 383-417. Frame, M. C., 2002. Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta 1602, 114-130. Funk, C. D., 2001. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871-1875. Gabarra-Niecko, V., Schaller, M. D., Dunty, J. M., 2003. FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev 22, 359-374. Gasic, G. P., Hollmann, M., 1992. Molecular neurobiology of glutamate receptors. Annu Rev Physiol 54, 507-536. Ge, Q. F., Wei, E. Q., Zhang, W. P., Hu, X., Huang, X. J., Zhang, L., Song, Y., Ma, Z. Q., Chen, Z., Luo, J. H., 2006. Activation of 5-lipoxygenase after oxygen-glucose deprivation is partly mediated via NMDA receptor in rat cortical neurons. J Neurochem 97, 992-1004. Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N. Q., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C. R., Nohadani, M., Eklund, A. C., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P. A., Swanton, C., 2012. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366, 883-892. Gonzalez-Periz, A., Claria, J., 2007. New approaches to the modulation of the cyclooxygenase-2 and 5-lipoxygenase pathways. Curr Top Med Chem 7, 297-309. Green, A. R., Shuaib, A., 2006. Therapeutic strategies for the treatment of stroke. Drug Discov Today 11, 681-693. group, I. S. T. c., Sandercock, P., Wardlaw, J. M., Lindley, R. I., Dennis, M., Cohen, G., Murray, G., Innes, K., Venables, G., Czlonkowska, A., Kobayashi, A., Ricci, S., Murray, V., Berge, E., Slot, K. B., Hankey, G. J., Correia, M., Peeters, A., Matz, K., Lyrer, P., Gubitz, G., Phillips, S. J., Arauz, A., 2012. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 379, 2352-2363. Guise, T. A., 2009. Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases. Genes Dev 23, 2117-2123. Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Davalos, A., Guidetti, D., Larrue, V., Lees, K. R., Medeghri, Z., Machnig, T., Schneider, D., von Kummer, R., Wahlgren, N., Toni, D., Investigators, E., 2008. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359, 1317-1329. Hawkins, B. T., Egleton, R. D., Davis, T. P., 2005. Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors. Am J Physiol Heart Circ Physiol 289, H212-219. He, C., Wu, Y., Lai, Y., Cai, Z., Liu, Y., Lai, L., 2012. Dynamic eicosanoid responses upon different inhibitor and combination treatments on the arachidonic acid metabolic network. Mol Biosyst 8, 1585-1594. Helgadottir, A., Gretarsdottir, S., St Clair, D., Manolescu, A., Cheung, J., Thorleifsson, G., Pasdar, A., Grant, S. F., Whalley, L. J., Hakonarson, H., Thorsteinsdottir, U., Kong, A., Gulcher, J., Stefansson, K., MacLeod, M. J., 2005. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet 76, 505-509. Helgadottir, A., Manolescu, A., Thorleifsson, G., Gretarsdottir, S., Jonsdottir, H., Thorsteinsdottir, U., Samani, N. J., Gudmundsson, G., Grant, S. F., Thorgeirsson, G., Sveinbjornsdottir, S., Valdimarsson, E. M., Matthiasson, S. E., Johannsson, H., Gudmundsdottir, O., Gurney, M. E., Sainz, J., Thorhallsdottir, M., Andresdottir, M., Frigge, M. L., Topol, E. J., Kong, A., Gudnason, V., Hakonarson, H., Gulcher, J. R., Stefansson, K., 2004. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 36, 233-239. Henderson, W. R., Jr., 1994. The role of leukotrienes in inflammation. Ann Intern Med 121, 684-697. Hoehn, B., Ringer, T. M., Xu, L., Giffard, R. G., Sapolsky, R. M., Steinberg, G. K., Yenari, M. A., 2001. Overexpression of HSP72 after induction of experimental stroke protects neurons from ischemic damage. J Cereb Blood Flow Metab 21, 1303-1309. Hoehn, M. M., Yahr, M. D., 1967. Parkinsonism: onset, progression and mortality. Neurology 17, 427-442. Honn, K. V., Grossi, I. M., Diglio, C. A., Wojtukiewicz, M., Taylor, J. D., 1989a. Enhanced tumor cell adhesion to the subendothelial matrix resulting from 12(S)-HETE-induced endothelial cell retraction. FASEB J 3, 2285-2293. Honn, K. V., Grossi, I. M., Steinert, B. W., Chopra, H., Onoda, J., Nelson, K. K., Taylor, J. D., 1989b. Lipoxygenase regulation of membrane expression of tumor cell glycoproteins and subsequent metastasis. Adv Prostaglandin Thromboxane Leukot Res 19, 439-443. Huang, C., Jacobson, K., Schaller, M. D., 2004. MAP kinases and cell migration. J Cell Sci 117, 4619-4628. Huang, Z. G., Xue, D., Preston, E., Karbalai, H., Buchan, A. M., 1999. Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can J Neurol Sci 26, 298-304. Humphries, M. J., 2001. Cell adhesion assays. Mol Biotechnol 18, 57-61. Hung, S. Y., Liou, H. C., Kang, K. H., Wu, R. M., Wen, C. C., Fu, W. M., 2008. Overexpression of heme oxygenase-1 protects dopaminergic neurons against 1-methyl-4-phenylpyridinium-induced neurotoxicity. Mol Pharmacol 74, 1564-1575. Hunger-Glaser, I., Salazar, E. P., Sinnett-Smith, J., Rozengurt, E., 2003. Bombesin, lysophosphatidic acid, and epidermal growth factor rapidly stimulate focal adhesion kinase phosphorylation at Ser-910: requirement for ERK activation. J Biol Chem 278, 22631-22643. Hynes, R. O., 2002. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673-687. Iadecola, C., Zhang, F., Xu, S., Casey, R., Ross, M. E., 1995. Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15, 378-384. Ishibe, S., Joly, D., Zhu, X., Cantley, L. G., 2003. Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis. Mol Cell 12, 1275-1285. Jain, M., Ratheesh, A., Gude, R. P., 2010. Pentoxifylline inhibits integrin-mediated adherence of 12(S)-HETE and TNFalpha-activated B16F10 cells to fibronectin and endothelial cells. Chemotherapy 56, 82-88. Janakiram, N. B., Mohammed, A., Rao, C. V., 2011. Role of lipoxins, resolvins, and other bioactive lipids in colon and pancreatic cancer. Cancer Metastasis Rev 30, 507-523. Jankun, J., Aleem, A. M., Malgorzewicz, S., Szkudlarek, M., Zavodszky, M. I., Dewitt, D. L., Feig, M., Selman, S. H., Skrzypczak-Jankun, E., 2006. Synthetic curcuminoids modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and reduce sprout formation of human endothelial cells. Mol Cancer Ther 5, 1371-1382. Jatana, M., Giri, S., Ansari, M. A., Elango, C., Singh, A. K., Singh, I., Khan, M., 2006. Inhibition of NF-kappaB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia. J Neuroinflammation 3, 12. Javitch, J. A., D'Amato, R. J., Strittmatter, S. M., Snyder, S. H., 1985. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci U S A 82, 2173-2177. Kahles, T., Brandes, R. P., 2013. Which NADPH oxidase isoform is relevant for ischemic stroke? The case for nox 2. Antioxid Redox Signal 18, 1400-1417. Kahles, T., Luedike, P., Endres, M., Galla, H. J., Steinmetz, H., Busse, R., Neumann-Haefelin, T., Brandes, R. P., 2007. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 38, 3000-3006. Katsuyama, M., Matsuno, K., Yabe-Nishimura, C., 2012. Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme. J Clin Biochem Nutr 50, 9-22. Khanna, S., Roy, S., Ryu, H., Bahadduri, P., Swaan, P. W., Ratan, R. R., Sen, C. K., 2003. Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J Biol Chem 278, 43508-43515. Khanna, S., Roy, S., Slivka, A., Craft, T. K., Chaki, S., Rink, C., Notestine, M. A., DeVries, A. C., Parinandi, N. L., Sen, C. K., 2005. Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke 36, 2258-2264. Kienast, Y., von Baumgarten, L., Fuhrmann, M., Klinkert, W. E., Goldbrunner, R., Herms, J., Winkler, F., 2010. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16, 116-122. Krishnamoorthy, S., Jin, R., Cai, Y., Maddipati, K. R., Nie, D., Pages, G., Tucker, S. C., Honn, K. V., 2010. 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells. Exp Cell Res 316, 1706-1715. Kuhn, H., Belkner, J., Wiesner, R., Brash, A. R., 1990. Oxygenation of biological membranes by the pure reticulocyte lipoxygenase. J Biol Chem 265, 18351-18361. Kuhn, H., Walther, M., Kuban, R. J., 2002. Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications. Prostaglandins Other Lipid Mediat 68-69, 263-290. Kumar, P., Kalonia, H., Kumar, A., 2011. Role of LOX/COX pathways in 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats: protective effect of licofelone. Br J Pharmacol 164, 644-654. Kuroiwa, T., Ting, P., Martinez, H., Klatzo, I., 1985. The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol 68, 122-129. Lambeth, J. D., 2007. Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med 43, 332-347. Lammers, C. H., Schweitzer, P., Facchinetti, P., Arrang, J. M., Madamba, S. G., Siggins, G. R., Piomelli, D., 1996. Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling. J Neurochem 66, 147-152. Lang, A. E., Lozano, A. M., 1998. Parkinson's disease. First of two parts. N Engl J Med 339, 1044-1053. Langston, J. W., Ballard, P., Tetrud, J. W., Irwin, I., 1983. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979-980. Lebeau, A., Terro, F., Rostene, W., Pelaprat, D., 2004. Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by beta-amyloid peptide. Cell Death Differ 11, 875-884. Lees, K. R., Bluhmki, E., von Kummer, R., Brott, T. G., Toni, D., Grotta, J. C., Albers, G. W., Kaste, M., Marler, J. R., Hamilton, S. A., Tilley, B. C., Davis, S. M., Donnan, G. A., Hacke, W., Ecass, A. N., Group, E. r.-P. S., Allen, K., Mau, J., Meier, D., del Zoppo, G., De Silva, D. A., Butcher, K. S., Parsons, M. W., Barber, P. A., Levi, C., Bladin, C., Byrnes, G., 2010. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375, 1695-1703. Li, J. H., Lv, K. Y., Li, H. Y., Xia, Z. F., 2009. Suppressed acute phase response to LPS-induced hepatic injury in Smad3-deficient mice. Mol Immunol 46, 362-365. Li, Y., Maher, P., Schubert, D., 1997. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19, 453-463. Lin, M. T., Beal, M. F., 2006. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795. Lindgren, J. A., Hokfelt, T., Dahlen, S. E., Patrono, C., Samuelsson, B., 1984. Leukotrienes in the rat central nervous system. Proc Natl Acad Sci U S A 81, 6212-6216. Ling, T. Y., Kuo, M. D., Li, C. L., Yu, A. L., Huang, Y. H., Wu, T. J., Lin, Y. C., Chen, S. H., Yu, J., 2006. Identification of pulmonary Oct-4+ stem/progenitor cells and demonstration of their susceptibility to SARS coronavirus (SARS-CoV) infection in vitro. Proc Natl Acad Sci U S A 103, 9530-9535. Lipton, S. A., Kater, S. B., 1989. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci 12, 265-270. Lipton, S. A., Rosenberg, P. A., 1994. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330, 613-622. Liu, B., Marnett, L. J., Chaudhary, A., Ji, C., Blair, I. A., Johnson, C. R., Diglio, C. A., Honn, K. V., 1994. Biosynthesis of 12(S)-hydroxyeicosatetraenoic acid by B16 amelanotic melanoma cells is a determinant of their metastatic potential. Lab Invest 70, 314-323. Liu, Z. X., Yu, C. F., Nickel, C., Thomas, S., Cantley, L. G., 2002. Hepatocyte growth factor induces ERK-dependent paxillin phosphorylation and regulates paxillin-focal adhesion kinase association. J Biol Chem 277, 10452-10458. Lo, E. H., Dalkara, T., Moskowitz, M. A., 2003. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4, 399-415. Lohmussaar, E., Gschwendtner, A., Mueller, J. C., Org, T., Wichmann, E., Hamann, G., Meitinger, T., Dichgans, M., 2005. ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke 36, 731-736. Loscalzo, J., 2008. Membrane redox state and apoptosis: death by peroxide. Cell Metab 8, 182-183. Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F., Groom, A. C., 1998. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153, 865-873. Maccarrone, M., Navarra, M., Corasaniti, M. T., Nistico, G., Finazzi Agro, A., 1998. Cytotoxic effect of HIV-1 coat glycoprotein gp120 on human neuroblastoma CHP100 cells involves activation of the arachidonate cascade. Biochem J 333 ( Pt 1), 45-49. Mackay, J., Mensah, G., 2004. The Atlas of Heart Disease and Stroke. WHO. Manev, H., Chen, H., Dzitoyeva, S., Manev, R., 2011. Cyclooxygenases and 5-lipoxygenase in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 35, 315-319. Marler, J. R., Tilley, B. C., Lu, M., Brott, T. G., Lyden, P. C., Grotta, J. C., Broderick, J. P., Levine, S. R., Frankel, M. P., Horowitz, S. H., Haley, E. C., Jr., Lewandowski, C. A., Kwiatkowski, T. P., 2000. Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 55, 1649-1655. Marnett, L. J., Riggins, J. N., West, J. D., 2003. Endogenous generation of reactive oxidants and electrophiles and their reactions with DNA and protein. J Clin Invest 111, 583-593. Martin-Belmonte, F., Perez-Moreno, M., 2012. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer 12, 23-38. Meldrum, B., Garthwaite, J., 1990. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci 11, 379-387. Mitic, L. L., Anderson, J. M., 1998. Molecular architecture of tight junctions. Annu Rev Physiol 60, 121-142. Moreno, J. J., 2009. New aspects of the role of hydroxyeicosatetraenoic acids in cell growth and cancer development. Biochem Pharmacol 77, 1-10. Mytilineou, C., Kramer, B. C., Yabut, J. A., 2002. Glutathione depletion and oxidative stress. Parkinsonism Relat Disord 8, 385-387. Nakashima, Y., Yano, M., Kobayashi, Y., Moriyama, S., Sasaki, H., Toyama, T., Yamashita, H., Fukai, I., Iwase, H., Yamakawa, Y., Fujii, Y., 2003. Endostatin gene therapy on murine lung metastases model utilizing cationic vector-mediated intravenous gene delivery. Gene Ther 10, 123-130. Natarajan, R., Nadler, J., 1998. Role of lipoxygenases in breast cancer. Front Biosci 3, E81-88. Natarajan, R., Nadler, J. L., 2004. Lipid inflammatory mediators in diabetic vascular disease. Arterioscler Thromb Vasc Biol 24, 1542-1548. Nguyen, D. X., Bos, P. D., Massague, J., 2009. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9, 274-284. Nie, D., Hillman, G. G., Geddes, T., Tang, K., Pierson, C., Grignon, D. J., Honn, K. V., 1998. Platelet-type 12-lipoxygenase in a human prostate carcinoma stimulates angiogenesis and tumor growth. Cancer Res 58, 4047-4051. Nony, P. A., Kennett, S. B., Glasgow, W. C., Olden, K., Roberts, J. D., 2005. 15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. J Biol Chem 280, 31413-31419. Olanow, C. W., Schapira, A. H., 2013. Therapeutic prospects for Parkinson disease. Ann Neurol 74, 337-347. Olney, J. W., de Gubareff, T., 1978. The fate of synaptic receptors in the kainate-lesioned striatum. Brain Res 140, 340-343. Othman, A., Ahmad, S., Megyerdi, S., Mussell, R., Choksi, K., Maddipati, K. R., Elmarakby, A., Rizk, N., Al-Shabrawey, M., 2013. 12/15-Lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase. PLoS One 8, e57254. Pfefferkorn, T., Rosenberg, G. A., 2003. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke 34, 2025-2030. Phillis, J. W., Horrocks, L. A., Farooqui, A. A., 2006. Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev 52, 201-243. Playford, M. P., Schaller, M. D., 2004. The interplay between Src and integrins in normal and tumor biology. Oncogene 23, 7928-7946. Poste, G., Fidler, I. J., 1980. The pathogenesis of cancer metastasis. Nature 283, 139-146. Preston, E., Sutherland, G., Finsten, A., 1993. Three openings of the blood-brain barrier produced by forebrain ischemia in the rat. Neurosci Lett 149, 75-78. Rauhala, P., Andoh, T., Chiueh, C. C., 2005. Neuroprotective properties of nitric oxide and S-nitrosoglutathione. Toxicol Appl Pharmacol 207, 91-95. Roger, V. L., Go, A. S., Lloyd-Jones, D. M., Adams, R. J., Berry, J. D., Brown, T. M., Carnethon, M. R., Dai, S., de Simone, G., Ford, E. S., Fox, C. S., Fullerton, H. J., Gillespie, C., Greenlund, K. J., Hailpern, S. M., Heit, J. A., Ho, P. M., Howard, V. J., Kissela, B. M., Kittner, S. J., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Makuc, D. M., Marcus, G. M., Marelli, A., Matchar, D. B., McDermott, M. M., Meigs, J. B., Moy, C. S., Mozaffarian, D., Mussolino, M. E., Nichol, G., Paynter, N. P., Rosamond, W. D., Sorlie, P. D., Stafford, R. S., Turan, T. N., Turner, M. B., Wong, N. D., Wylie-Rosett, J., American Heart Association Statistics, C., Stroke Statistics, S., 2011. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation 123, e18-e209. Rosenberg, G. A., Estrada, E. Y., Dencoff, J. E., 1998. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29, 2189-2195. Samuelsson, B., 1983. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220, 568-575. Sandoval, K. E., Witt, K. A., 2008. Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 32, 200-219. Saran, M., 2003. To what end does nature produce superoxide? NADPH oxidase as an autocrine modifier of membrane phospholipids generating paracrine lipid messengers. Free Radic Res 37, 1045-1059. Schaller, M. D., 2001. Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta 1540, 1-21. Schewe, T., Halangk, W., Hiebsch, C., Rapoport, S. M., 1975. A lipoxygenase in rabbit reticulocytes which attacks phospholipids and intact mitochondria. FEBS Lett 60, 149-152. Schoch, H. J., Fischer, S., Marti, H. H., 2002. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 125, 2549-2557. Scholz, M., Ulbrich, H. K., Dannhardt, G., 2008. Investigations concerning the COX/5-LOX inhibiting and hydroxyl radical scavenging potencies of novel 4,5-diaryl isoselenazoles. Eur J Med Chem 43, 1152-1159. Schwartz, M. A., Ginsberg, M. H., 2002. Networks and crosstalk: integrin signalling spreads. Nat Cell Biol 4, E65-68. Seiler, A., Schneider, M., Forster, H., Roth, S., Wirth, E. K., Culmsee, C., Plesnila, N., Kremmer, E., Radmark, O., Wurst, W., Bornkamm, G. W., Schweizer, U., Conrad, M., 2008. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab 8, 237-248. Seyfried, J., Soldner, F., Kunz, W. S., Schulz, J. B., Klockgether, T., Kovar, K. A., Wullner, U., 2000. Effect of 1-methyl-4-phenylpyridinium on glutathione in rat pheochromocytoma PC 12 cells. Neurochem Int 36, 489-497. Shen, Y., Schaller, M. D., 1999. Focal adhesion targeting: the critical determinant of FAK regulation and substrate phosphorylation. Mol Biol Cell 10, 2507-2518. Silletti, S., Timar, J., Honn, K. V., Raz, A., 1994. Autocrine motility factor induces differential 12-lipoxygenase expression and activity in high- and low-metastatic K1735 melanoma cell variants. Cancer Res 54, 5752-5756. Simionescu, M., Simionescu, N., Palade, G. E., 1976. Segmental differentiations of cell junctions in the vascular endothelium. Arteries and veins. J Cell Biol 68, 705-723. Soberman, R. J., Christmas, P., 2003. The organization and consequences of eicosanoid signaling. J Clin Invest 111, 1107-1113. Sorce, S., Krause, K. H., 2009. NOX enzymes in the central nervous system: from signaling to disease. Antioxid Redox Signal 11, 2481-2504. Soumya, S. J., Binu, S., Helen, A., Anil Kumar, K., Reddanna, P., Sudhakaran, P. R., 2012. Effect of 15-lipoxygenase metabolites on angiogenesis: 15(S)-HPETE is angiostatic and 15(S)-HETE is angiogenic. Inflamm Res. 61, 707-718 Srivastava, K., Kundumani-Sridharan, V., Zhang, B., Bajpai, A. K., Rao, G. N., 2007. 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF. Cancer Res 67, 4328-4336. Subauste, M. C., Pertz, O., Adamson, E. D., Turner, C. E., Junger, S., Hahn, K. M., 2004. Vinculin modulation of paxillin-FAK interactions regulates ERK to control survival and motility. J Cell Biol 165, 371-381. Subbaram, S., Dipersio, C. M., 2011. Integrin alpha3beta1 as a breast cancer target. Expert Opin Ther Targets 15, 1197-1210. Talmadge, J. E., Fidler, I. J., 2010. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 70, 5649-5669. Tang, D. G., Grossi, I. M., Chen, Y. Q., Diglio, C. A., Honn, K. V., 1993. 12(S)-HETE promotes tumor-cell adhesio | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58659 | - |
dc.description.abstract | 神經性疾病與癌症在已開發國家是很嚴重的醫療與經濟問題。兩者的致病原因都十分複雜,所以截至目前為止,在這領域中雖有許多研究,但仍然無法窺見全貌。我們從2002年起,在生技製藥國家型科技計畫辦公室支持下以小鼠腦中風模式篩選了多種化合物,來評估對中樞神經保護的作用,一共篩選超過1000種化合物。其中只有由中國醫藥大學侯曼貞教授合成的化合物MJ-39效果最為優良。其在大、小鼠腦中風模式下,皆能有效減少中樞神經損傷,並且能提高中風後老鼠的運動能力,經由計畫辦公室委由汎球藥理公司進行一般藥理實驗,證實其選擇性對5-脂氧酶 (lipoxygense) 與12/15-脂氧酶具有抑制的作用。脂氧酶是一類含鐵的酵素,主要催化花生四烯酸 (arachidonic acid) 產生白三烯 (leukotriene) 或羥花生四烯酸 (hydroxyeicosatetraenoic acid, HETE)。這些代謝物很多參與發炎反應或具有抗發炎的作用,因此脂氧酶也常常被認為與神經疾病或癌症有關。最近有許多研究指出脂氧酶在腦中風、阿茲海默症、巴金森氏症都扮演重要的角色。
我們發現MJ-39與其衍生物也有許多具有神經保護的效果,我們以中腦神經與神經膠細胞來測試這些衍生物對MPP+所造成的神經毒性影響,發現其仍然具有不錯的保護效果;而在動物實驗方面,亦能保護中風老鼠大腦皮質的損傷,並能拮抗MPTP造成多巴胺神經元的損傷。 我們實驗發現,12/15-脂氧酶的下游代謝產物羥花生四烯酸,在小鼠腦中風模式下,加重血腦障壁滲透性增加的情形,此一現象在12/15-脂氧酶基因剔除小鼠上,觀察到顯著的改善。在離體實驗中,羥花生四烯酸亦會增加血腦障壁的滲透性增加,還會破壞其緊密連接蛋白 (tight junction protein)。而這些作用我們認為是經由煙醯胺腺嘌呤二核苷酸磷酸氧化酶 (NADPH oxidase) 訊息傳遞路徑而來。 我們進一步研究發現在小鼠注射MPTP後,星狀神經膠細胞 (astrocytes)的5-脂氧酶表現會增加。另一方面5-脂氧酶活化蛋白的抑制劑MK-886,在中腦細胞培養以及SHSY5Y細胞株,皆可有效改善MPP+造成的多巴胺神經死亡。此外,5-脂氧酶下游產物,白三烯B4不論在活體或離體的巴金森氏症模式下,皆會增加多巴胺神經的損傷。根據這些結果我們認為5-脂氧酶抑制劑,有潛力可以做為治療巴金森氏症的候選藥物,而白三烯B4在巴金森氏症的致病機轉,可能也扮演重要角色。 癌症之所以可怕,不在於腫瘤組織不斷的增殖,而在於它會在原發病灶附近造成破壞之外,更會產生遠端轉移,導致病患的死亡。癌症轉移相當複雜,且牽涉到癌細胞的生長、擴散與血管新生。我們發現到羥花生四烯酸會增加黑色素瘤細胞B16F10黏著能力,增加癌細胞轉移。在分離培養小鼠的肺部表皮細胞中,與野生型小鼠相比發現黑色素瘤細胞較少黏著在12/15-脂氧酶剔除小鼠的組別上。我們進一步羥花生四烯酸增加細胞黏著的作用與磷酸化局部沾黏激酶 (Focal Adhesion kinase)有關,且此一現象會被ERK抑制劑抑制。綜合以上所知,我們認為未被癌細胞入侵的器官,因其12/15-脂氧酶活化,進而產生過多的羥花生四烯酸,使得局部沾黏激酶磷酸化促進黑色素瘤的粘著,進而導致癌細胞轉移;可以推論,抑制12/15-脂氧酶活化可以降低癌細胞轉移。 從上述所有實驗可以知道,脂氧酶抑制劑可以開發成為中樞神經保護劑或抑制癌症細胞轉移之藥物。在這兩大領域雖然各大藥廠皆投入大量心血研發,但市場仍然十分需要更有效之藥物,我們的研究提供了一個未來藥物研發的方向。 | zh_TW |
dc.description.abstract | Neurological illnesses and cancer are among the most common and most serious health problems in industrialized nations. The causes of them are diverse, complex, and only partially understood. Since 2002, we have used the stroke model of mice to screen over 1000 testing compounds under the support office of National Science and Technology Program for Biotechnology and Pharmaceuticals. Only one potential compound was found among all tested sample, with code number of MJ-39, which is provided by the professor M.J Hour in China Medical University. The biochemical assay results show that MJ-39 is a potent and specific inhibitor for 5-lipoxygenase (5-LOX) and 12/15-lipoxygenase (12/15-LOX). LOXs are a family of lipid-oxidizing enzymes that generate a wide array of pro- and anti-inflammatory mediators. The well-known 5-lipoxygenase and its activating protein have recently been intensely studied because of a genetic linkage to stroke and Alzheimer's disease. In addition, 12/15-LOX is also one of the key mediators in stroke and neurodegenerative disease.
We have screened several MJ-39 derivatives and found some more effective compounds. MJ serial compounds also exhibit a good neuprotective efficacy after ischemia/reperfusion (I/R) injury. Here we also found that MJ serial compounds significantly inhibited the cell death of dopaminergic neurons after injection of MPTP in vivo and significantly inhibited MPP+-induced neuronal death in vitro. We further examined the role of LOX in the increase of blood brain barrier (BBB) permeability following stoke. It was found that 12/15-LOX metabolites enhanced brain damage and BBB hyperpermeability after I/R injury and these effects were reduced in 12/15-LOX KO mice. In addition, 12(S)- and 15(S)-HETE caused an increase of BBB endothelial permeability and a destruction of ZO-1 in vitro. NADPH oxidase pathway may be involved in 12/15-LOX metabolites enhanced endothelial barrier disruption. It was found that 5-LOX was over-expressed in astrocytes after the injection of MPTP into mice. MK-886, a specific inhibitor of 5-LOX activating protein (FLAP), significantly increased [3H]-dopamine uptake, a functional indicator of the integrity of dopaminergic neurons, in midbrain cultures or the SH-SY5Y human dopaminergic cell line following MPP+ treatment. In addition, LTB4, one of 5-LOX’s downstream products, was increased in the striatum and substantia nigra following MPTP injection in mice. LTB4 also enhanced MPP+-induced neurotoxicity in primary midbrain cultures. MK-886 administration increased the number of tyrosine hydroxylase-positive neurons in the substantia nigra and the dopamine content in the striatum in MPTP-induced parkinsonian mice. These results suggest that 5-LOX inhibitors may be developed as novel neuroprotective agents and LTB4 may play an important pathological role in Parkinson’s disease. Metastasis is the leading cause of cancer-related death. Metastasis is a very complex cascade of events such as tumor growth, invasion and angiogenesis. Here we found that HETEs released from host organ played a critical role in tumor metastasis. In vitro studies showed that 12(S)-HETE and 15(S)-HETE treatment resulted in a concentration-dependent increase of adhesion of B16F10 cells on collagen or fibronectin. It was found that the adhesion of melanoma cells on the epithelial cells isolated from 12/15-LOX null mice was reduced in comparison with those isolated from WT mice. Treatment of 12(S)-HETE increased the pFAK in melanoma cells adhering on collagen-coated slide. The enhancement of adherence elicited by 12(S)-HETE in B16F10 cells could be antagonized by FAK inhibitor or ERK inhibitor. 12(S)-HETE increased the phosphorylation of FAK and ERK in adhering melanoma cells. The FAK phosphorylation induced by 12(S)-HETE was further inhibited by PD98059, indicating that FAK is the downstream target of ERK. These results demonstrate that 12(S)-HETE/15(S)-HETE activates ERK and FAK signaling pathways, thereby upregulates the adhesion and metastatic potential of melanoma cells. The endogenous release of 12(S)-HETE/15(S)-HETE in host organ may affect the metastatic potential of melanoma. In summary, LOX inhibitors may be developed for the treatment of ischemic stroke and PD. Furthermore, 12/15-LOX is a potential therapeutic target for developing drugs to inhibit the progression of melanoma. LOXs may play a pivotal role in neurological illnesses and cancer metastasis. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:24:24Z (GMT). No. of bitstreams: 1 ntu-103-D95443007-1.pdf: 13992510 bytes, checksum: a641b4a4e7967a5f8adb89d3c02b8747 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | Contents
Pages Abbreviations………………………………………………………………… 1 Abstract in Chinese…………………………………………………………... 7 Abstract in English…………………………………………………………… 13 Chapter 1. Introduction………………………………………………………. 19 1-1. Stroke and its drug developmental status…………………………... 21 1-2. Neurodegenerative disease: Parkinson’s disease………...………… 34 1-3. Cancer metastasis…………………………………………………... 38 1-4. The biological and pathological function of lipoxygense………….. 45 Chapter 2. Materials and Methods………………………..………………….. 55 Chapter 3. Compounds targeting on lipoxygenase and their pharmaceutical uses thereof……………………………………………………….. 71 Chapter 4. Enhancement of hypoxia-induced increase of Blood-Brain Barrier permeability by 12/15-Lipoxygenase-derived lipid metabolites……………………………………………………….. 97 Chapter 5. Protection of dopaminergic neurons by 5-lipoxygenase inhibitor... 115 Chapter 6. Enhancement role of host 12/15-lipoxygenase in melanoma progression……………………………………………………….. 137 Chapter 7. Conclusion and Perspective………………………………………. 173 References……………………………………………………………………. 181 Publications…………………………………………………………………... 201 Figure Contents Pages Chapter 1 Figure 1-1-1. A diagram of an ischemic stroke and a hemorrhagic stroke 29 Figure 1-1-2. Major pathways implicated in ischemic cell death: excitotoxicity, ionic imbalance, oxidative and nitrosative stresses and apoptotic-like mechanisms. 31 Figure 1-1-3. Blood-brain barrier (BBB) neurovascular-unit (NVU) 33 Figure 1-2-1. The Sites of neurodegeneration involved in Parkinson’s disease. 36 Figure 1-2-2. A Typical Lewy Body 37 Figure 1-3-1. The main steps in the formation of a metastasis. 43 Figure 1-3-2. Src and FAK integrate signals from both integrins and growth factor receptors on the cell membrane. 44 Figure 1-4-1. The main pathways of the biosynthesis of leukotrienes, lipoxins and HETEs 53 Chapter 3 Figure 3-1. Effects of testing compounds on the Ischemia/reperfusion-induced neuronal death in rat 85 Figure 3-2. CTS-12 inhibits ischemia/reperfusion-induced infarction in a dose-dependent manner 87 Figure 3-3. Effect of LOX downstream products and testing compounds on MPP+-induced dopaminergic neuronal death in midbrain neuron-glia co-cultures 89 Figure 3-4. Testing compounds inhibits MPP+-induced neurotoxicity in rat midbrain neuron-glia co-culture in a concentration-dependent amnner 91 Figure 3-5. Testing compounds inhibit MPTP-induced decrease of dopamine and its metabolites contents in mice striatum 93 Figure 3-6. Inhibition of MPTP-induced neuronal death in substantia nigra by testing compounds in mice 95 Chapter 4 Figure 4-1. 12/15-LOX inhibition and gene deletion reduce the MCAO-induced infarct volume in mice 109 Figure 4-2. Enhancement of neuronal death by 12/15-LOX downstream products 110 Figure 4-3. I/R-induced BBB permeability is reduced in 12/15-LOX KO mice 111 Figure 4-4. HETE increases cellular permeability in ARBECs 112 Figure 4-5. HETE inhibits ZO-1 expression in ARBECs 113 Figure 4-6. Increase of ROS generation and NOX2 expression by HETE in ARBEC 114 Chapter 5 Figure 5-1. MPP+ reduces neuronal function in a concentration-dependent manner 126 Figure 5-2. MK-886 protects neuron against MPP+-induced cellular death in differentiated SH-SY5Y cells 127 Figure 5-3. Increased 5-LOX and FLAP expression in the striatum due to MPTP treatment 129 Figure 5-4. Neuroprotection of MK-886 in midbrain neuron-glia co-cultures 131 Figure 5-5. LTB4 enhances MPP+-induced neurotoxicity in midbrain neuron-glia co-cultures 133 Figure 5-6. MK-886 protects neurons against MPTP-induced neurotoxicity and reduces LTB4 levels in mice 135 Chapter 6 Figure 6-1. Inhibition of melanoma tumor growth and lung metastasis in 12/15-LOX knockout mice 153 Figure 6-2. Reduction of size of metastatic foci but not melanoma cells proliferation in 12/15-LOX knockout mice 155 Figure 6-3. 12(S)-HETE and 15(S)-HETE increase the cell adhesion of B16F10 melanoma cells on type I collagen or fibronectin 157 Figure 6-4. 5(S)-HETE or 13(S)-HODE does not affect the viability of B16F10 melanoma cells. 158 Figure 6-5. 12(S)-HETE or 15(S)-HETE does not affect the proliferation of melanoma cells 159 Figure 6-6. 12(S)-HETE enhances the adhesion of B16F10 melanoma cells in lung tissue of mice 161 Figure 6-7. 12(S)-HETE-induced B16F10 cell adhesion is inhibited by FAK or ERK inhibitor 163 Figure 6-8. 12(S)-HETE increases FAK and ERK phosphorylation in B16F10 melanoma cells. 165 Figure 6-9. Phosphorylation of FAK following adhesion in B16F10 cells. 167 Figure 6-10. 12(S)-HETE increases the adhesion of human melanoma cells both in vitro and in vivo 169 Figure 6-11. Schematic diagram showing the effect of host 12/15-LOX on the regulation of signaling pathways and cell adhesion of melanoma cells 171 Chapter 7 Figure 7-1. Role of LOX in neuronal injury 178 Figure 7-2. Involvement of 12/15-LOX in cancer metastasis 179 | |
dc.language.iso | en | |
dc.title | 脂氧酶在中樞神經疾病與癌症轉移之研究 | zh_TW |
dc.title | Role of lipoxygenase in CNS disease and cancer metastasis | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林琬琬,劉宏輝,劉興華,楊榮森,楊春茂 | |
dc.subject.keyword | 脂氧?,中風,巴金森氏症,中樞神經保護劑,癌症轉移, | zh_TW |
dc.subject.keyword | Lipoxygenase,stroke,neuprotectant,cancer metastasis, | en |
dc.relation.page | 206 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-01-23 | |
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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