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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46115完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賴凌平(Ling-Ping Lai) | |
| dc.contributor.author | Nan-Lan Huang | en |
| dc.contributor.author | 黃南嵐 | zh_TW |
| dc.date.accessioned | 2021-06-15T04:54:26Z | - |
| dc.date.available | 2015-09-13 | |
| dc.date.copyright | 2010-09-13 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-07-30 | |
| dc.identifier.citation | 1 Lusis AJ. Atherosclerosis. Nature 2000; 407 233-41.
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A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis. Eur Heart J 2007; 28: 664-72. 9 Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334: 574-79. 10 Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 2005; 65: 385-411. 11 UK Prospective Diabetes Study G. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-65. 12 Hardie DG. New roles for the LKB1-->AMPK pathway. Curr Opin Cell Biol 2005; 17: 167-73. 13 Carling D. The AMP-activated protein kinase cascade - a unifying system for energy control. Trends Biochem Sci 2004; 29: 18-24. 14 Hardie DG. The AMP-activated protein kinase pathway – new players upstream and downstream. J Cell Sci 2004; 117: 5479-87. 15 Aronne LJ, Isoldi KK. Cannabinoid-1 receptor blockade in cardiometabolic risk reduction: Efficacy. Am J Cardiol 2007; 100: S18-S26. 16 Howlett AC. Pharmacology of Cannabinoid Receptors. Annu Rev Pharmacol 1995; 35: 607-34. 17 Gelfand EV, Cannon CP. Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. J Am Coll Cardiol 2006; 47: 1919-26. 18 Esposito I, Proto MC, Gazzerro P, Laezza C, Miele C, Alberobello AT, et al. The cannabinoid CB1 receptor antagonist rimonabant stimulates 2-deoxyglucose uptake in skeletal muscle cells by regulating the expression of phosphatidylinositol-3-kinase. Mol Pharmacol 2008; 74: 1678-86. 19 Rukwied R, Gauter B, Schley M, Konrad C. Cannabinoide—signaltransduktion und wirkung. Schmerz 2005; 19: 528-34. 20 Felder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol 1998; 38: 179-200. 21 Tasken K, Aandahl EM. Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A. Physiol Rev 2004; 84: 137-67. 22 Taylor SS, Buechler JA, Yonemoto W. Camp-Dependent Protein Kinase: Framework for a Diverse Family of Regulatory Enzymes. Annu Rev Biochem 1990; 59: 971-1005. 23 Manni S, Mauban JH, Ward CW, Bond M. Phosphorylation of the PKA regulatory subunit modulates PKA-AKAP interaction, substrate phosphorylation and calcium signaling in cardiac cells. J Biol Chem 2008; 283: 24145-54. 24 Koga S, Morris S, Ogawa S, Liao H, Bilezikian JP, Chen G, et al. TNF modulates endothelial properties by decreasing cAMP. Am J Physiol Cell Physiol 1995; 268: C1104-13. 25 Xu S-Q, Mahadev K, Wu X, Fuchsel L, Donnelly S, Scalia RG, et al. Adiponectin Protects Against Angiotensin II or Tumor Necrosis Factor α-Induced Endothelial Cell Monolayer Hyperpermeability: Role of cAMP/PKA Signaling. Arterioscler Thromb Vasc Biol 2008; 28: 899-905. 26 Kobashi C, Urakaze M, Kishida M, Kibayashi E, Kobayashi H, Kihara S, et al. Adiponectin Inhibits Endothelial Synthesis of Interleukin-8. Circ Res 2005; 97: 1245-52. 27 Liang Y-J, Shyu K-G, Wang B-W, Lai L-P. C-reactive protein activates the nuclear factor-κB pathway and induces vascular cell adhesion molecule-1 expression through CD32 in human umbilical vein endothelial cells and aortic endothelial cells. J Mol Cell Cardiol 2006; 40: 412-20. 28 Huang N-L, Chiang S-H, Hsueh C-H, Liang Y-J, Chen Y-J, Lai L-P. Metformin inhibits TNF-α-induced IκB kinase phosphorylation, IκB-α degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. Int J Cardiol 2009; 134: 169-75. 29 Huang N-L, Juang J-M, Wang Y-H, Hsueh C-H, Liang Y-J, Lin J-L, et al. Rimonabant inhibits TNF-α-induced endothelial IL-6 secretion via CB1 receptor and cAMP-dependent protein kinase pathway. Acta Pharmacol Sin 2010; APS-11278.R1. 30 Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol Rev 2002; 54: 161-202. 31 Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor-κB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006; 47: 1183-88. 32 Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells. Arterioscler Thromb Vasc Biol 2006; 26: 611-17. 33 Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-Aminoimidazole-4-carboxamide ribonucleoside. Eur J Biochem 1995; 229: 558-65. 34 Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003; 3: 745-56. 35 Carlsen H, Alexander G, Austenaa LMI, Ebihara K, Blomhoff R. Molecular imaging of the transcription factor NF-κB, a primary regulator of stress response. Mut Res 2004; 551: 199-211. 36 Zou M-H, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WGIV, Schlattner U, et al. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochndrial reactive nitrogen species. J Biol Chem 2004; 279: 43940-51. 37 Kovacic S, Soltys CLM, Barr AJ, Shiojima I, Walsh K, Dyck JRB. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 2003; 278: 39422-27. 38 Bertrand L, Ginion A, Beauloye C, Hebert AD, Guigas B, Hue L, et al. AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B. Am J Physiol - Heart Circ Physiol 2006; 291: H239-50. 39 Horman S, Vertommen D, Heath R, Neumann D, Mouton V, Woods A, et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase α-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem 2006; 281: 5335-40. 40 Beauloye C, Marsin AS, Bertrand L, Krause U, Hardie DG, Vanoverschelde JL, et al. Insulin antagonizes AMP-activated protein kinase activation by ischemia or anoxia in rat hearts, without affecting total adenosine nucleotides. FEBS Lett 2001; 505: 348-52. 41 Despre´s J-P, Ross R, Boka G, Alme´ras N, Lemieux I, Investigators ftA-L. Effect of rimonabant on the high-triglyceride/ low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-lipids trial. Arterioscler Thromb Vasc Biol 2009; 29: 416-23. 42 Dol-Gleizes F, Paumelle R, Visentin V, Marés A-M, Desitter P, Hennuyer N, et al. Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2009; 29: 12-18. 43 Schafer A, Pfrang J, Neumuller J, Fiedler S, Ertl G, Bauersachs J. The cannabinoid receptor-1 antagonist rimonabant inhibits platelet activation and reduces pro-inflammatory chemokines and leukocytes in Zucker rats. Br J Pharmacol 2008; 154: 1047-54. 44 Marini P, Moriello AS, Cristino L, Palmery M, De Petrocellis L, Di Marzo V. Cannabinoid CB1 receptor elevation of intracellular calcium in neuroblastoma SH-SY5Y cells: Interactions with muscarinic and [delta]-opioid receptors. BBA-Mol Cell Res 2009; 1793: 1289-303. 45 Sugiura T, Kodaka T, Nakane S, Kishimoto S, Kondo S, Waku K. Detection of an endogenous cannabimimetic molecule, 2-arachidonoylglycerol, and cannabinoid CB1 receptor mRNA in human vascular cells: is 2-arachidonoylglycerol a possible vasomodulator? Biochem Biophys Res Commun 1998; 243: 838-43. 46 Lepicier P, Lagneux C, Sirois MG, Lamontagne D. Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts. Life Sci 2007; 81: 1373-80. 47 Schley M, Ständer S, Kernerd J, Vajkoczy P, Schüpfer G, Dusch M, et al. Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain Res Bull 2009; 79: 333-37. 48 Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994; 350: 240. 49 Hillard CJ, Manna S, Greenberg MJ, Dicamelli R, Ross RA, Stevenson LA, et al. Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 1999; 289: 1427-33. 50 A. Lochner JAM. The Many Faces of H89: A Review. Cardiovasc Drug Rev 2006; 24: 261-74. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46115 | - |
| dc.description.abstract | 研究背景
根據近年的基礎研究結果顯示，血管發炎反應在動脈粥狀硬化的病程發生中扮演著相當重要的角色。而在現今可取得的治療藥物當中，口服降血糖劑metformin與抗肥胖劑rimonabant (SR141716)，都有研究報告指出其改善病人的整體代謝功能。本篇研究之宗旨在於調查metformin和rimonabant對於血管內皮細胞是否具有抗發炎的功效，以及其中相關的分子機轉。 實驗方法 本篇採用人類臍靜脈內皮細胞，以及TNF-α處理細胞所引起之IL-6生成和NF-κB路徑之活化，作為發炎反應的研究模式，測試metformin和rimonabant對於此發炎反應所產生的影響，同時也利用調節相關路徑的方法來找出參與其中的訊息傳遞分子。 實驗結果 TNF-α促使人類臍靜脈內皮細胞的IL-6生成量增加。此誘發量與TNF-α的濃度成正相關。而NF-κB抑制劑則會阻止該誘發反應。 若以metformin (100-1000 umol/L)預處理內皮細胞，會抑制TNF-α所誘發之IL-6生成，IKKα/β磷酸化，以及IκB-α的分解。此預處理metformin而減弱IκB-α分解的效果，若同時以wortmannin (PI3K抑制劑)預處理則會抵消。Metformin使AMPK的磷酸化增加，而此增幅亦為wortmannin所消除。AMPK活化劑AICRA對於TNF-α所誘發之IL-6具有與metformin相似的抑制效果。利用轉染siRNA的方式減少內皮細胞的AMPK表現量，則可阻止metformin對其抑制作用，顯示AMPK在此抑制效果中的必要性。 Rimonabant是一種CB1 antagonist。無論是以1或10 umol/L的rimonabant，預處理15, 30或60分鐘，對於TNF-α所誘發之IL-6生成皆具有顯著的抑制效果。Rimonabant同時也抑制了誘發性的IKKα/β磷酸化，以及IκB-α的分解。若在rimonabant之前預處理CB1致活劑ACEA，則能阻止前述抑制效果。PKA抑制劑H-89亦能消除此抑制作用。Rimonabant增加了細胞內的cAMP含量以及PKA調節性次單位(PKA-RII)的磷酸化，顯示PKA的活化對於rimonabant作用之必要性。預處理wortmannin則不影響rimonabant抑制TNF-α所誘發IL-6生成的效果。 結論 在人類臍靜脈內皮細胞，TNF-α所誘發之IL-6生成、IKKα/β磷酸化、以及IκB-α的分解，皆為metformin與rimonabant所抑制。Metformin的作用機轉與AMPK的磷酸化相關，且此AMPK磷酸化反應具有PI3K依賴性。而另一方面，rimonabant的抗發炎功效則依賴CB1受體拮抗效果以及PKA的活化。 | zh_TW |
| dc.description.abstract | Background
Recent evidence in basic research has shown that vascular inflammation plays an important role in the pathogenesis of atherosclerosis. Among currently available therapeutic agents, the oral hypoglycemic metformin and the anti-obesity rimonabant (SR141716) have been reported to improve metabolic profile of patients. The purpose of the present study was to investigate the possible anti-inflammatory effects of metformin and rimonabant on vascular endothelial cells and the related molecular mechanisms. Methods Human umbilical vein endothelial cell (HUVEC) was used for the experiments. The effects of metformin and rimonabant on TNF-α-induced IL-6 production and NF-κB pathway were investigated. Modulation of related signal transduction pathway was also performed. Results TNF-α increased IL-6 secretion by HUVEC in a concentration-dependent manner but inhibitors of NF-κB abolished the TNF-α-induced IL-6 production. Pre-treatment with metformin (100–1000 μmol/L) also inhibited TNF-α-induced IL-6 production, phosphorylation of IKKα/β and IκB-α degradation. Metformin increased phosphorylation of AMPK but wortmannin, a PI3K inhibitor, negated its effects on AMPK phosphorylation and TNF-α-induced IκB-α degradation. AICAR, a direct AMPK activator, had inhibitory effects on TNF-α-induced IL-6 production, similar to that of metformin. Transfection of siRNA against α1-AMPK eradicated the inhibitory effects of metformin on TNF-α-induced IL-6, implying the essential role of AMPK. Rimonabant at 1 and 10 μmol/L significantly inhibited TNF-α-induced IL-6 production when added at 15, 30 and 60 minutes before TNF-α treatment. Rimonabant also inhibited TNF-α-induced phosphorylation of IKK α/β and IκB-α degradation. ACEA, a CB1 agonist, added before rimonabant abolished the former effects of rimonabant. H-89, an inhibitor of PKA, abolished the inhibitory effects of rimonabant on TNF-α induced IL-6 production. Rimonabant also increased cellular cAMP contents and the phosphorylation of PKA regulatory subunit II (PKA-RII), implying the essential role of PKA activation in the inhibitory effects of rimonabant. Treatment with wortmannin did not abolish the inhibitory effects of rimonabant on TNF-α induced IL-6 production. Conclusions Both metformin and rimonabant inhibited TNF-α-induced IKKα/β phosphorylation, IκB-α degradation and IL-6 production in HUVEC. This effect of metformin was related to PI3K-dependent AMPK phosphorylation. On the other hand, the anti-inflammatory effect of rimonabant was dependent on CB1 antagonism and PKA activation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T04:54:26Z (GMT). No. of bitstreams: 1 ntu-99-F93443002-1.pdf: 2788127 bytes, checksum: c0b065ea315c87078e331643f25523aa (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 口試委員會審定書…………………………………………………… i
誌謝…………………………………………………………………… ii 中文摘要…………………………………………………………… iii Abstract…………………………………………………………… vii Abbreviations……………………………………………………… xi Chapter 1 Introduction…………………………………………… 1 Chapter 2 Materials and Methods……………………………… 18 Chapter 3 Results………………………………………………… 24 3.1 The experiment model of vascular inflammation……… 25 3.2 Effects and mechanisms of metformin ………………… 25 3.3 Effects and mechanisms of rimonabant………………… 33 Chapter 4 Discussion…………………… ……………………… 43 4.1 Potential molecular mechanisms of metformin………… 44 4.2 Potential signal pathways of rimonabant……………… 47 Chapter 5 Perspective…………………………………………… 53 Chapter 6 References……………………………………………… 57 | |
| dc.language.iso | en | |
| dc.subject | 血管內皮細胞 | zh_TW |
| dc.subject | 發炎反應 | zh_TW |
| dc.subject | Metformin | zh_TW |
| dc.subject | 致活蛋白激脢 | zh_TW |
| dc.subject | Rimonabant | zh_TW |
| dc.subject | 單磷酸腺苷 | zh_TW |
| dc.subject | 類大麻鹼受體拮抗劑 | zh_TW |
| dc.subject | 動脈粥狀硬化 | zh_TW |
| dc.subject | cAMP 依賴性蛋白激脢 | zh_TW |
| dc.subject | Rimonabant | en |
| dc.subject | Atherosclerosis | en |
| dc.subject | AMP-activated protein kinase | en |
| dc.subject | Cannabinoid receptor antagonist | en |
| dc.subject | cAMP-dependent protein kinase | en |
| dc.subject | Vascular endothelial cells | en |
| dc.subject | Inflammation | en |
| dc.subject | Metformin | en |
| dc.title | Metformin 與Rimonabant (SR141716)對於TNF-α 所引起
內皮細胞發炎反應之抑制作用與機轉 | zh_TW |
| dc.title | Inhibitory effects and mechanisms of metformin and
rimonabant on TNF-α induced endothelial inflammatory response | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 蘇銘嘉(Ming-Ja Su) | |
| dc.contributor.oralexamcommittee | 蔡佳醍(Chia-Ti Tsai),江福田(Fu-Tien Chiang),林正一(Cheng-I Lin),顏茂雄(Mao-Hsiung Yen) | |
| dc.subject.keyword | 動脈粥狀硬化,單磷酸腺苷,致活蛋白激脢,類大麻鹼受體拮抗劑,cAMP 依賴性蛋白激脢,血管內皮細胞,發炎反應,Metformin,Rimonabant, | zh_TW |
| dc.subject.keyword | Atherosclerosis,AMP-activated protein kinase,Cannabinoid receptor antagonist,cAMP-dependent protein kinase,Vascular endothelial cells,Inflammation,Metformin,Rimonabant, | en |
| dc.relation.page | 65 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-07-30 | |
| 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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