臺灣博碩士論文加值系統

過度醣化最終產物(advanced glycosylation end products, AGEs)被認為與老化及長期糖尿病病人體內所形成之蛋白質結構改變、功能異常有關。在本篇論文中，我們將大白鼠RAW 264.7巨噬細胞給予poly-L-lysine (PLL)-AGEs處理以探討環氧酵素-2 (cyclooxygenase-2, COX-2)蛋白的表現。在外加花生四烯酸(arachidonic acid)的情況下測量前列腺素E2 (prostaglandin E2, PGE2)的產量可發現PLL-AGEs在RAW 264.7巨噬細胞裡可促使環氧酵素-2活性呈劑量、時間依賴性的增加。PLL-AGEs亦可引發環氧酵素-2蛋白的表現，然而此作用並不影響環氧酵素-1 (cyclooxygenase-1, COX-1)蛋白的表現。Gamma-glutamylcysteine synthetase的抑制劑─L-buthionine-[S, R]-sulfoximine (BSO)或glutathione的前驅物─L-nitro-acetyl-cysteine (L-NAC)並不會影響PLL-AGEs刺激環氧酵素-2蛋白的表現，表示PLL-AGEs所引發之環氧酵素-2蛋白的表現並不源自於氧化壓力。另外，環氧酵素-2蛋白的表現也不受一氧化氮合成酶(nitric oxide synthase, NOS)之競爭型抑制劑─L-gamma-nitro-L-arginine methyl ester (L-NAME)以及脂多醣體(lipopolysacchride, LPS)之抑制劑─polymyxin B所抑制，表示此作用也不是經由誘導型一氧化氮合成酶的誘導或脂多醣體的污染而來。Tyrosine kinase的抑制劑─genistein和tyrphostin AG 126以及p38 mitogen-activated protein kinase (MAPK)的抑制劑─SB 203580可以抑制PLL-AGEs誘導環氧酵素-2之蛋白表現，但Ras的抑制劑─FPT II和MEK的抑制劑─PD 98059對PLL-AGEs所誘導之環氧酵素-2蛋白表現並沒有任何作用。利用PLL-AGEs刺激RAW 264.7巨噬細胞可活化p38 MAPK，此反應可被genistein和SB 203580所抑制。綜合以上結果可知protein tyrosine kinase及p38 MAPK的活化的確參與PLL-AGEs誘導環氧酵素-2蛋白表現之訊號傳遞路徑。

Advanced glycosylation end products (AGEs) have been implicated in the structural and functional alterations of proteins that occur during aging and long-term diabetes. In the present study, murine RAW 264.7 macrophages were incubated with poly-L-lysine (PLL)-AGEs to examine cyclooxygenase-2 (COX-2) protein expression. Treatment of RAW 264.7 cells with PLL-AGEs caused a dose-dependent increase in COX activity as reflected by PGE2 secretion (measured in the presence of exogenous arachidonic acid). Furthermore, treatment of RAW 264.7 cells with PLL-AGEs induced COX-2 but not COX-1 expression. The induction was affected by neither L-buthionine-[S, R]-sulfoximine (BSO), a gamma-glutamylcysteine synthetase inhibitor, nor by L-nitro-acetyl-cysteine (L-NAC), a known glutathione precursor, suggesting that AGEs-induced COX-2 expression is not due to reactive oxygen species. Moreover, COX-2 expression was affected by neither N-gamma-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of nitric oxide synthase (NOS), nor polymyxin B, a lipopolysaccharide (LPS) inhibitor, suggesting that COX-2 induction is not secondary to iNOS induction or LPS contamination. The tyrosine kinase inhibitor, genistein and tyrphostin AG 126, and the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 203580, inhibited PLL-AGEs-induced COX-2 expression, while the Ras inhibitor, FPT inhibitor II, and the MEK inhibitor, PD 98059, had no effect on PLL-AGEs-induced COX-2 expression. Incubation of RAW 264.7 cells with PLL-AGEs resulted in activation of p38 MAPK, and this activation was suppressed by genistein and SB 203580. Taken together, our results suggest that activation of protein tyrosine kinase and p38 MAPK is involved in AGEs-induced COX-2 expression in RAW 264.7 macrophages.

目錄 (Table of Contents)I
圖目錄 (List of Figures)III
縮寫表 (List of Abbreviations)V
中文摘要1
英文摘要3
第一章 前言 (Chapter 1 Introduction)5
壹、研究目的6
貳、文獻回顧8
一、過度醣化最終產物(Advanced glycosylation end products, AGEs) 8
二、前列腺素(Prostaglandins, PGs)10
三、環氧酵素(cyclooxygenase, COX)12
四、與過度醣化最終產物相關之訊號傳遞路徑14
五、與環氧酵素-2相關之訊號傳遞路徑14
第二章實驗儀器與材料 (Chapter 2 Experimental Instruments & Materials)17
壹、實驗儀器18
貳、實驗材料19
第三章 實驗方法 (Chapter 3 Experimental Methods) 22
一、PLL-AGEs的製備23
二、大白鼠巨噬細胞株RAW 264.7的培養23
三、前列腺素E2的測定24
四、西方墨點分析法24
五、p38 MAPK活性的測定25
六、數據分析26
第四章 實驗結果 (Chapter 4 Results)27
一、PLL-AGEs刺激環氧酵素活性和環氧酵素-2蛋白表現 28
二、PLL-AGEs刺激環氧酵素-2表現不是歸因於誘導型一氧化氮
合成酶、氧化壓力的產生或脂多醣體的污染33
三、PLL-AGE誘導環氧酵素活性和環氧酵素-2表現之作用機轉39
四、PLL-AGEs活化p38 Mitogen-Activated Protein Kinase47
第五章 討論 (Chapter 5 Discussion)50
第六章 參考文獻 (Chapter 6 References)55
圖目錄 (List of Figures)
Fig. 1. Concentration-dependent effects of poly-L-lysine-advanced glycosylation end products (PLL-AGEs) on COX activity and COX-2 expression in RAW 264.7 macrophages.29
Fig. 2. Time—dependent effects of PLL-AGEs on COX activity and COX-2 expression in RAW 264.7 macrophages.31
Fig. 3. Effects of N-gamma-nitro-L-arginine methyl ester (L-NAME), L-buthionine-[S, R]-sulfoximine (BSO) and L-nitro-acetyl-cysteine (L-NAC) on COX-2 expression induced by PLL-AGEs in RAW 264.7 macrophages.35
Fig. 4. Comparison between the effects of polymyxin B (PolB) on COX-2 expression induced by lipopolysaccharide (LPS) and PLL-AGEs in RAW 264.7 macrophages.37
Fig. 5. Effects of genistein and tyrphostin on COX activity and COX-2 expression induced by PLL-AGEs in RAW 264.7 macrophages. 40
Fig. 6. Effects of SB 203580 on COX activity and COX-2 expression induced by PLL-AGEs in RAW 264.7 macrophages. 43
Fig. 7. Effects of FPT inhibitor II (FPT) and PD 98059 (PD) on COX-2 expression induced by PLL-AGEs in RAW 264.7 macrophages. 45
Fig. 8. Effects of genistein and SB 203580 on p38 mitogen-activated protein kinase (MAPK) activity induced by PLL-AGEs in RAW 264.7 macrophages.48

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