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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉興華 | |
| dc.contributor.author | Ken-Tzu Fan | en |
| dc.contributor.author | 范耿慈 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:18:39Z | - |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-07-26 | |
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Mamputu JC, Renier G: Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide. Diabetes, Obesity & Metabolism 2004, 6(2):95-103. 52. Noguchi T, Sado T, Naruse K, Shigetomi H, Onogi A, Haruta S, Kawaguchi R, Nagai A, Tanase Y, Yoshida S et al: Evidence for activation of Toll-like receptor and receptor for advanced glycation end products in preterm birth. Mediators of Inflammation 2010, 2010:490406. 53. Chavakis T, Bierhaus A, Nawroth PP: RAGE (receptor for advanced glycation end products): a central player in the inflammatory response. Microbes and Infection / Institut Pasteur 2004, 6(13):1219-1225. 54. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P et al: RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999, 97(7):889-901. 55. Koch AE, Kunkel SL, Burrows JC, Evanoff HL, Haines GK, Pope RM, Strieter RM: Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. Journal of Immunology (Baltimore, Md : 1950) 1991, 147(7):2187-2195. 56. Scheinecker C, Redlich K, Smolen JS: Cytokines as therapeutic targets: advances and limitations. Immunity 2008, 28(4):440-444. 57. Ishihara K, Tsutsumi K, Kawane S, Nakajima M, Kasaoka T: The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS letters 2003, 550(1-3):107-113. 58. Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT, Tilton RG, Denner L: Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 2001, 50(6):1495-1504. 59. Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M: Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. The Journal of Rheumatology 1997, 24(2):365-371. 60. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B: Synovial tissue inflammation in early and late osteoarthritis. Annals of the Rheumatic Diseases 2005, 64(9):1263-1267. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17527 | - |
| dc.description.abstract | 老年人為罹患退化性關節炎(osteoarthritis, OA)的高風險族群，其重要病理現象為滑膜增生、軟骨退化及骨頭的破壞等。糖化終產物(advanced glycation end products, AGEs)在老年人糖尿病患者體內大量累積，尤其在關節處。過去研究指出，AGEs 會 經 由 mitogen-activated protein kinase (MAPK) 以 及 nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)途徑增加 OA 軟骨細胞及滑膜
細胞中 receptor for AGEs (RAGE)及基質金屬蛋白酶(matrix metalloproteinases, MMPs)表現量，並誘導關節軟骨細胞表現cyclooxygenase 2 (COX-2)、prostaglandin E2 和 MMPs 等，造成軟骨受損；另外，文獻指出類風溼性關節炎滑膜細胞增生乃經由誘導 receptor activator of NF-κB ligand (RANKL)引發巨噬細胞分化為蝕骨細胞， 蝕骨細胞會吸收骨質造成骨頭受損。目前 AGEs 在糖尿病患者引起關節炎的角色， 研究尚未透徹。本研究利用糖尿病老鼠模式以及人類滑膜細胞探討 AGEs 在生理 病理所扮演的角色及分子機制的調控。在 in vivo 部分，利用streptozoticin 誘導的糖尿病老鼠，由免疫組織染色觀察到糖尿病老鼠軟骨及滑膜大量累積 AGEs；由Safranin O.染色結果有軟骨受損及滑膜增生的現象。持續在糖尿病老鼠的每日飲水給予 aminoguanidine 五週，降低軟骨及滑膜 AGEs 的累積量，並有效預防關節受損及滑膜增生，顯示關節傷害是由 AGEs 造成。在 in vitro 部分，以人類滑膜處理 AGEs 24 小時，MTT 及 BrdU assay 結果顯示 AGEs 在劑量 200 μg/ml 時有細胞增生的現象；西方墨點法結果發現AGEs 誘導 p-ERK, p-Akt, p-P65 和發炎介質 COX-2 的表現量；處理 p-ERK 抑制劑降低 AGEs 所引起的滑膜細胞增生；處理 RAGE 抗體有效抑制 AGEs 所誘導 p-ERK, p-Akt 和 p-P65 的表現量。另外，AGEs 增加滑膜細胞 RANKL 表現量，誘導巨噬細胞分化成蝕骨細胞，由 TRAP 染色結果顯示蝕骨細胞的生成。實驗結果顯示，AGEs在關節中的累積的確造成滑膜增厚及關節傷害，且透過 RAGE-MAPK-NF-κB 誘導滑膜細胞的增生引起發炎生成，並促進蝕骨細胞分化。根據以上研究顯示，AGEs 為糖尿病患者罹患退化性關節炎的一項風險因 子。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:18:39Z (GMT). No. of bitstreams: 1 ntu-102-R00447001-1.pdf: 4055835 bytes, checksum: 16c8b1f5e8f7ecd779264a5474395501 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 碩士學位論文口試委員會審定書 I
誌謝 II 中文摘要 III Abstract V Abbreviations VII CHAPTER I Introduction 1-16 1 Diabetes mellitus 1 2 Knee arthritis 3 Figure 1. The synovial joint: normal versus rheumatoid. 5 Figure 2. Synoviocytes of normal knee joint versus arthritis knee joint. 6 Fig 3. Major tissue destructive pathways in the rheumatoid joint. 8 3 Advanced glycation end-products (AGEs) 9 4 Diabetic articular cimplications 11 Table 1 Cross-sectional studies on OA and diabetes 13 Figure 6.A general paradigm for a diabetes-induced OA phenotype. 15 5 Aims 16 6. Experimental design 16 Figure 8 Experimental design 16 CHAPTER II Materials and Methods 17-24 Figure A. In Vivo flow chart 18 Figure B Flow chart of osteoclastogenesis 21 CHAPTER III Results 25-30 1. Diabetes increased the progression osteoarthritis 25 2. AGEs influenced diabetes-induced osteoarthritis 26 3. AGEs increased synoviocytes cell viability 26 4. AGEs increased synoviocytes proliferation 27 5. Synoviocytes proliferation was regulated by p-ERK 28 6. AGEs induced protein expression of RAGE, p-ERK, p-Akt and p-P65 28 7. AGEs induced protein expression of COX-2 29 8. AGEs induced RANKL production and increase osteoclastogenesis in synoviocytes 30 CHAPTER IV Discussion 31-35 Figures 36-62Figure 1. H&E staining of cartilage destruction in STZ-induced mice. 36 Figure 2. Safranin O. staining of cartilage destruction in STZ-induced mice. 38 Figure 3. Cartilage was protected from destruction result from AG treatment in AG-treated STZ-diabetic mice. 39 Figure 4. Cartilage was protected from destruction result from AG treatment in AG-treated STZ-diabetic mice. 40 Figure 5. Epithelial layer of synovial hyperplasia in STZ-diabetic mice, AG prevent synovial membrane from hyperplasia in AG-treated STZ-diabetic mice. 41 Figure 6. Epithelial layer of synovial hyperplasia in STZ-diabetic mice, AG prevent synovial membrane from hyperplasia in AG-treated STZ-diabetic mice. 42 Figure 7. Immunohistochemical analysis of AGE expression of cartilage in STZ-diabetic and AG-treated- STZ-diabetic mice. 44 Figure 8. Immunohistochemical analysis of AGE expression of synovial membrane in STZ-diabetic and AG-treated- STZ-diabetic mice. 46 Figure 9. AGEs induce cell proliferation in synoviocytes 47 Figure 10. AGEs induce cell proliferation in synoviocytes 48 Fig11. AGE-induced synoviocytes proliferation was regulated by ERK signaling pathway. 50 Figure 12. ERK, Akt and NF-κB is involved in AGE-induced FLS proliferation. 52 Figure 13. ERK, P65, JNK, and RAGE is involved in AGE-induced synoviocytes proliferation. 54 Figure 14. Akt signaling is involved in AGE-induced FLS proliferation. 55 Figure 15. COX-2 but not mTOR is involved in AGE-induced synoviocytes inflammation. 56 Figure 16. AGEs increase p-ERK, p-Akt and p-P65 expression in synoviocyte through RAGE signaling pathway. 58 Figure17. The proposed schematic representation of AGEs-induced synoviocytes proliferation and inflammatory signaling pathway. 59 Figure18.The proposed schematic representation of RAGE down regulated AGEs-induced synoviocytes proliferation and inflammatory signaling pathway. 59 Figure19. AGEs induce RANKL production in FLS, and increase osteoclastogenesis in RAW264.7. 62 Supplementary Figures 63 References 64-74 | |
| dc.language.iso | en | |
| dc.title | 糖化終產物於滑膜增生之生理病理作用及機制探討 | zh_TW |
| dc.title | The physiopathological effect and mechanism of advanced
glycation end-products on synovial hyperplasia | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蕭水銀,楊榮森 | |
| dc.subject.keyword | 糖化終產物,細胞增生,滑膜細胞, | zh_TW |
| dc.subject.keyword | Advanced glycation end products (AGEs),cell proliferation,synoviocytes, | en |
| dc.relation.page | 74 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-07-26 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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