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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林俊宏(Chun-Hung Lin) | |
| dc.contributor.author | Meng-Jung Ho | en |
| dc.contributor.author | 何孟容 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:13:47Z | - |
| dc.date.copyright | 2010-08-18 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-13 | |
| dc.identifier.citation | 1. Watanabe, K. (1936) Biochemical Studies on Carbohydrates: XXII. On Animal beta-N-Monoacetylglucosaminidase. Preliminary Report, J. Biochem. 24, 297-303.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22208 | - |
| dc.description.abstract | 退化性關節炎是一種常見的關節病變，其主要病症為關節軟骨組織中的胞外間質被不正常代謝降解，有報導指出在退化性關節炎病人的軟骨組織中，大量的乙醯胺基葡萄糖水解酶會被釋放到細胞外，進而可能降解胞外間質的主成分－醣胺多醣。本實驗室近年來開發出具有高度選擇性的乙醯胺基葡萄糖水解酶抑制劑(三號及四號化合物，Ki值分別為1.2 nM及0.69 nM)，在此研究中，將檢測其在退化性關節炎中減緩醣胺多糖降解的能力。研究結果顯示，在軟骨肉瘤細胞及事先給予發炎刺激的軟骨細胞中投以三號或四號化合物，都能夠有效增加細胞表面醣胺多醣的含量，對於從退化性關節炎病人身上分離得到之病變軟骨細胞給予200 nM三號化合物平均能夠提升三成之細胞表面醣胺多醣含量；除此之外，此二化合物經過證實也在細胞實驗中，對於乙醯胺基葡萄糖水解酶的相似酵素－葡萄胺醣水解酶，具有大於一千八百倍以上之選擇性，可減少用於治療時副作用發生的可能性。本研究成果提供了開發減緩退化性關節炎症狀之藥物的新方向。 | zh_TW |
| dc.description.abstract | Osteoarthritis (OA) is characterized by the degeneration of extracellular matrix glycosaminoglycans (GAGs) in articular cartilage. N-Acetyl-β-D-hexosaminidase (Hex) is reported to be the dominant GAG-degrading glycosidase released by chondrocytes in the synovial fluid of OA patients. On the basis of our previous study, discovery of potent and selective Hex inhibitors (compound 3, Ki = 1.2 nM ; compound 4, Ki = 0.69 nM), herein we demonstrated the levels of cell-associated GAGs to be significantly enhanced by addition of compound 3 or 4 in either human chondrosarcoma cells or IL-1β-treated human chondrocytes. Treatment of 200 nM compound 3 to chondrocytes from patients with OA increased 30% cell-associated GAGs in average. Moreover, the same compounds exhibited more than 1,800-fold higher in vivo selectivity for Hex than for O-GlcNAcase. The efficacy and selectivity of compound 3 and 4 support further investigations in the therapeutic development of OA. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:13:47Z (GMT). No. of bitstreams: 1 ntu-99-R97b46007-1.pdf: 3145609 bytes, checksum: 3ecd22df180a04a9386e8fc671edffd6 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | Table of contents
Abbreviations i 中文摘要 iii Abstract iv 1. Introduction 1 1.1 Hexosaminidase 1 1.2 Diseases related to hexosaminidase 2 1.2.1 Osteoarthritis 2 1.2.2 Lysosomal storage disorders 8 1.3 Development of potent and selective hexosaminidase inhibitors 13 1.3.1 Catalytic mechanism and active site 13 1.3.2 Review of developed hexosaminidase inhibitors 15 1.4 Specific aims 18 2. Material and methods 19 2.1 Materials 19 2.2 Assay for glycosidase activity 19 2.3 Cell culture 21 2.4 Analysis of O-GlcNAc-modified proteins 22 2.5 Detection of [35S]glycosaminoglycans 23 2.6 Detection of cell viability 24 2.7 Confocal flrorescence microscopy and imaging 25 2.8 Statisitcal analysis 25 3. Results and discussion 26 3.1 Model study － chondrosarcoma cells (SW1353) 26 3.1.1 Identification of hexosaminidase as the dominant extracellular glycosaminoglycan-degrading glycosidase 26 3.1.2 Effect of hexosaminidase inhibitors on glycosaminoglycan content 27 3.2 Normal human chondrocytes with cytokine stimulation 28 3.2.1 Identification of hexosaminidase as the dominant extracellular glycosaminoglycan-degrading glycosidase under cytokine stimulation 28 3.2.2 Effect of hexosaminidase inhibitors on glycosaminoglycan content 30 3.3 Chondrocytes from patients with osteoarthritis 31 3.3.1 Identification of hexosaminidase as the dominant extracellular glycosaminoglycan-degrading glycosidase 31 3.3.2 Effect of hexosaminidase inhibitors on glycosaminoglycan content 32 3.4 In vivo selectivity and effective dosage range of hexosaminidase inhibitors 33 4. Conclusion 36 5. References 37 6. Figures 56 | |
| dc.language.iso | en | |
| dc.subject | 退化性關節炎 | zh_TW |
| dc.subject | 醣胺多醣 | zh_TW |
| dc.subject | 乙醯胺基葡萄糖水解酶 | zh_TW |
| dc.subject | 抑制劑 | zh_TW |
| dc.subject | 葡萄胺醣 | zh_TW |
| dc.subject | hexosaminidase | en |
| dc.subject | osteoarthritis | en |
| dc.subject | O-GlcNAc | en |
| dc.subject | inhibitor | en |
| dc.subject | glycosaminoglycan | en |
| dc.title | 應用乙醯胺基葡萄糖水解酶抑制劑減緩退化性關節炎中醣胺多醣之降解 | zh_TW |
| dc.title | Hexosaminidase Inhibitors Reduce the Degradation of glycosaminoglycans in Osteoarthritis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊榮森(Rong-Sen Yang),陳佩燁(Pei-Yeh Chen),張崇毅(Chung-I Chang) | |
| dc.subject.keyword | 醣胺多醣,乙醯胺基葡萄糖水解酶,抑制劑,葡萄胺醣,退化性關節炎, | zh_TW |
| dc.subject.keyword | glycosaminoglycan,hexosaminidase,inhibitor,O-GlcNAc,osteoarthritis, | en |
| dc.relation.page | 73 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2010-08-15 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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