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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉興華(Shing-Hwa Liu) | |
| dc.contributor.author | Meei-Ling Sheu | en |
| dc.contributor.author | 許美鈴 | zh_TW |
| dc.date.accessioned | 2021-06-13T17:25:20Z | - |
| dc.date.available | 2005-02-16 | |
| dc.date.copyright | 2005-02-16 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-01-25 | |
| dc.identifier.citation | Reference
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/39281 | - |
| dc.description.abstract | 糖尿病為一常見的內分泌代謝疾病，目前已經成為公共衛生問題的一部份。在世界各地隨著肥胖人數日驅增加，糖尿病的人數也隨之顯著提高。而糖尿病對身體造成最大的問題是對實質性組織器官的傷害；尤其是心血管系統以及腎臟的影響。也由於在世界各地糖尿病的病人愈來愈多，其導致的複雜變化以及合併病發症更值得我們去重視。
糖尿病病人體內血糖過高的訊息是不可逆的並且最後導致組織器官的功能障礙或損傷。由過去的文獻報導以及臨床病人報告中已知：糖尿病的病理過程可引起血管內皮細胞功能缺失，造成的血管功能障礙、加速冠狀動脈硬化並對預後不佳。然而進一步地導致血管內皮細胞凋亡的機制至今仍不十分清楚。探討此一異常訊息是如何造成人類血管內皮細胞凋亡？其機制為何？進而如何避免糖尿病在人類心血管系統功能障礙及合併症的產生，以及病程的惡化是十分重要的課題。於本論文第一部分的研究主要為探討高血糖的狀態下誘導人類血管內皮細胞凋亡之機制，以及PI3K所調控之環氧化蛋白酶表現在其中的角色。本實驗發現暴露於高血糖的環境中皆可測得早期血管內皮細胞凋亡訊號。在細胞凋亡的形態學上以Hoechst染色觀察細胞形態以及以Annexin V/Propidium Iodide偵測早期細胞凋亡訊號。高血糖狀態也會誘導環氧化蛋白酶的表現增加，同時也誘導環氧化蛋白酶的下游產物PGE2生成，進而促使凋亡酶-3 (caspase-3)活性增強而導致細胞走向凋亡。出乎意外地，給予PI3K抑制劑皆可有效地抑制高血糖狀態之環氧化蛋白酶蛋白表現、環氧化蛋白酶的下游產物PGE2生成、凋亡酶-3活性和細胞凋亡。高血糖誘導PI3K活化也依序促使Akt的磷酸化。更進一步地，高血糖引發氧化自由基的生成和NF | zh_TW |
| dc.description.abstract | Diabetes has become a public health crisis. With the incidence of obesity rising in the world, the number of diabetics will grow considerably. Of greatest concern is the impact this trend will have on damage to the kidneys and cardiovascular disease. The incidence of diabetes is increasing worldwide, with subsequent increase in the incidence of diabetic complication. The hyperglycemic signal exchange occurs ubiquitously and irreversibly in patients with diabetes mellitus, and its consequences are especially relevant to organ dysfunctions. In type-2 diabetes, a greater proportion of patients have overt nephropathy at shortly and vascular complications after diagnosis of diabetes. In this thesis, the studies are divided into two parts for description. Diabetes has been demonstrated to accelerate vascular dysfunction, coronary atherosclerosis, and the prognosis were worse following cardiac events. Therefore, the part I will investigate the regulation of abnormal signalings that promote human umbilical vein endothelial cells apoptosis under high glucose condition and relevant in understanding the intracellular signaling associated with vascular disease and preventing the development of vascular complication in diabetics, principally the evolution of this practice from its beginning until cell death. Diabetes mellitus causes endothelial dysfunction. The precise molecular mechanisms by which hyperglycemia causes apoptosis in endothelial cells are not yet well understood. The aim of this study was to explore the role of cyclooxygenases-2 (COX-2) and the possible involvement of phosphoinositide 3-kinase (PI3K) signaling in high glucose (HG)-induced apoptosis in human umbilical vein endothelial cells (HUVECs). For detection of apoptosis, the morphological Hoechst staining and Annexin V/Propidium Iodide staining were used. Glucose up-regulated COX-2 protein expression, which was associated with the induction of prostaglandin E2 (PGE2), caspase-3 activity and apoptosis. Unexpectedly, we found that PI3K inhibitors could suppress COX-2 expression, PGE2 production, caspase-3 activity, and the subsequent apoptosis under HG condition. Glucose-induced activation of PI3K resulted in the down stream effector Akt phosphorylation. PI3K inhibitors effectively attenuated the intracellular reactive oxygen species (ROS) generation and NF- | en |
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| dc.description.tableofcontents | TABLE OF CONTENTS
中文摘要 1 Abstract 5 List of abbreviations 9 PART I CHAPTER 1 Introduction 1.1 Diabetes 'Basics' 11 1.2 Classification 11 1.3 Signs and complications 14 1.4 Endothelium cellS in cardiovascular system 16 1.5 The role of transcription factors in human umbilical vein endothelial cells pathophysiology of diabetes 17 1.6 The role of cyclooxygenase-2 (COX-2) in human umbilical vein endothelial cells pathophysiology of diabetes 18 1.7 The functions of glomerular mesangial cell 20 1.8 The role of glomerular mesangial cell in pathophysiology of diabetes 20 1.9 The role of COX-2 in glomerular mesangial cell 22 1.10 The role of NF- B in glomerular mesangial cell 24 1.11 The role of PI3K in glomerular mesangial cell 25 1.12 Purpose and rationales of present research 27 CHAPTER 2 Materials and Methods 28 2.1 Primary culture HUVECs 29 2.2 Apoptosis and Caspase-3/cpp32 activity 29 2.3 Phosphoinositide 3-kinase (PI3K) activity 30 2.4 Immunoblotting 30 2.5 Electrophoretic mobility shift assay (EMSA) 31 2.6 Reactive oxygen species production 31 2.7 PGE2 production 32 2.8 Mesangial cell culture 32 2.9 Cell proliferation assay MTS Assay 33 [3H]Thymidine incorporation 33 2.10 RT-PCR for COX-2 expression 34 2.11 Preparation of nuclear extracts 35 2.12 Transient transfection with dominant-negative vectors-DN-P85 and DN-Akt 35 2.13 Immunofluorescence staining for NF- B 36 2.14 Statistical analyses 36 CHAPTER 3 Results in endothelial cells 38 3.1 COX-2 protein expression and involvement in high glucose (HG)-induced apoptosis 38 3.2 PI3K activity and involvement in HG-induced COX-2 protein expression and apoptosis 38 3.3 Effects of PI3K inhibitors on HG-induced NF- | |
| dc.language.iso | en | |
| dc.subject | 訊息傳遞 | zh_TW |
| dc.subject | 高血糖 | zh_TW |
| dc.subject | 細胞增殖 | zh_TW |
| dc.subject | 死亡 | zh_TW |
| dc.subject | COX-2 | en |
| dc.subject | PI3K | en |
| dc.subject | apoptosis | en |
| dc.subject | proliferation | en |
| dc.subject | NFkB | en |
| dc.subject | HG | en |
| dc.title | 高血糖狀態調控細胞增殖及死亡訊息機制之探討 | zh_TW |
| dc.title | Studies on the cellular signaling pathways in hyperglycemia-induced cell proliferation and apoptosis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 林琬琬(Wan-Wan Lin),周逸鵬(Yat-Pang Chau),郭明良(Ming-Liang Kuo),蕭水銀(Shoei Yn Shiau) | |
| dc.subject.keyword | 高血糖,細胞增殖,死亡,訊息傳遞, | zh_TW |
| dc.subject.keyword | apoptosis,proliferation,NFkB,COX-2,HG,PI3K, | en |
| dc.relation.page | 108 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-01-25 | |
| 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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