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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/86459完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王淑慧(Shu-Huei Wang) | |
| dc.contributor.author | Ting-Yu Chang | en |
| dc.contributor.author | 張庭瑜 | zh_TW |
| dc.date.accessioned | 2023-03-19T23:57:04Z | - |
| dc.date.copyright | 2022-10-03 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-08-17 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/86459 | - |
| dc.description.abstract | 血管支架再狹窄(In-stent restenosis)普遍被視為血管支架植入所導致的後遺症。支架的裝設易導致血管內膜損傷，使血管平滑肌細胞直接接觸到血流中的生長因子及促發炎物質，誘導平滑肌細胞的表型轉換，從收縮型往合成型轉變。越來越多證據顯示，合成型平滑肌細胞會有異常增生、移行的表現，導致血管新生內膜的過度增厚(neointimal hyperplasia)。因此，抑制異常的血管平滑肌細胞增生及移行，是血管再狹窄治療上的重要方針。 本篇選擇的研究藥物異黃腐酚(Isoxanthohumol, IXN)是一種從啤酒花及苦參中萃取出的天然黃酮類化合物，在眾多癌症研究中已證實其具有抑制細胞增生、移行及抗發炎的能力，然而IXN對於血管再狹窄的影響仍舊未知，因此本篇主旨在探討IXN是否對血管再狹窄具有治療作用。 實驗分為細胞及動物實驗進行，細胞實驗以大鼠主動脈平滑肌細胞及U937細胞，觀察IXN是否能抑制經血小板衍生生長因子(PDGF)和腫瘤壞死因子(TNF-α)誘導之平滑肌細胞增生、移行，及發炎反應；動物實驗使用C57BL/6小鼠建立股動脈去內皮創傷模型，研究IXN對於抑制血管內膜過度增厚的效果。研究結果表明，在體外試驗中IXN能透過抑制AKT磷酸化降低細胞週期調控蛋白(CDK4、Cyclin D1、CDK2和p21)和平滑肌細胞移行前緣的F-actin表現，抑制PDGF誘導之平滑肌細胞增生及移行。另外，IXN通過抑制AKT磷酸化來降低經TNF-α誘導之黏附因子(VCAM-1、ICAM-1)的表現，並減少單核球黏附平滑肌細胞。在動物實驗的結果表明，IXN顯著降低因血管內膜受損所導致的新生內膜過度增厚。根據目前研究結果顯示，IXN具有預防及治療血管相關之增生性疾病的潛力。 | zh_TW |
| dc.description.abstract | In-stent restenosis (ISR) is widely recognized as an sequelae of vascular stent implantation. Stent implantation causes the tunica intima layer damage, which causes vascular smooth muscle cells (VSMCs) directly exposing to growth factors and inflammatory mediators and bring to phenotypic switching of VSMCs from contractile to synthetic phenotype. Growing evidence showed that synthetic type of VSMCs possesses abnormal proliferation, and migration in the tunica intima layer, resulting in neointimal hyperplasia (NIH). Inhibition of abnormal VSMC proliferation and migration has become the most important strategy on therapy and treatment of restenosis. Isoxanthohumol (IXN), a nature flavonoid extracted from Humulus lupulus and Sophora flavescens, has been reported to have various effects, including anti-proliferative, anti-migratory and anti-inflammatory in numerous cancer research. Even though it is very effective against cancer cells, the effects of IXN in restenosis is still unclear. The aim of this study is to investigate whether IXN has therapeutic effects on vascular restenosis. In cell experiments, Rat aortic smooth muscle cells (RASMCs) and U937 cells were used to examine the anti-proliferation, anti-migration and anti-inflammation of IXN on platelet-derived growth factor (PDGF)- and tumor necrosis factor-alpha (TNF-α)-treated RASMCs. In animal experiments, we used C57BL/6 mice to establish a vascular endothelial damage model to study the therapeutic effect of IXN on neointimal hyperplasia. In the in vitro assay, the present study showed that IXN has the ability to inhibit PDGF induced proliferation and migration of RASMCs through downregulating the expression of cell cycle regulatory protein (CDK4, Cyclin D1, CDK2, and p21) and F-actin. In addition, IXN significantly decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte adhesion induced by TNF-α by AKT phosphorylation. In the in vivo study, IXN reduced the neointimal hyperplasia induced by endothelial-denudation. Based on the above results, IXN represent a therapeutic candidate for the prevention and treatment of vascular proliferative diseases. | en |
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| dc.description.tableofcontents | 口試委員會審定書 I 誌謝 II 摘要 III Abstract IV 目錄 VI 壹、 緒論 1 前言 1 動脈粥樣硬化(Atherosclerosis)之形成 1 血管支架再狹窄化(In-stent restenosis)的成因 2 平滑肌細胞與血管支架再狹窄化的關係 3 細胞週期與平滑肌細胞增生之關聯 3 細胞骨架與平滑肌細胞移行之關聯 3 單核球細胞與平滑肌細胞發炎之關聯 4 平滑肌細胞受PDGF、TNF-α誘導之分子機制 4 異黃腐酚(Isoxanthohumol)和心血管疾病之關聯 4 研究動機和實驗設計 5 貳、 實驗材料 7 儀器設備 7 實驗材料 7 藥品 7 細胞培養 7 結晶紫染色 8 乳酸脫氫酶細胞毒性試驗 8 西方墨點法 8 免疫細胞螢光染色 9 流式細胞儀 10 動物實驗 10 免疫組織化學染色 10 免疫組織螢光染色 10 溶液配置 11 參、 實驗方法 13 細胞實驗(In vitro) 13 細胞株之培養 13 結晶紫染色 13 乳酸脫氫酶細胞毒性試驗 13 BrdU細胞增殖試驗 14 流式細胞儀分析 14 西方墨點法 15 細胞傷口癒合試驗&細胞移行能力試驗 16 Phalloidin染色 17 單核球黏附試驗 18 動物實驗(In vivo) 18 小鼠股動脈去內皮傷害模式 18 Weigert’s resorcin fuchsin染色 19 免疫螢光染色 19 數據統計分析 20 肆、 實驗結果 21 IXN對於平滑肌細胞的毒性測試 21 IXN降低PDGF誘導轉型成合成型平滑肌細胞的標誌蛋白表現 21 IXN具有抑制經PDGF誘導之平滑肌細胞增生的功能 21 IXN經調控細胞週期及相關蛋白表現來抑制平滑肌細胞增生 22 IXN具有抑制經PDGF誘導之平滑肌細胞移行的功能 22 IXN具有抑制經TNF-α誘導之平滑肌細胞發炎的功能 23 IXN具有抑制血管受損後內膜異常增厚的效果 24 IXN能降低血管平滑肌細胞之合成型平滑肌細胞標誌蛋白表現 24 IXN能抑制血管內膜之平滑肌細胞增生 24 IXN能降低血管內膜增生之平滑肌細胞發炎反應 25 IXN藉由AKT路徑調控平滑肌細胞反應 25 IXN藉由抑制AKT磷酸化降低PDGF誘導之平滑肌細胞表型轉換 26 IXN藉由抑制AKT磷酸化降低PDGF誘導之平滑肌細胞增生 26 IXN藉由抑制AKT磷酸化降低PDGF誘導之平滑肌細胞移行 27 IXN藉由抑制AKT磷酸化降低TNF-α誘導之平滑肌細胞發炎反應 28 伍、 討論 29 陸、 附圖 34 圖一、 IXN對平滑肌細胞的毒性測試 34 圖二、 IXN降低PDGF誘導轉型成合成型平滑肌細胞的標誌蛋白表現 35 圖三、 IXN能抑制經PDGF誘導之平滑肌細胞增生 36 圖四、 IXN經調控細胞週期及相關蛋白抑制平滑肌細胞增生 37 圖五、 IXN具有抑制經PDGF誘導之平滑肌細胞移行的功能 38 圖六、 IXN降低平滑肌細胞移行前緣之F-actin堆積 39 圖七、 IXN抑制平滑肌細胞經TNF-α誘導之黏附因子表現 40 圖八、 IXN能抑制TNF-α誘導之平滑肌細胞發炎反應 41 圖九、 IXN具有抑制血管受損後內膜異常增厚的效果 42 圖十、 IXN能降低血管平滑肌細胞之合成型平滑肌細胞標誌蛋白表現 43 圖十一、 IXN能抑制血管內膜之平滑肌細胞增生 44 圖十二、 IXN能降低血管內膜增生之平滑肌細胞黏附因子表現 45 圖十三、 IXN能降低血管內膜增生之平滑肌細胞發炎反應 46 圖十四、 IXN藉由AKT路徑調控平滑肌細胞 47 圖十五、 IXN能降低血管內膜增生之平滑肌細胞內p-AKT表現 48 圖十六、 IXN藉由抑制AKT磷酸化降低PDGF誘導之細胞表型轉換 49 圖十七、 IXN藉由抑制AKT磷酸化降低PDGF誘導之平滑肌細胞增生 50 圖十八、 IXN藉由AKT路徑調控細胞週期調控蛋白表現 51 圖十九、 IXN藉由抑制AKT磷酸化降低PDGF誘導之平滑肌細胞移行 52 圖二十、 IXN藉由抑制AKT磷酸化降低F-actin於細胞移行前緣聚集 53 圖二十一、 IXN藉由抑制AKT磷酸化降低TNF-α誘導之黏附因子表現 54 圖二十二、 IXN藉由抑制AKT磷酸化降低TNF-α誘導之細胞發炎反應 55 圖二十三、 IXN調控AKT路徑降低平滑肌細胞之增生、移行和發炎反應 56 柒、 參考文獻 57 | |
| dc.language.iso | zh-TW | |
| dc.subject | 血管支架再狹窄 | zh_TW |
| dc.subject | 異黃腐酚 | zh_TW |
| dc.subject | 平滑肌細胞 | zh_TW |
| dc.subject | 增生 | zh_TW |
| dc.subject | 移行 | zh_TW |
| dc.subject | 發炎 | zh_TW |
| dc.subject | 異黃腐酚 | zh_TW |
| dc.subject | 血管支架再狹窄 | zh_TW |
| dc.subject | 平滑肌細胞 | zh_TW |
| dc.subject | 增生 | zh_TW |
| dc.subject | 移行 | zh_TW |
| dc.subject | 發炎 | zh_TW |
| dc.subject | in-stent restenosis | en |
| dc.subject | migration | en |
| dc.subject | inflammation | en |
| dc.subject | Isoxanthohumol | en |
| dc.subject | smooth muscle cells | en |
| dc.subject | Isoxanthohumol | en |
| dc.subject | inflammation | en |
| dc.subject | migration | en |
| dc.subject | proliferation | en |
| dc.subject | in-stent restenosis | en |
| dc.subject | smooth muscle cells | en |
| dc.subject | proliferation | en |
| dc.title | Isoxanthohumol在血管支架再狹窄化的治療效果及相關機制 | zh_TW |
| dc.title | The therapeutic effects and the relative mechanisms of Isoxanthohumol on Restenosis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王仰高(Yang-Kao Wang),龔秀妮(Hsiu-Ni Kung) | |
| dc.subject.keyword | 異黃腐酚,血管支架再狹窄,平滑肌細胞,增生,移行,發炎, | zh_TW |
| dc.subject.keyword | Isoxanthohumol,in-stent restenosis,smooth muscle cells,proliferation,migration,inflammation, | en |
| dc.relation.page | 63 | |
| dc.identifier.doi | 10.6342/NTU202202258 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2022-08-17 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
| dc.date.embargo-lift | 2027-08-16 | - |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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|---|---|---|---|
| U0001-1008202214420800.pdf 此日期後於網路公開 2027-08-16 | 5 MB | Adobe PDF |
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