三唑化合物作為自噬促進劑用於疾病治療 ; Triazole derivatives as autophagy enhancers
| العنوان: | 三唑化合物作為自噬促進劑用於疾病治療 ; Triazole derivatives as autophagy enhancers |
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| المؤلفون: | 謝長亨, Hsieh, Chang-Heng |
| المساهمون: | 方剛, Fang, Kang |
| سنة النشر: | 2019 |
| المجموعة: | National Taiwan Normal University: NTNU Institutional Repository / 國立臺灣師範大學圖書館 |
| مصطلحات موضوعية: | 細胞自噬, 多麩醯胺酸, 聚集物清除, 三唑化合物, JNK訊息傳遞, 神經退化疾病, 人類非小細胞肺癌細胞, 細胞凋亡, autophagic flux, polyglutamine, aggregates clearance, triazole, JNK pathway, neuronal disorders, human non-small-cell-lung-cancer cells, apoptosis |
| الوصف: | 本論文目的是鑑定三唑衍生物潛在用於治療神經退化疾病及非小細肺癌細胞的藥物。多麩醯胺酸造成的神經退化性疾病是因為神經細胞中基因座上出現過度CAG三核甘酸的重複序列所導致的疾病。利用增加細胞自噬清除多麩醯胺酸堆積，是一種可能的方式用來治療多麩醯胺酸相關神經疾病。在第一部分的論文中，利用表現多麩醯胺酸的細胞模式篩選一系列的候選藥物。從一系列三唑衍生物中篩選出化合物的藥物OC-13,它可以透過增強自噬特性，清除外來質體衍生的蛋白質ΔC-TBP-Q79-EGFP或Httex1-Q97-GFP造成多麩醯胺酸堆積，卻不會影響細胞活性。由螢光顯微鏡下觀察，表現擴增多麩醯胺酸的細胞經OC-13處理增加自噬小體，會清除超過５０％的蛋白質堆積。由西方墨點法分析顯示，OC-13促進LC3-I轉換為LC3-II以增進自噬體形成，而自噬抑制劑能阻斷OC-13清除多麩醯胺酸的功能。 論文第二部分利用增強細胞自噬主導的第二型計畫性細胞死亡可以用作於癌症的治療。透過細胞活性分析, colony forming assay, Annexin V染色及西方墨點法分析，可以確認另一個三唑衍生物BTO會抑制人類非小細胞肺癌細胞的增生，並能隨著時間及濃度誘導自噬相關蛋白，並且促進凋亡，這都是透過自噬小體增加與溶酶體的形成。利用Annexin V染色及西方墨點法分析可以顯示促進自噬的BTO造成肺癌細胞的凋亡。此外由腫瘤組織的西方墨點分析和螢光顯微鏡中顯示，BTO可以抑制在小鼠模型中異種移植的A549腫瘤生長，並且誘導凋亡和自噬標記物的增生。 這兩種三唑衍生物化合物可以是抑制人類疾病的一種潛在治療藥劑。 ; Strategies that enhance autophagy clearance of polyQ accumulation have become an attractive approach to revive neuronal cell viabilities. In the part I of the dissertation, a selected autophagic enhancer candidate was identified as a cell model for polyQ aggregation clearance. The polyQ diseases were caused by expansion of CAG trinucleotide repeats in the coding region of gene. After screening a series of triazole derivatives, a newly identified synthetic compound, 5,5′-(4,4′-(1,3-phenylene-bis(oxy))-bis(methylene)-bis(1H-1,2,3-triazole-4,1-diyl))-bis(methylene)-bis(3-(naphthalene-1-yl)-oxazolidin-2-one (OC-13), was shown capable of enhancing clearance of the aggregated polyQ in neuroblastoma cells. Human neuroblastoma cells SK-N-SH with ectopic expression of ΔC-TBP-Q79-EGFP or Httex1-Q97-GFP mutant protein can be cleared of mutated aggregates without affecting cell viabilities. Treatment of OC-13 increased autophagosome formation and more than 50% the accumulated aggregates were eradicated as determined by fluorescence microscopy. Western blot showed that OC-13 converted LC3-I to LC3-II in the transfected cells and activated autophagy-mediated elimination of polyQ aggregation. The effects were repressed by autophagic inhibitors. Autophagic enhancer is also a valid treatment strategy as cancer therapeutics. In the part II of the ... |
| نوع الوثيقة: | other/unknown material |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | G080143010S; http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22G080143010S%22.&%22.id.&; http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/103965 |
| الاتاحة: | http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/103965 https://hdl.handle.net/20.500.12235/103965 http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22G080143010S%22.&%22.id.& |
| رقم الانضمام: | edsbas.68C18CCD |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |