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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張震東(Geen-Dong Chang) | |
| dc.contributor.author | Bo-En Hong | en |
| dc.contributor.author | 洪柏恩 | zh_TW |
| dc.date.accessioned | 2021-06-16T07:14:07Z | - |
| dc.date.available | 2015-07-16 | |
| dc.date.copyright | 2014-07-16 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-02 | |
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Wade, Jr., Organic Chemistry 7th Edition | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57957 | - |
| dc.description.abstract | 天然物是一類從生物體內製造並且被純化出來的小分子。許多從中草藥萃取出來的天然物，都有抗發炎和抗癌的功效，而且從結構上看，其中有許多可能是共價藥物。天然物piperlongumine是從胡椒屬的植物長胡椒(Piper longum)中，所萃取出來的一種小分子。目前研究發現，piperlongumine可以殺死某些癌細胞，但是不影響正常細胞；除此之外，還有抑制血小板活化的功效。另外，長胡椒的萃取物可以抗發炎，而piperlongumine也是萃取物的成分之一；但它在抗發炎的機制依舊不明。NF-κB是一種轉錄因子，可活化許多和細胞生長相關的基因表現，包括使白血球分泌細胞激素去促進細胞增生，因此NF-κB為影響細胞生長的關鍵調控者。在NF-κB過度活化的情況下，會造成慢性發炎，進而造成其他疾病，包括提高癌症風險。Piperlongumine從結構上分析，我們預測它可能是一種共價藥物。藉由麥可加成反應的方式，piperlongumine可以被半胱胺酸殘基攻擊可進行麥可加成反應的位置，進而和蛋白質形成共價鍵，對蛋白質進行修飾。我們的研究，以新的方法學：抗piperlongumine多株抗體的方式，發現以piperlongumine處理細胞之後，NF-κB會被piperlongumine所修飾。在子宮頸癌細胞，以腫瘤壞死因子-α (tumor necrosis factor-α) 去誘導NF-κB的活化的模式中，我們發現先以piperlongumine處理的細胞，NF-κB從細胞質到細胞核的移動會被抑制。因此，我們推測NF-κB上的某些半胱胺酸殘基被piperlongumine修飾後，可能會影響NF-κB移動至細胞核和NF-κB的活化；甚至有其他piperlongumine的目標蛋白也可能一起影響NF-κB的活化。 | zh_TW |
| dc.description.abstract | Natural compounds are small molecules extracted from organisms. Many natural compounds from herbals have the properties of anti-inflammation and anti-cancer and they may be covalent drugs according to their structures. The natural compound, piperlongumine, is a small molecule from the Piper species plant, Piper longum. Piperlongumine has been shown to kill certain cancer cells but not the normal cells; furthermore, piperlongumine has the activities for anti-platelet. The extracts of Piper longum also have the ability for anti-inflammation, and piperlongumine is a component of the extracts. However, the anti-inflammatory mechanism of piperlongumine is still unknown. NF-κB is a transcription factor that can activate many genes required for the cell proliferation including inducing secretion of interleukins from leukocytes to increase the activities of cell growth. Therefore, NF-κB is a key regulator of the cell proliferation. The NF-κB hyper-activation can lead to chronic inflammation and diseases such as the cancers. We analyzed the structure of piperlongumine and predicted that piperlongumine may be a covalent drug. Piperlongumine can be attacked by the cysteine residues of some proteins through Michael addition to form the covalent bonds. We used a new methodology to generate anti-piperlongumine polyclonal antibody for target identification, and found that the NF-κB can be modified by piperlongumine after piperlongumine treatment in the cells. In the TNF-α (tumor necrosis factor-α) induced NF-κB activation model, we found that the NF-κB translocation from the cytoplasm to the nucleus can be inhibited in cervical cancer cells. Therefore, we predicted that modifications of some cysteine residues on NF-κB can affect the NF-κB translocation and activation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T07:14:07Z (GMT). No. of bitstreams: 1 ntu-103-R99b46022-1.pdf: 1942816 bytes, checksum: c8f7d6f0f1406950d56b737bb435ea95 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 誌謝...ii
中文摘要...iii 英文摘要...iv 縮寫表...vi 目錄...viii 第一章 緒論...1 1.1 NF-κB訊號傳遞路徑...1 1.1.1 NF-κB轉錄因子...1 1.1.2 TNF-α誘導NF-κB活化的模型...2 1.1.3 NF-κB訊號的終止...3 1.1.4 NF-κB與發炎反應和癌症的關係...4 1.2 小分子藥物的目標鑑定...4 1.2.1 小分子藥物的發展...4 1.2.2 藥物目標鑑定方法...5 1.3 共價藥物...8 1.4 半胱胺酸...10 1.5 麥可加成反應...11 1.6 天然物...12 1.6.1 天然物的歷史...12 1.6.2 天然物的發展...12 1.7 天然物Piperlongumine...13 1.8 研究動機...14 第二章 材料與實驗方法...15 2.1 細胞實驗方法...15 2.1.1 細胞培養...15 2.1.2 細胞繼代...15 2.1.3 藥物處理細胞...15 2.1.4 TNF-α 處理細胞...16 2.1.5 藥物...16 2.2 蛋白質實驗方法...17 2.2.1 細胞蛋白質樣本製備...17 2.2.2 十二烷基硫酸鈉聚丙烯醯胺凝膠電泳...17 2.2.3 蛋白質轉印...19 2.2.4 西方墨點法...19 2.2.5 免疫沉澱...20 2.2.6 細胞核質分離....20 2.2.7 抗體...21 2.2.8 藥物抗原製備...21 2.3 質譜儀分析Piperlongumine反應產物...21 2.3.1 質譜儀分析Piperlongumine與合成胜肽反應的產物...21 2.3.2 質譜儀分析Piperlongumine與半胱胺酸在不同pH值的反應產物...22 2.4 人類介白素-6酵素免疫分析...22 第三章 結果...23 3.1 Piperlongumine於HeLa細胞中修飾蛋白質的訊號模式...23 3.2 Piperlongumine對蛋白質的修飾訊號會隨pH值變動...23 3.3 Piperlongumine可以對p65進行修飾...24 3.4 Piperlongumine對TNF-α誘發NF-κB進細胞核之現象的影響.....24 3.5 Piperlongumine抑制p65的目標基因蛋白IL-6的分泌...25 3.6 Piperlongumine和Parthenolide的競爭性試驗...25 3.7 質譜儀分析piperlongumine反應後的產物...26 第四章 討論...28 4.1 藥物的專一性...28 4.2 以抗體尋找藥物的目標蛋白...29 4.3 Piperlongumine抑制NF-κB 訊號傳遞路徑的機制... 29 4.4 Piperlongumine反應後的產物...30 第五章 結語...32 第六章 實驗結果圖表...33 圖 1 HeLa細胞處理不同時間與濃度piperlongumine的訊號模式...33 圖 2 Piperlongumine修飾蛋白的訊號會隨pH升高而增加...36 圖 3 p65會被piperlongumine所修飾...37 圖 4 Piperlongumine處理細胞15分鐘即可明顯抑制p65進入細胞核...38 圖 5 10 μM piperlongumine處理細胞1小時就可抑制TNF-α誘導IL-6的表現...41 圖 6 Piperlongumine和parthenolide同時處理細胞做競爭性試驗...42 圖 7 質譜儀分析piperlongumine和合成胜肽或半胱胺酸反應產物....44 第七章 參考文獻...47 第八章 附錄...56 附圖 1 Piperlongumine在有血清和無血清培養液中處理細胞的差別56 附圖 2 Piperlongumine可以進入細胞核對蛋白質作修飾...57 附圖 3 NF-κB 家族的5個成員及其所含的domain...58 附圖 4 兩種主要NF-κB訊號傳遞路徑...59 附圖 5 NF-κB可以活化許多不同的基因...60 附圖 6 Activity-based protein profiling (ABPP) 鑑定小分子藥物目標的一般流程...61 附圖 7 小分子藥物目標鑑定方法：正向選擇和負向選擇的差別...62 附圖 8 麥可加成反應的反應機制...63 附圖 9 Piperlongumine結構和可被親和基攻擊的位置...64 | |
| dc.language.iso | zh-TW | |
| dc.subject | 麥可加成反應 | zh_TW |
| dc.subject | piperlongumine | zh_TW |
| dc.subject | 共價藥物 | zh_TW |
| dc.subject | NF-κB | zh_TW |
| dc.subject | piperlongumine | en |
| dc.subject | covalent drug | en |
| dc.subject | Michael addition | en |
| dc.subject | NF-κB | en |
| dc.title | 探討天然物Piperlongumine對TNF-α誘導HeLa細胞的發炎反應中NF-κB p65的影響 | zh_TW |
| dc.title | The Effects of Piperlongumine on NF-κB p65 in TNF-α Induced Inflammatory Response in HeLa Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李明亭(Ming-Ting Lee),陳宏文(Hung-Wen Chen),張茂山(Mau-Sun Chang) | |
| dc.subject.keyword | piperlongumine,共價藥物,麥可加成反應,NF-κB, | zh_TW |
| dc.subject.keyword | piperlongumine,covalent drug,Michael addition,NF-κB, | en |
| dc.relation.page | 64 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-03 | |
| 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 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-103-1.pdf 未授權公開取用 | 1.9 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。