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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林淑萍(Shwu-Bin Lin) | |
dc.contributor.author | Ting-Yu Lin | en |
dc.contributor.author | 林亭妤 | zh_TW |
dc.date.accessioned | 2021-05-16T16:28:26Z | - |
dc.date.available | 2018-03-04 | |
dc.date.available | 2021-05-16T16:28:26Z | - |
dc.date.copyright | 2013-03-04 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-01-11 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6405 | - |
dc.description.abstract | 先前研究發現烯烷基對苯二酚,10’(Z), 13’(E), 15’(E)-heptadecatrienylhydroquinone [HQ17(3)]為具有抗癌活性 (anti-cancer)的天然抗氧化小分子 (antioxidant)。已知HQ17(3)屬於不可逆的拓樸異構酶II抑制劑 [topoisomerase II (Topo II)],可於HL-60血癌細胞中造成Topo II poison、引發氧化壓力及細胞毒性。本篇研究發現以高濃度HQ17(3) (10 μM)處理Huh7肝癌細胞時,同樣導致Topo II poison。進一步以質譜儀分析發現HQ17(3)與細胞內Topo IIα的半胱胺酸-427 (Cys-427)形成共價鍵結,HQ17(3)的處理並造成細胞中Topo IIα-DNA複合體增加、DNA雙股斷裂、數個DNA損傷基因的表現量上升及細胞凋亡。HQ17(3)也造成細胞氧化性傷害,然而以N-acetylcysteine抗氧化物前處理細胞,並無法有效拯救細胞的存活率,顯示Topo II poison為HQ17(3)造成Huh7細胞死亡的主要原因。
本論文另以人類皮膚纖維母細胞 (WS1)的研究模式,發現細胞經處理低濃度HQ17(3) (<1 μM)後,可降低過氧化氫所造成的氧化性傷害。HQ17(3)並透過修飾Kelch-like ECH associated protein 1 (Keap1)的半胱胺酸並活化Keap1所調控的nuclear factor-E2 p45-related factor 2 (Nrf2)轉錄因子。以質譜儀分析發現HQ17(3)與細胞內Keap1的Cys-77、-249、-288及-297形成共價鍵結。HQ17(3)的處理進而促進Nrf2活化並誘導Nrf2下游所調控的heme oxygenase-1抗氧化酵素的表現,因此引發Nrf2分子相關的細胞保護機制。 綜合以上結果,HQ17(3)此種結構的小分子可作為Topo II poison發展外,也可當作研發相關預防性化合物的參考。 | zh_TW |
dc.description.abstract | We previously reported that the botanical compound 10’(Z), 13’(E), 15’(E)-heptadecatrienylhydroquinone [HQ17(3)], an antioxidant, possesses anti-cancer activity. The cytotoxicity of HQ17(3) toward HL-60 leukemia cells is attributed to irreversible topoisomerase II (Topo II) poisoning and induction of oxidative damages. This study further explored that the cytotoxicity of HQ17(3) (10 μM) in Huh7 hepatoma cells was attributed to Topo II poison. Proteomic analyses revealed that HQ17(3) reacted with Cys-427 of cellular Topo IIα. This HQ17(3) modification caused the accumulation of Topo II-DNA complexes, DNA strand breaks, consequently induced the expression of DNA damage-related genes and apoptosis. HQ17(3) also caused oxidative damages in Huh7 cells. However, pretreatment of N-acetylcysteine, the antioxidant, did not diminish HQ17(3)-induced cell death. These results suggest that the cytotoxicity of HQ17(3) is attributed significantly to Topo II poisoning.
In the WS1 skin fibroblast cell model, HQ17(3), at low concentration, was demonstrated to diminish H2O2-caused oxidative damages. HQ17(3) was found to modify Kelch-like ECH associated protein 1 (Keap1) and activate nuclear factor-E2 p45-related factor 2 (Nrf2), a transcription factor involved in the cytoprotection pathway. Proteomic analyses indicated that HQ17(3) modified Cys-77、-249、-288 and -297 of cellular Keap1. The nuclear translocation of Nrf2 and increase of HO-1 expression, an anti-oxidation enzyme regulated by Nrf2, in WS1 cells upon HQ17(3) treatment were observed. The activated Nrf2 pathway was found to be involved in HQ17(3)-mediated cytoprotection. In conclusion, the structural feature of HQ17(3) could be used as a model for Topo II poison design as well as preventive agent design. | en |
dc.description.provenance | Made available in DSpace on 2021-05-16T16:28:26Z (GMT). No. of bitstreams: 1 ntu-102-F93424014-1.pdf: 13102793 bytes, checksum: 8b5f2a4620a95055751810b658fa66fd (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 目錄
目錄 I 示意圖目錄 IV 表目錄 V 圖目錄 VI 附表圖目錄 VIII 中文摘要 IX 英文摘要 X 縮寫表 XII 一、序論 1 1.1漆樹及其有效成分:漆酚 (Urushiol) 1 1.2 HQ17(3)為拓樸異構酶II抑制劑 1 1.3氧化壓力 2 1.4拓樸異構酶 3 1.5拓樸異構酶作用 3 1.6拓樸異構酶II抑制劑 (Topo II inhibitor) 5 1.7小分子修飾拓樸異構酶的硫醇基 (-SH) 6 1.8拓樸異構酶導致DNA斷裂之細胞反應 7 1.9細胞凋亡 (Apoptosis) 8 1.10小分子之抗氧化作用 8 1.11 Nrf2與其調控相關因子 10 1.12研究目的 14 二、實驗方法與材料 15 2.1 HQ17(3)的純化 15 2.2細胞培養及藥物處理條件 15 2.3蛋白質萃取及西方墨點法 16 2.4人類recombinant Keap1蛋白質的純化 17 2.5 HQ17(3)修飾蛋白質硫醇基的產物分析 18 2.6試管實驗分析Topo II誘導DNA斷裂的形成 19 2.7試管實驗分析Topo II活性 20 2.8 Immunodetection of in vivo complexes of enzyme to DNA (ICE bioassay) 20 2.9免疫螢光組織染色 21 2.10細胞存活率測定 (ACP assay) 22 2.11流式細胞儀測定 22 2.12基因表現之分析 24 2.13 ARE活性測定 25 2.14 Knockdown of Nrf2 26 三、實驗結果 27 3.1 HQ17(3)抗癌活性之分子機制探討 27 3.1.1 HQ17(3)修飾Topo IIα的半胱胺酸 27 3.1.2 HQ17(3)抑制Topo IIα酵素的解螺旋活性 28 3.1.3 HQ17(3)造成Topo IIα導致的DNA斷裂 29 3.1.4 HQ17(3)促進DNA受損相關基因的表現 29 3.1.5 HQ17(3)促進Huh7細胞進行細胞凋亡 30 3.1.6氧化壓力為HQ17(3)促進Huh7細胞的凋亡原因之一 31 3.2 HQ17(3)之抗氧化性損傷機制探討 32 3.2.1 HQ17(3)對於WS1細胞株活性的影響 32 3.2.2 HQ17(3)降低H2O2造成的脂質過氧化 33 3.2.3 HQ17(3)減少H2O2造成的細胞死亡 33 3.2.4 HQ17(3)修飾Keap1的半胱胺酸 34 3.2.5 HQ17(3)活化Nrf2 34 3.2.6 HQ17(3)促進HO-1的表現 35 3.2.7 HQ17(3)透過活化Nrf2路徑而具有保護細胞的效果 36 四、結論 38 五、討論 39 六、參考文獻 77 藥品清單 83 已發表之論文 86 個人履歷表 97 | |
dc.language.iso | zh-TW | |
dc.title | 天然物烯烷基對苯二酚[HQ17(3)]與硫醇基反應引發分子及細胞反應之研究 | zh_TW |
dc.title | A study on cellular response and molecular mechanism induced by a thiol-reactive botanical alkylenehydroquinone [HQ17(3)] | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-1 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 張雅雯(Ya-Wen Chang) | |
dc.contributor.oralexamcommittee | 歐樂君(Lo-Chun Au),林亮音(Liang-In Lin),胡忠怡(Chung-Yi Hu) | |
dc.subject.keyword | 烯烷基對苯二酚,抗癌,抗氧化性傷害,拓樸異構?IIα,Nrf2,Keap1, | zh_TW |
dc.subject.keyword | alkylenehydroquinone,anti-cancer,anti-oxidative damages,topoisomerase IIα,Nuclear factor-E2 p45-related factor 2,Kelch-like ECH associated protein 1, | en |
dc.relation.page | 101 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2013-01-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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ntu-102-1.pdf | 12.8 MB | Adobe PDF | 檢視/開啟 |
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