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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 孔繁璐(Fan-Lu Kung) | |
dc.contributor.author | Fan-Lun Liu | en |
dc.contributor.author | 劉凡綸 | zh_TW |
dc.date.accessioned | 2021-06-16T08:06:05Z | - |
dc.date.available | 2019-10-20 | |
dc.date.copyright | 2014-10-20 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-06-23 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58107 | - |
dc.description.abstract | 老年化相關疾病是現今人口高齡化所必須面對的問題。醫療資源花費在老年化相關疾病如阿茲海默症(Alzheimer’s disease, AD)及癌症逐年增高,而對於疾病的治療方法仍然有限。本篇論文中,將在第一部分探討阿茲海默症的一種可能成因以及做為藥物標靶的可能效果;在第二部分中,著重於對多形性神經膠母細胞瘤的藥物篩選及探討這些藥物的抗癌機轉。
本論文的第一部分,在延續實驗室過去研究結果的基礎下,將過去在酵母菌的實驗系統移植到人類細胞株中,觀察是否能重現過去實驗的結果。實驗室過去使用酵母菌雙雜交實驗,發現與阿茲海默症相關的穿膜蛋白質amyloid precursor protein (APP)其中在細胞內的片段APP intracellular domain (AICD)與一種peptidyl prolyl isomerase─FK506 binding protein 12 (FKBP12)的片段有交互作用,且這個交互作用可以被外加FK506抑制。在第一部分的實驗,我們在人類細胞株內過量表現APP與FKBP12,並觀察FKBP12的表現量是否會影響APP被水解產生C99或C83的過程,及FK506對此現象的影響。我們也使用APPT668E這個突變來模擬pT668的結構,及APPT668V來模擬T668未磷酸化,以免疫共同沉澱法測試FKBP12與各種突變APP的交互作用。第一部分實驗結果顯示使用FK506抑制劑在細胞膜型中可以抑制FKBP12引起的amyloidogenic途徑。 第二部分我們使用SRB來篩選對於多形性神經膠母細胞瘤細胞株有抗增生活性的天然物。我們篩選出了兩個天然物─calanquinone A及epi-reevesioside F對於多形性神經膠母細胞瘤有抗癌活性。Calanquinone A對於我們實驗室的三株細胞株─A172,T98及U87都有抗增生活性。calanquinone A對於細胞內的glutathione含量皆有抑制。以彗星試驗及propidium iodide-γH2A.X雙染實驗可以觀察到calanquinone A可造成DNA損傷,而外加N-acetyl cysteine或glutathione都可以抑制此現象。DNA損傷同時會造成細胞週期S phase的停滯。Calanquinone A也會導致細胞reactive oxygen species及鈣離子增加。AMPK可以調控細胞能量,當細胞內ATP降低時會活化AMPK。本實驗中,calanquinone A會造成glutathione相關的AMPK活化作用,但是詳細的訊息傳遞則需要更深入的研究。 Epi-reevesioside F對於三株神經膠母細胞瘤的效果不同─對於A172細胞無效,對T98細胞可以產生細胞凋亡,而對T98及U87細胞則產生抗細胞增生作用。深入研究epi-reevesioside F的影響可以發現,epi-reevesioside F對於T98及U87產生的抗增生活性皆可以被外加鉀離子而部分回復。Epi-reevesioside F會造成細胞內鈉離子的累積,但是對鈣離子沒有影響。鈉離子的上升導致細胞酸度增加,且細胞酸度增加與藥物的抗細胞增生活性有相關性。綜合以上結果,天然物calanquinone A及epi-reevesioside F對於多形性神經膠母細胞瘤具有抗癌活性:calanquinone A主要是降低細胞內glutathione濃度,而epi-reevesioside F則造成細胞內pH值下降,而達到抗增生效果。 | zh_TW |
dc.description.abstract | Population aging causes problems associated with age related diseases. Medical resources spending for age related diseases such as Alzheimer’s disease (AD) and cancer has increased year by year, but therapeutic options for these diseases are still limited. In this doctoral thesis, we have investigated one possible cause of Alzheimer’s disease and the potential effect of drugs targeting in the first part. In the second part, we have screened compounds especially for anti-glioblastoma and have investigated the anticancer mechanisms of these compounds.
In the first part, based on our past results in yeast system, we transfered the model from yeast to human cell lines, and determined whether we could reproduce the past results. We have found that a fragment of the transmembrane protein associated with Alzheimer’s disease, amyloid precursor protein (APP) intracellular domain (AICD), interacts with a truncated prolyl isomerase named FK506 binding protein 12 (FKBP12) by yeast-two hybrid screening, and the interaction between AICD and FKBP12 can be inhibited by FK506. In the experiments of the first part, we observed the effects of FKBP12 overexpression on APP processing and C99/ C83 production and whether FK506 can alter this effect in human cell lines overexpression APP and FKBP12. We also used APPT668E and APPT668V to mimic the phosphorylated and non-phosphorylated states of T668, testing the interactions between FKBP12 and various APP mutants by co-immunoprecipitation. The results of the first part show that FKBP12 triggered amyloidogenic pathway can be reversed by FK506. In the second part, we have screened natural products with anti-proliferative activities against glioblastoma. We have found two natural products, calanquinone A and epi-reevesioside F, with anti-glioblastoma activity. Calanquinone A inhibited cell growth of three glioblastoma cell lines, A172, T98 and U87 cells. The data showed that calanquinone A depleted cellular glutathione. Calanquinone A induced DNA damage effect by comet assay and propidium iodide-γH2A.X double staining. N-acetyl cysteine and glutathione significantly inhibited the DNA damage effect. Furthermore, calanquinone A-mediated DNA damage was able to cause cell cycle arrest at S phase. Calanquinone A also induced the production of reactive oxygen species and an increase in intracellular Ca2+ levels. AMPK is responsible for regulating cellular energy and, therefore, a decrease in cellular ATP levels may trigger AMPK activity. As a result, calanquinone A induced glutathione-dependent AMPK activation. However, the related signal transduction pathways need further investigation. Epi-reevesioside F showed varied effects in three glioblastoma cell lines, A172, T98 and U89. It had no effect on A172 cells but induced apoptosis in T98 cells and anti-proliferative activity in T98 and U87 cells. The addition of extracellular K+ could partly inhibited epi-reevesioside F-mediated anti-proliferative effects in T98 and U87 cells. Epi-reevesioside F induced an increase of intracellular Na+ levels, but had little effect on intracellular Ca2+ concentration. Furthermore, the increase of intracellular Na+ levels could in turn induce a decrease of cellular pH which was highly correlated with the anti-proliferative effect. In conclusion, both calanquinone A and epi-reevesioside F can inhibit cell proliferation of glioblastoma through different mechanisms. Calanquinone A decreases cellular glutathione, leading to DNA damage and S phase arrest of the cell cycle, and epi-reevesioside F induces an increase of intracellular Na+ levels, which in turn decreases intracellular pH and inhibits cell proliferation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:06:05Z (GMT). No. of bitstreams: 1 ntu-103-D98423004-1.pdf: 9026839 bytes, checksum: 55ff6160ef6bb79c95d34b9d6a039a35 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 縮寫表......i
中文摘要......iii 英文摘要......v 實驗材料與方法......vii 第一章 FKBP12在APP水解過程之角色探討......1 背景......2 實驗結果......7 討論與結論......10 圖......12 第二章 天然物在神經膠母細胞瘤的抗癌機轉研究......21 背景......22 第一節Calanquinone A藉由glutathione相關DNA損傷和AMPK的活化引起抗神經膠母細胞瘤作用......31 實驗結果......32 討論與結論......37 圖......41 第二節epi-Reevesioside F藉由影響離子平衡及細胞粒線體功能失調引起抗神經膠母細胞瘤作用......57 實驗結果......58 討論與結論......63 圖......68 總結與展望......81 著作......83 參考文獻......84 | |
dc.language.iso | zh-TW | |
dc.title | 天然物在抗阿茲海默症及抗神經膠母細胞瘤的作用和機轉研究 | zh_TW |
dc.title | Mechanism study of natural products on anti-Alzheimer’s disease and anti-glioblastoma | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 顧記華(Jih-Hwa Guh) | |
dc.contributor.oralexamcommittee | 黃聰龍(Tsong-Long Hwang),蕭哲志(George Hsiao),許麗卿(Lih-Ching Hsu) | |
dc.subject.keyword | Alzheimer’s disease,FK506,FKBP12,amyloid precursor protein,AICD,glioblastoma,apoptosis,A172,T98,U87,calanquinone A,glutathione,epi-reevesioside F,Na+/K+-ATPase, | zh_TW |
dc.relation.page | 100 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-06-23 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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