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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳燕惠(Yen-Hui Chen) | |
dc.contributor.author | Shih-Feng Yu | en |
dc.contributor.author | 游士峯 | zh_TW |
dc.date.accessioned | 2021-06-08T06:15:14Z | - |
dc.date.copyright | 2007-02-13 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-01-31 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25482 | - |
dc.description.abstract | 第一部分 守宮木活性成分的減重效果之體外及體內研究
守宮木 (Sauropus androgynus)的葉子與嫩莖曾被廣泛使用為高營養蔬菜,具有減肥的效果,故又稱減肥菜。民眾常每天打汁生喝150 g以上,若食用超過三個月,會造成呼吸困難。過去曾在臺灣發生過守宮木引起的大規模肺病變,嚴重時需做肺臟移植。本研究中,我們取葉莖之乙醇抽取物,依極性大小分離出氯仿層、乙酸乙酯層、正丁醇層等三部分並由正丁醇層分離純化出山奈酚-3-雙葡萄糖(GGK),探討守宮木活性成份對於減重效果進行之體外及體內研究。 在毒性方面的研究發現氯仿層對NIH3T3及 Bcl-2/NIH3T3細胞(Bcl-2蛋白過量表現的細胞株)都產生細胞膜破裂現象;而正丁醇層對NIH3T3纖維母細胞產生細胞DNA片段化現象,對Bcl-2/NIH3T3纖維母細胞則無此現象。動物試驗中,正丁醇層組的老鼠血清中GOP和膽固醇低於控制組,但病理組織切片發現有支氣管阻塞、肝臟脂肪變性及細胞凋亡的現象。氯仿層組的老鼠肺部組織切片有組織發炎及出血現象及肝中的微小及大空泡脂肪改變。毒性研究結果顯示守宮木中的正丁醇層會引起細胞凋亡的現象,而氯仿層則引起細胞壞死的現象。 守宮木的嫩枝及嫩葉曾被使用當作健康食品作為減肥之用,這意味者守宮木含有某些化學物質可能具有減肥的活性。氯仿層及正丁醇層對3T3-L1脂肪前趨細胞中脂肪的數目及油滴大小有明顯的抑制作用,但由流氏細胞儀分析得知,氯仿層比正丁醇層有較大的毒性作用。而進一步純化正丁醇層的主要成份山奈酚-3-雙葡萄糖(GGK),發現GGK對前趨細胞中脂肪數目及油滴的抑制效果為同量正丁醇的10倍,並會抑制脂肪細胞分化的中間時期,核苷三磷酸酶活性及抑制脂肪分化的主要蛋白PPARγ的蛋白質表現。 我們每日定時餵6 mg/kg及60 mg/kg GGK;給予雄的Wistar老鼠連續28天。觀察GGK對動物減重的影響,發現60 mg/kg GGK給予老鼠28天後,食量明顯下降15%,而減肥菜的部分純化物乙酸乙酯層及正丁醇層,卻只有些微的食量下降。不論是60 mg/kg GGK組或6 mg/kg GGK組與控制組相比都有明顯抑制體重增加的效果,GGK組的老鼠其血中的三酸甘油減少35%,但膽固醇卻增加31%。由於給予GGK餵食的老鼠每日的食量及體重減少,且在病理切片上也沒觀察到毒性。總和這些特質。也許GGK經適當設計後可以發展為一種新的減重藥物。 進一步探討GGK的體內分佈及代謝,以三隻老鼠為一組投予60 mg/kg的GGK 0至24小時。血中含量最多的代謝物是山奈酚-3-葡萄糖-單葡萄糖醛酸(GKG`),約在第12小時最大血中濃度達30 μM。收集24小時後的尿液,發現其代謝物與血中代謝物相似,而糞便中則偵測到山奈酚-3-葡萄糖(GK) 及山奈酚(kaempferol)。GK可能會被直接吸收進入體內循環,而在肝中結合葡萄糖醛酸。而來自GGK水解的GK也許在體內循環中是一個重要的化合物來抑制體重增加。 第二部份 多噻吩衍生物之抗癌活性篩選及其機轉之研究 山防風為一種解熱解毒中藥並已被長期使用,其主要活性成份為多噻吩。根據文獻報導,合成或經化學修飾的多噻吩具有抑制蛋白質激酶A、有絲分裂活化蛋白激酶和蛋白酪胺酸激酶的作用。進一步,我們研究四種合成的多噻吩化合物: NSC-646270、NSC-647455、NSC-663561及NSC-658878,對11種人類癌細胞株的抑制作用。發現多噻吩化合物對A498(腎癌) 、SW480(結腸癌)、NPC-039及NPC-039N1(鼻咽癌)細胞株有很強的細胞毒性作用,IC50均低於0.5 μM。其中以NSC-646270化合物對抑制A498細胞株的生長率效果最好,約10 μM的濃度以上可與EtBr競爭A498之DNA結合,並且引起很明顯的DNA片段化作用。 在研究其機轉方面,選用對多噻吩最敏感的A498細胞株來進行實驗。加入1 μM NSC-646270後12小時,細胞中的TNFα及TNFα接受器蛋白增加50%的表現量。同時caspase 8蛋白質量約為控制組的两倍;caspase 3約為1.5倍;bid蛋白質量則明顯下降。另一方面,Bcl-2蛋白表現量在第12小時明顯減少;Bax及Bad蛋白在第12小時明顯增加。而細胞色素C在第12小時大量於細胞質測到。進一步發現,在第12至24小時,caspase 2, 3, 6和9蛋白活性都明顯增加,其中caspase 3, 6和9蛋白約增加了兩倍的活性。我們的結論是多噻吩引起細胞凋亡的機轉可能包含兩條細胞死亡路徑 (1)TNFα接受器相關的caspase 8蛋白路徑 (2)粒腺體相關的caspase 9蛋白路徑。多噻吩未來是否有可能發展為有效的抗癌藥物,值得我們進一步去評估。 | zh_TW |
dc.description.abstract | Part I. Studies of the Active Ingredient of Sauropus Androgynus on Reduction of the Body Weight Gain in vitro and in vivo.
The raw juice of young sticks and leaves of Sauropus androgynus (SA) has been widely used as a natural food for body weight reduction in Taiwan and Southeast Asia. When taking for more than three months, an endemic of SA-associated obliterative bronchiolitis develops. Lung transplantation is carried out in severe cases. To study the toxic effect and perhaps anti-obesity activity, we separated the SA extract into three parts, namely CHCl3, EtOAc and n-BuOH fractions. The n-BuOH fraction was further purified to 3-O-β-D-glucosyl-(1→6)-β-D-glucosyl-kaempferol (GGK). When CHCl3 and n-BuOH fractions treated Bcl-2/NIH3T3 (a Bcl-2 overexpressed cell line) and NIH3T3 cells for 36 h, the genomic DNA of cells upon CHCl3 fraction treatment appeared smearing in both cells. DNA appeared fragmenting in NIH3T3 cells treated with n-BuOH fraction, while Bcl-2/NIH3T3 cells were not affected. In animal studies, Wistar rats received SA fractions for 28 day. Serum GOP and cholesterol levels in the n-BuOH group were significantly lower than that in control group. The n-BuOH group exhibited bronchiolitis obliterans and organizing pneumonia (BOOP) in lung and fatty change with occasional apoptosis in liver from histopathological observations. CHCl3 group showed organizing pneumonia with hemorrhage in lung and micro and macrovesicular fatty change in liver. Results indicate that n-BuOH fraction of SA extract induces apoptosis, that is distinctive from the effect of CHCl3 fraction of SA extract. SA, used as health supplement for control of body weight, may contain certain active ingredients responsible for anti-obesity. A preadipocyte 3T3-L1 cell line was employed to study the effect of SA on adipogenesis. Cells treated with the toxic fractions CHCl3 and n-BuOH displayed a significant reduction in number and size of oil droplets although CHCl3 fraction is more cytotoxic than n-BuOH fraction by PI flow cytometry assay. Furthermore, GGK purified from n-BuOH fraction demonstrates inhibition of the middle stage of adipogenesis progress through preventing oil droplets maturation, ATPase activation and the key protein PPARγ. We next looked at weight reduction by SA in animals. Wistar rats received 6 or 60 mg/kg of GGK as well partial purified fractions of SA extract daily for 28 days. Sixty milligrams per kilogram GGK treatment significantly reduced food intake in rats by 15% (p < 0.05). The reduced food intake corresponded to decreases in body weight in the high or low dose GGK groups, as compared to the control groups. Serum levels of free triglyceride decreased in GGK-treated rats; in contrast, the cholesterol concentration increased. GGK treatment led to maintainable reductions in daily food intake and body weight without any obvious toxicity to Wistar rats. Thus, after appropriate modification GGK might be potentially a safe novel compound for anti-obesity treatment. Distribution and metabolism of GGK is important for its development to be clinically applicable. Wistar rats were orally administered with GGK 60 mg/kg. We then collect plasma, urine and feces for high-performance liquid chromatography (HPLC) analysis. The HPLC chromatogram of plasma, collected at 12th h, appeared a major peak of which did not overlap with GGK peak. The major GGK metabolite peak was assumed to be 3-O-β-D-glucosyl-kaempferol-monoglucuronide (GKG`) using either glucosidase or glucuronidase enzyme reactions. HPLC analysis of urine collected at 24th h revealed the presence of glucurono-conjugated derivative, 3-O-β-D-glucosyl-kaempferol (GK) and kaempferol (K). Like urine, GK and K were found in feces. GK maybe absorbed into the body directly and was conjugated with glucuronide in liver, and then enter systemic circulation. GK hydrolyzed from GGK may be an important entity to reduce adipogenesis and become an so called anti-obesity agent. Part II. Screening of Terthiophene Derivatives for Anticancer Activity and Studies of Their Mechanisms. Echinops grijisii, a Chinese herbal medicine, has been used as antipyretic and antidote over a long period of time. Synthetic terthiophenes via chemical modification could inhibit protein kinase A, mitogen activated protein kinase and protein tyrosine kinase. We investigated the effect of four terthiophenes: NSC-646270, NSC-647455, NSC-663561 and NSC-658878, in 11 human cancer cell lines. All terthiophenes exhibited strong cytotoxicity in A498, SW480, NPC-039 and NPC-039N1 cells with the IC50 < 0.5 μM. Among them, A498 cells had the strongest response to terthiophenes cytotoxicity. Terthiophenes at 10 μM were able to compete with ethidium bromide for DNA intercalation and at 1μM induce intracellular DNA fragmentation in A498. The fragmenting DNA accumulated in sub G1 phase of cell cycle distribution by flowcytometry analysis. Cytotoxic effect of terthiophenes may be related to induction of apoptosis in A498 cells. The mechanism of terthiophenes was extensively studied in A498 upon NSC-646270 treatment. There was a 50% increase in TNFα and TNFR1 expression levels after 1 μM NSC-646270 treatment in A498 cells for 12 h. At the same time, caspases 8 increased 2 folds and caspase 3 increased 1.5 folds, while Bid decreased significantly. Furthermore, a large reduction of Bcl-2 protein started from 12th h and Bax and Bad were significantly induced. The release of cytochrome c from mitocondria into the cytosol was detected in cells upon NSC-646270 treatment for 9 h. The enzyme activity of caspase-3, -6 and -9 increased around 2 folds when cells were exposed to NSC-646270 for 24 h. In conclusion, the mechanism of terthiophenes on induction of apoptosis in A498 involves two pathways of caspase activation: (i) death receptor-mediated caspase-8 and (ii) mitochondria-mediated caspase-9. Development of terthiophenes as anticancer drugs needs to be further evaluated. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T06:15:14Z (GMT). No. of bitstreams: 1 ntu-96-D88423002-1.pdf: 4305249 bytes, checksum: 75951872cf1ca0b3cd66fb0b4972c0b8 (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 口試委員會審定書…………………………………………………… i
中文摘要………………………………………………………………ii 英文摘要……………………………………………………………… v 目錄……………………………………………………………………ix 圖目錄…………………………………………………………………xii 表目錄…………………………………………………………………xiv 附錄………………………………………………………………… xv 縮寫表………………………………………………………………xvi Part I: Studies of the Active Ingredient of Sauropus androgynus on Reduction of the Body Weight Gain in vitro and in vivo. Chapter 1. The Distinctive Toxic Effect of Different fractions of Sauropus Androgynus Extract in Bcl-2/NIH3T3 Cells and the Histopathological Association in Wistar Rats………………………………………………………2 1.1.1 Introduction ………………………………………………3 1.1.2 Materials and Methods ………………………………………6 1.1.3 Results ………………………………………………………10 1.1.4 Discussion ……………………………………………………13 1.1.5 Figures and Tables …………………………………………16 Chapter 2. Inhibition of Adipocyte Differentiation by 3-O-β-D-Glucosyl-(1→6)-β-D-glucosyl-kaempferol Isolated from Sauropus androgenus………………………………vv23 1.2.1 Introduction …………………………………………………24 1.2.2 Materials and Methods ……………………………………29 1.2.3 Results ………………………………………………………33 1.2.4 Discussion ……………………………………………………39 1.2.5 Figures and Tables …………………………………………45 Chapter 3. 3-O-β-D-Glucosyl-(1→6)-β-D-glucosyl-kaempferol Isolated from Sauropus androgenus Reduces Body Weight Gain in Wistar Rats………………………57 1.3.1 Introduction .………………………………………………58 1.3.2 Materials and Methods ……………………………………60 1.3.3 Results ………………………………………………………63 1.3.4 Discussion ……………………………………………………65 1.3.5 Figures and Tables …………………………………………69 Chapter 4. Metabolic Study of 3-O-β-D-glucosyl-(1→6)-β-D-glucosyl-kaempferol Isolated Sauropus androgynus in Wistar Rats………………………………73 1.4.1 Introduction …………………………………………………74 1.4.2 Materials and Methods ……………………………………77 1.4.3 Results ………………………………………………………81 1.4.4 Discussion ……………………………………………………84 1.4.5 Figures and Tables …………………………………………88 Part II: Screening of Terthiophene Derivatives for Anticancer Activity and Studies of Their Mechanisms. Chapter 1. Cytotoxic Screening of a Series of Terthiophenes in Human Cancer Cell Lines……………………………………………………96 2.1.1 Introduction …………………………………………………97 2.1.2 Materials and Methods ……………………………………101 2.1.3 Results ………………………………………………………105 2.1.4 Discussion …………………………………………………108 2.1.5 Figures and Tables ………………………………………111 Chapter 2. The Thiophene Derivative NSC-646270 Induces Apoptosis through the Death Receptor and Mitochondrial Pathways in a Renal Carcinoma Cell Line A498…………………………………………………117 2.2.1 Introduction ………………………………………………118 2.2.2 Materials and Methods ……………………………………123 2.2.3 Results ………………………………………………………129 2.2.4 Discussion …………………………………………………137 2.2.5 Figures and Tables…………………………………………142 Reference……………………………………………………………149 Supplement……………………………………………………………165 | |
dc.language.iso | en | |
dc.title | 第一部分:守宮木活性成分的減重效果之體外及體內研究 第二部分:多噻吩衍生物之抗癌活性篩選及其機轉之研究 | zh_TW |
dc.title | Part I: Studies of the Active Ingredients of Sauropus androgynus on Reduction of the Body Weight Gain in vitro and in vivo.
Part II: Screening of Terthiophene Derivatives for Anticancer Activity and Studies of Their Mechanisms. | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 李水盛(Shoei-Sheng Lee),徐鳳麟(Feng-Lin Hsu),蘇瑀(Yeu Su),周辰熹(Chen-Hsi Chou),孫家楝(Chia-Tung Shun) | |
dc.subject.keyword | 守宮木,細胞凋亡,山奈酚-3-雙葡萄糖,細胞分化,抑制體重,多噻,吩化合物,細胞毒性。, | zh_TW |
dc.subject.keyword | Sauropus androgynus,bronchiolitis obliterans,apoptosis,3-O-β-D-glucosyl-(1→6)-β-D-glucosyl-kaempferol,adipogenesis,terthiophene,cytotoxicity., | en |
dc.relation.page | 174 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2007-02-01 | |
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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