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研究生:陳嘉南
研究生(外文):Chia-Nan Chen
論文名稱:台灣蜂膠之抗癌機制與促進神經幹細胞生長及分化的探討及茶成分對神經幹細胞分化之研究
論文名稱(外文):Studies on the anti-cancer mechanism and promoted neural stem cells growth and the differentiation from Taiwanese propolis and tea
指導教授:林仁混林仁混引用關係
指導教授(外文):Jen-Kun Lin
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生物化學暨分子生物學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:92
語文別:英文
論文頁數:300
中文關鍵詞:台灣蜂膠巴西蜂膠類黃酮神經幹細胞神經細胞兒茶素分化
外文關鍵詞:Taiwanese propolisBrazilian propolisflavonoidsNeural stem cellsneuron cellsteaEGCgdifferentiation
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part 1
蜂膠乃是由工蜂採集植物之è80;芽或樹皮之汁液所得之一種膠狀黏性物質。蜜蜂將蜂膠帶回巢穴並修飾與混合其它物質,包括有蜂蠟與蜜蜂之唾液。將蜂膠萃取,發現蜂膠成分含有非常複雜組成,這可能與當地之地理環境與植物林相有密切關聯。蜂膠長久以來已廣汎在許多的地方當做民俗療法之用藥。目前已發表文獻,已經顯示蜂膠具有抗腫瘤、抗氧化、抗發炎、免役調控、抗病毒及抗菌活性。而這些藥理特性一般認為與蜂膠含有大量之類黃酮有關。目前,從蜂膠分離並鑑定之類黃酮,包括有caffeic acid、 ferulic acid、 cinnamic acid、 chlorogenic acid 及它的酯類衍生物。這其中最有名的,是由巴西蜂膠所分離之CAPE (caffeic acid phenethyl ester) 具有強效抗發炎、抗氧化及抗腫瘤活性。
許多文獻已經報導天然物(natural products) 應用於癌症之化學治療,例如taxol、adriamycin、VP16、camptothecin及 carnosol,這些化合物皆具有誘導癌細胞自我凋亡之活性。本論文研究台灣蜂膠的成分組成及生物活性,到目前為止,已有六個成分被分離鑑定,由核磁共振(NMR)光譜顯示,這些化合物的化學結構屬於prenylflavanone類。這六個化合物中,四個是新的化合物,分別命名為propolin A、propolin B、propolin E、及propolin F;另外二個已知化合物,我們稱為propolin C (nymphaeol-A)及propolin D (nymphaeol-B)。後二者雖為已知結構,但是尚未發現有相關生物活性方面的報告。
本篇論文研究台灣蜂膠之抗癌生物活性顯示,propolin C 及propolin D比CAPE擁有更強之誘導人類黑色素細胞瘤 (human melanoma cell)自我凋亡的活性,IC50 約為8.5μM。但是,這六個化合物所造成之癌細胞自我凋亡機制是相同的。Propolins是經由活化caspase-8、Bid、cytochrome c 從粒線體釋放至細胞質,再活化caspase-9、caspase3、PARP最後造成DNA之片段化;這個過程稱為粒線體有關(mitochondrial-dependent pathway)之活化機制。在抗癌方面六種propolins有不同程度的抗癌活性propolins D≧C>E>A>B>F它們的IC50分別是8.5, 8.5, 11.7, 13.6, 17.0, 35.4 μM。在抗氧化活性方面評估了這六個化合物抑制Xanthine Oxidase之活性。結果顯示propolin C、propolinE、propolin D比CAPE擁有更強的抑制活性;IC50分別為17.0 μM、17.0 μM 、22.0 μM、45.0 μM。在清除自由基方面,結果顯示propolin C、propolin A、及propolin B比CAPE擁有更強清除自由基的活性。
台灣蜂膠擁有豐富之prenylflavanones類黃酮化合物,並且顯示具有強效誘導多種癌細胞自我凋亡及抗氧化的活性。進一步比較台灣蜂膠與巴西蜂膠之多酚類(polyphenols)含量、清除自由基能力、抗癌活性及化學組成。結果顯示,台灣蜂膠含有較高量之多酚類及具有較強之自由基清除能力。在抗癌方面,台灣蜂膠擁有較強之抗癌活性,約比巴西蜂膠強十倍,最後利用HPLC分析七種台灣不同產地及四種不同巴西產地之蜂膠,結果顯示,台灣蜂膠含大量之propolin C、propolin D、及propolin F。然而,巴西蜂膠則含有豐富之CAPE。本研究結果顯示,propolins是台灣蜂膠所特有的成分,並足以解釋為何台灣蜂膠比巴西蜂膠擁有更強的抗癌及抗氧化活性。
part 2
治療神經退化性疾病是挽救受損的神經細胞並且刺激神經再生較理想之策略。神經幹細胞不僅存在於發育中的哺乳類神經系統,同時亦存在成年的哺乳類器官中,包括人類。神經幹細胞可以由胚胎幹細胞衍生。然而,調控內生性之神經幹細胞之機制,還不是非常清楚。目前已經開始使用神經幹細胞來修補受損之細胞,並且活化內生性神經幹細胞來提供“自我更新”。對於神經幹細胞,我們已有初步的瞭解。然而,我們必須能夠控制它們的增生或者分化為各種子代細胞。許多的報告顯示,神經幹細胞在哺乳類中樞神經系統發育至成熟過程中被發現,這些細胞可以被分離,並且放大數量在有生長因子的培養條件下,而這些因子目前已知包括有bFGF及EGF。假若將這些生長因子去除,再適量補充一些物質或者其它生長因子或親神經性因子,神經幹細胞會分化為neurons, astrocytes及oligodendrocytes。 許多的親神經性因子已被發現,包括有GDNF,BDNF,NGF, NT3, NT4, PDGF,這些因子都是非常有活性促進神經細胞存活。然而它們在臨床使用上受到許多的限制,原因是投予這些因子時不易到達腦部,然而,假若有一些小分子化合物能夠活化內生性神經幹細胞,促進細胞的增生或分化或者加強親神經性因子之訊息傳遞,或許可以提供另外一種預防退化性神經疾病或治療的策略。
在這篇論文,我們評估propolin A,propolin B,及propolin C可否促進腦皮質神經細胞的存活,或者影響神經幹細胞的形成,或者分化的命運。結果顯示,propolin A及propolin B在低密度神經細胞培養條件下,明顯抑制神經細胞的死亡,增加細胞的存活。在神經幹細胞的形成方面,結果顯示propolin A比 bFGF或EGF更明顯地會促進神經球的形成,並且維持這種球狀特性。訊息傳遞的研究顯示,造成這個原因可能是propolin A及propolinB 促進幹細胞磷酸化AKT及ERK,並且增加Trk-B蛋白表現。更進一步,我們評估propolin A 是否可以影響神經幹細胞分化為神經細胞,結果顯示propolin A 比bFGF或者EGF更有能力誘導。 在神經保護方面,propolin A明顯的保護腦皮質神經細胞免於rotenone或過氧化氫攻擊所造成的死亡。所有的這些結果顯示propolin A可能具有親神經性因子活性。
茶是世界上受歡迎的飲料之一,它具有美好的滋味及濃郁的芳香,近幾年很多報導都認為對身體之健康有益。並使用毛細管電泳分析新鮮茶葉及烏龍茶的theanine、caffeine、及catechins,我們評估這些茶湯對神經幹細胞分化活性之影響,結果顯示未處理之幹細胞能夠貼附於培養皿底部,並且促進神經幹細胞分化,可觀察到神經纖維往外生長。然而,處理茶湯之細胞則無法貼附培養皿底部,抑制了神經幹細胞分化。為了探討何種茶成分能夠擁有這個作用,我們進一步處理0到50μg/mL之EGCg,發現在20μg/mL就能明顯抑制細胞分化,然而,當我們使用高劑量的caffeine (50μg/mL)及theanine (348μg/mL),發現這二個化合物並不會抑制神經幹細胞分化。這個結果暗示EGCg可能影響神經幹細胞分化,並且在濃度約20-30μg/mL可能有部份細胞毒性。
總結來看,我們認為台灣蜂膠之多酚類,尤其是propolin A,可以有效促進神經幹細胞存活,並且可以誘導神經幹細胞分化為神經細胞,但茶多酚,特別是EGCg,可能有部份細胞毒性,並且影響神經幹細胞的分化命運。
part 1
Propolis designates a series of gums, resins, and balms of viscous consistency which are gathered by honeybees from certain parts of plants, mainly the buds and barks. Bees bring propolis back to the hive, where it is modified and mixed with other substances like wax and salivary secretions. Crude extracts of propolis have very complicated compositions, resulting from variation in geographical and botanical origin. Propolis has been used in folk medicine all over the world. It has been shown to possess antitumor, antioxidant, antiinflammatory, immunomodulatory, antiviral, and antibacterial activities. The pharmacological properties of propolis can be mainly attributed to the large amount of flavonoids. In addition to flavonoids, propolis contains cinnamic derivatives such as caffeic, ferulic, cinnamic, and chlorogenic acids and their esters. Recently, it was reported that a component of Brazilian propolis, caffeic acid phenethyl ester (CAPE), exerts potent antiinflammatory, antioxidant, and antitumor activities.
Much in the literature has demonstrated that natural products used in cancer chemotherapy including taxol, adriamycin, VP16, camptothecin, and carnosol have apoptosis-inducing activity. We are interested in the composition and biological properties of Taiwanese propolis. We recently demonstrated that six compounds isolated and characterized from Taiwanese propolis by NMR displayed absorptions characteristic of the prenylflavanones-type. The six flavonoid compounds included four novel ones: propolin A, propolin B, propolin E, and propolin F. Both propolin C and propolin D were identical to the reported prenylflavanone compounds nymphaeol-A and nymphaeol-B. However, no biological activities of these two compounds have yet been reported.
In the report, we evaluate Taiwanese propolis for anticancer activities. Our results indicated that both propolin C and propolin D were markedly more active than CAPE in induction of apoptosis on the human melanoma cells. The IC50 values of propolin C and propolin D on the human melanoma cells was 8.5 μM. However, the six compounds may trigger apoptosis of human melanoma cells through similar pathways. Propolin C-induced apoptosis may be via the activation of caspase-8, Bid, and the induction of cytochrome c release from mitochondria to the cytosol, activating caspase-9, and caspase-3, and leading to cleavage of PARP, causing DNA fragmentation, and ultimately apoptosis. The activation process is called“mitochondrial-dependent pathway.”We evaluated the six flavonoid compounds on their ability to inhibit Xanthine Oxidase activity. Our data indicated that propolin C, propolin E and propolin D were more active inhibitors than CAPE. The IC50 values of propolin C, propolin E, propolin D and CAPE were 17.0μM, 17.0μM, 22.0μM, and 45.0μM, respectively. On free radical scavenging abilities, our data indicated that propolin C, propolin A, and propolin B were more active than CAPE to scavengers of free radicals.
Taiwanese propolis was found to be richer in prenylflavanones, effective at inducing apoptosis in many cancer cell lines, and strong in antioxidant properties. Furthermore, we evaluated Taiwanese propolis and Brazilian propolis for free radical scavenging activity, phenolic concentrations; apoptosis trigger activity, and propolis composition analysis. Our results indicated that Taiwanese propolis contained a higher level of phenolic compounds and showed more capability to scavenge free radicals than Brazilian propolis. Our results indicated that the anticancer activity of Taiwanese propolis was much stronger, about ten fold that of Brazilian propolis. Finally, seven kinds of Taiwanese propolis and four kinds of Brazilian propolis were used for HPLC analysis. Our results demonstrated that Taiwanese propolis contained a higher level of propolin C, propolin D, and propolin F. However, Brazilian propolis was found to be richer in CAPE. The findings suggest that Taiwanese propolis is more active at inducing apoptosis or antioxidant activity than Brazilian propolis, perhaps due to its higher level of propolins.
part 2
Rescue of damaged neurons and stimulation of neurogenesis are theoretically attractive strategies for the treatment of neurogenerative diseases. Neural stem cells exist not only in the developing mammalian nervous system but also in the adult nervous system of all mammalian organisms, including humans. Neural stem cells can be derived from embryonic stem cells. The mechanisms that regulate endogenous neural stem cells are poorly understood. Potential uses of neural stem cells in repair include transplantation to repair missing cells and the activation of endogenous neural stem cells to provide “self-renewal”. Neural stem cells can be realized; however, we must control their proliferation or differentiation available to their daughter cells. Many reports have demonstrated that neural stem cells are present in the mammalian CNS during development and throughout adulthood. These cells can be isolated and expanded in culture in the presence of mitogens such as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Upon removal of the mitogens and provision of appropriate substance and growth factors, or neurotrophic factors, neural stem cells differentiate into neurons, astrocytes, and oligodendrocytes. Several neurotrophic factors have been reported. Glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophic factor 3 and 4 (NT3 and NT4), and platelet-derived growth factor (PDGF) were the most potent and acted by increasing neuronal survival. However, their clinical use is limited by their inability to reach the brain after systemic administration. However, small molecules (natural products) with the ability to activate endogenous neural stem cells to promote proliferation or differentiation, or enhance neurotrophic signaling might provide another means of preventing neurogenerative diseases or a therapeutic approach.
In this report, we evaluated the possibility that propolin A, propolin B, and propolin C could promote cortical neuron survival and influence neural stem cell formation and differentiation fates. Our results indicated that both propolin A and propolin B treatment significantly reduced cell loss, increased cell viability, and inhibited apoptosis in low cell density cultured conditions. On neural stem cell formation, our data also indicated that propolin A markedly promoted neural stem cell (neurospheres) formation and maintained neural stem cell properties, more than either bFGF or EGF. Signaling study indicated that both propolin A and propolin B promoted neural stem cell formation due to the phosphorylation of both AKT and ERK and up-regulated Trk-B expression. Additionally, we investigated whether propolin A can influence the generation of neuronal progenitors from neural stem cells. Our results demonstrated that the propolin A is more potent in the regard than bFGF or EGF. On neuroprotective study, propolin A significantly prevented cell death induced by rotenone- or H2O2-treatment. All these results suggest that propolin A has neurotrophic-like effects and is a good neuroprotective agent.
Tea is one of the most popular beverages in the world because of its taste, aroma, and lately, its reported health benefits. We used capillary electrophoresis (CE) to determine of theanine, caffeine, and catechins in fresh tea leaves and Oolong tea. We evaluated the effect of fresh tea leaves or Oolong tea extract liquors on neural stem cells by migration assay. Our results indicated an untreated group can attach to the bottom of the plate and induce neural stem cell migration and neurite outgrowth. However, fresh tea leaves or Oolong tea extract liquors markedly inhibited neural stem cell attachment to the bottom of the plate and did not induce cell migration or neurite outgrowth. We remain interested in what kind of tea compositions can inhibit neural stem cells adhesion or migration. Treatment of neural stem cell with 0 to 50μg/mL of EGCg for 24 h resulted in dramatic inhibition of cell adhesion at a concentration of 20μg/mL. However, caffeine and theanine did not influence neural stem cell adhesion or migration at the high concentration of 50μg/mL (caffeine) or 348μg/mL (theanine). The results obtained in the experiments suggest that EGCg might influence neural stem cell differentiation fates and have a partial cytotoxicity effect at the level of 20-30μg/mL.
We conclude that Taiwaneses propolis polyphenols (especially in propolin A) have potential promote neural stem cell survival and differentiation into neurons, but tea polyphenols (especially in EGCg) are potentially cytotoxic to neural stem cell and influence stem cell differentiation fates.
目 錄 (Content)
Studies on the anti-cancer mechanism from Taiwanese propolis
中文摘要………………………………………………………………………………1
Abstract…………………………………………………………………………….3
Introduction………………………………………………………………………...6
Materials and Methods…………………………………………………………….8
Results
Part 1 Cytotoxic prenylflavanones from Taiwanese propolis…………………….16
Tables and Figures………………………………………………………………….20
Part 2 Apoptosis of human melanoma cells induced by the novel compounds propolin A and propolin B from Taiwanese propolis…………………..27
Figures………………………………………………………………………….32
Part 3 Propolin C from propolis induces apoptosis through activating caspases, Bid and cytochrome c release in human melanoma cells……..………..45
Tables and Figures……………………………………………………………51
Part 4 Propolins D, E, and F from Taiwanese propolis induce apoptosis through the activation of caspases via mitochondrial-independent pathway in human melanoma A2058 cells………………………………….………..69
Tables and Figures…………………………………………………………………74
Part 5 Comparison of the radical scavenging activity, cytotoxic effects, and
apoptosis induction in human melanoma cells by Taiwanese propolis and Brazilian propolis…………………………………………………89
Tables and Figures……………………………………………………………93
Discussion………………………………………………………………………...107
References………………………………………………………………………...118
Studies on the promoted neural stem cells growth and the differentiation mechanism from Taiwanese propolis and tea.
中文摘要…………………………………………………………………………...125
Abstract……………………………………………………………………127
Introduction……………………………………………………………………130
Materials and Methods………………………………………………………136
Results
Part 1 Propolin A, a novel compound from Taiwanese propolis, induced generation of neuronal progenitors from neural stem cells………….143
Figures…………………………………………………………………………153
Part 2 Capillary electrophoretic determination of theanine, caffeine, and catechins in fresh tea leaves and Oolong tea and their effects on rat neurospheres adhesion and migration………………………………...177
Tables and Figures ……………………………………………………………...181
Discussion………………………………………………………………………….194
References…………………………………………………………………………203
part 1
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part 2
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