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研究生:蔡聿奇
研究生(外文):Yu-Chi Tsai
論文名稱:新型跨界活性篩選模式建立暨類雌激素、抗血小板凝集與抗人類&;#30129;疹病毒活性之天然物研究
論文名稱(外文):Establishment of a New Cross Kingdom Assay Model and Studieson Natural Products with Estrogenic, Antiplatelet, and Anti-Epstein-Barr Virus Activities
指導教授:張芳榮張芳榮引用關係
指導教授(外文):Fang-Rong Chang
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:天然藥物研究所博士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:259
中文關鍵詞:跨界活性篩選天然物雌激素血小板人類皰疹病毒
外文關鍵詞:Cross Kingdom AssayNatural ProductsEstrogenPlateletEpstein-Barr Virus
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中草藥化學成分研究與其藥理活性的證明對提供醫藥及民間用途科學性的證據是至關重要的。特別的是,由於台灣獨特的地理環境、豐富的歷史,以及生物多樣性,造就天然物研究與藥物開發的優勢。
本研究為首次將轉殖基因阿拉伯芥pER8:GUS 之癒傷組織(callus)應用於跨界活性篩選,以評估雌激素與天然物雌激素活性。此基因轉殖植物被用於生產大量的癒傷組織,且這些癒傷組織因無性繁殖而能穩定表現轉殖之基因。癒傷組織最適化的誘導配方測試了十六種培養基,而量產用的培養基則測試了六種。固態培養基1DK1 能誘導最大量且健康的癒傷組織,且於組織染色法與螢光測定法中能表現具有藥物濃度依賴性的GUS 活性,故1DK1 的癒傷組織被選定進行後續懸浮培養之最佳化測試。液態培養基&;#617;1N1B 與&;#617;1/2 1N1B 之癒傷組織對雌激素展現了顯著的敏感度且於組織染色法與螢光測定法可觀察到藥物濃度依賴性。此開發之模式能用於檢測二次代謝產物、環境廢物、農藥及其他物質與雌激素受體之交互作用,且亦能用於評估營養補充品及先導藥物之雌激素活性。
本 研 究 更針對台灣本土草藥闊葉麥門冬(Liriope platyphylla, 百合科
Liliaceae)與藍豬耳(Lindernia crustacea, 玄參科Scrophulariaceae)的之天然物化學及其生物活性進行研究。自闊葉麥門冬乙醇萃取物中分離得到三十八個成分,其中包含八個新化合物(1&;#8210;8) 以及三十個已知化合物。這些成分可分類為十二種骨架, 包含phenyl-isocoumarin (1) 、benzofuroisocoumarins (2&;#8210;4) 、benzyl-benzofuran (5)、ethyl butanoate (3)、homoisoflavonoids (7&;#8210;14)、chalcone (15)、flavonoids (16&;#8210;25)、amides (26&;#8210;31)、lignan (32)、fatty acid derivative (33 與34)、indole (35)以及benzenoids (36&;#8210;38). 化合物9、11、19 與22 表現最顯著的雌激素活性且呈現藥物濃度依賴性,而其他具有類似結構之化合物應亦具有潛力,可作為開發植物雌激素相關營養補充品的標的。此外,化合物11 與12 表現了最強的抑制血小板凝活性。我們的成果是第一次展示了闊葉麥門冬中具有雌激素與抗血小板凝集活性的成分,也表示他們在膳食補充品與功能性食品產品應用上的潛力。
自另一個中草藥,藍豬耳乙醇萃取物分離得到三十三成分,這些成分可歸類為一個diterpene (39)、四個anthraquinones (40&;#8210;43)、兩個iridoides (44 與45)、十四個phenylpropanoid glycosides (46&;#8210;59)、五個flavonoids (60&;#8210;64)、一個lignanglycoside (65)、一個phenethyl alcohol glycoside (66)、一個phenylpropeneglycoside (67)、一個glucosylglycerol derivative (68)、一個furanone (69),以及兩個cinnamic acid derivatives (70 與71)。化合物39、40、45–49 及63 於免疫墨點分析法中,對第四型人類皰疹病毒(EBV)的裂解週期(或稱增殖感染期productive infection)展現顯著抑制影響,而化合物44、50、51 與62 則表現中等程度的抗EBV 活性。這次第一次進行藍豬耳的植物化學與生物活性研究,所有化合物均是首次自母草屬(Lindernia)中分離得到。

The investigation of the chemical constituents of herbal medicines and the demonstration of their pharmacological activities are crucial to provide scientific evidence to medical and folk uses. The distinctive geographical nature, rich history, and biodiversity of Taiwan offer a superior advantage for the research and development of drugs from natural products.
Initially, we tried to establish a new model for screening estrogen-like substances. The application of the transgenic pER8:GUS Arabidopsis callus in a cross-kingdom assay to evaluate
the estrogenic activity of 17β-estradiol (E2) and natural products is discussed for the first time. The transgenic plants were utilized to produce a large number of calli, which stably expressed transfer
genes by asexual reproduction. The optimum formula for calli induction and production were selected from sixteen solid media and six liquid media, respectively. The solid medium 1DK1
induced the largest number of healthy calli, which showed dose-dependent GUS activity in the histochemical and fluorometric assay. Therefore, 1DK1 calli were selected for further optimization
for the suspension culture. The calli of liquid media &;#617;1N1B and &;#617;1/2 1N1B exhibited significant sensitivity towards E2 in a dose-dependent manner as demonstrated by the histochemical and
fluorometric assay. This protocol can be used to detect the estrogenic activity of secondary metabolites, environmental waste products, pesticides and other substances interacting with
estrogenic receptors. It can be also used in the evaluation of nutritional supplements and candidate drugs possessing estrogenic activity.
This study also focuses on natural product chemistry and their bioactivities of native Taiwanese herbs, Liriope platyphylla (Liliaceae) and Lindernia crustacea (Scrophulariaceae). Phytochemical investigation of L. platyphylla ethanolic extract led to the isolation of thirty-eight components, including eight new compounds (1&;#8210;8) and thirty known compounds (9&;#8210;38). Those isolates were summarized in twelve skeletons, including phenyl-isocoumarin (1), benzofuroisocoumarins (2&;#8210;4), benzyl-benzofuran (5), ethyl butanoate (3), homoisoflavonoids (7&;#8210;14), chalcone (15), flavonoids (16&;#8210;25), amides (26&;#8210;31), lignan (32), fatty acid derivative (33 and 34), indole (35), and benzenoids (36&;#8210;38). Compounds 9, 11, 19, and 22 exhibited the most potent estrogenic activity in a dose-dependent manner, rendering those compounds and similar structures as potential candidates for phytoestrogen nutritional supplements. Furthermore, compounds 11 and 12 showed the highest inhibitory activity in platelet aggregation assay. Our results provided the first insight of L. platyphylla active components with estrogenic and antiplatelet activities suggesting the potential utilization of this herb and other components in dietary supplements and functional food products.
Phytochemical investigation of the other herb, L. crustacea ethanolic extract resulted in the isolation of thirty-three compounds. Those isolates were classified as a diterpene (39), four anthraquinone (40&;#8210;43), two iridoides (44 and 45), fourteen phenylpropanoid glycosides (46&;#8210;59), five flavonoids (60&;#8210;64), a lignan glycoside (65), a phenethyl alcohol glycoside (66), a
phenylpropene glycoside (67), a glucosylglycerol derivative (68), a furanone (69), and two cinnamic acid derivatives (70 and 71). Compounds 39, 40, 44–64, 66, 68, and 71 were evaluated
for their anti-Epstein-Barr virus (EBV) activity. Compounds 39, 40, 45–49, 62, and 63 exhibited significant inhibitory effect on EBV lytic cycle in immunoblot analysis, while 44, 50, and 51 showed moderate anti-EBV activity. This is the first phytochemical and biological investigation of L. crustacea. All isolates were identified for the first time from Lindernia sp.

Publications……………………….……………………………………I.
中文摘要………………………………………………………………...III.
Abstract………..………………………………………………………..V.
Chapter 1– Natural Products in Discovery…………..………………1.
1.1 Phytoestrogens……………………………………...……………..2.
1.2 Antiplatelet Effects…………………………………………………5.
1.3 Anti-Epstein-Barr Virus (Anti-EBV) Effects………...…..………..6.
1.4 References……………………………………….…………………7.
Chapter 2 – Objectives………………………………………………12.
Chapter 3 –The Evolution of a Transgenic Arabidopsis Assay System…13.
3.1 Cross Kingdom Assay as a Tool for the Detection of Estrogenic Activity..…13.
3.2 Materials and Methods……………………………………..……16.
3.3 Results and Discussion…………………………………...……19.
3.4 References………………………………………………………22.
Chapter 4 – Constituents and Bioactivities of Liriope platyphylla.25.
4.1 Description of L. platyphylla……………………………………..25.
4.2 Phytochemical Constituents and Biological Activities of Liriope sp.………...26.
4.3 Materials and Methods…………………………………………33.
4.4 Results and Discussion………………………………………...38.
4.5 References…………………………………………………………...97.
Chapter 5 – Constituents and Bioactivities of Lindernia crustacea…………102.
5.1 Description of L. crustacea……………………………………102.
5.2 Phytochemical Constituents and Biological Activities of Lindernia sp……103.
5.3 Materials and Methods…………………………………………106.
5.4 Results and Discussion……………………………………….109.
5.5 References………………………………………………………….113.
Chapter 6 – Conclusions…….………………………………...….116.
Appendix A. Spectroscopic Data of L. platyphylla Isolates……..119.
Appendix B. Spectroscopic Data of L. crustacea Isolates..........189.

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