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研究生:孫秀珍
研究生(外文):Show-Jane Sun
論文名稱:用蛋白質體技術探討牛樟芝子實體萃取物之抗發炎與神經保護作用
論文名稱(外文):Anti-inflammatory and Neuroprotective Functions of Antrodia cinnamomea Fruiting Body Extracts Through Gel-based Proteomic Approach
指導教授:龔瑞林龔瑞林引用關係余惠敏余惠敏引用關係
指導教授(外文):Zwe-Ling KongHui-Ming Yu
學位類別:碩士
校院名稱:國立臺灣海洋大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:130
中文關鍵詞:牛樟芝人類巨噬細胞株U937人類神經膠瘤細胞株YKG-1乙醯膽鹼酯酶抑制劑神經保護
外文關鍵詞:Antrodia cinnamomeahuman macrophages U937 cell linehuman glioblastoma YKG-1 cell linesacetylcholinesterase inhibitorneuroprotection
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牛樟芝 (Antrodia cinnamomea ) 是台灣特有的真菌類,具有廣泛的生物活性,包括抗癌、抗氧化、抗發炎、抗B型肝炎、抗高血壓作用、抗高脂血症、抗血管生成、抗菌、免疫調節活性、保護肝臟、及抗阿茲海默症等作用,但其抗阿茲海默症作用機制則尚不明確。本研究旨在有效分離牛樟芝之神經保護成分及探討其可能作用機制。將椴木栽培牛樟芝子實體,分別以酒精及熱水、正己烷、乙酸乙酯、正丁醇進行萃取分離,並利用人類巨噬細胞株U937,篩選出細胞發炎模式下具保護作用的成分。其次以人類神經膠瘤細胞株YKG-1利用蛋白質體技術分析,其對神經細胞的相關作用基因表現,並與阿茲海默症治療藥乙醯膽鹼酯酶抑制劑 donepezil HCl 進行比較。結果顯示熱水乙酸乙酯分離物 (W-EA) 顯著且具劑量依賴性地抑制U937發炎因子TNF-α、IL-6、IL-8及CCL5/RANTES的生成量。蛋白質體學分析結果顯示,經由 LC-MS/MS 鑑定出十種關鍵調節蛋白: 與氧化壓力相關之基因表現UQCRC1是上升,而CLIC1、PSMC3、TXNDC5、FTL及PRDX3則是下降,與鈣結合相關之基因表現ANXA2上升,而與細胞週期及細胞分裂有關之基因RPLP2及LMAN是上升,但ACTB下降。本研究結果顯示牛樟芝之抗發炎及神經保護有效成分屬於疏水性,且與donepezil HCl 具有相似之基因調節作用機制。
Antrodia cinnamomea, a unique fungi in Taiwan, possesses a wide range of biological activity, including anti-cancer, anti-oxidation, anti-inflammatory, anti-hepatitic B virus-induced illness, anti-hypertention, anti-hyperlipidemia, anti-angiogenesis, anti-bacterial infection, immuno-moldulation, hepato-protection and anti-Alzheimer's disease effects. However, its molecular mechanism remains elusive. In this study, we initially fractionate the fruiting body of basswood-cultivated A. cinnamomea. Different fractions are examined their effect on the protection of neurons and explored the potential mechanism, respectively. The A. cinnamomea fruiting body is sequentially fractionated by alcohol, hot water, hexane, ethyl acetate, and n-butanol. The human macrophage cell line U937 is used as the in vitro experimental model to evaluate the anti-inflammation effect of different fractions. Our results demonstrate that the hot water layer of ethyl acetate (W-EA) isolate significantly inhibits the production of TNF-α, IL-6, IL-8 and CCL5/RANTES of U937 cells in a dose-dependent manner. In addition, we use proteomics to profile the protein profiles of human glioma cell lines YKG-1 exposed to W-EA and donepezil HCl, an acetylcholinesterase inhibitor, respectively. Results show that W-EA and donepezil HCl significant alter the expression of ten identified proteins. Gene expression associated with oxidative stress the UQCRC1 is rising, CLIC1, PSMC3, TXNDC5, FTL and PRDX3 decline. The up-regulation of ANXA2 which is associated with calcium binding related genes. In regard to cell cycle/division-related gene RPLP2 and LMAN are increased. On the contrary, a decrease in ACTB expression is monitored. This study first presents the anti-inflammatory and neuroprotection of a hydrophobic active fraction, W-EA in the fruiting body of A. cinnamomea, and its gene regulation mechanism is similar to donepezil HCl.
謝 誌 II
目 錄 III
摘 要 XII
ABSTRACT XIII
名詞縮寫 (ABBREVIATION) XV
壹、前 言 1
貳、文獻回顧 4
一、發炎與疾病的產生 4
1. 發炎與氧化壓力 4
2. 發炎與神經細胞損傷 6
3. 發炎反應與細胞激素 (Cytokine) 6
4. 發炎與趨化因子 (Chemokine) 8
二、神經退化性疾病 (NEURODEGENERATIVE DISEASE) 9
1. 神經退化性疾病成因 9
2. 阿茲海默症 (Alzheimer’s disease, AD) 發生原因 9
3. 阿茲海默症與發炎 11
4. 阿茲海默症與中樞膽鹼能系統 (Central Cholinergic System) 12
三、乙醯膽鹼酯酶抑制劑 13
1. 乙醯膽鹼與神經細胞發炎 13
2. 乙醯膽鹼酯酶抑制劑與阿茲海默症 13
3. 乙醯膽鹼酯酶抑制劑donepezil HCl之藥理機制 14
四、牛樟芝簡介 15
1. 牛樟芝特性 15
2. 牛樟芝之藥理功能相關研究 16
2-1. 保護肝臟作用 16
2-2. 抗發炎之活性 16
2-3. 抗腫瘤之活性 17
2-4. 保護神經 18
2-5. 抗氧化活性 18
叁、整體實驗設計 19
一、牛樟芝子實體萃取方法 19
二、細胞實驗設計 20
三、蛋白質學實驗設計 21
肆、實驗材料與方法 22
一、實驗材料 22
1. 材料來源 22
2. 細胞株 22
3. 試驗藥品 22
4. 儀器設備 24
二、實驗方法 26
1. 牛樟芝子實體粗萃取 26
2.人類巨噬細胞株 U937培養 28
3. 細胞存活率試驗 (MTS assay) 28
4. TNF-α ELISA分析 29
5. IL-6 ELISA 分析 29
6. IL-8 ELISA 分析 30
7. CCL5/RANTES ELISA分析 31
8. HPLC高效液相層析法 31
9. 人類神經膠瘤細胞株YKG-1之培養 32
10. 人類神經膠瘤細胞株YKG-1細胞凋亡觀察 32
11. 人類神經膠瘤YKG-1細胞株蛋白質萃取 33
12. 二維凝膠電泳分析與影像處理 34
13. 蛋白質膠內水解 (in-gel digestion) 34
14. 蛋白質質譜儀鑑定 (LC- MS/MS) 35
15. 蛋白質資料庫蒐尋比對 35
16. PANTHER蛋白質分類分析 36
17. STRING 蛋白質交互作用分析 36
18. Ingenuity Pathway Analysis (IPA) 軟體分析生物學路徑 36
19. 統計方法 36
伍、結果與討論 37
一、 牛樟芝子實體萃取物之萃取 37
二、 牛樟芝子實體萃取物對 U937細胞株之抗發炎之作用 37
1. 牛樟芝子實體不同萃取物對 U937細胞存活率之影響 37
2. 牛樟芝子實體不同萃取物對U937細胞抑制TNF-α之影響 38
3. 牛樟芝子實體萃取物W-EA對U937細胞株劑量依賴性存活率之影響 39
4. 牛樟芝子實體萃取物W-EA對U937細胞株抑制TNF-α活性之影響 40
5. 牛樟芝子實體萃取物W-EA對U937細胞株抑制IL-6活性之影響 40
6. 牛樟芝子實體萃取物W-EA對U937細胞株抑制IL-8活性之影響 41
7. 牛樟芝子實體萃取物W-EA對U937 細胞株抑制CCL5/RANTES活性之影響 41
三、利用蛋白質體技術比較牛樟芝子實體萃取物 (W-EA) 和DONEPEZIL HCL 對YKG-1神經細胞株之保護作用 42
1. 牛樟芝子實體萃取物W-EA對YKG-1神經膠瘤細胞劑量依賴性存活率之影響 42
2. 乙醯膽鹼酯酶抑制劑Donepezil HCl對YKG-1神經膠瘤細胞劑量依賴性存活率之影響 42
3. 二維凝膠電泳分析 43
4. 蛋白質鑑定分析 (LC-ESI MS/MS) 44
5. 生物資訊蛋白質分類分析 44
陸、結論 50
柒、參考文獻 51
捌、圖表目錄 69
玖、附錄目錄 110

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