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研究生:歐俞秀
研究生(外文):Yu-Shiou
論文名稱:PI3K/Akt路徑調控穿心蓮萃出物及穿心蓮內酯誘發大鼠初代肝細胞pi屬麩胱甘肽硫轉移酶表現機制之探討
論文名稱(外文):Role of PI3K/Akt pathway in up-regulation of Andrographis paniculata extracts- and Andrographolide-induced expression of pi class of glutathione S-transferase in rat primary hepatocytes
指導教授:陳暉雯
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:營養學研究所
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:62
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現代人注重健康及養生,因此,近年來將傳統中草藥應用於日常保健養生或疾病療養上的人口越來越多。穿心蓮,拉丁學名 Andrographis paniculata (Burm. F.) Nees,是一種來源廣且毒性副作用低的中草藥,普遍使用於東南亞及中國大陸等國家。穿心蓮具有清熱解毒、涼血消腫、抗血小板凝集、降血糖和血壓、抗發炎、抗癌等生理功效,穿心蓮內酯是穿心蓮當中重要的活性成分之一。過去研究指出,穿心蓮內酯可藉由活化PI3K/Akt 訊息傳遞路徑而抑制內皮細胞的細胞凋亡反應;實驗室先前研究發現,穿心蓮乙醇、乙酸乙酯萃出物及穿心蓮內酯皆可顯著增加大鼠初代肝細胞生物轉換酵素系統pi屬麩胱甘肽硫轉移酶表現,預處理PI3K抑制劑wortmannin則會抑制穿心蓮誘發pi屬麩胱甘肽硫轉移酶表現,推論PI3K/Akt訊息傳遞路徑可能參與穿心蓮調控pi屬麩胱甘肽硫轉移酶表現。因此,本實驗利用大鼠初代肝細胞培養模式,以穿心蓮乙醇、乙酸乙酯萃出物、穿心蓮內酯及PI3K抑制劑wortmannin和LY294002,深入探討PI3K/Akt路徑是否參與穿心蓮誘發pi屬麩胱甘肽硫轉移酶表現的過程。大鼠初代肝細胞預處理PI3K抑制劑25 μM LY294002或1 μM wortmannin 1小時,再加入100 μg/ml 穿心蓮乙醇、乙酸乙酯萃出物或40 μM穿心蓮內酯繼續培養48小時,觀察GSTP蛋白質表現情形。結果顯示,LY294002及wortmannin皆可顯著降低穿心蓮誘發GSTP表現 (p < 0.05)。進一步探討穿心蓮萃出物及穿心蓮內酯是否影響細胞磷酸化Akt蛋白質表現,細胞處理100 μg/ml穿心蓮萃出物或40 μM穿心蓮內酯1小時,觀察磷酸化Akt (p-Akt)蛋白質表現情形。結果顯示,穿心蓮萃出物及穿心蓮內酯皆可顯著增加細胞磷酸化Akt蛋白質表現 (p < 0.05),此外,以LY294002或wortmannin預處理1小時,可顯著降低穿心蓮誘發磷酸化Akt蛋白質表現 (p < 0.05)。綜合以上實驗結果得知,PI3K/Akt訊息傳遞路徑參與穿心蓮萃出物及穿心蓮內酯誘發細胞GSTP表現。

Andrographis paniculata (Ap) has been widely used as a traditional medicine in Asia for the prevention and treatment of common cold, inflammation, cancer, hyperglycemia and hypertension. Our previous study showed that the ethanol (ApEE) or ethyl acetate (ApEAE) extracts of Ap and andrographolide, the major active diterpene lactone of Ap, induced pi class of glutathione S-transferase (GSTP) expression in rat primary hepatocytes. Also, the induction of GSTP protein expression by Ap extracts and andrographolide was significantly inhibited by wortmannin, an inhibitor of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (p &lt; 0.05). In the present study, we investigated the role of the PI3K/Akt pathway in GSTP induction by ApEE, ApEAE or andrographolide in rat primary hepatocytes. In the GSTP expression experiment, cells were pretreated with or without 25 µM LY294002 or 1 µM wortmannin for 1 h before the addition of 100 µg/ml of ApEE, ApEAE or 40 µM andrographolide for 48 h. In the Akt phosphorylation experiment, cells were pretreated with or without 25 µM LY294002 or 1 µM wortmannin for 1 h before the addition of 100 µg/ml ApEE, ApEAE or 40 µM andrographolide for 1 h. The total protein was collected and determined for GSTP and phospho-Akt (p-Akt) protein expression by Western blot analyses. The results showed that ApEE, ApEAE and andrographolide significantly induced GSTP and p-Akt protein expression (p &lt; 0.05). In addition, the induction of GSTP and p-Akt protein expression by Ap extracts and andrographolide was significantly inhibited by LY294002 and wortmannin (p &lt; 0.05). These results indicate that the PI3K/Akt pathway is involved in the regulation of pi class of glutathione S-transferase expression induced by Ap extracts and andrographolide in rat primary hepatocytes.

圖目錄................................................III
表目錄.................................................IV
摘要....................................................1
Abstract................................................3
第一章 文獻回顧.........................................5
1-1 穿心蓮..............................................5
1-1.1 穿心蓮簡介........................................5
1-1.2 穿心蓮與心血管疾病................................7
1-1.3 穿心蓮與免疫功能..................................7
1-1.4 穿心蓮與生物轉換酵素系統..........................8
1-2 PI3K/Akt訊息傳遞路徑..............................10
1-2.1 PI3K (phosphatidylinositol 3-kinases)...........10
1-2.2 PTEN (phosphatase and tensin homolog)...........14
1-2.3 The serine/threonine protein kinase Akt.........15
1-3 pi屬麩胱甘肽硫轉移酶 (pi class of glutathione S-
transferase, GSTP).................................17
1-3.1 生物轉換酵素系統.................................17
1-3.2 GSTP簡介.........................................19
1-3.3 GSTP基因結構調控機轉.............................20
第二章 研究動機........................................22
第三章 實驗材料與方法..................................23
3-1 實驗架構...........................................23
3-2 實驗材料與試劑.................................... 24
3-2.1 實驗動物.........................................24
3-2.2 實驗材料.........................................24
3-2.3 化學試劑.........................................24
3-3 實驗方法...........................................28
3-3.1 大白鼠初代肝細胞分離與培養.......................28
3-3.2 穿心蓮萃取.......................................29
3-3.3 細胞處理.........................................30
3-3.4 總蛋白製備.......................................31
3-3.5 蛋白質定量.......................................31
3-3.6 西方墨點法 (Western blotting)....................31
3-4 統計分析 (Statistical analysis)....................34
第四章 實驗結果........................................35
4-1 不同溶劑對穿心蓮之萃出率...........................35
4-2 預處理PI3K抑制劑wortmannin及LY294002對穿心蓮萃出物
及穿心蓮內酯誘發大鼠初代肝細胞GSTP蛋白質表現之影響.35
4-3 穿心蓮乙醇、乙酸乙酯萃出物及穿心蓮內酯對大鼠初代肝細胞磷
酸化Akt蛋白質表現之影響............................35
4-3.1預處理PI3K抑制劑LY294002對穿心蓮萃出物及穿心蓮內酯誘發
大鼠初代肝細胞磷酸化Akt蛋白質表現之影響...........36
4-3.2預處理PI3K抑制劑wortmannin對穿心蓮萃出物及穿心蓮內酯誘
發大鼠初代肝細胞磷酸化Akt蛋白質表現之影響.........36
第五章 討論............................................41
第六章 結論............................................46
第七章 附錄............................................47
第八章 參考文獻........................................49


圖目錄................................................III

文獻回顧
圖一、穿心蓮............................................6
圖二、存在穿心蓮中的diterpenes..........................6
圖三、磷酸肌醇.........................................11
圖四、PI3K活化之模式...................................12
圖五、PtdIns代謝途徑...................................13
圖六、PI3K抑制劑Wortmannin和LY294002...................14
圖七、Akt活化之調控路徑................................15
圖八、PI3K/PTEN/Akt途徑................................16

結果
圖一、預處理PI3K抑制劑wortmannin及LY294002對穿心蓮萃出物
及穿心蓮內酯誘發初代肝細胞GSTP蛋白質表現之影響...38
圖二、預處理PI3K抑制劑LY294002對穿心蓮乙醇、乙酸乙酯萃出物及穿心蓮內酯誘發大鼠初代肝細胞磷酸化Akt蛋白質表現之影響.....................................39
圖三、預處理PI3K抑制劑wortmannin對穿心蓮乙醇、乙酸乙酯萃出物及穿心蓮內酯誘發大鼠初代肝細胞磷酸化Akt蛋白質表現之影響...................................40

附錄
圖一、探討有無含ITS+之細胞培養液對大鼠初代肝細胞磷酸化
Akt蛋白質表現之影響..............................47
圖二、探討穿心蓮萃出物及穿心蓮內酯處理不同時間誘發大鼠
初代肝細胞磷酸化Akt蛋白質表現之影響..............48


表目錄.................................................IV

文獻回顧
表一、PI3K家族成員.....................................11
表二、生物轉換酵素系統負責的催化反應及作用部位.........18


結果
表一、95%乙醇及乙酸乙酯穿心蓮萃出率....................37



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