臺灣博碩士論文加值系統

第一篇
中文摘要
本論文首先是以半枝蓮的萃取成分baicalein、baicalin與wogonin處理人類的肝癌細胞株Hep G2，比較這三種萃取成分對人類肝癌細胞株hepatoblastoma G2 (Hep G2)的毒性與生長的抑制情形。結果發現以baicalein對Hep G2的毒性與生長的抑制情形最強。再以baicalein處理其他的人類肝癌細胞株Hep J2、Hep 3B與Hep J5等，發現baicalein對這些人類肝癌細胞株的毒性與生長抑制具有選擇性。以baicalein處理人類非肝癌的肝細胞株Chang liver cell line，發現高濃度的baicalein對Chang liver cell line的毒性與生長的抑制較小，且細胞還有繼續增殖的能力。
在terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)實驗中，發現baicalein處理Hep G2細胞24小時後，有計畫性死亡(apoptosis)的情形發生。在細胞週期的實驗中，發現baicalein對Hep G2細胞週期的影響以抑制S phase為主。另一方面， baicalein在處理Hep G2細胞的早期即可誘導Hep G2細胞內產生較多的ROS，細胞膜的完整性被破壞，顯示有部份細胞產生壞死(necrosis)，但此時Hep G2細胞的apoptosis現象並不明顯，且Hep G2細胞內glutathione (GSH)耗空的現象並不明顯，因此baicalein誘導Hep G2細胞內產生的ROS，並不是造成Hep G2細胞產生apoptosis的主要因素。
由於粒線體功能的破壞與細胞產生apoptosis有密切的關係，baicalein處理Hep G2細胞後，會隨處理時間的延長而增加m降低的百分率。存於粒線體上的Bcl-2蛋白質具有抗氧化的能力且與細胞產生apoptosis有密切的關係， baicalein亦可藉由影響粒線體中Bcl-2的表現引起Hep G2細胞產生apoptosis。粒線體內的cytochrome c一旦釋放到細胞質中，就會趨動下游的訊息。最後造成細胞的apoptosis。baicalein會使Hep G2細胞粒線體中的cytochrome c釋放到細胞質中，引起Hep G2細胞產生apoptosis的訊息。
綜合以上結果本論文所得的結論是baicalein誘導Hep G2細胞內產生的ROS並不是造成Hep G2細胞apoptosis的主要因素。baicalein誘導Hep G2細胞產生apoptosis，主要是藉由降低m、cytochrome c從粒線體釋放到細胞質中以及影響粒線體Bcl-2的表現，最後導致Hep G2細胞產生apoptosis。
第二篇
中文摘要
本論文以紫草的萃取成分shikonin處理人類的肝癌細胞株Hep G2，結果發現以shikonin對Hep G2產生細胞毒性並降低細胞存活率。shikonin處理Hep G2細胞24小時後，有計畫性死亡(apoptosis)的情形發生。本論文接著探討shikonin誘導Hep G2細胞內產生reactive oxygen species (ROS)與Hep G2細胞死亡的關係，結果顯示shikonin在處理Hep G2細胞1-3小時後，即可使Hep G2細胞內大量產生ROS，在細胞內ROS產生時期，細胞膜完整性被破壞得最嚴重，顯示有部份細胞產生壞死(necrosis)。Shikonin處理Hep G2細胞24小時的期間中，會降低Hep G2細胞內的glutathione (GSH)。因此本論文推論shikonin誘導Hep G2細胞內產生的ROS，可能是造成Hep G2細胞產生apoptosis的一個關鍵因素。
在粒線體膜電位(m)實驗中發現，shikonin會降低Hep G2細胞的m，並造成粒線體中的cytochrome c釋出，累積至細胞質中，顯示shikonin會對Hep G2細胞的粒線體造成損壞。Shikonin處理Hep G2細胞後首先會活化caspase-8，其後再活化caspase-9，接著再活化caspase-3與caspase-2。由於caspase-8的活化與粒線體中的cytochrome c釋出至細胞質中發生在同一時間，因此本論文推論shikonin對Hep G2細胞內各種caspase的活化進而誘導apoptosis存有兩條途徑：第一條途徑為shikonin活化caspase-8造成細胞產生apoptosis，第二條途徑為shikonin經由破壞粒線體，造成m降低與粒線體中的cytochrome c釋放到細胞質中，接著活化caspase-9，再接著活化caspase-3使細胞走向apoptosis。另一方面，shikonin亦會造成Hep G2細胞p53與bax兩種蛋白質表現增加，降低Bcl-2蛋白質的表現，調控c-myc蛋白質的表現，來造成Hep G2細胞進行apoptosis。
此外，在apoptosis發生的過程中，發現shikonin會影響細胞週期調控蛋白的表現，造成細胞週期之S phase有增加的現象，可能是Hep G2細胞為了要對抗shikonin的毒殺而增加DNA的合成，以維持細胞族群的生存。
綜合以上結果，本論文所得的結論是shikonin在處理Hep G2細胞的早期以使細胞內生大量自由基、細胞內GSH的耗空、破壞細胞膜的完整性同時造成細胞壞死的作用為主。然而在早期造成m的下降以及cytochrome c從粒線體釋放到細胞質中，並造成細胞內相關caspase的活化，可能是shikonin誘導Hep G2細胞產生apoptosis的關鍵原因之一。另一方面，shikonin亦可使Hep G2大量表現p53與Bax，降低Bcl-2蛋白質的表現，調控c-myc蛋白質的表現來使Hep G2進行apoptosis。

Part I
This study has demonstrated that baicalein has anti-cancer effectiveness against human hepatoma cells. The dose response of baicalein in Hep G2 and Hep J2 cells indicates that baicalein decreased viability more than 90%. In comparison, baicalein had only minimal effects on the viability of control Chang liver cells. Flow cytometric analysis showed that baicalein inhibited the cell cycle of Hep G2 cells in the S phase. In addition, baicalein treatment resulted in a decreased mitochondrial transmembrane potential and damaged the integrity of the cell membrane. The TUNEL assay results indicated that baicalein elicited a significant increase of DNA fragmentation in Hep G2 cells after incubation for 24 and 48 hours. These results indicate that baicalein is an effective anti-hepatoma agent with minimal influence on non-cancer cells. The effects of baicalein on Hep G2 cells include inhibition of the S phase of the cell cycle. Flow cytometric studies revealed that baicalein maintained the ability to increase the presence of intracellular reactive oxygen species (ROS). Intracellular glutathione (GSH) depletion, however, did not appear apparently during the periods of baicalein treatment, suggesting that intracellular ROS generation does not constitute a critical event in baicalein-induced apoptosis. In this paper, we reveal that the mitochondrial transmembrane potential (m) decreased dramatically subsequent to baicalein treatment. On the other hand, the level of Bcl-2 decreased after 24 hours incubation of Hep G2 cells in the presence of baicalein, suggesting that the decrease of Bcl-2 may be an important element in apoptosis induced by baicalein. In addition, results indicate that cytochrome c, released from mitochondria into the cytosol. Our data are consistent with the hypothesis that baicalein could contribute to Hep G2 cell apoptosis through mitochondrial dysfunction, cytochrome c release and the initiation of apoptosis.
Part II
Shikonin has been demonstrated to exhibit anti-cancer activity, but the mechanisms are poorly understood. In this paper, we reveal that the administration of shikonin induced the cytotoxicity of the human hepatofibroblastoma G2 (Hep G2) cell line, and stimulated necrotic and apoptotic cell death. Flow cytometric studies indicated that shikonin maintained the ability of the cells to increase the presence of intracellular reactive oxygen species (ROS). In this study, we reveal that the mitochondrial transmembrane potential (m) decreased dramatically following shikonin treatment. In addition, results indicated that cytochrome c, released from mitochondria into the cytosol, and caspase-2, -3, -8, and -9, were activated during shikonin-induced apoptosis. This paper also demonstrated that shikonin induced the increasing of p53 and bax proteins expression, decreasing of Bcl-2 protein expression on Hep G2. The p53 may play an critical role in the apoptosis signiling pathway in shikonin-induced Hep G2 apoptosis.

封面
第一章Baicalein引發人類肝癌細胞計畫性死亡作用機轉的研究
第一章、中文摘要
第二章、英文摘要
第三章、緒論
第四章、材料與方法
第五章、結果
第六章、討論
第七章、總結論
第八章、參考文獻
第九章、圖表
第二篇　Shikonin引發人類肝癌細包計畫性死亡作用機轉的研究
第一章、中文摘要
第二章、英文摘要
第三章、緒論
第四章、材料與方法
第五章、結果
第六章、討論
第七章、總結論
第八章、參考文獻
第九章、圖表
學會及期刊發表的論文

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