臺灣博碩士論文加值系統

細胞凋亡是正常細胞維持恆定的重要機轉;細胞凋亡依路徑的不同，又分為死亡受體路徑、粒線體路徑、內質網壓力路徑： 死亡受體路徑: 將死亡的訊息經由各種不同的死亡受體例如:Fas、Fas-L、DR 4、DR 5 (Death receptor)和TNF (Tumor Necrosis Factor)等誘發一連串凋亡事件產生，粒線體路徑:此路徑所誘使細胞凋亡以粒線體做為開端，內質網壓力路徑: 經由通過內質網壓力路徑觸發的細胞凋亡。
本篇所使用的CTX III經由調控Bcl-2家族走向粒線體路徑，造成cytochrome C和Endonuclease G釋出，Caspase-9和Caspase-3活化走向凋亡，同時CTX III也誘發內質網路徑造成鈣離子釋出，Caspase-12走向凋亡。而IQDMA則是經由Fas-L活化走向死亡受體路徑，接著Caspase-8、Caspase-3活化，PARP斷裂造成凋亡。THDA亦由調控Bax增加，造成Caspase-9和Caspase-3活化走向凋亡。可得知CTX III和THDA為粒線體路徑，其中CTX III還包含內質網路徑。而IQDMA則為死亡受體路徑。
在細胞週期抑制方面；細胞週期可分為G0/G1、S、G2/M期。細胞週期分別受到不同的cyclins、cyclins-dependent kinase(CDKs)和cyclin-dependent kinases inhibitors(CDKI)所調控。本篇所使用的CTX III、IQDMA都是屬於G2/M停滯的試劑；CTX III藉由抑制細胞週期調控蛋白Cyclin A、Cyclin B1和Cdk2造成G2/M停滯，而IQDMA藉由增加p21造成G2/M停滯。
Mitogen-activated protein kinase (MAPK)與細胞生長、分化、發育及細胞死亡皆有關聯。MAPK家族分為Extracellular signal-regulated protein kinase (ERK)、c-Jun N-terminal kinase (JNK)和p38三大類。本篇所使用的CTX III和IQDMA是經由JNK去調控細胞凋亡和細胞週期停滯；THDA則是經由ERK和JNK去調控細胞凋亡表現。
Janus Kinases (JAKs)/ Signal Transducers and Activators of Transcription (STATs) 訊息傳遞途徑引導人體內許多重要的生理程序，不僅在細胞的存活、生長以及分化中扮演很重要的角色。本篇所使用的IQDMA會經由抑制EGFR、Src和Bcr-Abl的磷酸化，去調控JAK/STATs路徑及其下游表現，去抑制細胞生長情形。
本論文中，主要針對三種不同類型的試劑作細胞凋亡和細胞週期停滯探討，包含了凋亡現象、訊息傳遞機制、MAPK的調控和JAK/STATs路徑的影響，藉由此機制探討以作為藥物研發的依據。

Apoptosis plays an important role in the regulation of cellular activities in eukaryotes. Three predominant apoptotic pathways are the mitochondria-mediated intrinsic pathway, the death receptor-induced extrinsic pathway and apoptotic signalling evoked by endoplasmic reticulum (ER) stress. The mitochondria-mediated intrinsic pathway involves the release of the mitochondrial protein cytochrome c, resulting in activation of caspase 9. The receptor-induced extrinsic pathway involves cellular ligands, such as Fas ligand and tumour necrosis factor, and results in activation of caspase 8. ER stress initiates apoptosis through at least two different mechanisms, namely the unfolded protein response and Ca2+ signalling, which, together, may activate calpain and caspase 12.
CTX III-induced apoptotic cell death was accompanied by regulation of Bcl-2 family and release cytochrome C and endonuclease G (Endo G) from mitochondrial. And activation of both caspase-9 and -3. IQDMA induced apoptosis through upregulated FasL protein expression, Leading to activate caspases-8, -3. THDA-induced apoptosis was associated with the upregulation of Bax, downregulation of X-linked inhibitor of apoptosis (XIAP), as well as the activation of caspase-9 and caspase-3.
Cell cycle control is the major regulatory mechanism of cell growth. Many cytotoxic agents and/or DNA damaging agents arrest the cell cycle at the G1, S or G2/M phase and then induce apoptotic cell death. CTX III resulted in G2/M phase arrest in the cell cycle progression, which was associated with a marked decrease expressions of cyclin A, cyclin B1, and Cdk 2. IQDMA-induced G2/M arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p21.
Mitogen-activated protein kinase (MAPK) members have been identified as an important signaling in the control of cell proliferation and differentiation..In contrast to the lack of appreciable effect on the phosphorylation of ERK and p38 MAPK, activation of JNK was noted when K562 cells were exposed to CTX III and IQDMA. However, THDA suppressed including c-Jun N-terminal kinase (JNK),extracellular signal-regulated protein kinase (ERK) kinases, and the transcription factor c-Jun.
Signal transducer and activator of transcription (STAT) proteins have been shown to have a major role in survival, proliferation, angiogenesis, and immune evasion of tumors. IQDMA inhibits phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr-Abl, and Janus-activated kinase (JAK2) in a time dependent manner. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling is also blocked by IQDMA.
Collectively, the studies used three types of compounds for apoptosis and cell cycle arrest study. These results provide the impetus for developing new therapeutic strategies in which synthetic compounds.

中文摘要 1
英文摘要 3
序論 6
材料與方法 17

第一部份 心臟毒素III (CTX III) 29
中文摘要 30
英文摘要 32
前言 35
結果 38
討論 42
圖 48

第二部份 IQDMA 62
中文摘要 63
英文摘要 65
前言 67
結果 69
討論 72
圖 75
第三部份 THDA 83
中文摘要 84
英文摘要 85
前言 87
結果 90
討論 92
圖 94

總結 103
參考論文 105
論文發表 116

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