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系統識別號 U0026-0812200910450375
論文名稱(中文) NF-kB及Bcl-2和麩氨基硫在3-nitropropionic acid所導致的人類神經腫瘤細胞死亡中的相互關係
論文名稱(英文) The interaction of NF-kB, Bcl-2 and glutathione on 3-nitropropionic acid-induced toxicity in human SK-N-SH neuroblastoma cells
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 91
學期 2
出版年 92
研究生(中文) 潘金銘
研究生(英文) Chin-Ming Pan
學號 s3690107
學位類別 碩士
語文別 中文
論文頁數 70頁
口試委員 召集委員-湯銘哲
口試委員-劉校生
口試委員-黃阿敏
指導教授-莊季瑛
中文關鍵字 NF-kB  Bcl-2  麩氨基硫 
英文關鍵字 NF-kB  Bcl-2  glutathione 
學科別分類
中文摘要 3-nitropropionic acid (3-NP) 是粒線體電子傳遞鏈succinate dehydrogenase (complex Ⅱ) 的不可逆性抑制劑,在老鼠身上給予3-NP會造成選擇性的破壞腦部紋狀體神經細胞,因而被用來誘發亨丁頓氏症 (Huntington’s disease, HD) 動物實驗模式的神經毒物。雖然很多分子及路徑都和粒線體的能量損傷所產生的氧化壓力有關,但這些分子相互之間的關係,目前仍不清楚。所以本研究將探討,在3-NP所導致的神經毒性中,對氧化還原狀態敏感的分子:NF-kB,Bcl-2和麩氨基硫 (glutathione, GSH) 的相互關係為何?實驗結果顯示,以3-NP處理人類神經腫瘤細胞 (SK-N-SH neuroblastoma cells) 24小時後,呈現隨劑量增高而增加的細胞膜PS (phosphatidylserine) 外翻,細胞核濃染但無斷裂的死亡。另外,我們發現在3-NP處理後30分鐘,首先觀察到細胞核內NF-kB的p65蛋白質表現上升,但其DNA binding activity下降,此現象隨著時間增長而愈趨顯著並持續至24小時,之後在2小時偵測到反應氧化壓力的氧化態GSH (GSSG) 與還原態GSH比值顯著上升,而還原態GSH含量下降,最後於18小時觀察到Bcl-2蛋白質表現量下降及Bax表現上升並持續至24小時。除此之外,我們選用抗氧化劑褪黑激素 (melatonin)、NF-kB抑制劑- bay、可通透細胞膜的GSH和以IPTG誘發或短暫大量表現Bcl-2的細胞株,以期進一步釐清3-NP所啟動的死亡路徑。我們的結果證實,外加給予GSH或褪黑激素,可顯著減緩3-NP所造成的氧化壓力增高、NF-kB活性下降和Bcl-2表現量降低的現象,進而具有明顯的神經細胞保護效果,但是以NF-kB抑制劑bay處理細胞,雖然明顯抑制細胞核內p65蛋白質表現和DNA binding activity,卻無法扭轉3-NP所造成的GSSG/GSH比值上升、Bcl-2/Bax表現量下降和細胞死亡情形。此外,Bcl-2大量表現的細胞,可以抑制3-NP所造成的Bcl-2蛋白質表現量下降和明顯減緩3-NP的毒殺作用,但卻無法改變Bax的表現上升、氧化壓力上升和NF-kB活性下降。因此我們的實驗結果顯示3-NP所驅動的死亡傳遞路徑可能為GSSG/GSH 氧化壓力上升,NF-kB活性下降,Bcl-2/Bax比值下降,最後導致細胞死亡。另外,相較於GSH,褪黑激素具有最顯著的保護作用,因為最近文獻指出褪黑激素能增強粒線體功能和避免粒線體的損傷,所以我們推測褪黑激素的作用位置應在最上游的部分,的確我們的結果證實抑制粒線體功能的3-NP,顯著的抑制與能量傳遞酵素群密切相關的轉錄因子Nrf-1 (nuclear respiratory factor 1, Nrf-1) 的活性,而褪黑激素藉由避免3-NP所造成的Nrf-1活性下降,阻斷死亡訊息的傳遞而達到了最佳的神經保護作用。
英文摘要 3-nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase (complexⅡ) in the mitochondria. Systemic administration of 3-NP causes selective striatal lesions in rats and has gained acceptance as an experimental model of huntington’s disease (HD). Although a number of molecules and pathways in response to oxidative stress induced by mitochondrial energy impairment have been implicated, the interaction of these molecules remains unclear. In this study, the relationship of GSH, NF-κB and Bcl-2 protein family that are redox sensitive and responsible for 3-NP neurotoxicity has been explored. The results indicated that 3-NP causes human SK-N-SH neuroblastoma cell death, which represents PS (phosphatidylserine) and DNA condensation but not fragmentation, in a dose dependent manner 24 h after treatment. We also found an increase of the nuclear NF-kB-p65 protein expression as earlier as 30 min after 3-NP treatment, but a decrease of its DNA binding activity in a time dependent manner, and an elevation of the oxidative stress indicated by the high GSSG/GSH ratio and a reduction of glutathione (GSH) level at 2 h, as well as the final down-regulation of Bcl-2 and up-regulation of Bax at 18 h. To further clarify the death signaling cascade triggered by 3-NP, we used antioxidant of melatonin and NF-kB inhibitor of bay and cell permeable GSH and IPTG-induced or transient Bcl-2 overexpressed cells. Our results demonstrated that co-treatment of GSH or melatonin significantly attenuated the 3-NP-induced oxidative stress, the decrease of NF-kB activity and Bcl-2/Bax expression, as well as cell death. However, the inhibition of NF-kB activation by its inhibitor of bay did not prevent the high GSSG/GSH ratio and the low Bcl-2 expression and cell death induced by 3-NP. In addition, the Bcl-2 overexpressed SK cells could significantly attenuated 3-NP cytotoxicity, but the changes of GSH redox status, NF-kB activity, Bax expression induced by 3-NP could not be prevented. These results suggest that 3-NP-trigged death signal cascade was the impairment of GSH redox system, inhibition of NF-kB activity, and the final down-regulation of Bcl-2/Bax expression. Furthermore, the present and other previous results demonstrated that melatonin significantly blocked the oxidative stress of initial death signal and preserved the mitochondrial function to effectively protect cells from the attack of mitochondrial toxins. The novel finding demonstrates here that melatonin dramatically prevents the inhibition of Nrf-1 (nuclear respiratory factor 1, Nrf-1) activity, which is characterized as a transcriptional activator of many genes encoding subunits from all five mitochondrial respiratory complexes, induced by 3-NP to achieve a well neuroprotective effect.
論文目次 中文摘要……………………………………………Ⅰ
英文摘要……………………………………………Ⅲ
致謝…………………………………………………Ⅴ
目錄…………………………………………………Ⅵ
圖目錄………………………………………………Ⅶ
表目錄………………………………………………Ⅹ
緒論…………………………………………………1
材料方法……………………………………………9
結果…………………………………………………16
討論…………………………………………………25
參考資料……………………………………………35
圖……………………………………………………46
作者簡介……………………………………………70
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