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研究生:陳貞均
研究生(外文):CHEN,JHEN-JYUN
論文名稱:易解鐵對Hep G2細胞保護效應之研究
論文名稱(外文):The Protective Effects of Deferasirox (DFX) in Hep G2 Cell
指導教授:邱雅鈴邱雅鈴引用關係
指導教授(外文):CHIOU,YA-LING
口試委員:柯萬盛錢新南
口試委員(外文):KO,WANG-SHENGCHENG,SHING-NAN
口試日期:2017-01-05
學位類別:碩士
校院名稱:弘光科技大學
系所名稱:營養醫學研究所
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:2017
畢業學年度:105
語文別:中文
論文頁數:107
中文關鍵詞:易解鐵Hep G2細胞氧化壓力細胞凋亡
外文關鍵詞:DeferasiroxHep G2 cell lineOxidative stressApoptosis
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鐵是必需的營養素,鐵對於幾乎所有生物來說是很重要的,因為它參與各種代謝過程,包括氧運輸,DNA合成和電子傳遞。然而鐵負荷(overloading)會增加Fenton反應和活性氧(Reactive oxygen species)形成如超氧化物陰離子(O2‧-),過氧化氫(H2O2)和高毒性氫氧自由基(OH-),這些自由基可能引起脂質過氧化和肝細胞損傷。此外,鐵誘導的氧化壓力被認為是肝損傷和肝細胞癌發展一個潛在的機制。易解鐵(Deferasirox, DFX)是一種新的口服螯合劑,對於鐵有高度的結合性與選擇性。DFX降低血清鐵蛋白並有效降低血清丙氨酸氨基轉移酶(Alanine aminotransferase, ALT)的濃度。然而,DFX是否降低自由基的濃度以保護肝細胞目前尚未清楚。本研究的目的是利用鐵離子刺激肝細胞,以產生自由基造成肝細胞凋亡,加入不同濃度DFX,觀察由鐵離子誘導出來的自由基濃度和細胞凋亡的影響。在本研究中,肝細胞(Hep G2細胞)給予檸檬酸鐵銨(100μM Ferric ammonium citrate, FAC)和不同濃度DFX(50μM、100μM或200μM)處理0、18和24小時。使用WST-1、流式細胞儀、即時定量聚合酶連鎖反應和西方墨點法,測量細胞存活率、細胞凋亡、細胞自由基濃度和凋亡蛋白表現。FAC顯著降低Hep G2細胞生長,DFX(50μM、100μM或200μM)可以改善鐵所引起的減少細胞生長。DFX(50μM、100μM或200μM)亦減少鐵所誘導的ROS形成和細胞凋亡。這些數據表明過多的FAC會增加ROS形成進而導致細胞凋亡並減少細胞生長。DFX可以通過減少ROS的生成,在保護Hep G2細胞的功能中扮演一個重要的角色。
Iron is an essential nutrient. Iron is vital for almost all living organisms as it participates in a wide variety of metabolic processes, including oxygen transport, DNA synthesis, and electron transport. The overload of iron increase Fenton reaction and the formation of reactive oxygen species (ROS) such as superoxide anion (O2.-), hydrogen peroxide (H2O2) and the highly toxic hydroxyl radicals (HO-). These radicals are likely to cause lipid peroxidation and liver cell damage.Iron-induced oxidative stress has been considered to be an underlying mechanism of liver injury and development of hepatocellular carcinoma. Deferasirox (DFX) is a new oral chelator with high iron-binding potency and selectivity. DFX reduces serum ferritin and effectively reduces the concentration of serum alanine aminotransaminase (ALT). However, whether DFX reduces the concentration of free radicals to protect the hepatic cells remains unclear. The aim of this study, the liver cells stimulate with overload of iron ions to produce free radicals that caused liver cell apoptosis, different concentrations of DFX were added to observe the effects of free radical concentration and apoptosis induced by iron ion. In this study, the Hep G2 cell line was used as the target cells. The Hep G2 cells were treated with overload iron (100 μM ferric ammonium citrate, FAC) and different concentrations (50μM, 100μM or 200μM) of DFX for 0, 18, and 24 hours.The cell viability, cell apoptosis and cell radical concentration measure was measured using the WST-1、flow cytometry、Real-time PCR and Western blotting. Overloaded FAC (100μM) reduced cell growth significantly. DFX (50μM, 100μM or 200μM) could improve iron-reduced cell growth. DFX (50μM, 100μM or 200μM) reduced iron-induced ROS formation from cells and cell apoptosis. These data suggest that overloaded FAC inhibited hepatic cells growth and lead to apoptosis of hepatic cells through increased ROS formation. DFX may play a role in reducing damage of Hep G2 cells by reducing the level of ROS formation.
致謝……………………………………………………………. Ⅰ
中文摘要………………………………………………………..... Ⅱ
英文摘要…………………………………………………………. Ⅲ
目錄………………………………………………………………. Ⅴ
圖目錄…………………………………………………………..... Ⅶ
縮寫表…………………………………………………………..... Ⅷ
緒論……………………………………………………………..... 1
文獻回顧………………………………………………………..... 3
研究材料及方法………………………………………………. 20
結果……………………………………………………………. 34
討論……………………………………………………………. 48
結論……………………………………………………………. 55
參考文獻………………………………………………………. 56
附錄一 鐵在體內的分佈
附錄二 鐵的調控機制
附錄三 影響鐵吸收率的因素
附錄四 評估體內鐵質的指標
附錄五 鐵的氧化作用
附錄六 過多的不穩定鐵造成身體器官的損害
附錄七 鐵參與在肝癌的進展
附錄八 造成肝癌的危險因子
附錄九 在亞洲,造成肝癌的原因
附錄十 巴塞隆納臨床肝癌分類(Barcelona Clinic Liver Cancer, BCLC)
附錄十一 三種排鐵劑的結構式
附錄十二 臨床上使用的三種排鐵劑比較
附錄十三 動物與人體劑量換算表
附錄十四 螢光化合物DCF通過ROS的形成
附錄十五 cDNA逆轉錄套組
附錄十六 qPCR所需試劑體積
附錄十七 qPCR引子序列
附錄十八 西方墨點法分離膠體Separating gel藥品配製
附錄十九 西方墨點法焦集膠體Stacking gel藥品配製
附錄二十 鐵負荷造成肝癌的機制
附錄二十一 鐵負荷疾病的分類
附錄二十二 研討會摘要
附錄二十三 發表海報

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