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研究生:吳美德
論文名稱:植化素預防Doxorubicin慢性心臟毒性功效篩選平台之建立
論文名稱(外文):Establishment of a Screening Model for Evaluating Protective Function of Phytochemicals Against Doxorubicin Cardiotoxicity
指導教授:林淑美林淑美引用關係
學位類別:碩士
校院名稱:國立嘉義大學
系所名稱:食品科學系研究所
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
畢業學年度:102
語文別:中文
中文關鍵詞:Doxorubicin心肌肥大粒線體動力學粒線體生合成
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Doxorubicin (DOX) 是高效力,且廣泛用於治療各種類型癌症的化療藥物之一。但因為具心臟毒性副作用,限制了在臨床上的應用。DOX心臟毒性主要為誘發擴張性心臟衰竭 (dilated cardiac failure),一般認為與使用之累計劑量有關。半世紀以來,醫藥界持續尋求預防DOX心臟毒性的策略,但DOX誘導心肌病變的分子機制仍未完全明確。目前臨床上為預防的DOX心臟毒性通常限制使用累計劑量於400至550 mg/m2範圍。許多研究指出心肌細胞粒線體是DOX心臟毒性的主要標的胞器。粒線體為動態的胞器,依細胞能量需求改變其型態、膜電位及數量,於維持心肌細胞正常生理功能扮演相當重要的角色,而此機制的異常則影響細胞存活,與心臟變病理機制應有極高關聯性。故本研究目的為探討DOX心肌病變的分子機制,並期建立植化素對DOX心肌病變毒性之預防功效篩選平台。利用H9c2大鼠胚胎心肌細胞為模式,以0.05 μM DOX 處理24小時,並每間隔60小時重覆處理一次,使DOX累計劑量分別為0.05、0.01及0.15 μM,並以單一劑最高劑量(0.15 μM)為急性毒性對照組,處理後細胞檢測其細胞型態、粒線體功能及動力學等相關指標。結果顯示,DOX 累計劑量處理造成心肌細胞面積擴張,細胞外基質金屬蛋白酶活性及細胞內活性氧分子含量增加。粒線體膜電位隨著DOX累計劑量增加而上升;以三劑DOX處理的細胞粒線體膜電位上升為正常細胞的4.5倍,同時伴隨ATP耗竭。以NAO偵測cardiplipin結果顯示,重複以DOX處理的細胞粒線體數量增加,但粒線體生合成調節因子包括: PGC-1α、mTFA及COX I表現量未受影響。高累計劑量DOX導致粒線體型態點狀化,同時抑制粒線體融合蛋白Mfn2與OPA1的基因表現,並提升分裂蛋白Drp1與Fis1的基因表現量。而單一高劑量DOX對上述細胞指標則無顯著影響。綜合上述結果,DOX 低劑量多次累積與單一高劑量對心肌細胞造成不同影響,雖然最終使用累計劑量相同,但是重複使用低劑量較單一高劑量對心肌細胞影響較劇。而DOX誘發累積性心臟毒性與心肌細胞肥大、ROS 生成增加、粒線體動態和功能異常等有關,此心肌病變模式可發展為植物化合物預防抗癌藥物心臟毒性的保健功效篩選平台,以利癌症化療輔助食品之開發。
中文摘要 I
Abstract III
壹、緒論 1
貳、文獻回顧 2
一、Doxorubicin介紹 2
二、Doxorubicin 心臟毒性副作用 4
(一)、Doxorubicin 心肌病變 5
(二)、Doxorubicin 心肌病變機制 7
三、粒線體 10
(一)、粒線體型態構造與生理功能 11
(二)、粒線體動態學 12
(三)、粒線體生合成 14
四、降低 Doxorubicin 心臟毒性之策略 17
叁、實驗材料與方法 22
一、實驗材料與細胞 22
二、實驗設備 22
三、實驗耗材 23
四、實驗藥劑 24
五、PCR primer sequence 25
六、PCR 條件 27
七、實驗架構 29
八、實驗方法 30
(一)、細胞來源與培養 30
(二)、細胞解凍活化 30
(三)、細胞繼代 30
(四)、細胞冷凍保存 31
(五)、H9c2 實驗處理 31
(六)、細胞增生試驗 31
(七)、細胞存活率試驗 32
(八)、細胞型態分析 33
(九)、細胞超氧陰離子測定 33
(十)、細胞內活性含氧分子測定 34
(十一)、粒線體膜電位檢測 34
(十二)、粒線體數量及型態分析 35
(十三)、粒線體質量分析 36
(十四)、ATP 生成分析 37
(十五)、Zymography 明膠酶活性電泳分析 38
(十六)、Total RNA 萃取 39
(十七)、反轉錄聚合酶連鎖反應 40
(十八)、即時聚合酶連鎖反應 42
(十九)、統計分析 43
肆、結果 44
一、Doxorubicin 心臟毒性分子機制探討 44
(一)、Doxorubicin 對H9c2心肌細胞毒性分析 44
(二)、Doxorubicin 對H9c2心肌細胞型態之影響 45
(三)、Doxorubicin 對H9c2心肌細胞中基質金屬蛋白酶之影響 46
(四)、Doxorubicin 對H9c2 心肌細胞ROS生成之影響 47
(五)、Doxorubicin 對H9c2 心肌細胞粒線體功能之影響 48
(六)、Doxorubicin 對H9c2 心肌細胞粒線體生合成之影響 50
(七)、Doxorubicin 對H9c2 心肌細胞粒線體型態之影響 51
二、Arachidin-1 對 Doxorubicin 處理之心肌細胞保護功效評估 52
伍、討論 54
陸、結論 60
柒、參考文獻 84
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