臺灣博碩士論文加值系統

敗血症以及嚴重敗血症所引發的多重器官衰竭在加護病房中一直是個主要的死因之一，不管抗生素藥物的進步、液體補充方式及器官保護作用的進步，敗血症病人的死亡率仍是上升的。從牛樟芝所萃取出來的輔酶衍生物在目前的研究中已證實有抗氧化、抗發炎、以及抗癌的生理效果。本研究的主要目的是想去探討此輔酶衍生物在LPS所誘導的敗血症模式中，是否有抗發炎的效果。小鼠腹腔滲出細胞在同時處理LPS (100 ng/ml) 以及不同濃度的輔酶衍生物 (1-10?慊/ml) 處理24小時後，將上清液取出，偵測培養液中發炎物質，如：tumor necrosis factor-? (TNF-?? 以及 interleukin-6 (IL-6) 的濃度，其發炎物質的量有顯著的下降。偵測小鼠體內血清發炎物質濃度的變化，在同時給予LPS (10 mg/kg) 以及不同濃度輔酶衍生物 (0.3-3 ?慊/ml) 2小時後，將小鼠犧牲採血，分離出的血清則進行發炎物質的檢測，結果發現發炎物質也有顯著的下降。因此進而探討LPS在訊息傳遞路徑的影響，結果發現，對於LPS所誘導的訊息傳遞路徑蛋白，如：extracellular signal-regulated kinase 1/2 (ERK1/2) 以及c-Jun N-terminal kinase (JNK)，其磷酸化程度在給予不同濃度的輔酶衍生物 (1-10?慊/ml) 後都有顯著的下降。然而此輔酶衍生物對於小鼠腹腔滲出細胞的移行能力也有顯著的劑量依賴性效果。而在細胞毒性的檢測中，不論是前處理或是後處理給予不同濃度的輔酶衍生物皆不影響細胞的存活率。因此我們推測此輔酶衍生物可用於敗血症的病患作為治療的一種新方法。

Sepsis and multiple organ dysfunction syndrome is one of most main causes of death. Ubiquinone-derivate isolated from Antrodia cinnamomea which have been shown to antioxidation, anti-inflammation and antitumor activities. The purpose of this study is to examine whether this ubiquinone-derivative has the anti-inflammation on sepsis model induced by endotoxicant, LPS. The production of cytokines, such as tumor necrosis factor-? (TNF-?? and interleukin-6 (IL-6), in supernatants was measured by ELISA. Male ICR mice were co-treat with LPS (10 mg/kg) with different concentration of this ubiquinone-derivative (0.3-3 ?慊/ml) 2 and 16 hour, the cytokines in serum was measured by ELISA. After mice peritoneal cell co-treat LPS (100 ng/ml) with different concentration of this ubiquinone-derivative (1-10?慊/ml) 24 hour, the cytokine release induced by LPS was significantly inhibited by this ubiquinone-derivate. The mice were co-treat LPS (10 mg/ml) with different concentration of this ubiquinone-derivative (0.3-3?慊/ml) 2 hour, the cytokine release induced by LPS was also significantly inhibited by this ubiquinone-derivate.The signal transduction induced by LPS including extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) tyrosine phosphorylation were significantly inhibited by this ubiquinone-derivative in mice peritoneal cell. This ubiquinone-derivative also suppressed LPS-induced mice peritoneal cell migration dose dependently. However, neither co-treatment nor pre-treatment of this ubiquinone-derivative affect the cell viability. In conclusion, this ubiquinone-derivate may have the therapeutic potential on sepsis.

第壹章、 緒論 1
第一節、 敗血症 1
壹、 敗血症與多重器官衰竭 1
貳、 臨床敗血症與治療 2
參、 敗血症動物模式 5
肆、 內毒素LPS (Lipopolysaccharide) 6
第二節、 敗血症之相關機轉 7
壹、 巨噬細胞 (macrophage) 7
貳、 Toll-like receptors (TLRs) 接受器 8
參、 Mitogen-activated protein kinases (MAPKs)蛋白質 9
肆、 核轉錄因子κB (Nuclear factor-κB) 11
伍、 ERK 1/2 的活化 12
第三節、 牛樟芝萃取輔酶衍生物 14
壹、 牛樟芝的分類 14
貳、 牛樟芝的生理活性 15
參、 牛樟芝毒性 17
第四節、 研究動機與目的 19
第貳章、 研究方法與材料 20
第一節、 試藥與材料 20
壹、 儀器設備 20
貳、 試劑藥品 22
參、 抗體 23
第二節、 細胞株與細胞培養 24
壹、 老鼠巨噬細胞株 ( Murine macrophage cell line) 24
貳、 小鼠腹腔滲出細胞 (Mice peritoneal cell) 24
參、 人類周邊血液單核淋巴細胞 (Peripheral blood mononuclear cell, PBMNC) 25
肆、 培養液配製 25
伍、 牛樟芝萃取輔酶衍生物 (Ubiquinone-derivative, UD) 26
陸、 細胞解凍與次代培養 26
柒、 細胞庫建立 27
捌、 Trypan Blue染色存活率檢測 28
第三節、 細胞存活分析 30
第四節、 蛋白質表達分析 30
壹、 細胞檢體收集 30
貳、 蛋白質萃取 31
參、 蛋白質定量 31
肆、 蛋白質電泳膠體配製 32
伍、 蛋白質電泳 ( SDS-PAGE ) 32
陸、 西方墨點法 ( Bio-Sciences System ) 33
第五節、 發炎物質 (TNF-?恁BIL-6) 測定 34
第六節、 細胞移行能力分析 (Trans-well Migration Assay) 36
第七節、 淋巴細胞增生分析 37
第八節、 統計分析 37
第參章、 研究結果與資料分析 38
第一節、 輔酶衍生物對於細胞的生長影響 38
第二節、 輔酶衍生物對體內免疫細胞增生的影響亡 39
第三節、 輔酶衍生物對發炎物質的影響 40
第四節、 輔酶衍生物對小鼠腹腔滲出細胞移行能力的影響 41
第五節、 輔酶衍生物影響發炎物質產生路徑相關蛋白質的表達 42
第六節、 輔酶衍生物對小鼠體內發炎物質的影響 42
第肆章、 討論 44
第伍章、 圖表 49
第陸章、 參考文獻 76

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