由於台灣社會的人口老化，發炎性疾病正在普遍地增加，發炎反應常常會造成一些疾病像是類風溼性關節炎、退化性骨關節炎、慢性氣喘及多發性硬化症等。現今一般臨床用於治療發炎疾病的用藥蘊藏著許多副作用以及相當昂貴，因此，非常迫切需要去尋找新的替代藥物。海洋天然物提供了發炎性疾病藥物開發的一個大契機，在本研究中，我們發現Chao-10，一種主要由台灣產的軟珊瑚中所分離出來的化合物之衍生物，可以顯著地抑制脂多醣所誘發巨噬細胞株(RAW 264.7)的一氧化氮合成酶（inducible nitric oxide synthase; iNOS）的蛋白質表現量，因此我們認為Chao-10可能具有成為新的抗發炎藥物之潛力。然而，Chao-10其詳細抗發炎作用之調節機轉仍然是不清楚的，所以我們使用蛋白質二維膠體電泳嘗試去釐清Chao-10其調節發炎反應之機轉。從蛋白質二維膠體電泳我們得到一些蛋白質可能參與了調節反應，我們利用了免疫共沉澱發現到其中一個蛋白質(Nucleophosmin; NPM) 會與核因子(Nuclear factor-kappaB; NF-κB) 產生蛋白質交互作用。我們推測Chao-10也許是藉由nucleophosmin去抑制NF-κB轉錄作用達到降低iNOS之表現量。總結來說，Chao-10可能經由NPM這條路徑或伴隨其他路徑達到抗發炎之效果，此外，本研究更重要的是提供了一些新的發炎指標提供未來抗發炎藥物開發的新方向。

Many inflammatory diseases are growing increasing common in the aging society of Taiwan. Inflammation cascades can cause diseases such as rheumatoid arthritis, osteoarthritis, chronic asthma, multiple sclerosis, and so on. The clinically used anti-inflammatory drugs have many side effects and are expensive. Therefore, it is imperative that we find alternatives to these drugs. Marine natural compounds offer great hope in the development of drugs for treating inflammatory diseases. In the present study, we found that Chao-10, which is a marine-derived compound isolated from Formosan soft coral, significantly inhibited the expression of the pro-inflammatory protein, inducible nitric oxide synthase (iNOS), in the lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophage cell line. We suggest that Chao-10 may serve as a potential new anti-inflammatory agent. However, the mechanism by which the anti-inflammatory effects of Chao-10 are mediated is yet unclear. Therefore, we performed two-dimensional electrophoresis (2-DE) to investigate the regulatory mechanism for the anti-inflammatory effect of Chao-10. We isolated some proteins that may be involved in the anti-inflammatory mechanism of Chao-10. In addition, we used immunoprecipitation to find that nucleophosmin (NPM) could interact with nuclear factor kappa B (NF-κB). Therefore, we hypothesize that nucleophosminmay be involved in the regulation of NF-κB to enhance the down-regulation of iNOS proteins. In summary, the anti-inflammatory effects of Chao-10 are probably mediated through the some other signaling pathway. Importantly, Chao-10 not only offers some new biomarkers of inflammation but also provides an encouraging outlook on therapeutic approaches.

目錄……………………………I
圖目錄…………………………II
表目錄…………………………IV
摘要…………………………V
Abstract…………………………VI
第壹章、 前言………………………….1
第貳章、 實驗材料與方法…………………………5
第參章、 實驗結果…………………………13
第肆章、 實驗討論…………………………64
參考文獻…………………………74
附錄…………………………88

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