動脈粥狀硬化被認為是一種發炎反應的疾病且臨床醫學有許多藥物可以用來它。然而，臨床上用於抗動脈硬化的藥物有許多副作用如simvastatin。最近許多研究顯示獨特的海洋化合物被分離出來且具有多樣的生物活性。我們之前的研究就發現一個austrasulfone海洋化合物的合成前驅物dihydroaustrasulfone alcohol (簡稱WA-25)，在離體實驗中具有抗動脈硬化的效果，然而，這其中的詳細機轉尚不清楚。因此，為了釐清WA-25 的抗動脈硬化的機轉，我們運用RAW264.7巨噬細胞離體模組實驗來評估WA-25的抗動脈硬化的效果。實驗結果發現，WA-25能夠有意義的降低受到LPS刺激後的RAW264.7細胞所釋放的發炎前驅蛋白質：誘發性一氧化氮合成酶 (iNOS) 和環氧合酶 (COX-2)的表現。 相對於WA-25的效果，simvastatin 增加COX-2發炎前驅蛋白質的表現。此外，WA-25能阻礙泡沫細胞的形成，也能增加細胞內的lysosome 和cAMP訊號路徑。我們也觀察到WA-25 和simvastatin可以增加受到LPS刺激後的RAW264.7細胞內的transforming growth factor β1 (TGF-β1)表現，而這個抗動脈硬化的效果可以藉由阻斷TGF- β1信號傳遞所破壞。此外， WA-25的作用可能透過增加酯質分解而非改變酯質排出作用。綜合而論，實驗資料顯示WA-25具有的抗發炎效果，未來有潛能開發成為抗動脈硬化的藥物。

Atherosclerosis is an inflammatory disease that can be treated with medications in the clinic. Nonetheless, some anti-atherosclerotic drugs, such as simvastatin, used in clinically have several side effects. Recently, several unique marine compounds have reported to have various bioactivities. One of our previous studies revealed that dihydroaustrasulfone alcohol (WA-25), a synthetic precursor of the marine compound (austrasulfone), has anti-atherosclerotic effects in vivo. However, the detailed mechanisms remain unclear. Therefore, to clarify the mechanisms by which WA-25 exerts anti-atherosclerotic activity, we used RAW 264.7 macrophages as an in vitro model to evaluate the effects of WA-25. In lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, WA-25 significantly inhibited the expression of the pro-inflammatory proteins, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In contrast, simvastatin increased the COX-2 expression compared to that with WA-25. In addition, WA-25 inhibited foam cell formation and up-regulated the lysosomal and cyclic adenosine monophosphate (cAMP) signaling pathway. Moreover, transforming growth factor β1 (TGF-β1) was up-regulated by WA-25 and simvastatin in LPS-induced RAW 264.7 cells, and the promising anti-atherosclerotic effects of WA-25 were disrupted by blockade of TGF- β1 signaling. In addition, WA-25 might act by increasing lipolysis than by alteration of lipid export. Taken together, these data demonstrate that WA-25 may have potential as an anti-atherosclerotic drug with an anti-inflammatory effect.

Acknowledgment ii
Chinese abstract iii
English abstract iv
Table of contents v
List of figures vi
List of abbreviations viii

Introduction 01
Specific aim 28
Materials and methods 34
Results 41
Discussion 62
Conclusion 68
Future study 70
References 72
Appendix 99

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