來自海洋的天然物是近年來新藥開發的重點來源，我們實驗室過去研究發現臺灣產瘤軟珊瑚(Cladiella australis)具有許多生物活性之海洋天然物(bioactive marine natural products)，如austrasulfone、dihydroaustrasulfone alcohol已被證實在神經保護(neuroprotection)及抗發炎(anti-inflammation)具有絕佳的活性。因此，此篇研究亦是以來自Cladiella australis的海洋天然物相關衍生物為對象，首先以抗發炎活性及細胞毒殺性對十幾種化合物進行篩選，我們觀察到MRSW-1此一海洋天然衍生物有極佳的抗發炎活性及不具強烈的細胞毒性。便以MRSW-1為研究目標進一步探討其在美白活性與燒燙傷傷口治療的表現情形。
在美白活性相關實驗結果顯示MRSW-1可以明顯抑制黑色素形成，其機轉有可能是藉由非競爭性的抑制作用來減少酪胺酸酶(tyrosinase)的活性表現，與已知的黑色素抑制劑熊果素(arbutin)及N-苯基硫脲(phenylthiourea, PTU)相比，MRSW-1展現了更優越的黑色素與酪胺酸酶活性抑制效果。MRSW-1也能夠減少小眼球伴生轉錄因子(microphthalmia-associated transcription factor, MITF)、酪氨酸酶相關蛋白1 (tyrosinase-related protein-1, Trp-1)、酪氨酸酶相關蛋白2 (tyrosinase-related protein-2, Trp-2)又稱為多巴色素互變異構酶 (dopachrome tautomerase, DCT)、前驅黑色素小體蛋白 (glycoprotein 100, gp100)等黑色素形成相關蛋白的表現。在斑馬魚活體美白活性測試模組實驗中，MRSW-1同樣表現了優越的黑色素抑制能力。
在燒燙傷傷口治療相關實驗結果方面，首先經由離體細胞進行細胞遷移之實驗證實MRSW-1能夠同時促進纖維母細胞及靜脈內皮細胞的爬行移動範圍。
燒燙傷傷口活體試驗則是透過大白鼠活體動物模式進行分析。在大鼠燒燙傷模式中，結果顯示出給予MRSW-1後，明顯助於傷口癒合速率，利用HE染色分析受傷後第27天病理組織切片，也可以觀察到MRSW-1治療的燒燙傷口，大量降低白血球浸潤情形，表皮層變薄且角質層復原完整，整體復原情形較為良好。在傷口癒合分子機轉方面，MRSW-1能顯著增加傷口組織膠原蛋白含量並且增加第一型與第三型膠原蛋白比值，表示MRSW-1對於傷口組織恢復完整性與強韌度極有幫助。另外，對於主要作用為負責分解細胞外基質的基質金屬蛋白酶(matrix metalloproteinases, MMPs)的表現，給予MRSW-1後皆有顯著增加MMP-9及MMP-2之表現量，說明可促進細胞爬行有助於傷口組織的重塑及修復。
綜而言之，離體與活體的許多生理活性分析實驗結果顯示海洋天然物衍生物MRSW-1具有顯著的抗發炎、抗黑色素生成作用和促進燒燙傷傷口癒合活性，未來應用於皮膚保護相關醫藥治療領域將有無限潛力。

Marine natural products have been a source of new drug development research in recent years, our group have discovered that several compounds which were isolated from soft corals with neuroprotective and anti-inflammatory activities. In this study, we screened compounds with anti-inflammatory activities and favorable safety profiles from a series of marine related natural products, which were isolated from Formosan soft coral Cladiella australis. We observed MRSW-1 has substantial anti-inflammatory properties with minor cytotoxic mechanism. A series of experiments was performed to determine skin whitening properties and burn wound healing effects in MRSW-1.
The results of skin whitening analysis indicated that MRSW-1 could successfully inhibit pigment generation processes in mushroom tyrosinase platform assay, probably through the suppression of tyrosinase activity to be a non-competitive inhibitor of tyrosinase. It exhibited stronger inhibitions of melanin production and tyrosinase activity than arbutin or 1-phenyl-2-thiourea (PTU). Moreover, we observed that MRSW-1 reduces the protein expressions of melanin synthesis-related proteins, including the microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (Trp-1), dopachrome tautomerase (DCT, Trp-2), and glycoprotein 100 (Gp100). In an in vivo zebrafish model, it presented a remarkable suppression in melanogenesis after 48 h.
We assessed the burn wound healing activity by adopting migration assay and the results support the notion that that MRSW-1 promoted cell migration in both dermal fibroblast, human genital skin fibroblast cell line (Hs68) and endothelial hybrid cell line (EA.hy926). The results in the evaluation of in vivo wound healing rate and activities demonstrated that 27 days after the induction of burn injury in the scald-burned rat model, the topical application of MRSW-1 faclitated the wound healing and attenuated the leukocyte infiltration and inflammation in the injured epidermal layer and dermis. Conspicuously, in the molecular analysis of wound healing, the results indicated that MRSW-1 treatement effectively increased collagen amount and the ratio of type I to type III collagen in the wound, suggesting that MRSW-1 potentiallly contributed to the integrity and stability of injured skin. Subsequent to this, matrix metalloproteinases, (MMPs) play important role for degradation of extracellular matrix and the results showed that MRSW-1 promoted expression of MMP-2 and MMP-9.
Taken together, our findings and the in vitro and in vivo biological assays indicated that marine-derivative MRSW-1 possesses anti-melanogenic properties and repair of burn-injury wounds that are significant in medical cosmetology which represent a promising therapeutic option for skin protection.

論文審定書 i
誌謝 ii
摘要 iv
Abstract vi
目錄 viii
圖目錄 ix
表目錄 xii
縮寫表 xiii
第一部分 海洋天然衍生物MRSW-1之美白作用 1
前言 2
實驗材料與方法 26
結果 34
討論 61
第二部分 海洋天然衍生物MRSW-1之促進傷口癒合作用 75
前言 76
實驗材料與方法 84
結果 89
討論 114
結論及未來展望 123
參考文獻 126
個人履歷 140
附錄 144

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