臺灣博碩士論文加值系統

異位性皮膚炎(Atopic dermatitis, AD)是一種長期慢性發炎、反覆發作並且會造成皮膚乾癢的發炎性皮膚病，與皮膚對環境觸發的過度反應有關。氧化壓力是造成細胞損傷的途徑之一，已知與發炎反應息息相關，是影響過敏反應的一項重要因素，可能使皮膚過敏反應加重，進而導致反覆性皮膚炎。
酚類化合物是一類具有抗氧化活性的天然產物，目前已被證實具有多種生物活性，包括抗癌、抗氧化、抗發炎、抗糖尿病、神經保護、心血管保護和調節代謝功能等作用，常是保健食品或功能性食品的原料。因此，本論文擬純化五種酚類化合物，分析比較其抗氧化能力差異，並以TNF-α誘導HaCaT細胞發炎模式探討五種酚類化合物對發炎皮膚的抗發炎活性，以作為未來保健產品或化妝品原料開發之來源及生物活性參考依據。
利用層析分離、純化出五種酚類化合物：resveratrol (res)、curcumin (cur)、rutin (rut)、verbascoside (VB)和isoverbascoside (isoVB)，以光譜數據及文獻比對確認其結構。抗氧化實驗結果發現rut、cur、VB、isoVB在DPPH清除試驗的IC50分別為86.4、142.7、98.9及52.6 μΜ；res、rut、cur、VB、isoVB在TEAC試驗中的IC50分別為30.6、19.5、28.3、14.2及19.3 μΜ；還原力試驗中EC50分別為93.1、28.8、31、22.5及25.3 μΜ。由此可知五種化合物均有抗氧化活性，其中以VB和isoVB較佳。
以TNF-α誘導HaCaT細胞進行細胞內氧化壓力測定，發現五個化合物在1~10 μΜ均能抑制ROS生成，而VB及isoVB效果較佳。五個化合物在10 μΜ時，對TNF-α誘導HaCaT細胞絲聚蛋白(filaggrin, FLG)的表現量，均有顯著增加；在細胞核內NF-κB (p65)含量，則以res、VB和iosVB具有顯著的抑制作用；而在IL-6含量測定中，res及isoVB可顯著抑制IL-6的分泌。綜合以上結果顯示，本論文所純化的五種酚類化合物中可能經由抗氧化、抑制發炎因子分泌與修復細胞障壁而有抗炎活性，可能可以作為抗炎皮膚相關產品開發之來源。

Atopic dermatitis (AD), a chronic, relapsing, highly pruritic, inflammatory skin disease, is associated with cutaneous hyperreactivity to environmental triggers. Oxidative stress is an important factor that causes cell damage, and lead to inflammation. It may aggravate allergic to skin reactions and lead to recurrent dermatitis.
Polyphenol is a class of natural products that exhibited antioxidative activity. Phytochemical study showed that polyphenol has a variety of biological activities, including anti-cancer, anti-oxidative, anti-inflammatory, anti-diabetic, neuroprotective, cardiovascular protection and metabolic function regulation activities. Therefore, polyphenol is a natural source for developing healthy and functional foods. However, the evidence of their therapeutic effects on AD remains unclear. In the present study, we will isolate five polyphenols, and their protective effects against TNF-α induced HaCaT cells was assessed by evaluating its 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging, Trolox equivalent antioxidant capacity (TEAC) assay, reducing power and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay. In addition, filaggrin (FLG), cellular IL-6 secretion and anti-inflammatory mechanism were also evaluated and clarified.
Five polyphenols were separated and purified by chromatography method, their structures were evaluated as resveratrol (res), curcumin (cur), rutin (rut), verbascoside (VB) and isoverbascoside (isoVB) by spectroscopy analysis and comparison with the literature data. Rut, cur, VB, and isoVB exhibited DPPH scavenging activities with IC50 of 86.4, 142.7, 98.9, and 52.6 μΜ, respectively. Res, rut, cur, VB, and isoVB showed TEAC activities with IC50 of 30.6,19.5, 28.3, 14.2, and 19.3 μΜ. The EC50 of res, rut, cur, VB, and isoVB was 93.1, 28.8, 31, 22.5 and 25.3 μΜ for reducing power assay. Moreover, all compounds decreased intracellular ROS production at 1~10 μΜ on TNF-α induced HaCaT cells by DCFH-DA assay. The FLG levels were increased at 10 μΜ of five polyphenols on TNF-α induced HaCaT cells, significantly. Only res and isoVB reduced IL-6 secretion at 10 μΜ treatment concentrations. Further analysis showed that the anti-inflammatory effects of res, VB and isoVB likely occurred via nuclear factor-κB pathway inhibition, which attenuates IL-6 secretion in cells.
Based on the above results, all of five polyphenols exhibited potent antioxidative activities. Res, VB, and isoVB showed the potent anti-inflammatory effects on TNF-α induced HaCaT cells. This study is the first report to clarify the therapeutic effects of polyphenols in an AD cells model. We provide supportive evidence for the use of natural antioxidants, which has been used in functional food as well as in cosmetic and medicine.

摘要..............................................i
Abstract.........................................ii
誌謝.............................................iv
目錄.............................................v
表目錄...........................................viii
圖目錄............................................ix
附圖目錄..........................................x
縮寫對照表........................................xi
第一章 緒論...................................... 1
1.1前言..........................................1
1.2化合物介紹....................................4
1.2.1 Rutin介紹..................................4
1.2.2 Curcumin介紹...............................4
1.2.3 Resveratrol介紹............................4
1.2.4 Verbascoside介紹...........................5
1.2.5 Isoverbascoside介紹........................5
1.3研究目的......................................6
第二章 文獻回顧..................................7
2.1活性回顧......................................7
2.1.1 Rutin活性回顧..............................7
2.1.2 Curcumin活性回顧...........................9
2.1.3 Resveratrol活性回顧........................11
2.1.4 Verbascoside活性回顧.......................14
2.1.5 Isoverbascoside活性回顧....................15
2.2專利檢索......................................16
2.2.1 Rutin專利檢索..............................16
2.2.2 Curcumin專利檢索...........................18
2.2.3 Resveratrol專利檢索........................20
2.2.4 Verbascoside專利檢索.......................22
2.2.5 Isoverbascoside專利檢索....................23
第三章 化合物分離與純化...........................25
3.1 Rutin分離純化................................25
3.2 Curcumin分離純化.............................26
3.3 Resveratrol分離純化..........................27
3.4 Verbasscosiude and isoverbascoside分離純化...28
第四章 實驗材料與方法.............................29
4.1 實驗材料與儀器...............................29
4.2 溶液配製.....................................32
4.3 實驗方法.....................................33
4.3.1分離與純化..................................33
4.3.2化合物純度分析...............................34
4.3.3 DPPH自由基清除試驗..........................34
4.3.4 TEAC試驗...................................35
4.3.5還原力試驗...................................35
4.3.6細胞培養 ....................................35
4.3.7細胞存活率測定................................35
4.3.8細胞內ROS含量測定.............................36
4.3.9 IL-6表現量測定...............................36
4.3.10細胞核內NF-κB表現量測定.......................36
4.3.11 Filaggrin表現量測定.........................37
4.3.12西方墨點法...................................37
4.3.13數據分析.....................................37
第五章 實驗結果與討論...............................38
5.1化合物結構與鑑定.................................38
5.2自由基清除能力與氧化還原能力......................38
5.3細胞內抗氧化能力.................................38
5.4細胞存活率試驗...................................39
5.5抗發炎能力.......................................39
5.6 Filaggrin蛋白表現的影響.........................39
5.7討論............................................40
第六章 結論.........................................48
參考文獻............................................49
附錄................................................60
附圖................................................62
Extended Abstract...................................70

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