臺灣博碩士論文加值系統

皮膚屏障的功能障礙，例如皮脂膜缺乏或角質細胞增殖與分化的失衡，會導致皮膚疾病的產生，如異位性皮膚炎、牛皮癬和汗孔角化症。曾有研究使用中草藥萃取物做為替代性藥物，發現富含類黃酮化合物的黃芩萃取物，具有抗發炎、抗氧化、抗癌、抗菌、抗病毒、抗老化等的活性。
Oroxylin A (5,7-dihydroxy-6-methoxyflavone)，為黃芩中類黃酮化合物之一，含量雖少但具有廣泛的藥理活性，包括抗發炎、抗癌、抗過敏與抗菌的效果，此外也發現具有抑制皮膚表皮黑素體運送與減少細胞內黑色素含量之活性，但是卻缺乏應用於皮膚表皮角質層的相關研究。Oroxylin A天然來源含量稀少且萃取步驟十分繁瑣，而先前有文獻提出不同的合成方法，其合成條件毒性較高且有爆炸疑慮，本研究透過較溫和、耗時短且安全性與產率皆高的特殊一鍋式反應，來合成所需的oroxylin A。
以oroxylin A處理人類角質細胞後，於檢測期間並未出現細胞毒性反應，隨後進行人類全基因微陣列晶片分析，並利用基因富集分析產生顯著變化的基因調控路徑，再以即時定量聚合酶連鎖反應針對目標基因分析表現情形。發現oroxylin A具有調節角質細胞中脂質代謝的作用，以及可能影響細胞分化與增殖。推測當皮膚受到環境刺激誘發過敏現象，或者受到外部的機械應力導致皮膚損傷，可能藉由加速角質代謝達到修復皮膚之效果。此外本研究所使用的基因微陣列分析技術，可以得知化合物施予細胞可能影響的基因調控路徑，未來可應用於檢測化粧品對於皮膚的合適性，評估原料的安全性及有效性，具有成為建立替代性實驗檢測方法之潛力。

Dysfunction of the epidermal barrier of the skin, such as sebum deficiency or imbalance of keratinocyte proliferation and differentiation, can lead to skin diseases, for example, atopic dermatitis, psoriasis and porokeratosis. The extracts of Chinese herbal medicine have been reported to be alternative drugs. S. baicalensis extracts contain various flavonoids and have anti-inflammatory, antioxidant, anti-cancer, antibacterial, anti-viral, and anti-aging effects.
Oroxylin A (5,7-dihydroxy-6-methoxyflavone), the least abundant flavonoid in S. baicalensis extracts, has a wide range of pharmacological activities, including anti-inflammatory, anti-cancer, anti-allergic and antibacterial effects. Oroxylin A has the inhibitory activity of the transport of melanosome and reducing the intracellular melanin content, but lacks the relevant literature on the application of oroxylin A to the stratum corneum of the skin. Oroxylin A has a rare natural source and is very cumbersome to extract. Previous studies showed different synthetic methods to produce oroxylin A, but the synthetic conditions are highly toxic and explosive. In this study, a milder, time-consuming, safe and high-yield one-pot reaction was used to synthesize the required oroxylin A.
Keratinocytes were treated with different concentrations of oroxylin A, and there was no cytotoxicity in the periods of treatments. Human whole-genome microarray analysis was used to identify significantly expressed genes that may contribute to the response, and then the gene ontology enrichment analysis could perform the signaling pathways by gene expression profiling. After quantitative polymerase chain reaction analysis, the results indicated lipid metabolism and the regulation of differentiation and proliferation of keratinocytes maybe involved. Therefore, we speculated that when the skin is stimulated by environmental changes or external mechanical stress, if it can accelerate the metabolism of keratinocytes, it might be able to achieve the effect of repairing skin abnormalities. In addition, the gene microarray analysis used in this study can be used to clarify the possible regulatory pathways of the compounds administered to cells, which can be applied to evaluate the safety and effectiveness of raw materials of cosmetics for the skin in the future.

致謝.....I
中文摘要.....II
Abstract.....IV
目錄.....VI
圖目錄.....IX
表目錄.....X
英文縮寫表.....XI

第一章 緒論.....01
1.1 人體皮膚結構.....01
1.2 表皮屏障異常對皮膚健康之影響.....03
1.3 黃芩中的類黃酮化合物.....10
1.4 Oroxylin A背景與藥理活性.....14
1.5 人類HaCaT角質細胞 (Human keratinocyte HaCaT cells).....16
1.6 研究目的.....17
1.7 研究架構與實驗流程.....19
第二章 實驗材料和方法.....20
2.1 藥品.....20
2.2 儀器.....21
2.2.1 合成實驗儀器.....21
2.2.2 生物活性實驗儀器.....22
2.3 Oroxylin A合成方法.....23
2.4 高效能液相層析.....24
2.5 Oroxylin A之細胞存活率分析.....25
2.5.1 細胞培養.....25
2.5.2 細胞冷凍保存.....26
2.5.3 細胞解凍.....26
2.5.4 細胞計數.....27
2.5.5 細胞存活率試驗 (MTT assay).....28
2.6 基因表現分析.....28
2.6.1 Total RNA萃取.....28
2.6.2 基因微陣列分析 (microarray analysis).....29
2.6.3 cDNA合成.....31
2.6.4 引子設計與基因表現分析.....31
2.6.5 瓊脂凝膠電泳.....33
2.6.6 即時定量聚合酶連鎖反應.....34
2.6.7 統計分析.....34
第三章 結果.....35
3.1 Oroxylin A合成.....35
3.2 Oroxylin A之細胞存活率分析.....35
3.3 基因微陣列分析與基因富集分析.....36
3.4 參與甲羥戊酸路徑與keratin家族之候選基因RT-PCR分析.....37
3.5 即時定量聚合酶連鎖反應分析.....37
第四章 討論.....38
4.1 Oroxylin A合成.....38
4.2 Oroxylin A對HaCaT角質細胞之影響.....39
第五章 結論.....44
參考文獻.....45
附錄.....67

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