臺灣博碩士論文加值系統

對於紫外光造成皮膚色素沉著的探討， UVA 的探討仍尚未多，而紅球薑 (Z. zerumbet) 中的環狀倍半萜烯類成分 ZER 具有廣泛的生物活性，但現今仍未有 ZER 美白功效相關的研究。經 UVA 照射後的角質細胞會釋放出α-黑色素细胞刺激素 (α-MSH) ，此激素會誘導黑色素細胞生成黑色素，因此本篇以人類正常皮膚角質細胞 (HaCaT) 與小鼠黑色素瘤細胞 (B16F10) 進行探討添加 ZER 後對降低 UVA 造成的色素沉著的改善之功效以及機制進行深入探討。
本篇首先探討 ZER 在 HaCaT 中的抗氧化功效， HaCaT 在 ZER濃度 10 μM 以下時都沒有顯著死亡，且能顯著促進抗氧化轉錄因子 (Nrf2) 及抗氧化相關因子的蛋白表現量，這意味著 Nrf2 途徑的活化可能達到抗氧化的作用。之後再來探討 ZER 在 B16F10 中的抗黑色素生成功效。首先 ZER 顯著降低黑色素含量且無細胞毒性，且下調了黑色素生成中起作用的關鍵蛋白質小眼畸形相關轉錄因子 (MITF) 、酪胺酸酶和酪胺酸脢相關蛋白-1的蛋白表現量。加入 ZER 的 B16F10 細胞表現出 p-ERK 表現量增加的現象，這意味著 MAPK/ERK 途徑的活化可能造成抑制黑色素生成的作用。
結論， ZER 能通過調節 MAPK / ERK 途徑來抑制 MITF 和黑色素生成酶的表現進而抑制黑色素合成以達到美白效果。最後在斑馬魚的部分，分別在黑色素生成前及生成後加入 ZER ，結果顯示， ZER 不但能預防黑色素生成，也能達到淡斑效果。

For the study of skin pigmentation caused by ultraviolet light, the investigation of UVA has not yet been much, and the cyclic sesquiterpenoid component ZER in Z. zerumbet has extensive biological activity, but there is still no whitening efficacy related research of ZER.. The keratinocytes after UVA irradiation release α-melanocyte stimulating hormone (α-MSH), which induces the production of melanin by melanocytes, so this article uses human normal skin keratinocytes (HaCaT) and mouse melanoma cells ( B16F10) to investigate the effect and mechanism of improving the pigmentation caused by UVA after adding ZER. This article first explores the antioxidant efficacy of ZER in HaCaT. HaCaT has no significant death at ZER concentrations below 10 μM and can significantly promote protein expression of antioxidant transcription factor (Nrf2) and antioxidant-related factors, which means activation of the Nrf2 pathway may achieve antioxidant effects. Then we will discuss the anti-melanogenesis efficiency of ZER in B16F10. First, ZER significantly reduced melanin content and was non-cytotoxic, and down-regulated the protein expression of key protein-deficient transcription factor (MITF), tyrosinase, and tyrosine-related protein-1, which play a key role in melanogenesis. B16F10 cells added to ZER showed an increase in the expression of p-ERK, suggesting that activation of the MAPK/ERK pathway may result in inhibition of melanin production. In conclusion, ZER can inhibit the expression of MITF and melanin producing enzyme by regulating the MAPK/ERK pathway and inhibit melanin synthesis to achieve whitening effect. Finally, in the part of the zebrafish, ZER was added before and after the formation of melanin. The results showed that ZER can not only prevent melanin production, but also achieve the effect of blemishes.

目錄
中文摘要 I
ABSTRACT II
表目錄 VIII
圖目錄 IX
縮寫表 XI
第一章、前言 1
第二章、文獻探討 3
第2-1節 皮膚 4
2-1-1. 皮膚的介紹 4
2-1-3. 皮膚的功能 6
第2-2節紫外線 7
2-2-1. 紫外線介紹 7
2-2-2. 紫外線的分類 8
2-2-3. 紫外線對於身體的影響 9
第2-3節 自由基 11
2-3-1. 自由基的介紹 11
2-3-2. 自由基的來源 11
2-3-3. 紫外線與自由基 12
2-3-4. UVA誘導細胞生成ROS 12
2-3-5. 自由基的種類 14
第2-4節 抗氧化訊息傳遞路徑 15
2-4-1. 抗氧化轉錄因子Nrf2 15
2-4-2. Keap1 16
2-4-3. ARE 16
2-4-4. Nrf2的活化機制 16
第2-5節 抗氧化防禦系統 18
2-5-1. 酵素抗氧化系統 19
2-5-2. 非酵素抗氧化系統 21
第2-6節 黑色素 24
2-6-1. 黑色素生成的途徑 25
2-6-2. 影響黑色素生合成的相關因子 26
第2-7節 斑馬魚 30
2-7-1. 斑馬魚的簡介 30
2-7-2. 斑馬魚胚胎發育過程及各時期特徵 30
2-7-3. 斑馬魚研究 32
2-7-4. 斑馬魚與黑色素 33
2-7-5. 斑馬魚飼養方式 33
2-7-6. 斑馬魚飼料 35
第2-8節 ZER 39
2-8-1. ZER 的簡介 39
2-8-2. ZER 的來源 40
2-8-3. ZER 的生物醫學特性及應用 41
第三章、研究動機與實驗架構 44
第3-1節 研究背景 45
第3-2節 研究目的 46
第3-3節 實驗架構圖 46
第四章、實驗材料與方法 48
第4-1節 實驗材料 49
第4-2節 實驗方法 53
4-2-1. 細胞培養 53
4-2-2. 細胞存活率 (cell viability)分析 - MTT assay 57
4-2-3. ROS產量測定 59
4-2-4. 細胞總蛋白質萃取 60
4-2-5. 細胞核與細胞質蛋白質萃取 62
4-2-6. 蛋白質定量 64
4-2-7. 西方墨點法 65
4-2-8. 免疫螢光染色 71
4-2-9. GSH含量測定 73
4-2-10. α-MSH濃度測定 75
4-2-11. RNA干擾 79
4-2-12. 黑色素含量檢測 81
4-2-13. 條件培養基 83
4-2-14. 斑馬魚黑色素含量測定 84
4-2-15. 斑馬魚酪胺酸酶活性測定 85
4-2-14. Zerumbone配製 86
4-2-15. 統計分析 86
第五章、結果 87
第5-1節 ZER透過Nrf2路徑促進抗氧化酵素大量表現，以保護人類皮膚角質細胞(HaCaT)降低UVA誘導的氧化壓力傷害並減少黑色素細胞刺激激素(α-MSH)的生成 88
5-1-1. ZER調控HaCaT細胞株中Nrf2進行抗氧化壓力的能力 88
5-1-2. ZER活化抗氧化系統抑制UVA誘導生成黑色素細胞刺激相關因子 93
第5-2節 ZER抑制黑色素細胞生成黑色素之機制探討 96
5-2-1. ZER調控B16F10細胞株進行抗黑色素生成的能力 96
5-2-2. ZER抑制α-MSH誘導調控相關訊息傳導路徑 103
5-2-3. ZER活化ERK途徑調控相關訊息傳導路徑 105
第5-3節 ZER減少斑馬魚黑色素細胞的生成 111
5-3-1. ZER降低斑馬魚黑色素的生成量 111
第六章、討論 120
第6-1節 ZER透過Nrf2路徑調節第二型解毒酵素保護HaCaT細胞降低UVA所誘導的氧化壓力與促黑激素 121
6-1-1. UVA與ZER的背景 121
6-1-2. ZER促進HaCaT細胞Nrf2路徑活化抵抗UVA造成的氧化壓力 121
6-1-3. ZER對HaCaT細胞抑制UVA誘導生成黑色素細胞刺激相關因子 122
第6-2節 ZER抑制B16F10細胞黑色素生成之機制探討 123
6-2-1. ZER對α-MSH(條件培養液)誘導B16F10細胞Tyrosinase之影響 123
6-2-2. ZER對α-MSH誘導B16F10細胞的抗黑色素生成功效 124
6-2-3. ZER對B16F10細胞ERK路徑之影響 124
第6-3節. ZER抑制Zebrafish黑色素生成之機制探討 125
6-3-1. ZER對在黑色素形成之前的斑馬魚美白功效 125
6-3-2. ZER對在黑色素形成之後的斑馬魚美白作用 126
第七章、結論 127
第7-1節ZER對人類皮膚角質細胞誘導Nrf2路徑保護細胞免於UVA誘導的氧化壓力 128
第7-2節ZER對B16F10細胞抑制α-MSH誘導生成黑色素之機制探討 129
參考文獻 130

 

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