臺灣博碩士論文加值系統

皮膚中的膠原蛋白之降解與基質金屬蛋白酶 [matrix metalloproteinases (MMP)] 有關，並會引起皮膚失去彈性和形成皺紋，最後導致皮膚老化。在馬來西亞，帝皇烏藍 [Cosmos caudatus Kunth (CC)] 傳統上被稱為抗皮膚老化劑，常被馬來族群使用。多項現代研究已證明CC具有抗氧化活性，但其抗皮膚老化活性尚未得到驗證。本論文旨在研究 CC 萃取物和其劃分層的抗皮膚老化活性，並特別針對它們對人類皮膚纖維母細胞CCD-966SK中collagenase、MMP-1 和 MMP-3 之抑製作用進行研究，然后針對其有效層進行化學成分分離、鑑定和分析。首先，在活性導引分離中，使用DPPH assay 測試CC萃取物和其劃分層之抗氧化活性，MTS assay則被用於測試細胞存活率。透過活性導引分離法，本研究從CC 75% 乙醇分配層 (CC-E) 中分離出CC-E2 和CC-E3 兩個劃分層，兩者皆具有抗氧化活性 (IC50值分別為44.83 μg/mL和52.13 μg/mL)，且在25 μg/mL的濃度下對CCD-966SK 沒有細胞毒性。

在細胞實驗中，使用collagenase assay 測量collagenase 活性，並使用 qRT-PCR和western blotting測量MMP-1和MMP-3之表現。實驗結果顯示CC-E2和CC-E3皆可抑制CCD-966SK中由TNF-α誘導的collagenase活性、MMP-1 和 MMP-3 之mRNA和蛋白質表現，且與抑制 NF-κB 活化有關。 從CC-E2和CC-E3的分離中，共獲得了十四個純化合物，並使用 ESIMS、1H 和 13C NMR 光譜進行化學結構鑑定。使用當中的八個純化合物，主要由黃酮類化合物及其苷類組成，作爲HPLC分析的標準化合物。透過 HPLC 定量后，得知quercitrin (14.79% w/w) 和quercetin (11.20% w/w) 分別是CC-E2和CC-E3中的主要化合物。有趣的是，與單獨劃分層相比，CC-E2和 CC-E3也可協同抑制MMP-3之蛋白質表現。作爲總結，富含類黃酮苷的CC有效層可通過NF-κB途徑抑制collagenase活性及MMP-1和MMP-3之表現，而表現出抗皮膚老化作用。這是首次關於CC可抑制MMP-1和MMP-3表現的研究，同時還附上其主要化學成分的定量，證明了它在未來具有被開發為抗皮膚老化產品的潛力。

Skin aging, which characterized by loss of skin elasticity and formation of wrinkles, is associated with degradation of collagen by matrix metalloproteinases (MMPs). In Malaysia, Cosmos caudatus Kunth (CC) has been traditionally claimed as a skin anti-aging agent and commonly used by the Malay community. However, the skin anti-aging properties of CC was not validated despite its well-known antioxidant activity revealed by many studies. The aim of this research was to investigate the skin anti-aging potential of CC plant by evaluating the collagenase, MMP-1 and MMP-3 inhibitory effects in human dermal fibroblasts CCD-966SK, together with the isolation, identification and analysis of chemical constituents in the CC bioactive fractions. Firstly, the antioxidant activity-guided fractionation was performed using DPPH assay. Cell viability was determined using MTS assay. During screening, fractions CC-E2 and CC-E3 were obtained from CC 75% ethanol partitioned layer (CC-E) and selected for further evaluation due to their high antioxidant activity (IC50 values were 44.83 μg/mL and 52.13 μg/mL, respectively) and insignificant toxicity towards CCD-966SK cells at 25 μg/mL.

Collagenase activity was examined using collagenase assay, while MMP-1 and MMP-3 mRNA and protein expression were measured using qRT-PCR and western blotting. CC-E2 and CC-E3 significantly inhibited collagenase activity, MMP-1 and MMP-3 mRNA and protein expression induced by TNF-α in CCD-966SK. The inhibitory activities might be related with the suppression of NF-κB activation induced by TNF-α. Followed by this, a total of 14 compounds were isolated from both fractions and identified using ESIMS, 1H and 13C NMR spectroscopies. Eight compounds, which consisted of flavonoid and their glycosides, were selected as biomarkers for HPLC quantification. Quercitrin (14.79% w/w) and quercetin (11.20% w/w) were major compounds in CC-E2 and CC-E3, respectively. Interestingly, the combination of both fractions also inhibited the MMP-3 protein expression synergistically, compared with treatment alone. In conclusion, CC fractions rich in flavonoid and their glycosides exhibited skin anti-aging effects via the inhibition of collagenase activity, and MMP-1 and MMP-3 expression, probably through NF-κB pathway. So far, this is the first study reported on MMP-1 and MMP-3 inhibitory expression of CC with its chemical profile, which revealed its potential to be developed as skin anti-aging products in the future.

Acknowledgement..........3
Abstract..........5
中文摘要..........7
Table of contents..........9
List of Figures..........12
List of Tables..........16
Abbreviations..........18

CHAPTER 1
Introduction..........20
1.1 Overview..........20
1.2 Specific aims..........23

CHAPTER 2
Literature Review..........24
2.1 Development of natural-based cosmetic products in Malaysia..........24
2.2 Cosmos caudatus Kunth..........26
2.2.1 Botanical description, traditional use and distribution..........26
2.2.2 Phytochemistry..........28
2.2.3 Biological Activities..........44
2.3 Skin aging..........52
2.3.1 Inflammaging and the skin..........52
2.3.2 Matrix metalloproteinases (MMPs) and the skin..........55

CHAPTER 3
Materials and Methods..........61
3.1 Chemicals and reagents..........61
3.2 Plant materials..........62
3.3 Extraction, fractionation and isolation..........62
3.3.1 Isolation scheme description..........63
3.4 Structural elucidation..........64
3.5 HPLC analysis..........66
3.6 DPPH free radical scavenging assay..........67
3.7 Cell culture and treatment..........67
3.8 Cell viability assay..........68
3.9 Collagenase assay..........69
3.10 Quantitative real-time reverse transcription polymerase chain reactions (qRT-PCR)..........69
3.11 Western blotting..........70
3.12 Detection of intracellular reactive oxygen species (ROS)..........70
3.13 Statistical analysis..........71

CHAPTER 4
Results and Discussions..........72
4.1 Screening of CC fractions using DPPH assay..........72
4.2 Effects of CC fractions on viability of CCD-966SK cells...........76
4.3 CC fractions inhibited collagenase, MMP-1, and MMP-3 activity in CCD-966SK cells..........78
4.4 CC fractions exhibited skin anti-aging activity in CCD-966SK cells by suppressing nuclear factor-kappa B (NF-κB) activation..........79
4.5 Relationships between CC components and skin anti-aging properties 83
4.5.1 Structural elucidation of luteolin (1)..........85
4.5.2 Structural elucidation of diosmetin (2)..........90
4.5.3 Structural elucidation of quercetin (3)..........94
4.5.4 Structural elucidation of avicularin (4)..........99
4.5.5 Structural elucidation of guaijaverin (5)..........104
4.5.6 Structural elucidation of quercitrin (6)..........109
4.5.7 Structural elucidation of hyperin (7)..........114
4.5.8 Structural elucidation of isoquercetin (8)..........121
4.5.9 Structural elucidation of kaempferol (9)..........127
4.5.10 Structural elucidation of afzelin (10)..........131
4.5.11 Structural elucidation of trifolin (11)..........136
4.5.12 Structural elucidation of trans-caffeic acid (12)..........141
4.5.13 Structural elucidation of ethyl caffeate (13)..........144
4.5.14 Structural elucidation of methyl 4-hydroxycinnamic acid (14)..........149
4.6 HPLC fingerprint and quantification of CC bioactive fractions..........153
4.7 Synergistic activity of CC-E2 and CC-E3 in inhibiting MMP-3..........157

CHAPTER 5
Conclusion..........159
References..........160

Publication and other research projects..........173

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