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Title Page
Contents
ABBREVIATIONS 10
ABSTRACT 13
I. INTRODUCTION 15
1. Skin aging and melanogenesis 15
(1) Skin aging 15
(2) Photoaging 20
(3) Melanogenesis 21
(4) Tyrosinase and signaling pathways leading to tyrosinase expression 25
2. Skin-lightening agents 30
(1) Tyrosinase inhibitors 30
(2) Synthesis of (Z)-5-(2,4-dihydroxybenzylidene)thiazolidine-2,4-dione(MHY498) 31
3. Purpose of this study 32
II. MATERIALS AND METHODS 36
1. Materials 36
2. Cell culture system 37
3. MTT assay 38
4. Assay of mushroom tyrosinase activity 38
5. Kinetics of tyrosinase inhibition 39
6. Griess assay 39
7. Quantitative assay of cGMP in B16F10 melanoma cells 40
8. Assay of murine tyrosinase activity 41
9. Assay of melanin contents 42
10. Cell lysis 42
11. Western blot analysis 43
12. Docking simulation 45
13. Pharmacophore prediction 45
14. Statistical analysis 45
III. RESULTS 47
Part I. Inhibitory effect of MHY498 on mushroom tyrosinase activity 47
1. Inhibitory effect of MHY498 on mushroom tyrosinase activity 47
2. Kinetics of MHY498 in the inhibition of mushroom tyrosinase 47
3. Docking simulation of tyrosinase and binding residues that interact with MHY498 51
Part II. Effects of MHY498 on cAMP-dependent signaling pathway leading to melanogenesis 54
1. Effect of MHY498 on B16F10 melanoma cell viability 54
2. Effects of MHY498 on the expression level of tyrosinase and on the cAMP-dependent signaling pathway 54
3. Inhibition of tyrosinase activity in B16F10 melanoma cells by MHY498 56
4. Inhibition of melanin production in B16F10 melanoma cells by MHY498 60
Part III. Effect of MHY498 on NO levels and NO-induced signaling pathway related to melanogenesis 62
1. Inhibition of NO levels in SNP-treated B16F10 melanoma cells by MHY498 62
2. Inhibition of cGMP content in SNP-treated B16F10 melanoma cells by MHY498 62
3. Effect of MHY498 on the levels of CREB, MITF and tyrosinase in SNP-treated B16F10 melanoma cells 66
4. Inhibitory effect of tyrosinase activity in SNP-treated B16F10 melanoma cells by MHY498 69
5. Effect of MHY498 on melanin contents in SNP-treated B16F10 melanoma cells 69
IV. DISCUSSION AND CONCLUSION 73
V. REFERENCES 87
국문요약 99
Table 1. Characteristics of intrinsically and extrinsically aged skin 19
Table 2. Primary antibodies used in Western blot analysis 44
Table 3. IC50 values for tyrosinase inhibition by MHY498 and kojic acid(이미지참조) 48
Table 4. Kinetic analysis of MHY498 50
Table 5. Mushroom tyrosinase inhibition of MHY498, kojic acid and 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives in screening test 77
Fig. 1. Structure of skin. 16
Fig. 2. Skin aging. 18
Fig. 3. Process of melanin synthesis. 23
Fig. 4. Structure of human tyrosinase. 26
Fig. 5. Two signaling pathways leading to expression of tyrosinase. 27
Fig. 6. Synthetic rationale of MHY498. 33
Fig. 7. Lineweaver-Burk plot of mushroom tyrosinase in the presence of MHY498. 49
Fig. 8. Docking simulation of MHY498 and kojic acid using AutoDock4.2. 52
Fig. 9. Interaction residues of MHY498 or kojic acid with tyrosinase (by LigandScout 3.1). 53
Fig. 10. Effect of MHY498 on the viability of B16F10 melanoma cells. 55
Fig. 11. Effect of MHY498 on activation of PKA and CREB. 57
Fig. 12. Effect of MHY498 on expression of MITF and tyrosinase. 58
Fig. 13. Inhibitory effect of MHY498 on tyrosinase activity in α-MSH-treated B16F10 melanoma cells. 59
Fig. 14. Effect of MHY498 on melanin contents in α-MSH-treated B16F10 melanoma cells. 61
Fig. 15. Effect of MHY498 on NO levels in SNP-treated B16F10 melanoma cells. 63
Fig. 16. Effect of MHY498 on cGMP content in B16F10 melanoma cells. 64
Fig. 17. Effect of MHY498 on the levels of CREB, MITF and tyrosinase in SNP-treated B16F10 melanoma cells. 67
Fig. 18. Inhibitory effect of tyrosinase activity in SNP-treated B16F10 melanoma cells by MHY498. 70
Fig. 19. Effect of MHY498 on melanin contents in SNP-treated B16F10 melanoma cells. 72
Fig. 20. Inhibitory mechanism of MHY498 in α-MSH-induced melanogenesis. 79
Fig. 21. Inhibitory mechanism of MHY498 in NO-induced melanogenesis. 83
Fig. 22. Inhibitory mechanism of MHY498 in melanogenesis. 84
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