3, 4, 5-Trimethoxycinnamate thymol ester inhibits melanogenesis in normal human melanocytes and 3D human epidermal equivalents via the PGC-1α-independent PPARγ partial agonism. Issue 1 (April 2022)

• Record Type: Journal Article
• Authors: Ko, Hyejin; Choi, Hyunjung; Han, Yujia; An, Seungchan; Min, Daejin; Park, Won-Seok; Jin, Sun Hee; Kim, Hyoung-June; Noh, Minsoo
• Is Part Of: Journal of dermatological science. Volume 106:Issue 1(2022)
• Page Start: 12
• Page End: 20
• Publication Date: 2022-04
• Subjects: α-MSH; alpha-melanocyte stimulating hormone -- 3D three-dimensional -- DMEM Dulbecco Modified Eagle's Medium -- DRIP-1 vitamin D receptor-interacting protein-1 -- EC50 half-maximal effective concentration -- FBS fetal bovine serum -- H helix -- hBM-MSCs human bone marrow mesenchymal stem cells -- HMGS human melanocyte growth supplement -- IBMX 3-isobutyl-1-methylxanthine -- LBD ligand binding domain -- MITF microphthalmia-associated transcription factor -- NCoR1 nuclear receptor corepressor 1 -- NHMs normal human melanocytes -- PBS phosphate-buffered saline -- PDB Protein Data Bank -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- PPAR peroxisome proliferator-activated receptor -- PRIP peroxisome proliferator-activated receptor gamma-interacting protein -- RAP250 nuclear receptor-activating protein 250 -- SMRT silencing mediator of retinoic acid and thyroid hormone receptor -- SRC steroid/nuclear receptor coactivator -- TCTE 3, 4, 5-trimethoxycinnamate thymol ester -- TRAP220 thyroid hormone receptor-associated protein complex 220 -- TR-FRET time-resolved fluorescence resonance energy transfer; 3 -- 4 -- 5-Trimethoxycinnamate thymol ester -- Adiponectin -- Peroxisome proliferator-activated receptor gamma -- Melanogenesis -- 3D human epidermis model; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2022.02.010
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: TCTE, an anti-melanogenic agent, increased adiponectin production. TCTE acted as a PPARγ partial agonist. A PPARγ antagonist attenuated the effect of TCTE on 3D melanogenesis models. TCTE-bound PPARγ recruited coactivator proteins, SRC-1, SRC-3, and TRAP220/DRIP-1. TCTE-bound PPARγ failed to recruit the pro-melanogenic PGC-1α. Graphical Abstract: ga1 Abstract: Background: 3, 4, 5-Trimethoxycinnamate thymol ester (TCTE), an anti-melanogenic cosmetic agent prescribed currently, promotes adiponectin synthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Adiponectin inhibits melanin biosynthesis and its biosynthesis is directly regulated by peroxisome proliferator-activated receptor (PPAR) γ. In this regard, TCTE may potentially affect PPARγ activity. However, contradicting effects of PPARγ agonists with different chemical structures on human melanogenesis have been reported. Objective: A molecular target of TCTE was investigated to elucidate the association of both adiponectin and PPARγ with anti-melanogenic activity. Methods: The adiponectin secretion-promoting activity of TCTE was tested in an adipogenesis model of hBM-MSCs. A molecular target of TCTE for adiponectin secretion was evaluated via time-resolved fluorescence resonance energy transfer-based receptor binding and transactivation of PPARs. Results: TCTE significantly promoted adiponectin secretion (EC50, 27.9 μM) during adipogenesis in hBM-MSCs and directly bound to PPARγ ( Ki, 13.2 μM). The TCTE-bound PPARγ increased the recruitment of SRC-1, SRC-3, and TRAP220/DRIP-1 coactivator peptides without affecting PGC-1α coactivation. In the docking analysis, the optimal ligand binding mode of TCTE exhibited typical ligand-receptor interactions of PPARγ partial agonists. The PPARγ partial agonism of TCTE was established experimentally and the anti-melanogenic activity of TCTE was decreased by treatment with a PPARγ antagonist in cultured normal human melanocytes and a 3D model of human epidermis. Conclusion: The anti-melanogenic activity of TCTE was associated with a PGC-1α-independent PPARγ partial agonism.