Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
AmorePacific Corporation R&D Center, Yongin, Gyeonggi-do, Republic of Korea.
J Dermatol Sci. 2022 Apr;106(1):12-20. doi: 10.1016/j.jdermsci.2022.02.010. Epub 2022 Feb 28.
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.
A molecular target of TCTE was investigated to elucidate the association of both adiponectin and PPARγ with anti-melanogenic activity.
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.
TCTE significantly promoted adiponectin secretion (EC, 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.
The anti-melanogenic activity of TCTE was associated with a PGC-1α-independent PPARγ partial agonism.
3,4,5-三甲氧基肉桂酸香茅酯（TCTE）是目前处方中使用的一种抗黑色素生成的化妆品成分，它能促进人骨髓间充质干细胞（hBM-MSCs）成脂分化过程中脂联素的合成。脂联素能抑制黑色素的生物合成，其生物合成直接受到过氧化物酶体增殖物激活受体（PPAR）γ的调控。因此，TCTE 可能会影响 PPARγ 的活性。然而，不同化学结构的 PPARγ 激动剂对人黑色素生成的影响效果相反。
研究 TCTE 的分子靶标，阐明脂联素和 PPARγ 与抗黑色素生成活性的关系。
在 hBM-MSCs 的成脂分化模型中，检测 TCTE 促进脂联素分泌的活性。通过基于时间分辨荧光共振能量转移的受体结合和 PPAR 转激活，评估 TCTE 促进脂联素分泌的分子靶标。
TCTE 能显著促进 hBM-MSCs 成脂分化过程中的脂联素分泌（EC50，27.9 μM），并直接与 PPARγ 结合（Ki，13.2 μM）。TCTE 结合的 PPARγ 增加了 SRC-1、SRC-3 和 TRAP220/DRIP1 共激活物肽的募集，而不影响 PGC-1α 的共激活。在对接分析中，TCTE 的最佳配体结合模式表现出典型的 PPARγ 部分激动剂的配体-受体相互作用。实验证实 TCTE 具有 PPARγ 部分激动剂的作用，在培养的正常人黑素细胞和人表皮 3D 模型中，用 PPARγ 拮抗剂处理可降低 TCTE 的抗黑色素生成活性。
TCTE 的抗黑色素生成活性与 PGC-1α 无关的 PPARγ 部分激动作用有关。
