Abstract
Skin hyperpigmentation is generally characterized by increased synthesis and deposition of melanin in the skin. UP256, containing bakuchiol, is a well-known medication for acne vulgaris. Acne sometimes leaves dark spots on the skin, and we hypothesized that UP256 may be effective against hyperpigmentation-associated diseases. UP256 was treated for anti-melanogenesis and melanocyte dendrite formation in cultured normal human epidermal melanocytes as well as in the reconstituted skin and zebrafish models. Western blot analysis and glutathione S-transferase (GST)-pull down assays were used to evaluate the expression and interaction of enzymes related in melanin synthesis and transportation. The cellular tyrosinase activity and melanin content assay revealed that UP256 decreased melanin synthesis by regulating the expression of proteins related on melanogenesis including tyrosinase, TRP-1 and -2, and SOX9. UP256 also decreased dendrite formation in melanocytes via regulating the Rac/Cdc42/α-PAK signaling proteins, without cytotoxic effects. UP256 also inhibited ciliogenesis-dependent melanogenesis in normal human epidermal melanocytes. Furthermore, UP256 suppressed melanin contents in the zebrafish and the 3D human skin tissue model. All things taken together, UP256 inhibits melanin synthesis, dendrite formation, and primary cilium formation leading to the inhibition of melanogenesis.
Highlights
Hyperpigmentation is a skin pigmentation disorder that is discolored, blotchy, or darker than normal skin
Our results showed that UP256 decreased SOX9 expression, followed by a reduction in TRP-1, TRP-2, and tyrosinase, resulting in low melanin production in Normal human epidermal melanocytes (NHEM)
The upstream signaling intermediates that regulate Rac1 and RhoA activity require more extensive studies as well as the potential crosstalk between dendrites and the keratinocyte membrane at the attachment site. It is contradictory regarding the relationship between melanogenesis and cilia formation when we measured the cilia formation and melanin contents in NHEM over time (24, 48, and 72 h) (Figure 4a), Interestingly, we found that the formation of cilia increased at 48 and 72 h passed with time, but the melanin was slightly increased at that time
Summary
Hyperpigmentation is a skin pigmentation disorder that is discolored, blotchy, or darker than normal skin. We hypothesized that UP256 may be effective in treating hyperpigmentation, since dark spots on the skin are caused by acne. It would be great compliance if a medicine or cosmeceutical agent could double as a treatment for inflammatory as well as undesirable hyperpigmentation conditions. We investigated the anti-melanogenic effect of UP256 containing bakuchiol, and its mechanism of action on melanogenesis in melanocytes. UP256 treatment decreased approximately 20% of cilia formation in melanocytes compared to the control group, but PTU treatment did not change the cilia (Figure 4e). The melanin amount in zebrafish was slightly decreased after treating the UP256 sample when compared to the control group, but not as much as the PTU group (Figure S3). Yellow arrows indicate the primary cilia in the representative fluorescence image for each group. (e) The ciliated cells out of more than 500 cells were counted at the image overlaid with three fluorescence. * p < 0.05 and ** p < 0.01
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