Sallow and/or dull skin appearance is greatly attributable to the yellow components of skin tone. Bilirubin is a yellow chromophore known to be made in the liver and/or spleen and is transported throughout the body via the blood stream. Recent publications suggest bilirubin may be synthesized in other cells/organs, including the skin. We found human keratinocytes express the transcripts involved in bilirubin biosynthesis. In parallel, we also found human keratinocytes could indeed synthesize bilirubin in monolayer keratinocytes and in a 3D human skin-equivalent model. The synthesized amount was substantial enough to contribute to skin yellowness. In addition, oxidative stress enhanced bilirubin production. Using UnaG, a protein that forms a fluorescent species upon binding to bilirubin, we also visualized the intracellular expression of bilirubin in keratinocytes. Finally, we screened a compound library and discovered that the sucrose laurate/dilaurate (SDL) combination significantly reduced bilirubin levels, as well as bilirubin-mediated yellowness. In conclusion, bilirubin is indeed synthesized in epidermal keratinocytes and can be upregulated by oxidative stress, which could contribute to chronic or transient yellow skin tone appearance. Application of SDL diminishes bilirubin generation and may be a potential solution to mitigate yellowish and/or dull skin appearance.

Skin yellowness is a hallmark of dull or unhealthy skin, particularly among Asians. Previous research has indicated a link between skin glycation and skin yellowness. However, the specific glycated chemicals contributing to yellowish skin appearance have not been identified yet. Using HPLC-PDA-HRMS coupled with native and artificially glycated human epidermal explant skin, we identified intensely yellow colored glycated chromophores “(1R, 8aR) and (1S, 8aR)-4-(2-furyl)-7-[(2-furyl)-methylidene]-2-hydroxy-2H,7H,8AH-pyrano-[2,3-B]-pyran-3-one” (abbreviated as AGEY) from human skin samples for the first time. The abundance of AGEY was strongly correlated with skin yellowness in the multiple skin explant tissues. We further confirmed the presence of AGEY in cultured human keratinocytes and 3D reconstructed human epidermal (RHE) models. Additionally, we demonstrated that a combination of four cosmetic compounds with anti-glycation properties can inhibit the formation of AGEY and reduce yellowness in the RHE models. In conclusion, we have identified specific advanced glycation end products with an intense yellow color, namely AGEY, in human skin tissues for the first time. The series of study results highlighted the significant contribution of AGEY to the yellow appearance of the skin. Furthermore, we have identified a potential cosmetic solution to mitigate AGEY formation, leading to a reduction in yellowness in the in vitro RHE models.

Dullness or lack of radiance in facial appearance is a common concern among females. Previous studies have linked skin dullness to aging and revealed alterations in skin pigments. However, younger individuals (ages ≤ 35) also report concerns about dull skin in their hectic daily lives, which may not involve pigmentation changes. We hypothesized that the mechanisms underlying dullness in youth differ from those associated with aging. To investigate this, we measured cellular and molecular changes in 132 healthy Japanese and Chinese females aged 18 to 35 using biophotonic multiphoton tomography and biochemical tape-strip analysis. Our findings revealed that dull skin exhibited a thicker stratum granulosum and less densely packed keratinocytes in deeper layers. Biochemical analysis showed upregulation of interleukin-36γ and downregulation of E-cadherin in dull skin, with interleukin-36γ levels negatively correlating (p = 0.023) with metabolites of filaggrin. These alterations resemble those observed in inflammatory skin conditions, suggesting an additional mechanism of skin dullness beyond pigmentation. In vitro cultured cell models evaluated the efficacy of three skincare ingredients: galactomyces fermentation filtrate, bisabolol, and batyl alcohol. Galactomyces suppressed interleukin-36γ (p = 0.037), while both batyl alcohol (p = 0.006) and bisabolol (p = 0.049) showed beneficial effects on filaggrin. Targeting these biomarkers may improve the appearance of dull skin.