Superior even skin tone and anti-ageing benefit of a combination of 4-hexylresorcinol and niacinamide.

OBJECTIVES: To demonstrate the synergistic effect of 4-hexylresorcinol (4-HR) with niacinamide in boosting anti-melanogenic efficacy in vitro and establish the in vivo efficacy and safety of the combination in a human trial. METHODS: Primary human epidermal melanocytes and 3D pigmented skin equivalents were treated with 4-HR, niacinamide, and their combinations for their effect on pigmentation. This was followed by a randomized, double-blind, split-face clinical study in Chinese subjects, and effects on skin tone, hyperpigmentation, fine lines and wrinkles, hydration, and skin firmness were measured for a 12-week study period. RESULTS: In vitro tyrosinase enzyme activity studies showed that 4-HR is one of the most potent tyrosinase inhibitors. The combination of 4-HR and niacinamide showed a synergistic reduction in melanin production in cultured melanocytes and lightened the 3D skin equivalent model. In vitro as well as in the human trial, the combination of 4-HR and niacinamide showed significantly improved efficacy over niacinamide alone on hyperpigmentation spots as measured by L*, the visual appearance of fine lines and wrinkles in crow's feet and perioral area and skin firmness, with no product-related adverse events. CONCLUSIONS: A formulation containing a combination of 4-HR and niacinamide delivered superior skin tone and anti-ageing benefits significantly better than niacinamide alone with no adverse events. This study demonstrates that a product designed to affect multiple pathways of melanogenesis, inflammation, and ageing may provide an additional treatment option, beyond hydroquinone and retinoids, for hyperpigmentation and ageing.

OBJECTIFS: Démontrer l'effet synergique du 4-hexylrésorcinol (4-HR) associé au niacinamide pour stimuler in vitro l'efficacité antimélanogène, et établir l'efficacité et la sécurité d'emploi in vivo de cette association dans un essai chez l'homme. MÉTHODES: Des mélanocytes épidermiques humains primaires et des équivalents cutanés pigmentés en 3D ont été traités avec du 4-HR, du niacinamide et leurs combinaisons pour leur effet sur la pigmentation. Ceci a été suivi d'une étude clinique randomisée, en double aveugle en hémi-visage chez des sujets chinois, et les effets sur le teint, l'hyperpigmentation, les rides et ridules, l'hydratation et la fermeté de la peau ont été mesurés pendant une durée d'étude de 12 semaines. RÉSULTATS: Les études in vitro sur l'activité enzymatique de la tyrosinase ont montré que le 4-HR est l'un des inhibiteurs de la tyrosinase les plus puissants. L'association du 4-HR et du niacinamide a montré une réduction synergique de la production de mélanine dans les mélanocytes de culture et donné de la luminosité au modèle cutané 3D équivalent. Également in vitro avec l'étude chez l'homme, l'association du 4-HR et du niacinamide a fait ressortir une efficacité significativement plus élevée qu'avec le niacinamide seul sur les taches d'hyperpigmentation mesurées par L*, l'aspect visuel des rides et ridules des pattes d'oie et de la zone périorale, et la fermeté de la peau, sans événements indésirables liés au produit. CONCLUSIONS: Une formulation contenant une association de 4-HR et de niacinamide a permis d'obtenir un teint et un effet anti-âge nettement supérieurs à ceux du niacinamide seul, sans événements indésirables. Cette étude démontre qu'un produit conçu pour toucher plusieurs voies de mélanogenèse, d'inflammation et de vieillissement peut constituer une nouvelle option thérapeutique, au-delà de l'hydroquinone et des rétinoïdes, pour l'hyperpigmentation et le vieillissement.

Correction: Keratinocyte differentiation promotes ER stress-dependent lysosome biogenesis.

Following publication of this article, the authors realized there was an error in Figure 2b that needed correction. The TFEB panel of Figure 2b (total lysate) appears to be the same as the TFEB panel of Figure 2e (cytosolic fraction); the TFE3 panels of Figure 2b (total lysate) appear to be the same as the TFE3 panels of Figure 2e (cytosolic fraction) which happened during image assembly.This error did not impact the scientific conclusions of the article.

Keratinocyte differentiation promotes ER stress-dependent lysosome biogenesis.

Keratinocytes maintain epidermal integrity through cellular differentiation. This process enhances intraorganelle digestion in keratinocytes to sustain nutritional and calcium-ionic stresses observed in upper skin layers. However, the molecular mechanisms governing keratinocyte differentiation and concomitant increase in lysosomal function is poorly understood. Here, by using primary neonatal human epidermal keratinocytes, we identified the molecular link between signaling pathways and cellular differentiation/lysosome biogenesis. Incubation of keratinocytes with CaCl2 induces differentiation with increased cell size and early differentiation markers. Further, differentiated keratinocytes display enhanced lysosome biogenesis generated through ATF6-dependent ER stress signaling, but independent of mTOR-MiT/TFE pathway. In contrast, chemical inhibition of mTORC1 accelerates calcium-induced keratinocyte differentiation, suggesting that activation of autophagy promotes the differentiation process. Moreover, differentiation of keratinocytes results in lysosome dispersion and Golgi fragmentation, and the peripheral lysosomes showed colocalization with Golgi-tethering proteins, suggesting that these organelles possibly derived from Golgi. In line, inhibition of Golgi function, but not the depletion of Golgi-tethers or altered lysosomal acidity, abolishes keratinocyte differentiation and lysosome biogenesis. Thus, ER stress regulates lysosome biogenesis and keratinocyte differentiation to maintain epidermal homeostasis.