Increased 1-Deoxysphingolipids and Skin BarrierDysfunction in the Skin of X-ray or Ultraviolet BIrradiation and Atopic Dermatitis Lesion Could BePrevented by Moisturizer with Physiological LipidMixture

Background@#Skin diseases characterized by epithelial barrierdysfunction show altered sphingolipid metabolism,which results in changes in the stratum corneum intercellularlipid components and structure. Under pathological conditions,1-deoxysphingolipids form as atypical sphingolipidsfrom de novo sphingolipid biosynthesis. @*Objective@#Thisstudy investigated the potential role of 1-deoxysphingolipidsin skin barrier dysfunction secondary to X-ray and ultravioletB (UVB) irradiation in vitro and in vivo. It was also evaluatedchanges in the expression of 1-deoxysphingolipids in lesionalhuman skin of atopic dermatitis. @*Methods@#In thisstudy, the changes in these 1-deoxysphingolipids levels ofskin and serum samples were investigated in skin barrier dysfunctionassociated with X-ray and UVB irradiation in vitroand in vivo. @*Results@#Increased 1-deoxysphingolipids were observed in cultured normal human epidermal keratinocytesafter X-ray irradiation. X-ray or UVB irradiation increased theproduction of 1-deoxysphingosine in a reconstituted 3-dimensional(3D) skin model. Interestingly, treatment with aphysiological lipid mixture (multi-lamellar emulsion containedpseudoceramide), which can strengthen the epidermalpermeability barrier function, resulted in decreased1-deoxysphingosine formation in a reconstituted 3D skinmodel. Further investigation using a hairless mouse modelshowed similar preventive effects of physiological lipid mixtureagainst 1-deoxysphingosine formation after X-ray irradiation.An increased level of 1-dexoysphingosine in the stratumcorneum was also observed in lesional skin of atopic dermatitis. @*Conclusion@#1-deoxysphingosine might be a novelbiomarker of skin barrier dysfunction and a physiological lipidmixture treatment could prevent 1-deoxysphingosine productionand consequent skin barrier dysfunction.

Aquatide Activation of SIRT1 Reduces Cellular Senescence through a SIRT1-FOXO1-Autophagy Axis

Ultraviolet (UV) irradiation is a relevant environment factor to induce cellular senescence and photoaging. Both autophagy- and silent information regulator T1 (SIRT1)-dependent pathways are critical cellular processes of not only maintaining normal cellular functions, but also protecting cellular senescence in skin exposed to UV irradiation. In the present studies, we investigated whether modulation of autophagy induction using a novel synthetic SIRT1 activator, heptasodium hexacarboxymethyl dipeptide-12 (named as Aquatide), suppresses the UVB irradiation-induced skin aging. Treatment with Aquatide directly activates SIRT1 and stimulates autophagy induction in cultured human dermal fibroblasts. Next, we found that Aquatide-mediated activation of SIRT1 increases autophagy induction via deacetylation of forkhead box class O (FOXO) 1. Finally, UVB irradiation-induced cellular senescence measured by SA-β-gal staining was significantly decreased in cells treated with Aquatide in parallel to occurring SIRT1 activation-dependent autophagy. Together, Aquatide modulates autophagy through SIRT1 activation, contributing to suppression of skin aging caused by UV irradiation.

Vitamin C Stimulates Epidermal Ceramide Production by Regulating Its Metabolic Enzymes

Ceramide is the most abundant lipid in the epidermis and plays a critical role in maintaining epidermal barrier function. Overall ceramide content in keratinocyte increases in parallel with differentiation, which is initiated by supplementation of calcium and/or vitamin C. However, the role of metabolic enzymes responsible for ceramide generation in response to vitamin C is still unclear. Here, we investigated whether vitamin C alters epidermal ceramide content by regulating the expression and/or activity of its metabolic enzymes. When human keratinocytes were grown in 1.2 mM calcium with vitamin C (50 mug/ml) for 11 days, bulk ceramide content significantly increased in conjunction with terminal differentiation of keratinocytes as compared to vehicle controls (1.2 mM calcium alone). Synthesis of the ceramide fractions was enhanced by increased de novo ceramide synthesis pathway via serine palmitoyltransferase and ceramide synthase activations. Moreover, sphingosine-1-phosphate (S1P) hydrolysis pathway by action of S1P phosphatase was also stimulated by vitamin C supplementation, contributing, in part, to enhanced ceramide production. However, activity of sphingomyelinase, a hydrolase enzyme that converts sphingomyelin to ceramide, remained unaltered. Taken together, we demonstrate that vitamin C stimulates ceramide production in keratinocytes by modulating ceramide metabolic-related enzymes, and as a result, could improve overall epidermal barrier function.