250 Combination of niacinamide, a tripeptide, and yeast extract show synergistic induction of autophagy and stress response biothemes in human epidermal keratinocytes

Abstract

Niacinamide (N, aka nicotinamide, Vitamin B3) has been used in skin care formulations for decades and clinically proven to improve skin’s surface barrier integrity, appearance of skin color, and topographical attributes. To improve N’s effectiveness, we screened for chemistries that would significantly increase protection against stress-induced processes when combined with N in in vitro models. Human hTERT keratinocytes were used to screen for inhibitors of UVB-induced PGE2 synthesis (15 mJ/cm2) and for inducers of autophagy. A hydrolyzed Saccharomyces cerevisiae yeast extract was found to reduce PGE2 levels by 63%. A tripeptide Val-Try-Val (VYV) was found to increase autophagy by 9% as measured by CytoID, an assay that measures autophagic flux in cells. Gene expression profiling was performed to identify potential additive or synergistic effects from the combination of N, VYV, and yeast extract on canonical biothemes under basal and UV-stressed conditions. hTERT keratinocytes were treated with N, VYV, and yeast extract alone and in combination for 18 hrs prior to stress by UVA/B (18/2 mJ/cm2) or unstressed conditions and processed for microarray chip analysis. Bioinformatic analyses identified the N, VYV, and yeast extract combination as inducing the highest number of differentially regulated probesets with the highest absolute fold change under basal and stressed conditions. Additionally, there was a synergistic activation of multiple autophagy-related pathways. Under non-stress conditions, the combination activated canonical pathways of epithelial junction/gap junction signaling and inhibited ER stress response. Under UV stress conditions, the combination showed inhibition of DNA damage and apoptosis of skin, as well as activation of fatty acid metabolism. In summary, we have identified a combination of N, VYV, and yeast extract that shows synergistic impact on stress associated pathways, including autophagy induction.