Abstract
Environmental stimuli attack the skin daily resulting in the generation of reactive oxygen species (ROS) and inflammation. One pathway that regulates oxidative stress in skin involves Protein Phosphatase 2A (PP2A), a phosphatase which has been previously linked to Alzheimer’s Disease and aging. Oxidative stress decreases PP2A methylation in normal human dermal fibroblasts (NHDFs). Thus, we hypothesize agents that increase PP2A methylation and activity will promote skin health and combat aging. To discover novel inhibitors of PP2A demethylation activity, we screened a library of 32 natural botanical extracts. We discovered Grape Seed Extract (GSE), which has previously been reported to have several benefits for skin, to be the most potent PP2A demethylating extract. Via several fractionation and extraction steps we developed a novel grape seed extract called Activated Grape Seed Extract (AGSE), which is enriched for PP2A activating flavonoids that increase potency in preventing PP2A demethylation when compared to commercial GSE. We then determined that 1% AGSE and 1% commercial GSE exhibit distinct gene expression profiles when topically applied to a 3D human skin model. To begin to characterize AGSE’s activity, we investigated its antioxidant potential and demonstrate it reduces ROS levels in NHDFs and cell-free assays equal to or better than Vitamin C and E. Moreover, AGSE shows anti-inflammatory properties, dose-dependently inhibiting UVA, UVB and chemical-induced inflammation. These results demonstrate AGSE is a novel, multi-functional extract that modulates methylation levels of PP2A and supports the hypothesis of PP2A as a master regulator for oxidative stress signaling and aging in skin.
Highlights
Introduction published maps and institutional affilProtein phosphatase 2A (PP2A) is a heterotrimeric protein comprised of A,C and B subunits
By studying and characterizing coffee, we demonstrated that eicosanoyl-5-hydroxytryptamide (EHT) and coffee extracts enriched for this molecule and other bioactive tryptamides elevate PP2A methylation levels and activity resulting in protection from several diseases of aging such as Alzheimer’s [11,12] and Parkinson’s disease [11,13,14] in in vivo models
We evaluated ethanolic extracts produced from the seed, fruit, bark, leaves, and root compartments of 32 different botanicals (Table 1)
Summary
Levels of phytochemical abundance can vary across different regions of the plant For this reason, we evaluated ethanolic extracts produced from the seed, fruit, bark, leaves, and root compartments of 32 different botanicals (Table 1). Extracts generated from the seeds of grape, fennel and red raspberry exhibited the highest potencies overall with IC50 values of 0.4, 1, and 1 μg/mL, respectively. To the best of our knowledge, no reports far currently link grape, fennel, and/or red raspberry seed extracts to boosting PP2A methylation levels by inhibiting its demethylation. Due to its potency against PP2A demethylation and widely valued research on additional beneficial properties, we sought to evaluate individual components of the grape seed extract which is rich in polyphenols and flavonoids [20,21,22,23].
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