SIG1191 dose-response analysis of the human PPARγ (ligand-dependent transcription factor) activity was performed using INDIGO Biosciences’ luciferase reporter cells and compared to rosiglitasone as reference agonist ligand.
Isoprenylcysteine compounds that modulate the intracellular signal transduction activity of Gproteins have been shown to regulate the in vitro responses of inflammatory cells. Topical in vivo anti-inflammatory activity of the archetype of this class: N-acetyl-S-farnesylcysteine (AFC), was subsequently established leading to its use as a cosmetic ingredient in skin care products. We report here, a second generation IPC derivative of AFC, SIG1191 shows antiinflammatory activity in the TPA-induced pro-inflammatory cytokine production in primary human keratinocytes. SIG1191 also demonstrates anti-inflammatory properties in vitro reducing UVA-induced cytokines in cultured dermal fibroblasts. Furthermore, SIG1191 inhibits inflammatory mediator COX-2 gene expression in cultured skin equivalents. In addition to its anti-inflammatory properties, we present here that SIG1191 potentially targets skin hydration and aging by modulating Aquaporin-3 (AQP3) expression. Aquaporin-3 (AQP3) and Aquaporin-9 (AQP9) regulate osmotic balance as integral pore forming cell membrane proteins facilitating water, urea and glycerol transport across cell membranes. They are both constitutively expressed by keratinocytes at the basal layer of the epidermis and are thus involved in regulating skin hydration. AQP3 expression levels have also been shown to decrease in response to both UVB exposure and skin aging. Here, we report SIG1191 dosedependently stimulates AQP3 gene expression in both monolayer keratinocytes and 3D skin equivalent cultures. Results show that only AQP3 is dose-dependently increased by SIG1191, whereas AQP9 is not affected. Increase of AQP3 expression was independent of PPARγ activation. Altogether, these studies demonstrate SIG1191 is a novel cosmetic ingredient that can potentially provide skin hydration by increasing Aquaporin-3 and possesses anti-inflammatory properties to help protect the skin.
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Date of publication: 2015; Signum Dermalogix
Author information: José R. Fernández (1); Karl Rouzard (1); Michael Voronkov (1); Kristen L. Huber (1); Corey Webb (1); Jeffry B. Stock (2); Maxwell Stock (1); Joel S. Gordon (1); & Eduardo Pérez (1)
(1) Signum Dermalogix, 133 Wall Street, Princeton, NJ
(2) Princeton University, Department of Molecular Biology, Princeton, NJ