N-Acetylglutaminoyl-S-farnesyl-l-cysteine (SIG-1191): an anti-inflammatory molecule that increases the expression of the aquaglyceroporin, aquaporin-3, in human keratinocytes

Abstract

Isoprenylcysteine (IPC) small molecules were discovered as signal transduction modulating compounds ~25 years ago. More recently, IPC molecules have demonstrated antioxidant and anti-inflammatory properties in a variety of dermal cells as well as antimicrobial activity, representing a novel class of compounds to ameliorate skin conditions and disease. Here, we demonstrate a new IPC compound, N-acetylglutaminoyl-S-farnesyl-l-cysteine (SIG-1191), which inhibits UVB-induced inflammation blocking pro-inflammatory cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) production. To investigate further the previously reported hydrating potential of IPC compounds, SIG-1191 was tested for its ability to modulate aquaporin expression. Specifically, aquaporin 3 (AQP3) the most abundant aquaporin found in skin has been reported to play a key role in skin hydration, elasticity and barrier repair. Results show here for the first time that SIG-1191 increases AQP3 expression in both cultured normal human epidermal keratinocytes as well as when applied topically in a three-dimensional (3D) reconstructed human skin equivalent. Additionally, SIG-1191 dose dependently increased AQP3 protein levels, as determined by specific antibody staining, in the epidermis of the 3D skin equivalents. To begin to elucidate which signaling pathways SIG-1191 may be modulating to increase AQP3 levels, we used several pharmacological pathway inhibitors and determined that AQP3 expression is mediated by the Mitogen-activated protein kinase/Extracellular signal-regulated kinase kinase (MEK) pathway. Altogether, these data suggest SIG-1191 represents a new IPC derivative with anti-inflammatory activity that may also promote increased skin hydration based on its ability to increase AQP3 levels.

In Vitro and Clinical Evaluation of Cannabigerol (CBG) Produced via Yeast Biosynthesis: A Cannabinoid with a Broad Range of Anti-Inflammatory and Skin Health-Boosting Properties

“…For instance, a topical study applying a 1% CBD solution daily to hairless mice for 14 days was shown to improve skin moisturization [36]. The authors demonstrate that CBD upregulates aquaporin-3 (AQP3), the most abundant aquaporin found in skin shown to play a key role in water and glycerol transport, skin hydration, elasticity and barrier repair [37]. However, when TEWL measurements were taken, the 1% CBD solution did not have any significant effects.…”

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Induces Dry Skin via Decreased in Aquaporin-3 Expression

“…To date, various inflammatory cytokines are known to decrease the expression of AQPs. For example, TNF-α and IL-6 reportedly decrease the expression of AQP3 in epidermal keratinocytes [37,38]. Although erlotinib administration to mice did not cause skin inflammation, a significant decrease in AQP3 expression was noted ( Figure 1B).…”

N-Succinyl-S-Farnesyl-L-Cysteine (SFC): A Novel Isoprenylcysteine Analog with In Vitro Anti-Inflammatory Activity and Clinical Skin Protecting Properties

“…Several other farnesyl-cysteine derivatives have been reported to successfully inhibit inflammation and oxidative stress release [21]. Moreover, another farnesylated IPC molecule, SIG-1191, has been shown to possess anti-inflammatory activity in NHEKs, and potential moisturizing activity when topically applied to 3D human skin [10]. Altogether, these results highlight the potential for this class of compounds to be utilized to ameliorate skin conditions and/or treat skin disease.…”

“…Cosmetics 2021, 8, 110 2 of 11 (GPCR)-induced pro-inflammatory cytokine release, edema, and neutrophil infiltration when applied topically [9]. For instance, N-acetylglutaminoyl-S-farnesyl-L-cysteine (SIG-1191) demonstrates anti-inflammatory and hydration properties in human keratinocytes and human 3D skin [10]. More recent studies demonstrate that IPC analogs also downregulate non-G-protein mediated inflammation in human epidermal keratinocytes, human dermal fibroblasts, human dermal endothelial cells, and peripheral blood mononuclear cells by abrogating toll-like receptors 2, 4, and 6 (TLR2, TLR4, TLR6) and T-cell receptor (TCR) signaling [11,12].…”