In vitro and clinical evaluation of SIG1273: a cosmetic functional ingredient with a broad spectrum of anti‐aging and antioxidant activities

Abstract

SummaryBackground Isoprenylcysteine (IPC) small molecules were identified as a new class of anti-inflammatory compounds over 20 years ago. Since then, they have been developed as novel cosmetic functional ingredients (CFI) and topical drug candidates. SIG1273 is a second generation CFI that has previously been shown to provide a broad spectrum of benefits for the skin through its anti-inflammatory and antimicrobial properties. Objective To determine whether SIG1273 possesses anti-aging properties in vitro and evaluate the tolerability and activity of SIG1273 when applied topically to human subjects. Methods To model photoaging in vitro, human dermal fibroblasts (HDFs) were exposed in culture to UVA to induce collagenase (MMP-1) production. An in vitro woundhealing model was based on the activation of HDF migration into cell-free tissue culture surface. Hydrogen peroxide-induced oxidative stress was performed using HDFs to measure intracellular ROS activity. Radical scavenging capacity was determined using a colorimetric antioxidant assay kit (ABTS method). Lastly, a 4-week, 29-subject study was performed in which SIG1273 was applied topically as a cream to assess its tolerance and activity in reducing the appearance of aging.Results In vitro studies demonstrate SIG1273 inhibits UVA-induced MMP-1 production, hydrogen peroxide-induced oxidative stress and promotes wound healing. Moreover, SIG1273 was shown to be a radical scavenging antioxidant. Clinical assessment of SIG1273 cream (0.25%) showed it was well tolerated with significant improvement in the appearance of fine lines, coarse wrinkles, radiance/luminosity, pore size, texture/smoothness, hydration and increased firmness. Conclusions SIG1273 represents a novel CFI with antioxidant, anti-aging, and antiinflammatory properties that when applied topically is well tolerated and provides benefits to individuals with aging skin.

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

“…1a) in which a glutamine is thioacetylated to the cysteine residue possesses anti-inflammatory properties by inhibiting UV-induced pro-inflammatory mediators in human keratinocytes, similar to previous IPC compounds [15, 16]. Furthermore, we demonstrate for the first time that SIG-1191 upregulates AQP3 gene expression in monolayer keratinocytes and both gene expression and protein production in reconstructed three-dimensional human skin cultured at the air–liquid interface.…”

“…UVB exposure damages skin water barrier function as determined by increased transepidermal water loss (TEWL) [ 24 ] and potentially downregulation of AQPs [ 26 ]. Since IPC compounds have been shown to improve hydration and skin firmness in a clinical study [ 16 ], we sought to determine if SIG-1191 could modulate the expression of human skin epidermal aquaporins (AQP3, AQP9). To investigate aquaporin gene expression activity, NHEK cells were treated with the indicated concentrations of SIG-1191 in media for 24 h. After incubation, cells were collected and gene expression was assessed by quantitative PCR (qPCR).…”

“…Interestingly, the water loss prevention of the stratum corneum is linked to the specific expression of AQP3 between the dermis and basal layers of the epidermis, thus operating as a “water-clamp” to prevent water loss gradient from the dermis to the stratum corneum [ 47 ]. Since we have previously demonstrated that IPCs enhance skin hydration in human use studies [ 16 ] we utilized SIG-1191 to elucidate the possible molecular basis for this enhancement of skin hydration. To this end, we selected AQP3 and AQP9 as initial targets.…”

“…IPC analogs have been initially identified as a novel class of topical anti-inflammatory compounds [ 15 , 16 , 19 ]. In vitro studies have shown IPC compounds to be effective down modulators of inflammatory responses in platelets, macrophages and neutrophils [ 25 , 30 , 41 , 50 ].…”

“…Furthermore, IPC analogs have also been shown to inhibit ultraviolet A (UVA), ultraviolet B (UVB), phorbol 12-myristate 13-acetate (TPA) and bacteria-induced pro-inflammatory cytokine release [ 14 , 15 , 19 ] in skin cells, highlighting the effectiveness of this class of compounds in blocking cutaneous inflammation. Interestingly, we have also shown that in a human use study, IPCs have the potential to enhance skin hydration [ 16 ].…”