A Zingerone Analog, Acetyl Zingerone, Bolsters Matrisome Synthesis, Inhibits Matrix Metallopeptidases, and Represses IL-17A Target Gene Expression

Abstract

Zingerone (Z) is a phenolic alkanone derived from natural sources with anti-inflammatory and antioxidant effects. Acetyl zingerone (AZ) is a recently designed molecule that shares structural features with Z but is expected to have improved stability and antioxidant function. This study utilized microarrays to compare the effects of Z and AZ on gene expression in reconstituted human epidermis. Both Z and AZ increased Notch pathway gene expression (NOTCH1 and MAML3) and decreased expression of genes linked to extracellular matrix disassembly (MMP3 and CTSV) and reactive oxygen species metabolism (PMAIP1 and ARG2). Although Z and AZ each inhibited in vitro matrix metallopeptidase (MMP)-1, MMP-3, and MMP-12 activity, inhibition of MMP-3 and MMP-12 was greater with AZ. Moreover, AZ led to more consistent increases in the expression of genes encoding collagens (COL11A2), proteoglycans (VCAN), and extracellular matrix glycoproteins (SPARC). Finally, AZ opposed gene expression patterns associated with fibroblast senescence, keratinocyte differentiation, and IL-17A stimulation. These effects were AZ-specific and not replicated by Z. These results show that AZ improves extracellular matrix integrity with retinoid-like effects on differentiation and inflammation. Our findings provide a rationale for clinical studies to understand the benefits of AZ in the treatment or prevention of skin aging, or potentially, as a treatment for other human skin diseases.

Randomized double‐blind vehicle controlled study of the effects of topical acetyl zingerone on photoaging

“…24 Although the exact mechanism of action of AZ on the skin is still under investigation, genomic analysis of AZ effects on fibroblasts shows support of collagen synthesis and inhibition of collagen breakdown enzymes such as the matrix metalloproteinases. 26 The in vitro findings further support the cosmetic findings in our clinical study.…”

CTSV (cathepsin V) promotes bladder cancer progression by increasing NF-κB activity

“…Indeed, Anti-CTSV treatment has anti-inflammation effect in the thoracic aorta of hyperhomocysteinemia mice [ 52 ]. CTSV expression is associated with IL-17A stimulation, which is pro-inflammatory [ 53 ]. The NF-κB pathway links inflammation to cancers [ 54 , 55 ].…”

A hybrid systems biology and systems pharmacology investigation of Zingerone’s effects on reconstructed human epidermal tissues

“…Exercising could also affect interleukin-15 levels, thus preventing skin aging [ 59 ]. Interleukin 17 (or IL-17A) has a direct relationship with the stimulation of IL-23, making them a golden IL-23/IL-17 axis in age-associated inflammation and attenuates skin aging via acetyl Zingerone treatment through IL-17A stimulation [ 60 , 61 ].…”