TY - JOUR
T1 - A Zingerone Analog, Acetyl Zingerone, Bolsters Matrisome Synthesis, Inhibits Matrix Metallopeptidases, and Represses IL-17A Target Gene Expression
AU - Swindell, William R.
AU - Bojanowski, Krzysztof
AU - Chaudhuri, Ratan K.
N1 - Funding Information:
The authors thank Stephanie Ma (Sunny Biodiscovery), Tony Chang, and Marsha Sintara (International Chemistry Testing, Milford, MA) for excellent technical assistance in carrying out experiments. Conceptualization: KB, RKC; Formal Analysis: WRS; Investigation: KB, RKC; Project Administration: RKC; Writing - Original Draft Preparation: WRS; Writing - Review and Editing: WRS, KB, RKC.
Publisher Copyright:
© 2019 The Authors
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jid.2019.07.715
DO - 10.1016/j.jid.2019.07.715
M3 - Article
C2 - 31465741
AN - SCOPUS:85074393984
SN - 0022-202X
VL - 140
SP - 602-614.e15
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 3
ER -