Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Abstract

A number of natural phytochemicals have anti‐photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase‐1 (MMP‐1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB‐induced MMP‐1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3‐dimensional (3‐D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm2) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB‐induced MMP‐1 expression and AP‐1 activity, and strongly suppressed UVB‐induced phosphorylation of Fos‐related antigen (FRA)‐1 at Ser265. Importantly, UVB irradiation‐induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen‐activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB‐induced extracellular signal‐regulated kinase 2 (ERK2) activity and subsequently attenuated UVB‐induced phosphorylation of p90RSK by competitively binding with ATP. Constitutively active MEK (CA‐MEK) increased FRA1 phosphorylation and expression and also induced MMP‐1 expression, whereas dominant‐negative ERK2 (DN‐ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP‐1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB‐induced wrinkle formation, trans‐epidermal water loss and MMP‐13 expression. Naringenin exerts potent anti‐photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down‐regulation of AP‐1 transactivation and MMP‐1 expression.

Gold lotion from citrus peel extract ameliorates imiquimod‐induced psoriasis‐like dermatitis in murine

“…Gold lotion (GL), a formulated product extracted from the peels of six citrus fruits (navel oranges, Citrus hassaku , Citrus limon , Citrus natsudaidai , Citrus miyauchi Iyo and Satsuma), has been developed in Japan. GL contains various flavonoids that have potential to protect the skin against UV‐induced damage and aging . In addition to skin protection, GL has also been demonstrated to suppress azoxymethane‐induced aberrant crypt foci formation in mice by downregulating inflammation‐related protein levels that may subsequently prevent inflammation‐associated colon tumorigenesis .…”

Inhibitory effect of naringenin via IL‐13 level regulation on thymic stromal lymphopoietin‐induced inflammatory reactions

“…48,49 NG inhibited UVB-induced ERK2 activity by binding to ERK2 and had anti-aging effects. 49 NG bound to phosphoinositide 3-kinase, increased phosphoinositide 3-kinase inhibition activity, and had anti-cancer effects. 50 Thus, we speculate that the regulatory effects of NG would be the results of its binding to various receptors or intracellular signalling molecules.…”

“…Immunosuppressive activity of NG was regulated by its direct interaction with the ligand‐binding site of aryl hydrocarbon receptor . NG was also found to enter cells, interact with intracellular signalling molecules, and thus, regulate signalling . NG inhibited UVB‐induced ERK2 activity by binding to ERK2 and had anti‐aging effects .…”

“…NG was also found to enter cells, interact with intracellular signalling molecules, and thus, regulate signalling . NG inhibited UVB‐induced ERK2 activity by binding to ERK2 and had anti‐aging effects . NG bound to phosphoinositide 3‐kinase, increased phosphoinositide 3‐kinase inhibition activity, and had anti‐cancer effects .…”

Pterocarpus santalinus L. Regulated Ultraviolet B Irradiation‐induced Procollagen Reduction and Matrix Metalloproteinases Expression Through Activation of TGF‐β/Smad and Inhibition of the MAPK/AP‐1 Pathway in Normal Human Dermal Fibroblasts

“…In 2015, Jung et al . reported that naringenin suppressed UVB‐induced MMP‐1 expression via ERK/AP‐1 signaling pathway in keratinocytes. Similarly, our results also suggested that treatment of naringenin quenched the UVB irradiation‐induced increase of MMP‐1 mRNA in fibroblasts.…”