Activation of Nrf2 Reduces UVA-Mediated MMP-1 Upregulation via MAPK/AP-1 Signaling Cascades: The Photoprotective Effects of Sulforaphane and Hispidulin

Abstract

UVA irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds that can activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant gene expression, should therefore serve as effective antiphotoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling using human keratinocyte cell line (HaCaT). Antiphotoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38), c-Jun, and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA-induced MMP-1 and AP-1 activities. Moreover, pretreatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA-mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun, and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising antiphotoaging candidates.

Grape Peel Extract and Resveratrol Inhibit Wrinkle Formation in Mice Model Through Activation of Nrf2/HO‐1 Signaling Pathway

“…Considering that NF‐κB partially upregulates MMP‐1 and ‐9 (Fanjul‐Fernandez, Folgueras, Cabrera, & Lopez‐Otin, ), resveratrol could exert anti‐wrinkle effect through activation of Nrf2 signaling pathway which antagonizes NF‐κB signaling. In addition, it is worthwhile to study the crosstalk between AP1 and Nrf2 signaling pathway to better understand the anti‐wrinkle mechanism of Nrf2 activators as the transcriptional regulation of MMP‐1 is mediated by activation of activator protein‐1 (AP‐1) and its upstream mitogen‐activated protein kinase signaling pathway (Chaiprasongsuk et al., ). Currently existing evidence also suggest that resveratrol behaves as an inhibitor of inflammation which is associated with photoaging and wrinkle formation (Kundu, Shin, & Surh, ).…”

“…Although it is not clear yet how Nrf2 and MMPs are regulated in opposite ways, Nrf2 suppresses the upregulation of MMPs most presumably by scavenging ROS (Chaiprasongsuk et al, 2017). In addition, NF-κB/p65 was reported to antagonize Nrf2 signaling pathway by depriving CREB binding protein (CBP) from Nrf2 (Liu, Qu, & Shen, 2008).…”

Thai herbal antipyretic 22 formula (APF22) inhibits UVA‐mediated melanogenesis through activation of Nrf2‐regulated antioxidant defense

“…We previously reported that the extracts of the APF22 and its components provided inhibitory effects on UVA-stimulated matrix metalloproteinase-1 (MMP-1) in correlation to their antioxidant actions in keratinocyte HaCaT cells . Moreover, GA (Panich, Onkoksoong, Limsaengurai, Akarasereenont, & Wongkajornsilp, 2012), FA, quercetin (Chaiprasongsuk, Onkoksoong, Pluemsamran, Limsaengurai, & Panich, 2016), and hispidulin (Chaiprasongsuk et al, 2017), which could be active constituents isolated from the APF22 formula, were demonstrated to have abilities to suppress UVA-induced melanogenesis in our previous in vitro and in vivo studies.…”

Protective effect of sucupira oil nanoemulsion against oxidative stress in UVA-irradiated HaCaT cells

“…Regarding the response to intracellular ROS generation, the Nrf2 is a key transcription factor activated in response to alterations in cell redox status, which promotes expression of several genes related to antioxidant defence mechanisms . Therefore, cosmetic products that trigger this pathway activation are considered promising as protective against photoageing and UVA‐induced skin damage processes . In the present study, sucupira NE did not modulate this pathway, although a significant decrease of intracellular oxidative stress was observed in NE treated groups (Figure ).…”

“…[47,48] Therefore, cosmetic products that trigger this pathway activation are considered promising as protective against photoageing and UVA-induced skin damage processes. [49,50] In the present study, sucupira NE did not modulate this pathway, although a significant decrease of intracellular oxidative stress was observed in NE treated groups (Figure 8). We thus hypothesize that this effect is associated with direct ROS neutralization by sucupira oil phytoconstituents, as already reported by other authors.…”