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Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon and ubiquitous environmental toxin with known harmful effects to human health. Abnormal phenotypes of keratinocytes are closely associated with their exposure to B[a]P. Resorcinol is a component of argan oil with reported anticancer activities, but its mechanism of action and potential effect on B[a]P damage to the skin is unknown. In this study, we investigated the effects of resorcinol on B[a]P-induced abnormal keratinocyte biology and its mechanisms of action in human epidermal keratinocyte cell line HaCaT. Resorcinol suppressed aryl hydrocarbon receptor (AhR) activity as evidenced by the inhibition of B[a]P-induced xenobiotic response element (XRE)-reporter activation and cytochrome P450 1A1 (CYP1A1) expression. In addition, resorcinol attenuated B[a]P-induced nuclear translocation of AhR, and production of ROS and pro-inflammatory cytokines. We also found that resorcinol increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activity. Antioxidant response element (ARE)-reporter activity and expression of ARE-dependent genes NAD(P)H dehydrogenase [quinone] 1 (NQO1), heme oxygenase-1 (HO-1) were increased by resorcinol. Consistently, resorcinol treatment induced nuclear localization of Nrf2 as seen by Western analysis. Knockdown of Nrf2 attenuated the resorcinol effects on ARE signaling, but knockdown of AhR did not affect resorcinol activation of Nrf2. This suggests that activation of antioxidant activity by resorcinol is not mediated by AhR. These results indicate that resorcinol is protective against effects of B[a]P exposure. The mechanism of action of resorcinol is inhibition of AhR and activation of Nrf2-mediated antioxidant signaling. Our findings suggest that resorcinol may have potential as a protective agent against B[a]P-containing pollutants.

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA.

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA.

Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon formed during the incomplete combustion of organic matter, has harmful effects. Therefore, much research is ongoing to develop agents that can mitigate the effects of B[a]P. The aim of this study was to examine the effect of maclurin, one component of the branches of Morus alba L., on the B[a]P-induced effects in HaCaT cells, a human keratinocyte cell line. Maclurin treatment inhibited aryl hydrocarbon receptor (AHR) signaling as evidenced by reduced xenobiotic response element (XRE) reporter activity, decreased expression of cytochrome P450 1A1 (CYP1A1), and reduced nuclear translocation of AHR. The B[a]P-induced dissociation of AHR from AHR-interacting protein (AIP) was suppressed by maclurin. Maclurin also inhibited the production of intracellular reactive oxygen species (ROS) induced by B[a]P. In addition, the antioxidant property of maclurin itself was demonstrated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Furthermore, maclurin activated antioxidant response element (ARE) signaling through enhancement of ARE luciferase reporter activity and the expression of ARE-dependent genes including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). Nrf2 activation and its nuclear translocation were promoted by maclurin through p38 MAPK activation. These data indicate that maclurin had antagonistic activity against B[a]P effects through activation of Nrf2-mediated signaling and inhibition of AHR signaling and, suggesting its potential in protecting from harmful B[a]P-containing pollutants.

While harmful effects of blue light on skin cells have been recently reported, there are few studies regarding natural products that alleviate its negative effects. Therefore, we investigated ameliorating effects of yellow chaste weed (YCW) (Helichrysum arenarium) extract and its components, apigenin and galangin, on blue light-irradiated HaCaT cells. In this study, we found that YCW extract improved the reduced proliferation of HaCaT cells induced by blue light-irradiation and reduced blue light-induced production of reactive oxygen species (ROS) levels. We also found that apigenin and galangin, the main components of YCW extract, showed the same activities as YCW extract. In experiments examining molecular mechanisms of YCW extract and its components such as apigenin and galangin, they all reduced expression of transient receptor potential vanilloid member 1 (TRPV1), its phosphorylation, and calcium ion (Ca2+) influx induced by blue light irradiation. In addition, apigenin and galangin regulated phosphorylation of mitogen-activated protein kinases (MAPKs). They also reduced phosphorylation of mammalian sterile 20-like kinase-1/2 (MST-1/2), inducing phosphorylation of Akt (protein kinase B), one downstream molecule of MST-1/2. Moreover, apigenin and galangin promoted translocation of Forkhead box O3 (FoxO3a) from the nucleus to the cytosol by phosphorylating FoxO3a. Besides, apigenin and galangin interrupted blue light influences on expression of nuclear and secretory clusterin. Namely, they attenuated both upregulation of nuclear clusterin and downregulation of secretory clusterin induced by blue light irradiation. We also found that they downregulated apoptotic protein Bcl-2 associated X protein (Bax) and conversely upregulated anti-apoptotic protein B-cell lymphoma 2 (Bcl-2). Collectively, these findings indicate that YCW extract and its components, apigenin and galangin, antagonize the blue light-induced damage to the keratinocytes by regulating TRPV1/clusterin/FoxO3a and MAPK signaling.

Although blue light has been reported to affect skin cells negatively, little is known about its action mechanisms in skin cells. Therefore, we investigated the role of the transient receptor potential vanilloid 1 (TRPV1) in blue light-induced effects on human keratinocytes and its underlying mechanisms. Blue light decreased cell proliferation and upregulated TRPV1 expression. Blue light also suppressed the epidermal growth factor receptor- (EGFR-) mediated signaling pathway by reducing the protein levels of EGFR and suppressing the EGFR/PI3K/AKT/GSK3β/FoxO3a pathway. The blue light-induced effect in cell proliferation was reversed by TRPV1 siRNA, but not capsazepine, a TRPV1-specific antagonist. In addition, blue light irradiation increased the production of reactive oxygen species (ROS) and tumor necrosis factor-α (TNF-α). Blue light irradiation also increased both phosphorylation levels of TRPV1 and calcium influx. The blue light-induced increase in production of ROS and TNF-α was reversed by capsazepine. Furthermore, the blue light-induced increase in production of TNF-α was attenuated by SP600125 or PDTC. These findings show that blue light regulates cell survival and production of ROS and TNF-α; its effects are mediated via TRPV1. Specifically, the effects of blue light on cell proliferation are mediated by upregulating TRPV1, a negative regulator of EGFR-FoxO3a signaling. Blue light-induced production of ROS and TNF-α is also mediated through increased calcium influx via TRPV1 activation.