Ultraviolet Radiation Biological and Medical Implications.

Ultraviolet (UV) radiation plays a crucial role in the development of melanoma and non-melanoma skin cancers. The types of UV radiation are differentiated by wavelength: UVA (315 to 400 nm), UVB (280 to 320 nm), and UVC (100 to 280 nm). UV radiation can cause direct DNA damage in the forms of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). In addition, UV radiation can also cause DNA damage indirectly through photosensitization reactions caused by reactive oxygen species (ROS), which manifest as 8-hydroxy-2'-deoxyguanine (8-OHdG). Both direct and indirect DNA damage can lead to mutations in genes that promote the development of skin cancers. The development of melanoma is largely influenced by the signaling of the melanocortin one receptor (MC1R), which plays an essential role in the synthesis of melanin in the skin. UV-induced mutations in the BRAF and NRAS genes are also significant risk factors in melanoma development. UV radiation plays a significant role in basal cell carcinoma (BCC) development by causing mutations in the Hedgehog (Hh) pathway, which dysregulates cell proliferation and survival. UV radiation can also induce the development of squamous cell carcinoma via mutations in the TP53 gene and upregulation of MMPs in the stroma layer of the skin.

Amaranthus cruentus L. Seed Oil Counteracts UVA-Radiation-Induced Inhibition of Collagen Biosynthesis and Wound Healing in Human Skin Fibroblasts.

The effect of Amaranthus cruentus L. seed oil (AmO) on collagen biosynthesis and wound healing was studied in cultured human dermal fibroblasts exposed to UVA radiation. It was found that UVA radiation inhibited collagen biosynthesis, prolidase activity, and expression of the ß1-integrin receptor, and phosphorylated ERK1/2 and TGF-ß, while increasing the expression of p38 kinase. The AmO at 0.05-0.15% counteracted the above effects induced by UVA radiation in fibroblasts. UVA radiation also induced the expression and nuclear translocation of the pro-inflammatory NF-κB factor and enhanced the COX-2 expression. AmO effectively suppressed the expression of these pro-inflammatory factors induced by UVA radiation. Expressions of ß1 integrin and IGF-I receptors were decreased in the fibroblasts exposed to UVA radiation, while AmO counteracted the effects. Furthermore, AmO stimulated the fibroblast's migration in a wound healing model, thus facilitating the repair process following exposure of fibroblasts to UVA radiation. These data suggest the potential of AmO to counteract UVA-induced skin damage.

Discussion Abounds on the Potential Carcinogenic Risks Associated With the Use of UV Curing Lamps for Permanent Nail Polish.

BACKGROUND: Controversy has recently broken out over the potential carcinogenic risk associated with exposure to UV lamps for permanent nail polish. The new LED-based polymerization devices, and their potential biological effect has not been analyzed to this date. OBJECTIVE: To evaluate the emission power and its potential biological effects on the skin of 2 types of UV LED and fluorescent curing lamps under normal use conditions compared to doses of sunlight exposure. MATERIAL AND METHODS: The emission spectrum (290nm to 450nm) of curing lamps and the Sun at noon on an average summer day in mid-latitude Spain was analyzed. The effective biological irradiance potential for erythema, non-melanoma skin cancer, DNA damage, photoimmunosuppression and permanent pigmentation was also characterized. RESULTS: The high-energy UVA-visible irradiance emitted by these devices was similar to the one coming from the Sun in that spectral range while the effective biological doses were lower or similar to those also coming from the Sun. The total UV and high-energy visible dose per manicure session corresponded to that obtained from 3.5min to 6min exposures to the Sun at noon in the summer days at our latitudes. CONCLUSIONS: The exposure times and doses received with the common use of artificial lamp nail drying correspond to sunlight exposures of 3min to 5min in the central hours of the day. This represents a very low carcinogenic potential compared to sunlight exposure, although similar regarding immunosuppressive potential. Photoprotective measures would further minimize the risks.

The Assessment of the Phototoxic Action of Chlortetracycline and Doxycycline as a Potential Treatment of Melanotic Melanoma-Biochemical and Molecular Studies on COLO 829 and G-361 Cell Lines.

Melanoma is still one of the most dangerous cancers. New methods of treatment are sought due to its high aggressiveness and the relatively low effectiveness of therapies. Tetracyclines are drugs exhibiting anticancer activity. Previous studies have also shown their activity against melanoma cells. The possibility of tetracycline accumulation in pigmented tissues and the increase in their toxicity under the influence of UVA radiation creates the possibility of developing a new anti-melanoma therapy. This study aimed to analyze the phototoxic effect of doxycycline and chlortetracycline on melanotic melanoma cells COLO 829 and G-361. The results indicated that tetracycline-induced phototoxicity significantly decreased the number of live cells by cell cycle arrest as well as a decrease in cell viability. The simultaneous exposure of cells to drugs and UVA caused the depolarization of mitochondria as well as inducing oxidative stress and apoptosis. It was found that the combined treatment activated initiator and effector caspases, caused DNA fragmentation and elevated p53 level. Finally, it was concluded that doxycycline demonstrated a stronger cytotoxic and phototoxic effect. UVA irradiation of melanoma cells treated with doxycycline and chlortetracycline allows for the reduction of therapeutic drug concentrations and increases the effectiveness of tested tetracyclines.

Protective Effect of Amaranthus cruentus L. Seed Oil on UVA-Radiation-Induced Apoptosis in Human Skin Fibroblasts.

Since the exposure of fibroblasts to prolonged UVA radiation induces oxidative stress and apoptosis, there is a need for effective skin protection compounds with cytoprotective and antioxidant properties. One of their sources is Amaranthus cruentus L. seed oil (AmO), which is rich in unsaturated fatty acids, squalene, vitamin E derivatives and phytosterols. The aim of this study was to evaluate whether AmO evokes a protective effect on the apoptosis induced by UVA radiation in human skin fibroblasts. UVA radiation at an applied dose of 10 J/cm2 caused a significant reduction in the survival of human skin fibroblasts and directed them into the apoptosis pathway. Increased expression of p53, caspase-3, caspase-9 and PARP proteins in UVA-treated fibroblasts suggests the intrinsic mechanism of apoptosis. Application of the oil at 0.1% and 0.15% concentrations to UVA-treated cells decreased the expression of these proteins, which was accompanied by increased cell survival. Similarly, the UVA-dependent decrease in the expression of p-Akt and mTOR proteins was restored under the effect of the studied oil. The molecular mechanism of this phenomenon was related to the stimulation of antioxidant processes through the activation of Nrf2. This suggests that AmO stimulated the antioxidant system in fibroblasts, preventing the effects of UVA-induced oxidative stress, which may lead to pharmaceutical and cosmetological applications as a sun-protective substance.

UVA as environmental signal for alginate production in Pseudomonas aeruginosa: role of this polysaccharide in the protection of planktonic cells and biofilms against lethal UVA doses.

Pseudomonas aeruginosa is an extremely versatile microorganism that survives in a wide variety of niches. It is capable to respond rapidly to changes in the environment by producing secondary metabolites and virulence factors, including alginate. Alginate is an extracellular polysaccharide that protects the bacteria from antibiotics and oxidative agents, and enhances cell adhesion to solid surfaces in the process of biofilm formation. In the present study, we analyzed the role of alginate in the response of P. aeruginosa to lethal doses of ultraviolet-A (UVA) radiation, the major fraction of solar UV radiation reaching the Earth's surface. We also studied the role of alginate in the context of the adaptive responses generated when P. aeruginosa is exposed to sublethal doses of UVA radiation. The survival studies demonstrated that alginate has a key role in the resistance of P. aeruginosa to the oxidative stress generated by lethal UVA doses, both in planktonic cells and in static biofilms. In addition, the presence of alginate proved to be essential in the occurrence of adaptive responses such as induction of biofilm formation and cross-protection against hydrogen peroxide and sodium hypochlorite, both generated by exposure to low UVA doses. Finally, we demonstrated that the increase of biofilm formation is accompanied by an increase in alginate concentration in the biofilm matrix, possibly through the ppGpp-dependent induction of genes related to alginate regulation (algR and algU) and biosynthesis (algD operon). Given the importance of alginate in biofilm formation and its protective roles, better understanding of the mechanisms associated to its functions and synthesis is relevant, given the normal exposure of P. aeruginosa to UVA radiation and other types of oxidative stresses.

Effect of the flavonoids quercetin and taxifolin on UVA-induced damage to human primary skin keratinocytes and fibroblasts.

The ultraviolet (UV) part of solar radiation can permanently affect skin tissue. UVA photons represent the most abundant UV component and stimulate the formation of intracellular reactive oxygen species (ROS), leading to oxidative damage to various biomolecules. Several plant-derived polyphenols are known as effective photoprotective agents. This study evaluated the potential of quercetin (QE) and its structurally related flavonoid taxifolin (TA) to reduce UVA-caused damage to human primary dermal fibroblasts (NHDF) and epidermal keratinocytes (NHEK) obtained from identical donors. Cells pre-treated with QE or TA (1 h) were then exposed to UVA light using a solar simulator. Both flavonoids effectively prevented oxidative damage, such as ROS generation, glutathione depletion, single-strand breaks formation and caspase-3 activation in NHDF. These protective effects were accompanied by stimulation of Nrf2 nuclear translocation, found in non-irradiated and irradiated NHDF and NHEK, and expression of antioxidant proteins, such as heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and catalase. For most parameters, QE was more potent than TA. On the other hand, TA demonstrated protection within the whole concentration range, while QE lost its protective ability at the highest concentration tested (75 µM), suggesting its pro-oxidative potential. In summary, QE and TA demonstrated UVA-protective properties in NHEK and NHDF obtained from identical donors. However, due to the in vitro phototoxic potential of QE, published elsewhere and discussed herein, further studies are needed to evaluate QE safety in dermatological application for humans as well as to confirm our results on human skin ex vivo and in clinical trials.

Chlorogenic Acid Prevents UVA-Induced Skin Photoaging through Regulating Collagen Metabolism and Apoptosis in Human Dermal Fibroblasts.

Skin aging is categorized as chronological aging and photo-aging that affected by intrinsic and extrinsic factors. The present study aimed to investigate the anti-aging ability and its underlying mechanism of chlorogenic acid (CGA) on human dermal fibroblasts (HDFs). In this study, CGA specifically up-regulated collagen I (Col1) mRNA and protein expressions and increased the collagen secretion in the supernatant of HDFs without affecting the cell viability, the latter was also demonstrated in BioMAP HDF3CGF system. Under ultraviolet A (UVA)-induced photoaging, CGA regulated collagen metabolism by increasing Col1 expression and decreasing matrix metalloproteinase 1 (MMP1) and MMP3 levels in UVA-irradiated HDFs. The activation of transforming growth factor-ß (TGF-ß)-mediated Smad2/3 molecules, which is crucial in Col1 synthesis, was suppressed by UVA irradiation and but enhanced at the presence of CGA. In addition, CGA reduced the accumulation of UVA-induced reactive oxygen species (ROS), attenuated the DNA damage and promoted cell repair, resulting in reducing the apoptosis of UVA-irradiated HDFs. In conclusion, our study, for the first time, demonstrate that CGA has protective effects during skin photoaging, especially triggered by UVA-irradiation, and provide rationales for further investigation of CGA being used to prevent or treat skin aging.

Ketoprofen Combined with UVA Irradiation Exerts Higher Selectivity in the Mode of Action against Melanotic Melanoma Cells than against Normal Human Melanocytes.

Malignant melanoma is responsible for the majority of skin cancer-related deaths. The methods of cancer treatment include surgical removal, chemotherapy, immunotherapy, and targeted therapy. However, neither of these methods gives satisfactory results. Therefore, the development of new anticancer therapeutic strategies is very important and may extend the life span of people suffering from melanoma. The aim of this study was to examine the effect of ketoprofen (KTP) and UVA radiation (UVAR) therapy on cell proliferation, apoptosis, and cell cycle distribution in both melanotic melanoma cells (COLO829) and human melanocytes (HEMn-DP) in relation to its supportive effect in the treatment of melanoma. The therapy combining the use of pre-incubation with KTP and UVAR causes a significant increase in the anti-proliferative properties of ketoprofen towards melanoma cells and the co-exposure of melanotic melanoma cells induced apoptosis shown as the mitochondrial membrane breakdown, cell-cycle deregulation, and DNA fragmentation. Moreover, co-treatment led to GSH depletion showing its pro-apoptotic effect dependent on ROS overproduction. The treatment did not show a significant effect on normal cells-melanocytes-which indicates its high selectivity. The results suggest a possible benefit from the use of the ketoprofen and ultraviolet A irradiation as a new concept of melanotic melanoma therapy.

Minocycline Impact on Redox Homeostasis of Normal Human Melanocytes HEMn-LP Exposed to UVA Radiation and Hydrogen Peroxide.

Minocycline is a semisynthetic tetracycline antibiotic. In addition to its antibacterial activity, minocycline shows many non-antibiotic, beneficial effects, including antioxidative action. The property is responsible, e.g., for anti-inflammatory, neuroprotective, and cardioprotective effects of the drug. However, long-term pharmacotherapy with minocycline may lead to hyperpigmentation of the skin. The reasons for the pigmentation disorders include the deposition of the drug and its metabolites in melanin-containing cells and the stimulation of melanogenesis. The adverse drug reaction raises a question about the influence of the drug on melanocyte homeostasis. The study aimed to assess the effect of minocycline on redox balance in human normal melanocytes HEMn-LP exposed to hydrogen peroxide and UVA radiation. The obtained results indicate that minocycline induced oxidative stress in epidermal human melanocytes. The drug inhibited cell proliferation, decreased the level of reduced thiols, and stimulated the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The described changes were accompanied by an increase in the intracellular level of ROS. On the other hand, pretreatment with minocycline at the same concentrations increased cell viability and significantly attenuated the oxidative stress in melanocytes exposed to hydrogen peroxide and UVA radiation. Moreover, the molecular docking analysis revealed that the different influence of minocycline and other tetracyclines on CAT activity can be related to the location of the binding site.

UVA Radiation Enhances Lomefloxacin-Mediated Cytotoxic, Growth-Inhibitory and Pro-Apoptotic Effect in Human Melanoma Cells through Excessive Reactive Oxygen Species Generation.

Melanoma, the most dangerous type of cutaneous neoplasia, contributes to about 75% of all skin cancer-related deaths. Thus, searching for new melanoma treatment options is an important field of study. The current study was designed to assess whether the condition of mild and low-dose UVA radiation augments the lomefloxacin-mediated cytotoxic, growth-inhibitory and pro-apoptotic effect of the drug in melanoma cancer cells through excessive oxidative stress generation. C32 amelanotic and COLO829 melanotic (BRAF-mutant) melanoma cell lines were used as an experimental model system. The combined exposure of cells to both lomefloxacin and UVA irradiation caused higher alterations of redox signalling pathways, as shown by intracellular reactive oxygen species overproduction and endogenous glutathione depletion when compared to non-irradiated but lomefloxacin-treated melanoma cells. The obtained results also showed that lomefloxacin decreased both C32 and COLO829 cells' viability in a concentration-dependent manner. This effect significantly intensified when melanoma cells were exposed to UVA irradiation and the drug. For melanoma cells exposed to lomefloxacin or lomefloxacin co-treatment with UVA irradiation, the concentrations of the drug that decreased the cells' viability by 50% (EC50) were found to be 0.97, 0.17, 1.01, 0.18 mM, respectively. Moreover, we found that the redox imbalance, mitochondrial membrane potential breakdown, induction of DNA fragmentation, and changes in the melanoma cells' cell cycle distribution (including G2/M, S as well as Sub-G1-phase blockade) were lomefloxacin in a dose-dependent manner and were significantly augmented by UVA radiation. This is the first experimental work that assesses the impact of excessive reactive oxygen species generation upon UVA radiation exposure on lomefloxacin-mediated cytotoxic, growth-inhibitory and pro-apoptotic effects towards human melanoma cells, indicating the possibility of the usage of this drug in the photochemotherapy of malignant melanoma as an innovative medical treatment option which could improve the effectiveness of therapy. The obtained results also revealed that the redox imbalance intensification mediated by the phototoxic potential of fluoroquinolones may be considered as a more efficient treatment model of malignant melanoma and may constitute the basis for the development of new compounds with a high ability to excessive oxidative stress generation upon UVA radiation in cancer cells.

Silymarin: Friend or Foe of UV Exposed Keratinocytes?

The application of natural plant extracts in UV-protection is popular and intensively studied. Silymarin (from Silibum marianum), a naturally occurring polyphenol, has recently received attention due to its antioxidant, anti-inflammatory and anti-apoptotic effects. However, its role in the UV-mediated keratinocyte cell response is still controversial. In this study, we investigated the effects of Silibum marianum extracts with different origins and formulations on UVA-exposed HaCaT keratinocytes in vitro. Our results show, that silymarin treatment caused an inverse dose-dependent photosensitivity relationship (at higher doses, a decrease in cell viability and ROS production) after UVA exposure. The attenuation of the UVA-induced ROS generation after silymarin treatment was also observed. Moreover, silymarin pre-treatment increased the cyclobutane pyrimidine dimer photolesions in keratinocytes after UVA exposure. These results indicated the dual role of silymarin in UVA-exposed keratinocytes. It scavenges ROS but still induces phototoxicity. Based on our results dermatological applications of silymarin and related compounds should be considered very carefully.

UVA-1 exposure in vivo leads to an IL-6 surge within the skin.

UVA-1 is a known promotor of skin ageing. Cytokines like IL-1α, Il-1ß or TNF-α, VEGF and IL-6 orchestrate UV effects, and IL-6 is furthermore an effector of UVA-induced photoageing. We investigated how fractionated UVA-1 doses influence the cytokine milieu and especially the IL-6 levels in the skin in vivo. In a study with 35 participants, we exposed previously unirradiated human skin to three UVA-1 irradiation regimes. Cytokine levels in interstitial skin fluid were measured up to 48 hours postexposure and compared to unirradiated control skin fluid. Our results show that IL-6 levels increased significantly after UVA-1 exposure at selected time points. The other candidates IL-1α, Il-1ß or TNF-α and VEGF show no significant response after UVA-1 exposure in vivo. UVA-1 thus raises selectively IL-6 levels in vivo, a fact that underlines its role in photoageing and has potential implications for its modulatory effect on photoageing pathology.

Monopersulfate photocatalysis under 365 nm radiation. Direct oxidation and monopersulfate promoted photocatalysis of the herbicide tembotrione.

Oxone(®) (potassium monopersulfate, MPS) has been used to oxidize the herbicide tembotrione in aqueous solution. Tembotrione elimination kinetics by MPS direct oxidation has been studied. The influence of the main operating variables affecting the process (MPS concentration, temperature and pH) has been evaluated. The process follows 2/3 and first orders in MPS and tembotrione concentrations, respectively. Optimal pH is located around circumneutral conditions. MPS decomposition in the presence of 365 nm UVA radiation and titanium dioxide has also been studied. A kinetic mechanism that simulates MPS decomposition has been proposed, showing the positive effect of titania load and MPS concentration. The system MPS/UVA/TiO2 significantly improves tembotrione and mineralization rate abatement if compared to runs conducted in the absence of MPS. Tembotrione total abatement was achieved in 20 min when 0.05 g L(-1) of titania and 10(-4) M of Oxone(®) were used. TOC conversion was roughly 70% in 90 min under similar operating conditions. An experimental design (Plackett-Burman) has been considered to study the influence of the main variables affecting tembotrione photocatalytic oxidation promoted by MPS.

A Pilot Study of the Photoprotective Effects of Strawberry-Based Cosmetic Formulations on Human Dermal Fibroblasts.

Strawberry polyphenols have been extensively studied over the last two decades for their beneficial properties. Recently, their possible use in ameliorating skin conditions has also been proposed; however, their role in preventing UVA-induced damage in cosmetic formulation has not yet been investigated. Skin is constantly exposed to several environmental stressors, such as UVA radiation, that induce oxidative stress, inflammation and cell death via the production of reactive oxygen species (ROS). In the present study, we assessed the potential photoprotective capacity of different strawberry-based formulations, enriched with nanoparticles of Coenzyme Q10 and with sun protection factor 10 (SPF10), in human dermal fibroblasts (HuDe) exposed to UVA radiation. We confirmed that strawberries are a very rich source of polyphenols, anthocyanins and vitamins, and possess high total antioxidant capacity. We also showed that strawberry extracts (25 µg/mL-1 mg/mL) exert a noticeable photoprotection in HuDe, increasing cell viability in a dose-dependent way, and that these effects are potentiated by the presence of CoQ10red (100 µg/mL). We have demonstrated for the first time that the topical use of strawberry extract may provide good photoprotection, even if more in-depth studies are strongly encouraged in order to evaluate the cellular and molecular effects of strawberry protection.

The Influence of the Terminal Phosphorothioate Diester Bond on the DNA Oxidation Process. An Experimental and Theoretical Approach.

In this study, the influence of the terminal phosphorothioate (PT) internucleotide bond in ds-DNA on the oxidation process was taken into consideration. The interaction of UV with the targeted oligonucleotide leads to an electron ejection and radical cation "hole" migration through the ds-DNA until it is trapped irreversibly in a suitable place. Phosphorothiate internucleotide bonds were detected in the bacterial genome; however, their role is still unclear. In this study a PAGE analysis of irradiated ds-DNA showed that the degradation rea ction was slowed down by the presence PT next to the anthraquinone moiety. Further, theoretical study shows that [RP] AQ-PS-dG can adopt a slightly lower ionisation potential energy and triplet excited state with a subsequent slightly higher adiabatic electron affinity value in comparison with [SP] AQ-PS-dG and AQ-PO-dG. Moreover, the energy gap between HOMO and LUMO, indicated the radical stabilisation properties of [RP] AQ-PS-dG, which can hinder the charge transfer through ds-DNA.

Role of caffeine in DNA recognition of a potential food-carcinogen benzo[a]pyrene and UVA induced DNA damage.

Electron transfer (ET) reactions are important for their implications in both oxidative and reductive DNA damages. The current contribution investigates the efficacy of caffeine, a xanthine alkaloid in preventing UVA radiation induced ET from a carcinogen, benzo[a]pyrene (BP) to DNA by forming stable caffeine-BP complexes. While steady-state emission and absorption results emphasize the role of caffeine in hosting BP in aqueous medium, the molecular modeling studies propose the energetically favorable structure of caffeine-BP complex. The picosecond-resolved emission spectroscopic studies precisely explore the caffeine-mediated inhibition of ET from BP to DNA under UVA radiation. The potential therapeutic activity of caffeine in preventing DNA damage has been ensured by agarose gel electrophoresis. Furthermore, time-gated fluorescence microscopy has been used to monitor caffeine-mediated exclusion of BP from various cell lines including squamous epithelial cells, WI-38 (fibroblast), MCF-7 (breast cancer) and HeLa (cervical cancer) cells. Our in vitro and ex vivo experimental results provide imperative evidences about the role of caffeine in modified biomolecular recognition of a model carcinogen BP by DNA resulting dissociation of the carcinogen from various cell lines, implicating its potential medicinal applications in the prevention of other toxic organic molecule induced cellular damages.

Modulation of Redox and Inflammatory Signaling in Human Skin Cells Using Phytocannabinoids Applied after UVA Irradiation: In Vitro Studies.

UVA exposure disturbs the metabolism of skin cells, often inducing oxidative stress and inflammation. Therefore, there is a need for bioactive compounds that limit such consequences without causing undesirable side effects. The aim of this study was to analyse in vitro the effects of the phytocannabinoids cannabigerol (CBG) and cannabidiol (CBD), which differ in terms of biological effects. Furthermore, the combined use of both compounds (CBG+CBD) has been analysed in order to increase their effectiveness in human skin fibroblasts and keratinocytes protection against UVA-induced alternation. The results obtained indicate that the effects of CBG and CBD on the redox balance might indeed be enhanced when both phytocannabinoids are applied concurrently. Those effects include a reduction in NOX activity, ROS levels, and a modification of thioredoxin-dependent antioxidant systems. The reduction in the UVA-induced lipid peroxidation and protein modification has been confirmed through lower levels of 4-HNE-protein adducts and protein carbonyl groups as well as through the recovery of collagen expression. Modification of antioxidant signalling (Nrf2/HO-1) through the administration of CBG+CBD has been proven to be associated with reduced proinflammatory signalling (NFκB/TNFα). Differential metabolic responses of keratinocytes and fibroblasts to the effects of the UVA and phytocannabinoids have indicated possible beneficial protective and regenerative effects of the phytocannabinoids, suggesting their possible application for the purpose of limiting the harmful impact of the UVA on skin cells.

Melanopsin (OPN4) is a novel player in skin homeostasis and attenuates UVA-induced effects.

The presence of melanopsin (OPN4) has been shown in cultured murine melanocytes and was associated with ultraviolet A radiation (UVA) reception. Here we demonstrated the protective role of OPN4 in skin physiology and the increased UVA-induced damage in its absence. Histological analysis showed a thicker dermis and thinner hypodermal white adipose tissue layer in Opn4-/- (KO) mice than in wild-type (WT) animals. Proteomics analyses revealed molecular signatures associated with proteolysis, remodeling chromatin, DNA damage response (DDR), immune response, and oxidative stress coupled with antioxidant responses in the skin of Opn4 KO mice compared to WT. Skin protein variants were found in Opn4 KO mice and Opn2, Opn3, and Opn5 gene expressions were increased in the genotype. We investigated each genotype response to UVA stimulus (100 kJ/m2). We found an increase of Opn4 gene expression following stimulus on the skin of WT mice suggesting melanopsin as a UVA sensor. Proteomics findings suggest that UVA decreases DDR pathways associated with ROS accumulation and lipid peroxidation in the skin of Opn4 KO mice. Relative changes in methylation (H3-K79) and acetylation sites of histone between genotypes and differentially modulated by UVA stimulus were also observed. We also identified alterations of molecular traits of the central hypothalamus-pituitary- adrenal (HPA) and the skin HPA-like axes in the absence of OPN4. Higher skin corticosterone levels were detected in UVA-stimulated Opn4 KO compared to irradiated WT mice. Taken altogether, functional proteomics associated with gene expression experiments allowed a high-throughput evaluation that suggests an important protective role of OPN4 in regulating skin physiology in the presence and absence of UVA radiation.