While ozone depletion and recreational exposure make us prone to sun overexposure, the benefits of sunlight, such as vitamin D production and mood boosting, are overwhelmed by its deleterious effects on skin. Solar erythema, photodermatosis, photoaging and skin cancers are well documented examples of such effects, the latter ones being the most devastating. The WHO estimates that between 2 and 3 million non-melanoma skin cancers and approximately 130,000 malignant melanomas occur globally each year . So despite the use of sunscreens, i.e. UV filters, photoprotection remains currently a major issue and complementary strategies need to be implemented.
Figure 1: UVA-induced oxidative stress and skin damage
UV radiation is a well-recognized generator of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which play a key role in mediating its biological effects. Under the control of endogenous antioxidants, these species participate in redox-dependent regulation of cell metabolism in response to UV stress, but unbalanced, they induce oxidative damage whose accumulation is considered as a risk factor in photoaging, photoimmunosuppression and photocarcinogenesis. Antioxidant supply, orally or topically, is therefore a strategy that deserves further attention. Suitable intervention requires to define relevant targets and we will focus below on the oxidative pathways that may result in skin damage following UVA exposure.
If UVA involvement in malignant melanoma is still being debated [2-4], its contribution to inflammation  and to the deleterious effects observed in photoaging , immunosuppression  and skin cancer [8-10] has been demonstrated. Two main interconnected pathways prove to underlie UVA-induced oxidative stress.
The first one involves the production of ROS such as singlet oxygen (1O2), superoxide anion (O2•¯) and hydrogen peroxide (H2O2). 1O2 plays a key role in this pathway and direct evidence of its production in the skin has been obtained following UVA irradiation . It is generated by photoenergy transfer from excited endogenous photosensitizers to oxygen [12-18] (figure 1, 1), i.e., a type II photosensitizing mechanism. The high redox potential of 1O2 allows it to react with all major classes of biomolecules, leading to protein oxidation [19-20], lipid peroxidation [19,23-25] and DNA damage [20,26], and it may trigger the generation of other ROS, as suggested in human keratinocytes  (figure 1, 2). One electron transfer between UVA-photoexcited sensitizers and substrate (type I photosensitizing mechanism) has also been described and may contribute to oxidative stress  (figure 1, 3) and DNA oxidation  (figure 1, 4). Redox active metals such as iron  and copper  are also supposed to participate in UVA-induced oxidative stress. These metals can undergo redox cycling and generate strong oxidizing species such as hydroxyl radical, lipid-derived alkoxyl and peroxyl radicals, thereby promoting lipid peroxidation. This process may in turn contribute to 1O2 production [32-35] (figure 1, 5).
The second pathway involves the formation of RNS such as nitric oxide (NO•) and peroxynitrite anion (ONOO¯). It has been shown that NO• can be generated through UVA-induced decomposition of endogenous nitrite anion (NO2¯) and nitrosothiols (RSNO), (figure 1, 6) . This pathway is connected to the ROS producing one. Indeed, O2•¯ rapidly reacts with NO• to produce ONOO¯, a highly reactive entity leading to oxidation and/or nitration of proteins, lipids and DNA .
The modifications caused by ROS and RNS may result in gene mutation and membrane alterations, as it has been shown for the tumor suppressor gene p53  and ceramide release , respectively, following UVA irradiation. In addition, through the morphological and functional alterations that they induce, ROS and RNS participate in cell signaling. MAP kinases and the transcription factors AP-1, AP-2 and NF-κB are examples of signaling pathways involved in UVA-irradiated skin cells, that have been shown to be activated by 1O2, ONOO¯ or hydroperoxides [38-42]. Transactivation of these factors leads to the expression or the production of ICAM-1 , IL-8 , IL-1 and IL-6 [41,43], E-selectin , PAF [45,46], PDGF , metalloproteinases (MMP-1, MMP-2 and MMP-9) [41,48-50], which are involved in the UVA-induced inflammatory response, immunosuppression or carcinogenesis, and which may amplify oxidative stress thereby eliciting a damaging cycle (figure 1, 7).
To cope with oxidative stress, skin is endowed with antioxidant defenses [51,52] which prevent from ROS- and RNS-mediated alterations or damage. The activation of the transcription factor Nrf2 appears to play an important role in providing antioxidant protection against UVA [53-55]. However, antioxidant defenses have been shown to be depleted following UVA irradiation [56-60].
The mechanisms underlying the biological effects of UVA radiation are complex phenomenons in which cell type, sub-cellular localization, source of stress, intensity of stimuli determine the outcome of the interaction between ROS, RNS and endogenous biomolecules. Integration of damage and redox-regulated signaling networks will result in cell proliferation, connective tissue degradation, inflammation, cell death or cell survival, and finally in skin damage.
While such mechanisms remain to be fully elucidated, these patchy observations emphasize the pivotal role of excited photosensitizers and singlet oxygen in initiating UVA-induced skin damage, as well as the key role of peroxides in mediating such damage.
In this context, appropriate antioxidants may have potential benefits and may complement the effect of UV filters. We are open to discuss potential opportunities in this area.
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