1,25-Dihydroxyvitamin D3 Suppresses UV-Induced Poly(ADP-Ribose) Levels in Primary Human Keratinocytes, as Detected by a Novel Whole-Cell ELISA.

Photoprotective properties of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to reduce UV-induced DNA damage have been established in several studies. UV-induced DNA damage in skin such as single or double strand breaks is known to initiate several cellular mechanisms including activation of poly(ADP-ribose) (pADPr) polymerase-1 (PARP-1). DNA damage from UV also increases extracellular signal-related kinase (ERK) phosphorylation, which further increases PARP activity. PARP-1 functions by using cellular nicotinamide adenine dinucleotide (NAD+) to synthesise pADPr moieties and attach these to target proteins involved in DNA repair. Excessive PARP-1 activation following cellular stress such as UV irradiation may result in excessive levels of cellular pADPr. This can also have deleterious effects on cellular energy levels due to depletion of NAD+ to suboptimal levels. Since our previous work indicated that 1,25(OH)2D3 reduced UV-induced DNA damage in part through increased repair via increased energy availability, the current study investigated the effect of 1,25(OH)2D3 on UV-induced PARP-1 activity using a novel whole-cell enzyme- linked immunosorbent assay (ELISA) which quantified levels of the enzymatic product of PARP-1, pADPr. This whole cell assay used around 5000 cells per replicate measurement, which represents a 200-400-fold decrease in cell requirement compared to current commercial assays that measure in vitro pADPr levels. Using our assay, we observed that UV exposure significantly increased pADPr levels in human keratinocytes, while 1,25(OH)2D3 significantly reduced levels of UV-induced pADPr in primary human keratinocytes to a similar extent as a known PARP-1 inhibitor, 3-aminobenzamide (3AB). Further, both 1,25(OH)2D3 and 3AB as well as a peptide inhibitor of ERK-phosphorylation significantly reduced DNA damage in UV-exposed keratinocytes. The current findings support the proposal that reduction in pADPr levels may be critical for the function of 1,25(OH)2D3 in skin to reduce UV-induced DNA damage.

The Skin-Brain Axis: From UV and Pigmentation to Behaviour Modulation.

The skin-brain axis has been suggested to play a role in several pathophysiological conditions, including opioid addiction, Parkinson's disease and many others. Recent evidence suggests that pathways regulating skin pigmentation may directly and indirectly regulate behaviour. Conversely, CNS-driven neural and hormonal responses have been demonstrated to regulate pigmentation, e.g., under stress. Additionally, due to the shared neuroectodermal origins of the melanocytes and neurons in the CNS, certain CNS diseases may be linked to pigmentation-related changes due to common regulators, e.g., MC1R variations. Furthermore, the HPA analogue of the skin connects skin pigmentation to the endocrine system, thereby allowing the skin to index possible hormonal abnormalities visibly. In this review, insight is provided into skin pigment production and neuromelanin synthesis in the brain and recent findings are summarised on how signalling pathways in the skin, with a particular focus on pigmentation, are interconnected with the central nervous system. Thus, this review may supply a better understanding of the mechanism of several skin-brain associations in health and disease.

Exploring the complexities of plant UV responses; distinct effects of UV-A and UV-B wavelengths on Arabidopsis rosette morphology.

UV-B radiation can substantially impact plant growth. To study UV-B effects, broadband UV-B tubes are commonly used. Apart from UV-B, such tubes also emit UV-A wavelengths. This study aimed to distinguish effects of different UV-B intensities on Arabidopsis thaliana wildtype and UVR8 mutant rosette morphology, from those by accompanying UV-A. UV-A promotes leaf-blade expansion along the proximal-distal, but not the medio-lateral, axis. Consequent increases in blade length: width ratio are associated with increased light capture. However, petiole length is not affected by UV-A exposure. This scenario is distinct from the shade avoidance driven by low red to far-red ratios, whereby leaf blade elongation is impeded but petiole elongation is promoted. Thus, the UV-A mediated elongation response is phenotypically distinct from classical shade avoidance. UV-B exerts inhibitory effects on petiole length, blade length and leaf area, and these effects are mediated by UVR8. Thus, UV-B antagonises aspects of both UV-A mediated elongation and classical shade avoidance. Indeed, this study shows that accompanying UV-A wavelengths can mask effects of UV-B. This may lead to potential underestimates of the magnitude of the UV-B induced morphological response using broadband UV-B tubes.

Skin Barrier- and Immune Response-Related Biomarkers of Solar UVR Exposure Comparing Indoor and Outdoor Workers.

Outdoor workers have increased risk of developing keratinocyte cancer due to accumulated skin damage resulting from chronic and excessive exposure to UVR. This study aims to identify potential noninvasive biomarkers to assess chronic UVR exposure. We analyzed stratum corneum biomarkers collected from 2 skin locations and 2 occupational groups with contrasting solar UVR exposure: the forehead and retroauricular skin among outdoor workers and indoor workers. Using a linear mixed model adjusting for age and skin phototype, we compared biomarkers between both skin sites in indoor and outdoor workers. We measured markers of the immune response and skin barrier, including cytokines, GFs, 15-hydroxyeicosatetraenoic acid, cis- and trans-urocanic acid, and corneocyte topography, indicated by circular nano objects. Differences between the 2 skin sites were found for cis-urocanic acid, total urocanic acid, IL-1α, IL-1RA, IL-1RA/IL-1α, IL-18, 15-hydroxyeicosatetraenoic acid, CCL4, and circular nano objects. The levels of cis-urocanic acid and CCL4 also differed between indoor and outdoor workers. These findings underscore changes in both immune response and skin barrier induced by UVR. They indicate the potential utility of stratum corneum biomarkers in detecting both chronic UVR exposure in occupational setting and aiding in the development of preventive measures.

Sunlight: Time for a Rethink?

UVR is a skin carcinogen, yet no studies link sun exposure to increased all-cause mortality. Epidemiological studies from the United Kingdom and Sweden link sun exposure with reduced all-cause, cardiovascular, and cancer mortality. Vitamin D synthesis is dependent on UVB exposure. Individuals with higher serum levels of vitamin D are healthier in many ways, yet multiple trials of oral vitamin D supplementation show little benefit. Growing evidence shows that sunlight has health benefits through vitamin D-independent pathways, such as photomobilization of nitric oxide from cutaneous stores with reduction in cardiovascular morbidity. Sunlight has important systemic health benefit as well as risks.

Adjuvant PD-1 Checkpoint Inhibition in Early Cutaneous Melanoma: Immunological Mode of Action and the Role of Ultraviolet Radiation.

Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected stage III/IV melanoma. However, not all patients benefit equally. Current strategies for improving outcomes involve adjuvant treatment in earlier disease stages (IIB/C) as well as perioperative treatment approaches. Interfering with T-cell exhaustion to counteract cancer immune evasion and the immunogenic nature of melanoma is key for anti-PD-1 effectiveness. Yet, the biological rationale for the efficacy of adjuvant treatment in clinically tumor-free patients remains to be fully elucidated. High-dose intermittent sun exposure (sunburn) is a well-known primary risk factor for melanomagenesis. Also, ultraviolet radiation (UVR)-induced immunosuppression may impair anti-cancer immune surveillance. In this review, we summarize the current knowledge about adjuvant anti-PD-1 blockade, including a characterization of the main cell types most likely responsible for its efficacy. In conclusion, we propose that local and systemic immunosuppression, to some extent UVR-mediated, can be restored by adjuvant anti-PD-1 therapy, consequently boosting anti-melanoma immune surveillance and the elimination of residual melanoma cell clones.

Comparative transcriptomics elucidates the cellular responses of an aeroterrestrial zygnematophyte to UV radiation.

The zygnematophytes are the closest relatives of land plants and comprise several lineages that adapted to a life on land. Species of the genus Serritaenia form colorful, mucilaginous capsules, which surround the cells and block harmful solar radiation, one of the major terrestrial stressors. In eukaryotic algae, this 'sunscreen mucilage' represents a unique photoprotective strategy, whose induction and chemical background are unknown. We generated a de novo transcriptome of Serritaenia testaceovaginata and studied its gene regulation under moderate UV radiation (UVR) that triggers sunscreen mucilage under experimental conditions. UVR induced the repair of DNA and the photosynthetic apparatus as well as the synthesis of aromatic specialized metabolites. Specifically, we observed pronounced expressional changes in the production of aromatic amino acids, phenylpropanoid biosynthesis genes, potential cross-membrane transporters of phenolics, and extracellular, oxidative enzymes. Interestingly, the most up-regulated enzyme was a secreted class III peroxidase, whose embryophyte homologs are involved in apoplastic lignin formation. Overall, our findings reveal a conserved, plant-like UVR perception system (UVR8 and downstream factors) in zygnematophyte algae and point to a polyphenolic origin of the sunscreen pigment of Serritaenia, whose synthesis might be extracellular and oxidative, resembling that of plant lignins.

UVR8-TCP4-LOX2 module regulates UV-B tolerance in Arabidopsis.

The phytohormone jasmonate (JA) coordinates stress and growth responses to increase plant survival in unfavorable environments. Although JA can enhance plant UV-B stress tolerance, the mechanisms underlying the interaction of UV-B and JA in this response remain unknown. In this study, we demonstrate that the UV RESISTANCE LOCUS 8 - TEOSINTE BRANCHED1, Cycloidea and PCF 4 - LIPOXYGENASE2 (UVR8-TCP4-LOX2) module regulates UV-B tolerance dependent on JA signaling pathway in Arabidopsis thaliana. We show that the nucleus-localized UVR8 physically interacts with TCP4 to increase the DNA-binding activity of TCP4 and upregulate the JA biosynthesis gene LOX2. Furthermore, UVR8 activates the expression of LOX2 in a TCP4-dependent manner. Our genetic analysis also provides evidence that TCP4 acts downstream of UVR8 and upstream of LOX2 to mediate plant responses to UV-B stress. Our results illustrate that the UV-B-dependent interaction of UVR8 and TCP4 serves as an important UVR8-TCP4-LOX2 module, which integrates UV-B radiation and JA signaling and represents a new UVR8 signaling mechanism in plants.

Skin Cancer Risk Is Increased by Somatic Mutations Detected Noninvasively in Healthy-Appearing Sun-Exposed Skin.

Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic mutations in healthy-appearing skin have not been used to calculate skin cancer risk. In this study, we developed a noninvasive test that quantifies somatic mutations in healthy-appearing sun-exposed skin and applied it to a 1038-subject cohort. Somatic mutations were combined with other known skin cancer risk factors to train a model to calculate risk. The final model (DNA-Skin Cancer Assessment of Risk) was trained to predict personal history of skin cancer from age, family history, skin tone, and mutation count. The addition of mutation count significantly improved model performance (OR = 1.3, 95% confidence interval = 1.14-1.48; P = 5.3 × 10-6) and made a more significant contribution than skin tone. Calculations of skin cancer risk matched the known United States population prevalence, indicating that DNA-Skin Cancer Assessment of Risk was well-calibrated. In conclusion, somatic mutations in healthy-appearing sun-exposed skin increase skin cancer risk, and mutations capture risk information that is not accounted for by other risk factors. Clinical utility is supported by the noninvasive nature of skin sample collection through adhesive patches.

Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature.

Mitochondria are eukaryotic cellular organelles that function in energy metabolism, ROS production, and programmed cell death. Cutaneous epithelial and hair follicle dermal papilla cells are energy-rich cells that thereby may be affected by mitochondrial dysfunction and DNA mutation accumulation. In this review, we aimed to summarize the medical literature assessing dermatologic conditions and outcomes associated with mitochondrial dysfunction. A search of PubMed and Embase was performed with subsequent handsearching to retrieve additional relevant articles. Mitochondrial DNA (mtDNA) deletions, mutation accumulation, and damage are associated with phenotypic signs of cutaneous aging, hair loss, and impaired wound healing. In addition, several dermatologic conditions are associated with aberrant mitochondrial activity, such as systemic lupus erythematosus, psoriasis, vitiligo, and atopic dermatitis. Mouse model studies have better established causality between mitochondrial damage and dermatologic outcomes, with some depicting reversibility upon restoration of mitochondrial function. Mitochondrial function mediates a variety of dermatologic conditions, and mitochondrial components may be a promising target for therapeutic strategies.

Recent advances in UV-B signalling: interaction of proteins with the UVR8 photoreceptor.

The photoreceptor UVR8 mediates many plant responses to UV-B and short wavelength UV-A light. UVR8 functions through interactions with other proteins which lead to extensive changes in gene expression. Interactions with particular proteins determine the nature of the response to UV-B. It is therefore important to understand the molecular basis of these interactions: how are different proteins able to bind to UVR8 and how is differential binding regulated? This concise review highlights recent developments in addressing these questions. Key advances are discussed with regard to: identification of proteins that interact with UVR8; the mechanism of UVR8 accumulation in the nucleus; the photoactivation of UVR8 monomer; the structural basis of interaction between UVR8 and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) and REPRESSOR OF UV-B PHOTOMORPHOGENESIS (RUP) proteins; the role of UVR8 phosphorylation in modulating interactions and responses to UV-B. Nevertheless, much remains to be understood and the need to extend future research to the growing list of interactors is emphasised.

Effects of ultraviolet radiation on cellular functions of the cyanobacterium Synechocystis sp. PCC 6803 and its recovery under photosynthetically active radiation.

Cyanobacteria are photosynthetic organisms and challenged by large number of stresses, especially by ultraviolet radiation (UVR). UVR primarily impacts lipids, proteins, DNA, photosynthetic performance, which lowers the fitness and production of cyanobacteria. UVR has a catastrophic effect on cyanobacterial cells and eventually leads to cell death. UVR tolerance in the Synechocystis was poorly studied. Therefore, we irradiated Synechocystis sp. PCC 6803 to varying hours of photosynthetically active radiations (PAR), PAR + UV-A (PA), and PAR + UV-A + UV-B (PAB) for 48 h. To study the tolerance of Synechocystis sp. PCC 6803 against different UVR. The study shows that Chl a and total carotenoids content increased up to 36 h in PAR and PA, after 36 h a decrease was observed. PC increased up to 4-fold in 48 h of PA irradiation compared to 12 h. Maximum increase in ROS was observed under 48 h PAB i.e., 5.8-fold. Flowcytometry (FCM) based analysis shows that 25% of cells do not give fluorescence of Chl a and H2DCFH. In case of cell viability 10% cells were found to be non-viable in 48 h of PAB irradiance compared to 12 h. From the above study it was found that FCM-based approaches would provide a better understanding of the variations that occurred within the Synechocystis cells compared to fluorescence microscopy-based methods.

Structural and Functional Shifts in the Microbial Community of a Heavy Metal-Contaminated Soil Exposed to Short-Term Changes in Air Temperature, Soil Moisture and UV Radiation.

The interplay between metal contamination and climate change may exacerbate the negative impact on the soil microbiome and, consequently, on soil health and ecosystem services. We assessed the response of the microbial community of a heavy metal-contaminated soil when exposed to short-term (48 h) variations in air temperature, soil humidity or ultraviolet (UV) radiation in the absence and presence of Enchytraeus crypticus (soil invertebrate). Each of the climate scenarios simulated significantly altered at least one of the microbial parameters measured. Irrespective of the presence or absence of invertebrates, the effects were particularly marked upon exposure to increased air temperature and alterations in soil moisture levels (drought and flood scenarios). The observed effects can be partly explained by significant alterations in soil properties such as pH, dissolved organic carbon, and water-extractable heavy metals, which were observed for all scenarios in comparison to standard conditions. The occurrence of invertebrates mitigated some of the impacts observed on the soil microbial community, particularly in bacterial abundance, richness, diversity, and metabolic activity. Our findings emphasize the importance of considering the interplay between climate change, anthropogenic pressures, and soil biotic components to assess the impact of climate change on terrestrial ecosystems and to develop and implement effective management strategies.

Expression of active caspase 3 in the rat lens after in vivo exposure to subthreshold dose of UVR-B.

PURPOSES: The aim of this study is to investigate the time evolution of active caspase 3 within first 120 h in the rat lens after in vivo exposure to subthreshold dose of UVR-B. METHODS: Twenty three six-week-old female albino Sprague-Dawley rats were exposed to subthreshold dose (1 kJ/m2) of UVR-B unilaterally and sacrificed at 24, 41, 70 and 120 h after exposure. Lenses were enucleated and active caspase 3 was detected by Western Blot. The time evolution of active caspase 3 was then plotted as a function of relative mean difference in active caspase 3 between exposed and nonexposed lenses. RESULTS: There is expression of active caspase 3 in both exposed and nonexposed lenses but there is no difference in relative mean difference in active caspase 3 between exposed and nonexposed lenses in all four postexposure groups. CONCLUSIONS: Exposure to subthreshold dose of UVR-B does not induce apoptosis in the rat lens in vivo within first 120 h though there is a non-significant increase of active caspase 3 at 120 h. Increase in sample size might reduce the variation level in expression of active caspase 3 in the rat lenses.

Sunscreen does not alter sweating responses or critical environmental limits in young adults (PSU HEAT project).

Outdoor athletes often eschew using sunscreen due to perceived performance impairments, which many attribute in part to the potential for reduced thermoregulatory heat loss. Past studies examining the impact of sunscreen on thermoregulation are equivocal. The purpose of this study was to determine the effects of mineral and chemical-based sunscreens on sweating responses and critical environmental limits in hot-dry (HD) and warm-humid (WH) environments. Nine subjects (3 M/6 F; 25 ± 2 yr) were tested with 1) no sunscreen (control), 2) chemical-, and 3) mineral-based sunscreen. Subjects were exposed to progressive heat stress with either 1) constant dry-bulb temperature (Tdb) at 34°C and increasing water vapor pressure (Pa) (WH trials) or 2) constant Pa at 12 mmHg and increasing Tdb (HD trials). Subjects walked at 4.9 ± 0.5 metabolic equivalents (METs) until an upward inflection in gastrointestinal temperature was observed (i.e., the critical environmental limit). Compared with control (39.9 ± 3.0°C), critical Tdb was not different in mineral (39.2 ± 3.5°C, P = 0.39) or chemical (39.7 ± 3.0°C, P = 0.98) sunscreen trials in HD environments. Compared with control (18.8 ± 4.0 mmHg), critical Pa was not different in mineral (18.9 ± 4.8 mmHg, P = 0.81) or chemical (19.5 ± 4.6 mmHg, P = 0.81) sunscreen trials in WH environments. Sweating rates, evaporative heat loss, skin wettedness, and sweating efficiency were not different among the three trials in the WH (all P ≥ 0.48) or HD (all P ≥ 0.87) environments. Critical environmental limits are unaffected by sunscreen application, suggesting sunscreen does not alter integrative thermoregulatory responses during exercise in the heat.NEW & NOTEWORTHY Our findings demonstrate that neither sweating nor critical environmental limits were affected by mineral-based and chemical-based sunscreen applications. The rates of change in core temperature during compensable and uncompensable heat stress were not changed by wearing sunscreen. Evaporative heat loss, efficiency of sweat evaporation, skin wettedness, and sweating rates were unaffected by sunscreen. Sunscreen did not alter integrative thermoregulatory responses during exercise in the heat.

Genome-wide characterization of regulator of chromosome condensation 1 (RCC1) gene family in Artemisia annua L. revealed a conservation evolutionary pattern.

BACKGROUND: Artemisia annua is the major source for artemisinin production. The artemisinin content in A. annua is affected by different types of light especially the UV light. UVR8, a member of RCC1 gene family was found to be the UV-B receptor in plants. The gene structures, evolutionary history and expression profile of UVR8 or RCC1 genes remain undiscovered in A. annua. RESULTS: Twenty-two RCC1 genes (AaRCC1) were identified in each haplotype genome of two diploid strains of A. annua, LQ-9 and HAN1. Varied gene structures and sequences among paralogs were observed. The divergence of most RCC1 genes occurred at 46.7 - 51 MYA which overlapped with species divergence of core Asteraceae during the Eocene, while no recent novel RCC1 members were found in A. annua genome. The number of RCC1 genes remained stable among eudicots and RCC1 genes underwent purifying selection. The expression profile of AaRCC1 is analogous to that of Arabidopsis thaliana (AtRCC1) when responding to environmental stress. CONCLUSIONS: This study provided a comprehensive characterization of the AaRCC1 gene family and suggested that RCC1 genes were conserved in gene number, structures, constitution of amino acids and expression profiles among eudicots.

Equipment developed for simplifying routine phototesting in dermatology.

Some people react abnormally when exposed to sunlight by getting easily burned or develop a rash. When testing a patient's level of photosensitivity in the clinic, the UVR dose to provoke erythema is determined by the minimal erythema dose (MED) test. Subsequently, a photoprovocation test is performed to detect abnormal skin reactions by daily exposing the skin to UVR for several consecutive days. Associated problems in MED testing include choice of an even skin area for testing, patients keeping still during the test, testing with different UVR doses simultaneously, and securing clear borders of erythema. To address these issues, a MED Test Patch was developed which adheres closely to the skin to ensure sharp erythema borders and provides six irradiation fields with decremental doses of 20%. For MED testing, we constructed a solar simulator and LED lamps with peak emissions at 309 and 370 nm, small enough to be mounted directly on to the MED Test Patch and accommodate patient movements. These lamps and a 415 nm LED can also be used for provocation testing which is best performed on the back where the skin is assumed to have identical UVR sensitivity, and the area is large enough for adjacent MED and provocation test fields. Reading of erythema is still performed by visual and tactile evaluation. The UVA and UVB MED test can be performed in 1 h. The advantage of these developments is an easy-to-use, standardized test method with improved accuracy of the results.

Sunscreens - another endangered species?

Skin cancer continues to increase in incidence year-on-year and represents the most common form of cancer across the globe. Every human undergoes premature ageing, particularly on the face, neck and hands. Both phenomena are driven primarily by chronic, daily exposure to solar ultraviolet radiation (UVR). While sunscreen products play a primary role in the prevention of UVR skin damage, the active ingredients, i.e., UVR filters, are facing unprecedented challenges in the coming 10 years and their future is by no means certain. This article, therefore, reviews afresh the facts around photoprotection and the role of sunscreen products in the prevention of acute (sunburn) and chronic (cancer, photoageing) skin damage and compares/contrasts these with various emerging questions and opinions around UVR filter technology. We present a passionate defence of this remarkable technology, but also attempt to imagine a world without it.

L'incidence du cancer de la peau continue d'augmenter année après année, et ce cancer est le plus fréquent dans le monde. Tous les êtres humains connaissent un vieillissement prématuré, en particulier au niveau du visage, du cou et des mains. Les deux phénomènes sont causés principalement par une exposition quotidienne chronique aux rayons ultraviolets (UVR) du soleil. Bien que les protections solaires jouent un rôle essentiel dans la prévention des lésions cutanées dues aux UVR, les principes actifs, c'est-à-dire les filtres UVR, seront confrontés à des difficultés sans précédent dans les 10 prochaines années, et leur avenir n'est en aucun cas certain. Cet article examine donc les faits concernant la photoprotection et le rôle des produits de protection solaire dans la prévention des lésions cutanées aiguës (coups de soleil) et chroniques (cancer, photovieillissement) ; et les compare/oppose aux différentes questions et opinions émergentes concernant la technologie des filtres UVR. Nous présentons une défense passionnée de cette technologie remarquable, mais nous essayons également d'imaginer un monde sans elle.