Activation of transient receptor potential melastatin 8 reduces ultraviolet B‐induced prostaglandin E2 production in keratinocytes

Transient receptor potential melastatin 8 (TRPM8) is a member of the TRP family, and is activated at temperatures below 22°C, or by cooling compounds such as menthol. In this study, it was found that a new role of TRPM8 activation on prostaglandin E2 (PGE2), an inflammatory cytokine and dendritogenesis stimulator of normal human melanocytes. Normal human keratinocytes were pretreated with menthol or incubated at 22°C for TRPM8 activation before ultraviolet (UV)‐B irradiation. To examine the specificity between TRPM8 activation and PGE2 release, we inhibited TRPM8 with the antagonist (capsazepine), or introduced TRPM8 siRNA for a gene silencing experiment. UV‐B irradiation significantly induced PGE2 release in normal human keratinocytes. Interestingly, activation of TRPM8 at 22°C or with menthol inhibited UV‐B‐induced PGE2 release. The effect of the TRPM8 agonist was completely blocked by pretreatment with the TRPM8 antagonist, capsazepine. When TRPM8 expression was suppressed by siRNA, UV‐B irradiation still upregulated PGE2 in keratinocytes, but pretreatment of menthol or low temperature did not inhibit UV‐B‐induced PGE2. In conclusion, the activation of TRPM8 inhibits UV‐B‐induced PGE2 production in keratinocytes, and the activation of TRPM8 may reduce inflammatory responses in skin.     

Narrowband ultraviolet B course improves vitamin D balance in women in winter

Background Vitamin D insufficiency is common in winter in the Nordic countries. Objectives  To examine whether a short course of narrowband ultraviolet B (NB‐UVB) improves vitamin D balance. Methods Fifty‐six healthy, white women (mean age 41 years) volunteered and 53 completed the study. NB‐UVB exposures were given on seven consecutive days either on the whole body (n = 19), on the head and arms (n = 9) or on the abdomen (n = 14). Similarly, seven solar simulator exposures were given on the face and arms (n = 11). The cumulative UVB dose was 13 standard erythema doses in all regimens. Serum calcidiol (25‐hydroxyvitamin D) concentration was measured by radioimmunoassay before and after the NB‐UVB exposures. Follow‐up samples were taken from the whole‐body NB‐UVB group at 2 months. Results At onset 41 women (77%) had vitamin D insufficiency (calcidiol < 50 nmol L^?1) and six (11%) had vitamin D deficiency (calcidiol < 25 nmol L^?1). Calcidiol concentration increased significantly, by a mean of 11·4 nmol L^?1 when NB‐UVB was given on the whole body, by 11·0 nmol L^?1 when given on the head and arms and by 4·0 nmol L^?1 when given on the abdomen. Solar simulator exposures given on the face and arms increased calcidiol by 3·8 nmol L^?1. After 2 months serum calcidiol was still higher than initially in the group who received NB‐UVB exposures on the whole body. Conclusions NB‐UVB exposures given on seven consecutive days on different skin areas of healthy women significantly improved serum calcidiol concentration. A short low‐dose NB‐UVB course can improve vitamin D balance in winter.     

Z‐ligustilide ameliorated ultraviolet B‐induced oxidative stress and inflammatory cytokine production in human keratinocytes through upregulation of Nrf2/HO‐1 and suppression of NF‐κB pathway

Ultraviolet B (UVB), a harmful environmental factor, is responsible for a variety of skin disorders including skin inflammation through reactive oxygen species (ROS) and inflammatory mediator production. Here, we investigated the effect of Z‐ligustilide (Z‐lig), an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba, on UVB‐induced ROS generation and inflammatory mediator production in normal human epidermal keratinocytes (NHEKs) as well as its underlying mechanisms. Z‐lig significantly rescued UVB‐induced NHEKs damage in a dosage‐dependent manner. Pretreatment of NHEKs with Z‐lig inhibited UVB‐induced ROS production in NHEKs. Both silencing the nuclear factor E2‐related factor 2 (Nrf2) and the supplement of tin protoporphyrin IX (SnPP), a haeme oxygenase‐1 (HO‐1) inhibitor, cancelled the inhibitory effect of Z‐lig on UVB‐induced ROS upregulation in NHEKs. Moreover, pretreatment of NHEKs with Z‐lig reduced UVB‐induced nuclear factor kappa B (NF‐κB)‐dependent inflammatory mediators (IL‐6, IL‐8 and MCP‐1) production at both mRNA and protein level. In the presence of Z‐lig, UVB‐induced NF‐κB subunit p65 nuclear translocation was abolished, and the IκBα degradation was suppressed. Taken together, these findings suggest that Z‐lig can suppress UVB‐induced ROS generation through Nrf2/HO‐1 upregulation and inflammation by suppressing the NF‐κB pathway, suggesting that Z‐lig may be beneficial in protecting skin from UVB exposure.     

The challenge of follow-up in narrowband ultraviolet B phototherapy

BACKGROUND: The use of narrowband ultraviolet (UV) B phototherapy to treat psoriasis and other disorders has increased markedly since the TL-01 lamps were introduced in the 1980s. While broadband UVB phototherapy has generally been considered to be a relatively safe treatment, some concern has been raised about the potential increased skin cancer risk with narrowband UVB. OBJECTIVES: The likelihood of a patient who is free of nonmelanoma skin cancer (NMSC) at the start of phototherapy developing a malignancy after a certain follow-up period will be dependent not only on the carcinogenic potential of the treatment but also on the age-conditional probability of natural occurrence. We were interested to explore the potential difficulty of designing studies to separate these two events. Methods Mathematical models were developed that combined age-conditional probabilities of developing NMSC due to natural causes with the risk of inducing these cancers from narrowband UVB phototherapy in order to estimate the excess number of cancers resulting from this therapeutic intervention in a cohort of patients. RESULTS: Within-department studies will be most unlikely to demonstrate that the number of NMSCs observed in follow-up studies is significantly different from that expected in an untreated population, even for a follow-up period of 20 years. CONCLUSIONS: Determination of the carcinogenic potential associated with narrowband UVB will require large multicentre studies typically involving several thousand new patients per year and followed up for 10 years or more.     

Measurements of the upper body ultraviolet exposure to golfers: non-melanoma skin cancer risk, and the potential benefits of exposure to sunlight

Background: Geographically, Queensland presents an extreme ultraviolet exposure climate to members of the public engaged in outdoor recreational activity. The risk of developing a skin cancer or an eye disease as a result of incidental exposure to naturally occurring ultraviolet radiation in the outdoor environment is proportionately high in a Queensland population compared with fair‐skinned population groups residing in comparable Northern Hemisphere latitudes. In contrast to these risks, elderly members of this high growth population group have been reported to be vitamin D deficient. The risks and potential benefits of exposure to sunlight in southern Queensland are assessed in this study with respect to recreational golfing. This sport is a popular recreational activity for the Queensland population and must be played during daylight hours. Methods: The erythemal and vitamin D effective ultraviolet exposure measured to the forearm, upper back and vertex are presented for individuals playing golf under various atmospheric conditions in a 7‐month period extending from summer to winter. Results: Mean summertime exposures were measured in the 2008 study period as be 1.4, 2.2 and 3.2 standard erythema doses (SED) at forearm, upper back and vertex sites, respectively, compared with respective wintertime forearm, upper back and vertex exposures of 0.2, 0.3 and 0.5 SED, where summertime exposures were recorded in the mean solar zenith angle (SZA) ranges of 56–59° and wintertime exposures were recorded in the mean SZA range 74–83°. Vitamin D₃ effective exposures were determined to vary from between 225, 325 and 475 J/m² during summer and 48, 59 and 88 J/m² during winter for the respective forearm, upper back and vertex body sites measured in the above mean SZA ranges. Conclusion: Exposures to ambient ultraviolet during winter on the golf course between 15:00 and 17:30 hours could be beneficial for office workers for the production of vitamin D. Optimizing exposure periods to late afternoon in the winter months and taking adequate sun protection measures in the summer months are important strategies that golfers can utilize for long‐term preventative health.     

Incidence of skin cancers in 3867 patients treated with narrow-band ultraviolet B phototherapy

Background  Narrow‐band ultraviolet B (NB‐UVB) phototherapy is a widely used treatment. Psoralen‐UVA photochemotherapy (PUVA) increases skin cancer risk and some animal studies have raised the possibility of an increased risk with NB‐UVB. The risk of skin cancer in humans following treatment with NB‐UVB is unknown. Objectives  This current analysis forms part of an ongoing study ultimately aiming to define the long‐term carcinogenic risk of NB‐UVB treatment in humans. Methods  Details of all patients receiving NB‐UVB treatment until 31/12/2002 in Tayside, Scotland, were accessed from a treatment database and linked to the Scottish Cancer Registry. Indirect standardization was used to compare skin cancer incidence in the study population with age and sex matched cancer registry data for the Tayside population. We also assessed the effect of NB‐UVB exposure treatment numbers on the risk of developing skin cancer. Results  Of 4690 records reviewed, 4665 were suitable for analysis with 3886 records linked with the cancer registry and 3867 followed‐up for at least 6 months before 31/12/02 (the date at which cancer registration was deemed to be complete). The median number of NB‐UVB treatments was 29 with 352 patients receiving ≥ 100 treatments. The study gave 24 753 person‐years of follow up. First skin cancers recorded in study patients were 27 basal cell carcinomas (BCC), seven squamous cell carcinomas (SCC) and six melanomas. No association was found between NB‐UVB exposure alone (without PUVA) and any skin cancer. For NB‐UVB and PUVA treated patients there was an association with BCC, with 27 BCCs found compared with 14·1 expected in the matched population. Conclusion  We found no significant association between NB‐UVB treatment and BCC, SCC or melanoma. There was a small increase in BCCs amongst those also treated with PUVA. These reassuring results do not demonstrate the early increase in skin cancers that was found associated with PUVA treatment. However, cautious interpretation is required as the cohort contained relatively few patients who had a high treatment number and because the slow evolution of skin cancers may result in a delayed incidence peak. Ongoing risk assessment is therefore essential.     

Neue und etablierte Indikationen der UV‐B‐311‐nm‐Phototherapie

Phototherapy with ultraviolet (UV) irradiation of wavelengths between 280 and 320 nm (UV‐B) is a safe and effective treatment for a variety of inflammatory skin diseases. In addition to standard broad band UVB, narrow band phototherapy with fluorescent bulbs emitting near monochromatic UV between 310 – 315 nm has become an important treatment for diseases such as psoriasis, atopic dermatitis or vitiligo. Other diseases respond favorably to narrow band UV‐B phototherapy, the number of potential indications for such phototherapy is continuously growing. The differential effects of narrow band UV‐B phototherapy in comparison to other UV phototherapies, as well as new and established indications for this treatment modality are reviewed.     

Curcumin inhibits UVB‐induced matrix metalloproteinase‐1/3 expression by suppressing the MAPK‐p38/JNK pathways in human dermal fibroblasts

Curcumin (diferuloylmethane) is a polyphenol derived from turmeric (Curcuma longa), which is commonly used as a spice. Recent studies have shown that curcumin has a wide range of pharmacological activities, including anticarcinogenic, antioxidant, anti‐inflammatory and antiangiogenic activities. However, the antiphotoageing effects of curcumin have yet to be characterized. In this study, we investigated the inhibitory effects of curcumin on matrix metalloproteinase (MMP)‐1 and MMP‐3 expression in human dermal fibroblast cells. Western blot analysis revealed that curcumin inhibited ultraviolet (UV) B‐induced MMP‐1 and MMP‐3 expression. Furthermore, curcumin significantly blocked UVB‐induced reactive oxygen species generation in fibroblasts. Curcumin treatment significantly blocked the UVB‐induced activation of nuclear factor (NF)‐κB and activator protein (AP)‐1. Additionally, curcumin strongly repressed the UVB‐induced phosphorylation of p38 and c‐Jun N‐terminal kinase. Curcumin prevented UVB‐induced MMP expression through mitogen‐activated protein kinase/NF‐κB inhibition and AP‐1 activation. In conclusion, curcumin may be useful for preventing and treating skin photoageing.     

Environment‐induced lentigines: formation of solar lentigines beyond ultraviolet radiation

There is no doubt that ultraviolet radiation (UVR) contributes to the generation of acquired lentigines in human skin, as indicated by the term solar lentigo. A growing number of recent epidemiological and mechanistic studies, however, strongly suggest that in addition to UVR, other environmental factors contribute to lentigines’ formation as well. We therefore here introduce the term ‘environment‐induced lentigo’ (EIL) to refer to acquired pigment spots of human skin. In this view point, we (i) summarize the existing evidence to support a role of environmental toxicants other than UVR in the pathogenesis of EILs, (ii) we argue that activation of aryl hydrocarbon receptor (AHR) signalling by UVR and environmental toxicants is critically involved in triggering and sustaining a crosstalk between melanocytes, keratinocytes and fibroblasts, which then causes the development and persistence of EILs in human skin, and (iii) we discuss clinical implications for the prevention and treatment of EILs resulting from this concept.     

Narrow‐band ultraviolet B as a potential alternative treatment for resistant psychogenic excoriation: an open‐label study

Narrow‐band ultraviolet therapy has been used successfully for the treatment of inflammatory skin disorders and generalized pruritus. We have prospectively evaluated seven consecutive patients with resistant psychogenic excoriation (PE) treated with narrow‐band ultraviolet B (NB‐UVB). Approximately 70% of all patients showed improvement in their condition. NB‐UVB therapy was well tolerated, with no serious side effects. We may conclude that, when treating a patient with PE, NB‐UVB in combination with other approaches may provide extra benefit in resistant cases.     

Loss of INK4a/Arf gene enhances ultraviolet radiation‐induced cutaneous tumor development

The CDKN2A locus encodes for tumor suppressor genes p16^INK4a and p14^Arf which are frequently inactivated in human skin tumors. The purpose of this study was to determine the relationship between loss of INK4a/Arf activity and inflammation in the development of ultraviolet (UV) radiation‐induced skin tumors. Panels of INK4a/Arf^‐/? mice and wild‐type (WT) mice were treated with a single dose of UVB (200 mJ/cm²). For long‐term studies, these mice were irradiated with UVB (200 mJ/cm²) three times weekly for 30 weeks. At the end of the experiment, tissues were harvested from mice and assayed for inflammatory biomarkers and cytokines. A single dose of UVB resulted in a significant increase in reactive oxygen species (ROS) and 8‐dihydroxyguanosine (8‐oxo‐dG) lesions in INK4a/Arf^?/? mice compared to WT mice. When subjected to chronic UVB, we found that 100% of INK4a/Arf^?/‐ mice had tumors, whereas there were no tumors in WT controls after 24 weeks of UVB exposure. The increase in tumor development correlated with a significant increase in nuclear factor (NF)‐κB, cyclooxygenase‐2 (COX‐2), prostaglandin E₂ (PGE₂) and its receptors both in UVB‐exposed skin and in the tumors. A significant increase was seen in inflammatory cytokines in skin samples of INK4a/Arf^‐/‐ mice following treatment with chronic UVB radiation. Furthermore, significantly more CD11b⁺Gr1⁺ myeloid cells were present in UVB‐exposed INK4a/Arf^‐/‐ mice compared to WT mice. Our data indicate that by targeting UVB‐induced inflammation, it may be possible to prevent UVB‐induced skin tumors in individuals that carry CDKN2A mutation.     

Tea polyphenols for the prevention of UVB‐induced skin cancer

Skin cancer is the most common type of cancer with increasing incidence rate and public health burden. Solar ultraviolet (UV) radiation causes an array of damaging cellular and molecular events that eventually lead to the development of skin cancer. Despite increased awareness about sun protection, the exposure rate remains high with less than 15% of men and 30% of women using sunscreen on a regular basis. Therefore, there is an imperative need for the development of novel preventive approaches. Skin cancer chemoprevention using phytochemicals either as dietary supplements or by topical applications has gained considerable attention due to their low toxicity, availability, and anticarcinogenic properties. Tea, the second most commonly consumed beverage in the world, is a rich source of promising phytochemicals known as polyphenols. In this review, we discuss the findings of various in vitro, in vivo and human studies signifying the chemopreventive effects of tea polyphenols against UVB‐induced skin cancer. This is accomplished by exploring the role of tea polyphenols in DNA repair, inflammation, oxidative stress, signaling pathways, and epigenetics. Finally, this review discusses a variety of innovative delivery methods that enhance the photochemopreventive effects of tea polyphenols against skin cancer.     

Photo‐induced graft‐versus‐host disease

Overlap chronic graft‐versus‐host disease (GVHD) associates both features of acute and chronic GVHD. Trigger factors for chronic GVHD are unclear. We describe two patients who received allogenic haematopoietic stem‐cell transplantation, and who later developed overlap chronic GVHD after sun exposure. Available data from in vivo investigations suggest ultraviolet B radiation (UVB) has a beneficial effect on acute and chronic GVHD. The role of sun irradiation as a trigger for isomorphic cutaneous GVHD has been rarely reported in the literature. Herein, we demonstrate for the first time, using repetitive broadband phototesting, that UVB triggers chronic GVHD.     

Reversal of ultraviolet B-induced immunosuppression by inhibition of the extracellular signal-regulated mitogen-activated protein kinase

Objective: Topical treatment of the specific inhibitor PD98059 (PD) for extracellular signal-regulated kinase (ERK)1/2 combined with ultraviolet B (UVB) exposure in an in vivo study was proposed to confirm the effectiveness of ERK1/2 involved in UVB-induced immunosuppression that was reversed by PD.
Methods: Based on the mouse model of local UVB-induced immunosuppression [UVB exposure, followed by sensitization with dinitrofluorobenzene (DNFB) on the abdomen skin before challenge on the ear site], the PD was applied on the abdomen-irradiated area 1 h, immediately before and 6 h after UVB exposure, respectively. The baseline of ear thickness was measured and remeasured 24 h after the challenge of DNFB for evaluation of ear-swelling response. Histopathologically, the ear biopsies were taken for hematoxylin and eosin staining.
Results: Mice that received PD post-irradiation treatment showed a statistically significant contact hypersensitivity compared with the UVB-irradiated mice ( P <0.05), and paralleled with the biopsy showing a thickened epidermis with lymphocyte infiltration. Thus, the PD had abrogated the UV-induced local suppression of contact hypersensitivity.
Conclusion: The ERK1/2 mitogen-activated protein kinase (MAPK) pathway plays an important role in the local UVB-induced immunosuppression, and its specific inhibitor PD can arrest its function, resulting in protection against UVB-induced immunosuppression in the present in vivo study.