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The effects of sunlight on the skin
Abstract
Michael Roberts – School of Medicine, University of Queensland, Australia
... The skin is the organ most exposed to environmental sunlight. Many studies on skin cells have established that UVR can damage the skin [25,[29][30][31][33][34][35][36][37][38][39][40]. This may result in changes of cellular function. ...
... Melanoma is the skin cancer most likely to metastasize, typically beginning as a radial proliferation of non-proliferating melanocytes and when the lesion begins growing vertically, metastasis is possible [36,39,42]. SCC and BCC are tumours of keratinocytes, which are cells that routinely proliferate, differentiate and are then shed from the skin. ...
... BCCs seem to arise without precursors, seemingly from keratinocytes in hair follicles. They are usually diploid and rarely metastasize, although they invade locally [36,39,42]. All three cancers correlate with exposure to sunlight. ...
Background:
Sunlight represents the primary threat to mitochondrial integrity in skin given the unique nature of the mitochondrial genome and its proximity to the electron transport chain. The accumulation of mitochondrial DNA (mtDNA) mutations is a key factor in many human pathologies and this is linked to key roles of mitochondrial function in terms of energy production and cell regulation.
Objective:
The main objective of this study was to evaluate solar radiation induced changes in mitochondrial integrity, function and dynamics in human skin cells using a Q-Sun solar simulator to deliver a close match to the intensity of summer sunlight.
Methods:
Spontaneously immortalised human skin epidermal keratinocytes (HaCaT) and Human Dermal Fibroblasts (HDFn) were divided into two groups. Group A were irradiated once and Group B twice 7days apart and evaluated using cell survival, viability and mitochondrial membrane potential (MMP) and mass at 1, 4 and 7days post one exposure for Group A and 1, 4, 7 and 14days post second exposure for Group B.
Results:
Viability and survival of HaCaT and HDFn cells decreased after repeat exposure to Simulated Sunlight Irradiation (SSI) with no recovery. HDFn cells showed no loss in MMP after one or two exposures to SSI compared to HaCaT cells which showed a periodic loss of MMP after one exposure with a repeat exposure causing a dramatic decrease from which cells did not recover. Mitochondrial Mass in exposed HDFn cells was consistent with control after one or two exposures to SSI; however mitochondrial mass was significantly decreased in HaCaT cells.
Conclusion:
Data presented here suggests that mitochondria in epidermal cells are more sensitive to sunlight damage compared to mitochondria in dermal cells, despite their origin, confirming a skin layer specific sensitivity to sunlight, but not as expected.
... The absorption of UVR by different chromophores such as DNA-generated photoproducts, urocanic acid (UCA) transformed in cis-UCA or membrane components that lead to oxidative stress (Halliday et al., 2008;Nghiem et al., 2002) can induce stimulation of immunosuppressive cytokines (e.g. IL4 and IL10), alteration of the function of epidermal dendritic Langerhans cells and mast cells, thus leading to defects in antigen presentation and suppression of IL12 production (an immunoproliferative cytokine) (Halliday et al., 2008). ...
... The absorption of UVR by different chromophores such as DNA-generated photoproducts, urocanic acid (UCA) transformed in cis-UCA or membrane components that lead to oxidative stress (Halliday et al., 2008;Nghiem et al., 2002) can induce stimulation of immunosuppressive cytokines (e.g. IL4 and IL10), alteration of the function of epidermal dendritic Langerhans cells and mast cells, thus leading to defects in antigen presentation and suppression of IL12 production (an immunoproliferative cytokine) (Halliday et al., 2008). The net result is suppression of cell-mediated immunity. ...
... The net result is suppression of cell-mediated immunity. In turn, UVR-induced immunosuppression can further impact on critical stages of specific diseases, as occurs in herpes-virus infections or skin cancer (Halliday et al., 2008). ...
... UV radiation increases the risk of lip, basal cell, and squamous cell skin carcinoma, cutaneous malignant melanoma, and non-melanoma skin cancers, and may increase the risk of several eye diseases such as cataracts, certain conjunctival neoplasms, and ocular melanoma [160]. Sun exposure may also suppress the immune system [161], and results in the production of reactive oxygen species, which may indirectly disrupt cellular pathways [4,161]. ...
... UV radiation increases the risk of lip, basal cell, and squamous cell skin carcinoma, cutaneous malignant melanoma, and non-melanoma skin cancers, and may increase the risk of several eye diseases such as cataracts, certain conjunctival neoplasms, and ocular melanoma [160]. Sun exposure may also suppress the immune system [161], and results in the production of reactive oxygen species, which may indirectly disrupt cellular pathways [4,161]. ...
This review examines the beneficial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-inflammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultraviolet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ultraviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non-Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Thus, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -independent pathway is necessary to understand how they influence the course of many human diseases.
... Ultraviolet (UV) radiation exposure is the most important cause of sunburn and erythema, acting also as a carcinogenic component even if only a small percentage of UVB radiation reaches the earth (around 0,5%) [84][85][86][87][88]. The continuous exposure to sunlight is also the cause of premature skin aging [89,90]. Kim et al., in 2008 [91] investigated the effects of haginin A, a metabolite of Lespedeza cyrtobotrya, on melanogenesis in Melan-a cells considering the extracellular signal-regulated protein kinase (ERK) and Akt/protein kinase B (PKB) pathway activation, using the zebrafish as experimental model. ...
... Kim et al., in 2008 [91] investigated the effects of haginin A, a metabolite of Lespedeza cyrtobotrya, on melanogenesis in Melan-a cells considering the extracellular signal-regulated protein kinase (ERK) and Akt/protein kinase B (PKB) pathway activation, using the zebrafish as experimental model. The Lespedeza species (Leguminosae) are known to produce a number of unique isoflavonoids and also have antioxidant activity [89]. A down-regulation of melanin synthesis in Melan-a cells was induced by haginin A, causing hypopigmentary effects. ...
The zebrafish is considered one of the most versatile experimental animal models. The transparency of the embryos, the small size, the rapid development and the homology with higher vertebrates have made the zebrafish a valuable model also for drug screening. Its use is closely related for the determination of bioactivity, toxicity and off-target side effects of novel drug candidates, which also allows a thorough evaluation of new targets; thus, it may represent a suitable model for drug screening and the optimization of novel candidates. Flavonoids are polyphenolic compounds widely present in fruits, vegetables and cereals. Polyphenols are important for both plants and humans, considering their involvement in defense mechanisms, particularly against oxidative stress. They protect plants from biotic and abiotic stressors and prevent or treat oxidative-based human diseases. For these reasons, polyphenols are used as nutraceuticals, functional foods and supplements by the pharmaceutical industry. Therefore, the most relevant findings on zebrafish as a useful experimental model to study oxidative stress-linked disorders, focusing on the biological activities of flavonoids, are here summarized and reviewed.
... There is evidence that risk of melanoma is also related to intermittent exposure to UV, especially in childhood, and to exposure to sunlamps. However the latter results are still preliminary (Gary, 2008;Richard et al, 2006;Rona, 2006;Karen et al, 2005). The risk of UV radiation-related health effects on the eye and immune system is independent of skin type (Vladislava, 2005). ...
... The Solar radiation which reaches the surface of the Earth consists of a direct component (Sunlight) and a diffuse or scattered component (skylight). The total radiation, sunlight plus skylight, is designated global radiation (Sara et al., 2011;Gary et al., 2008;Sara, 2006;Jean, 2000;Defey, 1982). The global UV radiation is attenuated in the atmosphere principally by the following effects: a. Absorption by atmospheric ozone which is concentrated in a layer between 10 and 50km above sea level with a concentration maximum of about 10 ppm at an altitude of about 25 km. ...
Solar radiation data for 40 years collected from the meteorological center have been used to study the
variation of solar radiation. Also data from the health management board for disease of the skin and
subcutaneous tissue was used to correlate the solar insolation variation with the frequency of cases
reported. The result shows that; solar radiation intensity is increasing over the years. An individual
remaining in the sun in Yola receives an average solar insolation of 232.45 Js-1m-2 i.e. 1m2 of the body
exposed to the sun in Yola receives solar energy of about 232.45 J every second and 20.084 MJ every
day. An adult of average body surface area of about 1.8 m2, receives an average energy of about 418.4 J
every second he spends labouring outside. Also if likened to ionizing radiation and considering that the
size of a typical mammalian cell ˜ 10 μm, the energy mention above has the potential of cursing about
4.2663 x 107 ion pair per cell, with ion pairs giving rise to break in the chemical bond. There is a strong
positive correlation (R = 0.8138) between the solar insolation and number of reported cases of the
disease of the skin and subcutaneous tissue. A population growth weighed ratio of the disease cases with
years could be very useful for a comprehensive result.
... Ultraviolet (UV) radiation from sunlight is the main cause of skin cancer [1], and also causes chronic damage to the eye, including ocular cancer [2]. SWI/SNF is a chromatin-remodeling complex that regulates chromatin structure. ...
... Mean shown as horizontal line. Statistical comparisons as described in Fig. 2 1 Megalocytic cells were observed in these corneas. 2 Usually accompanied by some inflammatory cells. 3 A few megalocytic cells also present. ...
Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm-/- mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm-/- mice, with both or a single Trp53 allele were exposed to UV for 2 or 25 weeks. In wild type mice the central cornea and stroma became atrophic with increasing time of exposure while the peripheral regions became hyperplastic, presumably as a reparative process. Brm-/-, Trp53+/-, and particularly the Brm-/- Trp53+/- mice had an exaggerated hyperplastic regeneration response in the corneal epithelium and stroma so that the central epithelial atrophy or stromal loss was reduced. UV induced hyperplasia of the epidermis and corneal epithelium, with an increase in the number of dividing cells as determined by Ki-67 expression. This response was considerably greater in both the Brm-/- Trp53+/+ and Brm-/- Trp53+/- mice indicating that Brm protects from UV-induced enhancement of cell division, even with loss of one Trp53 allele. Cell division was disorganized in Brm-/- mice. Rather than being restricted to the basement membrane region, dividing cells were also present in the suprabasal regions of both tissues. Brm appears to be a tumour suppressor gene that protects from skin and ocular photocarcinogenesis. These studies indicate that Brm protects from UV-induced hyperplastic growth in both cutaneous and corneal keratinocytes, which may contribute to the ability of Brm to protect from photocarcinogenesis.
... UV is a critical environmental component that causes sunburn, photoaging, and cancer (2). UV can also lead to alteration of the immune environment, thereby increasing our susceptibility to cancer (3). ...
... UV can also lead to alteration of the immune environment, thereby increasing our susceptibility to cancer (3). However, the beneficial effects of both UVA and UVB radiation are numerous, including synthesis of vitamin D and production of antimicrobial peptides (2,4). UV has been used as a therapy in several diseases such as psoriasis, graft-versus-host disease, and atopic dermatitis (5)(6)(7). ...
Ultraviolet radiation is a pervasive stimulus with wide-ranging effects on all living forms. The effects of UV vary from physiological to pathological, depending on levels of exposure, but the immune response at the organismal level is not well understood. We use the zebrafish embryo and larva to study immune responses to UV stress in vivo. UV exposure causes inflammation characterized by systemic induction of proinflammatory cytokines. Leukocytes are an important component of this systemic response and upregulate IL-1β expression proportional to the dose of UV exposure. Increased levels of this proinflammatory cytokine counteract the lethal effect of high doses of UV.
... Solutions of different concentrations of the purified fraction of I. edulis leaves extract (2,5,10,20,40,60, 80 and 100 µg/mL) were prepared from a stock solution (1 mg/ mL) solubilized in phosphate-buffered saline (PBS) (pH 7.4). The concentrations of the solutions added into the wells were chosen since they are not cytotoxic (100% of cell viability at 156 µg/mL), according to results of previous studies performed with this fraction in L929 fibroblast cells using neutral red as a marker of cell [10]. ...
Natural antioxidants have attracted attention for their therapeutic use as photochemopreventive agents. Inga edulis leaves extract and its purified fraction have high polyphenolic content and high antioxidant capacity. In addition, they presented UV photostability and low citotoxicity in fibroblast cells. In this context, this study first aimed at development of topical formulation containing purified fraction of I. edulis extract and the evaluation of skin penetration of the compounds. Moreover, the photoprotective/photochemopreventive potential of the formulation containing I. edulis purified fraction were investigated in vitro and in vivo. The topical formulation containing 1% of the purified fraction of I. edulis increased the endogenous antioxidant potential of the skin, and vicenin-2 and myricetin compounds were able to penetrate the epidermis and dermis. Additionally, the purified fraction (25 and 50 mg/mL) showed a photoprotective effect against UVA and UVB radiation in L929 fibroblast cells. In vivo studies have shown that the formulation added with purified fraction provided an anti-inflammatory effect on the skin of animals after UVB exposure, since it was observed a reduction in MPO activity, IL-1β and TNF-α cytokines, and CXCL1/KC chemokine concentrations. In conclusion, the purified fraction of I. edulis, rich in phenolic compounds, when incorporated in topical formulation, appears as an alternative to prevent skin damages induced by UV radiation, due to its antioxidant and anti-inflammatory properties.
... While solar ultra violet beam (UVB) is the major natural source of vitamin D by triggering its dermal biosynthesis (Pike and Christakos, 2017), direct exposure to the same wavelengths of UVB has been known as the main culprit in development of skin cancers (Pfeifer and Besaratinia, 2012;Wyatt et al., 2015). It is believed that UVB causes molecular damage to the skin whereby suppresses immune system and contributes to immune-based skin conditions including hyperkeratosis and malignancies (Halliday et al., 2008). On the contrary, melanoma, the deadliest skin cancer, is commonly seen skin cancers (NMSC) have been investigated (Lee and Gyu Song, 2015;Von Schuckmann et al., 2016;Morgado-Águila et al., 2020). ...
Background and objective:
Sunlight exposure, the main source of endogenous vitamin D synthesis, may increase the risk of non-melanoma skin cancers (NMSC) development. Vitamin D receptor (VDR) polymorphisms are associated with various malignancies. This study aimed to examine the associations between vitamin D status and VDR FokI polymorphisms in Iranian subjects with NMSC.
Materials and methods:
This case-control study included 73 diagnosed cases of NMSC and 72 healthy controls from dermatology clinics at Razi Hospital, Tehran, Iran. A questionnaire was used to assess sunlight exposure. The extracted DNA from whole blood samples was genotyped and serum concentrations of 25-hydroxycalciferol (25(OH)D)) and intact parathyroid hormone (iPTH) were measured.
Results:
We found a significant higher duration of cumulative sunlight exposure in cases compared with controls (p<0.001). However, 25(OH)D and iPTH concentrations were not significantly different between cases and controls (30±15 vs. 29±15 ng/mL, p=0.78 and 46.0±20 vs. 40.5±23 pg/mL, p=0.14, respectively). We did not observe any significant increased risk of NMSC due to f allele, as compared with FF (OR =2.33, 95% CI 0.81-6.75, p=0.12).
Conclusion:
Though sunlight exposure was associated with increased NMSC risk, there were no significant associations between vitamin D status or VDR FokI polymorphisms with NMSC development in our subjects.
... The sunlight elevates the production of reactive oxygen species (ROS) and some mediators such as prostaglandins, histamine, IL-4, IL-1β, and TNF-α, promotes mast cell, DC, NK-T, T-reg, and macrophage functions, and decreases IL-12 and Th-1 cytokine production (28). Although sunlight can be immunosuppressive, it is beneficial for vitamin D synthesis. ...
... Today the most common skin classification system is the Fitzpatrick Scale ranging from Type One; very fair skin that always burns and never tans, to Type Seven, dark skin that never burns (Roberts 2009). We also know more about the effects of sun exposure; UV light is a potential mutagen, producing oncogenic DNA mutations; inactivation of tumor suppressors, and also stimulates clonal expansion of cells bearing these defects (Halliday et al. 2008). Particularly vulnerable is mitochondrial DNA (mtDNA) as it has limited repair mechanisms (Cline 2012); however, damage to mtDNA can serve as a marker of sun exposure, with the percentage of genomes carrying several deletions indicative of cumulative damage (Powers et al. 2016). ...
Purpose: In the 60 years since the inaugural edition of the International Journal of Radiation Biology, much of our understanding of the biological effects of solar radiation has changed. Earlier in the century sunlight played a “hero’s” role in reducing disabling rickets, while today debate still continues on the amount of sun required before exposure reveals the “villainous” side of solar radiation. Although knowledge of the Ultra Violet (UV) component of sunlight as a carcinogen has become widespread, skin cancer rates are still rising yearly. Twentieth century attitudes have seen an about-face in the field of dermatological sun protection, with sunscreens changing from recipes designed to promote a ‘healthy tan’ to formulations proven to block both ultraviolet B (UVB) and more recently, ultraviolet A (UVA), in order to minimise premature sun-aging and skin cancer risk. In the early 1960s, DNA was first found to exist within mitochondria, while recently the connections between mitochondrial changes and UV radiation exposure have been expanded. Sixty years ago, understanding of the endocrine systems of mammals was enjoying its infancy.
Conclusion: Early discoveries that light, particularly natural light, could have profound effects on functions such as sleep patterns and hormonal balance were made, while today more advanced knowledge has led to lighting improvements having pronounced effects on human wellbeing. Photosensitisation 60 years ago was a health concern for both humans and their domestic animals, while today chemically engineered photosensitising drugs can be administered along with highly directed light to pinpoint delivery targets for drug action. Life on earth is inextricably bound up with solar radiation. This review attempts to outline many of the ways in which our opinions about solar radiation have changed since the Journal’s inception.
... According to several bibliographical sources, thermal water can act as moisturizing (ELKHYAT et al., 2004;RAWLINGS, HARDING, 2004), presents anti-irritant, anti-pruritic, anti-inflammatory, immunomodulatory and skin-repairer barriers properties (FAÍLDE, MOSQUEIRA, 2006;PRISTA, BAHIA, VILAR, 1992;WILHELM, FREITAG, WOLFF, 1994;SALMON, ARMSTRONG, ANSEL, 1994;HALEVY, SUKENIK, 1998;MATZ, ORION, WOLF, 2003;BOCK, SCHURER, SCHWANITZ, 2004;YURTKURAN et al., 2006). It can also aid on the control of the pH of the skin (WILLIAMS et al., 2007) and acts as analgesic and in the circulatory system (MATZ, ORION, WOLF, 2003;ROQUES, DE BOISSEZON, QUENEAU, 2009;POENSIN et al., 2003), besides of their (GOMES, SILVA, 2007;VILE, TYRRELL, 1995;HALLIDAY et al., 2008). ...
... Keratinocytes, the major population of the epidermis cells, exposed to UVB radiation synthesize and release pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-10 and IL-8 (Grone, 2002). Acute UVB radiation can be directly absorbed by DNA or by other chromophores, which can result in the production of ROS that induce an inflammatory response and sunburn in the skin (Halliday et al., 2008). The responses generated by the induction of ROS are complex and can eventually lead to the oxidation of proteins and DNA and the peroxidation of lipids. ...
Solar ultraviolet radiation exposure, particularly UVB rays (280–320 nm), can lead to skin lesions, photo-carcinogenesis and acceleration of skin photoaging since UVB radiation may reach both the epidermal and dermal layers of the skin. Treatments that can ameliorate UVB-induced skin damage include natural extracts, which can act as skin photochemoprotective agents. Byrsonima crassifolia is widely used in the folk medicine. Previously studies have shown high antioxidant activity of BC leaves extracts. In this study we described the first photochemoprotective potential of Byrsonima crassifolia extract (BCP) and fraction (BCF) against UVB-induced damage in keratinocytes and the ability of topical formulations with BCP or BCF to increase the antioxidant activity in pig ear skin. The results of characterization of BCP and BCF indicate that the phenolic content was increased twofold after an enrichment process for obtaining BCF. Despite differences in the phenolic content, both BCP and BCF exhibited similar IC 50 values for lipid peroxidation and the DPPH% method during the an-tioxidant activity study. However, for the chemiluminescence assay using the xanthine/luminol/XOD, BCF exhibited higher antioxidant activity than BCP. The different phenolic content in BCP and BCF did not influence their photochemoprotective activity in HaCaT cells, and both samples exhibited similar levels of protection. After treatment with BCP and BCF (1.2–5 μg/mL) and UVB irradiation exposure, the effect of lipid peroxidation in vitro was maintained in cell culture, and both IL-6 and TNF-α secretion and NF-κB activation were suppressed. After the development of the different formulations, BCP and BCF increased the antioxidant activity on skin and the formulation containing BCF showed higher skin retention, especially for (+) catechin, which was able to pass through the stratum corneum. Based on these findings, BCF could be topically applied to prevent/treat the damage induced by UVB radiation in the skin.
... However, porous structures expose the skin to dangerous UV rays. Though a certain degree of UV exposure is required for vitamin D synthesis in human body, over exposure can result in erythema, sun-tanning, skin-cancer, etc. [2][3][4][5][6]. The UV resistance of textile clothing is expressed by UPF (ultraviolet protection factor), which rates the extent of sunburn protection provided by the textile. ...
The present study deals with the optimization of multiple quality parameters of single jersey and 1×1 rib knitted fabrics using the desirability function approach. Comfort properties such as air permeability, thermal conductivity and safety properties such as UV protection are combined to yield an ‘overall desirability’ varying from zero to one. The overall desirability has been maximized versus target values for air permeability, thermal conductivity and UV resistance. Experimental validation confirms that the proposed method can be used to design a knitted fabric with desired comfort and UV resistance characteristics. © 2016, Association Nonwoven Fabrics Industry. All rights reserved.
... Thus, the solar radiation which reaches the earth surface consists of ultraviolet rays (290 -380 nm), visible rays (380 -770 nm), and infrared rays (more than 770 nm). The UV rays have significant impact on human health, affecting the skin, immune system, eye etc. [6][7][8]. The UV rays affect the top layer of the skin, leading to premature aging, roughing, wrinkles and basal cell cancer. ...
The ultraviolet protection factors (UPF) of single jersey and 1×1 rib knitted fabrics have been investigated using Taguchi experimental design. The effects of loop length, knitting speed or carriage speed, yarn input tension and yarn fineness have been studied in the presence of two unavoidable and uncontrolled noise parameters. The results show that the yarn count and loop length have significant impact on the UPF for both single jersey and 1×1 knitted fabrics. A ranking of the four controlled parameters and the percentage contribution of each of these parameters have also been determined. The optimum parameters that correspond to the highest S/N ratio of UPF have also been evaluated.
... Thus, the solar radiation which reaches the earth surface consists of ultraviolet rays (290 -380 nm), visible rays (380 -770 nm), and infrared rays (more than 770 nm). The UV rays have significant impact on human health, affecting the skin, immune system, eye etc. [6][7][8]. The UV rays affect the top layer of the skin, leading to premature aging, roughing, wrinkles and basal cell cancer. ...
The ultraviolet protection factors (UPF) of single jersey and 1×1 rib knitted fabrics have been investigated using Taguchi experimental design. The effects of loop length, knitting speed or carriage speed, yarn input tension and yarn fineness have been studied in the presence of two unavoidable and uncontrolled noise parameters. The results show that the yarn count and loop length have significant impact on the UPF for both single jersey and 1×1 knitted fabrics. A ranking of the four controlled parameters and the percentage contribution of each of these parameters have also been determined. The optimum parameters that correspond to the highest S/N ratio of UPF have also been evaluated.
... Over exposure to UVR may lead to several fatal diseases, such as erythema, basal cell and squamous cell carcinoma, photokeratitis and immune-suppression. (Gallagher & Lee, 2006;Halliday, Norval, Byrne, Huang, & Wolf, 2008;MacKie, 2000). Hence, adequate level of protection from UVR is essential. ...
The effect of porous yarn structure on ultraviolet (UV) radiation protection by cotton fabric has been investigated. Fabrics with porous yarn structure showed higher ultraviolet protection factor (UPF) in comparison with that of fabrics woven from equivalent normal yarns. Fabric samples having different thickness and individual pore size, at same cover %, were produced by adjusting yarn count and thread density. UPF of UV absorber treated cotton fabrics increased continuously with decreasing thickness and reducing individual pore size when the fabric cover was kept constant at relatively higher levels (93 and 96%). For UV absorber treated cotton fabrics, individual pore size is the dominating factor for determining the UPF.
... At present, there is also an increasing need for antioxidant products including formulations to prevent skin oxidative dam- age [15,16]. Approximately 95% of UV radiation that reaches the earth's surface is composed of UVA and only 5% of UVB [17]. UV radiation produces free radicals in the skin, UVB directly affects the DNA while UVA radiation acts indirectly, through reactive oxygen species (ROS) intermediates formation which can promote lipid and protein oxidative damage181920. ...
Sunscreens are destined to topical application and should protect skin against ultraviolet radiation; furthermore they are toxic substances and should not reach the bloodstream, so they have to be retained in the skin. In the present work, an oil-in-water (O/W) photoprotective and antioxidant nanoemulsion (NE) containing chitosan was developed. Preliminary studies were performed aiming to choose the surfactant to be used in this nanoemulsion; stability of the formulas was determined by dynamic light scattering after their preparation and after 7 days. A blend of surfactants, polyoxyethylene sorbitan monooleate and sorbitan monooleate was selected for the preparation of the nanoemulsion, as well as the following organic sunscreens: benzophenone-3, diethylamino hydroxybenzoyl hexylbenzoate, octocrylene and octylmethoxycinnamate, and also pomegranate antioxidant extract and chitosan. The antioxidant extract with the highest antioxidant activity was chosen based on a screening of plant extracts by DPPH• (2,2-diphenyl-1-picrylhydrazyl) assay. Photostability of the sunscreens and in vitro efficacy and safety of the formulations were also evaluated. Results showed that the developed photoprotective and antioxidant nanoemulsion containing chitosan was stable for at least six months, photostable when irradiated in a solar simulator and effective. Additionally, chitosan acted by promoting retention of the formulation in epidermis, thus increasing formulation safety.This article is protected by copyright. All rights reserved
... Sunburn, erythema, cancer of the lip, basal cell, and squamous cell carcinoma are some of the most common skin diseases caused by UV radiation. Eye diseases includes photokeratitis, photo conjunctivitis, and cataracts [2,3]. Clothing, sunscreen, sunglasses, umbrellas, and hats are commonly used for sun protection [4][5][6][7]. ...
Ultraviolet protection factor (UPF) of woven fabrics is modeled by using two soft computing approaches, namely adaptive network based fuzzy inference system (ANFIS) and artificial neural network (ANN). Three fabric parameters: proportion of polyester in weft yarns, weft count, and pick density are used as input parameters for predicting fabric UPF. Two levels (low and high) of membership function for each of the input parameters are used to reduce the complexity of ANFIS. The eight linguistic fuzzy rules trained by ANFIS are able to explain the relationship between fabric parameters and UPF. A comparison between ANFIS and ANN models is also presented. Both the models predict the UPF of fabrics with very good prediction accuracy in the testing data sets. © 2014, Association Nonwoven Fabrics Industry. All rights reserved.
... Sunburn, erythema, cancer of lip, basal cell and squamous cell carcinomas are some of the common skin diseases which are caused by UVR. Eye diseases include photokeratitis, photoconjunctivitus and cataracts (Gallagher & Lee, 2006;Halliday, Norval, Byrne, Huang, & Wolf, 2008). A sharp increase in the number of newly identified skin cancer patients has been noticed in countries with high solar exposure such as Australia and South Africa. ...
Ultraviolet protection factor (UPF) of fabrics made of 100% cotton and 100% bamboo viscose yarns were studied and a comparative analysis carried out using curve fitting technique. Bamboo viscose fabrics showed higher shrinkage, cover percentage, areal density and UPF compared to its cotton counterpart woven with identical yarn counts and fabric sett. However, the predictive model of cotton fabric UPF using fabric areal density as the input was able to estimate the UPF of bamboo viscose fabrics with very good accuracy. Furthermore, the 100% cotton and 100% bamboo viscose fabrics showed the same UPF if their cover percentage and areal density is similar. It is inferred from the analysis that the apparently higher UPF of bamboo viscose fabrics can be attributed to their higher cover percentage and areal density instead of bamboo’s inherent UV protective property which has been claimed in various literatures.
... In addition, UVB acts on the initiation, promotion and progression of cancer through the direct attack in the pyrimidine bases promoting dimerization and damaging the cell DNA (Tsilimigaki et al., 2003;Afaq, 2011). UVA are completely transmitted to Earth and this radiation penetrates deeper into the skin and produces reactive oxygen species (ROS) such as hydroxyl radicals, singlet oxygen and hydrogen peroxide (Matts, 2006;Halliday et al., 2008). These radicals damage proteins, lipids and DNA causing serious tissue lesions (Ichihashi et al., 2003;Jiang et al., 2010;Afaq & Katiyar, 2011). ...
Plant extracts have been considered viable options to be used in combination with organic sunscreens to
increase the solar protection factor. The aim of the present study was to evaluate the total phenol and
flavonoid contents and the antioxidant and photoprotective potential of plant extracts associated with
synthetic organic filter in new proposal gel and emulsion formulations. Hydroalcoholic extracts of Mikania
glomerata, Aesculus hippocastanum, Matricaria chamomilla and Ginkgo biloba at 50% and glycolic
extract of Achillea millefolium at 20% were commercially obtained. The quantification of total phenol and
flavonoid contents was determined by spectrophotometric method. Antioxidant activity was evaluated by
DPPH assay. Gel and emulsion formulations with these plant extracts were prepared and the absorption
spectra were obtained in the range of 290 to 450 nm. The Sun Protection Factor (SPF) was determined by
applying the Mansur equation. The total phenol content varied from 0.02±0.010 to 1.52±0.04 g/mL, while
the flavonoid values were from 0.00 ± 0.000 to 222.30±5.00 mg/mL in the extracts. The highest radical
scavenging activity was showed by A. hippocastanum with IC50 = 82.69±3.88 μg/mL. Considering the gel
formulations, except the only one containing extracts of M. chamomilla (SPF = 11.55), there was an
increase in SPF value when compared to the standard (organic filter with SPF = 11.66). The SPF of the
emulsion formulations varied from 13.39 to 15.40. The obtained results suggest that the plant extracts can
constitute an important strategy to develop new products with improved photoprotective effect.
... Sunburn, erythema, cancer of the lip, basal cell and squamous cell carcinoma are some of the most common skin diseases which are caused by UVR. Eye diseases include photokeratitis, photoconjunctivitis and cataracts (2,3). ...
Ultraviolet protection factor (UPF) of fabric is mainly influenced by fabric cover which is dependent on the primary fabric construction parameters like yarn count and thread density. UPF can be modeled by using these primary fabric parameters as inputs by the help of nonlinear regression as well as artificial neural network (ANN).
The objective of this study is to develop prediction models for fabric UPF using nonlinear regression and ANN techniques and compare their relative efficacy.
Thirty-six woven fabric samples were produced by varying weft related parameters like proportion of polyester, weft count and pick density. Nonlinear regression and ANN models were developed from same experimental data sets. Prediction accuracy of both the models was evaluated and compared. Trend analysis was performed to check the generalization ability of the ANN model.
UPF was well estimated from the three primary fabric parameters by both the nonlinear regression and ANN models. However, ANN model demonstrated better prediction accuracy than the nonlinear regression model.
Fabric UPF can be predicted with high degree of accuracy using ANN and nonlinear regression models. These models can be used to estimate the UPF of woven fabrics without spectrophotometer based test.
... Nonphagocytic NADPH oxidases also exist and are thought to function in intracellular signaling pathways [3]. 1 O 2 formation occurs mainly in light-exposed tissue such as skin and eye [20,21]. In this respect, it has been suggested that 1 O 2 but also O 2 •can be produced when endogenous chromophores such as flavins, NADH/NADPH, and some sterols absorb ultraviolet radiations (mainly UVA) [22]. ...
Plants have evolved antioxidant molecules to help them withstand environmental stresses. Humans may also benefit from these defense molecules through their consumption in fruits and vegetables. Dietary antioxidants are indeed believed to play a very important role in the human body defense system, protecting, as in plants, against oxidative damage induced by Reactive Oxygen Species (ROS), which are known to be involved in the pathogenesis of aging and many degenerative diseases such as cardiovascular diseases and cancers. In this review, we compare the systems involved in ROS production and scavenging in humans and in plants. We focus mainly on the description of the best-known dietary antioxidants: ascorbate (vitamin C), tocopherols (vitamin E), carotenoids, and phenolic compounds. Their redox properties, metabolism and functions are discussed from both a human and a plant perspective.
... The development of topical and systemic acting photoprotective agents is increasing due particularly to the number of disorders related to ultraviolet (UV) radiation exposure. Single overexposure to sun results in erythema and sunburn; on the other hand, repetitive exposure to sun causes premature skin aging (Halliday et al., 2008;Marrot and Meunier, 2008) and skin cancer (Afaq et al., 2005;Gonzalez et al., 2008;de Gruijl and Ananthaswamy, 2010;Sambandan and Ratner, 2011). In the eye, photochemical damage includes oxidative events and retinal cell death by apoptosis (Young, 2006) which causes a progressive vision loss (Boulton et al., 2001). ...
... Surgery is usually well tolerated, but occasionally may result in significant morbidity, wound infection, and excessive scarring. Chronic solar ultraviolet radiation exposure is the most important risk factor for the development of SCC, inducing DNA damage which can lead to keratinocyte transformation and modification of the cutaneous immune response [2,3]. Understanding the molecular alterations that underlie SCC may allow the identification of novel therapeutic targets and facilitate the development of rational therapies. ...
Retinoid therapy is used for chemo-prevention in immuno-suppressed patients at high risk of developing skin cancer. The retinoid signalling molecule, tripartite motif protein 16 (TRIM16), is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid-sensitive neuroblastoma. We sought to determine the role of TRIM16 in skin squamous cell carcinoma (SCC) pathogenesis. We have shown that TRIM16 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC. SCC cell lines exhibited lower cytoplasmic and nuclear TRIM16 expression compared with primary human keratinocyte (PHK) cells due to reduced TRIM16 protein stability. Overexpressed TRIM16 translocated to the nucleus, inducing growth arrest and cell differentiation. In SCC cells, TRIM16 bound to and down regulated nuclear E2F1, this is required for cell replication. Retinoid treatment increased nuclear TRIM16 expression in retinoid-sensitive PHK cells, but not in retinoid-resistant SCC cells. Overexpression of TRIM16 reduced SCC cell migration, which required the C-terminal RET finger protein (RFP)-like domain of TRIM16. The mesenchymal intermediate filament protein, vimentin, was directly bound and down-regulated by TRIM16 and was required for TRIM16-reduced cell migration. Taken together, our data suggest that loss of TRIM16 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity.
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
... (Enseleit et al., 2006; Ammoury et al., 2008 ). UV light exposition increases the density of neutrophils , differentiated macrophages and mononuclear cells with prominent lysosomes in skin (Cooper et al., 1993; Kabashima et al., 2007; Halliday et al., 2008). These infiltrating cells may capture amiodarone with high efficiency, especially cells of the monocyte–macrophage lineage, already known to be prominent in the physiopathology of the lung and kidney diseases induced by the drug (Myers et al., 1987; Pintavorn and Cook, 2008), and abundant in the pigmented skin of the affected patients (paraffin sections; Ammoury et al., 2008; electron microscopy, Miller and McDonald, 1984). ...
Tissue deposits of the anti-arrhythmic drug amiodarone are a major source of side effects (skin discoloration, etc.). We addressed the mechanism of the concentration of amiodarone in cells, and characterized the resulting vacuolar cytopathology and its evolution towards macroautophagy.
Sequestration of amiodarone in human cells (macrophages, smooth muscle cells, HEK 293a cells) was evaluated using its violet fluorescence and cytopathology using GFP-conjugated subcellular markers. Autophagic signalling was probed by immunoblotting for the effector protein LC3. A patient biopsy of amiodarone-induced blue-gray skin discoloration was investigated for the presence of macroautophagy (immunofluorescence for LC3).
Most of the amiodarone (1-20 microM, 4-24 h) captured by cultured cells (macrophages were most avid) was present in enlarged vacuoles. The specific vacuolar ATPase (V-ATPase) inhibitors, bafilomycin A1 or FR167356, prevented vacuolization and drug uptake. Vacuoles in HEK 293a cells were positive for markers of late endosomes and lysosomes (GFP-Rab7, -CD63) and for an effector of macroautophagy, GFP-LC3. The vacuoles accumulated endogenous LC3 and filled with lipids (Nile red staining) following longer amiodarone treatments (> or =24 h). The electrophoretic mobility of both GFP-LC3 and endogenous LC3 changed, showing activation in response to amiodarone. Paraffin tissue sections of the pigmented skin exhibited granular LC3 accumulation in superficial dermis macrophages.
Vacuolar sequestration of amiodarone occurs at concentrations close to therapeutic levels, is mediated by V-ATPase and evolves towards persistent macroautophagy and phospholipidosis. This cytopathology is not cell type specific, but tissue macrophages appear to be particularly susceptible.
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.
Nanoemulsions (NEs), which is an attractive emulsion, has been widely used in a wide range of applications such as cosmetics, pharmaceuticals, medicine, and food and beverages. In cosmetics, it has been indicated that there is a close relationship between body care products and NEs; and NEs play a vital role in the development of advanced cosmetic formulations. In body care cosmetic formulations, NEs are commonly applied as medium for protection and controlled delivery of active agents in a diversity of formulations including shampoos, sunscreens, lotions, conditioners, deodorants, and hair serums. In this chapter, we provide a general description and definition about structural components, common preparation techniques, and outstanding characteristics of NEs in the cosmetic field. Furthermore, some detailed body care products designed and developed based on NEs are also discussed and depicted in deep.
Despite ever-increasing investment in biomedical research, there has been a significant decline in the number of new drug approvals in recent years. In an effort to improve productivity, the drug discovery community has increasingly looked to biotherapeutics such as antibodies, vaccines, nucleic acids, and peptides.
Chemical biology is an emerging field at the interface between chemistry and biology. It utilises the tools and techniques of chemical synthesis to study and influence biological systems. Recent developments in this area have great potential in addressing the productivity challenges expressed above. For example, chemical biology studies have already led to the identification of novel targets with exciting therapeutic potential and it is clear that the field will prove a key enabler of target discovery in the future. Moreover, the precise synthetic manipulation of biological molecules involved in many chemical biology approaches is now fuelling a new wave of chemically-modified biologics, 'chemologics', with unique properties. In these, and many other ways, chemical biology is a key discipline within 21st century drug discovery and the purpose of this book is to highlight the most important developments. It provides a valuable resource for scientists in academia and industry who are looking to build their knowledge of this hot topic.
The individual chapters cover crucial areas including chemical proteomics, chemical genetics, post-translational modifications, epigenetics, RNA interference, PROTACS, antibody-drug conjugates, and chemologics.
Protective textiles are saving human beings from various adverse environmental conditions like fire, heat, bullets, microorganisms, mosquito bites, etc. In connection with flame-resistant textiles, fish DNA, casein, whey protein, and wastage plantbased bio-macromolecules, such as spinach juice, banana pseudostem sap, coconut shell extract, and so on, are well reported as flame-resistant materials on cellulosic, lignocellulosic, and protein-based textile products. Apart from it, different nanobased metal oxides are also very popular because of their fire-retardant efficacy at low add-on percentage. Recently, bulletproof and the stab-resistant textile materials are also capturing the defense market very quickly. Concerning this area, designing lightweight bulletproof materials is the major target for the researchers for its wide application. As regards mosquito-repellent protective textiles, different synthetic-based products and eco-friendly plant-based oils (like citronella, clove, eucalyptus) are explored by researchers for their efficient mosquito- repellent properties. Besides, to evaluate the efficacy of mosquito repellency, cone tests, cage tests, etc., are also developed by research societies. Wastage plant extracts like coconut shell extract, neem, aloe vera, etc., are reported to have excellent microorganism protective efficacy when it is applied on the fabric surface.
Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, causes mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together these changes facilitate the development of skin tumors. The vitamin D hormone, 1,25-dihydroxyvitamin D3, working via the vitamin D receptor and at least in part, through endoplasmic reticulum protein 57, reduces oxidative DNA damage by decreasing reactive oxygen and nitrogen species. This is facilitated by increased metallothionein expression and increased nuclear factor-erythroid-2-related factor 2 transcriptional activity. 1,25-Dihydroxyvitamin D3 also enhances DNA repair, through decreased reactive oxygen and nitrogen species, increased p53 expression and/or activation, increased energy availability in the cell, increased phosphatase and tensin homolog deleted on chromosome 10, and increased repair proteins. Reduced DNA damage and reduced reactive oxygen and nitrogen species reduce UV-induced immune suppression. Several related metabolites and vitamin D-like compounds also reduce DNA damage and immune suppression after UV. These protective effects of 1,25-dihydroxyvitamin D and some related compounds result in less skin tumor formation after chronic exposure to UV.
Cotton knitted fabrics are popular for summer-wear and outer-wear due to their comfort. The typical porous structure of knitted fabrics, however, increases the risk of exposure of human skin to UV rays, resulting in skin cancer. Therefore a trade-off is required between the comfort and UV ray resistance of the fabric. In this study, an attempt was made to engineer single jersey and 1×1 rib knitted fabrics with optimum comfort and desired UV resistance. It was found that 1×1 rib knitted fabrics could provide better comfort and UV protection with respect to single jersey fabrics manufactured on the same gauge knitting machine. © 2016, Institute of Biopolymers and Chemical Fibres. All rights reserved.
Ultraviolet (UV) wavelengths in sunlight are the prime cause of skin cancer in humans with both the UVA and UVB wavebands making a contribution to photocarcinogenesis. UV has many different biological effects on the skin that contribute to carcinogenesis, including suppression of adaptive immunity, sunburn and altering the migration of mast cells into and away from irradiated skin. Many molecular mechanisms have been identified as contributing to skin responses to UV. Recently, using gene set enrichment analysis of microarray data, we identified the alternative complement pathway with a central role for factor B (fB) in UVA-induced immunosuppression. In the current study we used mice genetically deficient in fB (fB-/- mice) to study the functional role of the alternative complement pathway in skin responses to UV. We found that fB is required for not only UVA but also UVB-induced immunosuppression and solar-simulated UV induction of the oedemal component of sunburn. Factor B-/- mice had a larger number of resident skin mast cells than control mice, but unlike the controls did not respond to UV by increasing mast cell infiltration into the skin. This study provides evidence for a function role for fB in skin responses to UV radiation. Factor B regulates UVA and UVB induced immunosuppression, UV induced oedema and mast cell infiltration into the skin. The alternative complement pathway is therefore an important regulator of skin responses to UV.
The objective of this study was to characterize the bactericidal effect of 461nm visible-light LED on three common foodborne bacteria: Escherichia coli O157:H7, Staphylococcus aureus and Vibrio parahaemolyticus. Tests were conducted against pathogen strains that were treated with 461nm LED for 10 h at . The E. coli (ATCC 43894, ATCC 8739 and ATCC 35150) and the S. aureus (ATCC 27664, ATCC 19095 and ATCC 43300) had average reductions of 2.5, 6.6, 1.5, 2.5 and 2.0 log CFU/mL, respectively, after they were exposed for 10 h to 461nm LED light (p
The objective of this work was to develop and evaluate the physical–chemical properties of oil-in-water nanoemulsions for application as nanocosmetics for sun protection. Oil-in-water dispersions were processed by ultrasound (US) to obtain small emulsion droplets. These emulsions were obtained in the presence of commercial nonionic surfactants based on polyoxides and avocado oil as the oil phase. The US generated small but unstable droplets. This problem was solved by using a different surfactant, with a longer ethylene oxide chain, able to promote stabilization by steric mechanisms. The light scattering technique was used to characterize the nanoemulsions by their dispersed droplets’ size, size distribution and variation of distribution with time (stability). Chemical and physical sunscreens – octyl methoxycinnamate (OMC) and titanium dioxide (TiO2), respectively – were added to the stable system. The anti-UVB activity of the nanoemulsions and their components were evaluated by the method of Mansur et al. (1986) and spectral transmittance. The solar protection factor (SPF) was proportional to the OMC and TiO2 concentrations. The in vitro OMC release was evaluated, and the presence of TiO2 in the nanoemulsion did not affect the release profile, which showed the diffusion-dependent kinetics of the active ingredient in the formulation.
– Photodynamic Therapy (PDT) is a promising modality to pre-cancerous and cancerous cutaneous lesions treatment. PDT is based on the combination by photo sensitizer which is selectively accumulated in the target tissue and illumination of the lesion with visible light, resulting in photo damage and subsequent cell death. Intensive basic and clinical research culminated in the worldwide PDT approval to non-melanoma skin cancer treatment such as basal cell carcinoma, scamous cell carcinoma and Bowen's syndrome. Pre-cancerous lesions like actinic keratoses have been successfully treated through the PDT. The article summarizes the basic PDT concepts including historical, photo sensitizers, light sources, mechanisms involved in PDT-mediated cancerous cell destruction, as well as the indications and limitations in photodynamic skin cancers' treatment. KEYWORDS – Skin cancer, photo sensitizers, photodynamic therapy. RESUMO – Terapia Fotodinâmica (TFD) é uma modalidade promissora para o tratamento de lesões cutâneas pré-cancerosas e cancerosas. TFD é baseada na combinação de um fotossensibilizante que se acumula seletiva-mente no tecido alvo e luz visível, resultando em fotodano e subsequente morte celular. Intensas pesquisas nas áreas básica e clinica ao redor do mundo levaram à aprovação da TFD para o tratamento de câncer de pele do tipo não-melanoma como, por exemplo, o carcinoma de células basais (CCB), o carcinoma de células escamosas (CCE) e a Síndrome de Bowen (SB). Lesões pré-cancerosas como a queratose aquitínica (QA) têm sido tratadas com sucesso por essa terapia. O artigo resume os conceitos básicos da TFD, incluindo histórico, conhecimento dos fotossensibilizantes, fontes de luz para iluminação, mecanismos envolvidos na destruição das células cance-rosas, bem como, as indicações e limitações do tratamento fotodinâmico dos cânceres de pele. PALAVRAS-CHAVE – Câncer de pele, fotossensibilizantes, Terapia Fotodinâmica.
Brm is an ATPase subunit of the SWI/SNF chromatin-remodelling complex. Previously, we identified a novel hotspot mutation in Brm in human skin cancer, which is caused by exposure to ultraviolet radiation (UVR). As SWI/SNF is involved in DNA repair, we investigated whether Brm-/- mice had enhanced photocarcinogenesis. P53+/- and Brm-/-p53+/- mice were also examined as the p53 tumor suppressor gene is mutated early during human skin carcinogenesis. Mice were exposed to a low-dose irradiation protocol that caused few skin tumors in wild-type mice. Brm-/- mice with both p53 alleles intact had an increased incidence of skin and ocular tumors compared to Brm+/+p53+/+ controls. Brm loss in p53+/- mice did not further enhance skin or ocular cancer incidence beyond the increased photocarcinogenesis in p53+/- mice. However, the skin tumors that arose early in Brm-/- p53+/- mice had a higher growth rate. Brm-/- did not prevent UVR-induced apoptotic sunburn cell formation, which is a protective response. Unexpectedly, Brm-/- inhibited UVR-induced immunosuppression, which would be predicted to reduce rather than enhance photocarcinogenesis. In conclusion, the absence of Brm increased skin and ocular photocarcinogenesis. Even when one allele of p53 is lost, Brm has additional tumor suppressing capability.
The cellular and molecular mechanisms by which UV radiation modulates inflammation and immunity while simultaneously maintaining skin homeostasis is complex and not completely understood. Similar to the effects of UV, IL-33 has potent immune-modulating properties that are mediated by the downstream induction of cytokines and chemokines. We have discovered that exposure of mice in vivo or human skin samples ex vivo to inflammatory doses of UVB induced IL-33 expression within the epidermal and dermal skin layers. Using a combination of murine cell lines and primary human cells, we demonstrate that both UV and the oxidized lipid platelet activating factor induce IL-33 expression in keratinocytes and dermal fibroblasts. Highlighting the significance of these results, we found that administering IL-33 to mice in vivo suppressed the induction of Th1-mediated contact hypersensitivity responses. This may have consequences for skin cancer growth because UV-induced squamous cell carcinomas that evade immunological destruction were found to express significantly higher levels of IL-33. Finally, we demonstrate that dermal mast cells and skin-infiltrating neutrophils closely associate with UV-induced IL-33-expressing fibroblasts. Our results therefore identify and support a role for IL-33 as an important early danger signal produced in response to inflammation-inducing UV radiation.
This article describes the basic principles of photoprotection with classic sunscreens containing chemical and/or physical UV filters and standard methods of sun protection factor (SPF) determination. In addition, the new governmental regulations and recommendations of the European Commission for photoprotection are presented and compared to regulations in other regions of the world. Finally, the efficacy of sunscreens in sunlight-induced non-sunburn effects, such as immune suppression and carcinogenesis are discussed.
Exposing the skin of mice to UV radiation interferes with the induction of delayed and contact hypersensitivity immune responses initiated at nonirradiated sites. The identity of the molecular target in the skin for these immunosuppressive effects of UV radiation remains controversial. To test the hypothesis that DNA is the target for UV-induced systemic immunosuppression, we exposed C3H mice to UV radiation and then used liposomes to deliver a dimer-specific excision repair enzyme into the epidermis in situ. The application of T4 endonuclease V encapsulated in liposomes to UV-irradiated mouse skin decreased the number of cyclobutane pyrimidine dimers in the epidermis and prevented suppression of both delayed and contact hypersensitivity responses. Moreover, the formation of suppressor lymphoid cells was inhibited. Control, heat-inactivated endonuclease encapsulated in liposomes had no effect. These studies demonstrate that DNA is the major target of UV radiation in the generation of systemic immunosuppression and suggest that the primary molecular event mediating these types of immunosuppression by UV radiation is the formation of pyrimidine dimers. Furthermore, they illustrate that the delivery of lesion-specific DNA repair enzymes to living skin after UV irradiation is an effective tool for restoring immune function and suggest that this approach may be broadly applicable to preventing other alterations caused by DNA damage.
Nitric oxide and superoxide, which are produced by several cell types, rapidly combine to form peroxynitrite. This reaction can result in nitric oxide scavenging, and thus mitigation of the biological effects of superoxide. Also, superoxide can trap and hence modulate the effects of nitric oxide; superoxide dismutase, by controlling superoxide levels, therefore can influence the reaction pathways open to nitric oxide. The production of peroxynitrite, however, causes its own sequelae of events: Although neither .NO nor superoxide is a strong oxidant, peroxynitrite is a potent and versatile oxidant that can attack a wide range of biological targets. The peroxynitrite anion is relatively stable, but its acid, peroxynitrous acid (HOONO), rearranges to form nitrate with a half-life of approximately 1 s at pH 7, 37 degrees C. HOONO exists as a Boltzmann distribution of rotamers; at 5-37 degrees C HOONO has an apparent acidity constant, pKa,app, of 6.8. Oxidation reactions of HOONO can involve two-electron processes (such as an SN2 displacement) or a one-electron transfer (ET) reaction in which the substrate is oxidized by one electron and peroxynitrite is reduced. These oxidation reactions could involve one of two mechanisms. The first mechanism is homolysis of HOONO to give HO. and .NO2, which initially are held together in a solvent cage. This caged pair of radicals (the "geminate" pair) can either diffuse apart, giving free radicals that can perform oxidations, or react together either to form nitrate or to reform HOONO (a process called cage return). A large amount of cage return can explain the small entropy of activation (Arrhenius A-factor) observed for the decomposition of HOONO. A cage mechanism also can explain the residual yield of nitrate that appears to be formed even in the presence of high concentrations of all of the scavengers studied to date, since scavengers capture only free HO. and .NO2 and not caged radicals. If the cage mechanism is correct, the rate of disappearance of peroxynitrite be slower in solvents of higher viscosity, and we do not find this to be the case. The second mechanism is that an activated isomer of peroxynitrous acid, HOONO*, can be formed in a steady state. The HOONO* mechanism can explain the inability of hydroxyl radical scavengers to completely block either nitrate formation or the oxidation of substrates such as methionine, since HOONO* would be less reactive, and therefore more selective, than the hydroxyl radical itself.(ABSTRACT TRUNCATED AT 400 WORDS)
Information on the variation in carcinogenicity with wavelength is crucial in risk assessments for skin cancers induced by UV radiation. Until recently the wavelength (lambda) dependencies of other detrimental UV effects, such as sunburn, have been used as substitutes. Direct information on the lambda dependency can only be obtained from animal experiments. To this end we accumulated a large data set on skin tumors induced by chronic UV exposure of albino SKH:HR1 mice (14 different broadband UV sources and about 1100 mice); the data come from the Photobiology Unit of the former Skin and Cancer Hospital in Philadelphia and from the Department of Dermatology of the University of Utrecht. The lambda dependency was extracted from this data set (a statistically satisfactory description with chi 2 = 13.4, df = 7) and represented by the Skin Cancer Utrecht-Philadelphia action spectrum, i.e., a set of factors to weight the exposures at different wavelengths according to their respective effectiveness (inversely proportional to the daily exposure required for a median tumor induction time of 300 days). The fits obtained with other already available action spectra proved to be poor (chi 2 > 60, df = 11). The maximum effectiveness was found at 293 nm, and above 340 nm the effectiveness showed a shoulder at about 10(-4) of the maximum. A sensitivity analysis of the final solution for the lambda dependency showed a large margin of uncertainty above 340 nm and an information gap below 280 nm. The large variation in tumor responses in the present data set can be transformed to a coherent, common dose-response relationship by proper spectral weighting with this single action spectrum.
Skin cancer incidence is highest in white-skinned people. Within this group, skin types I/II (sun sensitive/tan poorly) are at greater risk than skin types III/IV (sun tolerant/tan well). Studies in mice demonstrate that ultraviolet radiation (UVR)-induced suppression of cell-mediated immune function plays an important role in the development of skin cancer and induces a susceptibility to infectious disease. A similar role is suspected in humans, but we lack quantitative human data to make risk assessments of ambient solar exposure on human health. This study demonstrates that ambient levels of solar UVR, typically experienced within 1 h of exposure to noonday summer sunlight, can suppress contact hypersensitivity (CHS) responses in healthy white-skinned humans in vivo (n = 93). There was a linear relationship between increase in erythema and suppression of CHS (P < 0.001), and a moderate sunburn (two minimal erythema doses [2 MED]) was sufficient to suppress CHS in all volunteers by 93%. However, a single suberythemal exposure of either 0.25 or 0.5 MED suppressed CHS responses by 50 and 80%, respectively, in skin types I/II, whereas 1 MED only suppressed CHS by 40% in skin types III/IV. The two- to threefold greater sensitivity of skin types I/II for a given level of sunburn may play a role in their greater sensitivity to skin cancer.
Ultraviolet (UV) radiation is carcinogenic and immunosuppressive. UV-induced immune suppression is mediated by antigen-specific T cells, which can transfer suppression to normal recipients. These cells are essential for controlling skin cancer development in the UV-irradiated host and in suppressing other immune responses, such as delayed-type hypersensitivity. Despite their importance in skin cancer development, their exact identity has remained elusive. We show here that natural killer T cells from UV-irradiated donor mice function as suppressor T cells and play a critical role in regulating the growth of UV-induced skin cancers and suppressing adaptive immune responses in vivo.
Skin cells containing excessive ultraviolet (UV) radiation-induced DNA damage are eliminated by apoptosis that involves the p53 pathway and Fas/Fas-Ligand (Fas-L) interactions. To determine whether dysregulation of apoptosis plays a role in skin cancer development through disruption of Fas/Fas-L interactions, hairless SKH-hr1 mice were exposed to chronic UV irradiation from Kodacel-filtered FS40 lamps for 30 weeks. Their skin was analyzed for the presence of sunburn cells (apoptotic keratinocytes) and for Fas and Fas-L expression at various time points. A dramatic decrease in the numbers of morphologically identified sunburn cells and TUNEL-positive cells was detected as early as 1 week after chronic UV exposure began. After 4 weeks of chronic UV exposure, these cells were barely detectable. This defect in apoptosis was paralleled by an initial decrease in Fas-L expression during the first week of chronic UV irradiation and a complete loss of expression after 4 weeks. Fas expression, however, increased during the course of chronic UV exposure. p53 mutations were detected in the UV-irradiated epidermis as early as 1 week after irradiation began and continued to accumulate with further UV exposure. Mice exposed to chronic UV began to develop skin tumors after approximately 8 weeks, and all mice had multiple skin tumors by 24 weeks. Most of the tumors expressed Fas but not Fas-L. We conclude that chronic UV exposure may induce a loss of Fas-L expression and a gain in p53 mutations, leading to dysregulation of apoptosis, expansion of mutated keratinocytes, and initiation of skin cancer.
Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E(2), interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.
UVB exposure can alter immune responses in experimental animals and humans. In an earlier human volunteer study, we demonstrated that hepatitis B-specific humoral and cellular immunity after vaccination on average were not significantly affected by UVB exposure. However, it is known that individuals differ in their susceptibility to UVB-induced immunomodulation, and it was hypothesized that polymorphisms in specific cytokines may play a role in this susceptibility. In this respect, we previously demonstrated that immune responses after hepatitis B vaccination are influenced by the minor allelic variant of IL-1 beta in the general population. For all volunteers, single nucleotide polymorphisms were determined for the following UV response-related cytokines: IL-1 receptor antagonist (+2018), IL-1 alpha (+4845), IL-1 beta (+3953), TNF-alpha (-308), and TNF-alpha (-238). Exposure to UVB significantly suppressed Ab responses to hepatitis B in individuals with the minor variant for the IL-1 beta polymorphism. Increased minimal erythema dose values (just perceptible), which resulted in higher absolute UVB exposures, were observed in the same individuals. There were no associations observed between UVB-induced immunomodulation and the other cytokine polymorphisms examined. This study indicates that individual susceptibility to UVB radiation needs to be considered when studying the effects of UVB in humans.
Epicutaneous application of haptens to UV-exposed skin induces hapten-specific tolerance. This is mediated via regulatory T cells (Tr), as i.v. injection of T cells from UV-tolerized mice into naive animals renders the recipients unresponsive to the respective hapten. However, when UV-induced Tr are injected i.v. into sensitized mice, contact hypersensitivity (CHS) is not suppressed, suggesting that Tr inhibit the induction, but not the elicitation, of CHS and are inferior to T effector cells. As sensitization takes place in the lymph nodes, but elicitation occurs in the area of challenge, we postulated that Tr injected i.v. locate to the lymph nodes and not to the periphery and therefore only suppress the induction, not the elicitation, of CHS. Indeed, i.v. injection of Tr into sensitized mice did not inhibit CHS, although injection of Tr into the ears of sensitized mice suppressed the challenge. Inhibition was hapten specific, as injection of dinitrofluorobenzene (DNFB)-specific Tr into the ears of oxazolone (OXA)-sensitized mice did not affect challenge with OXA. However, when ears of OXA-sensitized mice were injected with DNFB-specific Tr and painted with DNFB before OXA challenge, CHS was suppressed. Inhibition correlated with the local expression of IL-10. Depletion studies and FACS analysis revealed that Tr express the lymph node-homing receptor L-selectin, but not the ligands for the skin-homing receptors E- and P-selectin, suggesting that UV-induced Tr, although able to inhibit T effector cells, do not suppress the elicitation of CHS upon i.v. injection, because they obviously do not migrate into the skin.
Solar radiation is the primary source of human exposure to ultraviolet (UV) radiation. Overexposure without suitable protection (i.e., sunscreen and clothing) has been implicated in mutagenesis and the onset of skin cancer. These effects are believed to be initiated by UV-mediated cellular damage, with proteins and DNA as primary targets due to a combination of their UV absorption characteristics and their abundance in cells. UV radiation can mediate damage via two different mechanisms: (a) direct absorption of the incident light by the cellular components, resulting in excited state formation and subsequent chemical reaction, and (b) photosensitization mechanisms, where the light is absorbed by endogenous (or exogenous) sensitizers that are excited to their triplet states. The excited photosensitizers can induce cellular damage by two mechanisms: (a) electron transfer and hydrogen abstraction processes to yield free radicals (Type I); or (b) energy transfer with O2 to yield the reactive excited state, singlet oxygen (Type II). Direct UV absorption by DNA leads to dimers of nucleic acid bases including cyclobutane pyrimidine species and pyrimidine (6-4) pyrimidone compounds, together with their Dewar isomers. These three classes of dimers are implicated in the mutagenicity of UV radiation, which is typified by a high level of CC-->TT and C-->T transversions. Single base modifications can also occur via sensitized reactions including Type 1 and Type II processes. The main DNA product generated by (1)O2 is 8-oxo-Gua; this is a common lesion in DNA and is formed by a range of other oxidants in addition to UV. The majority of UV-induced protein damage appears to be mediated by (1)O2, which reacts preferentially with Trp, His, Tyr, Met, Cys and cystine side chains. Direct photo-oxidation reactions (particularly with short-wavelength UV) and radicals can also be formed via triplet excited states of some of these side chains. The initial products of (1)O2-mediated reactions are endoperoxides with the aromatic residues, and zwitterions with the sulfur-containing residues. These intermediates undergo a variety of further reactions, which can result in radical formation and ring-opening reactions; these result in significant yields of protein cross-links and aggregates, but little protein fragmentation. This review discusses the formation of these UV-induced modifications and their downstream consequences with particular reference to mutagenesis and alterations in protein structure and function.
Acute graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation. We performed a phase II study on patients with acute steroid-refractory GVHD grades II to IV given extracorporeal photochemotherapy (ECP) weekly and analyzed response and long-term survival. Complete resolution of GVHD was achieved in 82% of patients with cutaneous involvement, 61% with liver involvement, and 61% with gut involvement. The probability of survival was 59% among patients who responded completely to ECP compared to 11% in patients not responding completely. We conclude that intensified ECP is highly effective in acute GVHD and that sustained responses are associated with over 50% long-term survival.
Systemic sclerosis is a multisystemic connective tissue disease with marked involvement of the skin and joints for which few effective evidence based therapies are available. To further investigate the efficacy of extracorporeal photochemotherapy on early aggressive cutaneous disease, a randomized, double-blind, placebo-controlled trial was performed.
Our aim was to evaluate the efficacy of photopheresis in the treatment of patients with systemic sclerosis (scleroderma).
This randomized, double-blind, placebo-controlled clinical trial was conducted at 16 investigational sites in the United States, Canada, and Europe. Sixty-four patients with typical clinical and histologic findings of scleroderma, of less than 2 years' duration, were studied. Patients did not receive any other concomitant treatment for scleroderma. Patients were randomized to receive either active or sham photopheresis treatment on two consecutive days monthly for 12 months. Severity of skin (skin scores assessed in 22 body regions) and joint involvement (60 joints examined for contractures) were assessed on a monthly basis.
A statistically significant improvement in skin scores as compared with baseline was observed at 6 months (P = .0024) and 12 months (P = .008) among those who received active photopheresis, but not among those who received sham photopheresis. Comparison of skin scores between the two study arms did not achieve statistical significance because of the small sample size of the study arms. Joint involvement was also significantly improved after 6 months (P = .002) and 12 months (P = .001) of active photopheresis when compared with baseline.
The study lacks sufficient statistical power to reveal a significant difference in skin and joint manifestations between the active and sham photopheresis arms.
Photopheresis induced significant improvement of skin and joint involvement in patients with scleroderma of recent onset; however, any effect when compared with sham treatment and a possible placebo effect may be modest.
A significant number of Australians are deficient in vitamin D - it is a fallacy that Australians receive adequate vitamin D from casual exposure to sunlight. People at high risk of vitamin D deficiency include elderly people (particularly those in residential care), people with skin conditions where avoidance of sunlight is advised, those with dark skin (particularly if veiled), and those with malabsorption. Exposure of hands, face and arms to one-third of a minimal erythemal dose (MED) of sunlight (the amount that produces a faint redness of skin) most days is recommended for adequate endogenous vitamin D synthesis. However, deliberate sun exposure between 10:00 and 14:00 in summer (11:00-15:00 daylight saving time) is not advised. If this sun exposure is not possible, then a vitamin D supplement of at least 400 IU (10 mu g) per day is recommended. In vitamin D deficiency, supplementation with 3000-5000 IU ergocalciferol per day (Ostelin [Boots]; 3-5 capsules per day) for 6-12 weeks is recommended. Larger-dose preparations of ergocalciferol or cholecalciferol are available in New Zealand, Asia and the United States and would be useful in Australia to treat moderate to severe vitamin D deficiency states in the elderly and those with poor absorption; one or two annual intramuscular doses of. 300 000 IU of cholecalciferol have been shown to reverse vitamin D deficiency states.
In the skin of albino hairless mice (Skh:HR-l) there is a basal level of non-heme iron. Chronic exposure of mice to sub-erythemal doses of ultraviolet (UV) B radiation results in an increased skin level of non-heme iron. The iron increase may be the result of a UVB radiation-induced increase in vascular permeability, which we measured in vivo with the dye marker Evans Blue. We also observed greater non-heme iron in sun-exposed vs non-exposed body sites of human skin, suggesting that similar events occur in man.
Iron may have a role in skin photodamage by participating in formation of reactive oxygen species. These species have been implicated in skin photodamage. It is known that iron can contribute to oxygen radical production by acting catalytically in the formation of species such as hydroxyl radical. While the basal level of skin iron may be available for catalysis, the elevated iron content of UV-exposed skin increases the potential for iron-catalyzed radical production.
Topical application of certain iron chelators to Skh albino hairless mice dramatically delayed the onset of UVB radiation-induced skin photodamage. Non-chelating analogs provided no significant protection.
Abstract— Ultraviolet radiation produces free radicals in Skh-1 mouse skin, contributing to photoaging and carcinogenesis. If a mouse model is a general indicator of free radical processes in human skin photobiology, then radical production observed in mouse and human skin should be directly comparative. In this work we show that UV radiation (Λ > 300 nm, 14 μW/cm2 UVB; 3.5 mW/cm2 UVA) increases the ascorbate free radical (Asc.-) electron paramagnetic resonance (EPR) signal in both Skh-1 mouse skin (45%) and human facial skin biopsies (340%). Visible light (Λ > 400 nm; 0.23 mW/cm2 UVA) also increased the Asc.- signal in human skin samples (45%) but did not increase baseline mouse Asc.-, indicating that human skin is more susceptible to free radical formation and that a chromophore for visible light may be present. Using EPR spin-trapping techniques, UV radiation produced spin adducts consistent with trapping lipid alkyl radicals in mouse skin (-[4-pyridyl 1-oxide]-N-tert-butyl nitrone/alkyl radical adduct; aN= 15.56 G and aH= 2.70 G) and lipid alkoxyl radicals in human skin (5,5-dimethylpyrroline-l-oxide/alkoxyl radical adduct; aN= 14.54 G and aH= 16.0 G). Topical application of the iron chelator Desferal to human skin significantly decreases these radicals (±50%), indicating a role for iron in lipid peroxidation; Desferal has previously been shown to decrease radical production in mouse skin. This work supports the use of the Skh-1 mouse as a predictive tool for free radical formation in human skin. These results provide the first direct evidence for UV radiation-induced free radical formation at near physiological temperatures in human skin and suggest that iron chelators may be useful as photoprotective agents.
In the skin of albino hairless mice (Skh:HR-1) there is a basal level of non-heme iron. Chronic exposure of mice to sub-erythemal doses of ultraviolet (UV) B radiation results in an increased skin level of non-heme iron. The iron increase may be the result of a UVB radiation-induced increase in vascular permeability, which we measured in vivo with the dye marker Evans Blue. We also observed greater non-heme iron in sun-exposed vs non-exposed body sites of human skin, suggesting that similar events occur in man. Iron may have a role in skin photodamage by participating in formation of reactive oxygen species. These species have been implicated in skin photodamage. It is known that iron can contribute to oxygen radical production by acting catalytically in the formation of species such as hydroxyl radical. While the basal level of skin iron may be available for catalysis, the elevated iron content of UV-exposed skin increases the potential for iron-catalyzed radical production. Topical application of certain iron chelators to Skh albino hairless mice dramatically delayed the onset of UVB radiation-induced skin photodamage. Non-chelating analogs provided no significant protection.
Our recent studies have shown that polyphenols present in green tea (GTP) possess significant antigenotoxic activity and afford
protection against polycyclic aromatic hydrocarbon induced skin tumor initiation in mice. In this study we assessed the effect
of oral feeding and topical application of GTP on ultraviolet B (UVB) radiation-induced skin carcinogenesis in female SKH-1
hairless mice. Chronic oral feeding of GTP (0.1%, w/v) in drinking water resulted in significantly (P < 0.01) lower tumor
yield (percent of animals with tumors and number of tumors per mouse) and extended TDT50 (P < 0.05), as compared to animals receiving normal drinking water. Topical application of GTP before UVB irradiation also
afforded protection against photocarcinogenesis; however, the protective response was lower than that observed by oral feeding
of GTP in drinking water. These results, in conjunction with our prior publications, suggest that consumption of green tea
may reduce the risk of some forms of human cancer induced by both physical and chemical environmental carcinogens.
Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, we find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid sequence. Involvement of UV light in these p53 mutations is indicated by the presence in three of the tumors of a CC----TT double-base change, which is only known to be induced by UV. UV is also implicated by a UV-like occurrence of mutations exclusively at dipyrimidine sites, including a high frequency of C----T substitutions. p53 mutations in internal malignancies do not show these UV-specific mutations. The dipyrimidine specificity also implicates dipyrimidine photoproducts containing cytosine as oncogenic photoproducts. We believe these results identify a carcinogen-related step in a gene involved in the subsequent human cancer.
Immunological unresponsiveness can be initiated by exposure of mice to UV radiation, followed by the introduction of certain antigens. These antigens include epicutaneously applied chemicals that induce contact hypersensitivity (CHS), and antigens that occur on skin cancers induced by UV radiation. Mice exposed repeatedly to high doses of UV radiation during UV carcinogenesis develop immunological unresponsiveness to UV radiation-induced skin cancers, which are highly antigenic. This unresponsiveness is associated with the appearance of suppressor T lymphocytes that are specific for tumors induced by UV radiation, even though these tumors express individually specific transplantation rejection antigens. Thus, the occurrence of suppressor cells with specificity for a set of non-cross-reacting tumors suggests that a common, UV-associated regulatory antigen or determinant may be present on UV-induced skin cancers. Suppression of CHS in mice by UV radiation can be induced by two different procedures. One involves applying the sensitizer directly on skin exposed to low doses of UV-B radiation and is thought to result from a direct effect of UV radiation on cutaneous Langerhans cells. The second involves application of the sensitizer to the unirradiated skin of mice or guinea pigs exposed several days earlier to a higher dose of UV-B radiation. The mechanism of the latter phenomenon is not well understood, but there is evidence that it results from an alteration of antigen presentation by splenic macrophages. Both forms of suppression are associated with the appearance of antigen-specific suppressor lymphocytes in the animals' spleens, which prevent the induction of CHS upon transfer to a normal recipient. Either or both of these pathways could be responsible for the formation of the suppressor cells involved in UV carcinogenesis. Recent studies suggest that UV radiation may also affect immunological responsiveness in humans as well as in animals. However, the extent of such alterations and the mechanisms by which they occur are still unknown.
Peroxynitrite causes single-strand breaks in pBR322 supercoiled DNA as evidenced by agarose gel electrophoresis analysis. The effect of three free radical scavengers, namely mannitol, benzoate and dimethylsulfoxide, were studied. Mannitol failed to protect DNA from damage by peroxynitrite while benzoate and dimethylsulfoxide amplified the damage. These results suggest the damage caused by peroxynitrite alone is not mediated by free radicals since typical free radical scavengers fail to prevent the damage.
During the past 25 years, the field of free radical biology has germinated, sprouted, and flowered. Free radicals derived from molecular oxygen, formerly of interest only to radiation chemists, are now known to play multiple roles in living systems. We will here consider the generalities of this field with some special focus on skin as a site of oxygen radical production and as a target upon which the damaging propensities of these radicals are exerted.
Topical photodynamic therapy with endogenous porphyrins consists of irradiation of a tumor with visible light after the application of exogenous 5-aminolevulinic acid.
To assess the effectiveness of this modality, patients with precancerous conditions and various skin cancers were treated.
Thirteen patients with 70 skin lesions were enrolled. Standard treatment involved the topical application of 20% 5-aminolevulinic acid in an oil-in-water emulsion. The emulsion was applied under an occlusive dressing for 4 to 8 hours before exposure to photoactivating light.
We observed a complete response after a single treatment for all 9 solar keratoses, 5 of 6 early invasive squamous cell carcinomas, and 36 of 37 superficial basal cell carcinomas. Only 1 of 10 nodulo-ulcerative basal cell carcinomas completely resolved. Eight cutaneous metastases of malignant melanoma were therapeutic failures.
Topical photodynamic therapy with endogenous porphyrins is effective for superficial epithelial skin tumors.
The inducible isoform of nitric oxide (NO) synthase produces large quantities of NO, a cytotoxic free radical. Recent studies show that treatment with exogenous NO produces DNA strand breaks, activating the nuclear repair enzyme poly(ADP)ribosyltransferase (PARS), which results in ADP ribosylation, NAD+ consumption, and exhaustion of intracellular energy stores. Here we have characterized the cytotoxic effect of endogenous NO and peroxynitrite, a reactive oxidant formed from NO and superoxide. Immunostimulation of J774.2 macrophages with endotoxin resulted in the generation of superoxide (within 1 h) and NO (after 8 h). NO production paralleled an increase in peroxynitrite formation and DNA strand breakage, and a decrease in intracellular NAD+ content and mitochondrial respiration. Inhibition of NO synthase by NG-methyl-L-arginine or S-methyl-isothiourea or inhibition of PARS activity by 3-aminobenzamide or nicotinamide prevented the decrease in mitochondrial respiration and the depletion of NAD+. A similar pattern of free radical formation and cytotoxicity was observed in peritoneal macrophages from endotoxemic rats (formation of NO, superoxide, peroxynitrite, and DNA strand breaks). In vivo treatment with 3-aminobenzamide preserved mitochondrial respiration, NAD+, and ATP. Our data suggest that inflammatory cell injury involved DNA strand breakage and PARS, triggering an energy-consuming, futile repair cycle leading to cellular energy depletion. The active species responsible for the development of DNA strand breaks is peroxynitrite, rather than NO, since exogenous peroxynitrite, but not NO, induces DNA strand breaks. Inhibition of PARS may improve cellular energy homeostasis in patho-physiologic conditions associated with peroxynitrite generation.
Experimental data are reviewed that lend support to the hypothesis that formation of DNA damage is the initiation event of local suppression of contact hypersensitivity (CHS) after exposure to ultraviolet (UV) radiation and that the antigen-presenting cell (APC) is an important target for this DNA damage.
Exposure to UV is a recognised risk factor for skin cancer and it also induces immunosuppression to a variety of antigens encountered following the irradiation. The latter property has been demonstrated in rodent models of infections with the microbial agents including viruses, bacteria, protozoa and helminths. In the majority of cases the severity of the symptoms and the microbial load in the host are increased as a result of the immunomodulation. UV can also affect the pathogenesis of some natural microbial infections of human subjects, such as causing recrudescence of herpes simplex virus and contributing to the oncogenic potential of papillomaviruses. Sufficient data have been generated from the animal models to construct a risk assessment in humans for suppression of microbial immune responses induced by sunlight exposure. This estimation requires verification from epidemiological studies and from further work to assay modulation in human immunity to particular pathogens experienced before and after the UV radiation.
Genetic stability is an important prerequisite for the maintenance of the integrity and functions of each cell. Several environmental agents, as well as endogenous sources, are known to play a significant role in the formation of DNA lesions. Most of these lesions are repaired, but a few may escape and can lead to mutagenesis during trans-lesion replication or to chromosomal aberrations, and, finally, to tumorigenesis or cell death. The causal relationship between solar ultraviolet (UV) radiation and carcinogenesis has been well established. UVB radiation (290-320 nm) causes the direct formation of DNA photoproducts and gives rise to mutations in proto-oncogenes and tumor suppressor genes that eventually lead to skin cancer. Genotoxicity of UVA radiation (320-400 nm), which represents more than 90% of the terrestrial UV solar energy, is most likely induced by indirect mechanisms. After UVA photon absorption by an unidentified endogenous photosensitizer, reactive oxygen species are generated that could react with DNA without further intermediates (type I photosensitized reaction) or via singlet oxygen (type II photosensitized reaction). The singlet oxygen appears to be an early intermediate of UVA cellular response, judging by its involvement in signal transduction and gene induction. It belongs to reactive oxygen species (ROS) that are ubiquitous oxidizing agents generated in all aerobic organisms, endogenously as byproducts of respiration and inflammatory response and also exogenously after exposure to a variety of agents. This chapter discusses data on DNA lesions, DNA repair, and mutation spectra, which characterize the genotoxic potential of both singlet oxygen and UVA radiation, essentially in mammalian species.
Exposure to ultraviolet radiation can modulate immune responses in animal and humans. Remarkably, the ultraviolet-induced immunosuppression is not restricted to the exposed skin but is also found at other body sites, i.e., systemic immunosuppression. Effects of ultraviolet radiation on infections cannot be determined by experimentation on humans, but the effects of ultraviolet on vaccination may serve as a model. Moreover, it is important in its own right to assess whether ultraviolet radiation affects vaccination responses. In this study the effect of ultraviolet B exposure on the development of immune responses after hepatitis B vaccination in human volunteers was investigated. To this end, 191 human volunteers were vaccinated against hepatitis B with the Engerix-B vaccine. Ninety-seven of them were prior to the first vaccination exposed to ultraviolet B on 5 consecutive days with one personal minimal erythema dose per day. At several time-points before and after the ultraviolet B exposure regimen and the vaccination, blood samples were taken. Parameters for specific as well as nonspecific cellular and humoral immunity were analyzed. It was demonstrated that ultraviolet B exposure prior to hepatitis B vaccination did not alter the cellular (lymphocyte stimulation test) nor the humoral (antibody titers) immune response against hepatitis B surface antigen significantly. In contrast, contact hypersensitivity to diphenylcyclopropenone was significantly suppressed after ultraviolet B exposure, as was natural killer cell activity. These latter results confirm earlier findings and demonstrate immunosuppressive effectiveness of the ultraviolet regimen. In summary, although natural killer cell activity and contact hypersensitivity responses were suppressed, the ultraviolet B radiation protocol did not alter the humoral nor the cellular immune responses against hepatitis B surface antigen after vaccination.
Exposure to ultraviolet (UV) radiation, particularly the UVB wavelengths, leads not only to DNA damage but also to suppression of cell-mediated immunity to antigens encountered shortly after the irradiation. One initiator of this complex process is cis-urocanic acid (cis-UCA), which is formed from the naturally occurring trans isomer in the epidermis on absorption of UV. cis-UCA has been shown to have immunomodulating properties in a variety of in vivo and in vitro experimental systems, although its mechanism of action is not yet clear. This article covers methods of preparing cis-UCA and of analyzing UCA isomers in various human and mouse tissues. Experiments that demonstrate that cis-UCA is immunosuppressive are described. The final section deals with the preparation and characterization of a monoclonal antibody with specificity for cis-UCA.
Sun exposure is accepted as the major risk factor for developing skin cancer, the most common cancer in the western world. Ultraviolet-B (UV-B) radiation is considered the causative agent, but recently several findings suggest a role also for ultraviolet-A (UV-A) radiation. Repeated suberythemal doses of ultraviolet-A1 (UV-A1) on healthy human skin induce an increase of p53 immunoreactive cells in epidermis, which may indicate cell cycle arrest and/or occurrence of p53 mutations.
We have investigated the possible mutagenic effect of UV-A1 on skin by sequencing exons 4-11 and adjacent intron sequence of the p53 gene in immunoreactive single cells from three healthy individuals. Previously unexposed buttock skin was irradiated three times a week for 2 weeks with physiological fluences (40 J/cm2) of UV-A1. Punch biopsies were taken before and at different time-points after the exposure, and from these single p53 immunoreactive cells were isolated by using laser-assisted microdissection.
Three mutations--all being indicative of oxidative damage and most likely related to UV-A exposure--were found among the 37 single cells from exposed skin, whereas no mutations were found in the 22 single cells taken before exposure.
The findings indicate a mutagenic effect of low-dose UV-A1 on healthy human skin, which further demonstrates the importance of considering UV-A when taking protective measures against skin cancer.
Extracorporeal photochemotherapy was originally conceived for the treatment of cutaneous T-cell lymphoma (CTCL) and as well as other T-cell mediated diseases. Evidence collected in the past 17 years has demonstrated that this treatment modality can have a very significant effect on the course of a subset of CTCL patients. The evidence available is positive but for a variety of reasons has been controversial within the medical community. A number of very well-designed multi-center trials which have been lacking since the first publication by Edelson et al. are being carried out so that hopefully a number of open questions will be resolved with greater clarity in the coming years. The fact remains that this innovative approach for the treatment of CTCL and T-cell mediated diseases has certainly opened new avenues of therapy and thought in photoimmunology and photomedicine. Clearly the very low side effect profile of this therapy has made it more attractive than the chemotherapeutic and immunosuppressive substances that are presently available or in experimental protocols. If and when the mechanisms of action are fully understood and appropriate studies investigating different treatment schedules and different combination therapies and modifications of its present form are performed the place of photopheresis in the therapeutics of CTCL as well as other T-cell mediated diseases and oncology will be better placed.
Sunscreens have been advocated as an important means of preventing skin cancer. Ultraviolet radiation induced immunosuppression is recognized as an important event in skin cancer development, yet the effectiveness of sunscreens in protecting the human immune system from ultraviolet radiation (i.e. ultraviolet radiation) is still unclear. The only currently accepted method of sunscreen rating is the sun protection factor system based on the prevention of erythema. We determined immune protection factors for six commercially available sunscreens using a nickel contact hypersensitivity model in humans. Both sun protection factor and immune protection factor testing was performed using the same solar simulated ultraviolet radiation source and dose-responses were used to determine endpoints both with and without sunscreens. We found that the immune protection factor did not correlate with the sun protection factor; however, immune protection factor was significantly correlated to the ultraviolet A protective capability of the sunscreens, indicating that sunscreen protection from ultraviolet A is important for the prevention of ultraviolet immunosuppression, when there is constant ultraviolet B protection. We recommend that sunscreens should be rated against their immune protective capability to provide a better indication of their ability to protect against skin cancer.
Topical application of NG-methyl-L-arginine and 2,2'-dipyridyl were used to examine the respective roles of nitric oxide and reactive oxygen species in solar-simulated ultraviolet radiation-induced immunosuppression in humans in vivo. Immunosuppression was studied using a nickel contact hypersensitivity recall model. Ultraviolet radiation dose-responses were generated to determine the extent to which NG-methyl-L-arginine and 2,2'-dipyridyl affected the immune response. NG-methyl-L-arginine but not 2,2'-dipyridyl protected the immune system from ultraviolet radiation-induced suppression. Both NG-methyl-L-arginine and 2,2'-dipyridyl inhibited nitrite production. Nitrite is a degradation product of peroxynitrite, a cytotoxic mediator resulting from reactions between nitric oxide and reactive oxygen species. This suggests that nitric oxide, not its downstream product peroxynitrite, was likely to be responsible for solar-simulated ultraviolet radiation-induced immunosuppression. In contrast, both nitric oxide and reactive oxygen species were mediators of solar-simulated ultraviolet radiation-induced apoptosis and loss of dendritic S-100+ cells (probably Langerhans cells) from the epidermis. It is likely that different mechanisms are involved in these ultraviolet-induced endpoints and that events in addition to Langerhans cell depletion are important for local immune suppression to recall antigens in humans. Understanding the mechanisms of cutaneous ultraviolet-induced oxidative stress will assist in the future design of novel products that protect skin from photoaging and skin cancer.
Photodynamic therapy (PDT) is increasingly used as a noninvasive treatment for nodular basal cell carcinoma (BCC), without a sound evidence base.
To compare topical PDT, with the use of the sensitizer methyl aminolevulinate, and standard excision surgery in nodular BCC.
Prospective, randomized study.
University dermatology departments.
A total of 101 adults with previously untreated nodular BCC.
Patients received methyl aminolevulinate PDT (n = 52) or surgery (n = 49). The PDT was given twice, 7 days apart, with methyl aminolevulinate cream (160 mg/g) and 75 J/cm(2) red light (570-670 nm). Thirteen patients with a noncomplete response to PDT at 3 months (24% lesions) were retreated.
Primary end point was clinically assessed lesion clearance at 3 months after treatment. Secondary end points were sustained response rate at 12 months and cosmetic outcome at 3 and 12 months. Cosmesis and lesion recurrence were further assessed at 24 months.
Data from 97 patients (105 lesions) were included in the 3-month per-protocol analysis. Complete response rates did not differ significantly between groups (51/52 [98%] lesions with surgery vs 48/53 [91%] lesions with methyl aminolevulinate PDT; difference [95% confidence interval], 4.8% (-3.4% to 13.0%]; P =.25). At 12 months, tumor-free rates were 50 (96%) of 52 lesions with surgery vs 44 (83%) of 53 with methyl aminolevulinate PDT (P =.15). More patients treated with methyl aminolevulinate PDT than surgery had an excellent or good cosmetic outcome at all time points (significant at 12 and 24 months on patient assessment, P<.05, and at 3, 12, and 24 months on investigator evaluation, P<.001). At 24 months, 5 lesions that had initially cleared with methyl aminolevulinate PDT had recurred, compared with 1 after surgery.
Methyl aminolevulinate PDT is an effective treatment for nodular BCC, and while there is a trend for higher recurrence with this modality, it conveys the advantage over surgery of better cosmesis.
Ultraviolet A (UVA) radiation received from the sun and from the widespread use of tanning beds by populations residing in areas of northern latitude represents a potential risk factor for human health. The genotoxic and cancer-causing effects of UVA have remained controversial. A mutagenic role for UVA based on DNA damage formation by reactive oxygen species as well as by generation of photoproducts such as cyclobutane pyrimidine dimers (CPDs) has been suggested. Here, we investigated the mutagenicity of UVA in relation to its DNA damaging effects in transgenic Big Blue mouse embryonic fibroblasts. We determined the formation of a typical oxidative DNA lesion, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), and of CPDs, as well as quantified the induction of mutations in the cII transgene in cells irradiated with a 2000 W UVA lamp. UVA irradiation at a dose of 18 J/cm(2) produced significant levels of 8-oxo-dG in DNA (P < 0.03) but did not yield detectable CPDs. UVA irradiation also increased the cII mutant frequency almost 5-fold over background (P < 0.01) while showing moderate cytotoxicity (70% cell viability). UVA-induced mutations were characterized by statistically significant increases in G-to-T transversions and small tandem base deletions (P = 0.0075, P = 0.008, respectively) relative to spontaneously derived mutations. This mutational spectrum differs from those previously reported for UVA in other test systems; however, it corresponds well with the known spectrum of mutations established for oxidative base lesions such as 8-oxo-dG. We conclude that UVA has the potential to trigger carcinogenesis owing to its mutagenic effects mediated through oxidative DNA damage.
Inducible nitric oxide (NO) synthase (iNOS), heme oxygenase (HO)-1, and indoleamine 2,3-dioxygenase (IDO) are simultaneously expressed in murine macrophages stimulated with interferon (IFN)-gamma and lipopolysaccharide (LPS). NO produced by iNOS suppresses IDO expression and also induces HO-1 expression. The antioxidant 3-hydroxyanthranilic acid (HA), one of metabolites of tryptophan via IDO pathway, has been previously reported to suppress iNOS expression. Because HO-1 expression can suppress iNOS expression, we investigated whether HA could suppress iNOS expression by affecting HO-1 expression in murine RAW 264.7 macrophages stimulated with IFN-gamma plus LPS. Treatment with exogenous HA dose-dependently suppressed iNOS expression and coincidently enhanced HO-1 expression. This suppressive effect of HA on iNOS expression was reversed by blocking HO-1 activity, and proven to be due to carbon monoxide (CO) produced by HO-1. In addition, either blocking of iNOS activity or addition of exogenous CO further enhanced IDO expression and activity. These results show for the first time that HA is able to suppress iNOS expression by enhancing HO-1 expression, thereby resulting in further increases in IDO expression and activity.
The carcinogenic potential of 8-methoxypsoralen photochemotherapy (psoralen-UVA [PUVA]) is correlated with the total number of treatments and cumulative UVA dose applied during oral PUVA therapy.
We sought to determine whether reducing treatment frequency and UVA dose affects the therapeutic efficacy of oral PUVA for patients with chronic plaque psoriasis.
This was a prospective, randomized, half-side study performed in a photodermatology department in a dermatology hospital. Eighteen consecutive patients with chronic plaque psoriasis received paired PUVA regimens (0.5 minimal phototoxic dose [MPD] 4 times/wk vs 1 MPD twice/wk, 0.5 MPD twice/wk vs 1 MPD twice/wk, and 0.5 MPD twice/wk vs 0.75 MPD twice/wk). The PUVA regimens were assessed for reduction of Psoriasis Area and Severity Index (PASI) score and the number of treatments and cumulative UVA dose required to reduce PASI score to defined end points (ie, PASI reductions of 25%, 50%, and 75%) or to induce complete remission (PASI < 3).
Reducing the number of treatments while maintaining the same UVA dose per week did not reduce overall therapeutic efficacy. Reducing the number of treatments to twice a week and reducing the UVA dose from 1 MPD to 0.75 or 0.5 MPD per treatment only slightly affected intermediate therapeutic efficacy (between the second and seventh weeks of therapy) but had no effect on final clearance rates. The time to complete clearance did not significantly differ between regimens. The mean cumulative UVA dose was significantly lower for the least intensive dose regimen (0.5 MPD twice/wk) than for the more intensive regimens.
Reducing treatment frequency and UVA dose does not substantially compromise the therapeutic efficacy of PUVA.
The high and steadily increasing incidence of ultraviolet-B (UV-B)-induced skin cancer is a problem recognized worldwide. UV introduces different types of damage into the DNA, notably cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs). If unrepaired, these photolesions can give rise to cell death, mutation induction, and onset of carcinogenic events, but the relative contribution of CPDs and 6-4PPs to these biological consequences of UV exposure is hardly known. Because placental mammals have undergone an evolutionary loss of photolyases, repair enzymes that directly split CPDs and 6-4PPs into the respective monomers in a light-dependent and lesion-specific manner, they can only repair UV-induced DNA damage by the elaborate nucleotide excision repair pathway.
To assess the relative contribution of CPDs and 6-4PPs to the detrimental effects of UV light, we generated transgenic mice that ubiquitously express CPD-photolyase, 6-4PP-photolyase, or both, thereby allowing rapid light-dependent repair of CPDs and/or 6-4PPs in the skin. We show that the vast majority of (semi)acute responses in the UV-exposed skin (i.e., sunburn, apoptosis, hyperplasia, and mutation induction) can be ascribed to CPDs. Moreover, CPD-photolyase mice, in contrast to 6-4PP-photolyase mice, exhibit superior resistance to sunlight-induced tumorigenesis.
Our data unequivocally identify CPDs as the principal cause of nonmelanoma skin cancer and provide genetic evidence that CPD-photolyase enzymes can be employed as effective tools to combat skin cancer.
Ultraviolet (UV) radiation causes inflammation, gene mutation and immunosuppression in the skin. These biological changes are responsible for photocarcinogenesis. UV radiation in sunlight is divided into two wavebands, UVB and UVA, both of which contribute to these biological changes, and therefore probably to skin cancer in humans and animal models. Oxidative damage caused by UV contributes to inflammation, gene mutation and immunosuppression. This article reviews evidence for the hypothesis that UV oxidative damage to these processes contributes to photocarcinogenesis. UVA makes a larger impact on oxidative stress in the skin than UVB by inducing reactive oxygen and nitrogen species which damage DNA, protein and lipids and which also lead to NAD+ depletion, and therefore energy loss from the cell. Lipid peroxidation induces prostaglandin production that in association with UV-induced nitric oxide production causes inflammation. Inflammation drives benign human solar keratosis (SK) to undergo malignant conversion into squamous cell carcinoma (SCC) probably because the inflammatory cells produce reactive oxygen species, thus increasing oxidative damage to DNA and the immune system. Reactive oxygen or nitrogen appears to cause the increase in mutational burden as SK progress into SCC in humans. UVA is particularly important in causing immunosuppression in both humans and mice, and UV lipid peroxidation induced prostaglandin production and UV activation of nitric oxide synthase is important mediators of this event. Other immunosuppressive events are likely to be initiated by UV oxidative stress. Antioxidants have also been shown to reduce photocarcinogenesis. While most of this evidence comes from studies in mice, there is supporting evidence in humans that UV-induced oxidative damage contributes to inflammation, gene mutation and immunosuppression. Available evidence implicates oxidative damage as an important contributor to sunlight-induced carcinogenesis in humans.
Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme present in dendritic cells and macrophages. It is a known modulator of T-cell response and contributes to the UV protection of the lens. There yet is no information on IDO activity in the corneal endothelium, protecting the endothelial cells from light mediated damage. We exposed murine corneal endothelial cells (MCEC) with different doses of UV-B light 280-320 nm, probed for IDO mRNA (real-time PCR) and assessed apoptosis rate (flow cytometry) and caspase-3-activity in the cells. The metabolites of the IDO catalysed reaction, l-kynurenine, was also measured. Malondialdehyde was detected for quantification of UV-B-induced oxidative stress. To investigate specificity, IDO effects were blocked by 1-methyl-tryptophan. The effects of IDO overexpression in the MCEC were assessed by transfection of an expression vector. MCEC consistently express IDO at low levels. Exposure to UV-B light led to a dose-responding upregulation of IDO; IDO was found competent converting l-tryptophan into l-kynurenine. Irradiation led to increased apoptosis and caspase-3-activity of MCEC. Supplementation of l-kynurenine or overexpression of IDO in the MCEC could reduce apoptosis significantly following UV-B irradiation. Inhibition of IDO by 1-MT was potent to reverse this effect. IDO and its metabolite l-kynurenine can protect corneal endothelial cells from UV-B-induced oxidative stress and apoptosis. It may be an active protection mechanism against corneal endothelial damage.
While the mutagenic and carcinogenic properties of longwave UV light (UVA) are well established, mechanisms of UVA mutagenesis remain a matter of debate. To elucidate the mechanisms of mutation formation with UVA in human skin, we determined the spectra of UVA- and UVB-induced mutations in primary human fibroblasts. As with UVB, we found the majority of mutations to be C-to-T transitions also with UVA. For both UVA and UVB, these transitions were found within runs of pyrimidines, at identical hotspots, and with the same predilection for the nontranscribed strand. They also included CC-to-TT tandem mutations. Therefore, these mutations point to a major role of pyrimidine dimers not only in UVB but also in UVA mutagenesis. While some differences were noted, the similarity between the spectra of UVA- and UVB-induced mutations further supports similar mechanisms of mutation formation. A non-dimer type of DNA damage does not appear to play a major role in either UVA or UVB mutagenesis. Therefore, the previously reported increasing mutagenicity per dimer with increasing wavelengths cannot be due to non-dimer DNA damage. Differences in the cellular response to UVA and UVB, such as the less prominent activation of p53 by UVA, might determine a different mutagenic outcome of UVA- and UVB-induced dimers.
Both bath psoralen plus ultraviolet A (PUVA) and oral PUVA with 8-methoxypsoralen (8-MOP) have been successfully used for the treatment of recalcitrant palmoplantar psoriasis. This trial was designed to assess the efficacy and side effects of the different treatment modalities in a randomized half-side comparison. Methods: Eight patients with moderate-to-severe psoriasis on soles (n = 6) and/or palms (n = 8) were randomly assigned to receive bath PUVA treatment on one side and oral PUVA on the other. Initial treatment dose was 50% of the minimal phototoxic dose evaluated for bath PUVA and oral PUVA. Treatment was given three times a week for 4 weeks. Before treatment and every week a severity index (SI) was assessed by summing the scores of erythema, infiltration, scaling and vesicles evaluated on a scale from 0 to 4. After 4 weeks of treatment the half-side trial was finished and the treatment was continued on both sides with the more effective treatment regimen.
Both bath PUVA and oral PUVA achieved a reduction of the mean initial SI from 5.9 (95% confidence intervals (CI) 4.5-8.0) to 3.3 (1.8-6.0) (44% SI reduction, P < 0.005, Student's paired t-test) and 6.0 (5.0-7.8) to 2.9 (1.8-4.0) (52% SI reduction; P < 0.005), respectively. The statistical comparison of the entire 4-week study period revealed a significant better effect in lesions treated with oral PUVA compared with bath PUVA (P = 0.033). However, at 4 weeks, there was no significant difference between the achieved SI reduction of oral PUVA and bath PUVA. Systemic side effects (nausea and/or dizziness) were only observed after oral PUVA.
This study gives evidence that in the first 4 treatment weeks oral PUVA is slightly more effective than bath PUVA but the former has more systemic side effects.
Psoralen plus ultraviolet (UV) A (PUVA) is the standard treatment for early stage mycosis fungoides (MF). When 8-methoxypsoralen (8-MOP) is used in PUVA therapy, it often produces intolerance reactions such as nausea, vomiting and headache.
To investigate whether 5-methoxypsoralen (5-MOP) is a safe and effective alternative to 8-MOP in PUVA therapy for MF.
A retrospective database search and chart review was done to identify patients with MF who received PUVA with either 5-MOP or 8-MOP as initial monotherapy at our institution. Between 1990 and 2004, 14 patients [seven men and seven women; mean age 70 years, range 51-82; National Cancer Institute disease stages IA (n = 6) and IB (n = 8)] received 5-MOP, and 24 patients [21 men and three women; mean age 58 years, range 28-89; disease stages IA (n = 11), IB (n = 12) and IIB (n = 1)] received 8-MOP.
Twelve of 14 patients (86%) in the 5-MOP group and 22 of 24 (92%) in the 8-MOP group had a complete response to PUVA. These two subgroups of complete responders did not differ significantly in terms of PUVA therapy duration, number of treatments or cumulative UVA dose. They also did not differ significantly in terms of relapse-free rate [8% (one of 12) vs. 23% (five of 22)] or time to relapse [17 months (range 4-31) vs. 14 months (range 4-33)]. Moreover, PUVA maintenance therapy with either 5-MOP or 8-MOP in a subset of patients [26% (nine of 34)] did not affect long-term relapse-free status either.
5-MOP and 8-MOP have comparable therapeutic efficacy when used in PUVA therapy for MF.
In this review, changes that we have observed in the prevalence of mast cells in human sun-exposed skin, and their potential immunoregulatory role, are discussed. More specifically, in a study of Australian volunteers, the prevalence of dermal mast cells was increased in back-of-hand skin, anecdotally the most sun-exposed site of the body, but not in skin from buttock, inner arm or shoulder. By histological analysis of back-of-hand skin, there was a significant correlation between dermal mast cell prevalence and elastin content suggesting increased mast cell prevalence with photodamage. We hypothesised that these mast cells were immunomodulatory upon activation by sun exposure. However, no link was found between dermal mast cell prevalence in hand skin and the presence of basal cell carcinomas. Finally, we discuss other roles for increased numbers of mast cells in UV-exposed photodamaged skin.
Apperly [1941. The relation of solar radiation to cancer mortality in North America. Cancer Research 1, 191-195] first proposed that increased mortality from cancer in the north than in the south of the USA might be due to the south to north decrease in ambient solar radiation. This inverse association between ambient solar radiation and cancer mortality has been subsequently reported for cancers of the colon, breast, ovary and prostate. While the evidence that sunlight might be related to lower incidence or more favourable outcomes from cancer came initially from ecological studies, case-control and cohort studies have now shown a similar association of sun exposure with risks of colon, breast and prostate cancers in individuals, and other studies in individuals have found that serum and dietary vitamin D levels are associated with reduced risks of colorectal cancer and, less certainly, prostate cancer. Studies in individuals have recently also suggested an effect of sun exposure to reduce risk of non-Hodgkin lymphoma and to increase survival after a diagnosis of melanoma. Data on variation in survival from cancer by season of diagnosis suggest that sun exposure may also improve outcome from cancers of the breast, colon and prostate and Hodgkin lymphoma.
To compare the efficacy, tolerability, and cosmetic outcome of photodynamic therapy (PDT) using topical methyl aminolevulinate with cryotherapy or topical fluorouracil for treatment of squamous cell carcinoma in situ.
Randomized, placebo-controlled study, with follow-up at 3 and 12 months after last treatment.
Forty outpatient dermatology centers in 11 European countries.
Random sample of 225 patients with histologically confirmed squamous cell carcinoma in situ (lesion size, 6-40 mm) and no evidence of progression.
Treatment with PDT with methyl aminolevulinate (160 mg/g; n = 96) or matching placebo cream (n = 17), cryotherapy (n = 82), or topical fluorouracil (5% cream; n = 30). Methyl aminolevulinate or placebo cream was applied for 3 hours before illumination with broadband red light (75 J/cm2, 570-670 nm). Treatment was repeated 1 week later. Cryotherapy was performed with liquid nitrogen spray. Fluorouracil was applied for 4 weeks. Lesions with a partial response at 3 months were re-treated.
Clinically verified complete response of lesions; blinded and on-site assessment of cosmetic outcome (4-point rating scale).
At 12 months, the estimated sustained lesion complete response rate with methyl aminolevulinate PDT was superior to that with cryotherapy (80% vs 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P = .047), and better than that with fluorouracil (80% vs 69%; odds ratio, 1.64; 95% confidence interval, 0.78-3.45; P = .19). Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with methyl aminolevulinate PDT vs 66% with cryotherapy and 76% with fluorouracil, and was maintained at 12 months.
Methyl aminolevulinate PDT is an effective treatment option for squamous cell carcinoma in situ, with excellent cosmesis.
More effective strategies are required for the prevention of skin cancer, which is caused by ultraviolet (UV) radiation in sunlight. Sunscreens containing UV filters or reflectors offer some protection from sunlight. Pharmacologically active compounds that reduce UV damage offer considerable potential for improving sunscreen formulations. However, few studies have investigated whether the addition of such biological modifiers are an improvement.
In this study we supplemented a 2-ethyl hexyl methoxycinnamate-based sunscreen with the nitric oxide (NO) inhibitor NG-monomethyl-L-arginine acetate, the iron chelator 2,2'-dipyridyl, which reduces reactive oxygen species (ROS) production, or both. This was to determine whether inhibition of NO, ROS, or both could improve photoprotection by a sunscreen.
These sunscreens were compared for photoprotection from sunburn, immunosuppression and skin carcinogenesis in mice. To observe additional photoprotection by the NO and ROS inhibitors, UV doses were used that exceeded the protective capacity of the sunscreen.
The combined inhibition of both NO and ROS production, but neither alone, increased sunscreen protection from sunburn and immunosuppression. Similarly, inhibition of both NO and ROS but neither alone reduced tumour multiplicity and incidence, therefore improving sunscreen protection from photocarcinogenesis.
Whether NO and ROS inhibition were independently improving sunscreen photoprotection, with both being required for an observable effect, or whether inhibition of an interaction between NO and ROS was responsible for improved photoprotection by the sunscreen is unknown. These studies show that supplementation of a sunscreen with inhibitors of NO and ROS production improves the ability of the sunscreen to protect from sunburn, immunosuppression and photocarcinogenesis. Such an approach may be useful for reducing skin cancer incidence in humans.