Blackberry extract inhibits UVB-induced oxidative damage and inflammation through MAP kinases and NF-κB signaling pathways in SKH-1 mice skin.

Extensive exposure of solar ultraviolet-B (UVB) radiation to skin induces oxidative stress and inflammation that play a crucial role in the induction of skin cancer. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. In this study, we investigated whether blackberry extract (BBE) reduces chronic inflammatory responses induced by UVB irradiation in SKH-1 hairless mice skin. Mice were exposed to UVB radiation (100 mJ/cm(2)) on alternate days for 10 weeks, and BBE (10% and 20%) was applied topically a day before UVB exposure. Our results show that BBE suppressed UVB-induced hyperplasia and reduced infiltration of inflammatory cells in the SKH-1 hairless mice skin. BBE treatment reduced glutathione (GSH) depletion, lipid peroxidation (LPO), and myeloperoxidase (MPO) in mouse skin by chronic UVB exposure. BBE significantly decreased the level of pro-inflammatory cytokines IL-6 and TNF-α in UVB-exposed skin. Likewise, UVB-induced inflammatory responses were diminished by BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and inducible nitric oxide synthase (iNOS) levels in UVB-exposed skin. Treatment with BBE inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mouse skin. Immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG), cyclobutane pyrimidine dimers (CPD), proliferating cell nuclear antigen (PCNA), and cyclin D1 in UVB-exposed skin. Collectively, these data indicate that BBE protects from UVB-induced oxidative damage and inflammation by modulating MAP kinase and NF-κB signaling pathways.

Sunscreens in the United States: current status and future outlook.

Incidence rates of nonmelanoma skin cancer and melanoma has been on the rise in the United States for the past 20 years. UV radiation (UVR) exposure remains the most preventable environmental risk factor for these cancers. Aside from sun avoidance, sunscreens remain our best protection. UVR directly damages DNA and cause indirect cellular damage through the creation of reactive oxygen species, the sum of which leads to cutaneous immunosuppression and a tumorigenic milieu. The current generation of sunscreens protect from UVR through two main mechanisms: absorption and deflection. In the US, new Food and Drug Association rules require sunscreen manufacturers to evaluate their products not only on sun protection factor but also on broad spectrum UVA protection by the end of 2013. New labeling requirements will also be instituted. The American Academy of Dermatology and the American Academy of Pediatrics have provided specific recommendations for proper sun protection and sunscreen usage. Plant polyphenols such as those isolated from green tea, pomegranate, and grape seed remain an interesting avenue of research as additives to sunscreens or stand-alone products that appear to modulate the immunosuppressive effects of UVR on the skin. Additionally, although UVR induces endogenous cutaneous production of vitamin D, its damaging effects overshadow this positive benefit, especially in light of the ease of achieving recommended amounts of vitamin D through diet and supplementation.

Nutritional abrogation of photoimmunosuppression: in vivo investigations.

Skin cancer is a major public health concern, and the primary aetiological factor in the majority of skin cancers is ultraviolet radiation (UVR) exposure. UVR not only induces potentially mutagenic DNA damage but also suppresses cell-mediated immunity (CMI), allowing cancerous cells to escape destruction and progress to tumours. A considerable proportion of an individual's annual sun exposure is obtained outside the vacation period when topical and physical measures for photoprotection are irregularly used. Certain nutrients could provide an adjunctive protective role, and evidence is accruing from experimental studies to support their use in abrogation of photoimmunosuppression. Moreover, developments in clinical research methods to evaluate impact of solar-simulated radiation on cutaneous CMI allow the immune protective potential of nutritional agents to be examined in humans in vivo. This article summarises the mediation of CMI and its suppression by UVR, evaluates the methodology for quantitative assessment in vivo, reviews the human studies reported on nutritional abrogation of photoimmunosuppression including recent randomized controlled trials and discusses the mechanisms of photoprotection by the nutrients. This includes, in addition to antioxidants, novel studies of omega-3 polyunsaturated fatty acids and nicotinamide.

Lipoteichoic acid from Lactobacillus rhamnosus GG as an oral photoprotective agent against UV-induced carcinogenesis.

Probiotics are live micro-organisms that when administered in adequate amounts confer a health benefit on the host. Cell surface molecules of these micro-organisms are being studied in relation to their ability to interact with the host. The cell wall of lactobacilli possesses lipoteichoic acids (LTA) which are molecules with immunomodulatory properties. UV radiation (UVR) has been proposed as the main cause of skin cancer because of its mutagenic and immunosuppressive effects. Photoprotection with some nutrition interventions including probiotics has recently been shown. The aim of the present study was to investigate whether the oral administration of purified LTA from Lactobacillus rhamnosus GG can modulate the immune-suppressive effect of UVR and skin tumour development in female Crl:SKH-1-hrBR mice. For this purpose, two irradiation models were studied: (1) a chronic irradiation scheme consisting of daily irradiations during twenty consecutive days and (2) a long-term irradiation schedule, irradiating the animals three times per week, during 34 weeks for tumour development. The results showed that T-cells in the inguinal lymph node of LTA-treated mice produced higher levels of (1) interferon-γ and (2) a number of total, helper and cytotoxic T-cells compared with non-treated mice. Moreover, a significant delay in tumour appearance was found in LTA-treated mice. An increased IgA⁺ cell number was found in the small intestine together with a higher number of activated dendritic cells in the mesenteric lymph nodes. The latter results might be indicative of a direct effect of LTA in the gut, affecting the cutaneous immune system and restoring homeostasis through the gut-skin axis.

Oral niacin prevents photocarcinogenesis and photoimmunosuppression in mice.

Topical nicotinamide (niacinamide) has demonstrable preventive activity against photocarcinogenesis in mice. To better understand how this vitamin prevents ultraviolet (UV) carcinogenesis, we tested systemic administration of another form of the vitamin, niacin, and its capacity to elevate cutaneous nicotinamide-adenine dinucleotide (NAD) content as well as to decrease photoimmunosuppression and photocarcinogenesis. BALB/cAnNTacfBR mice were fed the AIN-76A diet supplemented with 0%, 0.1%, 0.5%, or 1.0% niacin throughout the experiment. UV irradiation consisted of five 30-minute exposures per week to banks of six FS40 Westinghouse sunlamps for 22 weeks in the carcinogenesis experiments, yielding a total cumulative dose of approximately 1.41 x 10(6) Jm-2 of UV-B radiation. Dietary supplementation with 0.1%, 0.5%, or 1.0% niacin reduced the control incidence of skin cancer from 68% to 60%, 48%, and 28%, respectively, at 26.5 weeks after the first UV treatment. Two potential mechanisms by which niacin prevents tumor formation were identified. Photoimmunosuppression, critical for photocarcinogenesis, is measured by a passive transfer assay. Syngeneic, antigenic tumor challenges grew to an average of 91.6 +/- 19.7, 79.8 +/- 11.5, 41.9 +/- 11.7, or 13.2 +/- 4.1 mm2 in naive recipients of splenocytes from UV-irradiated mice treated with 0%, 0.1%, 0.5%, or 1.0% niacin supplementation, respectively, demonstrating niacin prevention of immunosuppression. Niacin supplementation elevated skin NAD content, which is known to modulate the function of DNA strand scission surveillance proteins p53 and poly(ADP-ribose) polymerase, two proteins critical in cellular responses to UV-induced DNA damage. These results clearly demonstrate a dose-dependent preventive effect of oral niacin on photocarcinogenesis and photoimmunosuppression and establish the capacity of oral niacin to elevate skin NAD levels.

Dependence of photocarcinogenesis and photoimmunosuppression in the hairless mouse on dietary polyunsaturated fat.

A series of semi-purified diets containing 20% fat by weight, of increasing proportions (0, 5%, 10%, 15% or 20%) of polyunsaturated sunflower oil mixed with hydrogenated saturated cottonseed oil, was fed to groups of Skh:HR-1 hairless mice during induction and promotion of photocarcinogenesis. The photocarcinogenic response was of increasing severity as the polyunsaturated content of the mixed dietary fat was increased, whether measured as tumour incidence, tumour multiplicity, progression of benign tumours to squamous cell carcinoma, or reduced survival. At the termination of the study approximately 6 months following the completion of the 10-week chronic UV irradiation treatment, when most mice bore tumours, the contact hypersensitivity (CHS) reactions in those groups supporting the highest tumour leads (fed 15% or 20% polyunsaturated fat), were significantly suppressed in comparison with the mice bearing smaller tumour loads (fed 0, 5% or 10% polyunsaturated fat). When mice were exposed acutely to UV radiation (UVR), a diet of 20% saturated fat provided almost complete protection from the suppression of CHS, whereas feeding 20% polyunsaturated fat resulted in 57% suppression; the CHS of unirradiated mice was unaffected by the nature of the dietary fat. These results suggest that the enhancement of photocarcinogenesis by the dietary polyunsaturated fat component is mediated by an induced predisposition to persistent immunosuppression caused by the chronic UV irradiation, and supports the evidence for an immunological role in dietary fat modulation of photocarcinogenesis in mice.

Langerhans cells, immunomodulation and skin lesions. A quantitative, morphological and clinical study.

The epidermal Langerhans cell (LC) plays an important role in contact hypersensitivity reactions by presenting the antigens to T lymphocytes. LCs may also play a role in defence mechanisms against neo-antigens in skin tumours. Some studies have indicated that the LC population declines with age. Ultraviolet radiation induces a significant reduction in the number of epidermal LCs and most immunosuppressive drugs decrease the number and function of LCs as well. Such alterations in LCs might predispose to the development of skin tumours. To evaluate the importance of LCs in immunosurveillance of skin tumours, the number and the morphology of LCs was investigated in unaffected skin of patients with cutaneous tumours and in immunosuppressed patients. LCs within basal cell carcinoma (BCC) were examined as well. ATPase and CD1a staining was used to visualise LCs. The inflammatory response around BCC was estimated by the expression of HLA-DR+, CD3+ and ICAM-1+ cells. The prevalence of skin tumours was studied in renal transplant recipients on different immunosuppressive treatments such as azathioprine (Aza) and prednisolone (P), cyclosporin (CyA), azathioprine and prednisolone or cyclosporin and prednisolone. We found no difference in LC populations in patients treated with PUVA (psoralen and UVA-radiation) or in patients with skin tumours as compared with controls and no age-related reduction in LC numbers. However, immunosuppressed patients showed a reduced number of LCs, especially those who had received triple drug therapy (CyA+Aza+P). Patients treated with azathioprine and prednisolone (10-25 years) had a high prevalence of multiple warts (40%) and skin tumours (29%). In contrast, warts and skin tumours were not common in patients treated for 5 years with CyA+Aza+P or with CyA+P. Thus, the duration of immunosuppressive treatment seems crucial for the development of warts and skin tumours. However, the reduction in LC numbers was not more pronounced with time or in patients with skin lesions as compared with those without lesions. In the epidermis overlying basal cell carcinoma (BCC) the number of LCs was decreased and their morphology changed as compared with LCs in perilesional skin. These alterations were documented in horizontal sheets as well as in vertical sections of the epidermis analysed by light microscopy and with confocal laser scanning microscopy (CLSM). The latter technique permits a quantitative and morphological analysis of LCs in the same tissue volume. In vertical sections, numerous LCs were observed in the dermis surrounding BCC nests.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhanced resistance to an antigenic tumor in immunosuppressed mice by dietary retinyl palmitate plus canthaxanthin.

Retinoids and certain carotenoids, e.g., beta-carotene and canthaxanthin, have been found to prevent photocarcinogenesis in mice and also to act as immunoenhancers. The hypothesis that retinoids and carotenoids inhibit photocarcinogenesis by preventing UV induction of immunosuppression predicts that mice treated with these agents before and during periods of UV radiation treatments should be as resistant as unirradiated mice to an antigenic UV-induced tumor. To test this prediction, mice were fed 120 IU of retinyl palmitate per gram of diet, and/or 1% canthaxanthin, before UV irradiation treatments began, and during the entire experiment. After 4.95 x 10(5) Jm-2, delivered over 12 weeks, resistance of mice to antigenic UV-induced tumor implants (UV20) was studied. Dietary supplementation with retinyl palmitate plus canthaxanthin, but not with either agent alone at these doses, prevented the enhanced growth of UV20 in UV irradiated mice.

Immunogenicity and cross-reactivity of syngeneic murine melanomas.

Non-melanoma skin cancers induced in mice by chemical carcinogens or ultraviolet radiation are often antigenic but rarely induce cross-protective immunity when tested by in vivo transplantation methods. We wished to determine whether melanocytic skin tumors behave similarly or whether they exhibit cross-reactive antigens in vivo. Three melanomas induced in C3H/HeNCr(MTV-) mice by initiation with ultraviolet radiation and promotion with croton oil or initiation with 7,12-dimethyl-benz[a]anthracene and promotion with 12-O-tetradecanoyl-phorbol-13-acetate or croton oil plus ultraviolet radiation were tested for immunogenicity and cross-reactivity in vivo. The three melanomas were highly immunogenic, and all induced some degree of protection against the other melanomas. Non-melanoma skin cancers induced by the same carcinogens were less immunogenic and did not immunize against the melanomas. We conclude that unlike other skin cancers, melanocytic tumors induced by chemical carcinogens and ultraviolet radiation are highly cross-reactive in vivo and thus represent a unique subset of murine skin cancers.

Effects of methoxsalen plus near-ultraviolet radiation or mid-ultraviolet radiation on immunologic mechanisms.

Skin cancers induced in mice by UVB, i.e., 280-320 nm radiation, are highly antigenic. They grow progressively in UVB-irradiated hosts because of certain specific immunologic alterations that are induced in the mice. Comparative studies of the immunologic aspects of carcinogenesis by UVB or methoxsalen plus UVA, i.e., 320-400 nm radiation (PUVA), formed the basis for the following conclusions: 1) Skin cancers induced by PUVA in C3H/HeN mammary tumor virus-negative mice are not highly antigenic, in contrast to those induced by UVB; 2) PUVA-induced tumors also differ from those induced by UVB, in that they do not exhibit preferential growth in UVB-irradiated mice; 3) PUVA treatment of mice, unlike UVB, does not induce susceptibility to the transplantation of UVB-induced tumors; 4) both UVB and PUVA treatments suppress the induction of contact hypersensitivity by a mechanism that involves suppressor lymphocytes.

Differences in the immunologic reactivity of mice treated with UVB or methoxsalen plus UVA radiation.

Skin tumors induced in mice by chronic exposure to UVB radiation are often highly antigenic and regress when transplanted into normal syngeneic animals, but grow progressively in immunosuppressed mice. Exposure of mice to subtumorigenic doses of UVB radiation can abolish this immunologic rejection phenomenon. In this study, we have investigated the effects of treatment with 8-methoxypsoralen plus UVA radiation (PUVA) on the rejection of antigenic UVB-induced tumors. PUVA treatment, with either topical or systemic administration of the psoralen, did not alter the normal process of rejection of UVB-induced tumors. Mice treated with both minimally and markedly phototoxic doses of PUVA rejected tumors with a frequency similar to that seen in untreated animals, although these tumors grew progressively in UVB-irradiated mice. These results indicate that the effects of PUVA treatment differ from those of UVB irradiation in that PUVA treatment does not alter the immunologic rejection of UVB-induced tumors.