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.

Caspase-3 protects stressed organs against cell death.

The ability to generate appropriate defense responses is crucial for the survival of an organism exposed to pathogenesis-inducing insults. However, the mechanisms that allow tissues and organs to cope with such stresses are poorly understood. Here we show that caspase-3-knockout mice or caspase inhibitor-treated mice were defective in activating the antiapoptotic Akt kinase in response to various chemical and environmental stresses causing sunburns, cardiomyopathy, or colitis. Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs, marked deterioration of their physiological functions, and stronger disease development. Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response.

Polymorphisms of GSTM1 and GSTT1, sun exposure and the risk of melanoma: a case-control study.

Glutathione S-transferases (GSTs) are a family of enzymes that are known to play an important role in cellular protection against oxidative stress, including the oxidative stress caused by ultraviolet radiation. This study focused on the possible involvement of GSTM1 and GSTT1 polymorphisms in risk modulation of cutaneous melanoma. Within a case-control study, the presence of the null polymorphism at GSTM1 and GSTT1 was investigated in 188 cases of cutaneous melanoma and 152 controls. Information on socio-demographic characteristics, medical history, sun exposure and pigmentary characteristics were collected for all subjects. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI). An interaction was suggested between the GSTM1 and GSTT1 "null" genotype and episodes of sunburn in childhood OR of interaction (1.65, 95% CI (95% CI) 0.27-9.94). The risk of melanoma among the subset of participants who reported sunburns in childhood and who had both null variants, was nine (OR 9.16; 95% CI 1.18-70.9). The results suggest that subjects carrying both GSTM1 and GSTT1 null polymorphisms and experiencing sunburns in childhood have an extremely high risk of melanoma.

Leptin deficiency-induced obesity exacerbates ultraviolet B radiation-induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin.

Obesity has been implicated in several inflammatory diseases and in different types of cancer. Chronic inflammation induced by exposure to ultraviolet (UV) radiation has been implicated in various skin diseases, including melanoma and nonmelanoma skin cancers. As the relationship between obesity and susceptibility to UV radiation-caused inflammation is not clearly understood, we assessed the role of obesity on UVB-induced inflammation, and mediators of this inflammatory response, using the genetically obese (leptin-deficient) mouse model. Leptin-deficient obese (ob/ob) mice and wild-type counterparts (C57/BL6 mice) were exposed to UVB radiation (120 mJ/cm(2)) on alternate days for 1 month. The mice were then euthanized and skin samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. Here, we report that the levels of inflammatory responses were higher in the UVB-exposed skin of the ob/ob obese mice than those in the UVB-exposed skin of the wild-type non-obese mice. The levels of UVB-induced cyclooxygenase-2 expression, prostaglandin-E(2) production, proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser(473)) were higher in the skin of the ob/ob obese mice than the those in skin of their wild-type non-obese counterparts. Compared with the wild-type non-obese mice, the leptin-deficient obese mice also exhibited greater activation of NF-kappaB/p65 and fewer apoptotic cells in the UVB-irradiated skin. Our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced inflammatory responses and, therefore, obesity may increase susceptibility to UVB-induced inflammation-associated skin diseases, including the risk of skin cancer.

The effects of EGb 761 on lipid peroxide levels and superoxide dismutase activity in sunburn.

BACKGROUND/PURPOSE: Free oxygen radicals are involved in inflammatory skin reactions induced by ultraviolet B (UVB). In this study, the effect of a herbal antioxidant Ginkgo biloba extract (EGb 761) was investigated in UVB irradiated mice skin. METHODS: The study was carried out on four groups of mice (n = 6 in each group). The first group was a control group (G1). The second group (G2) was only exposed to acute UVB irradiation. The third group (G3) received 100 mg/kg/day of EGb 761 orally for 5 days before UVB irradiation and the fourth group (G4) was given only a single dose of EGb 761 immediately after UVB irradiation. Eighteen hours after exposing to UVB, lipid peroxide levels, and superoxide dismutase (SOD) activities were studied and UVB damage was evaluated histopathologically according to "sun-burn cell count". RESULTS: The SOD activities and Malondialdehyde (MDA) levels in G2, G3 and G4 were found to be decreased significantly when compared with G1 (P < 0.05). The SOD activities of G3 and G4 were higher when compared with G2 (P < 0.05). The number of sunburn cells (SBCs) was the highest in G2. CONCLUSIONS: Our results suggest that EGb 761 may have an important effect, both as a protective and therapeutic agent, in sunburn after UVB irradiation.

Expression of telomerase reverse transcriptase in radiation-induced chronic human skin ulcer.

The objective of this study was to investigate the expression of the catalytic subunit of telomerase, telomerase reverse transcriptase (TRT), and the possible relationship between the TRT expression and poor healing or cancer transformation in radiation-induced chronic human skin ulcer. Rabbit antibody to human TRT and SP immunohistochemical method were used to detect TRT expression in 24 cases of formalin-fixed, paraffin-embedded chronic human skin ulcer tissues induced by radiation, 5 cases of normal skin, 2 of burned skin, and 8 of cancer. The positive rate of TRT expression in chronic radiation ulcers was 58.3% (14/24), of which it was strongly positive in 41.7% cases (10/24) and weakly positive in 16.7% (4/24). TRT expression was 0% in normal (0/5) and burned skin (0/2), and 100% in cancer cases (8/8). The strongly positive expression of TRT was observed almost always in the cytoplasm and nucleus of squamous epithelial cells of the epidermis but it was negative or only weakly positive in the smooth muscle and endothelia of small blood vessels and capillaries, and in fibroblasts. Chronic inflammatory cells, plasmacytes, and lymphocytes were weakly positive for TRT. TRT expression could be involved in the poor healing caused by sclerosis of small blood vessels and lack of granulation tissue and in the cancer transformation of chronic radiation ulcer.

The effects of sunscreens on UVB erythema and Langerhans cell depression.

Langerhans cells (LCs) are epidermal antigen-presenting cells capable of initiating a specific T lymphocyte-mediated immune response. It is a well known fact that ultraviolet light B (UVB) suppresses LC number and function. In this study, we confirmed that the sunscreens CITY BLOCK, and TOTAL SUN SHIELD 28 (Clinique Laboratories Tokyo, Japan) protected the epidermis against the depletion of LC number. We also investigated whether or not sunscreens could provide LC protection from ultraviolet ray (UVR) damage other than the prevention of the decrease in the total number of cells. Our data showed that the LC population was depressed after irradiation by 100 mJ/cm2 or 10 mJ/cm2 of UVB, but recovered to within normal levels after 16 days. Both sunscreens provided protection against erythema and LC depression due to UVB irradiation. However, despite the fact that these sunscreens had completely suppressed UVB erythema, shrinkage of LC dendrites was seen. Apparently, sunscreens prevent UVB erythema, but do not protect against functional changes in LC due to UVB. Recently, it has been reported that sunscreens are less effective in protecting against systemic immunosuppression that against inflammation. The shrinkage of LC dendrites despite sunscreen application may help explain this discrepancy.

Photoprotective effect of topically applied superoxide dismutase on sunburn reaction in comparison with sunscreen.

Photoprotective effect of topically applied superoxide dismutase (SOD) to guinea pig skin was compared with a commercially available sunscreen agent after a single exposure to UVB. While cutaneous SOD activity was remarkably decrease in non-treated control animals, both topical SOD and sunscreen agent significantly reduced the decrease in skin SOD activity after UVB irradiation. However, only the sunscreen agent successfully reduced erythema reaction 24h after irradiation but topical SOD failed. These findings suggest that topical SOD protects skin from photo-oxidative damage without affecting erythema response, and thus, from a practical standpoint, sunscreen agents, when compared with topical antioxidants, seem better at present for daily photoprotection.