Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair

Human skin is constantly exposed to numerous noxious physical, chemical and environmental agents. Some of these agents directly or indirectly adversely affect the skin. Cutaneous overexposure to environmental solar ultraviolet (UV) radiation (290-400 nm) has a variety of adverse effects on human health, including the development of melanoma and nonmelanoma skin cancers. Therefore, there is a need to develop measures or strategies, and nutritional components are increasingly being explored for this purpose. The polyphenols present in green tea (Camellia sinensis) have been shown to have numerous health benefits, including protection from UV carcinogenesis. (-)-Epigallocatechin-3-gallate (EGCG) is the major and most photoprotective polyphenolic component of green tea. In this review article, we have discussed the most recent investigations and mechanistic studies that define and support the photoprotective efficacy of green tea polyphenols (GTPs) against UV carcinogenesis. The oral administration of GTPs in drinking water or the topical application of EGCG prevents UVB-induced skin tumor development in mice, and this prevention is mediated through: (a) the induction of immunoregulatory cytokine interleukin (IL) 12; (b) IL-12-dependent DNA repair following nucleotide excision repair mechanism; (c) the inhibition of UV-induced immunosuppression through IL-12-dependent DNA repair; (d) the inhibition of angiogenic factors; and (e) the stimulation of cytotoxic T cells in a tumor microenvironment. New mechanistic information strongly supports and explains the chemopreventive activity of GTPs against photocarcinogenesis.     

Differential effects of peptidoglycan recognition proteins on experimental atopic and contact dermatitis mediated by Treg and Th17 cells

Skin protects the body from the environment and is an important component of the innate and adaptive immune systems. Atopic dermatitis and contact dermatitis are among the most frequent inflammatory skin diseases and are both determined by multigenic predisposition, environmental factors, and aberrant immune response. Peptidoglycan Recognition Proteins (Pglyrps) are expressed in the skin and we report here that they modulate sensitivity to experimentally-induced atopic dermatitis and contact dermatitis. Pglyrp3(-/-) and Pglyrp4(-/-) mice (but not Pglyrp2(-/-) mice) develop more severe oxazolone-induced atopic dermatitis than wild type (WT) mice. The common mechanism underlying this increased sensitivity of Pglyrp3(-/-) and Pglyrp4(-/-) mice to atopic dermatitis is reduced recruitment of Treg cells to the skin and enhanced production and activation Th17 cells in Pglyrp3(-/-) and Pglyrp4(-/-) mice, which results in more severe inflammation and keratinocyte proliferation. This mechanism is supported by decreased inflammation in Pglyrp3(-/-) mice following in vivo induction of Treg cells by vitamin D or after neutralization of IL-17. By contrast, Pglyrp1(-/-) mice develop less severe oxazolone-induced atopic dermatitis and also oxazolone-induced contact dermatitis than WT mice. Thus, Pglyrp3 and Pglyrp4 limit over-activation of Th17 cells by promoting accumulation of Treg cells at the site of chronic inflammation, which protects the skin from exaggerated inflammatory response to cell activators and allergens, whereas Pglyrp1 has an opposite pro-inflammatory effect in the skin.     

Reduction,refinement and replacement: putting the immune system to work

Many chemicals are known to be, or have been implicated as, contact allergens, and allergic contact dermatitis is an important occupational and environmental health issue. It is the responsibility of toxicologists to identify those chemicals that have the potential to induce skin sensitisation, and to assess the conditions under which there will exist a risk to human health. This article describes progress that has been made in the development of new approaches to the toxicological evaluation of skin sensitisation, and the benefits to animal welfare that such developments have already produced, and are likely to produce in the future. In this context, the local lymph node assay is described with regard to hazard identification and risk assessment, and possible strategies for the development of in vitro approaches to safety assessment are discussed.     

Frequency of aggressive behavior and a case of mortal attack in wildMacaca sylvanus in the Middle Atlas region (Morocco)

We observed a mortal attack against an adult female in a wild population ofMacaca sylvanus in the Middle Atlas Cedar forest ecosystem near the town of Azrou, Morocco. This species is generally believed to be the least aggressive in the whole GenusMacaca. We investigated the possible factors responsible for such an extreme case of increased aggression such as: 1) density of population, 2) availability of food rescues, 3) male competition for females. During a twelve month behavioral observation, we compared the hourly agesex class aggression frequency in the population where the mortal attack occurred with another macaque population living in different ecological conditions relative to density, food distribution and distance from human settlements. The pattern of age-sex seasonal distribution of aggression shows that, in the Middle Atlas, the adult female is the age-sex class most involved in aggressions and especially during food shortage and when resources are patchily distributed, as in the case were the mortal attack occurred.     

Repair of bulky DNA lesions deriving from polycyclic aromatic hydrocarbons

Genomic DNA is damaged by a variety of factors exerting an adverse effect on human health, such as environmental pollution, UV light, ionizing radiation, and toxic compounds. Air pollution with products of incomplete combustion of hydrocarbon fuels and wastes of various industries are main sources of polycyclic aromatic hydrocarbons, whose metabolites can damage DNA by forming bulky DNA adducts, which potentially lead to mutations and cancer. Nucleotide excision repair is the main pathway that eliminates these lesions in eukaryotic cells. The excision efficiency of bulky adducts depends on many factors, including the structure of a bulky substituent and the degree of DNA double helix distortion induced by a lesion. Clustered DNA lesions are the most dangerous for the cell. Several DNA repair systems cooperate to recognize and remove such lesions. The review focuses on the mechanisms that repair DNA with single and clustered bulky lesions, taking the natural carcinogen benzo[a]pyrene as an example.     

Epidermal malignant tumors: pathogenesis, influence of UV light and apoptosis

Basal cell carcinoma and squamous cell carcinoma, collectively termed non-melanoma skin cancers are the most common malignant tumors in humans. Basal cell carcinoma grows slowly and metastatic spread is very rare. Squamous cell carcinoma is characterized by infiltrative, destructive growth and metastasis. Long-term exposure of skin to UV light has a great impact on development of these epidermal malignancies. UV light induces cascade of events like well known DNA damage of keratinocytes as well as still completely undetermined influence on apoptotic process through expression of proapoptotic and antiapoptotic molecules. The major role in development of skin cancer is given to proapoptotic p53 molecule or tumor suppressor gene which mutation due to UV exposure leads to resistance of DNA-damaged cell to apoptosis. Other proapoptotic molecules such as Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are strongly expressed in basal cell carcinoma and squamous cell carcinoma that could be explained by the ability of tumor to escape the attack of immune system.     

Die Genetik atopischer Erkrankungen

Allergic disorders (atopic dermatitis, asthma, hay fever) are common chronic inflammatory diseases of the skin and airways that are often associated with allergies (formation of specific IgE antibodies) to environmental allergens. They are complex genetic diseases, so that both genetic and environmental factors are involved in their causation. Most of the research effort devoted to the search for genes that might be responsible has so far focused on the mechanisms behind the immune response. More recent work on gene identification, however, documents the decisive importance of epithelial barrier defects in the pathogenesis of AD and allergic airways disease. These findings represent an important milestone in unraveling the genetic mechanisms underlying these complex diseases and allow new insight into the molecular mechanisms that lead illnesses to develop. In addition, they might point the way to novel preventive and therapeutic strategies for atopic disorders.     

Stepping up melanocytes to the challenge of UV exposure

Exposure to solar ultraviolet radiation (UV) is the main etiological factor for skin cancer, including melanoma. Cutaneous pigmentation, particularly eumelanin, afforded by melanocytes is the main photoprotective mechanism, as it prevents UV-induced DNA damage in the epidermis. Therefore, maintaining genomic stability of melanocytes is crucial for prevention of melanoma, as well as keratinocyte-derived basal and squamous cell carcinoma. A critical independent factor for preventing melanoma is DNA repair capacity. The response of melanocytes to UV is mediated mainly by a network of paracrine factors that not only activate melanogenesis, but also DNA repair, anti-oxidant, and survival pathways that are pivotal for maintenance of genomic stability and prevention of malignant transformation or apoptosis. However, little is known about the stress response of melanocytes to UV and the regulation of DNA repair pathways in melanocytes. Unraveling these mechanisms might lead to strategies to prevent melanoma, as well as non-melanoma skin cancer.     

Eicosanoids in skin inflammation

Eicosanoids play an integral part in homeostatic mechanisms related to skin health and structural integrity. They also mediate inflammatory events developed in response to environmental factors, such as exposure to ultraviolet radiation, and inflammatory and allergic disorders, including psoriasis and atopic dermatitis. This review article discusses biochemical aspects related to cutaneous eicosanoid metabolism, the contribution of these potent autacoids to skin inflammation and related conditions, and considers the importance of nutritional supplementation with bioactives such as omega-3 and omega-6 polyunsaturated fatty acids and plant-derived antioxidants as means of addressing skin health issues.     

Regulation of endonuclease activity in human nucleotide excision repair

Nucleotide excision repair (NER) is a DNA repair pathway that is responsible for removing a variety of lesions caused by harmful UV light, chemical carcinogens, and environmental mutagens from DNA. NER involves the concerted action of over 30 proteins that sequentially recognize a lesion, excise it in the form of an oligonucleotide, and fill in the resulting gap by repair synthesis. ERCC1-XPF and XPG are structure-specific endonucleases responsible for carrying out the incisions 5' and 3' to the damage respectively, culminating in the release of the damaged oligonucleotide. This review focuses on the recent work that led to a greater understanding of how the activities of ERCC1-XPF and XPG are regulated in NER to prevent unwanted cuts in DNA or the persistence of gaps after incision that could result in harmful, cytotoxic DNA structures.     

鞘磷脂酶通路与紫外线诱导的细胞凋亡

紫外线是一种重要的环境因素,对人类日常生活起着广泛的影响效应。大量的非保护的日光暴露不仅可以导致皮肤炎症、过度老化甚至皮肤癌症的发生,而且还能够诱导多种细胞凋亡。鞘磷脂酶-神经酰胺信号通路的激活与细胞凋亡关系密切,本文旨在探讨该通路在介导紫外线诱导细胞凋亡中的地位,重点描述了第二信使神经酰胺代谢的研究进展、鞘磷脂酶通路参与紫外线诱导细胞凋亡的机制。深入了解和研究紫外线诱导细胞凋亡的过程及其相关信号转导途径,有助于指导紫外线辐射的防护,开发新的治疗策略。     

Shedding light on proteins, nucleic acids, cells, humans and fish

I was trained as a physicist in graduate school. Hence, when I decided to go into the field of biophysics, it was natural that I concentrated on the effects of light on relatively simple biological systems, such as proteins. The wavelengths absorbed by the amino acid subunits of proteins are in the ultraviolet (UV). The wavelengths that affect the biological activities, the action spectra, also are in the UV, but are not necessarily parallel to the absorption spectra. Understanding these differences led me to investigate the action spectra for affecting nucleic acids, and the effects of UV on viruses and cells. The latter studies led me to the discovery of the important molecular nature of the damages affecting DNA (cyclobutane pyrimidine dimers) and to the discovery of nucleotide excision repair. Individuals with the genetic disease xeroderma pigmentosum (XP) are extraordinarily sensitive to sunlight-induced skin cancer. The finding, by James Cleaver, that their skin cells were defective in DNA repair strongly suggested that DNA damage was a key step in carcinogenesis. Such information was important for estimating the wavelengths in sunlight responsible for human skin cancer and for predicting the effects of ozone depletion on the incidence of non-melanoma skin cancer. It took experiments with backcross hybrid fish to call attention to the probable role of the longer UV wavelengths not absorbed by DNA in the induction of melanoma. These reflections trace the biophysicist's path from molecules to melanoma.     

Therapeutic Efficacy and Immunological Response of CCL5 Antagonists in Models of Contact Skin Reaction

Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, ⁴⁴AANA⁴⁷-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS) is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.     

Dds20 operates in cds1-independent mechanism of tolerance to UV-induced DNA damage in Schizosaccharomyces pombe cells

Repair of DNA double-stranded breaks caused by ionizing radiation or cellular metabolization, homologous recombination, is an evolutionary conserved process controlled by RAD52 group genes. Genes of recombinational repair also play a leading role in the response to DNA damage caused by UV light. Cells with deletion in gene dds20 of recombinational repair were shown to manifest hypersensitivity to the action of UV light at lowered incubation temperature. Epistatic analysis revealed that dds20+ is not a member of the NER and UVER gene groups responsible for the repair of DNA damage induced by UV light. The Dds protein has functions in the Cds1-independent mechanism of UV damage tolerance of DNA.     

UV irradiation increases ROS production via PKCdelta signaling in primary murine fibroblasts

Ultraviolet (UV) irradiation is a major environmental factor responsible for a high incidence of premature skin aging, referred to as photoaging, as well as skin cancer and melanoma. UVA irradiation represents 90% of the solar UV light reaching the earth's surface, and yet the mechanisms by which it exerts its biological effects are not clear. UVA penetrates into the skin tissue, reaching the basal layers of the active dividing cells and, therefore, the contribution of UVA to skin damage may be significant. The majority of UVA energy is absorbed by unidentified photosensitizers in the cells which are postulated to generate reactive oxygen species (ROS). It has been believed that both chronological aging and photoaging share the same molecular features and, as such, it is very common to utilize UV irradiation for induction of skin aging. To determine the involvement of protein kinase isoforms in chronological aging and photoaging, we utilized in vitro aging model systems of primary murine fibroblasts and primary fibroblasts isolated from PKC null mice. We show for the first time distinct involvement of PKC isoforms PKCdelta and PKCalpha in photoaging versus cellular senescence. While chronological aging is accompanied by overexpression and activation of PKCalpha, UV irradiation and ROS production are associated with photoaging accompanied by PKCdelta downregulation and nuclear translocation.     

UV activation of human immunodeficiency virus gene expression in transgenic mice.

Human immunodeficiency virus (HIV) infection is associated with a clinical latency of as long as 10 years before the development of disease. One explanation for this delay is the requirement of cofactors such as other DNA or RNA viruses, cytokines critical for immune modulation, or environmental UV light. At least in tissue culture studies, these agents are capable of inducing HIV gene expression in cell lines which either harbor the entire viral genome or contain a reporter gene under the control of the viral long terminal repeat regulatory region. The role of these cofactors in terminating clinical latency and inducing disease has been difficult to ascertain because of the lack of an appropriate animal model. We now report that UV light can markedly induce HIV gene expression in transgenic mice carrying both the cis-acting (long terminal repeat) and trans-acting (the tat gene) elements which are essential for viral transactivation and replication in infected cells. Our finding may explain the clinical observations that cutaneous lesions in HIV-infected individuals are often seen in the sunlight exposed areas of the skin, including the face and neck.