Abstract: A rapidly increasing number of people visit dermatologists for the prevention and treatment of aging skin. Sun avoidance and sunscreen use are widely accepted strategies of primary prevention against photoaging. Convincing evidence shows that topical application of retinoids has an effect on reversing, at least partially, mild to moderate photodamage. Antioxidants and alpha-hydroxy acids can alter the skin structure and function. Enzymes that repair DNA damage or oligonucleotides that enhance the endogenous capacity for DNA damage repair may prove to be future preventive/therapeutic interventions for aging skin.
Abstract: Human pigmentation involves production and dispersion of melanin by epidermal melanocytes to neighboring keratinocytes. Melanin synthesis or melanogenesis occurs within the specialized organelle termed melanosomes where the amino acid L-tyrosine serves as the starting precursor. Melanocytes from individuals of different pigmentary phenotypes differ in their rate and types of melanin synthesis, as well as in the rate and manner of melanosome transfer. Modern molecular biology methods and the use of transgenic animals have greatly advanced our understanding in the molecular and cellular mechanisms regulating human pigmentation and its disorders. This review examines recent advances in the regulation of human pigmentation and their implication in treatments for the pigmentary disorders.
Abstract: The major differentiated function of melanocytes is the synthesis of melanin, a pigmented heteropolymer that is synthesized in specialized cellular organelles termed melanosomes. Mature melanosomes are transferred to neighboring keratinocytes and are arranged in a supranuclear cap, protecting the DNA against incident ultraviolet light (UV) irradiation. The synthesis and distribution of melanin in the epidermis involves several steps: transcription of melanogenic proteins, melanosome biogenesis, sorting of melanogenic proteins into the melanosomes, transport of melanosomes to the tips of melanocyte dendrites and finally transfer into keratinocytes. These events are tightly regulated by a variety of paracrine and autocrine factors in response to endogenous and exogenous stimuli, principally UV irradiation.
Abstract: Bone Morphogenetic Protein (BMP-4) was shown to down-regulate melanogenesis, in part, by decreasing the level of tyrosinase [Yaar et al. (2006) JBC:281]. Results presented here show that BMP-4 down-regulated the protein levels of TRP-1, PKC-beta, and MCI-R. When paired cultures of human melanocytes were treated with vehicle or BMP-4 (25 ng/ml), MAPK/ERK were phosphorylated within one hour of BMP-4 treatment. Then the activated MAPK/ERK caused an acute phosphorylation of MITF, followed by proteosome-mediated degradation of MITF, the key transcription factor for melanogenic proteins [Wu et al. (2000) Gene & Development:14]. However, prolonged exposure of melanocytes to BMP-4 (up to 48 hours) caused a decrease in the level of MITF-M transcript. In addition, BMP-4 decreased the intracellular level of cAMP, the key regulator of MITF expression. These results demonstrate that BMP-4 activates MAPK/ERK signaling pathway to transiently activate MITF; however, chronic treatment of BMP-4 to melanocytes causes a down-regulation of the expression of MITF, possibly in a cAMP-dependent pathway.
Abstract: The color of the skin, hair and eye is controlled by multiple genes and is among the most visible examples of human phenotypic variation. Genetics correlate phenotypic with genotypic variation. Recent scientific work reveals DNA polymorphisms at least partially responsible for some of the differences observed in human pigmentation. These are the focus of this review.
Abstract: The popularity of sunscreens dramatically increased since ultraviolet irradiation was implicated in the pathogenesis of skin cancer and skin ageing. The absorption properties, safety, photostability of different organic and inorganic filters are reviewed: para-aminobenzoic acid, salicylates, cinnamates, benzophenones, butylmethoxydibenzoylmethane (Parsol 1789), drometrizole trisulphonic (Mexoryl XL), terephthalydene dicamphor sulphonic acid (Mexoryl SX), methylene bisbenzotriazol tetramethylbutylphenol (Tinasorb M), anisotriazine (Tinasorb S), titanium dioxide and zinc oxide. Furthermore, this review discusses the optimal methods for measuring the protection that a sunscreen offers, the role of sunscreen use in melanoma prevention and future trends in sunscreen filters development.
Abstract: BACKGROUND: Efalizumab (anti-CD11a antibody) targets T cell-mediated steps important in the immunopathogenesis of psoriasis. As efalizumab is intended to be administered on a continuous long-term basis in psoriasis, it is important to share experience concerning issues commonly occurring during its use in real daily practice. OBJECTIVE: To evaluate the efficacy and safety of efalizumab treatment in Greek patients with moderate-to-severe plaque psoriasis, and to investigate whether there are specific characteristics that predict the clinical outcome of therapy. PATIENTS: Seventy-two patients with moderate-to-severe plaque psoriasis, who had failed to respond to, or had a contraindication to, or were intolerant to other systemic therapies, received efalizumab (1 mg kg(-1) per week) for 12 weeks or more. RESULTS: After 12 weeks of efalizumab treatment, 65% of patients achieved 50% or more improvement from baseline Psoriasis Area and Severity Index (PASI) and 39% achieved at least 75% reduction in PASI score. The mean percentage PASI improvement from baseline was 62%. The most common side effects were a flu-like syndrome, a transient localized papular eruption, leucocytosis and lymphocytosis. There was no correlation between the occurrence of these side effects and the clinical response. Patients with a past history of unstable types of psoriasis were likely poor responders to efalizumab, and at an increased risk of developing generalized inflammatory flare. CONCLUSION: These results confirm previous reports suggesting that treatment with efalizumab is an efficacious and safe option for patients with moderate-to-severe plaque psoriasis. A detailed previous history of psoriasis is important in order to select possible candidates for efalizumab therapy.
Abstract: Recent work has substantially elucidated the mechanisms of skin aging and photoaging. In particular, a central role for telomere-based signaling can be inferred. Intrinsic aging is largely controlled by progressive telomere shortening, compounded by low grade oxidative damage to telomeres and other cellular constituents, the consequence of aerobic cellular metabolism. In sun exposed skin, UV irradiation also damages DNA and accelerates telomere shortening. Aging and photodamage appear to share a common final pathway that involves signaling through p53 following disruption of the telomere. These telomere-initiated responses, in combination with UV-induced damage to critical regulatory genes, lead to the familiar picture of "photoaging." These and other insights into the molecular basis for skin aging/photoaging may lead to enhanced management options.
Abstract: Vascular endothelial growth factor (VEGF) is a potent keratinocyte-derived angiogenic factor. Prior reports suggest that following UV irradiation VEGF in keratinocytes is induced primarily by tumor necrosis factor (TNF)- alpha, a cytokine synthesized and secreted by keratinocytes after UV irradiation. We investigated whether blocking TNF-alpha binding to its receptors would inhibit UV-induced VEGF expression and secretion in the keratinocyte-derived line SCC-12F. Irradiation with physiologic UV doses (30 mJ/cm2) substantially induced VEGF mRNA in this cell line, as expected, and mRNA induction was followed by increased VEGF in medium conditioned by UV-irradiated cells. Also as expected, TNF-alpha induced VEGF expression and secretion in a dose-dependent manner. Addition of a hexapeptide (Ac-KWIIVW-NH2), known to block TNF-alpha binding to its receptors, abrogated this TNF-alpha effect on VEGF mRNA induction. However, addition of the peptide to cells immediately after UV irradiation did not substantially affect VEGF mRNA induction or secretion into the medium. Our results suggest that VEGF induction after UV irradiation is mediated by multiple mechanisms and that blocking a single pathway does not affect the response.
Abstract: BACKGROUND: Ultraviolet (UV) irradiation to the skin causes apoptosis of keratinocytes. Melanocytes are more resistant to UV-induced apoptosis, due, in part, to high levels of antiapoptotic proteins such as Bcl-2. In vitro studies have shown that nerve growth factor (NGF), a neurotrophic polypeptide, is produced by keratinocytes and exerts a protective role for melanocytes by upregulating Bcl-2. The purpose of this study was to determine NGF and Bcl-2 modulations in UV-irradiated human skin. METHODS: Nine volunteers were irradiated with two minimal erythema doses using solar-simulated UV irradiation. Seventy-two hours post irradiation, skin biopsies were obtained from irradiated and sun-protected skin. The skin specimens were stained with anti-tyrosinase-related protein-1 monoclonal antibody IgG2a (Mel-5), anti-Bcl-2 (monoclonal antibody IgG-kappa), and with anti-NGF (polyclonal antibody IgG). RESULTS: NGF staining was identified within the cytoplasm of epidermal melanocytes, similar to the staining observed for TRP-1 and Bcl-2. While no significant difference in the number of TRP-1- and Bcl-2-positive melanocytes was observed between irradiated and non-irradiated skin within 72 h, the number of NGF-positive melanocytes decreased significantly, 72 h after UV irradiation (p < 0.024). NGF was also identified within keratinocytes, and while non-irradiated skin exhibited cytoplasmic NGF staining throughout the epidermis, NGF staining was reduced in the lower epidermal layers after UV irradiation. CONCLUSIONS: This is the first in vivo study showing NGF to be present in melanocytes, as well as showing modulations of NGF and Bcl-2 in melanocytes, following solar-simulated UV irradiation.
Abstract: OBJECTIVES: We investigated whether the mean platelet volume would be a useful marker in the evaluation of inflammatory bowel disease activity. METHODS: Complete blood count, C-reactive protein, erythrocyte sedimentation rate, serum thrombopoietin and erythropoietin, plasma beta-thromboglobulin, and platelet factor 4 were measured in 93 patients with ulcerative colitis, 66 patients with Crohn's disease, and 38 healthy blood donors. Disease activity was assessed by the Clinical Colitis Activity Index in patients with ulcerative colitis and by the Crohn's Disease Activity Index in patients with Crohn's disease. RESULTS: Mean platelet count was increased in patients with active compared to inactive ulcerative colitis (p < 0.05), and in patients with active compared to inactive Crohn's disease (p = 0.0002) or healthy controls (p < 0.0001). On the other hand, mean platelet volume was significantly decreased in patients with active compared to inactive ulcerative colitis (p = 0.02) or healthy controls (p < 0.0001), and in patients with active compared to inactive Crohn's disease (p = 0.0005) or healthy controls (p < 0.0001). Mean platelet volume was inversely correlated with the white blood cell count (r = -0.17, p = 0.02), C-reactive protein (r = -0.46, p = 0.009) and erythrocyte sedimentation rate (r = -0.28, p = 0.008). No significant correlations were found between mean platelet volume and serum thrombopoietin or erythropoietin levels; however, a strong negative correlation between mean platelet volume and beta-thromboglobulin (r = -0.34, p < 0.0001) and platelet factor 4 (r = -0.30, p = 0.0002) was observed. CONCLUSIONS: Mean platelet volume is significantly reduced in active inflammatory bowel disease and is negatively correlated with the known inflammatory bowel disease activity markers and the platelet activation products. We propose that mean platelet volume provides a useful marker of activity in inflammatory bowel disease.
