Skin and antioxidants.

It is estimated that total sun exposure occurs non-intentionally in three quarters of our lifetimes. Our skin is exposed to majority of UV radiation during outdoor activities, e.g. walking, practicing sports, running, hiking, etc. and not when we are intentionally exposed to the sun on the beach. We rarely use sunscreens during those activities, or at least not as much and as regular as we should and are commonly prone to acute and chronic sun damage of the skin. The only protection of our skin is endogenous (synthesis of melanin and enzymatic antioxidants) and exogenous (antioxidants, which we consume from the food, like vitamins A, C, E, etc.). UV-induced photoaging of the skin becomes clinically evident with age, when endogenous antioxidative mechanisms and repair processes are not effective any more and actinic damage to the skin prevails. At this point it would be reasonable to ingest additional antioxidants and/or to apply them on the skin in topical preparations. We review endogenous and exogenous skin protection with antioxidants.

The influence of the sleeping on the formation of facial wrinkles.

OBJECTIVE: The study addressed the influence of sleep as an important but overlooked contributory factor to the formation and progression of facial wrinkles and an alternative pillow was designed to reduce them. MATERIALS AND METHODS: Fifteen healthy young participants of both sexes (aged 26-42 years) volunteered for this study. We used a transparent PVC pillow filled with air to demonstrate mechanical forces and deformations of the face as a consequence of sleeping on a pillow. We used a Podometer (PDMTR) (integrated fluorescent luminaire lamp) as a diagnostic device to visualize and to document the imprint of facial deformities on a glass, as seen during sleeping. RESULTS: We observed various facial deformities and wrinkles during sleep ('crow's feet' fine lines, lines around the mouth, flattening of the forehead, blunting of the nasofrontal angle, melolabial and nasolabial folds) and design an alternative pillow to reduce them by redistributing the pressure from the wrinkling parts of the face.

Four novel ATP2A2 mutations in Slovenian patients with Darier disease.

BACKGROUND: Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene. It has been reported that depletion of Ca(2+) stores within the endoplasmic reticulum of keratinocytes is associated with impaired cell cycle regulation and terminal differentiation. Mechanical stress, heat, or UV irradiation might delay cell cycle exit and permit progression into the quiescent stage without repair. When there is associated DNA damage, this can lead to an accumulation of secondary somatic mutations and possible clonal proliferation of damaged keratinocyes within keratotic papules and plaques. OBJECTIVE: We sought to present clinical, demographic, and genetic analysis of the cohort of Slovenian patients with DD, which represents 52% of DD patients in the country. METHODS: We examined 28 Slovenians with DD and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations. RESULTS: The estimated prevalence of the disease in Slovenia is 2.7/100.000. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 463-6del6, and 1762-6del18. We also found two previously described polymorphisms in intron XVIII (2741 + 54 G>A) and in exon 15 (2172 G>A; A724A), with allele frequencies of 64.15% and 11.32%, respectively. There was a history of perceptive deafness in two DD patients from two families. LIMITATIONS: Analysis of SERCA2 expression, measurements of Ca(2+) uptake and their influence on desmosomal assembly in vitro would add additional value to the study. Although single-stranded conformational analysis (SSCP) is a common and accepted method for screening for the presence of mutations, it does miss 10% to 20% of mutations. CONCLUSIONS: We identified 4 novel ATP2A2 mutations in Slovenian patients with DD. Deafness seems to be a new phenotypic characteristic of DD patients.

Darier disease in Slovenia: spectrum of ATP2A2 mutations and relation to patients' phenotypes.

ATP2A2 encodes the sarco/endoplasmic reticulum Ca2+- ATPase (SERCA2) and has been identified as a defective gene in Darier disease (DD). It is an autosomal dominant genodermatosis, which is characterized by loss of adhesion between suprabasal epidermal keratinocytes (acantholysis) and abnormal keratinization (dyskeratosis). We examined 28 Slovenian patients with DD (the cohort of patients represents over 50% of all DD patients in Slovenia) and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 544+1del6, and 1762-6del18. We also found two previously described polymorphisms 2741+54 G>A in intron XVIII and 2172 G>A (A724A) in exon 15, with allele frequencies of 64.2% and 11.3%, respectively. The mutations are scattered throughout the gene and affect the actuator, phosphorylation, stalk and transmembrane domains of SERCA2. A P160L mutation in a Slovene patient with severe DD and a history of deafness is another consistent genotype-phenotype correlation. It seems that mutations of the ATP2A2 gene may also play a role in the pathogenesis of deafness, which seems to be a new phenotypic characteristic of DD patients.

Corrigendum to "The Role of Antioxidants in Skin Cancer Prevention and Treatment".

[This corrects the article DOI: 10.1155/2014/860479.].

Promontory sign--present in patch and plaque stage of angiosarcoma!

Kaposi sarcoma is characterized by a proliferation of irregular jagged vascular channels, which partly surround preexisting blood vessels in some areas. This characteristic appearance of a small vessel protruding into an abnormal vascular space has been termed "promontory sign". Cutaneous angiosarcoma (AS) is a malignant vascular neoplasm comprised of a meshwork of anastomosing irregular dilated vessels between collagen bundles and around skin appendages, lined by atypical endothelial cells. The presence of promontory sign has not been described as a histologic finding in AS. We retrieved all cases of cutaneous AS from the files of Yale Dermatopathology Laboratory between 1990 and 2007. Sixty-six biopsies from 15 patients (7 men and 8 women) were reviewed. The lesions were divided histologically in a patch, plaque, or tumor stage according to the depth of invasion of malignant cells. Forty of the 66 biopsies were from a patch or plaque stage of AS. The remaining 26 biopsies were from tumor stage of AS. In 13 of 40 biopsies (32.5%) of patch and plaque lesions of AS, promontory sign was identified, seen primarily in the upper reticular dermis. These biopsies were taken from 11 patients (6 men and 5 women), ranging in age from 36 to 86 years (median 69). Promontory sign was not found in any of the 26 biopsies of tumor stage AS. The presence of promontory sign has not been emphasized in lesions other than Kaposi sarcoma, but seems to be a feature that is not uncommon in patch/plaque stage AS.

The role of stem cells in anti-aging medicine.

Aging is the result of two overlapping processes, "intrinsic" and "extrinsic." Intrinsic structural changes occur as a consequence of physiologic aging and are genetically determined; extrinsic relates to exposure to harmful events and habits, like smoking, bad diet, alcohol consumption, lack of sleep, stress, sun exposure, environmental pollution, etc. Aging may be decelerated by improving bad habits or treating signs of aging with various esthetic methods, food supplements, and antioxidants. It is believed that we cannot stop aging entirely due to the intrinsic part, which leads to irreversible cell damage, as well as tissue and organ damage due to their limited ability to regenerate. Stem cells and their ability to exhibit telomerase activity, to self-renew, and to differentiate into all three embryonic tissues challenges aging as a process, which is not inevitable and can even possibly be reversed. Stem cells can promote regeneration of aged tissues and organs by replacing apoptotic and necrotic cells with healthy ones. In addition, they can have antiinflammatory and antiapoptotic properties by paracrine-secreting growth factors and cytokines on the site of administration. Autologous adipose-derived stem cells are the most promising because they can be easily harvested in huge numbers with minimally invasive liposuction and, as such, represent a powerful tool in anti-aging and regenerative medicine. In this contribution, the author discusses their properties and application in clinical practice.

Epidemiology of Darier's Disease in Slovenia.

AIM: To present a retrospective and prospective epidemiological and clinical study on Darier disease in Slovenia. RESULTS: Data on 77 DD patients was collected in the period 1973 to 2003 from the major dermatological departments and outpatient units in Slovenia. The prevalence of Darier disease in Slovenia is calculated at 3.8/100000 inhabitants. The ratio of affected/unaffected family members is 0.355. The comparison of two groups of DD patients (younger and older than 19 years) for the onset of the disease did not differ significantly although in two thirds of patients DD appeared for the first time before the age of 19 years. CONCLUSION: The epidemiological and clinical data on Darier's disease in Slovenia conform to similar reports with the exception of the higher prevalence of the disease in Slovenia. UV radiation seems to be an important triggering factor and therefore it is reasonable to advise DD patients to avoid sun exposure.

Successful treatment of Netherton's syndrome with topical calcipotriol.

We present a case of a 9-year-old boy with Netherton syndrome (NS) and skin manifestation of ichthyosis linearis circumflexa (ILC) who was successfully treated with topical 0.05% calcipotriol ointment bid. It was applied every fourth day on the same body area, which measured from 18% to 27% of the total body surface. Significant improvement of erythema and scaling was noted two weeks after the beginning of the treatment, with nearly total remission one week later, when the treatment was suspended. Remission lasted three to four weeks, when a few lesions of ILC appeared on his trunk and limbs and the treatment began again. The patient responded well each time he was treated. No adverse effects, suggestive of hypercalcemia or nephrocalcinosis, were noted during the treatment period which lasted for nine months. To evaluate calcipotriol's long-term efficacy and safety it should be tested on a larger group of patients with NS.

The role of antioxidants in skin cancer prevention and treatment.

Skin cells are constantly exposed to reactive oxygen species (ROS) and oxidative stress from exogenous and endogenous sources. UV radiation is the most important environmental factor in the development of skin cancer and skin aging. The primary products caused by UV exposure are generally direct DNA oxidation or generation of free radicals which form and decompose extremely quickly but can produce effects that can last for hours, days, or even years. UV-induced generation of ROS in the skin develops oxidative stress when their formation exceeds the antioxidant defense ability. The reduction of oxidative stress can be achieved on two levels: by lowering exposure to UVR and/or by increasing levels of antioxidant defense in order to scavenge ROS. The only endogenous protection of our skin is melanin and enzymatic antioxidants. Melanin, the pigment deposited by melanocytes, is the first line of defense against DNA damage at the surface of the skin, but it cannot totally prevent skin damage. A second category of defense is repair processes, which remove the damaged biomolecules before they can accumulate and before their presence results in altered cell metabolism. Additional UV protection includes avoidance of sun exposure, usage of sunscreens, protective clothes, and antioxidant supplements.

Skin photoaging and the role of antioxidants in its prevention.

Photoaging of the skin depends primarily on the degree of ultraviolet radiation (UVR) and on an amount of melanin in the skin (skin phototype). In addition to direct or indirect DNA damage, UVR activates cell surface receptors of keratinocytes and fibroblasts in the skin, which leads to a breakdown of collagen in the extracellular matrix and a shutdown of new collagen synthesis. It is hypothesized that dermal collagen breakdown is followed by imperfect repair that yields a deficit in the structural integrity of the skin, formation of a solar scar, and ultimately clinically visible skin atrophy and wrinkles. Many studies confirmed that acute exposure of human skin to UVR leads to oxidation of cellular biomolecules that could be prevented by prior antioxidant treatment and to depletion of endogenous antioxidants. Skin has a network of all major endogenous enzymatic and nonenzymatic protective antioxidants, but their role in protecting cells against oxidative damage generated by UV radiation has not been elucidated. It seems that skin's antioxidative defence is also influenced by vitamins and nutritive factors and that combination of different antioxidants simultaneously provides synergistic effect.

Intrinsic skin aging: the role of oxidative stress.

Skin aging appears to be the result of two overlapping processes, intrinsic and extrinsic. It is well accepted that oxidative stress contributes significantly to extrinsic skin aging, although findings point towards reactive oxygen species (ROS) as one of the major causes of and single most important contributor; not only does ROS production increase with age, but human skin cells' ability to repair DNA damage steadily decreases over the years. We extrapolated mechanisms of intrinsic oxidative stress in tissues other than skin to the skin cells in order to provide effective anti-aging strategies and reviewed the literature on intrinsic skin aging and the role of oxidative stress.

Darier disease: a guide to the physician.

Darier disease is an autosomal dominant skin disorder, characterized by follicular and extrafollicular keratotic papules, primarily in seborrheic areas. It is caused by mutations of ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2 protein). SERCA pumps maintain low cytosolic Ca2+ concentration by actively transporting Ca2+ from the cytosol into the sarco/endoplasmic reticulum. The assembly of desmosomes in epithelial cells in vitro is initiated through an increase in the extracellular Ca2+ concentration but variations in intracellular Ca2+ are also thought to be important. To date, 92 mutations of ATP2A2 gene in Darier disease patients have been identified, scattered throughout the gene. No hotspot mutation has been identified. Considerable phenotypic variations within and between families suggesting that compensatory mechanisms in intracellular Ca2+ homeostasis may include increased expression of the normal ATP2A2 allele and/or compensation by other SERCA pumps (SERCA1 and SERCA3). Alternatively, the activity of SERCA2 pumps required in different cutaneous areas may vary rapid depending on physiological and/or external factors.

P160L mutation in the Ca(2+) ATPase 2A domain in a patient with severe Darier disease.

Darier disease (DD) is caused by mutations of the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2). The mutations affect protein expression, degradation and activity. We report a patient with severe sporadic DD, who did not respond adequately to repeated courses of orally administered acitretin and isotretinoin. He was found to harbor the missense P160L mutation of the ATP2A2 gene in a heterozygous state in the A domain of SERCA2 and polymorphism in intron 18 (2741 + 54 G --> A). The A domain plays a key role in translocation of Ca(2+) from cytoplasm to endoplasmic reticulum lumen, thus establishing a low intracellular Ca(2+) concentration.