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miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In the present study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in lesional skin of psoriasis patients. The expression of miR-146a was about 2-fold higher than that of miR-146b in healthy human skin and it was more strongly induced by stimulation of pro-inflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of psoriasis patients, among which FERMT1 was verified as direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in miR-146a gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a−/− and skin fibroblasts from miR-146a−/− and miR-146b−/− mice stimulated with psoriasis-associated cytokines as compared to wild type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin.

Little is known about the functions of microRNAs (miRNAs) in skin pigmentation disorders. The aim of this study was to investigate the expression and potential role of miRNAs in vitiligo. Of 12 studied miRNAs with proven functions in cell proliferation, differentiation, immune responses and melanogenesis, miR-99b, miR-125b, miR-155 and miR-199a-3p were found to be increased and miR-145 was found to be decreased in the skin of patients with vitiligo. Combined pathway and target analysis revealed melanogenesis-associated targets for miR-99b, miR-125b, miR-155 and miR-199a-3p. In situ hybridization analysis demonstrated increased expression of miR-155 in the epidermis of patients with vitiligo. Correspondingly, miR-155 was induced by vitiligo-associated cytokines in human primary melanocytes and keratinocytes. When overexpressed, miR-155 inhibited the expression of melanogenesis-associated genes and altered interferon-regulated genes in melanocytes and keratinocytes. In conclusion, this study demonstrates that the expression of miRNAs is dysregulated in the skin of patients with vitiligo and suggests that miR-155 contributes to the pathogenesis of vitiligo.

Psoriasis is a chronic inflammatory disease that affects skin and is associated with systemic inflammation and many serious comorbidities ranging from metabolic syndrome to cancer. Important discoveries about psoriasis pathogenesis have enabled the development of effective biological treatments blocking the T helper 17 pathway. However, it has not been settled whether psoriasis is a T cell-mediated autoimmune disease or an autoinflammatory disorder that is driven by exaggerated innate immune signalling. Our comparative gene expression and hierarchical cluster analysis reveal important gene circuits involving innate receptors. Innate immune activation is indicated by increased absent in melanoma 2 (AIM2) inflammasome gene expression and active caspase 1 staining in psoriatic lesional skin. Increased eomesodermin (EOMES) expression in lesional and non-lesional skin is suggestive of innate-like virtual memory CD8+ T cell infiltration. We found that signs of systemic inflammation were present in most of the patients, correlated with the severity of the disease, and pointed to IL-6 involvement in the pathogenesis of psoriatic arthritis. Among the circulating T cell subpopulations, we identified a higher proportion of terminally differentiated or senescent CD8+ T cells, especially in patients with long disease duration, suggesting premature immunosenescence and its possible implications for psoriasis co-morbidities.

It is well known that administration of a single injection of testosterone propionate to newborn female rats results in permanent anovulatory sterility. After puberty these animals show permanent vaginal cornification and their ovaries contain follicles but no corpora lutea (Barraclough, 1961). One of the most important lesions in these rats seems to be a blockade of the pre-ovulatory discharge of luteinizing hormone releasing factor (LH-RF) from the median eminence.Porcine LH-RF has been shown to be a decapeptide, pyro Glu-His-Trp-Ser-Tyr\x=req-\ Gly-Leu-Arg-Pro-Gly(NH2), and when this polypeptide was synthesized it was found to have follicle-stimulating hormone releasing factor activity as well (Matsuo, Matsuo, Baba, Nair, Arimura & Schally, 1971). In the present experiments we posed the question of whether a subcutaneous injection of synthetic LH-RF could induce ovulation in androgen-sterilized female rats, and if so, whether this would be a dose-dependent effect.Albino rats of the Sprague\p=m-\Dawley strain kept in light-controlled quarters were used. On the morning of the 3rd day after birth female rats were given 10, 50, 100 or 1000/¿g testosterone propionate, subcutaneously. Two weeks before autopsy vaginal smears were taken and only rats showing persistent cornification of the vaginal mucosa were used. The LH-RF decapeptide was synthesized in our laboratory by a conventional fragment condensation method. Its homogeneity was examined by thin-layer chromatography and electrophoresis. The amino acid composition, amino acid sequence and optical rotation ([a]ff = -49°, in 1 % acetic acid) of the

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Atmospheric factors such as air pollution have been implicated in premature skin aging and also being associated with several skin pathologies. Among the pollutants to which cutaneous tissues is daily exposed, ozone has been shown to be one of the most noxious. The skin damage caused by ozone exposure is largely related to its ability to generate a complex cascade of oxidative stress related reactions. Indeed ozone is not able to penetrate the skin and although it is not a radical per se it is able to react with the stratum corneum fatty acids and generate oxidized lipids that can act as second messengers. This cascade of effects is able to initiate a pro-inflammatory skin response that, with the altered redox homeostasis, leads to a vicious cycle where inflammation and ROS aliment each other. In this contest the fine regulated balance between NFkB and Nrf2 activation is also compromise and the defensive ability of cutaneous cells is corrupted. In addition, the insufficient activation of NRF2 lead to the arousal of the inflammasome pathway that can eventually lead to cells damage and death. The action by which ozone affect skin has been evidenced in several cutaneous model (2D, 3D, biopsies) and also in human subjects. Therefore, knowing the exact mechanism by which ozone is able to affect skin can bring new insights on possible therapeutic and preventive interventions.