San Gallicano Dermatologic Institute IRCCS

Rome, Italy

San Gallicano Dermatologic Institute IRCCS

Rome, Italy
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Odorisio T.,Instituto Dermopatico dellImmacolata IDI IRCCS | di Salvio M.,Instituto Dermopatico dellImmacolata IDI IRCCS | Orecchia A.,Instituto Dermopatico dellImmacolata IDI IRCCS | di Zenzo G.,Instituto Dermopatico dellImmacolata IDI IRCCS | And 8 more authors.
Human Molecular Genetics | Year: 2014

Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis characterized by fragile skin forming blisters that heal invariably with scars. It is due to mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils connecting the cutaneous basement membrane to the dermis. Identical COL7A1 mutations often result in inter-and intra-familial disease variability, suggesting that additional modifiers contribute to RDEB course. Here, we studied amonozygotic twin pair with RDEB presenting markedly different phenotypic manifestations, while expressing similar amounts of collagen VII. Genome-wide expression analysis in twins' fibroblasts showed differential expression of genesassociated with TGF-βpathway inhibition. In particular, decorin, a skin matrix component with anti-fibrotic properties, was found to be more expressed in the less affected twin. Accordingly, fibroblasts from the more affected sibling manifested a profibrotic and contractile phenotype characterized by enhanced α-smooth muscle actin and plasminogen activator inhibitor 1 expression, collagen I release and collagen lattice contraction. These cells also produced increased amounts of proinflammatory cytokines interleukin 6 and monocyte chemoattractant protein-1. Both TGF-β canonical (Smads) and non-canonical (MAPKs) pathways were basally more activated in the fibroblasts of the more affected twin. The profibrotic behaviour of these fibroblasts was suppressed by decorin delivery to cells. Our data show that the amount of type VII collagen is not the only determinant of RDEB clinical severity, and indicate aninvolvementofTGF-βpathwaysin modulating disease variability. Moreover, our findings identify decorin asa possible anti-fibrotic/inflammatory agent for RDEB therapeutic intervention. © The Author 2014. Published by Oxford University Press. All rights reserved.

Salemme A.,University of Rome La Sapienza | Togna A.R.,University of Rome La Sapienza | Mastrofrancesco A.,San Gallicano Dermatologic Institute IRCCS | Cammisotto V.,University of Rome La Sapienza | And 3 more authors.
Brain Research Bulletin | Year: 2016

The activation of microglia and subsequent release of toxic pro-inflammatory factors are crucially associated with neurodegenerative disease, characterized by increased oxidative stress and neuroinflammation, including Alzheimer and Parkinson diseases and multiple sclerosis. Dihydroasparagusic acid is the reduced form of asparagusic acid, a sulfur-containing flavor component produced by Asparagus plants. It has two thiolic functions able to coordinate the metal ions, and a carboxylic moiety, a polar function, which may enhance excretion of the complexes. Thiol functions are also present in several biomolecules with important physiological antioxidant role as glutathione. The aim of this study is to evaluate the anti-inflammatory and antioxidant potential effect of dihydroasparagusic acid on microglial activation in an in vitro model of neuroinflammation. We have used lipopolysaccharide to induce an inflammatory response in primary rat microglial cultures. Our results suggest that dihydroasparagusic acid significantly prevented lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators such as nitric oxide, tumor necrosis factor-α, prostaglandin E2, as well as inducible nitric oxide synthase and cyclooxygenase-2 protein expression and lipoxygenase activity in microglia cells. Moreover it effectively suppressed the level of reactive oxygen species and affected lipopolysaccharide-stimulated activation of mitogen activated protein kinase, including p38, and nuclear factor-kB pathway. These results suggest that dihydroasparagusic acid's neuroprotective properties may be due to its ability to dampen induction of microglial activation. It is a compound that can effectively inhibit inflammatory and oxidative processes that are important factors of the etiopathogenesis of neurodegenerative diseases. © 2015 Elsevier Inc.

Barman-Aksozen J.,Triemli Hospital | Minder E.I.,Triemli Hospital | Schubiger C.,Triemli Hospital | Biolcati G.,San Gallicano Dermatologic Institute IRCCS | Schneider-Yin X.,Triemli Hospital
Blood Cells, Molecules, and Diseases | Year: 2015

The activity of the erythroid-specific isoenzyme of 5-aminolevulinic acid synthase (ALAS2), the first and rate-limiting enzyme in heme biosynthesis, is down-regulated during iron-deficiency. Ferrochelatase (FECH), the last enzyme of this pathway, inserts iron into protoporphyrin IX (PPIX) to form heme. Patients with erythropoietic protoporphyria (EPP), an inherited deficiency in FECH, often show signs of iron deficiency in addition to phototoxicity which is caused by PPIX accumulation. However, iron supplementation often leads to exacerbation of phototoxicity. We report three EPP patients who had reduced erythrocytic PPIX concentrations when they were iron-deficient and their microcytic and hypochromic anemia deteriorated. Additionally, we found a significant increase in the amount of ALAS2 mRNA and protein among EPP patients. To verify the connection between FECH deficiency and ALAS2 over-expression, we inhibited FECH in cultured cells and found a subsequent increase in ALAS2 mRNA. We conclude that the primary deficiency in ferrochelatase leads to a secondary increase in ALAS2 expression. The combined action of these two enzymes within the heme biosynthetic pathway contributes to the accumulation of PPIX. Furthermore, we hypothesize that EPP patients may benefit from a mild iron deficiency since it would limit PPIX production by restricting ALAS2 over-expression. © 2014 Elsevier Inc.

Bonifati C.,San Gallicano Dermatologic Institute | Elia F.,San Gallicano Dermatologic Institute IRCCS | Francesconi F.,San Gallicano Dermatologic Institute | Ceralli F.,San Camillo Forlanini Hospital | And 3 more authors.
Journal of the European Academy of Dermatology and Venereology | Year: 2012

Background Most of the data currently available on early psoriatic arthritis (EPsA) derive from studies performed in rheumatological settings. However, in recent years, there has been an increase in the amount of data from dermatologic centres. Objectives To describe the prevalence, clinical, laboratory and imaging characteristics of psoriatic patients with EPsA seen at a dermatological outpatient psoriasis centre. Methods From January 2007 to May 2010, all patients with psoriasis who visited the psoriasis centre were asked about inflammatory joint involvement. A diagnosis of psoriatic arthritis was made on the basis of clinical, laboratory and imaging studies. The patients were diagnosed with early PsA (EPsA) if their inflammatory articular symptoms had been present for ≤1 year. Results We diagnosed EPsA in 33 patients. Joint involvement was polyarticular (>5 joints involved) in 20 patients (60.6%) and oligoarticular (a;circ5 joints involved) in the remaining 13 patients. Quality of life due to skin involvement and the degree of functional impairment due to joint inflammation were only mildly affected, as measured by DLQI and HAQ, respectively. A direct correlation between the number of tender joints (ACR 68) and HAQ was found (r = 0.36; P = 0.04). Imaging studies showed that in spite of the absence of radiologic findings of peripheral joint damage, ultrasonography and contrast enhanced ultrasonography showed signs of articular inflammation in all patients. Conclusions A diagnosis of EPsA can be correctly performed in a dermatologic outpatient facility. To do so, a close collaboration among dermatologists, rheumatologists and radiologists is necessary. © 2011 European Academy of Dermatology and Venereology.

Kovacs D.,San Gallicano Dermatologic Institute IRCCS | Flori E.,San Gallicano Dermatologic Institute IRCCS | Maresca V.,San Gallicano Dermatologic Institute IRCCS | Ottaviani M.,San Gallicano Dermatologic Institute IRCCS | And 6 more authors.
Journal of Investigative Dermatology | Year: 2012

Interest in colorless intermediates of melanocyte metabolism has traditionally been related to their role as melanin precursors, though several lines of evidence scattered in the literature suggested that these compounds may exert an antioxidant and protective function per se unrelated to pigment synthesis. Herein, we disclose the remarkable protective and differentiating effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA), a diffusible dopachrome tautomerase (DCT)-dependent eumelanin intermediate, on primary cultures of human keratinocytes. At micromolar concentrations, DHICA induced: (a) time- and dose-dependent reduction of cell proliferation without concomitant toxicity; (b) enhanced expression of early (spinous keratins K1 and K10 and envelope protein involucrin) and late (loricrin and filaggrin) differentiation markers; (c) increased activities and expression of antioxidant enzymes; and (d) decreased cell damage and apoptosis following UVA exposure. The hitherto unrecognized role of DHICA as an antiproliferative, protective, and antiapoptotic endogenous cell messenger points to a reappraisal of the biological functions of melanocytes and DCT in skin homeostasis and photoprotection beyond the mere provision of melanin pigments, and provides, to our knowledge, a previously unreported possible explanation to the higher resistance of the dark-skinned eumelanic phenotypes to sunburn and skin cancer. © 2012 The Society for Investigative Dermatology.

Mastrofrancesco A.,San Gallicano Dermatologic Institute IRCCS | Ottaviani M.,San Gallicano Dermatologic Institute IRCCS | Aspite N.,San Gallicano Dermatologic Institute IRCCS | Cardinali G.,San Gallicano Dermatologic Institute IRCCS | And 5 more authors.
Experimental Dermatology | Year: 2010

Azelaic acid (AzA), a nine-carbon dicarboxylic acid, is an agent for the topical treatment of acne. It has also been shown to be effective in rosacea; however, the mechanism of action has not been clarified. Because inflammation is a common feature of both conditions, we investigated the effects of azelaic acid on the inflammatory response of normal human keratinocytes to ultraviolet B light, which is a photosensitizer agent in rosacea. AzA, at 20 m. m, a concentration achievable following topical application of a 15% gel, suppresses ultraviolet B light-induced interleukins-1β, -6 and tumor necrosis factor-α mRNA expression and protein secretion. Mechanistically, azelaic acid significantly reduced the ultraviolet B light-induced nuclear translocation of nuclear factor kB p65 subunit and the phosphorylation of the p38 mitogen and stress-activated protein kinase. Moreover, as peroxisome proliferators-activated receptor γ, (PPARγ) which has a crucial role in the control of inflammation, is activated by fatty acids and products of lipid peroxidation, we further investigated the effect of azelaic acid on the expression of this nuclear receptor. AzA induced peroxisome proliferators-activated receptor-γ mRNA and its transcriptional activity. The PPARγ antagonist GW9662 abrogated the inhibitory effects of AzA on the UVB-induced pro-inflammatory cytokines release and on the cell proliferation. Our study provides new insights into the molecular mechanisms of the activity of azelaic acid and lands additional evidences for its therapeutic effects on inflammatory skin diseases, such as rosacea. © 2010 John Wiley & Sons A/S.

Ardigo M.,San Gallicano Dermatologic Institute IRCCS | Tosti A.,University of Miami | Cameli N.,San Gallicano Dermatologic Institute IRCCS | Vincenzi C.,University of Bologna | And 2 more authors.
Archives of Dermatology | Year: 2011

Background: The presence of yellow dots is a characteristic dermoscopic finding in alopecia areata. The aim of this study was to investigate the yellow dot pattern observed at dermoscopy in alopecia areata with reflectance confocal microscopy (RCM) and correlate RCM findings with pathological features. Observations: Six patients affected by alopecia totalis entered the study. Patients were first submitted to scalp dermoscopy, which was followed by RCM examination of the same area. After RCM, a 5-mm punch biopsy specimen was also taken. Dermoscopic findings showed the yellow dot pattern in all patients, with round or polycyclic yellow-pink dots often containing miniaturized or broken hair shafts. At RCM, a Vivablock mosaic taken at the level of the spinous layer showed striking reduction of follicular adnexal structures and empty lumina containing highly refractile material corresponding to the yellow dots seen on dermoscopy. The pathological features showed that the yellow dots correspond to the dilated infundibula of the velluslike anagen and telogen follicles that characterize the chronic phase of alopecia areata. Conclusion: The RCM study of the yellow dot pattern showed a good correlation with the dermoscopic and pathological findings and confirms that the yellow dots correspond to inefficient follicular structures that often contain hair remnants. ©2011 American Medical Association. All rights reserved.

Kovacs D.,San Gallicano Dermatologic Institute IRCCS | Abdel-Raouf H.,Al Minya University | Al-Khayyat M.,Al Minya University | Abdel-Azeem E.,Al Minya University | And 4 more authors.
Journal of the European Academy of Dermatology and Venereology | Year: 2015

Background Punch grafting is a surgical technique mainly applied in therapy-resistant, stable and circumscribed vitiligo. Objective (i) To characterize in detail the features of the repigmented skin among punch grafts; and (ii) to correlate the ex vivo results with clinical data and punch grafting outcome. Methods We evaluated by immunohistochemistry and image analysis the expression of a panel of specific melanocyte markers including HMB45, MITF, c-kit, MART-1 and TRP1, the proliferation marker Ki67 and the cell-cell adhesion molecule E-cadherin in tissue samples collected from nine patients after punch grafting. Results Cells positive for MITF, c-kit, MART-1 and TRP1 were detected in the repigmented skin of all biopsies, whereas no reactivity was observed for HMB45. Melanocytes were identified along the entire length of the sections, and their mature state was assessed by the immuno-reactivity for the differentiation marker MART-1, the absence of cells positively stained for Ki67 and by the co-expression of c-kit and TRP1, a marker of a differentiated and pigmented state. Clinically, smaller punch grafts aimed at repigmenting lesional areas on the face gave the faster clinical results with no side-effects. Patients subjected to bigger punch grafts on the knee exhibited a longer repigmentation time and presented cobble stoning. Conclusion Our results suggest that the repigmentation observed in the areas between the grafts is due to the activation of the melanocytes located in the donor sites. These cells start to horizontally migrate towards the lesional skin thanks to successively the enlargement of intercellular spaces in relation to a decrease of E-cadherin reactivity and the up-modulation of pro-melanogenic mediators. Production and transfer of melanin in the surrounding keratinocytes and their persistence were assessed by the reactivity for MITF, c-kit, MART-1 and TRP1 but not for the pre-melanosome marker (HMB45). © 2014 European Academy of Dermatology and Venereology.

Picardo M.,San Gallicano Dermatologic Institute IRCCS | Ottaviani M.,San Gallicano Dermatologic Institute IRCCS
Journal of Clinical Gastroenterology | Year: 2014

The imbalance and/or the perturbation of the microbial populations that colonize the skin and that contribute to its defense may represent one of the causes of the development of noninfectious skin diseases. Atopic dermatitis, psoriasis, acne, and rosacea can be listed among these kinds of pathologies. In particular, considering that microbes have been long addressed as having a role in rosacea, this common dermatosis can be an interesting model to evaluate the correlation between microbiome alterations and the occurrence of clinical manifestations. Different microorganisms have been suggested to have a role in rosacea, but no direct correlation with the incidence of the pathology has been clearly defined. Skin microbiome composition is crucial for the correct skin immune functions and recent findings indicate an abnormal activation of innate immune system associated with the rosacea. The enhanced expression of toll-like receptor 2 in the epidermis of rosacea patients can represent a possible explanation for the amplified inflammatory response to external stimuli observed during the disease. In addition, significantly higher small intestinal bacterial overgrowth prevalence in rosacea subjects has been found and its eradication has been associated with a regression of the skin lesions. In conclusion, both skin and gut microbiome seem to have a role, even if synergistic with other factors, in the pathogenesis of rosacea. A deeper knowledge of human microbiome composition and microbe-host interactions will contribute to clarify the mechanism of development of rosacea and possibly will provide innovative therapeutic approaches. © 2014 by Lippincott Williams & Wilkins.

Maresca V.,San Gallicano Dermatologic Institute IRCCS | Flori E.,San Gallicano Dermatologic Institute IRCCS | Bellei B.,San Gallicano Dermatologic Institute IRCCS | Aspite N.,San Gallicano Dermatologic Institute IRCCS | And 2 more authors.
Pigment Cell and Melanoma Research | Year: 2010

We demonstrated a direct correlation between melanogenic and catalase activities on in vitro and ex vivo models. Here, we investigated whether the stimulation of Melanocortin-1 Receptor (MC1R) could influence catalase expression, activity and cellular localization. For this purpose, we treated B16-F0 melanoma cells with α-Melanocyte Stimulating Hormone (α-MSH) and we showed a rapid induction of catalase through a cAMP/PKA-dependent, microphthalmia-associated transcription factor (MITF) independent mechanism, acting at post-transcriptional level. Moreover, α-MSH promoted a partial re-distribution of catalase to the cell periphery and dendrites. This work strengthens the correlation between melanogenesis and anti-oxidants, demonstrating the induction of catalase in response to a melanogenic stimulation, such as α-MSH-dependent MC1R activation. Moreover, this study highlights catalase regulatory mechanisms poorly known, and attributes to α-MSH a protective role in defending melanocytes, and possibly keratinocytes, not only on the basis of its pigmentary action, but also for its capacity to stimulate a quick anti-oxidant defence. © 2010 John Wiley & Sons A/S.

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