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Barman-Aksozen J.,Institute of Laboratory Medicine | Minder E.I.,Institute of Laboratory Medicine | Schubiger C.,Institute of Laboratory Medicine | Biolcati G.,San Gallicano Dermatologic Institute IRCCS | Schneider-Yin X.,Institute of Laboratory Medicine
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.

Odorisio T.,Laboratory of Molecular and Cell Biology | di Salvio M.,Laboratory of Molecular and Cell Biology | Orecchia A.,Laboratory of Molecular and Cell Biology | di Zenzo G.,Laboratory of Molecular and Cell Biology | 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.

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.

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.

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