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Techniques used to screen PXE patients for causative mutations in the ABCC6 gene are described and compared in order to reach a better mutation detection rate
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Progressive calcification of elastic fibers is typical of Pseudoxanthoma elasticum (PXE), a rare genetic disease due to mutations in the ABCC6 gene.The pathogenesis of mineral- ization is only partially known.1 Previous studies on dermal... more
Progressive calcification of elastic fibers is typical of Pseudoxanthoma elasticum (PXE), a rare genetic disease due to mutations in the ABCC6 gene.The pathogenesis of mineral- ization is only partially known.1 Previous studies on dermal fibroblasts from PXE patients demonstrated that the calcifica- tion process is associated to impaired carboxylation of matrix- gla-protein that, in its active form, binds to calcium, therefore inhibiting mineralization.2 However, the recent observation that PXE fibroblasts exhibit also a significant upregulation of alka- line phosphatase (TNAP) activity suggested that an abnormal phosphate metabolism may take place within soft connective tis- sues, thus contributing to ectopic calcification.3 To improve the understanding of PXE it was developed a transgenic mouse model by specifically inactivating the Abcc6 gene.4 Consistently, Abcc6-/- mice recapitulate several histopathological findings typ- ical of PXE, including the slow progression of the disease.5 Aim of the present study was to isolate fibroblasts from Abcc6+/+ and Abcc6-/- mice of different ages (i.e. before and after the devel- opment of ectopic calcification) and to investigate proteins con- trolling phosphate levels in the extracellular matrix. Results demonstrate a down-regulation of pyrophosphatase/phosphodi- esterase 1, of progressive ankylosis protein and of osteopontin, whereas bone morphogenetic protein 2 and TNAP activity were up-regulated in fibroblasts from Abcc6-/- animals. These data support the hypothesis that in PXE the unbalanced ratio between factors locally controlling both calcium and phosphate homeostasis are crucial in triggering tissue calcification
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In vitro studies on the phenotype of dermal fibroblasts from patients with beta-thalassemia and PXE-like clinical manifestations are described and the the role of altered redox balance is discusse
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The objective of this study was to search for the deletion of exon 24 and exons 24-27 that had been previously reported in Italian patients affected by pseudoxanthoma elasticum, anb autosomal recessive disorder characterized by... more
The objective of this study was to search for the deletion of exon 24 and exons 24-27 that had been previously reported in Italian patients affected by pseudoxanthoma elasticum, anb autosomal recessive disorder characterized by calcification and fragmentation of elastic fibers as a conseguence of mutations in the ABCC6 gene. To detect deletions in the ABCC6 gene the development and use of long range PCR procedure using appropriately designed primers are described
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In patients infected by SARS‐CoV‐2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with... more
In patients infected by SARS‐CoV‐2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID‐19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID‐19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN‐γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro‐inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD‐1/PD‐L1. High plasma levels of several inflammatory cytokines and chemokines, including GM‐CSF, IL‐18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID‐19 immunopathogenesis.
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In vitro studies on the phenotype of dermal fibroblasts from patients with beta-thalassemia and PXE-like clinical manifestations are described and the the role of altered redox balance is discusse
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The objective of this study was to search for the deletion of exon 24 and exons 24-27 that had been previously reported in Italian patients affected by pseudoxanthoma elasticum, anb autosomal recessive disorder characterized by... more
The objective of this study was to search for the deletion of exon 24 and exons 24-27 that had been previously reported in Italian patients affected by pseudoxanthoma elasticum, anb autosomal recessive disorder characterized by calcification and fragmentation of elastic fibers as a conseguence of mutations in the ABCC6 gene. To detect deletions in the ABCC6 gene the development and use of long range PCR procedure using appropriately designed primers are described
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The objective of this study was to search for the deletion of exon 24 and exons 24-27 that had been previously reported in Italian patients affected by pseudoxanthoma elasticum, anb autosomal recessive disorder characterized by... more
The objective of this study was to search for the deletion of exon 24 and exons 24-27 that had been previously reported in Italian patients affected by pseudoxanthoma elasticum, anb autosomal recessive disorder characterized by calcification and fragmentation of elastic fibers as a conseguence of mutations in the ABCC6 gene. To detect deletions in the ABCC6 gene the development and use of long range PCR procedure using appropriately designed primers are described
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In patients infected by SARS‐CoV‐2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with... more
In patients infected by SARS‐CoV‐2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID‐19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID‐19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN‐γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro‐inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD‐1/PD‐L1. High plasma levels of several inflammatory cytokines and chemokines, including GM‐CSF, IL‐18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID‐19 immunopathogenesis.
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In vitro studies on the phenotype of dermal fibroblasts from patients with beta-thalassemia and PXE-like clinical manifestations are described and the the role of altered redox balance is discusse
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In patients infected by SARS‐CoV‐2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with... more
In patients infected by SARS‐CoV‐2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID‐19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID‐19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN‐γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro‐inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD‐1/PD‐L1. High plasma levels of several inflammatory cytokines and chemokines, including GM‐CSF, IL‐18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID‐19 immunopathogenesis.
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Research Interests: Biology, Scanning Electron Microscopy, Transmission Electron Microscopy, Biological Chemistry, Magnetic Resonance Spectroscopy, and 15 moreAtomic Force Microscopy, Medicine, Amyloid, Biological Sciences, Humans, Circular Dichroism, Peptides, CHEMICAL SCIENCES, Elastin, Protein Secondary Structure Prediction, Protein Conformation, Amino Acid Sequence, Congo Red, Molecular Sequence Data, and Medical and Health Sciences
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Elastin represents the structural component of the extracellular matrix providing elastic recoil to tissues such as skin, blood vessels and lungs. Elastogenic cells secrete soluble tropoelastin monomers into the extracellular space where... more
Elastin represents the structural component of the extracellular matrix providing elastic recoil to tissues such as skin, blood vessels and lungs. Elastogenic cells secrete soluble tropoelastin monomers into the extracellular space where these monomers associate with other matrix proteins (e.g., microfibrils and glycoproteins) and are crosslinked by lysyl oxidase to form insoluble fibres. Once elastic fibres are formed, they are very stable, highly resistant to degradation and have an almost negligible turnover. However, there are circumstances, mainly related to inflammatory conditions, where increased proteolytic degradation of elastic fibres may lead to consequences of major clinical relevance. In severely affected COVID-19 patients, for instance, the massive recruitment and activation of neutrophils is responsible for the profuse release of elastases and other proteolytic enzymes which cause the irreversible degradation of elastic fibres. Within the lungs, destruction of the ela...
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Elastin is an extracellular matrix component with key structural and biological roles in elastic tissues. Interactions between resident cells and tropoelastin, the monomer of elastin, underpin elastin's regulation of cellular... more
Elastin is an extracellular matrix component with key structural and biological roles in elastic tissues. Interactions between resident cells and tropoelastin, the monomer of elastin, underpin elastin's regulation of cellular processes. However, the nature of tropoelastin–cell interactions and the contributions of individual tropoelastin domains to these interactions are only partly elucidated. In this study, we identified and characterized novel cell‐adhesive sites in the tropoelastin N‐terminal region between domains 12 and 16. We found that this region interacts with αV and α5β1 integrin receptors, which mediate cell attachment and spreading. A peptide sequence from within this region, spanning domains 14 to mid‐domain 16, binds heparan sulfate through electrostatic interactions with peptide lysine residues and induces conformational ordering of the peptide. We propose that domains 14–16 direct initial cell attachment through cell‐surface heparan sulfate glycosaminoglycans, followed by αV and α5β1 integrin‐promoted attachment and spreading on domains 12–16 of tropoelastin. These findings advance our mechanistic understanding of elastin matrix biology, with the potential to enhance tissue regenerative outcomes of elastin‐based materials.
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Purpose To evaluate the retinal features of elderly patients affected by pseudoxanthoma elasticum (PXE). Materials and methods This is a retrospective case series of 62 eyes of 31 elderly PXE patients (age > 50 years). Clinical data,... more
Purpose To evaluate the retinal features of elderly patients affected by pseudoxanthoma elasticum (PXE). Materials and methods This is a retrospective case series of 62 eyes of 31 elderly PXE patients (age > 50 years). Clinical data, ultra-widefield fundus imaging (color, red-free (RF), infra-red imaging (IR), fundus autofluorescence (FAF)), and OCT examinations were collected. Diagnosis was confirmed by genetic testing or skin biopsy. Results Thirty-one patients (10 males and 21 females (mean age 61.3 years, range 50–74 years)) were included in our study. Visual acuity ranged from 20/20 Snellen equivalent to 20/200. The mean follow-up was 66.4 ± 20.7 months (range 10–88). Pattern dystrophy-like changes (PD) (52 eyes of 26 patients, 83.8%) and atrophy resembling the “diffuse trickling” pattern described in geographic atrophy were present in the majority of patients. Twenty-three eyes of 12 patients (67.6%) had peripapillary atrophy, 9 eyes of 5 patients (26.4%) macular atrophy, 6 eyes of 3 patients (17.6%) displayed posterior pole atrophy and in 6 eyes of 3 patients (17.6%), atrophy could be detected beyond the vascular arcades (mid-peripheral atrophy). End-stage atrophy covered the entire area indicated as “coquille d’oeuf” (eggshell). Choroidal neovascularization occurred in 49 eyes of 26 patients (94.2%) with PD and in 6 eyes of 3 patients (60%) without PD. Genetic examinations were available for 29 patients (29/31, 93.5%). Conclusions The elderly PXE patients were characterized by pattern dystrophy-like changes with more or less extensive atrophy, progressive over time, which in some cases affected the whole area of the coquille d’oeuf during the course of the disease.
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Heparan sulfates (HSs) modulate tissue elasticity in physiopathological conditions by interacting with various matrix constituents as tropoelastin and elastin-derived peptides. HSs bind also to protein moieties accelerating amyloid... more
Heparan sulfates (HSs) modulate tissue elasticity in physiopathological conditions by interacting with various matrix constituents as tropoelastin and elastin-derived peptides. HSs bind also to protein moieties accelerating amyloid formation and influencing cytotoxic properties of insoluble fibrils. Interestingly, amyloidogenic polypeptides, despite their supposed pathogenic role, have been recently explored as promising bio-nanomaterials due to their unique and interesting properties. Therefore, we investigated the interactions of HSs, obtained from different sources and exhibiting various degree of sulfation, with synthetic amyloidogenic elastin-like peptides (ELPs), also looking at the effects of these interactions on cell viability and cell behavior using in vitro cultured fibroblasts, as a prototype of mesenchymal cells known to modulate the soft connective tissue environment. Results demonstrate, for the first time, that HSs, with differences depending on their sulfation patte...
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Numerous cellular models have been developed to investigate calcification for regenerative medicine applications and for the identification of therapeutic targets in various complications associated with age-related diseases. However,... more
Numerous cellular models have been developed to investigate calcification for regenerative medicine applications and for the identification of therapeutic targets in various complications associated with age-related diseases. However, results have often been contradictory due to specific culture conditions, cell type ontogeny and aging status. Human platelet lysate (hPL) has been recently investigated as valuable alternative to fetal bovine serum (FBS) in cell culture and bone regeneration. A parallel comparison of how all these multiple factors may converge to influence mineralization has yet to be reported. To compare mineralization of human mesenchymal cell types known to differ in extracellular matrix calcification potency, bone marrow-derived mesenchymal stromal cells and dermal fibroblasts from neonatal and adult donors, at both low and high passages, were investigated in an ex vivo experimental model by supplementing the osteogenic induction medium with FBS or with hPL. Four ...