88 results on '"Lania G"'
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2. Erratum: Author Correction: Constitutive alterations in vesicular trafficking increase the sensitivity of cells from celiac disease patients to gliadin (Communications biology (2019) 2 (190))
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Lania G., Nanayakkara M., Maglio M., Auricchio R., Porpora M., Conte M., De Matteis M. A., Rizzo R., Luini A., Discepolo V., Troncone R., Auricchio S., Barone M. V., Lania, G., Nanayakkara, M., Maglio, M., Auricchio, R., Porpora, M., Conte, M., De Matteis, M. A., Rizzo, R., Luini, A., Discepolo, V., Troncone, R., Auricchio, S., and Barone, M. V.
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
3. Erratum: miR-194-5p/BCLAF1 deregulation in AML tumorigenesis
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Dell'Aversana, C, Giorgio, C, D'Amato, L, Lania, G, Matarese, F, Saeed, S, Di Costanzo, A, Belsito Petrizzi, V, Ingenito, C, Martens, J H A, Pallavicini, I, Minucci, S, Carissimo, A, Stunnenberg, H G, and Altucci, L
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- 2018
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4. The Italian Space Agency Web Portal DV and Its Interactions With Thesis Elaborations on Space Economy
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Sciortino, G, Lania, G, and Spena, A
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Settore ING-IND/11 - Published
- 2017
5. Erratum: miR-194-5p/BCLAF1 deregulation in AML tumorigenesis
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Dell'Aversana, C, primary, Giorgio, C, additional, D'Amato, L, additional, Lania, G, additional, Matarese, F, additional, Saeed, S, additional, Di Costanzo, A, additional, Belsito Petrizzi, V, additional, Ingenito, C, additional, Martens, J H A, additional, Pallavicini, I, additional, Minucci, S, additional, Carissimo, A, additional, Stunnenberg, H G, additional, and Altucci, L, additional
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- 2017
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6. miR-194-5p/BCLAF1 deregulation in AML tumorigenesis
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Dell'Aversana, C, primary, Giorgio, C, additional, D'Amato, L, additional, Lania, G, additional, Matarese, F, additional, Saeed, S, additional, Di Costanzo, A, additional, Belsito Petrizzi, V, additional, Ingenito, C, additional, Martens, J H A, additional, Pallavicini, I, additional, Minucci, S, additional, Carissimo, A, additional, Stunnenberg, H G, additional, and Altucci, L, additional
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- 2017
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7. Immunoregolatory pathways are active in the small intestinal mucosa of patients with potential celiac disease
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Borrelli M, Salvati MV, Zanzi D, Ferrara K, Santagata S, Ponticelli D, Mazzarella G, Lania G, MAGLIO, MARIANTONIA, AITORO, ROSITA, GIANFRANI, CARMELA, AURICCHIO, RENATA, TRONCONE, RICCARDO, Borrelli, M, Salvati, Mv, Maglio, Mariantonia, Zanzi, D, Ferrara, K, Santagata, S, Ponticelli, D, Aitoro, Rosita, Mazzarella, G, Lania, G, Gianfrani, Carmela, Auricchio, Renata, and Troncone, Riccardo
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- 2013
8. Ontogeny of FMRFamide-like immunoreactivity in the olfactory components of lower vertebrates
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FIORENTINO M, D’ANIELLO B, RAUCCI F, LANIA G, RASTOGI RK, PINELLI, Claudia, J.H.TH.GOOS, RASTOGI R.K., VAUDRY H., PIERANTONI R., Rastogi, RAKESH KUMAR, D'Aniello, Biagio, Claudia, Pinelli, Franca, Raucci, Lania, G., Rastogi, RAKESH K., GOOS HJT, RASTOGI RK, VAUDRY H, PIERANTONI R, Fiorentino, M, D’Aniello, B, Pinelli, Claudia, Raucci, F, Lania, G, and Rastogi, Rk
- Published
- 2001
9. The Role of Microdomains in Beta-Adrenoreceptor Signalling266Metoprolol induces cardiac beta-3 adrenergic receptor and Sphingosine 1 phosphate receptor 1 signals to prevent adverse Left-ventricle remodeling and dysfunction after myocardial infarction267PDE8 is a novel regulator of cAMP signaling in human atrial fibrillation268B-blocker therapy in heart failure reduces migratory and proliferative properties of primarily cultured failing cardiac fibroblasts via reduction of g protein-coupled receptor kinase-2 expression
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Cannavo, A, primary, E Molina, C, primary, Komici, K, primary, Liccardo, D, additional, Gambino, G, additional, D'amico, ML, additional, Rapacciuolo, A, additional, Paolocci, N, additional, Leosco, D, additional, Koch, WJ, additional, Ferrara, N, additional, Rengo, G, additional, Ghezelbash, S, additional, Garnier, A, additional, Fischmeister, R, additional, Dobrev, D, additional, Cannavo, A, additional, De Lucia, C, additional, D'Amico, ML, additional, Petraglia, L, additional, Formisano, R, additional, Lania, G, additional, and Barone, MV, additional
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- 2016
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10. Gliadin peptide P31-43 enhances IL-15 activity by interfering with its intracellular trafficking
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Barone MV, Zanzi D, Maglio M, Nanayakkara M, Santagata S, Lania G, Miele E, Ribecco MTS, Maurano F, Gianfrani C, Ferrini S, Troncone R, and Auricchio S.
- Abstract
BACKGROUND AND OBJECTIVES: Damage to intestinal mucosa in celiac disease (CD) is mediated both by inflammation due to adaptive and innate immune responses, with IL-15 as a major mediator of the innate immune response, and by proliferation of crypt enterocytes as an early alteration of CD mucosa causing crypts hyperplasia. We have previously shown that gliadin peptide P31-43 induces proliferation of cell lines and celiac enterocytes by delaying degradation of the active epidermal growth factor receptor (EGFR) due to delayed maturation of endocytic vesicles. IL-15 is increased in the intestine of patients affected by CD and has pleiotropic activity that ultimately results in immunoregulatory cross-talk between cells belonging to the innate and adaptive branches of the immune response. Aims of this study were to investigate the role of P31-43 in the induction of cellular proliferation and innate immune activation. METHODS/PRINCIPAL FINDINGS: Cell proliferation was evaluated by bromodeoxyuridine (BrdU) incorporation both in CaCo-2 cells and in biopsies from active CD cases and controls. We used real-time PCR to evaluate IL-15 mRNA levels and FACS as well as ELISA and Western Blot (WB) analysis to measure protein levels and distribution in CaCo-2 cells. Gliadin and P31-43 induce a proliferation of both CaCo-2 cells and CD crypt enterocytes that is dependent on both EGFR and IL-15 activity. In CaCo-2 cells, P31-43 increased IL-15 levels on the cell surface by altering intracellular trafficking. The increased IL-15 protein was bound to IL15 receptor (IL-15R) alpha, did not require new protein synthesis and functioned as a growth factor. CONCLUSION: In this study, we have shown that P31-43 induces both increase of the trans-presented IL-15/IL5R alpha complex on cell surfaces by altering the trafficking of the vesicular compartments as well as proliferation of crypt enterocytes with consequent remodelling of CD mucosa due to a cooperation of IL-15 and EGFR
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- 2011
11. Interplay between type-1 interferon and IL15 in celiac disease
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Discepolo, V., primary, Bouziat, R., additional, Durling, B., additional, Lania, G., additional, Auricchio, R., additional, Cuomo, M., additional, Sarno, M., additional, Auricchio, S., additional, Troncone, R., additional, Barone, M.V., additional, Guandalini, S., additional, Barreiro, L.B., additional, and Jabri, B., additional
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- 2013
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12. Effects of gliadin on dendritic cells from healthy subjects
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Santagata, S., primary, Nanayakkara, M., additional, Lania, G., additional, Cuomo, M., additional, Sarno, M., additional, Ferrara, K., additional, Gaito, A., additional, Carrella, A., additional, Ponticelli, D., additional, Auricchio, R., additional, Troncone, R., additional, Auricchio, S., additional, and Barone, M.V., additional
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- 2013
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13. CO33 BOTH GLIADIN PEPTIDE P31–43 AND TOLL-LIKE RECEPTOR 7 LIGAND, LOXORIBINE, ARE ABLE TO INDUCE IFN-ALPHA PATHWAY, INCREASING MXA EXPRESSION
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Sarno, M., primary, Nanayakkara, M., additional, Lania, G., additional, Maglio, M., additional, Gaito, A., additional, Ferrara, K., additional, Cuomo, M., additional, Ponticelli, D., additional, Aitoro, R., additional, Discepolo, V., additional, Jabri, B., additional, Troncone, R., additional, Auricchio, S., additional, and Barone, M.V., additional
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- 2012
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14. CO9 ALTERATIONS OF THE ENDOCYTIC TRAFFICKING, ACTIVATION OF SIGNALLING MOLECULES AND INCREASED ENTEROCYTE CRYPTS PROLIFERATION ARE PRESENT IN CELIAC DISEASE (CD) INDEPENDENTLY FROM GLUTEN CONTENT OF THE DIET
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Kosova, R., primary, Lania, G., additional, Nanayakkara, M., additional, Maglio, M., additional, Sarno, M., additional, Ferrara, K., additional, Discepolo, V., additional, Troisi, D., additional, Gaito, A., additional, Troncone, R., additional, Auricchio, S., additional, and Barone, M.V., additional
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- 2011
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15. PP19 IL15 IN MONOCYTES AND DENDRITIC CELLS FROM PATIENTS WITH COELIAC DISEASE
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Ferrara, K., primary, Zanzi, D., additional, Santagata, S., additional, Discepolo, V., additional, Kosova, R., additional, Sarno, M., additional, Nanayakkara, M., additional, Lania, G., additional, Auricchio, R., additional, Auricchio, S., additional, Troncone, R., additional, and Barone, M.V., additional
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- 2011
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16. CO10 FIBROBLASTS AND DENDRITIC CELLS FROM CELIAC PATIENTS: ALTERATION OF CELLULAR SHAPE
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Sarno, M., primary, Nanayakkara, M., additional, Lania, G., additional, Santagata, S., additional, Zanzi, D., additional, Discepolo, V., additional, Kosova, R., additional, Ferrara, K., additional, Gaito, A., additional, Troisi, D., additional, Ponticelli, D., additional, Troncone, R., additional, Auricchio, S., additional, and Barone, M.V., additional
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- 2011
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17. CO5 ALTERED ACTIN REARRANGEMENTS, SHAPE, ADHESION AND MOTILITY CAN DISCRIMINATE CD SKIN FIBROBLASTS FROM CONTROLS
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Kosova, R., primary, Nanayakkara, M., additional, Lania, G., additional, Santagata, S., additional, Discepolo, V., additional, Zanzi, D., additional, Ferrara, K., additional, Costa, S., additional, DeLuca, P., additional, Barone, M.V., additional, Troncone, R., additional, and Auricchio, S., additional
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- 2010
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18. PP22 GLIADIN PEPTIDE P31-43 ENHANCES IL15 ACTIVITY BY INTERFERING WITH ITS INTRACELLULAR TRAFFICKING
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Santagata, S., primary, Zanzi, D., additional, Maglio, M., additional, Nanayakkara, M., additional, Lania, G., additional, Discepolo, V., additional, Kosova, R., additional, Ferrara, K., additional, Troiano, R., additional, Vitale, V., additional, Costa, S., additional, Troncone, R., additional, Auricchio, S., additional, and Barone, M.V., additional
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- 2010
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19. Gliadin P31-43 peptide can delay EGFR (epidermal growth factor receptor) decay interifering with the endocytic pathway
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Nanayakkara, M., primary, Lania, G., additional, Vitale, V., additional, Discepolo, V., additional, Capone, P., additional, ten Eikelder, M., additional, Nista, I., additional, Troncone, R., additional, Auricchio, S., additional, and Barone, M.V., additional
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- 2008
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20. GLIADIN PEPTIDE P31‐43 DELAYS MATURATION OF EARLY ENDOCYTIC VESICLES IN CACO 2 CELLS
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Barone, M V, primary, Nanayakkara, M, additional, Ribecco, M T, additional, Lania, G, additional, Vitale, V, additional, Troiano, R, additional, Troncone, R, additional, and Auricchio, S, additional
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- 2006
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21. G6PD Haplotypes Spanning Xq28 from F8C to Red/Green Color Vision
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Filosa, S., primary, Calabrò, V., additional, Lania, G., additional, Vulliamy, T.J., additional, Brancati, C., additional, Tagarelli, A., additional, Luzzatto, L., additional, and Martini, G., additional
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- 1993
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22. Erratum: miR-194-5p/BCLAF1deregulation in AML tumorigenesis
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Dell'Aversana, C, Giorgio, C, D'Amato, L, Lania, G, Matarese, F, Saeed, S, Di Costanzo, A, Belsito Petrizzi, V, Ingenito, C, Martens, J H A, Pallavicini, I, Minucci, S, Carissimo, A, Stunnenberg, H G, and Altucci, L
- Abstract
Correction to: Leukemia (2017) 31, 2315–2325; doi:10.1038/leu.2017.64; published online 10 March 2017 Following the publication of this article, the authors noted a mistake in the author affiliations. 4. Centre for Research in Molecular Medicine, The University of Lahore, Lahore, Pakistan Should be replaced with:
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- 2018
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23. Inflammation Is Present, Persistent and More Sensitive to Proinflammatory Triggers in Celiac Disease Enterocytes
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Monia Porpora, Mariangela Conte, Giuliana Lania, Claudia Bellomo, Luciano Rapacciuolo, Fernando Gabriel Chirdo, Renata Auricchio, Riccardo Troncone, Salvatore Auricchio, Maria Vittoria Barone, Merlin Nanayakkara, Porpora, M., Conte, M., Lania, G., Bellomo, C., Rapacciuolo, L., Chirdo, F. G., Auricchio, R., Troncone, R., Auricchio, S., Barone, M. V., and Nanayakkara, M.
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Male ,Glutens ,Adolescent ,Catalysis ,NF-κB ,Inorganic Chemistry ,Diet, Gluten-Free ,Humans ,Physical and Theoretical Chemistry ,Intestinal Mucosa ,Child ,Molecular Biology ,Spectroscopy ,small intestine ,potential celiac disease ,ERK ,Inflammation ,Organic Chemistry ,Potential celiac disease ,General Medicine ,Small intestine ,Biomarker ,Computer Science Applications ,Celiac Disease ,Enterocytes ,Child, Preschool ,Enterocyte ,Female ,Biomarkers ,Gluten ,Human ,Signal Transduction - Abstract
Celiac disease (CD) is a chronic inflammatory disease caused by a genetic predisposition to an abnormal T cell-mediated immune response to the gluten in the diet. Different environmental proinflammatory factors can influence and amplify the T cell-mediated response to gluten. The aim of this manuscript was to study the role of enterocytes in CD intestinal inflammation and their response to different proinflammatory factors, such as gliadin and viruses. Intestinal biopsies from CD patients on a gluten-containing (GCD-CD) or a gluten-free diet (GFD-CD) as well as biopsies from potential CD patients (Pot-CD) before the onset of intestinal lesions and controls (CTR) were used to investigate IL-1β and IL-6 mRNA levels in situ. Organoids from CD patients were used to test the levels of NF-κB, ERK, IL-6, and IL-1β by Western blot (WB), ELISA, and quantitative PCR. The Toll-like receptor ligand loxoribine (Lox) and gliadin peptide P31-43 were used as proinflammatory stimuli. In CD biopsies inflammation markers IL-1β and IL-6 were increased in the enterocytes, and also in Pot-CD before the onset of the intestinal lesion and in GFD-CD. The inflammatory markers pNF-κB, pERK, IL-1β, and IL-6 were increased and persistent in CD organoids; these organoids were more sensitive to P31-43 and Lox stimuli compared with CTR organoids. Taken together, these observations point to constitutive inflammation in CD enterocytes, which are more sensitive to inflammatory stimuli such as food components and viruses.
- Published
- 2022
24. Membrane-anchorage of Cripto protein by glycosylphosphatidylinositol and its distribution during early mouse development
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Giovanna L. Liguori, C. T. Lago, Massimo Signore, Eileen D. Adamson, Gabriella Minchiotti, Gabriella Lania, Silvia Parisi, M. Graziella Persico, Minchiotti, G, Parisi, Silvia, Liguori, G, Signore, M, Lania, G, Adamson, Ed, Lago, Ct, Persico, Mg, Minchiotti, G., Parisi, S., Liguori, G., Signore, M., Lania, G., Adamson, E. D., Lago, C. T., and Persico, M. G.
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Embryology ,Glycosylphosphatidylinositols ,Cell ,Biology ,Cripto ,GPI-Linked Proteins ,Embryonic and Fetal Development ,Mice ,Epidermal growth factor ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Cell Line, Transformed ,Messenger RNA ,Binding Sites ,Membrane Glycoproteins ,Epidermal Growth Factor ,Phosphatidylinositol Diacylglycerol-Lyase ,Embryogenesis ,Cell Membrane ,Embryo ,Embryonic stem cell ,Molecular biology ,Neoplasm Proteins ,Gastrulation ,medicine.anatomical_structure ,Type C Phospholipases ,Intercellular Signaling Peptides and Proteins ,Rabbits ,hormones, hormone substitutes, and hormone antagonists ,Developmental Biology - Abstract
cripto is the original member of the family of EGF-CFC genes, recently recognized as novel extracellular factors essential for vertebrate development. During the early stages of mouse gastrulation, cripto mRNA is detected in mesodermal cells; later, cripto mRNA is detected only in the truncus arteriosus of the developing heart. Here we describe the in vivo distribution of Cripto protein throughout mouse embryo development and show that cripto mRNA and protein colocalize. By means of immunofluorescence analysis and biochemical characterization, we show that Cripto is a membrane-bound protein anchored to the lipid bilayer by a glycosylphosphatidylinositol (GPI) moiety. We suggest that presentation of Cripto on the cell surface via a GPI-linkage is important in determining the spatial specificity of cell-cell interactions that play a critical role in the early patterning of the embryo.
- Published
- 2000
25. Pharmacological Rescue of the Brain Cortex Phenotype of Tbx1 Mouse Mutants: Significance for 22q11.2 Deletion Syndrome
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Ilaria Favicchia, Gemma Flore, Sara Cioffi, Gabriella Lania, Antonio Baldini, Elizabeth Illingworth, Favicchia, I., Flore, G., Cioffi, S., Lania, G., Baldini, A., and Illingworth, E.
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TBX1 ,Cell type ,Mutant ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Biology ,medicine.disease_cause ,Cellular and Molecular Neuroscience ,stomatognathic system ,DiGeorge syndrome ,medicine ,Molecular Biology ,Gene ,Original Research ,Mutation ,VitaminB12 ,pharmacological action ,Tranylcypromine ,vitamin B12 ,medicine.disease ,Phenotype ,Cell biology ,embryonic structures ,TCP ,Haploinsufficiency ,Neuroscience ,RC321-571 - Abstract
ObjectivesTbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency.Experimental ApproachDisease model: Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain.MethodsIn situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved.ResultsCortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression.ConclusionTo our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region.
- Published
- 2021
26. Effect of pH control during rice fermentation in preventing a gliadin P31-43 entrance in epithelial cells
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Giuliana Lania, Francesca Passannanti, Dana Salameh, Merlin Nanayakkara, Francesca Parisi, Federica Nigro, Marianna Gallo, Maria Vittoria Barone, Andrea Budelli, Roberto Nigro, Gallo, M., Nigro, F., Passannanti, F., Nanayakkara, M., Lania, G., Parisi, F., Salameh, D., Budelli, A., Barone, M. V., and Nigro, R.
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0301 basic medicine ,Glutens ,fermented food ,Lactobacillus paracasei ,P31-43 ,030209 endocrinology & metabolism ,Bacterial growth ,Gliadin ,Coeliac disease ,functional food ,Diet, Gluten-Free ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,Lactic Acid ,Food science ,chemistry.chemical_classification ,030109 nutrition & dietetics ,biology ,Chemistry ,pH control ,food and beverages ,Epithelial Cells ,Oryza ,Lacticaseibacillus paracasei ,Hydrogen-Ion Concentration ,biology.organism_classification ,medicine.disease ,Gluten ,Peptide Fragments ,Lactic acid ,Celiac Disease ,Fermentation ,biology.protein ,Lactobacillus paracasei CBA L74 ,Caco-2 Cells ,Food Hypersensitivity ,coeliac disease ,Lactic acid fermentation ,Food Science - Abstract
Coeliac disease is an increasingly recognised pathology, induced by the ingestion of gluten in genetically predisposed patients. Undigested gliadin peptide can induce adaptive and innate immune response that unleash the typical intestinal mucosal alterations. A growing attention is paid to alternative therapeutic approaches to the gluten-free diet: one of these approaches is the use of probiotics and/or postbiotics. We performed lactic fermentation of rice flour with and without pH control, using Lactobacillus paracasei CBA L74 as fermenting strain. We evaluated bacterial growth, lactic acid production during fermentation and gliadin peptide P31-43 entrance in CaCo-2 cells with and without pH control. When pH control was applied no differences were observed in terms of bacterial growth; on the contrary, lactic acid production was greater, as expected. Both samples could inhibit the P31-43 entrance in CaCo-2 cells but the effect was significantly greater for samples obtained when the pH control was applied.
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- 2019
27. Pediatric Celiac Disease Patients Show Alterations of Dendritic Cell Shape and Actin Rearrangement
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Giuliana Lania, Renata Auricchio, Giovanni Paolella, Merlin Nanayakkara, Maria Leonarda Gertrude Ten Eikelder, Rossella Tufano, Riccardo Troncone, Maria Vittoria Barone, Salvatore Auricchio, Leandra Sepe, Valentina Discepolo, Discepolo, V., Lania, G., Eikelder, M. L. G. T., Nanayakkara, M., Sepe, L., Tufano, R., Troncone, R., Auricchio, S., Auricchio, R., Paolella, G., and Barone, M. V.
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0301 basic medicine ,Male ,RHOA ,actin cytoskeleton ,ARHGAP31 ,Monocyte ,Monocytes ,lcsh:Chemistry ,0302 clinical medicine ,Cytoskeleton ,Child ,lcsh:QH301-705.5 ,Spectroscopy ,biology ,medicine.diagnostic_test ,Chemistry ,GTPase-Activating Proteins ,HLA-DQ Antigen ,General Medicine ,Computer Science Applications ,adhesion ,030220 oncology & carcinogenesis ,Child, Preschool ,Phosphoprotein ,Female ,Human ,Human leukocyte antigen ,Immunofluorescence ,Dendritic Cell ,Catalysis ,Article ,cell shape ,Inorganic Chemistry ,03 medical and health sciences ,fibronectin ,HLA-DQ Antigens ,medicine ,Cell Adhesion ,Humans ,dendritic cells ,Physical and Theoretical Chemistry ,Molecular Biology ,Actin ,GTPase-Activating Protein ,Organic Chemistry ,RhoA ,Dendritic cell ,Actin cytoskeleton ,Phosphoproteins ,Molecular biology ,Actins ,Fibronectins ,Fibronectin ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,rhoA GTP-Binding Protein ,celiac disease - Abstract
Celiac disease (CD) is a frequent intestinal inflammatory disease occurring in genetically susceptible individuals upon gluten ingestion. Recent studies point to a role in CD for genes involved in cell shape, adhesion and actin rearrangements, including a Rho family regulator, Rho GTPase-activating protein 31 (ARHGAP31). In this study, we investigated the morphology and actin cytoskeletons of peripheral monocyte-derived dendritic cells (DCs) from children with CD and controls when in contact with a physiological substrate, fibronectin. DCs were generated from peripheral blood monocytes of pediatric CD patients and controls. After adhesion on fibronectin, DCs showed a higher number of protrusions and a more elongated shape in CD patients compared with controls, as assessed by immunofluorescence actin staining, transmitted light staining and video time-lapse microscopy. These alterations did not depend on active intestinal inflammation associated with gluten consumption and were specific to CD, since they were not found in subjects affected by other intestinal inflammatory conditions. The elongated morphology was not a result of differences in DC activation or maturation status, and did not depend on the human leukocyte antigen (HLA)-DQ2 haplotype. Notably, we found that ARH-GAP31 mRNA levels were decreased while RhoA-GTP activity was increased in CD DCs, pointing to an impairment of the Rho pathway in CD cells. Accordingly, Rho inhibition was able to prevent the cytoskeleton rearrangements leading to the elongated morphology of celiac DCs upon adhesion on fibronectin, confirming the role of this pathway in the observed phenotype. In conclusion, adhesion on fibronectin discriminated CD from the controls’ DCs, revealing a gluten-independent CD-specific cellular phenotype related to DC shape and regulated by RhoA activity.
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- 2021
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28. Chromatin and Transcriptional Response to Loss of TBX1 in Early Differentiation of Mouse Cells
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Monica Franzese, Gabriella Lania, Rosa Ferrentino, Andrea Cirino, Elizabeth Illingworth, Dario Righelli, Claudia Angelini, Ilaria Aurigemma, Antonio Baldini, Cirino, A., Aurigemma, I., Franzese, M., Lania, G., Righelli, D., Ferrentino, R., Illingworth, E., Angelini, C., and Baldini, A.
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0301 basic medicine ,TBX1 ,DiGeorge syndrome ,chromatin accessibility ,embryonic stell cell ,transcriptional response ,Cellular differentiation ,Biology ,Chromatin remodeling ,TBX1, chromatin accessibility, transcriptional response, DiGeorge syndrome, embryonic stem cell ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Gene expression ,Transcription factor ,lcsh:QH301-705.5 ,Gene knockdown ,Cell Biology ,Embryonic stem cell ,embryonic stem cell ,Chromatin ,Cell biology ,030104 developmental biology ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Developmental Biology - Abstract
The T-box transcription factor TBX1 has critical roles in the cardiopharyngeal lineage and the gene is haploinsufficient in DiGeorge syndrome, a typical developmental anomaly of the pharyngeal apparatus. Despite almost two decades of research, if and how TBX1 function triggers chromatin remodeling is not known. Here, we explored genome-wide gene expression and chromatin remodeling in two independent cellular models of Tbx1 loss of function, mouse embryonic carcinoma cells P19Cl6, and mouse embryonic stem cells (mESCs). The results of our study revealed that the loss or knockdown of TBX1 caused extensive transcriptional changes, some of which were cell type-specific, some were in common between the two models. However, unexpectedly we observed only limited chromatin changes in both systems. In P19Cl6 cells, differentially accessible regions (DARs) were not enriched in T-BOX binding motifs; in contrast, in mESCs, 34% (n = 47) of all DARs included a T-BOX binding motif and almost all of them gained accessibility in Tbx1 -/- cells. In conclusion, despite a clear transcriptional response of our cell models to loss of TBX1 in early cell differentiation, chromatin changes were relatively modest.
- Published
- 2020
29. Mir-194-5p/BCLAF1 deregulation in AML tumorigenesis
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Lucia Altucci, S. Minucci, Concetta Ingenito, Isabella Pallavicini, Loredana D’Amato, V Belsito Petrizzi, A. Di Costanzo, Carmela Dell'Aversana, Sadia Saeed, Filomena Matarese, Annamaria Carissimo, G Lania, Hendrik G. Stunnenberg, Joost H.A. Martens, Cristina Giorgio, Dell'Aversana, C., Giorgio, C, D'Amato, L., Lania, G., Matarese, F., Saeed, S., Di Costanzo, A., Belsito Petrizzi, V., Ingenito, C., Martens, J. H. A., Pallavicini, I., Minucci, S., Carissimo, A., Stunnenberg, H. G., and Altucci, Lucia
- Subjects
0301 basic medicine ,Cancer Research ,Myeloid ,medicine.drug_class ,Cellular differentiation ,Down-Regulation ,Apoptosis ,Biology ,medicine.disease_cause ,Acute myeloid leukaemia ,03 medical and health sciences ,Cancer epigenetics ,Cell Line, Tumor ,miR-194-5p/BCLAF1 ,microRNA ,medicine ,Humans ,Molecular Biology ,Oncogenesis ,Regulation of gene expression ,Tumor Suppressor Proteins ,Cell Cycle ,Histone deacetylase inhibitor ,Myeloid leukemia ,Cell Differentiation ,Hematology ,3. Good health ,Repressor Proteins ,Leukemia, Myeloid, Acute ,MicroRNAs ,Haematopoiesis ,Anesthesiology and Pain Medicine ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Oncology ,miRNAs ,Immunology ,Cancer research ,Original Article ,Erratum ,Carcinogenesis - Abstract
Contains fulltext : 168891.pdf (Publisher’s version ) (Open Access) Deregulation of epigenetic mechanisms, including microRNA, contributes to leukemogenesis and drug resistance by interfering with cancer-specific molecular pathways. Here, we show that the balance between miR-194-5p and its newly discovered target BCL2-associated transcription factor 1 (BCLAF1) regulates differentiation and survival of normal hematopoietic progenitors. In acute myeloid leukemias this balance is perturbed, locking cells into an immature, potentially /`immortal/' state. Enhanced expression of miR-194-5p by treatment with the histone deacetylase inhibitor SAHA or by exogenous miR-194-5p expression re-sensitizes cells to differentiation and apoptosis by inducing BCLAF1 to shuttle between nucleus and cytosol. miR-194-5p/BCLAF1 balance was found commonly deregulated in 60 primary acute myeloid leukemia patients and was largely restored by ex vivo SAHA treatment. Our findings link treatment responsiveness to re-instatement of miR-194-5p/BCLAF1 balance. 11 p.
- Published
- 2017
30. Lactobacillus paracaseiCBA L74 interferes with gliadin peptides entrance in Caco-2 cells
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Francesca Fasano, Roberto Nigro, M. Sarno, Riccardo Troncone, M. Cuomo, Federica Nigro, Francesca Passannanti, Maria Vittoria Barone, Giuliana Lania, Andrea Budelli, Salvatore Auricchio, Merlin Nanayakkara, Sarno, M, Lania, G, Cuomo, M, Nigro, F, Passannanti, F, Budelli, A, Fasano, F, Troncone, Riccardo, Auricchio, S, Barone, MARIA VITTORIA, Nigro, Roberto, and Nanayakkara, M.
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Lactobacillus paracasei ,Colon ,Biological effect ,Gliadin ,law.invention ,Microbiology ,Pathogenesis ,Probiotic ,law ,Humans ,Intestinal Mucosa ,Cells, Cultured ,Biological Products ,biology ,Probiotics ,food and beverages ,biology.organism_classification ,Acquired immune system ,Celiac disease, Lactobacillus paracasei CBA L74, fermented food, gliadin peptides, vesicular trafficking ,Celiac Disease ,Lactobacillus ,Enterocytes ,Biochemistry ,Caco-2 ,Fermentation ,biology.protein ,Caco-2 Cells ,Edible Grain ,Peptides ,Food Science - Abstract
Several recent reports describe a role of probiotics as a therapeutic approach for celiac disease (CD). Two undigested A-gliadin peptides, P31-43 and P57-68, are central to CD pathogenesis, inducing an innate and an adaptive immune response, respectively. They enter enterocytes and localize to vesicular compartment to induce their toxic/immunogenics effects. In this article, we tested the effect of probiotic Lactobacillus paracasei (LP) CBA L74 (International Depository Accession Number LMG P-24778), its supernatant and LP-fermented cereals on gliadin peptides, P31-43 and P57-68, entrance in Caco-2 cells. Both LP CBA L74 and its supernatant inhibit P31-43 (intensity of fluorescence; FI: 75%) and P57-68 (FI: 50%) entrance in Caco2 cells, indicating that this biological effect is due to some product included in LP CBA L74 supernatant. This effect was present also after fermentation of cereals. This study describes a novel effect of probiotics in the prevention of undigested gliadin peptides toxic effects.
- Published
- 2014
31. Enterocyte proliferation and signaling are constitutively altered in celiac disease
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Roberta Kosova, A. Gaito, Mariantonia Maglio, Riccardo Troncone, Maria Vittoria Barone, Giuliana Lania, Merlin Nanayakkara, Renata Auricchio, Salvatore Auricchio, M. Sarno, Valentina Discepolo, Nanayakkara, Merlin, Lania, G, Maglio, Mariantonia, Kosova, R, Sarno, M, Gaito, A, Discepolo, Valentina, Troncone, Riccardo, Auricchio, S, Auricchio, Renata, and Barone, M. V.
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Adolescent ,Enterocyte ,EGFR ,Biopsy ,lcsh:Medicine ,Immune system ,Growth factor receptor ,Intestinal mucosa ,Epidermal growth factor ,fibroblasts ,medicine ,Humans ,Intestinal Mucosa ,Phosphorylation ,lcsh:Science ,Child ,Extracellular Signal-Regulated MAP Kinases ,Cell Proliferation ,Multidisciplinary ,biology ,Epidermal Growth Factor ,extracellular signal-regulated kinase 1/ 2 ,lcsh:R ,food and beverages ,nutritional and metabolic diseases ,Infant ,Acquired immune system ,Molecular biology ,digestive system diseases ,ErbB Receptors ,Celiac Disease ,medicine.anatomical_structure ,Enterocytes ,Child, Preschool ,Immunology ,biology.protein ,lcsh:Q ,Signal transduction ,Gliadin ,Signal Transduction ,Research Article - Abstract
Celiac disease (CD) occurs frequently, and is caused by ingestion of prolamins from cereals in subjects with a genetic predisposition. The small intestinal damage depends on an intestinal stress/innate immune response to certain gliadin peptides (e.g., A-gliadin P31-43) in association with an adaptive immune response to other gliadin peptides (e.g., A-gliadin P57-68). Gliadin and peptide P31-43 affect epithelial growth factor receptor (EGFR) signaling and CD enterocyte proliferation. The reason why the stress/innate immune and proliferative responses to certain gliadin peptides are present in CD and not in control intestine is so far unknown. The aim of this work is to investigate if, in CD, a constitutive alteration of enterocyte proliferation and signaling exists that may represent a predisposing condition to the damaging effects of gliadin. Immunofluorescence and immunohistochemistry were used to study signaling in CD fibroblasts and intestinal biopsies. Western blot (WB) analysis, immunoprecipitation, and quantitative PCR were also used. We found in CD enterocytes enhancement of both proliferation and Epidermal Growth Factor Receptor (EGFR)/ligand system. In CD enterocytes and fibroblasts we found increase of the phosphorylated downstream signaling molecule Extracellular Signal Regulated Kinase (ERK); block of the ERK activation normalizes enterocytes proliferation in CD mucosa. In conclusion the same pathway, which gliadin and gliadin peptide P31-43 can interfere with, is constitutively altered in CD cells. This observation potentially explains the specificity of the damaging effects of certain gliadin peptides on CD intestine.
- Published
- 2013
32. Interplay of negative and positive signals controls endoderm-specific expression of the ascidian Cititf1 gene promoter
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Roberto Di Lauro, Albertina Fanelli, Gabriella Lania, Antonietta Spagnuolo, Fanelli, A., Lania, G., Spagnuolo, A., and DI LAURO, Roberto
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Mesoderm ,animal structures ,Ascidian ,Transcription, Genetic ,Molecular Sequence Data ,Biology ,03 medical and health sciences ,Transcriptional regulation ,0302 clinical medicine ,medicine ,Animals ,Ciona intestinalis ,Urochordata ,Enhancer ,Promoter Regions, Genetic ,Molecular Biology ,030304 developmental biology ,Homeodomain Proteins ,0303 health sciences ,Base Sequence ,Endoderm ,Gene Expression Regulation, Developmental ,Promoter ,Cell Biology ,biology.organism_classification ,Molecular biology ,Cititf1 ,Ciona ,medicine.anatomical_structure ,Enhancer Elements, Genetic ,Regulatory sequence ,embryonic structures ,030217 neurology & neurosurgery ,Developmental Biology ,Transcription Factors - Abstract
Cititf1 is an early and specific marker of endoderm development in Ciona intestinalis [Ristoratore, F., et al. (1999) Development 126, 5149]. Here, we examine Cititf1 transcriptional regulation focusing in particular on its endodermal restricted expression. Through the analysis of Ciona embryos, electroporated with different portions of Cititf1 5′-flanking region fused to lacZ, we characterized a minimal 300-bp cis-regulatory sequence able to closely reproduce the spatial and temporal expression pattern of the endogenous gene. This enhancer contains at least three distinct regulatory regions, two of which are responsible for activation of transcription in the endoderm and in the mesenchyme, respectively, while the third is a negative control element that represses mesenchyme transcription. We have further defined the sequences responsible for transcriptional activation in the endoderm by clustered point mutations and DNA-binding assays.
- Published
- 2003
33. G6PD haplotypes spanning Xq28 from F8C to Red/Green Colour vision
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Stefania Filosa, Tom Vulliamy, G. Martini, L. Luzzatto, Viola Calabrò, G. Lania, A. Tagarelli, C. Brancati, Filosa, S., Calabro', Viola, Lania, G., Vulliamy, T. J., Brancati, C., Tagarelli, A., Luzzatto, L., and Martini, G.
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Adult ,Genetic Markers ,Male ,Linkage disequilibrium ,X Chromosome ,Gene mapping, X chromosome, G6PD ,Molecular Sequence Data ,Population genetics ,Color Vision Defects ,Biology ,Glucosephosphate Dehydrogenase ,Linkage Disequilibrium ,Gene flow ,Gene mapping ,Gene Frequency ,Genetics ,Humans ,Genetic Testing ,Child ,X chromosome ,Alleles ,Base Sequence ,Haplotype ,Chromosome Mapping ,Xq28 ,Glucosephosphate Dehydrogenase Deficiency ,Haplotypes ,Italy ,Mutation (genetic algorithm) ,Retinal Pigments ,Polymorphism, Restriction Fragment Length - Abstract
The most telomeric region of the human X chomosome within band Xq28 consists of a gene-rich region of about 3 Mb which contains the genes for coagulation factor VIIIc, glucose-6-phosphate dehydrogenase (G6PD), and red/green color vision. We have studied five polymorphic sites from this region, in a sample of normal people from the Cosenza province of Southern Italy. These sites, which span a distance of some 350 kb, are in strong linkage disequilibrium. Of the 32 possible haplotypes only 10 were found, and 4 of these account for 80% of all X chromosomes analyzed. In addition, we found that all G6PD-deficient people with the G6PD Mediterranean mutation belong to only two haplotypes. One of these (Med 1) is found only within a small subregion of the area investigated, west of the Appennine mountain range. Most remarkably, all Med 1 G6PD-deficient individuals also had red/green color blindness. The more frequent haplotype (Med 2) is the same in Calabria and in Sardinia, where it accounts for about 90% of the G6PD Mediterranean mutations, despite the fact that gene flow between the populations of Sardinia and Southern Italy must have been limited. These data do not enable us to determine whether the two types of G6PD Mediterranean have arisen through two separate identical mutational events or through a single mutational event followed by recombination. However, the data indicate relatively little recombination over an extended region of the X chromosome and they suggest that the G6PD Mediterranean mutation is recent by comparison to the other polymorphisms investigated.
- Published
- 1993
34. Endothelial gene regulatory elements associated with cardiopharyngeal lineage differentiation.
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Aurigemma I, Lanzetta O, Cirino A, Allegretti S, Lania G, Ferrentino R, Poondi Krishnan V, Angelini C, Illingworth E, and Baldini A
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- Animals, Mice, Gene Expression Regulation, Developmental, Transcription Factors genetics, Transcription Factors metabolism, Cell Differentiation genetics, Endothelial Cells metabolism, Enhancer Elements, Genetic
- Abstract
Endothelial cells (EC) differentiate from multiple sources, including the cardiopharyngeal mesoderm, which gives rise also to cardiac and branchiomeric muscles. The enhancers activated during endothelial differentiation within the cardiopharyngeal mesoderm are not completely known. Here, we use a cardiogenic mesoderm differentiation model that activates an endothelial transcription program to identify endothelial regulatory elements activated in early cardiogenic mesoderm. Integrating chromatin remodeling and gene expression data with available single-cell RNA-seq data from mouse embryos, we identify 101 putative regulatory elements of EC genes. We then apply a machine-learning strategy, trained on validated enhancers, to predict enhancers. Using this computational assay, we determine that 50% of these sequences are likely enhancers, some of which are already reported. We also identify a smaller set of regulatory elements of well-known EC genes and validate them using genetic and epigenetic perturbation. Finally, we integrate multiple data sources and computational tools to search for transcriptional factor binding motifs. In conclusion, we show EC regulatory sequences with a high likelihood to be enhancers, and we validate a subset of them using computational and cell culture models. Motif analyses show that the core EC transcription factors GATA/ETS/FOS is a likely driver of EC regulation in cardiopharyngeal mesoderm., (© 2024. The Author(s).)
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- 2024
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35. PTPRK, an EGFR Phosphatase, Is Decreased in CeD Biopsies and Intestinal Organoids.
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Nanayakkara M, Bellomo C, Furone F, Maglio M, Marano A, Lania G, Porpora M, Nicoletti M, Auricchio S, and Barone MV
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- Humans, ErbB Receptors metabolism, Enterocytes metabolism, Biopsy, Genetic Predisposition to Disease, Receptor-Like Protein Tyrosine Phosphatases, Class 2 metabolism, Celiac Disease genetics, Celiac Disease metabolism
- Abstract
Background & Aims: Celiac disease (CeD) is an immune-mediated enteropathy triggered in genetically susceptible (HLA-DQ2/8) individuals by a group of wheat proteins and related prolamins from cereals. The celiac intestine is characterized by an inversion of the differentiation/proliferation program of the enterocytes, with an increase in the proliferative compartment and crypt hyperplasia, which are the mechanisms that regulate the increased proliferation in CeD that arenot completely understood.The aim of this study is to understand the role of Protein Tyrosine Phosphatase Receptor Type K (PTPRK), a nodal phosphatase that regulates EGFR activation in the proliferation of the enterocytes from CeD biopsies and organoids., Methods: The levels of PTPRK were evaluated by RT PCR, western blot (WB) and immunofluorescence techniques in intestinal biopsies and organoids from CeD patients and controls. Additionally, pEGFR and pERK were evaluated by WB and proliferation by BrdU incorporation. PTPRK si-RNA was silenced in CTR organoids and was overexpressed in CeD organoids., Results: PTPRK was reduced in Gluten Containing Diet-Celiac Disease (GCD-CeD) and Potential-Celiac Disease(Pot-CeD) biopsies ( p < 0.01- p < 0.05) whereas pEGFR ( p < 0.01 p < 0.01), pERK ( p < 0.01 p < 0.01) and proliferation were increased. ( p < 0.05 p < 0.05) respect to the controls.The CeD organoids reproduced these same alterations. Silencing of PTPRK in CTR organoids increased pEGFR, pERK and proliferation. The overexpression of PTPRK in CeD organoids reduced pEGFR, pERK and proliferation., Conclusions: modulation of PTPRK levels can reduce or increase pEGFR, pERK and proliferation in CeD or CTR organoids, respectively. The CeD organoids can be a good model to study the mechanisms of the disease.
- Published
- 2022
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36. A phenotypic rescue approach identifies lineage regionalization defects in a mouse model of DiGeorge syndrome.
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Lania G, Franzese M, Adachi N, Bilio M, Flore G, Russo A, D'Agostino E, Angelini C, Kelly RG, and Baldini A
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- Animals, Disease Models, Animal, Gene Expression Regulation, Developmental, Mesoderm metabolism, Mice, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism, Vitamin B 12, DiGeorge Syndrome genetics
- Abstract
TBX1 is a key regulator of pharyngeal apparatus (PhAp) development. Vitamin B12 (vB12) treatment partially rescues aortic arch patterning defects of Tbx1+/- embryos. Here, we show that it also improves cardiac outflow tract septation and branchiomeric muscle anomalies of Tbx1 hypomorphic mutants. At the molecular level, in vivo vB12 treatment enabled us to identify genes that were dysregulated by Tbx1 haploinsufficiency and rescued by treatment. We found that SNAI2, also known as SLUG, encoded by the rescued gene Snai2, identified a population of mesodermal cells that was partially overlapping with, but distinct from, ISL1+ and TBX1+ populations. In addition, SNAI2+ cells were mislocalized and had a greater tendency to aggregate in Tbx1+/- and Tbx1-/- embryos, and vB12 treatment restored cellular distribution. Adjacent neural crest-derived mesenchymal cells, which do not express TBX1, were also affected, showing enhanced segregation from cardiopharyngeal mesodermal cells. We propose that TBX1 regulates cell distribution in the core mesoderm and the arrangement of multiple lineages within the PhAp., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)
- Published
- 2022
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37. Inflammation Is Present, Persistent and More Sensitive to Proinflammatory Triggers in Celiac Disease Enterocytes.
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Porpora M, Conte M, Lania G, Bellomo C, Rapacciuolo L, Chirdo FG, Auricchio R, Troncone R, Auricchio S, Barone MV, and Nanayakkara M
- Subjects
- Adolescent, Biomarkers metabolism, Child, Child, Preschool, Diet, Gluten-Free, Female, Glutens metabolism, Humans, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Male, Signal Transduction physiology, Celiac Disease metabolism, Celiac Disease pathology, Enterocytes metabolism, Enterocytes pathology, Inflammation metabolism, Inflammation pathology
- Abstract
Celiac disease (CD) is a chronic inflammatory disease caused by a genetic predisposition to an abnormal T cell-mediated immune response to the gluten in the diet. Different environmental proinflammatory factors can influence and amplify the T cell-mediated response to gluten. The aim of this manuscript was to study the role of enterocytes in CD intestinal inflammation and their response to different proinflammatory factors, such as gliadin and viruses. Intestinal biopsies from CD patients on a gluten-containing (GCD-CD) or a gluten-free diet (GFD-CD) as well as biopsies from potential CD patients (Pot-CD) before the onset of intestinal lesions and controls (CTR) were used to investigate IL-1β and IL-6 mRNA levels in situ. Organoids from CD patients were used to test the levels of NF-κB, ERK, IL-6, and IL-1β by Western blot (WB), ELISA, and quantitative PCR. The Toll-like receptor ligand loxoribine (Lox) and gliadin peptide P31-43 were used as proinflammatory stimuli. In CD biopsies inflammation markers IL-1β and IL-6 were increased in the enterocytes, and also in Pot-CD before the onset of the intestinal lesion and in GFD-CD. The inflammatory markers pNF-κB, pERK, IL-1β, and IL-6 were increased and persistent in CD organoids; these organoids were more sensitive to P31-43 and Lox stimuli compared with CTR organoids. Taken together, these observations point to constitutive inflammation in CD enterocytes, which are more sensitive to inflammatory stimuli such as food components and viruses.
- Published
- 2022
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38. Pharmacological Rescue of the Brain Cortex Phenotype of Tbx1 Mouse Mutants: Significance for 22q11.2 Deletion Syndrome.
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Favicchia I, Flore G, Cioffi S, Lania G, Baldini A, and Illingworth E
- Abstract
Objectives: Tbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency., Experimental Approach: Disease model : Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain., Methods: In situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved., Results: Cortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression., Conclusion: To our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Favicchia, Flore, Cioffi, Lania, Baldini and Illingworth.)
- Published
- 2021
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39. Pediatric Celiac Disease Patients Show Alterations of Dendritic Cell Shape and Actin Rearrangement.
- Author
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Discepolo V, Lania G, Ten Eikelder MLG, Nanayakkara M, Sepe L, Tufano R, Troncone R, Auricchio S, Auricchio R, Paolella G, and Barone MV
- Subjects
- Celiac Disease pathology, Cell Adhesion, Child, Child, Preschool, Dendritic Cells pathology, Female, Fibronectins metabolism, GTPase-Activating Proteins metabolism, HLA-DQ Antigens metabolism, Humans, Male, Monocytes pathology, Phosphoproteins metabolism, rhoA GTP-Binding Protein metabolism, Actins metabolism, Celiac Disease metabolism, Cell Shape, Dendritic Cells immunology, Monocytes metabolism
- Abstract
Celiac disease (CD) is a frequent intestinal inflammatory disease occurring in genetically susceptible individuals upon gluten ingestion. Recent studies point to a role in CD for genes involved in cell shape, adhesion and actin rearrangements, including a Rho family regulator, Rho GTPase-activating protein 31 (ARHGAP31). In this study, we investigated the morphology and actin cytoskeletons of peripheral monocyte-derived dendritic cells (DCs) from children with CD and controls when in contact with a physiological substrate, fibronectin. DCs were generated from peripheral blood monocytes of pediatric CD patients and controls. After adhesion on fibronectin, DCs showed a higher number of protrusions and a more elongated shape in CD patients compared with controls, as assessed by immunofluorescence actin staining, transmitted light staining and video time-lapse microscopy. These alterations did not depend on active intestinal inflammation associated with gluten consumption and were specific to CD, since they were not found in subjects affected by other intestinal inflammatory conditions. The elongated morphology was not a result of differences in DC activation or maturation status, and did not depend on the human leukocyte antigen (HLA)-DQ2 haplotype. Notably, we found that ARH-GAP31 mRNA levels were decreased while RhoA-GTP activity was increased in CD DCs, pointing to an impairment of the Rho pathway in CD cells. Accordingly, Rho inhibition was able to prevent the cytoskeleton rearrangements leading to the elongated morphology of celiac DCs upon adhesion on fibronectin, confirming the role of this pathway in the observed phenotype. In conclusion, adhesion on fibronectin discriminated CD from the controls' DCs, revealing a gluten-independent CD-specific cellular phenotype related to DC shape and regulated by RhoA activity.
- Published
- 2021
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40. EZH2 is required for parathyroid and thymic development through differentiation of the third pharyngeal pouch endoderm.
- Author
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Caprio C, Lania G, Bilio M, Ferrentino R, Chen L, and Baldini A
- Subjects
- Animals, Cell Differentiation, Gene Expression Regulation, Developmental, Mice, Morphogenesis genetics, Organogenesis, Endoderm, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism
- Abstract
The Ezh2 gene encodes a histone methyltransferase of the polycomb repressive complex 2 that methylates histone H3 lysine 27. In this study, we investigated whether EZH2 has a role in the development of the pharyngeal apparatus and whether it regulates the expression of the Tbx1 gene, which encodes a key transcription factor required in pharyngeal development. To these ends, we performed genetic in vivo experiments with mouse embryos and used mouse embryonic stem cell (ESC)-based protocols to probe endoderm and cardiogenic mesoderm differentiation. Results showed that EZH2 occupies the Tbx1 gene locus in mouse embryos, and that suppression of EZH2 was associated with reduced expression of Tbx1 in differentiated mouse ESCs. Conditional deletion of Ezh2 in the Tbx1 expression domain, which includes the pharyngeal endoderm, did not cause cardiac defects but revealed that the gene has an important role in the morphogenesis of the third pharyngeal pouch (PP). We found that in conditionally deleted embryos the third PP was hypoplastic, had reduced expression of Tbx1, lacked the expression of Gcm2, a gene that marks the parathyroid domain, but expressed FoxN1, a gene marking the thymic domain. Consistently, the parathyroids did not develop, and the thymus was hypoplastic. Thus, Ezh2 is required for parathyroid and thymic development, probably through a function in the pouch endoderm. This discovery also provides a novel interpretational key for the finding of Ezh2 activating mutations in hyperparathyroidism and parathyroid cancer., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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41. Chromatin and Transcriptional Response to Loss of TBX1 in Early Differentiation of Mouse Cells.
- Author
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Cirino A, Aurigemma I, Franzese M, Lania G, Righelli D, Ferrentino R, Illingworth E, Angelini C, and Baldini A
- Abstract
The T-box transcription factor TBX1 has critical roles in the cardiopharyngeal lineage and the gene is haploinsufficient in DiGeorge syndrome, a typical developmental anomaly of the pharyngeal apparatus. Despite almost two decades of research, if and how TBX1 function triggers chromatin remodeling is not known. Here, we explored genome-wide gene expression and chromatin remodeling in two independent cellular models of Tbx1 loss of function, mouse embryonic carcinoma cells P19Cl6, and mouse embryonic stem cells (mESCs). The results of our study revealed that the loss or knockdown of TBX1 caused extensive transcriptional changes, some of which were cell type-specific, some were in common between the two models. However, unexpectedly we observed only limited chromatin changes in both systems. In P19Cl6 cells, differentially accessible regions (DARs) were not enriched in T-BOX binding motifs; in contrast, in mESCs, 34% ( n = 47) of all DARs included a T-BOX binding motif and almost all of them gained accessibility in Tbx1
-/- cells. In conclusion, despite a clear transcriptional response of our cell models to loss of TBX1 in early cell differentiation, chromatin changes were relatively modest., (Copyright © 2020 Cirino, Aurigemma, Franzese, Lania, Righelli, Ferrentino, Illingworth, Angelini and Baldini.)- Published
- 2020
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42. Author Correction: Constitutive alterations in vesicular trafficking increase the sensitivity of cells from celiac disease patients to gliadin.
- Author
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Lania G, Nanayakkara M, Maglio M, Auricchio R, Porpora M, Conte M, De Matteis MA, Rizzo R, Luini A, Discepolo V, Troncone R, Auricchio S, and Barone MV
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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43. Effect of pH control during rice fermentation in preventing a gliadin P31-43 entrance in epithelial cells.
- Author
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Gallo M, Nigro F, Passannanti F, Nanayakkara M, Lania G, Parisi F, Salameh D, Budelli A, Barone MV, and Nigro R
- Subjects
- Caco-2 Cells, Celiac Disease drug therapy, Celiac Disease prevention & control, Diet, Gluten-Free, Food Hypersensitivity prevention & control, Functional Food, Gliadin antagonists & inhibitors, Glutens, Humans, Lactic Acid metabolism, Lacticaseibacillus paracasei metabolism, Oryza metabolism, Peptide Fragments antagonists & inhibitors, Epithelial Cells metabolism, Fermentation, Gliadin metabolism, Hydrogen-Ion Concentration, Oryza microbiology, Peptide Fragments metabolism
- Abstract
Coeliac disease is an increasingly recognised pathology, induced by the ingestion of gluten in genetically predisposed patients. Undigested gliadin peptide can induce adaptive and innate immune response that unleash the typical intestinal mucosal alterations. A growing attention is paid to alternative therapeutic approaches to the gluten-free diet: one of these approaches is the use of probiotics and/or postbiotics. We performed lactic fermentation of rice flour with and without pH control, using Lactobacillus paracasei CBA L74 as fermenting strain. We evaluated bacterial growth, lactic acid production during fermentation and gliadin peptide P31-43 entrance in CaCo-2 cells with and without pH control. When pH control was applied no differences were observed in terms of bacterial growth; on the contrary, lactic acid production was greater, as expected. Both samples could inhibit the P31-43 entrance in CaCo-2 cells but the effect was significantly greater for samples obtained when the pH control was applied.
- Published
- 2019
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44. Constitutive alterations in vesicular trafficking increase the sensitivity of cells from celiac disease patients to gliadin.
- Author
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Lania G, Nanayakkara M, Maglio M, Auricchio R, Porpora M, Conte M, De Matteis MA, Rizzo R, Luini A, Discepolo V, Troncone R, Auricchio S, and Barone MV
- Subjects
- Adolescent, Case-Control Studies, Celiac Disease metabolism, Celiac Disease pathology, Child, Child, Preschool, Endocytosis immunology, Endosomes immunology, Endosomes metabolism, Enterocytes immunology, Enterocytes metabolism, Enterocytes pathology, ErbB Receptors metabolism, Fibroblasts immunology, Fibroblasts metabolism, Fibroblasts pathology, Gliadin metabolism, Humans, Immunity, Innate, Interleukin-15 metabolism, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Peptide Fragments metabolism, Th1 Cells immunology, Celiac Disease immunology, Gliadin immunology, Peptide Fragments immunology
- Abstract
Celiac Disease (CD) is an autoimmune disease characterized by inflammation of the intestinal mucosa due to an immune response to wheat gliadins. Some gliadin peptides (e.g., A-gliadin P57-68) induce an adaptive Th1 pro-inflammatory response. Other gliadin peptides (e.g., A-gliadin P31-43) induce a stress/innate immune response involving interleukin 15 (IL15) and interferon α (IFN-α). In the present study, we describe a stressed/inflamed celiac cellular phenotype in enterocytes and fibroblasts probably due to an alteration in the early-recycling endosomal system. Celiac cells are more sensitive to the gliadin peptide P31-43 and IL15 than controls. This phenotype is reproduced in control cells by inducing a delay in early vesicular trafficking. This constitutive lesion might mediate the stress/innate immune response to gliadin, which can be one of the triggers of the gliadin-specific T-cell response., Competing Interests: Competing interestsThe authors declare no competing interests.
- Published
- 2019
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45. P31-43, an undigested gliadin peptide, mimics and enhances the innate immune response to viruses and interferes with endocytic trafficking: a role in celiac disease.
- Author
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Nanayakkara M, Lania G, Maglio M, Auricchio R, De Musis C, Discepolo V, Miele E, Jabri B, Troncone R, Auricchio S, and Barone MV
- Subjects
- Adolescent, Caco-2 Cells, Celiac Disease immunology, Child, Child, Preschool, Diet, Gluten-Free, Enterocytes cytology, Enterocytes drug effects, Enterocytes metabolism, Female, Gliadin chemistry, Guanosine analogs & derivatives, Guanosine pharmacology, Humans, Interferon-alpha metabolism, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Male, Myxovirus Resistance Proteins metabolism, NF-kappa B metabolism, Peptide Fragments chemistry, Signal Transduction drug effects, Toll-Like Receptor 7 antagonists & inhibitors, Toll-Like Receptor 7 genetics, Toll-Like Receptor 7 metabolism, Celiac Disease pathology, Endocytosis drug effects, Gliadin pharmacology, Immunity, Innate drug effects, Peptide Fragments pharmacology
- Abstract
Celiac disease (CD) is an autoimmune disease characterized by inflammation of the intestinal mucosa due to an immune response to wheat gliadins. Some gliadin peptides are resistant to intestinal digestion (e.g., A-gliadin P31-43) and induce a stress/innate immune response, but the reason why they are dangerous in the intestines of patients with CD is unknown. In the present study, P31-43 activated IFN-α, a mediator of the innate immune response in CD, in the intestine of subjects with CD and an enterocyte cell line, CaCo-2. P31-43 cooperated with a viral ligand to activate the TLR7 pathway by interfering with endocytic trafficking. Based on these results, the vesicular pathway regulates the innate/inflammatory response to viral ligands and bioactive dietary peptides. Suggesting that together with viral infections, alimentary proteins able to mimic and potentiate the innate immune response to viruses, can trigger an autoimmune disease such as CD.
- Published
- 2018
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- View/download PDF
46. miR-194-5p/BCLAF1 deregulation in AML tumorigenesis.
- Author
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Dell'Aversana C, Giorgio C, D'Amato L, Lania G, Matarese F, Saeed S, Di Costanzo A, Belsito Petrizzi V, Ingenito C, Martens JHA, Pallavicini I, Minucci S, Carissimo A, Stunnenberg HG, and Altucci L
- Abstract
This corrects the article DOI: 10.1038/leu.2017.64.
- Published
- 2018
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- View/download PDF
47. Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome.
- Author
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Lania G, Bresciani A, Bisbocci M, Francone A, Colonna V, Altamura S, and Baldini A
- Published
- 2017
- Full Text
- View/download PDF
48. Intestinal Production of Anti-Tissue Transglutaminase 2 Antibodies in Patients with Diagnosis Other Than Celiac Disease.
- Author
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Maglio M, Ziberna F, Aitoro R, Discepolo V, Lania G, Bassi V, Miele E, Not T, Troncone R, and Auricchio R
- Subjects
- Celiac Disease diagnosis, Celiac Disease enzymology, Child, Duodenum enzymology, Enzyme-Linked Immunosorbent Assay, Female, Fluorescent Antibody Technique, Gastrointestinal Diseases diagnosis, Gastrointestinal Diseases enzymology, Humans, Immunity, Mucosal, Intestinal Mucosa enzymology, Male, Organ Culture Techniques, Protein Glutamine gamma Glutamyltransferase 2, Receptors, Antigen, T-Cell, gamma-delta immunology, Retrospective Studies, T-Lymphocytes immunology, Autoantibodies analysis, Autoimmunity, Celiac Disease immunology, Duodenum immunology, GTP-Binding Proteins immunology, Gastrointestinal Diseases immunology, Intestinal Mucosa immunology, Transglutaminases immunology
- Abstract
It has been hypothesized that gluten-dependent production of anti-tissue-transglutaminase 2 (anti-TG2) antibodies may occur only at an intestinal level. We have investigated intestinal production of anti-TG2 antibodies in 136 patients with normal serum levels of anti-TG2 antibodies and normal duodenal mucosa. Intestinal deposits of anti-TG2 antibodies were evaluated by immunofluorescence and anti-TG2 antibodies released in organ culture supernatants measured by ELISA. Intestinal antibody libraries were obtained from 10 subjects. Immunohistochemistry for CD25⁺, CD3⁺, and TCR-γδ⁺ was assessed in subjects with positive ( n = 32) and negative ( n = 31) intestinal anti-TG2 antibodies. Globally 33/136 (24%) seronegative patients produced anti-TG2 autoantibodies at an intestinal level. Antibody libraries analysis confirmed the anti-TG2 antibodies mucosal production in all ( n = 8) positive subjects. Lamina propria CD25⁺ cell count was significantly ( p < 0.05) higher in patients with intestinal anti-TG2. Moreover, 13/32 (41%) of them showed high TCR-γδ⁺/CD3⁺ ratios. Intestinal anti-TG2 antibody production does not show absolute specificity for CD. It is seen more often in association with inflamed mucosa. Further investigations are necessary to prove the possible role of dietary gluten.
- Published
- 2017
- Full Text
- View/download PDF
49. c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer.
- Author
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Nebbioso A, Carafa V, Conte M, Tambaro FP, Abbondanza C, Martens J, Nees M, Benedetti R, Pallavicini I, Minucci S, Garcia-Manero G, Iovino F, Lania G, Ingenito C, Belsito Petrizzi V, Stunnenberg HG, and Altucci L
- Subjects
- Acetylation, Cell Line, Tumor, Clinical Trials as Topic, Gene Expression Regulation, Leukemic drug effects, Histone Deacetylase 1 antagonists & inhibitors, Histone Deacetylase Inhibitors administration & dosage, Humans, Kruppel-Like Transcription Factors genetics, Neoplasms pathology, Protein Binding, Signal Transduction drug effects, Sp1 Transcription Factor genetics, Histone Deacetylase 1 genetics, Neoplasms drug therapy, Proto-Oncogene Proteins c-myc genetics, TNF-Related Apoptosis-Inducing Ligand genetics
- Abstract
Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood. Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC , the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc- TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials. Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542-55. ©2016 AACR ., (©2016 American Association for Cancer Research.)
- Published
- 2017
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- View/download PDF
50. Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome.
- Author
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Lania G, Bresciani A, Bisbocci M, Francone A, Colonna V, Altamura S, and Baldini A
- Subjects
- Animals, DiGeorge Syndrome embryology, DiGeorge Syndrome metabolism, Disease Models, Animal, High-Throughput Screening Assays, Mice, Mutation, T-Box Domain Proteins genetics, Vitamin B 12 therapeutic use, DiGeorge Syndrome drug therapy, Gene Expression Regulation, Developmental, Haploinsufficiency, T-Box Domain Proteins drug effects, Vitamin B 12 pharmacology
- Abstract
Abstract: Pathological conditions caused by reduced dosage of a gene, such as gene haploinsufficiency, can potentially be reverted by enhancing the expression of the functional allele. In practice, low specificity of therapeutic agents, or their toxicity reduces their clinical applicability. Here, we have used a high throughput screening (HTS) approach to identify molecules capable of increasing the expression of the gene Tbx1, which is involved in one of the most common gene haploinsufficiency syndromes, the 22q11.2 deletion syndrome. Surprisingly, we found that one of the two compounds identified by the HTS is the vitamin B12. Validation in a mouse model demonstrated that vitamin B12 treatment enhances Tbx1 gene expression and partially rescues the haploinsufficiency phenotype. These results lay the basis for preclinical and clinical studies to establish the effectiveness of this drug in the human syndrome.
- Published
- 2016
- Full Text
- View/download PDF
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