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1. Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling

Author

Marianna De Franceschi, Elisabetta Ciani, Renata Bartesaghi, Laura Calzà, Roberta Torricella, Cornelius Gross, Claudia Fuchs, Elena Amendola, Stefania Trazzi, Rocchina Viggiano, Fuchs C, Trazzi S, Torricella R, Viggiano R, De Franceschi M, Amendola E, Gross C, Calzà L, Bartesaghi R, and Ciani E

Subjects
Male, Cell Survival, Neurogenesis, CDKL5, CDKL5 disorder, Apoptosis, Hippocampal formation, Biology, Cell Enlargement, Protein Serine-Threonine Kinases, Article, lcsh:RC321-571, Glycogen Synthase Kinase 3, Neurodevelopmental disorder, Neural Stem Cells, medicine, Rett's syndrome, Animals, Neurogenesis impairment, Dendritic development, AKT/GSK-3β signaling, Maze Learning, Protein kinase B, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Cells, Cultured, Mice, Knockout, Neurons, Glycogen Synthase Kinase 3 beta, Dentate gyrus, Neurodevelopmental disorders, AKT/GSK-3β, Dendrites, medicine.disease, Phenotype, Neurology, Dentate Gyrus, Female, Signal transduction, Neuroscience, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdkl5 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdkl5 KO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdkl5 KO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus-dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3β signaling pathway. Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene., Highlights • Loss of Cdkl5 decreases survival of postmitotic granule cells. • Loss of Cdkl5 results in dendritic hypotrophy of newborn granule cells. • Loss of Cdkl5 impairs hippocampus-dependent behavior. • Loss of Cdkl5 alters the AKT/GSK-3β pathway.

Published
2014
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2. Prenatal pharmacotherapy rescues brain development in a Down’s syndrome mouse model

Author

Nyoman D. Kurniawan, Sandra Guidi, Alessandro Giuliani, Renata Bartesaghi, Laura Calzà, Karine Mardon, Fiorenza Stagni, Elisabetta Ciani, Marianna De Franceschi, Andrea Giacomini, Patrizia Bianchi, Randal X. Moldrich, Guidi S, Stagni F, Bianchi P, Ciani E, Giacomini A, De Franceschi M, Moldrich R, Kurniawan N, Mardon K, Giuliani A, Calzà L, and Bartesaghi R.

Subjects
Down syndrome, Neurogenesis, Subventricular zone, brain development, Mice, Transgenic, Subgranular zone, Mice, Down’s syndrome, Pregnancy, Fluoxetine, medicine, Animals, Cell Proliferation, Genetic disorder, Brain, Prenatal Care, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, preventive pharmacotherapy, medicine.anatomical_structure, Hypocellularity, Animals, Newborn, Forebrain, Female, Neurology (clinical), Down Syndrome, Psychology, Neural development, Neuroscience
Abstract

Intellectual impairment is a strongly disabling feature of Down's syndrome, a genetic disorder of high prevalence (1 in 700-1000 live births) caused by trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of intellectual disability in Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the pharmacotherapies designed to improve cognitive performance in Down's syndrome have been attempted in Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal pharmacotherapy with fluoxetine, a drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of Down's syndrome. Pregnant Ts65Dn females were treated with fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored dendritic development, cortical and hippocampal synapse development and brain volume. Importantly, these effects were accompanied by recovery of behavioural performance. The cognitive deficits caused by Down's syndrome have long been considered irreversible. The current study provides novel evidence that a pharmacotherapy with fluoxetine during embryonic development is able to fully rescue the abnormal brain development and behavioural deficits that are typical of Down's syndrome. If the positive effects of fluoxetine on the brain of a mouse model are replicated in foetuses with Down's syndrome, fluoxetine, a drug usable in humans, may represent a breakthrough for the therapy of intellectual disability in Down's syndrome.

Published
2013
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3. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial

Author

Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, Ap, Rivellese, Aa, Squatrito, S, Giorda, Cb, Sesti, G, Mocarelli, P, Lucisano, G, Sacco, M, Signorini, S, Cappellini, F, Perriello, G, Babini, Ac, Lapolla, A, Gregori, G, Giordano, C, Corsi, L, Buzzetti, R, Clemente, G, Di Cianni, G, Iannarelli, R, Cordera, R, La Macchia, O, Zamboni, C, Scaranna, C, Boemi, M, Iovine, C, Lauro, D, Leotta, S, Dall'Aglio, E, Cannarsa, E, Tonutti, L, Pugliese, G, Bossi, Ac, Anichini, R, Dotta, F, Di Benedetto, A, Citro, G, Antenucci, D, Ricci, L, Giorgino, F, Santini, C, Gnasso, A, De Cosmo, S, Zavaroni, D, Vedovato, M, Consoli, A, Calabrese, M, di Bartolo, P, Fornengo, P, Riccardi, G, IT) study group, Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA., Collaborators: Vaccaro O, Italian Diabetes Society., D'Angelo, F, Giansanti, R, Tanase, L, Lanari, L, Testa, I, Pancani, F, Ranchelli, A, Vagheggi, P, Scatona, A, Fontana, L, Laviola, L, Tarantino, L, Ippolito, C, Gigantelli, V, Manicone, M, Conte, E, Trevisan, R, Rota, R, Corsi, A, Dodesini, Ar, Reggiani, Gm, Montesi, L, Mazzella, N, Forlani, G, Caselli, C, Di Luzio, R, Mazzotti, A, Aiello, A, Barrea, A, Musto, A, D'Amico, F, Sinagra, T, Longhitano, S, Trowpea, V, Sparti, M, Italia, S, Lisi, E, Grasso, G, Pezzino, V, Insalaco, F, Carallo, C, Scicchitano, C, De Franceschi MS, Calbucci, G, Ripani, R, Cuneo, G, Corsi, S, Romeo, F, Lesina, A, Comoglio, M, Bonetto, C, Robusto, A, Nada, E, Asprino, V, Cetraro, R, Impieri, M, Lucchese, G, Donnarumma, G, Tizio, B, Lenza, L, Paraggio, P, Tomasi, F, Dozio, N, Scalambra, E, Mannucci, E, Lamanna, C, Cignarelli, M, Macchia, O, Fariello, S, Sorrentino, Mr, Franzetti, I, Radin, R, Annunziata, F, Bonabello, La, Durante, A, Dolcino, M, Gallo, F, Mazzucchelli, C, Aleo, A, Melga, P, Briatore, L, Maggi, D, Storace, D, Cecoli, F, D'Ugo, E, Pupillo, M, Baldassarre, Mpa, Salvati, F, Minnucci, A, De Luca, A, Zugaro, A, Santarelli, L, Bosco, A, Petrella, V, La Verghetta GG, De Gregorio, A, D'Andrea, S, Giuliani, Ae, Polidoro, Wl, Sperandio, A, Sciarretta, F, Pezzella, A, Carlone, A, Potenziani, S, Venditti, C, Foffi, C, Carbone, S, Cipolloni, L, Moretti, C, Leto, G, Serra, R, Petrachi, F, Romano, I, Lacaria, E, Russo, L, Goretti, C, Sannino, C, Dolci, M, Bruselli, L, Mori, Ml, Baccetti, F, Del Freo, M, Cucinotta, D, Giunta, L, Ruffo, Mc, Cannizzaro, D, Pintaudi, B, Perrone, G, Pata, P, Ragonese, F, Lettina, G, Mancuso, T, Coppolino, A, Piatti, Pm, Monti, L, Stuccillo, M, Lucotti, P, Setola, M, Crippa, Gv, Loi, C, Oldani, M, Bottalico, Ml, Pellegata, B, Bonomo, M, Menicatti, Lsm, Resi, V, Bertuzzi, F, Disoteo, Eo, Pizzi, G, Annuzzi, G, Capaldo, B, Nappo, R, Auciello, Sm, Turco, Aa, Costagliola, L, Corte, Gd, Vallefuoco, P, Nappi, F, Vitale, M, Cocozza, S, Ciano, O, Massimino, E, Garofalo, N, Avogaro, A, Guarneri, G, Fedele, D, Sartore, G, Chilelli, Nc, Burlina, S, Bonsembiante, B, Galluzzo, A, Torregrossa, V, Mancastroppa, G, Arsenio, L, Cioni, F, Caronna, S, Papi, M, Babini, M, Santeusanio, F, Calagreti, G, Timi, A, Tantucci, A, Marino, C, Ginestra, F, Di Biagio, R, Taraborelli, M, Miccoli, R, Bianchi, C, Garofolo, M, Politi, Ks, Penno, G, Livraga, S, Calzoni, F, Mancastroppa, Glf, Corsini, E, Tedeschi, A, Gaglianò, Ms, Ippolito, G, Salutini, E, Cervellino, F, Natale, M, Salvatore, V, Zampino, A, Sinisi, R, Arcangeli, A, Zogheri, A, Guizzotti, S, Longo, R, Di Bartolo, P, Pellicano, F, Scolozzi, P, Termine, S, Luberto, A, Ballardini, G, Trojani, C, Mazzuca, P, Bruglia, M, Ciamei, M, Genghini, S, Zannoni, C, Rangel, G, Salvi, L, Zappaterreno, A, Cordone, S, Simonelli, P, Meggiorini, M, Frasheri, A, Di Pippo, C, Maglio, C, Mazzitelli, G, Rinaldi, Me, Galli, A, Romano, M, D'Angelo, P, Suraci, C, Bacci, S, Palena, Ap, Genovese, S, Mancino, M, Rondinelli, M, Capone, F, Calabretto, E, Bulgheroni, M, Bucciarelli, L, Ceccarelli, E, Fondelli, C, Santacroce, C, Guarino, E, Nigi, L, Lalli, C, Di Vizia, G, Scarponi, M, Montani, V, Di Bernardino, P, Romagni, P, Dolcetti, K, Forte, E, Tamburo, L, Perin, Pc, Prinzis, T, Gruden, G, Bruno, G, Zucco, C, Perotta, M, Marena, S, Monsignore, S, Panero, F, Ponzi, F, Carpinteri, R, Casagrande, Ml, Coletti, Mf, Balini, A, Filopanti, M, Madaschi, S, Pulcina, A, Grimaldi, F, Venturini, G, Agus, S, Pagnutti, S, Guidotti, F, Cavarape, A, Cigolini, M, Pichiri, I, Brangani, C, Fainelli, G, Tomasetto, E, Zoppini, G, Galletti, A, Perrone, D, Capra, C, Bianchini, F, Ceseri, M, Di Nardo, B, Sasso, E, Bartolomei, B, Suliman, I, Fabbri, G, Romano, G, Maturo, N, Nunziata, G, Capobianco, G, De Simone, G, Villa, V, Rota, G, Pentangelo, C, Carbonara, O, Caiazzo, G, Cutolo, M, Sorrentino, T, Mastrilli, V, Amelia, U, Masi, S, Corigliano, G, Gaeta, I, Armentano, V, Calatola, P, Capuano, G, Angiulli, B, Auletta, P, Petraroli, E, Iodice, Ce, Agrusta, M., Vaccaro, Olga, Masulli, Maria, Nicolucci, Antonio, Bonora, Enzo, Del Prato, Stefano, Maggioni, Aldo P, Rivellese, Angela A, Squatrito, Sebastiano, Giorda, Carlo B, Sesti, Giorgio, Mocarelli, Paolo, Lucisano, Giuseppe, Sacco, Michele, Signorini, Stefano, Cappellini, Fabrizio, Perriello, Gabriele, Babini, Anna Carla, Lapolla, Annunziata, Gregori, Giovanna, Giordano, Carla, Corsi, Laura, Buzzetti, Raffaella, Clemente, Gennaro, Di Cianni, Graziano, Iannarelli, Rossella, Cordera, Renzo, La Macchia, Olga, Zamboni, Chiara, Scaranna, Cristiana, Boemi, Massimo, Iovine, Ciro, Lauro, Davide, Leotta, Sergio, Dall'Aglio, Elisabetta, Cannarsa, Emanuela, Tonutti, Laura, Pugliese, Giuseppe, Bossi, Antonio C, Anichini, Roberto, Dotta, Francesco, Di Benedetto, Antonino, Citro, Giuseppe, Antenucci, Daniela, Ricci, Lucia, Giorgino, Francesco, Santini, Costanza, Gnasso, Agostino, De Cosmo, Salvatore, Zavaroni, Donatella, Vedovato, Monica, Consoli, Agostino, Calabrese, Maria, Di Bartolo, Paolo, Fornengo, Paolo, Riccardi, Gabriele, Maggioni, Aldo Pietro, D'Angelo, Federica, Giansanti, Roberto, Tanase, Laura, Lanari, Luigi, Testa, Ivano, Pancani, Francesca, Ranchelli, Anna, Vagheggi, Paolo, Scatona, Alessia, Fontana, Lucia, Laviola, Luigi, Tarantino, Lucia, Ippolito, Claudia, Gigantelli, Vittoria, Manicone, Mariangela, Conte, Eleonora, Trevisan, Roberto, Rota, Rossella, Corsi, Anna, Dodesini, Alessandro R., Reggiani, Giulio Marchesini, Montesi, Luca, Mazzella, Natalia, Forlani, Gabriele, Caselli, Chiara, Di Luzio, Raffaella, Mazzotti, Arianna, Aiello, Antimo, Barrea, Angelina, Musto, Antonio, D'Amico, Fiorentina, Sinagra, Tiziana, Longhitano, Sara, Trowpea, Vanessa, Sparti, Maria, Italia, Salvatore, Lisi, Enrico, Grasso, Giuseppe, Pezzino, Vincenzo, Insalaco, Federica, Carallo, Claudio, Scicchitano, Caterina, De Franceschi, Maria Serena, Calbucci, Giovanni, Ripani, Raffaella, Cuneo, Giacomo, Corsi, Simona, Giorda, Carlo B., Romeo, Francesco, Lesina, Annalisa, Comoglio, Marco, Bonetto, Caterina, Robusto, Anna, Nada, Elisa, Asprino, Vincenzo, Cetraro, Rosa, Impieri, Michelina, Lucchese, Giuseppe, Donnarumma, Giovanna, Tizio, Biagio, Lenza, Lazzaro, Paraggio, Pia, Tomasi, Franco, Dozio, Nicoletta, Scalambra, Egle, Mannucci, Edoardo, Lamanna, Caterina, Cignarelli, Mauro, Macchia, Olga La, Fariello, Stefania, Sorrentino, Maria Rosaria, Franzetti, Ivano, Radin, Raffaella, Annunziata, Francesca, Bonabello, Laura Affinito, Durante, Arianna, Dolcino, Mara, Gallo, Fiorenza, Mazzucchelli, Chiara, Aleo, Anna, Melga, Pierluigi, Briatore, Lucia, Maggi, Davide, Storace, Daniela, Cecoli, Francesca, D'Ugo, Ercole, Pupillo, Mario, Baldassarre, Maria Pompea Antonia, Salvati, Filippo, Minnucci, Anita, De Luca, Angelo, Zugaro, Antonella, Santarelli, Livia, Bosco, Angela, Petrella, Vittorio, La Verghetta, Grazia Giovanna, De Gregorio, Antonella, D'Andrea, Settimio, Giuliani, Anna Elisa, Polidoro, W. Lorella, Sperandio, Alessandra, Sciarretta, Filomena, Pezzella, Alfonso, Carlone, Angela, Potenziani, Stella, Venditti, Chiara, Foffi, Chiara, Carbone, Salvatore, Cipolloni, Laura, Moretti, Chiara, Leto, Gaetano, Serra, Rosalia, Petrachi, Francesca, Romano, Isabella, Lacaria, Emilia, Russo, Laura, Goretti, Chiara, Sannino, Claudia, Dolci, Maria, Bruselli, Laura, Mori, Mary L., Baccetti, Fabio, Del Freo, Maria, Cucinotta, Domenico, Giunta, Loretta, Ruffo, Maria Concetta, Cannizzaro, Desiree, Pintaudi, Basilio, Perrone, Giovanni, Pata, Pietro, Ragonese, Francesco, Lettina, Gabriele, Mancuso, Teresa, Coppolino, Aldo, Piatti, Pier Marco, Monti, Lucilla, Stuccillo, Michela, Lucotti, Pietro, Setola, Manuela, Crippa, Giulia Valentina, Loi, Cinzia, Oldani, Matteo, Bottalico, Maria Luisa, Pellegata, Beatrice, Bonomo, Matteo, Menicatti, Laura Silvia Maria, Resi, Veronica, Bertuzzi, Federico, Disoteo, Eugenia Olga, Pizzi, Gianluigi, Rivellese, Angela Albarosa, Annuzzi, Giovanni, Capaldo, Brunella, Nappo, Rossella, Auciello, Stefania Michela, Turco, Anna Amelia, Costagliola, Lucia, Corte, Giuseppina Della, Vallefuoco, Pasquale, Nappi, Francesca, Vitale, Marilena, Cocozza, Sara, Ciano, Ornella, Massimino, Elena, Garofalo, Nadia, Avogaro, Angelo, Guarneri, Gabriella, Fedele, Domenico, Sartor, Giovanni, Chilelli, Nino Cristiano, Burlina, Silvia, Bonsembiante, Barbara, Galluzzo, Aldo, Torregrossa, Vittoria, Mancastroppa, Giovanni, Arsenio, Leone, Cioni, Federico, Caronna, Silvana, Papi, Matteo, Babini, Massimiliano, Santeusanio, Fausto, Calagreti, Gioia, Timi, Alessia, Tantucci, Alice, Marino, Cecilia, Ginestra, Federica, Di Biagio, Rosamaria, Taraborelli, Merilda, Miccoli, Roberto, Bianchi, Cristina, Garofolo, Monia, Politi, Konstantina Savina, Penno, Giuseppe, Livraga, Stefania, Calzoni, Fabio, Mancastroppa, Giovanni Luigi Francesco, Corsini, Elisa, Tedeschi, Anna, Gaglianã², Maria Sole, Ippolito, Giulio, Salutini, Elisabetta, Cervellino, Francesco, Natale, Maria, Salvatore, Vita, Zampino, Armando, Sinisi, Rosa, Arcangeli, Adolfo, Zogheri, Alessia, Guizzotti, Sandra, Longo, Rossella, Pellicano, Francesca, Scolozzi, Patrizia, Termine, Simona, Luberto, Alessandra, Ballardini, Giorgio, Trojani, Cristina, Mazzuca, Paolo, Bruglia, Matteo, Ciamei, Monica, Genghini, Silvia, Zannoni, Chiara, Vitale, Martina, Rangel, Graziela, Salvi, Laura, Zappaterreno, Alessandra, Cordone, Samantha, Simonelli, Paola, Meggiorini, Marilla, Frasheri, Aurora, Di Pippo, Clelia, Maglio, Cristina, Mazzitelli, Giulia, Rinaldi, Maria Elena, Galli, Angelica, Romano, Maria, D'Angelo, Paola, Suraci, Concetta, Bacci, Simonetta, Palena, Antonio Pio, Genovese, Stefano, Mancino, Monica, Rondinelli, Maurizio, Capone, Filippo, Calabretto, Elisabetta, Bulgheroni, Monica, Bucciarelli, Loredana, Ceccarelli, Elena, Fondelli, Cecilia, Santacroce, Clorinda, Guarino, Elisa, Nigi, Laura, Lalli, Carlo, Di Vizia, Giovanni, Scarponi, Maura, Montani, Valeria, Di Bernardino, Paolo, Romagni, Paola, Dolcetti, Katia, Forte, Elisa, Tamburo, Lucilla, Perin, Paolo Cavallo, Prinzis, Tania, Gruden, Gabriella, Bruno, Graziella, Zucco, Chiara, Perotta, Massimo, Marena, Saverio, Monsignore, Simona, Panero, Francesco, Ponzi, Fulvia, Bossi, Antonio Carlo, Carpinteri, Rita, Casagrande, Maria Linda, Coletti, Maria Francesca, Balini, Annalisa, Filopanti, Marcello, Madaschi, Sara, Pulcina, Anna, Grimaldi, Franco, Venturini, Giorgio, Agus, Sandra, Pagnutti, Stefania, Guidotti, Francesca, Cavarape, Alessandro, Cigolini, Massimo, Pichiri, Isabella, Brangani, Corinna, Fainelli, Giulia, Tomasetto, Elena, Zoppini, Giacomo, Galletti, Anna, Perrone, Dominica, Capra, Claudio, Bianchini, Francesca, Ceseri, Martina, Di Nardo, Barbara, Sasso, Elisa, Bartolomei, Barbara, Suliman, Irina, Fabbri, Gianna, Romano, Geremia, Maturo, Nicola, Nunziata, Giuseppe, Capobianco, Giuseppe, De Simone, Giuseppina, Villa, Valeria, Rota, Giuseppe, Pentangelo, Carmine, Carbonara, Ornella, Caiazzo, Gennaro, Cutolo, Michele, Sorrentino, Tommasina, Mastrilli, Valeria, Amelia, Umberto, Masi, Stefano, Corigliano, Gerardo, Gaeta, Iole, Armentano, Vincenzo, Calatola, Pasqualino, Capuano, Gelsomina, Angiulli, Bruno, Auletta, Pasquale, Petraroli, Ettore, Iodice, Cinzia E., Agrusta, Mariano, Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, A, Rivellese, A, Squatrito, S, Giorda, C, Sesti, G, Mocarelli, P, Lucisano, G, Sacco, M, Signorini, S, Cappellini, F, Perriello, G, Babini, A, Lapolla, A, Gregori, G, Giordano, C, Corsi, L, Buzzetti, R, Clemente, G, Di Cianni, G, Iannarelli, R, Cordera, R, La Macchia, O, Zamboni, C, Scaranna, C, Boemi, M, Iovine, C, Lauro, D, Leotta, S, Dall'Aglio, E, Cannarsa, E, Tonutti, L, Pugliese, G, Bossi, A, Anichini, R, Dotta, F, Di Benedetto, A, Citro, G, Antenucci, D, Ricci, L, Giorgino, F, Santini, C, Gnasso, A, De Cosmo, S, Zavaroni, D, Vedovato, M, Consoli, A, Calabrese, M, di Bartolo, P, Fornengo, P, Riccardi, G, D'Angelo, F, Giansanti, R, Tanase, L, Lanari, L, Testa, I, Pancani, F, Ranchelli, A, Vagheggi, P, Scatona, A, Fontana, L, Laviola, L, Tarantino, L, Ippolito, C, Gigantelli, V, Manicone, M, Conte, E, Trevisan, R, Rota, R, Dodesini, A, Reggiani, G, Montesi, L, Mazzella, N, Forlani, G, Caselli, C, Di Luzio, R, Mazzotti, A, Aiello, A, Barrea, A, Musto, A, D'Amico, F, Sinagra, T, Longhitano, S, Trowpea, V, Sparti, M, Italia, S, Lisi, E, Grasso, G, Pezzino, V, Insalaco, F, Carallo, C, Scicchitano, C, De Franceschi, M, Calbucci, G, Ripani, R, Cuneo, G, Corsi, S, Romeo, F, Lesina, A, Comoglio, M, Bonetto, C, Robusto, A, Nada, E, Asprino, V, Cetraro, R, Impieri, M, Lucchese, G, Donnarumma, G, Tizio, B, Lenza, L, Paraggio, P, Tomasi, F, Dozio, N, Scalambra, E, Mannucci, E, Lamanna, C, Cignarelli, M, Macchia, O, Fariello, S, Sorrentino, M, Franzetti, I, Radin, R, Annunziata, F, Bonabello, L, Durante, A, Dolcino, M, Gallo, F, Mazzucchelli, C, Aleo, A, Melga, P, Briatore, L, Maggi, D, Storace, D, Cecoli, F, D'Ugo, E, Pupillo, M, Baldassarre, M, Salvati, F, Minnucci, A, De Luca, A, Zugaro, A, Santarelli, L, Bosco, A, Petrella, V, La Verghetta, G, D'Andrea, S, Giuliani, A, Polidoro, W, Sperandio, A, Sciarretta, F, Pezzella, A, Carlone, A, Potenziani, S, Venditti, C, Foffi, C, Carbone, S, Cipolloni, L, Moretti, C, Leto, G, Serra, R, Petrachi, F, Romano, I, Lacaria, E, Russo, L, Goretti, C, Sannino, C, Dolci, M, Bruselli, L, Mori, M, Baccetti, F, Del Freo, M, Cucinotta, D, Giunta, L, Ruffo, M, Cannizzaro, D, Pintaudi, B, Perrone, G, Pata, P, Ragonese, F, Lettina, G, Mancuso, T, Coppolino, A, Piatti, P, Monti, L, Stuccillo, M, Lucotti, P, Setola, M, Crippa, G, Loi, C, Oldani, M, Bottalico, M, Pellegata, B, Bonomo, M, Menicatti, L, Resi, V, Bertuzzi, F, Disoteo, E, Pizzi, G, Annuzzi, G, Capaldo, B, Nappo, R, Auciello, S, Turco, A, Costagliola, L, Corte, G, Vallefuoco, P, Nappi, F, Vitale, M, Cocozza, S, Ciano, O, Massimino, E, Garofalo, N, Avogaro, A, Guarneri, G, Fedele, D, Sartore, G, Chilelli, N, Burlina, S, Bonsembiante, B, Galluzzo, A, Torregrossa, V, Mancastroppa, G, Arsenio, L, Cioni, F, Caronna, S, Papi, M, Santeusanio, F, Calagreti, G, Timi, A, Tantucci, A, Marino, C, Ginestra, F, Di Biagio, R, Taraborelli, M, Miccoli, R, Bianchi, C, Garofolo, M, Politi, K, Penno, G, Livraga, S, Calzoni, F, Corsini, E, Tedeschi, A, Gagliano, M, Ippolito, G, Salutini, E, Cervellino, F, Natale, M, Salvatore, V, Zampino, A, Sinisi, R, Arcangeli, A, Zogheri, A, Guizzotti, S, Longo, R, Pellicano, F, Scolozzi, P, Termine, S, Luberto, A, Ballardini, G, Trojani, C, Mazzuca, P, Bruglia, M, Ciamei, M, Genghini, S, Zannoni, C, Rangel, G, Salvi, L, Zappaterreno, A, Cordone, S, Simonelli, P, Meggiorini, M, Frasheri, A, Di Pippo, C, Maglio, C, Mazzitelli, G, Rinaldi, M, Galli, A, Romano, M, D'Angelo, P, Suraci, C, Bacci, S, Palena, A, Genovese, S, Mancino, M, Rondinelli, M, Capone, F, Calabretto, E, Bulgheroni, M, Bucciarelli, L, Ceccarelli, E, Fondelli, C, Santacroce, C, Guarino, E, Nigi, L, Lalli, C, Di Vizia, G, Scarponi, M, Montani, V, Di Bernardino, P, Romagni, P, Dolcetti, K, Forte, E, Tamburo, L, Perin, P, Prinzis, T, Gruden, G, Bruno, G, Zucco, C, Perotta, M, Marena, S, Monsignore, S, Panero, F, Ponzi, F, Carpinteri, R, Casagrande, M, Coletti, M, Balini, A, Filopanti, M, Madaschi, S, Pulcina, A, Grimaldi, F, Venturini, G, Agus, S, Pagnutti, S, Guidotti, F, Cavarape, A, Cigolini, M, Pichiri, I, Brangani, C, Fainelli, G, Tomasetto, E, Zoppini, G, Galletti, A, Perrone, D, Capra, C, Bianchini, F, Ceseri, M, Di Nardo, B, Sasso, E, Bartolomei, B, Suliman, I, Fabbri, G, Romano, G, Maturo, N, Nunziata, G, Capobianco, G, De Simone, G, Villa, V, Rota, G, Pentangelo, C, Carbonara, O, Caiazzo, G, Cutolo, M, Sorrentino, T, Mastrilli, V, Amelia, U, Masi, S, Corigliano, G, Gaeta, I, Armentano, V, Calatola, P, Capuano, G, Angiulli, B, Auletta, P, Petraroli, E, Iodice, C, Agrusta, M, di Bartolo, Paolo, Polidoro, w Lorella, Sartore, Giovanni, and Gaglianò, Maria Sole

Subjects
Male, Diabetes and Metabolism, ipoglycemic drugs, cardiovascualr event, Settore MED/09 - Medicina Interna, endocrine system diseases, IMPACT, pioglitazone versus sulfonylureas, Endocrinology, Diabetes and Metabolism, GLIMEPIRIDE, Diabetes, cardiovascular events, metformin, pioglitazone, sulphonylureas, Type 2 diabetes, 030204 cardiovascular system & hematology, Internal Medicine, Endocrinology, law.invention, Settore MED/13 - Endocrinologia, Glibenclamide, 0302 clinical medicine, Randomized controlled trial, law, GLYCEMIC CONTROL, Gliclazide, Internal medicine, diabetes and metabolism, RISK, education.field_of_study, diabetes, Incidence, endocrinology, diabetes and metabolism, endocrinology, Middle Aged, INSULIN, Metformin, Treatment Outcome, Editorial, sulphonylureas, Cardiovascular Diseases, Combination, Drug Therapy, Combination, Female, Type 2, medicine.drug, medicine.medical_specialty, Population, 030209 endocrinology & metabolism, Aged, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Pioglitazone, Sulfonylurea Compounds, Thiazolidinediones, Cardiovascular events, 03 medical and health sciences, GLUCOSE-LOWERING DRUGS, Drug Therapy, Diabetes Mellitus, medicine, sulfonylureas, education, TOSCA.IT, business.industry, MORTALITY, nutritional and metabolic diseases, Insulin resistance, medicine.disease, Surgery, Glimepiride, business, FOLLOW-UP
Abstract

Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p

Published
2017
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4. APP-dependent alteration of GSK3β activity impairs neurogenesis in the Ts65Dn mouse model of Down syndrome

Author

Elisabetta Ciani, Claudia Fuchs, Valentina Maria Mitrugno, Stefania Trazzi, Marianna De Franceschi, Renata Bartesaghi, Trazzi S, Fuchs C, De Franceschi M, Mitrugno VM, Bartesaghi R, and Ciani E

Subjects
Agonist, medicine.drug_class, Neurogenesis, Mice, Transgenic, Cell fate determination, Biology, lcsh:RC321-571, Amyloid beta-Protein Precursor, Glycogen Synthase Kinase 3, Mice, Fetus, Neural Stem Cells, Precursor cell, medicine, Animals, Humans, Neurogenesis impairment, 5-HT1A receptor, Phosphorylation, Receptor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 5-HT receptor, Cell Proliferation, AICD, Glycogen Synthase Kinase 3 beta, GSK3β, Brain, Disease Models, Animal, Neurology, Female, Down Syndrome, APP, Neuroscience
Abstract

Intellectual disability in Down syndrome (DS) appears to be related to severe neurogenesis impairment during brain development. The molecular mechanisms underlying this defect are still largely unknown. Accumulating evidence has highlighted the importance of GSK3β signaling for neuronal precursor proliferation/differentiation. In neural precursor cells (NPCs) from Ts65Dn mice and human fetuses with DS, we found reduced GSK3β phosphorylation and, hence, increased GSK3β activity. In cultures of trisomic subventricular-zone-derived adult NPCs (aNPCs) we found that deregulation of GSK3β activity was due to higher levels of the AICD fragment of the trisomic gene APP that directly bound to GSK3β. We restored GSK3β phosphorylation in trisomic aNPCs using either lithium, a well-known GSK3β inhibitor, or using a 5-HT receptor agonist or fluoxetine, which activated the serotonin receptor 5-HT1A. Importantly, this effect was accompanied by restoration of proliferation, cell fate specification and neuronal maturation. In agreement with results obtained in vitro, we found that early treatment with fluoxetine, which was previously shown to rescue neurogenesis and behavior in Ts65Dn mice, restored GSK3β phosphorylation. These results provide a link between GSK3β activity alteration, APP triplication and the defective neuronal production that characterizes the DS brain. Knowledge of the molecular mechanisms underlying neurogenesis alterations in DS may help to devise therapeutic strategies, potentially usable in humans. Results suggest that drugs that increase GSK3β phosphorylation, such as lithium or fluoxetine, may represent useful tools for the improvement of neurogenesis in DS.

Published
2013

5. Blood urea impairs brachial artery flow mediated dilation

Author

Tripolino, C., Irace, C., Carallo, C., Franceschi, M. S., Elisabetta DELLA VALLE, Gnasso, A., Tripolino, C, Irace, C, Carallo, C, De Franceschi, M, DELLA VALLE, Elisabetta, and Gnasso, A.

Subjects
Adult, Male, Brachial Artery, Cholesterol, HDL, Middle Aged, Vasodilation, Cross-Sectional Studies, Risk Factors, Creatinine, Humans, Kidney Failure, Chronic, Regression Analysis, Urea, Female, Endothelium, Vascular, Biomarkers, Aged, Glomerular Filtration Rate
Abstract

Urea, the main product of protein catabolism, is a biochemical marker of renal function. Though it is known that serum urea impairs vascular health, the relationship between its concentration and vascular reactivity in vivo has not been explored. Our study was undertaken to investigate possible association between serum urea and endothelial function in subjects without chronic kidney disease (CKD).Eighty free-living subjects with serum creatinine ≤1 mg/dL and without CKD were enrolled for the present study. Serum analyses and evaluation of endothelial function were performed in all subjects. Endothelial function was measured using the flow-mediated dilation (FMD) technique. Simple and multiple regression analyses were used to test the association between FMD and considered variables.In correlation analyses FMD was found directly associated with HDL cholesterol (r=0.21; P=0.05) and eGFR (r=0.25; P=0.02) and inversely associated with age (r=-0.26; P=0.02), serum urea (r=-0.37; P0.01), serum creatinine (r=-0.31; P0.01) and brachial artery baseline diameter (r=-0.41; P0.01). In multiple regression analysis only baseline artery diameter and serum urea predicted FMD; age, gender and cardiovascular risk factors did not relate with FMD.Our study demonstrates the association between serum urea and FMD, suggesting that the accumulation of waste products of protein metabolism may impair vascular health in subjects without CKD.

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