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1. Primary cilia sense glutamine availability and respond via asparagine synthetase.

Author

Steidl, M.E., Nigro, E.A., Nielsen, A.K.S., Pagliarini, R., Cassina, L., Lampis, M., Podrini, C., Chiaravalli, M., Mannella, V., Distefano, G., Yang, M., Aslanyan, M.G., Musco, G., Roepman, R., Frezza, C., Boletta, A., Steidl, M.E., Nigro, E.A., Nielsen, A.K.S., Pagliarini, R., Cassina, L., Lampis, M., Podrini, C., Chiaravalli, M., Mannella, V., Distefano, G., Yang, M., Aslanyan, M.G., Musco, G., Roepman, R., Frezza, C., and Boletta, A.

Abstract

Item does not contain fulltext, Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.

Published
2023

10. Glycyrrhizin binds to High Mobility Group Box 1 protein (HMGB1) and inhibits its cytokine activities

Author

MOLLICA L, DE MARCHIS F, SPITALERI A, DALLACOSTA C, PENNACCHINI D, ZAMAI M, AGRESTI A, TRISCIUOGLIO L, MUSCO G, BIANCHI M, Mollica, L, DE MARCHIS, F, Spitaleri, A, Dallacosta, C, Pennacchini, D, Zamai, M, Agresti, A, Trisciuoglio, L, Musco, G, and Bianchi, M

Abstract

High-mobility group box 1 protein (HMGB1) is anuclear component, but extracellularly it servesas a signaling molecule involved in acute andchronic inflammation, for example in sepsisand arthritis. The identification of HMGB1 inhibitorsis therefore of significant experimental andclinical interest. We show that glycyrrhizin, anatural anti-inflammatory and antiviral triterpenein clinical use, inhibits HMGB1 chemoattractantand mitogenic activities, and has aweak inhibitory effect on its intranuclear DNAbindingfunction. NMR and fluorescence studiesindicate that glycyrrhizin binds directly toHMGB1 (Kd 150 mM), interacting with twoshallow concave surfaces formed by the twoarms of both HMG boxes. Our results explainin part the anti-inflammatory properties of glycyrrhizin,and might direct the design of newderivatives with improved HMGB1-bindingproperties.

Published
2007

12. Nizp1-C2HR zinc finger structure

Author

Berardi, A., primary, Quilici, G., additional, Spiliotopoulos, D., additional, Corral-Rodriguez, M., additional, Martin, F., additional, Degano, M., additional, Tonon, G., additional, and Musco, G., additional

Published
2016
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14. An immunoglobulin-like fold in a major plant allergen: The solution structure of Phl p 2 from timothy grass pollen

Author

De Marino, Castiglione Morelli M.A., Fraternali F., Tamborini E., Musco G., Vrtala S., Dolecek C., Arosio P., Valenta R., Pastore A, De, Marino, Castiglione Morelli, M. A., Fraternali, F., Tamborini, E., Musco, G., Vrtala, S., Dolecek, C., Arosio, P., Valenta, R., and Pastore, A

Subjects
immunology, otorhinolaryngologic diseases, food and beverages, structure, allergy, immunoglobulin, NMR
Abstract

BACKGROUND: Grass pollen allergens are the most important and widespread elicitors of pollen allergy. One of the major plant allergens which millions of people worldwide are sensitized to is Phl p 2, a small protein from timothy grass pollen. Phl p 2 is representative of the large family of cross-reacting plant allergens classified as group 2/3. Recombinant Phl p 2 has been demonstrated by immunological cross-reactivity studies to be immunologically equivalent to the natural protein. RESULTS: We have solved the solution structure of recombinant Phl p 2 by means of nuclear magnetic resonance techniques. The three-dimensional structure of Phl p 2 consists of an all-beta fold with nine antiparallel beta strands that form a beta sandwich. The topology is that of an immunoglobulin-like fold with the addition of a C-terminal strand, as found in the C2 domain superfamily. Lack of functional and sequence similarity with these two families, however, suggests an independent evolution of Phl p 2 and other homologous plant allergens. CONCLUSIONS: Because of the high homology with other plant allergens of groups 1 and 2/3, the structure of Phl p 2 can be used to rationalize some of the immunological properties of the whole family. On the basis of the structure, we suggest possible sites of interaction with IgE antibodies. Knowledge of the Phl p 2 structure may assist the rational structure-based design of synthetic vaccines against grass pollen allergy.

Published
1999

20. RANDOMIZED CONTROLLED TRIAL OF STREPTOKINASE, ASPIRIN, AND COMBINATION OF BOTH IN TREATMENT OF ACUTE ISCHEMIC STROKE

Author

CANDELISE L, ARITZU E, CICCONE A, RICCI S, WARDLAW J, TOGNONI G, RONCAGLIONI MC, NEGRI E, COLOMBO F, BOCCARDI E, DEGRANDI C, SCIALFA G, ARGENTINO C, BERTELE V, MAGGIONI AP, PERRONE P, BARNETT HJM, BOGOUSSLAVSKY J, DELFAVERO A, LOI U, PETO R, WARLOW C, CANZI S, COMPARETTI S, CLERICI F, PALUMBO A, SGARONI G, POLONARA S, REGINELLI R, CERAVOLO MG, PROVINCIALI L, DELGOBBO M, SCARPINO O, BOTTACCHI E, DALESSANDRO G, DIGIOVANNI M, BLANC S, ROVEYAZ L, RALLI L, VANNI D, REFI C, FEDERICO F, CONTE C, INCHINGOLO V, INSABATO R, SALSA F, LORIZIO A, ROTTOLI MR, BRUNI L, DEFANTI CA, FERA L, CAMERLINGO M, CASTO L, CENSORI B, MAMOLI A, PORAZZI D, GRAMPA G, LASPINA I, GIGLIA L, AVENIA V, GUELI S, LOLLI V, MIELE V, SANTANGELO M, COPPOLA G, TRIANNI G, MARRA M, GRECO E, TONTI D, PRETOLANI E, STELLIO M, ARNABOLDI M, CIOLA R, DANIELI G, REZZONICO M, GUIDOTTI M, PELLEGRINI G, RAUDINO F, DELFAVERO C, FRATTINI T, RICCARDI T, LEVIMINZI C, LOCATELLI F, PASSERI F, LOMBARDO G, COCCO F, PRATESI M, SANTINI S, CARDOPATRI F, TAFANI O, LANDINI GC, PIERAGNOLI E, BELLESI R, BAGNOLI L, GHETTI A, MARRAZZA OB, MENEGAZZO P, SPOLVERI S, CAPPELLETTI C, CANDELIERE G, COSTANTINO G, DACUNO F, LOMUZIO T, RIZZITELLI FP, BOVIO G, GRILLI GP, ZOCCHI M, MAZZANTI I, PISAPIA G, NUZZI R, RUSSO G, LAMA G, BALDASSARRI G, BETTINI R, CANI E, CERIOLI E, DEGIORGI M, GARAGNANI A, PASQUALI S, CHIOMA V, FINI C, MARZARA G, BALOTTA A, BERTUZZI D, MASINA M, MATACENA C, MICHELINI M, PIRAZZOLI G, SACCHET C, MAROTTA P, CALVI L, SCACCABAROZZI C, MENOZZI C, SASANELLI F, BASCELLI C, PONTRELLI V, SCHIERONI F, BELVEDERE D, DECAPITANI E, DICOSTANZO M, RASCAROLI M, CITTERIO O, MILANI R, CAPIALBI R, ARENA G, MUSOLINO R, DIPERRI R, BONAVENTI C, FINZI F, MESSINA A, ROMANAZZI V, STERZI R, BOTTINI G, SANTILLI I, BRUCATO A, DEJULI E, PALMIERI G, RAGAINI S, THIELLA G, ALLI C, CAROSELLA L, RIZZATO G, BIANCHI M, MOTTO C, PINARDI G, SCARLATO G, BETTINELLI A, PORRO F, RANDAZZO A, MARINI U, LATTUADA P, PIETRA A, FRANCESCHI M, VOLOUTE MA, MALFERRARI G, BONDI M, GARUTI W, MELINI L, COLOMBO A, ALBORINI G, PANZETTI P, SCARPA M, SORGATO P, CRISI G, BONASERA N, BASSO F, NATALI E, MONACO P, GASPARRO AM, TRIOLO F, LECHI A, COLONNA F, DASCOLA I, GIORGI C, SCODITTI U, BASSI P, MENOZZI R, PIAZZA P, DEGLIANTONI G, DESIMONI M, GIANNINI A, MICILI G, BOSONE D, CAVALLINI A, MARTELLI A, BARZIZZA F, POLI M, BIAGINI S, CAPOCCHI G, CELANI MG, PICCHIARELLI A, RIGHETTI E, ZAMPOLINI M, CAPUTO N, BARTOLINI S, SANTONI M, SITA D, TAGLIOLI M, VOLPI G, ROSSI F, ALOY F, CASTELLANO AE, MINOTTA F, GATTA A, VINATTIERI A, CANTINI A, REBUCCI GG, BISSI G, DEBLASI F, PASCARELLI E, TURIAMO F, GUIDETTI D, BARATTI M, FERRARINI G, GHIDONI E, GRECO G, MARCELLO N, MOTTI L, SOLIME F, TERENZIANI S, ZUCCO R, TROISO A, VENEZIANI M, IORI I, CURATOLA L, BOLLETTINI G, CARBONI T, GOBBATO R, INFRICCIOLO P, SABATINI D, SFRAPPINI M, FANCELLU A, CASU G, DELEDDA MG, SPANU MA, PIRISI A, MARRAS FA, ROSATI G, BRAMBILLA A, ERLI GC, FELICE B, GRANDI R, MIRABILE D, ZADRA M, CAVESTRI R, GORI D, LONGHINI E, MIELE N, DIVIZIA G, GRASSELLI S, PEZZELLA F, ZUCCARI F, SALLUSTO L, LINCESSO F, SCARPATI C, IANNONE G, BARTOCCI A, COSTANTINI F, DESANTIS L, LANCIA G, MOSCHINI E, PACI A, SENSIDONI A, TRENTA A, BARTOLINI N, OTTAVIANO P, BISCOTTINI B, ALUNNI G, BARTOLINI I, BELLADONNA D, BOCCALI A, CRUCIANI M, IBBA R, LUCCIOLI R, MARCECA A, PACINI M, PALLONE M, GIRARDI P, ORRICO D, LANZA E, BALLINI A, GRANDI FC, MUSCO G, STEIDL L, SANTORO G, VEMCO A, DUDINE P, MILONE FF, MUNARI L, PERRETI A, PORTA M, LONGONI C, FERANI R, WATT M, SANDERCOCK P, FENNETRY A, BANNISTER P, CLARKE CE, BAMFORD J, VENABLES G, CORREIA M, CANDELISE L, ARITZU E, CICCONE A, RICCI S, WARDLAW J, TOGNONI G, RONCAGLIONI MC, NEGRI E, COLOMBO F, BOCCARDI E, DEGRANDI C, SCIALFA G, ARGENTINO C, BERTELE V, MAGGIONI AP, PERRONE P, BARNETT HJM, BOGOUSSLAVSKY J, DELFAVERO A, LOI U, PETO R, WARLOW C, CANZI S, COMPARETTI S, CLERICI F, PALUMBO A, SGARONI G, POLONARA S, REGINELLI R, CERAVOLO MG, PROVINCIALI L, DELGOBBO M, SCARPINO O, BOTTACCHI E, DALESSANDRO G, DIGIOVANNI M, BLANC S, ROVEYAZ L, RALLI L, VANNI D, REFI C, FEDERICO F, CONTE C, INCHINGOLO V, INSABATO R, SALSA F, LORIZIO A, ROTTOLI MR, BRUNI L, DEFANTI CA, FERA L, CAMERLINGO M, CASTO L, CENSORI B, MAMOLI A, PORAZZI D, GRAMPA G, LASPINA I, GIGLIA L, AVENIA V, GUELI S, LOLLI V, MIELE V, SANTANGELO M, COPPOLA G, TRIANNI G, MARRA M, GRECO E, TONTI D, PRETOLANI E, STELLIO M, ARNABOLDI M, CIOLA R, DANIELI G, REZZONICO M, GUIDOTTI M, PELLEGRINI G, RAUDINO F, DELFAVERO C, FRATTINI T, RICCARDI T, LEVIMINZI C, LOCATELLI F, PASSERI F, LOMBARDO G, COCCO F, PRATESI M, SANTINI S, CARDOPATRI F, TAFANI O, LANDINI GC, PIERAGNOLI E, BELLESI R, BAGNOLI L, GHETTI A, MARRAZZA OB, MENEGAZZO P, SPOLVERI S, CAPPELLETTI C, CANDELIERE G, COSTANTINO G, DACUNO F, LOMUZIO T, RIZZITELLI FP, BOVIO G, GRILLI GP, ZOCCHI M, MAZZANTI I, PISAPIA G, NUZZI R, RUSSO G, LAMA G, BALDASSARRI G, BETTINI R, CANI E, CERIOLI E, DEGIORGI M, GARAGNANI A, PASQUALI S, CHIOMA V, FINI C, MARZARA G, BALOTTA A, BERTUZZI D, MASINA M, MATACENA C, MICHELINI M, PIRAZZOLI G, SACCHET C, MAROTTA P, CALVI L, SCACCABAROZZI C, MENOZZI C, SASANELLI F, BASCELLI C, PONTRELLI V, SCHIERONI F, BELVEDERE D, DECAPITANI E, DICOSTANZO M, RASCAROLI M, CITTERIO O, MILANI R, CAPIALBI R, ARENA G, MUSOLINO R, DIPERRI R, BONAVENTI C, FINZI F, MESSINA A, ROMANAZZI V, STERZI R, BOTTINI G, SANTILLI I, BRUCATO A, DEJULI E, PALMIERI G, RAGAINI S, THIELLA G, ALLI C, CAROSELLA L, RIZZATO G, BIANCHI M, MOTTO C, PINARDI G, SCARLATO G, BETTINELLI A, PORRO F, RANDAZZO A, MARINI U, LATTUADA P, PIETRA A, FRANCESCHI M, VOLOUTE MA, MALFERRARI G, BONDI M, GARUTI W, MELINI L, COLOMBO A, ALBORINI G, PANZETTI P, SCARPA M, SORGATO P, CRISI G, BONASERA N, BASSO F, NATALI E, MONACO P, GASPARRO AM, TRIOLO F, LECHI A, COLONNA F, DASCOLA I, GIORGI C, SCODITTI U, BASSI P, MENOZZI R, PIAZZA P, DEGLIANTONI G, DESIMONI M, GIANNINI A, MICILI G, BOSONE D, CAVALLINI A, MARTELLI A, BARZIZZA F, POLI M, BIAGINI S, CAPOCCHI G, CELANI MG, PICCHIARELLI A, RIGHETTI E, ZAMPOLINI M, CAPUTO N, BARTOLINI S, SANTONI M, SITA D, TAGLIOLI M, VOLPI G, ROSSI F, ALOY F, CASTELLANO AE, MINOTTA F, GATTA A, VINATTIERI A, CANTINI A, REBUCCI GG, BISSI G, DEBLASI F, PASCARELLI E, TURIAMO F, GUIDETTI D, BARATTI M, FERRARINI G, GHIDONI E, GRECO G, MARCELLO N, MOTTI L, SOLIME F, TERENZIANI S, ZUCCO R, TROISO A, VENEZIANI M, IORI I, CURATOLA L, BOLLETTINI G, CARBONI T, GOBBATO R, INFRICCIOLO P, SABATINI D, SFRAPPINI M, FANCELLU A, CASU G, DELEDDA MG, SPANU MA, PIRISI A, MARRAS FA, ROSATI G, BRAMBILLA A, ERLI GC, FELICE B, GRANDI R, MIRABILE D, ZADRA M, CAVESTRI R, GORI D, LONGHINI E, MIELE N, DIVIZIA G, GRASSELLI S, PEZZELLA F, ZUCCARI F, SALLUSTO L, LINCESSO F, SCARPATI C, IANNONE G, BARTOCCI A, COSTANTINI F, DESANTIS L, LANCIA G, MOSCHINI E, PACI A, SENSIDONI A, TRENTA A, BARTOLINI N, OTTAVIANO P, BISCOTTINI B, ALUNNI G, BARTOLINI I, BELLADONNA D, BOCCALI A, CRUCIANI M, IBBA R, LUCCIOLI R, MARCECA A, PACINI M, PALLONE M, GIRARDI P, ORRICO D, LANZA E, BALLINI A, GRANDI FC, MUSCO G, STEIDL L, SANTORO G, VEMCO A, DUDINE P, MILONE FF, MUNARI L, PERRETI A, PORTA M, LONGONI C, FERANI R, WATT M, SANDERCOCK P, FENNETRY A, BANNISTER P, CLARKE CE, BAMFORD J, VENABLES G, and CORREIA M

Abstract

In ischaemic stroke, thrombolytic drugs speed the recanalisation of intracerebral arteries. The effects of aspirin are not known. A trial was conducted to determine whether, separately or together, streptokinase and aspirin have clinical benefits in acute ischaemic stroke similar to those in acute myocardial infarction. 622 patients with acute ischaemic stroke within 6 hours of symptom onset were randomised with a 2x2 factorial design to (i) a 1-hour intravenous infusion of 1 . 5 MU streptokinase, (ii) 300 mg/day buffered aspirin for 10 days, (iii) both active treatments, or (iv) neither. Early results raised a question whether the trial should be continued. Streptokinase (alone or with aspirin) was associated with an excess of 10-day case fatality (odds ratio 2 . 7; 95% confidence interval 1 . 7-4 . 3; 2p

Published
1995

21. NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease

Author

Bottomley, M., Stier, G., Pennacchini, D., Legube, G., Simon, B., Akhtar, A., Sattler, M., and Musco, G.

Abstract

Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal recessively inherited disease: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers. The first PHD finger of AIRE1 is a mutational hot spot, to which several pathological point mutations have been mapped. Using heteronuclear NMR spectroscopy, we determined the solution structure of the first PHD finger of AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the domain. We performed a conformational analysis of pathological AIRE1-PHD1 mutants that allowed us to rationalize the structural impact of APECED-causing mutations and to identify an interaction site with putative protein ligands of the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD finger fold, with a highly conserved tryptophan buried inside the structure. The PHD finger is stabilized by two zinc ions coordinated in an interleaved (cross-brace) scheme. This zinc coordination resembles RING finger domains, which can function as E3 ligases in the ubiquitination pathway. Based on this fold similarity, it has been suggested that PHD fingers might also function as E3 ligases, although this hypothesis is controversial. At variance to a previous report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3 ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1 and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure is clearly distinct from the RING finger fold. Our results point to a function of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in some APECED mutations.

Published
2005

23. An easy way to include weak alignment constraints into NMR structure calculations

Author

Sass, H. J., Musco, G., Stahl, S. J., Wingfield, P. T., and Grzesiek, S.

Abstract

We have recently shown that an energy penalty for the incorporation of residual tensorial constraints into molecular structure calculations can be formulated without the explicit knowledge of the Saupe orientation tensor (Moltke and Grzesiek. J. Biomol. NMR, 1999, 15, 77-82). Here we report the implementation of such an algorithm into the program X-PLOR. The new algorithm is easy to use and has good convergence properties. The algorithm is used for the structure refinement of the HIV-1 Nef protein using 252 dipolar coupling restraints. The approach is compared to the conventional penalty function with explicit knowledge of the orientation tensor's amplitude and rhombicity. No significant differences are found with respect to speed, Ramachandran core quality or coordinate precision.

Published
2001
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24. Solution NMR of proteins within polyacrylamide gels : diffusional properties and residual alignment by mechanical stress or embedding of oriented purple membranes

Author

Sass, H. J., Musco, G., Stahl, S. J., Wingfield, P. T., and Grzesiek, S.

Abstract

The diffusive properties of biomacromolecules within the aqueous phase of polyacrylamide gels are described. High quality NMR spectra can be obtained under such conditions. As compared to water, a fivefold reduction in the translational diffusion constant, but only a 1.6-fold decrease (1.4-fold increase) in amide-15N T2 (T1) are observed for human ubiquitin within a 10% acrylamide gel. Weak alignment of the solute macromolecules can be achieved within such gels by vertical or radial compression or by the embedding of magnetically oriented purple membrane fragments. The methods are applied to deriveresidual dipolar couplings for human HIV-1 Nef and ubiquitin.

Published
2000
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25. Assignment of the 1H, 15N, and 13C resonances of the C-terminal domain of frataxin, the protein responsible for Friedreich ataxia

Author

Musco, G., de Tommasi, T., Stier, G., Kolmerer, B., Bottomley, M., Adinolfi, S., Muskett, F., Gibson, T., Frenkiel, T., and Pastore, A.

Subjects
Carbon Isotopes, Magnetic Resonance Spectroscopy, Nitrogen Isotopes, ataxia, mitochondrial protein, Phosphotransferases (Alcohol Group Acceptor), neurodegenerative disease, Friedreich Ataxia, Iron-Binding Proteins, Humans, Amino Acid Sequence, structure, ataxia, mitochondrial protein, neurodegenerative disease, structure, Hydrogen
Published
1999

29. RANDOMIZED CONTROLLED TRIAL OF STREPTOKINASE, ASPIRIN, AND COMBINATION OF BOTH IN TREATMENT OF ACUTE ISCHEMIC STROKE

Author

CANDELISE, L, ARITZU, E, CICCONE, A, RICCI, S, WARDLAW, J, TOGNONI, G, RONCAGLIONI, M, NEGRI, E, COLOMBO, F, BOCCARDI, E, DEGRANDI, C, SCIALFA, G, ARGENTINO, C, BERTELE, V, MAGGIONI, A, PERRONE, P, BARNETT, H, BOGOUSSLAVSKY, J, DELFAVERO, A, LOI, U, PETO, R, WARLOW, C, CANZI, S, COMPARETTI, S, CLERICI, F, PALUMBO, A, SGARONI, G, POLONARA, S, REGINELLI, R, CERAVOLO, M, PROVINCIALI, L, DELGOBBO, M, SCARPINO, O, BOTTACCHI, E, DALESSANDRO, G, DIGIOVANNI, M, BLANC, S, ROVEYAZ, L, RALLI, L, VANNI, D, REFI, C, FEDERICO, F, CONTE, C, INCHINGOLO, V, INSABATO, R, SALSA, F, LORIZIO, A, ROTTOLI, M, BRUNI, L, DEFANTI, C, FERA, L, CAMERLINGO, M, CASTO, L, CENSORI, B, MAMOLI, A, PORAZZI, D, GRAMPA, G, LASPINA, I, GIGLIA, L, AVENIA, V, GUELI, S, LOLLI, V, MIELE, V, SANTANGELO, M, COPPOLA, G, TRIANNI, G, MARRA, M, GRECO, E, TONTI, D, PRETOLANI, E, STELLIO, M, ARNABOLDI, M, CIOLA, R, DANIELI, G, REZZONICO, M, GUIDOTTI, M, PELLEGRINI, G, RAUDINO, F, DELFAVERO, C, FRATTINI, T, RICCARDI, T, LEVIMINZI, C, LOCATELLI, F, PASSERI, F, LOMBARDO, G, COCCO, F, PRATESI, M, SANTINI, S, CARDOPATRI, F, TAFANI, O, LANDINI, G, PIERAGNOLI, E, BELLESI, R, BAGNOLI, L, GHETTI, A, MARRAZZA, O, MENEGAZZO, P, SPOLVERI, S, CAPPELLETTI, C, CANDELIERE, G, COSTANTINO, G, DACUNO, F, LOMUZIO, T, RIZZITELLI, F, BOVIO, G, GRILLI, G, ZOCCHI, M, MAZZANTI, I, PISAPIA, G, NUZZI, R, RUSSO, G, LAMA, G, BALDASSARRI, G, BETTINI, R, CANI, E, CERIOLI, E, DEGIORGI, M, GARAGNANI, A, PASQUALI, S, CHIOMA, V, FINI, C, MARZARA, G, BALOTTA, A, BERTUZZI, D, MASINA, M, MATACENA, C, MICHELINI, M, PIRAZZOLI, G, SACCHET, C, MAROTTA, P, CALVI, L, SCACCABAROZZI, C, MENOZZI, C, SASANELLI, F, BASCELLI, C, PONTRELLI, V, SCHIERONI, F, BELVEDERE, D, DECAPITANI, E, DICOSTANZO, M, RASCAROLI, M, CITTERIO, O, MILANI, R, CAPIALBI, R, ARENA, G, MUSOLINO, R, DIPERRI, R, BONAVENTI, C, FINZI, F, MESSINA, A, ROMANAZZI, V, STERZI, R, BOTTINI, G, SANTILLI, I, BRUCATO, A, DEJULI, E, PALMIERI, G, RAGAINI, S, THIELLA, G, ALLI, C, CAROSELLA, L, RIZZATO, G, BIANCHI, M, MOTTO, C, PINARDI, G, SCARLATO, G, BETTINELLI, A, PORRO, F, RANDAZZO, A, MARINI, U, LATTUADA, P, PIETRA, A, FRANCESCHI, M, VOLOUTE, M, MALFERRARI, G, BONDI, M, GARUTI, W, MELINI, L, COLOMBO, A, ALBORINI, G, PANZETTI, P, SCARPA, M, SORGATO, P, CRISI, G, BONASERA, N, BASSO, F, NATALI, E, MONACO, P, GASPARRO, A, TRIOLO, F, LECHI, A, COLONNA, F, DASCOLA, I, GIORGI, C, SCODITTI, U, BASSI, P, MENOZZI, R, PIAZZA, P, DEGLIANTONI, G, DESIMONI, M, GIANNINI, A, MICILI, G, BOSONE, D, CAVALLINI, A, MARTELLI, A, BARZIZZA, F, POLI, M, BIAGINI, S, CAPOCCHI, G, CELANI, M, PICCHIARELLI, A, RIGHETTI, E, ZAMPOLINI, M, CAPUTO, N, BARTOLINI, S, SANTONI, M, SITA, D, TAGLIOLI, M, VOLPI, G, ROSSI, F, ALOY, F, CASTELLANO, A, MINOTTA, F, GATTA, A, VINATTIERI, A, CANTINI, A, REBUCCI, G, BISSI, G, DEBLASI, F, PASCARELLI, E, TURIAMO, F, GUIDETTI, D, BARATTI, M, FERRARINI, G, GHIDONI, E, GRECO, G, MARCELLO, N, MOTTI, L, SOLIME, F, TERENZIANI, S, ZUCCO, R, TROISO, A, VENEZIANI, M, IORI, I, CURATOLA, L, BOLLETTINI, G, CARBONI, T, GOBBATO, R, INFRICCIOLO, P, SABATINI, D, SFRAPPINI, M, FANCELLU, A, CASU, G, DELEDDA, M, SPANU, M, PIRISI, A, MARRAS, F, ROSATI, G, BRAMBILLA, A, ERLI, G, FELICE, B, GRANDI, R, MIRABILE, D, ZADRA, M, CAVESTRI, R, GORI, D, LONGHINI, E, MIELE, N, DIVIZIA, G, GRASSELLI, S, PEZZELLA, F, ZUCCARI, F, SALLUSTO, L, LINCESSO, F, SCARPATI, C, IANNONE, G, BARTOCCI, A, COSTANTINI, F, DESANTIS, L, LANCIA, G, MOSCHINI, E, PACI, A, SENSIDONI, A, TRENTA, A, BARTOLINI, N, OTTAVIANO, P, BISCOTTINI, B, ALUNNI, G, BARTOLINI, I, BELLADONNA, D, BOCCALI, A, CRUCIANI, M, IBBA, R, LUCCIOLI, R, MARCECA, A, PACINI, M, PALLONE, M, GIRARDI, P, ORRICO, D, LANZA, E, BALLINI, A, GRANDI, F, MUSCO, G, STEIDL, L, SANTORO, G, VEMCO, A, DUDINE, P, MILONE, F, MUNARI, L, PERRETI, A, PORTA, M, LONGONI, C, FERANI, R, WATT, M, SANDERCOCK, P, FENNETRY, A, BANNISTER, P, CLARKE, C, BAMFORD, J, VENABLES, G, and CORREIA, M

Published
1995

39. Novel RNA-binding motif: The KH module

Author

Adinolfi, S., Bagni, C., Morelli, M. A. Castiglione, Fraternali, F., Musco, G., and Pastore, A.

Abstract

The KH motif has recently been identified in single or multiple copies in a number of RNA associated proteins. Here we review the current knowledge accumulated about the sequence, structure, and functions of the KH. The multidomain architecture of most of the KH-containing proteins inspired an approach based on the production of peptides spanning the sequence of an isolated KH motif. Correct identification of the minimal length necessary for producing a folded peptide has had a number of important consequences for interpreting functional data. The presence of the KH motifs in fmr1, the protein responsible for the fragile X syndrome, and their possible role in the fmr1 functions are also discussed. © 1999 John Wiley & Sons, Inc. Biopoly 51: 153–164, 1999

Published
1999
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41. Assessing Heterogeneity of Osteolytic Lesions in Multiple Myeloma by ¹H HR-MAS NMR Metabolomics

Author

Tavel L, Fontana F, Jm, Garcia Manteiga, Mari S, Mariani E, Caneva E, Roberto Sitia, Camnasio F, Marcatti M, Cenci S, Musco G, Tavel, L, Fontana, F, Garcia Manteiga, Jm, Mari, S, Mariani, E, Caneva, E, Sitia, Roberto, Camnasio, F, Marcatti, M, Cenci, S, and Musco, G.

Subjects
multiple myeloma, tumor markers, metabonomic
Abstract

Multiple myeloma (MM) is a malignancy of plasma cells characterized by multifocal osteolytic bone lesions. Macroscopic and genetic heterogeneity has been documented within MM lesions. Understanding the bases of such heterogeneity may unveil relevant features of MM pathobiology. To this aim, we deployed unbiased ¹H high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) metabolomics to analyze multiple biopsy specimens of osteolytic lesions from one case of pathological fracture caused by MM. Multivariate analyses on normalized metabolite peak integrals allowed clusterization of samples in accordance with a posteriori histological findings. We investigated the relationship between morphological and NMR features by merging morphological data and metabolite profiling into a single correlation matrix. Data-merging addressed tissue heterogeneity, and greatly facilitated the mapping of lesions and nearby healthy tissues. Our proof-of-principle study reveals integrated metabolomics and histomorphology as a promising approach for the targeted study of osteolytic lesions.

42. Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand

Author

Stefano Tomassi, Francesco Saverio Di Leva, Giovanna Musco, Salvatore Di Maro, Horst Kessler, Michael Weinmüller, Tatiana Gianni, Barbara Romano, Jussara Amato, Giacomo Quilici, Ettore Novellino, Angelo A. Izzo, Andrea Vannini, Florian Reichart, Vincenzo Maria D'Amore, Luciana Marinelli, Tomassi, S., D'Amore, V. M., Di Leva, F. S., Vannini, A., Quilici, G., Weinmuller, M., Reichart, F., Amato, J., Romano, B., Izzo, A. A., Di Maro, S., Novellino, E., Musco, G., Gianni, T., Kessler, H., Marinelli, L., Tomassi S., D'Amore V.M., Di Leva F.S., Vannini A., Quilici G., Weinmuller M., Reichart F., Amato J., Romano B., Izzo A.A., Di Maro S., Novellino E., Musco G., Gianni T., Kessler H., and Marinelli L.

Subjects
Integrins, Small interfering RNA, Molecular model, Integrin, Peptide, Herpesvirus 1, Human, Integrin ligand, Ligands, medicine.disease_cause, Peptides, Cyclic, 01 natural sciences, Article, 03 medical and health sciences, HEK293 Cell, Antigens, Neoplasm, Drug Discovery, medicine, Humans, 030304 developmental biology, chemistry.chemical_classification, Infectivity, 0303 health sciences, Binding Sites, biology, Binding Site, Virus Internalization, Combined approach, ddc, 0104 chemical sciences, Cell biology, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, HEK293 Cells, Herpes simplex virus, chemistry, biology.protein, Oligopeptide, Molecular Medicine, Oligopeptides, Human, Protein Binding
Abstract

Over recent years, αvβ6 and αvβ8 Arg-Gly-Asp (RGD) integrins have risen to prominence as interchangeable co-receptors for the cellular entry of herpes simplex virus-1 (HSV-1). In fact, the employment of subtype-specific integrin-neutralizing antibodies or gene-silencing siRNAs has emerged as a valuable strategy for impairing HSV infectivity. Here, we shift the focus to a more affordable pharmaceutical approach based on small RGD-containing cyclic pentapeptides. Starting from our recently developed αvβ6-preferential peptide [RGD-Chg-E]-CONH2 (1), a small library of N-methylated derivatives (2–6) was indeed synthesized in the attempt to increase its affinity toward αvβ8. Among the novel compounds, [RGD-Chg-(NMe)E]-CONH2 (6) turned out to be a potent αvβ6/αvβ8 binder and a promising inhibitor of HSV entry through an integrin-dependent mechanism. Furthermore, the renewed selectivity profile of 6 was fully rationalized by a NMR/molecular modeling combined approach, providing novel valuable hints for the design of RGD integrin ligands with the desired specificity profile.

Published
2021
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44. Dissecting FMR1, the protein responsible for fragile X syndrome, in its structural and functional domains

Author

Giovanna Musco, Toby J. Gibson, Lelio Mazzarella, Salvatore Adinolfi, Claudia Bagni, Annalisa Pastore, Adinolfi, S., Bagni, C., Musco, G., Gibson, T., Mazzarella, Lelio, Pastore, A., Adinolfi, S, Bagni, C, Musco, G, Gibson, T, Mazzarella, L, Pastore, A, L., Mazzarellainolfi, C., Bagni, G., Musco, T., Gibson, and A., Pastore

Subjects
Protein Folding, Magnetic Resonance Spectroscopy, sequence analysis, fragile X, Sequence Homology, polyguanylic acid, RNA-binding protein, localization, Fragile X Mental Retardation Protein, Protein sequencing, Models, binding affinity, rna-binding, fragile X syndrome, FMR1, Peptide sequence, Protein secondary structure, Blotting, Circular Dichroism, Settore BIO/13, article, fragile x, protein domain, RNA-Binding Proteins, RNA analysis, structure analysis, Recombinant Proteins, unclassified drug, reaction analysis, Amino Acid, priority journal, Biochemistry, Protein folding, nuclear export, protein RNA binding, Western, kh-domain, Research Article, Protein Binding, Sequence analysis, Blotting, Western, peptide mapping, Molecular Sequence Data, Nerve Tissue Proteins, in-vitro, Biology, fmr1, ribonucleoprotein, Structure-Activity Relationship, Genetic, modular proteins, Humans, Amino Acid Sequence, gene, Molecular Biology, mental-retardation protein, carboxy terminal sequence, fragile X mental retardation protein, RNA binding protein, amino terminal sequence, binding site, molecular dynamics, protein determination, protein folding, sequence homology, Fragile X Syndrome, Models, Genetic, Mutagenesis, RNA, Sequence Homology, Amino Acid, rna-binding proteins, FMR1, fragile sites, fragile X, modular proteins, RNA-binding proteins, Molecular biology, KH domain, polyribosomes, fragile sites, mutation
Abstract

FMR1 is an RNA-binding protein that is either absent or mutated in, patients affected by the fragile X syndrome, the most common inherited cause of mental retardation in humans. Sequence analysis of the FMR1 protein has suggested that RNA binding is related to the presence of two K-homologous (KH) modules and an RGG box. However, no attempt has been so far made to map the RNA-binding sites along the protein sequence and to identify possible differential RNA-sequence specificity. In the present article, we describe work done to dissect FMR1 into regions with structurally and functionally distinct properties. A semirational approach was followed to identify four regions: an :N-terminal stretch of 200 amino acids, the two KH-regions, and a C-terminal stretch. Each region was produced as a recombinant protein, purified, and probed for its state of folding by spectroscopical techniques. Circular,dichroism and NMR spectra of the N-terminus show formation of secondary structure with a strong tendency to aggregate. Of the two homologous KH motifs, only the first one is folded whereas the second remains unfolded even when it is extended both N-and C-terminally. The C-terminus is, as expected from its amino acid composition, nonglobular. Binding assays were then performed using the 4-nt homopolymers. Our results show that only the first KH domain but not the second binds to RNA, and provide the first direct evidence for RNA binding of both the N-terminal and the C-terminal regions. RNA binding for the N-terminus could not be predicted from sequence analysis because no known RNA-binding motif is identifiable in this region. Different sequence specificity was observed for the fragments: both the N-terminus of the protein and KH1 bind preferentially to poly-(ra). The C-terminal region, which contains the RGG box, is nonspecific, as it recognizes the bases with comparable affinity. We therefore conclude that FMR1 is a protein with multiple sites of interaction with RNA: sequence specificity is most likely achieved by the whole block that comprises the first approximate to 400 residues, whereas the C-terminus provides a nonspecific binding surface. ispartof: Rna-a publication of the rna society vol:5 issue:9 pages:1248-1258 ispartof: location:United States status: published

Published
1999

45. Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment

Author

Marco Bianchi, Giacomo Quilici, Alessandro Preti, Mario Tirone, Francesco De Marchis, Giovanna Musco, Rosanna Mezzapelle, Federica De Leo, Chiara Zucchelli, Alessandro Gori, Valeria Mannella, Maura Casalgrandi, De Leo, F., Quilici, G., Tirone, M., De Marchis, F., Mannella, V., Zucchelli, C., Preti, A., Gori, A., Casalgrandi, M., Mezzapelle, R., Bianchi, M. E., and Musco, G.

Subjects
Magnetic Resonance Spectroscopy, Diflunisal, Inflammation, chemical and pharmacologic phenomena, Pharmacology, HMGB1, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, In vivo, Genetics, medicine, Leukocytes, Animals, Humans, Disulfides, CXCL12, diflunisal, inflammation, NMR, HMGB1 Protein, Receptor, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, Chemistry, Chemotaxis, Macrophages, 3T3 Cells, Glycyrrhizic Acid, Chemokine CXCL12, TLR4, biology.protein, medicine.symptom, 030217 neurology & neurosurgery, medicine.drug, Reports
Abstract

Extracellular HMGB1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits invitro and invivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of diflunisal and open the way to the rational design of functionally specific anti-inflammatory drugs.

Published
2019
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46. A stapled chromogranin A-derived peptide is a potent dual ligand for integrins αvβ6 and αvβ8

Author

Fuxiang Chen, Flavio Curnis, Giacomo Quilici, Michela Ghitti, Angelo Corti, Wolfgang Bermel, Angelina Sacchi, Matteo Monieri, Greta Bergamaschi, Qingqiong Luo, Andrea Berardi, Alessandro Gori, Francesca Nardelli, Giovanna Musco, Nardelli, F., Ghitti, M., Quilici, G., Gori, A., Luo, Q., Berardi, A., Sacchi, A., Monieri, M., Bergamaschi, G., Bermel, W., Chen, F., Corti, A., Curnis, F., and Musco, G.

Subjects
Integrin, Ligand, Peptide, Plasma protein binding, Ligands, 010402 general chemistry, ligand, 01 natural sciences, Catalysis, Antigens, Neoplasm, Cell Line, Tumor, Materials Chemistry, Humans, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, Peptide sequence, chemistry.chemical_classification, biology, 010405 organic chemistry, Chemistry, Metals and Alloys, Chromogranin A, General Chemistry, peptide, 3. Good health, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Microscopy, Fluorescence, Biochemistry, Cell culture, Cancer cell, Ceramics and Composites, biology.protein, integrins, Peptides, Human, Protein Binding
Abstract

Combining 2D STD-NMR, computation, biochemical assays and click-chemistry, we have identified a chromogranin-A derived compound (5) that has high affinity and bi-selectivity for αvβ6 and αvβ8 integrins and is stable in microsomal preparations. 5 is suitable for nanoparticle functionalization and delivery to cancer cells, holding promise for diagnostic and/or therapeutic applications.

Published
2019
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47. Identification of TMPRSS6 cleavage sites of hemojuvelin

Author

Alessandro Campanella, Antonella Nai, Michela Ghitti, Clara Camaschella, Giovanna Musco, Alessia Pagani, Marco Rausa, Laura Silvestri, Rausa, M, Ghitti, M, Pagani, A, Nai, A, Campanella, A, Musco, G, Camaschella, Clara, and Silvestri, L.

Subjects
TMPRSS6, serine protease, Molecular Sequence Data, Mutation, Missense, Plasma protein binding, Biology, Molecular Dynamics Simulation, Cleavage (embryo), Arginine, GPI-Linked Proteins, HJV, Cell membrane, Protein structure, iron, Cell Line, Tumor, medicine, Humans, Amino Acid Sequence, Hemochromatosis Protein, Peptide sequence, homology modelling, Hemojuvelin, Binding Sites, Cell Membrane, Serine Endopeptidases, Membrane Proteins, Hydrogen Bonding, Cell Biology, Original Articles, RGM, Transmembrane protein, Protein Structure, Tertiary, medicine.anatomical_structure, Membrane protein, Biochemistry, Proteolysis, Molecular Medicine, Electrophoresis, Polyacrylamide Gel, Mutant Proteins, hepcidin, Protein Multimerization, HeLa Cells, Protein Binding
Abstract

Hemojuvelin (HJV), the coreceptor of the BMP-SMAD pathway that up-regulates hepcidin transcription, is a repulsive guidance molecule (RGMc) which undergoes a complex intracellular processing. Following autoproteolysis, it is exported to the cell surface both as a full-length and a heterodimeric protein. In vitro membrane HJV (m-HJV) is cleaved by the transmembrane serine protease TMPRSS6 to attenuate signalling and to inhibit hepcidin expression. In this study, we investigated the number and position of HJV cleavage sites by mutagenizing arginine residues (R), potential TMPRSS6 targets, to alanine (A). We analysed translation and membrane expression of HJV R mutants and the pattern of fragments they release in the culture media in the presence of TMPRSS6. Abnormal fragments were observed for mutants at arginine 121, 176, 218, 288 and 326. Considering that all variants, except HJV(R121A) , lack autoproteolytic activity and some (HJV(R176A) and HJV(R288A) ) are expressed at reduced levels on cell surface, we identified the fragments originating from either full-length or heterodimeric proteins and defined the residues 121 and 326 as the TMPRSS6 cleavage sites in both isoforms. Using the N-terminal FLAG-tagged HJV, we showed that residue 121 is critical also in the rearrangement of the N-terminal heterodimeric HJV. Exploiting the recently reported RGMb crystallographic structure, we generated a model of HJV that was used as input structure for all-atoms molecular dynamics simulation in explicit solvent. As assessed by in silico studies, we concluded that some arginines in the von Willebrand domain appear TMPRSS6 insensitive, likely because of partial protein structure destabilization.

Published
2015

48. Glycine N-methylation in NGR-Tagged Nanocarriers Prevents Isoaspartate formation and Integrin Binding without Impairing CD13 Recognition and Tumor Homing

Author

Silvia Valtorta, Martina Fiocchi, Anna Gasparri, Valentina Buttiglione, Angelo Corti, Alessandro Gori, Giovanna Musco, Angelina Sacchi, Laura Perani, Francesco Sudati, Flavio Curnis, Fabio Pastorino, Mirco Ponzoni, Rosa Maria Moresco, Michela Ghitti, Corti, A, Gasparri, A, Ghitti, M, Sacchi, A, Sudati, F, Fiocchi, M, Buttiglione, V, Perani, L, Gori, A, Valtorta, S, Moresco, R, Pastorino, F, Ponzoni, M, Musco, G, Curnis, F, Corti, Angelo, Gasparri, Anna Maria, Ghitti, Michela, Sacchi, Angelina, Sudati, Francesco, Fiocchi, Martina, Buttiglione, Valentina, Perani, Laura, Gori, Alessandro, Valtorta, Silvia, Moresco, Rosa Maria, Pastorino, Fabio, Ponzoni, Mirco, Musco, Giovanna, and Curnis, Flavio

Subjects
0301 basic medicine, Integrin, Peptide, Condensed Matter Physic, Article, Isoaspartate, Biomaterials, N-methylglycine, 03 medical and health sciences, 0302 clinical medicine, Electrochemistry, Asparagine, Deamidation, Receptor, Integrin binding, chemistry.chemical_classification, biology, Chemistry, Electronic, Optical and Magnetic Material, molecular docking, Condensed Matter Physics, Biomaterial, peptide, Electronic, Optical and Magnetic Materials, Cell biology, deamidation, enzyme, 030104 developmental biology, Biochemistry, Enzyme, 030220 oncology & carcinogenesis, Molecular docking, biology.protein, Nanocarriers
Abstract

NGR (asparagine-glycine-arginine) is a tumor vasculature-homing peptide motif widely used for the functionalization of drugs, nanomaterials and imaging compounds for cancer treatment and diagnosis. Unfortunately, this motif has a strong propensity to undergo rapid deamidation. This reaction, which converts NGR into isoDGR, is associated with receptor switching from CD13 to integrins, with potentially important manufacturing, pharmacological and toxicological implications. It is found that glycine N-methylation of NGR-tagged nanocarriers completely prevents asparagine deamidation without impairing CD13 recognition. Studies in animal models have shown that the methylated NGR motif can be exploited for delivering radiolabeled compounds and nanocarriers, such as tumor necrosis factor-α (TNF)-bearing nanogold and liposomal doxorubicin, to tumors with improved selectivity. These findings suggest that this NGR derivative is a stable and efficient tumor-homing ligand that can be used for delivering functional nanomaterials to tumor vasculature.

Published
2017

49. Safety and Efficacy of Transcranial Direct Current Stimulation in Acute Experimental Ischemic Stroke

Author

Marco Bacigaluppi, Marco Cursi, Luis Teneud, Giancarlo Comi, Edoardo Gaude, Mattia Gallizioli, Gianvito Martino, Marco Cambiaghi, Luca Peruzzotti-Jametti, Silvia Mari, Letizia Leocani, Stefano Sandrone, Giovanna Musco, Peruzzotti Jametti, L, Cambiaghi, M, Bacigaluppi, M, Gallizioli, M, Gaude, E, Mari, S, Sandrone, S, Cursi, M, Teneud, L, Comi, Giancarlo, Musco, G, Martino, Gianvito, and Leocani, ANNUNZIATA MARIA LETIZIA

Subjects
Male, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Neurology, medicine.medical_treatment, Ischemia, Glutamic Acid, Electric Stimulation Therapy, Stimulation, Blood–brain barrier, Brain Ischemia, Brain ischemia, Mice, medicine, Animals, Deep transcranial magnetic stimulation, Electrodes, Stroke, Inflammation, Advanced and Specialized Nursing, Transcranial direct-current stimulation, business.industry, neuroprotective agents, electric stimulation, mice, stroke, Brain, medicine.disease, Electric Stimulation, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Blood-Brain Barrier, Anesthesia, Neurology (clinical), Cardiology and Cardiovascular Medicine, business
Abstract

Background and Purpose— Transcranial direct current stimulation is emerging as a promising tool for the treatment of several neurological conditions, including cerebral ischemia. The therapeutic role of this noninvasive treatment is, however, limited to chronic phases of stroke. We thus ought to investigate whether different stimulation protocols could also be beneficial in the acute phase of experimental brain ischemia. Methods— The influence of both cathodal and anodal transcranial direct current stimulation in modifying brain metabolism of healthy mice was first tested by nuclear magnetic resonance spectroscopy. Then, mice undergoing transient proximal middle cerebral artery occlusion were randomized and treated acutely with anodal, cathodal, or sham transcranial direct current stimulation. Brain metabolism, functional outcomes, and ischemic lesion volume, as well as the inflammatory reaction and blood brain barrier functionality, were analyzed. Results— Cathodal stimulation was able, if applied in the acute phase of stroke, to preserve cortical neurons from the ischemic damage, to reduce inflammation, and to promote a better clinical recovery compared with sham and anodal treatments. This finding was attributable to the significant decrease of cortical glutamate, as indicated by nuclear magnetic resonance spectroscopy. Conversely, anodal stimulation induced an increase in the postischemic lesion volume and augmented blood brain barrier derangement. Conclusions— Our data indicate that transcranial direct current stimulation exerts a measurable neuroprotective effect in the acute phase of stroke. However, its timing and polarity should be carefully identified on the base of the pathophysiological context to avoid potential harmful side effects.

Published
2013
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50. 2-Deoxy-D-glucose ameliorates PKD progression

Author

Alessandra Boletta, Tamara Canu, Isaline Rowe, Patrizia D'Adamo, Antonia Gurgone, Giacomo Quilici, Marco Chiaravalli, Antonio Esposito, Veronica Bianchi, Giovanna Musco, Valeria Mannella, Sofia Antunes, Chiaravalli, M, Rowe, I, Mannella, V, Quilici, G, Canu, T, Bianchi, V, Gurgone, A, Antunes, S, D'Adamo, P, Esposito, Antonio, Musco, G, and Boletta, A.

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Autosomal dominant polycystic kidney disease, Carbohydrate metabolism, Deoxyglucose, urologic and male genital diseases, ADPKD, metabolism, polycystic kidney disease, Animals, Disease Models, Animal, Disease Progression, Female, Mice, Polycystic Kidney, Autosomal Dominant, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Polycystic kidney disease, medicine, Polycystic Kidney, Cystic kidney, PKD1, business.industry, Animal, Glucose analog, General Medicine, medicine.disease, Basic Research, 030104 developmental biology, Endocrinology, chemistry, Nephrology, Autosomal Dominant, Toxicity, Disease Models, 2-Deoxy-D-glucose, business
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-d-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of (13)C-glucose and conversion to (13)C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMP-activated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.

Published
2016

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