Latest PUBLICATIONS

  • Carbohydrate-based synthetic ion transporters.
    Publication Date: 15/07/2012, on Carbohydrate research
    by Montesarchio D, Coppola C, Boccalon M, Tecilla P
    DOI: 10.1016/j.carres.2012.03.009

    In this work, carbohydrate-based systems designed as artificial ion transporters have been surveyed. Despite the large structural diversity and ease of manipulations of carbohydrates, in principle endowed with a variety of desirable properties for ionophoric activity, only few examples of sugar-containing compounds have been reported in the literature for these purposes. The most remarkable example is the family of modified β-cyclodextrins, resulting in active cation and/or anion transporters when long, flexible n-alkyl or oligo-ethylene or butylene glycol chains are appended at the lower rim of the macrocycle. Interesting features have been also found in amphiphilic CyPLOS (Cyclic Phosphate-Linked Oligosaccharide) dimers, that is macrocycles with two phenyl-β-D-glucopyranoside residues, 4,6-linked through phosphodiester bonds, derivatized with tetraethylene glycol tentacles. A wider repertoire of available carbohydrate-based scaffolds is expected to largely stimulate the discovery of novel, efficient artificial ionophores, of great interest for both technological and biomedical applications.

  • Correlation between photoreceptor layer integrity and visual function in patients with Stargardt disease: implications for gene therapy.
    Publication Date: 03/07/2012, on Investigative ophthalmology & visual science
    by Testa F, Rossi S, Sodi A, Passerini I, Di Iorio V, Della Corte M, Banfi S, Surace EM, Menchini U, Auricchio A, Simonelli F
    DOI: 10.1167/iovs.11-8201

    To perform a clinical characterization of Stargardt patients with ABCA4 gene mutation, and to investigate the correlation between the inner and outer segment (IS/OS) junction morphology and visual acuity, fundus lesions, electroretinogram abnormalities, and macular sensitivity.

  • Resolution of the effects induced by W → F substitutions on the conformation and dynamics of the amyloid-forming apomyoglobin mutant W7FW14F.
    Publication Date: 01/07/2012, on European biophysics journal : EBJ
    by Infusini G, Iannuzzi C, Vilasi S, Birolo L, Pagnozzi D, Pucci P, Irace G, Sirangelo I
    DOI: 10.1007/s00249-012-0829-1

    Myoglobin is an alpha-helical globular protein containing two highly conserved tryptophanyl residues at positions 7 and 14 in the N-terminal region. The simultaneous substitution of the two residues increases the susceptibility of the polypeptide chain to misfold, causing amyloid aggregation under physiological condition, i.e., neutral pH and room temperature. The role played by tryptophanyl residues in driving the folding process has been investigated by examining three mutated apomyoglobins, i.e., W7F, W14F, and the amyloid-forming mutant W7FW14F, by an integrated approach based on far-ultraviolet (UV) circular dichroism (CD) analysis, fluorescence spectroscopy, and complementary proteolysis. Particular attention has been devoted to examine the conformational and dynamic properties of the equilibrium intermediate formed at pH 4.0, since it represents the early organized structure from which the native fold originates. The results show that the W → F substitutions at position 7 and 14 differently affect the structural organization of the AGH subdomain of apomyoglobin. The combined effect of the two substitutions in the double mutant impairs the formation of native-like contacts and favors interchain interactions, leading to protein aggregation and amyloid formation.

  • Sporadic human prion diseases: molecular insights and diagnosis.
    Publication Date: 01/07/2012, on The Lancet. Neurology
    by Puoti G, Bizzi A, Forloni G, Safar JG, Tagliavini F, Gambetti P
    DOI: 10.1016/S1474-4422(12)70063-7

    Human prion diseases can be sporadic, inherited, or acquired by infection. Distinct clinical and pathological characteristics separate sporadic diseases into three phenotypes: Creutzfeldt-Jakob disease (CJD), fatal insomnia, and variably protease-sensitive prionopathy. CJD accounts for more than 90% of all cases of sporadic prion disease; it is commonly categorised into five subtypes that can be distinguished according to leading clinical signs, histological lesions, and molecular traits of the pathogenic prion protein. Three subtypes affect prominently cognitive functions whereas the other two impair cerebellar motor activities. An accurate and timely diagnosis depends on careful clinical examination and early performance and interpretation of diagnostic tests, including electroencephalography, quantitative assessment of the surrogate markers 14-3-3, tau, and of the prion protein in the CSF, and neuroimaging. The reliability of CSF tests is improved when these tests are interpreted alongside neuroimaging data.

  • Chronic somatoparaphrenia: a follow-up study on two clinical cases.
    Publication Date: 01/06/2012, on Cortex; a journal devoted to the study of the nervous system and behavior
    by Cogliano R, Crisci C, Conson M, Grossi D, Trojano L
    DOI: 10.1016/j.cortex.2011.08.008

    Somatoparaphrenia consists in abnormal or bizarre verbal reports about some parts of the body. Such a pathological condition usually lasts for days or weeks and is variably associated with other cognitive defects. In the present paper we describe exceptionally long-lasting somatoparaphrenia in two focal brain-damaged patients: GA who had a right hemorrhagic fronto-parieto-temporal stroke and AC who developed a left ischemic parieto-occipital lesion. The presence and severity of somatoparaphrenia did not change in either patient during a 2-year follow-up, whereas the two patients showed different evolution of anosognosia for motor disorders, severity of extrapersonal neglect and cognitive impairments. Moreover, impairment of position sense was associated with somatoparaphrenia in one patient only; neither patient showed personal neglect. The reported clinical observations suggest that somatoparaphrenia can be observed as a body-related chronic disorder and can outlast other cognitive defects, even if it arose in conjunction with them.

  • Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors.
    Publication Date: 01/06/2012, on Breast cancer research and treatment
    by Fedele C, Riccio G, Coppola C, Barbieri A, Monti MG, Arra C, Tocchetti CG, D'Alessio G, Maurea N, De Lorenzo C
    DOI: 10.1007/s10549-011-1783-9

    Two novel human antitumor immunoconjugates, made up of a human anti-ErbB2 scFv, Erbicin, fused with either a human RNase or the Fc region of a human IgG1, are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. The Erbicin-derived immunoagents (EDIA) target an epitope different from that of trastuzumab, the only humanized antibody currently prescribed for treatment of ErbB2-positive breast cancer (BC). As Trastuzumab has shown cardiotoxic effects, in this study, we evaluated if any side effects were exerted also by EDIA, used as single agents or in combination with anthracyclines. Furthermore, we compared the in vitro and in vivo cardiotoxic effects of EDIA with those of the other available anti-ErbB2 drugs: Trastuzumab, 2C4 (Pertuzumab), and Lapatinib. In this article, we show that EDIA, in contrast with Trastuzumab, 2C4, and Lapatinib, have no toxic effects on human fetal cardiomyocytes in vitro, and do not induce additive toxicity when combined with doxorubicin. Furthermore, EDIA do not impair cardiac function in vivo in mice, as evaluated by Color Doppler echocardiography, whereas Trastuzumab significantly reduces radial strain (RS) at day 2 and fractional shortening (FS) at day 7 of treatment in a fashion similar to doxorubicin. Also 2C4 and Lapatinib significantly reduce RS after only 2 days of treatment, even though they showed cardiotoxic effects less pronounced than those of Trastuzumab. These results strongly indicate that RS could become a reliable marker to detect early cardiac dysfunction and that EDIA could fulfill the therapeutic need of patients ineligible to Trastuzumab treatment because of cardiac dysfunction.

  • Chalinulasterol, a chlorinated steroid disulfate from the Caribbean sponge Chalinula molitba. Evaluation of its role as PXR receptor modulator.
    Publication Date: 01/06/2012, on Marine drugs
    by Teta R, Della Sala G, Renga B, Mangoni A, Fiorucci S, Costantino V
    DOI: 10.3390/md10061383

    Chalinulasterol (1) a new chlorinated sterol disulfate was isolated from the Caribbean sponge Chalinula molitba. Its structure was elucidated using mass spectrometry and NMR experiments. The possible role of chalinulasterol as modulator of the PXR nuclear receptor was investigated but, in spite of the close structural relationship with the PXR agonist solomonsterol A (2), it showed no activity. The structural requirements for the PXR nuclear receptor activity were discussed.

  • Loss of expression of the oncosuppressor PTEN in thyroid incidentalomas associates with GLUT1 plasmamembrane expression.
    Publication Date: 01/06/2012, on Panminerva medica
    by Morani F, Pagano L, Prodam F, Aimaretti G, Isidoro C
    DOI:

    Molecular imaging diagnosis with FDG-PET ((18)F-fluorodeoxyglucose positron emission tomography with computed tomography) can reveal the presence of un-suspected thyroid cancer that are referred to as "incidentaloma" because of the incidental finding. The glucose analogue (18)FDG is internalized in the cells by glucose transporters belonging to the GLUTs family. The surface expression of GLUT is under the control of the PI3k/Akt pathway. PTEN is an oncosuppressor frequently mutated or deleted in thyroid cancers. The lipid phosphatase activity of wild type PTEN switches off the Akt pathway. Here we tested the hypothesis that PTEN expression might affect the surface expression of GLUT1 and therefore influence the possibility of "incidental" detection of thyroid cancer based on FDG-PET.

  • Role of cytosolic calcium-dependent phospholipase A2 in Alzheimer's disease pathogenesis.
    Publication Date: 01/06/2012, on Molecular neurobiology
    by Gentile MT, Reccia MG, Sorrentino PP, Vitale E, Sorrentino G, Puca AA, Colucci-D'Amato L
    DOI: 10.1007/s12035-012-8279-4

    Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aβ) fragments is well established although still more elusive are the molecular events of the cascade that from the Aβ accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.

  • Widespread microstructural white matter involvement in amyotrophic lateral sclerosis: a whole-brain DTI study.
    Publication Date: 01/06/2012, on AJNR. American journal of neuroradiology
    by Cirillo M, Esposito F, Tedeschi G, Caiazzo G, Sagnelli A, Piccirillo G, Conforti R, Tortora F, Monsurrò MR, Cirillo S, Trojsi F
    DOI: 10.3174/ajnr.A2918

    The extensive application of advanced MR imaging techniques to the study of ALS has undoubtedly improved our knowledge of disease pathophysiology, even if the actual spread of the neurodegenerative process throughout the central nervous system is not fully understood. The present study aimed to detect WM patterns of microstructural abnormalities to better investigate the pathologic process in ALS, within but also beyond CSTs, in a whole-brain analysis.

  • A family GH51 α-L-arabinofuranosidase from Pleurotus ostreatus: identification, recombinant expression and characterization.
    Publication Date: 01/05/2012, on Applied microbiology and biotechnology
    by Amore A, Amoresano A, Birolo L, Henrissat B, Leo G, Palmese A, Faraco V
    DOI: 10.1007/s00253-011-3678-4

    An α-L-arabinofuranosidase produced by Pleurotus ostreatus (PoAbf) during solid state fermentation on tomato pomace was identified and the corresponding gene and cDNA were cloned and sequenced. Molecular analysis showed that the poabf gene carries 26 exons interrupted by 25 introns and has an open reading frame encoding a protein of 646 amino acid residues, including a signal peptide of 20 amino acid residues. The amino acid sequence similar to the other α-L-arabinofuranosidases indicated that the enzyme encoded by poabf can be classified as a family 51 glycoside hydrolase. Heterologous recombinant expression of PoAbf was carried out in the yeasts Pichia pastoris and Kluyveromyces lactis achieving the highest production level of the secreted enzyme (180 mg L(-1)) in the former host. rPoAbf produced in P. pastoris was purified and characterized. It is a glycosylated monomer with a molecular weight of 81,500 Da in denaturing conditions. Mass spectral analyses led to the localization of a single O-glycosylation site at the level of Ser160. The enzyme is highly specific for α-L-arabinofuranosyl linkages and when assayed with p-nitrophenyl α-L-arabinofuranoside it follows Michaelis-Menten kinetics with a K (M) of 0.64 mM and a k (cat) of 3,010 min(-1). The optimum pH is 5 and the optimal temperature 40°C. It is worth noting that the enzyme shows a very high stability in a broad range of pH. The more durable activity showed by rPoAbf in comparison to the other α-L-arabinofuranosidases enhances its potential for biotechnological applications and increases interest in elucidating the molecular bases of its peculiar properties.

  • Executive functions are impaired in heterozygote patients with oculopharyngeal muscular dystrophy.
    Publication Date: 01/05/2012, on Journal of neurology
    by Dubbioso R, Moretta P, Manganelli F, Fiorillo C, Iodice R, Trojano L, Santoro L
    DOI: 10.1007/s00415-011-6255-y

    Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder caused by a small expansion of a short polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). It presents with adult onset of progressive eyelid drooping, swallowing difficulties and proximal limb weakness, usually without involvement of central nervous system (CNS). However, cognitive decline with relevant behavioural and psychological symptoms has been recently described in homozygous patients. In this study, we performed for the first time an extensive neuropsychological and neuropsychiatric evaluation on 11 OPMD heterozygote patients. We found that they were less efficient than a matched control sample on several tests, particularly those tapping executive functions. Moreover, the presence of negative correlation between GCN expansion size and some neuropsychological scores raises the issue that CNS involvement might be linked to the genetic defect, being worse in patients with larger expansion. Our results might be consistent with the toxic gain-of-function theory in the pathogenesis of OPMD and hint at a possible direct role of PABPN1 in the CNS also in heterozygote patients.

  • Ruthenium-based complex nanocarriers for cancer therapy.
    Publication Date: 01/05/2012, on Biomaterials
    by Mangiapia G, D'Errico G, Simeone L, Irace C, Radulescu A, Di Pascale A, Colonna A, Montesarchio D, Paduano L
    DOI: 10.1016/j.biomaterials.2012.01.057

    A new organometallic ruthenium complex, named AziRu, along with three amphiphilic nucleoside-based ruthenium complexes, ToThyRu, HoThyRu and DoHuRu, incorporating AziRu in their skeleton, have been synthesized, stabilized in POPC phospholipid formulations and studied for their antineoplastic activity. Self-aggregation behavior of these complexes was investigated, showing that the three synthesized AziRu derivatives able to form liposomes and, under specific conditions, elongated micelles. The formulations prepared in POPC proved to be stable for months and showed high in vitro antiproliferative activity. The here described results open new scenarios in the design of innovative transition metal-based supramolecular systems for anticancer drugs vectorization.

  • Chain termini cross-talk in the swapping process of bovine pancreatic ribonuclease.
    Publication Date: 01/05/2012, on Biochimie
    by Merlino A, Picone D, Ercole C, Balsamo A, Sica F
    DOI: 10.1016/j.biochi.2012.01.010

    3D domain swapping is the process by which two or more protein molecules exchange part of their structure to form intertwined dimers or higher oligomers. Bovine pancreatic ribonuclease (RNase A) is able to swap the N-terminal α-helix (residues 1-13) and/or the C-terminal β-strand (residues 116-124), thus forming a variety of oligomers, including two different dimers. Cis-trans isomerization of the Asn113-Pro114 peptide group was observed when the protein formed the C-terminal swapped dimer. To study the effect of the substitution of Pro114 on the swapping process of RNase A, we have prepared and characterized the P114A monomeric and dimeric variants of the enzyme. In contrast with previous reports, the crystal structure and NMR data on the monomer reveals a mixed cis-trans conformation for the Asn113-Ala114 peptide group, whereas the X-ray structure of the C-terminal swapped dimer of the variant is very close to that of the corresponding dimer of RNase A. The mutation at the C-terminus affects the capability of the N-terminal α-helix to swap and the stability of both dimeric forms. The present results underscore the importance of the hydration shell in determining the cross-talk between the chain termini in the swapping process of RNase A.

  • Interaction between aging and neurodegeneration in amyotrophic lateral sclerosis.
    Publication Date: 01/05/2012, on Neurobiology of aging
    by Tedeschi G, Trojsi F, Tessitore A, Corbo D, Sagnelli A, Paccone A, D'Ambrosio A, Piccirillo G, Cirillo M, Cirillo S, Monsurrò MR, Esposito F
    DOI: 10.1016/j.neurobiolaging.2010.07.011

    We assessed the spontaneous blood-oxygen-level-dependent signal fluctuations in the resting-state brain networks of amyotrophic lateral sclerosis patients and their relation to physiologically sensitive and disease modified functional magnetic resonance imaging parameters. Resting-state functional magnetic resonance imaging was performed at 3 Tesla on 20 amyotrophic lateral sclerosis patients with minimal frontal cognitive dysfunction and 20 age- and sex-matched healthy volunteers. Resting-state network maps were extracted with independent component analysis and group-level statistical analyses were performed to detect disease and disease-by-age interaction effects. Whole-brain global and regional atrophy measures were obtained from same-session structural scans. The sensori-motor network showed significant disease effects, with signals suppressed in patients bilaterally in the primary motor cortex. The default-mode network showed a significant disease-by-age interaction in the posterior cingulate cortex, where signals correlated with age positively in patients and negatively in controls. Both disease and disease-by-age interaction effects were detected in the right fronto-parietal network. Although global atrophy did not show significant differences, regions of reduced gray matter volume were detected in patients compared with controls adjacent to regions of reduced functional connectivity. Our results confirm that resting-state functional magnetic resonance imaging signals in the sensori-motor network are suppressed in amyotrophic lateral sclerosis. A similar suppression is evident in the right fronto-parietal network, possibly reflecting the patients' frontal dysfunction and right-lateralized patterns of regional atrophy. The interaction between disease and aging in the default-mode network unravels a possible mechanism of compensation between motor and extramotor systems emerging as a supplementary functional push to help motor disturbances.