Latest PUBLICATIONS

  • Low dose radiation induced senescence of human mesenchymal stromal cells and impaired the autophagy process.
    Publication Date: 10/04/2015, on Oncotarget
    by Alessio N, Del Gaudio S, Capasso S, Di Bernardo G, Cappabianca S, Cipollaro M, Peluso G, Galderisi U
    DOI: 10.18632/oncotarget.2692

    Low doses of radiation may have profound effects on cellular function. Individuals may be exposed to low doses of radiation either intentionally for medical purposes or accidentally, such as those exposed to radiological terrorism or those who live near illegal radioactive waste dumpsites.We studied the effects of low dose radiation on human bone marrow mesenchymal stromal cells (MSC), which contain a subpopulation of stem cells able to differentiate in bone, cartilage, and fat; support hematopoiesis; and contribute to body's homeostasis.The main outcome of low radiation exposure, besides reduction of cell cycling, is the triggering of senescence, while the contribution to apoptosis is minimal. We also showed that low radiation affected the autophagic flux. We hypothesize that the autophagy prevented radiation deteriorative processes, and its decline contributed to senescence.An increase in ATM staining one and six hours post-irradiation and return to basal level at 48 hours, along with persistent gamma-H2AX staining, indicated that MSC properly activated the DNA repair signaling, though some damages remained unrepaired, mainly in non-cycling cells. This suggested that the impaired DNA repair capacity of irradiated MSC seemed mainly related to the reduced activity of a non-homologous end-joining (NHEJ) system rather than HR (homologous recombination).

  • Impact of body posture on laterality judgement and explicit recognition tasks performed on self and others' hands.
    Publication Date: 01/04/2015, on Experimental brain research
    by Conson M, Errico D, Mazzarella E, De Bellis F, Grossi D, Trojano L
    DOI: 10.1007/s00221-015-4210-3

    Judgments on laterality of hand stimuli are faster and more accurate when dealing with one's own than others' hand, i.e. the self-advantage. This advantage seems to be related to activation of a sensorimotor mechanism while implicitly processing one's own hands, but not during explicit one's own hand recognition. Here, we specifically tested the influence of proprioceptive information on the self-hand advantage by manipulating participants' body posture during self and others' hand processing. In Experiment 1, right-handed healthy participants judged laterality of either self or others' hands, whereas in Experiment 2, an explicit recognition of one's own hands was required. In both experiments, the participants performed the task while holding their left or right arm flexed with their hand in direct contact with their chest ("flexed self-touch posture") or with their hand placed on a wooden smooth surface in correspondence with their chest ("flexed proprioceptive-only posture"). In an "extended control posture", both arms were extended and in contact with thighs. In Experiment 1 (hand laterality judgment), we confirmed the self-advantage and demonstrated that it was enhanced when the subjects judged left-hand stimuli at 270° orientation while keeping their left arm in the flexed proprioceptive-only posture. In Experiment 2 (explicit self-hand recognition), instead, we found an advantage for others' hand ("self-disadvantage") independently from posture manipulation. Thus, position-related proprioceptive information from left non-dominant arm can enhance sensorimotor one's own body representation selectively favouring implicit self-hands processing.

  • Gene therapy of inherited retinal degenerations: prospects and challenges.
    Publication Date: 01/04/2015, on Human gene therapy
    by Trapani I, Banfi S, Simonelli F, Surace EM, Auricchio A
    DOI: 10.1089/hum.2015.030

    Because of its favorable anatomical and immunological characteristics, the eye has been at the forefront of translational gene therapy. Dozens of promising proofs of concept have been obtained in animal models of inherited retinal degenerations (IRDs), and some of them have been relayed to the clinic. The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans. However, this progress has also generated new questions and posed challenges that need to be addressed to further expand the applicability of gene therapy in the eye, including safe delivery of viral vectors to the outer retina, treatment of dominant IRDs as well as of IRDs caused by mutations in large genes, and, finally, selection of the appropriate IRDs and patients to maximize the efficacy of gene transfer. This review summarizes the strategies that are currently being exploited to overcome these challenges and drive the clinical development of retinal gene therapy.

  • Normative data for the Montreal Cognitive Assessment in an Italian population sample.
    Publication Date: 01/04/2015, on Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
    by Santangelo G, Siciliano M, Pedone R, Vitale C, Falco F, Bisogno R, Siano P, Barone P, Grossi D, Santangelo F, Trojano L
    DOI: 10.1007/s10072-014-1995-y

    The Montreal Cognitive Assessment (MoCA) is a rapid screening battery, also including subtests to assess frontal functions such as set-shifting, abstraction and cognitive flexibility. MoCA seems to be useful to identify non-amnestic mild cognitive impairment (MCI) and subcortical dementia; it has high sensitivity and specificity in distinguishing MCI from mild Alzheimer's Disease. Previous studies revealed that certain items of MoCA may be culturally biased and highlighted the need for population-based norms for the MoCA. The aim of present study was to collect normative values in a sample of Italian healthy subjects. Four hundred and fifteen Italian healthy subjects (252 women and 163 men) of different ages (age range 21-95 years) and educational level (from primary to university) underwent MoCA and Mini Mental State Examination (MMSE). Multiple linear regression analysis revealed that age and education significantly influenced performance on MoCA. No significant effect of gender was found. From the derived linear equation, a correction grid for MoCA raw scores was built. Inferential cut-off score, estimated using a non-parametric technique, is 15.5 and equivalent scores were computed. Correlation analysis showed a significant but weak correlation between MoCA adjusted scores with MMSE adjusted scores (r = 0.43, p < 0.001). The present study provided normative data for the MoCA in an Italian population useful for both clinical and research purposes.

  • Preserved outer retina in AIPL1 Leber's congenital amaurosis: implications for gene therapy.
    Publication Date: 01/04/2015, on Ophthalmology
    by Aboshiha J, Dubis AM, van der Spuy J, Nishiguchi KM, Cheeseman EW, Ayuso C, Ehrenberg M, Simonelli F, Bainbridge JW, Michaelides M
    DOI: 10.1016/j.ophtha.2014.11.019

  • Looking for efficient G-quadruplex ligands: evidence for selective stabilizing properties and telomere damage by drug-like molecules.
    Publication Date: 01/04/2015, on ChemMedChem
    by Pagano B, Amato J, Iaccarino N, Cingolani C, Zizza P, Biroccio A, Novellino E, Randazzo A
    DOI: 10.1002/cmdc.201402552

    There is currently significant interest in the development of G-quadruplex-interactive compounds, given the relationship between the ability to stabilize these non-canonical DNA structures and anticancer activity. In this study, a set of biophysical assays was applied to evaluate the binding of six drug-like ligands to DNA G-quadruplexes with different folding topologies. Interestingly, two of the investigated ligands showed selective G-quadruplex-stabilizing properties and biological activity. These compounds may represent useful leads for the development of more potent and selective ligands.

  • Missing gold atoms in lysozyme crystals used to grow gold nanoparticles.
    Publication Date: 01/04/2015, on Nature nanotechnology
    by Merlino A, Caterino M, Russo Krauss I, Vergara A
    DOI: 10.1038/nnano.2015.53

  • Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment.
    Publication Date: 01/04/2015, on Diabetes
    by Balestrieri ML, Rizzo MR, Barbieri M, Paolisso P, D'Onofrio N, Giovane A, Siniscalchi M, Minicucci F, Sardu C, D'Andrea D, Mauro C, Ferraraccio F, Servillo L, Chirico F, Caiazzo P, Paolisso G, Marfella R
    DOI: 10.2337/db14-1149

    The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic patients is unknown. We evaluated SIRT6 expression and the effect of incretin-based therapies in carotid plaques of asymptomatic diabetic and nondiabetic patients. Plaques were obtained from 52 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Twenty-two diabetic patients were treated with drugs that work on the incretin system, GLP-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors for 26 ± 8 months before undergoing the endarterectomy. Compared with nondiabetic plaques, diabetic plaques had more inflammation and oxidative stress, along with a lesser SIRT6 expression and collagen content. Compared with non-GLP-1 therapy-treated plaques, GLP-1 therapy-treated plaques presented greater SIRT6 expression and collagen content, and less inflammation and oxidative stress, indicating a more stable plaque phenotype. These results were supported by in vitro observations on endothelial progenitor cells (EPCs) and endothelial cells (ECs). Indeed, both EPCs and ECs treated with high glucose (25 mmol/L) in the presence of GLP-1 (100 nmol/L liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression compared with cells treated only with high glucose. These findings establish the involvement of SIRT6 in the inflammatory pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin, the effect of which is associated with morphological and compositional characteristics of a potential stable plaque phenotype.

  • Imidazole-stabilized gold nanoparticles induce neuronal apoptosis: an in vitro and in vivo study.
    Publication Date: 01/04/2015, on Journal of biomedical materials research. Part A
    by Imperatore R, Carotenuto G, Di Grazia MA, Ferrandino I, Palomba L, Mariotti R, Vitale E, De Nicola S, Longo A, Cristino L
    DOI: 10.1002/jbm.a.35289

    Gold nanoparticles are increasingly being employed in innovative biological applications thanks to their advantages of material- and size-dependent physics and chemical interactions with the cellular systems. On the other hand, growing concern has emerged on the toxicity which would render gold-based nanoparticles harmful to cell cultures, animals, and humans. Emerging attention is focused on the interaction of gold nanoparticles with nervous system, especially regarding the ability to overcome the blood-brain barrier (BBB) which represents the major impediment to the delivery of therapeutics into the brain. We synthesized highly stable 2-mercapto-1-methylimidazole-stabilized gold-nanoparticles (AuNPs)-mmi to investigate their entry, accumulation, and toxicity in vitro (SH-SY5Y human neuroblastoma cells) and in vivo (brain of C57BL/6 mice) through optical and electron microscopy. After incubation in the cell culture medium at the lowest dose of 0.1 mg/mL the (AuNPs)-mmi nanoparticles were found compacted and recruited into endosome/lysosomes (1 h) before their fusion (2 h) and the onset of neuronal death by apoptosis (4 h) as proved by terminal-transferase-mediated dUTP nick end labeling assay and caspase-3 immunoreactivity. The ability of (AuNPs)-mmi to cross the BBB was assessed by injection in the caudal vein of C57BL/6 mice. Among different brain regions, the nanoparticles were found in the CaudatoPutamen area, mainly in the striatal neurons 4 h after injection. These neurons showed the typical hallmarks of apoptosis. Our findings provide, for the first time, the dynamic of 2-mercapto-1-methylimidazole nanogold uptake. The molecular mechanism which underlies the nanogold-driven apoptotic event is analyzed and discussed in order to take into account when designing nanomaterials to interface with biological structures.

  • Variably Protease-sensitive Prionopathy in an Apparent Cognitively Normal 93-Year-Old.
    Publication Date: 01/04/2015, on Alzheimer disease and associated disorders
    by Ghoshal N, Perry A, McKeel D, Schmidt RE, Carter D, Norton J, Zou WQ, Xiao X, Puoti G, Notari S, Gambetti P, Morris JC, Cairns NJ
    DOI: 10.1097/WAD.0000000000000049

  • Automatic prediction of cardiovascular and cerebrovascular events using heart rate variability analysis.
    Publication Date: 20/03/2015, on PloS one
    by Melillo P, Izzo R, Orrico A, Scala P, Attanasio M, Mirra M, De Luca N, Pecchia L
    DOI: 10.1371/journal.pone.0118504

    There is consensus that Heart Rate Variability is associated with the risk of vascular events. However, Heart Rate Variability predictive value for vascular events is not completely clear. The aim of this study is to develop novel predictive models based on data-mining algorithms to provide an automatic risk stratification tool for hypertensive patients.

  • Ruta graveolens L. induces death of glioblastoma cells and neural progenitors, but not of neurons, via ERK 1/2 and AKT activation.
    Publication Date: 18/03/2015, on PloS one
    by Gentile MT, Ciniglia C, Reccia MG, Volpicelli F, Gatti M, Thellung S, Florio T, Melone MA, Colucci-D'Amato L
    DOI: 10.1371/journal.pone.0118864

    Glioblastoma multiforme is a highly aggressive brain tumor whose prognosis is very poor. Due to early invasion of brain parenchyma, its complete surgical removal is nearly impossible, and even after aggressive combined treatment (association of surgery and chemo- and radio-therapy) five-year survival is only about 10%. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases, including cancer. Here, we report that the water extract of Ruta graveolens L., commonly known as rue, induces death in different glioblastoma cell lines (U87MG, C6 and U138) widely used to test novel drugs in preclinical studies. Ruta graveolens' effect was mediated by ERK1/2 and AKT activation, and the inhibition of these pathways, via PD98058 and wortmannin, reverted its antiproliferative activity. Rue extract also affects survival of neural precursor cells (A1) obtained from embryonic mouse CNS. As in the case of glioma cells, rue stimulates the activation of ERK1/2 and AKT in A1 cells, whereas their blockade by pharmacological inhibitors prevents cell death. Interestingly, upon induction of differentiation and cell cycle exit, A1 cells become resistant to rue's noxious effects but not to those of temozolomide and cisplatin, two alkylating agents widely used in glioblastoma therapy. Finally, rutin, a major component of the Ruta graveolens water extract, failed to cause cell death, suggesting that rutin by itself is not responsible for the observed effects. In conclusion, we report that rue extracts induce glioma cell death, discriminating between proliferating/undifferentiated and non-proliferating/differentiated neurons. Thus, it can be a promising tool to isolate novel drugs and also to discover targets for therapeutic intervention.

  • Standard versus trans-epithelial collagen cross-linking in keratoconus patients suitable for standard collagen cross-linking.
    Publication Date: 18/03/2015, on Clinical ophthalmology (Auckland, N.Z.)
    by Rossi S, Orrico A, Santamaria C, Romano V, De Rosa L, Simonelli F, De Rosa G
    DOI: 10.2147/OPTH.S73991

    Evaluating the clinical results of trans-epithelial collagen cross-linking (CXL) and standard CXL in patients with progressive keratoconus.

  • Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics.
    Publication Date: 11/03/2015, on Frontiers in behavioral neuroscience
    by Speranza L, Giuliano T, Volpicelli F, De Stefano ME, Lombardi L, Chambery A, Lacivita E, Leopoldo M, Bellenchi GC, di Porzio U, Crispino M, Perrone-Capano C
    DOI: 10.3389/fnbeh.2015.00062

    Recent studies have indicated that the serotonin receptor subtype 7 (5-HT7R) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life. Here we show that pharmacological stimulation of 5-HT7R using a highly selective agonist, LP-211, enhances neurite outgrowth in neuronal primary cultures from the cortex, hippocampus and striatal complex of embryonic mouse brain, through multiple signal transduction pathways. All these signaling systems, involving mTOR, the Rho GTPase Cdc42, Cdk5, and ERK, are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth. Indeed, our data indicate that neurite elongation stimulated by 5-HT7R is modulated by drugs affecting actin polymerization. In addition, we show, by 2D Western blot analyses, that treatment of neuronal cultures with LP-211 alters the expression profile of cofilin, an actin binding protein involved in microfilaments dynamics. Furthermore, by using microfluidic chambers that physically separate axons from the soma and dendrites, we demonstrate that agonist-dependent activation of 5-HT7R stimulates axonal elongation. Our results identify for the first time several signal transduction pathways, activated by stimulation of 5-HT7R, that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation. Therefore, the activation of 5-HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development.

  • α-Thalassemia associated with hb instability: a tale of two features. the case of Hb Rogliano or α1 Cod 108(G15)Thr→Asn and Hb Policoro or α2 Cod 124(H7)Ser→Pro.
    Publication Date: 02/03/2015, on PloS one
    by Bisconte MG, Caldora M, Musollino G, Cardiero G, Flagiello A, La Porta G, Lagona L, Prezioso R, Qualtieri G, Gaudiano C, Medulla E, Merlino A, Pucci P, Lacerra G
    DOI: 10.1371/journal.pone.0115738

    We identified two new variants in the third exon of the α-globin gene in families from southern Italy: the Hb Rogliano, α1 cod108 ACC>AAC or α1[α108(G15)Thr→Asn] and the Hb Policoro, α2 cod124 TCC>CCC or α2[α124(H7)Ser→Pro]. The carriers showed mild α-thalassemia phenotype and abnormal hemoglobin stability features. These mutations occurred in the G and H helices of the α-globin both involved in the specific recognition of AHSP and β1 chain. Molecular characterization of mRNA, globin chain analyses and molecular modelling studies were carried out to highlight the mechanisms causing the α-thalassemia phenotype. The results demonstrated that the α-thalassemia defect associated with the two Hb variants originated by different defects. Hb Rogliano showed an intrinsic instability of the tetramer due to anomalous intra- and inter-chain interactions suggesting that the variant chain is normally synthesized and complexed with AHSP but rapidly degraded because it is unable to form the α1β1 dimers. On the contrary in the case of Hb Policoro two different molecular mechanisms were shown: the reduction of the variant mRNA level by an unclear mechanism and the protein instability due to impairment of AHSP interaction. These data highlighted that multiple approaches, including mRNA quantification, are needed to properly identify the mechanisms leading to the α-thalassemia defect. Elucidation of the specific mechanism leads to the definition of a given phenotype providing important guidance for the diagnosis of unstable variants.