Latest PUBLICATIONS

  • GC/MS and proteomics to unravel the painting history of the lost Giant Buddhas of Bāmiyān (Afghanistan).
    Publication Date: 05/04/2017, on PloS one
    by Lluveras-Tenorio A, Vinciguerra R, Galano E, Blaensdorf C, Emmerling E, Perla Colombini M, Birolo L, Bonaduce I
    DOI: 10.1371/journal.pone.0172990

    A chemical investigation of the organic paint binders of the Giant Buddhas of Bāmiyān was performed using an analytical approach based on mass spectrometry, combining traditional gas chromatography/mass spectrometry protocols with advanced proteomics methodologies. The research was carried out on a selection of rescued fragments. The data revealed the use of egg proteins as the paint binders of the original layers, in accordance with the traditional use of this proteinaceous medium in antiquity, spanning from the Mediterranean basin to the Far East, and already in the Bronze Age. Egg tempera was thus known to artists of the region in the first centuries AD, probably also due to the position of the Bāmiyān valley, which was connected to the Silk Road. Milk was found in the first historical overpaintings. A new proteomics approach was used, which was able to identify the source of the milk proteins present in the restoration layers, despite their age and degradation. In particular cow's and goat's milk were both found, in agreement with the documented presence of rich pastures in the Bāmiyān valley when the historical restorations were carried out. Investigating the materials of the Giant Buddhas not only enabled us to obtain isolated data on these invaluable works of art, which are now lost, but contributes to understanding the big "puzzle" of our past and the development of our culture, by implementing and supporting written sources, stylistic and anthropological studies with molecular data.

  • Ergothioneine Antioxidant Function: From Chemistry to Cardiovascular Therapeutic Potential.
    Publication Date: 01/04/2017, on Journal of cardiovascular pharmacology
    by Servillo L, DʼOnofrio N, Balestrieri ML
    DOI: 10.1097/FJC.0000000000000464

    Ergothioneine (ESH), the betaine of 2-mercapto-L-histidine, is a water-soluble naturally occurring amino acid with antioxidant properties. ESH accumulates in several human and animal tissues up to millimolar concentration through its high affinity transporter, namely the organic cation transporter 1 (OCTN1). ESH, first isolated from the ergot fungus (Claviceps purpurea), is synthesized only by Actinomycetales and non-yeast-like fungi. Plants absorb ESH via symbiotic associations between their roots and soil fungi, whereas mammals acquire it solely from dietary sources. Numerous evidence demonstrated the antioxidant and cytoprotective effects of ESH, including protection against cardiovascular diseases, chronic inflammatory conditions, ultraviolet radiation damages, and neuronal injuries. Although more than a century after its discovery has gone by, our understanding on the in vivo ESH mechanism is limited and this compound still intrigues researchers. However, recent evidence about differences in chemical redox behavior between ESH and alkylthiols, such as cysteine and glutathione, has opened new perspectives on the role of ESH during oxidative damage. In this short review, we discuss the role of ESH in the complex machinery of the cellular antioxidant defense focusing on the current knowledge on its chemical mechanism of action in the protection against cardiovascular disease.

  • Biological bases of human musicality.
    Publication Date: 01/04/2017, on Reviews in the neurosciences
    by Perrone-Capano C, Volpicelli F, di Porzio U
    DOI: 10.1515/revneuro-2016-0046

    Music is a universal language, present in all human societies. It pervades the lives of most human beings and can recall memories and feelings of the past, can exert positive effects on our mood, can be strongly evocative and ignite intense emotions, and can establish or strengthen social bonds. In this review, we summarize the research and recent progress on the origins and neural substrates of human musicality as well as the changes in brain plasticity elicited by listening or performing music. Indeed, music improves performance in a number of cognitive tasks and may have beneficial effects on diseased brains. The emerging picture begins to unravel how and why particular brain circuits are affected by music. Numerous studies show that music affects emotions and mood, as it is strongly associated with the brain's reward system. We can therefore assume that an in-depth study of the relationship between music and the brain may help to shed light on how the mind works and how the emotions arise and may improve the methods of music-based rehabilitation for people with neurological disorders. However, many facets of the mind-music connection still remain to be explored and enlightened.

  • Ecotoxicological survey of MNEI and Y65R-MNEI proteins as new potential high-intensity sweeteners.
    Publication Date: 01/04/2017, on Environmental science and pollution research international
    by Rega MF, Siciliano A, Gesuele R, Lofrano G, Carpentieri A, Picone D, Guida M
    DOI: 10.1007/s11356-017-8626-0

    Low-calorie sweeteners are widespread. They are routinely introduced into commonly consumed food such as diet sodas, cereals, and sugar-free desserts. Recent data revealed the presence in considerable quantities of some of these artificial sweeteners in water samples qualifying them as a class of potential new emerging contaminants. This study aimed at evaluating the ecotoxicity profile of MNEI and Y65R-MNEI, two engineered products derived from the natural protein monellin, employing representative test organism such as Daphnia magna, Ceriodaphnia dubia, and Raphidocelis subcapitata. Potential genotoxicity and mutagenicity effects on Salmonella typhimurium (strain TA97a, TA98, TA100, and TA1535) and Escherichia coli (strain WP2 pkM101) were evaluated. No genotoxicity effects were detected, whereas slight mutagenicity was highlighted by TA98 S. typhimurium. Ecotoxicity results evidenced effects approximately up to 14 and 20% with microalgae at 500 mg/L of MNEI and Y65R-MNEI, in that order. Macrophytes and crustaceans showed no significant effects. No median effective concentrations were determined. Overall, MNEI and Y65R-MNEI can be classified as not acutely toxic for the environment.

  • PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.
    Publication Date: 01/04/2017, on Brain : a journal of neurology
    by Zollo M, Ahmed M, Ferrucci V, Salpietro V, Asadzadeh F, Carotenuto M, Maroofian R, Al-Amri A, Singh R, Scognamiglio I, Mojarrad M, Musella L, Duilio A, Di Somma A, Karaca E, Rajab A, Al-Khayat A, Mohan Mohapatra T, Eslahi A, Ashrafzadeh F, Rawlins LE, Prasad R, Gupta R, Kumari P, Srivastava M, Cozzolino F, Kumar Rai S, Monti M, Harlalka GV, Simpson MA, Rich P, Al-Salmi F, Patton MA, Chioza BA, Efthymiou S, Granata F, Di Rosa G, Wiethoff S, Borgione E, Scuderi C, Mankad K, Hanna MG, Pucci P, Houlden H, Lupski JR, Crosby AH, Baple EL
    DOI: 10.1093/brain/awx014

    PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

  • A preliminary study on the application of natural sweet proteins in agar-based gels.
    Publication Date: 01/04/2017, on Journal of texture studies
    by Miele NA, Di Monaco R, Dell'Amura F, Rega MF, Picone D, Cavella S
    DOI: 10.1111/jtxs.12215

    Natural sweet proteins may be used as sugar replacer in simple liquid food systems but their applicability in more complex matrices has not been investigated yet. Gelling agent nature and texture characteristics as well as type and distribution of a stimulus in a gel could affect taste perception through inhibition or enhancement of tastants migration to the receptors. The mechanical, nonoral texture and time-intensity sweetness characteristics of sweet proteins MNEI and super sweet Y65R mutant, aspartame and saccharin added at a concentration iso-sweet to 40 g/L of sucrose in three agar gel concentrations (1%, 1.5%, and 2%) were evaluated. The results have shown that agar concentration and agar sweetener interaction particularly affect mechanical fracture stress and non oral hardness of the sweetened gels. Time intensity results illustrated that unlike in solution, the intensity of sweet taste in a gelled system over time decreases. Indeed, the behavior of the sweet proteins differed greatly in the gelled system compared to when they are in solution.

  • Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action.
    Publication Date: 28/03/2017, on Scientific reports
    by Irace C, Misso G, Capuozzo A, Piccolo M, Riccardi C, Luchini A, Caraglia M, Paduano L, Montesarchio D, Santamaria R
    DOI: 10.1038/srep45236

    Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols.

  • Identifying fallers among ophthalmic patients using classification tree methodology.
    Publication Date: 23/03/2017, on PloS one
    by Melillo P, Orrico A, Chirico F, Pecchia L, Rossi S, Testa F, Simonelli F
    DOI: 10.1371/journal.pone.0174083

    To develop and validate a tool aiming to support ophthalmologists in identifying, during routine ophthalmologic visits, patients at higher risk of falling in the following year.

  • Corrigendum to "Altered functional connectivity of interoception in illness anxiety disorder" [Cortex 86 (2017) 22-32].
    Publication Date: 22/03/2017, on Cortex; a journal devoted to the study of the nervous system and behavior
    by Grossi D, Longarzo M, Quarantelli M, Salvatore E, Cavaliere C, De Luca P, Trojano L, Aiello M
    DOI: 10.1016/j.cortex.2017.03.001

  • The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells.
    Publication Date: 22/03/2017, on Oncotarget
    by Morra F, Merolla F, Napolitano V, Ilardi G, Miro C, Paladino S, Staibano S, Cerrato A, Celetti A
    DOI: 10.18632/oncotarget.16463

    Reduced levels of the tumor suppressor protein CCDC6 sensitize cancer cells to the treatment with PARP-inhibitors. The turnover of CCDC6 protein is regulated by the de-ubiquitinase USP7, which also controls the androgen receptor (AR) stability. Here, we correlated the expression levels of CCDC6 and USP7 proteins in primary prostate cancers (PC). Moreover, we tested the efficacy of the USP7 inhibitors, in combination with PARP-inhibitors as a novel therapeutic option in advanced prostate cancer.Experimental techniques: PC cells were exposed to USP7 inhibitor, P5091, together with cycloheximide, to investigate the turnover of the USP7 substrates, AR and CCDC6. As outcome of the AR downregulation, transcription targets of AR and its variant V7 were examined by qPCR. As a result of CCDC6 degradation, the induction of PARP inhibitors sensitivity was evaluated by analyzing PC cells viability and foci formation. We scored and correlated CCDC6 and USP7 expression levels in a prostate cancer tissue microarray (TMA).

  • Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-Italian version: regression based norms and equivalent scores.
    Publication Date: 22/03/2017, on Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
    by Siciliano M, Trojano L, Trojsi F, Greco R, Santoro M, Basile G, Piscopo F, D'Iorio A, Patrone M, Femiano C, Monsurrò M, Tedeschi G, Santangelo G
    DOI: 10.1007/s10072-017-2919-4

    Cognitive assessment for individuals with Amyotrophic Lateral Sclerosis (ALS) can be difficult because of frequent occurrence of difficulties with speech, writing, and drawing. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is a recent multi-domain neuropsychological screening tool specifically devised for this purpose, and it assesses the following domains: executive functions, social cognition, verbal fluency and language (ALS-specific), but also memory and visuospatial abilities (Non-ALS specific). ECAS total score ranges from 0 (worst performance) to 136 (best performance). Moreover, a brief caregiver interview provides an assessment of behaviour changes and psychotic symptoms usually associated with ALS patients. The aim of the present study was to provide normative values for ECAS total score and sub-scores in a sample of Italian healthy subjects. Two hundred and seventy-seven Italian healthy subjects (151 women and 126 men; age range 30-79 years; educational level from primary school to university) underwent ECAS and Montreal Cognitive Assessment (MoCA). Multiple linear regression analysis revealed that age and education significantly influenced performance on ECAS total score and sub-scale scores. From the derived linear equation, a correction grid for raw scores was built. Inferential cut-off scores were estimated using a non-parametric technique and equivalent scores (ES) were computed. Correlation analysis showed a good significant correlation between adjusted ECAS total scores with adjusted MoCA total scores (r rho = 0.669, p < 0.0001). The present study provided normative data for the ECAS in an Italian population useful for both clinical and research purposes.

  • Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells.
    Publication Date: 15/03/2017, on Human molecular genetics
    by Izzo A, Nitti M, Mollo N, Paladino S, Procaccini C, Faicchia D, Calì G, Genesio R, Bonfiglio F, Cicatiello R, Polishchuk E, Polishchuk R, Pinton P, Matarese G, Conti A, Nitsch L
    DOI: 10.1093/hmg/ddx016

    Alterations in mitochondrial activity and morphology have been demonstrated in human cells and tissues from individuals with Down syndrome (DS), as well as in DS mouse models. An impaired activity of the transcriptional coactivator PGC-1α/PPARGC1A due to the overexpression of chromosome 21 genes, such as NRIP1/RIP140, has emerged as an underlying cause of mitochondrial dysfunction in DS. We tested the hypothesis that the activation of the PGC-1α pathway might indeed reverse this mitochondrial dysfunction. To this end, we investigated the effects of metformin, a PGC-1α-activating drug, on mitochondrial morphology and function in DS foetal fibroblasts. Metformin induced both the expression of PGC-1α and an augmentation of its activity, as demonstrated by the increased expression of target genes, strongly promoting mitochondrial biogenesis. Furthermore, metformin enhanced oxygen consumption, ATP production, and overall mitochondrial activity. Most interestingly, this treatment reversed the fragmentation of mitochondria observed in DS and induced the formation of a mitochondrial network with a branched and elongated tubular morphology. Concomitantly, cristae remodelling occurred and the alterations observed by electron microscopy were significantly reduced. We finally demonstrated that the expression of genes of the fission/fusion machinery, namely OPA1 and MFN2, was reduced in trisomic cells and increased by metformin treatment. These results indicate that metformin promotes the formation of a mitochondrial network and corrects the mitochondrial dysfunction in DS cells. We speculate that alterations in the mitochondrial dynamics can be relevant in the pathogenesis of DS and that metformin can efficiently counteract these alterations, thus exerting protective effects against DS-associated pathologies.

  • Structure of a Stable G-Hairpin.
    Publication Date: 15/03/2017, on Journal of the American Chemical Society
    by Gajarský M, Živković ML, Stadlbauer P, Pagano B, Fiala R, Amato J, Tomáška L, Šponer J, Plavec J, Trantírek L
    DOI: 10.1021/jacs.6b10786

    In this study, we report the first atomic resolution structure of a stable G-hairpin formed by a natively occurring DNA sequence. An 11-nt long G-rich DNA oligonucleotide, 5'-d(GTGTGGGTGTG)-3', corresponding to the most abundant sequence motif in irregular telomeric DNA from Saccharomyces cerevisiae (yeast), is demonstrated to adopt a novel type of mixed parallel/antiparallel fold-back DNA structure, which is stabilized by dynamic G:G base pairs that transit between N1-carbonyl symmetric and N1-carbonyl, N7-amino base-pairing arrangements. Although the studied sequence first appears to possess a low capacity for base pairing, it forms a thermodynamically stable structure with a rather complex topology that includes a chain reversal arrangement of the backbone in the center of the continuous G-tract and 3'-to-5' stacking of the terminal residues. The structure reveals previously unknown principles of the folding of G-rich oligonucleotides that could be applied to the prediction of natural and/or the design of artificial recognition DNA elements. The structure also demonstrates that the folding landscapes of short DNA single strands is much more complex than previously assumed.

  • Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations.
    Publication Date: 14/03/2017, on Proceedings of the National Academy of Sciences of the United States of America
    by Moraca F, Amato J, Ortuso F, Artese A, Pagano B, Novellino E, Alcaro S, Parrinello M, Limongelli V
    DOI: 10.1073/pnas.1612627114

    G-quadruplexes (G4s) are higher-order DNA structures typically present at promoter regions of genes and telomeres. Here, the G4 formation decreases the replicative DNA at each cell cycle, finally leading to apoptosis. The ability to control this mitotic clock, particularly in cancer cells, is fascinating and passes through a rational understanding of the ligand/G4 interaction. We demonstrate that an accurate description of the ligand/G4 binding mechanism is possible using an innovative free-energy method called funnel-metadynamics (FM), which we have recently developed to investigate ligand/protein interaction. Using FM simulations, we have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 (d[AG3(T2AG3)3]), computing also the binding free-energy landscape. Two ligand binding modes have been identified as the lowest energy states. Furthermore, we have found prebinding sites, which are preparatory to reach the final binding mode. In our simulations, the ions and the water molecules have been explicitly represented and the energetic contribution of the solvent during ligand binding evaluated. Our theoretical results provide an accurate estimate of the absolute ligand/DNA binding free energy ([Formula: see text] = -10.3 ± 0.5 kcal/mol) that we validated through steady-state fluorescence binding assays. The good agreement between the theoretical and experimental value demonstrates that FM is a most powerful method to investigate ligand/DNA interaction and can be a useful tool for the rational design also of G4 ligands.

  • Macular hole surgery: the healing process of outer retinal layers to visual acuity recovery.
    Publication Date: 10/03/2017, on European journal of ophthalmology
    by Caprani SM, Donati S, Bartalena L, Vinciguerra R, Mariotti C, Testa F, Porta G, Azzolini C
    DOI: 10.5301/ejo.5000905

    To evaluate optical coherence tomography (OCT) modifications of outer retinal layers as determinants for functional recovery after surgery for idiopathic macular hole (IMH).