Latest PUBLICATIONS

  • The Use of Immunosuppressant Therapy for Multiple Sclerosis in Italy: A Multicenter Retroprospective Study.
    Publication Date: 27/06/2016, on PloS one
    by D'Amico E, Leone C, Graziano G, Amato MP, Bergamaschi R, Cavalla P, Coniglio G, Di Battista G, Ferrò MT, Granella F, Granieri E, Lugaresi A, Lus G, Millefiorini E, Pozzilli C, Tedeschi G, Zappia M, Comi G, Trojano M, Lepore V, Patti F
    DOI: 10.1371/journal.pone.0157721

    Immunosuppressive agents (ISA) have been used in multiple sclerosis (MS) for decades, frequently as off label licensed therapies. Given the new MS treatment landscape, what place do ISA have in combating MS?

  • Molecular Dynamics Driven Design of pH-Stabilized Mutants of MNEI, a Sweet Protein.
    Publication Date: 24/06/2016, on PloS one
    by Leone S, Picone D
    DOI: 10.1371/journal.pone.0158372

    MNEI is a single chain derivative of monellin, a plant protein that can interact with the human sweet taste receptor, being therefore perceived as sweet. This unusual physiological activity makes MNEI a potential template for the design of new sugar replacers for the food and beverage industry. Unfortunately, applications of MNEI have been so far limited by its intrinsic sensitivity to some pH and temperature conditions, which could occur in industrial processes. Changes in physical parameters can, in fact, lead to irreversible protein denaturation, as well as aggregation and precipitation. It has been previously shown that the correlation between pH and stability in MNEI derives from the presence of a single glutamic residue in a hydrophobic pocket of the protein. We have used molecular dynamics to study the consequences, at the atomic level, of the protonation state of such residue and have identified the network of intramolecular interactions responsible for MNEI stability at acidic pH. Based on this information, we have designed a pH-independent, stabilized mutant of MNEI and confirmed its increased stability by both molecular modeling and experimental techniques.

  • Toward the Development of Specific G-Quadruplex Binders: Synthesis, Biophysical, and Biological Studies of New Hydrazone Derivatives.
    Publication Date: 23/06/2016, on Journal of medicinal chemistry
    by Amato J, Morigi R, Pagano B, Pagano A, Ohnmacht S, De Magis A, Tiang YP, Capranico G, Locatelli A, Graziadio A, Leoni A, Rambaldi M, Novellino E, Neidle S, Randazzo A
    DOI: 10.1021/acs.jmedchem.6b00129

    G-Quadruplex-binding compounds are currently perceived as possible anticancer therapeutics. Here, starting from a promising lead, a small series of novel hydrazone-based compounds were synthesized and evaluated as G-quadruplex binders. The in vitro G-quadruplex-binding properties of the synthesized compounds were investigated employing both human telomeric and oncogene promoter G-quadruplexes with different folding topologies as targets. The present investigation led to the identification of potent G-quadruplex stabilizers with high selectivity over duplex DNA and preference for one G-quadruplex topology over others. Among them, selected derivatives have been shown to trap G-quadruplex structures in the nucleus of cancer cells. Interestingly, this behavior correlates with efficient cytotoxic activity in human osteosarcoma and colon carcinoma cells.

  • Coordinated Metabolic Changes and Modulation of Autophagy during Myogenesis.
    Publication Date: 16/06/2016, on Frontiers in physiology
    by Fortini P, Iorio E, Dogliotti E, Isidoro C
    DOI: 10.3389/fphys.2016.00237

    Autophagy undergoes a fine tuning during tissue differentiation and organ remodeling in order to meet the dynamic changes in the metabolic needs. While the involvement of autophagy in the homeostasis of mature muscle tissues has been intensively studied, no study has so far addressed the regulation of autophagy in relation to the metabolic state during the myogenic differentiation. In our recently published study (Fortini et al., 2016) we investigated the metabolic profile and regulation of autophagy that accompany the differentiation process of mouse skeletal muscle satellite cells (MSC)-derived myoblasts into myotubes. Here, we briefly present these findings also in the light of similar studies conducted by other authors. We show that during myogenic differentiation mitochondrial function and activity are greatly increased, and the activation of autophagy accompanies the transition from myoblasts to myotube. Autophagy is mTORC1 inactivation-independent and, remarkably, is required to allow the myocyte fusion process, as shown by impaired cell fusion when the autophagic flux is inhibited either by genetic or drug manipulation. Further, we found that myoblasts derived from p53 null mice show defective terminal differentiation into myotubes and reduced activation of basal autophagy. Of note, glycolysis prevails and mitochondrial biogenesis is strongly impaired in p53-null myoblasts. Thus, autophagy, mitochondrial homeostasis, and differentiation are finely tuned in a coordinate manner during muscle biogenesis.

  • Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells.
    Publication Date: 09/06/2016, on Oncotarget
    by Pascucci B, D'Errico M, Romagnoli A, De Nuccio C, Savino M, Pietraforte D, Lanzafame M, Calcagnile AS, Fortini P, Baccarini S, Orioli D, Degan P, Visentin S, Stefanini M, Isidoro C, Fimia GM, Dogliotti E
    DOI: 10.18632/oncotarget.9913

    The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti-apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches.

  • Effects of an High-Fat Diet Enriched in Lard or in Fish Oil on the Hypothalamic Amp-Activated Protein Kinase and Inflammatory Mediators.
    Publication Date: 09/06/2016, on Frontiers in cellular neuroscience
    by Viggiano E, Mollica MP, Lionetti L, Cavaliere G, Trinchese G, De Filippo C, Chieffi S, Gaita M, Barletta A, De Luca B, Crispino M, Monda M
    DOI: 10.3389/fncel.2016.00150

    The high fat diet (HFD) rich in lard induces obesity, inflammation and oxidative stress, and the deregulation of hypothalamic nuclei plays an important role in this mechanism. One important factor involved in the food intake and inflammation is adenosine monophosphate-dependent kinase (AMPK), a serine/threonine kinase activated by phosphorylation. Omega (ω)3-polyunsaturated fatty acids (PUFA) are dietary compounds known to attenuate the obesity-related diseases, although the molecular mechanisms underlying their actions in the hypothalamus are not completely understood. We hypothesized that the beneficial effects of PUFA may be mediated by AMPK in the hypothalamus. To this aim, rats were fed a control diet (CD), or isocaloric HFD containing either fish oil (FD; rich in ω3-PUFA) or lard for 6 weeks, and the activation of AMPK, inflammatory state (IKKβ, TNF-α) and oxidative stress were analyzed in the hypothalamus. In addition, we also studied serum lipid profile, homeostatic model assessment (HOMA) index, and pro-inflammatory parameters. Our results showed, at the hypothalamic level of LD-fed rats, an increase of AMPK activation, inflammation and oxidative stress, while no modifications were detected in FD-fed animals compared to CD. In addition body weight gain, serum lipid profile, pro-inflammatory parameters and insulin resistance were reduced in FD animals compared to LD. In conclusion, our data indicate that the substitution of saturated by unsaturated fatty acids in the diet has beneficial effects on modulation of hypothalamic inflammation and function in obesity, underlying, at hypothalamic level, the interaction among insulin and/or leptin resistance, AMPK activation and hyperphagia.

  • The Brain from Within.
    Publication Date: 08/06/2016, on Frontiers in human neuroscience
    by di Porzio U
    DOI: 10.3389/fnhum.2016.00265

    Functional magnetic resonance imaging (fMRI) provides a powerful way to visualize brain functions and observe brain activity in response to tasks or thoughts. It allows displaying brain damages that can be quantified and linked to neurobehavioral deficits. fMRI can potentially draw a new cartography of brain functional areas, allow us to understand aspects of brain function evolution or even breach the wall into cognition and consciousness. However, fMRI is not deprived of pitfalls, such as limitation in spatial resolution, poor reproducibility, different time scales of fMRI measurements and neuron action potentials, low statistical values. Thus, caution is needed in the assessment of fMRI results and conclusions. Additional diagnostic techniques based on MRI such as arterial spin labeling (ASL) and the measurement of diffusion tensor imaging (DTI) provide new tools to assess normal brain development or disruption of anatomical networks in diseases. A cutting edge of recent research uses fMRI techniques to establish a "map" of neural connections in the brain, or "connectome". It will help to develop a map of neural connections and thus understand the operation of the network. New applications combining fMRI and real time visualization of one's own brain activity (rtfMRI) could empower individuals to modify brain response and thus could enable researchers or institutions to intervene in the modification of an individual behavior. The latter in particular, as well as the concern about the confidentiality and storage of sensitive information or fMRI and lie detectors forensic use, raises new ethical questions.

  • Intrafamilial heterogeneity of congenital optic disc pit maculopathy.
    Publication Date: 08/06/2016, on Ophthalmic genetics
    by Rossi S, De Rosa G, D'Alterio FM, Orrico A, Banfi S, Testa F, Simonelli F
    DOI: 10.1080/13816810.2016.1188120

    Optic disc pit is a very rare clinical entity. The main complication of this condition is the maculopathy.

  • Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells.
    Publication Date: 07/06/2016, on Oncotarget
    by Pascucci B, D'Errico M, Romagnoli A, De Nuccio C, Savino M, Pietraforte D, Lanzafame M, Calcagnile AS, Fortini P, Baccarini S, Orioli D, Degan P, Visentin S, Stefanini M, Isidoro C, Fimia GM, Dogliotti E
    DOI: 10.18632/oncotarget.9913

    The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti-apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches.

  • Contrast-Enhanced Ultrasound: a Simple and Effective Tool in Defining a Rapid Diagnostic Work-up for Small Nodules Detected in Cirrhotic Patients during Surveillance.
    Publication Date: 01/06/2016, on Journal of gastrointestinal and liver diseases : JGLD
    by Giorgio A, Montesarchio L, Gatti P, Amendola F, Matteucci P, Santoro B, Merola MG, Merola F, Coppola C, Giorgio V
    DOI:

    Disappearance of portal blood flow and arterial vascularization is the hallmark of hepatocarcinogenesis. The capability of a dynamic imaging modality detecting arterial hypervascularization of small nodules is crucial to promote a rapid diagnostic and therapeutic work-up improving survival. We aimed to evaluate the capability of CEUS to detect arterial vascularization of ≤ 2 cm HCC nodules arising during surveillance so as to shorten the diagnostic and therapeutic work-up.

  • Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants.
    Publication Date: 01/06/2016, on Hepatology (Baltimore, Md.)
    by Chesi G, Hegde RN, Iacobacci S, Concilli M, Parashuraman S, Festa BP, Polishchuk EV, Di Tullio G, Carissimo A, Montefusco S, Canetti D, Monti M, Amoresano A, Pucci P, van de Sluis B, Lutsenko S, Luini A, Polishchuk RS
    DOI: 10.1002/hep.28398

    Wilson disease (WD) is an autosomal recessive disorder that is caused by the toxic accumulation of copper (Cu) in the liver. The ATP7B gene, which is mutated in WD, encodes a multitransmembrane domain adenosine triphosphatase that traffics from the trans-Golgi network to the canalicular area of hepatocytes, where it facilitates excretion of excess Cu into the bile. Several ATP7B mutations, including H1069Q and R778L that are two of the most frequent variants, result in protein products, which, although still functional, remain in the endoplasmic reticulum. Thus, they fail to reach Cu excretion sites, resulting in the toxic buildup of Cu in the liver of WD patients. Therefore, correcting the location of these mutants by leading them to the appropriate functional sites in the cell should restore Cu excretion and would be beneficial to help large cohorts of WD patients. However, molecular targets for correction of endoplasmic reticulum-retained ATP7B mutants remain elusive. Here, we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and c-Jun N-terminal kinase signaling pathways, which favor the rapid degradation of the mutant. Suppression of these pathways with RNA interference or specific chemical inhibitors results in the substantial rescue of ATP7B(H1069Q) (as well as that of several other WD-causing mutants) from the endoplasmic reticulum to the trans-Golgi network compartment, in recovery of its Cu-dependent trafficking, and in reduction of intracellular Cu levels.

  • Standard EEG in diagnostic process of prolonged disorders of consciousness.
    Publication Date: 01/06/2016, on Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology
    by Estraneo A, Loreto V, Guarino I, Boemia V, Paone G, Moretta P, Trojano L
    DOI: 10.1016/j.clinph.2016.03.021

    This cross-sectional study assessed the ability of standard EEG in distinguishing vegetative state (VS) from minimally conscious state plus (MCS+) or MCS minus (MCS-), and to correlate EEG features with aetiology and level of responsiveness assessed by Coma Recovery Scale-Revised (CRS-R).

  • Lymphocytosis as a response biomarker of natalizumab therapeutic efficacy in multiple sclerosis.
    Publication Date: 01/06/2016, on Multiple sclerosis (Houndmills, Basingstoke, England)
    by Signoriello E, Lanzillo R, Brescia Morra V, Di Iorio G, Fratta M, Carotenuto A, Lus G
    DOI: 10.1177/1352458515604381

    Natalizumab is an effective therapy in relapsing-remitting multiple sclerosis (RRMS), as it reduces lymphocyte transmigration through the blood-brain barrier (BBB) and induces lymphocytosis.

  • Cerebellar cathodal tDCS interferes with recalibration and spatial realignment during prism adaptation procedure in healthy subjects.
    Publication Date: 01/06/2016, on Brain and cognition
    by Panico F, Sagliano L, Grossi D, Trojano L
    DOI: 10.1016/j.bandc.2016.03.002

    The aim of this study is to clarify the specific role of the cerebellum during prism adaptation procedure (PAP), considering its involvement in early prism exposure (i.e., in the recalibration process) and in post-exposure phase (i.e., in the after-effect, related to spatial realignment). For this purpose we interfered with cerebellar activity by means of cathodal transcranial direct current stimulation (tDCS), while young healthy individuals were asked to perform a pointing task on a touch screen before, during and after wearing base-left prism glasses. The distance from the target dot in each trial (in terms of pixels) on horizontal and vertical axes was recorded and served as an index of accuracy. Results on horizontal axis, that was shifted by prism glasses, revealed that participants who received cathodal stimulation showed increased rightward deviation from the actual position of the target while wearing prisms and a larger leftward deviation from the target after prisms removal. Results on vertical axis, in which no shift was induced, revealed a general trend in the two groups to improve accuracy through the different phases of the task, and a trend, more visible in cathodal stimulated participants, to worsen accuracy from the first to the last movements in each phase. Data on horizontal axis allow to confirm that the cerebellum is involved in all stages of PAP, contributing to early strategic recalibration process, as well as to spatial realignment. On vertical axis, the improving performance across the different stages of the task and the worsening accuracy within each task phase can be ascribed, respectively, to a learning process and to the task-related fatigue.

  • A first-in-class and a fished out anticancer platinum compound: cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] compared for their reactivity towards DNA model systems.
    Publication Date: 28/05/2016, on Dalton transactions (Cambridge, England : 2003)
    by Musumeci D, Platella C, Riccardi C, Merlino A, Marzo T, Massai L, Messori L, Montesarchio D
    DOI: 10.1039/c6dt00294c

    Contrary to what was believed for many years, cis-PtI2(NH3)2, the diiodido analogue of cisplatin, displays high in vitro antiproliferative activity toward a set of tumour cell lines, overcoming resistance to cisplatin in a platinum-resistant cancer cell line. In the context of a general reappraisal of iodinated Pt(ii) derivatives, aiming at a more systematic evaluation of their chemical and biological profiles, here we report on the reactivity of cis-PtI2(NH3)2 with selected DNA model systems, in single, double strand or G-quadruplex form, using cisplatin as a control. A combined approach has been exploited in this study, including circular dichroism (CD), UV-visible spectroscopy and electrospray mass spectrometry (ESI-MS) analyses. The data reveal that cis-PtI2(NH3)2 shows an overall reactivity towards the investigated oligonucleotides significantly higher than cisplatin.