Latest PUBLICATIONS

  • Analysis of proautophagic activities of Citrus flavonoids in liver cells reveals the superiority of a natural polyphenol mixture over pure flavones.
    Publication Date: 26/04/2018, on The Journal of nutritional biochemistry
    by Lascala A, Martino C, Parafati M, Salerno R, Oliverio M, Pellegrino D, Mollace V, Janda E
    DOI: 10.1016/j.jnutbio.2018.04.005

    Autophagy dysfunction has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Natural compounds present in bergamot polyphenol fraction (BPF) prevent NAFLD and induce autophagy in rat livers. Here, we employed HepG2 cells expressing DsRed-LC3-GFP, a highly sensitive model system to screen for proautophagic compounds present in BPF. BPF induced autophagy in a time- and dose-dependent fashion and the effect was amplified in cells loaded with palmitic acid. Autophagy was mediated by the hydrophobic fraction of acid-hydrolyzed BPF (A-BPF), containing six flavanone and flavone aglycones as identified by liquid chromatography-high-resolution mass spectrometry. Among them, naringenin, hesperitin, eriodictyol and diosmetin were weak inducers of autophagy. Apigenin showed the strongest and dose-dependent proautophagic activity at early time points (6 h). Luteolin induced a biphasic autophagic response, strong at low doses and inhibitory at higher doses. Both flavones were toxic in HepG2 cells and in differentiated human liver progenitors HepaRG upon longer treatments (24 h). In contrast, BPF and A-BPF did not show any toxicity, but induced a persistent increase in autophagic flux. A mixture of six synthetic aglycones mimicking A-BPF was sufficient to induce a similar autophagic response, but it was mildly cytotoxic. Thus, while six main BPF flavonoids fully account for its proautophagic activity, their combined effect is not sufficient to abrogate cytotoxicity of individual compounds. This suggests that a natural polyphenol phytocomplex, such as BPF, is a safer and more effective strategy for the treatment of NAFLD than the use of pure flavonoids.

  • DNA in Squid Synaptosomes.
    Publication Date: 19/04/2018, on Molecular neurobiology
    by Cefaliello C, Prisco M, Crispino M, Giuditta A
    DOI: 10.1007/s12035-018-1071-3

    The synthesis of brain metabolic DNA (BMD) is modulated by learning and circadian oscillations and is not involved in cell division or DNA repair. Data from rats have highlighted its prevalent association with the mitochondrial fraction and its lack of identity with mtDNA. These features suggested that BMD could be localized in synaptosomes that are the major contaminants of brain mitochondrial fractions. The hypothesis has been examined by immunochemical analyses of the large synaptosomes of squid optic lobes that are readily prepared and identified. Optic lobe slices were incubated with 5-bromo-2-deoxyuridine (BrdU) and the isolated synaptosomal fraction was exposed to the green fluorescent anti-BrdU antibody. This procedure revealed that newly synthesized BrdU-labeled BMD is present in a significant percent of the large synaptosomes derived from the nerve terminals of retinal photoreceptor neurons and in synaptosomal bodies of smaller size. Synaptosomal BMD synthesis was strongly inhibited by actinomycin D. In addition, treatment of the synaptosomal fraction with Hoechst 33258, a blue fluorescent dye specific for dsDNA, indicated that native DNA was present in all synaptosomes. The possible role of synaptic BMD is briefly discussed.

  • Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine.
    Publication Date: 19/04/2018, on OncoTargets and therapy
    by De Lorenzo C, Paciello R, Riccio G, Rea D, Barbieri A, Coppola C, Maurea N
    DOI: 10.2147/OTT.S157294

    Pertuzumab, a novel anti-epidermal growth factor receptor 2 humanized monoclonal antibody, and trastuzumab-emtansine (TDM1), a novel antibody-drug conjugate made up of trastuzumab covalently linked to the highly potent microtubule inhibitory agent DM1, have been recently approved by the US Food and Drug Administration for increasing the efficiency and safety of breast cancer therapy with trastuzumab. We investigated for the first time the potential cardiotoxic effects of pertuzumab and TDM1, which are not yet fully elucidated, and we tested whether ranolazine could blunt their cardiotoxicity.

  • The Effect of Low-Dose Ionizing Radiation on Stem Cell Biology: A Contribution to Radiation Risk.
    Publication Date: 17/04/2018, on Stem cells (Dayton, Ohio)
    by Squillaro T, Galano G, De Rosa R, Peluso G, Galderisi U
    DOI: 10.1002/stem.2836

    Exposure to high levels of ionizing radiation (IR) (>0.5Gy), negatively affect health. but, less is known about the effects of low dose IR (LDIR) but recent, evidence suggests that it may have profound effects on cellular functions. We are commonly exposed to LDIR over natural background levels from numerous sources: people may be exposed to low dose IR for medical diagnosis and therapy, air travel, illegal IR waste dumpsites or by occupational exposures in the nuclear and medical sectors. Stem cells reside for long periods of time in our bodies, and this increases the possibility that they may be accumulate genotoxic damage derived from extrinsic LDIR or intrinsic sources (such as DNA replication). In this review we provide an overview of LDIR effects on biology of stem cell compartments. The principal findings and issues reported in the scientific literature are discussed in order to present the current understanding of the LDIR exposure risk, and assess whether it may impact human health. We first consider the general biological consequences of LDIR exposure. Following this, we discuss the effects of LDIR on stem cells as discovered through in vitro and in vivo studies. This article is protected by copyright. All rights reserved.

  • LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response.
    Publication Date: 15/04/2018, on Cancer research
    by Ha JH, Radhakrishnan R, Jayaraman M, Yan M, Ward JD, Fung KM, Moxley K, Sood AK, Isidoro C, Mukherjee P, Song YS, Dhanasekaran DN
    DOI: 10.1158/0008-5472.CAN-17-1624

    Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase and generation of reactive oxygen species, resulting in activation of HIF1α. HIF1α in turn induced expression of glucose transporter-1 and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate, attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer. These findings establish LPA as a potential therapeutic target in ovarian cancer, revealing its role in the activation of HIF1α-mediated metabolic reprogramming in this disease. .

  • Pro-inflammatory cytokines activate hypoxia-inducible factor 3α via epigenetic changes in mesenchymal stromal/stem cells.
    Publication Date: 11/04/2018, on Scientific reports
    by Cuomo F, Coppola A, Botti C, Maione C, Forte A, Scisciola L, Liguori G, Caiafa I, Ursini MV, Galderisi U, Cipollaro M, Altucci L, Cobellis G
    DOI: 10.1038/s41598-018-24221-5

    Human mesenchymal stromal/stem cells (hMSCs) emerged as a promising therapeutic tool for ischemic disorders, due to their ability to regenerate damaged tissues, promote angiogenesis and reduce inflammation, leading to encouraging, but still limited results. The outcomes in clinical trials exploring hMSC therapy are influenced by low cell retention and survival in affected tissues, partially influenced by lesion's microenvironment, where low oxygen conditions (i.e. hypoxia) and inflammation coexist. Hypoxia and inflammation are pathophysiological stresses, sharing common activators, such as hypoxia-inducible factors (HIFs) and NF-κB. HIF1α and HIF2α respond essentially to hypoxia, activating pathways involved in tissue repair. Little is known about the regulation of HIF3α. Here we investigated the role of HIF3α in vitro and in vivo. Human MSCs expressed HIF3α, differentially regulated by pro-inflammatory cytokines in an oxygen-independent manner, a novel and still uncharacterized mechanism, where NF-κB is critical for its expression. We investigated if epigenetic modifications are involved in HIF3α expression by methylation-specific PCR and histone modifications. Robust hypermethylation of histone H3 was observed across HIF3A locus driven by pro-inflammatory cytokines. Experiments in a murine model of arteriotomy highlighted the activation of Hif3α expression in infiltrated inflammatory cells, suggesting a new role for Hif3α in inflammation in vivo.

  • miR-34b/c Regulates Wnt1 and Enhances Mesencephalic Dopaminergic Neuron Differentiation.
    Publication Date: 10/04/2018, on Stem cell reports
    by De Gregorio R, Pulcrano S, De Sanctis C, Volpicelli F, Guatteo E, von Oerthel L, Latagliata EC, Esposito R, Piscitelli RM, Perrone-Capano C, Costa V, Greco D, Puglisi-Allegra S, Smidt MP, di Porzio U, Caiazzo M, Mercuri NB, Li M, Bellenchi GC
    DOI: 10.1016/j.stemcr.2018.02.006

    The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons. Induced dopaminergic (iDA) cells synthesize dopamine and show spontaneous electrical activity, reversibly blocked by tetrodotoxin, consistent with the electrophysiological properties featured by brain dopaminergic neurons. Our findings point to a role for miR-34b/c in neuronal commitment and highlight the potential of exploiting its synergy with key transcription factors in enhancing in vitro generation of dopaminergic neurons.

  • ASSOCIATION BETWEEN GENOTYPE AND DISEASE PROGRESSION IN ITALIAN STARGARDT PATIENTS: A Retrospective Natural History Study.
    Publication Date: 10/04/2018, on Retina (Philadelphia, Pa.)
    by Di Iorio V, Orrico A, Esposito G, Melillo P, Rossi S, Sbordone S, Auricchio A, Testa F, Simonelli F
    DOI: 10.1097/IAE.0000000000002151

    To investigate the natural history of Stargardt disease over a multiyear follow-up.

  • Stress and stem cells: adult Muse cells tolerate extensive genotoxic stimuli better than mesenchymal stromal cells.
    Publication Date: 10/04/2018, on Oncotarget
    by Alessio N, Squillaro T, Özcan S, Di Bernardo G, Venditti M, Melone M, Peluso G, Galderisi U
    DOI: 10.18632/oncotarget.25039

    Mesenchymal stromal cells (MSCs) are not a homogenous population but comprehend several cell types, such as stem cells, progenitor cells, fibroblasts, and other types of cells. Among these is a population of pluripotent stem cells, which represent around 1-3% of MSCs. These cells, named multilineage-differentiating stress enduring (Muse) cells, are stress-tolerant cells. Stem cells may undergo several rounds of intrinsic and extrinsic stresses due to their long life and must have a robust and effective DNA damage checkpoint and DNA repair mechanism, which, following a genotoxic episode, promote the complete recovery of cells rather than triggering senescence and/or apoptosis. We evaluated how Muse cells can cope with DNA damaging stress in comparison with MSCs. We found that Muse cells were resistant to chemical and physical genotoxic stresses better than non-Muse cells. Indeed, the level of senescence and apoptosis was lower in Muse cells. Our results proved that the DNA damage repair system (DDR) was properly activated following injury in Muse cells. While in non-Muse cells some anomalies may have occurred because, in some cases, the activation of the DDR persisted by 48 hr post damage, in others no activation took place. In Muse cells, the non-homologous end joining (NHEJ) enzymatic activity increases compared to other cells, while single-strand repair activity (NER, BER) does not. In conclusion, the high ability of Muse cells to cope with genotoxic stress is related to their quick and efficient sensing of DNA damage and activation of DNA repair systems.

  • Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease.
    Publication Date: 09/04/2018, on Neuromuscular disorders : NMD
    by Savarese M, Torella A, Musumeci O, Angelini C, Astrea G, Bello L, Bruno C, Comi GP, Di Fruscio G, Piluso G, Di Iorio G, Ergoli M, Esposito G, Fanin M, Farina O, Fiorillo C, Garofalo A, Giugliano T, Magri F, Minetti C, Moggio M, Passamano L, Pegoraro E, Picillo E, Sampaolo S, Santorelli FM, Semplicini C, Udd B, Toscano A, Politano L, Nigro V
    DOI: 10.1016/j.nmd.2018.03.011

    Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T >G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results.

  • Effects of iron on the aggregation propensity of the N-terminal fibrillogenic polypeptide of human apolipoprotein A-I.
    Publication Date: 05/04/2018, on Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine
    by Del Giudice R, Pesce A, Cozzolino F, Monti M, Relini A, Piccoli R, Arciello A, Monti DM
    DOI: 10.1007/s10534-018-0101-y

    Specific mutations in APOA1 gene lead to systemic, hereditary amyloidoses. In ApoA-I related amyloidosis involving the heart, amyloid deposits are mainly constituted by the 93-residue N-terminal region of the protein, here indicated as [1-93]ApoA-I. Oxidative stress is known to be an enhancing factor for protein aggregation. In healthy conditions, humans are able to counteract the formation and the effects of oxidative molecules. However, aging and atmospheric pollution increase the concentration of oxidative agents, such as metal ions. As the main effect of iron deregulation is proposed to be an increase in oxidative stress, we analysed the effects of iron on [1-93]ApoA-I aggregation. By using different biochemical approaches, we demonstrated that Fe(II) is able to reduce the formation of [1-93]ApoA-I fibrillar species, probably by stabilizing its monomeric form, whereas Fe(III) shows a positive effect on polypeptide fibrillogenesis. We hypothesize that, in healthy conditions, Fe(III) is reduced by the organism to Fe(II), thus inhibiting amyloid formation, whereas during ageing such protective mechanisms decline, thus exposing the organism to higher oxidative stress levels, which are also related to an increase in Fe(III). This alteration could contribute to the pathogenesis of amyloidosis.

  • Inositol trisphosphate receptor type 3-mediated enhancement of EGFR and MET co-targeting efficacy in non-small cell lung cancer detected by 18F-fluorothymidine.
    Publication Date: 04/04/2018, on Clinical cancer research : an official journal of the American Association for Cancer Research
    by Iommelli F, De Rosa V, Terlizzi C, Monti M, Panico M, Fonti R, Del Vecchio S
    DOI: 10.1158/1078-0432.CCR-17-3657

    Our aim was to test whether imaging with F-fluorothymidine (F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination.

  • Palatability and oral cavity tolerability of THC:CBD oromucosal spray and possible improvement measures in multiple sclerosis patients with resistant spasticity: a pilot study.
    Publication Date: 01/04/2018, on Neurodegenerative disease management
    by Lus G, Cantello R, Danni MC, Rini A, Sarchielli P, Tassinari T, Signoriello E
    DOI: 10.2217/nmt-2017-0056

    Complaints about Δ-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex; GW Pharma Ltd, Salisbury, UK) in the management of multiple sclerosis spasticity include unpleasant taste and oral mucosal anomalies. This pilot study assessed the use of sugar-free chewing gum and/or a refrigerated bottle of THC:CBD oromucosal spray to mitigate these effects.

  • Cerebellar contribution to spatial realignment: A tDCS study during multiple-step prism adaptation.
    Publication Date: 01/04/2018, on Neuropsychologia
    by Panico F, Sagliano L, Nozzolillo C, Trojano L, Rossetti Y
    DOI: 10.1016/j.neuropsychologia.2018.03.008

    Several processes are devoted to error reduction in response to a visual displacement, such as the one induced by wedge prisms. Strategic calibration and spatial realignment contribute to the iteratively process that allows a progressive adjustment of motor commands to reduce the magnitude of errors. Isolating the specific contributions to motor behaviour coming from these distinct processes is not possible using traditional single-step Prism Adaptation (PA), where participants are directly exposed to full prismatic shift. Here, we selectively investigated the effect of realignment on motor behaviour by means of a PA paradigm (the multiple-step PA) that allows to elude the development of strategic calibration. We tested for a specific cerebellar contribution to realignment by means of transcranial Direct Current Stimulation (tDCS) in healthy subjects. Confirming and expanding previous imaging and stimulation results, our study causally demonstrates cerebellar involvement in spatial realignment. Additionally, our results point to a possible contribution of the cerebellum in automatic online control. The role of a cortico-cerebellar network accounting for this results and possible clinical applications are proposed and discussed.

  • Famous people recognition through personal name: a normative study.
    Publication Date: 01/04/2018, on Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
    by Piccininni C, Quaranta D, Papagno C, Trojano L, Ferrara A, Luzzi S, Carlesimo GA, Marra C, Gainotti G
    DOI: 10.1007/s10072-018-3251-3

    In this normative study, we investigated famous people recognition through personal name, using as stimuli the names of the same 40 Italian famous persons whose faces and voices had been utilized for the normative study of the Famous People Recognition Battery. For each famous people, we assessed name familiarity, person identification (when the name had been considered as familiar), and false alarms. The investigation was carried out on 143 normal subjects who varied in age and education. Name familiarity and semantic scores were affected by educational level, whereas age influenced false alarms. A comparison between results obtained with names in this research and with faces and voices of the same famous people in our previous study showed that familiarity scores were higher for personal names than those for faces and voices, which obtained the worst scores. Person identification scores were not significantly different from names and from faces, but both these scores were significantly higher than the semantic scores obtained by voices. Taken together, these results are inconsistent with the influential interactive activation and competition model of person recognition.