Latest PUBLICATIONS

  • Successful long-term therapy with flecainide in a family with paramyotonia congenita.
    Publication Date: 27/02/2018, on Journal of neurology, neurosurgery, and psychiatry
    by Terracciano C, Farina O, Esposito T, Lombardi L, Napolitano F, De Blasiis P, Ciccone G, Todisco V, Tuccillo F, Bernardini S, Di Iorio G, Melone MAB, Sampaolo S
    DOI: 10.1136/jnnp-2017-317615

  • Tissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice.
    Publication Date: 22/02/2018, on PLoS genetics
    by Freschi A, Hur SK, Valente FM, Ideraabdullah FY, Sparago A, Gentile MT, Oneglia A, Di Nucci D, Colucci-D'Amato L, Thorvaldsen JL, Bartolomei MS, Riccio A, Cerrato F
    DOI: 10.1371/journal.pgen.1007243

    Differential DNA methylation defects of H19/IGF2 are associated with congenital growth disorders characterized by opposite clinical pictures. Due to structural differences between human and mouse, the mechanisms by which mutations of the H19/IGF2 Imprinting Control region (IC1) result in these diseases are undefined. To address this issue, we previously generated a mouse line carrying a humanized IC1 (hIC1) and now replaced the wildtype with a mutant IC1 identified in the overgrowth-associated Beckwith-Wiedemann syndrome. The new humanized mouse line shows pre/post-natal overgrowth on maternal transmission and pre/post-natal undergrowth on paternal transmission of the mutation. The mutant hIC1 acquires abnormal methylation during development causing opposite H19/Igf2 imprinting defects on maternal and paternal chromosomes. Differential and possibly mosaic Igf2 expression and imprinting is associated with asymmetric growth of bilateral organs. Furthermore, tissue-specific imprinting defects result in deficient liver- and placenta-derived Igf2 on paternal transmission and excessive Igf2 in peripheral tissues on maternal transmission, providing a possible molecular explanation for imprinting-associated and phenotypically contrasting growth disorders.

  • Increase of natural killer cells in children with liver transplantation-acquired food allergy.
    Publication Date: 15/02/2018, on Allergologia et immunopathologia
    by Mori F, Angelucci C, Cianferoni A, Barni S, Indolfi G, Casini A, Mangone G, Materassi M, Pucci N, Azzari C, Novembre E
    DOI: 10.1016/j.aller.2017.09.030

    Transplantation-acquired food allergies (TAFA) are frequently reported and considered to be caused by immunosuppressive therapy. The aim of this study was to investigate the allergic and immunologic responses in children who had liver or kidney transplantations.

  • Effects of different extracts of curcumin on TPC1 papillary thyroid cancer cell line.
    Publication Date: 15/02/2018, on BMC complementary and alternative medicine
    by Perna A, De Luca A, Adelfi L, Pasquale T, Varriale B, Esposito T
    DOI: 10.1186/s12906-018-2125-9

    The thyroid gland is one of the largest endocrine glands in the body. The vast majority of TCs (> 90%) originate from follicular cells and are defined as differentiated thyroid cancers (DTC) and the two histological subtypes are the papillary TC with its variants and the follicular TC. Curcumin possesses a wide variety of biological functions, and thanks to its properties, it has gained considerable attention due to its profound medicinal values (Prasad, Gupta, Tyagi, and Aggarwal, Biotechnol Adv 32:1053-1064, 2014). We have undertaken the present work in order to define the possible role of curcumin in modulating the genetic expression of cell markers and to understand the effectiveness of this nutraceutical in modulating the regression of cancer phenotype.

  • The carnitine system and cancer metabolic plasticity.
    Publication Date: 14/02/2018, on Cell death & disease
    by Melone MAB, Valentino A, Margarucci S, Galderisi U, Giordano A, Peluso G
    DOI: 10.1038/s41419-018-0313-7

    Metabolic flexibility describes the ability of cells to respond or adapt its metabolism to support and enable rapid proliferation, continuous growth, and survival in hostile conditions. This dynamic character of the cellular metabolic network appears enhanced in cancer cells, in order to increase the adaptive phenotype and to maintain both viability and uncontrolled proliferation. Cancer cells can reprogram their metabolism to satisfy the energy as well as the biosynthetic intermediate request and to preserve their integrity from the harsh and hypoxic environment. Although several studies now recognize these reprogrammed activities as hallmarks of cancer, it remains unclear which are the pathways involved in regulating metabolic plasticity. Recent findings have suggested that carnitine system (CS) could be considered as a gridlock to finely trigger the metabolic flexibility of cancer cells. Indeed, the components of this system are involved in the bi-directional transport of acyl moieties from cytosol to mitochondria and vice versa, thus playing a fundamental role in tuning the switch between the glucose and fatty acid metabolism. Therefore, the CS regulation, at both enzymatic and epigenetic levels, plays a pivotal role in tumors, suggesting new druggable pathways for prevention and treatment of human cancer.

  • Brain Metabolic DNA in Rat Cytoplasm.
    Publication Date: 09/02/2018, on Molecular neurobiology
    by Giuditta A, Rutigliano B
    DOI: 10.1007/s12035-018-0932-0

    Brain metabolic DNA (BMD) is not involved in cell division or DNA repair but is modulated by memory acquisition, sleep processing, and circadian oscillations. Using routine methods of subcellular fractionation, newly synthesized BMD from male rats is shown to be localized in crude nuclear, mitochondrial, and microsomal fractions and in two fractions of purified nuclei. Sub-fractionation of the mitochondrial fraction indicates the prevalent localization of BMD in free mitochondria and to a lesser degree in synaptosomes and myelin. Cesium density profiles of homogenate, subcellular fractions, and purified nuclei obtained after incorporation periods from 30 min to 4 h indicate that BMD synthesis takes place by reverse transcription in cytoplasmic organelles. Following the acquisition of the double-stranded structure, BMD is transferred to nuclei. Kinetic analyses lasting several weeks highlight the massive BMD turnover in subcellular fractions and purified nuclei and its dependence on age. Data are in agreement with the role of BMD as a temporary information store of cell responses of potential use in comparable forthcoming experiences.

  • Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production.
    Publication Date: 06/02/2018, on Frontiers in physiology
    by Riccio G, Antonucci S, Coppola C, D'Avino C, Piscopo G, Fiore D, Maurea C, Russo M, Rea D, Arra C, Condorelli G, Di Lisa F, Tocchetti CG, De Lorenzo C, Maurea N
    DOI: 10.3389/fphys.2018.00038

    The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab. Trastuzumab cardiotoxicity was accompanied by elevations in natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated with co-treatment with ranolazine. Trastuzumab also increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Interestingly, Neonatal Rat Ventricular Myocytes (NRVMs), labeled with MitoTracker Red and treated with trastuzumab, showed only a small increase in ROS compared to baseline conditions. We then stressed trastuzumab-treated cells with the beta-agonist isoproterenol to increase workload, and we observed a significant increase of probe fluorescence, compared with cells treated with isoproterenol alone, reflecting induction of oxidative stress. These effects were blunted by ranolazine, supporting a role for Na inhibition in the regulation of redox balance also in trastuzumab cardiotoxicity.

  • Verapamil Inhibits Ser202/Thr205 Phosphorylation of Tau by Blocking TXNIP/ROS/p38 MAPK Pathway.
    Publication Date: 05/02/2018, on Pharmaceutical research
    by Melone MAB, Dato C, Paladino S, Coppola C, Trebini C, Giordana MT, Perrone L
    DOI: 10.1007/s11095-017-2276-2

    Oxidative stress is a hallmark of Alzheimer's Disease (AD) and promotes tau phosphorylation. Since Thioredoxin Interacting protein (TXNIP), the inhibitor of the anti-oxidant system of Thioredoxin, is up regulated in the hippocampus of AD patients, we investigated whether TXNIP plays a role in promoting tau phosphorylation and whether Verapamil, an inhibitor of TXNIP expression, prevents TXNIP downstream effects.

  • Fingolimod reduces the clinical expression of active demyelinating lesions in MS.
    Publication Date: 01/02/2018, on Multiple sclerosis and related disorders
    by Signoriello E, Landi D, Monteleone F, Saccà F, Nicoletti CG, Buttari F, Sica F, Marfia GA, Di Iorio G, Lus G, Centonze D
    DOI: 10.1016/j.msard.2018.02.002

    Fingolimod is a modulator of Central and peripheral sphingosine pathways, which is currently approved for treatment of Multiple Sclerosis (MS). In animal models it reduces inflammation, but it is also able to potentiate glutamatergic transmission and synaptic plasticity. We aimed to explore whether Fingolimod is able to modify the clinical expression of new demyelinating lesions with respect to IFNβ-1a in relapsing remitting MS (RRMS) patients suboptimal responders to IFNβ-1a.

  • The renal lesions in Bardet-Biedl Syndrome: history before and after the discovery of BBS genes.
    Publication Date: 01/02/2018, on Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia
    by Viggiano D, Zacchia M, Simonelli F, Di Iorio V, Anastasio P, Capasso G, De Santo NG
    DOI:

  • Cognitive and behavioral disorders in Parkinson's disease: an update. I: cognitive impairments.
    Publication Date: 01/02/2018, on Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
    by Papagno C, Trojano L
    DOI: 10.1007/s10072-017-3154-8

    Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor symptoms such as rigidity, rest tremor, and bradykinesia. However, a growing body of evidence demonstrated that PD encompasses several non-motor disturbances as well, such as cognitive impairment. Cognitive defects can be present since early stages of the disease but tend to dominate the clinical picture as the disease progresses. Around 40% of patients with PD present with cognitive impairments in several cognitive domains including attention, working memory and executive functions, language, visuospatial skills, and episodic memory; in later stages of the disease, cognitive defects and associated behavioral disorders concur to determine clinically relevant PD-associated dementia. Part of these defects is ascribed to a dopamine-dependent dysfunction of fronto-striatal pathways, but there is a considerable heterogeneity in the cognitive impairments as well as a suggestion of the role of other neurotransmitter systems, such as the cholinergic one, mainly responsible for Parkinson-dementia syndrome. In this paper, we review recent literature with particular attention to the last 5 years on the main cognitive deficits described in PD patients as well as on the hypothesized neuro-functional substrate of such impairments. Finally, we provide some suggestions on how to test cognitive functions in PD appropriately.

  • Human Milk and Donkey Milk, Compared to Cow Milk, Reduce Inflammatory Mediators and Modulate Glucose and Lipid Metabolism, Acting on Mitochondrial Function and Oleylethanolamide Levels in Rat Skeletal Muscle.
    Publication Date: 30/01/2018, on Frontiers in physiology
    by Trinchese G, Cavaliere G, De Filippo C, Aceto S, Prisco M, Chun JT, Penna E, Negri R, Muredda L, Demurtas A, Banni S, Berni-Canani R, Mattace Raso G, Calignano A, Meli R, Greco L, Crispino M, Mollica MP
    DOI: 10.3389/fphys.2018.00032

    Milk from various species differs in nutrient composition. In particular, human milk (HM) and donkey milk (DM) are characterized by a relative high level of triacylglycerol enriched in palmitic acid in sn-2 position. These dietary fats seem to exert beneficial nutritional properties through N-acylethanolamine tissue modulation. The aim of this study is to compare the effects of cow milk (CM), DM, and HM on inflammation and glucose and lipid metabolism, focusing on mitochondrial function, efficiency, and dynamics in skeletal muscle, which is the major determinant of resting metabolic rate. Moreover, we also evaluated the levels of endocannabinoids and N-acylethanolamines in liver and skeletal muscle, since tissue fatty acid profiles can be modulated by nutrient intervention. To this aim, rats were fed with CM, DM, or HM for 4 weeks. Then, glucose tolerance and insulin resistance were analyzed. Pro-inflammatory and anti-inflammatory cytokines were evaluated in serum and skeletal muscle. Skeletal muscle was also processed to estimate mitochondrial function, efficiency, and dynamics, oxidative stress, and antioxidant/detoxifying enzyme activities. Fatty acid profiles, endocannabinoids, and N-acylethanolamine congeners were determined in liver and skeletal muscle tissue. We demonstrated that DM or HM administration reducing inflammation status, improves glucose disposal and insulin resistance and reduces lipid accumulation in skeletal muscle. Moreover, HM or DM administration increases redox status, and mitochondrial uncoupling, affecting mitochondrial dynamics in the skeletal muscle. Interestingly, HM and DM supplementation increase liver and muscle levels of the N-oleoylethanolamine (OEA), a key regulator of lipid metabolism and inflammation. HM and DM have a healthy nutritional effect, acting on inflammatory factors and glucose and lipid metabolism. This beneficial effect is associated to a modulation of mitochondrial function, efficiency, and dynamics and to an increase of OEA levels in skeletal muscle.

  • Autosomal dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation.
    Publication Date: 24/01/2018, on Clinical genetics
    by Napolitano F, Di Iorio V, Testa F, Tirozzi A, Reccia MG, Lombardi L, Farina O, Simonelli F, Gianfrancesco F, Di Iorio G, Melone MAB, Esposito T, Sampaolo S
    DOI: 10.1111/cge.13217

    We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A>G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

  • RUTA GRAVEOLENS WATER EXTRACT INHIBITS CELL-CELL NETWORK FORMATION IN HUMAN UMBILICAL ENDOTHELIAL CELLS VIA MEK-ERK1/2 PATHWAY.
    Publication Date: 20/01/2018, on Experimental cell research
    by Gentile M, Russo R, Pastorino O, Cioffi S, Barbieri F, Illingworth EA, Grieco M, Chambery A, Colucci-D'Amato L
    DOI: 10.1016/j.yexcr.2018.01.025

    Angiogenesis is a process encompassing several steps such as endothelial cells proliferation, differentiation and migration to form a vascular network, involving different signal transduction pathways. Among these, ERK1/2 signaling mediates VEGF-dependent signaling pathway. Here we report that the water extract of Ruta graveolens (RGWE), widely known as a medicinal plant, is able to impair in a dose-dependent manner, cell network formation without affecting cell viability. Biochemical analysis showed that the major component of RGWE is rutin, unable to reproduce RGWE effect. We found that RGWE inhibits ERK1/2 phosphorylation and that this event is crucial in cell network formation since the transfection of HUVEC with a constitutively active MEK (caMEK), the ERK1/2 activator, induces a robust cell network formation as compared to untransfected and/or mock transfected cells and, more importantly, caMEK transfected cells became unresponsive to RGWE. Moreover, RGWE inhibits VEGF and nestin gene expression, necessary for vessel formation, and the caMEK transfection induces their higher expression. In conclusion, we report that RGWE is able to significantly impair vessels network formation without affecting cell viability, preventing ERK1/2 activation and, in turn, down-regulating VEGF and nestin expression. These findings point to RGWE as a potential therapeutic tool capable to interfere with pathologic angiogenesis.

  • Targeting BCL2 Gene Promoter G-quadruplex with a New Class of Furopyridazinone-Based Molecules.
    Publication Date: 18/01/2018, on ChemMedChem
    by Amato J, Pagano A, Capasso D, Di Gaetano S, Giustiniano M, Novellino E, Randazzo A, Pagano B
    DOI: 10.1002/cmdc.201700749

    Targeting of G-quadruplex-forming DNA in BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein represents an attractive opportunity in cancer treatment. So far, efforts made in the discovery of molecules able to target BCL2 G-quadruplex mainly succeeded in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity. Moreover, one of such ligands appreciably inhibited BCL2 gene transcription, with a substantial reduction of protein expression level, and showed significant cytotoxicity on the human T lymphoblastoid cell line Jurkat.