Latest PUBLICATIONS

  • Ophthalmic acid is a marker of oxidative stress in plants as in animals.
    Publication Date: 01/04/2018, on Biochimica et biophysica acta
    by Servillo L, Castaldo D, Giovane A, Casale R, D'Onofrio N, Cautela D, Balestrieri ML
    DOI: 10.1016/j.bbagen.2018.01.015

    Ophthalmic acid (OPH), γ-glutamyl-L-2-aminobutyryl-glycine, a tripeptide analogue of glutathione (GSH), has recently captured considerable attention as a biomarker of oxidative stress in animals. The OPH and GSH biosynthesis, as well as some biochemical behaviors, are very similar. Here, we sought to investigate the presence of OPH in plants and its possible relationship with GSH, known to possess multiple functions in the plant development, growth and response to environmental changes.

  • Anti-HIV activity of new higher order G-quadruplex aptamers obtained from tetra-end-linked oligonucleotides.
    Publication Date: 28/03/2018, on Organic & biomolecular chemistry
    by Nici F, Oliviero G, Falanga AP, D'Errico S, Marzano M, Musumeci D, Montesarchio D, Noppen S, Pannecouque C, Piccialli G, Borbone N
    DOI: 10.1039/C7OB02346D

    By combining the ability of short G-rich oligodeoxyribonucleotides (ODNs) containing the sequence 5'CGGA3' to form higher order G-quadruplex (G4) complexes with the tetra-end-linked (TEL) concept to produce aptamers targeting the HIV envelope glycoprotein 120 (gp120), three new TEL-ODNs (1-3) having the sequence 5'CGGAGG3' were synthesized with the aim of studying the effect of G4 dimerization on their anti-HIV activity. Furthermore, in order to investigate the effect of the groups at the 5' position, the 5' ends of 1-3 were left uncapped (1) or capped with either the lipophilic dimethoxytrityl (DMT) (2) or the hydrophilic glucosyl-4-phosphate (3) moieties. The here reported results demonstrate that only the DMT-substituted TEL-ODN 2 is effective in protecting human MT-4 cell cultures from HIV infection (76% max protection), notwithstanding all the three new aptamers proved to be capable of forming stable higher order dimeric G4s when annealed in K+-containing buffer, thus suggesting that the recognition of a hydrophobic pocket on the target glycoprotein by the aptamers represents a main structural feature for triggering their anti-HIV activity.

  • Neurofibromatous neuropathy: An ultrastructural study.
    Publication Date: 27/03/2018, on Ultrastructural pathology
    by Terracciano C, Pachatz C, Rastelli E, Pastore FS, Melone MAB, Massa R
    DOI: 10.1080/01913123.2018.1454562

    Plexiform neurofibroma is pathognomonic of neurofibromatosis 1 (NF1). An NF1-associated peripheral neuropathy has been described in a small minority of NF1 patients but its histopathological features are poorly characterized. We report the case of a 46-year-old woman presenting with bilateral supraclavicular painful masses without other stigmata of NF1. MRI showed bilateral plexiform lesions extending from cervical roots to the elbows. Nerve conduction studies documented a sensory motor polyneuropathy. Morphometric analysis of sural nerve biopsy showed a preferential loss of large-caliber myelinated fibers with a g ratio of 0.515, and the presence of regeneration clusters. By electron microscopy, marked and diffuse endoneurial fibrosis with an altered relationship between Schwann cells (SC) and collagen fibrils was observed. Moreover both myelinating and non-myelinating SC were characterized by the presence of various cell degradation products. These changes suggest that, in neurofibromatous neuropathy, a widespread axonal atrophy and degeneration take place independently on the presence of tumoral infiltration, possibly due to an impairment in SC-axon cross talk. In this case, the coexistence of plexiform neurofibromas with a peripheral neuropathy strongly suggests a diagnosis of NF1 even without fulfillment of clinical criteria. We propose that in the presence of plexiform neurofibromas, electrophysiological studies should be performed also in asymptomatic patients, in order to detect the existence of a subclinical neuropathy.

  • The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma.
    Publication Date: 25/03/2018, on Journal of cellular physiology
    by Sanna L, Marchesi I, Melone MAB, Bagella L
    DOI: 10.1002/jcp.26545

    Nowadays, epigenetics covers a crucial role in different fields of science. The enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), is a big proponent of how epigenetic changes can affect the initiation and progression of several diseases. Through its catalytic activity, responsible for the tri-methylation of lysine 27 of the histone H3 (H3K27me3), EZH2 is a good target for both diagnosis and therapy of different pathologies. A large number of studies have demonstrated its crucial role in cancer initiation and progression. Nevertheless, only recently its function in virus diseases has been uncovered; therefore, EZH2 can be an important promoter of viral carcinogenesis. This review explores the role of EZH2 in viral epigenetics based on recent progress that demonstrated the role of this protein in virus environment. In particular, the review focuses on EZH2 behavior in Hepatitis B Virus, analyzing its role in the rise of Hepatocellular Carcinoma.

  • Boosting phagocytosis and anti-inflammatory phenotype in microglia mediates neuroprotection by PPARγ agonist MDG548 in Parkinson's disease.
    Publication Date: 23/03/2018, on British journal of pharmacology
    by Lecca D, Janda E, Mulas G, Diana A, Martino C, Angius F, Spolitu S, Antonietta Casu M, Simbula G, Boi L, Batetta B, Spiga S, Carta AR
    DOI: 10.1111/bph.14214

    Microglia phenotype and phagocytic activity are deregulated in Parkinson's disease (PD). Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are neuroprotective in experimental PD, but their role in regulating microglial phenotype and phagocytosis has been poorly investigated. We addressed it by using the PPARγ agonist MDG548.

  • Neural stem cells from a mouse model of Rett syndrome are prone to senescence, show reduced capacity to cope with genotoxic stress, and are impaired in the differentiation process.
    Publication Date: 22/03/2018, on Experimental & molecular medicine
    by Alessio N, Riccitiello F, Squillaro T, Capasso S, Del Gaudio S, Di Bernardo G, Cipollaro M, Melone MAB, Peluso G, Galderisi U
    DOI: 10.1038/s12276-017-0005-x

    Several aspects of stem cell life are governed by epigenetic variations, such as DNA methylation, histone modifications, and chromatin remodeling. Epigenetic events are also connected with the impairment of stem cell functions. For example, during senescence, there are significant changes in chromatin organization that alter transcription. The MECP2 protein can bind methylated cytosines and contribute to regulating gene expression at one of the highest hierarchical levels. Researchers are particularly interested in this protein, as up to 90% of Rett syndrome patients have an MECP2 gene mutation. Nevertheless, the role of MECP2 in this disease remains poorly understood. We used a mouse model of Rett syndrome to evaluate whether residual MECP2 activity in neural stem cells (NSCs) induced the senescence phenomena that could affect stem cell function. Our study clearly demonstrated that the reduced expression of MECP2 is connected with an increase in senescence, an impairment in proliferation capacity, and an accumulation of unrepaired DNA foci. Mecp2 NSCs did not cope with genotoxic stress in the same way as the control cells did. Indeed, after treatment with different DNA-damaging agents, the NSCs from mice with mutated Mecp2 accumulated more DNA damage foci (γ-H2AX+) and were more prone to cell death than the controls. Senescence in Mecp2 NSCs decreased the number of stem cells and progenitors and gave rise to a high percentage of cells that expressed neither stem/progenitor nor differentiation markers. These cells could be senescent and dysfunctional.

  • Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets.
    Publication Date: 15/03/2018, on Molecular medicine (Cambridge, Mass.)
    by Izzo A, Mollo N, Nitti M, Paladino S, Calì G, Genesio R, Bonfiglio F, Cicatiello R, Barbato M, Sarnataro V, Conti A, Nitsch L
    DOI: 10.1186/s10020-018-0004-y

    Trisomy of chromosome 21 (TS21) is the most common autosomal aneuploidy compatible with postnatal survival with a prevalence of 1 in 700 newborns. Its phenotype is highly complex with constant features, such as mental retardation, dysmorphic traits and hypotonia, and variable features including heart defects, susceptibility to Alzheimer's disease (AD), type 2 diabetes, obesity and immune disorders. Overexpression of genes on chromosome-21 (Hsa21) is responsible for the pathogenesis of Down syndrome (DS) phenotypic features either in a direct or in an indirect manner since many Hsa21 genes can affect the expression of other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function and energy conversion, and play a central role in the mitochondrial dysfunction and chronic oxidative stress, consistently observed in DS subjects.Recent studies highlight the deep interconnections between mitochondrial dysfunction and DS phenotype. In this short review we first provide a basic overview of mitochondrial phenotype in DS cells and tissues. We then discuss how specific Hsa21 genes may be involved in determining the disruption of mitochondrial DS phenotype and biogenesis. Finally we briefly focus on drugs that affect mitochondrial function and mitochondrial network suggesting possible therapeutic approaches to improve and/or prevent some aspects of the DS phenotype.

  • Are ultra-short heart rate variability features good surrogates of short-term ones? State-of-the-art review and recommendations.
    Publication Date: 14/03/2018, on Healthcare technology letters
    by Pecchia L, Castaldo R, Montesinos L, Melillo P
    DOI: 10.1049/htl.2017.0090

    Ultra-short heart rate variability (HRV) analysis refers to the study of HRV features in excerpts of length <5 min. Ultra-short HRV is widely growing in many healthcare applications for monitoring individual's health and well-being status, especially in combination with wearable sensors, mobile phones, and smart-watches. Long-term (nominally 24 h) and short-term (nominally 5 min) HRV features have been widely investigated, physiologically justified and clear guidelines for analysing HRV in 5 min or 24 h are available. Conversely, the reliability of ultra-short HRV features remains unclear and many investigations have adopted ultra-short HRV analysis without questioning its validity. This is partially due to the lack of accepted algorithms guiding investigators to systematically assess ultra-short HRV reliability. This Letter critically reviewed the existing literature, aiming to identify the most suitable algorithms, and harmonise them to suggest a standard protocol that scholars may use as a reference in future studies. The results of the literature review were surprising, because, among the 29 reviewed papers, only one paper used a rigorous method, whereas the others employed methods that were partially or completely unreliable due to the incorrect use of statistical tests. This Letter provides recommendations on how to assess ultra-short HRV features reliably and proposes an inclusive algorithm that summarises the state-of-the-art knowledge in this area.

  • Synthesis and Biological Evaluation of a New Structural Simplified Analogue of cADPR, a Calcium-Mobilizing Secondary Messenger Firstly Isolated from Sea Urchin Eggs.
    Publication Date: 10/03/2018, on Marine drugs
    by D'Errico S, Borbone N, Catalanotti B, Secondo A, Petrozziello T, Piccialli I, Pannaccione A, Costantino V, Mayol L, Piccialli G, Oliviero G
    DOI: 10.3390/md16030089

    Herein, we reported on the synthesis of cpIPP, which is a new structurally-reduced analogue of cyclic ADP-ribose (cADPR), a potent Ca-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts. To obtain cpIPP the "northern" ribose of cADPR was replaced by a pentyl chain and the pyrophosphate moiety by a phophono-phosphate anhydride. The effect of the presence of the new phosphono-phosphate bridge on the intracellular Ca release induced by cpIPP was assessed in PC12 neuronal cells in comparison with the effect of the pyrophosphate bridge of the structurally related cyclic N1-butylinosine diphosphate analogue (cbIDP), which was previously synthesized in our laboratories, and with that of the linear precursor of cpIPP, which, unexpectedly, revealed to be the only one provided with Ca release properties.

  • Differentiation by nerve growth factor (NGF) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling.
    Publication Date: 09/03/2018, on Cell death & disease
    by Martorana F, Gaglio D, Bianco MR, Aprea F, Virtuoso A, Bonanomi M, Alberghina L, Papa M, Colangelo AM
    DOI: 10.1038/s41419-018-0429-9

    Neuronal differentiation involves extensive modification of biochemical and morphological properties to meet novel functional requirements. Reorganization of the mitochondrial network to match the higher energy demand plays a pivotal role in this process. Mechanisms of neuronal differentiation in response to nerve growth factor (NGF) have been largely characterized in terms of signaling, however, little is known about its impact on mitochondrial remodeling and metabolic function. In this work, we show that NGF-induced differentiation requires the activation of autophagy mediated by Atg9b and Ambra1, as it is disrupted by their genetic knockdown and by autophagy blockers. NGF differentiation involves the induction of P-AMPK and P-CaMK, and is prevented by their pharmacological inhibition. These molecular events correlate with modifications of energy and redox homeostasis, as determined by ATP and NADPH changes, higher oxygen consumption (OCR) and ROS production. Our data indicate that autophagy aims to clear out exhausted mitochondria, as determined by enhanced localization of p62 and Lysotracker-red to mitochondria. In addition, we newly demonstrate that NGF differentiation is accompanied by increased mitochondrial remodeling involving higher levels of fission (P-Drp1) and fusion proteins (Opa1 and Mfn2), as well as induction of Sirt3 and the transcription factors mtTFA and PPARγ, which regulate mitochondria biogenesis and metabolism to sustain increased mitochondrial mass, potential, and bioenergetics. Overall, our data indicate a new NGF-dependent mechanism involving mitophagy and extensive mitochondrial remodeling, which plays a key role in both neurogenesis and nerve regeneration.

  • Huntingtin protein: A new option for fixing the Huntington's disease countdown clock.
    Publication Date: 08/03/2018, on Neuropharmacology
    by Caterino M, Squillaro T, Montesarchio D, Giordano A, Giancola C, Melone MAB
    DOI: 10.1016/j.neuropharm.2018.03.009

    Huntington's disease is a dreadful, incurable disorder. It springs from the autosomal dominant mutation in the first exon of the HTT gene, which encodes for the huntingtin protein (HTT) and results in progressive neurodegeneration. Thus far, all the attempted approaches to tackle the mutant HTT-induced toxicity causing this disease have failed. The mutant protein comes with the aberrantly expanded poly-glutamine tract. It is primarily to blame for the build-up of β-amyloid-like HTT aggregates, deleterious once broadened beyond the critical ∼35-37 repeats threshold. Recent experimental findings have provided valuable information on the molecular basis underlying this HTT-driven neurodegeneration. These findings indicate that the poly-glutamine siding regions and many post-translation modifications either abet or counter the poly-glutamine tract. This review provides an overall, up-to-date insight into HTT biophysics and structural biology, particularly discussing novel pharmacological options to specifically target the mutated protein and thus inhibit its functions and toxicity.

  • Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations.
    Publication Date: 07/03/2018, on Cell death & disease
    by Fasano D, Parisi S, Pierantoni GM, De Rosa A, Picillo M, Amodio G, Pellecchia MT, Barone P, Moltedo O, Bonifati V, De Michele G, Nitsch L, Remondelli P, Criscuolo C, Paladino S
    DOI: 10.1038/s41419-018-0410-7

    Recently, a new form of autosomal recessive early-onset parkinsonism (PARK20), due to mutations in the gene encoding the phosphoinositide phosphatase, Synaptojanin 1 (Synj1), has been reported. Several genes responsible for hereditary forms of Parkinson's disease are implicated in distinct steps of the endolysosomal pathway. However, the nature and the degree of endocytic membrane trafficking impairment in early-onset parkinsonism remains elusive. Here, we show that depletion of Synj1 causes drastic alterations of early endosomes, which become enlarged and more numerous, while it does not affect the morphology of late endosomes both in non-neuronal and neuronal cells. Moreover, Synj1 loss impairs the recycling of transferrin, while it does not alter the trafficking of the epidermal growth factor receptor. The ectopic expression of Synj1 restores the functions of early endosomes, and rescues these trafficking defects in depleted cells. Importantly, the same alterations of early endosomal compartments and trafficking defects occur in fibroblasts of PARK20 patients. Our data indicate that Synj1 plays a crucial role in regulating the homeostasis and functions of early endosomal compartments in different cell types, and highlight defective cellular pathways in PARK20. In addition, they strengthen the link between endosomal trafficking and Parkinson's disease.

  • Prevalent use of combined prophylaxis of hepatitis B after liver transplantation in Italy: results of a national survey in a large cohort.
    Publication Date: 01/03/2018, on Minerva gastroenterologica e dietologica
    by Marzano A, Andreone P, Boccagni P, Burra P, Caneschi F, Conoscitore PF, Coppola C, DE Carlis L, Fagiuoli S, Forte P, Gaeta GB, Iemmolo RM, Lotti Suffredini A, Mazzola M, Merli M, Parrilli G, Piai G, Piras MR, Salizzoni M, Tamè M, Tisone G, Toniutto P, Vennarecci G, Volpes R, Zamboni F, Caccamo L,
    DOI: 10.23736/S1121-421X.17.02407-2

    Prophylaxis of hepatitis B after liver transplantation with antiviral(s) and immunoglobulins efficiently protect the majority of recipients; however recent experiences suggest a decline of HBsAg-positive candidates and the use of hepatitis B Immunoglobulin-free schedules.

  • Visual Cortex Activation in Patients With Stargardt Disease.
    Publication Date: 01/03/2018, on Investigative ophthalmology & visual science
    by Melillo P, Prinster A, Di Iorio V, Olivo G, D'Alterio FM, Cocozza S, Orrico A, Quarantelli M, Testa F, Brunetti A, Simonelli F
    DOI: 10.1167/iovs.17-22900

    Primary visual cortex (PVC) contains a retinotopic map in which the central visual field (CVF) is highly magnified compared to the peripheral field. Several studies have used functional magnetic resonance imaging (fMRI) in patients with macular degeneration to assess the reorganization of visual processing in relationship with the development of extrafoveal preferred retinal locus (PRL). We evaluated the functional response in PVC and its correlation with retinal parameters in patients with Stargardt disease due to ABCA4 mutations (STGD1).

  • S-glutathionylation exerts opposing roles in the regulation of STAT1 and STAT3 signaling in reactive microglia.
    Publication Date: 01/03/2018, on Free radical biology & medicine
    by Butturini E, Cozzolino F, Boriero D, Carcereri de Prati A, Monti M, Rossin M, Canetti D, Cellini B, Pucci P, Mariotto S
    DOI: 10.1016/j.freeradbiomed.2018.02.005

    STAT1 and STAT3 are two transcription factors involved in a lot of cellular functions such as immune response, proliferation, apoptosis, and cell survival. A number of literature evidences described a yin-yang relationship between activation of STAT1 and STAT3 in neurodegenerative disorders where STAT1 exerts a pro-apoptotic effect whereas STAT3 shows neuroprotective properties through the inhibition of apoptosis. Although the role of oxidative-stress in the pathogenesis of neurodegeneration is clearly described, its influence in the regulation of these pathways is poorly understood. Herein, we demonstrate that HO rapidly induces phosphorylation of STAT1 whereas it is not able to influence phosphorylation of STAT3 in mouse microglia BV2 cells. The analysis of the molecular mechanism of STATs signaling reveals that HO induces S-glutathionylation of both STAT1 and STAT3. The same post-translational event exerts an opposing role in the regulation of STAT1 and STAT3 signaling. These data not only confirm redox sensibility of STAT3 signaling but also reveal for the first time that STAT1 is susceptible to redox regulation. A deep study of the molecular mechanism of STAT1 redox regulation, identifies Cys324 and Cys492 as the main targets of S-glutathionylation and confirms that S-glutathionylation does not impair JAK2 mediated STAT1 tyrosine phosphorylation. These results demonstrate that both phosphorylation and glutathionylation contribute to activation of STAT1 during oxidative stress and underline that the same post-translation event exerts an opposing role in the regulation of STAT1 and STAT3 signaling in microglia cells.