Latest PUBLICATIONS

  • The abasic site lesions in the human telomeric sequence d[TA(G(3)T(2)A)(3)G(3)]: a thermodynamic point of view.
    Publication Date: 01/12/2012, on Biochimica et biophysica acta
    by Virgilio A, Petraccone L, Esposito V, Citarella G, Giancola C, Galeone A
    DOI: 10.1016/j.bbagen.2012.09.011

    The abasic sites represent one of the most frequent lesions of DNA and most of the events able to generate such modifications involve guanine bases. G-rich sequences are able to form quadruplex structures that have been proved to be involved in several important biological processes.

  • Shooting for selective druglike G-quadruplex binders: evidence for telomeric DNA damage and tumor cell death.
    Publication Date: 26/11/2012, on Journal of medicinal chemistry
    by Cosconati S, Rizzo A, Trotta R, Pagano B, Iachettini S, De Tito S, Lauri I, Fotticchia I, Giustiniano M, Marinelli L, Giancola C, Novellino E, Biroccio A, Randazzo A
    DOI: 10.1021/jm301019w

    Targeting of DNA secondary structures, such as G-quadruplexes, is now considered an appealing opportunity for drug intervention in anticancer therapy. So far, efforts made in the discovery of chemotypes able to target G-quadruplexes mainly succeeded in the identification of a number of polyaromatic compounds featuring end-stacking binding properties. Against this general trend, we were persuaded that the G-quadruplex grooves can recognize molecular entities with better drug-like and selectivity properties. From this idea, a set of small molecules was identified and the structural features responsible for G-quadruplex recognition were delineated. These compounds were demonstrated to have enhanced affinity and selectivity for the G-quadruplex over the duplex structure. Their ability to induce selective DNA damage at telomeric level and to induction of apoptosis and senescence on tumor cells is herein experimentally proven.

  • Heart rate variability and target organ damage in hypertensive patients.
    Publication Date: 15/11/2012, on BMC cardiovascular disorders
    by Melillo P, Izzo R, De Luca N, Pecchia L
    DOI: 10.1186/1471-2261-12-105

    We evaluated the association between linear standard Heart Rate Variability (HRV) measures and vascular, renal and cardiac target organ damage (TOD).

  • Neuropathic pain and reactive gliosis are reversed by dialdehydic compound in neuropathic pain rat models.
    Publication Date: 14/11/2012, on Neuroscience letters
    by Bianco MR, Cirillo G, Petrosino V, Marcello L, Soleti A, Merizzi G, Cavaliere C, Papa M
    DOI: 10.1016/j.neulet.2012.08.088

    The role of the purinergic system in the modulation of pain mechanisms suggests that it might be promising target for treating neuropathic pain. In this study we evaluated the effects of two different dialdehydic compounds: a modified stable adenosine (2-[1-(6-amminopurin-9-il)-2-osso-etossi]prop-2-enale, named MED1101), and oxidized ATP (Ox-ATP), in two different neuropathic pain rat models: the sciatic spared nerve injury (SNI) and paclitaxel evoked painful peripheral neuropathy (pPPN). Neuropathic animals were divided in groups as follows: (a) treated with intraperitoneal (i.p.) MED1101 or Ox-ATP for 21 days; (b) receiving vehicle (VEH) and (c) control (CTR) rats. The allodynic and hyperalgesic behavior was investigated by Von Frey filament test and thermal Plantar test, respectively. We evaluated by immunocytochemistry the astrocytic (GFAP) and microglial (Iba1) response on lumbar spinal cord sections. In either experimental models and using either substances, treated animals showed reduced allodynia and thermal hyperalgesia paralleled by a significant reduction of glial reaction in the spinal cord. These data prompt to hypothesize a potential role of dialdehydes as analgesic agent in chronic neuropathic pain and a possible role as anti-gliotic molecules.

  • A complex of α6 integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin-like 6.
    Publication Date: 01/11/2012, on EMBO molecular medicine
    by Marchiò S, Soster M, Cardaci S, Muratore A, Bartolini A, Barone V, Ribero D, Monti M, Bovino P, Sun J, Giavazzi R, Asioli S, Cassoni P, Capussotti L, Pucci P, Bugatti A, Rusnati M, Pasqualini R, Arap W, Bussolino F
    DOI: 10.1002/emmm.201101164

    Homing of colorectal cancer (CRC) cells to the liver is a non-random process driven by a crosstalk between tumour cells and components of the host tissue. Here we report the isolation of a liver metastasis-specific peptide ligand (CGIYRLRSC) that binds a complex of E-cadherin and α(6) integrin on the surface of CRC cells. We identify angiopoietin-like 6 protein as a peptide-mimicked natural ligand enriched in hepatic blood vessels of CRC patients. We demonstrate that an interaction between hepatic angiopoietin-like 6 and tumoural α(6) integrin/E-cadherin drives liver homing and colonization by CRC cells, and that CGIYRLRSC inhibits liver metastasis through interference with this ligand/receptor system. Our results indicate a mechanism for metastasis whereby a soluble factor accumulated in normal vessels functions as a specific ligand for circulating cancer cells. Consistently, we show that high amounts of coexpressed α(6) integrin and E-cadherin in primary tumours represent a poor prognostic factor for patients with advanced CRC.

  • Polyvalent nucleic acid aptamers and modulation of their activity: a focus on the thrombin binding aptamer.
    Publication Date: 01/11/2012, on Pharmacology & therapeutics
    by Musumeci D, Montesarchio D
    DOI: 10.1016/j.pharmthera.2012.07.011

    Nucleic acid-based aptamers can be selected from combinatorial libraries of synthetic oligonucleotides to bind, with affinity and specificity similar to antibodies, a wide range of biomedically relevant targets. Compared to protein therapeutics, aptamers exhibit significant advantages in terms of size, non-immunogenicity and wide synthetic accessibility. Various chemical modifications have been introduced in the natural oligonucleotide backbone of aptamers in order to increase their half-life, as well as their pharmacological properties. Very effective alternative approaches, devised in order to improve both the aptamer activity and stability, were based on the design of polyvalent aptamers, able to establish multivalent interactions with the target: thus, multiple copies of an aptamer can be assembled on the same molecular- or nanomaterial-based scaffold. In the present review, the thrombin binding aptamers (TBAs) are analyzed as a model system to study multiple-aptamer constructs aimed at improving their anticoagulation activity in terms of binding to the target and stability to enzymatic degradation. Indeed - even if the large number of chemically modified TBAs investigated in the last 20 years has led to encouraging results - a significant progress has been obtained only recently with bivalent or engineered dendritic TBA aptamers, or assemblies of TBAs on nanoparticles and DNA nanostructures. Furthermore, the modulation of the aptamers activity by means of tailored drug-active reversal agents, especially in the field of anticoagulant aptamers, as well as the reversibility of the TBA activity through the use of antidotes, such as porphyrins, complementary oligonucleotides or of external stimuli, are discussed.

  • Synthesis, self-aggregation and bioactivity properties of a cationic aminoacyl surfactant, based on a new class of highly functionalized nucleolipids.
    Publication Date: 01/11/2012, on European journal of medicinal chemistry
    by Simeone L, Irace C, Di Pascale A, Ciccarelli D, D'Errico G, Montesarchio D
    DOI: 10.1016/j.ejmech.2012.06.044

    A highly functionalized aminoacyl nucleolipid based on uridine is here proposed as a novel cationic surfactant. To achieve this, a straightforward, high yielding and versatile protocol has been devised, in principle providing synthetic access to a variety of different, related analogs. Self-aggregation properties of this nucleolipid were determined by using a combined approach, including surface tension, conductivity and DLS measurements. Above the critical micellar concentration of 4 × 10(-5) mol kg(-1), large supramolecular assemblies with a counterion condensation degree of 0.25 were observed. The bioactivity profile of this new compound was investigated on cancer and non cancer cell lines.

  • DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity.
    Publication Date: 01/11/2012, on Cell death and differentiation
    by Fortini P, Ferretti C, Pascucci B, Narciso L, Pajalunga D, Puggioni EM, Castino R, Isidoro C, Crescenzi M, Dogliotti E
    DOI: 10.1038/cdd.2012.53

    DNA single-strand breaks (SSB) formation coordinates the myogenic program, and defects in SSB repair in post-mitotic cells have been associated with human diseases. However, the DNA damage response by SSB in terminally differentiated cells has not been explored yet. Here we show that mouse post-mitotic muscle cells accumulate SSB after alkylation damage, but they are extraordinarily resistant to the killing effects of a variety of SSB-inducers. We demonstrate that, upon SSB induction, phosphorylation of H2AX occurs in myotubes and is largely ataxia telangiectasia mutated (ATM)-dependent. However, the DNA damage signaling cascade downstream of ATM is defective as shown by lack of p53 increase and phosphorylation at serine 18 (human serine 15). The stabilization of p53 by nutlin-3 was ineffective in activating the cell death pathway, indicating that the resistance to SSB inducers is due to defective p53 downstream signaling. The induction of specific types of damage is required to activate the cell death program in myotubes. Besides the topoisomerase inhibitor doxorubicin known for its cardiotoxicity, we show that the mitochondria-specific inhibitor menadione is able to activate p53 and to kill effectively myotubes. Cell killing is p53-dependent as demonstrated by full protection of myotubes lacking p53, but there is a restriction of p53-activated genes. This new information may have important therapeutic implications in the prevention of muscle cell toxicity.

  • Spontaneous regression of syringomyelia in a young patient with Chiari type I malformation.
    Publication Date: 01/11/2012, on The neuroradiology journal
    by Tortora F, Napoli M, Caranci F, Cirillo M, Pepe D, Cirillo S, Briganti F
    DOI: 10.1177/197140091202500513

    Syringomyelia is a disorder in which a cyst or cavity forms within the spinal cord. This cyst, called syrinx, can expand and elongate over time, destroying the spinal cord. We describe the case of a young patient with partial spontaneous regression of syringomyelia in Chiari I malformation, confirmed by magnetic resonance imaging three years after the diagnosis. During this period the patient did not experience any clinical symptoms. Although described in literature, spontaneous regression is an unusual event and very few cases have been reported. This case report supports the belief that conservative management together with both clinical and imaging periodic controls should be preferred in stable mild-symptomatic patients.

  • Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study.
    Publication Date: 01/11/2012, on Acta neurologica Scandinavica
    by Lanzillo R, Quarantelli M, Bonavita S, Ventrella G, Lus G, Vacca G, Prinster A, Orefice G, Tedeschi G, Brescia Morra V
    DOI: 10.1111/j.1600-0404.2011.01622.x

    No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS).

  • Synthesis of a cholesteryl-HEG phosphoramidite derivative and its application to lipid-conjugates of the anti-HIV 5'TGGGAG³' Hotoda's sequence.
    Publication Date: 22/10/2012, on Molecules (Basel, Switzerland)
    by Musumeci D, Montesarchio D
    DOI: 10.3390/molecules171012378

    A novel phosphoramidite derivative of cholesterol, with an ether-linked hexaethylene glycol (HEG) spacer arm, has been obtained through simple and reproducible solid phase modified oligonucleotide synthesis manipulations. This building block and the known phosphoramidite derivative of 3b-(2-hydroxyethoxy)cholesterol have been exploited in standard oligonucleotide synthesis protocols for the preparation of 5'- conjugates of the G-quadruplex-forming ⁵'TGGGAG³' oligomer, known as the Hotoda's sequence, to produce new potential anti-HIV agents.

  • Isolation and functional characterization of peptide agonists of PTPRJ, a tyrosine phosphatase receptor endowed with tumor suppressor activity.
    Publication Date: 19/10/2012, on ACS chemical biology
    by Paduano F, Ortuso F, Campiglia P, Raso C, Iaccino E, Gaspari M, Gaudio E, Mangone G, Carotenuto A, Bilotta A, Narciso D, Palmieri C, Agosti V, Artese A, Gomez-Monterrey I, Sala M, Cuda G, Iuliano R, Perrotti N, Scala G, Viglietto G, Alcaro S, Croce CM, Novellino E, Fusco A, Trapasso F
    DOI: 10.1021/cb300281t

    PTPRJ is a receptor-type protein tyrosine phosphatase whose expression is strongly reduced in the majority of investigated cancer cell lines and tumor specimens. PTPRJ negatively interferes with mitogenic signals originating from several oncogenic receptor tyrosine kinases, including HGFR, PDGFR, RET, and VEGFR-2. Here we report the isolation and characterization of peptides from a random peptide phage display library that bind and activate PTPRJ. These agonist peptides, which are able to both circularize and form dimers in acqueous solution, were assayed for their biochemical and biological activity on both human cancer cells and primary endothelial cells (HeLa and HUVEC, respectively). Our results demonstrate that binding of PTPRJ-interacting peptides to cell cultures dramatically reduces the extent of both MAPK phosphorylation and total phosphotyrosine levels; conversely, they induce a significant increase of the cell cycle inhibitor p27(Kip1). Moreover, PTPRJ agonist peptides both reduce proliferation and trigger apoptosis of treated cells. Our data indicate that peptide agonists of PTPRJ positively modulate the PTPRJ activity and may lead to novel targeted anticancer therapies.

  • Visual resting-state network in relapsing-remitting MS with and without previous optic neuritis.
    Publication Date: 02/10/2012, on Neurology
    by Gallo A, Esposito F, Sacco R, Docimo R, Bisecco A, Della Corte M, D'Ambrosio A, Corbo D, Rosa N, Lanza M, Cirillo S, Bonavita S, Tedeschi G
    DOI: 10.1212/WNL.0b013e31826d5eea

    To investigate functional connectivity of the visual resting-state network (V-RSN) in normal-sighted relapsing-remitting multiple sclerosis (RRMS) patients with and without previous optic neuritis (ON).

  • Dissimilar sweet proteins from plants: oddities or normal components?
    Publication Date: 01/10/2012, on Plant science : an international journal of experimental plant biology
    by Picone D, Temussi PA
    DOI: 10.1016/j.plantsci.2012.07.001

    The fruits of a few tropical plants contain intensely sweet proteins. Their common property points to a protein family. Generally, proteins belonging to the same family share similar folds, similar sequences and, at least in part, similar function but sweet proteins constitute an exception to this rule. Apart from sharing the rather unusual taste function, they show no obvious similarities either in their sequences or in three-dimensional structures. In this review we describe the nature, structure and mechanism of action of the best known sweet tasting proteins, including two taste modifying proteins. Sweet proteins stand out among sweet molecules because their volume is not compatible with an interaction with orthosteric active sites of the sweet taste receptor. The best explanation of their mechanism of action is the interaction with the external surface of the sweet taste receptor, according to a model that has been named "wedge model". It is hypothesized that this mode of action may be related to the ability of other members of their protein families to inhibit different enzymes.

  • Cerebellar-parietal dysfunctions in multiple sclerosis patients with cerebellar signs.
    Publication Date: 01/10/2012, on Experimental neurology
    by Cerasa A, Passamonti L, Valentino P, Nisticò R, Pirritano D, Gioia MC, Chiriaco C, Mangone G, Perrotta P, Quattrone A
    DOI: 10.1016/j.expneurol.2012.07.020

    Consistent findings have shown that the cerebellum is critically implicated in a broad range of cognitive processes including executive functions. Of note, cerebellar symptoms and a number of cognitive deficits have been widely reported in patients with multiple sclerosis (MS). This study investigated for the first time the role of cerebellar symptoms in modulating the neural networks associated with a cognitive task broadly used in MS patients (Paced Visual Serial Addition Test (PVSAT)). Twelve relapsing-remitting (RR) MS patients with prevalent cerebellar signs and symptoms (RR-MSc), 15 RR-MS patients without cerebellar manifestation (RR-MSnc) and 16 matched-healthy controls were examined during functional magnetic resonance imaging (fMRI). We tested whether the RR-MSc patients displayed abnormal activations within "cognitive" cerebellar regions and other areas typically engaged in working memory and tightly connected with the cerebellum. Despite similar behavioral performances during fMRI, RR-MSc patients displayed, relatively to both RR-MSnc patients and controls, significantly greater responses in the left cerebellar Crus I/Lobule VI. RR-MSc patients also displayed reduced functional connectivity between the left cerebellar Crus I and the right superior parietal lobule (FWE<.05). These results demonstrated that the presence of the cerebellar signs drastically impacts on the neurofunctional networks underlying working memory in MS. The altered communication between the cerebellum and a cortical area implicated in short-term buffering and storage of relevant information, offer new insights into the pathophysiological mechanisms of cognition in MS.