CNR Institute of Neurobiology and Molecular Medicine

Roma, Italy

CNR Institute of Neurobiology and Molecular Medicine

Roma, Italy
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Calissano P.,CNR Institute of Neurobiology and Molecular Medicine | Calissano P.,European Brain Research Institute | Matrone C.,CNR Institute of Neurobiology and Molecular Medicine | Amadoro G.,CNR Institute of Neurobiology and Molecular Medicine
Developmental Neurobiology | Year: 2010

Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, β-secretase, and active form of γ-secretase) are up-regulated, leading to an increased production of amyloid β peptide (Aβ) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Aβ released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKβ-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain- I- mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by β and γ secretase inhibitors or anti-Aβ antibodies and appear to be causally correlated to TrkA, p75CTF, Aβ, and PS1 molecular association in an Aβ-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity. © 2010 Wiley Periodicals, Inc.

Vene R.,Italian National Cancer Institute | Castellani P.,Italian National Cancer Institute | Delfino L.,Italian National Cancer Institute | Lucibello M.,CNR Institute of Neurobiology and Molecular Medicine | And 2 more authors.
Antioxidants and Redox Signaling | Year: 2011

Aims: Cancer chemoresistance is often due to upregulation of antioxidant systems. Therapeutic targeting of these systems is however hampered by their redundancy. Here, we have performed a functional dissection of the antioxidant systems in different melanoma cases aimed at the identification of the most effective redox active drug. Results: We have identified two crucial antioxidant mechanisms: glutathione (GSH), the major intracellular redox buffer, and the cystine/cysteine cycle, which switches the extracellular redox state from an oxidized to a reduced state. The two mechanisms are independent in melanoma cells and may be substitutes for each other, but targeting both of them is lethal. Exposure to the pro-oxidant compound As 2O 3 induces an antioxidant response. However, while in these cells the intracellular redox balance remains almost unaffected, a reduced environment is generated extracellularly. GSH depletion by buthioninesulfoximine (BSO), or cystine/cysteine cycle inhibition by (S)-4-carboxyphenylglycine (sCPG), enhanced the sensitivity to As 2O 3. Remarkably, sCPG also prevented the remodeling of the microenvironment redox state. Innovation: We propose that the definition of the prevalent antioxidant system(s) in tumors is crucial for the design of tailored therapies involving redox-directed drugs in association with pro-oxidant drugs. Conclusion: In melanoma cells, BSO is the best enhancer of As 2O 3 sensitivity. However, since the strong remodeling of the microenvironmental redox state caused by As 2O 3 may promote tumor progression, the concomitant use of cystine/cysteine cycle blockers is recommended. © 2011 Mary Ann Liebert, Inc.

Sornelli F.,CNR Institute of Neurobiology and Molecular Medicine | Lambiase A.,Biomedical University of Rome | Mantelli F.,Biomedical University of Rome | Aloe L.,CNR Institute of Neurobiology and Molecular Medicine
Molecular Vision | Year: 2010

Purpose: Several growth factors, including nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), play an important role in the homeostasis of the ocular surface. The involvement of both these growth factors in the pathophysiology of intraocular tissues has been extensively investigated. Despite the expression of NGF receptors by corneal endothelium, to date the role of NGF on the endothelial cell remains to be determined. Using a clonal cell line of human corneal endothelial cells, the aim of this study was to investigate the expression of the NGF-receptor and the potential partnership of NGF and VEGF in maintaining cell viability in vitro. Methods: A human endothelial cell line (B4G12), was cultured under serum-free conditions as previously described with and without addition of different concentrations of NGF, anti-NGF-antibody (ANA), or VEGF for 4 days and these cells were used for immuno-istochemical, biochemical, and molecular analyses. Results: NGF induces overexpression of NGF-receptors and synthesis and release of VEGF by endothelial cells and these cells are able to produce and secrete NGF. Conclusions: These observations indicate that human corneal endothelial cells are receptive to the action of NGF and that these cells may regulate NGF activity through autocrine/paracrine mechanisms. © 2010 Molecular Vision.

Chiarella P.,Biomedical University of Rome | Chiarella P.,CNR Institute of Neurobiology and Molecular Medicine | Fazio V.M.,Biomedical University of Rome | Signori E.,Biomedical University of Rome | Signori E.,CNR Institute of Neurobiology and Molecular Medicine
Current Gene Therapy | Year: 2010

Vaccination is historically one of the most important methods for preventing infectious diseases in humans and animals. Due to recent advances in understanding the biology of the immune system, a more rational design of vaccines and vaccination strategies such as those based on gene transfer has been proposed. In particular, naked DNA vaccination is emerging as a promising approach for introducing foreign antigens into the host, inducing protective immunity against infectious diseases and malignant tumours. Plasmid DNA vaccines offer several advantages in comparison to traditional vaccines such as safety, tolerability and feasibility in manufacture. Nevertheless, because of their poor immunogenicity, plasmid DNA vaccines need further implementation. Recent data suggest electroporation as a useful strategy to improve DNA-based vaccination protocols, being able to stimulate both the humoural and cellular immune responses. In preclinical trials, electroporation is successfully used in prime-boost combination protocols and its efficacy and tolerability have been demonstrated in Phase I clinical trials. Since these initial results appear promising, in the next future we will assist further developments of naked DNA vaccination associated to the electroporation technology. This approach not only provides the basis for human studies but also a practical application to veterinary medicine. © 2010 Bentham Science Publishers Ltd.

Fioretti D.,CNR Institute of Neurobiology and Molecular Medicine | Iurescia S.,CNR Institute of Neurobiology and Molecular Medicine | Fazio V.M.,The Interdisciplinary Center | Fazio V.M.,Instituto Of Ricovero E Cura A Carattere Scientifico Casa Sollievo Della Sofferenza | Rinaldi M.,CNR Institute of Neurobiology and Molecular Medicine
Journal of Biomedicine and Biotechnology | Year: 2010

Due to their rapid and widespread development, DNA vaccines have entered into a variety of human clinical trials for vaccines against various diseases including cancer. Evidence that DNA vaccines are well tolerated and have an excellent safety profile proved to be of advantage as many clinical trials combines the first phase with the second, saving both time and money. It is clear from the results obtained in clinical trials that such DNA vaccines require much improvement in antigen expression and delivery methods to make them sufficiently effective in the clinic. Similarly, it is clear that additional strategies are required to activate effective immunity against poorly immunogenic tumor antigens. Engineering vaccine design for manipulating antigen presentation and processing pathways is one of the most important aspects that can be easily handled in the DNA vaccine technology. Several approaches have been investigated including DNA vaccine engineering, co-delivery of immunomodulatory molecules, safe routes of administration, prime-boost regimen and strategies to break the immunosuppressive networks mechanisms adopted by malignant cells to prevent immune cell function. Combined or single strategies to enhance the efficacy and immunogenicity of DNA vaccines are applied in completed and ongoing clinical trials, where the safety and tolerability of the DNA platform are substantiated. In this review on DNA vaccines, salient aspects on this topic going from basic research to the clinic are evaluated. Some representative DNA cancer vaccine studies are also discussed. © 2010 Daniela Fioretti et al.

Gurtner A.,Regina Elena Cancer Institute | Starace G.,CNR Institute of Neurobiology and Molecular Medicine | Norelli G.,Regina Elena Cancer Institute | Piaggio G.,Regina Elena Cancer Institute | And 2 more authors.
Journal of Biological Chemistry | Year: 2010

Mitogen-activated protein kinase kinase 3 (MAP2K3) is a member of the dual specificity kinase group. Growing evidence links MAP2K3 to invasion and tumor progression. Here, we identify MAP2K3 as a transcriptional target of endogenous gain-of-function p53 mutants R273H, R175H, and R280K. We show thatMAP2K3modulation occurred at the mRNA and protein levels and that endogenous mutant p53 proteins are capable of binding to and activate the MAP2K3 promoter. In addition, we found that the studied p53 mutants regulate MAP2K3 gene expression through the involvement of the transcriptional cofactors NF-Y and NF-κB. Finally, functional studies showed that endogenous MAP2K3 knockdown inhibits proliferation and survival of human tumor cells, whereas the ectopic expression of MAP2K3 can rescue the proliferative defect induced by mutant p53 knockdown. Taken together, our findings define a novel player through which mutant p53 exerts its gain-of-function activity in cancer cells. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Lanzuolo C.,Dulbecco Telethon Institute | Lanzuolo C.,CNR Institute of Neurobiology and Molecular Medicine | Sardo F.L.,Dulbecco Telethon Institute | Diamantini A.,Cervello | Orlando V.,Dulbecco Telethon Institute
PLoS Genetics | Year: 2011

Polycomb group (PcG) proteins are part of a conserved cell memory system that conveys epigenetic inheritance of silenced transcriptional states through cell division. Despite the considerable amount of information about PcG mechanisms controlling gene silencing, how PcG proteins maintain repressive chromatin during epigenome duplication is still unclear. Here we identified a specific time window, the early S phase, in which PcG proteins are recruited at BX-C PRE target sites in concomitance with H3K27me3 repressive mark deposition. Notably, these events precede and are uncoupled from PRE replication timing, which occurs in late S phase when most epigenetic signatures are reduced. These findings shed light on one of the key mechanisms for PcG-mediated epigenetic inheritance during S phase, suggesting a conserved model in which the PcG-dependent H3K27me3 mark is inherited by dilution and not by de novo methylation occurring at the time of replication. © 2011 Lanzuolo et al.

Ceccanti M.,University of Rome La Sapienza | Mancinelli R.,Instituto Superiore Of Sanita | Tirassa P.,CNR Institute of Neurobiology and Molecular Medicine | Laviola G.,CNR Institute of Neuroscience | And 3 more authors.
Neurobiology of Aging | Year: 2012

Prenatal ethanol exposure produces severe changes in brain, liver, and kidney through mechanisms involving growth factors. These molecules regulate survival, differentiation, maintenance, and connectivity of brain, liver, and kidney cells. Despite the abundant available data on the short and mid-lasting effects of ethanol intoxication, only few data show the long-lasting damage induced by early ethanol administration. The aim of this study was to investigate changes in nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) in brain areas, liver, and kidney of 18-mo-old male mice exposed perinatally to ethanol at 11% vol or to red wine at the same ethanol concentration. The authors found that ethanol per se elevated NGF, BDNF, HGF, and VEGF measured by ELISA in brain limbic system areas. In the liver, early exposure to ethanol solution and red wine depleted BDNF and VEGF concentrations. In the kidney, red wine exposure only decreased VEGF. In conclusion, the present study shows that, in aged mice, early administration of ethanol solution induced long-lasting damage at growth factor levels in frontal cortex, hippocampus, and liver but not in kidney. Otherwise, in mice exposed to red wine, significant changes were observed in the liver and kidney but not in the hippocampus and frontal cortex. The brain differences in ethanol-induced toxicity when ethanol is administered alone or in red wine may be related to compounds with antioxidant properties present in the red wine. © 2012.

Vilardo E.,CNR Institute of Neurobiology and Molecular Medicine | Barbato C.,CNR Institute of Neurobiology and Molecular Medicine | Barbato C.,EBRI European Brain Research Institute Fondazione EBRI Rita Levi Montalcini | Ciotti M.,CNR Institute of Neurobiology and Molecular Medicine | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

The amyloid precursor protein (APP) and its proteolytic product amyloid beta (Aβ) are associated with both familial and sporadic forms of Alzheimer disease (AD). Aberrant expression and function of microRNAs has been observed in AD. Here, we show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. Using site-directed mutagenesis, a microRNA responsive element (RE) for miR-101 was identified in the 3′-untranslated region (UTR) of APP. The inhibition of endogenous miR-101 increased APP levels, whereas lentiviral-mediated miR-101 overexpression significantly reduced APP and Aβ load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1β (IL-1β). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of Aβ, suggesting a possible role for miR-101 in neuropathological conditions. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Colafrancesco V.,CNR Institute of Neurobiology and Molecular Medicine | Coassin M.,CNR Institute of Neurobiology and Molecular Medicine | Rossi S.,CNR Institute of Neurobiology and Molecular Medicine | Aloe L.,CNR Institute of Neurobiology and Molecular Medicine
Annali dell'Istituto Superiore di Sanita | Year: 2011

The aim of this study was to investigate the effect of nerve growth factor (NGF) administration on retinal ganglion cells (RGCs) in experimentally induced glaucoma (GL) and diabetic retinopathy (DR). GL was induced in adult rats by injection of hypertonic saline into the episcleral vein of the eye and diabetes (DT) was induced by administration of streptozoticin. Control and experimental rats were treated daily with either ocular application of NGF or vehicle solution. We found that both animal models present a progressive degeneration of RGCs and changing NGF and VEGF levels in the retina and optic nerve. We then proved that NGF eye drop administration exerts a protective effect on these models of retinal degeneration. In brief, our findings indicate that NGF can play a protective role against RGC degeneration occurring in GL and DR and suggest that ocular NGF administration might be an effective pharmacological approach.

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