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Search Results: 1 - 10 of 32251 matches for " Antonio Porcellini "
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Oxidative Stress Posttranslationally Regulates the Expression of Ha-Ras and Ki-Ras in Cultured Astrocytes
Samantha Messina,Luigi Frati,Antonio Porcellini
Oxidative Medicine and Cellular Longevity , 2012, DOI: 10.1155/2012/792705
Abstract: Addition of hydrogen peroxide to cultured astrocytes induced a rapid and transient increase in the expression of Ha-Ras and Ki-Ras. Pull-down experiments with the GTP-Ras-binding domain of Raf-1 showed that oxidative stress substantially increased the activation of Ha-Ras, whereas a putative farnesylated activated form of Ki-Ras was only slightly increased. The increase in both Ha-Ras and Ki-Ras was insensitive to the protein synthesis inhibitor, cycloheximide, and was occluded by the proteasomal inhibitor, MG-132. In addition, exposure to hydrogen peroxide reduced the levels of ubiquitinated Ras protein, indicating that oxidative stress leads to a reduced degradation of both isoforms through the ubiquitin/proteasome pathway. Indeed, the late reduction in Ha-Ras and Ki-Ras was due to a recovery of proteasomal degradation because it was sensitive to MG-132. The late reduction of Ha-Ras levels was abrogated by compound PD98059, which inhibits the MAP kinase pathway, whereas the late reduction of Ki-Ras was unaffected by PD98059. We conclude that oxidative stress differentially regulates the expression of Ha-Ras and Ki-Ras in cultured astrocytes, and that activation of the MAP kinase pathway by oxidative stress itself or by additional factors may act as a fail-safe mechanism limiting a sustained expression of the potentially detrimental Ha-Ras.
Oxidative Stress Posttranslationally Regulates the Expression of Ha-Ras and Ki-Ras in Cultured Astrocytes
Samantha Messina,Luigi Frati,Antonio Porcellini
Oxidative Medicine and Cellular Longevity , 2012, DOI: 10.1155/2012/792705
Abstract: Addition of hydrogen peroxide to cultured astrocytes induced a rapid and transient increase in the expression of Ha-Ras and Ki-Ras. Pull-down experiments with the GTP-Ras-binding domain of Raf-1 showed that oxidative stress substantially increased the activation of Ha-Ras, whereas a putative farnesylated activated form of Ki-Ras was only slightly increased. The increase in both Ha-Ras and Ki-Ras was insensitive to the protein synthesis inhibitor, cycloheximide, and was occluded by the proteasomal inhibitor, MG-132. In addition, exposure to hydrogen peroxide reduced the levels of ubiquitinated Ras protein, indicating that oxidative stress leads to a reduced degradation of both isoforms through the ubiquitin/proteasome pathway. Indeed, the late reduction in Ha-Ras and Ki-Ras was due to a recovery of proteasomal degradation because it was sensitive to MG-132. The late reduction of Ha-Ras levels was abrogated by compound PD98059, which inhibits the MAP kinase pathway, whereas the late reduction of Ki-Ras was unaffected by PD98059. We conclude that oxidative stress differentially regulates the expression of Ha-Ras and Ki-Ras in cultured astrocytes, and that activation of the MAP kinase pathway by oxidative stress itself or by additional factors may act as a fail-safe mechanism limiting a sustained expression of the potentially detrimental Ha-Ras. 1. Introduction An increased formation of reactive oxygen species (ROS) has been implicated in the pathogenesis of several CNS disorders including Alzheimer’s disease, Parkinson’s disease, acute and chronic cerebrovascular disorders, and brain ageing. In particular, oxidative stress in the CNS occurs after ischemic, traumatic, or excitotoxic insults when the excessive generation of ROS overwhelms the intracellular antioxidant capacity [1]. Neurons are highly sensitive to oxidative damage, whereas astrocytes exert a protective function acting as cell scavengers and producing neurotrophic factors in response to ROS [2–6]. Astrocytes respond to ROS with the activation of MAP kinases (MAPKs), including the extracellular signal-regulated kinases ERK1/2, JUN kinases (JNKs), and p38 MAPKs [7, 8]. The monomeric GTP-binding protein, Ras, has an established role in activating these pathways and has been implicated in the cellular response to oxidative stress [9, 10]. Mammalian cells contain three ubiquitously expressed Ras isoforms, Ha-, Ki-, and N-Ras that share a high degree of structural homology [11]. Ha- and Ki-Ras generate opposing effects on the redox state of cells in heterologous expression systems. Ki-Ras exerts an
Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma
Calogero Antonella,Lombari Vincenza,De Gregorio Giorgia,Porcellini Antonio
Cancer Cell International , 2004,
Abstract: Background The aim of this work was to investigate in vitro the putative role of EGR-1 in the growth of glioma cells. EGR-1 expression was examined during the early passages in vitro of 17 primary cell lines grown from 3 grade III and from 14 grade IV malignant astrocytoma explants. The explanted tumors were genetically characterized at the p53, MDM2 and INK4a/ARF loci, and fibronectin expression and growth characteristics were examined. A recombinant adenovirus overexpressing EGR-1 was tested in the primary cell lines. Results Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082). Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1–2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus. Conclusions Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene.
Regenerative medicine: a review
Porcellini, Adolfo;
Revista Brasileira de Hematologia e Hemoterapia , 2009, DOI: 10.1590/S1516-84842009000800017
Abstract: regenerative medicine is a technique to replace or repair defective or diseased tissue or organs by in vitro design with in vivo usage. it can be considered a relatively new branch of medicine born in 1997 when whithman dh et al. proposed to integrate platelet enriched plasma (prp) in fibrin glue. in 1998 marx et al. demonstrated that prp was able to induce bone regeneration of the jaw. in the same period it was discovered that a fraction of stem cells of bone marrow origin was able to repair several mesenchymal tissues or organs.
Sensitivity to cisplatin in primary cell lines derived from human glioma correlates with levels of EGR-1 expression
Antonella Calogero, Antonio Porcellini, Vincenza Lombari, Cinzia Fabbiano, Antonietta Arcella, Massimo Miscusi, Donatella Ponti, Giuseppe Ragona
Cancer Cell International , 2011, DOI: 10.1186/1475-2867-11-5
Abstract: Cytotoxicity assays were performed on cells derived from fresh tumor explants of 18 human cases of malignant glioma. In addition to EGR-1, tumor cultures were investigated for genetic alterations and the expression of cancer regulating factors, related to the p53 pathway.We found that sensitivity to cisplatin correlates significantly with levels of EGR-1 expression in tumors with wild-type p53/INK4a/p16 status.Increased knowledge of the mechanisms regulating EGR-1 expression in wild-type p53/INK4a/p16 cases of glioma may help in the design of new chemotherapeutic strategies for these tumors.Malignant brain tumors of glial origin are highly invasive and poorly sensitive to anti-proliferative drugs, with only 20-30% of patients responding to chemotherapy. The biological basis of drug resistance in these tumors is complex, being dependent to some extent on the genetic make-up of the tumor. The prognostic value of molecular markers has been investigated either retrospectively, in patients treated with standard therapy, or in tumor cells cultured in vitro and exposed to different chemotherapics, but no clear results have emerged [1]. The role of p53 gene status [2], the presence of deletions in the INK4a/INK4b locus coding for the tumor suppressors and cell cycle regulators p16, p15 and p14ARF [3], the MGMT (O6-methylguanine DNA methyltransferase) levels [4] and the levels of expression for several players and regulators of apoptosis [5] were all studied to predict the response of the tumor to specific drugs. The rationale of these studies was that tumor cells react to the genotoxic insult by p53-dependent cell cycle arrest, or by undergoing apoptosis [6]. However, from these studies none of these factors, except MGMT, emerged as a major determinant of chemoresistance [7].Many genes are found to be defective and others are deregulated in gliomas [8]. We have recently found that EGR-1 expression is downregulated in malignant gliomas [9]. EGR-1 encodes a nuclear transcript
Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma
Antonella Calogero, Vincenza Lombari, Giorgia De Gregorio, Antonio Porcellini, Severine Ucci, Antonietta Arcella, Riccardo Caruso, Franco Gagliardi, Alberto Gulino, Gaetano Lanzetta, Luigi Frati, Dan Mercola, Giuseppe Ragona
Cancer Cell International , 2004, DOI: 10.1186/1475-2867-4-1
Abstract: Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082). Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1–2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus.Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene.EGR-1 encodes a nuclear phosphoprotein that binds to DNA and regulates transcription through a GC-rich consensus sequence [1-4]. EGR-1 is involved in the regulation of cell responses to a wide array of stimuli such as mitogens, growth factors and stress stimuli [5-7]. Recent studies have shown that EGR-1 expression is altered in several types of neoplasia, compared to normal tissue [1,8,9]. Gene deletion or EGR-1 mutations have been reported in sporadic hematological malignancies [10]. EGR-1 expression has been found to be either decreased or undetectable in human breast cancer tissue and small cell lung carcinoma [11,12]. EGR-1 is altered in a different manner in prostate cancer, where higher levels of EGR-1 expression are found correlated to more advanced stages of malignancy [13]. Later studies confirmed in two independent mouse models that EGR-1 up-regulates tumor progression [14,15]. From these various studies it is clear that EGR-1 is involved in regulation of
Pro-inflammatory genetic profile and familiarity of acute myocardial infarction
Manuela Ianni, Sergio Callegari, Antonio Rizzo, Paolo Pastori, Paolo Moruzzi, Domenico Corradi, Elisa Porcellini, Gianluca Campo, Roberto Ferrari, Marco M Ferrario, Stefania Bitonte, Ilaria Carbone, Federico Licastro
Immunity & Ageing , 2012, DOI: 10.1186/1742-4933-9-14
Abstract: This study showed that a genetic signature consisting of the concomitant presence of the CC genotype of VEGF, the A allele of IL-10 and the A allele of IFN-γ was indeed present in the Offs population. In fact, the above genetic markers were more frequent in unaffected Offs (46.4%) and patients with sporadic AMI (31.8%) than in the CTR (17.3%) and the differences were highly statistically significant (Offs vs CTR: p?=?0.0001, OR?=?4.129; AMI vs CTR: p?=?0.0001, OR?=?2.224). During the 24-year follow-up, Offs with a positive familiarity in spite of a relatively young age showed an increased prevalence of diabetes, ischemic heart disease and stroke. These findings reinforce the notion that subjects with a familial history of AMI are at risk of an accelerated aging of cardiovascular system resulting in cardiovascular events.Our data suggest that selected genes with immune regulatory functions are part of the complex genetic background contributing to familiarity for cardiovascular diseases. This inflammatory genetic profile, along with classical cardiovascular risk factors, may be used for better defining individual risk of AMI in unaffected subjects.
DNA Damage, Homology-Directed Repair, and DNA Methylation
Concetta Cuozzo equal contributor,Antonio Porcellini equal contributor,Tiziana Angrisano,Annalisa Morano,Bongyong Lee,Alba Di Pardo,Samantha Messina,Rodolfo Iuliano,Alfredo Fusco,Maria R Santillo,Mark T Muller,Lorenzo Chiariotti,Max E Gottesman ,Enrico V Avvedimento
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030110
Abstract: To explore the link between DNA damage and gene silencing, we induced a DNA double-strand break in the genome of Hela or mouse embryonic stem (ES) cells using I-SceI restriction endonuclease. The I-SceI site lies within one copy of two inactivated tandem repeated green fluorescent protein (GFP) genes (DR-GFP). A total of 2%–4% of the cells generated a functional GFP by homology-directed repair (HR) and gene conversion. However, ~50% of these recombinants expressed GFP poorly. Silencing was rapid and associated with HR and DNA methylation of the recombinant gene, since it was prevented in Hela cells by 5-aza-2′-deoxycytidine. ES cells deficient in DNA methyl transferase 1 yielded as many recombinants as wild-type cells, but most of these recombinants expressed GFP robustly. Half of the HR DNA molecules were de novo methylated, principally downstream to the double-strand break, and half were undermethylated relative to the uncut DNA. Methylation of the repaired gene was independent of the methylation status of the converting template. The methylation pattern of recombinant molecules derived from pools of cells carrying DR-GFP at different loci, or from an individual clone carrying DR-GFP at a single locus, was comparable. ClustalW analysis of the sequenced GFP molecules in Hela and ES cells distinguished recombinant and nonrecombinant DNA solely on the basis of their methylation profile and indicated that HR superimposed novel methylation profiles on top of the old patterns. Chromatin immunoprecipitation and RNA analysis revealed that DNA methyl transferase 1 was bound specifically to HR GFP DNA and that methylation of the repaired segment contributed to the silencing of GFP expression. Taken together, our data support a mechanistic link between HR and DNA methylation and suggest that DNA methylation in eukaryotes marks homologous recombined segments.
Alzheimer's disease gene signature says: beware of brain viral infections
Elisa Porcellini, Ilaria Carbone, Manuela Ianni, Federico Licastro
Immunity & Ageing , 2010, DOI: 10.1186/1742-4933-7-16
Abstract: In this report we suggest that the polymorphism association in 8 of these genes is consistent with a non conventional interpretation of AD etiology.Nectin-2 (NC-2), apolipoprotein E (APOE), glycoprotein carcinoembryonic antigen related cell adhesion molecule- 16 (CEACAM-16), B-cell lymphoma-3 (Bcl-3), translocase of outer mitochondrial membrane 40 homolog (T0MM-40), complement receptor-1 (CR-l), APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A) result in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging, leading to neuronal loss, inflammation and amyloid deposition.We hypothesized that such genetic trait may predispose to AD via complex and diverse mechanisms each contributing to an increase of individual susceptibility to brain viral infectionsThe incidence of Alzheimer's disease (AD) is rising sharply and a large fraction of the elderly population will ultimately be affected by the disease. Because of an urgent need for effective preventative and therapeutic measures, extensive research has focused on pathogenetic mechanisms of the disease. However, effective therapy is not already available. AD pathology is characterized by neuronal loss leading to brain atrophy and a decrement of the cerebral metabolism. Major neuropathologic lesions are: (i) synapse and neuron loss; (ii) extracellular amyloid deposits and amyloid plaques, principally composed of amyloid beta (Aβ) peptide; (iii) intraneuronal accumulation of hyperphosphorylated Tau proteins leading to neurofibrillary degeneration; (iv) reactive astrogliosis; (v) brain inflammation. Current views of AD pathogenetic mechanisms describe amyloid deposition and neuritic plaque formation as a central mechanisms leading to neuro-degeneration, cognitive impairment and sporadic AD [1]. Therefore, therapeutic approaches have focused on reducing amyloid load and plaque deposition or clearance of brain amyloid. Other mechanisms may b
T- Lymphoblastic lymphoma in adults
Santini, Gino;Porcellini, Adolfo;Zupo, Simona;Truini, Mauro;
Revista Brasileira de Hematologia e Hemoterapia , 2008, DOI: 10.1590/S1516-84842008000800012
Abstract: adult t-lymphoblastic lymphoma is rare and has a poor prognosis. in the 80s, following the introduction of sequential, intensified chemotherapy, complete remissions in the order of 75%-95% of treated patients, were achieved. however, several patients, namely those with advanced disease, continued to relapse either in remission or during maintenance therapy. moreover, all these early studies were not able to detect any valuable prognostic index to predict the outcome. in an attempt to reduce the relapse rate, upfront autologous stem cell transplantation in patients in complete remission was introduced. the results obtained with this approach were quite homogeneous, indicating a probability of disease-free survival of about 65%-75% and an overall survival rate of 60%. successive therapies designed since 2000 were able to obtain complete remissions of above 90%, with a relapse rate in the order of 30% and an overall survival comparable to that obtained with the transplant procedure. yet, these studies were also unable to detect valuable prognostic factors predictive of the outcome. moreover, no study on the biologic profile of the disease has been developed. to improve the prognosis of t-lymphoblastic lymphoma it seems necessary to create national registries to collect both clinical and biological data of all lymphoblastic lymphoma patients. in this way it will be possible to reach critical numbers of data with which valid statistical analysis may be performed that is able to detect factors influencing the outcome. moreover, subsets of patients needing intensified procedures such as stem cell transplant may be detected at diagnosis.
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