88 results on '"BERRINO, Liberato"'
Search Results
2. The role of A3 adenosine receptors in central regulation of arterial blood pressure
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STELLA L, MARABESE, Ida, BERRINO, Liberato, MAIONE, Sabatino, FILIPPELLI A, ROSSI F., DE NOVELLIS, Vito, Stella, L, DE NOVELLIS, Vito, Marabese, Ida, Berrino, Liberato, Maione, Sabatino, Filippelli, A, and Rossi, F.
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Central Nervous System ,Male ,Purinergic P1 ,Intraventricular ,Receptors, Purinergic P1 ,Blood Pressure ,Injections ,Rats ,Rats, Sprague-Dawley ,Heart Rate ,Animals, Blood Pressure ,physiology, Central Nervous System ,physiology, Heart Rate ,physiology, Injections ,Intraventricular, Male, Rats, Rats ,Sprague-Dawley, Receptors ,physiology ,Receptors ,Papers ,Animals ,Sprague-Dawley ,Injections, Intraventricular - Abstract
1. Pharmacological studies have suggested that A3 receptors are present on central neurons. Recently this adenosine receptor subtype has been identified in the rat and its presence in the central nervous system has been confirmed. 2. In this study we investigated the effects of acute intracerebroventricular (i.c.v.) injections of N6-2-(4-aminophenyl)-ethyladenosine (APNEA), a non-selective A3 adenosine receptor agonist, on arterial blood pressure (ABP) and heart rate (HR), after treatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective antagonist of A1 adenosine receptors. 3. Anaesthetized rats, after DPCPX (12 microg(-1) kg i.c.v.), were treated with APNEA (0.4-4 microg kg(-1) i.c.v.) resulting in a transitory and dose-dependent decrease in arterial blood pressure without a change in heart rate. APNEA also induced hypotensive responses after i.c.v. pretreatment with aminophylline, at a dose of 20 microg kg(-1). In contrast, pretreatment 48 h before, with 4 microg kg(-1) i.c.v. of pertussis toxin reduced the hypotensive effect induced by APNEA. Administration of APNEA at a higher dose (20 microg kg(-1) i.c.v.), after DPCPX, induced a decrease in ABP of -66+/-5.4 mmHg and after 3 min a decrease in heart rate of -62+/-6.0 beats min(-1). Transection of the spinal cord abolished this significant fall in ABP, but not the decrease of HR. 4. These results suggest that a population of A3-receptors is present in the CNS, whose activation induces a decrease in blood pressure with no change of heart rate.
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- 1998
3. Bioavailability of timolol and aceclidine after ocular instillation in the rabbit
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MATERA, Maria Gabriella, LAMPA E, IMPERATORE A, BERRINO, Liberato, RUSSO F, BOLDRINI E, ROSSI, Francesco, Matera, Maria Gabriella, Lampa, E, Imperatore, A, Berrino, Liberato, Russo, F, Boldrini, E, and Rossi, Francesco
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Male ,Quinuclidines ,Administration, Topical ,Adrenergic beta-Antagonists ,Biological Availability ,Pupil ,Eye ,Aqueous Humor ,Parasympathomimetics ,Area Under Curve ,Timolol ,Animals ,Spectrophotometry, Ultraviolet ,Rabbits ,Half-Life - Abstract
The bioavailability of timolol and aceclidine after the ocular instillation of each drug (timolol 0.5% or aceclidine 2%) or both combined (timolol 0.5% + aceclidine 2%) has been evaluated in rabbits. 15 male albino rabbits were treated by the instillation of timolol and aceclidine alone or combined in the conjunctival sac of the right eye. Timolol concentrations in humor aqueous were assayed at 10 min, 30 min, 1 hr, 2 hr, 4 hr and 6 hr after instillation by high-performance liquid chromatography (HPLC). Aceclidine was assayed by a pharmacodynamic method: pupillary diameter at the following time intervals 0 (basal value), 1 min, 5 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr after treatment. Our results demonstrated that no differences in timolol and aceclidine bioavailability were found between simple-drug preparations and their combination.
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- 1998
4. Evidence that arcaine increases the N-methyl-D-aspartate-induced cardiovascular effects into the periaqueductal gray area of anesthetized rats
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MAIONE, Sabatino, BERRINO, Liberato, PIZZIRUSSO A, LEYVA J, STELLA L, ROSSI, Francesco, Maione, Sabatino, Berrino, Liberato, Pizzirusso, A, Leyva, J, Stella, L, and Rossi, Francesco
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Male ,N-Methylaspartate ,Dose-Response Relationship, Drug ,Biguanides ,Hemodynamics ,Blood Pressure ,Receptors, N-Methyl-D-Aspartate ,Rats ,Rats, Sprague-Dawley ,2-Amino-5-phosphonovalerate ,Heart Rate ,Animals ,Periaqueductal Gray ,Anesthesia ,Dizocilpine Maleate - Abstract
In the present study the influence of arcaine (0.01-1 microgram/rat), an in vitro putative non-competitive antagonist of the NMDA receptors, on cardiovascular changes induced by intracerebral administration of N-methyl-D-aspartate (NMDA) (0.1 microgram/rat) has been evaluated. Both NMDA and arcaine were microinjected into the periaqueductal gray (PAG) area of anesthetized rats. Arcaine did not decrease NMDA-induced arterial hypertension and tachycardia, but, in a dose-related manner, increased the NMDA-induced cardiovascular effects. Moreover, treatment with arcaine was not able per se to modify arterial blood pressure and heart rate basal values. Although updated in vitro reports indicate arcaine as a blocker of the NMDA receptors by an open channel mechanism, our in vivo results, at the level of the PAG area, show this not to be true. Indeed the drug may facilitate NMDA receptor activation.
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- 1994
5. Central arrhythmogenic effects of N-methyl-D-aspartate (NMDA) in anesthetized rats: influence of the denervation of the carotid-sinus baroreceptors on the susceptibility to arrhythmias
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BERRINO, Liberato, CUPARENCU B, DE NOVELLIS, Vito, STELLA L, MAGRELLA M, ROSSI, Francesco, Berrino, Liberato, Cuparencu, B, DE NOVELLIS, Vito, Stella, L, Magrella, M, and Rossi, Francesco
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Male ,N-Methylaspartate ,Brain ,Arrhythmias, Cardiac ,Pressoreceptors ,Denervation ,Urethane ,Rats ,Electrocardiography ,Carotid Sinus ,Sodium Glutamate ,Animals ,Anesthesia ,Female ,Disease Susceptibility ,Rats, Wistar ,Injections, Intraventricular - Abstract
The intracerebroventricular (i.c.v.) administration of NMDA into urethane anesthetized rats could induce centrogenic cardiac arrhythmias. There were some important differences between sodium glutamate- and NMDA-induced arrhythmias which rendered it difficult to accept the assumption that glutamate-induced arrhythmias were due to the stimulation of only NMDA receptors. Denervation of the carotid-sinus baroreceptor zones enhanced the central arrhythmogenic activity of both sodium glutamate and NMDA.
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- 1992
6. Effects of gadolinium on N-methyl-D-aspartate (NMDA)-induced centrogenic arrhythmias
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BERRINO, Liberato, MAIONE, Sabatino, CUPARENCU B, ROSSI F., DE NOVELLIS, Vito, Berrino, Liberato, DE NOVELLIS, Vito, Maione, Sabatino, Cuparencu, B, and Rossi, F.
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Male ,Neurotransmitter Agents ,N-Methylaspartate ,Brain ,Arrhythmias, Cardiac ,Gadolinium ,Exocytosis ,Rats ,Heart Rate ,Animals ,Anesthesia ,Female ,Rats, Wistar ,Injections, Intraventricular - Abstract
In urethane-anesthetized rats, the intracerebroventricular (i.c.v.) administration of N-methyl-D-aspartate (NMDA)-induced central arrhythmias. These cardiac rhythm disorders could be prevented by the i.c.v. microinjection of gadolinium, an inhibitor of exocytosis. These findings suggest that inhibition of central neurotransmitter exocytosis could protect against centrogenic arrhythmias.
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- 1992
7. Research on heterocyclic compounds. XXX. Synthesis and pharmacological activity of 2-methylimidazo[1,2-b]pyridazine-3-carboxylic acids
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ABIGNENTE E, ARENA F, LURASCHI E, SATURNINO C, ROSSI, Francesco, BERRINO, Liberato, CENICOLA ML, Abignente, E, Arena, F, Luraschi, E, Saturnino, C, Rossi, Francesco, Berrino, Liberato, and Cenicola, Ml
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Male ,Magnetic Resonance Spectroscopy ,Prostaglandin Antagonists ,Anti-Inflammatory Agents, Non-Steroidal ,Pain ,In Vitro Techniques ,Rats ,Pyridazines ,Mice ,Structure-Activity Relationship ,Pregnancy ,Malondialdehyde ,Animals ,Edema ,Humans ,Cyclooxygenase Inhibitors ,Female ,Spectrophotometry, Ultraviolet ,Stomach Ulcer - Abstract
A group of ethyl 2-methylimidazo[1,2-b]pyridazine-3-carboxylates were prepared by reaction in anhydrous ethanol of some substituted 3-amino-pyridazines with ethyl 2-chloroacetoacetate. The corresponding carboxylic acids were obtained via alkaline or acid hydrolysis and then tested both in vivo to evaluate their antiinflammatory, analgesic and ulcerogenic actions and in vitro for their ability to inhibit the prostaglandin biosynthesis. The pharmacological results are discussed in terms of both structure-activity relationships and mechanism of action.
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- 1992
8. Effects of tetanus toxin, Salmonella typhimurium porin, and bacterial lipopolysaccharide on platelet aggregation
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MATERA C, FALZARANO C, BERRINO, Liberato, ROSSI, Francesco, Matera, C, Falzarano, C, Berrino, Liberato, and Rossi, Francesco
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Lipopolysaccharides ,Male ,Salmonella typhimurium ,Platelet Aggregation ,Tetanus Toxoid ,Animals ,Humans ,Porins ,Female ,Rabbits ,Bacterial Outer Membrane Proteins - Abstract
Endotoxins may interfere with platelet aggregation by interacting with the platelet membrane. The aim of this study was to evaluate the effects of tetanus toxin, Salmonella typhimurium porin, and bacterial lipopolysaccharide (LPS) on platelet aggregation induced by ADP and thrombin in vitro. Spontaneous platelet aggregation and platelet aggregation induced by ADP and thrombin were measured. Our results show that Salmonella typhimurium porin and bacterial LPS enhanced human and rabbit platelet aggregation induced by ADP and thrombin. Tetanus toxin did not affect platelet aggregation.
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- 1992
9. Experimental analysis of antihypertensive properties of S 5984 and its constituents: tertatolol and indapamide
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MARMO E, LAMPA E, ROSATTI F, RUSSO S, ROMANO AR, MATERA C., BERRINO, Liberato, Marmo, E, Lampa, E, Rosatti, F, Berrino, Liberato, Russo, S, Romano, Ar, and Matera, C.
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Male ,Propanolamines ,Drug Combinations ,Dogs ,Adrenergic beta-Antagonists ,Indapamide ,Animals ,Blood Pressure ,Rats, Inbred Strains ,Thiophenes ,Desoxycorticosterone ,Diuretics ,Rats - Abstract
S 5984 is a combination of tertatolol (S 2395-1) and indapamide. A positive synergism between these two constituents with regard to antihypertensive activity was demonstrated in the rat and the dog.
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- 1985
10. Glutamergic transmission and cardiovascular apparatus in normotensive rats
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LAMPA E, BERRINO, Liberato, SUSANNA V, ANGRISANI M, MARRAZZO R, MAIONE, Sabatino, DE SANTIS D, FICI F, MARMO E., Lampa, E, Berrino, Liberato, Susanna, V, Angrisani, M, Marrazzo, R, Maione, Sabatino, DE SANTIS, D, Fici, F, and Marmo, E.
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Male ,Glutamates ,Heart Rate ,Hypertension ,Animals ,Brain ,Glutamic Acid ,Blood Pressure ,Excitatory Amino Acid Antagonists ,Rats - Abstract
The cardiovascular effects induced by L-glutamic acid (G) on the cardiovascular apparatus of normotensive ethyl urethane-anaesthetized rats have been evaluated. (a) When administered i.v. (1 to 100 mg/kg) G induced a transitory and dose-dependent increase of arterial pressure (AP) with very moderate sinus bradycardia. It was antagonized by L-glutamic acid diethyl ester (GDEE, 0.1 to 100 mg/kg i.v.). (b) The intracerebroventricular (i.c.v.) administration of G (third ventricle, right lateral ventricle, posterior hypothalamus and striatum) at a dose of 0.1 to 10 mg/an induced a transitory and dose-dependent increase of AP, abolished by i.c.v. GDEE (1 to 10 mcg/an). (c) G hypertension was reduced by several procedures, i.e. catecholamine depletion, alpha 1, alpha 1 and alpha 2 or beta adrenergic blocks, alpha 2 central adrenergic stimulation, Ca2+ transmembrane or gangliary block, surrenectomy, and spinal transection at C7. (d) Atropine, bilateral vagotomy and sinus carotidal denervation increased G hypertension. (e) Therefore the bradycardia does seem to be due to a reflex-mediated effect via sinus carotid and aortic baroreceptors. (f) These data show that glutamergic transmission also participates through a central mechanism in the regulation of cardiovascular function in rats, via an increase in central sympathetic efferent activity.
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- 1988
11. Systemic and ocular effects of alpha 2-adrenergic stimulating and beta 2-blocking agents
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APPONI BATTINI G, BARRA A, DE SIMONE C, ROSSI, Francesco, BERRINO, Liberato, CAZZOLA M, MARMO E., APPONI BATTINI, G, Barra, A, DE SIMONE, C, Rossi, Francesco, Berrino, Liberato, Cazzola, M, and Marmo, E.
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Male ,Adrenergic beta-Antagonists ,Hemodynamics ,Blood Pressure ,Eye ,Aqueous Humor ,Vitreous Body ,Glucose ,Heart Rate ,Cations ,Animals ,Rabbits ,Adrenergic alpha-Agonists ,Intraocular Pressure - Abstract
The effects of alpha 2-adrenergic stimulating agents (clonidine and guanabenz) and beta-adrenolytic agents (atenolol and propranolol) on the systemic arterial pressure, heart-rate, blood glucose level and intraocular pressure, as well as on the concentrations of glucose, Na+, K+ and Ca++ in the lens and aqueous and vitreous humours, are evaluated in the rabbit. alpha 2-adrenergic stimulating agents cause a significant increase of the glucose concentration in the blood, lens, aqueous and vitreous humours; whereas the beta-adrenolytic agents cause insignificant effects. Neither of the two drugs alters the concentration of Na+, K+ and Ca++ in the lens and aqueous and vitreous humours.
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- 1984
12. Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc
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Colin C Schwarzwald, Christos Gkolfos, Shafeeq A. Mohammed, Francesco Cosentino, Thomas F. Lüscher, Massimo Volpe, Sarah Costantino, Francesco Paneni, Liberato Berrino, Shafaat Hussain, Katharyn J Mitchell, University of Zurich, Cosentino, Francesco, Costantino, Sarah, Paneni, Francesco, Mitchell, Katharyn, Mohammed, Shafeeq A., Hussain, Shafaat, Gkolfos, Christo, Berrino, Liberato, Volpe, Massimo, Schwarzwald, Colin, and Lüscher, Thomas Felix
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Male ,0301 basic medicine ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,medicine.medical_treatment ,DNMT3B ,miR-218 ,Diabetic cardiomyopathy ,030204 cardiovascular system & hematology ,2705 Cardiology and Cardiovascular Medicine ,Diabetes Mellitus, Experimental ,Epigenesis, Genetic ,11459 Center for Molecular Cardiology ,Mice ,Ventricular Dysfunction, Left ,03 medical and health sciences ,0302 clinical medicine ,34a ,Downregulation and upregulation ,microRNA ,Animals ,Medicine ,Gene silencing ,Epigenetics ,miRNA ,630 Agriculture ,business.industry ,Insulin ,Epigenetic ,miR ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Oxidative stress ,Hyperglycemia ,Heart failure ,epigenetics ,miR-34a ,miRNAs ,oxidative stress ,cardiology and cardiovascular medicine ,Cancer research ,Oxidative stre ,570 Life sciences ,biology ,10090 Equine Department ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Hyperglycaemia-induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. Intensive glycaemic control (IGC) has failed to reduce risk of heart failure in patients with diabetes but the underlying mechanisms remain to be elucidated. The present study investigates whether epigenetic regulation of the pro-oxidant adaptor p66Shc contributes to persistent myocardial dysfunction despite IGC. Methods and results p66Shc expression was increased in the heart of diabetic mice, and 3-week IGC by slow-release insulin implants did not revert this phenomenon. Sustained p66Shc upregulation was associated with oxidative stress, myocardial inflammation and left ventricular dysfunction, as assessed by conventional and 2D speckle-tracking echocardiography. In vivo gene silencing of p66Shc, performed during IGC, inhibited ROS production and restored cardiac function. Furthermore, we show that dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 causes CpG demethylation and histone 3 acetylation on p66Shc promoter, leading to persistent transcription of the adaptor. Altered DNMT3b/SIRT1 axis in the diabetic heart was explained by upregulation of miR-218 and miR-34a. Indeed, in human cardiomyocytes exposed to high glucose, inhibition of these miRNAs restored the expression of DNMT3b and SIRT1 and erased the adverse epigenetic signatures on p66Shc promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66Shc expression and ROS generation. Conclusions In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66Shc transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy.
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- 2018
13. Imatinib mesylate-induced cardiomyopathy involves resident cardiac progenitors
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Gallia Graiani, Emilia Corradini, Serena Galati, Donato Cappetta, Federica Galaverna, Costanza Lagrasta, Giulia Mazzaschi, Liberato Berrino, Caterina Frati, Lucia Prezioso, Angela Falco, Annamaria Buschini, Denise Madeddu, Franco Aversa, Monia Savi, Antonella De Angelis, Federico Quaini, Stefano Cavalli, Konrad Urbanek, Savi, M, Frati, C, Cavalli, S, Graiani, G, Galati, S, Buschini, A, Madeddu, D, Falco, A, Prezioso, L, Mazzaschi, G, Galaverna, F, Lagrasta, Cam, Corradini, E, De Angelis, A, Cappetta, D, Berrino, L, Aversa, F, Quaini, F, Urbanek, K, Savi, Monia, Frati, Caterina, Cavalli, Stefano, Graiani, Gallia, Galati, Serena, Buschini, Annamaria, Madeddu, Denise, Falco, Angela, Prezioso, Lucia, Mazzaschi, Giulia, Galaverna, Federica, Lagrasta, Costanza Anna Maria, Corradini, Emilia, De Angelis, Antonella, Cappetta, Donato, Berrino, Liberato, Aversa, Franco, Quaini, Federico, and Urbanek, Konrad
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0301 basic medicine ,Male ,Programmed cell death ,medicine.drug_class ,Cardiomyopathy ,Hemodynamics ,030204 cardiovascular system & hematology ,Pharmacology ,Tyrosine-kinase inhibitor ,Cardiac progenitor cell ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Cells, Cultured ,Cardiotoxicity ,Cell Death ,Dose-Response Relationship, Drug ,business.industry ,Myocardium ,Stem Cells ,Kit ,medicine.disease ,Rats ,030104 developmental biology ,Imatinib mesylate ,Imatinib Mesylate ,Myocardial fibrosis ,business ,Cardiomyopathies ,Tyrosine kinase - Abstract
Cardiovascular complications are included among the systemic effects of tyrosine kinase inhibitor (TKI)-based therapeutic strategies. To test the hypothesis that inhibition of Kit tyrosine kinase that promotes cardiac progenitor cell (CPC) survival and function may be one of the triggering mechanisms of imatinib mesylate (IM)-related cardiovascular effects, the anatomical, structural and ultrastructural changes in the heart of IM-treated rats were evaluated. Cardiac anatomy in IM-exposed rats showed a dose-dependent, restrictive type of remodeling and depressed hemodynamic performance in the absence of remarkable myocardial fibrosis. The effects of IM on rat and human CPCs were also assessed. IM induced rat CPC depletion, reduced growth and increased cell death. Similar effects were observed in CPCs isolated from human hearts. These results extend the notion that cardiovascular side effects are driven by multiple actions of IM. The identification of cellular mechanisms responsible for cardiovascular complications due to TKIs will enable future strategies aimed at preserving concomitantly cardiac integrity and anti-tumor activity of advanced cancer treatment.
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- 2018
14. AXL is an oncotarget in human colorectal cancer
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Rosa Marina Melillo, Vincenzo Rosario Iaffaioli, Anna Nappi, Teresa Troiani, Gerardo Botti, Giuseppina Liguori, Floriana Morgillo, Claudia Cardone, Fortunato Ciardiello, Liberato Berrino, Federica Liotti, Stefania Napolitano, Davide Ciardiello, Giulia Martini, Fiorella Angelica Valeria Ferraiolo, Barbara Rinaldi, Loreta Pia Ciuffreda, Roberto Bianco, Donata Vitagliano, Erika Martinelli, Martinelli, Erika, Martini, G, Cardone, C, Troiani, Teresa, Liguori, G, Vitagliano, D, Napolitano, S, Morgillo, Floriana, Rinaldi, Barbara, Melillo, Rm, Liotti, F, Nappi, A, Bianco, R, Berrino, Liberato, Ciuffreda, Lp, Ciardiello, D, Iaffaioli, V, Botti, G, Ferraiolo, F, Ciardiello, F., Martini, Giulia, Cardone, Claudia, Liguori, Giuseppina, Vitagliano, Donata, Napolitano, Stefania, Melillo, ROSA MARINA, Liotti, Federica, Nappi, Anna, Bianco, Roberto, Ciuffreda, Loreta Pia, Ciardiello, Davide, Iaffaioli, Vincenzo, Botti, Gerardo, Ferraiolo, Fiorella, and Ciardiello, Fortunato
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Male ,Colorectal cancer ,Angiogenesis ,Receptor tyrosine kinase ,chemistry.chemical_compound ,Mice ,Cell Movement ,GAS6 ,Anilides ,In Situ Hybridization, Fluorescence ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,Middle Aged ,Immunohistochemistry ,Oncology ,Quinolines ,Intercellular Signaling Peptides and Proteins ,Female ,RNA Interference ,Colorectal Neoplasms ,Adult ,foretinib ,Cell Survival ,Mice, Nude ,colorectal cancer ,Antineoplastic Agents ,Biology ,FISH ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Pathology Section ,medicine ,Gene silencing ,Animals ,Humans ,Gene Silencing ,neoplasms ,Aged ,Cell Proliferation ,Cell growth ,Foretinib ,AXL ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,HCT116 Cells ,Axl Receptor Tyrosine Kinase ,digestive system diseases ,Research Paper: Pathology ,chemistry ,Cancer research ,biology.protein ,Neoplasm Transplantation - Abstract
AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC.
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- 2015
15. Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research
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Amalia Forte, Marilena Cipollaro, Barbara Rinaldi, Liberato Berrino, Francesco Rossi, Umberto Galderisi, Forte, A, Rinaldi, Barbara, Berrino, Liberato, Rossi, Francesco, Galderisi, Umberto, and Cipollaro, Marilena
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Male ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Anti-Inflammatory Agents ,Restenosi ,Disease ,Bioinformatics ,Revascularization ,Antioxidants ,Coronary Restenosis ,Transcriptome ,Mice ,Pharmacogenomic ,Percutaneous Coronary Intervention ,Postoperative Complications ,Gene therapy ,Restenosis ,Angioplasty ,medicine ,Animals ,Regeneration ,Animal model ,Rats, Wistar ,Progenitor cell ,Endarterectomy ,Stem cell ,microRNA ,business.industry ,Stem Cells ,Genetic Therapy ,General Medicine ,medicine.disease ,MicroRNAs ,Stenosis ,Models, Animal ,business - Abstract
Restenosis is the pathophysiological process occurring in 10–15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.
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- 2014
16. Long-term administration of ranolazine attenuates diastolic dysfunction and adverse myocardial remodeling in a model of heart failure with preserved ejection fraction
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De Angelis A, Cappetta D, Piegari E, Rinaldi B, Ciuffreda LP, Esposito G, Ferraiolo FAV, Rivellino A, Russo R, Donniacuo M, Rossi F, Urbanek K, Berrino, L, DE ANGELIS, Antonella, Cappetta, Donato, Piegari, Elena, Rinaldi, Barbara, Ciuffreda, Loreta Pia, Esposito, Grazia, Ferraiolo, Fiorella Angelica Valeria, Rivellino, Alessia, Russo, Rosa, Donniacuo, Maria, Rossi, Francesco, Urbanek, Konrad, Berrino, Liberato, De Angelis, A, Cappetta, D, Piegari, E, Rinaldi, B, Ciuffreda, Lp, Esposito, G, Ferraiolo, Fav, Rivellino, A, Russo, R, Donniacuo, M, Rossi, F, Urbanek, K, Berrino, and L
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Male ,0301 basic medicine ,medicine.medical_specialty ,Diastole ,Ranolazine ,030204 cardiovascular system & hematology ,Drug Administration Schedule ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Animals ,Humans ,Medicine ,Ventricular remodeling ,Dahl salt-sensitive rat ,Heart Failure ,Rats, Inbred Dahl ,Ventricular Remodeling ,business.industry ,Nitrotyrosine ,Cardiovascular Agents ,Stroke Volume ,medicine.disease ,Rats ,Disease Models, Animal ,Preload ,Treatment Outcome ,030104 developmental biology ,Endocrinology ,Heart failure with preserved ejection fraction ,chemistry ,Heart failure ,Hypertension ,Cardiovascular agent ,Cardiology ,Diastolic dysfunction ,business ,Cardiology and Cardiovascular Medicine ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,medicine.drug - Abstract
Background To investigate the effects of chronic administration of ranolazine (RAN) on experimental model of heart failure with preserved ejection fraction. Methods Seven-weeks old Dahl salt-sensitive rats were fed a high salt diet for 5weeks to induce hypertension. Afterwards, rats continued with a high salt diet and were administered either with vehicle or RAN (20mg/kg/die, ip) for the following 8weeks. Control rats were maintained on a low salt diet. Results While systolic parameters were not altered, diastolic parameters were changed in high salt animals. Hemodynamic analysis showed a decreased dP/dt min, increased LVEDP, longer time constant and steeper slope of the end-diastolic pressure–volume relationship. Treatment with RAN attenuated these alterations and determined a reduction in mortality. Additionally, the magnitude of myocardial hypertrophy and activation of PI3K/Akt pathway were reduced. Alteration in diastolic compliance as a consequence of elevated myocardial stiffness was confirmed by an increase of collagen deposition and activation of pro-fibrotic TGF-β/SMAD3/CTGF signaling. These effects were counteracted by RAN. High salt rats had a decrease in SERCA2 and an increase in Na + /Ca 2+ exchanger (NCX). Treatment with RAN reduced NCX expression and determined an increment of SERCA2. Moreover, the levels of nitrotyrosine and oxidized dyhydroethidium were higher in high salt rats. RAN induced a decrement of oxidative stress, supporting the concept that reduction in ROS may mediate beneficial effects. Conclusions Our findings support the possibility that diastolic dysfunction can be attenuated by RAN, indicating its ability to affect active relaxation and passive diastolic compliance.
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- 2016
17. Campania Region (Italy) spontaneous reporting system and preventability assessment through a case-by-case approach: a pilot study on psychotropic drugs
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Liberata Sportiello, Annamaria Mascolo, Liberato Berrino, Annalisa Capuano, Maurizio Sessa, Alessandra Maccariello, Francesco Rossi, Michele Fabrazzo, Cristina Scavone, T. Iannaccone, Concetta Rafaniello, Sessa, Maurizio, Rafaniello, Concetta, Sportiello, Liberata, Mascolo, Annamaria, Scavone, Cristina, Maccariello, Alessandra, Iannaccone, Teresa, Fabrazzo, Michele, Berrino, Liberato, Rossi, Francesco, and Capuano, Annalisa
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Adult ,Male ,Drug ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,media_common.quotation_subject ,Pilot Projects ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Adverse events, preventability, psychotropic drugs, drug-drug interactions, pharmacovigilance, drug safety ,Pharmacovigilance ,medicine ,Adverse Drug Reaction Reporting Systems ,Humans ,Pharmacology (medical) ,Drug reaction ,Adverse effect ,Psychiatry ,Aged ,media_common ,Psychotropic Drugs ,Dose-Response Relationship, Drug ,business.industry ,General Medicine ,Middle Aged ,Mood ,Italy ,030220 oncology & carcinogenesis ,Spontaneous reporting ,Emergency medicine ,Female ,business ,030217 neurology & neurosurgery - Abstract
Objective: We conducted the first pilot Italian study to assess the preventability of adverse drug reactions involving psychotropic drugs reported through spontaneous reporting system from 01/07/2012 to 31/12/2014 in Campania Region. Methods: Preventability was assessed, case-by-case, using an adapted version of the P-method. The evaluation was performed only for those reports that had, as suspected drug, antipsychotics, mood stabilizers, antidepressants, anxiolytic and/or sedative-hypnotic. Results: Eighty-one cases (19.2%) out of 421 reported during the study period were preventable. In seventy-seven (95.1%) out of 81 preventable cases, the underlying mechanism of the adverse drug reactions was dose-related, in four (4.9%) preventable cases the underlying mechanism of the adverse drug reactions was respectively susceptibility- (1; 1.2%), unknown- (1; 1.2%) and time-related (2; 2.5%). In the 81 preventable cases, 97 critical criteria were detected of which 29/97 (29.9%) related to healthcare professionals’ practices, 0/97 (0.0%) to drug quality and 68/97 (70.1%) to patient behaviour. Conclusions: We proved that it was possible to apply and adapt the P-Method to assess the preventability of the adverse drug reactions involving psychotropic drugs, analysing individual case safety report sent through Campania Region spontaneous reporting system. Information acquired will be used to organize educational activities for both physicians and patients to promote a more appropriate drug use.
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- 2016
- Full Text
- View/download PDF
18. Stem Cell Therapy for Arterial Restenosis: Potential Parameters Contributing to the Success of Bone Marrow-Derived Mesenchymal Stromal Cells
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Barbara Rinaldi, Marisa De Feo, Pasquale Santè, Umberto Galderisi, Amalia Forte, Liberato Berrino, Marilena Cipollaro, Loredana Sodano, Mario Grossi, Chiara Botti, Mauro Finicelli, Francesco Rossi, Gilda Cobellis, Forte, A, Rinaldi, Barbara, Sodano, L, Berrino, Liberato, Rossi, Francesco, Finicelli, M, Grossi, M, Cobellis, Gilda, Botti, C, DE FEO, Marisa, Sante', Pasquale, Galderisi, Umberto, and Cipollaro, Marilena
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Male ,Vascular Endothelial Growth Factor A ,Pathology ,medicine.medical_treatment ,Apoptosis ,chemistry.chemical_compound ,Restenosis ,Carotid Stenosis ,Pharmacology (medical) ,Cells, Cultured ,Mesenchymal stromal cell ,Cell Cycle ,Cell Differentiation ,General Medicine ,Stem-cell therapy ,Vascular endothelial growth factor ,Carotid Arteries ,medicine.anatomical_structure ,8-Hydroxy-2'-Deoxyguanosine ,Cardiology ,Cytokines ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Restenosi ,Bone Marrow Cells ,Arteriotomy ,Mesenchymal Stem Cell Transplantation ,Revascularization ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Cell Proliferation ,Inflammation ,Pharmacology ,business.industry ,Mesenchymal stem cell ,Deoxyguanosine ,Mesenchymal Stem Cells ,medicine.disease ,Toll-Like Receptor 2 ,Rats ,Toll-Like Receptor 4 ,Stenosis ,chemistry ,Bone marrow ,Carotid Artery Injuries ,business ,DNA Damage - Abstract
Purpose: Restenosis is a complex and heterogeneous pathophysiological phenomenon occurring in patients submitted to revascularization procedures. Previous studies proved the antirestenotic properties of injected allogenic mesenchymal stromal cells (MSCs) in an experimental model of rat carotid (re)stenosis induced through arteriotomy. In this study we describe some of the effects subsequent to MSC treatment of rats submitted to carotid arteriotomy and possibly responsible for their antirestenotic effect. Methods: Rat MSCs were isolated from bone marrow, expanded in vitro and characterized. Subsequently, we evaluated the effects of MSC administration via tail vein at 3 and 7 days after carotid arteriotomy both in rat serum and in injured carotids, focusing on DNA oxidative damage (8-oxo-dG detection), cell proliferation index (BrdU incorporation assay), apoptotic index (TUNEL assay), the expression of inflammation- and proliferation-related genes (RT-PCR), the release of growth factors and of inflammation-related cytokines (antibody arrays and ELISA). Results: MSC administration induced a greater cell proliferation in carotids after arteriotomy, together with an increased level of VEGF in the serum and with the higher expression of VEGF mRNA in injured carotids. Serum analysis also revealed a decreased level of the pro-inflammatory cytokines CXCL1, CXCL5, L-Selectin, ICAM-1 and LIX, and of TIMP1 and SDF-1alpha in MSC-treated rats. The MSC immunomodulatory activity was confirmed by the decreased expression of TLR2 and TLR4 in injured carotids. Conclusions: MSCs play an immunomodulatory paracrine role when injected in rats submitted to carotid arteriotomy, accompanied by the release of VEGF, possibly contributing to the accelerated repair of the injured vascular wall.
- Published
- 2011
19. A single subcutaneous injection of ozone prevents allodynia and decreases the over-expression of pro-inflammatory caspases in the orbito-frontal cortex of neuropathic mice
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Dario Siniscalco, Paola Capodanno, Carlo Fuccio, Biagio Lettieri, Liberato Berrino, Maria Antonietta Scafuro, Francesco Rossi, Catia Giordano, Sabatino Maione, Carlo Luongo, Fuccio, C., Luongo, Carlo, Capodanno, P., Giordano, C., Scafuro, Mariantonietta, Siniscalco, D., Lettieri, B., Rossi, Francesco, Maione, Sabatino, and Berrino, Liberato
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Male ,medicine.medical_specialty ,caspase ,Injections, Subcutaneous ,Interleukin-1beta ,Pain ,Apoptosis ,neuropathic mice ,Gene Expression Regulation, Enzymologic ,Mice ,Ozone ,Cortex (anatomy) ,Internal medicine ,Animals ,Medicine ,Inflammation ,Pharmacology ,Behavior, Animal ,business.industry ,Peripheral Nervous System Diseases ,Nerve injury ,medicine.disease ,Ozone therapy ,Sciatic Nerve ,pro-inflammatory ,Frontal Lobe ,Endocrinology ,Peripheral neuropathy ,medicine.anatomical_structure ,Allodynia ,Hyperalgesia ,Astrocytes ,Caspases ,Anesthesia ,Neuropathic pain ,Sciatic nerve ,medicine.symptom ,business - Abstract
The neuropathic pain model consisting of the spared nerve injury of the sciatic nerve was used in the mouse to examin e wheth er peripheral neuropathy is capable of generating over-exp ression of pro-infl ammatory and pro-apoptotic genes in the orbito-frontal cortex, together with allodynia and hyperalgesia. RT-PCR analysis showed increased expression of caspase-1, caspase-12 and caspase-8 genes in the orbito-frontal cortex 14 days af ter spared nerve injury of the sciatic nerve. Conversely, the expression of caspase-3 wa s decreased by spared nerve injury of the sciatic nerve in the same brain area. A single subcutaneous injectio n of ozone performed 12 h af ter the surgical procedure decreased mechanical allodynia and normalized the mRNA caspase-1, caspase-12 and caspase-8 gene levels, but did not the decrease caspase-3 level, 14 days post-spared nerve injury. Ozone also reduced IL-1 β staining in the orbito-frontal cortex in neuropathic mice. This study provides evidence that a single subcutaneous administration of ozone decreased neuropathic pain type behaviour, normalized the expression of pro-infl ammatory caspa ses and reduced IL-1 β staining in the orbito-frontal cortex astrocytes in SNI mice. These preliminary data show that periph eral neuropathy induced over-exp ression of pro-inflammatory/pro-apoptotic caspases in the orbi to-frontal cortex and that ozone, by mechanisms that are as yet unknown, can regulate the expression of the genes that play a pivotal role in the onset and main tenance of allodynia.
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- 2009
20. Injury to rat carotid arteries causes time-dependent changes in gene expression in contralateral uninjured arteries
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Francesco Rossi, Francesco Onorati, Pasquale Santè, Attilio Renzulli, Umberto Galderisi, Maurizio Cotrufo, Liberato Berrino, Mauro Finicelli, Antonino Cascino, Per Hellstrand, Cesare Quarto, Marisa De Feo, Ina Nordström, Amalia Forte, Marilena Cipollaro, Pasquale De Luca, Forte, A., Finicelli, M., DE LUCA, P., Nordström, I., Onorati, F., Quarto, C., Sante', Pasquale, Renzulli, A., Galderisi, Umberto, Berrino, Liberato, DE FEO, Marisa, Hellstrand, P., Rossi, Francesco, Cotrufo, M., Cascino, A., and Cipollaro, Marilena
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Male ,Pathology ,medicine.medical_specialty ,Carotid Artery, Common ,medicine.medical_treatment ,Blotting, Western ,Arteriotomy ,rat carotid arterie ,Rats, Inbred WKY ,Lesion ,vascular injury ,Restenosis ,Renin–angiotensin system ,medicine ,Animals ,remodelling ,Oligonucleotide Array Sequence Analysis ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Gene Expression Profiling ,General Medicine ,Anatomy ,Vascular surgery ,medicine.disease ,Angiotensin II ,Rats ,medicine.anatomical_structure ,Gene Expression Regulation ,inflammation ,medicine.symptom ,Carotid Artery Injuries ,business ,microarray ,Signal Transduction ,Blood vessel ,Artery - Abstract
Vascular surgery aimed at stenosis removal induces local reactions often leading to restenosis. Although extensive analysis has been focused on pathways activated in injured arteries, little attention has been devoted to associated systemic vascular reactions. The aim of the present study was to analyse changes occurring in contralateral uninjured rat carotid arteries in the acute phase following unilateral injury. WKY (Wistar–Kyoto) rats were subjected to unilateral carotid arteriotomy. Contralateral uninjured carotid arteries were harvested from 4 h to 7 days after injury. Carotid arteries were also harvested from sham-operated rats and uninjured rats. Carotid morphology and morphometry were examined. Affymetrix microarrays were used for differential analysis of gene expression. A subset of data was validated by real-time RT–PCR (reverse transcription–PCR) and verified at the protein level by Western blotting. A total of 1011 genes were differentially regulated in contralateral uninjured carotid arteries from 4 h to 7 days after arteriotomy (P
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- 2008
21. Mesenchymal stem cells effectively reduce surgically induced stenosis in rat carotids
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Amalia Forte, Marilena Cipollaro, Francesco Rossi, Maurizio Cotrufo, Antonino Cascino, Liberato Berrino, Umberto Galderisi, Monica Mattia, Marisa De Feo, Mauro Finicelli, Forte, A, Finicelli, M, Mattia, M, Berrino, Liberato, Rossi, Francesco, DE FEO, Marisa, Cotrufo, M, Cipollaro, Marilena, Cascino, A, and Galderisi, Umberto
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Male ,Pathology ,medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,Cell- and Tissue-Based Therapy ,Muscle Proteins ,Bone Marrow Cells ,Arteriotomy ,Constriction, Pathologic ,Osteocytes ,Rats, Inbred WKY ,Injections ,S Phase ,Restenosis ,In vivo ,Adipocytes ,medicine ,Animals ,CD90 ,Antigens ,Cells, Cultured ,Cellular Senescence ,Inflammation ,business.industry ,Microfilament Proteins ,Mesenchymal stem cell ,G1 Phase ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Anatomy ,medicine.disease ,Rats ,Stenosis ,Carotid Arteries ,Phenotype ,medicine.anatomical_structure ,Gene Expression Regulation ,Osteocyte ,business ,Vascular Stenosis - Abstract
Restenosis following vascular injury remains a pressing clinical problem. Mesenchymal stem cells (MSCs) promise as a main actor of cell-based therapeutic strategies. The possible therapeutic role of MSCs in vascular stenosis in vivo has been poorly investigated so far. We tested the effectiveness of allogenic bone marrow-derived MSCs in reduction of stenosis in a model of rat carotid arteriotomy. MSCs were expanded in vitro retaining their proliferative and differentiation potentiality. MSCs were able to differentiate into adipocyte and osteocyte mesenchymal lineage cells, retained specific antigens CD73, CD90, and CD105, expressed smooth muscle alpha-actin, were mainly in proliferative phase of cell cycle and showed limited senescence. WKY rats were submitted to carotid arteriotomy and to venous administration with 5 × 106 MSCs. MSCs in vivo homed in injured carotids since 3 days after arteriotomy but not in contralateral uninjured carotids. Lumen area in MSC-treated carotids was 36% greater than in control arteries (P = 0.016) and inward remodeling was limited in MSC-treated carotids (P = 0.030) 30 days after arteriotomy. MSC treatment affected the expression level of inflammation-related genes, inducing a decrease of IL-1β and Mcp-1 and an increase of TGF-β in injured carotids at 3 and 7 days after arteriotomy (P
- Published
- 2008
22. An open randomized study of the treatment of escitalopram alone and combined with γ-hydroxybutyric acid and naltrexone in alcoholic patients
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Giovanni Addolorato, Liberato Berrino, L. Stella, Barbara Rinaldi, Francesca Rossi, Sabatino Maione, Annalisa Capuano, Stella, L, Addolorato, G, Rinaldi, Barbara, Capuano, Annalisa, Berrino, Liberato, Rossi, Francesco, and Maione, Sabatino
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Adult ,Male ,medicine.drug_class ,Narcotic Antagonists ,media_common.quotation_subject ,Serotonin reuptake inhibitor ,Hydroxybutyrates ,Citalopram ,Naltrexone ,law.invention ,Randomized controlled trial ,law ,mental disorders ,medicine ,Humans ,Escitalopram ,γ-Hydroxybutyric acid, Alcohol-dependence, Escitalopram, Naltrexone ,media_common ,Pharmacology ,business.industry ,Alcohol dependence ,Middle Aged ,Abstinence ,Alcoholism ,Anesthesia ,Drug Therapy, Combination ,Female ,business ,Selective Serotonin Reuptake Inhibitors ,Opioid antagonist ,Alcohol Abstinence ,medicine.drug - Abstract
gamma-hydroxybutyric acid (GHB) and the selective serotonin reuptake inhibitor escitalopram are effective in inducing and maintaining abstinence in alcohol. Naltrexone (NTX), an opioid antagonist, may be effective in preventing relapse in alcohol-dependent subjects. To evaluate whether each drug and its combination help to maintain alcohol abstinence, we determined the relapse rate over 6 months in 3 groups of patients. Group 1 (11 patients) received escitalopram (20 mg/day) orally administered; group 2 (12 patients) received NTX (50 mg/day) and escitalopram (20 mg/day); group 3 (12 patients) received GHB (75 mg/kg body weight) and escitalopram (20 mg/day); and group 4 (12 patients) received NTX (50mg/day) plus GHB (75 mg/kg) and escitalopram (20 mg/day). All groups received psychological support and underwent urine tests for alcohol metabolites twice a week. In group 1 (escitalopram only), 6 patients relapsed within 3 months and 3 after 6 months; whereas 2 patients remained abstinent. In group 2 (SSRI+NTX), 5 patients relapsed after 3 months and 3 after 6 months; whereas 4 patients remained abstinent. In group 3 (GHB+SSRI), 3 patients relapsed after 3 months and 3 after 6 months; whereas 6 patients remained abstinent. Finally, in group 4 (NTX+GHB+SSRI), 1 patient relapsed after 3 months and 1 after 6 months, whereas 10 patients remain abstinent. In conclusion, the combination of NTX+GHB+SSRI was the most effective in preventing relapses.
- Published
- 2008
23. Endothelin-1 receptor antagonists reduce cardiac electrical instability induced by high glucose in rats
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Clara Di Filippo, Michele D'Amico, Raffaele Marfella, Dario Giugliano, Francesco Rossi, Liberato Berrino, DI FILIPPO, Clara, D'Amico, Michele, Marfella, Raffaele, Berrino, Liberato, Giugliano, Dario, and Rossi, Francesco
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Endothelin Receptor Antagonists ,Male ,medicine.medical_specialty ,Indoles ,In Vitro Techniques ,QT interval ,Electrocardiography ,Endothelin-1 Receptor ,Piperidines ,Heart Conduction System ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Receptor ,Pharmacology ,Dose-Response Relationship, Drug ,Receptors, Endothelin ,business.industry ,Antagonist ,Heart ,Azepines ,General Medicine ,Receptor, Endothelin A ,medicine.disease ,Rats ,Long QT Syndrome ,Glucose ,Endocrinology ,Indans ,cardiovascular system ,Coronary perfusion pressure ,Cardiology ,business ,Antagonism ,Oligopeptides ,Perfusion - Abstract
Endothelin-1 (ET-1) influences the electrical activity of the heart by causing arrhythmias associated with lengthening of the QT interval in the electrocardiogram. Recent results from our laboratory have shown a primary role for a high plasma glucose concentration in determining cardiac QT prolongation. Since high glucose up-regulates the ET-1 system, the aim of the present study was to determine whether the increase of the QT interval and coronary vascular tone induced by high glucose in the heart involves increased activity of the ET system. Perfusion of isolated hearts with a high glucose concentrations (33.3 mM) prolonged the QT interval significantly and increased coronary perfusion pressure (CPP) ( P0.01). The increases in the QT interval and CPP induced by high glucose were accompanied by increases in cardiac ET-1 levels, and were significantly reduced by an ET-1 antiserum ( P0.01). Perfusion of the hearts with the selective ET(A) receptor antagonist FR139317 or with the non-selective ET(A)/ET(B) antagonist SB209670, but not with the selective ET(B) receptor antagonist BQ-788, reduced the glucose-induced QT prolongation. In addition, the increase in cardiac vascular tone, as evidenced by the increase in CPP, induced by high glucose was reversed partially by cardiac perfusion with either the non-selective ET(A)/ET(B) receptor antagonist or the ET(B)-selective BQ-788, whereas the ET(A) antagonist was without effect. By increasing the production of ET-1, a high glucose concentration may activate parallel pathways that contribute to a state of increased vasomotor tone and electrical ventricular instability. Antagonism at cardiac ET receptors could be helpful in these cardiovascular complications of diabetes.
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- 2002
24. Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1
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Michele D'Amico, Dario Giugliano, Elena Piegari, Raffaele Marfella, C Di Filippo, Francesca Rossi, Katherine Esposito, Francesco Nappo, Liberato Berrino, Marfella, Raffaele, D'Amico, Michele, DI FILIPPO, Clara, Piegari, Elena, Nappo, F, Esposito, Katherine, Berrino, Liberato, Rossi, Francesco, and Giugliano, Dario
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Blood Glucose ,Male ,rac1 GTP-Binding Protein ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Myocardial Infarction ,Ischemia ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,Basal (phylogenetics) ,chemistry.chemical_compound ,Reference Values ,In vivo ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Animals ,Myocardial infarction ,business.industry ,Myocardium ,Hemodynamics ,Nuclear Proteins ,Glutathione ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Streptozotocin ,Rats ,DNA-Binding Proteins ,Endocrinology ,chemistry ,Hyperglycemia ,Hypoxia-Inducible Factor 1 ,business ,Perfusion ,Diabetic Angiopathies ,Transcription Factors ,medicine.drug - Abstract
Aims/hypothesis. This study aimed to evaluate the effects of hyperglycaemia on the evolution of myocardial infarction and the expression of the transcriptional factor for angiogenesis hypoxia-inducible factor 1α (HIF-1α) in the rat. Methods. We studied the effects of streptozotocin induced diabetes on infarct size and HIF-1 α gene expression. These parameters were also evaluated in isolated hearts of non-diabetic rat, in condition of high glucose concentration. Results. In streptozotocin (STZ)-diabetic rats (in vivo study), myocardial infarct size was greater (p
- Published
- 2002
25. A multicenter, open-label phase II study of metformin with erlotinib in second-line therapy of stage IV non-small-cell lung cancer patients: treatment rationale and protocol dynamics of the METAL trial
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Floriana Morgillo, Fortunato Ciardiello, Ferdinando Carlo Sasso, Carminia Maria Della Corte, Annalisa Capuano, Federica Papaccio, Morena Fasano, Liberato Berrino, Fasano, M, DELLA CORTE, Carminia Maria, Capuano, Annalisa, Sasso, Ferdinando Carlo, Papaccio, F, Berrino, Liberato, Ciardiello, Fortunato, and Morgillo, Floriana
- Subjects
Oncology ,Research design ,Male ,Cancer Research ,Lung Neoplasms ,Phases of clinical research ,Pharmacology ,NSCLC ,Clinical Protocols ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Drug Dosage Calculations ,Aged, 80 and over ,Medicine (all) ,2-Part trial ,Middle Aged ,Metformin ,Treatment Outcome ,Erlotinib ,Research Design ,Female ,Open label ,Recurrent ,medicine.drug ,Human ,Drug Dosage Calculation ,Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Disease-Free Survival ,Erlotinib Hydrochloride ,Young Adult ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Lung cancer ,Clinical Protocol ,Aged ,Neoplasm Staging ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Quinazoline ,medicine.disease ,Lung Neoplasm ,EGFR tyrosine kinase inhibitor ,Quinazolines ,business - Abstract
We present the rationale and study design of the METAL (METformin in Advanced Lung cancer) trial (EudraCT number: 2014-000349-59), a multicenter, open label phase II study, designed to evaluate the safety and activity of metformin combined with erlotinib as second-line therapy in patients with stage IV nonesmall-cell lung cancer. This is a 2-part trial, consisting of a safety run-in part followed by a phase II part. The primary end point for the first part is the maximum tolerated dose and the identification of the recommended phase II dose of metformin in combination with erlotinib. Secondary end points are the study of pharmacokinetics and the antitumor activity evaluation of the experimental combination. The primary end point of part II is the time to disease progression with the combination, and antitumor activity as a secondary end point. Based on the statistical design, we plan to enroll approximately 60 patients.
- Published
- 2014
26. Effects of persistent nociception on periaqueductal gray glycine release
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Luigia Trabace, Sabatino Maione, Ida Marabese, Enza Palazzo, Liberato Berrino, F. sca Rossi, Francesca Rossi, Maione, Sabatino, Marabese, Ida, Rossi, Francesca, Berrino, Liberato, Palazzo, Enza, and Trabace, L.
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Male ,medicine.medical_specialty ,Microdialysis ,Glutamine ,Glycine ,Tetrodotoxin ,Periaqueductal gray ,Formaldehyde ,Internal medicine ,medicine ,Animals ,Periaqueductal Gray ,Rats, Wistar ,Glycine receptor ,Endogenous opioid ,Chemistry ,General Neuroscience ,Hindlimb ,Rats ,Kinetics ,Endocrinology ,Nociception ,Hyperalgesia ,NMDA receptor ,medicine.symptom ,Neuroscience - Abstract
Glycine is a candidate nociception inhibitory transmitter in specific brain regions, like for example the spinal cord, the thalamic nuclei and the periaqueductal gray matter. However, quantitative changes in glycine released in these brain regions during peripheral inflammation episodes have not been characterized in awake animals. To address this issue, an in vivo microdialysis study was carried out in freely moving rats in order to analyse periaqueductal gray matter extracellular glycine concentration following unilateral formalin injection into the dorsal skin of the right hind-paw. The extracellular concentration of glutamine was also evaluated in order to analyse whether or not a non-neurotransmitter amino acid was equally modified. Intra-periaqueductal gray matter tetrodotoxin perfusion reduced extracellular glycine concentration (−44±5%), but did not change the glutamine dialysate values. Peripheral injection of formalin reduced the glycine release during the early phase (−62±8%) and the late phase (−36±6%) of hyperalgesia, although not during the analgesic period. Perfusion with naloxone (300 μM) neither prevented the formalin-induced decreases in extacellular glycine concentration, nor modified the perfusate basal values of glycine and glutamine. These results show that, contrary to what has been recognized on the interactive role of opioids and GABA into the periaqueductal gray matter (i.e. opioid disinhibition), endogenous opioids seem not to modulate the activity of glycinergic neurons in the same midbrain area. In the light of these preliminary data, it is reasonable to suppose that GABA and glycine are probably not co-released at the level of periaqueductal gray matter of the rat.
- Published
- 2000
27. Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area
- Author
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Michele D'Amico, Anna Pizzirusso, Patrizia Oliva, Francesco Rossi, Liberato Berrino, Sabatino Maione, Pizzirusso, A, Oliva, P, Maione, Sabatino, D'Amico, Michele, Rossi, Francesco, and Berrino, Liberato
- Subjects
Male ,medicine.medical_specialty ,Vasopressin ,N-Methylaspartate ,Ganglionic Blockers ,Ganglionic blocker ,Glutamic Acid ,Blood Pressure ,Hexamethonium ,Periaqueductal gray ,Losartan ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Periaqueductal Gray ,Pharmacology ,Chemistry ,Glutamate receptor ,Rats, Brattleboro ,General Medicine ,Acetylcholine ,Rats ,Arginine Vasopressin ,Endocrinology ,nervous system ,NMDA receptor ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of 1-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2+/-1 mmHg to 16+/-3 mmHg; glutamate in Long Evans rats: from +16+/-2 mmHg to +36+/-4 mmHg; NMDA in Brattleboro rats: from +5+/-2 mmHg to +34 +/-8 mmHg; NMDA in Long Evans rats: from +18+/-7 mmHg to 80+/-9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15+/-3 mmHg vs +24+/-4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25+/-3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation.
- Published
- 1998
28. Effects of imipramine on raphe nuclei and prefrontal cortex extracellular serotonin levels in the rat
- Author
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Sabatino Maione, M. Pallotta, Francesca Rossi, J. Leyva, Liberato Berrino, Enza Palazzo, Maione, Sabatino, Palazzo, Enza, Pallotta, M, Leyva, J, Berrino, Liberato, and Rossi, F.
- Subjects
Male ,Imipramine ,Serotonin ,Microdialysis ,medicine.medical_specialty ,Adrenergic beta-Antagonists ,Prefrontal Cortex ,Antidepressive Agents, Tricyclic ,chemistry.chemical_compound ,Internal medicine ,medicine ,Extracellular ,Animals ,Rats, Wistar ,Neurotransmitter ,Pindolol ,Prefrontal cortex ,Pharmacology ,Rats ,Endocrinology ,chemistry ,Raphe Nuclei ,Extracellular Space ,Raphe nuclei ,medicine.drug - Abstract
The effect of acute administrations of three doses of imipramine (1, 5 and 10 mg/kg s.c.), a widely used tricyclic antidepressant, on extracellular levels of serotonin (5-HT) has been studied by intracerebral microdialysis in raphe nuclei and prefrontal cortex of conscious rats. Imipramine 1 mg/kg s.c. did not change extracellular 5-HT in either raphe nuclei and prefrontal cortex. However, with the dose of 5 mg/kg s.c. imipramine induced in raphe nuclei, a brief increase of extracellular 5-HT followed by a lowering (55-65% basal release) of the neurotransmitter. The same dose of imipramine decreased (60-70% of basal value) extracellular 5-HT in prefrontal cortex. Imipramine 10 mg/kg s.c. significantly increased 5-HT levels in both raphe nuclei (190 +/- 20% above basal value) and prefrontal cortex (280 +/- 15% above basal value). Pretreatment with (-)pindolol (5 mg/kg s.c.), a non-selective 5-HT1A subtype receptor antagonist, 30 min before imipramine 5 mg/kg, modified the effect of the antidepressant: an increase, instead of a decrease, on prefrontal cortex dialysate 5-HT was observed. (-)Pindolol (10 mg/kg s.c.) increased extracellular 5-HT in both raphe nuclei (155 +/- 20% above basal value) and prefrontal cortex (160 +/- 8% above basal value). These data show that acute administration of imipramine modifies extracellular 5-HT at the level of the raphe nuclei and prefrontal cortex. 5-HT1A autoreceptors in the raphe nuclei, which this study suggests to be tonically active, may be stimulated after systemic administration of high doses of imipramine.
- Published
- 1997
29. AT1 receptors mediate pressor responses induced by angiotensin II in the periaqueductal gray area of rats
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Michele D'Amico, Liberato Berrino, Clara Di Filippo, Francesco Rossi, D'Amico, Michele, DI FILIPPO, Clara, Berrino, Liberato, and Rossi, Francesco
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,Blood Pressure ,Periaqueductal gray ,General Biochemistry, Genetics and Molecular Biology ,Rats, Sprague-Dawley ,Internal medicine ,medicine ,Animals ,Periaqueductal Gray ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor ,Microinjection ,Receptors, Angiotensin ,Angiotensin II receptor type 1 ,Dose-Response Relationship, Drug ,Chemistry ,Angiotensin II ,Antagonist ,General Medicine ,Receptor antagonist ,Rats ,Endocrinology ,Losartan ,nervous system ,cardiovascular system ,hormones, hormone substitutes, and hormone antagonists ,circulatory and respiratory physiology ,medicine.drug - Abstract
Microinjection of angiotensin II (ANGII) (0.01 to 1 nmol) into the periaqueductal gray area (PAG) of anaesthetised rats caused dose-dependent increases in blood pressure. Preinjection (10 min before) of losartan (a selective non-peptide AT1 receptor antagonist; 50 nmol) to the PAG reduced the pressor response to ANGII whereas PD123319 (a selective non-peptide AT2 receptor antagonist; 50 nmol) did not affect the ANGII-induced hypertension. Thus, our data suggest that the activation of AT1 but not AT2 receptors mediates ANGII-induced blood pressure changes in the PAG area.
- Published
- 1997
30. Local inhibition of ornithine decarboxylase reduces vascular stenosis in a murine model of carotid injury
- Author
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Anders Holm, Liberato Berrino, Mario Grossi, Kaj A. Svedberg, Amalia Forte, Karolina M. Turczyńska, Mariano Vicchio, Barbara Rinaldi, Marilena Cipollaro, Maria Donniacuo, Umberto Galderisi, Bo Baldetorp, Per Hellstrand, Pasquale Santè, Bengt-Olof Nilsson, Francesco Rossi, Marisa De Feo, Forte, A, Grossi, M, Turczynska, Km, Svedberg, K, Rinaldi, Barbara, Donniacuo, Maria, Holm, A, Baldetorp, B, Vicchio, M, DE FEO, Marisa, Sante', Pasquale, Galderisi, Umberto, Berrino, Liberato, Rossi, Francesco, Hellstrand, P, Nilsson, Bo, and Cipollaro, Marilena
- Subjects
Male ,medicine.medical_specialty ,Eflornithine ,Endothelial cells ,Cell ,Restenosi ,α- Difluoromethylornithine ,Cell Line ,Cell cycle phase ,Ornithine decarboxylase ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,Restenosis ,Endothelial cell ,Animals ,Medicine ,Carotid Stenosis ,Cardiac and Cardiovascular Systems ,Viability assay ,Rats, Wistar ,Cells, Cultured ,Cell Proliferation ,business.industry ,Cell growth ,Ornithine Decarboxylase Inhibitors ,medicine.disease ,Rats ,Surgery ,alpha-Difluoromethylornithine ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Smooth muscle cells ,Apoptosis ,Cancer research ,Negative remodeling ,Cardiology and Cardiovascular Medicine ,business ,Polyamine - Abstract
Objectives: Polyamines are organic polycations playing an essential role in cell proliferation and differentiation, as well as in cell contractility, migration and apoptosis. These processes are known to contribute to restenosis, a pathophysiological process often occurring in patients submitted to revascularization procedures. We aimed to test the effect of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, on vascular cell pathophysiology in vitro and in a rat model of carotid arteriotomy-induced (re) stenosis. Methods: The effect of DFMO on primary rat smooth muscle cells (SMCs) and mouse microvascular bEnd. 3 endothelial cells (ECs) was evaluated through the analysis of DNA synthesis, polyamine concentration, cell viability, cell cycle phase distribution and by RT-PCR targeting cyclins and genes belonging to the polyamine pathway. The effect of DFMO was then evaluated in arteriotomy-injured rat carotids through the analysis of cell proliferation and apoptosis, RT-PCR and immunohistochemical analysis of differential gene expression. Results: DFMO showed a differential effect on SMCs and on ECs, with a marked, sustained anti-proliferative effect of DFMO at 3 and 8 days of treatment on SMCs and a less pronounced, late effect on bEnd. 3 ECs at 8 days of DFMO treatment. DFMO applied perivascularly in pluronic gel at arteriotomy site reduced subsequent cell proliferation and preserved smooth muscle differentiation without affecting the endothelial coverage. Lumen area in DFMO-treated carotids was 49% greater than in control arteries 4 weeks after injury. Conclusions: Our data support the key role of polyamines in restenosis and suggest a novel therapeutic approach for this pathophysiological process. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
- Published
- 2013
31. Doxorubicin Induces Senescence and Impairs Function of Human Cardiac Progenitor Cells
- Author
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Donato Cappetta, Sarah Costantino, Elena Piegari, Caterina Frati, Rosa Russo, Lucia Prezioso, Gallia Graiani, Antonella De Angelis, Liberato Berrino, Federico Quaini, Grazia Esposito, Francesco Rossi, Konrad Urbanek, Piegari, E, De Angelis, A, Cappetta, D, Russo, R, Esposito, G, Costantino, S, Graiani, G, Frati, C, Prezioso, L, Berrino, L, Urbanek, K, Quaini, F, Rossi, F., Piegari, Elena, DE ANGELIS, Antonella, Berrino, Liberato, and Rossi, Francesco
- Subjects
Male ,Physiology ,Cardiomyopathy ,030204 cardiovascular system & hematology ,Cardiac progenitor cell ,0302 clinical medicine ,Cell Movement ,Fluorescent Antibody Technique, Indirect ,Cells, Cultured ,Cellular Senescence ,0303 health sciences ,education.field_of_study ,Antibiotics, Antineoplastic ,Cell Death ,Stem Cells ,Middle Aged ,3. Good health ,Proto-Oncogene Proteins c-kit ,Female ,Cardiology and Cardiovascular Medicine ,Myoblasts, Cardiac ,medicine.drug ,Adult ,Cardiomyopathy, Dilated ,Senescence ,medicine.medical_specialty ,Anthracycline ,Blotting, Western ,Population ,Biology ,03 medical and health sciences ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Doxorubicin ,education ,Cell Proliferation ,030304 developmental biology ,Cardiotoxicity ,Telomere Homeostasis ,beta-Galactosidase ,medicine.disease ,Telomere ,Endocrinology ,Apoptosis ,Cancer research ,DNA Damage - Abstract
The increasing population of cancer survivors faces considerable morbidity and mortality due to late effects of the antineoplastic therapy. Cardiotoxicity is a major limiting factor of therapy with doxorubicin (DOXO), the most effective anthracycline, and is characterized by a dilated cardiomyopathy that can develop even years after treatment. Studies in animals have proposed the cardiac progenitor cells (CPCs) as the cellular target responsible for DOXO-induced cardiomyopathy but the relevance of these observations to clinical settings is unknown. In this study, the analysis of the DOXO-induced cardiomyopathic human hearts showed that the majority of human CPCs (hCPCs) was senescent. In isolated hCPCs, DOXO triggered DNA damage response leading to apoptosis early after exposure, and telomere shortening and senescence at later time interval. Functional properties of hCPCs, such as migration and differentiation, were also negatively affected. Importantly, the differentiated progeny of DOXO-treated hCPCs prematurely expressed the senescence marker p16(INK4a). In conclusion, DOXO exposure severely affects the population of hCPCs and permanently impairs their function. Premature senescence of hCPCs and their progeny can be responsible for the decline in the regenerative capacity of the heart and may represent the cellular basis of DOXO-induced cardiomyopathy in humans.
- Published
- 2013
32. Effects of sildenafil on the gastrocnemius and cardiac muscles of rats in a model of prolonged moderate exercise training
- Author
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Giulia Gritti, Annalisa Capuano, Simona Signoriello, Elisabetta Parretta, Liberato Berrino, Konrad Urbanek, Barbara Rinaldi, Francesco Rossi, Maria Donniacuo, Loredana Sodano, Rinaldi, Barbara, Donniacuo, Maria, Sodano, L, Gritti, G, Signoriello, Simona, Parretta, E, Berrino, Liberato, Urbanek, K, Capuano, Annalisa, and Rossi, Francesco
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Muscle Proteins ,Cardiovascular ,Piperazines ,Diagnostic Radiology ,Tripartite Motif Proteins ,chemistry.chemical_compound ,Sulfones ,Multidisciplinary ,Reverse Transcriptase Polymerase Chain Reaction ,Forkhead Box Protein O3 ,Statistics ,Forkhead Transcription Factors ,Animal Models ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Muscle atrophy ,medicine.anatomical_structure ,Echocardiography ,cardiovascular system ,Medicine ,medicine.symptom ,Radiology ,Immunohistochemical Analysis ,Perfusion ,Research Article ,Drugs and Devices ,medicine.medical_specialty ,Sildenafil ,Ubiquitin-Protein Ligases ,Science ,Blotting, Western ,Immunology ,Physical exercise ,Biostatistics ,Biology ,Sildenafil Citrate ,Model Organisms ,Atrophy ,Physical Conditioning, Animal ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Sports and Exercise Medicine ,Muscle, Skeletal ,Myocardium ,Hemodynamics ,Skeletal muscle ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Mitochondria, Muscle ,Rats ,Endocrinology ,Erectile dysfunction ,chemistry ,Mitochondrial biogenesis ,Purines ,Immunologic Techniques ,Rat ,Mathematics ,Transcription Factors - Abstract
Moderate exercise training improves energetic metabolism, tissue perfusion and induces cardiac and skeletal muscle remodeling. Sildenafil, a potent phosphodiesterase-5 inhibitor used to treat erectile dysfunction, reduces infarct size and increases tissue oxygenation in experimental models of cardiovascular disease. We have evaluated the effects of prolonged moderate exercise training and a repeat administration of sildenafil on the rat gastrocnemius and cardiac muscles. Animals were divided into two groups: sedentary and trained. Each group was subdivided into animals treated with vehicle or with two doses of sildenafil (10 or 15 mg/kg/day) during the last week of training. Physical exercise did not induce cardiac hypertrophy, whereas it increased mRNA levels of the PGC-1 alpha, HIF-1 alpha and VEGF genes, which are involved in mitochondrial biogenesis and angiogenesis, and reduced mRNA levels of FoxO3a, MuRF-1 and Atrogin-1. Sildenafil dose-dependently promoted both angiogenesis, as shown by increased capillary density, and muscle atrophy, as shown by muscle fibre size. These effects were more pronounced in trained animals. Our data confirm the beneficial effects of a moderate and prolonged training on cardiovascular and skeletal systems and document the positive and negative effects of sildenafil on these tissues at doses higher than those used in clinical practice. This report may impact on the use of sildenafil as a substance able to influence sports performance.
- Published
- 2013
33. Involvement of Nitric Oxide in Cardiorespiratory Regulation in the Nucleus Tractus Solitarii
- Author
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Michele D'Amico, Francesca Rossi, Sabatino Maione, S. Vitagliano, Liberato Berrino, V. De Novellis, Vitagliano, S, Berrino, Liberato, D'Amico, Michele, Maione, Sabatino, DE NOVELLIS, Vito, and Rossi, Francesco
- Subjects
Male ,medicine.medical_specialty ,chemistry.chemical_element ,Blood Pressure ,Calcium ,Nitric Oxide ,Nitric oxide ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Internal medicine ,Solitary Nucleus ,medicine ,Animals ,Diltiazem ,Enzyme Inhibitors ,Pharmacology ,Chemistry ,Respiration ,Solitary nucleus ,Endothelium-derived relaxing factor ,Apnea ,Rats ,Endocrinology ,Blood pressure ,Molsidomine ,Anesthesia ,Sodium nitroprusside ,medicine.symptom ,medicine.drug - Abstract
The aim of this study was to investigate whether nitric oxide (NO) is involved in cardiorespiratory regulation in the nucleus tractus solitarii (NTS). Unilateral microinjections (50 nl) of the NO-donor, sodium nitroprusside (SNP, 40-100-200 mM), into the NTS of anaesthetized rats elicited dose-dependent apnea (7.3 +/- 2.3 sec; 28.6 +/- 5.7 sec; 35.6 +/- 6.4 sec, respectively; n = 6) and a decrease in arterial blood pressure (8.4 +/- 3.1 mmHg; 18.2 +/- 5.8 mmHg; 25.8 +/- 6.7 mmHg, respectively; n = 6). Similarly, unilateral micro-injections (50 nl) of another NO-donor, 3-morpholinosydnonimine (SIN-1, 20-40-100 mM), also induced apnea (5.1 +/- 2.4 sec; 8.7 +/- 4.3 sec; 26.3 +/- 6.4 sec, respectively; n = 6) and a decrease in arterial blood pressure (6.2 +/- 2.3 mmHg; 11.1 +/- 3.3 mmHg; 18.3 +/- 6.1 mmHg, respectively; n = 6). The SNP- and SIN-1-induced apnea and arterial blood pressure decrease were significantly (p < 0.01) blocked by a 3 min pretreatment with two calcium-channel blockers, diltiazem (0.1 mM) and cobalt (10 mM), while lower doses (diltiazem 0.01 and cobalt 1) were ineffective. Microinjections of diltiazem (0.01 mM) and cobalt (1 mM) alone did not induce any change in basal cardiorespiratory values like diltiazem (0.1 mM) and cobalt (10 mM). These data suggest that NO may be involved in NTS cardiorespiratory regulation via calcium-channel activation.
- Published
- 1996
34. Metabotropic and ionotropic glutamate receptors mediate opposite effects on periaqueductal gray matter
- Author
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J. Leyva, M. Pallotta, Francesco Rossi, Sabatino Maione, Liberato Berrino, Leyva, J, Maione, Sabatino, Pallotta, M, Berrino, Liberato, and Rossi, F.
- Subjects
Male ,medicine.medical_specialty ,N-Methylaspartate ,Microinjections ,Blood Pressure ,Receptors, Metabotropic Glutamate ,Periaqueductal gray ,Partial agonist ,Rats, Sprague-Dawley ,Internal medicine ,Excitatory Amino Acid Agonists ,medicine ,Animals ,Periaqueductal Gray ,Cycloleucine ,Receptor ,Neurons ,Pharmacology ,Alanine ,Dose-Response Relationship, Drug ,Chemistry ,Glutamate receptor ,Antagonist ,Rats ,Metabotropic receptor ,Endocrinology ,2-Amino-5-phosphonovalerate ,Receptors, Glutamate ,NMDA receptor ,Excitatory Amino Acid Antagonists ,Ionotropic effect - Abstract
Microinjections, into the dorso-lateral periaqueductal gray matter, of N-methyl-D-aspartic acid (NMDA, 0.07-7 nmol/rat) significantly (P0.01) increased arterial blood pressure in a dose-related manner. Pretreatment, 5 min before NMDA (7 nmol/rat), in the same area with 2-amino-5-phosphonovaleric acid (2-APV, 5 nmol/rat), a selective antagonist of NMDA receptors, significantly (P0.01) reduced NMDA-induced arterial hypertension. trans-(+/-)-1-Amino-1,3-cyclopentanedicarboxylic acid (t-ACPD, 6-30 nmol/rat), an agonist of metabotropic glutamate receptors (mGlu receptors), significantly (P0.01) decreased arterial blood pressure when microinjected into the dorsal-lateral periaqueductal gray matter. Pretreatment, 5 min before t-ACPD (30 nmol/rat), in the same area with L-2-amino-3-phosphono-propionate (L-AP-3, 30 nmol/rat), a putative antagonist of the mGlu receptors, was not able to prevent t-ACPD-induced hypotension. Microinjections of L-AP-3 (30 nmol/rat) induced a hypotension similar to the one obtained with t-ACPD at the dose of 6 nmol/rat. From these data we can suggest that mGlu receptors act inversely to the NMDA receptors in the dorso-lateral periaqueductal gray area and that L-AP-3 is a partial agonist rather than an antagonist of mGlu receptors within the periaqueductal gray area.
- Published
- 1995
35. Involvement of opioid receptors in N-Methyl-d-aspartate-induced arterial hypertension in periaqueductal gray matter
- Author
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J. Leyva, M. Pallotta, Sabatino Maione, Liberato Berrino, V. De Novellis, Francesca Rossi, Maione, Sabatino, Leyva, J, Pallotta, M, Berrino, Liberato, DE NOVELLIS, Vito, and Rossi, Francesco
- Subjects
Male ,medicine.medical_specialty ,N-Methylaspartate ,medicine.drug_class ,(+)-Naloxone ,Periaqueductal gray ,Rats, Sprague-Dawley ,Naltrindole ,Opioid receptor ,Internal medicine ,medicine ,Animals ,Periaqueductal Gray ,Pharmacology ,Analysis of Variance ,Chemistry ,General Medicine ,Bicuculline ,Rats ,Endocrinology ,Opioid ,Hypertension ,Receptors, Opioid ,μ-opioid receptor ,Opioid antagonist ,medicine.drug - Abstract
Arterial hypertension induced by microinjections of N-methyl-D-aspartate (NMDA) (2 nmol/rat) into the midbrain periaqueductal gray matter was used to assess the involvement of opioid receptors (mu, delta and kappa) in modulating pressor periaqueductal gray neurons. Groups (n = 5-8) of urethane-anaesthetised rats received, 5 min before NMDA, microinjections of selective opioid receptor antagonists in the periaqueductal gray area and arterial blood pressure was monitored. Pretreatments with naloxone (5 nmol/rat), a non selective mu receptor antagonist, or naltrindole hydrochloride (5 nmol/rat), a selective delta receptor antagonist, significantly (P < 0.05) decreased by 31% and 37%, respectively, NMDA-induced hypertension. The latency for the maximum increase of NMDA-induced hypertension was also significantly (P < 0.05) increased with naloxone. Pretreatment with nor-binaltorphimine (5 nmol/rat), a selective kappa receptor antagonist, only increased the latency of NMDA-induced hypertension. Each opioid antagonist failed per se to alter arterial blood pressure. Microinjection of morphine (13 nmol/rat), a non selective mu receptor agonist, significantly decreased (P < 0.05) by 57.5% NMDA-induced arterial hypertension and this effect was antagonised by naloxone. Combined pretreatments in the periaqueductal gray area with naloxone and the GABAA antagonist bicuculline (2.5 nmol/rat; 5 min before naloxone) antagonised the effect of naloxone on NMDA-induced hypertension. In contrast, bicuculline significantly (P < 0.05) potentiated morphine-induced decrease of NMDA hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
36. Metabotropic glutamate receptors are involved in the control of breathing at the medulla oblongata level of anaesthetized rats
- Author
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V. Calderaro, Michele D'Amico, Liberato Berrino, Sabatino Maione, Anna Pizzirusso, S. Vitagliano, Francesca Rossi, Vitagliano, S, Berrino, Liberato, Pizzirusso, A, D'Amico, Michele, Calderaro, V, Maione, Sabatino, and Rossi, Francesco
- Subjects
Male ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Neurotoxins ,Glutamic Acid ,Blood Pressure ,Biology ,Receptors, Metabotropic Glutamate ,Injections ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Internal medicine ,Solitary Nucleus ,medicine ,Animals ,Anesthesia ,Cycloleucine ,Pharmacology ,Medulla Oblongata ,Alanine ,Solitary nucleus ,Glutamate receptor ,Rats ,Metabotropic receptor ,Endocrinology ,chemistry ,Metabotropic glutamate receptor ,Control of respiration ,Respiratory Mechanics ,Medulla oblongata ,ACPD - Abstract
The goal of the present study was to identify sites in the medulla oblongata where metabotropic glutamate receptors are involved in regulating respiration. Unilateral microinjections (50 nl) of l -glutamate ( l -glu) (10–25–50 mM) into the nucleus tractus solitarii (NTS) of anaesthetized rats elicited apnea (8.6 ± 0.3 sec; 21.3 ± 3.6 sec; 66.3 ± 16.5 sec respectively; N = 6) and arterial hypotension (7.3 ± 2.4 mmHg; 10.1 ± 2.3 mmHg; 35.3 ± 7.5 mmHg respectively; N = 6). Similarly, in other rats 1-aminocyclopentane-1, 3-dicarboxylic acid (ACPD) (1–5–10 mM), a selective agonist of metabotrophic glutamate receptors, also induced apnea (22.4 ± 2.5 sec; 32.5 ± sec; 92.5 ± 1.4 sec respectively; N = 6) and arterial hypotension (12.7 ± 2.2 mmHg; 19.6 ± 4.3 mmHg; 26.5 ± 1.5 mmHg respectively; N = 6). Paired experiments showed that unilateral microinjections of l -glu (50 mM) and ACPD (1 mM) into the nucleus retroambigualis (NRA) of anaesthetized rats elicited apnea (20.2 ± 2.6 sec and 33.8 ± 3.2 sec respectively; N = 6) and arterial hypotension (15.7 ± 3.7 mmHg and 22.5 ± 4.5 mmHg respectively; N = 6). The ACPD effects on apnea and hypotension in NTS and NRA were not prevented by a 3 min pretreatment with L-AP3 (30 mM), a putative antagonist of metabotropic glutamate receptors (19.5 ± 1.4 sec; 12.3 ± 3.2 mmHg and 30.6 ± 2.9 sec; 23.4 ± 3.8 mmHg respectively; N = 6). These data suggest that metabotropic glutamate receptors are involved in NTS and NRA regulation of cardiorespiratory functions. Moreover, these findings may also indicate that at particular doses L-AP3 could be considered a partial agonist of the metabotropic glutamate receptors in the medulla oblongata in anaesthetized rats.
- Published
- 1994
37. Involvement of periaqueductal gray area NMDA receptors in endothelin-induced behavioural effects
- Author
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Sabatino Maione, Liberato Berrino, J. Leyva, Michele D'Amico, Amelia Filippelli, Francesco Rossi, Maione, Sabatino, D'Amico, Michele, Berrino, Liberato, Filippelli, A, Leyva, J, and Rossi, Francesco
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,Motor Activity ,Receptors, N-Methyl-D-Aspartate ,Periaqueductal gray ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Quinoxalines ,Internal medicine ,medicine ,Animals ,Periaqueductal Gray ,2-Amino-5-phosphonovalerate ,6-Cyano-7-nitroquinoxaline-2,3-dione ,Pharmacology ,Behavior, Animal ,Dose-Response Relationship, Drug ,Endothelins ,Receptor antagonist ,Endothelin 1 ,Rats ,Endocrinology ,nervous system ,Mechanism of action ,chemistry ,CNQX ,NMDA receptor ,medicine.symptom ,Endothelin receptor ,Neuroscience - Abstract
We investigated the behavioural effects induced by endothelin-1 injected into the lateral-caudal periaqueductal gray matter of freely moving rats. Endothelin-1 induced a dose-dependent longitudinal rolling of the body (barrel rolling) which was prevented by D,L-2-amino-5-phosphonovalerate (2-APV), an N-methyl-D-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist. This effect, not reproducible with NMDA alone, indicates that the activation of the NMDA receptors in the periaqueductal gray area may be a necessary, but not sufficient, step for the triggering of endothelin-1-induced barrel-rolling behaviour.
- Published
- 1993
38. Relationship between A-line Autoregressive Index, Spectral Entropy and steady state predicted site-effect effective concentrations at 05-50-95 of propofol at different clinical endpoints
- Author
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E, Iannuzzi, M, Iannuzzi, B, Mora, L, Sidro, L, Berrino, M, Chiefari, R, Tufano, Iannuzzi, E, Iannuzzi, Michele, Mora, B, Sidro, L, Berrino, L, Chiefari, M, Tufano, Rosalba, Iannuzzi, M, Berrino, Liberato, and Tufano, R.
- Subjects
Male ,Electromyography ,Entropy ,Anesthesia, Intravenous ,Humans ,Electroencephalography ,Female ,Middle Aged ,Infusions, Intravenous ,Propofol ,Anesthetics, Intravenous - Abstract
AIM: Target controlled infusion intravenous anesthesia is a growing phenomenon. Nowadays, many anesthesiologists feel the need to monitor depth of anesthesia during total intravenous anesthesia, even though it is not a standard technique worldwide. Spectral Entropy (SE) is a relatively new depth of anesthesia index. The aim of this study was to investigate whether predicted site-effect propofol concentrations, A-line Autoregressive Index (AAI) and SE values are useful for predicting loss of verbal contact (LVC) and loss of consciousness (LOC) during steady-state conditions. METHODS: Forty-four patients scheduled for elective major abdominal surgery were recruited. All patients were unpremedicated. A target controlled infusion of propofol was administered using Schnider's pharmacokinetic model. The initial propofol infusion provided a site-effect concentration of 1.0 mcg mL-1, and was increased stepwise by 1.0 mcg mL-1 every 4 minutes until the concentration reached 6.0 mcg mL-1. A 4 minute interval was chosen to assure that steady state site-effect concentrations were obtained. AAI, SE and propofol site-effect concentrations were recorded when LVC occurred and also when LOC occurred. Population values for predicted site-effect concentrations at the clinical endpoints were estimated and correlated with AAI and SE values. RESULTS: In our study for LOC the effect-site concentration to include 90% of patients was 5.85 ?mcg mL-1 (5.70-5.90) and 3.4 mcg mL-1 (3.24-3.60) for LVC. In this study, 90% of patients lost verbal contact at an AAI value of 68 (64.6-71.4) and an SE value of 68.2 (66.2-70.2). LOC occurred in 90% of patients at an AAI value of 39.2 (37.2-41.1) and an SE value of 40.2 (38.1-41.3). CONCLUSIONS: LOC and LVC occur within a defined range of predicted site-effect concentrations. More emphasis should be given to site-effect concentrations. SE and AAI have similar values at different endpoints and similar correlation with Ceprop. AAI and SE are both useful tools in predicting both LVC and LOC.
- Published
- 2009
39. DNA damage and repair in a model of rat vascular injury
- Author
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Francesco Rossi, Amalia Forte, Maurizio Cotrufo, Mario Grossi, Marisa De Feo, Marilena Cipollaro, Pasquale Santè, Mariano Vicchio, Nicola Alessio, Liberato Berrino, Mauro Finicelli, Umberto Galderisi, Forte, A, Finicelli, M, Grossi, M, Vicchio, M, Alessio, N, Sante', Pasquale, DE FEO, Marisa, Cotrufo, M, Berrino, Liberato, Rossi, Francesco, Galderisi, Umberto, and Cipollaro, Marilena
- Subjects
Male ,Programmed cell death ,Pathology ,medicine.medical_specialty ,Time Factors ,DNA damage ,DNA repair ,medicine.medical_treatment ,proliferation ,Blotting, Western ,Gene Expression ,Arteriotomy ,Apoptosis ,Biology ,medicine.disease_cause ,DNA Glycosylases ,Histones ,restenosis ,Adventitia ,medicine ,Animals ,Rats, Wistar ,Cell Proliferation ,BRCA2 Protein ,oxidative stre ,Reverse Transcriptase Polymerase Chain Reaction ,8-Hydroxy-2'-deoxyguanosine ,Deoxyguanosine ,General Medicine ,Vascular System Injuries ,Catalase ,Phosphoproteins ,Immunohistochemistry ,apoptosi ,Blot ,DNA-Binding Proteins ,Disease Models, Animal ,medicine.anatomical_structure ,Carotid Arteries ,8-Hydroxy-2'-Deoxyguanosine ,Tumor Suppressor Protein p53 ,Oxidative stress ,DNA Damage - Abstract
Restenosis rates following vascular interventions still limit their long-term success. Oxidative stress plays a relevant role in this pathophysiological phenomenon, but less attention has been devoted to its effects on DNA damage and to the subsequent mechanisms of repair. In the present study, we analysed in a model of arteriotomy-induced stenosis in rat carotid arteries the time-dependent expression of DNA damage markers and of DNA repair genes, together with the assessment of proliferation and apoptosis indexes. The expression of the oxidative DNA damage marker 7,8-dihydro-8-oxo-2′-deoxyguanosine was increased at 3 and 7 days after arteriotomy, with immunostaining distributed in the injured vascular wall and perivascular tissue. Expression of the DNA damage marker phospho-H2A.X was less relevant, but increased from 4 h to 7 days after arteriotomy, with immunostaining prevalently present in the adventitia and, to a lesser extent, in medial smooth muscle cells at the injury site. RT (reverse transcription)–PCR indicated a decrease in eight out of 12 genes involved in the DNA repair machinery we selected from 4 h to 7 days after arteriotomy, with the exception of an increase in the Mutyh and Slk genes (P
- Published
- 2009
40. Expression profiles in surgically induced carotid stenosis: A combined transcriptomic and proteomic investigation
- Author
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Cesare Quarto, Francesco Onorati, Liberato Berrino, Amalia Forte, P. De Luca, Marilena Cipollaro, A. Cascino, M. De Feo, Pasquale Santè, Mauro Finicelli, Umberto Galderisi, Attilio Renzulli, Maurizio Cotrufo, Francesco Rossi, Forte, A, Finicelli, M, DE LUCA, P, Quarto, C, Onorati, F, Sante', Pasquale, Renzulli, A, Galderisi, Umberto, Berrino, Liberato, DE FEO, Marisa, Rossi, Francesco, Cotrufo, M, Cascino, A, and Cipollaro, Marilena
- Subjects
Male ,Transcription, Genetic ,medicine.medical_treatment ,Arteriotomy ,gene array analysis ,Biology ,Proteomics ,Rats, Inbred WKY ,Transcriptome ,proteomics ,medicine ,Animals ,Carotid Stenosis ,remodelling ,KEGG ,gene array analysi ,cardiovascular surgery ,Gene Expression Profiling ,RNA ,Cell Biology ,Articles ,Molecular biology ,Rats ,Gene expression profiling ,Carotid Arteries ,Proteome ,Molecular Medicine ,DNA microarray - Abstract
Vascular injury aimed at stenosis removal induces local reactions often leading to restenosis. The aim of this study was a concerted transcriptomic-proteomics analysis of molecular variations in a model of rat carotid arteriotomy, to dissect the molecular pathways triggered by vascular surgical injury and to identify new potential anti-restenosis targets. RNA and proteins extracted from inbred Wistar Kyoro (WKY) rat carotids harvested 4 hrs, 48 hrs and 7 days after arteriotomy were analysed by Affymetrix rat microarrays and by bidimensional electrophoresis followed by liquid chromatography and tandem mass spectrometry, using as reference the RNA and the proteins extracted from uninjured rat carotids. Results were classified according to their biological function, and the most significant Kyoro Encyclopedia of Genes and Genomes (KEGG) pathways were identified. A total of 1163 mRNAs were differentially regulated in arteriotomy-injured carotids 4 hrs, 48 hrs and 7 days after injury (P < 0.0001, fold-change ≥2), while 48 spots exhibited significant changes after carotid arteriotomy (P < 0.05, fold-change ≥2). Among them, 16 spots were successfully identified and resulted to correspond to a set of 19 proteins. mRNAs were mainly involved in signal transduction, oxidative stress/ inflammation and remodelling, including many new potential targets for limitation of surgically induced (re)stenosis (e.g. Arginase I, Kruppel like factors). Proteome analysis confirmed and extended the microrarray data, revealing time-dependent post-translational modifications of Hsp27, haptoglobin and contrapsin-like protease inhibitor 6, and the differential expression of proteins mainly involved in contractility. Transcriptomic and proteomic methods revealed functional categories with different preferences, related to the experimental sensitivity and to mechanisms of regulation. The comparative analysis revealed correlation between transcriptional and translational expression for 47% of identified proteins. Exceptions from this correlation confirm the complementarities of these approaches.
- Published
- 2008
41. Neutralization of interleukin-18 inhibits neointimal formation in a rat model of vascular injury
- Author
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Paola Di Meglio, Rosa Carnuccio, Armando Ialenti, Angela Ianaro, Pasquale Maffia, Gianluca Grassia, Paul Garside, Liberato Berrino, Maffia, Pasquale, Grassia, Gianluca, DI MEGLIO, P, Carnuccio, Rosa, Berrino, L, Garside, P, Ianaro, Angela, Ialenti, Armando, Maffia, P., Grassia, G., DI MEGLIO, P., Carnuccio, R., Berrino, Liberato, Garside, P., Ianaro, A., and Ialenti, A.
- Subjects
Neointima ,Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Endothelium ,medicine.medical_treatment ,rat carotid artery ,Muscle, Smooth, Vascular ,Angina ,Interferon-gamma ,Restenosis ,Cell Movement ,Physiology (medical) ,Angioplasty ,Medicine ,Animals ,balloon ,RNA, Messenger ,Rats, Wistar ,carotid arterie ,Cell Proliferation ,business.industry ,Interleukin-6 ,Interleukin-8 ,Interleukin-18 ,NF-kappa B ,angioplasty ,neointima ,Balloon Occlusion ,medicine.disease ,Actins ,Surgery ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,interleukins ,Carotid Arteries ,Gene Expression Regulation ,Cardiovascular Diseases ,Immunoglobulin G ,Circulatory system ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,business ,Carotid Artery Injuries ,Tunica Intima ,Blood vessel ,Artery - Abstract
Background— Studies in humans and animal models suggest that interleukin-18 (IL-18) plays a crucial role in vascular pathologies. IL-18 is a predictor of cardiovascular death in angina and is involved in atherotic plaque destabilization. Higher IL-18 plasma levels also are associated with restenosis after coronary artery angioplasty performed in patients with acute myocardial infarction. We investigated the effective role of IL-18 in neointimal formation in a balloon-induced rat model of vascular injury. Methods and Results— Endothelial denudation of the left carotid artery was performed by use of a balloon embolectomy catheter. Increased expression of IL-18 and IL-18Rα/β mRNA was detectable in carotid arteries from days 2 to 14 after angioplasty. The active form of IL-18 was highly expressed in injured arteries. Strong immunoreactivity for IL-18 was detected in the medial smooth muscle cells at days 2 and 7 after balloon injury and in proliferating/migrating smooth muscle cells in neointima at day 14. Moreover, serum concentrations of IL-18 were significantly higher among rats subjected to vascular injury. Treatment with neutralizing rabbit anti-rat IL-18 immunoglobulin G significantly reduced neointimal formation (by 27%; P Conclusions— These results identify a critical role for IL-18 in neointimal formation in a rat model of vascular injury and suggest a potential role for IL-18 neutralization in the reduction of neointimal development.
- Published
- 2006
42. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism
- Author
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Giovanni Cimmino, Raffaele Calabrò, Salvatore Notaristefano, Paolo Golino, Gianfranco Abbate, Francesco Del Galdo, Raffaele De Palma, Isabella Tritto, Liberato Berrino, Claudio Giombolini, Lavinia Forte, Maria Francesca Papa, Giuseppe Ambrosio, Maria Giovanna Russo, Massimo Chiariello, Francesco Rossi, DE PALMA, R, DEL GALDO, F, Abbate, G, Chiariello, Massimo, Calabro, R, Forte, L, Cimmino, G, Papa, Mf, Russo, Mg, Ambrosio, G, Giombolini, C, Tritto, I, Notaristefano, S, Berrino, L, Rossi, F, Golino, P., DE PALMA, Raffaele, DEL GALDO, F., Abbate, G., Chiariello, M., Calabro', Raffaele, Forte, L., Cimmino, Giovanni, Papa, M., Russo, Maria Giovanna, Ambrosio, G., Giombolini, C., Tritto, I., Notaristefano, S., Berrino, Liberato, Rossi, Francesco, and Golino, Paolo
- Subjects
Male ,lymphocytes ,Acute coronary syndrome ,Pathology ,medicine.medical_specialty ,T cell ,T-Lymphocytes ,Inflammation ,Coronary Disease ,T-Cell Antigen Receptor Specificity ,lymphocyte ,plaque ,Immune system ,Physiology (medical) ,medicine ,Humans ,Aged ,Cell Proliferation ,Mechanism (biology) ,business.industry ,immune system ,inflammation ,Middle Aged ,medicine.disease ,Atherosclerosis ,Complementarity Determining Regions ,Peripheral blood ,Pathophysiology ,Clone Cells ,Chemotaxis, Leukocyte ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Acute Disease ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background— Recent studies indicate that T-cell activation may play an important role in the pathophysiology of acute coronary syndromes (ACS). However, although those studies detected T-cell expansion in peripheral blood cells, demonstration of specific T-cell expansion within the plaque of patients with ACS is lacking. The present study aims to address whether a specific, immune-driven T-lymphocyte recruitment occurs within the unstable plaque of patients with ACS. Methods and Results— We simultaneously examined the T-cell repertoire using CDR3 size analysis both in coronary plaques (obtained by directional atherectomy) and in peripheral blood of patients with either ACS (n=11) or chronic stable angina (n=10). Unstable plaques showed a 10-fold increase in T-cell content by quantitative PCR. Using spectratyping analysis, we found several specific T-cell clonotype expansions only in unstable plaque from each patient with ACS, indicating a specific, antigen-driven recruitment of T cells within unstable lesions. Conclusions— For the first time, T-cell repertoire was investigated directly into coronary plaques; using this approach, we demonstrate that coronary plaque instability in the setting of ACS is associated with immune-driven T-cell recruitment, specifically within the plaque.
- Published
- 2006
43. Role of periaqueductal grey prostaglandin receptors in formalin-induced hyperalgesia
- Author
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Enza Palazzo, Ida Marabese, Vito de Novellis, Francesco Rossi, Patrizia Oliva, Dario Siniscalco, Loredana Mariani, Liberato Berrino, Sabatino Maione, Mariantonietta Scafuro, Oliva, P., Berrino, Liberato, DE NOVELLIS, Vito, Palazzo, Enza, Marabese, Ida, Siniscalco, D., Scafuro, Mariantonietta, Mariani, L., Rossi, Francesco, and Maione, Sabatino
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Microdialysis ,Prostaglandin Antagonists ,Mouse ,medicine.drug_class ,Prostaglandin ,Xanthones ,Glutamic Acid ,Stimulation ,Thiophenes ,Acetates ,Naphthalenes ,chemistry.chemical_compound ,Mice ,GABA ,Internal medicine ,Formaldehyde ,Benzyl Compounds ,medicine ,Animals ,Periaqueductal Gray ,Receptors, Prostaglandin E ,Dimethyl Sulfoxide ,Prostaglandin receptor ,gamma-Aminobutyric Acid ,Injections, Intraventricular ,Pain Measurement ,Pharmacology ,Acrylamides ,Glutamate receptor ,Extracellular Fluid ,Triazoles ,Formalin ,Nociception ,Endocrinology ,chemistry ,Hyperalgesia ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Glutamate ,Misoprostol - Abstract
In this study we have investigated the role of periaqueductal grey prostaglandin receptors in formalin-induced hyperalgesia in mice. Glutamate and GABA release changes have been monitored by in vivo microdialysis. Intra-periaqueductal grey microinjections of misoprostol, a non-selective prostaglandin receptor agonist, increased nociceptive responses in the formalin test only during the late phase. Prostanoid EP(1) (L-335677), EP(2) (AH 6809), EP(3) (L-826266) and EP(4) (L-161982) receptor antagonists prevented the nociceptive response induced by misoprostol in formalin-injected mice. Prostanoid EP(1), EP(2), EP(3) and EP(4) antagonists reduced, per se, the late hyperalgesic phase. Intra-periaqueductal grey perfusion with misoprostol increased periaqueductal grey glutamate, whereas it produced an increase followed by a decrease in GABA. Likewise, formalin increased glutamate and produced a biphasic response on GABA. When misoprostol was perfused in combination with the peripheral injection of formalin, we observed an increase of glutamate and an increase followed by a stronger decrease in GABA release. These data show that periaqueductal grey prostaglandin receptor stimulation increased formalin-induced nociceptive response in the late phase by increasing glutamate release and by producing a biphasic change in GABA release.
- Published
- 2006
44. c-Myc antisense oligonucleotides preserve smooth muscle differentiation and reduce negative remodelling following rat carotid arteriotomy
- Author
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Antonino Cascino, Francesco Rossi, Attilio Renzulli, Umberto Galderisi, Maurizio Cotrufo, Per Hellstrand, L. Agozzino, Liberato Berrino, Salvatore Esposito, Amalia Forte, Maria F. Gomez, Marisa De Feo, Marilena Cipollaro, Pasquale Santè, Forte, A, Galderisi, Umberto, DE FEO, Marisa, Gomez, Mf, Esposito, S, Sante', Pasquale, Renzulli, A, Agozzino, Lucio, Hellstrand, P, Berrino, Liberato, Cipollaro, Marilena, Cotrufo, M, Rossi, Francesco, and Cascino, A.
- Subjects
Male ,Adventitia ,medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Cellular differentiation ,Genes, myc ,Muscle Proteins ,Arteriotomy ,Apoptosis ,Biology ,Rats, Inbred WKY ,Muscle, Smooth, Vascular ,Restenosis ,medicine ,Animals ,Antisense oligonucleotide ,Postoperative Period ,RNA, Messenger ,SM22 ,Stenosi ,Oligonucleotide ,Microfilament Proteins ,Apoptosi ,Cell Differentiation ,Oligonucleotides, Antisense ,medicine.disease ,Surgery ,Rats ,c-Myc ,medicine.anatomical_structure ,Carotid Arteries ,Cancer research ,Cardiology and Cardiovascular Medicine ,Blood vessel ,Artery - Abstract
Objectives: The vascular biology of restenosis is complex and not fully understood, thus explaining the lack of effective therapy for its prevention in clinical settings. The role of c-Myc in arteriotomy-induced stenosis, smooth muscle cell (SMC) differentiation and apoptosis was investigated in rat carotids applying full phosphorothioate antisense (AS) oligonucleotides (ODNs). Methods: Carotid arteries from WKY rats were submitted to arteriotomy and to local application of ODNs through pluronic gel. Apoptosis (deoxynucleotidyl transferase-mediated dUTP nick end-labelling), SMC differentiation (SM22 immunofluorescence) and vessel morphology and morphometry (image analysis) were determined 2, 5 and 30 days after injury, respectively. Results: AS ODNs induced a 60% decrease of target c-Myc mRNA 4 h after surgery in comparison to control sense (S) and scrambled ODN-treated carotids (p < 0.05). A significant 37 and 50% decrease in SM22 protein in the media of S ODN-treated and untreated carotids was detected when compared to uninjured contralateral arteries (p < 0.05). This reduction in SM22 expression was prevented in AS ODN-treated carotids. Stenosis was mainly due to adventitial constrictive remodelling. Lumen area in AS ODN-treated carotids was 35% greater than in control arteries 30 days after surgery (p < 0.05). TUNEL assay revealed increased apoptosis in AS ODN-treated carotids (p < 0.05). Conclusions: c-Myc AS ODNs reduce arteriotomy-induced negative remodelling. This is accompanied by maintained SMC differentiation and greater apoptosis. The combination of reduced c-Myc-induced proliferation and increased apoptosis may thus underlie the less severe remodelling upon treatment with c-Myc mRNA AS ODN.
- Published
- 2004
45. M40403 prevents myocardial injury induced by acute hyperglycaemia in perfused rat heart
- Author
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Liberato Berrino, Clara Di Filippo, Dario Giugliano, Raffaele Marfella, Giuseppe Scollo, Salvatore Cuzzocrea, Francesco Rossi, Michele D'Amico, Valentina Fabbroni, DI FILIPPO, Clara, Cuzzocrea, S, Marfella, Raffaele, Fabbroni, V, Scollo, G, Berrino, Liberato, Giugliano, Dario, Rossi, Francesco, and D'Amico, Michele
- Subjects
Male ,medicine.medical_specialty ,Myocardial Reperfusion Injury ,In Vitro Techniques ,Antioxidants ,Nitric oxide ,Rats, Sprague-Dawley ,Superoxide dismutase ,chemistry.chemical_compound ,Superoxides ,Malondialdehyde ,Internal medicine ,Organometallic Compounds ,medicine ,Animals ,Humans ,Cells, Cultured ,Pharmacology ,Manganese ,biology ,Superoxide Dismutase ,Superoxide ,Myocardium ,Nitrotyrosine ,Endothelial Cells ,Heart ,Mitochondria ,Rats ,Glucose ,Endocrinology ,chemistry ,Cardiovascular Alteration ,biology.protein ,Coronary perfusion pressure ,Tyrosine ,Endothelium, Vascular ,Lipid Peroxidation ,Poly(ADP-ribose) Polymerases ,Perfusion ,Peroxynitrite ,DNA Damage - Abstract
M40403 is a low-molecular-weight, synthetic manganese-containing biscyclohexylpyridine superoxide dismutase mimetic (SODm) that removes superoxide anions (O(2)(-)) without interfering with other reactive species known to be involved in cardiovascular alterations (e.g. nitric oxide [NO] and peroxynitrite [ONOO(-)]). As such, M40403 represents an important pharmacological tool to dissect the roles of O(2)(-) in functional and biochemical cardiovascular alterations induced by perfusion of high glucose concentrations into the heart. Perfusion of a high glucose concentration of glucose into the heart elicited important cardiovascular alterations characterized by QT interval prolongation, increase in coronary perfusion pressure (CPP), lipid peroxidation, decrease in MnSOD activity and DNA damage. All parameters of cardiovascular alteration were attenuated by M40403 (1-10 mg/l). Furthermore, perfusion of a high of glucose concentration induced a significant formation of nitrotyrosine as well as an activation of poly(adenosine diphosphate [ADP]-ribose) synthetase (PARS), as determined by immunohistochemical analysis of heart tissue. The extent of staining for nitrotyrosine and PARS was reduced by M40403. These results clearly indicate that O(2)(-) plays a critical role in the development of the functional and biochemical cardiovascular alterations induced by perfusion of a high concentration of glucose into the heart. Therefore, synthetic enzymes of SOD, such as M40403, offer a novel therapeutic approach for the management of various cardiovascular diseases where these radicals have been postulated to play a role.
- Published
- 2004
46. Behavioural effects induced by microinjection of ?-BOAA into the ventrolateral PAG matter of the mouse
- Author
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J. Leyva, V. De Novellis, Liberato Berrino, Francesca Rossi, M. Pallotta, Sabatino Maione, Maione, Sabatino, Berrino, Liberato, Leyva, J, DE NOVELLIS, Vito, Pallotta, M, and Rossi, F.
- Subjects
Male ,medicine.medical_specialty ,Microinjections ,Brachyura ,Clinical Biochemistry ,AMPA receptor ,Toxicology ,Biochemistry ,Mice ,Behavioral Neuroscience ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Periaqueductal Gray ,Neurotoxin ,Microinjection ,Biological Psychiatry ,Pharmacology ,Analysis of Variance ,Behavior, Animal ,Antagonist ,Amino Acids, Diamino ,Clonus ,Metabotropic receptor ,Endocrinology ,nervous system ,chemistry ,Evaluation Studies as Topic ,Anesthesia ,beta-Alanine ,CNQX ,NMDA receptor ,medicine.symptom - Abstract
L-BOAA (1 microgram/mouse), microinjected into the ventrolateral periaqueductal gray (PAG) matter, induced a strong reaction of forward avoidance (running) for 20-30 s in 18% of the mice and immobility for 7 +/- 2 min in 72% of the mice from a total of 68 treated animals. Effects were also observed for grooming and clonus in 6% and 4% of the mice, respectively. Duration of L-BOAA-induced immobility was significantly (p0.05) reduced by a pretreatment with CNQX (0.5 microgram/mouse), a selective antagonist of AMPA glutamergic subtype receptors, but not by a pretreatment with 2-APV (0.5 microgram/mouse), a selective antagonist of NMDA glutamergic subtype receptors, nor by 2-AP3 (0.5 microgram/mouse), a weak antagonist of metabotropic glutamergic subtype receptors. AMPA (0.05 microgram/mouse), also microinjected into ventrolateral PAG, induced the same pattern of behavioural effects as L-BOAA. Forward avoidance, grooming, and clonus induced by L-BOAA or AMPA were also significantly antagonised by a pretreatment with CNQX (data not shown).
- Published
- 1995
47. Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor antagonists in the formalin test
- Author
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Patrizia Oliva, Liberato Berrino, Francesco Massimo, Francesco Rossi, Antonio Grella, Sabatino Maione, Caterina Aurilio, Berrino, Liberato, Oliva, P, Massimo, F, Aurilio, Caterina, Maione, Sabatino, Grella, Antonio, and Rossi, Francesco
- Subjects
Male ,CGP-37849 ,Analgesic ,Pain ,Pharmacology ,Dextromethorphan ,chemistry.chemical_compound ,Mice ,Memantine ,Excitatory Amino Acid Antagonist ,Formaldehyde ,medicine ,Animals ,Ketamine ,Behavior, Animal ,Dose-Response Relationship, Drug ,business.industry ,Animal ,Nociceptor ,Nociceptors ,Anesthesiology and Pain Medicine ,Nociception ,chemistry ,NMDA receptor ,Dizocilpine Maleate ,Licking ,business ,Excitatory Amino Acid Antagonists ,Injections, Intraperitoneal ,medicine.drug - Abstract
Although the antinociceptive effect of NMDA antagonists in the formalin test is well recognised, these compounds can induce adverse motor effects. The aim of this study was to identify the systemic doses of NMDA antagonists that induce analgesia without causing side effects. Male Swiss mice (30-40g) received a subcutaneous (sc) injection of 1.25% formalin (50 micro l) in the dorsal surface of the right hind-paw and, 15min before or after formalin, an ip injection of one of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05mg/kg), memantine (0.1, 0.5, and 1mg/kg), ketamine (0.125, 0.25, and 0.5mg/kg), dextromethorphan (5, 10, and 20mg/kg), and CGP 37849 (4, 6, and 8mg/kg). Pain-related behaviour (licking, lifting, favouring, shaking, and flinching of the treated paw) was recorded at 5-min intervals for 60min. The NMDA receptor antagonists significantly (pmemantine>ketamine>dextromethorphan>CGP37849. The NMDA antagonists administered after formalin (during the analgesic interval) did not affect the late phase of the formalin test. In conclusion, systemic administration of NMDA receptor antagonists decreases the nociception observed during the late phase of the formalin test.
- Published
- 2003
48. Group I metabotropic glutamate receptors modulate glutamate and gamma-aminobutyric acid release in the periaqueductal grey of rats
- Author
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Luigi Fabrizio Rodella, Vito de Novellis, Francesco Rossi, Francesca Rossi, Ida Marabese, Enza Palazzo, Rossella Bianchi, Liberato Berrino, Sabatino Maione, DE NOVELLIS, Vito, Marabese, Ida, Palazzo, Enza, Rossi, Francesca, Berrino, Liberato, Rodella, Luigi, Bianchi, Rossella, Rossi, Francesco, Maione, Sabatino, Rodella, L, Bianchi, R, and Rossi, F
- Subjects
Male ,Pyridines ,Microdialysis ,Glycine ,Tetrodotoxin ,Pharmacology ,Receptors, Metabotropic Glutamate ,Receptors, N-Methyl-D-Aspartate ,Piperazines ,Amino acid neurotransmitter ,chemistry.chemical_compound ,Cellular and Molecular Neuroscience ,Glutamates ,Excitatory Amino Acid Agonists ,Animals ,Periaqueductal Gray ,Glutamate receptor antagonist ,mglu receptor ,Rats, Wistar ,gamma-Aminobutyric Acid ,Phenylacetates ,Metabotropic glutamate receptor 5 ,Chemistry ,Metabotropic glutamate receptor 7 ,Metabotropic glutamate receptor 6 ,Dendrites ,Resorcinols ,Periaqueductal grey ,Rats ,Microscopy, Electron ,Microdialysi ,Metabotropic glutamate receptor ,Chromones ,NMDA receptor ,Metabotropic glutamate receptor 1 ,Metabotropic glutamate receptor 2 - Abstract
In this study, we investigated the effects of group I metabotropic glutamate (mglu) receptor ligands on glutamate and gamma-aminobutyric acid (GABA) extracellular concentrations at the periaqueductal grey level by using in vivo microdialysis. An agonist of group I mglu receptors, (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG, 1 and 2 mM], as well as a selective agonist of mglu(5) receptors, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 2 and 4 mM), both increased dialysate glutamate and GABA concentrations. 7-(Hydroxyimino)cyclopropa-[b]-chromen-1alpha-carboxylate ethyl ester (CPCCOEt, 1 mM), a selective mglu(1) receptor antagonist, and 2-methyl-6-(phenylethynyl)pyridine (MPEP, 0.5 mM), a selective mglu(5) receptor antagonist, perfused in combination with DHPG, antagonized the effect induced by DHPG on the extracellular glutamate and GABA concentrations. MPEP (0.5 mM), perfused in combination with CHPG, antagonized the increased glutamate and GABA extracellular levels induced by CHPG. MPEP (1 mM) decreased the extracellular concentrations of glutamate but did not modify the dialysate GABA concentrations. Moreover, as the intra-periaqueductal grey perfusion of (RS)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid [(RS)-CPP, 100 microM], a selective N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, did not change the extracellular concentrations of glutamate, this suggests that the MPEP-induced decrease in glutamate is not a consequence of NMDA receptor blockade. These data show that group I mglu receptors in the periaqueductal grey may modulate the release of glutamate and GABA in awake, freely moving rats. In particular, mglu(5), but not mglu(1), receptors seem to be functionally active on glutamate terminals.
- Published
- 2003
49. Interactive role of adenosine and dopamine in the opiate withdrawal syndrome
- Author
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Vito de Novellis, Maria Redenta Vitelli, Amelia Filippelli, L. Stella, Francesco Rossi, Annalisa Capuano, Filomena Mazzeo, Liberato Berrino, Stella, L, DE NOVELLIS, Vito, Vitelli, Mr, Capuano, Annalisa, Mazzeo, F, Berrino, Liberato, Rossi, Francesco, and Filippelli, A.
- Subjects
Male ,medicine.medical_specialty ,Adenosine ,Dopamine ,Injections, Subcutaneous ,Microdialysis ,Wistar ,blood/metabolism ,Pharmacology ,Injections ,SCH-58261 ,Receptors, Dopamine ,chemistry.chemical_compound ,Adenosine A1 receptor ,Internal medicine ,Caffeine ,Receptors ,Adenosine A1 Receptor Agonists, Adenosine A2 Receptor Antagonists, Adenosine ,analogs /&/ derivatives/metabolism/pharmacology, Animals, Caffeine ,analogs /&/ derivatives/pharmacology, Chromatography ,High Pressure Liquid, Dopamine ,blood/metabolism, Injections ,Subcutaneous, Male, Microdialysis, Morphine ,adverse effects, Pyrimidines ,pharmacology, Rats, Rats ,Wistar, Receptors ,metabolism, Substance Withdrawal Syndrome ,metabolism, Triazoles ,pharmacology ,medicine ,Animals ,Rats, Wistar ,Chromatography, High Pressure Liquid ,Chromatography ,Morphine ,business.industry ,Subcutaneous ,Opiate Withdrawal Syndrome ,General Medicine ,Purinergic signalling ,Triazoles ,Adenosine A3 receptor ,Adenosine receptor ,Adenosine A1 Receptor Agonists ,Adenosine A2 Receptor Antagonists ,Rats ,Substance Withdrawal Syndrome ,Endocrinology ,Pyrimidines ,chemistry ,High Pressure Liquid ,CCPA ,adverse effects ,analogs /&/ derivatives/pharmacology ,business ,metabolism ,analogs /&/ derivatives/metabolism/pharmacology ,medicine.drug - Abstract
Adenosine reduces opioid withdrawal symptoms by activating A(1) adenosine receptors, probably by inhibiting excitatory amino acid release. Since blockade of A(2A) adenosine receptors seems to enhance dopaminergic striatopallidal transmission, we evaluated the role of the purinergic system in the opiate withdrawal syndrome by using two A(1) receptor agonists [ N(6)-cyclohexyladenosine, CHA and 2-chloro- N(6)-cyclopentyladenosine, CCPA], and two A(2A) receptor antagonists (SCH 58261 and 8-(3-chlorostyryl)caffeine, CSC). Male adult rats received increasing doses of morphine sulphate suspended in 5 ml/kg of a sustained release preparation (40-100 mg/kg s.c.) daily for 4 days and 20 h after the last administration, the withdrawal syndrome was evoked by naloxone (5 mg/kg i.p.). Animals were observed for 30 min for signs of opiate withdrawal. Other groups of rats were implanted with concentric probes for microdialysis and dopamine levels were measured in the nucleus accumbens. CHA and CCPA (0.05, 0.1 or 0.5 mg/kg i.p.) significantly reduced "wet-dog" shakes, diarrhoea, teeth chattering, jumping and writhing. SCH 58261 and CSC (0.1, 0.5 or 1 mg/kg i.p.), given 10 min before naloxone, also reduced signs of opiate withdrawal. CHA plus SCH 58261 and CCPA plus CSC greatly enhanced the reduction of withdrawal signs observed with CHA and CCPA or CSC and SCH 58261 alone. In vivo microdialysis showed that naloxone significantly decreased DA release; this effect was prevented by pretreatment with systemic SCH 58261 and CSC, but not with CHA and CCPA. Our results demonstrate that A(1) and A(2A) adenosine receptors mediate the effect induced by adenosine in opiate withdrawal syndrome and suggest that adenosine A(1) agonists and adenosine A(2A) antagonists may be beneficial in the treatment of this syndrome.
- Published
- 2002
50. Effects of docosahexaenoic acid on [Ca(2+)](i) increase induced by doxorubicin in ventricular rat cardiomyocytes
- Author
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S. Rossi, Barbara Rinaldi, M. R. Vitelli, Amelia Filippelli, Liberato Berrino, Enza Palazzo, Francesca Rossi, Vitelli, M. R., Filippelli, A, Rinaldi, Barbara, Rossi, Settimio, Palazzo, Enza, Rossi, Francesco, and Berrino, Liberato
- Subjects
Male ,medicine.medical_specialty ,Fura-2 ,Docosahexaenoic Acids ,Stereochemistry ,Heart Ventricles ,chemistry.chemical_element ,Cell Separation ,Biology ,Calcium ,In Vitro Techniques ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Homeostasis ,General Pharmacology, Toxicology and Pharmaceutics ,Fluorescent Dyes ,Calcium metabolism ,Antibiotics, Antineoplastic ,Endoplasmic reticulum ,Myocardium ,Heart ,General Medicine ,Microfluorimetry ,Rats ,Perfusion ,Endocrinology ,chemistry ,Docosahexaenoic acid ,Doxorubicin ,Caffeine - Abstract
The clinical use of doxorubicin (DXR) is limited by cardiotoxicity partially due to interference with intracellular Ca(2+) homeostasis and involving the activation of the sarcoplasmic reticulum (SR) Ca(2+) release channels. It is known that docosahexaenoic acid (DHA) is able to potentiate the sensitivity of cancer cells to DXR. The aim of our study was to further evaluate the effects of DHA on [Ca(2+)](i) overload induced by DXR in adult rat ventricular cardiomyocytes in order to verify if DHA interferes with DXR-induced cardiotoxicity too. [Ca(2+)](i) was measured by microfluorimetry. Our data demonstrated that 100 microM DXR induced a statistically significant [Ca(2+)](i)-increase in cardiomyocytes perfused with CaCl(2) Krebs solution (from 135.7 +/- 15 nM to 560.2 +/- 49 nM, n = 9, p < 0.01) and with Ca(2+)-free Krebs solution (from 89.3 +/- 15 nM to 551.1 +/- 35 nM, n = 9, p < 0.01). Treatment with 10 microM DHA for 20 min significantly suppressed DXR [Ca(2+)](i)- increase in cells perfused with CaCl(2) Krebs solution (142.3 +/- 12 nM, n = 9, p < 0.01) and in Ca(2+)-free procedures (100.4 +/- 12 nM, n = 9, p < 0.01). Caffeine 10 mM significantly increased [Ca(2+)](i) in cardiomyocytes perfused with CaCl(2) Krebs solution (from 135.7 +/- 15 nM to 979.2 +/- 17.8 nM, n = 9, p < 0.01) and with Ca(2+)-free Krebs solution (from 89.3 +/- 15 nM to 891.1 +/- 30 nM, n = 9, p < 0.01). Treatment with 10 microM DHA for 20 min suppressed caffeine [Ca(2+)](i)-increase in cardiomyocytes perfused with CaCl(2) Krebs solution (174.2 +/- 28 nM, n = 9, p < 0.01) and in Ca(2+)-free procedures (161.9 +/- 34 nM, n = 9, p < 0.01). In conclusion, our results suggest that DHA is able to prevent acute modifications of calcium homeostasis induced by DXR probably interfering with SR Ca(2+) release channels.
- Published
- 2002
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