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Dive into the research topics where Giuseppina Costantino is active.

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Featured researches published by Giuseppina Costantino.


Immunity | 2008

The TSC-mTOR Signaling Pathway Regulates the Innate Inflammatory Response

Thomas Weichhart; Giuseppina Costantino; Marko Poglitsch; Margit Rosner; Maximilian Zeyda; Karl M. Stuhlmeier; Thomas Kolbe; Thomas M. Stulnig; Walter H. Hörl; Markus Hengstschläger; Mathias Müller; Marcus D. Säemann

The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-kappaB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift. Rapamycin-hyperactivated monocytes displayed a strong T helper 1 (Th1) cell- and Th17 cell-polarizing potency. Inhibition of mTOR in vivo regulated the inflammatory response and protected genetically susceptible mice against lethal Listeria monocytogenes infection. These data identify the TSC2-mTOR pathway as a key regulator of innate immune homeostasis with broad clinical implications for infectious and autoimmune diseases, vaccination, cancer, and transplantation.


Cardiovascular Research | 2000

Effects of n-acetylcysteine in a rat model of ischemia and reperfusion injury

Salvatore Cuzzocrea; Emanuela Mazzon; Giuseppina Costantino; Ivana Serraino; Angela De Sarro; Achille P. Caputi

OBJECTIVE Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of n-acetylcysteine (NAC), a free radical scavenger, in rats subjected to SAO shock. METHODS AND RESULTS Treatment of rats with NAC (applied at 20 mg/kg, 5 min prior to reperfusion, followed by an infusion of 20 mg/kg/h) attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. NAC also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine in the plasma of the SAO-shocked rats after reperfusion. Immunohistochemical analysis for nitrotyrosine and for poly(ADP-ribose) synthetase (PARS) revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine and PARS were markedly reduced in tissue sections obtained from SAO-shocked rats which had received NAC. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localised in the vascular endothelial cells. Ileum tissue section obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. NAC treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). NAC treatment improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and significantly improved survival. CONCLUSION Taken together, our results clearly demonstrate that NAC treatment exert a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite-related pathways and subsequent reduction of neutrophil-mediated cellular injury.


Journal of Pineal Research | 2000

Protective effects of melatonin in ischemic brain injury

Salvatore Cuzzocrea; Giuseppina Costantino; Eloisa Gitto; Emanuela Mazzon; Francesco Fulia; Ivana Serraino; Santina Cordaro; Ignazio Barberi; Angela De Sarro; Achille P. Caputi

Recent studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. NO, peroxynitrite (formed from NO and superoxide anion), and poly (ADP‐Ribose) synthetase (PARS) have been implicated as mediators of neuronal damage following focal ischemia. In the present study, we have investigated the effects of melatonin treatment in Mongolian gerbils subjected to cerebral ischemia. Treatment of gerbils with melatonin (10 mg kg−1, 30 min before reperfusion and 1, 2, and 6 hr after reperfusion) reduced the formation of post‐ischemic brain edema, evaluated by water content. Melatonin also attenuated the increase in the brain levels malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischemia. Positive staining for nitrotyrosine was found in the hippocampus of Mongolian gerbils subjected to cerebral ischemia. Hippocampus tissue sections, from Mongolian gerbils subjected to cerebral ischemia, also showed positive staining for PARS. The degrees of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received melatonin. Melatonin treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischemia and reperfusion. Histological observations of the pyramidal layer of CA‐1 showed a reduction of neuronal loss in animals that received melatonin. These results show that melatonin improves brain injury induced by transient cerebral ischemia.


The FASEB Journal | 2000

Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion

Salvatore Cuzzocrea; Thomas P. Misko; Giuseppina Costantino; Emanuela Mazzon; Antonio Micali; Achille P. Caputi; Heather Macarthur; Daniela Salvemini

The aim of the present study was to investigate the protective effect of the peroxynitrite decomposition catalyst 5,10,15,20‐tetrakis(2,4,6‐tri‐methyl‐3,5‐disulfonatophenyl)‐porphyrinato iron (III) (FeTMPS) in a model of splanchnic artery occlusion shock (SAO). SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp (reperfusion). At 60 min after reperfusion, animals were killed for histological examination and biochemical studies. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite‐induced oxidative processes) in the plasma of the SAO‐shocked rats after reperfusion, but not during ischemia alone. Immunohistochemical examination demonstrated a marked increase in the immunore‐activity to nitrotyrosine, an index of nitrogen species such as peroxynitrite, in the necrotic ileum in shocked rats. SAO‐shocked rats developed a significant increase of tissue myeloperoxidase and malon‐aldehyde activity, and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival at 2 h after reperfusion). Reperfused ileum tissue sections from SAO‐shocked rats showed positive staining for P‐selectin localized mainly in the vascular endothelial cells. Ileum tissue sections obtained from SAO‐shocked rats and stained with antibody to ICAM‐1 showed a diffuse staining. Administration of FeT‐MPS significantly reduced ischemia/reperfusion injury in the bowel, and reduced lipid and the production of peroxynitrite during reperfusion. Treatment with PN catalyst also markedly reduced the intensity and degree of P‐selectin and ICAM‐1 staining in tissue sections from SAO‐shocked rats and improved survival. Our results clearly demonstrate that per‐oxynitrite decomposition catalysts exert a protective effect in SAO and that this effect may be due to inhibition of the expression of adhesion molecules and the tissue damage associated with peroxynitrite‐related pathways.—Cuzzocrea, S., Misko, T. P., Costantino, C., Mazzon, E., Micali, A., Caputi A. P., Macarthur, H., Salvemini, D. Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion. FASEB J. 14, 1061–1072 (2000)


Journal of Pineal Research | 2000

Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion

Salvatore Cuzzocrea; Giuseppina Costantino; Emanuela Mazzon; Antonio Micali; Angela De Sarro; Achille P. Caputi

The aim of the present study was to investigate the protective effect of the pineal secretary product melatonin in a model of splanchnic artery occlusion shock (SAO). SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, animals were sacrificed for tissue histological examination and biochemical studies. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite‐induced oxidative processes) in the plasma of the SAO‐shocked rats after reperfusion, but not during ischemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, an index of nitrogen species such as peroxynitrite, in the necrotic ileum in shocked rats. SAO‐shocked rats developed a significant increase of tissue myeloperoxidase and malondialdehyde activity, and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival at 2 hr after reperfusion). Reperfused ileum tissue sections from SAO‐shocked rats showed positive staining for P‐selectin, which was mainly localized in the vascular endothelial cells. Ileum tissue sections obtained from SAO‐shocked rats with anti‐intercellular adhesion molecule (ICAM‐1) antibody showed a diffuse staining. Melatonin (applied at 3 mg/kg, 5 min prior to reperfusion, followed by an infusion of 3 mg/kg per hr), significantly reduced ischemia/reperfusion injury in the bowel as evaluated by histological examination. This prevented the infiltration of neutrophils into the reperfused intestine, as evidenced by reduced myeloperoxidase activity and reduced lipid peroxidation. This was evaluated by malondialdehyde activity which reduced the production of peroxynitrite during reperfusion, markedly reduced the intensity and degree of P‐selectin and ICAM‐1 in tissue section from SAO‐shocked rats and improved their survival. Taken together, our results clearly demonstrate that melatonin treatment exerts a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite‐related pathways and subsequent reduction of neutrophil‐mediated cellular injury.


Brain Research | 2000

Effects of tempol, a membrane-permeable radical scavenger, in a gerbil model of brain injury.

Salvatore Cuzzocrea; Michelle C. McDonald; Emanuela Mazzon; Dilani Siriwardena; Giuseppina Costantino; Francesco Fulia; Giovanni Cucinotta; Eloisa Gitto; S. Cordaro; Ignazio Barberi; A. De Sarro; Achille P. Caputi; Christoph Thiemermann

There is evidence that the excessive generation of reactive-oxygen radicals contributes to the brain injury associated with transient, cerebral ischemia. This study investigates the effects of tempol, a small, water-soluble molecule, that crosses biological membranes, on the brain injury caused by bilateral occlusion and reperfusion of both common carotid arteries in the gerbil (BCO). Treatment of gerbils with tempol (30 mg/kg i.p. at 30 min prior to reperfusion and at 1 and 6 h after the onset of reperfusion) reduced the formation of post-ischemic brain oedema. Tempol also attenuated the increase in the cerebral levels of malondialdehyde (MDA) and the hippocampal levels of myeloperoxidase (MPO) caused by cerebral ischemia and reperfusion. The immunohistochemical analysis of the hippocampal region of brains subjected to ischemia-reperfusion exhibited positive staining for nitrotyrosine (an indicator of the generation of peroxynitrite) and poly(ADP-ribose) synthetase (PARS) (an indicator of the activation of this nuclear enzyme secondary to single strand breaks in DNA). In gerbils subjected to BCO, which were treated with tempol, the degree of staining for nitrotyrosine and PARS was markedly reduced. Tempol increased survival and reduced the hyperactivity (secondary to the ischemia-induced neurodegeneration) caused by cerebral ischemia and reperfusion. The loss of neurons from the pyramidal layer of the CA1 region caused by ischemia and reperfusion was also attenuated by treatment of gerbils with tempol. This is the first evidence that the membrane-permeable, radical scavenger tempol reduces the cerebral injury caused by transient, cerebral ischemia in vivo.


Fitoterapia | 1999

Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat : a preliminary report

Gioacchino Calapai; Fabio Firenzuoli; A. Saitta; Francesco Squadrito; Maria R. Arlotta; Giuseppina Costantino; Giuseppina Inferrera

Abstract The effects of repeated oral administration of 2.5–20 mg/kg of two Citrus aurantium fruit extracts standardized to different concentrations of synephrine (4 and 6%, respectively) on food intake, body weight gain, arterial blood pressure, electrocardiogram (ECG) and mortality have been investigated in the rat. C. aurantium administration significantly reduced food intake and body weight gain. However, mortality (not observed in controls) was present in all C. aurantium treated groups. Arterial blood pressure was not modified, but ECG alterations (ventricular arhythmias with enlargement of QRS complex) were evident in animals treated with both extracts. Our data indicate that, in the rat, antiobesity effects of C. aurantium are accompanied by toxic effects probably due to cardiovascular toxicity.


Journal of Leukocyte Biology | 1999

IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock.

Salvatore Cuzzocrea; Giovambattista De Sarro; Giuseppina Costantino; Gennaro Ciliberto; Emanuela Mazzon; Angela De Sarro; Achille P. Caputi

We used IL‐6 knock‐out (KO) mice to evaluate a possible role for IL‐6 in the pathogenesis of splanchnic artery occlusion shock (SAO). SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk, followed by release of the clamp. There was a marked increase in the peroxynitrite formation in the plasma of the SAO‐shocked IL‐6 wild‐type (WT) mice after reperfusion. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the necrotic ileum in shocked IL‐6 WT mice. SAO‐shocked WT mice developed a significant increase of tissue myeloperoxidase (MPO) and malondialdehyde (MDA) activity and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival). Reperfused ileum tissue sections from SAO‐shocked WT mice showed positive staining for P‐selectin. Little specific staining was observed in sham‐WT mice. Staining of ileum tissue obtained from sham‐operated WT mice with anti‐ICAM‐1 antibody showed weak but diffuse staining, demonstrating that ICAM‐1 is constitutively expressed. However, after SAO shock the staining intensity increased substantially in the ileum section from WT mice. Intensity and degree of P‐selectin and ICAM‐1 were markedly reduced in tissue section from SAO‐shocked IL‐6 KO mice. SAO‐shocked IL‐6 KO mice also show significant reduction of neutrophil infiltration into the reperfused intestine, as evidenced by reduced MPO activity, improved histological status of the reperfused tissues, reduced peroxynitrite formation, reduced MDA levels, and improved survival. In vivo treatment with anti‐IL‐6 significantly prevents the inflammatory process. Our results clearly demonstrate that IL‐6 plays an important role in ischemia and reperfusion injury and allows the hypothesis that inhibition of IL‐6 may represent a novel and possible strategy. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil‐mediated cellular injury. J. Leukoc. Biol. 66: 471–480; 1999.


Journal of Pharmacy and Pharmacology | 1999

Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat

Gioacchino Calapai; A. Crupi; F. Firenzuoli; Giuseppina Costantino; G. Inferrera; Giuseppe M. Campo; Achille P. Caputi

The plant Hypericum perforatum is used in folk medicine to treat several diseases and research attention has been recently focused on its antidepressant action. Hypericin and flavonoids are the most important constituents of the plant, but the exact role of these compounds in the effects of hypericum on mood disorders is not well known. We have investigated the contribution of these compounds to the antidepressant effects of hypericum.


Free Radical Biology and Medicine | 1999

Beneficial effects of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic, in carrageenan-induced pleurisy

Salvatore Cuzzocrea; Basilia Zingarelli; Giuseppina Costantino; Achille P. Caputi

Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of NO with superoxide anion, has been proposed to have major pathogenetic role in inflammatory process. Here we have investigated the therapeutic efficacy of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a novel superoxide dismutase mimetic that possesses peroxynitrite scavenging effect, in rats subjected to carrageenan-induced pleurisy. In vivo treatment with MnTBAP (3 and 10 mg/kg 5 min before carrageenan) prevented in a dose-dependent manner the carrageenan-induced the degree of pleural exudation, polymorphonuclear migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase (MPO) activity and histological organ injury was significantly reduced by MnTBAP. However, MnTBAP did not inhibit the inducible NO synthase in lung samples. Immunohistochemical analysis for nitrotyrosine, a footprint of peroxynitrite, revealed a positive staining in lungs from carrageenan-treated rats. No positive nitrotyrosine staining was found in the lungs of the carrageenan-treated rats that received MnTBAP (10 mg/kg) treatment. In addition, in vivo MnTBAP treatment significantly reduced in a dose-dependent manner peroxynitrite formation as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, prevented the appearance of DNA damage, the decrease in mitochondrial respiration and partially restored the cellular level of NAD+ in ex vivo macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. Our study demonstrates that the MnTBAP exerts multiple protective effects in carrageenan-induced pleurisy. We suggest peroxynitrite produced during the inflammatory process trigger DNA strand breakage and subsequent cellular dysfunction. Part of these anti-inflammatory effects may be related to: (1) reduction of superoxide formation due to the superoxide dismutase-like activity of the compound and (2) scavenging of peroxynitrite.

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Basilia Zingarelli

Cincinnati Children's Hospital Medical Center

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Christoph Thiemermann

Queen Mary University of London

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Lidia Sautebin

University of Naples Federico II

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Michelle C. McDonald

Queen Mary University of London

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