Biomedical subjects

Salvatore Cuzzocrea

Publications and source records attributed to Salvatore Cuzzocrea.

At least 145 records · Page 8Linked to original sources

PubMed2004

WY 14643, a potent exogenous PPAR-alpha ligand, reduces intestinal injury associated with splanchnic artery occlusion shock.

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. WY 14643 is a potent PPAR-alpha ligand that modulates the transcription of target genes. The aim of this study was to investigate the effect of WY 14643 on the tissue injury caused by ischemia-reperfusion (I/R) of the gut. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp, allowing reperfusion for 2 h or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 20% of the animals survived for the entire 4-h reperfusion period. Surviving animals were sacrificed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity, significant increases in plasma tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels, and marked injury to the distal ileum. Increased immunoreactivity to nitrotyrosine and polyadenosine diphosphate [ADP]-ribose (PAR) was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-1) antibody or with anti-P-selectin antibody resulted in diffuse staining. Administration of WY 14643 (1 mg/kg i.v.) 30 min before the onset of gut ischemia significantly reduced the (a) fall in mean arterial blood pressure, (b) mortality rate, (c) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (d) production of proinflammatory cytokines (TNF-alpha and IL-1beta), and (e) histological evidence of gut injury. Administration of WY 14643 also markedly reduced the nitrotyrosine formation, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) activation, up-regulation of ICAM-1, and expression of P-selectin during reperfusion. These results demonstrate that the PPAR-alpha agonist WY 14643 significantly reduces I/R injury of the intestine.

Animals↗

PubMed2004

5-Aminoisoquinolinone reduces renal injury and dysfunction caused by experimental ischemia/reperfusion.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the development of ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of a water-soluble and potent PARP inhibitor, 5-aminoisoquinolinone (5-AIQ), on the renal injury and dysfunction caused by oxidative stress of the rat kidney in vitro and in vivo. METHODS: Primary cultures of rat renal proximal tubular cells, subjected to oxidative stress caused by hydrogen peroxide (H2O2), were incubated with increasing concentrations of 5-AIQ (0.01 to 1 mmol/L) after which PARP activation, cellular injury, and cell death were measured. In in vivo experiments, anesthetized male Wistar rats were subjected to renal bilateral ischemia (45 minutes) followed by reperfusion (6 hours) in the absence or presence of 5-AIQ (0.3 mg/kg) after which renal dysfunction, injury and PARP activation were assessed. RESULTS: Incubation of proximal tubular cells with H2O2 caused a substantial increase in PARP activity, cellular injury, and cell death, which were all significantly reduced in a concentration-dependent by 5-AIQ [inhibitory concentration 50 (IC50) approximately 0.03 mmol/L]. In vivo, renal I/R resulted in renal dysfunction, injury, and PARP activation, primarily in the proximal tubules of the kidney. Administration of 5-AIQ significantly reduced the biochemical and histologic signs of renal dysfunction and injury and markedly reduced PARP activation caused by I/R. CONCLUSION: This study demonstrates that 5-AIQ is a potent, water soluble inhibitor of PARP activity, which can significantly reduce (1) cellular injury and death caused to primary cultures of rat proximal tubular cells by oxidative stress in vitro, and (2) renal injury and dysfunction caused by I/R of the kidney of the rat in vivo.

Anesthesia↗

PubMed2004

Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo.

BACKGROUND: Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is known to be up-regulated during states of hypoxia. Here we investigate the effects of renal ischemia/reperfusion (I/R) on the degree of renal dysfunction and injury with recombinant human EPO in mice when given as either a 3-day pretreatment, or upon reperfusion of the kidney. METHODS: Mice were treated with EPO (1000 IU/kg/day subcutaneously) for 3 days, or treated with EPO (1000 IU/kg subcutaneously) upon reperfusion, and subsequently subjected to bilateral renal artery occlusion (30 minutes) and reperfusion (24 hours). At the end of experiments, the following indicators and markers of renal injury and dysfunction were measured: plasma urea, creatinine, and aspartate aminotransferase (AST), tissue myeloperoxidase (MPO) activity [for polymorphonuclear leukocyte (PMN) infiltration], and tissue malonaldehyde (MDA) levels (for tissue lipid peroxidation). Kidneys were used for histologic evaluation of renal injury. RESULTS: EPO was able to significantly attenuate the renal dysfunction and injury associated with I/R, as well as the tissue injury. The increase in renal MPO activity and, hence, the degree of PMN infiltration were also significantly reduced in EPO-treated mice. In addition, lipid peroxidation as a result of renal I/R injury was also attenuated in EPO-treated mice. CONCLUSION: The protection afforded by the pretreatment regime of EPO was greater than that of administering EPO as a single bolus upon reperfusion. We propose that different mechanisms underlie the protective effects seen with EPO when given as either a daily pretreatment or as a single bolus, which need to be further investigated.

Animals↗

PubMed2004

Reduction of renal ischemia-reperfusion injury in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton.

The role of 5-lipoxygenase (5-LOX) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Here we investigate the effects of 1) the 5-LOX inhibitor zileuton and 2) 5-LOX gene knockout (5-LOX(-/-)) mice on renal dysfunction and injury caused by I/R of the kidney in mice. Wild-type mice treated with zileuton (3 mg/kg i.v.) or 5-LOX(-/-) mice were subjected to bilateral renal artery occlusion (30 min) followed by reperfusion (24 h). Plasma urea, creatinine, and aspartate aminotransferase (AST) were measured as markers of renal dysfunction and reperfusion injury. Kidneys were used for histological evaluation of renal injury. Renal myeloperoxidase activity was measured and used as an indicator of polymorphonuclear leukocyte (PMN) infiltration and renal expression of intercellular adhesion molecule-1 (ICAM-1) was determined using immunohistochemistry. Administration of zileuton before I/R significantly reduced the degree of renal dysfunction (urea, creatinine) and injury (AST, histology). In addition, zileuton reduced the expression of ICAM-1 and the associated PMN infiltration caused by I/R of the mouse kidney. Compared with wild-type mice, the degree of renal dysfunction, injury, and inflammation caused by I/R in 5-LOX(-/-) mice was also significantly reduced, confirming the pathophysiological role of 5-LOX in the development of renal I/R injury. We propose that 1) endogenous 5-LOX metabolites enhance the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules, and 2) inhibitors of 5-LOX may be useful in the treatment of conditions associated with I/R of the kidney.

Animals↗

PubMed2004

Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice.

Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1(KI/KI)) mouse model, in which the caspase cleavage site of PARP-1, DEVD(214), was mutated to render the protein resistant to caspases during apoptosis. While PARP-1(KI/KI) mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-kappaB to DNA, NF-kappaB-mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies.

Animals↗

PubMed2004

Potential therapeutic effect of antioxidant therapy in shock and inflammation.

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. A considerable body of recent evidence suggests that oxidant stress plays a major role in several aspects of acute and chronic inflammation and is the subject of this review. Immunohistochemical and biochemical evidence demonstrate the significant role of reactive oxygen species (ROS) in acute and chronic inflammation. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of ROS. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation and ischemia and reperfusion. (2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit peroxynitrite, or with SODm's, which selectively mimic the catalytic activity of the human superoxide dismutase (SOD) enzymes, have been shown to prevent in vivo the delayed tissue injury and the cellular energetic failure associated with inflammation. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Antioxidant treatment inhibits the activation of PARS, and prevents the organ injury associated with acute and chronic inflammation.

Animals↗

PubMed2004

Absence of inducible nitric oxide synthase reduces myocardial damage during ischemia reperfusion in streptozotocin-induced hyperglycemic mice.

We investigated the role of inducible nitric oxide synthase (iNOS) on ischemic myocardial damage and angiogenic process in genetically deficient iNOS (iNOS(-/-)) mice and wild-type littermates (iNOS(+/+)), with and without streptozotocin-induced (70 mg/kg intravenously) diabetes. After ischemia (25 min) and reperfusion (120 min), both iNOS(+/+) and iNOS(-/-) diabetic mice (blood glucose 22 mmol/l) had myocardial infarct size greater than their respective nondiabetic littermates (P < 0.01). Myocardial infarct size (P < 0.05), apoptotic index (P < 0.005), and tissue levels of tumor necrosis factor (P < 0.01), interleukin-6 (P < 0.01), and interleukin-18 (P < 0.01) were higher in nondiabetic iNOS(-/-) mice compared with nondiabetic iNOS(+/+) mice. As compared with diabetic iNOS(-/-) mice, diabetic iNOS(+/+) mice showed a greater infarct size (P < 0.01) associated with the highest tissue levels of nitrotyrosine and proinflammatory cytokines, as well as apoptosis. The beneficial role of iNOS in modulating defensive responses against ischemia/reperfusion injury seems to be abolished in diabetic mice.

Animals↗

PubMed2004

Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes.

Inadequate angiogenic response to ischemia in diabetic myocardium could result in poor collateral formation. Because hypoxia-inducible factor (HIF)-1alpha is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating angiogenic responses to hypoxia, we investigated the expression of HIF-1alpha and VEGF in specimens of human heart tissue to elucidate the molecular responses to myocardial ischemia in diabetic patients during unstable angina. Moreover, accumulation of a marker of protein nitration nitrotyrosine, as well as the superoxide anion (O(2)(-)) levels and inducible nitric oxide synthase (iNOS), were evaluated. Ventricular biopsy specimens from 15 type 2 diabetic and 14 nondiabetic patients presenting with unstable angina (ischemic group) and from 20 patients (11 type 2 diabetic and 9 nondiabetic patients) who underwent coronary bypass surgery without angina within the preceding 10 days (control group) were collected during coronary bypass surgery. Nondiabetic patients had higher HIF-1alpha and VEGF expressions compared with diabetic patients (P < 0.001). As compared with nondiabetic specimens, diabetic specimens showed higher levels of both iNOS mRNA and protein levels (P < 0.001) associated with the highest tissue levels of nitrotyrosine and O(2)(-) (P < 0.001). Diabetes is associated with increased myocardial tissue levels of iNOS, O(2)(-), and nitrotyrosine and reduced expression of myocardial angiogenesis factors during ischemia.

Acute Disease↗

PubMed2004

Inhibition of the nuclear factor-kappaB activation with pyrrolidine dithiocarbamate attenuating inflammation and oxidative stress after experimental spinal cord trauma in rats.

OBJECT: The nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a pivotal role in the induction of genes involved in physiological processes and in the response to inflammation. The authors of recent studies have demonstrated that NF-kappaB and oxidative stress contribute to secondary injury after impact-induced spinal cord injury (SCI) in the rat. Dithiocarbamates are antioxidants that are potent inhibitors of NF-kappaB. The authors postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate NF-kappaB-related inflammatory and oxidative events that occur after SCI. METHODS: Spinal cord injury was induced by the application of vascular clips (force of 50 g) to the dura mater after a four-level T5-8 laminectomy. The authors investigated the effects of PDTC (30 mg/kg administered 30 minutes before SCI and 6 hours after SCI) on the development of the inflammatory response associated with SCI in rats. Levels of myeloperoxidase activity were measured as an indicator of polymorphonuclear infiltration; malondialdehyde levels in the spinal cord tissue were determined as an indicator of lipid peroxidation. The following studies were performed: immunohistochemical analysis to assess levels of inducible nitric oxide synthase (iNOS), nitrotyrosine formation, poly([adenosine diphosphate]-ribose) polymerase (PARP) activity; Western blot analysis to determine cytoplasmic levels of inhibitory-kappaB-alpha (IkappaB-alpha); and electrophoretic mobility-shift assay to measure the level of DNA/NF-kappaB binding. The PDTC treatment exerted potent antiinflammatory effects with significant reduction of polymorphonuclear cell infiltration, lipid peroxidation, and iNOS activity. Furthermore, administration of PDTC reduced immunohistochemical evidence of formation of nitrotyrosine and PARP activation in the spinal cord section obtained in the SCI-treated rats. Additionally, PDTC treatment significantly prevented the activation of NF-kappaB (electrophoretic mobility-shift assay and immunoblot analysis). CONCLUSIONS: Overall, the results clearly demonstrate that PDTC-related prevention of the activation of NF-kappaB reduces the development of some secondary injury events after SCI. Therefore, inhibition of NF-kappaB may represent a novel approach in the treatment of SCIs.

Analysis of Variance↗

PubMed2003

Pyrrolidine dithiocarbamate reduces renal dysfunction and injury caused by ischemia/reperfusion of the rat kidney.

Dithiocarbamates can modulate the expression of genes associated with inflammation or development of ischemia/reperfusion injury. Here, we investigate the effects of pyrrolidine dithiocarbamate, an inhibitor of nuclear factor (NF)-kappaB activation, on the renal dysfunction and injury caused by ischemia/reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Pyrrolidine dithiocarbamate (100 mg/kg, administered i.v.) significantly reduced biochemical and histological evidence of renal dysfunction and injury caused by ischemia/reperfusion of the rat kidney. Furthermore, pyrrolidine dithiocarbamate markedly reduced the expression of inducible nitric oxide synthase (iNOS) protein and significantly reduced serum levels of nitric oxide. Finally, pyrrolidine dithiocarbamate inhibited the activation of NF-kappaB by preventing its translocation from the cytoplasm into the nuclei of renal cells. These results demonstrate that pyrrolidine dithiocarbamate reduces renal ischemia/reperfusion injury and that dithiocarbamates may provide beneficial actions against ischemic acute renal failure.

Animals↗

PubMed2003

2-Cyclopenten-1-one and prostaglandin J2 reduce restenosis after balloon angioplasty in rats: role of NF-kappaB.

The aim of this study was to evaluate, using a rat model of balloon angioplasty, whether prostaglandin (PG) J(2) and 2-cyclopenten-1-one are able to reduce restenosis. We found that both PGJ(2) and 2-cyclopenten-1-one, administered by local application on carotid arteries, caused a dose-dependent inhibition of neointimal formation. Furthermore, both agents prevented vascular negative remodeling. The effect of these compounds on restenosis was correlated with an inhibition of nuclear factor-kappaB (NF-kappaB) activation as well as of intercellular adhesion molecule-1 (ICAM-1) protein expression in injured carotid arteries of control animals. Our results show that cyclopentenone PGs and their derivatives reduce restenosis and may have therapeutic relevance for the prevention of human restenosis.

Angioplasty, Balloon, Coronary↗

PubMed2003

Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, ligands of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), reduce ischaemia/reperfusion injury of the gut.

1. The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin (PG)D2 metabolite, 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2), are two PPAR-gamma ligands, which modulate the transcription of target genes. 2. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the tissue injury caused by ischaemia/reperfusion (I/R) of the gut. 3. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp allowing reperfusion for 2 or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. 4. Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 10% of the animals survived for the entire 4 h reperfusion period. Surviving animals were killed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significant increases in plasma tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels and marked injury to the distal ileum. 5. Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-1) antibody resulted in diffuse staining. 6. Administration at 30 min prior to the onset of gut ischaemia of the two PPAR-gamma agonists (rosiglitazone (0.3 mg kg-1 i.v.) and 15d-PGJ2 (0.3 mg kg-1 i.v.)) significantly reduced the (i) fall in mean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (iv) lipid peroxidation (MDA levels), (v) production of proinflammatory cytokines (TNF-alpha and IL-1beta) and (vi) histological evidence of gut injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine formation and the upregulation of ICAM-1 during reperfusion. 7. In order to elucidate whether the protective effects of rosiglitazone and 15d-PGJ2 are related to the activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone and 15d-PGJ2. BADGE (1 mg kg-1 administered i.v. 30 min prior to the treatment of rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists and thus abolished the protective effect against gut I/R. 8. These results demonstrate that the two PPAR-gamma agonists, rosiglitazone and 15d-PGJ2, significantly reduce I/R injury of the intestine.

Animals↗

PubMed2003

Protective effects of cyanidin-3-O-glucoside from blackberry extract against peroxynitrite-induced endothelial dysfunction and vascular failure.

Anthocyanins are a group of naturally occurring phenolic compounds as colorants in several plants, flowers and fruits. These pigments have a great importance as quality indicators, as chemotaxonomic markers and antioxidants. The content of blackberry (Rubus species) juice was investigated by HPLC/ESI/MS using narrow bore HPLC columns. Using this method we demonstrated that cyanidin-3-O-glucoside represents about 80% of the total anthocyanin contents in blackberry extract. Here we investigated antioxidant activity of the blackberry juice and cyanidin-3-O-glucoside on the endothelial dysfunction in cells and in vascular rings exposed to peroxynitrite. In human umbilical vein endothelial cells (HUVEC) in vitro, peroxynitrite caused a significant suppression of mitochondrial respiration (38 +/- 2.1% of control cells), as measured by the mitochondrial-dependent conversion of the dye MTT to formazan. Peroxynitrite caused DNA strand breakage (63 +/- 1.9% single strand vs 3 +/- 0.9% single strand in control cells), as measured by the alkaline unwinding assay, and caused an activation of PARS, as measured by the incorporation of radiolabeled NAD(+) to nuclear proteins. Blackberry juice (different dilutions that contained 80 ppm;40 ppm;14.5 ppm of cyanidin-3-O-glucoside) and cyanidin-3-O-glucoside (as chloride) (0.085 microM; 0.028 microM; 0.0085 microM) reduced the peroxynitrite-induced suppression of mitochondrial respiration, DNA damage and PARS activation in HUVECs. Vascular rings exposed to peroxynitrite exhibited reduced endothelium-dependent relaxant responses in response to acetylcholine as well as a vascular contractility dysfunction in response to norepinephrine. The development of this peroxynitrite-induced vascular dysfunction was ameliorated by the blackberry juice (different dilutions that contained 80 ppm;40 ppm;14.5 ppm of cyanidin-3-O-glucoside) and cyanidin-3-O-glucoside (as chloride) (0.085 microM;0.028 microM;0.0085 microM). In conclusion our findings clearly demonstrate that blackberry juice containing cyanidin-3-O-glucoside is a scavenger of peroxynitrite and that exert a protective effect against endothelial dysfunction and vascular failure induced by peroxynitrite.

Anthocyanins↗

PubMed2003

Pyrrolidine dithiocarbamate attenuates the development of organ failure induced by zymosan in mice.

OBJECTIVE: Nuclear factor (NF) kappaB is a transcription factor which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and inflammation. Dithiocarbamates are anti-oxidants which are potent inhibitors of NF-kappaB. We postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate multiple-organ failure (MOF). DESIGN AND SETTING: Rats in a university research laboratory. INTERVENTIONS AND MEASUREMENTS: We investigated the effects of PDTC (10 mg/kg) on the MOF caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in mice. MOF in mice was assessed 18 h after administration of zymosan and/or PDTC and monitored for 7 days (for loss of body weight and mortality). RESULTS: Treatment of mice with PDTC (10 mg/kg i.p., 1 and 6 h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. PDTC also attenuated the lung, liver and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde levels caused by zymosan in the lung, liver and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine and poly(ADP-ribose) revealed positive staining in lung, liver and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine and poly(ADP-ribose) were markedly reduced in tissue sections obtained from zymosan-treated mice which received PDTC. Furthermore, treatment of mice with PDTC significantly reduced the expression of nitric oxide synthase in lung, liver and intestine. CONCLUSIONS: This study provides the first evidence that PDTC attenuates the degree of zymosan-induced MOF in mice.

Animals↗

PubMed2003

Agonists of peroxisome-proliferator activated receptor-gamma reduce renal ischemia/reperfusion injury.

BACKGROUND/AIMS: Recent evidence indicates that peroxisome-proliferator activated receptor (PPAR) agonists protect against ischemia/reperfusion (I/R) injury. Here we investigate the effects of the PPAR-gamma agonists, rosiglitazone and ciglitazone, on the renal dysfunction and injury caused by I/R of the rat kidney in vivo. METHODS: Rosiglitazone or ciglitazone were administered to male Wistar rats prior to and during reperfusion. Biochemical indicators of renal dysfunction and injury were measured and histological scoring of kidney sections was used to assess renal injury. Expression of PPAR isoforms and intercellular adhesion molecule-1 during renal I/R were assessed using RT-PCR and Northern blot, respectively. Myeloperoxidase activity and activation of poly(ADP-ribose) polymerase (PARP) were used as indicators of polymorphonuclear (PMN) cell infiltration and oxidative stress, respectively. RESULTS: Expression of PPAR-alpha, PPAR-beta and PPAR-gamma 1 (but not PPAR-gamma 2) was observed in kidneys with down-regulation of PPAR-alpha expression during renal I/R. Rosiglitazone and ciglitazone significantly reduced biochemical and histological signs of renal dysfunction and injury. Renal expression of ICAM-1 caused by I/R was reduced by rosiglitazone and ciglitazone which was reflected by decreased PMN infiltration into reperfused renal tissues. Both rosiglitazone and ciglitazone reduced PARP activation indicating a reduction of oxidative stress. CONCLUSION: These results suggest that the PPAR-gamma agonists rosiglitazone and ciglitazone reduce the renal dysfunction and injury associated with I/R of the kidney. We propose that one mechanism underlying the protective effects involves inhibition of the expression of ICAM-1, a reduction of PMN infiltration into renal tissues and subsequent reduction of oxidative stress.

Animals↗

PubMed2003

Copper induces type II nitric oxide synthase in vivo.

Intravenous administration of copper (up to a final concentration of ca. 35 micromol/l in the plasma) led to a progressive, dramatic fall of mean arterial pressure in rats. Copper-induced pressure changes were comparable to those elicited by 2 mg/kg LPS, and were greatly prevented by previous infusion of the inducible NOS (NOS-II) inhibitors aminoguanidine or l-N(6)-(L-imino-ethyl)lysine. RT-PCR analysis showed a significant transcriptional induction of NOS-II in a number of tissues, including aorta, liver, and lungs. Immunohistochemistry revealed that NOS-II was massively synthesized in these tissues upon copper or LPS treatment. The protein was active, as revealed by enzymatic assays on lung homogenates and by the large increase of nitrite/nitrate levels in the plasma. Copper-challenged rats displayed elevated plasma levels of TNFalpha. Extensive formation of nitrotyrosines, indicative of peroxynitrite production, was accompanied by marked morphological changes in examined tissues. Our results clearly show that copper can act as a proinflammatory agent through activation of the nitric oxide pathway, leading to the same pathological frame induced by bacterial lipopolysaccharide.

Animals↗

PubMed2003

A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects.

Interleukin-2 (IL-2) is used to treat metastatic renal cell carcinoma and malignant melanoma, but its use is limited by the severe hypotension it produces. We have shown here that M40403, a superoxide dismutase (SOD) mimetic, blocked IL-2-induced hypotension and allowed the dose of IL-2 to be increased in mice. The reversal of IL-2-mediated hypotension was associated with an increase in plasma catecholamines. In addition, M40403 increased lymphokine-activated killer (LAK) cell cytotoxicity in vitro and in vivo, through inhibition of macrophage superoxide production. Treatment of methylcholanthrene-induced (Meth A) ascites tumors with IL-2 and > or =3 mg per kg body weight M40403 induced 50% complete remissions lasting for more than 200 d, which was longer than those of untreated mice (15-d median survival) or mice treated with IL-2 alone (22-d median). Growth of subcutaneous implants of RENCA renal carcinoma was also inhibited by the combination of IL-2 and M40403. These results established that M40403 prevented IL-2 from causing dose-limiting hypotension, while enhancing its anticancer activity.

Animals↗

PubMed2003

A superoxide dismutase mimetic with catalase activity (EUK-8) reduces the organ injury in endotoxic shock.

Reactive oxygen species contribute to the multiple organ failure in endotoxic shock. Here, we investigate the effects of a salen-manganese complex, which exhibits both superoxide dismutase and catalase activity (EUK-8), on the circulatory failure, renal and liver injury and dysfunction caused by endotoxin in the anaesthetised rat. Endotoxaemia (6 mg/kg i.v., Escherichia coli lipopolysaccharide) for 6 h caused hypotension, renal dysfunction and liver injury. Treatment of rats with EUK-8 (0.3 or 1 mg/kg bolus injection followed by an infusion of 0.3 or 1 mg/kg/h) attenuated the renal and liver injury and dysfunction in a dose-related fashion. In addition, the higher dose of EUK-8 attenuated the delayed hypotension caused by endotoxin in the rat. Thus, an enhanced formation of reactive oxygen species importantly contributes to the circulatory failure, as well as the organ injury and dysfunction associated with endotoxic shock. We propose that small molecules, which have the catalytic activity of both superoxide dismutase and catalase, may represent a novel therapeutic approach for the therapy of endotoxic shock.

Animals↗