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Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation of the gastrointestinal (GI) tract, and it is associated with different neurological disorders. Recent evidence has demonstrated that the gut-brain-axis has a central function in the perpetuation of IBS, and for this reason, it can be considered a possible therapeutic target. N-Palmitoylethanolamine-oxazoline (PEA-OXA) possesses anti-inflammatory and potent neuroprotective effects. Although recent studies have explained the neuroprotective properties of PEA-OXA, nothing is known about its effects on the gut-brain axis during colitis. The aim of this study is to explore the mechanism and the effect of PEA-OXA on the gut-brain axis in rats subjected to experimental colitis induced by oral administration of dextran sulfate sodium (DSS). Daily oral administration of PEA-OXA (10 mg/kg daily o.s.) was able to decrease the body weight loss, macroscopic damage, colon length, histological alteration, and inflammation after DSS induction. Additionally, PEA-OXA administration enhanced neurotrophic growth factor release and decreased the astroglial and microglial activation induced by DSS. Moreover, PEA-OXA restored intestinal permeability and tight junctions (TJs) as well as reduced apoptosis in the colon and brain. In our work, we demonstrated, for the first time, the action of PEA-OXA on the gut-brain axis in a model of DSS-induced colitis and its implication on the “secondary” effects associated with colonic disturbance.

Aim: Recent studies revealed that pharmacological modulation of NAE-hydrolyzing acid amidase (NAAA) can be achieved with PEA oxazoline (PEA-OXA). Hence, the aim of the present work was to thoroughly evaluate the anti-inflammatory and neuroprotective effects of PEA-OXA in an experimental model of vascular dementia (VaD) induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, animals were orally administered with 10 mg/kg of PEA-OXA daily for 15 days. Results: Brain tissues were handled for histological, immunohistochemical, western blot, and immunofluorescence analysis. PEA-OXA treatment evidently reduced the histological alterations and neuronal death induced by VaD and additionally improved behavioral deficits. Further, PEA-OXA decreased GFAP and Iba-1, markers of astrocytes, and microglia activation, as well as increased MAP-2, a marker of neuron development. Moreover, PEA-OXA reduced oxidative stress, modulated Nrf2-mediated antioxidant response, and inhibited the apoptotic process. Innovation: Some drugs may demonstrate their healing potential by regulating neuroinflammation, rather than by their habitually attributed actions only. Palmitoylethanolamide (PEA) is a prototype ALIAmide, well-known for its analgesic, anti-inflammatory, and neuroprotective properties. The inhibition of PEA degradation by targeting NAAA, its catabolic enzyme, is a different approach for treating neuroinflammation. This research offers new insight into the mechanism of PEA-OXA-induced neuroprotection. Conclusion: Thus, the modulation of intracellular NAAA by PEA-OXA could offer a novel means of controlling neuroinflammatory conditions associated with VaD.

Hypertension is one of the major risk factor able to promote development and progression of several cardiovascular diseases, including left ventricular hypertrophy and dysfunction, myocardial infarction, stroke, and congestive heart failure. Also, it is one of the major driven of high cardiovascular risk profile in patients with metabolic complications, including obesity, metabolic syndrome and diabetes, as well as in those with renal disease. Thus, effective control of hypertension is a key factor for any preventing strategy aimed at reducing the burden of hypertension-related cardiovascular diseases in the clinical practice. Among various regulatory and contra-regulatory systems involved in the pathogenesis of cardiovascular and renal diseases, renin-angiotensin system (RAS) plays a major role. However, despite the identification of renin and the availability of various assays for measuring its plasma activity, the specific pathophysiological role of RAS has not yet fully characterized. In the last years, however, several notions on the RAS have been improved by the results of large, randomized clinical trials, performed in different clinical settings and in different populations treated with RAS inhibiting drugs, including angiotensin converting enzyme (ACE) inhibitors and antagonists of the AT1 receptor for angiotensin II (ARBs). These findings suggest that the RAS should be considered to have a central role in the pathogenesis of different cardiovascular diseases, for both therapeutic and preventive purposes, without having to measure its level of activation in each patient. The present document will discuss the most critical issues of the pathogenesis of different cardiovascular diseases with a specific focus on RAS blocking agents, including ACE inhibitors and ARBs, in the light of the most recent evidence supporting the use of these drugs in the clinical management of hypertension and hypertension-related cardiovascular diseases.

Brain nitric oxide is involved in the mechanisms that regulate ingestive behavior. To test whether this compound plays a role in alcohol preference, we studied the effects of different doses of NG-nitro-L-arginine (L-NO arg), an inhibitor of nitric oxide synthase (NOS), on voluntary consumption of ethanol and on blood alcohol levels produced by a single intraperitoneal dose of alcohol in the rat. L-NO arg produced a significant and dose-dependent reduction of ethanol intake (P < 0.001) without influencing total fluid consumption or feeding behavior. L-NO arg did not influence the kinetics of alcohol. Our data show that inhibition of nitric oxide formation accompanies reduction of ethanol intake and suggest a possible role for nitric oxide in ethanol self-administration

Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This paper introduces the emerging role of exogenous molecules in hormetic-based neuroprotection and the mitochondrial redox signaling concept of hormesis and its applications to the field of neuroprotection and longevity. Maintenance of optimal long-term health conditions is accomplished by a complex network of longevity assurance processes that are controlled by vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-carnitine, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. Hormesis provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose response relationships, their mechanistic foundations, their relationship to the concept of biological plasticity as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways including sirtuin, Nrfs and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases.

Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by co-ordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as carnosine, carnitines or polyphenols, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. In this review we discuss the most current and up to date understa

VGX-1027 is a novel, low molecular weight, immunomodulatory compound that has shown efficacy against a variety of immuno-inflammatory disease models in animals including autoimmune diabetes in NOD mice, collagen-induced arthritis and chemically induced inflammatory colitis. Here, we have studied the effects of VGX-1027 on the development of endotoxin-induced uveitis (EIU) in male Lewis rats, as a model of inflammatory ocular diseases in humans.

BACKGROUND AND PURPOSE: VGX-1027 is a novel, low molecular weight, immunomodulatory compound that has shown efficacy against a variety of immuno-inflammatory disease models in animals including autoimmune diabetes in NOD mice, collagen-induced arthritis and chemically induced inflammatory colitis. Here, we have studied the effects of VGX-1027 on the development of endotoxin-induced uveitis (EIU) in male Lewis rats, as a model of inflammatory ocular diseases in humans. EXPERIMENTAL APPROACH: EIU was induced by a single footpad injection of 200 microg lipopolysaccharide (LPS). Groups of rats were treated with either VGX-1027 (25 mg kg(-1)) or its vehicle at different time points (30 min, 6 h or 12 h) after the challenge with LPS or, as positive control, with dexamethasone. The rats were killed within 16 h after LPS challenge, and the eyes and aqueous humor were collected to study serological, immunological and histological signs of EIU. KEY RESULTS: The rats treated with VGX-1027 within 6 h after LPS challenge exhibited milder clinical, histological and laboratory signs of EIU than those treated with vehicle. CONCLUSION AND IMPLICATIONS: This study provides the first evidence that systemic treatment with VGX-1027 counteracts the uveitis-inducing effect of LPS in rats and suggests that this drug may have potential in the treatment of immuno-inflammatory conditions of the eye in humans Udgivelsesdato: 2008/11

VGX-1027 is a novel, low molecular weight, immunomodulatory compound that has shown efficacy against a variety of immuno-inflammatory disease models in animals including autoimmune diabetes in NOD mice, collagen-induced arthritis and chemically induced inflammatory colitis. Here, we have studied the effects of VGX-1027 on the development of endotoxin-induced uveitis (EIU) in male Lewis rats, as a model of inflammatory ocular diseases in humans.

Poly(ADP-ribose) polymerase (PARP)-1, which plays a key role in DNA repair, inflammation and transcription, has recently been shown to be involved in angiogenesis. The aim of this study was to investigate PARP-1 role in melanoma aggressiveness and chemoresistance in vivo using clones stably silenced for PARP-1 expression. Whilst the growth characteristics of PARP-1-deficient melanoma cells were comparable to those of PARP-1-proficient cells in vitro, their tumourigenic potential in vivo was significantly compromised. In fact, mice challenged intra-muscle with PARP-1-deficient cells showed a delayed development of measurable tumour nodules, which were also significantly reduced in size with respect to those of mice inoculated with PARP-1-proficient cells. Moreover, animals challenged intra-cranially with PARP-1-deficient cells, a model that mimics CNS localisation of melanoma, showed an increased survival. Immunohistochemical analyses of PARP-1-depleted melanoma grafts indicated a reduced expression of the angiogenesis marker PECAM-1/CD31 and of the pro-inflammatory mediators TNF-alpha and GITR. Notably, PARP-1-silenced melanoma was extremely sensitive to temozolomide, an anticancer agent used for the treatment of metastatic melanoma. These results provide novel evidence for a direct role of PARP-1 in tumour aggressiveness and chemoresistance.

BACKGROUND AND PURPOSE: VGX-1027 is a novel, low molecular weight, immunomodulatory compound that has shown efficacy against a variety of immuno-inflammatory disease models in animals including autoimmune diabetes in NOD mice, collagen-induced arthritis and chemically induced inflammatory colitis. Here, we have studied the effects of VGX-1027 on the development of endotoxin-induced uveitis (EIU) in male Lewis rats, as a model of inflammatory ocular diseases in humans. EXPERIMENTAL APPROACH: EIU was induced by a single footpad injection of 200 microg lipopolysaccharide (LPS). Groups of rats were treated with either VGX-1027 (25 mg kg(-1)) or its vehicle at different time points (30 min, 6 h or 12 h) after the challenge with LPS or, as positive control, with dexamethasone. The rats were killed within 16 h after LPS challenge, and the eyes and aqueous humor were collected to study serological, immunological and histological signs of EIU. KEY RESULTS: The rats treated with VGX-1027 within 6 h after LPS challenge exhibited milder clinical, histological and laboratory signs of EIU than those treated with vehicle. CONCLUSION AND IMPLICATIONS: This study provides the first evidence that systemic treatment with VGX-1027 counteracts the uveitis-inducing effect of LPS in rats and suggests that this drug may have potential in the treatment of immuno-inflammatory conditions of the eye in humans Udgivelsesdato: 2008/11

Udgivelsesdato: 2007

Udgivelsesdato: 2007

Item does not contain fulltext, In the present study, by comparing the responses in wild-type mice (iNOSWT) and mice lacking (iNOSKO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the correlation between endogenous nitric oxide (NO) and prostaglandin (PG) generation in carrageenan-induced pleurisy. The inflammatory response in iNOSKO mice was significantly reduced in respect to iNOSWT animals, as demonstrated by the exudate volume (-63%) and numbers of infiltrating cells (-62%). The levels of NOx in the pleural exudate from carrageenan-treated mice were significantly (p < 0.01) decreased in iNOSKO mice (16 +/- 7.6 nmoles/mice) compared to iNOSWT animals (133 +/- 9 nmoles/mice). Similarly, the amounts of PGE2 in the pleural exudates of carrageenan-treated animals were significantly (p < 0.01) lower in iNOSKO compared to iNOSWT mice (120 +/- 20 pg/mice vs. 308 +/- 51 pg/mice). Also the amounts of 6-keto-PGF(1 alpha) produced by lungs from carrageenan-treated iNOSKO mice (1.01 +/- 0.10 ng/tissue mg) were significantly (p < 0.01) reduced compared to iNOSWT carrageenan-treated mice (2.1 +/- 0.09 ng/tissue mg). In conclusion our results confirm, by the use of iNOSKO mice that in carrageenan-induced pleurisy NO positively modulates PG biosynthesis.

Item does not contain fulltext, Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement C3 were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-alpha, interleukin-1alpha, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-kappaB ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage.

Item does not contain fulltext, Several clinical studies have shown that bone loss may be attributed to osteoclast recruitment induced by mediators of inflammation. In different experimental paradigms we have recently demonstrated that estrogen exhibits antiinflammatory activity by preventing the induction of inducible nitric oxide synthase (iNOS) and other components of the inflammatory reaction. To verify whether this could explain the estrogen-dependent blockade of osteoporosis, we investigated the effect of ovariectomy in mice in which iNOS activity had been blunted by genetic or pharmacological manipulation. The consequences of iNOS blockade were evaluated initially on bone formation and resorption by histomorphometric analysis. The proximal tibiae of mice with iNOS genotypes revealed that 32 d after ovariectomy bone volume and bone formation rate were significantly decreased, and osteoclast surface was increased. Conversely, in iNOS knockout (iNOSKO) and wild-type (WT) mice treated with a specific inhibitor of iNOS, N-iminoethyl-L-lysine, ovariectomy did not result in bone depletion. In WT mice, ovariectomy also affected bone formation, as shown by a decreased mineral apposition rate. Also in this case, iNOS inactivation prevented the effect of ovariectomy. Immunocytochemical analysis showed that after ovariectomy iNOS protein accumulates in chondrocytes, and a significant increase in nitrotyrosine and poly(ADP-ribose) synthetase staining was observed in the femur metaphyses. The increase in nitrotyrosine and poly(ADP-ribose) synthetase formation induced by ovariectomy was significantly reduced in sections from iNOSKO mice. These data indicate that in WT mice the observed induction of iNOS has functional relevance, because it leads to overproduction of nitric oxide and accumulation of highly reactive molecules, triggering a local inflammatory reaction. These inflammatory foci attract cytokines, well known actors in the mechanism of osteoclastogenesis. In iNOSKO mice the measurements of IL-1

Item does not contain fulltext, In the present study, by comparing the responses in wild-type mice (iNOSWT) and mice lacking (iNOSKO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the correlation between endogenous nitric oxide (NO) and prostaglandin (PG) generation in carrageenan-induced pleurisy. The inflammatory response in iNOSKO mice was significantly reduced in respect to iNOSWT animals, as demonstrated by the exudate volume (-63%) and numbers of infiltrating cells (-62%). The levels of NOx in the pleural exudate from carrageenan-treated mice were significantly (p < 0.01) decreased in iNOSKO mice (16 +/- 7.6 nmoles/mice) compared to iNOSWT animals (133 +/- 9 nmoles/mice). Similarly, the amounts of PGE2 in the pleural exudates of carrageenan-treated animals were significantly (p < 0.01) lower in iNOSKO compared to iNOSWT mice (120 +/- 20 pg/mice vs. 308 +/- 51 pg/mice). Also the amounts of 6-keto-PGF(1 alpha) produced by lungs from carrageenan-treated iNOSKO mice (1.01 +/- 0.10 ng/tissue mg) were significantly (p < 0.01) reduced compared to iNOSWT carrageenan-treated mice (2.1 +/- 0.09 ng/tissue mg). In conclusion our results confirm, by the use of iNOSKO mice that in carrageenan-induced pleurisy NO positively modulates PG biosynthesis.

Item does not contain fulltext, Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement C3 were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-alpha, interleukin-1alpha, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-kappaB ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage.

Item does not contain fulltext, Several clinical studies have shown that bone loss may be attributed to osteoclast recruitment induced by mediators of inflammation. In different experimental paradigms we have recently demonstrated that estrogen exhibits antiinflammatory activity by preventing the induction of inducible nitric oxide synthase (iNOS) and other components of the inflammatory reaction. To verify whether this could explain the estrogen-dependent blockade of osteoporosis, we investigated the effect of ovariectomy in mice in which iNOS activity had been blunted by genetic or pharmacological manipulation. The consequences of iNOS blockade were evaluated initially on bone formation and resorption by histomorphometric analysis. The proximal tibiae of mice with iNOS genotypes revealed that 32 d after ovariectomy bone volume and bone formation rate were significantly decreased, and osteoclast surface was increased. Conversely, in iNOS knockout (iNOSKO) and wild-type (WT) mice treated with a specific inhibitor of iNOS, N-iminoethyl-L-lysine, ovariectomy did not result in bone depletion. In WT mice, ovariectomy also affected bone formation, as shown by a decreased mineral apposition rate. Also in this case, iNOS inactivation prevented the effect of ovariectomy. Immunocytochemical analysis showed that after ovariectomy iNOS protein accumulates in chondrocytes, and a significant increase in nitrotyrosine and poly(ADP-ribose) synthetase staining was observed in the femur metaphyses. The increase in nitrotyrosine and poly(ADP-ribose) synthetase formation induced by ovariectomy was significantly reduced in sections from iNOSKO mice. These data indicate that in WT mice the observed induction of iNOS has functional relevance, because it leads to overproduction of nitric oxide and accumulation of highly reactive molecules, triggering a local inflammatory reaction. These inflammatory foci attract cytokines, well known actors in the mechanism of osteoclastogenesis. In iNOSKO mice the measurements of IL-1

Item does not contain fulltext, Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement C3 were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-alpha, interleukin-1alpha, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-kappaB ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage.

Item does not contain fulltext

Item does not contain fulltext, The aim of this study was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) and NO on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. A severe model of mesenteric ischemia and reperfusion was produced by subjecting mice to 45 min occlusion followed by reperfusion of the superior mesenteric artery and celiac trunk. In this experimental protocol, wild-type mice treated with GW274150 (5 mg/kg i.p.), a novel, potent, and selective inhibitor of iNOS activity, and mice lacking of the gene for iNOS (iNOS 'knock-out', iNOS-KO) exhibited no difference in the rate of mortality in comparison with wild-type control mice. In a second study, using a less severe model of mesenteric injury obtained by occlusion of the superior mesenteric artery only for 45 min, we evaluated the survival rate. Under these conditions, wild-type mice treated with GW274150 and iNOS-KO mice showed a significant difference in the rate of mortality in comparison with wild-type. Therefore, wild-type mice treated with GW274150 and iNOS-KO mice when compared with wild-type littermates showed a significant reduction of the mesenteric injury, upregulation of P-selectin and intercellular adhesion molecule-1, and neutrophil infiltration, as well as a significant inhibition of the degree of oxidative and nitrosative damage, indicated by malondialdehyde levels, formation of nitrotyrosine and poly(ADP-ribose)polymerase (PARP), respectively. Plasma levels of the proinflammatory cytokines tumour necrosis factor-alpha, interleukin (IL) 6, and IL-1beta were also significantly reduced in iNOS-KO mice in comparison with control wild-type mice. Wild-type mice treated with GW274150 and iNOS-KO mice were also found to have reduced activation of the transcriptional factor nuclear factor-kappaB in the ileum. These results suggest that the induction of iNOS and NO production are essential for the upregulation of the inflammatory response in splanchnic ischemia/rep

Item does not contain fulltext

Item does not contain fulltext, The aim of this study was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) and NO on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. A severe model of mesenteric ischemia and reperfusion was produced by subjecting mice to 45 min occlusion followed by reperfusion of the superior mesenteric artery and celiac trunk. In this experimental protocol, wild-type mice treated with GW274150 (5 mg/kg i.p.), a novel, potent, and selective inhibitor of iNOS activity, and mice lacking of the gene for iNOS (iNOS 'knock-out', iNOS-KO) exhibited no difference in the rate of mortality in comparison with wild-type control mice. In a second study, using a less severe model of mesenteric injury obtained by occlusion of the superior mesenteric artery only for 45 min, we evaluated the survival rate. Under these conditions, wild-type mice treated with GW274150 and iNOS-KO mice showed a significant difference in the rate of mortality in comparison with wild-type. Therefore, wild-type mice treated with GW274150 and iNOS-KO mice when compared with wild-type littermates showed a significant reduction of the mesenteric injury, upregulation of P-selectin and intercellular adhesion molecule-1, and neutrophil infiltration, as well as a significant inhibition of the degree of oxidative and nitrosative damage, indicated by malondialdehyde levels, formation of nitrotyrosine and poly(ADP-ribose)polymerase (PARP), respectively. Plasma levels of the proinflammatory cytokines tumour necrosis factor-alpha, interleukin (IL) 6, and IL-1beta were also significantly reduced in iNOS-KO mice in comparison with control wild-type mice. Wild-type mice treated with GW274150 and iNOS-KO mice were also found to have reduced activation of the transcriptional factor nuclear factor-kappaB in the ileum. These results suggest that the induction of iNOS and NO production are essential for the upregulation of the inflammatory response in splanchnic ischemia/rep

Item does not contain fulltext

Item does not contain fulltext, In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenan-treated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated iNOS-WT mice. Lung tissue sections from carrageenan-treated iNOS-WT mice showed positive staining for poly adenosine diphosphate (ADP)-ribose synthetase that was mainly localized in alveolar macrophages and in airway epithelial cells. The intensity and degree of staining for nitrotyrosine and poly-ADP-ribose synthetase were markedly reduced in tissue sections from carrageenan-treated iNOS-KO mice. The inflamed lungs of iNOS-KO mice also showed an improved histologic status. Furthermore, a significant reduction in the suppression of energy status, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD(+)) was observed ex vivo in macrophages harvested from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an important role in the acute inflammatory response.

Item does not contain fulltext, In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenan-treated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated iNOS-WT mice. Lung tissue sections from carrageenan-treated iNOS-WT mice showed positive staining for poly adenosine diphosphate (ADP)-ribose synthetase that was mainly localized in alveolar macrophages and in airway epithelial cells. The intensity and degree of staining for nitrotyrosine and poly-ADP-ribose synthetase were markedly reduced in tissue sections from carrageenan-treated iNOS-KO mice. The inflamed lungs of iNOS-KO mice also showed an improved histologic status. Furthermore, a significant reduction in the suppression of energy status, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD(+)) was observed ex vivo in macrophages harvested from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an important role in the acute inflammatory response.

Item does not contain fulltext, In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenan-treated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated iNOS-WT mice. Lung tissue sections from carrageenan-treated iNOS-WT mice showed positive staining for poly adenosine diphosphate (ADP)-ribose synthetase that was mainly localized in alveolar macrophages and in airway epithelial cells. The intensity and degree of staining for nitrotyrosine and poly-ADP-ribose synthetase were markedly reduced in tissue sections from carrageenan-treated iNOS-KO mice. The inflamed lungs of iNOS-KO mice also showed an improved histologic status. Furthermore, a significant reduction in the suppression of energy status, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD(+)) was observed ex vivo in macrophages harvested from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an important role in the acute inflammatory response.