Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superoxide has been implicated in the regulation of endothelial cell adhesion molecule expression and the subsequent initiation of leukocyte-endothelial cell adhesion in different experimental models of inflammation. The objective of this study was to assess the contribution of oxygen radicals to P-selectin expression in a murine model of whole body ischemia-reperfusion, i.e., hemorrhage-resuscitation (H/R), with the use of different strategies that interfere with either the production (allopurinol, CD11/CD18-deficient or p47(phox)-/- mice) or accumulation [intravenous superoxide dismutase (SOD), mutant mice that overexpress SOD] of oxygen radicals. P-selectin expression was quantified in different regional vascular beds by use of the dual-radiolabeled monoclonal antibody technique. H/R elicited a significant increase in P-selectin expression in all vascular beds. This response was blunted in SOD transgenic mice and in wild-type mice receiving either intravenous SOD or the xanthine oxidase inhibitor allopurinol. Mice genetically deficient in either a subunit of NADPH oxidase or the leukocyte adhesion molecule CD11/CD18 also exhibited a reduced P-selectin expression. These results implicate superoxide, derived from both xanthine oxidase and NADPH oxidase, as mediators of the increased P-selectin expression observed in different regional vascular beds exposed to hemorrhage and retransfusion.
 ...
PMID:Role of superoxide in hemorrhagic shock-induced P-selectin expression. 1092 79

Statins have recently been shown to exert neuronal protection in ischemic stroke. Reactive oxygen species, specifically superoxide formed during the early phase of reperfusion, augment neuronal injury. NADPH oxidase is a key enzyme for superoxide production. The present study tested the hypothesis that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia. Transient focal ischemia was created in halothane-anesthetized adult male Sprague-Dawley rats (250-300 g) by middle cerebral artery occlusion (MCAO). Atorvastatin (Lipitor, 10 mg/kg sc) was administered three times before MCAO. Infarct volume was measured by triphenyltetrazolium chloride staining. NADPH oxidase enzymatic activity and superoxide levels were quantified in the ischemic core and penumbral regions by lucigenin (5 microM)-enhanced chemiluminescence. Expression of NADPH oxidase membrane subunit gp91(phox) and membrane-translocated subunit p47(phox) and small GTPase Rac-1 was analyzed by Western blot. NADPH oxidase activity and superoxide levels increased after reperfusion and peaked within 2 h of reperfusion in the penumbra, but not in the ischemic core, in MCAO rats. Atorvastatin pretreatment prevented these increases, blunted expression of membrane subunit gp91(phox), and prevented translocation of cytoplasmic subunit p47(phox) to the membrane in the penumbra 2 h after reperfusion. Consequently, cerebral infarct volume was significantly reduced in atorvastatin-treated compared with nontreated MCAO rats 24 h after reperfusion. These results indicate that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia.
 ...
PMID:Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. 1676 36

Abrupt reduction of flow (ischemia) leads to endothelial cell membrane depolarization, NADPH oxidase activation, and reactive oxygen species (ROS) generation in isolated rat and mouse lungs and in flow-adapted endothelial cells in vitro. Here we evaluated the role of PI-3-kinase and rac in activation of endothelial NADPH oxidase. Endothelium of isolated perfused mouse lungs labeled with 2',7'-dichlorodihydrofluorescein (H(2)DCF) or hydroethidine (HE) showed increased ROS generation with ischemia; these results were supported by TBARS measurement in whole-lung homogenate and by in vitro studies using flow-adapted mouse pulmonary microvascular endothelial cells. Ischemia-induced ROS generation in intact lung or isolated cells was blocked by pretreatment with Clostridium difficile toxin B, a rac inhibitor, and by wortmannin or LY294002, PI3 kinase inhibitors. In cells, immunofluorescence and immunoblot after subcellular fractionation showed ischemia-induced translocation of rac, p47(phox), and p67(phox) to the plasma membrane. Increased extracellular K(+) also resulted in rac translocation, providing evidence that this pathway is sensitive to alterations of endothelial cell membrane potential. These results indicate that PI-3-kinase and the small G protein rac are involved in the activation of endothelial cell NADPH oxidase that is associated with the acute loss of shear stress.
 ...
PMID:Rac and PI3 kinase mediate endothelial cell-reactive oxygen species generation during normoxic lung ischemia. 1816 54

Nitroalkene derivatives of linoleic acid (nitrolinoleic acid; LNO2) and nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties. The present study was undertaken to evaluate the therapeutic potential of OA-NO2 in a mouse model of renal ischemia-reperfusion (I/R) injury. B6129SF2/J mice were subjected to bilateral renal ischemia for 30 min, followed by 24 h of reperfusion. Fifty minutes after ischemia, mice received intraperitoneal (ip) injections of OA-NO2 (500 microg/kg; I/R OA-NO2), vehicle for OA-NO2 (i.e., 0.8 ml/kg ethanol; I/R veh), or oleic acid (500 microg/kg; I/R OA) every 6 h during the 24-h recovery period. A sham-operated group was not subjected to ischemia and received 0.8 ml/kg ethanol ip every 6 h during the 24-h recovery period (sham veh). While plasma urea and creatinine were elevated (P<0.05) in I/R veh vs. sham veh mice, the severity was less (P<0.05) in I/R OA-NO2 animals. Indices of histological damage, polymorphonucleocyte infiltration, together with expression of intracellular adhesion molecule-1, interleukin-1beta, and tumor necrosis factor-alpha, p47(phox), and gp91(phox) were greater in I/R veh vs. sham veh mice, but were attenuated (P<0.05) in I/R OA-NO2 animals. Because indices of renal dysfunction were similar between I/R veh and I/R OA mice (P>0.05), but less (P<0.05) in I/R OA-NO2 animals compared with both groups, protection from bilateral renal ischemia is afforded by the nitrated but not free form of oleic acid. Together, delayed administration of nitrated fatty acid OA-NO2 attenuates renal I/R injury in the mouse likely via inhibition of the inflammatory response.
 ...
PMID:Nitro-oleic acid protects the mouse kidney from ischemia and reperfusion injury. 1875

Reactive oxygen species (ROS) play a crucial role in ischemia-reperfusion (IR) injury after lung transplantation. We hypothesized that NADPH oxidase derived from bone marrow (BM) cells contributes importantly to lung IR injury. An in vivo mouse model of lung IR injury was employed. Wild-type C57BL/6 (WT) mice, p47(phox) knockout (p47(phox)-/-) mice, or chimeras created by BM transplantation between WT and p47(phox)-/- mice were assigned to either Sham (left thoracotomy) or six study groups that underwent IR (1 h left hilar occlusion and 2 h reperfusion). After reperfusion, pulmonary function was assessed using an isolated, buffer-perfused lung system. Lung injury was assessed by measuring vascular permeability (via Evans blue dye), edema, neutrophil infiltration (via myeloperoxidase [MPO]), lipid peroxidation (via malondialdyhyde [MDA]), and expression of proinflammatory cytokines. Lung IR resulted in significantly increased MDA in WT mice, indicative of oxidative stress. WT mice treated with apocynin (an NADPH oxidase inhibitor) and p47(phox)-/- mice displayed significantly reduced pulmonary dysfunction and injury (vascular permeability, edema, MPO, and MDA). In BM chimeras, significantly reduced pulmonary dysfunction and injury occurred after IR in p47(phox)-/--->WT chimeras (donor-->recipient) but not WT-->p47(phox)-/- chimeras. Induction of TNF-alpha, IL-17, IL-6, RANTES (CCL5), KC (CXCL1), MIP-2 (CXCL2), and MCP-1 (CCL2) was significantly reduced after IR in NADPH oxidase-deficient mice and p47(phox)-/--->WT chimeras but not WT-->p47(phox)-/- chimeras. These results indicate that NADPH oxidase-generated ROS specifically from BM-derived cells contributes importantly to lung IR injury. NADPH oxidase may represent a novel therapeutic target for the treatment of IR injury after lung transplantation.
 ...
PMID:NADPH oxidase in bone marrow-derived cells mediates pulmonary ischemia-reperfusion injury. 1878 74

The generation of reactive oxygen species (ROS) in the vasculature plays a major role in the genesis of endothelial cell (EC) activation and barrier function. Of the several potential sources of ROS in the vasculature, the endothelial NADPH oxidase family of proteins is a major contributor of ROS associated with lung inflammation, ischemia/reperfusion injury, sepsis, hyperoxia, and ventilator-associated lung injury. The NADPH oxidase in lung ECs has most of the components found in phagocytic oxidase, and recent studies show the expression of several homologues of Nox proteins in vascular cells. Activation of NADPH oxidase of nonphagocytic vascular cells is complex and involves assembly of the cytosolic (p47(phox), p67(phox), and Rac1) and membrane-associated components (Noxes and p22(phox)). Signaling pathways leading to NADPH oxidase activation are not completely defined; however, they do appear to involve the cytoskeleton and posttranslation modification of the components regulated by protein kinases, protein phosphatases, and phospholipases. Furthermore, several key components regulating NADPH oxidase recruitment, assembly, and activation are enriched in lipid microdomains to form a functional signaling platform. Future studies on temporal and spatial localization of Nox isoforms will provide new insights into the role of NADPH oxidase-derived ROS in the pathobiology of lung diseases.
 ...
PMID:Regulation of NADPH oxidase in vascular endothelium: the role of phospholipases, protein kinases, and cytoskeletal proteins. 1882 98

Reactive oxygen species (ROS) generation, particularly by the endothelial NADPH oxidase family of proteins, plays a major role in the pathophysiology associated with lung inflammation, ischemia/reperfusion injury, sepsis, hyperoxia, and ventilator-associated lung injury. We examined potential regulators of ROS production and discovered that hyperoxia treatment of human pulmonary artery endothelial cells induced recruitment of the vesicular regulator, dynamin 2, the non-receptor tyrosine kinase, c-Abl, and the NADPH oxidase subunit, p47(phox), to caveolin-enriched microdomains (CEMs). Silencing caveolin-1 (which blocks CEM formation) and/or c-Abl expression with small interference RNA inhibited hyperoxia-mediated tyrosine phosphorylation and association of dynamin 2 with p47(phox) and ROS production. In addition, treatment of human pulmonary artery endothelial cells with dynamin 2 small interfering RNA or the dynamin GTPase inhibitor, Dynasore, attenuated hyperoxia-mediated ROS production and p47(phox) recruitment to CEMs. Using purified recombinant proteins, we observed that c-Abl tyrosine-phosphorylated dynamin 2, and this phosphorylation increased p47(phox)/dynamin 2 association (change in the dissociation constant (K(d)) from 85.8 to 6.9 nm). Furthermore, exposure of mice to hyperoxia increased ROS production, c-Abl activation, dynamin 2 association with p47(phox), and pulmonary leak, events that were attenuated in the caveolin-1 knock-out mouse confirming a role for CEMs in ROS generation. These results suggest that hyperoxia induces c-Abl-mediated dynamin 2 phosphorylation required for recruitment of p47(phox) to CEMs and subsequent ROS production in lung endothelium.
 ...
PMID:Dynamin 2 and c-Abl are novel regulators of hyperoxia-mediated NADPH oxidase activation and reactive oxygen species production in caveolin-enriched microdomains of the endothelium. 1983 21

Reactive oxygen species are known to be derived from NADPH oxidase in several tissues. Angiotensin II was suggested to be involved in the activation of NADPH oxidase; however, its role in the gastric mucosa is unclear. We examined the roles of angiotensin II receptor and NADPH oxidase in ischemia/reperfusion-induced gastric damage in rats. Under urethane anesthesia, male Sprague-Dawley rat stomachs were mounted in an ex-vivo chamber, had 100 mM HCl applied to them, and then a catheter was passed through the femoral vein. Ischemia/reperfusion was accompanied by blood collection and reperfusion through the catheter. Losartan, candesartan, valsartan, which are AT1 receptor blockers (ARB); PD123319, an AT2 receptor blocker; enalapril, an ACE inhibitor; or diphenylene iodonium, a NADPH oxidase inhibitor, was given i.v. 10 mins, and beta-NADPH, a NADPH oxidase substrate, was given i.v. 5 mins before reperfusion. The gastric damage by ischemia/reperfusion was attenuated by treatment with any of ARB or enalapril, but was not affected by PD123319. The increase in gastric H(2)O(2) production and microvascular permeability by ischemia/reperfusion was also suppressed by treatment with any of ARB or enalapril. In rat gastric mucosa, the NADPH oxidase subunit p47(phox) was detected. Additionally, diphenylene iodonium had similar effects to ARB against ischemia/reperfusion-caused gastric damage, increased H(2)O(2) production, and microvascular permeability. Ischemia/reperfusion activated NADPH oxidase in the gastric mucosa, and the activation was significantly attenuated by treatment with losartan or diphenylene iodonium. These results suggest that ischemia/reperfusion generated reactive oxygen species are derived from NADPH oxidase activation via AT1 receptor in rat stomachs.
 ...
PMID:Evidence for the involvement of NADPH oxidase in ischemia/reperfusion-induced gastric damage via angiotensin II. 2043 17

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown that resveratrol provided neuroprotective effects against ischemia, seizure, and neurodegenerative disorders, the mechanisms underlying its beneficial effects on dopaminergic neurodegeneration are poorly defined. In this study, rat primary midbrain neuron-glia cultures were used to elucidate the molecular mechanisms underlying resveratrol-mediated neuroprotection. The results clearly demonstrated that resveratrol protected DA neurons against lipopolysaccharide (LPS)-induced neurotoxicity in concentration- and time-dependent manners through the inhibition of microglial activation and the subsequent reduction of proinflammatory factor release. Mechanistically, resveratrol-mediated neuroprotection was attributed to the inhibition of NADPH oxidase. This conclusion is supported by the following observations. First, resveratrol reduced NADPH oxidase-mediated generation of reactive oxygen species. Second, LPS-induced translocation of NADPH oxidase cytosolic subunit p47 to the cell membrane was significantly attenuated by resveratrol. Third and most importantly, resveratrol failed to exhibit neuroprotection in cultures from NADPH oxidase-deficient mice. Furthermore, this neuroprotection was also related to an attenuation of the activation of mitogen-activated protein kinases and nuclear factor-kappaB signaling pathways in microglia. These findings suggest that resveratrol exerts neuroprotection against LPS-induced dopaminergic neurodegeneration, and NADPH oxidase may be a major player in resveratrol-mediated neuroprotection.
 ...
PMID:Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. 2055 4

Our laboratory demonstrated that training program attenuated the inflammatory responses in lung ischemia/reperfusion (IR). Considering the importance of the inflammatory responses on the cardiovascular system, we evaluate the effect of physical training on the vascular responsiveness and its underlying mechanism after lung IR. Male Wistar rats were submitted to run training and lung IR. Concentration-response curves for relaxing and contracting agents were obtained. Protein expressions of SOD-1 and p47(phox), plasma nitritre/nitrate (NO (x) (-) ) and interleukin 6 (IL-6) were evaluated. A decreased in the potency for acetylcholine and phenylephrine associated with an upregulation of the p47(phox) expression were found after Lung IR as well as an increase in IL-6 and NO (x) (-) levels. Run training attenuated the vascular dysfunction that was accompanied by reduction of the p47(phox) protein expression and IL-6 levels. Our findings show the beneficial effect of training on the vascular function that was associated with reduction in inflammatory response in lung IR.
 ...
PMID:Beneficial effects of physical training on the cardio-inflammatory disorder induced by lung ischemia/reperfusion in rats. 2068 Apr 26


1 2 3 Next >>