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

Inhibition of neurotoxic events that lead to delayed cellular damage may prevent motor function loss after transient spinal cord ischemia. An important effect of the neuroprotective substance aminoguanidine (AG) is the inhibition of inducible nitric oxide synthase (iNOS), a perpetrator of focal ischemic damage. The authors studied the protective effects of AG on hind limb motor function and histopathologic outcome in an experimental model for spinal cord ischemia, and related these findings to the protein content of iNOS in the spinal cord. Temporary spinal cord ischemia was induced by 28 minutes of infrarenal balloon occlusion of the aorta in 40 anesthetized New Zealand White rabbits. Animals were assigned randomly to two treatments: saline (n = 20) or AG (n = 20; 100 mg/kg intravenously before occlusion). Postoperatively, treatment was continued with subcutaneous injections twice daily (saline or 100 mg/kg AG). Normothermia (38 degrees C) was maintained during ischemia, and rectal temperature was assessed before and after subcutaneous injections. Animals were observed for 96 hours for neurologic evaluation (Tarlov score), and the lumbosacral spinal cord was examined for ischemic damage after perfusion and fixation. Lastly, iNOS protein content was determined using Western blot analysis 48 hours after ischemia in five animals from each group. Neurologic outcome at 96 hours after reperfusion was the same in both groups. The incidence of paraplegia was 67% in the saline-treated group versus 53% in the AG-treated group. No differences in infarction volume, total number of viable motoneurons, or total number of eosinophilic neurons were present between the groups. At 48 hours after reperfusion, iNOS protein content in the spinal cord was increased in one animal in the AG-treated group and in three animals in the control group. The data indicate that peri-ischemic treatment with high-dose AG in rabbits offers no protection against a period of normothermic spinal cord ischemia. There was no conclusive evidence of spinal cord iNOS inhibition after treatment with AG.
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PMID:Peri-ischemic aminoguanidine fails to ameliorate neurologic and histopathologic outcome after transient spinal cord ischemia. 1177 21

Changes in the nitric oxide (NO) system of the rat cerebral cortex were investigated by immunohistochemistry, immunoblotting, NO synthase (NOS) activity assay, and magnetic resonance imaging (MRI) in an experimental model of global cerebral ischemia and reperfusion. Brains were perfused transcardially with an oxygenated plasma substitute and subjected to 30 minutes of oxygen and glucose deprivation, followed by reperfusion for up to 12 hours with oxygenated medium containing glucose. A sham group was perfused without oxygen or glucose deprivation, and a further group was treated with the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) before and during perfusion. Global ischemia led to cerebrocortical injury as shown by diffusion MRI. This was accompanied by increasing morphologic changes in the large type I interneurons expressing neuronal NOS (nNOS) and the appearance of nNOS immunoreactivity in small type II neurons. The nNOS-immunoreactive band and calcium-dependent NOS activity showed an initial increase, followed by a fall after 6 hours of reperfusion. Inducible NOS immunoreactivity appeared in neurons, especially pyramidal cells of layers IV-V, after 4 hours of reperfusion, with corresponding changes on immunoblotting and in calcium-independent NOS activity. Immunoreactive protein nitrotyrosine, present in the nuclear area of neurons in nonperfused controls and sham-perfused animals, showed changes in intensity and distribution, appearing in the neuronal processes during the reperfusion period. Prior and concurrent L-NAME administration blocked the changes on diffusion MRI and attenuated the morphologic changes, suggesting that NO and consequent peroxynitrite formation during ischemia-reperfusion contributes to cerebral injury.
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PMID:Effects of oxygen and glucose deprivation on the expression and distribution of neuronal and inducible nitric oxide synthases and on protein nitration in rat cerebral cortex. 1179 55

Basic fibroblast growth factor (bFGF) is an important angiogenic factor produced by hearts subjected to ischemia. However, the direct effects of bFGF on myocardial cells are unknown. Primary cultured cardiac myocytes from neonatal rats were stimulated with lipopolysaccharide (LPS), a potent inducer of inducible nitric oxide synthase (iNOS), in the presence or the absence of bFGF. LPS induced the expression of iNOS in cardiac myocytes, demonstrated at both mRNA and protein levels. We showed that LPS activated the apoptotic pathway, evidenced by TUNEL staining, DNA ladder formation, and morphologic features. LPS-induced apoptosis was blocked by the administration of L-NAME, an inhibitor of NOS. This indicates that LPS induces apoptosis via an iNOS-dependent pathway. Administration of bFGF completely inhibited myocardial cell apoptosis induced by hydrogen peroxide or acidic medium as well as LPS. To determine signaling pathways for this inhibitory effect, we utilized PD098059, an MEK-1-specific inhibitor. PD098059 blocked bFGF-induced activation of ERK (extracellularly responsive kinase)-1/2 and neutralized the apoptotic inhibitory effect of bFGF. These findings demonstrate that LPS induces myocardial cell apoptosis in an iNOS-dependent manner. The results also suggest that bFGF is a protective factor against myocardial cell apoptosis and that this protection requires the MEK-1-ERK pathway.
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PMID:Basic fibroblast growth factor protects cardiac myocytes from iNOS-mediated apoptosis. 1180 11

Recent evidence has shown that the cardioprotection afforded by the late phase of ischemic preconditioning (PC) is mediated by upregulation of inducible nitric oxide synthase (iNOS). However, the specific cardiac cell type(s) that express(es) iNOS in response to ischemic PC remains unknown. Thus, mice underwent a sequence of six cycles of 4-min coronary occlusion/4-min reperfusion, which induces late PC, and tissue samples were collected at serial times for measurement of mRNA (Northern) and protein levels (Western). In addition, whole heart samples were cryosectioned for in situ hybridization and immunohistochemistry. The steady-state levels of iNOS mRNA in the ischemic regions started to increase at 1 h after ischemic PC, peaked at 3 h (201+/-31% of sham, n=5 P<0.01) and remained elevated at 24 h (177+/-22% of sham, n=5 P<0.01). In accordance with these data, iNOS protein expression was increased at 24 h (219+/-41% of sham, n=5 P<0.01). In contrast, neither endothelial nitric oxide synthase (eNOS) mRNA levels nor its protein expression changed at any time-point. The magnitude of iNOS upregulation after ischemic PC was mild compared with that noted 66 h after permanent coronary occlusion (360+/-53% of sham) or 8 h after endotoxin (3117+/-61% of control). After ischemic PC, diffuse iNOS signals were detected with in situ hybridization and immunohistochemistry in the cytoplasmic space of cardiac myocytes and, to a lesser degree, in the wall of large vessels, but were absent in smooth muscle and endothelium of small vessels and in fibroblasts. This pattern contrasted with that observed in mouse hearts subjected to permanent coronary occlusion where strong iNOS signals were concentrated in inflammatory cells but absent in cardiac myocytes. Thus, not only the degree of iNOS expression but also its cellular distribution were profoundly different in reversibly injured (preconditioned) v infarcted myocardium. We conclude that iNOS is rapidly upregulated after ischemic PC and that cardiac myocytes are the main source of ischemic PC-induced iNOS expression. This study demonstrates, for the first time, a differential pattern of iNOS expression in sublethal (PC) v lethal ischemia, which may have important implication for the role of iNOS in these two settings.
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PMID:Ischemic preconditioning upregulates inducible nitric oxide synthase in cardiac myocyte. 1181 60

This overview provides information on the pathophysiology of the inducible nitric oxide synthase/nitric oxide (iNOS/NO) system in the injury to cultured renal tubular epithelia, freshly isolated proximal tubules, and the whole organ after hypoxic or ischemic insult. The findings emphasize the role of concomitant oxidative and nitrosative stress and the role of peroxynitrite in the ensuing renal dysfunction. Scavenging peroxynitrite using seleno-organic compounds like ebselen provides renoprotection against ischemic injury. These sequelae of renal ischemia are a result of endothelial dysfunction, which is most probably responsible for the "no-reflow" phenomenon and further aggravation of tubular ischemia during the early reperfusion period. Recent studies have demonstrated that transplantation of functional endothelial cells into ischemic kidney provided a dramatic renoprotective effect. In conclusion, the intricate relations between endothelial and epithelial cells, based in part on the relations between endothelial and inducible nitric oxide synthases, are perturbed in renal ischemia primarily as a result of endothelial dysfunction precipitating epithelial injury.
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PMID:Nitric oxide in acute renal failure: NOS versus NOS. 1184 38

Protein arginine N-methyltransferases (PRMTs) catalyse the methylation of guanidinonitrogen(s) of arginine to produce NG-monomethyl-L-arginine (L-NMMA), asymmetric NG,NG-dimethyl-L-arginine (ADMA) and symmetric NG,NG-dimethyl-L-arginine (SDMA), which are subsequently released into the cytoplasm following proteolysis. Free intracellular L-NMMA and ADMA, but not SDMA, are inhibitors of all three isoforms of nitric oxide synthases (nNOS, eNOS and iNOS). L-NMMA and ADMA, but not SDMA, are actively metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and methylamine (and dimethylamine). Free methylarginines are detectable in cell cytosol, plasma and tissues. Elevated ADMA has been detected in the plasma of patients or experimental animals with hypercholesterolemia, renal failure, atherosclerosis, hypertension, thrombotic microangiopathy, peripheral arterial occlusive disease and in the regenerated endothelial cells after angioplasty. Moreover, in the non-cardiovascular field, ADMA was increased in the urethral tissue following ischemia and in the plasma of patients with schizophrenia and multiple sclerosis. Altered biosynthesis of NO has been implicated in the pathogenesis of these diseases, and it is possible to consider that the accumulation of endogenous L-NMMA and ADMA underlies the impaired NO generation and increased O2- production. We described herein the biosynthesis, transmembrane transport, metabolic pathway and possible pathophysiological roles of endogenous methylarginines.
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PMID:[Biological and pathophysiological roles of endogenous methylarginines as inhibitors of nitric oxide synthase]. 1186 54

OBJECTIVE: To investigate the modulation of nitric oxide synthase (NOS) isoenzymes in skeletal muscle during 3 h ischemia/reperfusion (I/R, 3 h ischemia followed by 3 h reperfusion). METHODS: The extensor digitorum longuses (EDLs) from 20 adult rats were divided into 4 groups: the normal, the sham operation, the ischemia (3 h), and the ischemia/reperfusion group. One normal EDL from each rat was used as the non-operated control, and the opposite ones are distributed into the 3 remaining groups. All the samples were studied with Western blotting technique and immunohistochemistry staining. RESULTS: Three sizes of protein bands verified with the proteins of relative molecule to be of 155000, 140000 and 135000, were detected in the EDL homogenate by Western blotting, which were comparable with the positive controls for nNOS, eNOS and iNOS, respectively. Immunostaining demonstrated that nNOS was present in the muscle fiber, with a similar location of the muscle stria, eNOS was found apparently in microvascular endothelia, but not found in muscle fibers, and iNOS was found in the leukocytes around the muscle fiber and some endothelia cells. Immunostaining paralleled the Western blotting results. CONCLUSIONS: It suggests that the constitutive nNOS and eNOS protein can be regulated by I/R, and I/R results in a down regulation of nNOS and up-regulation of eNOS and iNOS in reperfused skeletal muscle. The fact that nNOS is present around stria suggests that nNOS may have a close relationship with muscle function. The localization of eNOS in endothelial cell indicates its role in regulating blood supply of the muscle. Based on these findings, it is possible that NO produced by distinct NOS may play a different role in I/R injury.
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PMID:Modulation of nitric oxide synthase isoenzymes in reperfused skeletal muscle. 1187 45

Despite extensive research, the exact mechanisms of cyclosporine A (CsA)-induced hypertension and nephrotoxicity remain obscure. Several lines of evidence suggest an involvement of the renin-angiotensin system (RAS) in CsA toxicity, but the issue is still controversial in more ways than one. Some interesting data of the interaction of CsA and RAS have been presented by us and others during the last years. In rats, activation of RAS by CsA is a consistent finding while the results from clinical studies show controversial results. The mechanisms of activation of RAS may be multifactorial. CsA increases renin release directly from juxtaglomerular cells. However, RAS activation may at least partly account for glomerular ischemia by vasoconstriction. A totally different view about the interaction of CsA and RAS has recently been presented. CsA antagonised the harmful effects of RAS over-expression on renal damage in double transgenic rats harbouring human renin and angiotensinogen genes. The protection was due to anti-inflammatory properties of CsA by inhibition of interleukin-6 and inducible nitric oxide synthase (iNOS) expression. Other studies have confirmed the inhibitory effect of CsA on iNOS. Calcium antagonists have been proposed to be the antihypertensive drugs of choice in treatment of CsA-induced hypertension because of their favourable haemodynamic effects on the kidneys. However, because angiotensin II plays a major role in the development of CsA-induced structural renal damage, pharmacological inhibition of RAS in CsA-treatment may have some beneficial effects beyond blood pressure control.
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PMID:Interaction of cyclosporine A and the renin-angiotensin system; new perspectives. 1187 76

We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) protects intestinal epithelial cells (IEC) from necrosis and apoptosis in vitro and from intestinal ischemia/reperfusion injury in vivo; however, the mechanisms of HB-EGF cytoprotection are unclear. Overproduction of iNOS and NO have been implicated in the pathogenesis of several forms of ischemia/reperfusion injury. We therefore studied whether HB-EGF could down-regulate proinflammatory cytokine-induced iNOS and NO production in intestinal epithelial cells in vitro. DLD-1 human intestinal epithelial cells were exposed to the proinflammatory cytokines interleukin-1beta (IL-1beta) (20 ng/ml) and interferon-gamma (IFN-gamma) (10 ng/ml) to stimulate iNOS induction and NO production. Cells were treated with HB-EGF (0-100 ng/ml) either before or with cytokine exposure, and cells and supernatants were harvested 24 and 48 h later. Accumulated NO was measured in supernatants by chemiluminescence. Total RNA was extracted from cell lysates for iNOS mRNA quantification using real-time reverse transcription-polymerase chain reaction (RT-PCR), and total protein was extracted from cell lysates for detection of iNOS protein. HB-EGF significantly decreased cytokine-induced NO production in a dose dependent manner, and NO reduction was associated with iNOS suppression at both the mRNA and protein levels. While cytokine exposure resulted in a significant increase in iNOS mRNA expression in these cells (109 plus minus 9 fold), HB-EGF reduced iNOS expression by 5.7-fold (P < 0.05). These results suggest that HB-EGF may exert its cytoprotective effects, in part, by down-regulating iNOS and NO production, and provides further rationale for additional testing of the effects of HB-EGF in the treatment of intestinal ischemia/reperfusion injury in vivo.
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PMID:Heparin-binding EGF-like growth factor down regulates proinflammatory cytokine-induced nitric oxide and inducible nitric oxide synthase production in intestinal epithelial cells. 1189 Jul 38

We investigated the role of galectin-3 in metastasis of human breast carcinoma BT549 cells using the experimental liver metastasis model. Underlying mechanisms were then elucidated using the liver/tumor co-culture and cell culture systems. After intrasplenic injection, galectin-3 cDNA transfected BT549 cells (BT549(gal-3 wt)) formed metastatic colonies in the liver, while galectin-3 null BT549 cells (BT549(par)) did not, demonstrating that galectin-3 enhances metastatic potential. More than 90% of BT549(gal-3 wt) cells survived after 24 hours-co-culture with the liver fragments isolated following ischemia treatment. In contrast, more than half of BT549(par) cells showed metabolic death following co-culture with the liver fragments. When the liver from inducible nitric oxide synthase (iNOS) knockout mice was used, no cytotoxicity to BT549(par) cells was observed. Thus, iNOS exerts cytotoxicity on BT549(par) cells and galectin-3 can protect against iNOS-induced cytotoxicity. BT549(gal-3 wt) also exhibited enhanced survival against peroxynitrite (up to 400 micromol/L) in vitro. A single mutation in the NWGR motif of galectin-3 obliterated both metastatic capability and cell survival, indicating that the antiapoptotic function of galectin-3 is involved in enhanced metastasis. In conclusion, galectin-3 enhances the metastatic potential of BT549 cells through resistance to the products of iNOS, possibly through its bcl-2-like antiapoptotic function.
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PMID:Role of galectin-3 in breast cancer metastasis: involvement of nitric oxide. 1189 Dec 3


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