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)

Ischemia and reperfusion stimulate several adenosine triphosphate (ATP)-dependent processes involving release of substances including free radicals. This cellular response is mediated through receptors responsive to transcriptional products of gene expression; c-fos acts as a transcriptional factor involved in the regulation of genes associated with cellular proliferation and differentiation. We hypothesized that nitrone free-radical spin traps promote restoration of cytosolic ATP during reperfusion and prevent c-fos induction. Four control rats had no ischemia. Global hepatic ischemia was induced in 19 rats in four groups: saline solution, phenyl-N-tert-butyl nitrone (PBN), alpha 1-pyridyl-N-oxide N-tert-butyl nitrone (POBN), and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). ATP and intracellular pH were measured at intervals before, during, and after ischemia. At 90 minutes of reperfusion, liver c-fos mRNA was measured. A fourfold elevation of c-fos occurred in the saline-treated group (p less than 0.001). PBN and POBN groups did not differ from the saline group. DMPO resulted in significantly less induction of c-fos than did NS. ATP depletion and recovery in all treatment groups was similar to that of the saline group. We conclude that (1) nitrone spin traps do not prevent c-fos induction or alter the pattern of ATP recovery after hepatic ischemia and reperfusion and (2) c-fos induction is not necessary for restoration of ATP, but the rate of ATP restoration is inversely related to c-fos induction.
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PMID:Induction of the protooncogene c-fos and recovery of cytosolic adenosine triphosphate in reperfused liver after transient warm ischemia: effect of nitrone free-radical spin-trap agents. 171 56

The transcriptional factor nuclear factor-kappaB (NFkappaB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes that might be involved in myocardial damage after ischemia and reperfusion. Therefore, we hypothesized that synthetic double-stranded DNA with high affinity for NFkappaB could be introduced in vivo as "decoy" cis elements to bind the transcriptional factor and to block the activation of genes mediating myocardial infarction, thus providing effective therapy for myocardial infarction. Treatment before and after infarction by transfection of NFkappaB decoy, but not scrambled decoy, oligodeoxynucleotides before coronary artery occlusion or immediately after reperfusion had a significant inhibitory effect on the area of infarction. Here, we report the first successful in vivo transfer of NFkappaB decoy oligodeoxynucleotides to reduce the extent of myocardial infarction following reperfusion, providing a new therapeutic strategy for myocardial infarction.
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PMID:In vivo transfection of cis element "decoy" against nuclear factor-kappaB binding site prevents myocardial infarction. 925 69

The cellular processes with a potential to lead to delayed death of neurons following transient (5 min) ischemia in gerbil hippocampus were evaluated. Neuronal apoptosis, visualized by the terminal transferase dUTP nick-end labelling (TUNEL) reaction, selectively appeared in the CA1 region of the pyramidal cell layer between the third and fourth days after the insult. Concomitantly, an enhanced immunoreactivity to anti-cJun/AP1 (N) antibody as a major component of activator protein 1 (AP1) transcriptional factor was observed in CA1 neurons. In contrast, in the early postischemic phase, the cJun/AP1 reaction was noticed in numerous neurons and glia-like cells of the CA2/CA3 region, hilus of the dentate gyrus, and region of mossy fiber terminals. In parallel, hippocampal protein binding to AP1, measured by the electrophoretic mobility shift assay (EMSA), showed biphasic enhancement at 3 and then 72-120 hours after ischemia. Supershifts, with antibodies against c-Fos and phospho-c-Jun constituencies of the AP1 dimer, revealed an increased amount of phosphorylated c-Jun in the late postischemic phase. Collectively, these results suggest diversity of AP1 complex function, regulated by its dimer composition as well as time and place of expression during postischemic reperfusion. The early, survival-supporting AP1 response, located mainly in ischemia-resistant areas of CA2/3, is followed by the delayed phase, characteristic of massive neuronal apoptosis in CA1 with concomitant increase of phospho-c-Jun in AP1 dimer.
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PMID:AP1 transcriptional factor activation and its relation to apoptosis of hippocampal CA1 pyramidal neurons after transient ischemia in gerbils. 1046 55

The transcriptional factor p53 is a regulatory protein which contributes to the preservation of tissue integrity by promoting either DNA repair or apoptosis. To establish the pathophysiological role of this protein in ischemia, we produced 1 h transient middle cerebral artery (MCA) occlusion in normal and in p53-deficient mice and investigated the resulting tissue damage by multiparametric imaging. Possible genetic influences on the angioarchitecture of the MCA territory and blood flow were examined by intravascular latex infusion and laser-Doppler flowmetry. Wild-type (p53(+/+)), heterozygous (p53(+/-)) and homozygous (p53(-/-)) mice deficient for the p53 gene did not differ in respect to angioarchitecture or the effect of vascular occlusion on blood flow and general physiological parameters. Twenty-four hours after 1 h MCA occlusion, mice revealed a gene dose-dependent decline in the size of metabolic disturbances (ATP depletion and inhibition of protein synthesis) and histological injury (Cresyl Violet staining). DNA fragmentations detected by terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) did not differ in the three groups and were only present in ATP-depleted tissue. Our findings suggest that after transient focal brain ischemia p53 prevents rather than aggravates brain injury, and that this effect is brought about by mechanisms that are unrelated to the pro-apoptotic properties of this gene.
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PMID:Aggravation of brain injury after transient focal ischemia in p53-deficient mice. 1129 31

Spatial and temporal relations between transcriptional factor NF kappa B activation and glia reaction in gerbil hippocampus after transient cerebral ischemia has been studied. Activation of protein binding to NF kappa B consensus oligonucleotide was determined by electrophoretic mobility gel shift assay (EMSA) in homogenates from dorsal (DP- an equivalent of CA1 sector) and abdominal (AbP- containing CA2-4 and gyrus dentatus) parts of hippocampus. A significant activation of NF kappa B binding was observed exclusively in DP as early as 3 h after ischemia and at this time that response preceded any other morphological signs of postischemic tissue injury. This early enhancement of NF kappa B binding was followed by microglia activation visualized in CA1 pyramidal region at 24 h of recovery by histochemical staining with lectin from Ricinus communis (RCA-120). Simultaneously, only a moderate increase of immunostaining against glial fibrillary acidic protein (GFAP) was observed homogeneously in all parts of hippocampus. This uniform pattern of astrogliosis was preserved until postischemic day 3-4, when apoptotic DNA fragmentation in CA1 pyramidal neurons had been clearly documented by TUNEL staining. At this period however, continuous elevation of NF kappa B binding in DP corresponded with similar response manifested also in AbP of the hippocampus. These results evidence a preferential NF kappa B involvement in an early microglia activation in the apoptogenic CA1 sector, although its role in a later astrocytic response to ischemia could not be neglected too.
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PMID:Interrelations between nuclear-factor kappa B activation, glial response and neuronal apoptosis in gerbil hippocampus after ischemia. 1131 21

Preconditioning is an endogenous mechanism of cardioprotection that develops secondary to a brief ischemia and a dramatic reduction in infarct size is observed when the myocardium undergoes a subsequent and long period of ischemia after the induction of preconditioning. Since its initial discovery, it appears that the kinetic of preconditioning is biphasic. Early preconditioning is effective within 1 to 3 hours after the initial brief ischemia. A second windows of preconditioning has been also described within the following 24-48 h. Although late preconditioning against myocardial stunning is well established, its protection against infarction still remains debated. Whereas nitric oxide is not involved in the early preconditioning, its role during the late phase of preconditioning has been recently well described. Indeed, nitric oxide triggers the delayed cardioprotection through the formation of oxiradicals. This leads to the translocation of protein kinase C. Secondary, the activation of the tyrosine kinases pathway and the transcriptional factor NF kappa B induces iNOS. Therefore, nitric oxide also plays a key role in the late preconditioning phenomenon as a mediator of this cardioprotection, although its final effector still remains unknown. The knowledge of the mechanisms responsible for preconditioning is necessary in order to develop new pharmacological concepts in order to protect the heart against ischemia. It is interesting to underline that nitric oxide donors are able to mimic late preconditioning.
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PMID:[Nitric oxide and myocardial ischemic preconditioning]. 1132 15

No information is available on transcription factors (TF), the main regulators of gene expression, in perinatal asphyxia (PA), and as pathomechanisms in PA are different, data on TFs from ischemia or hypoxia cannot be simply extrapolated to PA, and no studies have been reported to show an expressional pattern or the concerted action of TFs. We, therefore, used a gene-hunting technique, subtractive hybridization, to show sequences different in brains of normoxic and perinatally asphyxiated (10 and 20 min of asphyxia) rats. These subtracted sequences were identified by gene bank and assigned to individual genes. At 10 min of PA the TFs NFI/CAAT-binding protein, NF-kappa-B p65, N-myc, basic helix loop helix protein D82868, and c-myc intron binding protein were upregulated. At 20 min of PA the TFs SOX4 and neuronal death factor were upregulated, whereas the TFs c-maf, PEBP major transcription factor, brn-2, homeodomain protein Af004431, and zinc finger transcriptional factor M65008 were downregulated. The biological meaning of our findings is the demonstration of a pathophysiological pattern of TFs including POU, zinc finger, homeodomain, and basic helix-loop helix motifs in PA, proposing pathomechanisms for brain damage from PA, explaining transcriptional changes in general (as, e.g., NF-kappa-B p65, etc.) or in specific terms (as, e.g., neuronal death factor).
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PMID:Expression of transcription factors in the brain of rats with perinatal asphyxia. 1201 71

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/reperfusion and participate in end organ damage under these conditions.
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PMID:Role of induced nitric oxide in the initiation of the inflammatory response after postischemic injury. 1216 82

Cardiac remodeling, CR, is a complex and rather controversial issue and results from the, sometimes opposite, trophic effects of pure mechanical overload, and susceptibility factors, as senescence, aetiologies, as ischemia, and the neurohormonal reaction. The molecular mechanisms of CR are heritable and had, in the past, increased fitness, as such CR belongs to evolutionary medicine. Aldosterone production plays an important role in the remodeling of the heart. (i) There are numerous evidences that aldosterone induces fibrosis in all the cardiovascular system in the presence of high sodium diet. The aldosterone receptor is a transcriptional factor and the pathways that lead to aldosterone-induced fibrosis are multiple. Aldosterone induces the expression of the angiotensin II receptors subtype I and that of the glucocorticoid receptors. The RALES trial have recently evidenced a significant beneficial effect of spironolactone on both mortality and morbidity in heart failure, and a substudy has shown that these effects are linked to a reduction is fibrosis. (ii) An intracardiac production of aldosterone and corticosterone have been evidenced in the rat. Aldosterone production is regulated by low sodium/high potassium diets and by angiotensin II and is predominant in atria, cardiac production is low as compared to the adrenal production, nevertheless it results in high local concentrations, just like angiotensin II. In rats, myocardial infarction activates aldosterone production and this activation is prevented by losartan. Heart failure, in human, activates aldosterone production and is accompanied by a significant increase of the arteriovenous difference in aldosterone by the myocardium. To conclude (i) after a myocardial infarction local production of aldosterone and angiotensin II are likely to play a major role in regulating collagen turnover and fibrous tissue formation; (ii) during heart failure, the activation of adrenal and cardiovascular production of aldosterone belongs to the neurohormonal reaction and would play a detrimental role in producing reactive fibrosis.
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PMID:Molecular mechanisms of myocardial remodeling. The role of aldosterone. 1250 56

Nuclear factor-kappaB is a transcriptional factor required for the gene expression of many inflammatory mediators. Nuclear factor-kappaB activation requires removal and degradation of its inhibitor kappaB, an event that occurs after phosphorylation of inhibitor kappaB by a complex of inhibitor kappaB kinases. These events allow nuclear factor-kappaB to translocate into the nucleus, where it binds to kappaB elements and initiates transcription. Inappropriate and prolonged activation of nuclear factor-kappaB has been linked to several diseases associated with inflammatory events, including septic shock, acute respiratory distress syndrome, ischemia, and reperfusion injury. Thus, the key role of nuclear factor-kappaB in regulating inflammation makes this factor a therapeutic target for reducing tissue and organ damage. Regulation and control of nuclear factor-kappaB can be achieved by gene modification strategies or by pharmacologic inhibition of the key components of the cascade that leads to nuclear factor-kappaB activation. The purpose of our review is to describe these novel therapeutic approaches and their potential efficacy.
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PMID:Nuclear factor-kappaB as a therapeutic target in critical care medicine. 1254 84


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