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)

Small intestinal mucosal weight and nutrient absorption are significantly diminished early after cutaneous thermal injuries. Because these intestinal properties are highly dependent on rates of nucleic acid and protein synthesis, in vivo incorporation of thymidine, uridine, and leucine into small intestinal deoxyribonucleic acid, ribonucleic acid, and proteins were measured. Deoxyribonucleic acid synthesis was markedly decreased with the lowest thymidine incorporation in the jejunum (p less than 0.01); these findings were confirmed by autoradiographic identification of radiolabeled nuclei in the intestinal crypts. Protein synthesis was decreased by 6 h postinjury (p less than 0.01) but had returned to normal by 48 h. Consistent with a decreased rate of protein synthesis, ribonucleic acid synthesis was also decreased 18 h postinjury (p less than 0.01). These decreased deoxyribonucleic acid, ribonucleic acid, and protein synthesis rates are not likely a result of ischemia because in other studies of this injury model, intestinal blood flow was not significantly changed by the burn injury. Potentially, factors initiating the acute inflammatory reaction may directly inhibit nucleic acid and protein synthesis and lead to alterations in nutrient absorption and intestinal barrier function after injury.
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PMID:Injury-induced inhibition of small intestinal protein and nucleic acid synthesis. 169 45

Prostacyclin (PGI2) improves regional contractility of postischemically dysfunctional ("stunned") myocardium. We determined whether defibrotide, a fraction of mammalian DNA known to stimulate endogenous formation of PGI2, also improves contractile recovery of stunned myocardium. Anesthetized, open-chest minipigs were subjected to coronary occlusion of 5 min (left anterior descending branch, LAD) followed by 120 min of reperfusion. The animals were treated with defibrotide (32 mg x kg-1 x h-1, intravenously, i.v.) or vehicle throughout the experimental period. Defibrotide improved regional contractility in the ischemic reperfused area from 30 (vehicle) to 78% of the preischemic control without altering the contractility of nonischemic myocardium. Transcardiac PGI2 formation, determined from the difference between coronary venous and arterial plasma concentrations, was elevated from 437 (preischemic control) to 869 pmol x l-1 in defibrotide-treated animals, but was unchanged in the vehicle-treated and a sham-operated group. Thromboxane A2 (TXA2) release was not modified. Defibrotide reduced ischemia-induced formation of platelet aggregates but did not affect the activity of polymorphonuclear neutrophil granulocytes. The data demonstrate an improvement of contractile recovery from stunning by defibrotide that may be related to an inhibition of ischemia-induced platelet activation and (or) membrane protection owing to enhanced transcardiac formation of PGI2.
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PMID:Stimulation of prostacyclin synthesis by defibrotide: improved contractile recovery from myocardial "stunning". 170 43

Hydrogen peroxide produces marked antigonadotropic and lytic actions in luteal cells, but the effects of superoxide, the archetypal oxygen radical, are unknown. Xanthine oxidase generates superoxide, and the activity of this enzyme, and purine substrate, are increased under ischemia, such as that seen at luteal regression. We therefore examined the actions of xanthine oxidase on luteal cells to assess the effects of this enzyme and the superoxide anion on luteal function. Xanthine oxidase, in the presence of hypoxanthine (50 microM), produced marked inhibition of LH-sensitive cAMP and progesterone production with complete inhibition at 25 mU/ml and half-maximal inhibition at about 5 mU/ml. These antigonadotropic actions of xanthine oxidase were rapid with maximal effects within 5 min, followed several minutes later by substantial depletion of ATP. Heat, superoxide dismutase, and catalase or catalase alone abolished the actions of xanthine oxidase. While depletion of ATP by xanthine oxidase was prevented by 3-amino-benzamide, an inhibitor of DNA repair, inhibition of cAMP and progesterone production was still evident. Xanthine oxidase also inhibited progesterone synthesis stimulated by 8-bromo-cAMP. Isobutylmethylxanthine, a cAMP phosphodiesterase inhibitor, did not reverse the inhibition of cAMP accumulation by xanthine oxidase, and the enzyme had no effect on LH receptor binding activity. Since catalase reversed the effects of xanthine oxidase, we conclude that superoxide was rapidly dismuted to hydrogen peroxide and mediated the antigonadotropic and antisteroidogenic actions of xanthine oxidase in luteal cells. The sensitivity of luteal cells to xanthine oxidase raises the possibility that this enzyme may serve as a significant source of hydrogen peroxide in the corpus luteum.
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PMID:Inhibition of gonadotropin action and progesterone synthesis by xanthine oxidase in rat luteal cells. 170 32

Since mitochondria occupy a pivotal position in energy metabolism, mitochondrial dysfunction is directly linked with disturbances in cellular function. Mitochondria possess their own DNA, which codes 13 subunits of the mitochondrial energy transducing system; the other subunits are coded by nuclear DNA. Recent advances in gene technology, especially the polymerase chain reaction (PCR), permit us to analyze mitochondrial DNA mutations in a small quantity of tissue. We devised rapid and accurate methods to detect mitochondrial DNA mutations, i.e., the primer shift PCR method and the PCR-Southern method. We also developed a method to determine DNA sequences directly without cloning. Using these methods, we revealed that multiple mitochondrial DNA mutations exist in the myocardium of patients with cardiomyopathy. One mutation was based on the following directly repeated sequence: 5'-CATCAACAACCG-3'. This sequence exists in both the ATPase6 gene and the D-loop region, and pseudo-recombination occurs at that directly repeated sequence resulting in a 7.4 kbp deletion. Accordingly, some subunits of the mitochondrial energy transducing system can not be biosynthesized by these deleted mitochondrial DNA, and energy transduction is substantially depleted. Even without reduction of blood supply, mitochondrial DNA mutations can induce a chronic ischemia-like state in the myocardium, which might be a factor in the genesis of cardiomyopathy.
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PMID:Mitochondrial DNA mutations and disturbances of energy metabolism in myocardium. 174 73

The effect of fructose-1,6-diphosphate (FDP) on cellular viability after partial hepatectomy in partial ischemic liver was investigated in rats. The administration of FDP did not increase blood flow in the hepatic tissue; however, it significantly suppressed the elevation of serum liver functions for 24 hours after partial hepatectomy. Levels of DNA synthesis, protein synthesis, and labeling index were significantly higher in the groups administered divided doses of FDP before and after partial hepatic ischemia than in the control group (P less than 0.01). Thus, these findings indicate that FDP has cytoprotective and hepatotrophic effects on liver with ischemic injury and that divided dose administration of FDP is more effective than bolus doses in decreasing damage following ischemic and reperfusion injury.
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PMID:Beneficial effects of fructose-1,6-diphosphate infusion on liver regeneration after ischemic liver injury. 175 92

Global metabolic insults such as ischemia/hypoxia, damage neural cells through release of excitatory amino acids and their subsequent actions at the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are highly expressed in neonatal rat brain, and the current study examines the effects of receptor blockade with MK-801 on DNA synthesis under normoxic and hypoxic conditions. At one day of age, hypoxia alone caused a decrease in [3H]thymidine incorporation into DNA throughout the brain, whereas MK-801 alone decreased incorporation selectively in regions known to be enriched in NMDA receptors. MK-801 afforded no protection from hypoxia and instead exacerbated the effects of hypoxia in the cerebellum. At 8 days of age, hypoxia alone or MK-801 alone still produced the same patterns of inhibition of DNA synthesis, but MK-801 neither prevented nor exacerbated the effects of hypoxia; animals receiving MK-801 showed a significant incidence of hypoxia-induced mortality. These data suggest that excitatory actions exerted at the NMDA receptor serve to maintain cell replication in neonatal brain and, as distinct from the situation for excitatory amino acid-induced cell death, these receptors do not participate in adverse effects of hypoxia on DNA synthesis.
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PMID:Effects of MK-801 on DNA synthesis in neonatal rat brain regions under normoxic and hypoxic conditions. 182 44

Experimental studies were conducted into 170 adult male Wistar rats for the purpose of analysis of cellular adaptation processes of the myocardium to acute ischemia. One group of the animals were exposed to physical endurance training, i.e. 180 h of swimming exercises, up to 3 h daily. Positive verification of cardiac hypertrophy was considered a measure of accomplished cellular adaptation. Training-induced increase of relative and absolute heart weight was 25 and 30%, respectively. Acute myocardial ischemia had been produced by ligature of the left coronary artery. There were no significant differences between trained and untrained animals for incidence and size of infarction and postoperative lethality, while cardiac decompensation was less often recorded from trained animals. To study cellular adaptation as well as differences between trained and untrained animals, tissue samples were taken from the non-ischemic part of the left ventricle and checked by means of histology, electron microscopy, morphometry, quantitative histochemistry, and histo-autoradiography 1, 2, 4, 7, and 14 days after occlusion of the coronary artery. The studies have shown endurance training to result in unambiguous modification of structural as well as functional response of the nonischemic heart. Included in such structural modification at cellular level are significant changes in mitochondrial membranes, sarcoplasmic reticulum, and T-system. Structural modification was reflected in changes to the oxidative enzymes and DNA metabolism. Different patterns of cellular reaction could be positively verified up to 14 days after myocardial infarction.
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PMID:Morphometric, histochemical and autoradiographic studies on myocardial cells in experimental cardiac hypertrophy and ischemia. 182 34

Iron-mediated peroxidation of brain lipids is known to occur during reperfusion following cardiac arrest. Since in vitro damage to DNA is caused by similar iron-dependent peroxidation, we tested whether free radical damage to genomic DNA also develops during reperfusion following cardiac arrest and resuscitation. Genomic DNA was isolated from the cerebral cortex in (i) normal dogs, (ii) dogs subjected to a 20-min cardiac arrest, and (iii) dogs resuscitated from a 20-min cardiac arrest and then allowed to reperfuse for 2 or 8 h. DNA strand nicks were evaluated by in vitro labeling of newly created 3' and 5' termini. DNA base damage was evaluated utilizing reaction with piperidine prior to labeling of 5' termini. The 3' DNA termini were labeled before and after digestion with exonuclease III, and the 5' DNA termini were labeled before and after treatment with piperidine. In vitro experiments with genomic DNA damaged by oxygen radicals verified that these labeling methods identified radical damage. In the experimental animal groups, terminal incorporation and electrophoretic mobility of brain nuclear DNA are not significantly changed either by 20 min of complete brain ischemia or during the first 8 h of reperfusion. We conclude that genomic DNA is not extensively damaged during cardiac arrest and early reperfusion, and therefore such DNA damage does not appear to be an important early aspect of the neurologic injury that accompanies cardiac arrest and resuscitation.
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PMID:Brain nuclear DNA survives cardiac arrest and reperfusion. 184 65

Free-radical reactions, known to occur in the reperfused brain, damage DNA in vitro. We therefore examined the hypothesis that thymine glycols and thymine dimers, which are known to block transcription and are formed by free radical mechanisms, are formed in brain DNA during reoxygenation following ischemia. Such biochemical lesions could account for the failure of protein synthesis that occurs following an ischemic insult. Large dogs were anesthetized, instrumented, and divided into four groups: (1) non-ischemic controls; (2) 20-min cardiac arrest without resuscitation; (3) 20-min cardiac arrest, resuscitation and 2 h reperfusion; and (4) 20-min cardiac arrest, resuscitation and 8 h reperfusion. Genomic DNA was isolated from the cerebral cortex. Thymine glycols were labeled by reduction with [3H]NaBH4. Pyrimidine dimers were determined by ELISA using antibody prepared against ultraviolet irradiated DNA. The data was evaluated by Kruskal-Wallis ANOVA with alpha = 0.05. The rabbit antibodies detected the thymine dimer content in 10 pg UV irradiated DNA but did not react with normal DNA. Borohydride labeling qualitatively detected thymine glycols generated by treatment of DNA with osmium tetroxide. There was no difference between the DNAs from the experimental groups in the content of thymine glycols or pyrimidine dimers (P = 0.608 and P = 0.219, respectively). We conclude that significant quantities of thymine glycols and thymine dimers are not formed in brain DNA during post-ischemic reperfusion. Therefore, the inhibition of brain protein synthesis during reperfusion, observed by other investigators, is unlikely to be caused by interruption of transcription by these species.
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PMID:Thymine glycols and pyrimidine dimers in brain DNA during post-ischemic reperfusion. 185 64

Recent data suggest that uric acid is generated locally in the vessel wall by the action of xanthine oxidase. This enzyme, activated during ischemia/reperfusion by proteolytic conversion of xanthine dehydrogenase, catalyzes the oxidation of xanthine, thereby generating free radicals and uric acid. Because of the potential role of ischemia/reperfusion in vascular disease, we studied the effects of uric acid on rat aortic vascular smooth muscle cell (VSMC) growth. Uric acid stimulated VSMC DNA synthesis, as measured by [3H]thymidine incorporation, in a concentration-dependent manner with half-maximal activity at 150 microM. Maximal induction of DNA synthesis by uric acid (250 microM) was approximately 70% of 10% calf serum and equal to 10 ng/ml platelet-derived growth factor (PDGF) AB or 20 ng/ml fibroblast growth factor. Neither uric acid precursors (xanthine and hypoxanthine) nor antioxidants (ascorbic acid, glutathione, and alpha-tocopherol) were mitogenic for VSMC. Uric acid was mitogenic for VSMC but not for fibroblasts or renal epithelial cells. The time course for uric acid stimulation of VSMC growth was slower than serum, suggesting induction of an autocrine growth mechanism. Exposure of quiescent VSMC to uric acid stimulated accumulation of PDGF A-chain mRNA (greater than 5-fold at 8 h) and secretion of PDGF-like material in conditioned medium (greater than 10-fold at 24 h). Uric acid-induced [3H]thymidine incorporation was markedly inhibited by incubation with anti-PDGF A-chain polyclonal antibodies. Thus uric acid stimulates VSMC growth via an autocrine mechanism involving PDGF A-chain. These findings suggest that generation of uric acid during ischemia/reperfusion contributes to atherogenesis and intimal proliferation following arterial injury.
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PMID:Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. 202 72


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