UMLS:C0432222 - FACTA Search

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We investigated the role of singlet oxygen (generated from photoactivation of rose bengal) on the calcium transport and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum (SR). Isolated cardiac SR exposed to rose bengal (10 nM) irradiated at 560 nm resulted in significant inhibition of Ca2+ uptake (from 2.27 +/- 0.05 to 0.62 +/- 0.05 mumol Ca2+/mg.min [mean +/- SEM], p less than 0.01) and Ca(2+)-ATPase activity (from 2.08 +/- 0.05 to 0.28 +/- 0.04 mumol Pi/min.mg [mean +/- SEM], p less than 0.01). The inhibition of calcium uptake and Ca(2+)-ATPase activity by rose bengal-derived activated oxygen (singlet oxygen) was dependent on the duration of exposure and intensity of light. Singlet oxygen scavengers ascorbic acid and histidine significantly protected SR Ca(2+)-ATPase against rose bengal-derived activated oxygen species, but superoxide dismutase and catalase did not attenuate the inhibition. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of SR exposed to photoactivated rose bengal for up to 14 minutes demonstrated complete loss of the Ca(2+)-ATPase monomer band, which was significantly protected by histidine. The addition of dithiothreitol (5 mM) had a slight protective effect, showing that new disulfide bond formation was not a major cause of aggregation. The results were also confirmed by high-performance liquid chromatography of the SR exposed to irradiated rose bengal. Irradiation of rose bengal also caused an 18% loss of total sulfhydryl groups of SR. On the other hand, superoxide radical (generated from xanthine oxidase action on xanthine) and hydroxyl radical (in the presence of Fe(3+)-EDTA or 0.5 mM H2O2 plus Fe(2+)-EDTA) as well as H2O2 (0.25-12 mM) were without any effect on the 97,000-d Ca(2+)-ATPase band of SR. Generation of radical species (superoxide and hydroxyl radical) from rose bengal was studied by electron paramagnetic resonance spectroscopy using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). The results showed that irradiation of rose bengal formed a 1:2:2:1 quartet, characteristic of the DMPO-OH adduct, which was scavenged by ethanol but not by superoxide dismutase, catalase, or histidine. No radical species could be detected from irradiated rose bengal or irradiated DMPO under the assay conditions used. Peroxy adducts of DMPO might be produced but would be observed only at very low temperatures. Similarly, we could not detect any measurable.O2- anion from irradiation of rose bengal as indicated by either cytochrome c reduction at 550 nm or nitro blue tetrazolium reduction at 560 nm. These results show that SR is damaged most likely by singlet oxygen derived from rose bengal.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Singlet oxygen interaction with Ca(2+)-ATPase of cardiac sarcoplasmic reticulum. 165 35

In a previous study, we reported that fragment Bb of bovine complement factor B activated bovine monocytes, as demonstrated by the uptake of 3H-deoxyglucose. In the present study, the effects of Bb on the production of superoxide anion and hydrogen peroxide by bovine monocytes was investigated. The production of superoxide was measured by the superoxide dismutase inhibitable reduction of cytochrome c. The change in absorbance was determined by a spectrophotometer at a wavelength of 550 nm. Hydrogen peroxide production was measured by the horse-radish peroxidase-dependent oxidation of phenol red. The resulting color change was measured by a spectrophotometer at a wavelength of 620 nm. Fragment Bb (20 micrograms/mL) induced the generation of 0.96 +/- 0.2 (mean +/- SEM) nanomoles of superoxide/2.5 x 10(5) monocytes at 5 min. The production of superoxide peaked at 15 min (1.24 +/- 0.3 nanomoles). The production of hydrogen peroxide was also rapid: 0.195 +/- 0.05 nanomoles/2.5 x 10(5) monocytes at 5 min with a peak at 15 min (0.250 +/- 0.04 nanomoles). These observations show that fragment Bb, which has serine protease activity, induces bovine monocytes to generate reactive oxygen intermediates such as superoxide and hydrogen peroxide.
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PMID:Bb fragment of bovine complement factor B: stimulation of the oxidative burst in bovine monocytes. 217 93

Liver membrane vesicles were prepared from operative liver biopsies from six patient volunteers undergoing abdominal surgery for non-hepatic disease. Neutrophils were extracted from their blood. The liver membrane vesicles were exposed to 1 mmol/l acetaldehyde with or without reduction of the resultant adducts formed. The production of superoxide anion by the neutrophils upon exposure to the liver membrane vesicles prepared from the same patient was assessed by measuring the rate of cytochrome c reduction before and after the addition of superoxide dismutase. Preincubation with acetaldehyde significantly increased superoxide production in response to both the reduced (from 35.5 +/- 7.1 nmol O2-/10(8) cells/min to 128 +/- 25, mean +/- SEM, p less than 0.01) and the non-reduced liver cell membranes (from 17.2 +/- 4.3 to 81 +/- 17, p less than 0.01); 1 mmol/l acetaldehyde alone caused no superoxide production. Neutrophil free radical production in response to acetaldehyde altered hepatocyte membranes could be an important mechanism of cellular injury in acute alcoholic hepatitis.
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PMID:Free radical generation by neutrophils: a potential mechanism of cellular injury in acute alcoholic hepatitis. 282 1

(1) Biopsies from the gastrocnemius muscle of patients with Duchenne dystrophy were partitioned into a myofibrillar plus nuclear fraction, a mitochondrial fraction and a supernatant fraction. The fractions were assayed for mitochondrial enzymes and protein, in order to obtain information about the integrity of mitochondrial structure and function. Muscles from boys and adults without neuromuscular disease were treated likewise. (2) In adults, muscle possesses a significantly higher specific activity (on protein basis) of monoamine oxidase and rotenone-insenitive NADH-cytochrome c reductase (RINCR) than in boys. In childhood, monoamine oxidase activity increases with age. At the age of 5 yr, the specific activity is 50% of the adult value. RINCR activity is constant in childhood. With adolescence it increases from 20 +/- 2 (SEM) to 35 +/- 6 mumoles cytochrome c reduced per min per g protein, and it remains at this level. Palmitoyl-CoA synthetase activity remains constant with age. (3) In Duchenne dystrophy the extractable protein content from muscle is decreased to 75%. The specific activities of the matrix enzymes propionyl-CoA carboxylase and glutamate dehydrogenase are 1.8 and 2.8 times increased, the inner membrane enzyme cytochrome c oxidase is 2.8 times increased, the inner membrane enzyme cytochrome c oxidase is 2.8 times increased. Of the outer membrane enzymes RINCR is 2.0 times increased, while palmitoyl-CoA synthetase is not changed in acitivity. In Duchenne dystrophy monoamine oxidase activity also increases with age. In part this may be due to mitochondria from adipose tissue and macrophages, which are increasingly present in older patients. The specific activities of enzymes with a predominant cytosolic localisation, creatine kinase and adenylate kinase, are increased by a factor of 1.5 and 1.7. (4) The subcellular distribution of the studied enzymes in human skeletal muscle was found to be similar as in animal studies. In mitochondrial fractions from Duchenne patients the recoveries of the following enzymes are decreased: glutamate dehydrogenase (from 25 to 9%), creatine kinase (1.1-0.66%), adenylate kinase (0.44-0.22%), hexokinase (7.1-2.7%), monoamine oxidase (36-21%), RINCR (30-17%), and palmitoyl-CoA synthetase (40-21%). The recoveries of last 3 mitochondrial outer membrane enzymes in the supernatant fractions are correspondingly increased. These results indicate an increased fragility of the mitochondrial membranes in dystrophic muscles. (5) The reported changes are clearly evident in a one-year-old patient, which indicates that the mitochondria are involved early in the disease process.
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PMID:Early changes of muscle mitochondria in Duchenne dystrophy. Partition and activity of mitochondrial enzymes in fractionated muscle of unaffected boys and adults and patients. 624 85

Allergen inhalation causes airway hyperresponsiveness and airway inflammation in dogs. The purpose of this study was to determine whether allergen-induced airway hyperresponsiveness is associated with increases in oxygen radical production from bronchoalveolar lavage (BAL) cells. A group of 10 random-source dogs were studied twice, 4 wk apart. On each occasion, acetylcholine (ACh) airway responsiveness was measured before and 24 h after inhalation of Ascaris suum or its diluent, followed by BAL. The response to ACh was expressed as the concentration causing an increase in lung resistance of 5 cm H2/O/L/s above baseline. Spontaneous and phorbol myristate acetate (PMA)-stimulated (2.4 mumol/L) oxygen radical release were measured, for 10 min each, from washed BAL cells (4 x 10(6) cells/ml) by luminol-enhanced chemiluminescence in a luminometer at 37 degrees C. Superoxide anion production was measured using a cytochrome c assay. Allergen inhalation caused bronchoconstriction, airway inflammation, and airway hyperresponsiveness. The acetylcholine provocative concentration fell from 7.47 mg/ml (% SEM 1.61) before to 1.23 mg/ml (% SEM 1.62) after allergen (p < 0.0001). Allergen inhalation significantly increased absolute neutrophil (p = 0.03) and eosinophil (p = 0.02) counts in BAL. Spontaneous (p < 0.0003) and PMA-stimulated (p < 0.0005) chemiluminescence and superoxide anion production (p = 0.039) were increased after allergen inhalation. The allergen-induced increases in chemiluminescence were significantly correlated with the increases in ACh airway hyperresponsiveness (r = 0.75, p < 0.012). These results indicate that inhaled allergen increases oxygen radical release from bronchoalveolar lavage cells and supports the hypothesis that oxygen radicals are important in causing allergen-induced airway hyperresponsiveness.
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PMID:Allergen-induced oxygen radical release from bronchoalveolar lavage cells and airway hyperresponsiveness in dogs. 773 10

Previous studies have suggested that nitric oxide (NO) can modulate neutrophil function. Exposure to inhaled NO for pulmonary vasodilation could thus potentially affect neutrophil involvement in lung inflammation and infection. We evaluated the effect of exogenous NO gas exposure at clinically relevant concentrations in vitro on the oxidative function of human neutrophils. Isolated neutrophils were exposed for 2 h to either room air (RA), 80% oxygen (O2), or NO at 20 or 5 ppm blended with room air (NO20/RA, NO5/RA) or blended with 80% oxygen (NO20/O2) (NO5/O2). Neutrophils were then evaluated for superoxide anion generation with the cytochrome c reduction assay, for oxygen consumption with the Clark oxygen electrode technique, and for myeloperoxidase (MPO) release by enzyme-linked immunosorbent assay (ELISA). Neutrophil viability was determined by both trypan blue dye exclusion and fluorescence viability/cytotoxicity assay. Neutrophils exposed to NO at 20 ppm demonstrated a significant decrease in superoxide anion generation in both NO20/RA (97 +/- 46 nmol/10(6) neutrophils) and NO20/O2 (102 +/- 54 nmol/10(6) neutrophils) groups as compared with RA (190 +/- 41 nmol/10(6) neutrophils) (mean +/- SEM, P < 0.005 by analysis of variance [ANOVA] and the Student-Newman-Keuls test). No significant difference was seen at 5 ppm NO exposure. Neutrophil oxygen consumption was decreased with NO20/O2 (6.5 +/- 1.2 nmol O2/ml/min/10(7) neutrophils) as compared with RA (13.7 +/- 3.9 nmol O2/ml/min/10(6) neutrophils) or O2 alone (11.6 +/- 3.1 nmol O2/ml/min/10(7) neutrophils) (P < 0.002). MPO levels were significantly decreased with NO20/O2 (2.3 +/- 0.4 microg/ml) as compared with RA (4.0 +/- 0.4 microg/ml, P < 0.005), and also with NO5/O2. Cell viability as reflected by trypan blue dye exclusion was decreased with O2 (70 +/- 2.3%), NO20/RA (61 +/- 4%), and NO20/O2 (58 +/- 2.5%) exposure as compared with RA control (84.4 +/- 0.9%) (P < 0.0001). Decreased neutrophil viability was confirmed by live/dead assay for O2 (80.8 +/- 2.8%), NO20/RA (62.8 +/- 6.1%), and NO20/O2 (31.7 +/- 5.6%) groups as compared with RA control (95.8 +/- 1.4%, P < 0.0001). Adjusting neutrophil superoxide anion generation, oxygen consumption, and MPO values for cell viability abolished differences between exposure groups. We conclude that exogenous NO exposure at clinically relevant concentrations decreases neutrophil oxidative function, primarily as a result of reduced cell viability. Further studies are necessary to determine if these effects serve an in vivo immunoregulatory or immunosuppressive role in neutrophil response to lung injury and infection.
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PMID:Effects of exogenous nitric oxide on neutrophil oxidative function and viability. 911 51

Platelet activating factor (PAF) enhances polymorphonuclear leukocyte (PMN) superoxide (.O2-) production, CD11b expression, and elastase release, all essential components in the pathophysiology of multiple-organ failure. This study was designed to determine the effects of Lexipafant, a PAF receptor antagonist, on PAF-mediated PMN functions. PMNs from 10 healthy volunteers were isolated and pretreated with various concentrations of Lexipafant (0-100 microM). PMNs were then incubated for 5 min with 200 nM PAF for .O2- detection or 2000 nM PAF for elastase measurement and activated with 1 microM N-formylmethionylleucylphenylalanine. The mean rate of .O2- production was determined by a cytochrome c reduction assay (nmole .O2-/min/1.33 x 10(5) PMN +/- SEM). Elastase release was measured by the cleavage of the synthetic elastase substrate Meo-Suc-Ala-Ala-Pro-Val-pNA (mean elastolytic activity +/- SEM). In parallel experiments, PMNs were incubated with 200 nM PAF for 30 min following pre-treatment with Lexipafant and CD11b expression was determined by flow cytometry (mean fluorescence intensity +/- SEM). Statistical analysis was performed using repeated-measures ANOVA (P < 0.05). Lexipafant inhibited PAF-enhanced PMN .O2- generation, CD11b expression and elastase release in a dose dependent fashion. The IC50 of Lexipafant for .O2- production, CD11b expression, and elastase release was 0.046, 0.285, and 0.05 microM, respectively. Lexipafant attenuated the PAF-mediated upregulation of PMN .O2- production, CD11b expression, and elastase release in a dose dependent fashion. These data support the hypothesis that Lexipafant may reduce the severity of the inflammatory response to injury produced by PAF-enhanced activation of PMNs.
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PMID:Lexipafant inhibits platelet activating factor enhanced neutrophil functions. 922 89

The activation of the neutrophil respiratory burst is a two-step process involving an initial 'priming' phase followed by a 'triggering' event. The biochemical mechanisms which underlie these events are yet to be fully elucidated, but the evidence suggests a crucial role for stimulus-induced tyrosine phosphorylation. The enhanced tyrosine phosphorylation observed upon triggering primed cells may reflect an increase in tyrosine kinase activity or a reduction in the levels of the opposing phosphotyrosine phosphatases (PTPases). We have investigated the latter by examining the possibility that lipopolysaccharide (LPS)-induced priming of the neutrophil respiratory burst involves the suppression of cellular PTPase activity. Purified human neutrophils were incubated for 60 min with and without LPS. Priming of the respiratory burst was confirmed by fMet-Leu-Phe-induced cytochrome c reduction. The level of PTPase activity was assessed by dephosphorylation of [32P]RR-src peptide as substrate. Pretreatment of human neutrophils with 200 ng/ml LPS induced a 2.9 +/- 0.3 (mean +/- SEM, n = 3, P = 0.022) fold increase in the fMet-Leu-Phe-triggered respiratory burst. In the same cells, LPS did not induce a significant change in the total cellular PTPase activity (1.02 +/- 0.02-fold, mean +/- SEM, n = 3, P = 0.63). Similarly, stimulation of neutrophils with fMet-Leu-Phe or phorbol myristate acetate did not significantly affect the cellular PTPase activity (P = 0.94 and 0.68, respectively). Our results suggest that suppression of PTPase activity is not the mechanism underlying the priming and/or triggering of the neutrophil respiratory burst.
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PMID:Lipopolysaccharide-induced priming of the human neutrophil is not associated with a change in phosphotyrosine phosphatase activity. 1039 19

N-Tosyl-L-phenylalanyl-chloromethyl ketone (TPCK) reduces apoptosis in vitro. Pretreatment with TPCK reduces brain injury. Would treatment after injury reduce damage? Seven-day-old rats had the right carotid artery ligated and were subjected to 2.5 h of 8% oxygen and were treated intraperitoneally 3 h after hypoxia with 10 mg/kg of TPCK or vehicle. Brain damage was measured 22 days after injury. bcl-2, bax, and cytochrome c where measured by Western blot 24 h after injury. Caspase-9 and caspase-3 activity were measured enzymatically 24 h after injury. Treatment with TPCK reduced the loss of the right hemisphere caused by injury from 27.6 +/- 2.8% SEM (vehicle, n = 56) to 19.8 +/- 2.8% (TPCK, n = 61, p < 0.05). Hypoxic ischemia increased cytosolic cytochrome c from 0.25 +/- 0.04 to 0.4 +/- 0.04 optical density (OD; p < 0.05), but TPCK had no effect (0.31 +/- 0.03 OD). TPCK reduced caspase-9 activity from 72 +/- 30 to 43 +/- 5 fluorescence units/h/mg (p < 0.05 vs. vehicle), and caspase-3 activity from 66 +/- 10 to 39 +/- 3.7 fluorescence units/h/mg (p < 0.05 vs. vehicle). Treatment with TPCK 3 h after hypoxic ischemia reduced brain infarct size. TPCK may act by reducing caspase-9 activation by cytochrome c.
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PMID:Treatment of hypoxic-ischemic brain injury in newborn rats with TPCK 3 h after hypoxia decreases caspase-9 activation and improves neuropathologic outcome. 1287 29

Levels of components of the cytochrome P450 (CYP)-dependent monooxygenase system were characterised in microsomes of major biotransformation tissues, or whole bodies, of 33 species from six phyla of aquatic invertebrates. The phylogenetic distribution of benzo[a]pyrene hydroxylase (BPH) activity in the absence of added NADPH (so-called 'NADPH-independent BPH activity') and presence of NADPH was also examined. Microsomal protein yield was higher in individual tissues than whole tissues. The main components (total CYP and cytochrome b5; NADPH-dependent cytochrome c (CYP) reductase, NADH-dependent cytochrome c reductase and NADH-dependent ferricyanide (b5) reductase activities) were found in most species of the Porifera, Cnidaria, Mollusca, Polychaeta, Crustacea and Echinodermata examined. The so-called '418-peak' of the carbon-monoxide difference spectrum of reduced microsomes was found in all species, indicating the wide distribution of this protein. Total CYP levels (pmol mg(-1) protein; mean+/-SEM) were similar in molluscs (50+/-7), crustaceans (61+/-11) and echinoderms (56+/-9), with the exception of high levels (223-266) in two crustacean species. NADPH-dependent BPH activity (pmol min(-1) mg(-1) protein) was found in 32 species, being lowest in Porifera and Cnidaria (3-4), intermediate in Mollusca (7.8+/-1.3), and highest in Crustacea (25+/-4) and Echinodermata (15+/-4). NADPH-independent BPH activity was evident in 13 out of 15 molluscan species examined, with the addition of NADPH either stimulating (8 species) or inhibiting (5 species) the activity. NADPH-independent BPH activity was also seen in two poriferan species and indicated in three crustacean species, suggesting that the phenomenon is not solely restricted to the Mollusca.
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PMID:Components of the cytochrome P450-dependent monooxygenase system and 'NADPH-independent benzo[a]pyrene hydroxylase' activity in a wide range of marine invertebrate species. 1597 46

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