Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NPC 15669, N-carboxy-L-leucine,N-[(2,7-dimethylfluoren-9-yl)methyl]ester, has been shown to inhibit several inflammatory reactions that depend upon recruitment of neutrophils into the primary lesion. In the present study we examined the effects of NPC 15669 in the reversed passive Arthus reaction, an inflammatory reaction occurring in the skin of rats in response to intracutaneous injection of antigen followed by intravenous administration of antibody. In this model, immune complex formation activates complement, resulting in rapid recruitment of neutrophils to the site, which releases free radicals and proteases that damage capillaries, resulting in plasma leak. NPC 15669 inhibited the increased capillary permeability occurring in the reversed passive Arthus reaction in a dose-dependent manner, with an ED50 of 4 mg/kg. The agent similarly inhibited the recruitment of radiolabeled neutrophils as well as the accumulation of myeloperoxidase, a neutrophil marker. NPC 15669 in vitro inhibited the adherence of formyl-L-Met-L-Leu-L-Phe- or human recombinant C5a-activated neutrophils to endothelium, with IC50 values of 15 to 30 microM (ca. 4-9 micrograms/ml). Measurement of plasma NPC 15669 showed that at the ED50 dose, the average circulating concentration of drug was 5 micrograms/ml, consistent with the hypothesis that NPC 15669 exerts its anti-inflammatory effects by inhibiting neutrophil adherence to endothelium and recruitment into the inflammatory lesion.
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PMID:NPC 15669 inhibits the reversed passive Arthus reaction in rats by blocking neutrophil recruitment. 146 49

The colocalization of the peptides neuropeptide Y (NPY) and Phe-Met-Arg-Phe-NH2 (FMRFamide) in the brain of the Atlantic salmon was investigated with double immunofluorescence labeling and peroxidase-antiperoxidase immunocytochemical techniques. Colocalization of NPY-like and FMRF amide-like immunoreactivities was observed in neuronal cell bodies and fibers in four brain regions: in the lateral and commissural nuclei of the area ventralis telencephali, in the nucleus ventromedialis thalami, in the laminar nucleus of the mesencephalic tegmentum, and in a group of small neurons situated among the large catecholaminergic neurons in the isthmal region of the brainstem. All cell bodies in these nuclei were immunoreactive to both NPY and FMRF. We consistently observed larger numbers of FMRF-immunoreactive than NPY-immunoreactive fibers. In the nucleus ventromedialis thalami NPY- and FMRFamide-like immunoreactivities were colocalized in cerebrospinal fluid (CSF)-contacting neurons. NPY-immunoreactive, but not FMRF-immunoreactive, neurons were found in the stratum periventriculare of the optic tectum, and at the ventral border of the nucleus habenularis (adjacent to the nucleus dorsolateralis thalami). Neurons belonging to the nucleus of the nervus terminalis were FMRF-immunoreactive but not NPY-immunoreactive. The differential labeling indicates, as do our cross-absorption experiments, that the NPY and FMRFamide antisera recognize different epitopes. Thus, it is probable that NPY-like and FMRF amide-like substances occur in the same neurons in some brain regions.
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PMID:Colocalization of neuropeptide Y (NPY)-like and FMRFamide-like immunoreactivities in the brain of the Atlantic salmon (Salmo salar). 148 97

The effects of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) on infarct size, myeloperoxidase (MPO) activity and plasma prostanoid levels were studied using coronary artery occlusion (1 h)-reperfusion (3 h) model in rabbits, comparing with acetylsalicylic acid (ASA). Myocardial infarct size, MPO activity in the infarcted region and plasma glutamate oxalo-acetate transaminase, lactate dehydrogenase and creatine kinase were significantly suppressed by treatment with KC-764 (2 mg/kg i.v.), but not by ASA (10 mg/kg i.v.). KC-764 completely depressed the increase in plasma TXB2 level during occlusion-reperfusion with a little influence on plasma 6-keto-PGF1 alpha. Thus, the ratio of 6-keto-PGF1 alpha to TXB2 levels was increased by KC-764. On the other hand, ASA treatment depressed both plasma TXB2 and 6-keto-PGF1 alpha levels to the same extent. The in vitro study with guinea-pig neutrophils showed that KC-764 reduced the chemotaxis induced by formyl-methionyl-leucyl- phenylalanine at 3 x 10(7)-3 x 10(-6) mol/l, while ASA did not influence the neutrophil chemotaxis. These results suggest that KC-764 may salvage the damaged ischemic myocardium by the selective inhibition of TXA2 synthesis and the suppression of leukocyte migration.
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PMID:Protective effect of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine on myocardial damage due to coronary occlusion and reperfusion in rabbit. 158 78

The posterior stomach was isolated from each male Donryu rat and separated into two parts: the tunicae mucosa and submucosa and the tunicae muscularis and serosa. Active and inactive tissue kallikrein were measured using sandwich type enzyme linked immunosorbent assay (s-ELISA) and H-Pro-Phe-Arg-MCA to complement each other. Inactive tissue kallikrein was determined (1) by measuring total tissue kallikrein and active tissue kallikrein in trypsin-treated samples and trypsin-nontreated ones, respectively; and (2) by subtracting active tissue kallikrein from total tissue kallikrein. Although tissue kallikrein was not demonstrable in the tunicae muscularis and serosa, inactive tissue kallikrein in the tunicae mucosa and submucosa reached 79.6% with s-ELISA and 99.1% with H-Pro-Phe-Arg-MCA. Water-immersion stress significantly decreased total tissue kallikrein at Stage IV of ulcers compared with the control value (p less than 0.001 in both measuring methods). Immunohistochemical staining was made using the avidin-biotin-horseradish peroxidase complex method. Tissue kallikrein was proved to be diffusely present as the inactive type within the epithelial cells of the pits in the gastric mucosa of the normal rats. With the progress of ulcers, however, it disappeared from the cells and appeared in the intercellular space. At Stage IV, it began to disappear even from the intercellular space. Based on the previously proposed process of tissue kallikrein release into blood in man, a possible interpretation of the above findings is that inactive tissue kallikrein may serve to maintain the gastric mucosa in a normal state; and that it may be transformed into the active type with ulceration and eliminated in a form of complex with some protease inhibitor in the course of aggravation.
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PMID:[Bio- and histochemical changes of tissue kallikrein in the rat stomach after water immersion-induced gastric ulcer]. 159 73

Aspirin selectively acetylates Ser-530 of prostaglandin endoperoxide (PGH) synthase-1. This causes inactivation of the cyclooxygenase activity of the enzyme, but does not appreciably affect its peroxidase activity. Although the aspirin-acetylated enzyme is inactive, we found that PGH synthase-1 in which Ser-530 had been replaced with an alanine was catalytically active; accordingly, we proposed that aspirin inhibits cyclooxygenase activity by placing a larger than normal side chain at position 530 thereby interfering with arachidonate binding (DeWitt, D.L., El-Harith, E. A., Kraemer, S. A., Andrews, M. J., Yao, E. F., Armstrong, R. L., and Smith, W. L. (1990) J. Biol. Chem. 265, 5192-5198). As a further test of this hypothesis we have used site-directed mutagenesis and transient expression in cos-1 cells to prepare and characterize five additional substitutions of Ser-530. Consistent with our proposal, the presence of amino acids with bulky side chains at position 530 inhibited cyclooxygenase activity and decreased the apparent affinity of the enzyme for arachidonate. In related work, we characterized a series of mutant PGH synthases-1 having substitutions at residues adjoining Ser-530, including Phe-529, Leu-531, Lys-532, and Gly-533, in order to evaluate the contributions of each residue to cyclooxygenase catalysis. The most significant conclusion of this part of the study is that residues 529-533 all are important for the peroxidase activity as well as the cyclooxygenase activity of PGH synthase-1. Phe-529, in particular, was found to be critical for PGH synthase-1 structure and catalysis; some substitutions at this position led to the production of proteins lacking about 100 amino acids from their COOH termini.
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PMID:Prostaglandin endoperoxide synthase. The aspirin acetylation region. 160 97

A horseradish peroxidase variant ([F41V] HRP-C*), in which Val replaces the conserved Phe at position 41 adjacent to the distal His, has been constructed. Its composition and spectroscopic, catalytic and substrate-binding properties were compared with those of the wild-type recombinant (HRP-C*) and plant (HRP-C) enzymes. Presteady-state kinetic measurements of the rate constant for compound I formation (k1) revealed an eightfold decrease in the reactivity of the Phe41----Val variant towards H2O2, in comparison with HRP-C or HRP-C*. Measurement of the remaining rate constants, k2 and k3, for the two single-electron reduction reactions of [F41V] HRP-C with para-aminobenzoic acid as reducing substrate, showed that they were 2.5-fold and 1.3-fold faster, respectively. In contrast, analysis of data from steady-state assays with 2,2'-azinobis(3-ethylbenzthiazoline-6-sulphonate) as reducing substrate, showed decreased reactivity of the mutant enzyme to this compound, indicating a change in substrate specificity. Over the substrate range studied, the data for HRP-C* and for [F41V] HRP-C conformed to a simple modification of the accepted peroxidase mechanism in which a first-order step (ku), assumed to be product dissociation, becomes rate-limiting under our standard assay conditions. Calculations of rate constants from steady-state data yielded values of k1 for both enzyme forms in adequate agreement with those from pre-steady state measurements. They showed, furthermore, that both k3 for 2,2'-azinobis(3-ethylbenzthiazoline-6-sulphonate) and ku were substantially decreased, fivefold and tenfold, respectively, in the mutant. Analogous to the decrease in ku, we observed a twofold increase in the affinity of the mutant variant for the inhibitor benzhydroxamic acid. The coordination-state equilibrium of the haem iron also appeared shifted towards the hexacoordinate high-spin form. These observations indicate that in addition to affecting reactivity to H2O2, mutations in the distal region and close to the haem iron also affect reactivity towards different reducing substrates, inducing perturbations in the neighbourhood of the aromatic-substrate-binding site, known to be 0.8-1.2 nm from the haem iron.
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PMID:Characterisation of a haem active-site mutant of horseradish peroxidase, Phe41----Val, with altered reactivity towards hydrogen peroxide and reducing substrates. 163 6

Wild-type recombinant horseradish peroxidase isoenzyme C and two protein variants, Phe41----Val and Arg38----Lys, have been characterised using both one- and two-dimensional NMR spectroscopy. Proton NMR spectra recorded in both resting and cyanide-ligated states of the proteins were compared with those of the corresponding plant peroxidase. The latter contains 18% carbohydrate in eight N-linked oligosaccharide side chains whereas the recombinant proteins are expressed in nonglycosylated form. The spectra of the plant enzyme and refolded recombinant protein are essentially identical with the exception of carbohydrate-linked resonances in the former, indicating that their solution structures are highly similar. This comparison also identifies classes of carbohydrate resonances in the plant enzyme which provides new information on the local environment and mobility of the oligosaccharide side chains. Comparison of the spectra of the cyanide-ligated states of the two variants and those of plant horseradish peroxidase C indicated that there were significant differences with respect to haem and haem-linked resonances. These could not be rationalised simply on the basis of the local perturbation expected from a single-site substitution. The two substitutions made to residues on the distal side of the haem apparently influenced the degree of imidazolate character of the proximal His170 imidazole ring thus perturbing the magnetic environment of the haem group. Inspection of the spectra of the Phe41----Val variant also showed that the resonances of a phenylalanine residue in the haem pocket had been incorrectly assigned to Phe41 in a previous study. A new assignment, based on additional information from two-dimensional nuclear Overhauser enhancement spectroscopy, was made to Phe152. The assignments made for the Phe41----Val variant were also used as a basis to investigate the structure of the complex formed with the aromatic donor molecule, benzhydroxamic acid.
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PMID:Structural studies by proton-NMR spectroscopy of plant horseradish peroxidase C, the wild-type recombinant protein from Escherichia coli and two protein variants, Phe41----Val and Arg38----Lys. 163 7

rTNF alpha facilitates highly reproducible adherence of polymorphonuclear leukocyte (PMN) to fibrinogen-coated surfaces in a concentration- and time-dependent manner. The adhesion was maximal with 1.0 nM rTNF alpha within 40-50 min at 37 degrees C. A monoclonal antibody (1B4) directed toward the beta 2-chain of the integrin receptor for fibrinogen (CD11b, CD18) completely inhibited the rTNF alpha induced adhesion. TNF alpha caused a time-dependent secretion of the granule markers gelatinase and lactoferrin but no liberation of myeloperoxidase and minimal production of A alpha(1-21), a specific cleavage product of fibrinogen generated by elastase, as markers for the azurophilic granule. PMN adhered to fibrinogen in the presence of rTNF alpha could be further stimulated with cytochalasin B and N-formyl-methionyl-leucyl-phenylalanine (FMLP) to release azurophilic granule markers as measured by increasing MPO activity and A alpha(1-21) production over time. Thus the rTNF alpha-facilitated adherence of PMN to a fibrinogen matrix provides a system for partial activation of PMN resulting in release of markers of specific and tertiary but not azurophilic granules. Moreover, these conditions should provide an opportunity to define more clearly the signal transduction processes involved in azurophilic granule release.
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PMID:rTNF alpha facilitates human polymorphonuclear leukocyte adherence to fibrinogen matrices with mobilization of specific and tertiary but not azurophilic granule markers. 164 33

The effect of auranofin on granule protein secretion from neutrophils was investigated by a haemolytic plaque assay which can detect release of lactoferrin and myeloperoxidase from single adherent neutrophils. Lactoferrin secretion in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) was enhanced at low (0.25-1.0 micrograms/ml) and inhibited at high concentrations of auranofin (50% inhibition (IC50) at 3.7 micrograms/ml). A similar biphasic effect was also seen on degranulation mediated by granulocyte-macrophage colony stimulating factor (GM-CSF) (IC50 1.8 micrograms/ml). In contrast, exocytosis mediated by tumour necrosis factor was inhibited even at low concentrations of auranofin (IC50 0.6 micrograms/ml). Secretion induced by phorbol 12-myristate 13-acetate and A23187 was only inhibited at very high auranofin concentrations (IC50 10 and 8 micrograms/ml respectively). The effect of auranofin on myeloperoxidase secretion was also assessed and the IC50 values for the respective agents were as follows: tumour necrosis factor 0.7 micrograms/ml, fMLP 1.6 micrograms/ml, and phorbol myristate acetate 7.6 micrograms/ml. When neutrophils were preincubated with auranofin (4 micrograms/ml) and then exposed to fMLP, tumour necrosis factor, or GM-CSF in the absence of auranofin, lactoferrin release was enhanced if the preincubation time was short (one to three minutes) and inhibited when the time of preincubation was longer. It was concluded that auranofin, at concentrations achieved in the serum of patients, is a potent inhibitor of cytokine induced release of granule proteins from adherent neutrophils. This finding may be of clinical importance and shed light on the mechanism by which auranofin acts in rheumatoid arthritis.
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PMID:Effect of auranofin on cytokine induced secretion of granule proteins from adherent human neutrophils in vitro. 164 54

We found inhibitors, designated aseanostatins P1 and P5, against myeloperoxidase (MPO) release from human polymorphonuclear leukocytes (PMN). Aseanostatins were extracted from an actinomycete isolated in Thailand and purified by a series of column chromatography of charcoal and silica gel, and HPLC. Physico-chemical characterization by gas liquid chromatography and GC-MS indicated that aseanostatins were fatty acids. The active forms of aseanostatins were recovered by hydrolyzing their methyl esters after HPLC. Two components P1 and P5 with the IC50 of 0.96 and 0.54 microgram/ml to the MPO release were obtained as pure forms, indicating aseanostatin P5 was higher activity than aseanostatin P1. The component P1 was identical with 12-methyltridecanoic acid and P5 was indistinguishable to 12-methyltetradecanoic acid (ante-i-15:0). Aseanostatin P5 (1 microgram/ml) did not inhibit beta-glucuronidase release, but O2- production a little. It has no effect on chemotaxis of PMN to fMet-Leu-Phe (10(-8)M), PMN adhesion or phosphorylation of a 64-kD protein in the PMN cell-lysate system.
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PMID:Purification and characterization of aseanostatins: actinomycete-derived fatty acid inhibitors to myeloperoxidase release from human polymorphonuclear leukocytes. 164 56


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