Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The aim of this work was to study the ability of human alveolar macrophages (AM) of 10 healthy smokers to inactivate alpha 1-proteinase inhibitor (alpha 1PI). Purified alpha 1PI was incubated for 45 min, with human alveolar macrophages before and after stimulation by phorbol myristate acetate (PMA) or opsonized zymosan. As a positive control, the same experiments were performed in parallel with blood human neutrophils (PMN). Results are expressed as percentage of inactivation of alpha 1PI as evaluated from its inhibitory activity against porcine pancreatic elastase. A strong correlation (r = 0.99) was shown when inhibitory activity of alpha 1PI was evaluated against porcine pancreatic elastase or human neutrophil elastase. Unstimulated AM (1.57 +/- 0.9%) as well as stimulated AM (PMA: 1 +/- 0.4%; zymosan: 3 +/- 0.6%) were unable to inactivate alpha 1PI. Gel electrophoresis of alpha 1PI demonstrated that AM before or after stimulation induced a slight proteolysis of alpha 1PI, whereas both cleaved and complexed alpha 1PI were found when alpha 1PI was incubated with activated PMN. Both unstimulated (22 +/- 2.6%) and activated PMN (PMA: 91.7 +/- 4.7%; zymosan: 90 +/- 5.5%) were responsible for a significant inactivation of alpha 1PI. Catalase, in contrast to superoxide dismutase, was responsible for a near complete protection of alpha 1PI inactivation by PMN. To better determine the role of PMN secretory products, especially myeloperoxidase (MPO), we also investigated the effect of zymosan-activated PMN supernatants or of purified MPO on the alpha 1PI-AM reaction. MPO assay in PMN supernatants demonstrated that activated neutrophils released significant amounts of MPO (16.8 +/- 4.1 U/ml), whereas MPO was undetectable in activated AM supernatants.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1991 Nov
PMID:Oxidative inactivation of alpha 1-proteinase inhibitor by alveolar macrophages from healthy smokers requires the presence of myeloperoxidase. 165 63

C-reactive protein (CRP) has been reported to deposit only to inflammatory sites, but not to normal sites. In present paper, we investigated involvements of fibronectin and lysophosphatidylcholine (lyso-PC) as responsible for this selectivity. In ELISA assay, CRP was found to bind to immobilized fibronectin with dose dependency, only in the presence of Ca2+ ions. Addition of 5 mM EDTA allowed CRP to abolish this binding. However, it could not be inhibited neither by phosphorylcholine nor by heparin. On the other hand, CRP could aggregate liposome consisted of lyso-PC and phosphatidylcholine (PC), but not that consisted of PC alone. Aggregation was found to be maximum when liposome with lyso-PC/PC molar ratio of 0.3 was used. Similar result was also observed in binding study with peroxidase-labelled CRP. In addition, phospholipase A2 treatment of liposome consisted of PC alone induced 3-fold higher binding than that found with untreated one. Ca2+ ions were required for binding to liposome.
Cell Mol Biol 1991
PMID:Involvements of fibronectin and lysophosphatidylcholine for selective binding of C-reactive protein. 165 91

During short term culture of murine resident peritoneal macrophages, increasing the temperature from 37 to 39 degrees C resulted in an increased activity of several surface receptors (FcR and receptor for gluteraldehyde-fixed sheep red blood cells), enhanced phagocytosis of yeast particles, improved spreading, and an accelerated reduction of nitroblue tetrazolium. At 41 degrees C, however, significant reduction of several functional properties (endocytosis of colloidal gold and horseradish peroxidase, phagocytosis of yeast particles) and a decrease in the reduction of nitroblue tetrazolium, the incorporation of tritiated uridine, and Fc and C3b surface receptor activity were observed. In addition morphological evidence of apoptosis, observed in a small number of cells cultured at 39 degrees C and in the majority of macrophages maintained at 41 degrees C, was confirmed by DNA electrophoresis. The data indicates that a reduction of several functional activities of macrophages occurs at 41 degrees C and apoptosis may largely account for these effects.
Exp Mol Pathol 1991 Oct
PMID:The effect of mild hyperthermia on the morphology and function of murine resident peritoneal macrophages. 165 30

EPR spectroscopy was used to study the effects of various nonsteroidal anti-inflammatory agents on the peroxidase-related tyrosyl radical present in prostaglandin H synthase (prostaglandin endoperoxide synthase; EC 1.14.99.1). Two types of perturbation of the tyrosyl radical by these anticyclooxygenase agents were observed. In the first case, aspirin, indomethacin, ibuprofen, (S)-flurbiprofen, and (S)-naproxen converted the doublet tyrosyl EPR signal seen on reaction of the uninhibited enzyme with ethyl hydroperoxide to a singlet bearing additional partially resolved hyperfine splittings. These compounds also decreased the maximum amount of radical generated, but they did not change the kinetics of formation and decay of the tyrosyl radical. In the second case, acetaminophen and three fenamate analogs (meclofenamate, flufenamate, and mefenamate) did not perturb the EPR line shape observed after reaction with hydroperoxide but did cause a more rapid decay of the tyrosine radical species. It would appear that, despite considerable variation in structure, the nonsteroidal anti-inflammatory agents may inhibit the cyclooxygenase activity of the synthase by two basic mechanisms.
Mol Pharmacol 1991 Nov
PMID:Prostaglandin H synthase: perturbation of the tyrosyl radical as a probe of anticyclooxygenase agents. 165 13

The use of clozapine, a unique antipsychotic drug, has been restricted due to a 1-2% incidence of drug-induced agranulocytosis. Metabolic activation of clozapine in neutrophils or stem cells could be the molecular mechanism underlying this side effect. Clozapine oxidation by human myeloperoxidase and horseradish peroxidase was evident from the disappearance of the UV absorbance at 290 nm. High performance liquid chromatography analysis revealed the formation of at least four radioactive peaks as a result of clozapine metabolism, including radioactivity coeluting with the protein. The tight association of radioactivity with the enzymatic protein was metabolism-dependent. This protein binding, which correlates with the total metabolism of clozapine, was reduced in the presence of glutathione and was absent in the presence of ascorbate. Similarly, in the presence of both reducing agents, the metabolite peaks in the high performance liquid chromatography radiogram, which are not associated with protein, disappeared. In contrast, in the presence of glutathione, two additional metabolites were found that could be isolated and identified by NMR and mass spectroscopy as clozapine glutathionyl adducts. Evidence for one-electron transfer reactions or the intermediate formation of a clozapine radical during the peroxidase-mediated metabolism of clozapine stems from the observation of thiyl and ascorbyl radicals in the presence of glutathione and ascorbate, respectively. The ascorbyl radical was detected by direct ESR spectroscopy in a peroxidase system. Its steady state concentration was significantly increased in the presence of clozapine. Glutathionyl radical formation was demonstrated by radical trapping with 5,5-dimethyl-1-pyrroline N-oxide in a peroxidase system. Again, the radical adduct concentration was significantly increased in the presence of clozapine. Similarly, when oxygen consumption was measured in peroxidase systems in the presence of glutathione or NADPH, the rate of oxygen uptake was markedly enhanced upon addition of clozapine. Thus, the data support the possibility of clozapine activation to free radical metabolites, which may cause oxidative stress or lead to adduct formation. Further, it can be concluded from these data that radical scavengers such as ascorbic acid, when coadministered with clozapine to patients, may reduce oxidative stress and protein adduct formation.
Mol Pharmacol 1991 Nov
PMID:Possible role of free radical formation in clozapine (clozaril)-induced agranulocytosis. 165 15

A myotoxic phospholipase A2, named bothropstoxin II (BthTX-II), was isolated from the venom of the South American snake Bothrops jararacussu and the pathogenesis of myonecrosis induced by this toxin was studied in mice. BthTX-II induced a rapid increase in plasma creatine kinase levels. Histological and ultrastructural observations demonstrate that this toxin affects muscle fibers by first disrupting the integrity of plasma membrane, as "delta lesions" were the earliest morphological alteration and since the plasma membrane was interrupted or absent in many portions. In agreement with this hypothesis, BthTX-II released peroxidase entrapped in negatively charged multilamellar liposomes and behaved as an amphiphilic protein in charge shift electrophoresis, an indication that its mechanism of action might be based on the interaction and disorganization of plasma membrane phospholipids. Membrane damage was followed by a complex series of morphological alterations in intracellular structures, most of which are probably related to an increase in cytosolic calcium levels. Myofilaments became hypercontracted into dense clumps which alternated with cellular spaces devoid of myofibrillar material. Later on, myofilaments changed to a hyaline appearance with a more uniform distribution. Mitochondria were drastically affected, showing high amplitude swelling, vesiculation of cristae, formation of flocculent densities, and membrane disruption. By 24 hr, abundant polymorphonuclear leucocytes and macrophages were observed in the interstitial space as well as inside necrotic fibers. Muscle regeneration proceeded normally, as abundant myotubes and regenerating myofibers were observed 7 days after BthTX-II injection. By 28 days regenerating fibers had a diameter similar to that of adult muscle fibers, although they presented two distinctive features: central location of nuclei and some fiber splitting. This good regenerative response may be explained by the observation that BthTX-II does not affect blood vessels, nerves, or basal laminae.
Exp Mol Pathol 1991 Dec
PMID:Skeletal muscle degeneration and regeneration after injection of bothropstoxin-II, a phospholipase A2 isolated from the venom of the snake Bothrops jararacussu. 166 Aug 22

Treatment of immature rats with estradiol (E2) produced a large increase in uterine peroxidase activity which was accompanied by an increase in eosinophil chemotactic factor (ECF-U). The synthesis of complement C3 was also induced in the uterus and the amount of this 180 kDa protein was determined both by immunoprecipitation and after separation by polyacrylamide gel electrophoresis. Testosterone (T) did not produce an increase in any of these parameters although it antagonized the estrogen-induced increase in uterine peroxidase activity and these effects were more pronounced in estrogen-primed animals. This antagonism was prevented by the antiandrogen, flutamide. Testosterone showed little effect on eosinophil chemotactic activity and did not inhibit the E2-stimulated synthesis of C3. The results with T were supported by the lack of any significant effect by flutamide which antagonizes receptor-mediated androgenic events. These findings are discussed in relation to the action of other types of hormonal steroids (progesterone, dexamethasone) in inhibiting these estrogen-induced molecular changes in the rat uterus and contribute to our understanding of steroid-steroid interaction and the regulation of uterine function.
Mol Cell Endocrinol 1991 Oct
PMID:Complement C3 synthesis, peroxidase activity and eosinophil chemotaxis in the rat uterus: effect of estradiol and testosterone. 166 25

Amyloid deposition in 11 inbred strains of mice (A/J, SJL/J, DDD, C57BL/6J, B10.BR, C57BL/10, B10A/SgSn, C3H/HeMs, B10A(5R), DBA/2 and C57BL/6Cr5/c) was studied using the peroxidase antiperoxidase (PAP) method and antisera against ASSAM and murine protein AA. Among the 170 mice examined, in 77 (45.3%) from the nine strains other than C3H/HeMs and DBA/2, there was evidence of spontaneous amyloid deposits in routine histological sections. Immunohistochemical studies using 54 mice with amyloid deposition, demonstrated ASSAM deposition in 45 mice (83.3%) in all nine strains, although the incidence and intensity of the deposition differed somewhat between strains. SJL/J and A/J had ASSAM deposits from the age of 8 months and the incidence increased with advancing age. In the other seven strains, ASSAM was first deposited at an older age than in the SJL/J and A/J strains. In A J, C57BL/6J, C57BL/10, B10.BR, B10A(5R) and C57BL/6Cr5/c, protein AA often coexisted with ASSAM. The distribution pattern of the ASSAM deposits was similar to that observed among the SAM strains. Thus, ASSAM is an ubiquitously distributed senile amyloid protein in the mouse. Determination of the molecular type of apoA-II, a serum precursor of ASSAM, among all 11 strains using the polymerase chain reaction (PCR) revealed the SAM-P/1 type apoA-II variant in SJL/J and A/J strains with a high susceptibility to ASSAM deposition. We concluded from this study that amino acid substitution in precursor apoA-II may be responsible for the early onset and severe amyloid deposition in the mouse.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Mouse senile amyloidosis. ASSAM amyloidosis in mice presents universally as a systemic age-associated amyloidosis. 168 11

For the electron microscopic identification of asialo GM1-positive cells, fresh-frozen sections fixed with cold acetone and PLP-fixed vibratome sections of adult rat livers were prepared immunocytochemically using the avidin-biotin-peroxidase complex method. Asialo GM1-positive cells were located mainly in the sinusoids, and rarely in Glisson's sheath and portal veins. In the sinusoids, most pit cells, showing the ultrastructural characteristics of large granular lymphocytes (LGL), were positive for asialo GM1 but a few pit cells were asialo GM1-negative. There were several, morphological differences between asialo GM1-positive and -negative pit cells. The asialo GM1-negative pit cells were smaller and had less-developed cell organelles and fewer dense granules, suggesting a more immature stage of development. Almost all the monocytes, segmented neutrophils and eosinophils, and small or large lymphocytes in the sinusoids also showed positive reaction for asialo GM1. In Glisson's sheath, in addition to pit cells and lymphocytes, mast cells were also positive for asialo GM1. In contrast, fixed cells such as liver parenchymal cells, endothelial cells, Kupffer cells and Ito cells within the liver lobules, as well as biliary epithelial cells, smooth muscle cells, fibroblasts, endothelial cells and pericytes in Glisson's sheath were all negative for asialo GM1. Thus, cell surface asialo GM1 expression is not specific for pit cells (LGL) in the rat liver.
Virchows Arch B Cell Pathol Incl Mol Pathol 1991
PMID:Immunoelectron microscopic identification of asialo GM1-positive cells in adult rat liver. 168 55

The antigenic sites on the major allergen from yellow mustard (Sinapis alba L.) seeds were studied using murine (BALB/c) monoclonal antibodies (mAb) and human IgE antibodies. Ten IgG1 (K) mAb from two fusions were analyzed. Competition and complementation studies performed with peroxidase labeled mAb reveal the existence of two main antigenic sites in Sin a I. All the described mAb failed to recognize the unordered carboxyamidomethylated polypeptide chains, with the single exception of 2B3, which binds the alkylated large chain. However, this mAB cannot react with the tetranitromethane-modified protein which retains the native conformation. This fact suggests that the only tyrosine of Sin a I, located in the large chain, may be part of a sequential epitope of the allergen. This chemical modification also alters the binding of the mAb 4A11 and 3F3 to the allergen, besides 2B3. The three mAb belong to the same complementation group. Specific IgE binding cannot be inhibited either by the large or small carboxyamidomethylated polypeptide chains, while the nitrated allergen shows a weaker inhibitory activity than the native Sin a I. 4A11, which is a tyrosine-dependent mAb, causes the greatest binding inhibition of the tested mAb on human IgE from atopic individuals, as determined from a reverse enzyme immunoassay, suggesting an important role played by tyrosine in the immunochemical recognition of Sin a I.
Mol Immunol 1990 Feb
PMID:Epitope mapping of the major allergen from yellow mustard seeds, Sin a I. 169 Aug 53


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