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:3.2.1.31 (beta-glucuronidase)
7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of nonsteroidal anti-inflammatory agents on superoxide production and granule enzyme release by human polymorphonuclear leukocytes stimulated with either formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe] or immune complexes were investigated. Cytochrome c reduction and the release of lysozyme, beta-glucuronidase, myeloperoxidase and gelatinase were measured. Auranofin, phenylbutazone, sulfasalazine and the phospholipase A2 inhibitor, 4-bromophenacyl bromide, strongly inhibited these responses in fMet-Leu-Phe stimulated cells, at concentrations below 50 microM. Indomethacin, piroxicam, mefenamic acid, primaquine and quinacrine at 50-250 microM were inhibitory. Up to 1 mM ibuprofen and chloroquine inhibited superoxide production but had little effect on degranulation. With cells stimulated by IgG aggregates (immune complexes), up to 1 mM ibuprofen, mefenamic acid and piroxicam did not inhibit either response. Indomethacin, phenylbutazone, sulfasalazine and primaquine inhibited, but considerably higher concentrations were required than with fMet-Leu-Phe. Quinacrine inhibited superoxide production equally well with both stimuli but inhibited enzyme release only with fMet-Leu-Phe. Only auranofin, 4-bromophenacyl bromide, and the weakly effective chloroquine exerted approximately the same effect with both stimuli. D-Penicillamine did not affect enzyme release with either stimulus and interfered in the superoxide assay. Gelatinase release induced by fMet-Leu-Phe was affected to the same extent, or slightly more, than release of the other granule enzymes. With immune complexes, there was only modest inhibition of gelatinase release by any of the drugs at 250-1000 microM. Our results reinforce previous observations that many anti-inflammatory drugs affect neutrophil functions, but their effects vary with stimulus. The relative insensitivity of immune complex-induced responses to most of the drugs must be taken into account when considering their mode of action.
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PMID:Inhibition by nonsteroidal anti-inflammatory drugs of superoxide production and granule enzyme release by polymorphonuclear leukocytes stimulated with immune complexes or formyl-methionyl-leucyl-phenylalanine. 303 27

Sphinganine has been proposed to be a specific inhibitor of protein kinase C. In the present study we have evaluated whether sphinganine is a convenient tool to probe for the role of protein kinase C in neutrophil function. Human neutrophils were loaded with the fluorescent probe quin2 and then tested in parallel for cytosolic free Ca2+, [Ca2+]i, membrane potential changes, O2- production, and exocytosis of primary granules (containing beta-glucuronidase) in response to various stimuli. In addition to inhibiting O2- production and exocytosis in a dose-dependent manner, sphinganine also blocked formyl-methionyl-leucyl-phenylalanine-induced [Ca2+]i, transients. Furthermore, sphinganine inhibited exocytosis elicited by the calcium ionophore ionomycin. Although sphinganine blocked O2- production due to phorbol 12-myristate 13-acetate, the most striking finding was that the drug rendered the cells leaky. Thus, at similar concentrations as those inhibiting cellular functions, sphinganine was shown to lead to cell permeabilization, as assessed by release of quin2 and cytoplasmic markers into the extracellular medium, and changes in plasma membrane potential. We conclude, therefore, that sphinganine does not appear to be a suitable compound for the evaluation of the involvement of protein kinase C in neutrophil activation.
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PMID:Nonselective inhibition of neutrophil functions by sphinganine. 303 65

In order to determine whether cystic fibrosis neutrophils are affected in their secretory functions, lysosomal enzyme release and chemiluminescence (light emission from cells) were assayed in patients' cells and compared with those in normal control cells. We observed a decreased response of cystic fibrosis neutrophils in beta-glucuronidase release and chemiluminescence after stimulation by N-formyl-methionyl-leucyl-phenylalanine. There was no significant correlation of these results with the clinical score nor with the medical treatment. On the other hand, responses to the calcium ionophore A23187 and to opsonized zymosan showed no significant difference between normal and cystic fibrosis subjects in lysosomal enzyme release. N-formyl-methionyl-leucyl-phenylalanine receptor alterations did not seem involved in the observed effect as demonstrated by Scatchard plot analysis of N-formyl-methionyl-leucyl-phenylalanine binding to these receptors. These results clearly demonstrate a difference between normal and cystic fibrosis neutrophils in release and chemiluminescence responses to N-formyl-methionyl-leucyl-phenylalanine stimulation, a difference that might be located in the plasma membrane as both responses are membrane dependent.
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PMID:Alteration of the N-formyl-methionyl-leucyl-phenylalanine-induced response in cystic fibrosis neutrophils. 308 28

Recombinant human tumour necrosis factor alpha (rHuTNF alpha) was shown to inhibit human neutrophil migration in the presence or absence of a chemotactic gradient generated with the tripeptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), at doses of 20-100 U/10(6) cells. In contrast, neither recombinant human interleukin-1 alpha (rHuIL-1 alpha), rHuIL-1 beta, human leucocyte-derived IL-1 alpha (1HuIL-1 alpha) nor 1HuIL-1 beta contained neutrophil migration inhibition properties. However, both the interleukins (1HuIL-1 alpha, 1HuIL-1 beta and rHuIL-1 alpha) and rHuTNF alpha stimulated a neutrophil respiratory burst and significantly elevated the neutrophil respiratory response to fMLP (measured as chemiluminescence and H2O2 production). The stimulatory effects were observed at doses of between 5 and 100 U/5 x 10(5) cells. A characteristic feature of the effects of the cytokines was the range of variation observed in neutrophil responses from different individuals. However, a concentration-related effect was observed with each experiment, delineating suboptimal, optimal and supra-optimal cytokine concentrations. Neutrophils treated with rHuTNF alpha and rHuIL-1 alpha and washed free of exogenous cytokine retained the capacity to show an enhanced response to fMLP. Pretreatment of cells with cytochalasin B enhanced their response to fMLP, and this response was further increased if the cells had also been pretreated with the cytokines. The response to phorbol myristate acetate was also enhanced by rHuTNF alpha and rHuIL-1 alpha. The effects of these cytokines on neutrophils could be abolished by boiling the preparation but not by treating it with polymixin B, suggesting that bacterial lipopolysaccharide was not responsible for the activity of these preparations. The rHuIL-1 alpha increased the release of lysozyme, beta-glucuronidase and myeloperoxidase initiated by cytochalasin B/fMLP, while rHuTNF alpha only increased lysozyme release.
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PMID:Effects of tumour necrosis factor alpha and interleukin-1 alpha and beta on human neutrophil migration, respiratory burst and degranulation. 328 22

The effect of two synthetic serine esterase inhibitors, N-alpha-dansyl(p-guanidino)phenylalaninepiperidine hydrochloride (I 2581) and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (D-Phe-Pro-Arg-CH2Cl), on bone resorption in organ cultured mouse calvaria from neonatal mice has been examined. Mineral mobilization was assessed by analyzing the release of 45Ca, stable calcium (Ca2+) and inorganic phosphate (Pi). Organic matrix degradation was studied by analyzing the release of 3H from [3H]proline-labelled bones, and by quantifying the amounts of hydroxyproline in bone after culture. It was found that I 2581, at and above 30 mumol/l, dose-dependently inhibited 45Ca release induced by thrombin, parathyroid hormone (PTH), prostaglandin E2 and 1-alpha-hydroxyvitamin D-3. I 2581 (50 mumol/l) inhibited PTH-stimulated release of 3H from [3H]proline-labelled bones, and this effect was reversible after withdrawal of I 2581. I 2581 (50 mumol/l) inhibited the release of Ca2+, Pi, beta-glucuronidase and beta-N-acetylglucosaminidase in bones stimulated by PTH and 1-alpha-hydroxyvitamin D-3, without affecting the release of lactate dehydrogenase. In parallel, I 2581 decreased PTH and 1-alpha-hydroxyvitamin D-3 induced reduction of hydroxyproline levels in bones after culture. I 2581 (50 mumol/l) did not affect the basal release of 45Ca, Ca2+, beta-glucuronidase and beta-N-acetylglucosaminidase, nor the basal amounts of hydroxyproline in bones after culture. D-Phe-Pro-Arg-CH2Cl (100 mumol/l) significantly inhibited PTH- and PGE2-induced release of 45Ca without affecting basal release of radioactive calcium. These data indicate that activation of serine proteinase(s) may be a necessary step in the mechanism of action of several stimulators of bone resorption.
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PMID:Inhibition of bone resorption in vitro by serine-esterase inhibitors. 334 54

Previous studies have shown that hyperosmotic media inhibit secretion in many cells and this has been interpreted to be a direct effect on membrane fusion during exocytosis. This conclusion is complicated, however, by our recent study in neutrophils (Biochim. Biophys. Acta 931: 175-179, 1987) showing that both calcium signals and enzyme release are inhibited by hyperosmolality. In this report, we extend these observations by demonstrating that chemotactic peptide formylmethionyl-leucyl-phenylalanine (FMLP)-induced enzyme release, secretory granule-plasma membrane fusion, and cytosolic calcium signals are all inhibited by similar increases in medium osmolality. The extent of beta-glucuronidase release is decreased in hyperosmotic media and its dose dependence is shifted to higher FMLP concentrations. Inhibition is rapid, reversible, and independent of osmoticant. Freeze-fracture replicas of quick-frozen neutrophils show that granules of cells stimulated in hyperosmotic media do not undergo fusion nor do they have specialized interactions with the plasma membrane or with membranes of adjacent granules. Calcium signals monitored and quantitated by indo-1 fluorescence during secretion confirmed the presence of three phases the calcium dependence of which we have described previously: 1) an initial peak of calcium that is independent of extracellular calcium and is inhibited 70% at high osmolality; 2) a broad shoulder of elevated calcium levels 30-90 s after stimulation that is dependent on extracellular calcium and is totally blocked at high osmolality; and 3) a plateau of lower but above basal calcium 2-5 min after stimulation that is dependent on extracellular calcium but is relatively unaffected by high osmolality. These results suggest that the FMLP-elicited calcium signal is a composite of multiple signaling events and that hyperosmotic inhibition of secretion, at least in neutrophils, may result from an impaired calcium signal in addition to the direct effect it has on exocytosis.
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PMID:Hyperosmotic inhibition of calcium signals and exocytosis in rabbit neutrophils. 336 56

The effects of two co-carcinogenic phorbol esters (phorbol myristate acetate (PMA) and phorbol dibutyrate (PDBu] and a synthetic diacylglycerol (OAG, 1-oleoyl-2-acetyl-glycerol), which all stimulate protein kinase C, were compared with two inactive phorbol compounds (4 alpha-phorbol and 4 alpha-phorbol didecanoate (4 alpha-PDD)) on three functional properties of stimulated human polymorphonuclear leukocytes (PMNs): release of granular enzymes lysozyme and beta-glucuronidase, chemokinesis, and changes in cytoplasmic free calcium [Ca2+]i. PMA, PDBu and the diacylglycerol, OAG, all caused a dose-dependent and slow (max by 15 min) release of small amounts of lysozyme with much less beta-glucuronidase and no release of cytoplasmic lactate dehydrogenase. Release was unaffected by removal of extracellular Ca2+. PMA, PDBu and OAG inhibited random movement of the cells, did not cause chemokinesis and induced a slow reduction in the basal [Ca2+]i, as measured by the quin-2 method. PMA, PDBu and OAG increased the capacity of five independently-acting stimulants (N-formyl-Met-Leu-Phe, leukotriene B4, C5a des-Arg, platelet activating factor and A23187) to cause release of lysozyme and beta-glucuronidase but strongly inhibited PMN chemokinesis induced by the same five agents and reduced the stimulant-induced increases in [Ca2+]i. PMA was always more potent than PDBu and much more potent than OAG in eliciting these stimulatory or inhibitory effects on human PMNs. In all tests, 4 alpha-phorbol and 4 alpha-PDD were inactive. The results confirm that stimulation of the diacylglycerol/protein kinase C system in human PMN, either by active phorbol esters or the synthetic diacylglycerol, causes bidirectional effects on human PMN function. In particular, activation of the C-kinase causes inhibition of stimulated neutrophil motility, whereas the secretory functions of the cells are enhanced.
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PMID:Divergent effects of co-carcinogenic phorbol esters and a synthetic diacylglycerol on human neutrophil chemokinesis and granular enzyme secretion. 347 47

Human neutrophils can be permeabilized with the cholesterol complexing agent digitonin and then induced to secrete lysosomal constituents by increases in free Ca2+ alone. In order of increasing requirements for Ca2+, vitamin B-12 binding protein, lysozyme and beta-glucuronidase were released. A variety of guanine nucleotides were examined with respect to their abilities to modulate this response. GTP, along with its analogues 5'-guanylylimidodiphosphate (Gpp[NH]p) and guanosine-5'-O-[3-thio]-triphosphate (GTP[gamma S]) decreased the Ca2+ requirements for secretion of all three granule constituents by one third to one order of magnitude. This synergy was dependent upon the concentration of guanine nucleotides employed. The effects of Gpp[NH]p could be blocked with the inactive derivative GDP[beta-S]. The active guanine nucleotides, particularly GTP, served as stimuli in their own right. At high concentrations of Ca2+ and GTP, degranulation was strikingly inhibited; inhibition was also achieved with high concentrations of guanylyl[beta, gamma-methylene]diphosphate (Gpp[CH2]p). Both GDP and GMP were without any effect. When neutrophils were pretreated with pertussis toxin, granule discharge induced by fMet-Leu-Phe was almost completely blocked, as reported by others. If the neutrophils pretreated with pertussis toxin were then permeabilized with digitonin, the synergy between Ca2+ and the stimulatory guanine nucleotides was maintained. These data suggest the involvement of G-proteins in secretion induced by Ca2+; however, this response either uses a different G-protein or a different pool of G-proteins from those responses triggered by fMet-Leu-Phe.
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PMID:Guanine nucleotides reduce the free calcium requirement for secretion of granule constituents from permeabilized human neutrophils. 353 3

Culture medium conditioned by mononuclear leucocytes (MNL) stimulated by formalin-fixed heat-killed Staphylococcus aureus (sCM) modulated a number of neutrophil functions. The sCM inhibited the locomotion of human neutrophils in both the presence and absence of a chemotactic gradient generated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP). It also stimulated the oxygen-dependent respiratory burst as assessed by its ability to stimulate basal H2O2, superoxide and chemiluminescence production by neutrophils. Neutrophils treated with sCM also showed increased release of lysozyme but not beta-glucuronidase. In addition, the sCM-treated neutrophils showed a potentiated response to stimuli that bind surface receptors, i.e. FMLP and opsonized zymosan. The effects of sCM and either of the stimuli were synergistic. Examination of lysosomal enzyme release showed that sCM enhanced the release of lysozyme and beta-glucuronidase induced by either FMLP/cytochalasin B or zymosan. The response to phorbol myristate acetate (PMA), which bypasses the surface receptor, was also stimulated but compared poorly with the FMLP response. The sCM effects on the FMLP-induced chemiluminescence response occurred even when FMLP addition was delayed for 4 hr. Cells treated with sCM and washed retained the ability to show an enhanced FMLP response. The neutrophil-modulating activity was not produced by MNL cultured in the absence of bacteria.
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PMID:Staphylococcus aureus-stimulated human mononuclear leucocyte-conditioned medium augments the basal and stimuli-induced neutrophil respiratory burst and degranulation. 357 Mar 57

In vitro degranulation of polymorphonuclear leukocytes, which were stimulated either with synthetic chemotactic peptide (N-formyl-methionyl-leucyl-phenylalanine, FMLP) or with C3b-opsonized zymosan as a promotor of phagocytosis, was studied in 66 patients with psoriasis, 18 lesion-free psoriatics, 18 healthy subjects, and 14 other dermatological disorder controls. Stimulated release of lysozyme (from specific granules and azurophil granules) and beta-glucuronidase (from azurophil granules) in the presence of both FMLP and serum-activated zymosan was markedly reduced in patients with actively spreading guttate psoriatic lesions, in whom relapse of lesions lasted for less than 1 month and papules involved about 13-25% of skin surface. In contrast, stimulated degranulation was within normal range in active plaque psoriasis, stationary plaque psoriasis, symptomless psoriatics, and patients with disseminated eczema. Spontaneous release of lysozyme and beta-glucuronidase (background) was found to be not different in all groups studied; however, patients with active guttate psoriasis had significantly lower total lysozyme activity than those with active and stationary plaque psoriasis as well as psoriatics in the remission. These data are in favor of in vivo activation of neutrophils in active guttate psoriasis by some factors related to the early relapse of the lesions. This results in a possible combination of the following phenomena: (1) in vivo partial degranulation of neutrophils; (2) induction of "unresponsiveness state" of these cells to subsequent in vitro stimulation; and/or (3) migration of highly responsive neutrophils to skin lesions, which leaves in the circulation the subpopulation less reactive to chemotactic and phagocytic stimuli.
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PMID:Decreased extracellular release of granule enzymes from in vitro-stimulated polymorphonuclear leukocytes in guttate psoriasis. 371 May 63


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