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 nitrovasodilator and nitric oxide donor molsidomine and its metabolite SIN-I dilate vascular smooth muscle and inhibit platelet activation by increasing intracellular concentrations of cyclic GMP. We have therefore studied the effects of molsidomine and SIN-I on isolated human polymorphonuclear leucocytes (PMN) in vitro and ex vivo. In vitro molsidomine dose-dependently reduced beta-glucuronidase release and the generation of superoxide anions from non-activated and from FMLP- or PAF-stimulated human PMNs. SIN-I was equally effective in reducing beta-glucuronidase release and totally inhibited oxygen radical generation at a concentration of 580 mumol.l-1. In a double-blind, placebo-controlled, randomized trial we also studied beta-glucuronidase release and the generation of superoxide anions from isolated PMNs. Blood was drawn from 12 healthy volunteers before and 3 h after oral molsidomine (16 mg) or placebo. There was no statistically significant difference in beta-glucuronidase release and superoxide anion formation when the PMNs were isolated before or after molsidomine or placebo. This was the case for non-activated, as well as FMLP- or PAF-stimulated PMNs. Thus, the nitric oxide donors molsidomine and its metabolite SIN-I caused a dose-dependent inhibition of PMN functions in vitro, but no significant inhibition when the PMNs were isolated after oral molsidomine.
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PMID:The effects of the nitric oxide donors molsidomine and SIN-I on human polymorphonuclear leucocyte function in vitro and ex vivo. 133 22

Chemical alteration of the glucocorticoid, methylprednisolone, has led to the introduction of a new class of compounds called the 21-aminosteroids (21-ASs). The purpose of this study was to investigate the effect of the 21-AS, U74389G, on silica-induced acute lung injury. Male Fischer 344 rats were treated intraperitoneally with saline or U74389G in a total dose of 15 mg/kg divided into three injections of 5 mg/kg separated by 4 h. Following the first treatment, animals from the two groups were intratracheally instilled with silica (10 mg/100 g body wt in 0.5 ml of saline) or saline vehicle (0.5 ml). Twenty-four hours after the instillations, bronchoalveolar lavage (BAL) was performed. In the animals not receiving U74389G, marked increases in total protein, beta-glucuronidase, and lactate dehydrogenase (LDH) activities and number of neutrophils (PMNs) were demonstrated in the BAL fluid of the silica-treated animals compared to their controls. Silica also caused dramatic increases in the luminol-dependent chemiluminescence (CL) of lung tissue and BAL cells. The CL reaction was decreased by superoxide dismutase (SOD) and N-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide (NO) synthase inhibitor. In animals treated with U74389G, there was attenuation of the silica-induced increases in biochemical, cellular, and chemiluminescent indices of damage. This study demonstrates that U74389G significantly reduces acute lung injury caused by the intratracheal instillation of silica, and this drug may be of potential value for treatment of lung diseases in which damage caused by reactive oxygen species has been implicated.
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PMID:Attenuation of acute inflammatory effects of silica in rat lung by 21-aminosteroid, U74389G. 770 90

1. Xanthenone-4-acetic acid (XAA) is an experimental antitumour agent which resembles flavone-8-acetic acid in its induction of cytokine synthesis, nitric oxide production and tumour haemorrhagic necrosis. We have investigated the excretion and metabolic fate of XAA in the BDF1 mouse. 2. XAA was administered intravenously at the maximal tolerated dose (1090 mumol/kg). Urine, plasma and bile were collected and subjected to analysis by hplc. Urine samples demonstrated labile metabolites which released XAA following incubation with beta-glucuronidase/sulphatase or at pH 9.0. The structures of isolated XAA metabolites were characterized by ms or 1H-NMR spectra at 400 MHz. 3. The major metabolite pathway of XAA involves conjugation with glucuronic acid, since the resulting metabolite, XAA acyl glucuronide, accounts for 25% of the dose excreted in the urine. Other metabolite pathways include alpha-oxidation of the acetic acid side chain and aromatic hydroxylation of the xanthenone ring.
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PMID:Disposition of the novel antitumour agent xanthenone-4-acetic acid in the mouse: identification of metabolites and routes of elimination. 797 28

1. The study was designed to test the hypothesis that nitric oxide (NO)-releasing compounds increase guanosine 3':5'-cyclic monophosphate (cyclic GMP) production in human polymorphonuclear leucocytes (PMNs) and concomitantly inhibit PMN functions, i.e. leukotriene B4 (LTB4) synthesis, degranulation, chemotaxis and superoxide anion (O2-) release. The effects of two new NO-releasing compounds, GEA 3162 and GEA 5024 were compared to 3-morpholino-sydnonimine (SIN-1) and S-nitroso-N-acetyl-penicillamine (SNAP). 2. GEA 3162 and GEA 5024 (1-100 microM) inhibited Ca ionophore A23187-induced LTB4 and beta-glucuronidase release, chemotactic peptide FMLP-induced chemotaxis and opsonized zymosan-triggered chemiluminescence dose-dependently in human PMNs. SIN-1 and SNAP were weaker inhibitors. 3. Cellular cyclic GMP production was increased after exposure to NO-donors concomitantly with the inhibition of PMN functions. No alterations in the levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were detected. 4. The results suggest that NO, possibly through increased cyclic GMP, inhibits the activation of human PMNs and may thus act as a local modulator in inflammatory processes.
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PMID:Inhibition by nitric oxide-donors of human polymorphonuclear leucocyte functions. 839

Polymorphonuclear cells (PMN) are the dominating inflammatory cell population in acute tissue injury and contribute to host-defence mechanisms by formation and release of chemical mediators. The aim of the present study was to investigate whether chemoattractant-induced PMN stimulation can be synergistically antagonized by vasodilatory prostaglandins and nitric oxide (NO), both being formed by the vasculature in inflamed areas. PGE1 (10 nM-10 microM) inhibited concentration-dependently formyl-methionyl-leucyl-phenylalanine (fMLP)-induced beta-glucuronidase and oxygen radical (O2.) release from human PMN. The NO donor linsidomine (100 microM) was ineffective, but significantly enhanced PGE1 effects on oxygen radical generation and enzyme release. The non-selective phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) (0.5 mM) potentiated PGE1 effects on all parameters measured. The combination linsidomine (100 microM) plus IBMX (0.5 mM) did not additionally reduce beta-glucuronidase release, but abolished fMLP-stimulated O2. generation. There was a stimulation of cAMP formation by PGE1 but not by linsidomine, both in the absence and presence of IBMX. It is concluded that the effects of linsidomine on PMN function and its synergism with PGE1 are not tightly correlated with total cAMP accumulation. Alternatively, the inhibition of O2. generation by linsidomine may be related to its ability to modulate the activation of the NADPH oxidase system or to scavenge free oxygen radicals.
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PMID:Synergistic inhibition of human polymorphonuclear function by prostaglandin E1 and linsidomine. 886 34

This study was designed to clarify the mechanism of the inhibitory action of a nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) on human neutrophil degranulation. SIN-1 (100-1000 microM) inhibited degranulation (beta-glucuronidase release) in a concentration-dependent manner and concomitantly increased the levels of cGMP in human neutrophils in suspension. However, further studies suggested that neither NO nor increase in cGMP levels were mediating the inhibitory effect of SIN-1 on human neutrophil degranulation because 1) red blood cells or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl added as NO scavengers did not inhibit the effect; 2) inhibitors of cGMP synthesis (methylene blue) or phosphodiesterases (3-isobutyl-1-methylxanthine) did not produce changes in cell function correlating with the changes in cGMP. SIN-1 releases both nitric oxide and superoxide, which together form peroxynitrite. Chemically synthesized peroxynitrite (1-100 microM) did not inhibit, but at high concentrations (1000-2350 microM), it potentiated FMLP-induced beta-glucuronidase release from neutrophils. Thus formation of peroxynitrite from SIN-1 does not explain its inhibitory effects on neutrophil degranulation. The NO-deficient metabolite of SIN-1, SIN-1C (330-1000 microM) inhibited human neutrophil degranulation in a concentration-dependent manner similar to that of SIN-1 and reduced the increase in intracellular free calcium induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine. C88-3934 (330-1000 microM), another NO-deficient sydnonimine metabolite, also inhibited human neutrophil degranulation. In conclusion, the data shows that the NO-donor SIN-1 inhibits human neutrophil degranulation in a cGMP-, NO-, and peroxynitrite-independent manner, probably because of the formation of more stable active metabolites such as SIN-1C. The results demonstrate that studies on the role of NO and/or peroxynitrite carried out with SIN-1 and other NO-donors should be carefully re-evaluated as to whether the effects found are really attributable to NO or peroxynitrite and that in future studies, it will be crucial to carry out control experiments with the NO-deficient metabolites in any studies with sydnonimine NO-donors.
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PMID:3-Morpholino-sydnonimine-induced suppression of human neutrophil degranulation is not mediated by cyclic GMP, nitric oxide or peroxynitrite: inhibition of the increase in intracellular free calcium concentration by N-morpholino-iminoacetonitrile, a metabolite of 3-morpholino-sydnonimine. 914 27

Rat peritoneal macrophages in vitro were infected with Mycobacterium tuberculosis and the fate of M. tuberculosis inside macrophages was monitored. Alteration in the levels of nitric oxide (NO) measured in terms of nitrite formed, hydrogen peroxide (H2O2) and lysosomal enzymes such as acid phosphatase, cathepsin-D and beta-glucuronidase in macrophages following M. tuberculosis infection was also studied. Elevation in the levels of nitrite were observed from 72 h of M. tuberculosis infection. Irrespective of the time point, M. tuberculosis infected macrophages produced elevated levels of H2O2. Maximum increase in the level of acid phosphatase was observed from 72 h of M. tuberculosis infection, whereas maximum elevation in the level of beta-glucuronidase was observed 48 h after M. tuberculosis infection. However these microbicidal agents did not alter the intracellular viability of M. tuberculosis.
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PMID:Fate of Mycobacterium tuberculosis inside rat peritoneal macrophages in vitro. 935 49

The functional properties of infiltrating macrophages (Mphi) must be tightly regulated to facilitate appropriate responses to complex conditions in an inflammatory focus. This study was designed to ascertain whether uncommitted Mphi that have been exposed to combinations of cytokines with opposing functions develop properties dictated by one cytokine or by cytokine mixtures. Uncommitted rat bone marrow-derived Mphi (BMDMs) were incubated with IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, and IL-10 alone or sequentially in combinations. After 48 h, function was assessed by nitric oxide (NO) generation, uptake of apoptotic neutrophils, and beta-glucuronidase expression. IFN-gamma followed 4 h later by TNF-induced NO generation. The pretreatment of BMDMs before IFN-gamma priming with TNF, TGF-beta, and IL-4 suppressed NO generation by 87%, 92%, and 85%, respectively; IL-10 had no effect. The same cytokines administered at 4 h after IFN priming had no effect on NO generation. The uptake of apoptotic polymorphonuclear leukocytes was augmented by TNF (40% vs 29% controls; p < 0.05) and decreased by IFN-gamma, IL-10, and IL-4. The TNF response was unaffected by subsequent treatment with IFN-gamma, IL-4, or IL-10. Similarly, the decreased polymorphonuclear leukocyte uptake induced by IFN-gamma, IL-4, or IL-10 was unaffected by the subsequent addition of TNF. Beta-glucuronidase expression was increased by TGF-beta and decreased by IFN-gamma. These responses were not modified by cytokines with the opposing function. Thus, the functional response of BMDMs to complex mixtures of cytokines was determined by the first cytokine to which they were exposed. Once activated, BMDMs become unresponsive to alternative activating signals, a finding which has obvious implications for Mphi function in vivo.
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PMID:Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines. 971 70

This study examined the properties and responsiveness to cytokines of macrophages purified from normal and nephritic glomeruli to ascertain whether macrophages activated in vivo develop programmed unresponsiveness to cytokines as do bone marrow-derived macrophages in vitro when activated by interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), interleukin-4 (IL-4), or transforming growth factor-beta (TGF-beta). Macrophages from normal glomeruli did not generate nitric oxide (NO) spontaneously but only after treatment with IFN-gamma and TNF-alpha. NO generation by these macrophages was abrogated by administering IL-4, TGF-beta, or TNF-alpha before but not after IFN-gamma treatment. Glomerular macrophages also expressed beta-glucuronidase, which was increased by TGF-beta and decreased by IFN-gamma and TNF. By contrast, glomerular macrophages from rats with nephrotoxic nephritis did not express beta-glucuronidase even after exposure to TGF-beta. Furthermore, they generated NO spontaneously, and this spontaneous generation of NO was not suppressed by IL-4, TGF-beta, or TNF-alpha. Systemic treatment of nephritic rats with IL-4 reduced NO generation by 40% but did not prevent activation, which is similar to the effect of IL-4 on bone marrow-derived macrophages in vitro when given simultaneously with IFN-gamma. We conclude that macrophages infiltrating inflamed glomeruli have developed programmed unresponsiveness to activating cytokines. This may enable them to function appropriately in the complex conditions within an inflammatory focus.
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PMID:Macrophages from inflamed but not normal glomeruli are unresponsive to anti-inflammatory cytokines. 1062 78

This study was designed to evaluate the effects of voluntary exercise on macrophage and lymphocyte functions in mice. Male A/He inbred mice aged 19 weeks were divided into two groups: a group given voluntary exercise and a control group (n = 10 in each group). Exercise consisted of spontaneous running in wheels for 8 weeks (3 days week-1). Glucose consumption of peritoneal macrophages in the exercise group during incubation up to 72 h was significantly higher than that in the control group (70 and 13%, respectively). Also, activities of acid phosphatase (APH) (10.75 +/- 0.37 IU), beta-glucuronidase (GLU) (1.55 +/- 0.07 IU) and lactate dehydrogenase (LDH) (43.3 +/- 0.7 IU) in the peritoneal macrophages in the exercise group was significantly increased (P < 0.01). Compared with the control group, the exercise group had a significant increase of about twofold in macrophage production of nitric oxide (NO2-) stimulated by lipopolysaccharide (LPS) (11.1 +/- 0.1 vs. 5.9 +/- 0.1 microM mL-1 in exercise and control groups, respectively; P < 0.01). Stimulation indices both by concanavalin A (Con A) and phytohaemagglutinin were also significantly higher in the exercise group (P < 0.01). A significant increase in the splenocyte production of interleukin-2 (IL-2) stimulated by Con A was noticed in the exercise group (354.1 +/- 28.8 vs. 218.9 +/- 23.5 pg mL-1 in exercise and control groups, respectively; P < 0.01). These findings suggest that voluntary exercise enhances not only macrophage function but also lymphocyte responsiveness in mice. In the studies of voluntary exercise, evaluation of NO2- production, as an indicator of macrophage function, is recommended.
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PMID:Immunomodulation by 8-week voluntary exercise in mice. 1071 79


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