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)

Leupeptin, a nontoxic thiol protease inhibitor, has been proposed to have therapeutic use in hereditary muscular dystrophies. The purpose of this study was to characterize the in vivo changes in proteolytic activity of skeletal muscles induced by the repeated administration of leupeptin. Further, whether the modulation of proteolytic capacity by leupeptin affects the repair process of muscle injuries caused by heavy exercise was studied. Leupeptin was administered in mice intraperitoneally at a dose level of 15.5 mg/kg twice a day for 9 days. Leupeptin, known to be an inhibitor of cathepsin B both in vitro and after a single injection in vivo, paradoxically induced an increase of cathepsin B activity in mouse skeletal muscles after repeated administration. In addition, leupeptin administration for 9 days increased the activities of cathepsins C and D, as well as the rate of acid autolysis. The activity of beta-glucuronidase also increased, while those of arylsulfatase, ribonuclease, and alkaline protease were unaffected. No histopathologic changes were observed. At the low dosage used, leupeptin had no effect on the repair process of skeletal muscle after exercise injuries, although several proteolytic processes occur during the regeneration. It is suggested that the increase of acid protease activities in skeletal muscles is an adaptive response to the administration of the proteolytic inhibitor leupeptin and that leupeptin can be administered without prevention or delay of regenerative processes after the onset of myopathic changes.
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PMID:Effects of the protease inhibitor leupeptin on proteolytic activities and regeneration of mouse skeletal muscles after exercise injuries. 638 26

The activities per microgram DNA of five lysosomal enzymes [cathepsin D, cathepsin B, beta-N-acetylglucosaminidase (beta-NAG), beta-glucuronidase, and acid phosphatase] were measured in homogenates of female and male rat (Sprague-Dawley) hearts. Female rats were studied during stages of the estrous cycle and at 3 weeks after ovariectomy. Three-week-postovariectomized female rats and intact male rats were injected subcutaneously with 17 beta-estradiol-3-benzoate. Lysosomal enzyme activities in the male rat heart were more responsive to exogenous estradiol than were activities in the female rat heart. Cathepsin B, beta-NAG, and beta-glucuronidase were increased dramatically in the male rat heart upon short-term administration of estrogen (4 days). In both female and male rat hearts, activities of two lysosomal proteinases, cathepsins B and D, were reduced significantly (approximately 50%) by extended administration of estrogen for 10 days.
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PMID:Effect of estrogen on lysosomal enzyme activities in rat heart. 651 19

In dystrophic hamsters, increases in the levels of cathepsin B plus L and thiol proteinase inhibitor were marked in skeletal muscle, but only slight in heart muscle. The lysosomal hydrolases did not increase in parallel in dystrophic muscle: cathepsin B plus L and beta-glucuronidase increased, but cathepsin C and acid phosphatase did not. In immunohistochemical studies with antibodies against rat liver cathepsin B and thiol proteinase inhibitor, the proteinase and inhibitor were both stained in phagocytes, chiefly macrophages, but not in muscle cells, indicating that the increases in cathepsin B plus L and thiol proteinase inhibitor in dystrophic muscle are due to their presence in invading phagocytes. The levels of cathepsin B plus L, beta-glucuronidase and thiol proteinase inhibitor in isolated peritoneal macrophages were 50 to 180 times higher than those in skeletal muscle, but the levels of acid phosphatase and cathepsin C were only about 10 to 30 times those in skeletal muscle. Plots of the cathepsin B plus L activities versus the level of thiol proteinase inhibitor in homogenates of tissues of various animals showed an exponential rather than a linear relation between the two activities, suggesting that the syntheses of the proteinases are higher than that of the inhibitor in phagocytes invading dystrophic muscle.
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PMID:Increases in cathepsins B and L and thiol proteinase inhibitor in muscle of dystrophic hamsters. Their localization in invading phagocytes. 653 Apr

Chloroquine-resistant (CQr) clones (CQ-21 and CQ-22) have been isolated from mutagenized hamster lung V79 cells by exposing the cells to a high dose of chloroquine. CQ-21 and CQ-22 showed about 3-fold higher resistance to chloroquine than the parental V79 cells, and they showed specific cross-resistance to another amine, NH4Cl, which is also concentrated in lysosomes. CQr clone showed no cross-resistance to other unrelated agents. Chloroquine-induced inhibition of [125I]ricin internalization was observed in both cell lines at neutral pH, but the inhibition of uptake was less in the variant. Also, the degradation of endogenous protein was slowed in the mutant; further, treatment of cells with 30 micrograms/ml of chloroquine inhibited the degradation of endogenous proteins in the parental V79, but not in CQ-22 cells. Similar levels of acid phosphatase, beta-glucuronidase and cathepsin D were observed in V79 and CQ-22 cells, but the level of cathepsin B was lower in the mutant. Electron microscopy showed an increased number of electron-dense bodies, possibly autophagosomes/lysosomes, in the mutant cells grown for 4 days with 5 micrograms/ml of chloroquine. Similar aberrant structures were observed in the parental V79 cells treated for only 3 h with 5 micrograms/ml of chloroquine.
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PMID:Isolation of chloroquine-resistant Chinese hamster V79 cell variants that are also resistant to ammonium chloride. 665 68

Cultures of non-elicited mouse peritoneal macrophages were used as a test system to study the effect of sera from patients with rheumatoid arthritis (RA) on intra-cellular cathepsin B activity of macrophages. Sequential sera obtained during and after pregnancy from six RA patients, and sera from six actively ill, non-pregnant RA patients were compared to six healthy female controls and 3rd trimester healthy women. Sera from actively ill RA patients (both pregnant and non-pregnant) caused macrophage cathepsin B levels significantly above normal controls, while intra-cellular activities of beta-glucuronidase and N-acetyl-glucosaminidase did not differ from the controls. A significant correlation between activity of RA and intracellular cathepsin B was found in pregnant patients. It is suggested that a factor (or factors) present in serum from patients with active RA causes a rise of intracellular cathepsin B in macrophages.
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PMID:Stimulation of murine macrophage cathepsin B by serum from patients with rheumatoid arthritis: an indicator of disease activity. 683 68

In solid s.c. tumors of a variant of the murine B16 melanoma with high metastatic potential (B16F10), there was a 2- to 7-fold elevation of lysosomal cathepsin B activity when compared to the B16F1 variant with low metastatic potential. The highest activities (based on either protein or DNA) of cathepsin B were found in tumors of less than 1 g. When B16F1 and B16F10 melanoma variants were grown in tissue culture, the metastatic differential in cathepsin B activity was lost as the cells were subcultured. However, this differential in cathepsin B activity could be restored by reestablishing the cultured cells as s.c. tumors. The activities of four other lysosomal enzymes (cathepsin D, beta-N-acetylglucosaminidase, beta-glucuronidase, and acid phosphatase) showed little evidence of a positive correlation with the metastatic potential of the B16 melanoma variants. Eighty to 90% of cathepsin B activity has been localized to a fraction containing viable tumor cells which was isolated by centrifugal elutriation. In contrast, only 50% of cathepsin D activity was in the viable tumor cell fraction, and from 30 to 70% of beta-N-acetylglucosaminidase, beta-glucuronidase, and acid phosphatase. Elevated levels of cathepsin B in the high metastatic B16F10 variant are consistent with the idea that cathepsin B may play a direct or a regulatory role in tumor metastasis.
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PMID:Cathepsin B activity in B16 melanoma cells: a possible marker for metastatic potential. 705 93

The mononuclear cell fraction of rat hind-limb muscle was obtained by digestion with clostridial collagenase in the presence of calcium ions, filtration through nylon screens and washing to remove the enzyme. Final traces of contaminant myofibrillar debris were separated by isopycnic centrifugation in a Percoll density gradient. Whole muscle, washed cells and Percoll-fractionated cells were extracted in the presence of non-ionic detergent and the supernatants assayed for the lysosomal enzymes cathepsins B + L, N-acetyl-beta-glucosaminidase, beta-glucuronidase and protein. The enzyme levels were highest in the muscle from young rats, but the percentage of recovered activity in the mononuclear cell fraction was little altered by the age of the animal. The values obtained were: cathepsin B + L, 2.4-4.0%; N-acetyl-beta-glucuronidase, 4.3-7.6%; and beta-glucuronidase, 6.3-10.3%. Because of unavoidable losses in preparation these are minimal values and the actual levels of activity from the mononuclear cell fraction in muscle would be higher. The specific activity values of the cell lysates were raised after isopycnic centrifugation and were nearly constant over the age range 65-180 days. Substantially higher specific activity values were obtained for the cells from rats of 38 days. When grown in culture the mononuclear cell fractions were seen to contain mainly fibroblasts and myoblasts with only few leucocytes. The cultures reached confluence by the second week, at which time numerous myotubes had formed. In addition there were groups of large, circular cells with a prominent centrosphere. The origin of these latter cells is uncertain. It was concluded that although total lysosomal enzyme activity was higher in young rats there was little effect of age on the distribution of activity between muscle fibres and mononuclear cells in the muscle.
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PMID:The mononuclear cell population in rat leg muscle: its contribution to the lysosomal enzyme activities of whole muscle extracts. 718 82

The prion encephalopathies are characterized by accumulation in the brain of the abnormal form PrPsc of a normal host gene product PrPc. The mechanism and site of formation of PrPsc from PrPc are currently unknown. In this study, ME7 scrapie-infected mouse brain was used to show, both biochemically and by double-labelled immunogold electron microscopy, that proteinase K-resistant PrPsc is enriched in subcellular structures which contain the cation-independent mannose 6-phosphate receptor, ubiquitin-protein conjugates, beta-glucuronidase, and cathepsin B, termed late endosome-like organelles. The glycosylinositol phospholipid membrane-anchored PrPc will enter such compartment for normal degradation and the organelles may therefore act as chambers for the conversion of PrPc into infectious PrPsc in this murine model of scrapie.
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PMID:The abnormal isoform of the prion protein accumulates in late-endosome-like organelles in scrapie-infected mouse brain. 756 56

Osteoclast-mediated bone resorption is accomplished by secretion of lysosomal proteases into an acidic extracellular compartment. We have previously demonstrated that avian osteoclasts and human osteoclast-like giant cell tumor cells respond in vitro to treatment with 17 beta-estradiol (17 beta-E2) by decreased bone resorption activity. To better understand the mechanism by which this is accomplished, we have investigated the effects of 17 beta-E2 treatment on lysosomal enzyme production and secretion by isolated avian osteoclasts and multinucleated cells from human giant cell tumors in vitro. Isolated cells were cultured with bone particles in the presence of either vehicle or steroid. The conditioned media and cells were harvested, and the levels of cathepsin B, cathepsin L, beta-glucuronidase, lysozyme, and tartrate-resistant acid phosphatase (TRAP) activities were determined. There was a steroid dose-dependent decrease in secreted levels of these enzymes. Cell-associated levels of cathepsin L, beta-glucuronidase, and lysozyme decreased; whereas cell-associated levels of cathepsin B and TRAP increased. These changes were measurable at 10(-10) M and maximal at 10(-8) M 17 beta-E2. The changes were detectable at 4-18 h of treatment and increased through 24 h of treatment. The response was steroid specific, since the inactive estrogen isomer, 17 alpha-E2, failed to alter the activity levels. Moreover, the effects of 17 beta-E2 were blocked when the cells were treated simultaneously with the estrogen antagonist ICI182-780 in conjunction with 17 beta-E2. Human osteoclast-like cells obtained from giant cell tumors of bone responded similarly to estrogen with respect to cathepsin B, cathepsin L, and TRAP activities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Estrogen modulation of osteoclast lysosomal enzyme secretion. 775 64

Inactivators of cysteine proteinases (CPs) were tested as inhibitors of bone resorption in vitro and in vivo. The following four CP inactivators were tested: Ep475, a compound with low membrane permeability which inhibits cathepsins B, L, S, H, and calpain; Ep453, the membrane-permeant prodrug of Ep475; CA074, a compound with low membrane permeability which selectively inactivates cathepsin B; and CA074Me, the membrane-permeant prodrug of CA074. The test systems consisted of 1) monitoring the release of radioisotope from prelabelled mouse calvarial explants and 2) assessing the extent of bone resorption in an isolated osteoclast assay using confocal laser microscopy. Ep453, Ep475, and CA074Me inhibited both stimulated and basal bone resorption in vitro while CA074 was without effect; the inhibition was reversible and dose dependent. None of the inhibitors affected protein synthesis, DNA synthesis, the PTH-enhanced secretion of beta-glucuronidase, and N-acetyl-beta-glucosaminidase, or the spontaneous release of lactate dehydrogenase. Ep453, Ep475, and CA074Me dose-dependently inhibited the resorptive activity of isolated rat osteoclasts cultured on bone slices with a maximal effect at 50 microM. The number of resorption pits and their mean volume was reduced, whilst the mean surface area remained unaffected. Again, CA074 was without effect. Ep453, Ep475, and CA074Me, but not CA074, when administered subcutaneously at a dose of 60 micrograms/g body weight inhibited bone resorption in vivo as measured by an in vivo/in vitro assay, by about 20%. This study demonstrates that cathepsins B, L, and/or S are involved in bone resorption in vitro and in vivo. Whilst cathepsin L and/or S act extracellularly, and possibly intracellularly, cathepsin B mediates its effects intracellularly perhaps through the activation of other proteinases involved in subosteoclastic collagen degradation.
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PMID:Inhibition of bone resorption by selective inactivators of cysteine proteinases. 780 85


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