Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activities of four lysosomal and two nonlysosomal hydrolases were studied in skeletal muscle biopsy samples from patients with neuromuscular diseases and from controls. beta-Glucosaminidase activity was increased in polymyositis. beta-Glucuronidase and alkaline protease activities were elevated in muscular dystrophy in adults, whereas cathepsin D activity was increased in amyotrophic lateral sclerosis. There were significant correlations between the activities of lysosomal and nonlysosomal hydrolases. The activity of beta-glucuronidase, beta-glucosaminidase, alkaline protease, and dipeptidyl aminopeptidase IV showed a positive correlation with the severity of muscular atrophy. The activities of these hydrolases and the activity of dipeptidyl aminopeptidase I correlated positively with the activities of muscular galactosylhydroxylysyl glucosyltransferase and with the serum concentration of type III procollagen aminoterminal propeptide. The results suggest that in neuromuscular diseases the lysosomal and nonlysosomal pathways for muscle degradation are affected concomitantly with collagen biosynthesis.
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PMID:Lysosomal and nonlysosomal hydrolases of skeletal muscle in neuromuscular diseases. 635 16

Alcohol can be considered as a nutritional toxin when ingested in excess amounts and leads to skeletal muscle myopathy. We hypothesized that altered protease activities contribute to this phenomenon, and that differential effects on protease activities may occur when: (1) rats at different stages in their development are administered alcohol in vivo; (2) acute ethanol treatment is superimposed on chronic alcohol-feeding in vivo; and (3) muscles are exposed to alcohol and acetaldehyde in vivo and in vitro. In acute studies, rats weighing approximately 0.1 kg (designated immature) or approximately 0.25 kg (designated mature) body weight (BW) were dosed acutely with alcohol (75 mmol/kg BW; intraperitoneal [IP], 2.5 hours prior to killing) or identically treated with 0.15 mol/L NaCl as controls. In chronic studies, rats (approximately 0.1 kg BW) were fed between 1 to 6 weeks, with 35% of dietary energy as ethanol, controls were identically treated with isocaloric glucose. Other studies included administration of cyanamide (aldehyde dehydrogenase inhibitor) in vivo or addition of alcohol and acetaldehyde to muscle preparations in vitro. At the end of the treatments, cytoplasmic (alanyl-, arginyl-, leucyl-, prolyl-, tripeptidyl-aminopeptidase and dipeptidyl aminopeptidase IV), lysosomal (cathepsins B, D, H, and L, dipeptidyl aminopeptidase I and II), proteasomal (chymotrypsin-, trypsin-like, and peptidylglutamyl peptide hydrolase activities) and Ca(2+)-activated (micro- and milli-calpain and calpastatin) activities were assayed. (1) Acute alcohol dosage in mature rats reduced the activities of alanyl-, arginyl- and leucyl aminopeptidase (cytoplasmic), dipeptidyl aminopeptidase II (lysosomal), and the chymotrypsin- and trypsin-like activities (proteosomal). No significant effects were observed in similarly treated immature rats. (2) Alcohol feeding in immature rats did not alter the activities of any of the enzymes assayed at 6 weeks. (3) In immature rats, activities of cathepsins B and D were not overtly affected at either 3, 7, 14, 28, or 42 days. (4) Superimposing acute (2.5 hours) on chronic (4 weeks feeding of immature rats) ethanol treatment (ie, chronic + acute) reduced the activities of cytoplasmic proline aminopeptidase and the chymotrypsin- and trypsin-like activities of the proteasome. (5) Cathepsin D activities were reduced in muscle homogenates upon addition of alcohol and acetaldehyde in vitro. (6) Cyanamide pretreatment in combination with alcohol dosage in immature rats did not significantly alter any protease activities. The data suggests that mature rats are more sensitive to the effects of acute alcohol on muscle proteases. Protease activities may be affected by acetaldehyde or alcohol levels as indicated by in vitro experiments. The reduction in muscle protease activities in chronic + acute alcohol superimposition may reflect the effect of acute alcohol dosage alone. Overall, there was no evidence for increased protease activity in any of the experimental situations.
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PMID:Effect of acute and chronic alcohol treatment and their superimposition on lysosomal, cytoplasmic, and proteosomal protease activities in rat skeletal muscle in vivo. 1178 79

Rat gastrocnemius showed increased protein degradation (+75-115%) at 48 h after traumatic injury. Injured muscle showed increased cathepsin B activity (+327%) and mRNA encoding cathepsin B (+670%), cathepsin L (+298%), cathepsin H (+159%), and cathepsin C (+268%). In in situ hybridization, cathepsin B mRNA localized to the mononuclear cell infiltrate in injured muscle, and only background levels of hybridization were observed either over muscle cells in injured tissue or in uninjured muscle. Immunogold/electron microscopy showed specific staining for cathepsin B only in lysosome-like structures in cells of the mononuclear cell infiltrate in injured muscle. Muscle cells were uniformly negative in the immunocytochemistry. Matrix metalloproteinase-9 (granulocyte-macrophage gelatinase) mRNA and activity were not present in uninjured muscle but were expressed after trauma. There was no activation of the ATP-ubiquitin-proteasome-dependent proteolytic pathway in injured muscle, by contrast to diverse forms of muscle wasting where the activity of this system and the expression of genes encoding ubiquitin and proteasome elements rise. These results suggest that proteolytic systems of the muscle cells remain unstimulated after local injury and that lysosomal enzymes of the inflammatory infiltrated cells are likely to be the major participant in protein catabolism associated with local trauma.
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PMID:Increased muscle proteolysis after local trauma mainly reflects macrophage-associated lysosomal proteolysis. 1178 64

Recent studies have linked necrotic cell death and proteolysis of inflammatory proteins to the adaptive immune response mediated by the lysosome-destabilizing adjuvants, alum and Leu-Leu-OMe (LLOMe). However, the mechanism by which lysosome-destabilizing agents trigger necrosis and proteolysis of inflammatory proteins is poorly understood. The proteasome is a cellular complex that has been shown to regulate both necrotic cell death and proteolysis of inflammatory proteins. We found that the peptide aldehyde proteasome inhibitors, MG115 and MG132, block lysosome rupture, degradation of inflammatory proteins and necrotic cell death mediated by the lysosome-destabilizing peptide LLOMe. However, non-aldehyde proteasome inhibitors failed to prevent LLOMe-induced cell death suggesting that aldehyde proteasome inhibitors triggered a pleotropic effect. We have previously shown that cathepsin C controls lysosome rupture, necrotic cell death and the adaptive immune response mediated by LLOMe. Using recombinant cathepsin C, we found that aldehyde proteasome inhibitors directly block cathepsin C, which presumably prevents LLOMe toxicity. The cathepsin B inhibitor CA-074-Me also blocks lysosome rupture and necrotic cell death mediated by a wide range of necrosis inducers, including LLOMe. Using cathepsin-deficient cells and recombinant cathepsins, we demonstrate that the cathepsins B and C are not required for the CA-074-Me block of necrotic cell death. Taken together, our findings demonstrate that lysosome-destabilizing adjuvants trigger an early proteolytic cascade, involving cathepsin C and a CA-074-Me-dependent protease. Identification of these early events leading to lysosome rupture will be crucial in our understanding of processes controlling necrotic cell death and immune responses mediated by lysosome-destabilizing adjuvants.
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PMID:A proteolytic cascade controls lysosome rupture and necrotic cell death mediated by lysosome-destabilizing adjuvants. 2489 7