Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paper presents the results of study of 28 synovial exudations in which the uricase method was used for uric acid determination with simultaneous pyrophosphatase and cathepsin C and D activity determination. The presence of crystals in these exudations was investigated as well. From the study follows that a higher uric acid level and higher pyrophosphatase activity coincide with the finding of urate and pyrophosphate crystals. The reported method of examination applies also to other identifications of microcrystals or crystalline split of urates or calcium pyrophosphate dihydrate in the exudation. The activity of cathepsin D permits to conclude on potential participation of peptides and/or polypeptides in the formation of crystals in the exudation.
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PMID:[Study of crystals in synovial exudations with simultaneous determination of adequate enzymes]. 722 82

Adult rats fed proteins as a meal given during the daytime exhibit alterations of liver protein metabolism characterized by simultaneous stimulations of protein synthesis and degradation, particularly during the hours following protein ingestion. The purpose of the present work was to determine if the stimulation of liver protein breakdown could be related to biophysical alterations of the lysosomal system. There is a growing amount of evidence to suggest that the lysosomal vacuolar system is involved in the physiological regulation of overall proteolytic rate. Rats, trained to eat a protein meal 2 hrs after the onset of light, were killed 6, 9, 18, 21 and 24 hrs after protein intake. Three fractions were isolated from 0.25 M sucrose liver homogenates after differential centrifugation. The mitochondrial-lysosomal fraction was further analyzed by isopycnic centrifugation in sucrose gradients. Three specific lysosomal enzyme activities were assessed: N-acetyl-beta-D glucosaminidase (marker), cathepsin D and cathepsin C (proteolytic enzymes). Total activities remained unchanged at all time-points, but the distributions between the different fractions recovered after differential centrifugation were altered 6 and 9 hrs after protein intake. A significantly higher percentage of N-acetyl-beta-D-glucosaminidase, cathepsin D and cathepsin C activities were recovered in the M + L fraction, suggesting a shift towards lysosomal forms of lighter density. This was confirmed by density gradient analysis. Thus, even in adapted rats, acute administration of protein during the daytime quickly induced biophysical alterations in the lysosomal system. The lysosomal distribution pattern observed at 6 and 9 hrs after protein intake might be due to lysosome enlargement by active autophagy and/or by the sequestration of lighter cellular material.
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PMID:[Rapid modifications of the rat hepatic lysosomal system as a function of the nutritional state]. 734 31

Degradation of metallothionein (MT) from rat liver was examined. Degradation of apo-MT by liver homogenate was greater than that by cytosol. At pH 5.5, degradation by homogenate was more than that at pH 7.2. These findings suggest that proteases that function at acidic pH are probably involved in MT degradation. Because lysosomes are the principal subcellular organelles that contain acid proteases (cathepsins), we compared the degradation of apo-MT by lysosomes and cytosol. Apo-MT was degraded about 400 times faster by lysosomal fraction than by cytosolic fraction. To determine the relative importance of different cathepsins, we used different inhibitors. Leupeptin, which inhibits cathepsins B and L, inhibited the degradation of apo-MT by 80%, implying that cathepsins B and/or L might be very important in the intracellular turnover of MT. Cathepsin D appeared to be the least significant, because apo-MT degradation was reduced by about 20% by inhibiting cathepsin D. When we extended this study with purified cathepsins, we obtained the same answer, i.e., the ability of different cathepsins to degrade apo-MT was in the following order: cathepsin B >> cathepsin C > cathepsin D. While apo-MT was susceptible to degradation, ZnMT and CdMT were highly resistant to degradation. Coincubation of ZnMT or CdMT with either lysosomal extract or purified cathepsins did not result in any appreciable degradation even after 16 hr. However, longer incubations did result in some degradation, especially by purified cathepsin B. Interestingly, CdMT degraded little faster than ZnMT by both lysosomal extract as well as purified cathepsin B.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro and in vivo studies on the degradation of metallothionein. 784 89

To examine localization of cysteine and aspartic proteinases, and ubiquitin in rat and human urinary bladders, immunocytochemistry was applied to the tissues. In semi-thin sections, immunoreactivity for cathepsins B and D was densely localized throughout epithelial layers of rats and humans, while that for cathepsins H and L was mainly localized in rat superficial and human intermediate cells. Immunoreactivity for cathepsin C was relatively high in rat and human epithelia, especially in humans. Immunoreactivity for ubiquitin was detected in rat and human epithelial cells. By electron microscopy, vesicular or heterogeneously dense lysosomes labeled with immunogold particles indicating cathepsin B were seen in rat and human epithelial cells; particularly, they often appeared near fusiform vesicles in rat superficial cells and in human intermediate and superficial cells. By double immunostaining, lysosomes with or without vesicular structures were co-labeled with immunogold particles showing both cathepsin B and ubiquitin. The results suggest that cathepsins B, C, H, and L, and cathepsin D are involved in the lysosomal system of rat and human bladder epithelia. Moreover, considering that ubiquitin is a cofactor in the soluble ATP-dependent proteolysis, the results may also indicate that epithelial cells actively form autophagolysosomes.
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PMID:Lysosomal cysteine and aspartic proteinases and ubiquitin in rat and human urinary bladder epithelium. 887 57

To elucidate whether pesticide toxicity in higher animals involves pesticide-induced dysfunction of the intracellular protein catabolic process, we have determined the effect in vivo of the organophosphate insecticide pirimiphos-methyl on the activities of representative protein catabolising cytoplasmic and lysosomal proteases (responsible for the various stages of the protein degradation cascade and essential for normal cell functioning) in heart, kidney, brain and liver target tissues in the rat. In liver tissue (the major site of pesticide metabolism), the activities of all of the cytoplasmic proteases investigated (alanyl-, arginyl-, leucyl aminopeptidases, dipeptidyl aminopeptidase IV, tripeptidyl aminopeptidase, proline endopeptidase) were significantly inhibited (by 20-40% of control activity) following administration of 10 mg pirimiphos-methyl/kg bodyweight, whereas of the lysosomal proteases investigated, only the activities of dipeptidyl aminopeptidase I and cathepsin D were significantly reduced (by 15-20% of control activity). In contrast, there was no insecticide-induced inhibition of protease activities in heart, kidney or brain tissues; some lysosomal enzymes (dipeptidyl aminopeptidase I, cathepsins L and D) showed significantly increased activities in these tissues (the reason for which remains to be determined). We conclude that the effect of pirimiphos-methyl on proteolytic enzyme activities differs in different target tissues, and that pirimiphos-methyl induced inhibition of proteases in liver tissue may represent a previously unrecognised toxicity hazard in higher animals.
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PMID:Effect of pirimiphos-methyl on proteolytic enzyme activities in rat heart, kidney, brain and liver tissues in vivo. 920 12

Many parasites have deployed proteinases to accomplish some of the tasks imposed by a parasitic life style, including tissue penetration, digestion of host tissue for nutrition and evasion of host immune responses. Information on proteinases from trematodes, cestodes and nematode parasites is reviewed, concentrating on those worms of major medical and economical importance. Their biochemical characterization is discussed, along with their putative biological roles and, where available, their associated genes. For example, proteinases expressed by the various stages of the schistosome life-cycle, in particular the well-characterized cercarial elastase which is involved in the penetration of the host skin and the variety of proteinases, such as cathepsin B (Sm31), cathepsin L1, cathepsin L2, cathepsin D, cathepsin C and legumain (Sm32), which are believed to be involved in the catabolism of host haemoglobin. The various endo- and exoproteinases of Fasciola hepatica, the causative agent of liver fluke disease, are reviewed, and recent reports of how these enzymes have been successfully employed in cocktail vaccines are discussed. The various proteinases of cestodes and of the diverse superfamilies of parasitic nematodes are detailed, with special attention being given to those parasites for which most is known, including species of Taenia, Echinococcus, Spirometra, Necator, Acylostoma and Haemonchus. By far the largest number of papers in the literature and entries to the sequence data bases dealing with proteinases of parasitic helminths report on enzymes belonging to the papain superfamily of cysteine proteinases. Accordingly, the final section of the review is devoted to a phylogenetic analysis of this superfamily using over 150 published sequences. This analysis shows that the papain superfamily can be divided into two major branches. Branch A contains the cathepin Bs, the cathepsin Cs and a novel family termed cathepsin Xs, while Branch B contains the cruzipains, cathepsin Ls, papain-like and aleurain/cathepsin H-like proteinases. The relationships of the helminth proteinases, and similar proteinases from protozoan parasites and other organisms, within these groups are discussed.
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PMID:Proteinases and associated genes of parasitic helminths. 1021 92

Adverse effects of doxorubicin (adriamycin) have been reported to be due to iron-catalyzed free radical formation, which can be prevented with the cytoprotective chelating agent [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (dexrazoxane; ICRF-187). Affected tissues include the heart, gastrointestinal tract, and kidney. However, there is very little information on the effects of adriamycin on skeletal muscle, despite the fact that there is direct and indirect evidence to show that both adriamycin and ICRF-187 are myotoxic. To investigate the mechanisms of cytotoxicity of these agents in skeletal muscle, we have conducted a systematic investigation of the activities of the major lysosomal (dipeptidyl aminopeptidase I and II and cathepsins B, D, H, and L) and cytoplasmic (alanyl-, arginyl-, and leucyl aminopeptidase, dipeptidyl aminopeptidase IV, tripeptidyl aminopeptidase, and proline endopeptidase) muscle proteases. These enzymes play an important role in normal cellular function and represent potential targets for toxic and protective agents. Male Wistar rats (approx. 0.2 kg) were subjected to a pretreatment phase of 30 min followed by a treatment stage of either 2.5 or 24 h. The pretreatment involved injection of a single bolus of either saline (0.15 mol/l NaCl; 5 ml/kg ip) or ICRF-187 (100 mg/kg; 5 ml/kg ip). After 30 min, rats were injected again with a single bolus of either adriamycin (5 mg/kg; 10 ml/kg ip) or saline (0.15 mol/l NaCl; 10 ml/kg ip) in the treatment phase. At either 2.5 or 24 h after the last adriamycin or saline injection, rats were killed for subsequent dissection of the gastrocnemius muscle for analysis. In the 2.5-h study, there were significant reductions in cathepsin D activities of adriamycin-treated rats compared to saline injected control (p = 0.02). In both 2.5- and 24-h studies there were also significant differences (p = 0.05) in cathepsin H activities between rats treated with adriamycin and ICRF-187, although these differences were not significant when data were compared with corresponding saline-injected rats. There were no other overt effects for any of the other proteases at either 2.5 or 24 h. We conclude that both adriamycin and ICRF-187 have very little effect on the activities of muscle proteases and that altered proteolysis is not involved in the reported pathological reactions induced by these agents.
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PMID:Effects of Doxorubicin (Adriamycin) and [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) on skeletal muscle protease activities. 1124 12

Effect of three epsilon-aminocaproylaminoacids with significant antifibrinolytic activity on chymotrypsin, trypsin, cathepsin B, cathepsin C and cathepsin D activities was examined. Slight inhibition of trypsin and chymotrypsin activity was observed only at high concentrations of these compounds. All tested dipeptides did not influence activities of cathepsin B, cathepsin C and cathepsin D.
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PMID:Effect of epsilon-aminocaproylaminoacids on the activity of proteolytic enzymes. 1150 92

During the final steps of epidermal differentiation, extracellular calcium ions enter keratinocytes and induce transglutaminase activity and cornified envelope formation. In other cell types, entry of calcium mediated by ionophores has been reported to induce exocytosis of lysosomes. In this study, we investigated whether lysosomes of keratinocytes might exhibit a similar behaviour. Ionomycin treatment induced cornified envelope formation in keratinocytes, but also morphological changes including plasma membrane blebbing, although no immediate alteration in cell viability could be detected. The activity of the soluble lysosomal enzymes cathepsin C and beta-galactosidase in the culture medium was increased upon ionomycin treatment. Cell leakage did not seem to be responsible for this phenomenon, as suggested by measurements of the cytosolic enzymes adenylate kinase and dipeptidylpeptidase III in the culture medium. Metabolic labelling followed by immunoprecipitation showed that ionomycin induced release of cathepsin D into the culture medium. Simultaneously, lysosome-associated membrane proteins (Lamps) 1 and 2 were detected at the cell surface of ionomycin-treated keratinocytes by biochemical and morphological approaches. These results suggest that upon ionomycin treatment, calcium entry stimulates exocytosis of lysosomes in keratinocytes.
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PMID:Calcium entry into keratinocytes induces exocytosis of lysosomes. 1512 11

Dermatological diseases range from minor cosmetic problems to life-threatening conditions, as seen in some severe disorders of keratinization and cornification. These disorders are commonly due to abnormal epidermal differentiation processes, which result in disturbed barrier function of human skin. Elucidation of the cellular differentiation programs that regulate the formation and homeostasis of the epidermis is therefore of great importance for the understanding and therapy of these disorders. Much of the barrier function of human epidermis against the environment is provided by the cornified cell envelope (CE), which is assembled by transglutaminase (TGase)-mediated cross-linking of several structural proteins and lipids during the terminal stages of normal keratinocyte differentiation. The major constituents of the stratum corneum and the current knowledge on the formation of the stratum corneum will be briefly reviewed here. The discovery of mutations that underlie several human diseases caused by genetic defects in the protein or lipid components of the CE, and recent analyses of mouse mutants with defects in the structural components of the CE, catalyzing enzymes, and lipid processing, have highlighted their essential function in establishing the epidermal barrier. In addition, recent findings have provided evidence that a disturbed protease-antiprotease balance could cause faulty differentiation processes in the epidermis and hair follicle. The importance of regulated proteolysis in epithelia is well demonstrated by the recent identification of the SPINK5 serine proteinase inhibitor as the defective gene in Netherton syndrome, cathepsin C mutations in Papillon-Lefevre syndrome, cathepsin L deficiency infurless mice, targeted ablation of the serine protease Matriptase/MTSP1, targeted ablation of the aspartate protease cathepsin D, and the phenotype of targeted epidermal overexpression of stratum corneum chymotryptic enzyme in mice. Notably, our recent findings on the role of cystatin M/E and legumain as a functional dyad in skin and hair follicle cornification, a paradigm example of the regulatory functions exerted by epidermal proteases, will be discussed.
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PMID:Epidermal differentiation: the role of proteases and their inhibitors. 1567 20


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