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 inhibitory effect of a protein isolated from rat serum on lysosomal acid cholesteryl ester hydrolase (acid CEH; EC.3.1.1.13) activity was studied. An inhibitor was purified from rat serum following ultracentrifugation and heat treatment using column chromatography on Sephacryl S-200 and ultrafiltration. The purified inhibitor appeared as a single protein band in sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. The molecular weight of the inhibitor was 28,000 Daltons as judged by gel filtration on Sephacryl S-200 and SDS-polyacrylamide gel electrophoresis. The purified inhibitor was shown to be apolipoprotein A-I (apo A-I), the major apolipoprotein of high-density lipoprotein (HDL), using immunoprecipitation with rat anti-apo A-I immunoglobulin (Ig)G. Inhibition of acid CEH activity by apo A-I was dependent on the concentration of apo A-I. The values of Vmax obtained were similar with or without apo A-I. Apo A-I of various other mammalian species, including human, bovine and rabbit, also inhibited acid CEH activity. Other apolipoproteins, such as apo A-II and apo B, also showed inhibiting activity. On the other hand, apo A-I had no effect on the activity of other enzymes found in lysosomes, such as cathepsin D, beta-glucuronidase and acid phosphatase. The results suggest that apolipoproteins may play a role in the regulation of hydrolysis of cholesteryl esters in lipoproteins, that have been transferred to the liver, and that the inhibition of acid CEH activity by apo A-I may be a characteristic of the lipid-binding protein or be due to changes of the lipid/water interface.
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PMID:Properties of an acid cholesteryl ester hydrolase inhibitor from rat serum. 212 53

Intracisternal granules (ICGs) are insoluble aggregates of pancreatic digestive enzymes and proenzymes that develop within the lumen of the rough endoplasmic reticulum of exocrine pancreatic cells, especially in guinea pigs. These ICGs are eliminated by autophagy. By morphological criteria, we identified three distinct and sequential classes of autophagic compartments, which we refer to as phagophores, Type I autophagic vacuoles, and Type II autophagic vacuoles. Lobules of guinea pig pancreas were incubated in media containing HRP for periods of 5-120 min to determine the relationship between the endocytic and autophagic pathways. Incubations with HRP of 15 min or less labeled early endosomes at the cell periphery that were not involved in autophagy of ICGs, but after these short incubations none of the autophagic compartments were HRP positive. After 30-min incubation with HRP, early endosomes at the cell periphery, late endosomes in the pericentriolar region, and, in addition, Type I autophagic vacuoles containing ICGs were all labeled by the tracer. Type II autophagic vacuoles were not labeled after 30-min incubation with HRP but were labeled after incubations of 60-120 min. Phagophores did not receive HRP even after 120 min incubations. We concluded that the autophagic and endocytic pathways converge immediately after the early endosome level and that Type I autophagic vacuoles precede Type II autophagic vacuoles on the endocytic pathway. We studied the distribution of acid phosphatase, lysosomal proteases and cation-independent-mannose-6-phosphate receptor (CI-M6PR) in the three classes of autophagic compartments by histochemical and immunocytochemical methods. Phagophores, the earliest autophagic compartment, contained none of these markers. Type I autophagic vacuoles contained acid phosphatase but, at most, only very low levels of cathepsin D and CI-M6PR. Type II autophagic vacuoles, by contrast, are enriched for acid phosphatase, cathepsin D, and other lysosomal enzymes, and they are also enriched for CI-M6PR. Moreover, soluble fragments of bovine CI-M6PR conjugated to colloidal gold particles heavily labeled Type II but not Type I autophagic vacuoles, and this labeling was specifically blocked by mannose-6-phosphate. This indicates that the lysosomal enzymes present in Type II autophagic vacuoles carry mannose-6-phosphate monoester residues. Using 3-C2, 4-dinitroanilino-3'-amino-N-methyldipropylamine (DAMP), we showed that Type II autophagic vacuoles are acidic. We interpret these findings as indicating that Type II autophagic vacuoles are a prelysosomal compartment in which the already combined endocytic and autophagic pathways meet the delivery pathway of lysosomal enzymes.
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PMID:In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome. 216 50

The lysosomal proteolytic capacity of mouse brown adipose tissue (BAT) and its role during fasting were evaluated. The specific activities of acid phosphatase and cathepsins B, D, H, and L were measured in BAT of mice acclimated at 33, 21, and 4 degrees C and in BAT undergoing different rates of protein loss during a 24- to 48-h fast. The specific activities of lysosomal proteases in BAT did not vary with the acclimation status of the animals. Mice acclimated at 33 degrees C showed no significant atrophy of BAT after a fast. In mice kept at 21 degrees C, protein loss from BAT was observed after a fast without change in tissue DNA content. Protein loss from BAT was partially reduced by injection of the acidotropic agent chloroquine. Furthermore, tyrosine release from BAT during fasting was also reduced by injections of chloroquine or leupeptin, a thiol-protease inhibitor. Tyrosine release from BAT was maximum within 24 h and returned to prefast values by 36 h, suggesting rapid activation followed by inhibition of the tissue proteolytic activity. However, there was no change in acid protease specific activities, suggesting that these enzymes were not limiting for protein degradation. When cold-acclimated mice were fasted at 21 degrees C, BAT protein loss was markedly enhanced and increases in cathepsin D and L activities were observed, but there was no change in cathepsin B and H and acid phosphatase specific activities. These results indicate that BAT contains an important lysosomal proteolytic pathway that is involved in the rapid reduction of the tissue thermogenic capacity during a fast.
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PMID:Role of acid proteases in brown adipose tissue atrophy caused by fasting in mice. 218 82

The synthesis and secretion of pro-cathepsin D is increased by estrogens in MCF7 cells. We quantified the effect of estradiol on other lysosomal enzymes in order to investigate the mechanism of this hypersecretion. Precursors of beta-hexosaminidase, cathepsin B and beta-galactosidase, which are routed to lysosomes via the mannose-6-phosphate (Man-6-P) receptor, were secreted in much lower amounts than pro-cathepsin D, but their secretion was also increased by estradiol. The activity of acid phosphatase, which is routed to lysosomes via a different transmembrane mechanism, was not altered by estradiol. While estradiol stimulated gene expression of pro-cathepsin D, it had no effect on that of pro-cathepsin B. We conclude that estradiol stimulates the secretion of several lysosomal pro-enzymes in MCF7 cells, suggesting that a general mechanism is responsible for this derouting rather than a specific alteration of cathepsin D structure.
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PMID:Estradiol increases the secretion by MCF7 cells of several lysosomal pro-enzymes. 222 57

The enzymatic activity of creatine phosphokinase and the lysosomal enzymes cathepsin D and acid phosphatase was followed during skeletal muscle regeneration after partial excision to the gastrocnemius muscle in the rat. For each time interval (1, 2, 5, 14 and 45 days) following injury, the activity of the regenerated muscle was compared with the activity in the contralateral sham operated muscle. The specific activity of creatine phosphokinase of the regenerated muscle showed a significant decrease (25%) during the first 2 days post injury and thereafter was comparable to that of the uninjured control muscle. The activity of cathepsin D was 2.3-4-fold significantly higher in the regenerated muscle than in the control intact muscle from day 1 until day 14 post-injury. At 45 days after partial excision, the activity of this enzyme was comparable to a normal muscle. However, the activity of another lysosomal enzyme (acid phosphatase) did not show any distinct changes from the level of this enzyme in the uninjured muscle during the course of muscle regeneration. It is suggested that elevation of lysosomal enzymes in skeletal muscle may not be confined to conditions of muscle wasting and degradation but also to differentiation and development processes such as during muscle regeneration following injury.
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PMID:Proteolytic enzyme activities during regeneration of the rat gastrocnemius muscle. 224 25

Cytolytic lymphocytes contain specialized lytic granules whose secretion during cell-mediated cytolysis results in target cell death. Using serial section EM of RNK-16, a natural killer cell line, we show that there are structurally distinct types of granules. Each type is composed of varying proportions of a dense core domain and a multivesicular cortical domain. The dense core domains contain secretory proteins thought to play a role in cytolysis, including cytolysin and chondroitin sulfate proteoglycan. In contrast, the multivesicular domains contain lysosomal proteins, including acid phosphatase, alpha-glucosidase, cathepsin D, and LGP-120. In addition to their protein content, the lytic granules have other properties in common with lysosomes. The multivesicular regions of the granules have an acidic pH, comparable to that of endosomes and lysosomes. The granules take up exogenous cationized ferritin with lysosome-like kinetics, and this uptake is blocked by weak bases and low temperature. The multivesicular domains of the granules are rich in the 270-kD mannose-6-phosphate receptor, a marker which is absent from mature lysosomes but present in earlier endocytic compartments. Thus, the natural killer granules represent an unusual dual-function organelle, where a regulated secretory compartment, the dense core, is contained within a pre-lysosomal compartment, the multivesicular domain.
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PMID:The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments. 227 62

The enzymatic activity of two lysosomal enzymes, acid phosphatase and cathepsin D, was determined in fetus and during post-natal development of the rat gastrocnemius muscle in comparison to the histological differentiation of this muscle. The specific activity of cathepsin D and acid phosphatase was 7 and 2.5 fold higher in the muscle during development until 20 days after birth, than that of mature muscle, respectively. A trend of gradual decrease in the activity of these enzymes was observed concomitantly with the differentiation and maturation of the muscle from mononucleated cells in the fetus to myotubes formation at day 1 after birth, followed by the formation of "young" and then striated myofibers in 10- and 20-day old neonates, respectively. However, no correlation could be found between the lysosomal enzyme activity and the developmental stages of the muscle until 20 days after birth. It is suggested that the elevated activity of lysosomal acid hydrolases may be associated with late developmental processes from young to mature myofibers in normal skeletal muscle and not only in various pathological conditions.
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PMID:Proteolytic enzyme activity in rat hindlimb muscles in fetus and during post-natal development. 228 66

The specific activity of 4 lysosomal enzymes was studied in homogenate, hepatocytes, Kupffer and endothelial cells isolated from the livers of female Sprague-Dawley rats aged 3.5, 12 and 24 months. Cells were obtained by enzymatic digestion and centrifugal elutriation. Cell viability was not affected by age or diet. In hepatocytes, the activities of all enzymes (acid phosphatase, beta-galactosidase, arylsulfatase B and cathepsin D) increased with age in rats fed ad libitum (A) but were not altered significantly by dietary restriction. The activities of all enzymes except acid phosphatase were systematically higher at 3.5 months of age in Kupffer and endothelial cells than in hepatocytes. Acid phosphatase, arylsulfatase B and cathepsin D activities increased with age in both Kupffer and endothelial cells. Beta galactosidase was decreased significantly with age in Kupffer cells but was elevated in endothelial cells. Rats exposed to dietary restriction (R) showed higher activities of beta-galactosidase, arylsulfatase B and cathepsin D when compared to corresponding A animals with the exception of the younger age group. No clear cut pattern was observed in acid phosphatase activity. Thus, the activities of liver lysosomal enzymes increase with age but the pattern of change differs with respect to enzyme and cell populations. The heightened enzyme activity in Kupffer and endothelial cells from R rats may reflect a more efficient phagocytic capacity in these animals.
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PMID:Characterization of liver lysosomal enzyme activity in hepatocytes, Kupffer and endothelial cells during aging: effect of dietary restriction. 229 Mar 53

The mechanisms of hydrocortisone and adrenalin action on the structure and function of the lysosomal-vacuolar cell apparatus were studied in experiments on liver sections of Wistar rats. The sections were incubated in Krebs-Ringer bicarbonate buffer, pH 7.4 (95% O2 and 5% CO2) at 37 degrees C for 2 h. Hydrocortisone (10(-5) M) and adrenalin (10(-4) M), added to an incubation medium, were shown to produce a labilizing effect on lysosomal membranes, increasing free activity of acid phosphatase and cathepsin D and osmotic sensitivity of lysosomes. alpha-adrenergic blocker dihydroergotamine (3.4 x 10(-5) M) blocked an increase in free activity of acid phosphatase as a result of adrenalin action but did not eliminate hydrocortisone labilizing action. beta-adrenergic blocker propranolol (3 x 10(-4) M) lowered free activity indices and osmotic sensitivity of lysosomes to control values both in the presence of adrenalin and hydrocortisone. The labilization of lysosomal membranes in liver sections was also observed after adding dibutyril-cAMP (10(-8) M) or monobutyril-cGMP (10(-13)-10(-9) M) into the incubation medium.
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PMID:[The mechanism of action of hydrocortisone and adrenaline on the hepatic lysosomal apparatus]. 233 Mar 63

We have investigated the activities of four lysosomal enzymes in RPE cells isolated from three regions of the canine fundus: the tapetal area, the central pigmented area and the peripheral area. The results obtained with freshly isolated cells showed that the activities of acid phosphatase, B-glucuronidase and N-acetyl-B-glucosaminidase were significantly higher in RPE cells derived from the peripheral region when compared to those from the two central regions. In contrast, the activity of cathepsin D was significantly higher in the tapetal region than in the periphery. The regional distribution of both acid phosphatase and B-glucuronidase observed in fresh RPE cells was progressively lost when these cells were grown in culture. Estimations of photoreceptor density per RPE cell from each of the regions indicated that the number of photoreceptors per RPE cell did not vary significantly with retinal location and suggested that variations in enzyme content were not related to differences in photoreceptor cell distribution.
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PMID:Regional distribution of lysosomal enzymes in the canine retinal pigment epithelium. 233 35


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