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)

Casein-induced amyloidosis in hamsters was found to be of the AA-type, as shown by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and amino acid analysis of the major low-molecular weight component of the amyloid fibrils. Levels of serum amyloid A (SAA) and the activities of cathepsin D, beta-N-glucosaminidase, serine esterase, lactate dehydrogenase (LDH) and gamma glutamyl transpeptidase (GGT) were measured in the blood plasma during induction of amyloidosis. During the pre-amyloid phase an increase was observed in all these parameters. During the deposition of amyloid, an increase was observed in the activities of the lysosomal enzymes cathepsin D and beta-N-glucosaminidase, which was significantly correlated with amyloid deposition. Serine esterase activities did not show any relationship to amyloid deposition. LDH and GGT activities were normal in the amyloid phase. SAA levels were lower during amyloid deposition than during the pre-amyloid phase. These findings indicate that a specific release of lysosomal contents from mononuclear phagocytic cells is involved in the pathogenesis of AA-amyloidosis. Amyloid deposition may be the result of: (i) extrusion of intralysosomal protein AA or pre-amyloid, followed by extracellular formation of amyloid fibrils; (ii) secretion of lysosomal enzymes, followed by extracellular cleavage of SAA and subsequent aggregation of protein AA with other components.
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PMID:Activities of lysosomal enzymes and levels of serum amyloid A (SAA) in blood plasma of hamsters during casein induction of AA-amyloidosis. 286 Sep 18

As a first step in studies on the molecular mechanism(s) underlying gentamicin toxicity, the effect of treating rats with this aminoglycoside antibiotic (100 mg/kg once or twice daily for 3 days) on the analytical subfractionation of the kidney cortex has been examined. DNA was used as a marker for the nuclei, cytochrome oxidase for mitochondria, acid phosphatase for lysosomes, catalase for peroxisomes (with reservations; see the companion paper), NADPH-cytochrome c reductase for the endoplasmic reticulum, p-nitrophenyl-alpha-mannosidase (at pH 5.5) for the Golgi apparatus, AMPase for the plasma membrane in general and alkaline phosphatase for the brush border, and lactate dehydrogenase for the cytosol. In addition, the presumptive lysosomal hydrolases N-acetyl-beta-D-glucosaminidase, p-nitrophenyl-alpha-mannosidase (at pH 4.5), cathepsin D, and DNase II were monitored. Electron microscopy was also performed on the subfractions obtained. The only significant biochemical changes brought about by gentamicin treatment were that N-acetyl-beta-D-glucosaminidase demonstrated both a greater total activity and a larger enrichment in the 104,000gav pellet, while p-nitrophenyl-alpha-mannosidase at pH 4.5 demonstrated the same total activity and a greater enrichment in the 104,000gav pellet. Since myeloid bodies were shown by electron microscopy to sediment primarily with the 500gav and 10,000gav pellets, the biochemical changes seen cannot be associated with these morphological structures. These findings suggest that selective changes in a certain subpopulation(s) of lysosomes or in certain lysosomal enzymes may be involved in the early stages of gentamicin toxicity. On the other hand, no lysosomal membrane damage was observed here, since both the latency of acid phosphatase and the recovery of this activity in the soluble cytosol were unchanged. The present investigation may also have relevance for the dosage and duration of gentamicin treatment chosen in clinical situations.
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PMID:Biochemical effects of gentamicin on rat kidney cortex. II. Analytical subfractionation after short-term, high-dose treatment. 303 Aug

The effects of two new calcium entry blockers, anipamil and ronipamil, were studied during 150 min of normoxic or hypoxic perfusion in isolated perfused cat livers. Hypoxic livers in which the vehicle for these inhibitors (i.e., ethanol) was injected intravenously prior to isolation of the liver, exhibited significantly higher increases in perfusion pressure, perfusate lactate dehydrogenase and cathepsin D activities, compared to control normoxic perfused livers. In contrast, the livers isolated from cats pretreated with calcium entry blocker anipamil and subsequently perfused under hypoxic conditions showed no significant difference in any of these variables from the control normoxic perfused livers. Ronipamil given intravenously 30 minutes prior to isolation also significantly protected the liver during hypoxia. The protection afforded by anipamil and ronipamil appears to be related to their inhibition of Ca++ influx which has been linked to cell death in hepatocytes.
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PMID:Beneficial actions of two novel calcium entry blockers in the isolated perfused hypoxic cat liver. 383 86

Administration of leupeptin to rats induces the accumulation of numerous autophagic vacuoles in the liver. Furuno et al. (Furuno, K., Ishikawa, T., and Kato, K. (1982) J. Biochem. (Tokyo) 91, 1485-1494) have recently devised a method for Percoll density gradient equilibrium fractionation of crude lysosomal fractions to isolate a highly enriched preparation of autophagic vacuoles. This system was used to determine whether cytoplasmic enzymes are normally sequestered into autophagic vacuoles in fed animals. Within 30 min following the administration of leupeptin to fed rats, several cytoplasmic enzymes could be demonstrated in vacuolar fractions heavier than mitochondria and normal lyosomes. The activities of tyrosine aminotransferase and lactic dehydrogenase as well as antigens of fructose-bisphosphate aldolase were detectable in fractions with densities of 1.115 to 1.15 g/ml containing cathepsins and acid phosphatase. The cytoplasmic enzymes in these fractions exhibited latency and were sequestered within membranous organelles. Six hours after the administration of leupeptin, the autophagic vacuoles gradually disappeared from these fractions concurrently with the loss of both cytoplasmic and lysosomal marker enzymes. For 6 h after injection of leupeptin the activities of cathepsin D and acid phosphatase increased in autophagic vacuoles and decreased in the postvacuolar lysosomal fraction. Administration of dexamethasone, which induces the synthesis of tyrosine aminotransferase and cytosolic aspartate aminotransferase, selectively increased the sequestration of these enzymes to proportional degrees. Cycloheximide administered simultaneously with leupeptin rapidly inhibited formation of autophagic vacuoles and the sequestrations of both cytoplasmic and lysosomal enzymes. However, when cycloheximide was administered 1 h after leupeptin, the formation of autophagosomes and the sequestration of cytoplasmic enzymes were inhibited but the vacuolar uptake of acid phosphatase and cathepsin D continued to increase for several hours. When cycloheximide was injected 1 h after leupeptin, losses of lactic dehydrogenase and aldolase proteins were observed in autophagic vacuoles isolated 1 and 2 h later.
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PMID:Sequestration of cytoplasmic enzymes in an autophagic vacuole-lysosomal system induced by injection of leupeptin. 613 57

To define its pathogenesis, the acute degenerative hepatitis caused by frog virus 3 (FV3) has been reproduced in the rat, thus facilitating a greater number of biologic explorations than in the mouse. The histologic and ultrastructural study proves a massive hepatocellular necrosis perfectly compatible with the fatal outcome of the illness 30 hours after the inoculation of one LD100. Critical analysis of the FV3 rat hepatitis induces us to advance three arguments for excluding the direct role of the virus in hepatocytolysis. (1) The hepatocyte is neither the sole nor the first intrahepatic target of the virus. The endothelial barrier and especially the Kupffer cells are completely necrosed several hours prior to the appearance of the first signs of parenchymal cell disturbances. Morphologic observations and, in particular, the evolution in the site and chronology of the cytolysis are confirmed by the variation in the activity of cathepsin D, glutamic pyruvic transaminase, and lactic dehydrogenase in serum. (2) There is a close correlation between the structural alterations in the hepatocyte nuclei and the inhibition in the synthesis of the liver macromolecules. But the discovery of a rat strain sensitive to the virus and another more resistant strain provides evidence that there is no relationship between the sensitivity to the lethal power of the FV3 and the metabolic disorders. (3) The ways in which the FV3 spreads throughout the organism do not explain why the liver is the sole organ attacked. A second etiopathogenic factor, only found in the liver, must be invoked. The possible role of the plasma complement, strongly activated, is suggested, along with that of other toxic substances which can no longer be cleared. The metabolic inhibition directly connected with the FV3 would thus result not in producing the hepatocytolysis but in rendering any cellular regeneration impossible.
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PMID:Frog virus 3 induces a fatal hepatitis in rats. 616 20

Young rats, fed a low calcium and vitamin D deficient diet for 2 weeks, developed hypocalcemia, an increased activity of serum alkaline phosphatase and an increase in the serum concentration of immunoreactive parathyroid hormone. An increased activity of lactate dehydrogenase and cytochrome oxidase in odontoblasts was found. No shift in the general energy metabolic pathway was found as visualized in the lactate dehydrogenase iso-enzyme pattern. The dominating lactate dehydrogenase isoenzyme in odontoblasts from both the normal and the deficient rats was LDH 1 (H4, LD5), thus indicating primarily an aerobic energy-metabolism Also the activities of the lysosomal enzymes acid phosphatase, cathepsin D and hyaluronidase in the odontoblasts from the deficient animals were increased when compared to the normal animals. No significant change could be demonstrated for beta-glucuronidase and beta-N-acetylglucosaminidase. It was earlier found that this deficient diet caused an increase in odontoblast alkaline phosphatase activities and protein synthesis in vitro. In view of the present findings it might be concluded that the low calcium and vitamin D deficient diet causes a general increase in the odontoblast metabolism. It is not known whether this is due to the increase in parathyroid hormone or if it is a direct effect of the lowered serum calcium concentration.
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PMID:Odontoblast metabolism in rats deficient in vitamin D and calcium. IV. Lysosomal and energy metabolic enzymes. 625 18

It has been shown that low concentrations of E. coli lipopolysaccharides (LPS) greatly and selectively stimulate phagocytosis and related functions in mouse bone marrow-derived macrophages. Culture in the presence of 50 ng/ml LPS induced on average a 10-fold enhancement of phagocytosis of IgG-coated sheep erythrocytes. Activation was in two stages--a small increase observed during the first 8 to 12 hr, and the major increase noted between 16 and 24 hr. Phagocytic activity remained at the maximal level for 24 hr and then declined progressively. Stimulation by LPS was dose-dependent; significant effects could be observed at 0.8 ng/ml and the maximum was reached at 10 ng/ml. LPS-treated cells also showed a markedly increased tendency to form colonies. All these effects could be prevented by the addition of 100 ng/ml polymyxin B together with LPS, indicating that the active principle is lipid A. The LPS-dependent increase in phagocytic activity is probably mediated by increased Fc receptor capacity because both parameters were influenced in parallel by the stimulus. Phagocytosis-related events, such as enhanced hexose monophosphate shunt activity, H2O2 formation, and nitroblue tetrazolium reduction were also stimulated by LPS. By contrast, pinocytosis was unaffected. Measurements of cell-associated enzyme activities showed that lactate dehydrogenase, acid phosphatase, and cathepsin D were significantly increased. Beta-glucuronidase, beta-galactosidase, alkaline phosphodiesterase, and aminopeptidase were unchanged and NAD nucleosidase was markedly decreased after LPS treatment. 5'-Nucleotidase and glucosamine uptake were undetectable both in control and LPS-stimulated cells. LPS treatment induced a significant increase in cell-associated protein, but did not result in cell proliferation or increased cell loss as shown by the DNA content that remained constant. LPS-induced changes were dependent on de novo protein synthesis; cycloheximide prevented enhancement of phagocytosis, Fc receptor capacity, and colony formation.
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PMID:Stimulation of phagocytosis in bone marrow-derived mouse macrophages by bacterial lipopolysaccharide: correlation with biochemical and functional parameters. 673 51

Mice with generalized influenza or tularemia of similar lethality were studied in an effort to compare biochemical responses of the myocardium during infections of viral and bacterial etiology. A progressive loss of body weight characterized the course of both infections. Accompanying this, the myocardial content of protein and the activities of lactate dehydrogenase, citrate synthase, and cytochrome c oxidase all decreased. However, myocardial protein degradation appeared earlier and was more pronounced in influenza, and the protein changes were accompanied by a rapid decline of myocardial RNA. Activation of acid hydrolases, such as cathepsin D and beta-glucuronidase, occurred in tularemia but not in influenza, whereas leakage of beta-glucuronidase into the plasma occurred in both infections. Conversely, there was a considerably greater activation of myocardial catalase in influenza. These findings suggested that different control mechanisms or metabolic pathways were operative in the degradation of myocardial constituents in influenza as compared with tularemia. The absence of histological signs of myocarditis in either infection appeared to exclude any direct local effects of an inflammatory process on myocardial cells. Since the infections were of comparable lethality (based upon the inoculated dose of organisms), the observed differences in pattern and extent of metabolic responses of the myocardium to these infections may be attributed to different pathophysiological mechanisms evoked by the different microorganisms.
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PMID:Sequential metabolic alterations in the myocardium during influenza and tularemia in mice. 674 1

The effect of chlorpromazine (CPZ) and mepacrine on hypoxic liver cell damage was studied using an isolated perfused cat liver preparation. High concentrations of CPZ (10(-4) M) significantly augmented the hypoxic leakage of the lysosomal enzyme, cathepsin D, and the cytoplasmic enzyme, lactate dehydrogenase (LDH) into the perfusate. The per cent free cathepsin D activity of hepatic tissue was significantly higher in the 10(-4) M CPZ treated groups (87%) than in the vehicle group (65%). CPZ at a concentration of 10(-6) M also possessed a detrimental effect on hypoxic liver integrity but to a lesser extent compared to 10(-4) M. In contrast, low concentrations of CPZ (10(-7) M) showed a protective effect during hypoxia (i.e., significantly lower perfusate cathepsin D activity and per cent free cathepsin D activity) compared to livers receiving only the vehicle. Mepacrine, another phospholipase A2 inhibitor, showed no significant effect on hypoxic liver damage at concentration of 10(-6) and 5 x 10(-5) M. CPZ has a biphasic action on liver integrity during hypoxia, low concentrations being protective and high concentrations are deleterious. Mepacrine had no significant effect in the hypoxic liver.
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PMID:Biphasic actions of chlorpromazine and mepacrine on modulation of hepatic cell injury in the perfused cat liver. 722 15

The effects of the calcium antagonist nifedipine on isolated perfused cat livers were studied during 150 min of normoxic or hypoxic perfusion with Krebs-Henseleit solution. Hypoxic livers perfused with the nifedipine vehicle exhibited significantly higher increases in perfusion pressure, perfusate lactate dehydrogenase and cathepsin D activities, as well as amino-nitrogen concentrations compared to the control normoxic group. In contrast, the nifedipine + hypoxia group showed no significant difference in any of these variables from the control livers. Nifedipine (0.3 microgram/ml) protected the liver during hypoxia and that this protection may have stemmed from its inhibition of Ca++ influx which has been linked in irreversible cell death.
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PMID:Protective effect of nifedipine in the hypoxic perfused cat liver. 728 94


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