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:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interrelation between intracellular cAMP content and activity of lysosomal hydrolases was studied in rat liver and heart during ischemia of varying genesis and after recirculation. The activity of acid phosphatase (AP) and cathepsin D (CD) was determined in the fraction enriched with lysosomes (FEL) and in the supernatant fraction (SF) at 30,000 x g. Ischemia of isolated perfused heart of 20 to 60 min as described by Langendorff was accompanied by an increase in the SF/FEL ratio. Postischemic reperfusion resulted in a further increase in this ratio. In a terminal state induced by cardiac arrest of 10 min and within the first postresuscitation hours the SF/FEL ratio in the rat liver also increased. Processing of the liver FEL with 0.025% concentration of detergent Triton X-100 was also indicative of lability of lysosomal membranes during recirculation. The intracellular cAMP content changed differently. During ischemia of the myocardium, the cAMP level rose by 40 min and remained increased after 20 and 40 min of reperfusion. The cAMP content in the liver decreased after 10 min of circulatory arrest and increased in the postresuscitation period achieving its peak 4 h after resuscitation. Intra-abdominal injection of lyposomes with incapsulated cAMP to rats in the postresuscitation period and the study of the effect of dibutyryl-cAMP, caffeine and isoproterenol on the activity of acid hydrolases of ischemic heart and after postischemic reperfusion showed that an increase in the cAMP content achieved in various ways was conducive to stabilization of lysosomal membranes.
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PMID:Role of cAMP in regulation of activity of acid hydrolases of rat heart and liver during ischemia and after recirculation. 166 65

Cathepsin D preparations have been isolated from the heart of healthy animals and stress-surviving rats by the method of affine chromatography with the hemoglobin-biogel-P300 sorbent. To analysis of the obtained data permits concluding that acute stress stimulates activation of the catalytic function of cathepsin D in the heart. But the period after the stress accompanied by the consecutive proteolysis rate reduction, that can be explained, probably, by a change in enzyme conformation. The concentration of Ca2+ (10(-6), 10(-5) M) and cAMP (10(-7), 10(-6) M) exert a regulating influence on the cathepsin D activity in the heart in acute stress period and after it.
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PMID:[Kinetic properties of rat heart cathepsin D under normal conditions, during emotional-pain stress and in the post-stress period]. 178 75

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

The acid phosphatase and cathepsin D activities and cAMP and cGMP levels in isolated perfused rat heart were investigated during various periods of ischaemic myocardial injury and postischaemic reperfusion. The effect of phosphodiesterase inhibitor--caffeine was also studied. Free acid hydrolases activities and cyclic nucleotide content were increased under 40 and 60 min ischemia and 20 min postischaemic reperfusion. Addition of 50 microM caffeine to perfusion solution after 30 min of ischaemia resulted in increase of cAMP level, cAMP/cGMP ratio, lysosomal bound activities of acid hydrolase and decrease of free acid hydrolase activities. The obtained results suggested that defect in cAMP synthesis might be present in lysosomal membranes labilization in cardiomyocytes injured during ischaemic conditions. Addition of such agents, as caffeine, which increased heart cAMP level, may be effective in lysosomal membranes stabilization under reversible heart ischaemia and reperfusion.
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PMID:[Acid hydrolase activity and cyclic nucleotide contents in the rat heart during myocardial ischemia and postischemic reperfusion]. 255 45

The ADP-ribosylation site of histone H1 from calf thymus by purified hen liver nuclear ADP-ribosyltransferase was determined and effects of the ADP-ribose X histone-H1 adduct on cAMP-dependent phosphorylation of the histone H1 were investigated. ADP-ribosylated histone H1 was prepared by incubation of histone H1, 1 mM [adenylate-32P]NAD and the purified ADP-ribosyltransferase. N-Bromosuccinimide-directed bisection of ADP-ribosylated histone H1 showed that the NH2-terminal fragment (Mr = 6000) was modified and contained serine residue 38, the site of phosphorylation by cAMP-dependent protein kinase. Digestion of the NH2-terminal fragment with cathepsin D and trypsin, and purification of this fragment, using high-performance liquid chromatography, yielded a radiolabelled single peptide corresponding to residues 29-34 of histone H1, containing the arginine residue as the ADP-ribosylation site. These results indicate that ADP-ribosylation of histone H1 occurs at the arginine residue 34, sequenced at the NH2-terminal side of the phosphate-accepting serine residue 38. Phosphorylation of histone H1 from calf thymus by cAMP-dependent protein kinase was markedly reduced when histone H1 was ADP-ribosylated. Kinetic studies of phosphorylation revealed that ADP-ribosylated histone H1 was a linear competitive inhibitor of histone H1 and a linear non-competitive inhibitor of ATP.
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PMID:Amino acid sequence of histone H1 at the ADP-ribose-accepting site and ADP-ribose X histone-H1 adduct as an inhibitor of cyclic-AMP-dependent phosphorylation. 299 55

Protein synthesis and degradation and net uptake and release of amino acids and minerals were examined in the perfused hemicorpus of bilaterally nephrectomized and sham-operated control rats. Animals were studied 30 h after surgery. In comparison with controls, uremic rats had greater urea N appearance (net urea generation) and lower plasma and muscle concentrations of most amino acids. Muscle protein synthesis was not altered, but protein degradation was greater in uremic versus sham rats. There was greater net release of phenylalanine, tyrosine, alanine, total nonessential amino acids, total amino acids, potassium, and phosphorus from the perfused hemicorpus of uremic rats and greater release of citrulline from sham rats. ATP, creatine phosphate, cAMP, and activities of cathepsin B1, cathepsin D, and alkaline protease were not different in muscles of the uremic versus sham rats. Thus, in acutely uremic rats there is increased protein wasting in the hemicorpus due to enhanced protein degradation. The enhanced protein degradation does not appear to be due to increased muscle cathepsin B1, cathepsin D, or alkaline protease activities.
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PMID:Protein and amino acid metabolism in posterior hemicorpus of acutely uremic rats. 630 4

Levels of cyclic nucleotides (CN) in cardiac, cerebral, and hepatic tissues were measured in the early postresuscitation period in rats exposed to systemic circulation arrest induced by clamping of the cardiac vascular bundle. Changes of CN levels in the examined tissues were different in principle. In the heart cAMP levels progressively reduced 30 and 60 min after resuscitation, whereas cGMP levels were increasing. On the contrary, in the liver cAMP levels increased and cGMP content reliably reduced. Levels of cAMP and cGMP reliably reduced in the basis cerebri, with a trend to their reduction observed in the hemispheric cortex. Lysosomal hydrolases were activated in the said parts of the brain, their fraction was isolated in percoll gradient 30 min after resuscitation. In lysosomal fraction isolated from cardiac and hepatic tissues at the same period no activation of acid phosphatase and cathepsin D was observed in comparison with the control. It may be assumed that activation of lysosomal enzymes is governed by CN deficit.
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PMID:[Contents of cyclic nucleotides and activity of lysosomal enzymes in heart, brain and liver tissues in the early postresuscitation period]. 789 71

A cloned mouse genomic DNA fragment containing the gene encoding cathepsin D (Catd) encompasses 11 kb of genomic DNA and is composed of 9 exons. Using recombinant inbred strains, we localized the Catd gene on chromosome 4, tightly linked to the loci Mtv-13, Cyp4a, Ms15-1, and Pmv-19. The exon-intron organization of the Catd gene was shown to be very similar to that of its human counterpart. Presence of a CpG island, absence of a TATA box, and initiation of transcription at more than one site indicate that the Catd gene is a "housekeeping" gene. A 1.2-kb fragment containing the 5'-flanking region of the gene displayed promoter activity in BHK-21 cells. Comparison of the nucleotide sequences of mouse and human cathepsin D promoter regions revealed conservation of three potential regulatory elements: an E box, a GC box and a potential cAMP-responsive element. In contrast to the 5' region of human cathepsin D, the murine gene contains three CCAAT boxes but lacks any of the four AP2 binding sites found in the human gene.
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PMID:Mouse cathepsin D gene: molecular organization, characterization of the promoter, and chromosomal localization. 801 Nov 68

The FACS-analysis of diseases as different as cancer, autoimmune disorders and chronic (retro)viral infections, including HIV-infection, shows -at least temporarily- a common feature of lymphocyte hyperactivation, characterized by cellular activation markers (HLA-DR, CD26, CD38, CD69, CD2R and/or CD30), as well as by solubilized membrane structures, such as beta-2m, sICAM-I, sIL-2R/sCD25, sCD8, and by some oversecreted immunocyte products (e.g. neopterin, lysozyme and/or cathepsin D). We tested two potential approaches to down-regulate the pathologically elevated CD8+ and HLA-DR+ T cells: (a) In animal model, we tested the sensibility of these, disease inducing and maintaining T cell subsets to in vitro pretreated (cell death preprogrammed) semi-syngeneic and allogeneic donor T cells in tumor-bearing mice. (b) In the first clinical study, we used a novel combination of FDA-approved drugs which inhibits Ca(2+)-influx and concomitantly down-regulates cytosolic cAMP in patient's overstimulated immunocompetent cells. We could achieve a 94.6-100% long-term survival in tumor-bearing mice. In patients, large primary tumors and large metastases shrinked by 80-85% and small metastases disappeared completely. Since in HIV-infected persons, the increased number of HLA-DR+ CD38+T (T8) cells is associated with a fall in CD4-level and with development of AIDS, we are looking for the elimination of these HLA-DR+ targets by our novel technique in two AIDS-simulating (FIV/FeLV and SIV) animal models.
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PMID:Treatment of solid tumors should obligatorily be combined with the in vivo codepletion of tumor-protecting, CD8+/HLA-DR(+)-suppressor T cells by alloreactive donor T cells whose preprogrammed cell death allows a high GvL-effect before GvHD can be established. Results of animal experiments, including more than 6000 mice. 873 48

Enzymatic activity and isoform expression of cathepsin D (cath D) were studied in 107 cytosols from various human thyroid tissues including 21 normal tissues, 12 cold benign nodules, 17 toxic adenomas, 22 samples from Graves' disease patients, and 35 thyroid carcinomas. Cath D assay was optimized for human thyroid tissues. We found that mean cath D specific activities, expressed as units per milligrams protein minus thyroglobulin, were higher in carcinomas (P = 0.0001), toxic adenomas (P = 0.0001), and specimens from Graves' disease patients (P = 0.0001) than in normal thyroid tissues. Mean cath D activity in carcinomas was also significantly different from that in cold benign nodules (P < 0.001) and Graves' disease tissues (P < 0.05) but not from that of toxic adenomas. To determine possible mechanisms by which the observed increase in cath D activity might be regulated, we used Western blotting to measure relative amounts of cath D isoforms in the various thyroid tissues. We found that the 31-kDa major processing form of cath D was significantly increased in carcinomas and toxic adenomas compared with normal tissues (P < 0.01), cold benign nodules (P < 0.05), and Graves' disease tissues (P < 0.05). A positive correlation of cath D activity with relative expression of the 31-kDa form (r = 0.67, P = 0.0001) was observed in 104 thyroid cytosols. These data demonstrate a deregulation at the protein level, with resulting increases in cath D activity. Immunogold labeling of cath D showed particle concentration in lysosomes or phagosomes in both normal follicles and papillary carcinoma cells, indicating that cath D localization was not altered by malignant transformation in human thyroid cells. TSH induced cath D synthesis and secretion in extracellular fluid of normal human thyroid cells in primary culture; TSH had little effect on intracellular cath D level. In conclusion, TSH-induced cath D synthesis may explain high cath D levels in Graves' disease tissues and toxic adenomas, because these tissues possess a permanently stimulated cAMP transduction pathway. Furthermore, the overexpression of cath D in thyroid carcinomas in comparison with normal controls adds further arguments for the potential role of cath D in tumor growth and metastasis.
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PMID:Expression, localization, and thyrotropin regulation of cathepsin D in human thyroid tissues. 932 73


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