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)

Ascites fluid accumulation accompanying a mastocytoma or L1210 murine tumor is significantly retarded following the i.p. or s.c. injection of moderate quantities of pepstatin, a known acid protease inhibitor. No effect on cell count was noted by pepstatin treatment. The probable mechanism by which pepstatin acts is by inhigiting the enzymatic formation of chemical mediators known as leukokinins. These are pharmoacologically active peptiedes having potent permeability characteristics previously described by this laboratory. Leukokinins are formed by cathepsin D-like enzymes present in the invading cells and in the ascites fluid acting on a protein substrate, leukokininogen. present in the ascites fluid. Pestatin inhibits the action of these leukokinin-forming enzymes invitro but has no effect on kallikreins (bradykinin-forming enzymes) in vitro. Human ascites fluid from a patient with ovarian carcioma was found to have a paepstatin-inhibited, leukokinin-generating system, as does the mouse. A 'chemical mediator' theory is proposed for ascites fromation which broadens the previously held theory of lymphatic blockage (Holm-Nielsen) and may explain the recent findings of Hirabayashi and Graham of increased plasma-ascites exchange in peritoneal carcionmatosis. Pepstatin inhibition of chemical mediator formation may represent a new therapeutic approach to ascites fluid accumulation in neoplastic disease.
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PMID:Pepstatin, an inhibitor of leukokinin formation and ascitic fluid accumulation. 4 79

The effect of the protease inhibitor, aprotinin, was examined in rats during traumatic shock. In sham-operated control rats, intravenous administration of aprotinin (20,000 or 40,000 KIU/kg) showed no immediate changes in the mean arterial blood pressure and heart rate. In rats subjected to Noble-Collip drum trauma, aprotinin at a dose of 20,000 KIU/kg prolonged survival time to 2.1 +/- 0.3 hr (p less than 0.05) and 40,000 KIU/kg prolonged the survival time of rats to a greater extent (3.1 +/- 0.4 hr, p less than 0.001) compared to rats given only its vehicle (1.1 +/- 0.2 hr, mean +/- SE). The improved survival was accompanied by inhibition of the plasma accumulation of the cardiotoxic peptide, myocardial depressant factor (MDF). However, aprotinin showed no inhibitory effect on the plasma accumulation of the lysosomal enzyme, cathepsin D. Aprotinin has a beneficial effect on traumatic shock in rats possibly by its potent inhibitory action on MDF formation.
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PMID:Protective actions of aprotinin in acute traumatic shock. 31 92

A rapid and reliable method for coupling the protease inhibitor pepstatin to AH-Sepharose 48 was developed. The matrix prepared was used to purify cathepsin D from rat liver. The enzyme was eluted in one fraction and proved to be pure by gel electrophoresis, two types of ion exchange chromatography, molecular sieve chromatography, and immunologically homogenous by immunoelectrophoresis. This method is more rapid and gives a higher yield than previous techniques. The possibility to use this technique for the purification of other enzymes inhibitable by pepstatin should be considered.
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PMID:Purification fo cathepsin D by AH-sepharose affinity chromatography. 71 80

Incubation of bovine serum albumin (BSA), rat serum albumin or rat plasma with medium conditioned by endotoxin stimulated rat peritoneal macrophages produced an activity that released histamine from isolated rat serosal mast cells. The amount of histamine-releasing activity (HRA) produced increased with the length of the incubation period, with the concentration of albumin, with the number of macrophages stimulated, and with the duration of exposure of the macrophages to endotoxin. Moreover, the formation of the HRA showed a dependency on the pH of the incubation medium with an optimum at pH 4.5. Boiling the medium conditioned by stimulated macrophages before its incubation with albumin or including the acid protease inhibitor, pepstatin with the conditioned medium prevented the formation of HRA. The generation of HRA was not inhibited by pretreatment of the macrophages with the inhibitor of protein synthesis, cycloheximide. Media from macrophages not stimulated with endotoxin failed to generate HRA. Histamine release from mast cells in response to the HRA was inhibited by pretreatment of the cells with antimycin A and deoxyglucose or by preincubation in Ca-free Locke's solution containing a calcium chelating agent. When injected intradermally into anesthetized Evan's Blue treated rats, the generated HRA produced a change in vascular permeability that was prevented by the H1 antagonist, diphenhydramine. Treatment of the HRA with carboxypeptidase A reduced its ability to stimulate histamine release from mast cells. Histamine-Releasing Peptide (HRP), a neurotensin-related octapeptide, shown previously by us to be formed by the action of cathepsin D or pepsin on albumin, was identified by radioimmunoassay in acid:acetone extracts of the histamine-releasing activity. It is concluded that the formation of HRA is due to the actions of enzymes released from macrophages acting on albumin. It is suggested that such histamine-releasing activity could be formed during the later stages of the inflammatory response and that HRP is one of the peptides present.
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PMID:Formation of histamine-releasing activity from albumin by medium conditioned by endotoxin-stimulated rat peritoneal macrophages. 138 Jul 64

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Encoded by the HIV genome are several precursor proteins that undergo proteolytic cleavage to yield functional proteins. The env precursor protein is cleaved by a cellular protease. The gag precursor protein of HIV (p55), however, is cleaved by a virally encoded aspartate protease (HIV Protease). Cleavage of p55 is required for viral maturation and infectivity. There are also several host cell aspartate proteases that serve important homeostatic functions. Cathepsins D and E are lysosomal aspartate proteases which are believed to play an important role in macrophage function, and it has been suggested that inhibition of these enzymes by an HIV protease inhibitor may exacerbate immunosuppression in AIDS patients. We have studied the effect of SK&F 107461 (a hydroxyethylene dipeptide isostere inhibitor of HIV protease), on various host defense functions of human monocytes. Pepstatin A (an inhibitor of most aspartate proteases) and leupeptin (an inhibitor of serine and cysteine proteases) were included as controls. Although less potent than the prototypic aspartate protease inhibitor pepstatin, SK&F 107461 inhibited partially purified cathepsin D in vitro. However, in cell-based assays, SK&F 107461 had no effect on the degradation of hemoglobin, antigen processing of the protein antigen streptokinase, or secretion of 17-kD IL-1 beta by monocytes at concentrations which inhibit maturation of intracellular virus in HIV infected monocytes. Furthermore, SK&F 107461 had no effect on constitutive candidacidal activity. In contrast, leupeptin and pepstatin A partially inhibited accessory cell function of monocytes in the proliferative response to the recall antigen streptokinase. In addition, leupeptin partially inhibited degradation of hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of a human immunodeficiency virus protease inhibitor on human monocyte function. 149 45

The effect of NCO-700 (1), a protease inhibitor, on subcellular distribution of lysosomal enzymes was studied in the ischemic perfused rat heart. Ischemia was induced by lowering the afterload pressure of the working heart preparation. The subcellular distribution of lysosomal enzymes was estimated by the ratio of the activities of cathepsin D, beta,N-acetylglucosaminidase, and acid phosphatase in the cytoplasm to the total enzyme activities. Ischemia caused subcellular redistribution of lysosomal enzymes from the lysosomes to the cytoplasm, indicating the rupture of lysosomes. Compound 1 (1.75 x 10(-4) M) was provided for the heart 5 min before the onset of ischemia. Compound 1 appeared to inhibit the rupture of lysosomes being caused by ischemia. The mechanism by which 1 protects the myocardium against ischemic injury may involve the inhibition of lysosomal rupture in the ischemic myocardium.
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PMID:Effect of NCO-700, an inhibitor of protease, on lysosomal rupture in the ischemic myocardium. 205 42

Lysates of isolated rat polymorphonuclear leukocytes and macrophages were found to generate xenopsin-related peptides when incubated with a liver extract used as a source of precursor. The lysosomal enzyme, cathepsin D, was also shown to display this property and to share with the lysate a similar pH dependence (optimum, approximately pH 3.5) and sensitivity to the acid protease inhibitor, pepstatin A (ID50: lysate, 10 nM; cathepsin D, 30 nM). When subjected to HPLC on mu-Bondapak C-18, the xenopsin-related peptides generated by the lysate eluted near to those formed by cathepsin D and when tested in a radioreceptor assay for neurotensin, they displayed similar cross-reactivities (peak 2, approximately 50%; peak 1, approximately 100%). These results indicate that cathepsin D from lysed granulocytes can process precursor protein(s) to form radioreceptor-active xenopsin-related peptides.
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PMID:Xenopsin-related peptide(s) are formed from xenopsin precursor by leukocyte protease(s) and cathepsin D. 205 86

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

We reported previously using a murine model that the kidney is the organ involved in catabolism of exogenous human recombinant interleukin 2 (IL-2) and that cathepsin D, a major renal acid protease, is responsible for the degradation of IL-2. In the present report also using BALB/c mice we have investigated the effect of in vivo pepstatin, an acid protease inhibitor, treatment on serum half-life of IL-2, and generation of lymphokine-activated killer (LAK) cell activity. The in vivo pepstatin treatment by i.p. injection resulted in a significant reduction in the accumulation of 125I-IL-2 by the kidney in a reverse dose-response manner. Pepstatin treatment prolonged the serum half-life of 125I-IL-2, and the increase in serum half-life of 125I-IL-2 was pepstatin dose dependent. A significant reduction in renal cathepsin D activity, as monitored by the degradation of 125I-IL-2, was detected. In vivo pepstatin (0.6 mg/kg) treatment along with IL-2 (300,000 IU/mouse) daily for 3 or 6 days resulted in an augmentation of natural killer activity exhibited by freshly prepared and uncultured splenocytes against YAC-1 cells. An additional culturing of the splenocytes with IL-2 (3,000 IU/ml) in vitro for 1 day significantly enhanced the effect of in vivo pepstatin treatment; i.e., LAK cell activity generated from the splenocytes of animals treated with IL-2 plus pepstatin was greatly augmented in comparison with that treated with IL-2 alone. Phenotypic assessment by cell surface markers (Thy-1.2, Lyt-2, L3T4, and asialo-GM1) on the fresh splenocytes prepared from animals treated in vivo with pepstatin plus IL-2 revealed a decrease in the percentage of cells expressing Thy-1.2 and Lyt-2 and an increase in those carrying asialo-GM1. These results demonstrated that, as a result of in vivo pepstatin treatment, renal cathepsin D activity was greatly inhibited, which in turn reduced the degradation of circulating IL-2, then prolonged serum half-life of IL-2, and subsequently augmented natural killer and LAK cell activity. The in vivo pepstatin and IL-2 treatment decreased the T-cells and increased the natural killer-like LAK precursor cells, possibly also with an increase in its activity, which were further induced by in vitro IL-2 culture to generate an augmented LAK cell activity. This study also suggests the clinical potential of pepstatin in IL-2-related immunotherapy.
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PMID:Prolongation of serum half-life of interleukin 2 and augmentation of lymphokine-activated killer cell activity by pepstatin in mice. 229 59

The metabolic change of human recombinant interleukin-2 (IL-2) was investigated by the use of 125I-labeled IL-2 (125I-IL-2). After intravenous injection into mice, the distribution of 125I-IL-2 in various organs revealed that the major portion of injected 125I-IL-2 was rapidly accumulated in the kidney. Simultaneous injection of an excess amount of cold IL-2 greatly reduced the distribution of 125I-IL-2 to the kidney, suggesting that the accumulation of 125I-IL-2 by the kidney was a specific reactivity between 125I-IL-2 and the kidney. The gel filtration profile of 125I-IL-2 in the serum specimens remained the same as that of the originally injected sample, and differed completely from that in the urine specimens, suggesting that 125I-IL-2 was metabolized in the kidney. To confirm this notion, 125I-IL-2 was incubated in vitro with kidney homogenate, which degraded 125I-IL-2 in acidic pH. After subcellular fractionation, the cytosol fraction of the kidney was shown to hydrolyze 125I-IL-2 with an optimal pH of 4. The reactivity of the kidney cytosol fraction with 125I-IL-2 was inhibitable by pepstatin, an acid protease inhibitor, but not by TLCK or TPCK. Additional experiments using a heat-treated kidney cytosol fraction plus cathepsin D, and pepstatin inhibition on the degradation of 125I-IL-2 by cathepsin D, a major acid protease in the kidney, resulted in the identification of this enzyme to be responsible for the degradation of 125I-IL-2. Overall, these results demonstrated that the kidney is the organ to metabolize IL-2 and that cathepsin D, a renal acid protease, is involved in the degradation of IL-2.
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PMID:Role of the kidney in metabolic change of interleukin-2. 267 96


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