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)

We studied the effects of human superoxide dismutase (h-SOD) in splanchnic artery occlusion (SAO) shock. Pentobarbital anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 min developed a severe shock state usually resulting in a fatal outcome within 20 min after the release of the occlusion. h-SOD (10 mg/kg) was infused intravenously starting at reperfusion and lasting for 10 min. SAO shock rats treated with h-SOD maintained postreperfusion MABP at significantly higher values compared to rats receiving the vehicle (final MABP 84 +/- 6 vs 46 +/- 1 mm Hg, P less than 0.01, respectively). Treatment with h-SOD attenuated the plasma accumulation of free amino-nitrogen compounds (P less than 0.01 from vehicle) as well as the activity of the lysosomal protease cathepsin D (P less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in h-SOD-treated rats than in SAO rats receiving only the vehicle (27 +/- 1 vs 64 +/- 3 U/ml, P less than 0.01). SAO shock rats treated with h-SOD also exhibited a significantly higher survival rate than the SAO shock +/- vehicle group (88% vs 11%, P less than 0.01, respectively). These results support the role of oxygen-derived radicals in the pathophysiology of SAO shock, and indicate that h-SOD effectively ameliorates the deleterious effects of oxygen radicals in this severe model of ischemia and reperfusion.
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PMID:Anti-shock effects of human superoxide dismutase in splanchnic artery occlusion (SAO) shock. 339 43

The present investigation deals with the in vivo effects of oxygen free radicals (OFRs) in the absence and presence of scavengers of OFRs (superoxide dismutase, SOD, and catalase) on the cardiac function and contractility and with the in vitro effects of exogenous OFRs and various pH and pO2 on the release of acid hydrolases from dog myocardial lysosomes. The hemodynamic measurements were made before and at various intervals after administration of OFRs for up to 2 h. Xanthine plus xanthine oxidase (X-XO) and opsonized zymosan were used to generate OFRs. Oxygen free radicals produced a decrease in the cardiac function and indices of myocardial contractility. SOD alone or in combination with catalase tended to protect the cardiac function against the deleterious effects of OFRs. There was about a threefold increase in the release of cathepsin D activity in vitro from the lysosomes in the preparations treated with X-XO as compared to those without such treatment. The presence of SOD prevented the release of cathepsin D from the lysosomes. The changes in pH (4.5, 5.5, 6.0, 6.5, 7.4, 8.0) alone did not cause any increase in the enzyme release. However, the presence of OFRs at each pH resulted in a similar increase (about threefold) in the release of cathepsin D. Similarly the changes in pO2 alone did not cause the release of cathepsin D, but there were marked increases in the release of cathepsin D at each pO2 in the presence of OFRs. These data indicate that it is the oxygen free radicals and not the alterations in pH or pO2 that are primarily responsible for the release of lysosomal hydrolases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen free radicals and cardiac depression. 792 55

Cathepsin D is an estrogen (17 beta-estradiol, E2)-inducible lysosomal protease. A putative estrogen receptor (ER)-Sp1-like sequence (GGGCGG(n)23ACGGG) has been identified in the non-coding strand of the cathepsin D promoter (-199 to -165), and electromobility shift assays of nuclear extracts from MCF-7 and HeLa cells confirm that both the ER and Sp1 protein bind to 32P-labeled ER/Sp1 oligo. For example, nuclear extracts from MCF-7 cells bind to the 32P-labeled ER/Sp1 oligo; however, ER/Sp1 binding can be decreased by selective competition with excess unlabeled estrogen responsive element and Sp1 oligos, immunodepletion with ER or Sp1 antibodies, and by treating cells with ICI 164,384, an antiestrogen which inhibits formation of ER homodimer. Moreover, E2-induced chloramphenicol acetyltransferase (CAT) activity in MCF-7 cells cotransfected with a human estrogen receptor expression plasmid and a plasmid containing an ER/Sp1 sequence cloned upstream to a thymidine kinase promoter and a CAT reporter. In cotreatment studies, ICI 164,384 inhibited E2-induced CAT activity. In contrast, E2 did not induce CAT activity in MCF-7 cells transfected with plasmids containing mutations in the ER or Sp1 segments of the ER/Sp1 oligo, thus confirming that both cognate binding sites are required for estrogen responsiveness.
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PMID:Estrogen receptor-Sp1 complexes mediate estrogen-induced cathepsin D gene expression in MCF-7 human breast cancer cells. 819 46

Proteins modified by oxidants are rapidly degraded by intracellular proteases. Oxidatively modified superoxide dismutase (Ox-SOD) was degraded 2-8 times faster at both acidic and alkaline pH than the native protein in bovine cardiac tissue extracts. At acidic pH, Ox-SOD hydrolysis was stimulated by ATP and by non-hydrolyzable ATP analogs by up to 50%, but degradation was not stimulated by ATP at alkaline pH. The aspartic protease inhibitor pepstatin completely inhibited the acid Ox-SOD hydrolyzing activity and its stimulation by ATP. This activity eluted from gel filtration with a molecular size of 34-48 kDa and contained the single chain and two mature forms of cathepsin D. Purified cathepsin D degraded Ox-SOD and ATP enhanced the affinity of cathepsin D for oxidatively modified proteins. Thus cardiac tissue proteins modified by oxidants may be substrates for the lysosomal protease cathepsin D.
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PMID:ATP-stimulated degradation of oxidatively modified superoxide dismutase by cathepsin D in cardiac tissue extracts. 860 90

The HIV protease (or proteinase) enzyme is an essential component of the replicative cycle of HIV, performing the post-transitional processing of the gag and gag-pol gene products into the functional core proteins and viral enzymes. Inhibition of this enzyme leads to production of immature noninfectious viral progeny, and hence prevention of further rounds of infection. Structurally, the enzyme is a homodimer consisting of two identical 99 amino acid chains. HIV protease is a member of the aspartic protease family but is structurally dissimilar to human aspartic proteases such as renin, gastricsin and cathepsin D and E, suggesting the possibility of creating inhibitors with a wide therapeutic index. At least 6 inhibitors of HIV protease are currently in clinical development: saquinavir, indinavir, ritonavir, nelfinavir (AG-1343), KNI-272 and VX-478, the first four of which have shown antiretroviral activity and acceptable tolerability in initial phase I/II clinical trials. Resistance or reduced sensitivity to the leading protease inhibitors has been reported in vivo and appears to be associated with loss of therapeutic effect. However, resistance patterns appear to be distinct. Treatment for 1 year with indinavir has been reported to lead to selection of virus in 4 patients, which was cross-resistant to all other leading protease inhibitors. On the other hand, a larger series of clinical isolates from patients receiving saquinavir alone or in combination with zidovudine for up to 3 years did not lead to virus cross-resistant to either indinavir or ritonavir. This suggests that care should be exercised in designing the sequence of protease usage. Additionally, differing resistance patterns may be used to select combinations of protease inhibitors in future trials. Data from studies combining protease inhibitors with nucleoside analogues suggest value in terms of larger and more prolonged virological and immunological marker responses than are observed with single agent therapy, and this is likely to be the primary role for protease inhibitors; both in initial combinations for patients commencing therapy and as add-in therapies for patients previously treated with antiretrovirals. However, in vitro and animal pharmacokinetic studies also give evidence of the possibility of combining protease inhibitors, potentially leading to improved bioavailability, antiviral synergy and delay in emergence of viral resistance.
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PMID:Current knowledge and future prospects for the use of HIV protease inhibitors. 886 42

Estrogen receptor-alpha (ER alpha) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. The classic mechanism of ER alpha action is associated with estrogen-induced formation of a nuclear ER alpha homodimer, binding to 5'-regulatory estrogen response elements (EREs) in target gene promoters, interaction with other nuclear proteins, and general transcription factors to activate gene expression. ER alpha also interacts with Sp1 protein to transactivate genes through binding Sp1(N)xERE or Sp1(N)xERE half-site (1/2) motifs where both ER alpha and Sp1 bind DNA elements. Activation through Sp1(N)xERE1/2 requires interactions of both proteins with their cognate DNA elements as well as additional nuclear factors to form a functional ER alpha/Sp1-DNA complex. Recent studies also show that ER alpha and Sp1 physically interact and ER alpha preferentially binds to the C-terminal DNA-binding domain of Sp1 protein. Moreover, ER alpha/Sp1 can activate transcription from a consensus GC-rich Sp1 binding site in transient transfection studies in MCF-7 human breast cancer cells, and this response is also observed with ER alpha variants that do not contain the DNA-binding domain. Several genes that are induced by estrogens in MCF-7 cells are activated through one or more GC-rich sites in their regulatory regions and these include the cathepsin D, E2F1, bcl-2, c-fos, adenosine deaminase, insulinlike growth factor binding protein 4, and retinoic acid receptor alpha 1 genes. ER alpha/Sp1 and ER beta/Sp1 action is dependent on ligand structure and cell context and ER beta/Sp1 is primarily associated with decreased ligand-dependent gene expression. ER alpha/Sp1, like ER alpha/AP1, represents a pathway for hormone activation of genes in which the receptor does not bind DNA, and results of ongoing studies suggest that ER alpha/Sp1 plays an important role in transcriptional activation of multiple growth regulatory genes in breast cancer cells.
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PMID:Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. 1134

The effects of pleuran, beta-glucan isolated from Pleurotus ostreatus, were studied in a model of acute colitis in rats. Pleuran was given either as a 2% food component or as 0.44% pleuran hydrogel drink over 4 weeks. Colitis was induced by intraluminal instillation of 4% acetic acid and after 48 h the extent of colonic damage and several biochemical parameters were examined. Pleuran supplementation both in food and in drinking fluid significantly decreased the disposition to colitis. The macroscopic damage score was reduced by 51% or 67% by pleuran diet and pleuran hydrogel drink, respectively. Pleuran did not influence the final body weights of rats but prevented significantly colonic wet weight increase which was observed in the control diet group. The enhanced activity of myeloperoxidase in the inflamed colonic segment was reduced by pleuran diets, reflecting decreased neutrophil infiltration. The colonic damage was accompanied by decreased activities of lysosomal enzymes--acid phosphatase and cathepsin D--in the control untreated group, whereas in the pleuran groups the decrease was significantly attenuated. Both pleuran regimens reduced the content of conjugated dienes in the colon, liver and erythrocytes. In contrast to this fact, activities of antioxidant enzymes in erythrocytes and the colon were not so greatly influenced. Significant increase was found only in the case of SOD activity in sham operated rat erythrocytes under influence of both pleuran regimes and in the case of GST activity in erythrocytes of pleuran hydrogel group. The mechanism of the described protective effect of pleuran is not yet fully understood. Our results indicate that the pleuran-enhanced antioxidant defence of the colonic wall against the inflammatory attack may have come into play.
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PMID:Effect of pleuran (beta-glucan from Pleurotus ostreatus) in diet or drinking fluid on colitis in rats. 1171 51

The macrolide antibiotics are bacteriostatic agents interfering with protein synthesis but they are taken up by phagocytic cells, e.g. macrophages, neutrophils and fibroblasts which take up infectious organisms into phagosome-lysosomal vaculoes. Recent studies have suggested that these macrolide antibiotics block the spread of infections by mechanisms associated with the inflammation process. Herein is a study with clarithromycin using human THP-1 monocytes, a phagocytic cell which has not been studied to date. Clarithromycin was rapidly taken up by the monocytes (approximately 1%) utilizing both saturable carrier and passive processes at pH 7.4 but was exclusively passive at pH 6.8 and 5.0. The carrier process was energy and temperature dependent and appeared to be linked to certain ion channels. Efflux of the drug was rapid and complete in 1 hr. Intracellular disposition showed 74% in the cell sap and 11% in the nucleus. Upon stimulation with zymogen A or bacteria significant increases of uptake occurred in the isolated lysosome-phagosomes. Examination showed that initially clarithromycin treatment triggered the release of NO, H2O2, IL-1 and TNFalpha from the monocytes, known mediators of inflammation, but also mediators which cause bacterial cell death or apoptosis. The activity of the monocyte marker hydrolytic enzyme NAG was elevated at this time as well as protein kinase C activity. Treatment from 2-4 hr with clarithromycin appeared to reverse this process in that the chemical mediator release was reduced along with the activities of hydrolytic enzymes, e.g. NAG and cathepsin D with no evidence of lipid peroxidation and protective SOD enzyme activity elevation. The latter effects of the antibiotic would be useful in blocking the spread of infection or inflammation from the original site. The normal bacterial static killing effects of clarithromycin was evident at 24 but not 2 hr in both extracellular free bacteria and those bacteria phagocytosed by the THP-1 monocytes.
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PMID:Disposition and functions of clarithromycin in human THP-1 monocytes during stimulated and unstimulated conditions. 1276 Apr 88

Cathepsin E is an intracellular, non-lysosomal aspartic protease expressed in a variety of cells and tissues. The protease has proposed physiological roles in antigen presentation by the MHC class II system, in the biogenesis of the vasoconstrictor peptide endothelin, and in neurodegeneration associated with brain ischemia and aging. Cathepsin E is the only A1 aspartic protease that exists as a homodimer with a disulfide bridge linking the two monomers. Like many other aspartic proteases, it is synthesized as a zymogen which is catalytically inactive towards its natural substrates at neutral pH and which auto-activates in an acidic environment. Here we report the crystal structure of an activation intermediate of human cathepsin E at 2.35A resolution. The overall structure follows the general fold of aspartic proteases of the A1 family, and the intermediate shares many features with the intermediate 2 on the proposed activation pathway of aspartic proteases like pepsin C and cathepsin D. The pro-sequence is cleaved from the protease and remains stably associated with the mature enzyme by forming the outermost sixth strand of the interdomain beta-sheet. However, different from these other aspartic proteases the pro-sequence of cathepsin E remains intact after cleavage from the mature enzyme. In addition, the active site of cathepsin E in the crystal is occupied by N-terminal amino acid residues of the mature protease in the non-primed binding site and by an artificial N-terminal extension of the pro-sequence from a neighboring molecule in the primed site. The crystal structure of the cathepsin E/pro-sequence complex, therefore, provides further insight into the activation mechanism of aspartic proteases.
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PMID:Crystal structure of an activation intermediate of cathepsin E. 1534 44

Cultured human THP-1 monocytes were exposed to serial concentrations of gemifloxacin over 4 h after pre-stimulation with zymogen A for 1 h or Staphylococcus aureus for 2 h. The following parameters were assessed: pH, phagocytosis, c-AMP, NO, TNFalpha, IL-1, IL-6, IL-8 and H2O2 levels, enzyme activities of protein kinase C, NADPH oxidase, SOD, gluthathion reductase, NAG and cathepsin D as well as lipid peroxidation. The reversiblity of these changes was determined in the presence of known blockers of the phagocytic process. The effects of gemifloxacin on DNA synthesis and killing of S. aureus was assessed in bacteria alone and in those bacteria phagocytosed by THP-1 monocytes over 24 h. Gemifloxacin in stimulated THP-1 monocytes over the first 30 min caused an increase in c-AMP, NO, H2O2 and TNFalpha levels and protein kinase C, NADPH oxidase, glutathione reductase, NAG and cathepsin D activities. The pH became more acidic and phagocytosis was stimulated. These parameters were reversed at 1 h and continued to decline until 4 h. Lipid peroxidation was at the highest levels at 1 h and IL-8 levels at 2 h. DNA synthesis and bacterial growth were suppressed at 2 h in both S. aureus alone and bacteria phagocytosed by THP-1 monocytes. These effects were at a higher magnitude at 24 h. Gemifloxacin initiates a phagocyticidal effect of THP-1 monocytes at an early time of 30 min which plays a role in killing bacteria but a higher magnitude of killing of bacteria occurs later by a standard static mechanism. This early action of gemifloxacin should decrease the spread of infection and the inflammatory response since the tissue destruction process was attenuated at 4 h.
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PMID:In vitro anti-inflammatory effects and immunomodulation by gemifloxacin in stimulated human THP-1 monocytes. 1549 55


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