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 effects of a thromboxane receptor antagonist having lipoxygenase inhibitory activity, L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) (1 mg/kg per h) were studied in a standardized model of traumatic shock. Pentobarbital (35 mg/kg) anesthetized rats subjected to Noble-Collip drum trauma were characterized by a 82 +/- 12 min survival time, a 20-fold increase in plasma cathepsin D activity, and a 6-fold increase in plasma myocardial depressant factor (MDF) activity. L-655,240 significantly attenuated the accumulation of MDF activity in the plasma (74 +/- 3 vs. 46 +/- 4 units/ml), vehicle vs. drug, respectively, and significantly (P less than 0.01) prolonged survival time to 206 +/- 26 min. However, plasma cathepsin D was not significantly altered with L-655,240 administration during traumatic shock. L-655,240 at 20 micrograms/ml markedly attenuated minced rat lung fragments from producing LTC4 and LTD4.L-655,240 exhibited significant anti-proteolytic activity in pancreatic homogenates. Therefore, L-655,2340 does not stabilize lysosomal membranes directly, but exerts an anti-proteolytic action which appears to curtail the production of a myocardial depressant factor by the ischemic pancreas, thus protecting during traumatic shock. A combination anti-eicosanoid drug such as L-655,240 may therefore prove to be an important therapeutic agent in acute ischemic disorders including traumatic shock.
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PMID:Efficacy of a combination thromboxane receptor antagonist and lipoxygenase inhibitor in traumatic shock. 284 44

We have used three selective inhibitors of arachidonic acid metabolism in order to investigate the role of lipoxygenase metabolites in the pathogenesis of traumatic shock (LD90). The following inhibitors were used: CGS-5391B (2.5 mg/kg), a cyclooxygenase and lipoxygenase inhibitor, CGS-5677 (2.0 mg/kg), a selective lipoxygenase inhibitor, and U-60,257 (0.3 mg/kg), a putative inhibitor of glutathione-s-transferase. These inhibitors did not alter arterial blood pressure or heart rate when given to sham shock rats. The traumatic shock model was characterized by a 4.5-fold increase in plasma cathepsin D activity, a 4-fold increase in plasma myocardial depressant factor (MDF) activity, and a mean survival time of 1.5 +/- 0.2 h. Only the dual inhibitor significantly blunted the accumulation of cathepsin D in the plasma (7.5 +/- 0.8 vs 11.3 +/- 0.8 U/ml, p less than 0.01). However, all three inhibitors significantly suppressed plasma MDF accumulation by 50-60%: CGS-5391B, CGS-5677, and U-60,257 (p less than 0.01). Moreover, these three agents significantly improved survival time in traumatic shock. The increased survival time and reduced MDF activity afforded by these inhibitors suggest a significant role for lipoxygenase metabolites, particularly LTC4 and LTD4, in the pathogenesis of traumatic shock.
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PMID:Inhibitors of lipoxygenase products improve survival in traumatic shock. 644 Nov 86

Recent studies using mast cell-defined mice showed that the presence of mast cells was necessary for the increase in macrophage function observed after oral administration of malathion and reconstitution with bone marrow-derived mast cells restored the ability of malathion to increase macrophage function. In addition, the release of mast cell mediators (blocked by cromolyn) and histamine (action blocked by pyrilamine) was shown to be involved in the action of malathion on macrophage function. In the present study, the contribution of inflammatory mediators (i.e. arachidonic acid metabolites and tumor necrosis factor [TNF]) which may be generated by mast cells after oral administration of malathion, was examined. Controls in this study included the effects of the agent to be examined on: (1) resident peritoneal macrophages; and (2) macrophages elicited with pristane, and agent shown previously to stimulate macrophage function in the absence of mast cells. Intraperitoneal administration of indomethacin, and inhibitor of cycloxygenase, or neutralizing antibody to TNF 30 h before and 4 h after oral malathion blocked the ability of malathion to increase macrophage function, as measured by the generation of respiratory burst activity and the production of cathepsin D. On the other hand, administration of these agents to mice injected intraperitoneally with pristane did not affect the observed increase in cathepsin D production. Respiratory burst function after elicitation with pristane was slightly decreased (indomethacin) or not affected (antibody to TNF). The effect of intraperitoneal administration of nordihydroguaiaretic acid (NDGA), and inhibitor of both cycloxygenase and lipoxygenase, was also examined. Intraperitoneal administration of NDGA partially blocked the effects of oral administration of malathion on peritoneal macrophage function, but did not affect the function of resident pristane-elicited peritoneal macrophages. These data suggest that inflammatory mediators (potentially released from mast cells upon stimulation) contribute to the elevation in macrophage function observed after oral malathion administration.
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PMID:Contributions of inflammatory mast cell mediators to alterations in macrophage function after malathion administration. 930 54