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)

1. The total content of neutral sugars in skin of the weanling albino rats kept on the protein-deficient diet was increased by about 40%; this was mainly due to the increased concentration of galactose. The content of sialic acid was increased by about 20%. The collagen nitrogen was decreased significantly, with a concomitant increase of non-collagen nitrogen. At the same time, the content of sulphated glycosaminoglycans in skin was significantly decreased and that of non-sulphated glycosaminoglycans was increased. 2. Protein-deficient diet enhanced the activities of the protein-bound carbohydrate-degrading lysosomal hydrolases, viz. cathepsin D (EC 3.4.4.23), N-acetyl-beta-D-glucosaminidase (EC 3.2.1.30) and beta-D-glucuronidase (EC 3.2.1.31) both in liver and skin. The activity of liver hyaluronidase (EC 3.2.1.35) was also increased upon limitation of protein supply. 3. The changes observed in skin were accompanied by increased concentration of the protein-bound hexoses, hexosamines and sialic acids in serum, and of hexosamine and uronic acid in urine. The serum fucose remained unchanged.
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PMID:Effect of protein deficiency on the metabolism of glycoproteins and glycosaminoglycans in albino rat skin. 54 53

The present study was conducted to examine the effect of dopamine on arterial blood pressure, liver blood flow, cathepsin D activity, and free amino nitrogen concentration in hemorrhagic shock. Dopamine at a dose of 4 microgram/kg/min increased both mean arterial blood pressure and liver blood flow in postoligemic shock, but failed to prevent the marked increases in circulating cathepsin D and free amino nitrogen. In fact, dopamine infusion resulted in an increased plasma cathepsin D activity in shock. This increased accumulation of a lysosomal marker enzyme probably results from increased washout of the enzyme from the splanchnic or hepatic vascular bed in response to increased blood flow in these areas rather than from a direct effect of dopamine on lysosomal integrity. The increase in hepatic artery and portal vein flows appeared to result from stimulation of dopaminergic receptors since the dopamine dose was in the dopaminergic range and because haloperidol, a dopamine blocker, abolished the improved hemodynamic effects of dopamine. This study suggests that dopamine benefits the animal in hemorrhagic shock hemodynamically, but does not reverse the metabolic and cellular problems in shock. Perhaps, in combination with a drug opposing the biochemical basis of shock, dopamine may provide a greater anti-shock action.
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PMID:Influence of dopamine on liver dynamics in hemorrhagic shock. 59 4

The isolated cat liver perfused at a constant flow with Krebs-Henseleit solution containing low-molecular-weight dextran was employed to ascertain the direct effects of hypoxia or endotoxin on hepatic integrity. Hypoxia resulted in large increases in circulating lactate dehydrogenase (LDH) activity and in amino-nitrogen concentration, whereas endotoxin at a dose of 0.75 microgram/gm liver wet weight resulted in only small changes in these variables after 150 minutes of perfusion. Perfusion pressure and perfusate pH did not change significantly in response to either intervention. Both hypoxia and endotoxin significantly compromised lysosomal stability as evidenced by large increases in circulating levels of cathepsin D, large increases in the nonsedimentable fraction of tissue cathepsin D (ie, increased percentage of free activity), and changes in the ultrastructural appearance of liver lysosomes associated with enhanced fragility (eg, swelling, increased vacuolization). Both interventions also significantly impaired phagocytosis by reticuloendothelial cells within the liver. However, neither intervention altered BSP clearance, indicative of a lack of effect on parenchymal cell clearance. These findings indicate that both endotoxin and hypoxia induce direct cellular damage within the liver; however, endotoxin exerted a more selective action on lysosomes, whereas hypoxia produced more of a diffuse cytotoxic effect.
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PMID:Comparison of the cytotoxic actions of hypoxia and endotoxin in the perfused cat liver. 66 47

Anesthetized cats were hemorrhaged to a mean arterial blood pressure of 40 mm Hg for 120 minutes. Cats given dexamethasone (6 mg/kg, i.v.) at the time of hemorrhage and again (3 mg/kg, i.v.) at the time of reinfusion maintained post-reinfusion arterial blood pressure at a higher level than cats given the steroid vehicle. In addition, dexamethasone treated cats exhibited higher post-reinfusion liver blood flows than vehicle treated hemorrhaged cats. Dexamethasone significantly retarded the rise in plasma cathepsin D and amino-nitrogen activities during hemorrhage, and prevented the accumulation of a myocardial depressant factor (MDF) in the circulating blood. Dexamethasone had no significant effect on isolated cat papillary muscle or aortic strips. It appears that dexamethasone exerts its beneficial effect in hemorrhage shock primarily by stabilizing lysosomal membranes and the subsequent prevention of proteolysis and MDF formation rather than by a direct vasodilator or inotropic effect.
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PMID:Preservation of cellular integrity as a protective mechanism of dexamethasone in hemorrhagic shock in the cat. 67 64

Prostaglandin F2alpha concentrations were determined in hepatic portal venous plasma of dogs during splanchnic artery occlusion (SAO) shock and in nonshock control dogs. Dogs subjected to SAO shock exhibited a dramatic decrease in mean arterial blood pressure and significant increases in portal venous PGF2alpha and amino-nitrogen concentrations, as well as in cathepsin D and MDF activities. Dogs treated with indomethacin prior to SAO shock did not exhibit a significant increase in portal venous PGF2alpha. Indomethacin had no effect on the increase of plasma amino-nitrogen and only slightly reduced portal venous cathepsin D activity during SAO shock. Nevertheless, indomethacin significantly attenuated the severity of the postrelease hypotension observed in SAO shock and diminished the plasma accumulation of MDF. These studies indicate that prostaglandins are released from the splanchnic region during SAO shock and that this release can be prevented by pretreatment with indomethacin. The role of endogenously released prostaglandins in SAO shock is not clear, but the magnitude of the increase warrants further study.
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PMID:Release of prostaglandin F2alpha during splanchnic artery occlusion shock. 126 70

Splanchnic artery occlusion (SAO) with reperfusion results in a severe form of circulatory shock. To study the possible involvement of adenosine in this shock state, we have examined the effects of adenosine, an adenosine A1-receptor antagonist, and their combination in a rat model of SAO shock. Pentobarbital-anesthetized rats were subjected to a 90-min occlusion of both the celiac and superior mesenteric arteries followed by reperfusion. Rats given only the vehicle for adenosine (i.e., 0.9% NaCl) developed severe hypotension following reperfusion, and the survival rate was less than 30% 2 hr after reperfusion. Final plasma free amino-nitrogen concentrations, cathepsin D and myocardial depressant factor (MDF) activities were significantly elevated in rats receiving only the vehicle. Infusion of adenosine (i.e., 30 micrograms/kg/min, i.v.), starting 45 min postocclusion, did not significantly improve the survival rate but did attenuate the accumulation of MDF. Eighty percent (i.e., 4 of 5) rats given KF15372, an adenosine A1-antagonist, 45 min postocclusion (500 micrograms/kg), survived 2 hr. KF15372 also attenuated the increased plasma free amino-nitrogen and MDF. Seventy-five percent (i.e., 6 of 8) rats treated with KF15372 and adenosine survived 2 hr. This combined treatment significantly attenuated the increased plasma levels of free amino-nitrogen, cathepsin D, and MDF. These results suggest that endogenous adenosine plays a significant role in the pathogenesis of shock following SAO and reperfusion, and that blockade of the adenosine A1-receptor could be beneficial in shock states.
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PMID:Effects of adenosine, an adenosine-A1 antagonist, and their combination in splanchnic occlusion shock in rats. 158 7

The purpose of this study was to investigate the effect of the nonglucocorticoid steroid U74006F in the pathogenesis of a murine traumatic shock model. Pentobarbital-anesthetized (40 mg/kg) rats were subjected to Noble-Collip drum trauma and developed a lethal shock state characterized by a decreased mean arterial blood pressure (MABP) to 67 +/- 2 mm Hg and survival time (1.5 +/- 0.2 h). In contrast, sham trauma rats exhibited a MABP of 122 +/- 4 mm Hg at 5 h postanesthesia. Administration of U74006F at doses of 22.5 mg/kg at 15 to 20 min following trauma significantly maintained a higher MABP and prolonged survival compared to those trauma rats receiving only the vehicle for U74006F (0.002 N HCl). U74006F at 15 and 22.5 mg/kg prolonged survival time to 2.6 +/- 0.3 (p less than 0.05) and 3.1 +/- 0.6 h (p less than 0.02), respectively. U74006F also significantly attenuated the plasma accumulation of cathepsin D (p less than 0.02 to p less than 0.01) and free amino-nitrogen compounds (p less than 0.01) compared to the rats receiving only vehicle. Additionally, U74006F at 15 and 22.5 mg/kg blunted the production of the cardiotoxic peptide, myocardial depressant factor (MDF) (p less than 0.01 to p less than 0.001). Moreover, U74006F is a steroid without significant glucocorticoid or mineralocorticoid activity. These results suggest that U74006F may be useful as a therapeutic agent in traumatic shock.
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PMID:Protective effects of a novel nonglucocorticoid 21-aminosteroid (U74006F) during traumatic shock in rats. 168 14

We studied the effects of transforming growth factor-beta (TGF-beta), tissue plasminogen activator (tPA), and their combination in cats subjected to splanchnic artery occlusion (SAO) with reperfusion. Untreated anesthetized cats subjected to total occlusion of the celiac, superior, and inferior mesenteric arteries for 120 min, followed by reperfusion, uniformly died within 120 min after reperfusion. The mean survival time was 75 +/- 8 min. Plasma amino-nitrogen concentrations and cathepsin D and myocardial depressant factor (MDF) activities were markedly elevated following reperfusion. Superior mesenteric artery (SMA) rings isolated from cats subjected to SAO with reperfusion exhibited a significant loss of vasorelaxation to the endothelium-dependent dilators acetylcholine and A-23187. Administration of tPA (1 mg/kg) intravenously just before reperfusion did not prolong survival time (81 +/- 10 min) nor did it influence any biochemical or cardiovascular responses following reperfusion or ameliorate the depressed endothelium-dependent relaxation of SMA rings. In contrast, TGF-beta (50 micrograms/cat) ameliorated the SAO postreperfusion state in terms of survival rate and plasma MDF activity, and protected against depressed endothelium-dependent relaxation of SMA rings. TGF-beta alone slightly increased the survival time to 102 +/- 11 min. However, combined treatment with tPA (1 mg/kg) and TGF-beta (50 micrograms/cat) preserved endothelium-dependent relaxation and prevented increases in plasma amino-nitrogen more prominently than TGF-beta given alone and significantly increased the survival time to 118 +/- 3 min (p less than 0.01). These results indicate that TGF-beta exerts beneficial effects in SAO followed by reperfusion in cats, and tPA has an augmenting action on some of the beneficial effects of TGF-beta. These findings suggest that TGF-beta alone or in combination with tPA may be potentially useful therapeutic regimens in splanchnic ischemia shock by preserving splanchnic parenchymal and endothelial cells.
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PMID:Beneficial effects of transforming growth factor-beta and tissue plasminogen activator in splanchnic artery occlusion and reperfusion in cats. 171 97

The effect of suspension hypokinesia/hypodynamia on the protein metabolism in skeletal muscles (gastrocnemius and soleus) and visceral organs (liver and small intestine) was investigated in the rat. Suspension for 10 days resulted in atrophy of the visceral organs as well as the skeletal muscles, which was associated with decreases in the amounts of visceral and muscle protein. There was marked breakdown of muscle protein, which was reflected by increases in the urinary excretion of N7-methylhistidine and cathepsin D activity. Measurement of protein synthesis by the L-[4-3H]phenylalanine method revealed that the synthesis in the gastrocnemius, but not in the soleus, muscle was suppressed on suspension for 10 days. Thus, both the increased catabolism and decreased synthesis of protein in the muscles may be causally related to the muscle atrophy occurring in suspension. In the visceral organs, on the other hand, the protein synthesis was found to increase in hypokinetic rats. Moreover, the concentration of visceral protein was also increased, despite the decreased amount of muscle protein. These changes in protein metabolism in the liver and small intestine may explain, at least partly, the slightly positive nitrogen balance which was observed after long-term weightlessness.
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PMID:Effect of suspension hypokinesia/hypodynamia on tissue protein turnover in rats. 196 Aug 91

A series of renin inhibitors containing lactam-bridged P1-P1' dipeptide mimetics based on the ACHPA (4(S)-amino-5-cyclohexyl-3(S)-hydroxypentanoic acid) design was studied. The inhibitors were obtained by aldol addition of various lactams with N alpha-Boc-L-cyclohexylalaninal, followed by Boc group removal and acylation with Boc-Phe-His. The aldol diastereomer having the S configuration at the two newly generated stereogenic centers gave optimal enzyme inhibition. Potency was further enhanced in the gamma-lactam ring series by substitution with small hydrophobic groups to mimic the P1' side chain of the renin substrate. Thus, 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl-1 - (1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)propane (34) has an IC50 of 1.3 nM in the human plasma renin assay. A variety of substituents on the lactam nitrogen are tolerated and can be used to vary the physical properties of the inhibitor. By using a model of the human renin active site, the conformation of 34 in the enzyme-inhibitor complex is proposed. This modeled conformation is very similar to the solid-state conformation of 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl- 1-(1-methyl-2-oxopyrrolidin-3(S)-yl)propane (36), the structure of which was determined by single-crystal X-ray diffraction analysis. The most potent ACH-PA-lactam renin inhibitors show good selectivity when assayed against other types of aspartic proteinases. By varying the lactam ring substituents, potent and selective inhibitors of cathepsin D and cathepsin E can be obtained.
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PMID:Renin inhibitors containing conformationally restricted P1-P1' dipeptide mimetics. 200 69


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