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:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FUT-187, a newly synthesized compound, was studied on its inhibitory activities mainly on proteolytic enzymes, in comparison with those of FUT-175 and FOY-305, known serine protease inhibitors. FUT-187, as well as FUT-175 and FOY-305, had selective inhibitory activities on serine proteases including Clr, Cls, kallikrein, trypsin, plasmin and thrombin; its activities on these enzymes except Clr and pancreatic kallikrein were relatively lower than those of FUT-175 and FOY-305. Further studies were conducted focusing on complement-mediated reactions. In spite of its lower activities against Clr and Cls, inhibitions by FUT-187 on the complement-mediated hemolysis in vitro and in vivo were only a little weaker than or equivalent to that of FUT-175. FOY-305 was ineffective in these tests. Forssman shock in guinea pigs is known to be initiated by the activation of the complement system. The protective effect of intravenous or oral FUT-187 against this shock was definitely superior to that of FUT-175. Furthermore, FUT-187 inhibited changes accompanied with Forssman shock, such as increase in lung weight, the decrease in platelet counts and CH50, and histopathological changes. These results suggested that FUT-187 should be a more potent oral therapeutic agent than FUT-175 for various inflammatory diseases attributed to the excessive activation of the complement system followed by platelet aggregation.
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PMID:Pharmacological studies on 6-amidino-2-naphthyl[4-(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethane sulfonate (FUT-187). I: Inhibitory activities on various kinds of enzymes in vitro and anticomplement activity in vivo. 168 82

1. alpha-1-Antiproteinase (also called alpha-1-antitrypsin or alpha-1-proteinase inhibitor) with a molecular mass of 60 kDa was purified to apparent homogeneity from hamster plasma. 2. It inhibited elastase, chymotrypsin and trypsin, but did not significantly affect pancreatic kallikrein, plasma kallikrein or plasmin. 3. It has the same N-terminal heptapeptide sequence as that of rat alpha-1-antiproteinase. 4. Its plasma level decreased after injection of bacterial lipopolysaccharide.
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PMID:Purification, characterization, and acute phase response of plasma alpha-1-antiproteinase in the hamster, Mesacricetus auratus. 172 45

D-Gluconic acid and alpha-carboxymethyl-polyethylene-glycol-omega-methyl ether (PEG) (mol wt 550) were covalently bound at N alpha-amino group of H-Phe-Arg-pNa to study the effect on hydrolysis by arginyl-hydrolases of chromogenic substrates containing high hydrophilic and amphiphilic groups. For comparison, epsilon-aminocaproyl-, sarcosyl- and succinyl-Phe-Arg-pNa were also synthesized. The obtained compounds were assayed as substrates for porcine pancreatic kallikrein, horse urinary kallikrein, tonin and beta-trypsin. Both PEG- and gluconyl-Phe-Arg-pNa had kcat values of hydrolysis 2-4 times higher than the N-acetyl derivative for all the studied enzymes. epsilon-NH2caproyl-Phe-Arg-pNa resulted in the best chromogenic substrate described for the two tissue kallikreins. The PEG-derivative and D-gluconyl groups were also introduced in the N alpha-amino group of H-Arg-pNa and assayed as beta-trypsin substrates. In comparison with benzoyl-Arg-pNa, the D-gluconyl group had no effect on Km but reduced the kcat value more than 15 times; however, PEG-Arg-pNa was hydrolyzed with similar Km but with kcat 5 times higher. The presence of D-gluconyl and PEG groups in the chromogenic substrate molecules increased their water solubility significantly.
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PMID:Synthesis and hydrolysis by arginyl-hydrolases of p-nitroanilide chromogenic substrates containing polyethylene glycol and D-gluconyl moieties. 182 Nov 68

1. The effects of the alpha 2-adrenoceptor antagonist, yohimbine (0.5 mg kg-1, i.v.) on basal, sympathetic and parasympathetic stimulation-induced submaxillary kallikrein release were investigated in the anaesthetized dog. Kallikrein was measured by its kininogenase activity before and after trypsin activation which also allowed a study of the proportion of active to total enzyme. 2. Yohimbine induced a rapid, three fold increase in basal kallikrein release correlated with an increase in salivary flow rate which lasted for 60 min following injection. 3. Sectioning the chorda tympani did not affect basal kallikrein release but abolished yohimbine-induced rise in salivary kallikrein secretion. 4. Parasympathetic stimulation alone induced a 3 to 4 fold increase in basal kallikrein release correlated with an increase in salivary flow rate. Yohimbine induced a significant additional increase in parasympathetic-stimulated kallikrein release. 5. When the cervical sympathetic nerve was sectioned the basal kallikrein release decreased by 30 to 40%. 6. Sympathetic stimulation alone also induced a 3 to 4 fold increase in basal kallikrein. This was not correlated with the salivary flow and unaffected by yohimbine. 7. The results indicate that yohimbine increases submaxillary kallikrein release into the saliva by inhibition of presynaptic alpha 2-adrenoceptors located on the chorda tympani nerve endings.
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PMID:Yohimbine increases submaxillary kallikrein release into the saliva in dogs: evidence for alpha 2-adrenoceptor-mediated inhibition of cholinergic pathways. 184 66

To investigate the enzyme involved in the activation of plasma inactive renin in vivo, we measured the changes in plasma active renin, inactive renin and prekallikrein, and the levels of urinary kallikrein excretion in 10 primary glomerulonephritic patients before and after a low sodium (Na; 17 mEq/day) constant potassium (K; 40 mEq/day) diet for 5 days. Plasma inactive renin was activated by trypsin. Active renin was measured by the amount of angiotensin I generated when sheep substrate was added to the plasma. Plasma prekallikrein was measured by its activity on substrate S-2302 after activation. Urinary kallikrein was measured by its activity on substrate S-2266. The results showed that changes in plasma active renin (7.7 +/- 2.9 to 23.8 +/- 9.9 ng/ml/h), and inactive renin (61.5 +/- 10.2 to 145.7 +/- 53.9 ng/ml/h) and urinary kallikrein excretion (6.7 +/- 1.1 to 10.8 +/- 2.4 nkat) were significant. No significant change in plasma prekallikrein was observed. The correlation between plasma active renin and inactive renin was significant both before and after the low salt diet. The correlation between the ratio of active to total renin and urinary kallikrein was significant before the low salt diet. These results are compatible with the postulate that plasma inactive renin may be a renin precursor, but they do not support the theory that either plasma kallikrein or renal kallikrein is related to activation of inactive renin in vivo.
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PMID:Effect of sodium depletion on active renin, inactive renin and prekallikrein in plasma and urinary kallikrein excretion in glomerulonephritic patients. 197 41

In this study we investigated the effects of steroid hormones on glandular kallikrein gene expression in the rat pancreatic acinar cell line AR42J. Using a cloned complementary DNA probe and a polyclonal antibody we demonstrated expression of a true glandular kallikrein gene and protein in AR42J cells by Western and Northern blot analysis. Dexamethasone resulted in a time-dependent parallel decrease of kallikrein messenger RNA and protein with a maximum at 12 and 72 h (30 +/- 10 and 8 +/- 0.5% of control, respectively, P less than 0.05, n = 6). In contrast, dexamethasone stimulated gene expression of two other serine proteases, chymotrypsin and trypsin, approximately 3 to 4-fold. The decrease of kallikrein concentration was dose dependent with half-maximal effects at 5 x 10(-8) M and maximal effects at 10(-7) M dexamethasone (23 +/- 6% of control, n = 3). The glucocorticoid antagonist RU 38486 blocked the glucocorticoid-induced decrease in cellular kallikrein content in a dose-dependent manner. Complete inhibition was observed at equimolar doses of dexamethasone and the antagonist. The inhibitory effect of dexamethasone was completely reversible after hormone withdrawal for 24 h. Neither estrogen, progesterone, testosterone, or aldosterone had significant effects on kallikrein expression. These data suggest that down-regulation of pancreatic kallikrein gene expression occurs selectively in response to glucocorticoids at a pretranslational level, mediated most likely by the glucocorticoid receptor.
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PMID:Glandular kallikrein gene expression is selectively down-regulated by glucocorticoids in pancreatic AR42J cells. 201 48

A newly synthesized orally active renin inhibitor, N-morpholinoacetyl-(1-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-n-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat. ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n = 6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful.
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PMID:ES-8891, an orally active inhibitor of human renin. 211 12

Contrapsin and two isoforms, F (fast) and S (slow), of alpha-1-antiproteinase (also called alpha-1-proteinase inhibitor) were isolated in an apparently homogeneous state from plasma of inflamed guinea pigs. Contrapsin inactivated trypsin, but did not significantly affect chymotrypsin, pancreatic elastase, or pancreatic kallikrein. On the other hand, both isoforms of alpha-1-antiproteinase inhibited trypsin, chymotrypsin, and elastase, but not plasma or pancreatic kallikrein. The S isoform of alpha-1-antiproteinase was present in barely detectable amounts in healthy animals, but increased markedly when the acute-phase reaction was induced by subcutaneous injection of turpentine. On the other hand, the plasma levels of the F isoform, contrapsin, and alpha-macroglobulin showed moderate (1.5 to 2.3-fold) elevation during the acute-phase reaction. In contrast to the previous findings that rats and rabbits contain two different alpha-macroglobulins, one of which is an acute-phase reactant while the other is not, inflamed guinea pigs contained only one species of alpha-macroglobulin. Murinoglobulin, the most prominent acute-phase negative protein in both mice and rats, showed no significant change in guinea pigs. These results indicate that guinea pig plasma contains four major trypsin inhibitors, i.e., contrapsin, alpha-1-antiproteinase, alpha-macroglobulin, and murinoglobulin, the properties of which are very similar to those of the respective mouse homologues, but that the acute-phase response of these inhibitors differs greatly from that of the homologous proteins in rats or mice.
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PMID:Trypsin inhibitors in guinea pig plasma: isolation and characterization of contrapsin and two isoforms of alpha-1-antiproteinase and acute phase response of four major trypsin inhibitors. 211 21

1. An in vitro experiment was carried out to compare the inhibitory effect of SQ29,852 on human renal angiotensin converting enzyme (ACE) with those of captopril, enalapril and enalaprilat. 2. SQ29,852 strongly inhibited human renal ACE; its IC50 value was 1.5 x 10(-8) M. In terms of the IC50, SQ29,852's efficacy was about 1/10 of that of captopril and 1/28 of that of enalaprilat, but it was about 14 times more potent than enalapril. 3. SQ29,852 showed no inhibitory effects on cathepsin D, urinary kallikrein, renal renin, pepsin, trypsin and chymotrypsin. Its ACE-specificity was higher than that of captopril. 4. ACE inhibition by SQ29,852 was shown to be competitive, as revealed by Lineweaver-Burk plots. The affinity of SQ29,852 to ACE was shown to be high by a Ki value of 1.2 x 10(-8) M.
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PMID:Effect of SQ29,852, a new angiotensin converting enzyme (ACE) inhibitor with a phosphonic acid group, on the activity of angiotensin converting enzyme from human kidney. 216 61

We have studied rat vascular smooth muscle (VSM) cells in culture for the presence of key elements of the glandular kallikrein-kinin system. Direct radioimmunoassay (RIA) using antiserum against rat urinary kallikrein detected a glandular kallikrein-like enzyme (GKLE) in VSM cells and in media. VSM homogenates and culture media had kininogenase activity, generating kinins from dog kininogen. About half of the GKLE was enzymatically inactive which could be activated with trypsin. Kininogenase activity was inhibited completely by aprotinin but only 20% by soybean trypsin inhibitor (SBTI). Trypsin liberated kinins from homogenates and media, demonstrating that VSM cells contain kininogen. Homogenates and media rapidly degrade bradykinin. GKLE, kininogen, and bradykininase activity were all present in VSM cells grown in defined media that contain no serum, thus eliminating any contamination or artefacts from fetal calf serum in standard culture media. Blood vessels of the rat have been reported to contain GKLE. Our observations indicate that GKLE is synthesized by VSM cells, not deposited from plasma. Furthermore, VSM cells synthesize kininogen and bradykininase(s), the other key elements of the glandular kallikrein-kinin system. Thus it is possible that the system functions as an autocoid mechanism that regulates local vascular tone.
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PMID:Rat aortic smooth muscle cells in culture express kallikrein, kininogen, and bradykininase activity. 229 24


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