Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alternatively spliced type III connecting segment (IIICS) of fibronectin (Fn) contains an amino acid sequence, CS-1, which is recognized by the integrin receptor, alpha 4 beta 1. Plasma Fn inhibits alpha 4 beta 1-dependent binding of lymphocytes and monocytes to CS-1 containing Fn derivatives poorly, suggesting limited exposure of the CS-1 sequence in Fn. To test the availability of CS-1 in plasma Fn, an antibody was raised to the synthetic peptide CS-1. The CS-1 sequence was found to be minimally exposed in plasma Fn; and immobilization of Fn, a model of matrix deposition, caused only a modest increase in its exposure. Digestion of Fn with selected proteases, however, induced substantial expression of the CS-1 sequence. The acid protease cathepsin D generated fragments of 31-33.5 kDa from the COOH-terminal heparin-binding domain of Fn which possessed high immunoreactivity with anti-CS-1. Digestion of Fn with cathepsin B also resulted in the exposure of CS-1 sequence in a 140 kDa fragment. Although the digestion of Fn with neutral proteases (neutrophil elastase, cathepsin G, chymotrypsin, trypsin) generated fragments from the COOH-terminal heparin-binding domain of similar molecular weight as with cathepsin D, the exposure of CS-1 did not occur. Exposure of the CS-1 region by the cathepsins was supported by cell adhesion experiments; digestion of Fn with cathepsins D and B transformed inert plasma Fn to an effective inhibitor of adhesion of lymphoblastoid B and T cells (Ramos, Jurkat, Molt-4) to an immobilized CS-1 conjugate. These results suggest that exposure of the CS-1 sequence in plasma Fn by proteolysis with cathepsins D and B, enzymes implicated in several pathological processes, may serve a regulatory function in cell adhesion. The adhesive function of the CS-1 region in intact Fn appears to be suppressed by the native conformation of the molecule.
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PMID:Proteolysis regulates exposure of the IIICS-1 adhesive sequence in plasma fibronectin. 871 84

Gingival crevicular fluid (GCF) contains several different proteinase activities and the study sought to clarify their sources. Gingival tissue and GCF were collected from chronic periodontitis patients. Gel-filtration chromatography of crude tissue extracts yielded cathepsin B and tryptase fractions sensitive to cysteine and serine proteinase inhibitors, respectively. Cell sonicates of suspected periodontal pathogens were prepared from broth cultures of reference strains. Of these, Porphyromonas gingivalis showed much the strongest activity and this had an effector response consistent with the metal-dependent cysteine proteinase described by others. Banding patterns in GCF, tissue and bacterial samples were compared on substrate-impregnated overlay membranes applied to isoelectric focusing gels. On Z-Val-Lys-Lys-Arg-AFC overlays, GCF had bands corresponding to tissue cathepsin B and the enzyme from P. gingivalis, though a contribution from Treponema denticola could not be ruled out. Use of D-Val-Leu-Arg-AFC overlays showed GCF activity similar to tissue tryptase. In GCF there were additional bands that did not correspond to any tissue or bacterial samples and on Z-Ala-Ala-Lys-AFC overlays these closely resembled activity in parotid saliva. The results confirmed that GCF contains tissue cathepsin B and tryptase, while the apparent presence of enzymes from P. gingivalis and possibly T. denticola is consistent with previous reports linking activity to these organisms. The saliva bands demonstrated that contamination of GCF may occur despite rigorous collection procedures.
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PMID:A comparison of cysteine and serine proteinases in human gingival crevicular fluid with tissue, saliva and bacterial enzymes by analytical isoelectric focusing. 880 1

Effects of proteases and protease inhibitors on generation of long-term potentiation (LTP) were investigated in the CA1 and dentate regions of rat hippocampus. Plasmin, a serine protease, and its precursor plasminogen significantly enhanced short-term potentiation (STP) induced by a weak tetanic stimulation, without affecting basal responses. The STP-enhancing effect of plasmin disappeared by concomitant perfusion of alpha 2-antiplasmin, an endogenous plasmin inhibitor. Other proteases, such as thrombin, trypsin and cathepsin B, did not affect STP. On the other hand, alpha 2-antiplasmin and leupeptin significantly attenuated LTP induced by a strong tetanus though plasminogen or plasmin itself did not influence LTP. Furthermore, plasminogen and plasmin did not affect NMDA receptor-mediated synaptic responses in the absence of extracellular Mg2+. These results suggest that endogenous plasmin is involved in the mechanism of LTP in CA1 and dentate regions of rat hippocampus and that the STP-enhancing effect of plasmin is independent of NMDA receptors.
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PMID:Possible involvement of plasmin in long-term potentiation of rat hippocampal slices. 895 48

We studied the activity of lysosomal cathepsins B and D, neutral trypsin-like proteinase, and the content of trypsin inhibitors in the mammary glands of virgin, pregnant, and lactating rabbit females, as well as during the involution caused by lactostasis. The maximal activity of cathepsin D was found to occur in mammary glands under the condition of lactostasis. The activity of cathepsin B was practically identical in the mammary glands of virgin and pregnant animals and diminished during lactation. The activity of trypsin-like proteinase is low in the mammary glands of virgin animals, increases drastically during pregnancy, and diminishes during lactation. The content of trypsin inhibitors is maintained at a similar level in the mammary glands of virgin and pregnant animals and increases significantly during lactation. The caseinolytic activity of neutral proteinases has not been detected in the mammary glands of virgin rabbit females. At the lactation and involution stages, it is considerably lower than the activity of acidic proteinases and is possibly controlled by endogenous inhibitors.
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PMID:[The proteinase activity and content of trypsin inhibitors in the mammae of female rabbits in physiological states]. 899 89

The pathogenic role of acute ethanol abuse in acute pancreatitis (AP) is still obscure. The aim of the study was to evaluate the effect of antecedent intake of a high dose of 40% ethanol (5 g/kg body wt.), on trypsinogen activation, pancreatic lysosomal membrane labilization, and activities of phospholipase A2 and lipase in taurocholate AP in rats. In 80 male Wistar rats, AP or sham operation (SO) was produced 6 hr after intragastric saline (S) or ethanol (E) administration, and animals were sacrificed after 6, 12, and 18 hr. Free active trypsin (FAT) and total potential trypsin (TPT) were assayed in the pancreatic homogenate. Percentage free activity (%F/T) of cathepsin B was determined as an index of lysosomal membrane fragility. The most evident activation of trypsin occured at 6 hr AP (11.6% of TPT in S group and 16.4% in E group). Antecedent ethanol increased FAT 18 hr after SO from 0.105 +/- 0.048 microg/g protein to 0.258 +/- 0.054 and AP lasting 18 hr from 0.331 +/- 0.072 to 0.695 +/- 0.110. The %F/T of cathepsin B was highest at 18 hr of AP, suggesting maximal labilization of lysosomal membranes at this time. This labilization occurred earlier (at 12 hr of AP) in E group. The increasing effect of antecedent E on lipolytic enzymes was evident after 6 hr of AP. In conclusion, the antecedent intake of high dose of ethanol significantly promoted the conversion of trypsinogen to trypsin in taurocholate acute pancreatitis, whereas its additional effect toward labilization of pancreatic lysosomal membranes and the increase of lipolytic enzymes activities was less evident. Therefore, the promoting impact of acute ethanol intake in the development of acute pancreatitis could be mainly dependent on its increasing effect on trypsinogen activation.
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PMID:Does antecedent ethanol intake affect course of taurocholate pancreatitis in rats? 914 46

Previously our laboratory reported increased activity of the thiol proteinase cathepsin B in gastric juice after ethanol-induced mucosal injury. In this study we measured proteinase activity (PA) and proteinase inhibitory activity (PIA) with the general substrates hemoglobin, azocasein, and bovine serum albumin (BSA) at optimal pH (2.0, 5.6, and 7.4) of aspartic, cysteine, and serine proteinases. Homogenates of glandular stomach mucosa and gastric juice from fasted rats were incubated in the presence or absence of specific inhibitors and sulfhydryl (SH) alkylators N-ethylmaleimide and iodoacetate. PIA was measured after acid and heat inactivation of endogenous proteinases and addition of 20 micrograms/ml pepsin, 20 or 100 micrograms/ml thiol proteinase papain, or 20 micrograms/ml trypsin for 5 min before digestion at 37 degrees C. The highest proteolytic activity was found at pH 2.0 (pepsin) in juice and mucosal homogenate, but proteases were also found at pH 5.6 and 7.4, where pepsin was inactive. Pepstatin inhibited most proteolytic activity at pH 2.0. The SH protease inhibitor leupeptin diminished PA mainly at pH 5.6. N-ethylmaleimide or iodoacetate substantially reduced the PA in acidic milieu, with maximum effect at pH 5.6. Endogenous PIA, expressed as inhibition of the effect of 1 microgram of pepsin, papain, and trypsin on BSA, was 13.1, 1.4, and 9.2% in gastric mucosa and 15.3, 22.5, and 6.2% in gastric juice at pH 2.0, 5.6, and 7.4, respectively. We have concluded that 1) endogenous proteinases and inhibitors in rat stomach can be measured using BSA and hemoglobin as substrates, 2) of the proteinases found in the stomach, 98% was pepsin at pH 2.0 and up to 27% or 17% was SH sensitive at pH 5.6 or 7.4, respectively, and 3) proteinases and their specific endogenous inhibitors may play a role in gastric mucosal injury and protection.
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PMID:Characterization of proteases and protease inhibitors in the rat stomach. 917 25

Gingival crevicular fluid (GCF) was collected from chronic periodontitis patients using plastic micropipettes and coverslip smears stained with antibodies for leukocyte markers and Toluidine Blue for mast cells. The smears consisted of 70-80% granulocytes, 10-20% monocytes/macrophages, 5% mast cells and 5% T lymphocytes; no B lymphocytes were found. Proteases and inhibitors in GCF cells were investigated by enzyme cytochemistry using 2-methoxy-4-naphthylamine-linked peptide substrates and simultaneous coupling to Fast Blue B and immunocytochemistry using biotinylated secondary antibodies and an alkaline phosphatase/new fuchsin detecting system. Elastase was detected in granulocytes, cathepsin B in macrophages, dipeptidyl peptidases II and IV in a small proportion of macrophages, dipeptidyl peptidase IV in a few T lymphocytes, tryptase in mast cells and alpha-1-proteinase inhibitor and alpha-2-macroglobulin in some macrophages. GCF was also collected on filter paper strips and eluted into buffer for biochemical enzyme assays. Lysis of cells by addition of detergent to the elution buffer increased activities to 140-240% of control values. Removal of cells by centrifugation reduced measured activities to 1-30% of original figures; this effect was less if samples were pre-treated with detergent. Proteases from inflammatory cells therefore appear to make up most of the measured enzyme activity in GCF, and this association may explain recent correlations with periodontal disease progression.
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PMID:Investigations into the cellular contribution to host tissue proteases and inhibitors in gingival crevicular fluid. 920 22

The promoting effect of acute ethanol (E) abuse and protective effect of prostaglandin derivatives in acute pancreatitis (AP) remain obscure. The aim of this study was to assess the effect of previous intake of high-dose E on trypsinogen (Tn) activation and labilization of pancreatic lysosomal membranes (PLM), in taurocholate AP in rats, considering treatment with stable beta-thia-iminoprostacyclin (T). In 60 male Wistar rats taurocholate AP was induced or a sham operation was performed. Half of them received 40% E (5 g/kg body weight), 6 h earlier. T (0.3 mg/kg body weight i.g.) was applied before E or before the induction of AP. Free active (FAT) and total potential (TPT) trypsin, free (F) and total (T) cathepsin B, phospholipase A2 (PLA2), and lipase (L) activities were assayed. Percentage FAT/TPT was an index of Tn activation and fractional free (% F/T) activity of cathepsin B was an index of PLM fragility. FAT increased after 12 h of AP, and in E rats this increase was even more evident. Pretreatment and treatment with T partly prevented this increase, however, this effect was abolished or limited in rats previously given E-the changes were not effected by T. PLA2 and L activities in AP were not diminished after T. The promoting effect of acute E abuse prior to AP could be dependent on augmented activation of Tn and labilization of PLM. The protective effect of T seems to be dependent on the decrease in Tn activation in pancreatitic tissue. The potential therapeutic effect of this drug in AP could be limited by previous acute E intake, as evidenced by differences in histopathological changes.
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PMID:The effect of beta-thia-iminoprostacyclin in taurocholate acute pancreatitis in rats: the role of antecedent acute ethanol abuse. 921 98

The etiology of acute pancreatitis is based on several causes, among which idiopathic nature (< 30%) is second to biliary stone disease (60-70%). It is still under debate whether alcohol as the main cause of chronic pancreatitic disease can cause acute pancreatitis. Based on Opie's "obstruction theory" of 1901 and experimental data, it is now widely accepted that the gallstone passage into or through the terminal biliopancreatic ductal system triggers acute (necrotizing) pancreatitis by causing pancreatic ductal obstruction. However, the sequential intracellular mechanisms in the pathogenesis of acute pancreatitis remain unclear. A co-localization hypothesis has been proposed to explain the premature intracellular activation of trypsinogen to trypsin: due to a yet unknown defect in the intracellular protein transport and sorting system within the acinar cell, lysosomal hydrolases (i.e. cathepsin B) and secretory proteins (i.e. trypsinogen) co-localize in a fragile postgolgi vacuole where activation can occur. In addition, alterations of exo- and endocytosis at the apical pole exist (i.e. secretion block). The pathophysiological events are characterized by local and systemic hypovolemia and (micro)circulatory failure aggravating necrosis, followed by ARDS, renal failure and several other severe complications (i.e. sepsis and DIC). The systemic overflow of proteolytic enzymes (i.e. PLA-2) and kinins plays a major role as mediating factor in severe cases, resulting in multiorgan failure.
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PMID:[Etiology, pathogenesis and pathophysiology of acute pancreatitis]. 928 10

This study investigated whether protease treatment ameliorates the progressive course of chronic failure in the rat model of subtotal nephrectomy. Fourteen male Wistar rats underwent 5/6 nephrectomy, and were randomized into a control group (C, n = 7) given 2 ml of 0.9% NaCl intraperitoneally (i.p.) daily, and a study group (P, n = 7) treated with 12 mg Phlogenzym (combination of trypsin, bromelain, and rutosid) in 2 ml saline i.p. daily. After 6 weeks treatment, the Phlogenzym group showed lower proteinuria (C: 19.6 +/- 9.1 vs. 10.2 +/- 6.2 mg/24 h, p < 0.05). Endogenous creatinine clearance was higher (C: 192.3 +/- 99.4, P: 300.5 +/- 47.9 microliters/min per 100 g, p < 0.05), while plasma creatinine was decreased (C: 106.7 +/- 33.9, P: 76.0 +/- 6.3 mumol/l, p < 0.01). Blood urea nitrogen levels did not change, although urea clearance tended to a higher level in the protease-treated rats. Decreased renal formation of cytokines was reflected by a lower urinary excretion ratio of transforming growth factor (TGF)-beta/ creatinine (C: 0.363 +/- 0.183, P: 0.232 +/- 0.085 ng TGF-beta/mg creatinine, p < 0.05). Renal morphology revealed less infiltration of mononuclear cells and an amelioration of interstitial fibrosis as expressed by the volume index of the cortical region (C: 17.17 +/- 1.43; P: 12.3 +/- 0.5%, p < 0.001). In addition, the activities of lysosomal proteinases (cathepsin B, L + B, and H), which are decreased in the remnant kidney model of chronic renal failure, were significantly higher in the enzyme-treated group both in isolated glomeruli and proximal tubules. The body and kidney weight tended to be lower, probably due to a catabolic action of the enzymes. In summary, we provide evidence that protease treatment may be beneficial in a nonimmune mediated renal disease. Phlogenzym ameliorated the course of chronic renal failure in the rat model of subtotal nephrectomy and retarded the development of tubulointerstitial fibrosis. Decreased cytokine formation in the remnant kidney is supposed to play a key role.
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PMID:Effects of protease therapy in the remnant kidney model of progressive renal failure. 938 36


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