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 capacity of malignant cells to invade and disseminate throughout the tissues is partly due to the fact that these cells synthesize and secrete proteases and plasminogen activators. Its growth can be inhibited by antiproteolytic substances in vitro or by natural inhibitors such as alpha-1-antitrypsin (A1AT) and alpha-2-macroglobulin (A2MG). It is a known fact that in cervical cancer, serum A1AT levels are elevated, but so far it has not been determined if serum proteolytic activity is elevated and if both occur simultaneously in vaginal fluid. 32 cases of invasive carcinoma of the cervix, and 25 non-cancerous women were studied. A1AT, A2MG, cathepsin B, trypsin inhibitory capacity (TIC), plasminogen and proteins in plasma and vaginal fluid were studied. In cancer cases, proteolytic activity of serum and vaginal fluid (cathepsin B) is elevated, when compared to controls (p less than 0.001). A1AT and A2MG levels are clearly elevated in plasma, but not in the vaginal fluid; TIC was elevated in serum in cancer cases (1.31 vs. 1.74 p less than 0.005) but was not altered in vaginal fluid. It was found that in cases of carcinoma in situ cathepsin B, plasminogen, A1At and A2MG and CIT were significantly increased (p less than 0.001, p less than 0.001, p less than 0.001 and p less than 0.01 respectively). In vaginal fluid the only statistically significant figure increased was cathepsin B (p less than 0.001). These studies show an altered protease-antiprotease balance in patients with carcinoma of the cervix uteri.
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PMID:Protease and antiprotease concentrations in serum and vaginal fluid of patients with carcinoma of the cervix. 701 Dec 40

Thiol protease inhibitors were found in the cytosol fractions of various rat tissues. An inhibitor, named cytosol thiol protease inhibitor, was purified from rat liver cytosol by acid treatment and column chromatographies on Sephadex G-50, DEAE-Sephadex and Sephadex G-75. The purified inhibitor gave a single protein band on sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. The molecular weight of the inhibitor was found to be 12 400 by gel filtration on Sephadex G-75 and SDS-polyacrylamide gel electrophoresis, and its isoelectric point was found to be 5.04. This inhibitor inhibited rat liver lysosomal cathepsin B, B2, C, H and L and papain, but not cathepsin A or D, trypsin or chymotrypsin. The inhibitor caused noncompetitive inhibition of the hydrolytic activity of cathepsin H on alpha-N-benzoyl-DL-arginine 2-naphthylamide and its Ki value was 4.08 . 10(-8) M. Heat treatment at 80 degrees C for 10 min reduced the activity 40%.
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PMID:Purification and properties of thiol protease inhibitor from rat liver cytosol. 702 26

Several protease activities were measured in human tears by six specific substrates. The specific activity of cathepsin B-like enzyme was 7-fold higher in Orientals than in Caucasians. The trypsin-like and cathepsin C-like enzyme activities also showed 3 to 4-fold higher in Orientals than in Caucasians. However, the deviation in the activities of these two enzymes was high in both Orientals and Caucasians. Similar results were obtained when comparing the protease activities of tear collected by glass capillary and a filter-paper strip method. Since a surface-active small molecular weight fraction can be produced by incubation of freshly collected tears for 4 hours at 37 degrees C, the low molecular weight surfactant may be a proteolytic product.
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PMID:Protease activities in human tears. 703 Jun 34

Primitive biliary cells are known to migrate from the ductal plate into the mesenchyme during human intrahepatic bile duct development, and this migration process is essential for normal development of intrahepatic bile ducts. However, its molecular mechanism is unknown. Matrix proteinases play an important role in cell migration during cancer invasion and organ development. In this study, we therefore investigated in situ expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) during human intrahepatic bile duct development, using 32 human fetal livers. We also examined in situ expression of trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B, which are matrix proteinases and activators of MMP. MMP-1 expression was noted in the ductal plate and migrating primitive biliary cells. MMP-2, MMP-3, and MMP-9 were expressed in the ductal plate. TIMP-1 and TIMP-2 were expressed in the ductal plate and migrating primitive biliary cells. Trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B were also expressed in primitive biliary cells. These data suggest that MMP, trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B play a critical role in biliary cell migration during human intrahepatic bile duct development by degrading extracellular matrix proteins. The data also suggest that MMP inhibitors (TIMP-1 and TIMP-2) and MMP activators (trypsin, chymotrypsin, and cathepsin B) play an important role in biliary cell migration. The coordinated expression of MMP, MMP inhibitors, and MMP activators may be necessary for the normal development of human intrahepatic bile ducts.
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PMID:Expression of matrix proteinases during human intrahepatic bile duct development. A possible role in biliary cell migration. 748 84

Cathepsin B activity was demonstrated histochemically in unfixed cryostat sections of inflamed human gingiva using the 2-methoxy-4-naphthylamide (MNA) substrates Z-Val-Lys-Lys-Arg-MNA and Z-Ala-Arg-Arg-MNA with a post-azo-coupling technique. Enzyme localisation was confirmed by immunocytochemistry with polyclonal sheep anti-human cathepsin B. In both cases, staining was found in connective tissue fibroblasts and also in cells varying in shape from rounded to more irregular forms. The latter were present both in areas of cellular infiltration and in the oral and pocket epithelium. Examination of adjacent sections with monoclonal antibodies directed against leukocyte differentiation antigens showed that the rounded to irregular cells were CD68 positive macrophages and monocytes. The histochemical staining had the form of fine cytoplasmic particles consistent with the known lysosomal occurrence of cathepsin B. Cells stained by the post-coupling method using the tryptase substrates Z-Ala-Ala-Lys-MNA and D-Val-Leu-Arg-MNA showed a different distribution and morphology, with reaction product confined to mast cell granules. The differences between the cathepsin B and tryptase staining patterns were confirmed by differential extraction from cryostat sections with salt-free and high-salt buffers respectively. Biochemical characterisation of activities in the extracts with the 7-amino-4-trifluoromethyl coumarin (AFC) substrates Z-Val-Lys-Lys-Arg-AFC and Z-Ala-Ala-Lys-AFC and protease inhibitors confirmed the identity of the two enzymes. Selective inhibitors could also be used in histochemical incubations to distinguish between cathepsin B and tryptase staining.
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PMID:Comparative histochemical, biochemical and immunocytochemical studies of cathepsin B in human gingiva. 751 62

We have developed a monoclonal antibody AF-28 that specifically recognizes a neo-epitope on polypeptides with N-terminal FFGVG ... sequences. This sequence is found at the N-terminus of aggrecan fragments that have been digested with matrix metalloproteinases (MMPs). By immunoblotting, monoclonal antibody AF-28 specifically detected G2 fragments derived from an aggrecan G1-G2 substrate digested with stromelysin, collagenase, gelatinase and matrilysin, but failed to detect G2 fragments obtained from elastase, trypsin or cathepsin B digests. Undigested G1-G2 was not detected. In addition, AF-28 antibody detected fragments derived from whole aggrecan and this detection did not require prior treatment with chondroitinase or keratanase. Competition experiments confirmed that peptides containing internal ... FFGVG ... sequences were not detected by the antibody, while native MMP-digested aggrecan fragments and a synthetic 32-mer peptide with FFGVG ... N-termini were equally competitive on a molar basis. An FFGVG 5-mer, and an FGVGGEEDI9-mer which lacked the N-terminal phenylalanine residue, were 50 times and 230 times respectively less competitive than the FFGVG ... 32-mer. Two fragments from the interglobular domain, F342-F373 and F342-D441, that are predicted products of G1-G2 digestion by neutrophil collagenase but have not previously been detected, could be detected with AF-28. The epitope recognized by AF-28 was also detected in human synovial fluids by Western blot analysis. A broad band of 100-200 kDa was detected in some patients and a dominant band of 40-60 kDa was found in two patients. The size of this small fragment corresponds with that seen for the porcine F342-E373 product and may represent the natural physiological product of aggrecan cleaved in vivo at both the MMP site (... DIPEN341 decreases F342FGVG ...) and the aggrecanase site (... ITEGE373 decreases A374RGSVI ...).
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PMID:Development of a cleavage-site-specific monoclonal antibody for detecting metalloproteinase-derived aggrecan fragments: detection of fragments in human synovial fluids. 754 17

Kidney tubule dysfunction and lesions are frequent complications of myeloma, related to unknown properties of the monoclonal light chain. We have analyzed protease sensitivity and binding properties of urinary light chains from four patients with Fanconi's syndrome, 12 with cast nephropathy, and four control patients without myeloma-associated tubulopathy. All light chains were normal-sized, monomeric and/or dimeric, and none was N-glycosylated. Kinetic studies of light chain digestion by pepsin and the lysosomal enzyme cathepsin B showed the generation of a protease-resistant 12 kDa fragment, corresponding to the V domain of the kappa chain in the four Fanconi's syndrome patients; in two out of four the V domain was also completely resistant to trypsin. Western and dot blots revealed similar patterns of reactivity of light chains from patients with the Fanconi's syndrome towards other light chains. Properties of cast-nephropathy light chains were more heterogeneous but clearly differed from those of Fanconi's syndrome: (i) 9 out of 12 were of the lambda-type; (ii) only four yielded a transient 12 kDa fragment after cathepsin B digestion, but all showed some resistance to proteolysis of the entire molecule or a fragment thereof to at least one protease, at variance with control light chains; (iii) they displayed various patterns of reactivity with other light chains; (iv) 7 out of 12 reacted specifically with Tamm-Horsfall protein (THP) by ELISA, in contrast with those of Fanconi's syndrome. In one patient who presented with cast nephropathy and the Fanconi's syndrome, the light chain exhibited both partial resistance of the V kappa domain to cathepsin B and the highest reactivity with THP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. 756 94

We evaluated in situ expression of pancreatic trypsinogen (PT) and cathepsin B (CB) in 10 normal livers, 37 cholangiocarcinomas (CCs), and 36 hepatocellular carcinomas (HCCs). In normal livers, PT was expressed in intrahepatic large bile ducts, septal bile ducts, and peribiliary glands, and CB was present in hepatocytes and all epithelial cells of the intrahepatic biliary system. In CCs, PT was present in 26 (70%), of which 24 expressed PT both in CC cells and the CC stroma, and the remaining two showed PT only in CC cells. The ratio of PT-positive cases was high in well-differentiated CCs, moderate in moderately differentiated CCs, and low in poorly differentiated CCs. PT in the CC stroma was present in continuity with PT-positive CC cells, suggesting that PT was secreted from CC cells. The CC stroma positive for PT frequently showed destructive features. CB was present in 32 CCs (86%) and located in both CC cells and the CC stroma. All PT-positive CCs simultaneously expressed CB, suggesting a close association of PT and CB. In HCCs, in contrast, PT was not present in any cases. CB was present in 33 HCCs (92%) and located in both HCC cells and the HCC stroma. In positive specimens, PT immunoreactivity was finely granular in the cytoplasm, whereas CB immunoreactivity was diffuse in the entire cytoplasm. These data suggest that after malignant transformation CCs and HCCs continue to express PT and CB, and CB, respectively. It seems possible that PT secreted from CC cells is converted into trypsin by CB, and that trypsin and CB play a role in CC invasion by degrading extracellular matrix proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of pancreatic trypsinogen/trypsin and cathepsin B in human cholangiocarcinomas and hepatocellular carcinomas. 762 46

The effects of single and repeated short-term (4 hr) obstruction of pancreaticobiliary duct (PBDO), with or without exocrine stimulation (intraductal hypertension) by cerulein infusion (0.2 micrograms/kg.hr), on the exocrine pancreas were evaluated in the rat. Single blockage of pancreaticobiliary duct for 4 hr caused a significant rise in serum amylase levels, pancreatic water content, and redistribution of lysosomal enzyme, cathepsin B from the lysosomal fraction to the zymogen fraction, which was considered to mean the colocalization of lysosomal enzymes with pancreatic digestive enzymes in the same subcellular compartment in acinar cells. In addition, the accelerated lysosomal and mitochondrial fragility was observed in the single pancreaticobiliary-duct-obstructed animals. Moreover, the repeated PBDO for 4 hr (2 hr in each obstruction and 1 hr of free flowing of pancreaticobiliary juice between two obstructions) caused more marked changes in almost the all parameters, and the repeated PBDO with intraductal hypertension caused an activation of trypsinogen in the pancreas, making more marked changes in almost the all parameters than the repeated PBDO only group. These results indicate that the present model of repeated PBDO with exocrine stimulation seems to be a pertinent model for gallstone pancreatitis in humans, and that redistribution of lysosomal enzymes and subcellular organellar fragility seem to play an important role in the pathogenesis of pancreatic injuries induced by PBDO, particularly by repeated PBDO with exocrine stimulation, probably via activation of trypsinogen to trypsin by lysosomal enzyme, cathepsin B.
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PMID:A possible mechanism for gallstone pancreatitis: repeated short-term pancreaticobiliary duct obstruction with exocrine stimulation in rats. 767 5

Amyloid beta protein (beta/A4) is deposited in senile plaques of patients with Alzheimer's disease. This protein is derived from a larger membrane-associated protein, termed amyloid precursor protein (APP). The constitutive processing of APP occurs at the central portion of beta/A4, resulting in the release of large N-terminal peptides. We have purified these peptides from the culture medium of cDNA-transfected COS-1 cells. Some of the isoforms contain the Kunitz-type protease inhibitor (KPI) domain and strongly inhibit trypsin, chymotrypsin and plasmin, but do not inhibit kallikrein, prolyl endopeptidase or granzyme A. The peptides also do not inhibit cysteine proteases such as cathepsin B or calpain. Soluble APPs lacking the KPI domain fail to inhibit any of these proteases. The results indicate that the KPI domain in soluble APPs has protease inhibitory activity against certain serine proteases.
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PMID:Inhibitory spectra of purified protease nexin-II and related proteins towards cellular proteinases. 790 50


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