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)

Urokinase, streptokinase, Brinase, trypsin, and SN 687, a bacterial exoprotease, have been evaluated in an ex vivo assay system. These enzymes were injected into rabbits and the fibrinolytic activity as well as other coagulation parameters were measured by in vitro techniques. Dose-response correlations have been made using the euglobulin lysis time as a measure of fibrinolytic activity and the 50% effective dose has been determined for each enzyme. Loading doses, equal to four times the 50% effective dose were administered to monitor potential toxicity revealing that Brinase, trypsin and SN 687 were very toxic at this concentration. Having established the 50% effective dose for each enzyme, further testing was conducted where relevant fibrinolytic and coagulation parameters were measured for up to two days following a 50% effective dose bolus injection of each enzyme. Our results have demonstrated that urokinase and streptokinase are plasminogen activators specifically activating the rabbit fibrinolytic system while Brinase, trypsin and SN 687 increase the general proteolytic activity in vivo. The advantages of this ex vivo assay system for evaluating relative fibrinolytic potencies and side effects for plasminogen activators and fibrinolytic proteases have been discussed.
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PMID:A comparative ex vivo study of plasminogen activators and proteases for fibrinolytic activity and side effects in rabbits. 57 12

Plasminogen activator activity was detected in human gynecologic specimens using a synthetic fluorogenic peptide substrate assay and confirmed by an 125I-labeled fibrin plate assay. Epithelial cells in these samples contain enzymatic activity that biochemically resembles both the well-characterized plasminogen activator, urokinase, and the less-specific plasminogen activator, trypsin. Inhibition of the cervical cell activity by diisopropylfluorophosphate and p-nitrophenyl-p'-guanidinobenzoate demonstrates that, like urokinase and trypsin, this plasminogen activator is also a serine protease. Polyacrylamide gel electrophoresis of plasminogen that had been incubated with cervical cells indicated the same mechanism of plasminogen activation as exhibited by urokinase. We attempted to correlate plasminogen activator activity of each sample with cytomorphologic diagnosis. Three of the four dysplastic samples analyzed showed higher plasminogen activator activity than did the normal samples.
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PMID:Characterization of plasminogen activator in human cervical cells. 65 74

We have examined the ability of 5 tumour cell types to attach to plastic flasks in medium containing either 10% foetal calf serum or 10% normal human serum and compared this ability with cell-associated caseinolytic activity. The cell types used included fibrosarcoma cells which were obtained from a methylcholanthrene-induced tumour in a C57 BL/6 mouse, the SV40-transformed 3T3 (BALB/c) cells, the Walker carcinosarcoma cells and 2 lines of HeLa cells. All 5 cell types attached to the flasks and spread out efficiently in medium containing 10% foetal calf serum. The walker carcinosarcoma cells and the 2 lines of HeLa cells also attached efficiently in medium containing 10% normal human serum and grew into monolayers in this medium. These 3 cell types had no detectable caseinolytic activity. The fibrosarcoma cells and the SV40-transformed 3T3 (BALB/c) cells did not attach in normal human serum-containing medium. These 2 cell types had readily detected caseinolytic activity. Normal human serum and foetal calf serum were compared for levels of protease-inhibitor activity. Human serum was found to have less activity than foetal calf serum against both trypsin and plasmin as well as the cell-associated caseinolytic activity. The low level of protease inhibitor activity in normal human serum may contribute to the inability of this serum to support the attachment of cells with detectable protease activity because the addition of protease inhibitors such as soybean trypsin inhibitor, lima bean trypsin inhibitor and bovine pancreas trypsin inhibitor to normal human serum dramatically enhanced cell attachment. In contrast to this, the addition of E-amino-n-caproic acid to normal human serum and the removal of plasminogen from normal human serum did not enhance its capacity to support cell attachment.
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PMID:Comparison of cell attachment and caseinolytic activities of five tumour cell types. 74 34

Cultured mouse blastocysts produce plasminogen activator, a protease that converts the zymogen plasminogen into the trypsin-like enzyme, plasmin. We have fractionated the blastocyst and cultured the constituent cell types. Trophoblast outgrowths free of inner cell mass derivatives secrete plasminogen activator during a time period that closely parallels the invasive phase of trophoblast cells in utero. Isolated inner cell masses also produce plasminogen activator; further fractionation of the inner cell mass as well as studies with primary cultures obtained from midgestation tissues demonstrate that enzyme formation is restricted entirely to parietal endoderm cells. Secretion of the enzyme may facilitate the migration of parietal endoderm cells along the trophoblast layer as the yolk sac cavity enlarges during gestation. F9 embryonal carcinoma cells do not secrete detectable amounts of plasminogen activator. However, when these cells are induced to differentiate, the resulting parietal endoderm-like cells are capable of producing the enzyme. These results are consistent with previous findings suggesting that plasminogen activator production may be a characteristic of invasive and/or migratory cells.
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PMID:Differentiation of early mouse embryonic and teratocarcinoma cells in vitro: plasminogen activator production. 97 58

The incubation of lung tissue from premature infants with pulmonary hyaline membranes in fibrinolysis activating or fibrinolytically active solutions gave the following results. With streptokinase it was not possible to dissolve hyaline membranes (verification of the physiological lack of plasminogen in premature infants). The mean content of membranes after 24 hours showed to be 18.14 +/- 12.43% which almost corresponded to the control value of 20.24 +/- 10.54% after incubation in NaCl-solution. In comparison, solutions of plasmin, plasmin-activator or activator prepared from proactivator-plasminogen through activation with streptokinase led to a clear reduction in the membrane content, i.e. 11.00 +/- 6.50, 13.89 +/- 9.72, and 13.63 +/- 8.94%, respectively. A decrease in membranes equally strong to that after plasmin appeared after incubation for only 12 hours in trypsin (11.09 +/- 8.62%). Plasmin, plasmin-activator, and activator, but not streptokinase alone, caused also a considerable nonspecific proteolysis of the lung parenchyma which was equal to the trypsin effect, for example, with an only half as long incubation time. Since the lungs of premature infants contain the tissue activator of fibrinolysis we discuss the suggestion of Ambrus et al. (1974) to administer an injection of plasminogen to premature infants immediately after birth so that a spontaneous fibrinolysis can be favoured for developing hyaline membranes.
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PMID:[Experimental studies on proteolysis of hyaline membranes in vitro (author's transl)]. 121 51

Plasmin inhibition by alpha 2-antiplasmin (alpha 2AP) is regulated by the vascular components fibrin(ogen) fragments, plasminogen and lipoprotein (a). Kinetic analysis demonstrates that CNBr-derived fibrinogen fragments completely protect plasmin from alpha 2AP. Plasminogen and 6-aminohexanoic acid decrease the rate of inhibition by 5- and 10-fold respectively. These studies show that CNBr-derived fibrinogen fragments and 6-aminohexanoic acid bind plasmin kringle(s) with binding constants of 2 micrograms/ml and 120 microM respectively, and that plasminogen binds to alpha 2AP with an affinity of 0.5 nM. The unmodulated inhibition is not effected by the presence of lipoprotein (a), but in the presence of protective CNBr-derived fibrinogen fragments the rate of inhibition is increased by the presence of the lipoprotein. The kinetics demonstrate that lipoprotein (a) binds to CNBr-derived fibrinogen fragments with an affinity of 4 nM, displacing plasmin from the protective surface. In addition, tissue-type plasminogen activator and trypsin inhibition by alpha 2AP is not slowed by the presence of CNBr-derived fibrinogen fragments or plasminogen (Pg), respectively. These kinetics suggest that the initial reversible interaction between plasmin and alpha 2AP is mediated by binding of the inhibitor to the kringle 1 domain of plasmin, with a reversible inhibition constant (Ki) of 5.0 x 10(-10) M. Under conditions where this kringle-inhibitor interaction is blocked, the reversible inhibition still occurs between the plasmin and alpha 2AP, but the initial Ki is increased to 5.0 x 10(-9) M. These data suggest that, in the circulation, plasmin inhibition by alpha 2AP may be down-regulated by fibrin, fibrin(ogen) fragments and Pg, but up-regulated by lipoprotein (a) in the presence of fibrin or fibrin(ogen) fragments. The lipoprotein (a)-mediated promotion of plasmin inhibition may provide an additional mechanism by which the lipoprotein impairs fibrinolysis and promotes atherosclerosis.
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PMID:Lipoprotein (a) promotes plasmin inhibition by alpha 2-antiplasmin. 138 85

In physiological salt solutions, porcine plasminogen is refractory to activation by urokinase or trypsin and to proteolysis at Lys77 by plasmin or trypsin. Plasminogen becomes a substrate for urokinase (at Arg560), plasmin (at Lys77), and trypsin (at both bonds) if chloride ion is removed or if 6-aminohexanoate (2.5 mmol/L) is added. Irrespective of salts, activation of des(1-77)plasminogen is as efficient as activation of des(kringle1-4)plasminogen and is inhibited 50% by 2.5 mmol/L 6-aminohexanoate. In solutions lacking chloride or containing 6-aminohexanoate, plasminogen, des(1-77)plasminogen, and des(kringle1-4)plasminogen show no tendency to saturate urokinase in physiologically relevant concentrations (10 mumol/L). The findings are interpreted as indicating that plasminogen requires modification, either by proteolysis or by ligands, for activation.
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PMID:Requirement of zymogen modification for activation of porcine plasminogen. 144 89

We have examined the conditions for dissolution by live cells of an extracellular matrix composed of reconstituted type I collagen fibrils, using three different cell types which express varying constitutive or inducible levels of procollagenase and collagenase inhibitor. The two major conclusions from these studies were that (i) expression of collagenase is a necessary but not sufficient requirement for dissolution of the collagen fibrils and that (ii) activation of procollagenase is a rate-limiting step. Cells which secreted high levels of procollagenase dissolved collagen fibrils only to the extent that they were able to activate the enzyme. Cells which also expressed inhibitor failed to activate procollagenase in the culture medium and did not dissolve the collagen fibrils unless procollagenase-activation was assisted by exogenous proteinase activity. Cells that did not express inhibitor ultimately did activate procollagenase but the process was slow and incomplete. Introduction of exogenous proteinase activity either in the form of plasminogen, plasmin, or trypsin stimulated collagen breakdown by several fold. Analysis of the culture medium sampled from such cultures showed that the stimulating effect of exogenous proteinases could be ascribed to three separate, but synergistic events: elevated expression of procollagenase, conversion of procollagenase to active form and inactivation of collagenase inhibitor. Two lines of evidence suggested that the dissolution of collagen fibrils in these cultures was mediated by a collagenase-dependent pathway: (i) the rate of dissolution closely mirrored the level of expression of collagenase and (ii) the process was blocked by inhibitory collagenase-specific antibodies.
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PMID:Degradation of collagen fibrils by live cells: role of expression and activation of procollagenase. 148 62

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. Receptor-bound urokinase-type plasminogen activator (uPA) appears to play a key role in these events. uPA converts plasminogen into plasmin and thus mediates pericellular proteolysis during cell migration and tissue remodeling under physiological and pathophysiological conditions. uPA is secreted as an enzymatically inactive proenzyme (pro-uPA) by tumor cells and stroma cells. uPA exerts its proteolytic function on normal cells and tumor cells as an ectoenzyme after having bound to a high-affinity cell surface receptor. After binding, pro-uPA is activated by serine proteases (e.g. plasmin, trypsin or plasma kallikrein) and by the cysteine proteases cathepsin B or L, resp. Receptor-bound enzymatically active uPA converts plasminogen to plasmin which is bound to a different low-affinity receptor on tumor cells. Plasmin then degrades components of the tumor stroma (e.g. fibrin, fibronectin, proteoglycans, laminin) and may activate procollagenase type IV which degrades collagen type IV, a major part of the basement membrane. Hence receptor-bound uPA will promote plasminogen activation and thus the dissolution of the tumor matrix and the basement membrane which is a prerequisite for invasion and metastasis. Tissues of primary cancer and/or metastases of the breast, ovary, prostate, cervix uteri, bladder, lung and of the gastrointestinal tract contain elevated levels of uPA compared to benign tissues. In breast cancer uPA and PAI-1 antigen in tumor tissue extracts are independent prognostic factors for relapse-free and overall survival.
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PMID:Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. 151 91

Different proteases from various microorganisms present in the respiratory tract were capable of enhancing influenza virus infectivity and pathogenicity in mice by proteolytic activation of hemagglutinin (HA). Aerococcus viridans, isolated from a patient with pneumonia, secreted a protease that could activate HA directly, similarly to some Staphylococcus aureus strains. The protease of Pseudomonas aeruginosa could not activate HA directly, but combined application of P. aeruginosa protease and virus into mice enhanced virus titers and pathogenicity. Generation of trypsin-like activity in bronchoalveolar lavage fluids resulting from this combination treatment may be responsible for HA activation. A similar indirect effect on HA activation was induced by streptokinase and staphylokinase, which are known to generate plasmin by plasminogen activation. It was concluded that plasminogen-activating streptococci and staphylococci facilitate viral replication and pathogenicity of plasmin-sensitive influenza virus strains by amplification of the plasminogen/plasmin system.
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PMID:Interactions between bacteria and influenza A virus in the development of influenza pneumonia. 152 12


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