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:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebrospinal fluid contains several proteolytic enzymes that can degrade myelin basic protein (BP) under physiological conditions into peptide fragments of various sizes which still contain antigenic determinants capable of binding antibodies to BP. These enzymes are optimally active in either acid (pH 4) or nuetral (pH 7 to 8) conditions and can be characterized by the nature of the BP peptide fragments produced. Proteinases resembling cathepsin D, thrombin, plasmin (fibrinolysin), or kallikrein are present in variable amounts in CSF. No relationship to any particular disease has yet been established.
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PMID:Degradation of myelin basic protein by cerebrospinal fluid: preservation of antigenic determinants under physiological conditions. 9 75

Epsilon aminocaproic acid, an inhibitor of plasminogen and trypsinogen activators, can decrease the severity of experimental allergic encephalomyelitis (EAE) in rats. The drug was tried because of a number of observations suggesting that neutral proteases, such as plasmin, might be chemical mediators of demyelination. The highest concentrations of plasminogen activator are found in the walls of veins and venules, around which demyelination is common in many demyelinating diseases, including MS. Indeed, the earliest lesion in MS is often demyelination with little cellular infiltration. In vitro studies have shown that neutral proteases secreted by activated macrophages selectively lyse myelin basic protein.
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PMID:The modification of experimental allergic encephalomyelitis with epsilon aminocaproic acid. 56 43

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system commonly used as a model for multiple sclerosis. In both of these diseases demyelination occurs association with perivascular infiltrates of T-cells and macrophages. The similarities in immunopathology suggest that these two diseases share common mechanisms of tissue destruction. We have proposed a general mechanism to explain the clinical and histopathological features of EAE. T-cells sensitized to the inducing antigen, myelin basic protein (MBP), react with antigen-presenting cells (possibly endothelial cells, microglia or astrocytes) in the central nervous system. As a consequence of this reaction, T-cells release lymphokines which activate macrophages, stimulate an augmenting inflammatory response, and, through the action of vasoactive amines, induce vasospasm and breakdown of the blood-brain barrier. The activated macrophages secrete inflammatory mediators, including plasminogen activator and other proteinases, which, in concert with serum plasminogen and complement, initiate myelin destruction. The macrophage products also serve to enhance the inflammatory response and vascular permeability. In support of this hypothesis we find that: (1) macrophage-secreted proteinases can degrade MBP in lyophilized myelin and that proteolysis is amplified in the presence of plasminogen; (2) proteolysis of proteins in fresh myelin by macrophage proteinases and plasminogen or by plasmin is potentiated by complement; (3) removal of macrophages from the circulation suppresses EAE; (4) proteinase inhibitors suppress EAE; and (5) prazosin, an alpha 1-adrenergic receptor antagonist, suppresses the clinical signs of EAE and the increased vascular permeability but only delays the inflammatory response. We believe that prazosin acts on the vascular alpha 1-adrenergic receptor to inhibit vasospasm and prevent opening of the blood-brain barrier. Thus it is possible to suppress both clinical signs and pathology by interceding at several steps of the cell-mediated immune reaction.
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PMID:Mechanisms and suppression of inflammatory demyelination. 213 Jun 45

Rabbit myelin basic protein (BP) was subjected to partial cleavage with plasmin, and 15 cleavage products were isolated by a combination of gel filtration and ion-exchange chromatography. Their identification was achieved by amino acid analysis and tryptic peptide mapping, supplemented in some instances by carboxy-terminal analyses with carboxypeptidases A, B, and Y and amino-terminal analyses with dipeptidyl aminopeptidase I. The results showed that major plasmic cleavage sites included the Lys89-Asn90, Lys133-Ser134, and Lys153-Leu154 bonds. Cleavages also occurred at the Arg31-His32, Lys53-Arg54, and Arg25-His26 bonds, but these appeared to be less extensive. A large number of additional peptides were produced in relatively low yield. The smaller of these were isolated from heterogeneous fractions by high-voltage electrophoresis-TLC. Amino acid analysis of these peptides showed that minor cleavage sites included the Arg9-His10, Lys13-Tyr14, Lys103-Gly104, Lys137-Gly138, Lys140-Gly141, and Arg160-Ser161 bonds. In spite of a lower selectivity toward peptide bonds in BP as compared with pepsin, cathepsin D, and thrombin, plasmin has the advantage over the former proteinases in that it does not cleave at or near the Phe44-Phe45 bond. Instead it cleaves at the Arg31-His32 and Lys53-Arg54 bonds, thus preserving the entire hydrophobic sequence Ile-Leu-Asp-Ser-Ile-Gly-Arg-Phe-Phe as well as short sequences to either side.
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PMID:Cleavage of rabbit myelin basic protein by plasmin: isolation and identification of the major products. 241 69

Both bovine and human myelin basic protein (MBP) have been shown to have electrophysiological activity. As MBP is susceptible to proteolytic degradation, our aim was to discover whether the resulting peptides retained this activity. Bovine MBP was completely cleaved by plasmin into at least nine peptides. The electrophysiological activities of this peptide mixture and of bovine MBP were directly compared on the hemisected frog spinal cord. The peptide mixture and intact bovine MBP had quantitatively and qualitatively similar effects (dose-dependent long-lasting depolarization, about 100 times more active than glutamate). Four peptides (molecular weights 14,000, 10,500, 8,000, 4,500) from thrombin or cathepsin D cleavage of bovine MBP also showed electrophysiological activity, positively correlated to their molecular weights. As MBP-like material occurs in increased concentrations in the cerebrospinal fluid during demyelinating diseases, peptides resulting from proteolytic degradation of MBP, e.g. in demyelinating foci of multiple sclerosis, might cause neuronal disturbances.
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PMID:Effects of peptides from bovine myelin basic protein on the bioelectrical activity of the frog spinal cord. 245 64

Increased numbers of oligodendrocytes and remyelination are frequently observed in multiple sclerosis plaques. It is presumed the increased numbers of oligodendrocytes are due to cell division, but this has not been proven. The mitogens within the lesion which might be responsible for this are unknown. Since oligodendrocyte proliferation occurs in areas in which there is myelin breakdown, we undertook the present study to determine if myelin basic protein (MBP) or its breakdown products could induce oligodendrocyte proliferation. MBP, or MBP digested by the neutral proteinase plasmin, was added in three concentrations to the media of adult bovine oligodendrocytes in culture. Oligodendrocytes were identified by staining for galactocerebroside. Bromodeoxyuridine incorporation was used as a measure of cell division. Oligodendrocytes were found to divide only rarely in regular culture media, in the presence of MBP, plasmin, or MBP digested by plasmin. The results indicate that MBP is not a significant mitogen for the mature oligodendrocyte.
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PMID:Myelin basic protein does not have a mitogenic effect on adult oligodendrocytes. 754 24

Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes, capable of degrading proteins found in the extracellular matrix. MMPs 2 and 9 are known to be produced by microglia, the resident macrophages of the central nervous system. The control of the secretion of these proteases and the activation of proenzymes by other proteases such as plasmin, as well as the balance between MMP secretion and the secretion of their natural inhibitors (TIMPs), have an important relevance in the pathogenesis of multiple sclerosis (MS). The in vitro control of MMPs 2 and 9, TIMPs 1 and 2, and urokinase-type plasminogen activator by microglia was examined in response to a panel of chemokines (chemotactic cytokines), using ELISA and zymography techniques. The chemokines MCP1, MIP1beta, RANTES, IL-8, and Fractalkine were all found significantly to increase the secretion of MMPs and TIMPs by a human foetal microglial cell line, CHME3, after 24 h stimulation. The chemokines tested, MCP1, MIP1beta, and Fractalkine, were also shown to increase MMP9 secretion by primary isolated rat brain microglia in vitro. MCP1, MIP1alpha/beta, and RANTES significantly decreased the secretion of uPA into culture supernatants in ELISA experiments. These findings suggest an important potential role for the involvement of chemokines in the breakdown of the blood-brain barrier and also the destruction of myelin basic protein in MS.
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PMID:Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro. 1055 77

Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin. It plays an important role in the nervous system, including the processes of neuronal migration, neurite outgrowth, and neuronal plasticity. tPA has also been suggested to have a role in several neuropathological conditions, such as cerebral ischemia, seizures, and demyelinating diseases. To investigate the role of tPA in spinal cord injury, wild-type mice and mice with homozygous tPA deficiency (tPA(-/-) mice) were subjected to spinal cord contusion and the differences of hindlimb function, electrophysiological changes, and histopathological changes were assessed for 6 weeks. Functional recovery was greater in tPA(-/-) mice than in wild-type mice throughout the observation period. The time course of myoelectric motor-evoked potentials supported the hindlimb functional findings. Histological examination showed that injured areas were smaller in tPA(-/-) mice than wild-type mice on Luxol fast blue staining or myelin basic protein and neurofilament protein immunostaining at 6 weeks after contusion. Electron microscopy showed that the white matter was better preserved in tPA(-/-) mice than in wild-type mice. The expression of tPA protein was widespread on the first day after contusion and this expression was detected for at least a week. Activation of microglia/macrophages and apoptotic cell death were significantly reduced in tPA(-/-) mice after contusion. This study shows that neural damage is decreased in tPA(-/-) mice after spinal cord injury. Suppression of tPA production may help to decrease secondary injury after spinal cord contusion.
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PMID:Decreased neural damage after spinal cord injury in tPA-deficient mice. 1261 87

The germinal matrix of human brain gives rise to oligodendrocytes and astrocytes after mid-gestation. Hemorrhage in the germinal matrix of premature infants is associated with suppressed cell proliferation. We hypothesize that soluble blood constituents have an adverse effect on the proliferation of cultured rat subventricular zone (SVZ) cells and the proliferation, migration, and differentiation of oligodendrocyte progenitor cells (OPC). Using caspase 3 activation and lactate dehydrogenase release assays, rat plasma, serum, thrombin, and kallikrein killed SVZ cells when grown in the presence (but not absence) of platelet derived growth factor. Plasma and serum killed OPC at 1:1 to 1:100 dilutions. Using a bromodeoxyuridine incorporation assay OPC proliferation was reduced by plasma, serum, thrombin and plasmin. Blood proteins also suppressed OPC migration in a concentration dependent manner. However, differentiation of OPC into myelin basic protein expressing cells was suppressed only by thrombin. We conclude that soluble blood components, particularly thrombin, have an adverse effect on maturing SVZ cells and OPC derived from newborn rat brain.
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PMID:Toxic effect of blood components on perinatal rat subventricular zone cells and oligodendrocyte precursor cell proliferation, differentiation and migration in culture. 1947 44

Myelin basic protein (MBP) is a key component of myelin, the specialized lipid membrane that encases the axons of all neurons. Both plasminogen (Pg) and tissue-type plasminogen activator (t-PA) bind to MBP with high affinity. We investigated the kinetics and mechanisms involved in this process using immobilized MBP and found that Pg activation by t-PA is significantly stimulated by MBP. This mechanism involves the binding of t-PA via a lysine-dependent mechanism to the Lys⁹¹ residue of the MBP NH₂-terminal region Asp⁸² -Pro⁹⁹, and the binding of Pg via a lysine-dependent mechanism to the Lys¹²² residue of the MBP COOH-terminal region Leu¹⁰⁹-Gly¹²⁶. In this context, MBP mimics fibrin and because MBP is a plasmin substrate, our results suggest direct participation of the Pg activation system on MBP physiology.
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PMID:Myelin basic protein stimulates plasminogen activation via tissue plasminogen activator following binding to independent l-lysine-containing domains. 2864 98


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