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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitous connective tissues contain a wide range of cells including fibroblasts, osteoblasts and chondroblasts. Recently it has been demonstrated that another principal cell of the connective tissue is the smooth muscle cell in several organ systems. These have been shown to be responsible for the synthesis of the connective tissue matrix components of the uterine myometrium and of the arterial system, including collagen, both elastic fibre proteins and glycosaminoglycan. Microtubule inhibitors such as colchicine and vinblastine, and iron chelators such as alpha,alpha -dipyridyl have been used to study their morphologic and chemical effects on collagen synthesis and secretion. Colchicine produces an increase in large Golgi-associated vacuoles, which sometimes contain material reminiscent of aggregates of collagen macromolecules. Vinblastine produces alterations in the endoplasmic reticulum cisternae similar to alterations seen in ascorbic acid deficiency, and alpha,alpha-dipyridyl increases the frequency of regions in cells, interpretable as potential sites of communication of rough endoplasmic reticulum cisternae with the cell surface. Ferritin conjugated anti-procallagen sera were used to localize procollagen in cells and demonstrated procollagen not only in the cisternae of rough endoplasmic reticulum but in all of the elements of the Golgi complex as well. The studies reported in this review have shown that in cell culture arterial smooth muscle will produce not only the microfibrillar protein of the elastic fibre but soluble and/or insoluble elastin as well. Recent studies on serum factors responsible for the proliferation of connective tissue cells have demonstrated that at least one of the principal factors responsible for fibroblast and/or smooth muscle cell proliferation in culture is derived from thrombocytes. Medium containing serum derived from cell-free plasma lacks most of this proliferative effect which can be reinstated when platelets are present during recalcification to form serum. This effect is due to the platelet release reaction as shown by combining supernatant factors derived from platelets exposed to purified thrombin to cell-free, plasma derived serum. Studies with macrophages have also suggested that phagocytic macrophages release factor(s) into a cell culture medium that may also participate in stimulating fibroblasts to proliferate in vitro. The means by which these factors stimulate fibroblast proliferation and connective tissue synthesis remains to be elucidated.
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PMID:Connective tissue cells, cell proliferation and synthesis of extracellular matrix-a review. 23 19

This report details the results of studies performed in nine patients with homozygous beta-thalassemia evaluating platelet function and prostaglandin formation. Platelet malonyldialdehyde (MDA) formation in the presence of N-ethyl maleimide (NEM 1 mM) or thrombin (0.5 u/ml) was used as an indicator of platelet prostaglandin synthesis. The data on the nine patients revealed two distinct subgroups of patients. Six of nine thalassemics, demonstrated platelet abnormalities. Their mean bleeding time was 7.5 +/- 2.5 min (1 SD), significantly prolonged (P less than 0.005) when compared to a value of 3.5 +/- 1.0 min in normal controls. MDA formation in the presence of NEM was significantly decreased (P less than 0.005) to 2.41 +/- 0.49 (1 SD) when compared to a control value of 3.24 +/- 0.33 nmoles MDA/10(9) platelets. Similarly, the mean value for thrombin induced MDA was 0.98 +/- 0.18 nmoles which was decreased (P less than 0.02) when compared to a value of 1.26 +/- 0.2 in the controls. Platelet aggregations with adenosine diphosphate (ADP), epinephrine, and collagen were abnormal in all six patients. However, when platelets from these patients were mixed with platelets from donors who had ingested aspirin 2-8 hr before donation mutual correction and secondary irreversible aggregation of the mixture resulted. No mutual correction was observed when the thalassemic platelets were preincubated with aspirin in vitro before mixing with platelets from donors who had recently ingested aspirin. Although the total amount of platelet malonyldialdehyde formed by the thalassemic platelets in response to NEM and thrombin was decreased when compared to normal controls, this reduction was not the cause of the platelet aggregation abnormalities. This appears to be so because the amount of MDA, and, thus, prostaglandin endoperoxides synthesized by these platelets in response to external stimuli was sufficient to cause irreversible aggregation of platelets from donors who had recently ingested aspirin, and were, therefore, unable to synthesize their own endogenous platelet endoperoxides. In the remaining three patients, bleeding times, platelet aggregation, and MDA formation was normal. No correlation was observed between the platelet abnormalities noted and the magnitude of iron overload, presence of fibrin degradation products, liver function abnormalities, or the use of iron chelators in the individual patient. Family studies were normal. Although the platelet dysfunction does not appear to be of major significance in the usual patient with thalassemia major under normal circumstances, antiplatelet aggregating agents should be used with caution. Aspirin inhibits platelet endoperoxide and prostaglandin formation and this effect may potentiate the platelet dysfunction present in some patients with thalassemia major.
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PMID:Platelet dysfunction in homozygous beta-thalassemia. 52 94

Thrombin-antithrombin III complex concentrations (TAT-III) were measured in 18 anaemic haemodialysis patients treated with erythropoietin (Epo) and in four haemodialysis patients treated with i.v. iron dextran. There was a significant early increase in thrombin-antithrombin III in erythropoietin-treated patients which appeared to be independent of the response to erythropoietin (Epo responders (n = 14), pretreatment TAT-III median (range) 3.10 (2.70-9.10) micrograms/l; maximum TAT-III 19.48 (11.18-60.00) micrograms/l, P less than 0.001, Wilcoxon; Epo non-responders (n = 4), pretreatment TAT-III 3.15 (2.90-4.50) micrograms/l, maximum TAT-III 16.00 (10.31-36.12) micrograms/l, P less than 0.001). This was not seen in iron-dextran-treated patients (Pretreatment TAT-III 2.05 (1.90-9.48) micrograms/l, maximum TAT-III 5.60 (2.10-14.50) micrograms/l). The change was not related to haemoglobin, erythropoietin dose, or method of administration, and was transient in nature, thrombin-antithrombin III returning to pretreatment values after approximately 6 months in all patients (Epo responders 6.0(4.0-9.0) months, TAT-III 2.47 (1.30-9.23) micrograms/l; Epo non-responders 7.0 months, TAT-III 5.04 (2.10-7.00) micrograms/l). Increased thrombin-antithrombin III complex may reflect an effect of erythropoietin on microcirculatory factors, which could be relevant to the occurrence of adverse events during treatment.
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PMID:Prothrombotic effect of erythropoietin in dialysis patients. 131 96

The authors present a case of cystic fibrosis in a 3 months old infant. Clinically, the first manifestation was a severe anemia secondary to iron deperdition through a hemorrhage due to an acquired trouble of thrombin formation. The late was explained by the vitamin K malabsorption and by the hepatocellular insufficiency.
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PMID:[The diagnostic difficulties in a case of a hemorrhagic syndrome in an infant]. 133 78

In the present study performed on rats, we investigated the influence of an in vivo acute iron load on several platelet parameters and their modification after vitamin E supplementation. Iron load was achieved by injecting iron dextran corresponding to 0.1 mg Fe3+ per kg in the gluteus muscles. Control rats were injected with an equal amount of a dextran solution. Analyses were performed 18 h after injection. By comparison with controls, in iron-injected animals, we found significant increases of: (1) serum total iron (by 110%); (2) aggregation of isolated platelets induced by low concentration of thrombin and ADP (by 350% and 120%, respectively); (3) thrombin-induced endogenous serotonin secretion (by 94%). We also studied the mobilization of radiolabeled arachidonate preincorporated into platelet phospholipids. The results indicated that the thrombin-stimulated release of arachidonate and formation of cyclooxygenase and lipoxygenase products (particularly thromboxane B2), were significantly increased. We also found in plasma an increase (by 67%) of malondialdehyde (MDA) as well as a decrease of vitamin E (by 60%). When vitamin E was injected the day before iron injection, platelet hyperactivity and thromboxane biosynthesis were reduced as well as the plasma MDA concentration. Consequently, given the key role of calcium flux in the activation processes in platelets, we also investigated the thrombin-induced Ca2+ uptake by means of radiocalcium. We found that in platelets from iron-treated rats the Ca2+ uptake amounted to 3670 +/- 201 pmol/10(9) platelets (plt) and was significantly different from controls (1680 +/- 192 pmol/10(9) plt, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of vitamin E on acute iron load-potentiated aggregation, secretion, calcium uptake and thromboxane biosynthesis in rat platelets. 146 49

Human plasma fibronectin was denatured with 8 M urea and reduced with dithiothreitol. Dialysis or dilution of the solution led to formation of fibronectin dimers which migrated in non-reducing SDS/PAGE similarly to untreated control protein. When the redimerized fibronectin was reduced and re-electrophoresed it formed a doublet of alpha and beta chains of equal intensity indicating that it was a heterodimer. Low concentrations (less than 1 mM) of Fe3+ enhanced the redimerization of fibronectin, suggesting that metal ions may mediate oxidative reactions in the formation of the disulfides. Consequently, redimerization of fibronectin was completely prevented by deferoxamine, an iron chelator. Dimerization of fibronectin took place most effectively at pH greater than or equal to 8.8 but decreased strongly at lower pH, representing more unfavourable conditions for the action of the thiolate anion in the thiol/disulfide exchange reaction. Redimerized fibronectin, however, lost many of its binding properties to macromolecular ligands, suggesting that the disulfide bonding did not entirely regenerate the proper conformation of the protein. Pulse/chase experiments of fibroblast cultures showed that the initially monomeric fibronectin was rapidly and quantitatively dimerized under conditions representing natural pH and environment. SDS/PAGE analysis of the dialyzed urea-denatured/reduced thrombin and plasmin digests of fibronectin revealed that the NH2-terminal 30-kDa fragment and other fragments that contained intrachain disulfides quantitatively regained their non-reduced electrophoretic mobility. The results show that the dimerization and formation of intrachain disulfides of fibronectin may occur, in part, spontaneously, based on the amino acid sequence information of the protein. However, complete disulfide formation may also need other factors, present only in living cells, as suggested by pulse/chase experiments in fibroblasts.
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PMID:Disulfide-bonded dimerization of fibronectin in vitro. 176 Oct 59

The present in vitro study of the effects of iron on the blood coagulation mechanism in rats showed that addition of ferrous sulphate to pooled rat plasma resulted in inhibition of blood coagulation, as shown by prolongation of the clotting parameters tested, an effect which was dose-dependent. In vitro addition of ferrous sulphate to rat PRP in doses of 2-5 mg/ml significantly decreased platelet aggregation in response to ADP, while collagen-induced aggregation was significantly diminished in presence of the higher doses of ferrous sulphate (4-5 mg/ml). Also, preincubation of ferrous sulphate with thrombin or with pure fibrinogen indicated that iron could produce decrease of thrombin activity as well as impairment of fibrinogen clottability. In vitro addition of copper sulphate (300-1000 micrograms/ml) elicited an anticoagulant effect, though thrombin time was markedly shortened with all tested concentrations of copper sulphate. Addition of copper sulphate to PRP produced inhibition of platelet aggregation in response to PRP produced inhibition of platelet aggregation in response to ADP and to collagen. Preincubation of copper sulphate with thrombin resulted in slight enhancement of thrombin activity followed by inhibition, while preincubation of copper sulphate with pure fibrinogen caused only minimal impairment of fibrinogen clottability. Also, addition of gold chloride in doses of 50-500 micrograms/ml to plasma in vitro produced a dose-dependent progressive prolongation of all clotting parameters tested, the effects reaching a maximum after 30 min. incubation. Further the in vitro addition of gold chloride to rat PRP resulted in marked inhibition of platelet aggregation in response to both ADP and collagen. In addition, preincubation of gold chloride with thrombin or with pure fibrinogen showed that gold exerted an antithrombin action and prolonged the fibrinogen clotting time indicating impaired fibrinogen clottability.
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PMID:In vitro effects of trace elements on blood clotting and platelet function. A--Iron, copper, and gold. 180 Jun 20

The incorporation of tritiated thymidine into CCL-39 cells grown in the absence of fetal calf serum or other growth factors is greatly increased by low concentrations of ceruloplasmin. The stimulation is greater than observed with serum or thrombin. Addition of serum decreases the thymidine incorporation with ceruloplasmin to the level with serum alone. As with serum, the response to ceruloplasmin is high at both 20% and 1% oxygen, which is consistent with the action of ceruloplasmin as an oxidant with a high affinity for oxygen. Since transplasma membrane electron transport increases cell growth and thymidine incorporation, ceruloplasmin may act as a terminal oxidase for ferrous iron or ascorbate to stimulate transplasma membrane electron transport. The four electron transfer from ceruloplasmin to oxygen to form water will prevent peroxide formation at the cell surface. Alternatively, superoxide formation inside the cell or membrane could employ the superoxide dismutase function of ceruloplasmin to produce peroxide. Either mechanism would be consistent with the previously described stimulation of growth by external oxidants.
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PMID:Ceruloplasmin stimulates thymidine incorporation by CCL-39 cells in the absence of serum or growth factors. 195 52

Lytic H2O2-induced injury to human umbilical vein endothelial cells provides a model for endothelial cell damage in diverse states including acute respiratory distress and septic shock. Endothelial cell lysis is an extreme result of inflammatory cell activation. Functional alterations such as responsiveness to endothelial cell agonists and eicosanoid production might be impaired by exposure to inflammatory cell products including H2O2. Soluble mediators such as thrombin or histamine cause endothelial cell activation via a signal transduction mechanism that hydrolyzes phosphatidylinositol 4,5-bisphosphate (IP), liberating inositol trisphosphate (IP3). Accordingly, pretreatment of endothelial cells with H2O2 blocked the subsequent production of IP3 in response to thrombin and histamine. H2O2 inhibition of IP3 was time- and concentration-dependent. The endothelial cells were viable by trypan blue dye exclusion and chromium release. H2O2 inhibition of signaling was completely prevented by catalase. Iron-dependent oxidant radical formation appears critical because deferoxamine (10(-4) mol/L) pretreatment of endothelial cells prevented H2O2 inhibition of IP hydrolysis. Prostacyclin and platelet activating factor production in response to thrombin have been linked to IP hydrolysis. Pretreatment of endothelial cells with H2O2 reduced prostacyclin and platelet-activating factor production by thrombin by at least 50%. It appears H2O2 can induce defects in signaling pathways with sequelae (decreased prostacyclin and platelet-activating factor) short of endothelial cell death. The possible consequences of H2O2 interaction with endothelial cells is reviewed with the aim of presenting a hypothesis to integrate these various observations.
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PMID:Hydrogen peroxide alters signal transduction in human endothelial cells. 198 9

The presence of heterogeneous erythroid progenitor cells, contaminant cells, or serum may alter erythroid colony development in vitro. To obtain highly purified colony-forming units-erythroid (CFU-E), we cultured partially purified human blood burst-forming units-erythroid (BFU-E) in methylcellulose with recombinant human erythropoietin (rHuEPO) for 7 d and generated cells that consisted of 30-60% CFU-E, but no BFU-E. A serum-free medium was used that allowed development of the same number of erythroid colonies as serum containing medium, but with a greater percentage of larger colonies. This medium consisted of delipidated crystalline bovine serum albumin, iron saturated transferrin, lipid suspension, fibrinogen, thrombin, Iscove's modified Dulbecco's medium/F-12[HAM], and insulin plus rHuEPO. When CFU-E were cultured in a limiting dilution assay and the percentage of nonresponder wells was plotted against cell concentration, both serum-free cultures and serum-containing cultures yielded overlapping straight lines through the origin indicating that CFU-E development did not depend on accessory cells and that insulin acted directly on the CFU-E. Human recombinant interleukin 3 (IL-3) and/or granulocyte-macrophage colony-stimulating factor had no effect on CFU-E growth, while they markedly enhanced BFU-E growth. Physiological concentrations of recombinant human insulin-like growth factor I (IGF-I) enhanced CFU-E growth in the absence of insulin and, together with rHuEPO in serum-free medium, provided a plating efficiency equal to that of serum-containing medium. Limiting dilution analysis in serum-free medium with IGF-I showed a straight line through the origin indicating that IGF-I also acted directly on the CFU-E and not through an effect on accessory cells. These data demonstrate that CFU-E do not require accessory cells, but do require IGF-I and/or insulin which act directly on the CFU-E.
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PMID:Human colony-forming units-erythroid do not require accessory cells, but do require direct interaction with insulin-like growth factor I and/or insulin for erythroid development. 265 78


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