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)

Mammary tumor cell growth factor(s) has been identified in extracts of platelets from both male and female rats, as well as in extracts prepared from pooled outdated human platelets. When assayed by the growth promotion of MTW9/PL rat mammary tumor cells in culture, platelet extracts alone were able to support growth 50--75% as well as whole serum. The mitogenic activity from crude human platelet lysates was shown to be trypsin sensitive, relatively stable to extremes of pH, labile to heat treatment at 70 degrees, non-dialysable, ammonium sulfate precipitable, not removed by 56 degrees charcoal treatment, and of apparent molecular weight of 30,000 to 50,000 daltons as estimated by G-100 Sephadex chromatography. The platelet derived mammary growth factor activity was not replaced or potentiated by thrombin or known hormones and growth factors such as prolactin, insulin, 17-beta-estradiol, progesterone, hydrocortisone, L-thyroxine, and mouse epidermal growth factor. The experimental report demonstrates that platelets are a rich source growth factor activity for rat epithelial mammary tumor cells, and that the activity appears to be a polypeptide(s) different from other mitogenic activities known to influence growth of mammary tissue.
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PMID:Platelet derived growth factor(s) for a hormone-responsive rat mammary tumor cell line. 3 Jul 82

Factor D (C3 proactivator convertase) of human serum has been shown to be absolutely necessary for alternative pathway function, for activation of the C3/C5 convertase of that pathway and not to be a subunit of this enzyme. Factor D was found to be present in human plasma in active form only, at a concentration of 2 microgram/ml, and not to be controlled by plasma protease inhibitors or by spontaneous decay. Unlike trypsin, factor D cleaves and activates factor B only when it is in Mg++-dependent complex with C3b, has no esterolytic activity, and is unable to cleave the B chain of insulin. The alleged functional and antigenic relationship of factor D to alpha-thrombin could not be verified. The results of this study led to the description of the mechanism of action of factor D in terms of the cryptic site hypothesis.
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PMID:Mechanism of action of factor D of the alternative complement pathway. 8 4

All agree on altered platelet function in vitro (and increasingly in vivo) in diabetics of substantial duration and/or with clinical evidence of angiopathy. However, a platelet abnormality earlier in the disease remains uncertain. Three sets of data from Oxford will be reviewed: (1) Observations of Honour on platelet aggregation at sites of minimal injury within blood vessels of anesthetized rabbits, with greater sensitivity to superfused ADP when hyperglycemia has followed alloxan only days previously. This increased aggregatability (not hyperglycemia determined) is reversed by a few days of insulin treatment or by dipyrimadole (alone or with synergistic acetyl salicylic acid): (2) Beta-thromboglobulin is released from platelets and is increased in venesected blood from diabetics after a standardized procedure (no prostaglandin E1 in anticoagulant) with final radioimmunoassay. Results in diabetics after surgery, etc., will also be presented, and (3) in a prospective study of newly-diagnosed, mostly maturity-onset type diabetics, an increase in plasma fibrinogen (thrombin coagulation of plasma, controlled against normals) was observed during the first 3 yr, largely due to males treated with sulfonylureas; decreases in platelet count and in prothrombin concentration were also statistically significant.
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PMID:Direct animal and indirect human evidence of altered platelet function in diabetics. 16 73

Experiments probing the mechanism by which glucocorticoids modulate cell proliferation were carried out on serum-free cell cultures of quiescent human diploid foreskin (HF) cells. Added alone, the synthetic glucocorticoid dexamethasone had no effect on cell number. However, dexamethasone enhanced the mitogenic response of HF cells to epidermal growth factor (EGF) by 50% at all EGF concentrations. The mitogenic action of EGF was maximally promoted by a dexamethasone concentration of 100 ng/ml (0.25 muM). Binding studies with (125)I-labeled EGF ((125)I-EGF) suggested that dexamethasone caused this "permissive" effect by modulating cell surface receptors for EGF. Paralleling their increased responsiveness to EGF growth stimulation, dexamethasone-treated cells exhibited a 50-100% increased ability to bind physiological concentrations of (125)I-EGF. A binding increase was apparent after a 4-hr dexamethasone treatment. The dexamethasone-treated cells maintained an increased ability to bind (125)I-EGF during the prolonged exposure to EGF that was required to stimulate cell division. Moreover, the increase in (125)I-EGF binding exhibited a dexamethasone dose-dependence similar to that for the enhancement of EGF mitogenesis, suggesting a relationship between the dexamethasone effects on binding and growth. An investigation of the binding increase showed that it was specific for glucocorticoids, and required protein synthesis. The enhancement of (125)I-EGF binding diminished with increasing concentrations of (125)I-EGF, indicating that dexamethasone caused a qualitative change in the EGF receptors (possibly a change in receptor affinity or cooperativity). The alteration in (125)I-EGF binding may occur as part of a far-reaching dexamethasone-mediated change in the cell surface, because dexamethasone treatment slightly increased the ability of HF cells to bind (125)I-insulin, and decreased by half their ability to bind (125)I-thrombin.
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PMID:Dexamethasone modulates binding and action of epidermal growth factor in serum-free cell culture. 30 7

Recently, evidence has been reported to suggest that human platelets like several other circulating blood cells may bind insulin. To examine whether human platelets contain specific insulin receptors, washed human platelets suspended in Hepes buffer were incubated at 24 degrees C with 125I-insulin in the presence and absence of unlabeled insulin and specific insulin binding was determined. Insulin binding by platelets increased progressively with time of incubation to reach a maximum at 3 h and was proportional to the number of platelets in the incubation mixture. Maximum insulin binding was observed at pH 8. Insulin degradation by platelets as assessed by TCA precipitability and reincubation studies was minimal. Scatchard analysis of the binding data and dissociation studies revealed evidence of negative cooperativity of the platelet insulin receptor. A high affinity dissociation constant of approximately equal to 3 X 10(9) M-1 was determined and the concentration of platelet insulin receptors was estimated as 25 binding sites/micron2 platelet surface area. Binding of 125I-insulin by platelets was inhibited by unlabeled porcine insulin and to a lesser extent by catfish insulin and porcine proinsulin but not by glucagon, prolactin, growth hormone, and thrombin. The findings indicate that human platelets contain specific insulin receptors. The significance of the platelet insulin receptor, particularly with respect to altered platelet function in diabetes mellitus, remains to be determined.
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PMID:Demonstration and partial characterization of insulin receptors in human platelets. 44 28

The influence of various components of plasma hemostatic system on the assimilation of glucose by isolated rat hemidiaphragm in the presence of insulin was investigated. The addition of streptokinase and human plasminogen to the incubation medium decreased the rate of glucose assimilation. This effect did not occur when trasylol, an inhibitor of plasmin, was added to the assay system. The glucose assimilation by hemidiaphragms incubated in buffer with glucose and insulin was not influenced by thrombin, fibrinopeptides, fibrin degradation products, plasminogen, streptokinase or trasylol added separately to the assay system. The mechanism of the influence of plasmin on insulin action was partly elucidated in further experiments. Thus, less 125I-insulin was bound by isolated fat cells preincubated with plasmin than by control cells.
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PMID:Influence of plasma hemostasis on insulin action in vitro. 108 Oct 45

In 18 insulin-dependent diabetics (6 without retinopathy, 6 with proliferative retinopathy and 6 with proliferative retinopathy treated by hypophysectomy) matched for age and duration of diabetics, in vitro haemostasis was studied using ADP induced platelet aggregation, ristocetin induced platelet aggregation which allows von Willebrand factor (VIII VWF) assay, and determination of antihemophilic factor procoagulant activity (VII AHF). Using gel filtration-isolated platelets, the ADP induced hyperaggregation previously reported in diabetics with severe retinopathy untreated by hypophysectomy appeared to be related to a platelet and not a plasma factor; the normal results of thrombin induced aggregation suggests that the presumed abnormal platelet factor is related to the platelet plasma membrane. High level of plasma VII VWF was observed in diabetics with proliferative retinopathy while the VII AHF level was within normal limits.
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PMID:Platelet hyperaggregation and increased plasma level of Von Willebrand factor in diabetics with retinopathy. 108 63

The bradykinin (BK) B2 receptor cDNA was synthesized by rt-PCR and transfected into the Chinese hamster lung fibroblasts, CCL39. The CCL39 do not contain the mRNA for this receptor and do not bind BK. Clones of transfected cells were screened for BK receptor mRNA, binding of BK, and for [Ca2+]i response to BK. The clones showed various levels of receptor mRNA. Scatchard analysis of three clones, B6, B5 and B1, each gave a Kd of approximately 1.0nM while the Bmax for each clone differed at 320, 38.7, and 5.39 fmoles per 10(6) cells respectively. The [Ca2+]i response of the three clones to BK decreased with the receptor number/cell. Thus, levels of mRNA, BK binding and [Ca2+]i response proved proportionally related in the transfected clones. The actions of BK and alpha-thrombin, which has an endogenous receptor in these cells, were assessed in clone B6. BK proved active but also distinct from thrombin. BK at 10nM and thrombin at 2units/ml both effectively increased cytosolic [Ca2+]i. BK at 10nM stimulated PGE2 production three fold over basal, while thrombin only marginally elevated PGE2 levels. Alone, BK stimulated a small increase in 3H-thymidine incorporation into DNA. However, in combination with insulin, BK stimulated DNA synthesis to 76% of thrombin, a potent mitogen in these cells. These results illustrate that the BK-B2 receptor cDNA can be stably transfected into a mammalian cell and can activate transmembrane signalling pathways.
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PMID:Functional expression of the bradykinin-B2 receptor cDNA in Chinese hamster lung CCL39 fibroblasts. 128 Jan 23

In this investigation we correlated platelet Na-H antiport parameters with blood pressure and serum lipids in a sample population of non-insulin-dependent diabetic obese, nondiabetic obese, and nondiabetic nonobese black women. Parameters of the Na-H antiport were examined in aspirin-treated platelets. These parameters were not altered in resting or in thrombin-stimulated platelets of diabetic patients. The activity index of platelet Na-H antiport after thrombin stimulation was positively correlated with the blood pressure (systolic blood pressure, r = 0.5320 and p = 0.0001; diastolic blood pressure, r = 0.5123 and p = 0.0017). Lower high density lipoprotein cholesterol levels were associated with an alkaline shift in the cytosolic pH set point for activation of the Na-H antiport. Highly significant correlations were also observed between the total cholesterol/high density lipoprotein cholesterol ratio and the cytosolic pH set point for activation of the Na-H antiport. These correlations were independent of diabetes or the body mass index. Together, these observations indicate that parameters of platelet Na-H antiport are altered with an increase in blood pressure and a decrease in serum high density lipoprotein cholesterol.
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PMID:Platelet sodium-hydrogen antiport in obese and diabetic black women. 132 48

Treatment of human vascular smooth muscle cells (SMC) with human alpha-thrombin greatly increased DNA synthesis and cell proliferation. Both the integrity of the catalytic site and that of the anion binding exosite were required for expression of this activity. Experiments employing Northerns indicated induction of c-fos expression as well as a time-dependent induction of platelet-derived growth factor-A (PDGF-A) gene by thrombin. The thrombin mitogenic activity was potentiated by PDGF-BB, insulin and the vasoconstrictor peptide endothelin-1 suggesting synergism by convergence of intracellular growth-promoting signals. SMC treatment with pertussis toxin and forskolin indicated that the mitogenic activity of thrombin may be induced via signal transduction mechanism(s) involving changes in cAMP levels and activation of a Gi-like protein. These results suggest that thrombin may play a functional role in the regulation of human vascular SMC proliferation.
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PMID:Thrombin-induced proliferation and expression of platelet-derived growth factor-A chain gene in human vascular smooth muscle cells. 133 90


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