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)

Release of platelet-derived growth factor (PDGF) from platelets has been postulated to stimulate at least some of the cell proliferation seen at sites of tissue damage, both beneficially (wound healing) and perniciously (during formation of atherosclerotic lesions). Two other growth factors have been localized to the platelet: epidermal growth factor and transforming growth factor. These factors may function synergistically with PDGF in promoting smooth muscle cell proliferation in the injured vessel wall. PDGF-like molecules (PDGF-c) that bind to the PDGF receptor and are at least partially recognized by antiserum against PDGF may also be synthesized by vessel wall cells themselves under certain circumstances. Arterial endothelial cells secrete several mitogens, one of which is a PDGF-c. Release is greatly stimulated by exposure of the cells to physiologic concentrations of thrombin. Also, aortic smooth muscle cells from 2-week-old rats secrete mitogenic levels of PDGF-c. In this case, PDGF-c accounts for all the mitogenic activity in conditioned medium (when assayed on 3T3 cells). Smooth muscle cells obtained from adult rat aortae secrete 150-fold less PDGF-c. In a third example, when adult rat carotid arteries are damaged with a balloon catheter, smooth muscle cells migrate into the intima of the artery and proliferate. By 2 weeks, the number of smooth muscle cells in the artery has doubled. When these intimal smooth muscle cells are cultured, they are found to secrete PDGF-c. These findings suggest that activation of endogenous synthesis of PDGF-c may contribute to the smooth muscle cell proliferation seen in response to vascular injury.
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PMID:Locally acting growth factors for vascular smooth muscle cells: endogenous synthesis and release from platelets. 389 61

Tissue culture of human large vessel endothelium is now routine in many laboratories but tissue culture of human microvascular endothelium remains a difficult procedure, preventing study of features of endothelial function that may be peculiar to the microvasculature. This report describes an improved method for tissue culture of human dermal microvascular endothelium derived from foreskin. The method is rapid, reproducible, avoids contamination with nonendothelial cells, and does not require the use of a tumor-conditioned medium. The major modifications over existing techniques are the use of a Percoll density gradient to remove the majority of nonendothelial cells followed by a simplified weeding procedure that removes residual nonendothelial cells and leaves large numbers of endothelial cells to grow rapidly to confluence. The cells are identified as endothelial by their morphology and by positive immunofluorescence for Factor VIII. Proliferation experiments demonstrate their requirement for an exogenous matrix and for a high concentration of human serum. Whole serum was required as platelet-poor plasma serum had poor growth stimulatory activity. Proliferation could be enhanced by dibutyryl cyclic AMP or endothelial cell growth substance and was maximal with the combination of endothelial cell growth substance and heparin. However, the use of these agents did not remove the requirement for an exogenous matrix. Fibroblast growth factor, platelet-derived growth factor, epidermal growth factor, nerve growth factor, and thrombin did not increase proliferation.
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PMID:Human dermal microvascular endothelial cells: an improved method for tissue culture and a description of some singular properties in culture. 390 58

In primary cultures of rat hepatocytes, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and foetal-calf serum (FCS) prevented the stimulation of amino acid transport by glucagon (cyclic AMP-dependent) and by catecholamines (cyclic AMP-independent), but not by insulin. The insulin effect, as well as the effect of other hormones, were totally inhibited by thrombin through a mechanism independent of its proteolytic activity. The inhibitory effect of growth factors, not found in freshly isolated hepatocytes, was expressed very early in culture (4h). Induction of tyrosine aminotransferase by glucagon or dexamethasone, which, like stimulation of transport, represents a late hormonal effect, was not affected by EGF, PDGF or FCS, but was inhibited by thrombin. In contrast, none of the rapid changes in protein phosphorylation caused by hormones was altered by growth factors. Thus the inhibition by growth factors of hormonal stimulation of transport presumably involves late step(s) in the cascade of events implicated in this hormonal effect.
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PMID:Effects of growth factors on hormonal stimulation of amino acid transport in primary cultures of rat hepatocytes. 613 22

The biochemistry of platelets from two unrelated patients with the gray platelet syndrome, a deficiency of platelet alpha-granules, has been evaluated. Ultrastructural studies of their platelets revealed the number of alpha-granules to be less than 15% of normal, whereas the number of dense bodies was within normal limits. Platelets from both patients had severe deficiencies of platelet factor 4 and beta-thromboglobulin (less than 10% of normal). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a marked deficiency of thrombin-sensitive protein in both patients. Analysis of the platelet-derived growth factor in one patient showed it was also markedly reduced. Levels of lysosomal enzymes, adenine nucleotides, serotonin, and catalase, and conversion of arachidonic acid by the lipoxygenase and cyclo-oxygenase enzymes, were within normal limits. The results provide important evidence to define the contents of alpha-granules and to differentiate these contents from the contents of lysosomal granules, dense bodies, and peroxisomes. Functional studies of these platelets showed deficiencies in ADP, thrombin, and collagen aggregation. The results suggest that alpha-granules or their contents make a contribution to normal platelet aggregation.
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PMID:Biochemical studies of two patients with the gray platelet syndrome. Selective deficiency of platelet alpha granules. 615 48

A factor(s) from human platelets enhances IgE-mediated histamine release from human basophils and mast cells. This effect is directly related to the platelet number; at physiological platelet/leukocyte ratios (40:1), the enhancement was 66 +/- 11%. Platelet stimulation by thrombin more than doubled the enhancement, to 172 +/- 10% at 40:1. Mast cell release was also enhanced by platelets although the magnitude was more limited (86 +/- 13% at 40:1 with thrombin). Direct basophil/platelet contact was unnecessary in that platelet supernatants were fully active; a direct platelet factor/basophil interaction is suggested, however, by the fact that basophils purified 100-fold with respect to other leukocytes were enhanced by the platelet factors. The appearance of platelet-enhancing activity is associated with the release of an alpha-granule marker (PF4) rather than with products of arachidonic acid metabolism (thromboxane B2). The platelet factor(s) responsible for these effects are not dialyzable, are heat stable and do not appear to be identical to PF4 or platelet-derived growth factor (PDGF). Since anti-IgE-stimulated basophils cause PF4 release and this correlates with the release of enhancing factor, we suggest that a pro-inflammatory feed forward relationship exists. Together with our previous data showing that platelets are activated in vivo during antigen challenge of allergic asthmatic subjects, these results suggest that platelets may be important in modulating IgE-mediated allergic reactions in man.
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PMID:Platelet augmentation of IgE-dependent histamine release from human basophils and mast cells. 620 Apr 43

Insulin stimulates the growth and proliferation of a variety of somatic cells in culture, and evidence suggests that insulin is also an important regulator of growth in vivo. In cell culture, insulin interacts synergistically with other hormones and growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), tumor-promoting phorbol esters, and thrombin, to stimulate progression through the cell cycle of cells that have been arrested in G1 by deprivation for serum. In addition, insulin is required by most cells for optimal long term growth in hormone-supplemented serum-free media. In some cells, such as human skin fibroblasts, the growth-promoting effects of insulin appear to be mediated primarily by its low affinity interaction with receptors for insulin-like growth factor I (IGF-I). In other cells, such as hepatocytes, hepatoma cells, adrenocortical tumor cells, mammary carcinoma cells, and F9 embryonal carcinoma cells, insulin appears to stimulate growth by binding to high affinity insulin receptors. The insulin and IGF-I receptor proteins, like the receptor proteins for other growth-promoting hormones such as EGF and PDGF, are closely associated with tyrosine-specific protein kinase activities. The mechanism by which the binding of insulin to its receptor and activation of the receptor-associated tyrosine protein kinase activity control intracellular protein phosphorylation and dephosphorylation reactions, such as the phosphorylation of ribosomal protein S6, is a subject of considerable current interest. The phosphorylation of ribosomal protein S6 may be related mechanistically to the activation by insulin of protein synthesis, and hence the passage of cells through the G1 phase of the cell cycle. Malignant transformation does not generally result in a total loss of the growth requirement of cells for insulin or insulin-like growth factors, although transformation is accompanied in some cases by a qualitative reduction in the insulin/IGF requirement. Abnormalities in insulin production or sensitivity in vivo are accompanied by abnormalities in growth; thus, insulin appears to be an important regulator of growth in vivo. Some of the growth-promoting effects of insulin in vivo may be attributable to direct action of insulin, while other effects may be caused by the regulatory effect of insulin on somatomedin production, and possibly on somatomedin action.
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PMID:Growth-stimulatory actions of insulin in vitro and in vivo. 637 81

Adult rat hepatocytes in primary cultures are stimulated to synthesize DNA in response to rat serum, whereas rat plasma is considerably less active. Biological activity is present in rat platelets and is secreted during aggregation in response to thrombin. The material secreted by rat platelets is heat labile and is sensitive to digestion with trypsin, suggesting that it is a protein. When assayed on 3T3 cells this material also stimulates DNA synthesis; however, the trypsin-sensitive activity is heat stable (100 degrees C, 10 min). These results indicate that rat platelets contain hepatotrophic activities which by virtue of their heat sensitivity are distinct from heat-stable platelet-derived growth factor (PDGF)-like mitogenic activities required by 3T3 cells for growth. It is possible that hepatotrophic platelet factors might be involved in mediating liver regeneration in the rat after partial hepatectomy.
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PMID:Rat platelets contain growth factor(s) distinct from PDGF which stimulate DNA synthesis in primary adult rat hepatocyte cultures. 646 36

Depending on cell type and mode of growth stimulation, an intact cytoplasmic microtubule system may either support or suppress passage through the prereplicative G1 phase (growth and maturation) and entrance into the S phase (DNA synthesis) of the cell cycle. In peripheral blood lymphocytes exposed to mitogenic lectins, colchicine and other antimicrotubular drugs inhibit blast transformation and initiation of DNA synthesis. The inhibitory effect is not due to decreased cellular binding of lectin or lack of generation of a stimulatory signal. Rather, it can be explained by an inability of the cells to pass through the G1 phase at a normal rate in the absence of cytoplasmic microtubules. The formation of new organelles and the growth in cell size that occur during this phase is markedly delayed by the drugs. For example, the Golgi complex, an organelle system that participates in membrane biogenesis and other basic cellular functions, is reduced in size and structurally disorganized. In cells with a shorter prereplicative phase, such as fibroblasts and smooth muscle cells, antimicrotubular drugs inhibit DNA synthesis in growth-arrested cultures exposed to optimal concentrations of serum, thrombin or platelet-derived growth factor (PDGF). On the other hand, antimicrotubular drugs stimulate DNA replication in serum-free cultures and enhance the stimulatory effect of insulin, epidermal growth factor (EGF), fibroblast growth factor (FGF), and prostaglandin F2 alpha on entrance into S phase. Moreover, stabilization of cytoplasmic microtubules with taxol has been found to block microtubule disassembly and initiation of DNA synthesis by colchicine and to inhibit thrombin- and EGF-stimulated DNA synthesis under serum-free conditions. These findings suggest that partial microtubule disassembly is an inherent step in the reactions that precede DNA replication and mitosis. However, the cell biological and molecular details of these reactions and the exact role of microtubules remain enigmatic.
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PMID:The microtubular cytoskeleton and the initiation of DNA synthesis. 648 51

The role of platelets in cancer metastasis was studied by investigating the effects of the antiplatelet agents ticlopidine, diltiazem, dipyridamole and trapidil on artificial and spontaneous pulmonary metastases in mice. These agents were tested at their optimal inhibitory doses on adenosine diphosphate-induced platelet aggregation; namely, 100 mg/kg for ticlopidine, 2 mg/kg for diltiazem, 180 mg/kg for trapidil and 60 mg/kg for dipyridamole. At these doses, trapidil caused moderate inhibition of thrombin-induced platelet aggregation in mice, but the other agents had only slight effects. Artificial pulmonary metastasis was produced by inoculation of Lewis lung carcinoma (LLC) or B16 melanoma (B16) cells into C57BL/6 mice. For induction of spontaneous pulmonary metastases, these tumor cells were implanted subcutaneously into the footpads of mice. The resulting primary tumors of LLC and B16 were removed 9-10 and 17 days later, respectively. Artificial pulmonary metastases were inhibited significantly by all the antiplatelet agents tested. Spontaneous pulmonary metastases were markedly reduced only when these agents were given after removal of the primary tumor. The role of platelets is discussed with respect to thrombus formation in the lodgement of tumor cells and the participation of platelet-derived growth factor in the growth of metastatic foci.
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PMID:Effects of antiplatelet agents on pulmonary metastases. 672 29

Cells derived from the endothelium of human iliac arteries were cultured in vivo. The cells were isolated, grown, and subcultured in HEPES buffered Medium 199 supplemented with 20% heat inactivated human whole blood serum, human alpha-thrombin, and commercial endothelial cell growth supplement derived from bovine brain. The cells were viable in culture for 8 to 10 passages at a split ratio of 1:3. After the 10th passage, the cells began to enlarge and their growth rate was reduced. No cultures were viable after the 12th passage. The cells were determined to be of endothelial origin by their morphology at confluence; their ultrastructural characteristics, including the presence of Weibel-Palade bodies; the production and release of factor VIII-related antigen; and by their maintenance of a surface that prevented platelet attachment. The cultured arterial endothelial cells released prostacyclin in response to challenge with thrombin and protamine sulfate but not in response to bradykinin or the platelet-derived growth factor. Although the cultures described in this report were derived from patients with varying degrees of atherosclerotic disease, there were no significant differences in morphological or physiological parameters among these cultures or in comparison with commonly studied cells derived from human umbilical veins.
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PMID:Cultured endothelial cells derived from the human iliac arteries. 681 18


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