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)

Irradiation causes an increase in serum and plasma level of thromboxane in rabbits and an increase in thromboxane synthesis in blood platelets stimulated by thrombin. Thromboxane release from thoracic aorta is also increased upon irradiation of animals. H2O2 which stimulates thromboxane release from thoracic control aorta is without effect in the irradiated one.
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PMID:Increased thromboxane production after whole body irradiation. 208 99

Hydrogen peroxide (H2O2) and methyl mercury induced the liberation of arachidonate and its metabolites from human washed platelets. [14C]Eicosanoids were extracted from the supernatants of [14C] arachidonate-prelabelled platelets and analysed by thin layer chromatography and radioscanning. Thromboxane B2 (TXB2), 12(S)-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) were found as stable metabolites, together with unreacted arachidonate. In the presence of dazoxiben, a shift in eicosanoid metabolism was observed towards prostaglandin E2 (PGE2), prostaglandin D2 (PGD2) and prostaglandin F2 alpha (PGF2 alpha), while in the presence of indomethacin there was a shift towards 12-HETE and unmetabolized arachidonate. The concentration pattern of those metabolites resembled that found with the physiological agonist, thrombin. H2O2 and methyl mercury also induced platelet shape change, aggregation and secretion. The EC50 values for the induction of shape change and aggregation were 27 and 850 mumol/l for H2O2 and 0.33 and 2.7 mumol/l for methyl mercury, respectively. The [3H]serotonin release required higher stimulus concentrations and amounted to 45% with 2 mumol/l H2O2 and to 16% with 3 mumol/l methyl mercury. These effects on platelet function were absent in platelets exposed to acetylsalicylic acid and prevented by indomethacin, the prostaglandin H2 (PGH2)/thromboxane A2 (TXA2) receptor antagonist, daltroban, and the functional antagonist, iloprost. In contrast, none of these drugs suppressed the formation of [14C]eicosanoids, indicating that the platelet activation by H2O2 and methyl mercury essentially requires previous PGH2/TXA2 formation. As expected, the thromboxane synthase inhibitor, dazoxiben, did not prevent, but instead potentiated the activation by H2O2 and methyl mercury through accumulated PGH2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hydrogen peroxide and methyl mercury are primary stimuli of eicosanoid release in human platelets. 248 9

Diverse particulate and soluble stimuli trigger two metabolic bursts in mouse peritoneal macrophages important in the inflammatory and/or cytotoxic actions of the cells: release, oxygenation, and further metabolism of arachidonic acid from endogenous phospholipids and reduction of molecular oxygen to reactive intermediates. We tested the hypothesis that the release of arachidonic acid or formation of its metabolites are obligatory intermediate steps in triggering the NADPH oxidase that reduces O2 to O-2. With phorbol diesters as stimuli, the following inhibitors of phospholipase A2 and lipoxygenase suppressed release of H2O2 at nontoxic concentrations (microM range): p-bromophenacyl bromide, quinacrine, eicosatetraenoic acid, nordihydroguaiaretic acid, and phenidone. Indomethacin and acetylsalicylic acid were ineffective. However, the suppressive effect of the first five agents on H2O2 release could be attributed to their suppression of macrophage glucose uptake at the same concentrations, a previously unrecognized effect of these compounds. Further, concanavalin A, wheat germ agglutinin, and thrombin each stimulated abundant arachidonate release without H2O2 release. Finally, noncytolytic concentrations of cycloheximide and/or emetine suppressed arachidonate release without affecting H2O2 secretion triggered either by phorbol esters or zymosan. Release and metabolism of arachidonic acid and secretion of reactive oxygen intermediates appear to be two frequently coincident but mutually independent metabolic pathways in the mouse peritoneal macrophage.
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PMID:Release of arachidonate and reduction of oxygen. Independent metabolic bursts of the mouse peritoneal macrophage. 309 92

Interactions of human platelets with cadmium in vitro were studied with respect to the platelet activation process as indicated by malondialdehyde (MDA) formation and also to the components of the cellular antioxidant defence system such as catalase, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), glucose-6-phosphate dehydrogenase (G6PDH), and reduced glutathione (GSH). Cadmium treatment stimulated platelet MDA formation after a lag phase of at least 15 min and this effect was completely blocked by either 1 mM aspirin or 1 mM CaCl2. Cadmium pretreated platelets also displayed a much higher (5 fold) MDA formation when stimulated by thrombin. Platelet catalase activity was decreased by almost 50% after incubation with cadmium. There was also a moderate decline in platelet GSH and GR activity along with a stimulation of GST and G6PDH activity. These results suggest: (1) the cadmium effect on platelets as observed by enhanced formation of MDA via the cyclooxygenase pathway involves intraplatelet accumulation of cadmium which is inhibited by calcium, (2) a modest decline in GSH, presumably due to the inadequacy of H2O2 detoxification mechanism, does not adversely affect platelet function because of the adaptive response of G6PDH, and (3) intracellular accumulation of cadmium may result in platelet hyperactivity through higher intraplatelet free calcium levels resulting directly through cadmium action or indirectly through higher H2O2 levels due to catalase inhibition.
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PMID:Effects of cadmium treatment in vitro on the antioxidant protection mechanism and activation of human blood platelets. 313 42

The water extract of Hsien-Ho-T'sao (HHT) produced a dose-dependent inhibition on collagen-induced aggregation of platelet-rich plasma (PRP). The IC50 was about 3.5 mg/ml. In addition, HHT inhibited also the aggregation induced by ADP, A23187 or arachidonate in PRP. Greater inhibition was observed in the preparation of washed platelets. Increase of the calcium concentration in medium could not overcome the inhibitory effect of HHT. ATP release from platelets induced by collagen or A23187 was inhibited by HHT. In the presence of EDTA, ATP release caused by thrombin or A23187 was also inhibited by HHT. Malondialdehyde and thromboxane B2 formation was greatly inhibited by HHT in platelets challenged by collagen and thrombin. In arachidonate-stimulated platelets, thromboxane B2, but not malondialdehyde formation was inhibited. HHT showed more marked inhibition on aggregation in the presence of indomethacin, creatine phosphate/creatine phosphokinase or a combination of both. Hydrogen peroxide-induced hemolysis was marked reduced by HHT. It was concluded that HHT might have some membrane-active properties which interfered with the activation of phospholipase A2.
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PMID:Antiplatelet effect of hsien-ho-t'sao (Agrimonia pilosa). 392 4

Thrombin-stimulated platelet secretion is accompanied by a 30% reduction in the steady state level of cytosolic ATP, a breakdown that proceeds through ADP, AMP, IMP, and inosine to hypoxanthine. The ATP to hypoxanthine conversion could be blocked at the stage of AMP deamination by incubation of platelet-rich plasma for 6 h with 200 microM coformycin, a transition-state analog inhibitor of AMP deaminase. Abolition of AMP deaminase activity had no effect on thrombin-induced secretion from the dense granules, alpha-granules, or acid hydrolases measured in gel-filtered platelets. Coformycin treatment had no effect on thrombin-stimulated lactate production, even when oxidative phosphorylation was blocked by antimycin A, nor on the rate of thrombin-stimulated glycogenolysis. In addition, although it was clear that the adenylate energy charge was maintained by activation of AMP deaminase following thrombin treatment, the adenylate energy charge was also maintained in coformycin-treated platelets, albeit after a short lag, by stimulated ATP production and equilibration through the adenylate kinase reaction. Hydrogen peroxide brings about similar adenylate degradation which could also be inhibited by coformycin. The results indicate that AMP deamination and secretion, although temporally related, are not coupled. The role of AMP deaminase appears to be to maintain the adenylate energy charge in the absence of stimulation of ATP production or to buffer the adenylate charge before ATP production is stimulated.
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PMID:Coformycin inhibition of platelet AMP deaminase has no effect on thrombin-induced platelet secretion nor on glycolysis or glycogenolysis. 684 4

TNF is a strong secretagogue for surface-contacting neutrophils. During inflammation, endothelium offers the first substrate for neutrophil adherence and for modulation of the toxic response of neutrophils to soluble agonists such as TNF. In this in vitro study, evidence is presented that endothelium participates actively in TNF-induced neutrophil respiratory burst activity by expressing platelet-activating factor (PAF) in response to initial neutrophil H2O2 release. Three findings are shown that favor such a mechanism. First, PAF receptor antagonists reduced H2O2 release by TNF-activated neutrophils placed on endothelium approximately by 50%, whereas H2O2 responses by neutrophils placed on serum-coated polystyrene remained intact. Second, preincubation of HUVEC with known PAF-inducing agents PMA, H2O2, and thrombin, followed by fixation, enhanced neutrophil H2O2 release in response to TNF. H2O2 release by these neutrophils was sensitive to the presence of PAF receptor antagonists, whereas H2O2-release from neutrophils placed on fixed nonactivated endothelial cells was not. Finally, replacing endothelium by monolayers of human renal cortical epithelial cells and human fibroblasts, cells that are known to produce less PAF than endothelial cells, reduced the effect of PAF receptor antagonists. P-selectin expression and IL-8 release, two other ways by which endothelial cells might influence H2O2-release by TNF preincubated neutrophils, were examined in parallel, and were found not to influence TNF-induced neutrophil H2O2-release. We conclude that during neutrophil-endothelial interaction in inflammation, endothelium modulates the toxic response of neutrophils to TNF. Endothelial cell-associated PAF, but not endothelial cell IL-8 release and P-selectin expression, is likely to participate in TNF-induced neutrophil respiratory burst activity.
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PMID:Endothelial cell associated platelet-activating factor (PAF), a costimulatory intermediate in TNF-alpha-induced H2O2 release by adherent neutrophil leukocytes. 752 2

We have demonstrated that the endothelial cell-derived superoxide anion is deeply involved in the endothelial cell injury induced by activated neutrophils (Fujita, H., Morita, I. and Murota, S. (1994) Arch. Biochem. Biophys. 309, 62-69). To clarify the mechanism underlying the increase in the endothelial cell-derived superoxide anion induced by activated neutrophils, the conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO) in cultured endothelial cells isolated from bovine carotid arteries was investigated. Although the endothelial cells expressed both XD and XO activity, the XO activity of unstimulated cells comprised about 12% of the total (XD + XO) activity. When endothelial cells were exposed to neutrophils activated with phorbol 12-myristate 13-acetate (PMA), XO activity rapidly increased about 3-fold over the control. Whereas treatment of endothelial cells with PMA alone or unstimulated neutrophils alone did not increase the XO activity at all. The increase in XO activity in endothelial cells was also observed on the treatment of the cells with neutrophils activated with leukotriene B4 or thrombin. To determine whether or not proteases released from activated neutrophils are involved in the increased conversion of XD to XO in endothelial cells, the effects of the elastase specific inhibitor, ONO-5046, and protease inhibitors, such as aprotinin, gabexate mesylate and urinastatin, were examined. However, these protease inhibitors did not suppress the conversion of XD to XO induced by PMA-activated neutrophils. Moreover, the treatment of endothelial cells with purified human neutrophil elastase and H2O2 also did not affect the conversion at all. In contrast, monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD to XO induced by PMA-activated neutrophils. Moreover, tyrosine kinase inhibitors such as staurosporin and herbimysine also inhibited the increased conversion of XD to XO induced by PMA-activated neutrophils. These results indicate that the adhesion of activated neutrophils to endothelial cells via CD11a/CD18-ICAM-1 is involved in the conversion of XD to XO in endothelial cells induced by activated neutrophils.
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PMID:Conversion of xanthine dehydrogenase to xanthine oxidase in bovine carotid artery endothelial cells induced by activated neutrophils: involvement of adhesion molecules. 769 38

We examined the effects of taprostene (2.5 x 10(-8) M to 1 x 10(-7) M), a stable prostacyclin analog, on PMN-endothelial interaction (i.e., adherence) and subsequent vasocontraction and endothelial dysfunction. Taprostene effectively inhibited the adherence of leukotriene B4-stimulated autologous cat polymorphonuclear (PMN) leukocytes to isolated cat coronary artery endothelium. Taprostene also inhibited coronary artery vasocontraction to leukotriene B4-stimulated PMNs (p < 0.01). In isolated coronary artery rings stimulated with either 2 U/ml of thrombin or 100 microM hydrogen peroxide (H2O2), adherence of unstimulated PMNs to coronary endothelium was significantly increased, resulting in vasocontraction and subsequent endothelial dysfunction. However, taprostene (1 x 10(-7) M) significantly attenuated unstimulated PMN adherence to stimulated coronary endothelium. This antiadherence action effectively attenuated PMN-induced coronary artery vasocontraction (p < 0.01) and significantly blunted the subsequent PMN-induced endothelial dysfunction (p < 0.01) characterized by a loss of endothelium-derived nitric oxide (NO). Thus, taprostene exerts a profound inhibitory effect on PMN-endothelium interaction and subsequent PMN-mediated coronary endothelial dysfunction, which may be beneficial in ischemia-reperfusion and other inflammatory states.
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PMID:Effects of taprostene on neutrophil-endothelial interactions in isolated coronary arteries. 774 23

Heat-shock protein 27 (HSP27) is a major target of phosphorylation upon cell stimulation with a variety of agents and has been suggested to have a phosphorylation-regulated function at the level of actin filaments. Here we investigated comparatively the mechanisms of HSP27 phosphorylation by oxidative stresses, exposures to tumor necrosis factor (TNF), heat shock and growth factors. Extracts of Chinese hamster or human cells exposed to H2O2, xanthine/xanthine oxidase, menadione or TNF contained up to 15-fold more HSP27 kinase activity than comparable extracts obtained from control cells. Induction of HSP27 kinase activity by TNF or H2O2 was completely inhibited by first treating the cells with the antioxidant N-acetyl-L-cysteine, suggesting that generation of reactive oxygen metabolites was the key triggering element of this induction. In contrast, prior treatment with acetylcysteine had no or little effect on the induction by thrombin, serum and heat shock. The kinase activity in extracts of cells stimulated by heat shock, H2O2, sodium arsenite, TNF or growth factors was identified by in-gel renaturation and purified approximately 8000-fold by sequential chromatography. In all cases, the induced kinase activity was entirely associated with two polypeptides of 45 kDa and 54 kDa, identified as mitogen-activated-protein kinase-activated protein (MAPKAP) kinase-2 based on its reactivation in vitro by 42/44-kDa MAP kinases, its antigenic properties and its substrate specificity. The 45/54-kDa HSP27 kinase may play an important role in the cell response to oxidative stress. Overexpression of the wild-type HSP27 but not of a nonphosphorylatable form of human HSP27 in Chinese hamster cells conferred resistance to actin fragmentation by oxidative stress generated by H2O2. It is concluded that activation of the 45/54-kDa HSP27 kinase is a common mechanism of HSP27 phosphorylation to which converge both oxyradical-dependent and oxyradical-independent pathways and which may participate in a homeostatic response to stress at the level of actin microfilament.
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PMID:Characterization of 45-kDa/54-kDa HSP27 kinase, a stress-sensitive kinase which may activate the phosphorylation-dependent protective function of mammalian 27-kDa heat-shock protein HSP27. 785 16


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