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)

A 52-year-old previously healthy woman was admitted to our hospital for status epilepticus in November 1999. She had not taken oral contraceptives. After treatment with intravenous diazepam and phenytoin, she did not develop seizures anymore. When she became alert, there was a mild left hemiparesis. Lumbar puncture showed an opening pressure of 145 mm H2O, and the cerebrospinal fluid was acellular. Cranial MR imaging demonstrated thrombosis of the superior sagittal sinus and fresh infarction in the right frontal lobe. Plasma fibrinogen, fibrin degradation product, and prothrombin fragment 1 + 2 levels were elevated. Proteins S and C activities and anti-thrombin III levels were within the normal range. Lupus anticoagulant and anti-cardiolipin antibody were negative. She was treated with continuous heparin infusion for ten days and with oral warfarin thereafter. Six months after the first admission, platelet count became more than 400 x 10(3)/microliter. In July 2002, she developed slowly progressive monoplegia of the left arm. Cranial MR imaging demonstrated patent superior sagittal sinus, fresh infarction in the right parietal lobe, and old small infarction in the right corona radiata. The patient was maintained on warfarin and 100 mg of aspirin thereafter. In September 2002, platelet count was 737 x 10(3)/microliter. Bone marrow examination showed increased megakaryopoiesis with normal erythroid and myeloid series and no chromosomal aberrations. Serum C-reactive protein and iron levels were in the normal range. An abdominal ultrasound demonstrated mild splenomegaly. Thus, we made a diagnosis of essential thrombocythemia (ET). ET causes thrombotic events in the course of the disease at a rate of 7% per year. Cerebral infarction is not uncommon, but occurrence of cerebral sinus thrombosis has been rarely reported. Recently, several cases have been reported in which cerebral infarction was the first manifestation of ET even with platelet counts lower than 600 x 10(3)/microliter. To our knowledge, there have been no reported cases of ET presenting with cerebral venous sinus thrombosis. Platelet count should be monitored in the patients with venous sinus thrombosis of undetermined etiology.
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PMID:[Superior sagittal sinus thrombosis as first manifestation of essential thrombocythemia]. 1519 36

Chronic platelet activation may be involved in thromboembolic complications, a leading cause of morbidity and mortality in beta-thalassemia. Oxidative stress, with the generation of reactive oxygen species (ROS), is suspected to play a role in the patho-physiology of thalassemia and cardiovascular disorders. In the present study, we adapted flow cytometric techniques to measure oxidative state markers, ROS generation and reduced glutathione (GSH) content in platelets. Our results show that platelets obtained from beta-thalassemic patients contain higher ROS and lower GSH levels than do platelets from normal donors, indicating a state of oxidative stress. In the absence of any known inherent abnormality in thalassemia platelets, this may be attributed to continuous exposure to oxidative insults from extra-platelet sources. We found that exposure of platelets to oxidants such as hydrogen peroxide and tertbutylhydroperoxide or to the platelet activators thrombin, calcium ionophore or phorbol myristate acetate stimulated the platelets' oxidative stress. This was also increased by plasma of thalassemia patients, and decreased following treatment of the plasma with the iron-chelator Desferoxamin. Iron and hemin, the levels of which are augmented in plasma of thalassemia patients, stimulated the platelets' oxidative stress. The oxidative status of the platelets was also affected by red blood cells (RBC); it was higher in normal platelets incubated with thalassemic RBC than with normal RBC. Normal RBC stimulated with hydrogen peroxide had a greater effect on platelets than did unstimulated RBC. The platelets' oxidative stress was ameliorated by antioxidants such as N-acetyl-L-cysteine and vitamin C. Our findings indicate that in thalassemia, platelets undergo a state of oxidative stress, leading to their activation and potentially to thromboembolic consequences, and suggest that this hypercoagulable state might be treated with antioxidants.
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PMID:Oxidative status of platelets in normal and thalassemic blood. 1554 33

Four series of Schiff base copper(II) and iron(III) chelates were synthesized from 4-formyl-3-hydroxybenzamidine or 3-formyl-4-hydroxybenzamidine and various L- or D-amino acids. Their inhibitory activities for bovine alpha-thrombin (abbreviated as thrombin) were determined. The most potent thrombin inhibitor in this series is copper(II) chelate (1g') derived from 4-formyl-3-hydroxybenzamidine and D-Trp. Its Ki value, 2.7x10(-8) M, is comparable to that of Argatroban (MD-805), which is a clinically used compound. The iron(III) chelates derived from 4-formyl-3-hydroxybenzamidine and hydrophobic L-amino acids (Val, Ile, Leu, Phe, Trp, Met) also exhibited higher inhibitory potency. It appears that coordination geometry composed of metal ion, amidino group, amino acid side chain is well accommodated to the thrombin active site. From the Ki values of Schiff base metal chelates for thrombin, the structure-activity relationships between the chelates and active site of thrombin were discussed.
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PMID:Amidino-containing Schiff base copper(II) and iron(III) chelates as a thrombin inhibitor. 1563 23

Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypotension and vasorelaxation. The objective of the present study was to investigate the effect of labedipinedilol-A on vascular function of rat aortic rings and cultured human umbilical vein endothelial cells (HUVECs). Labedipinedilol-A induced vasorelaxation in rat aortic rings that had been precontracted with phenylephrine in a concentration-dependent manner. This labedipinedilol-A-induced relaxation was significantly reduced by endothelium removal and by exposure to L-NG-nitroarginine methyl ester (L-NAME), methylene blue, or 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (ODQ). In addition, the cyclic GMP content was significantly increased by labedipinedilol-A, which was inhibited by L-NAME in aorta. In cultured HUVECs, labedipinedilol-A induced concentration-dependent formation of NO and Ca2+ influx, and it increased the abundance of endothelial NO synthase (eNOS) protein. Furthermore, labedipinedilol-A suppressed basal, 10% FBS- and thrombin-stimulated endothelin-1 production, which were reversed by pretreatment with L-NAME, demonstrating that NO was able to inhibit production of ET-1 in HUVECs. Labedipinedilol-A significantly protected cultured HUVECs against dihydroxyfumarate/iron ion-induced decrease of glutathione and cell death. Moreover, labedipinedilol-A also inhibited iron-induced lipid peroxidation in rat brain homogenate and scavenged 2,2'-azobis (2-amidinopropane) dihydrochloride-derived peroxy radicals. Labedipinedilol-A acts as lacidipine with additional antioxidant effects and can protect endothelial cells against free radical-induced lipid peroxidation and cell injury. Our results indicate that the endothelium-dependent vasorelaxation by labedipinedilol-A is mediated through Ca2+-dependent activation of NO synthase and stimulation of NO/cyclic GMP pathway.
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PMID:The vasorelaxing action of labedipinedilol-A involves endothelial cell-derived NO and eNOS expression caused by calcium influx. 1572 48

Pretreatment with low-dose thrombin attenuates brain edema induced by iron or intracerebral hemorrhage (ICH). Ceruloplasmin is involved in iron metabolism by oxidizing ferrous iron to ferric iron. The present study examines whether thrombin modulates brain ceruloplasmin levels and whether exogenous ceruloplasmin reduces brain edema induced by ferrous iron in vivo. In the first set of experiments, rats received intracerebral infusion of saline or 1 U thrombin into the right basal ganglia. Rats were killed 1, 3, or 7 days later for Western blot analysis and RT-PCR analysis. In the second set of experiments, rats received either ferric iron, ferrous iron, or ferrous iron plus ceruloplasmin, then were killed 24 hours later for brain edema measurement. We found that ceruloplasmin protein levels in the ipsilateral basal ganglia increased on the first day after thrombin stimulation and peaked at day 3. Brain ceruloplasmin levels were higher after thrombin infusion than after saline injection. RT-PCR showed that brain ceruloplasmin mRNA levels were also up-regulated after thrombin injection (p < 0.05). We also found ipsilateral brain edema after intracerebral infusion of ferrous iron but not ferric iron at 24 hours. Co-injection of ferrous iron with ceruloplasmin reduced ferrous iron-induced brain edema (p < 0.05). Our results demonstrate that thrombin increases brain ceruloplasmin levels and exogenous ceruloplasmin reduces ferrous iron-induced brain edema, suggesting that ceruloplasmin up-regulation may contribute to thrombin-induced brain tolerance to ICH by limiting the injury caused by ferrous iron released from the hematoma.
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PMID:Up-regulation of brain ceruloplasmin in thrombin preconditioning. 1667 55

Key issues in the management of patients with hemophilia include a thorough understanding of the mechanisms of blood coagulation and the complications that follow recurrent joint bleeding. Monoclonal antibodies are powerful tools for dissecting the intrinsic coagulation pathway and deriving reagents that could lead, on the long term, to the identification of molecules that enhance, or perhaps even replace factor (F) VIII concentrates in the management of hemophilia A. In recent in vitro experiments, it was demonstrated that plasmatic thrombin generation and intrinsic FX activation was enhanced by each of two FIXa-specific monoclonal antibodies, one of which had FIXa-agonistic activity only, whereas the other enhanced the activity of the intrinsic FX-activating complex (FVIIIa/FIXa) by at least two distinct mechanisms. Hemophilic synovitis, an inflammatory and proliferative disorder in patients with hemophilia, is the result of bleeding into joints and can lead to debilitating arthritis and chronic arthropathy. A major causative factor in the development of hemophilic synovitis is blood-derived iron deposited in joints. FVIII-deficient knockout mice with trauma-induced hemarthrosis serve as a model system for hemophilic synovitis, reproducing the histological features observed in patients. In addition, this animal model recapitulates the observations made in vitro with synovial cell cultures stimulated by iron. These in vitro experiments suggested a role for iron as an agent capable of inducing proliferation and oncogene expression by human and murine synovial fibroblasts. A better understanding of iron-regulated pathways and oncogene expression may lay the groundwork for targeted molecular interventions in hemophilic synovitis.
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PMID:Future aspects of hemophilia research and care. 1680 34

Intracerebral hemorrhage (ICH) is a subtype of stroke with high morbidity and mortality. The mechanisms underlying ICH-induced brain injury have become better understood during the past decade. Experimental investigations have indicated that thrombin formation, red blood cell lysis, and iron toxicity play a major role in ICH-induced injury and that these mechanisms may provide new therapeutic targets. This article reviews the role of thrombin and iron in ICH-induced injury.
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PMID:Brain injury after intracerebral hemorrhage: the role of thrombin and iron. 1726 33

Heme oxygenase-1 (HO-1) is the chief regulatory enzyme in the oxidative degradation of heme to biliverdin. In the process of heme degradation, HO-1 receives the electrons necessary for catalysis from the flavoprotein NADPH cytochrome P450 reductase (CPR), releasing free iron and carbon monoxide. Much of the recent research involving heme oxygenase has been done using a 30 kDa soluble form of the enzyme, which lacks the membrane binding region (C-terminal 23 amino acids). The goal of this study was to express and purify a full-length human HO-1 (hHO-1) protein; however, due to the lability of the full-length form, a rapid purification procedure was required. This was accomplished by use of a glutathione-s-transferase (GST)-tagged hHO-1 construct. Although the procedure permitted the generation of a full-length HO-1, this form was contaminated with a 30 kDa degradation product that could not be eliminated. Therefore, attempts were made to remove a putative secondary thrombin cleavage site by a conservative mutation of amino acid 254, which replaces arginine with lysine. This mutation allowed the expression and purification of a full-length hHO-1 protein. Unlike wild type (WT) HO-1, the R254K mutant could be purified to a single 32 kDa protein capable of degrading heme at the same rate as the WT enzyme. The R254K full-length form had a specific activity of approximately 200-225 nmol of bilirubin h-1 nmol-1 HO-1 as compared to approximately 140-150 nmol of bilirubin h-1 nmol-1 for the WT form, which contains the 30 kDa contaminant. This is a 2-3-fold increase from the previously reported soluble 30 kDa HO-1, suggesting that the C-terminal 23 amino acids are essential for maximal catalytic activity. Because the membrane-spanning domain is present, the full-length hHO-1 has the potential to incorporate into phospholipid membranes, which can be reconstituted at known concentrations, in combination with other endoplasmic reticulum resident enzymes.
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PMID:Expression and characterization of full-length human heme oxygenase-1: the presence of intact membrane-binding region leads to increased binding affinity for NADPH cytochrome P450 reductase. 1791 53

This study concerned reactive oxygen species for their potential to activate human platelet GP IIb/IIIa receptors. All cells produce reactive oxygen species - radicals that can abstract electrons and hydrogen atoms from biological molecules to alter cell function. In many cells, radicals contribute to cellular signaling. In platelets, the predominant oxidant effect is platelet activation. Less is known concerning oxidants and GP IIb/IIIa receptor activation. The first aim of the current study was to confirm that although both H(2)O(2) and tert butyl hydroperoxide both predispose platelets to aggregation; neither directly activates GP IIb/IIIa receptors. The second aim was to demonstrate that even in the presence of extracellular redox iron; H(2)O(2) does not activate GP IIb/IIIa receptors. The third aim was to determine if extracellular superoxide anions evoke GP IIb/IIIa activation. Finally, a role for intra-platelet iron in GP IIb/IIIa activation was examined. Intracellular superoxide anions are produced in excess during platelet activation and curiously, they are uniquely able to increase intracellular free iron. This iron can, in a redox manner, generate radicals and these iron dependent species modulate signaling systems, including systems associated with adhesion receptor activation. In the current studies, platelets in suspension were exposed to H(2)O(2) and to tert butyl hydroperoxide, to H(2)O(2) plus ferrous or ferric chloride (+/- ascorbate to enhance iron redox cycling) and to xanthine plus xanthine oxidase to generate extra-platelet superoxide anions. Intra-platelet iron was increased with iron ionophore 8-hydroxyquinoline. During flow cytometry, intra-platelet oxidant state was assessed with the redox sensitive fluorescent indicator H2DCF, while GP IIb/IIIa activation was assessed using fluorescent antibody PAC-1. Results showed that although all the oxidizing systems examined increased intra-platelet oxidant state, GP IIb/IIIa receptors were not activated by H(2)O(2), by tert butyl hydroperoxide, by H(2)O(2) plus iron (+/- ascorbate) or by xanthine plus xanthine oxidase. In contrast, iron plus ionophore 8-hydroxyquinoline evoked GP IIb/IIIa activation. Platelet positivity for PAC-1 increased from 2 +/- 0.2 to 28 +/- 7% (P < 0.005). However this response, although vigorous, was less than 56 +/- 8% (P < 0.001) evoked by thrombin 0.1 milliunit/ml. In conclusion, the results indicated that oxidant systems external to platelets did not activate GP IIb/IIIa receptors while increased intra-platelet iron was associated with appearance of cytosolic oxidizing species and with GP IIb/IIIa receptor activation.
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PMID:Reactive oxygen species and human platelet GP IIb/IIIa receptor activation. 1804 53

Design of smart MRI contrast agent based on superparamagnetic iron oxide nanoparticles and aptamers has been described for the detection of human alpha-thrombin protein. The contrast agent is based on the assembly of the aptamer functionalized nanoparticles in the presence of thrombin. A detectable change in MRI signal is observed with 25 nM thrombin in human serum. Changes were neither observed with control analytes, streptavidin, or bovine serum albumin, nor with inactive aptamer functionalized nanoparticles.
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PMID:MRI detection of thrombin with aptamer functionalized superparamagnetic iron oxide nanoparticles. 1817 25


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