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)

Hemodynamic forces modulate various endothelial cell functions even in the presence of cytokines under gene regulation. We have investigated the effect of shear stress on the coagulation and fibrinolysis systems in cultured human umbilical vein endothelial cells (HUVECs) perturbed by cytokines, using modified cone-plate viscometer. Thrombomodulin (TM), a surface glycoprotein receptor for thrombin that catalyzes the activation of the protein C anticoagulant pathway, and tissue factor (TF), a transmembrane glycoprotein that plays a central role in blood coagulation, are important regulators for coagulation in endothelium. Shear stress of 18 dynes/cm2 increased the expression of TM either in the presence or absence of TNF alpha (100 U/ml). In contrast, shear stresses of 6 approximately 24 dynes/cm2 decreased the expression of TNF alpha-induced TF in a shear intensity- and exposure time- dependent manner Tissue plasminogen activator(t-PA), which converts plasminogen to plasmin to degrade fibrin clot, and plasminogen activator inhibitor-1 (PAI-1), which inhibits t-PA function, play central roles in fibrinolysis in the endothelium. Treatment of the cells with IL-1 beta or TNF-alpha under static conditions had no effect on t-PA secretion, while release of PAI-1 increased. When cells were exposed to increasing shear stress up to 24 dynes/cm2, levels of t-PA significantly increased relative to shear stress, while PAI-1 secretion decreased gradually. In the presence of IL-1 beta or TNF-alpha, the increased production of t-PA was further augmented. These results clearly indicate that shear forces act as an important regulators of the coagulation and fibrinolysis systems in endothelium, to maintain antithrombogenicity of blood vessels.
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PMID:[Regulation of antithrombogenicity in endothelium by hemodynamic forces]. 913 94

Pentoxifylline (POF) may suppress overproduction of tumor necrosis factor alpha (TNF alpha), which is thought to contribute to complications of human falciparum malaria. However, POF is believed to improve impaired capillary blood flow, which can be impaired in falciparum malaria. To test whether POF affects TNF alpha serum levels or other variables in this disease, we administered POF (20 mg/kg/day intravenously in 150 ml of saline for five days) randomized versus placebo (150 ml of saline without POF) in addition to standard antimalarial therapy. After recruitment of 51 patients with Plasmodium falciparum malaria, those receiving POF had more nausea and abdominal discomfort than the placebo group, as expected. Eleven of 27 patients receiving POF and three of 24 patients receiving placebo requested termination of the study medication (P < 0.05). Pentoxifylline did not change the decrease of TNF alpha levels or affect the clinical course in a significant way. Since POF failed to improve the clinical situation or to impact numerous laboratory parameters (including TNF alpha, thrombin-antithrombin III, thrombomodulin, and human neutrophil elastase), the study was terminated earlier than planned. While this study does not specifically address cerebral complications of malaria, the results suggest that POF is not useful as a routine adjunct to the standard therapy of falciparum malaria.
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PMID:Supportive pentoxifylline in falciparum malaria: no effect on tumor necrosis factor alpha levels or clinical outcome: a prospective, randomized, placebo-controlled study. 915 47

Binding of plasma factor VII(a) to tissue factor (TF) initiates the coagulation cascade. In health, TF is not expressed in endothelial cells. However, endothelial cells express TF in response to lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and other biological stimuli. TF expression by endothelial cells is implicated in thrombotic disorders in patients with a variety of clinical disorders. In the present study, we demonstrate that curcumin (diferulolylmethane), a known anticarcinogenic and anti-inflammatory agent, inhibited phorbol 12-myristate 13-acetate (PMA), LPS, TNF alpha, and thrombin-induced TF activity and TF gene transcription in human endothelial cells. The present data show that curcumin prevented the activation of c-Rel/p65, which is essential for TF gene activation in endothelial cells, by impairing the proteolytic degradation inhibitor protein, I kappa B alpha. The data also show that curcumin downregulated AP-1 binding activity. The present studies are the first to demonstrate that PMA, but not LPS, TNF alpha, and thrombin, induced Egr-1 binding to the second serum-responsive region (SRR-2) of TF promoter and that curcumin inhibited the PMA-induced Egr-1 binding to SRR-2. Overall, the data suggest that the anticarcinogenic and anti-inflammatory properties of curcumin may be related to its ability to inhibit cellular gene expression regulated by transcription factors NF-kappa B, AP-1, and Egr-1.
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PMID:Inhibition of tissue factor gene activation in cultured endothelial cells by curcumin. Suppression of activation of transcription factors Egr-1, AP-1, and NF-kappa B. 943 86

Thrombin is the central bioregulatory enzyme in hemostasis and is generated in vascular beds in which inflammatory responses are ongoing. In this study, we examined the effect of thrombin, both alone and in combination with TNF, on gene expression in porcine aortic endothelial cells (EC). Thrombin (1-10 U/ml) induced increased mRNA levels of E-selectin, monocyte chemoattractant protein-1, IL-8, plasminogen activator inhibitor-1, and IkappaB-alpha. These effects were mimicked by a thrombin receptor-activating peptide; preincubation of thrombin with hirudin blocked the induction of mRNA, suggesting that the increased gene expression was due to thrombin-specific activity. Because these genes are known to contain nuclear-factor-kappaB (NF-kappaB)-binding elements in their promoter region, we next examined the ability of thrombin to activate this transcription factor. As detected by electrophoretic mobility shift assay, thrombin (10 U/ml) or thrombin receptor-activating peptide (100 microM) stimulated increased NF-kappaB-binding activity. Supershift analysis revealed that these complexes were comprised principally of the RelA (p65) and NF-kappaB1 (p50) Rel family members. Thrombin alone did not substantively increase protein levels of E-selectin despite the increase in E-selectin mRNA levels. However, thrombin (3-10 U/ml) stimulated a 10-fold enhancement in the ability of TNF (0.3-1.0 ng/ml) to induce E-selectin surface expression. Similar potentiation of TNF-induced NF-kappaB activity and E-selectin transcription by thrombin was observed in experiments utilizing luciferase reporter constructs expressed in bovine aortic EC. The ability of thrombin to potentiate TNF-induced EC activation thus provides an important mechanism by which products of the coagulation cascade may enhance cytokine-mediated inflammatory responses.
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PMID:Thrombin activates nuclear factor-kappaB and potentiates endothelial cell activation by TNF. 954 5

The protein C/protein S anticoagulant pathway has been proposed to be a common link between coagulation and inflammation. Studies have suggested that a component of the anticoagulant pathway, activated protein C (APC), may play a role in the inflammatory response by modulating the effects of cytokines such as TNF and by blocking neutrophil activation. Cytokines are known to be intimately involved in the inflammatory response and to function in part to restore hemostatic balance. To begin to delineate what role APC may have in the inflammatory response, we have investigated the effect of APC on the production of the proinflammatory cytokines IL-6 and IL-8 in primary HUVEC, human microvascular endothelial cells, and human coronary artery endothelial cells. Our results have demonstrated that physiologic concentrations of APC significantly up-regulated the production of both IL-6 and IL-8. This increase, which was seen at both the RNA and protein level, was not due to either thrombin or LPS contamination of the APC preparation. Additional studies also showed that the APC-mediated up-regulation of IL-6 and IL-8 was IL-1 independent. Although neither purified protein C nor protein S alone had an effect on cytokine production, protein S, the cofactor for APC, significantly enhanced the ability of APC to up-regulate IL-6/IL-8 production. These results provide further evidence for a role for APC in the inflammatory response.
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PMID:The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. 972 57

Human thrombin has been shown to stimulate monocyte chemotaxis, phagocytosis, and interleukin (IL8) production, but the mechanisms responsible for stimulation are not well defined. In some cells, thrombin stimulation of proliferation appears to require both cleavage of the proteolytically activated receptor for thrombin (PAR1) and activation of a nonproteolytically activated thrombin receptor (N-PAR), while in others activation of either receptor alone may be sufficient for stimulation. We, therefore, have initiated studies to address thrombin receptor expression and cell responsiveness to thrombin in interferon gamma (IFNgamma)-differentiated and nondifferentiated U937 monocytic cells. Northern blot analysis shows that PAR1 expression is upregulated upon differentiation. Experiments with biotinylated and 125I-thrombin show that specific thrombin binding is dramatically increased by differentiation although it is not clear if this binding is to PAR1 or to a separate binding component such as N-PAR which is present on fibroblasts and other cells. Addition of thrombin at concentrations of 1-10 microg/ml (30-300 nM, concentrations where specific thrombin binding is observed) stimulates proliferation of IFNgamma-differentiated U937 cells but not of undifferentiated U937 cells. Thrombin also stimulates interleukin-6 (IL6) production in IFNgamma-differentiated U937 cells. Moreover, thrombin induces high levels of IL6, interleukin-1beta (IL1beta), and tumor necrosis factor-alpha (TNF alpha) production by peripheral blood mononuclear cells (PBMC) and monocytes. These results show that differentiated U937 cells and mature PBMC are responsive to thrombin whereas nondifferentiated U937 are not. Further, this responsiveness appears to correlate with expression of PAR1 and to a dramatic increase in specific thrombin binding. That thrombin stimulates cytokine production and proliferation in populations of differentiated monocytes suggests that thrombin may be an important regulator of inflammation and wound healing.
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PMID:Thrombin receptor expression and responsiveness of human monocytic cells to thrombin is linked to interferon-induced cellular differentiation. 973 47

Proinflammatory effects induced by the serine protease factor Xa were investigated in HUVEC. Exposure of cells to factor Xa (5-80 nM) concentration dependently stimulated the production of IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) and the expression of E-selectin, ICAM-1, and VCAM-1, which was accompanied by polymorphonuclear leukocyte adhesion. The effects of factor Xa were blocked by antithrombin III, but not by the thrombin-specific inhibitor hirudin, suggesting that factor Xa elicits these responses directly and not via thrombin. IL-1alpha and TNF-alpha were not implicated, since neither the IL-1 receptor antagonist nor a TNF-neutralizing Ab could suppress the factor Xa responses. Active site-inhibited factor Xa and factor Xa depleted from gamma-carboxyglutamic acid residues were completely inactive. The effector cell protease receptor-1 (EPR-1) seems not to be involved since anti-EPR-1 Abs failed to inhibit cytokine production. Moreover, neither the factor X peptide Leu83-Leu88, representing the inter-epidermal growth factor sequence in factor Xa that mediates ligand binding to EPR-1, nor the peptide AG1, corresponding to the EPR-1 sequence Ser123-Pro137 implicated in factor Xa binding, inhibited the factor Xa-induced cytokine production. In conclusion, these findings indicate that factor Xa evokes a proinflammatory response in endothelial cells, which requires both its catalytic and gamma-carboxyglutamic acid-containing domain. The receptor system involved in these responses induced by factor Xa remains to be established.
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PMID:Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. 978 Feb 8

Prostaglandins are involved in force-induced orthodontic tooth movement. Bradykinin (BK) and thrombin are known to cause a significant time- and concentration-dependent burst of prostanoid biosynthesis in cultured human periodontal-ligament (PDL) cells. The aim now was to investigate interactive effects between interleukin 1 alpha, -beta (IL-1 alpha, -1 beta), tumour necrosis factor-alpha,-beta (TNF-alpha, -beta) and BK or thrombin on prostaglandin biosynthesis in human PDL cells. IL-1 alpha and -1 beta produced time- and concentration-dependent stimulation of prostanoid biosynthesis [prostaglandin (PG)E2 and 6-keto-PGF1alpha]. Synergistic stimulation of prostanoid biosynthesis was demonstrated when BK or thrombin were added together with IL-1 alpha or -1 beta. BK and IL-1 beta both significantly stimulated the release of [3H]arachidonic acid. No synergistic effect on [3H]arachidonic acid release was seen when BK and IL-1 beta were added simultaneously. These data suggest that the synergistic effect of BK and IL-1 beta on prostanoid biosynthesis is not due to interactions at the receptor level nor to enhanced release of arachidonic acid, but may be due to increased activity of cyclo-oxygenase. Also, TNF-alpha and -beta produced a concentration-dependent stimulation of PGE2 formation in cultured human PDL cells. Synergistic effects of BK and thrombin were demonstrated when PGE2 production was stimulated in combination with TNF-beta. In addition, a synergistic effect on the PGE2 response to IL-1 alpha or -1 beta was demonstrated when added in combination with TNF-alpha. These experiments demonstrate synergistic interactions between BK, thrombin, IL-1 and TNF on prostaglandin biosynthesis in cultured human PDL cells. The findings suggest that inflammatory mediators may act in concert in stimulating prostanoid production in response to pro-inflammatory stimuli. As an inflammatory reaction is seen in the periodontal ligament when teeth are orthodontically treated, this synergistic interaction may be of importance in force-induced tooth movement.
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PMID:Synergistic interactions of bradykinin, thrombin, interleukin 1 and tumor necrosis factor on prostanoid biosynthesis in human periodontal-ligament cells. 983

To determine in vivo effects of interleukin (IL)-12 on host inflammatory mediator systems, 4 healthy chimpanzees received recombinant human IL-12 (1 microg/kg) by intravenous injection. IL-12 induced increases in plasma concentrations of IL-15, IL-18, and interferon-gamma (IFN-gamma), plus a marked antiinflammatory cytokine response (IL-10, soluble tumor necrosis factor [TNF] receptors, IL-1 receptor antagonist) and secretion of alpha-chemokines (IL-8, IFN-gamma-inducible protein 10) and beta-chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta). In addition, IL-12 elicited neutrophilic leukocytosis, neutrophil degranulation (elastase-alpha1-antitrypsin complexes), coagulation activation (F1 + 2 prothrombin fragment, thrombin-antithrombin III complexes), and fibrinolytic activation (tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes). IL-12-induced activation of multiple host mediator systems was found only after 8-24 h, remained detectable until the end of the 48-h observation period, and occurred in the absence of detectable TNF and IL-1beta. These data may contribute to understanding the role of IL-12 in the pathogenesis of sepsis syndrome and the toxicity found after repeated injections of IL-12.
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PMID:Interleukin-12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees. 995 71

The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 microgram. kg-1. h-1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4+/-9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (P<0. 05). ATIII significantly prevented the increase in thromboxane (TXB2) levels, which were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum group after 6 hours (P<0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 microgram. kg-1. h-1). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (P<0.05, chi2 test) a significant reduction of pulmonary hypertension (placebo, 42.0+/-11. 1 mm Hg; ATIII, 23.6+/-7.5 mm Hg, P<0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.
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PMID:Influence of antithrombin III on coagulation and inflammation in porcine septic shock. 1036 91


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