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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease- activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-a (TNF-a) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.
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PMID:Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis. 1713 80

Beta-thalassemia/hemoglobin (Hb) E is a hereditary hemolytic anemia with varying degrees of severity. Severely affected patients are treated with blood transfusion and/or splenectomy in order to maintain an optimum level of hemoglobin for normal growth and physical activities. As thrombosis has been observed among splenectomized patients, we have investigated alterations in coagulation and fibrinolysis in beta-thalassemia/Hb E patients. Plasma levels of prothrombin, fibrinogen, factors V, VII, VIII, IX and XI, protein C, protein S, thrombin activatable fibrinolysis inhibitor (TAFI) and prothrombin fragment 1+2 were determined in 61 patients (21 non-severe non-splenectomized, 18 severe non-splenectomized, 22 severe splenectomized) and 28 healthy individuals. Serum levels of D-dimer, ferritin, aspartate transaminase and alanine transaminase were also measured. All severe patients received regular blood transfusion. Prothrombin fragment 1+2 and D-dimer were significantly elevated in splenectomized patients compared to the healthy control subjects, whereas levels of proteins C, protein S, TAFI, fibrinogen, and factors V and VIII in the splenectomized groups were statistically lower than those in control group. There are no statistical differences for the other parameters measured between patients and controls. Coagulation tests showed only significantly reduction in TAFI and factor V and VIII levels in severe splenectomized group in comparison with severe non-splenectomized patients. These results demonstrate the existence of a low grade consumptive coagulopathy among blood-transfused splenectomized patients with severe clinical manifestations, indicating that these patients may have a higher risk for thrombosis than comparable patients with intact spleen.
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PMID:Hemostatic alterations in splenectomized and non-splenectomized patients with beta-thalassemia/hemoglobin E disease. 1738 94

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin K antagonists is limited by several factors. Oral direct thrombin inhibitors (ODTIs) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The Thrombin Inhibition in Venous Thromboembolism (THRIVE) program performed some studies developing the ODTI ximelagatran for this indication, and it is presented in the overview. The aim of the THRIVE I study was the dose finding, and that of the THRIVE IV study the applicability in hemodynamic stabile pulmonary embolism. A prospective, randomized, double blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-month treatment of acute venous thrombosis (THRIVE II and V). A second double blind study compared ximelagatran with placebo over 18 months after a 6-month anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis who received 2 infinity 36 mg ximelagatran was not inferior to that of patients who received a conventional anticoagulant for prophylaxis of recurrent events over 6 months. Ximelagatran 2 infinity 24 mg significantly reduced recurrent thromboembolic events compared to placebo without increasing the risk for hemorrhage. A reversible symptomless increase of alanine aminotransferase occurs in 6% to 9.6% of patients between months 2 and 4. The results of the follow-up studies suggest that thromboembolic events may recur in patients with acute venous thromboembolism after termination of treatment with both vitamin K antagonists and ximelagatran.
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PMID:Ximelagatran for treatment and prophylaxis of recurrent events in deep vein thrombosis. 1763 92

The blood hemostatic activity of the Tibetan medicinal herb Lamiophlomis rotata was evaluated in BALB/c mice and Wistar rats. L. rotata aqueous extract (LRAE) was given to mice at concentrations of 0.5, 1.0, 2.0 g/kg body weight and 0.75, 1.5, 3.0 g/kg to rats. The hemostatic activity of LRAE was estimated by changes in bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). At the same time hepatic function and blood fat indexes including AST, ALT, Alb, Chol and LDL-C were measured also. The results showed that an appropriate level of LRAE could shorten the BT and TT values and increase the Alb level paralleling that of FIB. However, the shortening of the PT was only possible by a high and long administration of LRAE, and no change in APTT was observed. On the other hand, LRAE showed some effects in improving the liver function and reducing blood lipids by decreasing the levels of AST, ALT, Chol and LDL-C. All these changes had a significant dose-effect and time-effect relationship. These results confirm the hemostatic and thromboplastic effects of L. rotata and these effects might be implemented by improving the synthetic function of the liver.
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PMID:Experimental study on the hemostatic activity of the Tibetan medicinal herb Lamiophlomis rotata. 1844 44

Severe sepsis remains a leading cause of death and disability because of less effective therapy available for this disease. A complex interplay between the inflammatory factors and the coagulation pathways seems to be the fundamental mechanisms for the pathogenesis of sepsis. Here we report that recombinant fibrinogenase II (rF II) from Agkistrodon acutus plasmin-independently degraded the thrombi, and inhibited inflammatory responses by direct and specific degradation of tumor necrosis factor alpha (TNF-alpha) induced by lipopolysaccharide (LPS) without showing proteolytic activities on interleukin-1 (IL-1), cluster of differentiation 68 (CD68) and some other serum proteins. We also report that rF II effectively protected against LPS induced sepsis in a rabbit model. Administration of rF II reduced hepatic and renal damage, decreased the levels of alanine aminotransferase (ALT) and blood urea nitrogen (BUN), and increased survival rate in LPS-induced sepsis rabbits. We further confirmed the rescue effect of rF II on severe sepsis in rat caecal ligation and puncture (CLP) model. Our findings suggest that rF II could effectively protect against sepsis via direct degradation of microthrombi and inflammatory factor TNF-alpha as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease.
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PMID:Recombinant fibrinogenase from Agkistrodon acutus venom protects against sepsis via direct degradation of fibrin and TNF-alpha. 1863 54

As the only oral anticoagulation option available in the United States, warfarin use remains widespread. However, concerns of safety remain a substantial issue. Additional anticoagulation options include unfractionated heparin, low-molecular-weight heparins (e.g., enoxaparin, dalteparin, and tinzaparin), and the indirect-acting factor Xa inhibitor, fondaparinux. Direct thrombin inhibitors represent a newer class of anticoagulants used primarily in the treatment of heparin-induced thrombocytopenia and percutaneous coronary interventions. Three intravenous agents are currently available-lepirudin, bivalirudin, and argatroban-with an oral agent, dabigatran etexilate, undergoing clinical investigation. Dabigatran etexilate offers a rapid onset of action after oral administration, reaching peak plasma concentrations and onset of anticoagulant effect within 0.5-2 hours after administration. Studies have demonstrated linear pharmacokinetics, a linear relationship between ecarin clotting time and international normalized ratio, and no known clinically significant drug or food interactions. Dabigatran etexilate has been studied in clinical trials as prophylaxis for venous thromboembolism in patients undergoing total knee replacement or total hip replacement surgeries, as well as for stroke prevention in patients with atrial fibrillation. Dabigatran etexilate has demonstrated superiority and noninferiority to enoxaparin as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery, with the most frequent adverse effects being gastrointestinal complaints. Elevations in alanine aminotransferase concentrations were noted in small percentages of patients in both the dabigatran etexilate and enoxaparin groups, with no observed dose association. The overall rates of major bleeding were low, with minor bleeding commonly noted, often at surgical sites. Clinical trials of dabigatran etexilate in patients with atrial fibrillation are ongoing. Results of short-term efficacy and safety appear promising. Further research is needed regarding long-term safety and efficacy for other anticoagulation indications.
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PMID:Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. 1895 96

The use of the fluoroquinolone antibiotic trovafloxacin (TVX) was severely restricted in 1999 due to its association with idiosyncratic hepatotoxicity. Previously, we reported that a nontoxic dose of TVX interacts with a nontoxic dose of lipopolysaccharide (LPS) to cause robust hepatocellular injury in mice. This interaction with LPS was not seen in mice treated with levofloxacin (LVX), a fluoroquinolone not associated with hepatotoxicity in people. TVX/LPS-coexposure caused an increase in plasma alanine aminotransferase (ALT) activity as early as 4.5 h after LPS administration which progressed through 15 h.We examined the role of the hemostatic system in TVX/LPS-induced liver injury. At the onset of liver injury, coexposure to TVX/LPS, but not exposure to TVX, LVX, LPS or LVX/LPS, caused increased plasma concentration of thrombin-antithrombin dimers and decreased plasma circulating fibrinogen. LPS treatment induced a small increase in plasma plasminogen activator inhibitor-1 (PAI-1) concentration, and TVX pretreatment enhanced this effect. TVX/LPS coexposure also resulted in hepatic fibrin deposition. Anticoagulant heparin administration reduced TVX/LPS-induced hepatic fibrin deposition and liver injury. PAI-1-/- mice treated with TVX/LPS exhibited similar fibrin deposition to wild-type mice but had significantly reduced hepatocellular injury. PAI-1-/- mice, but not heparin-treated mice, had reduced plasma concentrations of several cytokines compared to TVX/LPS-treated controls. In summary, TVX/LPS-coexposure caused an imbalance in the hemostatic system, resulting in thrombin activation increased, plasma concentration of PAI-1 and hepatic fibrin deposition. Both thrombin activation and PAI-1 play critical roles in the progression of TVX/LPS-induced liver injury, but through different modes of action.
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PMID:The role of the hemostatic system in murine liver injury induced by coexposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability. 1936 93

Plasma-derived antithrombin (pAT) is often used for the treatments of disseminated intravascular coagulation (DIC) patients. In this paper, the recombinant adenovirus vector encoding human antithrombin (AT) cDNA was constructed and directly infused into the mammary gland of two goats. The recombinant human antithrombin (rhAT) was purified by heparin affinity chromatography from the goat milk, and then used in the treatment of thirty lipopolysaccharide (LPS) induced DIC rats. A high expression level of rhAT up to 2.8 g/l was obtained in the milk of goats. After purification, the recovery rate and the purity of the rhAT were up to 54.7 +/- 3.2% and 96.2 +/- 2.7%, respectively. In blood of the DIC rat model treated with rhAT, the levels of antithrombin and thrombin-antithrombin (TAT) were augmented significantly; meanwhile the consumption of fibrinogen and platelet was reduced significantly, and the increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentration was restrained modest and non-significant. For the above DIC indexes, there were no differences between pAT and rhAT (P > 0.05). Our results demonstrated that the way we established is a pragmatic tool for large-scale production of rhAT, and the rhAT produced with this method has potential as a substitute for pAT in the therapy of DIC patients.
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PMID:Recombinant human antithrombin expressed in the milk of non-transgenic goats exhibits high efficiency on rat DIC model. 1945 83

Altered hepatic lipid homeostasis, hepatocellular injury, and inflammation are features of nonalcoholic steatohepatitis, which contributes significantly to liver-related morbidity and mortality in the Western population. A collection of inflammatory mediators have been implicated in the pathogenesis of steatohepatitis in mouse models. However, the pathways essential for coordination and amplification of hepatic inflammation and injury caused by steatosis are not completely understood. We tested the hypothesis that tissue factor (TF)-dependent thrombin generation and the thrombin receptor protease activated receptor-1 (PAR-1) contribute to liver inflammation induced by steatosis in mice. Wild-type C57Bl/6J mice fed a diet deficient in methionine and choline for 2 weeks manifested steatohepatitis characterized by increased serum alanine aminotransferase activity, macrovesicular hepatic steatosis, hepatic inflammatory gene expression, and lobular inflammation. Steatohepatitis progression was associated with thrombin generation and hepatic fibrin deposition. Coagulation cascade activation was significantly reduced in low TF mice, which express 1% of normal TF levels. Hepatic triglyceride accumulation was not affected in low TF mice or PAR-1-deficient mice. In contrast, biomarkers of hepatocellular injury, inflammatory gene induction, and hepatic accumulation of macrophages and neutrophils were greatly reduced by TF-deficiency and PAR-1-deficiency. The results suggest that TF-dependent thrombin generation and activation of PAR-1 amplify hepatic inflammation and injury during the pathogenesis of steatohepatitis.
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PMID:Tissue factor-deficiency and protease activated receptor-1-deficiency reduce inflammation elicited by diet-induced steatohepatitis in mice. 2000 34

Magnolol is a compound extracted from the Chinese medicinal herb Magnolia officinalis. It has multiple pharmacological effects, notably as an anti-oxidant. The aim of this study was to evaluate the effects of magnolol on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anaesthetized Wistar rats. Magnolol (4 microg/kg, i.v.) was administered at 30 min after LPS injection. Post-treatment with magnolol significantly attenuated the deleterious haemodynamic changes (e.g., hypotension and bradycardia) caused by LPS. Meanwhile, magnolol significantly inhibited the elevation of plasma levels of tumor necrosis factor alpha, glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase and blood urine nitrogen caused by LPS. The induction of inducible nitrous oxide (NO) synthase and the overproduction of NO and superoxide anions by LPS were also significantly reduced by post-treatment with magnolol. Moreover, the plasma level of the thrombin-antithrombin complex following administration of LPS was also reduced by post-treatment with magnolol. Thus, the beneficial effects of magnolol on LPS-induced sepsis result from its anti-inflammatory, anti-coagulatory, and anti-oxidant effects.
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PMID:Beneficial effects of magnolol in a rodent model of endotoxin shock. 2051 37


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