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)

To elucidate the role of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) in chronic hepatitis type C (CH(C], TNF alpha and IL-1 beta released from peripheral blood mononuclear cells were measured in 6 CH(C) patients before and during interferon therapy. During the therapy, TNF-alpha levels were significantly high in two patients whose serum ALT levels turned normal, while IL-1 beta levels did not show significant change. These results suggest that TNF-alpha takes part in improvement of CH(C).
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PMID:Production of tumor necrosis factor alpha and interleukin 1 beta by peripheral blood mononuclear cells from chronic hepatitis type C patients during interferon therapy. 170 36

The early stages of insulin-dependent diabetes mellitus are characterized by a selective inability to secrete insulin in response to glucose, coupled to a better response to nonnutrient secretagogues. The deficient glucose response may be a result of the autoimmune process directed toward the beta-cells. Interleukin-1 (IL-1) has been suggested to be one possible mediator of immunological damage of the beta-cells. In the present study we characterized the sensitivity of beta-cells to different secretagogues after human recombinant IL-1 beta (rIL-1 beta) exposure. Furthermore, experiments were performed to clarify the biochemical mechanisms behind the defective insulin response observed in these islets. Rat pancreatic islets were isolated and kept in tissue culture (medium RPMI-1640 plus 10% calf serum) for 5 days. The islets were subsequently exposed to 60 pM human recombinant IL-1 beta during 48 h in the same culture conditions as above and examined immediately after IL-1 exposure. The rIL-1 beta-treated islets showed a marked reduction of glucose-stimulated insulin release. Stimulation with arginine plus different glucose concentrations, and leucine plus glutamine partially counteracted the rIL-1 beta-induced reduction of insulin release. The activities of the glycolytic enzymes hexokinase, glucokinase, and glyceraldehyde 3-phosphate dehydrogenase, were similar in control and IL-1-exposed islets. Treatment with IL-1 also did not impair the activities of NADH+- and NADPH+-dependent glutamate dehydrogenase, glutamate-aspartate transaminase, glutamate-alanine transaminase, citrate synthase, and NAD+-linked isocitrate dehydrogenase. The oxidation of D-[6-14C]glucose and L-[U-14C]leucine were decreased by 50% in IL-1-treated islets. Furthermore, there was a significant decrease in the ratios of [2-14C]pyruvate oxidation/[1-14C]pyruvate decarboxylation and L-[U-14C]leucine oxidation/L-[1-14C]leucine decarboxylation, indicating that IL-1 decreases the proportion of generated acetyl-coenzyme-A residues undergoing oxidation. However, in the presence of IL-1 there was a significant increase in L-[U-14C]glutamate oxidation. These combined observations suggest that exposure to IL-1 induces a preferential decrease in glucose-mediated insulin release and mitochondrial glucose metabolism. This mitochondrial dysfunction seems to reflect an impairment in proximal steps of the Krebs cycle. It is conceivable that the IL-1-induced suppression and shift in islet metabolism can be an explanation for the beta-cell insensitivity to glucose observed in the early phases of human and experimental insulin-dependent diabetes mellitus.
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PMID:Differential sensitivity to beta-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1 beta. 266 6

Pretreatment with a low dose of recombinant human interleukin-1 beta (IL-1) (3 to 30 micrograms/kg) 24 h before a lethal Pseudomonas aeruginosa infection prolongs survival in neutropenic mice. We investigated the role of the type I IL-1 receptor (IL-1RI) and IL-1RII in this IL-1-induced protection by using a specific IL-1 receptor antagonist (IL-1-Ra), which blocks effects mainly via IL-1RI. Pretreatment with IL-1Ra before IL-1 partially blocked the IL-1-induced enhanced survival, whereas pretreatment with a specific neutralizing monoclonal antibody to IL-1RI (35F5) eliminated the IL-1 induced protection. The nonapeptide fragment 163-171 of recombinant human IL-1 beta, which possesses the immunoadjuvant but not the inflammatory effect of the entire molecule via a non-receptor-mediated signal transduction process, did not reproduce the IL-1-induced protection. IL-1-induced protection was associated with reduced serum aspartate aminotransferase and alanine aminotransferase concentrations in conjunction with ameliorated histopathology of the liver. These findings may be due to reduced cytokine production and cytokine sensitivity of target cells after infection. We conclude that the IL-1-induced nonspecific resistance to infection is mediated by cells bearing IL-1RI and is associated with a reduction of liver damage.
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PMID:Interleukin-1 (IL-1)-induced resistance to bacterial infection: role of the type I IL-1 receptor. 748 12

Multiple organ dysfunction (MOD) is the leading cause of mortality in septic patients with circulatory shock. Recent evidence suggests that the overproduction of the cytokine, tumor necrosis factor-alpha(TNF), and oxygen free radical molecules may mediate the progression of sepsis to MOD and death. In this study, we have examined the ability of MDL 101,002, a free radical scavenger, to reduce organ dysfunction and cytokine secretion induced by lipopolysaccharide (LPS) administration in rats. Treatment with MDL 101,002(10-60 ng/kg, i.p.) 30 min prior to an LPS challenge resulted in a dose-dependent reduction in several markers indicative of organ dysfunction and mortality. MDL 101,002 markedly decreased LPS-induced liver and kidney damage as indicated by serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or urea and creatinine, respectively. MDL 101,002 also prevented LPS-induced pulmonary edema, but did not prevent leukopenia and only partially reduced thrombocytopenia. Associated with these improvements in organ dysfunction and survival was a modest decrease in LPS-stimulated interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) secretion and a marked ( > 90%) inhibition of TNF secretion by MDL 101,002. The data are consistent with a role for oxygen free radicals in the development of endotoxin-induced organ dysfunction and shock and suggest that free radical scavengers could reduce the mortality consequent to sepsis by decreasing organ dysfunction, at least in part, through a reduction in free radical stimulated cytokine secretion.
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PMID:Reduction in endotoxin-induced organ dysfunction and cytokine secretion by a cyclic nitrone antioxidant. 858 85

We investigated the spontaneous and phytohemagglutinin-stimulated production of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) by peripheral blood mononuclear cells in patients with chronic hepatitis C during treatment with interferon-alpha (IFN-alpha). Spontaneous productions of these were significantly higher in patients with chronic hepatitis C than in healthy subjects. For patients prescribed interferon, stimulated production of TNF-alpha was significantly higher in complete responders than in partial responders, but the differences were small between the other cytokine levels and outcome of IFN treatment. Spontaneous production of these cytokines was higher in patients with genotype III with complete response than in genotype III patients with a partial response, but this was not the case in patients with genotype II. There was a negative correlation between these cytokines and histological activity index. Spontaneous production of cytokines was decreased only in complete responders after the administration of interferon. These data suggest that the elevated production of cytokines in patients with chronic hepatitis C may be due to host response to the virus, and monitoring cytokines along with alanine aminotransferase and hepatitis C virus RNA during treatment may provide more precise information of the effectiveness of therapy.
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PMID:IL-1 beta and TNF-alpha produced by peripheral blood mononuclear cells before and during interferon therapy in patients with chronic hepatitis C. 860 75

In the model of liver damage induced by acetaminophen of mice, injection of interleukin-1 beta (IL-1 beta, i.p. 50,000 U/kg) 1, 6 or 12 h before the administration of acetaminophen could reduce the leakages of GPT and GOT induced by acetaminophen, with the 12 h pretreatment being the most effective. Treatment with IL-1 beta 1 h after administration of acetaminophen had no effect. Treatment with IL-1 beta of different doses (10,000, 30,000 or 50,000 U/kg) 12 h before the administration of acetaminophen could reduce the leakages of transaminases in a dose dependent manner and decrease the mortality of mice. The protective effect of IL-1 beta on the liver could be abolished by IL-1 beta receptor antagonist. Further experiments showed that IL-1 beta could increase the content of reduced glutathione (GSH) in normal liver and reverse the decline of GSH and the increase of GSSG induced by acetaminophen. IL-1 beta could also reduce malondiadehyde (MDA) content enhanced by acetaminophen. The above results indicate that the preventive effect of IL-1 beta against liver damage due to acetaminophen may be mediated through IL-1 beta receptor by increasing glutathione synthesis and decreasing lipid peroxidation of the liver.
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PMID:[Protective effect of interleukin-1 beta on acetaminophen induced liver damage in mice]. 981 50

Cold preservation/reperfusion leads to sinusoidal endothelial cell (SEC) activation and damage in nearly every liver transplantation; the extent of these changes influences early graft function. Upon reperfusion, activated SEC show increased expression of adhesion molecules, including von Willebrand factor (vWF) which is released into the circulation. This study was designed to evaluate the levels of vWF measured in the caval effluent and correlate these findings with known markers of SEC damage and early graft function. Data were obtained from 35 patients undergoing orthotopic liver transplantation (LTx). Two samples were taken from each patient for measurement of vWF: a) from the portal vein immediately prior to reperfusion; and b) from the first 50 ml of the caval effluent. Commercial assays were used to measure vWF, as well as hyaluronic acid (HA), thrombomodulin (TM), IL-1 beta, IL-6, IL-8 and TNF-alpha. Patients were divided into two groups based on early graft function. Poor early graft function (PEGF) was defined as a peak aspartate transaminase (AST) or alanine transaminase (ALT) level > 2500 U/L during the first three postoperative days (POD) and a prothrombin time (PT) > 16 s on POD 2 (n = 8). The remaining 27 patients had good early graft function (GEGF). In patients with GEGF, vWF levels dropped significantly between the two time points. This change was not observed in those with PEGF. A positive linear correlation was observed in the PEGF group between vWF and HA and IL-6. The different pattern of change in vWF between the two groups, as well as the positive correlation between HA, IL-6 and vWF in PEGF, suggest that vWF may be a useful marker of early graft function.
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PMID:Correlation between von Willebrand factor levels and early graft function in clinical liver transplantation. 1008 31

Fulminant hepatic failure (FHF) is a clinical syndrome resulting from massive death of liver cells or sudden and severe impairment of liver function. The causes of FHF are diverse and the overall mortality is very high. Recently, it became clear that apoptosis of hepatocytes is the critical cause of acute hepatic failure in FHF. It is well known that a family of cysteine proteases called caspase is one of the key mediators of the apoptotic pathway. Thus, caspases are attractive potential targets for the treatment of disorders resulting from excessive apoptosis. In this report, we examined the activity of a new caspase inhibitor, Xyz 033 mp. This nonpeptide inhibitor showed broad-spectrum caspase-inhibiting activity and protected primary rat hepatocytes from apoptotic death. In a mouse model of FHF induced by concavalin A (Con A), Xyz 033 mp suppressed elevated AST and ALT and specifically reduced IL-1 beta concentration. Also, Xyz 033 mp rescued mice from lethal experimental hepatitis induced by Con A. In addition, histological examinations indicated that Xyz 033 mp protected hepatocytes from the fatal apoptogenic effect of Con A. These results suggest that Xyz 033 mp may be a candidate therapeutic agent for FHF caused by massive apoptotic death of hepatocytes.
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PMID:A broad-spectrum caspase inhibitor blocks concanavalin A-induced hepatitis in mice. 1111 61

Hepatic Kupffer cells and pulmonary alveolar macrophages together constitute a macrophage-axis involved in the regulation of regional and systemic inflammatory responses. Systemic inflammatory response syndrome induced by overproduced pro-inflammatory mediators is the major cause of adult respiratory distress syndrome. In the present study, we examined the anti-inflammatory role of nitric oxide (NO) in a rat model of acute lung injury induced by hepatic ischemia-reperfusion (HI/R). The left and median lobes of the liver were subjected to 30 min of ischemia by clamping the relevant branches of hepatic artery and portal vein, followed by a 4-h reperfusion achieved by removal of the vascular clamp. Four groups of animals were studied: sham control + saline; sham control + N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v., 10 min before reperfusion); HI/R + saline; HI/R + L-NAME. Results show that (1) administration of L-NAME to rats subjected to HI/R decreased plasma NO levels; however, the attenuation of NO increased plasma alanine aminotransferase (ALT) activity and superoxide generation in the ischemic lobes of liver, compared to HI/R alone. (2) Inhibition of NO synthesis with L-NAME in rats subjected to HI/R also enhanced systemic inflammatory response as assessed by the increase in the number of circulating leukocytes and levels of plasma tumor necrosis factor-alpha (TNFalpha) and interleukin 1-beta (IL-1beta). (3) The overwhelming systemic inflammatory response induced by administration of L-NAME in rats subjected to HI/R also augmented pulmonary vascular permeability and superoxide generation in the lung tissue. (4) Pulmonary alveolar macrophages isolated from rats subjected to HI/R + L-NAME produced higher levels of TNFalpha and IL-1beta in the supernatant of culture medium than that of rats subjected to HI/R alone. (5) There were no differences between the groups of sham + saline and sham + L-NAME in terms of plasma NO levels and ALT activity, circulating leukocytes, superoxide generation in the liver and lung, lavage protein levels, and TNFalpha and IL-1beta levels in plasma and bronchoalveolar lavage fluid. Our results suggest that inhibition of NO synthesis by L-NAME in rats subjected to HI/R not only augments ischemic liver injury, but also enhances the systemic inflammatory response and exacerbates remote lung injury. The increase in TNFalpha and IL-1beta production by alveolar macrophages may, in part, account for L-NAME-induced enhancement of acute lung injury.
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PMID:Inhibition of nitric oxide synthesis by L-name exacerbates acute lung injury induced by hepatic ischemia-reperfusion. 1153 Oct 23

Interferon regulates the activity of other cytokines. Alterations in non-specific immune response, particularly cytokine level changes result in therapeutic difficulties in patients with chronic hepatitis C. Serum levels of IL-1 beta, IL-2, IL-4, IL-6 and IFN-gamma were measured in patients with chronic hepatitis C before the interferon therapy, in the early phase of the treatment (after the 6th dose of the drug), and in the later stable phase of the treatment (after the 36th dose of the drug). Concentrations of cytokines during the interferon therapy were compared to the changes in alanine aminotransferase activity. The IL-1 beta, IL-2, IL-4 and IL-6 serum concentrations were initially elevated in all patients. The increase in IL-1 beta level after the 6th dose and the decrease after 36th dose of IFN appeared to be an indicator of a good response to treatment. High levels of IL-6 before the IFN therapy followed by a decrease after the 6th dose and high levels of IL-4 followed by a decrease after 36th IFN dose also indicated good response. High levels of IL-2, stable throughout the treatment suggested a poor response. No changes in the IFN-gamma values before or during the treatment were observed.
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PMID:The levels of IL-1 nu beta, IL-2, IL-4, IL-6 and IFN-gamma among patients with chronic hepatitis type C treated with IFN-alpha. 1171 33


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