Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the era of antiretroviral therapy, liver disease has emerged as an important cause of morbidity and mortality in HIV/hepatitis C virus (HCV) coinfected patients. It is believed that HCV is a non-cytopathic virus and that T-cell-mediated events (including the production of pro-inflammatory cytokines) have an important role in promoting both liver damage and viral clearance. Whether HIV coinfection or antiretroviral therapies influence such events is still unclear. In the current study, we compared the expression of NKp46 (a natural killer cell marker), CD3 (a T-cell marker), interferon-gamma (IFN-gamma), tumour-necrosis factor-alpha (TNF-alpha; pro-inflammatory cytokines) and interleukin-10 (IL-10; an anti-inflammatory cytokine) mRNA in the liver of naive HIV/HCV-coinfected patients (group one, n=14), coinfected patients treated with antiretroviral therapy (group two, n=23) and naive HCV mono-infected patients (group three, n=24). All three groups had comparable HCV viremia, with coinfected patients showing similar and relatively high CD4+ T-cell counts and significantly different HIV vireamia. Interestingly, when compared to groups two and three, group one showed significantly higher intrahepatic mRNA levels for CD3, IFN-gamma and TNF-alpha, whereas the expression of NKp46 and IL-10 were comparable in all three groups. Further, higher histopathological grading scores within each group were independently associated with higher mRNA contents for CD3 and IFN-gamma and higher serum alanine aminotransferase levels at the time of liver biopsy. Together, these results suggest that HIV infection may exacerbate the immune-mediated inflammatory response in the liver of patients chronically infected with HCV and antiretroviral therapy may prevent this effect.
 ...
PMID:Naive HIV/HCV-coinfected patients have higher intrahepatic pro-inflammatory cytokines than coinfected patients treated with antiretroviral therapy. 1675 56

The intravenous injection of concanavalin A (Con A) activates T cells and induces cytokine dependent liver injury in mice. However, the effect of repeated administrations of Con A has not been fully investigated. Female BALB/c mice were intravenously injected with Con A (20mg/kg) or saline once a week for six times. Mice were rechallenged with Con A 17 days after repeated administrations of Con A. Repeated Con A administrations elicited a sustained inhibition of rechallenged-Con A-induced liver injury. Plasma TNF-alpha and IFN-gamma levels after rechallenge of Con A were decreased compared with that of repeated saline treatments. By contrast, plasma IL-4 and IL-10 levels after rechallenge of Con A were increased. In spleen cells prepared from repeated Con A treated mice, the production of TNF-alpha and IFN-gamma 24h after co-incubation with Con A decreased, and that of IL-4 and IL-10 increased. In naive mice, plasma ALT level after Con A injection was decreased by the transfer of spleen cells prepared from the repeated Con A treated mice. The repeated administrations of Con A elicited Th1 to Th2 cytokine shift and the tolerant state against the Con A-induced liver injury in mice.
 ...
PMID:Repeated administrations of concanavalin A induce Th1 to Th2 cytokine shift and tolerance against liver injury in mice. 1682 Mar 20

The aim of the study was to assess the role of selected elements of innate immunity in the pathogenesis of chronic hepatitis C in children. The study comprised 20 children with chronic hepatitis C (group 1), nine healthy hepatitis C virus (HCV) seropositive children (group 2) and 18 healthy children (control group). We evaluated the expression of Toll-like receptor (TLR)2 and TLR4 on peripheral blood neutrophils, and generation of interleukin (IL)-8, IL-10, IL-12 and reactive oxygen species (ROS) by neutrophils. The performed tests demonstrated higher expression of TLR2 and TLR4 on stimulated neutrophils and of TLR4 on non-stimulated neutrophils in group 1 in comparison to HCV seropositive children and controls. In group 1, the expression of TLR2 after granulocyte colony-stimulating factor (GCSF) stimulation showed positive correlation with alanine aminotransferase and asparate aminotransferase activities, while the expression of TLR2 without stimulation and of TLR4 after GCSF stimulation also correlated with necrosis. IL-12 generation by lipopolysachcharide-stimulated neutrophils was higher in group 1 versus controls. In group 1, maximum chemiluminescence (CL) without pre-activation, both spontaneous and after formyl-methionyl-leucyl-phenylanine and phorbol-myristate-acetate (PMA) stimulation, was significantly lower than in the controls. CL after tumour necrosis factor-alpha pre-activation and PMA stimulation was still lower than in the controls, however, after opsonized zymosane stimulation it was significantly higher than in the controls. Our studies suggest the involvement of neutrophils in the pathogenesis of chronic hepatitis C in children. Neutrophils demonstrate increased expression of TLR2 and TLR4 (correlating with the features of hepatocytic damage and intensification of necrosis), inhibition of oxygen metabolism, and after TNF-alpha pre-activation higher ability to produce ROS.
 ...
PMID:Involvement of innate immunity in the pathogenesis of chronic hepatitis C in children. 1697 Jun 85

Hemorrhagic shock (HS) is a major cause of morbidity and mortality in trauma patients. The early growth response 1 (Egr-1) transcription factor is induced by a variety of cellular stresses, including hypoxia, and may function as a master switch to trigger the expression of numerous key inflammatory mediators. We hypothesized that HS would induce hepatic expression of Egr-1 and that Egr-1 upregulates the inflammatory response after HS. The Egr-1 mice and wild-type (WT) controls (n>or=5 for all groups) were subjected to HS alone or HS followed by resuscitation (HS/R). Other mice were subjected to a sham procedure which included general anesthesia and vessel cannulation but no shock (sham). After the HS, HS/R, or sham procedures, mice were euthanized for determination of serum concentrations of interleukin (IL) 6, IL-10, and alanine aminotransferase. Northern blot analysis was performed to evaluate Egr-1 messenger RNA (mRNA) expression. Liver whole cell lysates were evaluated for Egr-1 protein expression by Western blot analysis. Hepatic expression of IL-6, granulocyte colony-stimulating factor, and intracellular adhesion molecule 1 mRNA was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The Egr-1 DNA binding was assessed using the electrophoretic mobility shift assay. Hemorrhagic shock results in a rapid and transient hepatic expression of Egr-1 mRNA in WT mice by 1 h, whereas protein and DNA binding activity was evident by 2.5 h. The Egr-1 mRNA expression diminished after 4 h of resuscitation, whereas Egr-1 protein expression and DNA binding activity persisted through resuscitation. The Egr-1 mice exhibited decreased levels of hepatic inflammatory mediators compared with WT controls with a decrease in hepatic mRNA levels of IL-6 by 42%, granulocyte colony-stimulating factor by 39%, and intracellular adhesion molecule 1 by 43%. Similarly, Egr-1 mice demonstrated a decreased systemic inflammatory response and hepatic injury after HS/R compared with their WT counterparts. Early growth response 1 is rapidly upregulated in the liver during and after resuscitation from HS. Our results showing a blunted inflammatory response in Egr-1 mice provides evidence that Egr-1 functions as a proximal signal transduction mechanism responding to shock by amplifying the systemic inflammatory response.
 ...
PMID:Early growth response 1 mediates the systemic and hepatic inflammatory response initiated by hemorrhagic shock. 1722 90

IL-6 induction depending on the mode of carbon tetrachloride (CCl4) administration was investigated in rats. After the intraperitoneal (i.p.) administration of CCl4 in 50% corn oil at 1.0 ml/kg body weight, IL-6 level markedly increased in plasma and peaked at 4h. TNF-alpha and IL-1beta levels gradually increased, reaching the maximum at 24h. IL-10 level transiently peaked at 4h and then decreased, but later further increased, reaching the second peak at 24h. Plasma alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities peaked at 24h. As the vehicle-to-CCl4 ratio increased, the level of IL-6 decreased and the activities of ALT and SDH increased. After oral CCl4 administration, IL-6 was not significantly detected. IL-6 level in peritoneal exudate fluid (PEF) increased simultaneously with plasma IL-6 level after i.p. CCl4 administration, but the total amount of PEF IL-6 was 37-fold as much as that of plasma IL-6, in contrast to the result that the total amount of plasma IL-6 was 19-fold as much as that of PEF IL-6 after i.p. lipopolysaccharide administration. These results suggest that i.p. administration of CCl4 dissolved in a small amount of vehicle selectively induces a high production of IL-6 in the peritoneal cavity early after the administration. Since IL-6 is a protective cytokine against hepatotoxicity, its induction should be taken into consideration during analysis of data obtained using the CCl4-induced liver injury model.
 ...
PMID:Early induced, high-level interleukin-6 expression in the rat peritoneal cavity into which a hepatotoxicant carbon tetrachloride was administered. 1737 62

This study aims to investigate the potential role of endogenous interleukin (IL)-10 in long-term liver allograft survival induced by delayed immunosuppression (FK506 days 2-7). Liver transplantation was performed by using Dark Agouti and Lewis rats as donors and recipients, respectively. The delayed immunosuppression protocol induced indefinite allograft survival. A transient upregulation of plasma IL-10 levels was detected in the nontreatment and FK506 treatment groups. Macrophages were found to be one of the major sources of IL-10 produced from the liver allografts. Administration of IL-10-neutralizing antibody shortened the long-term isograft survival and FK506-induced indefinite allograft survival, particularly in the FK506 group. Damaged liver graft histology and increase of plasma alanine aminotransferase levels were detected in the groups with IL-10 antibody treatment. In an ex vivo setting, IL-10 recombinant protein augmented the expression of Foxp3, downregulated the expression of IL-2 and interferon gamma, and induced the generation of CD4(+)CD25(+)Foxp3(+) and CD8(+)CD25(+)Foxp3(+) cells, but this effect was blocked by the administration of IL-10 antibody. Finally, administration of IL-10 recombinant protein after the decline of endogenous IL-10 levels improved allograft survival, and a 100% long-term allograft survival was achieved by the combination of IL-10 with low-dose FK506. In conclusion, the delayed immunosuppression could induce long-term liver allograft survival in the presence of endogenous IL-10 produced by the tissue macrophages. Supplementary exogenous IL-10 administration combined with low-dose immunosuppressive drug may be a useful strategy to induce long-term liver allograft survival.
 ...
PMID:Induction of long-term liver allograft survival by delayed immunosuppression is dependent on interleukin-10. 1739 63

Multiorgan dysfunction ensuing from severe heatstroke includes hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. We attempted to assess whether human umbilical cord blood-derived CD34+ cell therapy improves survival during experimental heatstroke by attenuating multiorgan dysfunction. Anesthetized rats, immediately after the onset of heatstroke, were divided into 2 major groups and given CD34- or CD34+ cells (1 x 10(5)-5 x 10(5)/mL/kg body weight) i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Hypotension, hepatic and renal failure (evidenced by increased serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels in plasma), hypercoagulable state (evidenced by increased prothrombin time, activated partial thromboplastin time, and D-dimer, and decreased platelet count and protein C in plasma), activated inflammation (evidence by increased TNF-alpha levels in serum), and cerebral dysfunction (evidenced by intracranial hypertension, cerebral hypoperfusion and hypoxia, and cerebral ischemia and injury) were monitored. When the CD34- cell-treated or untreated rats underwent heat stress, their survival time values were found to be 19 to 23 min. Resuscitation with CD34+ cells significantly improved survival time (duration, 63-291 min). As compared with normothermic controls, all CD34- cell-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, CD34+ cell therapy significantly caused attenuation of all the above-mentioned heatstroke reactions. In addition, the levels of IL-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34+ cell therapy during heatstroke. Our data indicate that CD34+ cell therapy may resuscitate persons who had a heatstroke by reducing multiorgan dysfunction or failure.
 ...
PMID:Human umbilical cord blood-derived CD34+ cells cause attenuation of multiorgan dysfunction during experimental heatstroke. 1750 7

Vasoactive intestinal peptide (VIP) was administered in a model of zymosan-induced generalized inflammation (ZIGI). Its beneficial action was associated with reduced TNF-alpha and increased IL-10 production, lowered levels of creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin in circulation. VIP diminished the level of RANTES and MIP-1alpha in peritoneal exudate and circulation. The neuropeptide inhibited NO release from stimulated peritoneal macrophages. Decreased spleen, liver and kidney enlargement and less pathological changes in liver were observed. The effect of VIP was attenuated by pretreatment with VIP antagonist (anti-VIP) before the induction of shock.
 ...
PMID:Exogenous VIP limits zymosan-induced generalized inflammation (ZIGI) in mice. 1753 56

Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated signaling, inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-1beta, IL-6, IL-10, MIP-2, and NO metabolites. TAK-242 protected mice from LPS-induced lethality in a similar dose-dependent manner, and rescued 100% of mice at a dose of 1 mg/kg. Interestingly, TAK-242 worked quickly, and showed beneficial effects even when administered after LPS challenge. Even though increases in serum levels of IL-6 and hypothermia were already evident 2 h after LPS challenge, TAK-242 administration inhibited further increase in IL-6 levels and decrease in body temperature. LPS-induced increases in serum levels of organ dysfunction markers, such as alanine aminotransferase, total bilirubin, and blood urea nitrogen, were also significantly suppressed by post-treatment as well as pre-treatment. Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.
 ...
PMID:Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. 1763

High-mobility group box 1 (HMGB1) is a 30-kDa DNA-binding protein that displays proinflammatory cytokine-like properties. HMGB1-dependent inflammatory processes have been demonstrated in models of sterile injury, including ischemia-reperfusion injury and hemorrhagic shock. Here, we tested the hypothesis that the systemic inflammatory response and associated remote organ injury that occur after peripheral tissue injury are highly dependent on HMGB1. Toll-like receptor 4 (TLR4) wild-type (WT) mice subjected to bilateral femur fracture after treatment with neutralizing antibodies to HMGB1 had lower serum IL-6 and IL-10 levels compared with mice treated with nonimmune control IgG. Similarly, compared with injured mice treated with control IgG, anti-HMGB1 antibody-treated mice had lower serum alanine aminotransferase levels and decreased hepatic and gut mucosal NF-kappaB DNA binding. TLR4 mutant (C3H/HeJ) mice subjected to bilateral femur fracture had less systemic inflammation and liver injury than WT controls. Residual trauma-induced systemic inflammation and hepatocellular injury were not ameliorated by treatment with a polyclonal anti-HMGB1 antibody, even though HMGB1 levels were transiently elevated just 1 h after injury in both WT and C3H/HeJ mice. Collectively, these data demonstrate a critical role for a TLR4-HMGB1 pathway in the initiation of systemic inflammation and end-organ injury following isolated peripheral tissue injury.
 ...
PMID:Systemic inflammation and remote organ injury following trauma require HMGB1. 1765 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>