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)

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor that comprises the primary molecular target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack on the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of systemic inflammation in patients with the classical metabolic syndrome stems from falls in the white blood cell count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen. At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells. In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also in view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes.
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PMID:Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection. 1619 19

Expression of intracellular adhesion molecule-1 (ICAM-1) in an obstructive jaundice model and the potential protective role of platelet activating factor antagonist over small intestine and liver together with its effects on bacterial translocation are examined in this study. Forty-eight male Wistar albino rats were assigned into four equal groups of 12. In groups I and II, animals were sham operated. In groups III and IV, common bile duct ligation and division were performed. In group I and group III, 0.5 ml/day normal saline was applied intraperitoneally daily from day 2 to 6 of the study; in group II and group IV, 1 mg/kg/day BN 52021 was applied intraperitoneally daily from day 2 to 6 of the study. All animals were sacrificed on postoperative day 7. ICAM-1 expression (CD54 positivity) was analyzed in the liver and ileum tissue by immunohistochemical method. Samples from blood, liver mesenteric lymph nodes, and spleen were cultured under aerobic conditions. It is revealed that ICAM-1 expression was statistically higher in group III, with highest bacterial translocation and liver and spleen injury when compared to other groups. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), bilirubin, tumor necrosis factor alpha (TNFalpha), and interleukin 1beta(IL-1beta) values were at the highest level in group III, and there was a statistical decrease in group IV compared to group III. The administration of BN52021 in experimental obstructive jaundice is a useful way to reduce liver and intestinal mucosal villi damage by inhibiting bacterial translocation and systemic inflammatory response.
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PMID:The effect of platelet activating factor antagonist BN 52021 on bacterial translocation and ICAM-I expression in experimental obstructive jaundice. 1624 68

(5R)-5-hydroxytriptolide (LLDT-8) exhibits strong immunosuppressive activities in vitro and in vivo. Here, we investigated the effects of LLDT-8 on concanavalin A-induced hepatitis. Liver damage was evaluated by serum alanine transaminase (ALT) level and liver histology. The effects of LLDT-8 were determined by measurement of serum cytokines, lymphocyte proliferation assay, flow cytometry analysis of splenic T cell percentage and apoptosis, reverse-transcription polymerase chain reaction (RT-PCR) analysis for gene transcriptions. In LLDT-8-treated mice, serum ALT level and histological damage were markedly attenuated. The beneficial effect of LLDT-8 was closely associated with (i) reduction of serum tumor necrosis factor-alpha, interferon-gamma (IFN-gamma), interleukin-2, interleukin-12, and interleukin-6 levels; (ii) elimination of activated T cells by increasing proapoptotic genes signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor-1 (IRF-1) expression in spleens; (iii) blockade of mRNA expressions for chemokines (monokine induced by IFN-gamma, Mig; IFN-gamma-inducible protein-10, IP-10; IFN-inducible T cell-alpha chemoattractant, I-TAC), vascular adhesion molecule-1 (VCAM-1), and chemokine receptors (C-C chemokine receptor 1, CCR1; C-C chemokine receptor 5, CCR5; C-X-C chemokine receptor 3, CXCR3) in livers. These results suggested the therapeutic potential of LLDT-8 in IFN-gamma/STAT1/IRF-1 signaling- and inflammatory cytokines-mediated immune disorders.
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PMID:Preventive effects of (5R)-5-hydroxytriptolide on concanavalin A-induced hepatitis. 1660 50

We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-gamma) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1+ Gr-1+). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1-deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1-deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1-deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury.
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PMID:Neutrophil depletion protects against murine acetaminophen hepatotoxicity. 1753 19

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.
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PMID:Early growth response 1 mediates the systemic and hepatic inflammatory response initiated by hemorrhagic shock. 1722 90

1. The aim of the present study was to investigate the role of proteasome in the pathogenesis of liver injury induced by intestinal ischaemia-reperfusion (I/R) and the effect of the proteasome inhibitor lactacystin on neutrophil infiltration, intracellular adhesion molecule (ICAM)-1 and nuclear factor (NF)-kappaB expression in the liver tissues of rats. 2. Thirty-two Wistar rats were randomly divided into four groups (n = 8 in each group) as follows: (i) a control, sham-operated group; (ii) an I/R group subjected to 1 h intestinal ischaemia and 4 h reperfusion; (iii) a group pretreated with 0.2 mg/kg lactacystin 1 h before intestinal I/R; and (iv) a group pretreated with 0.6 mg/kg lactacystin 1 h before intestinal I/R. Liver and intestine histology were observed. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), as well as 20S proteasome activity in circulating white blood cells, were measured. Myeloperoxidase (MPO) activity in liver tissues and the immunohistochemical expression of liver NF-kappaB and ICAM-1 were assayed. In addition, a western blot of liver NF-kappaB was performed. 3. Compared with the sham-operated control group, liver and intestine injury was induced by intestinal I/R, characterized as histological damage including oedema, haemorrhage and infiltration by inflammatory cells, as well as a significant increase in serum AST (365 +/- 121 vs 546 +/- 297 IU/L, respectively; P < 0.05), ALT (65 +/- 23 vs 175 +/- 54 IU/L, respectively; P < 0.01) and LDH levels (733 +/- 383 vs 1434 +/- 890 IU/L, respectively; P < 0.05). Compared with the control group, MPO activity in the liver tissues increased significantly in the I/R group (2.05 +/- 0.69 vs 3.42 +/- 1.11 U/g, respectively; P < 0.05). Strong positive expression of liver ICAM-1 and NF-kappaB p65 was observed. 4. Compared with the intestinal I/R group, administration of 0.6 mg/kg lactacystin markedly reduced 20S proteasome activity in circulating white blood cells (15.47 +/- 4.00 vs 2.07 +/- 2.00 pmol 7-amino-4-methylcoumarin (AMC)/s per mg, respectively; P < 0.01) and ameliorated liver injury, which was demonstrated by decreased levels of serum AST (546 +/- 297 vs 367 +/- 86 IU/L, respectively; P < 0.05), ALT (175 +/- 54 vs 135 +/- 26 IU/L, respectively; P < 0.05) and LDH (1434 +/- 890 vs 742 +/- 218 IU/L, respectively; P < 0.05) and a reduced liver pathological score (2.13 +/- 0.64 vs 1.25 +/- 0.46, respectively; P < 0.01). Compared with the intestinal I/R group, MPO activity in liver tissues decreased significantly following lactacystin pretreatment (3.42 +/- 1.11 vs 2.58 +/- 0.61 U/g, respectively; P < 0.05) and the expression of liver NF-kappaB and ICAM-1 was markedly ameliorated. 5. The present study reveals that the proteasome inhibitor lactacystin ablates liver injury induced by intestinal I/R. One possible mechanism responsible for this effect is the inhibition of enhanced ICAM-1 and neutrophil infiltration by inhibition of NF-kappaB activity. The results suggest the feasibility of using proteasome inhibitor clinically in the treatment of intestinal I/R.
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PMID:Proteasome inhibitor lactacystin ablates liver injury induced by intestinal ischaemia-reperfusion. 1788 Mar 61

This study analyzes how toll-like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (IRI) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild-type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4 degrees C for 24 hours. Unlike WT OLTs, TLR4-deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4+ T cell infiltration, interferon (IFN)-gamma-inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM-1), as well as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2, and IFN-gamma, yet increased IL-4 and IL-10 expression. The well-functioning OLTs from TLR4 KO donors revealed attenuated activity of capase-3, and enhanced heme oygenase-1 (HO-1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI-dependent responses.
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PMID:Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. 1790 30

Endotoxemia is a life-threatening, inflammatory condition that involves multiple organ injury and dysfunction. Preprotachykinin-A (PPT-A) gene products, substance P (SP), and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products on multiple organ injury in LPS-induced endotoxemia, endotoxemia was induced by LPS administration (10 mg/kg, i.p.) in PPT-A gene-deficient mice (PPTA(-/-)) and the wild-type (WT) control mice (PPT-A+/+). I.p. administration of LPS to WT mice caused a significant increase in circulating levels of SP as well as in liver, lung, and kidney. PPT-A gene deletion significantly protected against liver, pulmonary, and renal injury following LPS-induced endotoxemia, as evidenced by tissue myeloperoxidase activities, plasma alanine aminotransferase, aspartate aminotransferase levels, and histological examination. Furthermore, PPT-A(-/-) mice had significantly attenuated chemokines, proinflammatory cytokines, and adhesion molecule levels in the liver, lung, and kidney. These results show that PPT-A gene products are critical proinflammatory mediators in endotoxemia and the associated multiple organ injury. In addition, the data suggest that deletion of the PPT-A gene protected mice against organ damage in endotoxemia by disruption in neutrophil recruitment.
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PMID:Role of preprotachykinin-A gene products on multiple organ injury in LPS-induced endotoxemia. 1799 2

Exhaled carbon monoxide concentration (ExCO-C) has been reported to increase in oxidative tissue injuries such as systemic inflammation, and is thought to reflect increased heme breakdown in the affected organ. As a transplanted liver undergoes ischemia-reperfusion, we hypothesized that ExCO-C might also increase following liver transplantation and might serve as a measure of the severity of the graft tissue injury. We prospectively studied 67 living donor liver transplantation (LDLT) patients in a consecutive fashion. During anesthesia, ExCO-C was determined at 6 time points, ranging from anesthesia induction, to admission to the intensive care unit. We also measured two markers of endothelial cellular injury, i.e., serum soluble thrombomodulin (sTM) and intercellular adhesion molecule (ICAM)-1. At 5 min after reperfusion of the grafted liver, ExCO-C markedly increased from 5.69+/-2.34 ppm at baseline, to 9.79+/-4.72 ppm (p<0.0001). There was an excellent correlation among an increase in CO concentration, arterial carboxyhemoglobin levels at the time of reperfusion (r(2)=0.19, p=0.0003), and postoperative total bilirubin levels (day 1, 2, and 3; r(2)=0.102, 0.109 and 0.100; p=0.008, 0.007 and 0.010, respectively). Serum sTM and ICAM-1 levels were also significantly increased after reperfusion (sTM: 3.3+/-0.8 to 5.1+/-1.7 FU/ml, p=0.0001; ICAM-1: 271.9+/-86.3 to 515.0+/-157.8 FU/ml, p=0.0001). ExCO-C had a positive relationship with sTM (r(2)=0.16, p=0.035) and ICAM-1 (r(2)=0.12, p=0.08). There was however, no correlation of ExCO-C with serum AST/ALT levels or clinical outcomes. This study demonstrated that ExCO-C significantly increased after reperfusion during LDLT. The increased ExCO-C may likely reflect increased heme breakdown and endothelial cell injury in the grafted liver.
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PMID:Increased exhaled carbon monoxide concentration during living donor liver transplantation. 1809 19

Emodin, 1,3,8-trihydroxy-6-methyl-anthraquinone, is an anthraquinone derivative from the roots of Rheum officinale Baill that has been used to treat many diseases in digestive system for thousands of years. This study is to disclose the mechanism of Emodin to treat cholestatic hepatitis via anti-inflammatory pathway. Rats were divided into Emodin, ursodeoxycholic acid, Dexamethasone, model and blank control groups with treatment of respective agent after administration of alpha-naphthylisothiocyanate. At 24 h, 48 h and 72 h time points after administration, liver function, pathological changes of hepatic tissue, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), cytokine-induced neutrophil chemoattractant (CINC)-1, macrophage inflammatory protein (MIP)-2, intercellular adhesion molecule (ICAM)-1, nuclear factor (NF)-kappaB and early growth response (Egr)-1, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) were detected. As a result, compared to the controls, Emodin had a notable effect on rat's living condition, pathological manifestation of hepatic tissue, total bilirubin, direct bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P<0.05), but had little effect on alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT) and total bile acid. With Emodin intervention, levels of TNF-alpha, IL-6, MPO, MDA, CINC-1, MIP-2, ICAM-1 and translocation of NF-kappaB were remarkably decreased, and levels of NO and iNOS were markedly increased (P<0.05). Emodin had no effect on Egr-1. In conclusion, Emodin has a protective effect on hepatocytes and a restoring activity on cholestatic hepatitis by anti-inflammation. The effects are mainly due to antagonizing pro-inflammatory cytokines and mediators, inhibiting oxidative damage, improving hepatic microcirculation, reducing impairment signals, and controlling neutrophil infiltration.
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PMID:Exploration of Emodin to treat alpha-naphthylisothiocyanate-induced cholestatic hepatitis via anti-inflammatory pathway. 1859 Jul 20


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