Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.109 (AST)
 6,066 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The overexpression of intercellular adhesion molecule-1 (ICAM-1) has been shown to be involved in the pathogenesis of various necroinflammatory diseases, including alcoholic hepatitis. Shedding of this molecule from cell surfaces results in a circulating form, soluble ICAM-1 (sICAM-1). In this work, the serum and ascitic concentrations of sICAM-1 were studied in relation to clinical and laboratory data in patients with alcoholic liver cirrhosis of different disease activities. Elevated circulating concentrations of this adhesion molecule were found in all cirrhotic patients, the highest in those with superimposed severe alcoholic hepatitis, and the levels in regularly drinking cirrhotics without severe alcoholic hepatitis were likewise significantly higher than in those who had stopped drinking. The serum sICAM-1 concentration was best related to the serum AST activity, and also exhibited significant correlations with the prothrombin activity, serum bilirubin, albumin, peripheral leukocyte count. Maddrey's discriminant function value, Child grading, and antecedent alcohol consumption. Multivariate regression analysis revealed that the serum AST and prothrombin activities were independent predictors of the circulating sICAM-1 concentration. The concentration of sICAM-1 in the uninfected ascitic fluid of cirrthotics was about seven times lower than that in the serum; the ratio of its ascitic and serum levels was lower than that of the ascitic and serum total protein concentrations. These data contradict a significant intraperitoneal production of the molecule. It is concluded that the serum sICAM-1 level may be useful as a marker for the current disease activity (the severity of underlying acute necroinflammatory reactions) in alcoholic liver cirrhosis.
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PMID:Serum and ascitic levels of soluble intercellular adhesion molecule-1 in patients with alcoholic liver cirrhosis: relation to biochemical markers of disease activity and alcohol intake. 886 70

beta-1,4-galactosyltransferase 1 (beta1,4-GT 1) is localized both in the Golgi complex where it catalyzes the transfer of galactose from UDP-galactose to terminal N-acetylglucosamine forming Galbeta1 --> 4GlcNAc structure, and on the cell surface where it serves as an adhesion molecule. It has previously been reported that the expression of beta1,4-GT 1 was cell-cycle-specific, regulated by cell growth. Transforming growth factor-beta1 (TGF-beta1) could regulate cell G1/S phase transition and modulate cell growth in many types of cells. In this study, we introduced the antisense-TGF-beta1 into SMMC-7721 cell, a human hepatocarcinoma cell line, for blocking its intrinsic TGF-beta1 expression, and changing its cell-cycle, and then analyzed the gene expression of beta1,4-GT 1 together with the beta1,4-GT activity. The result showed that the antisense-TGF-beta1 transfected SMMC-7721 cells (AST/7721) were growth enhanced, with more cells in S phase and less cells in G2/M phase compared with the mock transfected cells (pcDNA3/7721). At the same time, it was found that the gene expression of beta1,4-GT 1 in AST/7721 was decreased to one fifth that of pcDNA3/7721, and the cell surface beta1,4-GT activity was reduced to one fifth of the control, while the total activity of beta1,4-GT was decreased to one half that of the control. The results indicate that suppression of TGF-beta1 expression resulted in change of cell-cycle together with the decreased gene expression of beta1,4-GT 1 and beta1,4-GT activity in human hepatocarcinoma cells.
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PMID:Effect of suppression of TGF-beta1 expression on cell-cycle and gene expression of beta-1,4-galactosyltransferase 1 in human hepatocarcinoma cells. 1089 33

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

Advanced glycation end products (AGEs) are senescent macroprotein derivatives that are formed at an accelerated rate in patients with chronic renal failure (CRF). AGE formation and accumulation in plasma and vascular tissues contribute to accelerated atherosclerosis in this devastating disorder. AST-120 is an oral adsorbent that attenuates the progression of CRF by removing uremic toxins. Recently, AST-120 has been reported to reduce the progression of atherosclerosis as well. However, whether AST-120 decreases serum levels of AGEs and subsequently exerts atheroprotective properties remains to be elucidated. Ten nondiabetic CRF patients were enrolled in this study. All patients were kept on regular therapeutic diet and medications throughout the study. Serum AGE levels before and after AST-120 treatments were measured using enzyme-linked immunosorbent assay. Effects of patient-derived serum on atherosclerosis-related gene expression in cultured human umbilical vein endothelial cells (HUVECs) were analyzed by semiquantitative RT-PCR. Administration of AST-120 (6 g/day) for 3 months significantly decreased serum levels of AGEs in nondiabetic CRF patients, whereas AGE levels remained unchanged in age- and renal function-matched CRF patients without AST-120 treatment (n = 6). Patient serum after AST-120 treatment significantly reduced mRNA levels of receptor for AGEs, monocyte chemoattractant protein-1, and vascular adhesion molecule-1 in HUVECs compared with serum before treatment. Moreover, in vitro, AST-120 was found to adsorb carboxymethyllysine (CML), one of the well-characterized, digested food-derived AGEs. This study suggests that atheroprotective properties of AST-120 can be ascribed, at least in part, to its AGE-lowering ability via absorption of CML.
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PMID:Oral adsorbent AST-120 decreases serum levels of AGEs in patients with chronic renal failure. 1708 50

Several studies have investigated the role of neutrophils during endotoxin-mediated liver injury, yet the precise mechanism for endotoxin-mediated hepatic neutrophil transmigration is unknown. The primary objective of this study was to establish a reliable lipopolysaccharide (LPS)-mediated necro-hepatitis model to investigate the mechanisms of hepatic neutrophil infiltration following LPS administration. Male Sprague Dawley rats were administered a single (5 or 10 mg kg(-1), i.v.) or repeated injection of LPS (10 mg kg(-1), i.v., 24 h apart) with appropriate controls (i.v. saline) and were killed at various time points following LPS injection. Significant hematologic changes included neutrophilia, elevation of the neutrophil to lymphocyte ratio and toxic changes in neutrophils. Biochemical changes were observed in several liver (aspartate aminotransferase AST, gamma glutamyl transferase GGT) and kidney (blood urea nitrogen BUN) associated parameters generally at the earliest time points. Histopathology revealed a time-dependent neutrophil and mononuclear infiltration around the periportal areas in the single dose study and multifocal midzonal coagulative necrosis in the repeated dose study. The neutrophil adhesion molecule, CD 11b was up-regulated in single and repeat dose studies. Based on these studies, a reliable LPS-mediated hepatitis model with necrosis was developed by intravenous administration of LPS in a repeat dose fashion. Midzonal hepatic necrosis, peripheral neutrophilia, hepatic neutrophil infiltration and up-regulation of CD11b were the most significant and consistent markers of LPS mediated effects in this model.
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PMID:Characterization of a lipopolysaccharide mediated neutrophilic hepatitis model in Sprague Dawley rats. 1737 Feb 40

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