Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin, an adipocytokine, has been identified in adipose tissue, and its receptors are widely distributed in many tissues, including the liver. The present study was performed to clarify the role of adiponectin in lipopolysaccharide (LPS)-induced liver injury using KK-Ay obese mice. We analyzed the effects of adiponectin pretreatment on liver injury induced by D-galactosamine/LPS (GalN/LPS) in KK-Ay obese mice. GalN/LPS treatment induced significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood, apoptotic and necrotic changes in hepatocytes, and/or showed a high degree of lethality. The GalN/LPS-induced liver injury was more pronounced in KK-Ay obese mice than in lean controls. Pretreatment with adiponectin ameliorated the GalN/LPS-induced elevation of serum AST and ALT levels and the apoptotic and necrotic changes in hepatocytes, resulting in a reduction in lethality. In addition, pretreatment with adiponectin attenuated the GalN/LPS-induced increases in serum and hepatic tumor necrosis factor alpha (TNF-alpha) levels and increased peroxisome proliferator-activated receptor (PPAR) alpha messenger RNA expression in the liver. Furthermore, abdominal macrophages from KK-Ay obese mice pretreated with adiponectin in vitro exhibited decreased LPS-induced TNF-alpha production compared with controls. Finally, adiponectin pretreatment also ameliorated TNF-alpha-induced liver injury. In conclusion, these findings suggest that adiponectin prevents LPS-induced hepatic injury by inhibiting the synthesis and/or release of TNF-alpha of KK-Ay obese mice.
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PMID:Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. 1523 81

Mercury is a widespread metal in the environment and consequently large populations are currently exposed to low levels of mercury. Endotoxin, a component of the Gram-negative bacteria, promotes inflammatory responses. We recently reported that mercury modulates the production of nitric oxide and various inflammatory cytokines induced by endotoxin in a macrophage cell line (Nitric Oxide 2002, 7:67). The present study was designed to determine the impact of mercury on endotoxin-induced inflammatory cytokine expression and corresponding signal transduction in mouse liver. Male BALB/c mice were exposed continuously to 0, 0.3, 1.5, 7.5, or 37.5 ppm of mercury in drinking water for 14 days and at the end of the treatment period lipopolysaccharide (LPS, 0.5 mg/kg) was injected intraperitoneally 2 hr prior to euthanasia. The doses of mercury and LPS did not cause hepatotoxicity as indicated by unaltered circulating alanine aminotransferase and aspartate aminotransferase levels. Mercury decreased liver glutathione (GSH) and with LPS additively decreased GSH. Mercury activated p38 mitogen-activated protein kinase (MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. In contrast, mercury alone had no effect on activation of extracellular signal-regulated kinase (ERK) but inhibited LPS-induced ERK activation. Mercury increased the expression of tumor necrosis factor alpha (TNFalpha) and further potentiated LPS-induced TNFalpha expression. Mercury did not affect LPS-induced interleukin (IL)-1beta expression but decreased LPS-induced IL-6 expression. Results indicated that low levels of mercury augment LPS-induced TNFalpha expression by altering GSH and p38 MAPK. Mercury modulates LPS-induced p38 and ERK activation and downstream TNFalpha and IL-6 expression in mouse liver.
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PMID:Mercury alters endotoxin-induced inflammatory cytokine expression in liver: differential roles of p38 and extracellular signal-regulated mitogen-activated protein kinases. 1580 65

Diphenyl dimethyl bicarboxylate (DDB) is a hepatoprotectant and used in the treatment of chronic viral hepatitis patients in China. The aim of the present paper was to investigate the effect of DDB on liver injury mediated by immune response in concanavalin A (Con A)-treated mice. A dose of Con A 30 mg/kg was injected via the tailvein to induce liver injury in mice. Serum alanine transaminase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), total bilirubin (TBIL) and tumor necrosis factor alpha (TNF-alpha) level as well as liver TNF-alpha mRNA expression were determined. The following results were obtained: (1) Prior oral administration of DDB 150 mg/kg markedly reduced the elevated serum ALT, TBA and TBIL levels, and the liver lesions in Con A-treated mice; (2) DDB significantly inhibited the elevation of serum TNF-alpha and liver TNF-alpha mRNA expression 2 h after Con A injection; (3) DDB significantly inhibited hepatocyte nuclear DNA fragmentation 12 h after Con A injection; (4) DDB dose-dependently prevented the direct DNA damage induced by CuSO(4)-Phen-Vit C-H(2)O(2) system in vitro, and the ex vivo experiment also showed that the administration of DDB reduced the susceptibility of mouse liver nuclei DNA to CuSO(4)-Phen-Vit C-H(2)O(2) system. These results suggest that DDB could directly protect hepatocyte DNA from oxidative damage, and inhibit TNF-alpha mRNA expression in liver tissue, which resulted in prevention of liver damage induced by Con A in mice.
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PMID:Effect of diphenyl dimethyl bicarboxylate on concanavalin A-induced liver injury in mice. 1599 43

Relevant mechanisms of reperfusion injury after liver transplantation are most likely mediated by activated Kupffer cells. Recently, it has been demonstrated that taurine prevents Kupffer cell-activation in vitro. Thus, this study was designed to assess the effects of taurine after liver transplantation. Female Sprague-Dawley rats (210-240 g) were infused with taurine dissolved in normal saline, before organ harvest. Controls were infused with the same volume of normal saline without taurine. Following 4 hours of cold ischemia, liver transplantation was performed. Graft and animal survival, serum transaminases, liver histology, perfusion data of intravital microscopy, blood distribution at reperfusion, and both phagocytosis of Kupffer cells and expression of tumor necrosis factor alpha (TNF-alpha) to index cellular activation were investigated. For comparison, both, analysis of variance (ANOVA) and Fisher's exact test were used as appropriate. Results are presented as mean +/- SEM. Controls survived in 60% of cases. Taurine improved survival in a dose-dependent manner to 100% (P < 0.05). In controls, mean aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactic dehydrogenase (LDH) serum levels increased to 3,260 +/- 814; 1,703 +/- 432; and 14,071 +/- 3,177 U/L, respectively, after transplantation. In contrast, these values were between 20 and 45% of control values after taurine (P < 0.05). Histology taken after transplantation confirmed the significant protective effects of taurine, including the reduction of TNF-alpha expression. Time until homogeneous reperfusion of the graft improved to 50% of control values (P < 0.05). Further, taurine significantly decreased both phagocytosis of latex beads by Kupffer cells and leukocyte-endothelial cell interaction. In parallel, flow velocity of red blood cells as well as acinar and sinusoidal perfusion improved (P < 0.05). In conclusion, these data show for the first time in vivo that taurine minimizes reperfusion injury after liver transplantation. Decreased leukocyte-endothelial cell interaction and improved microcirculation are the proposed mechanisms, which are most likely Kupffer cell-dependent.
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PMID:Taurine improves graft survival after experimental liver transplantation. 1603 74

Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides, commonly present in corn and other cereals. Exposure to FB1 causes organ-specific diseases in various species, e.g., equine leukoencephalomalacia and porcine pulmonary edema; in mice the response is hepatotoxicity. We earlier reported that ceramide synthase inhibition by FB1, the initial biochemical effect of this mycotoxin, results in modulation of cytokine network in response to accumulated free sphingoid bases. In the current study we used NZB/NZW-F1 (NZBW) mice that have modified cytokine expression and develop lupus beginning at 5 months of age. The NZBW and C57BL/6J (CBL) mice (appropriate control) were given five daily subcutaneous injections of either saline or 2.25 mg FB1/kg/day and euthanized 24 h after the last treatment. Peripheral leukocyte counts were higher after exposure to FB1 in CBL but not in NZBW. FB1 treatment caused increases of plasma alanine aminotransferase and aspartate aminotransferase activity in CBL mice indicating hepatotoxicity; no elevation of circulating liver enzymes was recorded in NZBW mice. Hepatotoxic responses were confirmed by microscopic evaluation of apoptotic cells. The FB1-induced proliferation of cells observed in CBL strain was abolished in NZBW animals. The sphinganine accumulation in liver after FB1 was equal in both strains of mice. The NZBW strain lacked the FB1-induced increases in the expression of liver tumor necrosis factor alpha, interferon gamma, receptor interacting protein (RIP), and tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL), observed in CBL. Results confirmed our hypothesis that initial altered sphingolipid metabolism caused by FB1 leads to perturbation of liver cytokine network and ultimate cellular injury; the mice deficient in cytokine signaling are refractory to FB1 hepatotoxicity.
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PMID:Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine. 1615 91

To clarify the laboratory characteristics and deduce the pathogenesis of acute encephalopathy associated with multiple organ dysfunctions in Japan. We measured cytokine levels [tumor necrosis factor alpha (TNF-alpha), soluble tumor necrosis factor-receptor 1 (sTNF-R1), and interleukin-6 (IL-6)] in serum and cerebrospinal fluid (CSF) as well as general laboratory examinations in 27 patients with acute encephalopathy. Urea nitrogen (UN), creatinine (Cr), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and C-reactive protein (CRP) levels in blood, and CSF protein levels at the initial stage were significantly higher in patients with an unfavorable outcome. TNF-alpha, sTNF-R1, and IL-6 levels at the initial stage were higher in the serum than in the CSF of patients with acute encephalopathy. Serum cytokine levels correlated well with patient outcome. The high CSF protein level and the high UN, Cr, AST, LDH, and CRP levels in the blood represent the severity of vascular leakage through the blood-brain barrier and multiple organ dysfunctions, respectively, and thus suggest an unfavorable prognosis. The high serum inflammatory cytokine levels at the initial stage and the good correlation of those levels with the outcome suggest that intravascular inflammation has a significant role in vascular leakage and multiple organ dysfunctions in acute encephalopathy.
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PMID:Laboratory characteristics of acute encephalopathy with multiple organ dysfunctions. 1619 4

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

Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically involved in degradation of extracellular matrix, and their inhibition is discussed as a promising strategy against hepatic ischemia-reperfusion (I/R) injury. Here, we analyzed the role of MMP-2 and -9 for leukocyte migration and tissue injury in sham-operated mice and in mice after I/R, treated with a MMP-2/9 inhibitor or vehicle. Using zymography, we show that the MMP-2/9 inhibitor abolished I/R-induced MMP-9 activation, whereas MMP-2 activity was not detectable in all groups. As demonstrated by intravital microscopy, MMP-9 inhibition attenuated postischemic rolling and adherence of total leukocytes in hepatic postsinusoidal venules, CD4+ T cell accumulation in sinusoids, and neutrophil transmigration. These effects were associated with reduction of plasma tumor necrosis factor alpha (TNF-alpha) levels and endothelial expression of CD62P. Motility of interstitially migrating leukocytes was assessed by near-infrared reflected light oblique transillumination microscopy in the postischemic cremaster muscle. Upon MMP-9 blockade, leukocyte migration velocity and curve-line and straight-line migration distances were reduced significantly as compared with the vehicle-treated I/R group. Postischemic sinusoidal perfusion failure, hepatocellular apoptosis, and alanine aminotransferase activity were only slightly reduced after MMP-9 inhibition, whereas aspartate aminotransferase activity and mortality were significantly lower. In conclusion, MMP-9 is involved in the early recruitment cascades of neutrophils and CD4+ T cells, promotes neutrophil and T cell transmigration during hepatic I/R, and is required for motility of interstitially migrating leukocytes. MMP-9 blockade is associated with an attenuation of TNF-alpha release and endothelial CD62P expression, weakly protects from early microvascular/hepatocellular I/R damage, but improves postischemic survival.
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PMID:Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver. 1655 80

Hepatic injury secondary to warm ischemia-reperfusion (I/R) injury and alterations in haemostatic parameters are often unavoidable events after major hepatic resection. The release of inflammatory mediator is believed to play a significant role in the genesis of these events. It has been suggested that preoperative steroid administration may reduce I/R injury and improve several aspects of the surgical stress response. The aim of this prospective randomized study was to investigate the clinical benefits on I/R injury and systemic responses of preoperatively administered corticosteroids. Seventy-six patients undergoing liver resection were randomized either to a steroid group or to a control group. Patients in the steroid group received preoperatively 500 mg of methylprednisolone. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, coagulation parameters, and inflammatory mediators, interleukin 6 and tumor necrosis factor alpha were compared between the 2 groups. Length of stay, and type and number of complications were recorded as well. Postoperative serum levels of ALT, AST, total bilirubin, and inflammatory cytokines were significantly lower in the steroid than in the control group at postoperative days 1 and 2. Changes in hemostatic parameters were also significantly attenuated in the steroid group. In conclusion, the incidence of postoperative complications in the steroid group tended to be significantly lower than the control group. It is of clinical interest that preoperative steroids administration before major surgery may reduce I/R injury, maintain coagulant/anticoagulant homeostasis, and reduce postoperative complications by modulating the inflammatory response.
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PMID:Impact of preoperative steroids administration on ischemia-reperfusion injury and systemic responses in liver surgery: a prospective randomized study. 1671 Aug 58

Steatohepatitis enhances the severity of liver injury caused by acute inflammation. The purpose of this study was to test the hypothesis that fatty liver due to chronic choline-deficient diet exacerbates concanavalin A (ConA)-induced liver hepatitis, which is predominantly facilitated by T cells. Male C57BL/6 mice were fed either control choline-sufficient diet (CSD) or choline-deficient diet (CDD) for 6 weeks before ConA administration. Mice were sacrificed 3, 9, and 24 hours after ConA injection. Liver injury measured by aspartate aminotransferase (AST), alanine aminotransferase (ALT), pathology, and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining was minimal in mice fed either diet before ConA exposure. However, ConA-induced liver injury was significantly greater in CDD-fed mice compared with control-fed mice. Liver cytokines were assessed by quantitative real-time polymerase chain reaction (PCR). The expression of T helper (Th) 1 cytokines tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), and interferon gamma (IFN-gamma) were dramatically elevated after ConA in CDD-fed mice compared with control-fed mice. CDD also enhanced ConA-induced STAT4 activation, but not STAT6. Notably, regulators of T-cell differentiation were strongly shifted toward a predominant Th1 profile. T-bet, regulator of the Th1 response, was up-regulated in CDD-fed mice, whereas Th2 regulator GATA-3 was significantly suppressed in CDD-fed mice after ConA. Moreover, the expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3, and repressor of GATA-3 (ROG) favored a predominant Th1 cytokine response in CDD-fed mice. In conclusion, these data support the hypothesis that hepatosteatosis caused by CDD is associated with more severe ConA-induced hepatitis due to a predominant shift toward Th1 response.
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PMID:Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis. 1679 67


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