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)

The liver-selective nitric oxide (NO) donor, O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P-450 enzymes to release NO in the liver, and is shown to protect the liver from tumor necrosis factor alpha (TNF-alpha)-induced apoptosis and D-glactosamine/endotoxin-induced hepatotoxicity. This study was undertaken to examine the effects of V-PYRRO/NO on acetaminophen-induced hepatotoxicity in mice. Mice were given V-PYRRO/NO via osmotic pumps (1.8-5.4 mg/mL, 8 microL/h) 4 to 16 hours before a hepatotoxic dose of acetaminophen (600 mg/kg, intraperitoneally [ip]). V-PYRRO/NO administration dramatically reduced acetaminophen-induced hepatotoxicity in a dose- and time-dependent manner, as evidenced by reduced serum alanine aminotransferase (ALT) activity, reduced hepatic congestion, apoptosis, and improved hepatocellular pathology. The protection afforded by V-PYRRO/NO does not appear to be caused by a decrease in the formation of toxic acetaminophen metabolites, which consumes glutathione (GSH), because V-PYRRO/NO did not alter acetaminophen-induced hepatic GSH depletion. Acetaminophen-induced lipid peroxidation, as determined by the concentrations of 4-hydroxyalkenals (4-HNE) and malondialdehyde (MDA), was reduced significantly by V-PYRRO/NO treatment. Although pretreatment was most effective, administration of V-PYRRO/NO simultaneously with acetaminophen also was able to reduce acetaminophen hepatotoxicity. Genomic analysis of the liver samples 10 hours after acetaminophen intoxication showed the enhanced expression of genes associated with stress/oxidative stress, apoptosis/cell death, and DNA damage/repair. Acetaminophen-induced alterations in gene expression were attenuated significantly by V-PYRRO/NO. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western-blot analysis confirmed microarray results. In conclusion, V-PYRRO/NO is effective in blocking acetaminophen-induced hepatotoxicity in mice. This protection may involve the reduction of oxidative stress, the inhibition of apoptosis, and possibly the maintenance of hepatic vasculature to prevent congestion.
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PMID:The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. 1254 Jul 82

Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor alpha (TNF-alpha). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the intestine or inhibiting TNF-alpha improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-alpha activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet + VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-alpha messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNF-regulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor kappaB (NF-kappaB), the target of IKKbeta, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid beta-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions.
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PMID:Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. 1288 98

Vibrio vulnificus is the leading cause of death in the United States associated with the consumption of raw seafood, particularly oysters. In epidemiological studies, primary septicemia and inflammation-mediated septic shock caused by V. vulnificus is strongly associated with liver disease, often in the context of chronic alcohol abuse. The present study was undertaken to determine whether clinical biomarkers of liver function or cellular oxidative stress are associated with peripheral blood mononuclear cell inflammatory cytokine responses to V. vulnificus. Levels of interleukin-1 beta (IL-1 beta), IL-6, IL-8, and tumor necrosis factor alpha elicited in response to V. vulnificus and measured in cell supernatants were not associated with the liver biomarkers aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or the AST/ALT ratio. In contrast, reduced glutathione (GSH) levels were associated with the release of all four cytokines (IL-1 beta [R(2) = 0.382; P = 0.006], IL-6 [R(2) = 0.393; P = 0.005], IL-8 [R(2) = 0.487; P = 0.001], and TNF-alpha [R(2) = 0.292; P = 0.021]). Those individuals with below-normal GSH levels produced significantly less proinflammatory cytokines in response to V. vulnificus. We hypothesize that persons with markers for cellular oxidative stress have increased susceptibility to V. vulnificus septicemia.
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PMID:Inflammatory cytokine response to Vibrio vulnificus elicited by peripheral blood mononuclear cells from chronic alcohol users is associated with biomarkers of cellular oxidative stress. 1281 21

Mercury is a well-recognized health hazard and an environmental contaminant. Mercury modulates immune responses ranging from immune suppression to autoimmunity but the mechanisms responsible for these effects are still unclear. Male BALB/c mice were exposed continuously to 0, 0.3, 1.5, 7.5, or 37.5 ppm mercury in drinking water for 14 days. Body weight was reduced at the highest dose of mercury whereas the relative kidney and spleen weights were significantly increased. The dose range of mercury used did not cause hepatotoxicity as indicated by circulating alanine aminotransferase and aspartate aminotransferase levels. Circulating blood leukocytes were elevated in mice treated with the highest dose of mercury. Mercury ranging from 1.5 to 37.5 ppm dose-dependently decreased CD3(+) T lymphocytes in spleen; both CD4(+) and CD8(+) single-positive lymphocyte populations were decreased. Exposure to 7.5 and 37.5 ppm mercury decreased the CD8(+) T lymphocyte population in the thymus, whereas double-positive CD4(+)/CD8(+) and CD4(+) thymocytes were not altered. Mercury altered the expression of inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, and interleukin-12), c-myc, and major histocompatibility complex II, in various organs. Results indicated that a decrease in T lymphocyte populations in immune organs and altered cytokine gene expression may contribute to the immunotoxic effects of inorganic mercury.
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PMID:Oral exposure to inorganic mercury alters T lymphocyte phenotypes and cytokine expression in BALB/c mice. 1292 68

The pathogenesis of liver cell injury during chronic hepatitis C (CHC) is poorly understood. The cellular immune response is thought to play a key role in both inhibition of viral replication and liver pathology. However, little is currently known about which lymphocyte populations and which immune effectors contribute to or control liver damage. We investigated a panel of 15 phenotypic and functional markers of intrahepatic T-lymphocyte subsets irrespective of their antigen specificity in 48 hepatitis C virus (HCV)-infected patients and 8 healthy control subjects. Lymphocyte characteristics were evaluated from liver biopsy specimens both at gene expression level by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and by immunochemistry, in relation with the degree of liver injury and with intrahepatic HCV-RNA levels. As compared with controls, we found major changes in T-lymphocyte subsets in HCV-infected patients, with a significant decrease of T-cell antigen receptor (TCR) delta and CD56 gene expression, associated with a concomitant increase of TCRalpha and CD8beta that were correlated with cytotoxic factors, proinflammatory chemokines, and chemokine receptors including peforin, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), RANTES, and CXCR3. The gene expression of CD8beta, a specific marker for conventional TCRalpha+CD8+ lymphocytes, was correlated by multivariate analysis with both alanine aminotransferase (ALT) serum levels and histologic activity index. Furthermore, CD8 staining was observed by immunochemistry in the areas of lobular and piecemeal necrosis. In contrast, no lymphocyte marker was correlated with viral load, measured both in serum and in liver. In conclusion, these results strongly suggest key roles for CD8+ T cells as effectors of liver damage during chronic HCV infection and for their inability to control viral replication.
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PMID:Phenotypic and functional characterization of intrahepatic T lymphocytes during chronic hepatitis C. 1451 70

Although we have previously demonstrated that IL-12 stimulation increases the number of hepatic natural killer (NK) T (NKT) cells and enhances liver injury during the early phase of liver regeneration, the role of NKT cells has remained unknown. We therefore evaluated the influence of NKT cells activated by IL-12 or by alpha-galactosylceramide (alpha-GalCer) on murine liver regeneration using Valpha 14 NKT knockout (Jalpha 281(-/-)) mice. Levels of serum alanine aminotransferase (sALT) 24 hours after partial hepatectomy were enhanced in Jalpha 281(+/+) but not in Jalpha 281(-/-) mice by both procedures. Hepatic NKT cells expressed considerably more interferon (IFN) gamma and tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) after stimulation with both factors in Jalpha 281(+/+) mice. Either anti-IFN-gamma or TNF-alpha antibody inhibited the enhancement of liver injury. Furthermore, recombinant TNF-alpha injection similarly caused injury in hepatectomized livers of both Jalpha 281(+/+) and Jalpha 281(-/-) mice; indeed, adoptively transferred TNF-alpha(+/+) NKT cells enhanced liver injury after hepatectomy in TNF-alpha knockout mice. TNF receptor expressions on hepatocytes increased and peaked 24 hours after partial hepatectomy. In conclusion, simultaneous TNF-alpha synthesis and high levels of TNF receptor expression on hepatocytes cause severe liver damage by activated NKT cells during liver regeneration.
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PMID:Role of Valpha 14 NKT cells in the development of impaired liver regeneration in vivo. 1457 50

BACKGROUND/AIM: Concanavalin A (Con A) activates T cells and causes T cell-mediated liver injury in mice. Since autoimmune diseases predominantly occur in women, female is considered to have enhanced immune responses and T cell functions. We investigated the presence of gender-related differences on Con A-induced liver injury and cytokine production in mice. METHODS: Male and female BALB/c mice were given Con A (15mg/kg) intravenously at 7 weeks of age. Plasma alanine aminotransferase (ALT), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin (IL)-4 and IL-10 levels were determined 0, 2, 4, 6, 8 and 24h after Con A administration. To investigate the effects of sex hormones on liver injury and cytokine production, female and male mice were castrated at 3 weeks of age and were administered Con A 4 weeks after the operation. RESULTS: Plasma ALT level of females was significantly higher at 8 and 24h after Con A administration than those of males. Plasma levels of TNF-alpha and IFN-gamma at 2, 4, 6 and 8h, IL-4 at 2h, but not IL-10, after Con A administration were significantly elevated in females than those of males. Furthermore, the elevated plasma ALT, TNF-alpha and IFN-gamma levels decreased significantly by an ovariectomy. In contrast, those markers were exacerbated by an orchiectomy compared with sham operation. CONCLUSION: These findings indicate that Con A induces more severe liver injury in female mice than in male mice, and suggest that the effect of sex hormones on cytokine production may play a role in gender-related difference on Con A-induced liver injury.
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PMID:Gender-related differences in concanavalin A-induced liver injury and cytokine production in mice. 1458 99

Although thromboxanes (TXs), whose synthesis is regulated by cyclooxygenase (COX), have been suggested to promote inflammation in the liver, little is known about the role of TXA(2) in leukocyte endothelial interaction during endotoxemia. The present study was conducted to investigate the role of TXA(2) as well as that of COX in lipopolysaccharide (LPS)-induced hepatic microcirculatory dysfunction in male C57Bl/6 mice. We observed during in vivo fluorescence microscopic study that LPS caused significant accumulation of leukocytes adhering to the hepatic microvessels and non-perfused sinusoids. Levels of serum alanine transaminase (ALT) and tumor necrosis factor alpha (TNF alpha) also increased. LPS raised the TXB(2) level in the perfusate from isolated perfused liver. A TXA(2) synthase inhibitor, OKY-046, and a TXA(2) receptor antagonist, S-1452, reduced LPS-induced hepatic microcirculatory dysfunction by inhibiting TNF alpha production. OKY-046 suppressed the expression of an intercellular adhesion molecule (ICAM)-1 in an LPS-treated liver. In thromboxane prostanoid receptor-knockout mice, hepatic responses to LPS were minimized in comparison with those in their wild-type counterparts. In addition, a selective COX-1 inhibitor, SC-560, a selective COX-2 inhibitor, NS-398, and indomethacin significantly attenuated hepatic responses to LPS including microcirculatory dysfunction and release of ALT and TNF alpha. The effects of the COX inhibitors on hepatic responses to LPS exhibited results similar to those obtained with TXA(2) synthase inhibitor, and TXA(2) receptor antagonist. In conclusion, these results suggest that TXA(2) is involved in LPS-induced hepatic microcirculatory dysfunction partly through the release of TNF alpha, and that TXA(2) derived from COX-1 and COX-2 could be responsible for the microcirculatory dysfunction during endotoxemia.
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PMID:Role of thromboxane derived from COX-1 and -2 in hepatic microcirculatory dysfunction during endotoxemia in mice. 1475 32

Several studies have implicated a role of peptidoglycan (PepG) as a pathogenicity factor in sepsis and organ injury, in part by initiating the release of inflammatory mediators. We wanted to elucidate the structural requirements of PepG to trigger inflammatory responses and organ injury. Injection of native PepG into anesthetized rats caused moderate but significant increases in the levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and bilirubin (markers of hepatic injury and/or dysfunction) and creatinine and urea (markers of renal dysfunction) in serum, whereas PepG pretreated with muramidase to digest the glycan backbone failed to do this. In an ex vivo model of human blood, PepG containing different amino acids induced similar levels of the cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-8, and IL-10, as determined by plasma analyses (enzyme-linked immunosorbent assay). Hydrolysis of the Staphylococcus aureus cross-bridge with lysostaphin resulted in moderately reduced release of TNF-alpha, IL-6, IL-8, and IL-10, whereas muramidase digestion nearly abolished the ability to induce cytokine release and IL-6 mRNA accumulation in CD14(+) monocytes compared to intact PepG. However, additional experiments showed that muramidase-treated PepG synergized with lipopolysaccharide to induce TNF-alpha and IL-10 release in whole blood, despite its lack of inflammatory activity when administered alone. Based on these studies, we hypothesize that the structural integrity of the glycan chain of the PepG molecule is very important for the pathogenic effects of PepG. The amino acid composition of PepG, however, does not seem to be essential for the inflammatory properties of the molecule.
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PMID:Organ injury and cytokine release caused by peptidoglycan are dependent on the structural integrity of the glycan chain. 1497 33

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium verticillioides found on corn and corn-based foods. It causes equine leukoencephalomalacia, porcine pulmonary edema, and liver and kidney damage in most animal species. Fumonisin B(1) perturbs sphingolipid metabolism by inhibiting ceramide synthase activity, leading to the production of cell signaling factors including tumor necrosis factor alpha (TNF-alpha). The signal pathways of TNF-alpha are important factors in the pathogenesis of FB(1) hepatotoxicity. In the present study, female BALB/c mice were treated daily with 750 mg/kg silymarin by gavage and 2.25 mg/kg FB(1) subcutaneously for 3 days. Then, 1 day after the last FB(1) injection, the mice were euthanized and blood and tissues were sampled for analyses. Silymarin significantly diminished FB(1)-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase activities and the number of apoptotic hepatocytes, while it augmented hepatocyte proliferation indicated by an increase in proliferating cells. Silymarin dramatically potentiated FB(1)-induced accumulation of free sphinganine and sphingosine in both liver and kidney. Silymarin itself slightly increased expression of hepatic TNF-alpha; however, it prevented the FB(1)-induced increases in TNF-alpha, TNF receptor 1, TNF receptor-associated apoptosis-inducing ligand, lymphotoxin beta, and interferon gamma. The induction of transforming growth factor beta1 expression in liver following FB(1) treatment was not affected by silymarin. These findings suggest that silymarin protected against FB(1) liver damage by inhibiting biological functions of free sphingoid bases and increasing cellular regeneration.
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PMID:Silymarin protects against liver damage in BALB/c mice exposed to fumonisin B1 despite increasing accumulation of free sphingoid bases. 1510 51


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