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

Prolonged liver ischemia followed by reperfusion (I/R) causes functional and structural damage to liver cells, resulting in necrosis and apoptosis. c-jun N-terminal kinase 1/stress-activated protein kinase 1 (JNK(1)/SAPK(1)) is activated during I/R and participates in the onset of the apoptosis program. Excessive blood loss during surgery can hinder postoperative recovery. Intermittent portal triad clamping (PTC) is better tolerated than prolonged continuous ischemia. This study was designed to demonstrate that intermittent ischemia could improve postischemic survival rates by a decrease of JNK(1)/SAPK(1) and caspase 3 activation, which were involved in the apoptosis process. Rats were subjected to intermittent 1-hour ischemia (15-minute ischemia/5-minute reperfusion, 4 times), followed by 220-minute reperfusion, or to continuous ischemia (1 hour), followed by 240-minute reperfusion. Mortality rates were assessed on day 7. Serum aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase levels (LDH) were measured 6 hours after ischemia. This study was completed in primary cultured isolated rat hepatocytes, subjected to the same continuous or intermittent hypoxic conditions. The activation status of JNK(1)/SAPK(1) was evaluated by immunoprecipitation or Western blotting experiments. Apoptosis was assessed by measuring caspase activation and by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) reaction. Eighty percent of the intermittent-ischemia group was alive 7 days after surgery and serum enzyme levels were significantly decreased. Intermittent hypoxia or ischemia did not lead to JNK(1)/SAPK(1) activation, but at least 3 hypoxia-reoxygenation (H/R) sets were necessary to inhibit kinase activation. Consequently, caspase 3 activation and apoptosis were dramatically reduced. Intermittent ischemia is a powerful, protective way to reduce I/R damage of the liver, by reduction of JNK(1)/SAPK(1) activation associated with a down-regulation of caspase 3 activity, which leads to inhibition of hepatocyte apoptosis.
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PMID:Intermittent ischemia reduces warm hypoxia-reoxygenation-induced JNK(1)/SAPK(1) activation and apoptosis in rat hepatocytes. 1167 68

Previous studies showed that Pien Tze Huang, a Chinese folk medicine well known for its therapeutic activity in treating liver diseases, protected the liver against carbon tetrachloride (CCl4)-induced damage in mice. In the present study, natural musk, one of the important ingredients of Pien Tze Huang, was replaced by a formulated substitute, and the new formulation of Pien Tze Huang was shown to have similar chromatographic patterns to the original Pien Tze Huang in gas chromatography-mass spectrometry and high performance liquid chromatography. When used in treating mice with CCl4- or galactosamine-induced liver damage, both the original and new formulations of Pien Tze Huang were found to be able to suppress to a similar extent both the histopathological changes in the liver and the elevation of serum alanine aminotransferase and aspartate aminotransferase. Necrosis, cellular ballooning, microvesicular steatosis and lymphocytes infiltration were all significantly reduced in the damaged liver. In hepatoma cells, both formulations activated the activator protein 1 (AP1) enhancer sequence, indicating that both of them were able to act through the JNK signal transduction pathway. The results of the present study showed that the substitution for natural musk does not affect the hepatoprotective activities of Pien Tze Huang. It is also postulated that both formulations protect the liver through regulating signal transduction in the cell.
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PMID:Substitution for natural musk in Pien Tze Huang does not affect its hepatoprotective activities. 1502 14

Liver injury is an important prognostic indicator during acute pancreatitis. The aim of this study was to determine the role of Fas ligand (FasL) in hepatocyte injury. Liver parenchymal enzymes were measured in cocultures of hepatocytes and Kupffer cells treated with elastase. FasL and FasL mRNA were measured in elastase-treated Kupffer cells. Hepatocytes were treated with FasL and their viability was assessed by monotetrazolium (MTT), apoptosis by flow cytometry, as well as caspase-3 and p38-mitogen-activated protein kinase (MAPK) by immunoblotting. Elastase increased aspartate aminotransferase and lactate dehydrogenase in cocultures of hepatocyte and Kupffer cells (P<0.040). Elastase increased FasL production from Kupffer cells (P=0.02) and upregulated FasL mRNA (FasL/beta-2 microglobulin (BMG): 0.23+/-0.03 vs. 0.11+/-0.003; P=0.04). FasL increased alanine aminotransferase and lactate dehydrogenase (P<0.03) and reduced hepatocyte viability by 45% (P=0.01). FasL increased the number of dually labeled cells with AnnexinV/7AAD (P=0.03) while upregulating cleavage of caspase-3 and the phosphorylation of p38-MAPK. FasL antibody attenuated the FasL-related increase in dually labeled cells (P=0.02), the cleavage of caspase-3, and phosphorylation of p38-MAPK. Pancreatic elastase upregulates FasL within Kupffer cells. FasL induces hepatocyte injury and death and upregulates p38-MAPK and caspase-3 within hepatocytes. The ability to manipulate interactions between Kupffer cells and hepatocytes may have important therapeutic implications.
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PMID:Kupffer cell-derived Fas ligand plays a role in liver injury and hepatocyte death. 1503 92

Vinclozolin and procymidone are antiandrogens that are thought to share a common androgen receptor (AR) mediated mechanism of action. This assessment is based primarily on morphological, AR binding, and in vitro transcriptional activation studies. Studies designed to evaluate the gene expression profiles induced by these compounds have the potential to provide further information to test this hypothesis. We have used targeted gene arrays to examine gene expression in the ventral prostate (VP) of 100-day old Sprague Dawley male rats exposed to either vinclozolin or procymidone. Animals were castrated and administered silastic implants with or without testosterone. A subset of testosterone treated animals was then dosed with 200 mg/kg of either fungicide in corn oil. Four treatment groups were used: castrated (C), testosterone (T), testosterone+vinclozolin (V), and testosterone+procymidone (P). Tissue from the VP was collected from six animals per group (3 animals per block x 2 blocks) at 20 h and at 4 days after the start of treatment. Total RNA was then isolated and gene expression analyzed using Clontech Atlas Rat 1.2 Toxicology arrays. When compared to group T, similar changes in gene expression were observed in groups C, P and V at both the 20 h and 4 day time points. After 20 h of treatment, 20 genes were similarly affected across these three treatment groups. Down-regulated genes included various molecular chaperones, the 11-kDa diazepam binding inhibitor, cyclin D1, and mitochondrial aspartate aminotransferase. Genes such as the androgen receptor, PTEN, and ERK2 were up-regulated. Three of the down-regulated genes, GRP78 (BiP), Dad1, and mitochondrial aspartate aminotransferase have been previously shown to be directly androgen regulated. Fifty-four genes were affected at 20 h, whereas, 311 genes were altered 4 days after the start of treatment. These observations, in part, may reflect regression of the VP at the later time point. These results support the hypothesis that procymidone and vinclozolin share a common mechanism or mode of action, a critical step in a cumulative risk assessment.
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PMID:Gene expression analysis in the ventral prostate of rats exposed to vinclozolin or procymidone. 1568 71

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

Lead (Pb) increases lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), lipid peroxidation (LPO), and liver damage. In this study, we investigated the role of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (MAPK) and the causal relationships between TNF-alpha, NO, and LPO in Pb-increased LPS-induced liver damage in rats. Treatment with PKC and p42/44 MAPK inhibitors significantly reduced Pb + LPS-induced NO, TNF-alpha, LPO, and liver damage, which was revealed by elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Pb + LPS coexposure significantly increased phosphorylation of p42/44 MAPK and TNF-alpha expression in peripheral blood cells; however, exposure to Pb + LPS did not induce TNF-alpha, NO, or LPO production and p42/44 MAPK activation in the liver. Pentoxifylline, a TNF-alpha inhibitor, also reduced liver damage but did not alter NO or LPO in Pb + LPS-treated rats. Thus, Pb increased LPS-induced liver damage through PKC and p42/44 MAPK modulation of TNF-alpha and oxidative stress, but modulation of TNF-alpha did not affect NO or LPO in rats.
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PMID:Modulation of tumor necrosis factor-alpha and oxidative stress through protein kinase C and P42/44 mitogen-activated protein kinase in lead increases lipopolysaccharide-induced liver damage in rats. 1604 92

Carbon tetrachloride (CCl(4): 4 ml/kg body weight as a 1:1 mixture of CCl(4) and mineral oil) was orally administered to rats. After 12 h the activity of plasma AST (aspartate aminotransferase) and ALT (alanine aminotransferase) was significantly higher than that of the control group and plasma AST and ALT activities increased thereafter. These results indicated that the necrotic process was active at about 12 h and developed thereafter. After 2-24 h of CCl(4) administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced as early as 2 h after CCl(4) intoxication and thereafter. Phosphorylated JNK (c-Jun NH(2)-terminal kinase) and phospho-ERK1/2 (extracellular signal-regulated kinase1/2) were significantly increased transiently 1-3 h after treatment with CCl(4), while phosphorylated p38 decreased significantly 1-24 h after CCl(4) treatment. These results indicated that the change in MAPKs (mitogen activated protein kinases) slightly preceded that in vitamin C, the most sensitive chemical indicator of oxidative stress.
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PMID:Activation of mitogen activated protein kinase (MAPK) during carbon tetrachloride intoxication in the rat liver. 1728 12

Cisplatin is one of the most effective antineoplastic drugs, but it has undesirable side effects such as hepatotoxicity at high doses. This study investigated the protective effect of macelignan, isolated from Myristica fragrans HOUTT. (nutmeg), against cisplatin-induced hepatotoxicity and the possible mechanisms involved in these effects in mice. Pretreatment with macelignan for 4 d significantly prevented the increased serum enzymatic activities of alanine and aspartate aminotransferase in a dose-dependent manner. The results also showed that the protective effects of macelignan on cisplatin-induced hepatotoxicity may be associated with the mitogen activated protein kinase (MAPK) signaling pathway. Cisplatin-induced phosphorylation of c-Jun N-terminal kinase1/2 (JNK1/2) and extracellular signal-regulated kinase1/2 (ERK1/2) was abrogated by pretreatment with macelignan, however, that of p38 was not significantly affected. It was also found that macelignan attenuated the expression of phosphorylated c-Jun in cisplatin-treated mice. Accordingly, it is suggested that the hepatoprotective effects of macelignan could be related to activation of the MAPK signaling pathway, especially JNK and c-Jun, its substrate. The present findings suggest that co-treatment of cisplatin with macelignan may provide more advantage than cisplatin treatment alone in cancer therapy.
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PMID:Protective Effects of macelignan on cisplatin-induced hepatotoxicity is associated with JNK activation. 1823 86

Bacterial LPS (endotoxin) is implicated in the pathogenesis of acute liver failure and several chronic inflammatory liver diseases. To evaluate the effect of hepatocyte cyclooxygenase (COX)-2 in LPS-induced liver injury, we generated transgenic mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer driven vector and the animals produced were subjected to a standard experimental protocol of LPS-induced acute fulminant hepatic failure (i.p. injection of low dose of LPS in combination with d-galactosamine (d-GalN)). The COX-2 transgenic mice exhibited earlier mortality, higher serum aspartate aminotransferase and alanine aminotransferase levels and more prominent liver tissue damage (parenchymal hemorrhage, neutrophilic inflammation, hepatocyte apoptosis, and necrosis) than wild-type mice. Western blot analysis of the liver tissues showed that LPS/d-GalN treatment for 4 h induced much higher cleavage of poly(ADP-ribose) polymerase, caspase-3, and caspase-9 in COX-2 transgenic mice than in wild-type mice. Increased hepatic expression of JNK-2 in COX-2 transgenic mice suggest that up-regulation of JNK-2 may represent a potential mechanism for COX-2-mediated exacerbation of liver injury. Blocking the prostaglandin receptor, EP(1), prevented LPS/d-GalN-induced liver injury and hepatocyte apoptosis in COX-2 transgenic mice. Accordingly, the mice with genetic ablation of EP(1) showed less LPS/d-GalN-induced liver damage and less hepatocyte apoptosis with prolonged survival when compared with the wild-type mice. These findings demonstrate that COX-2 and its downstream prostaglandin receptor EP(1) signaling pathway accelerates LPS-induced liver injury. Therefore, blocking COX-2-EP(1) pathway may represent a potential approach for amelioration of LPS-induced liver injury.
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PMID:Transgenic expression of cyclooxygenase-2 in hepatocytes accelerates endotoxin-induced acute liver failure. 1901 95

Previous results showed that pyrazole potentiates lipopolysaccharide (LPS)-induced liver injury in mice. Mechanisms involved the overexpression of cytochrome P450 2E1 (CYP2E1), oxidative stress, and activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). The current study was carried out to test the hypothesis that the mitochondria permeability transition (MPT) plays a role in this pyrazole plus LPS toxicity. Mice were injected intraperitoneally with pyrazole for 2 days, followed by a challenge with LPS with or without treatment with cyclosporin A (CsA), an inhibitor of the MPT. Serum alanine aminotransferase and aspartate aminotransferase were increased by pyrazole plus LPS treatment, and CsA treatment could attenuate these increases. CsA also prevented pyrazole plus LPS-induced hepatocyte necrosis. Formation of 4-hydroxynonenal protein adducts and 3-nitrotyrosine protein adducts in liver tissue was increased by the pyrazole plus LPS treatment, and CsA treatment blunted these increases. Swelling, cytochrome c release from mitochondria to the cytosol, and lipid peroxidation were increased in mitochondria isolated from the pyrazole plus LPS-treated mice, and CsA treatment prevented these changes. CsA did not prevent the increased levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), pp38 MAPK, and p-JNK2. In conclusion, although CsA does not prevent elevations in upstream mediators of the pyrazole plus LPS toxicity (iNOS, TNF-alpha, CYP2E1, MAPK), it does protect mice from the pyrazole plus LPS-induced liver toxicity by preventing the MPT and release of cytochrome c and decreasing mitochondrial oxidative stress. These results indicate that mitochondria are the critical targets of pyrazole plus LPS in mediating liver injury.
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PMID:Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice. 1902 39


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