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)

1,1-Dichloroethylene (DCE) causes dysfunction of hepatic mitochondria. As mitochondria have been implicated in apoptosis through opening of the permeability transition pore (PTP), we have undertaken studies to test the hypothesis that DCE induces apoptosis, in addition to necrosis, in murine liver. Our primary objective was to identify the biochemical events associated with DCE-induced apoptosis. Female CD-1 mice were treated with a mildly hepatotoxic dose of DCE (125 mg/kg, i.p.). Using the fluorescent dye JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide), decreased hepatic mitochondrial membrane potential was detected at 2 h. Western blotting of liver cytosolic proteins showed greater immunoreactivity for cytochrome c in fractions from mice treated with DCE for 4 h than in controls. Furthermore, caspase-9 activity was significantly increased 6 h after DCE exposure. Immunohistochemical studies with an antibody to activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were used to detect apoptotic cells. In both experiments, positive reactivities were observed in centrilobular hepatocytes 12 and 24 h after DCE. Additionally, centrilobular hepatocytes showing morphological criteria of apoptosis were observed at 24 h. Apoptosis and all apoptotic events were inhibited by pretreatment for 20 min with cyclosporine A (CyA) (50 mg/kg), a specific inhibitor of the mitochondrial PTP. To determine a major role for mitochondrial permeability transition (MPT) in DCE hepatotoxicity, serum alanine aminotransferase (ALT) activity was evaluated. ALT activity was significantly elevated 2 to 24 h after DCE, and CyA failed to inhibit this activity. These data suggested that DCE produces apoptosis by inducing MPT, causing release of cytochrome c into the cytosol and caspase activation.
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PMID:Evidence that 1,1-dichloroethylene induces apoptotic cell death in murine liver. 1502 83

Nitric oxide (NO) is one of the smallest molecules synthesised in the human body. It is produced by three distinct nitric oxide synthase isoenzymes (NOS) and plays a number of physiological functions in many organs and tissues. Among its numerous properties is the ability to influence programmed cell death. NO can either inhibit or induce apoptosis depending on the context of its production. In the liver, NO is produced in greater amounts especially during inflammation. The effect of NO in liver physiology and pathophysiology can be both beneficial and detrimental. Therefore, the aim of our study was to examine NO effect on cell viability and cell death in primary rat hepatocyte culture. By using NO donor, S-nitroso-N-acetylpenicillamine (SNAP), the potential of exogenously delivered NO to influence spontaneous cell death in culture was examined. The morphological approach was used in order to discriminate between apoptotic and necrotic cell death. The nitrite level, urea production and alanine aminotransferase leakage were determined in the culture medium. The immunocytochemical detection of three apoptotic markers: cleaved caspase-3, cleaved caspase-9 and lamin A, was performed. Immunocytochemical analysis of hepatocyte apoptosis revealed different labelling pattern for each method, while the detection of cleaved caspase-3 best correlated with defined phenotypical criteria. Our data showed that under present conditions NO improved the viability of primary rat hepatocytes compared to untreated cells. This was manifested by the increase of viable hepatocytes in contrast to the decrease of necrotic and apoptotic hepatocytes as assessed by the morphological examination of cell culture. The NO effect was dose-dependent in the range of SNAP concentration between 200-800 microM.
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PMID:The morphological and immunocytochemical evaluation of primary rat hepatocytes undergoing spontaneous cell death: modulation by the nitric oxide donor S-nitroso-N-acetylpenicillamine. 1693 4

Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125, a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 microg/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained JNK activation. Administration of SP600125 diminished JNK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha, and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FHF by downregulating Bad and inhibiting Bid cleavage.
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PMID:An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins. 1730 Aug 14

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

Fatty livers are particularly susceptible to mitochondrial alterations after cold preservation. We thus aimed to improve graft integrity by brief hypothermic oxygenation prior to warm reperfusion. Macrovesicular steatosis was induced in rat livers by fasting and subsequent feeding of a fat-free diet enriched with carbohydrates. Fatty livers were retrieved and stored ischemically at 4 degrees C for 20 hours in histidine-tryptophan-ketoglutarate solution. Hypothermic reconditioning (HR) was performed in some livers by insufflation of gaseous oxygen via the caval vein during the last 90 minutes of preservation. Viability was assessed upon isolated reperfusion. HR resulted in a significant (approximately 5-fold) reduction of parenchymal (alanine aminotransferase and lactate dehydrogenase) and mitochondrial (glutamate dehydrogenase) enzyme release. Functional recovery (bile production, oxygen consumption, and tissue levels of adenosine triphosphate) was significantly improved by HR. In untreated grafts, cellular autophagy (cleavage of LC3B and protein expression of beclin-1) was significantly impaired (<50% of baseline) after preservation/reperfusion but was restored to normal values by HR. HR also increased cleavage of caspase 9 (P < 0.5) and caspase 3 enzyme activity (by a factor of 1.5). In contrast, histological signs of tissue necrosis were abundant after reperfusion in untreated livers and largely abrogated in reconditioned livers. In conclusion, HR limits mitochondrial defects and restores basal rates of cellular autophagy. This may represent a rescue mechanism for maintaining cellular homeostasis and tissue survival.
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PMID:Impaired autophagic clearance after cold preservation of fatty livers correlates with tissue necrosis upon reperfusion and is reversed by hypothermic reconditioning. 1956 17

Developing a quantifiable in vitro model of steatosis is critical in understanding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and searchingfor effective therapies. Using an ORO-based colorimetric measurement, we developed a convenient assay to qualify the degree of OA-induced steatosis in HepG2 cells. We demonstrated that in the absence of exogenous inflammatory mediators, OA-induced steatosis was associated with increased production and secretion of tumor necrosis factor alpha and decreased expression of peroxisome proliferators-activated receptor alpha in HepG2 cells. OA-induced steatosis was also associated with increased lipid peroxidation, apoptosis, but decreased proliferation in these cells. The increased lipid peroxidation was related to decreased SOD-1, a free radical scavenger enzyme; while increased apoptosis was related to increased active caspase-9. The decreased proliferation mediated by OA-induced steatosis was associated with increased production of p27 with unchanged alanine transaminase (ALT) level in the culture medium, indicating OA-induced steatosis alters cell cycle progression without direct toxicity to these cells. In conclusion, the present study developed a colorimetric assay that accurately quantifies OA-induced steatosis in HepG2 cells. In the absence of exogenous inflammatory mediators, OA-induced steatosis results in a series of pathophysilogical changes in HepG2 cells, indicating direct pathogenic roles of hepatocytes in NAFLD.
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PMID:Quantification and mechanisms of oleic acid-induced steatosis in HepG2 cells. 2018 86

The continuing threat to biodiversity lends urgency to the need of identification of sustainable source of natural products. This is not so much trouble if there is a microbial source of the compound. Herein, violacein, a natural indolic pigment extracted from Chromobacterium violaceum, was evaluated for its antitumoral potential against the Ehrlich ascites tumor (EAT) in vivo and in vitro. Evaluation of violacein cytotoxicity using different endpoints indicated that EAT cells were twofold (IC(50)=5.0 microM) more sensitive to the compound than normal human peripheral blood lymphocytes. In vitro studies indicated that violacein cytotoxicity to EAT cells is mediated by a rapid (8-12h) production of reactive oxygen species (ROS) and a decrease in intracellular GSH levels, probably due to oxidative stress. Additionally, apoptosis was primarily induced, as demonstrated by an increase in Annexin-V positive cells, concurrently with increased levels of DNA fragmentation and increased caspase-2, caspase-9 and caspase-3 activities up to 4.5-, 6.0- and 5.5-fold, respectively, after 72 h of treatment. Moreover, doses of 0.1 and 1.0 microg kg(-1) violacein, administered intraperitoneally (i.p.) to EAT-bearing mice throughout the lifespan of the animals significantly inhibited tumor growth and increased survival of mice. In view of these results, a 35-day toxicity study was conducted in vivo. Complete hematology, biochemistry (ALT, AST and creatinine levels) and histopathological analysis of liver and kidney indicated that daily doses of violacein up to 1000 microg kg(-1) for 35 days are well tolerated and did not cause hematotoxicity nor renal or hepatotoxicity when administered i.p. to mice. Altogether, these results indicate that violacein causes oxidative stress and an imbalance in the antioxidant defense machinery of cells culminating in apoptotic cell death. Furthermore, this is the first report of its antitumor activity in vivo, which occurs in the absence of toxicity to major organs.
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PMID:Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor. 2041 85

Acute liver failure (ALF) is a life-threatening disease that has proven difficult to cure. In Western countries, acetaminophen (APAP) poisoning is the most common cause of ALF. However, the mode of cell death in APAP-induced ALF cases is controversial. Previous studies have shown that administration of anti-interleukin-1 (anti-IL-1) antibody attenuated APAP-induced liver injury, and that administration of anti-IL-1 receptor antagonist (anti-IL-1Ra) antibody exacerbated organ injury. These results prompted us to investigate the roles of IL-1Ra in APAP-induced ALF mice. Our results show that administration of recombinant human IL-1Ra (rhIL-1Ra) could significantly improve the survival rate of mice with ALF induced by APAP. Furthermore, we found that rhIL-1Ras could dramatically inhibit the activities of alanine aminotransferase and aspartate aminotransferase in serum, reduce the death of hepatocytes and accelerate the proliferation of hepatocytes. In addition, we show that hepatocellular apoptosis rather than necrosis was the major cause of ALF-induced animal death, and that the anti-apoptosis role of rhIL-1Ra was mediated by reducing the release of cytochrome c from the mitochondria, and the activities of caspase-3, caspase-8 and caspase-9 in the liver tissue. In conclusion, these data indicate that rhIL-1Ra is a promising candidate for the treatment of APAP-induced ALF in mice through the reduction of hepatocellular apoptosis.
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PMID:rhIL-1Ra reduces hepatocellular apoptosis in mice with acetaminophen-induced acute liver failure. 2064 19

Pharmacological agents that are safe and can sensitize the lung cancer are urgently required. We investigated whether Atractylenolide III (ATL-III), the major component of Atractylodes rhizome can induce apoptosis of the lung carcinoma cells. ATL-III inhibited cell growth, increased lactate dehydrogenase release and modulated cell cycle on human lung carcinoma A549 cells. ALT-III induced the activation of caspase-3 and caspase-9 and cleavage of poly-(ADP)-ribose polymerase. ATL-III induced the release of cytochrome c, upregulation of bax expression, and translocation of apoptosis-inducing factor. In addition, ATL-III inhibited the proliferation and capillary tube formation of human umbilical vein endothelial cells. These data indicate that ATL-III is a potential candidate for treatment of human lung carcinoma.
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PMID:Atractylenolide III, a sesquiterpenoid, induces apoptosis in human lung carcinoma A549 cells via mitochondria-mediated death pathway. 2113 Aug 27

Sprague Dawley strain of male rats weighing 200 +/- 10.0 g, were exposed intramuscularly to non-lethal dose of mercury for short acute duration of 24 and 48 hr. Mercury treatment increased thio-barbituric acid reactive substance (TBARS) and conjugated diene (CD) content with increase in duration when compared with control. This reflects possible increase in lipid peroxidation, revealing that sufficient intoxication was generated by non-lethal dose of mercury. Furthermore, mercury treatment decreased tissue glutathione (GSH) content to 2.07 and 1.49 microg GSH mg protein(-1) with concomitant decrease in glutathione-S-transferase (GST) activity by 26.06 and 36.40% after 24 and 48 hr of exposure respectively. The elevations of aspartate transaminase (AST) and alanine transaminase (ALT) levels measured exhibited increase of 287.5 and 214.5% after 48 hr of exposure respectively which were found to be highly significant compared with control. Western blot analysis indicated upregulation of caspase-9 and upsurge in effect or caspase-3 activity leading to apoptosis. The concluded findings of the present investigation suggests possible role of early mercury exposure in inducing oxidative stress mediated apoptosis in mammalian model systems as an indicator component of environmental toxicology.
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PMID:Induction of oxidative stress by non-lethal dose of mercury in rat liver: possible relationships between apoptosis and necrosis. 2118 12


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