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)

Oxidative stress due to iron deposition in hepatocytes or Kupffer cells contributes to the initiation and perpetuation of liver injury. The aim of this study was to clarify the association between dietary iron and liver injuries in rats. Liver injury was initiated by the administration of thioacetamide or ligation of the common bile duct in rats fed a control diet (CD) or iron-deficient diet (ID). In the acute liver injury model induced by thioacetamide, serum levels of aspartate aminotransferase and alanine aminotransferase, as well as hepatic levels of lipid peroxide and 4-hydroxynonenal, were significantly decreased in the ID group. The expression of 8-hydroxydeoxyguanosine and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling positivity showed a similar tendency. The expression of interleukin-1beta and monocyte chemotactic protein-1 mRNA was suppressed in the ID group. In liver fibrosis induced by an 8-wk thioacetamide administration, ID suppressed collagen deposition and smooth muscle alpha-actin expression. The expressions of collagen 1A2, transforming growth factor beta, and platelet-derived growth factor receptor beta mRNA were all significantly decreased in the ID group. Liver fibrosis was additionally suppressed in the bile-duct ligation model by ID. In culture experiments, deferoxamine attenuated the activation process of rat hepatic stellate cells, a dominant producer of collagen in the liver. In conclusion, reduced dietary iron is considered to be beneficial in improving acute and chronic liver injuries by reducing oxidative stress. The results obtained in this study support the clinical usefulness of an iron-reduced diet for the improvement of liver disorders induced by chronic hepatitis C and alcoholic/nonalcoholic steatohepatitis.
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PMID:Attenuation of acute and chronic liver injury in rats by iron-deficient diet. 1803 66

In recent studies, the cytotoxic activity of NO has been investigated for its potential use in anticancer therapies. Nitrosated human serum albumin (NO-HSA) may act as a reservoir of NO in vivo. However, there are no published reports regarding the effects of NO-HSA on cancer. Therefore, the present study investigated the antitumor activity of NO-HSA. NO-HSA was prepared by incubating HSA, which had been sulfhydrylated using iminothiolane, with isopentyl nitrite (6.64 mol NO/mol HSA). Antitumor activity was examined in vitro using murine colon 26 carcinoma (C26) cells and in vivo using C26 tumor-bearing mice. Exposure to NO-HSA increased the production of reactive oxygen species in C26 cells. Flow cytometric analysis using rhodamine 123 showed that NO-HSA caused mitochondrial depolarization. Activation of caspase-3 and DNA fragmentation were observed in C26 cells after incubation with 100 muM NO-HSA for 24 h, and NO-HSA inhibited the growth of C26 cells in a concentration-dependent manner. The growth of C26 tumors in mice was significantly inhibited by administration of NO-HSA compared with saline and HSA treatment. Immunohistochemical analysis of tumor tissues demonstrated an increase in terminal deoxynucleotidyl transferase dUTP nickend labeling-positive cells in NO-HSA-treated mice, suggesting that inhibition of tumor growth by NO-HSA was mediated through induction of apoptosis. Biochemical parameters (such as serum creatinine, blood urea nitrogen, aspartate aminotransferase, and alanine aminotransferase) showed no significant differences among the three treatment groups, indicating that NO-HSA did not cause hepatic or renal damage. These results suggest that NO-HSA has the potential for chemopreventive and/or chemotherapeutic activity with few side effects.
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PMID:Design and evaluation of S-nitrosylated human serum albumin as a novel anticancer drug. 1821 31

The hepatoprotective effects of a diterpenoid acanthoic acid isolated from Acanthopanax koreanum NAKAI were evaluated in a D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure mouse model. Mice were pretreated orally with acanthoic acid 12 and 1 h before intraperitoneal injection of D-galactosamine and lipopolysaccharide. Pretreatment with the compound markedly reduced lethal liver injury in experimental animals. The effects were likely associated with a significant decrease in serum tumor necrosis factor (TNF)-alpha levels, which are correlated not only with those of alanine aminotransferase and aspartate aminotransferase but also with the reduced number of apoptotic hepatocytes in the liver as confirmed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and DNA fragmentation assay. These results suggest that acanthoic acid protects against D-galactosamine/lipopolysaccharide-induced fulminant liver failure at least in part by a mechanism associated with the down-regulation of TNF-alpha secretion.
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PMID:A diterpenoid acanthoic acid from Acanthopanax koreanum protects against D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure in mice. 1837 74

Oxidant stress is critically involved in various liver diseases. Superoxide formation causes c-Jun NH2-terminal kinase (JNK)- and caspase-dependent apoptosis in cultured hepatocytes. To verify these findings in vivo, male Fisher rats were treated with diquat and menadione. The oxidant stress induced by both compounds was confirmed by increased formation of glutathione disulfide and 4-hydroxynonenal protein adducts. Plasma alanine aminotransferase activities increased from 46+/-4 U/l in controls to 955+/-90 U/l at 6 h after diquat treatment. Hematoxylin and eosin staining of liver sections revealed large areas of necrotic cells at 3 and 6 h. DNA strandbreaks, evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, showed clusters of TUNEL-positive cells, where the staining was predominantly cytosolic and the cells were swollen, indicating oncotic necrosis. There was no significant increase in caspase-3 activities or relevant release of DNA fragments into the cytosol at any time between 0 and 6 h after diquat treatment. Despite the activation of JNK after high doses of diquat, the JNK inhibitor SP-600125 did not protect against diquat-induced necrosis. Menadione alone did not cause liver injury, but, in combination with phorone and FeSO4, induced moderate oncotic necrosis. On the other hand, if animals were treated with galactosamine/endotoxin as positive control for apoptosis, caspase-3 activities were increased by 259%, the number of TUNEL-positive cells with apoptotic morphology was increased 103-fold, and DNA fragmentation was enhanced 6-fold. The data indicate that liver cell death initiated by diquat-induced superoxide formation in vivo is mediated predominantly by oncotic necrosis and is independent of JNK activation.
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PMID:Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation. 1913 81

Prostaglandin E1 (PGE1) has wide-ranging effects on cytoprotection and may play a role in preventing liver failure following excessive hepatectomy. We examined the effect of PGE1 on hepatocyte apoptosis and liver regeneration after 95% hepatectomy in a rat model. PGE1 or vehicle was intravenously administered 30 minutes before and during hepatectomy. The extent of hepatocyte injury was evaluated by serum alanine aminotransferase and aspartate aminotransferase levels. To evaluate hepatocyte apoptosis and liver regeneration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and Ki67 labeling were performed. The expression levels of Bcl-xL, Bcl-2, Bax, Cyclin C, Cyclin D1, Cyclin E, p21, transforming growth factor-beta, plasminogen activator inhibitor-1, and glyceraldehyde-2-phosphate dehydrogenase mRNA were also examined by reverse transcription-polymerase chain reaction. Survival was improved in the PGE1 group (26.6%), whereas all rats in the vehicle group died within 60 hours. PGE1 significantly suppressed the release of alanine aminotransferase and aspartate aminotransferase at 12 hours postoperatively. Pretreatment with PGE1 significantly increased the Ki67-positive cell count and decreased the terminal deoxynucleotidyl transferase dUTP nick end labeling positive cell count after hepatectomy, and also significantly increased the expression levels of Bcl-xL, Cyclin C, and Cyclin D1. Our results suggest that pretreatment with PGE1 may increase survival following hepatectomy by salvaging the remaining liver tissue, which it does by inhibiting apoptosis and stimulating hepatocyte proliferation.
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PMID:Prostaglandin E1 prevents liver failure after excessive hepatectomy in the rat by up-regulating Cyclin C, Cyclin D1, and Bclxl. 1915 52

Epidemiological investigations suggest that increased age is associated with susceptibility to infection. Pseudomonas aeruginosa (P. aeruginosa) infection and associated exotoxin A (PEA) toxicity have been reported in hospitalized elderly patients and young children with cystic fibrosis. The present study investigated age-related differences in PEA-induced hepatotoxicity in post weaning (PW, 3 weeks), young adult (YA, 12 weeks), and mature adult (MA, 60-64 weeks) rats. PEA (20 microg/kg) was injected intraveneously and mortality, clinical chemistry, hepatic histopathology, TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling) and PCNA (Proliferating cell nuclear antigen) staining, and serum cytokine levels were assessed at specific time points, up to 72 hr post-exposure (HPE). Mortality in MA rats was 100% at less than 48 HPE. Serum ALT levels in MA rats were approximately 5-fold greater than levels in PW and YA rats at 36 HPE. MA rat liver histological sections showed diffuse hepatocellular necrosis. In contrast, hepatocellular apoptosis, demonstrable by the TUNEL method, was noted simply in the periportal and midzonal regions from 36 to 48 HPE. Increased morphological mitoses and PCNA-positive hepatocytes were seen in PW and YA rats at 72 HPE. These parameters were correlated with age-dependent significant increases in TNF-alpha, IL-2, IL-6, and IL-18 levels. These data suggest that inflammatory cytokines play an important role in age-related differences in PEA-induced hepatotoxicity. Moreover, these cytokines might correlate with different patterns histopathologic features at various ages.
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PMID:Influence of age on susceptibility to Pseudomonas aeruginosa exotoxin A-induced hepatotoxicity in Long-Evans rats. 1926 26

Human recombinant Erythropoietin (rHuEpo) has recently been shown to be a potent protector of ischemia- reperfusion injury in warm-liver ischemia. Significant enhancement of hepatic regeneration and survival after large volume partial hepatic resection has also been demonstrated. It was the aim of this study to evaluate the capacities of rHuEpo in the setting of rat liver transplantation. One-hundred-and-twenty Wistar rats were used: 60 recipients received liver transplantation following donor organ treatment (60 donors) with either 1000 IU rHuEpo or saline injection (controls) into portal veins (cold ischemia 18 h, University of Wisconsin (UW) solution). Recipients were allocated to two groups, which either received 1000 IU rHuEpo at reperfusion or an equal amount of saline (control). Animals were sacrificed at defined time-points (2, 4.5, 24, 48 h and 7 days postoperatively) for analysis of liver enzymes, histology [hematoxylin-eosin (HE) staining, periodic acid Schiff staining (PAS)], immunostaining [terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Hypoxyprobe] and real-time polymerase chain reaction (RT-PCR) of cytokine mRNA (IL-1, IL-6). Lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) values were significantly reduced among the epo-treated animals 24 and 48 h after liver transplantation (LT). The TUNEL and Hypoxyprobe analyses as well as necrotic index evaluation displayed significant reduction of apoptosis and necrosis in rHuEpo-treated graft livers. Erythropoietin reduces ischemia-reperfusion injury after orthotopic liver transplantation in rats.
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PMID:Erythropoietin reduces ischemia-reperfusion injury after liver transplantation in rats. 1931 9

Neutrophils are considered crucial effector cells in the pathophysiology of organ ischemia/reperfusion injury (IRI). Although neutrophil elastase (NE) accounts for a substantial portion of the neutrophil activity, the function of NE in liver IRI remains unclear. This study focuses on the role of NE in the mechanism of liver IRI. Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 minutes, and this was followed by 6 to 24 hours of reperfusion. Mice were treated with neutrophil elastase inhibitor (NEI; 2 mg/kg per os) at 60 minutes prior to the ischemia insult. NEI treatment significantly reduced serum alanine aminotransferase levels in comparison with controls. Histological examination of liver sections revealed that unlike in controls, NEI treatment ameliorated hepatocellular damage and decreased local neutrophil infiltration, as assessed by myeloperoxidase assay, naphthol AS-D chloroacetate esterase stains, and immunohistochemistry (anti-Ly-6G). The expression of pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin 6) and chemokines [chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2, and CXCL-10] was significantly reduced in the NEI treatment group, along with diminished apoptosis, according to terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and caspase-3 activity. In addition, toll-like receptor 4 (TLR4) expression was diminished in NEI-pretreated livers, and this implies a putative role of NE in the TLR4 signal transduction pathway. Thus, targeting NE represents a useful approach for preventing liver IRI and hence expanding the organ donor pool and improving the overall success of liver transplantation. Liver Transpl 15:939-947, 2009. (c) 2009 AASLD.
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PMID:The inhibition of neutrophil elastase ameliorates mouse liver damage due to ischemia and reperfusion. 1964 32

Liver ischemia-reperfusion injury (IRI) causes acute kidney injury (AKI) in mice characterized by renal endothelial cell apoptosis, renal tubular necrosis, inflammation, and filamentous (F)-actin disruption. Since heat shock protein 27 (HSP27) protects against apoptosis, necrosis, and stabilizes F-actin, we questioned whether overexpression of human HSP27 (huHSP27 OE) in mice would attenuate AKI after liver IRI. Twenty-four hours after hepatic IRI, HSP27 wild-type (WT) mice developed acute liver and kidney injury with elevated plasma alanine aminotransferase and creatinine, a reduced glomerular filtration rate, and histological evidence of renal endothelial cell apoptosis and tubular injury (necrosis, vacuolization, and F-actin disruption). The huHSP27 OE mice, however, were significantly protected against both liver and kidney injury after hepatic IRI. The huHSP27 OE mice also showed less induction of several proinflammatory mRNAs (TNF-alpha, MIP-2, and keratinocyte-derived cytokine), neutrophil infiltration, and reduction in apoptosis (terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling assay and DNA laddering) in the kidney compared with the HSP27 WT mice. Moreover, the huHSP27 OE mice showed significantly less disruption of F-actin in renal proximal tubules and better preserved vascular endothelial cell integrity compared with the huHSP27 OE mice. Finally, the kidney plays a major role in the hepatoprotective effects of huHSP27 overexpression as the hepatoprotection was reduced or abolished in mice subjected to unilateral or bilateral nephrectomy, respectively. Our results show that overexpression of huHSP27 protects against hepatic injury and AKI associated with liver IRI in vivo. Harnessing the mechanisms of cytoprotection with renal HSP27 may lead to new therapies for the perioperative AKI and liver injury associated with liver IRI.
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PMID:Human heat shock protein 27-overexpressing mice are protected against acute kidney injury after hepatic ischemia and reperfusion. 1965 12

Antitubercular drugs have been known to be potentially hepatotoxic and may lead to drug-induced liver injury. In this study, we aimed to investigate the protective effects of ursodeoxycholic acid (UDCA) on liver injury caused by co-administration with isoniazid and rifampicin, two famous antitubercular drugs. Liver injury was induced by co-treatment with isoniazid (75mg/kg) and rifampicin (150mg/kg) for one week. Mice were orally administered with UDCA (15, 50 and 150mg/kg) 30min before isoniazid and rifampicin. We show that serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were significantly increased in mice treated with isoniazid plus rifampicin. An obvious fatty accumulation, accompanied by mild necrosis and inflammation, was observed in liver of mice treated with rifampicin plus isoniazid. In addition, isoniazid plus rifampicin resulted in hepatic apoptosis, as determined by terminal dUTP nick-end labeling (TUNEL) staining and caspase-3 activation. Additional experiment showed that isoniazid plus rifampicin significantly increased the level of hepatic malondialdehyde (MDA) and caused glutathione (GSH) depletion and 3-nitrotyrosine (3-NT) residues in liver. UDCA pretreatment significantly attenuated isoniazid plus rifampicin induced oxidative stress in liver. Importantly, UDCA pretreatment significantly alleviated isoniazid plus rifampicin induced hepatic apoptosis. Moreover, UDCA-mediated anti-apoptotic effect seemed to be associated with its regulation of Bcl-2 and Bax gene expression in liver. These findings suggest that UDCA might protect against isoniazid and rifampicin induced liver injury through its anti-oxidative and anti-apoptotic effects.
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PMID:The protective effects of ursodeoxycholic acid on isoniazid plus rifampicin induced liver injury in mice. 2141 64


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