Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the importance of IL-6 in acetaminophen (APAP) toxicity, wild type (WT) and IL-6 knock out (KO) mice were dosed with APAP (300 mg/kg i.p.) and sacrificed at 4 and 24h. No differences were found between the two groups by analysis of serum AST levels or histopathology. Also, the relative amounts of APAP protein binding and nitrotyrosine formation were equal. Subsequently, WT and KO mice were dosed with APAP (300 mg/kg i.p.) and sacrificed at 24, 48, and 72 h. AST normalized by 48 h in the WT mice, but not until 72 h in the KO mice. The severity of the histopathological alterations was comparable in the two groups of mice; however, fewer regenerating hepatocytes were present in the KO mice. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed reduced staining in the KO mice. Pretreatment of KO mice with IL-6 lowered AST and normalized PCNA staining in the IL-6 KO mice. These data suggest that IL-6 is important in hepatocyte regeneration following APAP toxicity in the mouse.
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PMID:Interleukin 6 and hepatocyte regeneration in acetaminophen toxicity in the mouse. 1367 52

We have investigated the effects of chlordecone 1(CD)+CCl4 combination in adult (3 months), middle aged (14 months), and old aged (24 months) male Fischer 344 (F344) rats. After a non-toxic dietary regimen of CD (10 ppm) or normal powdered diet for 15 days, rats received a single non-toxic dose of CCl4 (100 microl/kg, i.p., 1:4 in corn oil) or corn oil (500 microl/kg, i.p.) alone on day 16. Liver injury was assessed by plasma ALT, AST, and histopathology during a time course of 0-96 h. Liver tissue repair was measured by [3H-CH3]-thymidine (3H-T) incorporation into hepatic nuclear DNA and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Hepatomicrosomal CYP2E1 protein, enzyme activity, and covalent binding of 14CCl4-derived radiolabel were measured in normal and CD fed rats. Exposure to CCl4 alone caused modest liver injury only in 14- and 24-month-old rats but neither progression of injury nor mortality. The CD+CCl4 combination led to 100% mortality in 3-month-old rats by 72 h, whereas none of the 14- and 24-month-old rats died. Both 3- and 14-month-old rats exposed to CD+Cl4 had identical liver injury up to 36 h indicating that bioactivation-mediated CCl4 injury was the same in the two age groups. Thereafter, liver injury escalated only in 3-month-old while it declined in 14-month-old rats. In 24-month-old rats initial liver injury at 6 h was similar to the 3- and 14-month-old rats and thereafter did not develop to the level of the other two age groups, recovering from injury by 96 h as in the 14-month-old rats. Neither hepatomicrosomal CYP2E1 protein nor the associated p-nitrophenol hydroxylase activity or covalent binding of 14CCl4-derived radiolabel to liver tissue differed between the age groups or diet regimens 2 h after the administration of 14CCl4. Compensatory liver tissue repair (3H-T, PCNA) was prompt and robust soon after CCl4 liver injury in the 14- and 24-month-old rats. In stark contrast, in the 3-month-old rats it failed allowing unabated progression of liver injury. These findings suggest that stimulation of early onset and robust liver tissue repair rescue the 14- and 24-month-old F344 rats from the lethal effect of the CD+CCl4 combination.
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PMID:Tolerance of aged Fischer 344 rats against chlordecone-amplified carbon tetrachloride toxicity. 1517 32

Pathogenesis of steatohepatitis, a common liver disease, remains controversial. It is proposed that fatty liver with a second hit capable of inducing necroinflammation results in nonalcoholic steatohepatitis. Long chain and very long chain fatty acids are considered important in induction of steatohepatitis. Peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in beta-oxidation of long chain and very long chain fatty acids and mitogenic effect caused by peroxisome proliferators in the liver. To determine the role of PPARalpha in the pathogenesis of steatohepatitis and compensatory liver cell hyperplasia, we have used PPARalpha null mice and methionine and choline deficient nutritional model. Male and female PPARalpha null mice and wild type mice were fed methionine and choline deficient diet (MCDD) or normal chow for 4 weeks. Livers were analyzed morphologically for steatosis, steatohepatitis and hepatocyte proliferation (PCNA labeling) and biochemically for triglyceride levels. In addition, serum alanine transaminase, aspartate transaminase and triglyceride levels were measured. In MCDD fed PPARalpha null mice there was severe steatohepatitis and very high liver triglyceride levels compared to wild type mice. Serum aspartate transaminase levels were also significantly higher in MCDD fed PPARalpha null mice compared to wild type mice. The severity of steatohepatitis in MCDD fed male and female PPARalpha null mice was greater compared to wild type mice fed the same diet. The PCNA labeling index was similar in PPARalpha null mice and wild type mice fed MCDD, and significantly higher in both the groups compared to the mice fed control diet. These findings indicate that defective fatty acid oxidation aggravates steatohepatitis caused by methionine and choline deficiency and further establishes the role of long chain and very long chain fatty acids in the pathogenesis of steatohepatitis. In addition, the results of this study also indicate that there is no difference between males and females in the severity of steatohepatitis induced by MCDD and lack of PPARalpha does not affect compensatory hyperplasia in the liver.
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PMID:Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis. 1551 75

There have been many reports about the severity of hepatic necrosis caused by fulminant hepatitis; however, the relation between proliferated bile ductules and osteopontin (OPN) expression in inflamed areas in each of the clinical forms of fulminant hepatitis has not been described. To analyze the mechanism in the onset of fulminant hepatitis, we classified not only 16 autopsy cases of fulminant hepatitis into two clinical forms--acute and subacute--but also 3 autopsy cases of late-onset hepatic failure (LOHF) associated with fulminant hepatitis, and examined liver specimens by light microscopy and immunohistochemistry and also serum transaminase levels. Histopathologic study revealed that some of the proliferated bile ductules were associated directly with deteriorating hepatocytes and that bile plugs were present in the proliferated bile ductules. The value of the proliferative cell nuclear antigen labeling index (PCNA-L I) for proliferated bile ductules was very high during the acute form of fulminant hepatitis. Immunohistochemical analysis revealed that OPN expression was higher in the proliferated bile ductules of acute-form fulminant hepatitis than in cirrhotic and normal liver bile ducts. Transaminase levels in acute-form fulminant hepatitis were significantly elevated in comparison with levels in the other forms of the disease. Comparison of acute form fulminant hepatitis with the subacute form and LOHF showed OPN expression in proliferated bile ductules and serum aspartate aminotransferase (ALT)max to be decreased in the subacute form of fulminant hepatitis. OPN expression is an important marker of the degree of liver inflammation, and its regulation mechanism is very important to understanding the pathophysiology of fulminant hepatitis.
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PMID:Osteopontin expression in proliferated bile ductules: the correlation with liver damage in fulminant hepatitis. 1571 59

Previously, we reported high hepatotoxic sensitivity of type 2 diabetic (DB) rats to three dissimilar hepatotoxicants. Additional work revealed that a normally nonlethal dose of CCl4 was lethal in DB rats due to inhibited compensatory tissue repair. The present study was conducted to investigate the importance of compensatory tissue repair in determining the final outcome of hepatotoxicity in diabetes, using another structurally and mechanistically dissimilar hepatotoxicant, thioacetamide (TA), to initiate liver injury. A normally nonlethal dose of TA (300 mg/kg, ip), caused 100% mortality in DB rats. Time course studies (0 to 96 h) showed that in the non-DB rats, liver injury initiated by TA as assessed by plasma alanine or aspartate aminotransferase and hepatic necrosis progressed up to 48 h and regressed to normal at 96 h resulting in 100% survival. In the DB rats, liver injury rapidly progressed resulting in progressively deteriorating liver due to rapidly expanding injury, hepatic failure, and 100% mortality between 24 and 48 h post-TA treatment. Covalent binding of 14C-TA-derived radiolabel to liver tissue did not differ from that observed in the non-DB rats, indicating similar bioactivation-based initiation of hepatotoxicity. S-phase DNA synthesis measured by [3H]-thymidine incorporation, and advancement of cells through the cell division cycle measured by PCNA immunohistochemistry, were substantially inhibited in the DB rats compared to the non-DB rats challenged with TA. Thus, inhibited cell division and compromised tissue repair in the DB rats resulted in progressive expansion of liver injury culminating in mortality. In conclusion, it appears that similar to type 1 diabetes, type 2 diabetes also increases sensitivity to dissimilar hepatotoxicants due to inhibited compensatory tissue repair, suggesting that sensitivity to hepatotoxicity in diabetes occurs in the absence as well as presence of insulin.
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PMID:Type 2 diabetic rats are sensitive to thioacetamide hepatotoxicity. 1615 71

On the basis of the recently recognized potential of hematopoietic stem cells (HSCs) to give rise to hepatocytes, we investigated whether HSCs mobilized by granulocyte colony-stimulating factor (G-CSF) or G-CSF per se could contribute to faster recovery and promote tissue reparation after rats' (cross-sex) partial orthotopic liver transplantation (PLTx). Sex-mismatched (female to male) syngeneic rat PLTx was established. The recipients were repeatedly administrated recombinant G-CSF for 5 consecutive days before (G-CSF + PLTx group) and after PLTx (PLTx + G-CSF group). Compared with those in PLTx group, CD34+ cells in peripheral blood and portal tract region increased from day 1 to 7 after transplantation in G-CSF + PLTx group and from day 3 to 14 after transplantation in PLTx + G-CSF group, respectively, which suggested that CD34+ HSCs were mobilized and migrated into liver graft. Compared with that in G-CSF + PLTx and PLTx groups, there was a higher survival rate in the PLTx + G-CSF group. On day 3 after surgery, the level of aspartate aminotransferase and alanine aminotransferase were lower, whereas the mitosis index, proliferating cell nuclear antigen-positive nuclei, bromodeoxyuridine (BrdU) incorporation, and graft-to-recipient weight ratio were higher in the PLTx + G-CSF group. In contrast, these parameters had no significant difference between G-CSF + PLTx and PLTx groups. To define the origin of proliferating cells reconstituting liver after injury, sry+ (sex-determining region for Y chromosome) and sry+/cytokeratin 19+ (CK19) cells were quantitated. Higher percentage of sry+ and sry+/CK19+ cells in PLTx + G-CSF was detected than in G-CSF + PLTx groups on day 14 after surgery, although the liver engraftment rate still remained rather low. Some of the sry+/CK19+ cells in the portal tract areas were similar to hepatic oval cells/cholangiocytes. In conclusion, G-CSF administration after PLTx greatly improved survival rate and liver regeneration of partial graft, partly by its mobilizing HSCs into the injured liver to differentiate into hepatocytes through hepatic oval cells'/cholangiocytes' engraftment.
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PMID:Hematopoietic stem cells mobilized by granulocyte colony-stimulating factor partly contribute to liver graft regeneration after partial orthotopic liver transplantation. 1679 53

Increasing evidence suggests that liver regeneration is suppressed in patients with chronic HCV infection; however, the underlying mechanisms remain unclear. Previously, we demonstrated that injection of the synthetic double-stranded RNA (dsRNA) poly I:C to mimic viral infection suppresses liver regeneration in the partial hepatectomy (PHx) model, whereby IFN-gamma contributes to the inhibition. In this study, we examined the role of the IFN-gamma-activated downstream signal (STAT1) and genes (IRF-1, p21(cip1), and SOCS1) in liver regeneration and hepatocyte proliferation. Results show that disruption of the STAT1 gene abolished poly I:C suppression of liver regeneration and the inhibitory effect of poly I:C on liver regeneration was diminished in IRF-1(-/-) and p21(cip1-/-)mice. Treatment with IFN-gamma in vitro inhibited cell proliferation of wild-type mouse hepatocytes, but not STAT1(-/-) hepatocytes. The inhibitory effect of IFN-gamma on cell proliferation was also diminished in IRF-1(-/-) and p21(cip1-/-) hepatocytes, but enhanced in SOCS1(-/-) hepatocytes. Hepatocyte proliferation was unaffected by treatment with poly I:C alone, but when hepatocytes were co-cultured with liver lymphocytes, proliferation was inhibited by IFN-gamma/STAT1-dependent mechanisms. Moreover, in HCV-infected livers with cirrhosis, activation of STAT1 was detected and correlated positively with liver injury (elevated serum levels of AST) but negatively with hepatocyte proliferation (hepatocyte PCNA and Ki-67 positive immunostaining). In conclusion, STAT1 is involved in dsRNA suppression of liver regeneration; not only does STAT1 activation contribute to liver injury, it may also block liver repair through inhibition of hepatocyte proliferation in HCV-infected patients, playing an important role in the pathogenesis of disease.
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PMID:STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice. 1700 30

Massive hepatectomy associated with infection induces liver dysfunction, or even multiple organ failure and death. Glycyrrhizin has been shown to exhibit anti-oxidant and anti-inflammatory activities. The aim of the present study was to investigate whether glycyrrhizin could attenuate endotoxin-induced acute liver injury after partial hepatectomy. Male Wistar rats (6 to 8 weeks old, weighing 200-250 g) were randomly assigned to three groups of 24 rats each: sham, saline and glycyrrhizin. Rats were injected intravenously with lipopolysaccharide (LPS) 24 h after 70% hepatectomy. Glycyrrhizin, pre-administered three times with 24 h intervals 48 h before hepatectomy, prolonged the survival of rats submitted to partial hepatectomy and LPS injection, compared with saline controls. Glycyrrhizin was shown to attenuate histological hepatic changes and significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase, at all the indicated times (6 rats from each were sacrificed 1, 3, 6, and 9 h after LPS injection), compared with saline controls. Glycyrrhizin also significantly inhibited hepatocyte apoptosis by down-regulating the expression of caspase-3 and inhibiting the release of cytochrome C from mitochondria into the cytoplasm. The anti-inflammatory activity of glycyrrhizin may rely on the inhibition of release of tumor necrosis factor-a, myeloperoxidase activity, and translocation of nuclear factor-kappa B into the nuclei. Glycyrrhizin also up-regulated the expression of proliferating cell nuclear antigen, implying that it might be able to promote regeneration of livers harmed by LPS. In summary, glycyrrhizin may represent a potent drug protecting the liver against endotoxin-induced injury, especially after massive hepatectomy.
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PMID:Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats. 1799 67

One of the focuses in current cancer chemoprevention studies is the search for nontoxic chemopreventive agents that inhibit the initiation of malignant transformation. Cancer biomarkers are quantifiable molecules involved in the physiologic or pathologic events occurring between exposure to carcinogens and the development, progression of cancer. Biomarkers may be the consequence of a continuous process, such as increased cell mass, or a discrete event, such as genetic mutation. Analysis of tumor markers can be used as an indicator of tumor response to therapy. Gallic acid is a naturally available polyphenol, possess strong antioxidant activity with a capacity to inhibit the formation of tumors in several cancer models. In the present study, we investigated the antiproliferative effect of gallic acid during diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in male wistar albino rats. DEN treatment resulted in increased levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, acid phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, 5'-nucleotidase, bilirubin, alpha-fetoprotein, carcinoembryonic antigen, argyophillic nucleolar organizing regions, and proliferating cell nuclear antigen. Gallic acid treatment significantly attenuated these alterations and decreased the levels of AgNORs and PCNA. These finding suggests that gallic acid is a potent antiproliferative agent against DEN-induced HCC.
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PMID:Antiproliferative potential of gallic acid against diethylnitrosamine-induced rat hepatocellular carcinoma. 1862 14

Zerumbone (ZER), a monosesquiterpene found in the subtropical ginger (Zingiber zerumbet Smith), possesses antiproliferative properties to several cancer cells lines, including the cervical, skin and colon cancers. In this study, the antitumourigenic effects of ZER were assessed in rats induced to develop liver cancer with a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and dietary 2-acetylaminofluorene (AAF) (0.02%). The rats also received intraperitoneal ZER injections at 15, 30 or 60 mg/kg body wt. twice a week for 11 weeks, beginning week four post-DEN injection. The hepatocytes of positive control (DEN/AAF) rats were smaller with larger hyperchromatic nuclei than normal, showing cytoplasmic granulation and intracytoplasmic violaceous material, which were characteristics of hepatocarcinogenesis. Histopathological evaluations showed that ZER protects the rat liver from the carcinogenic effects of DEN and AAF. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP) and alpha-fetoprotein (AFP) were significantly lower (P<0.05) in ZER-treated than untreated rats with liver cancer. The liver malondialdehyde (MDA) concentrations significantly (P<0.05) increased in the untreated DEN/AAF rats indicating hepatic lipid peroxidation. There was also significant (P<0.05) reduction in the hepatic tissue glutathione (GSH) concentrations. The liver sections of untreated DEN/AAF rats also showed abundant proliferating cell nuclear antigen (PCNA), while in ZER-treated rats the expression of this antigen was significantly (P<0.05) lowered. By the TUNEL assay, there were significantly (P<0.05) higher numbers of apoptotic cells in DEN/AAF rats treated with ZER than those untreated. Zerumbone treatment had also increased Bax and decreased Bcl-2 protein expression in the livers of DEN/AAF rats, which suggested increased apoptosis. Even after 11 weeks of ZER treatment, there was no evidence of abnormality in the liver of normal rats. This study suggests that ZER reduces oxidative stress, inhibits proliferation, induces mitochondria-regulated apoptosis, thus minimising DEN/AAF-induced carcinogenesis in rat liver. Therefore, ZER has great potential in the treatment of liver cancers.
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PMID:Potential chemoprevention of diethylnitrosamine-initiated and 2-acetylaminofluorene-promoted hepatocarcinogenesis by zerumbone from the rhizomes of the subtropical ginger (Zingiber zerumbet). 2045 35


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