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)

The authors previously reported the successful reversal of lethal D-Gal induced hepatic necrosis in rats by human hepatic stimulator substance (hHSS), a liver specific growth factor partially purified from human fetal liver cells, which promoted hepatocyte proliferation. In this study, they further investigated the mechanism of hHSS in improving survival of experimental acute hepatic failure. Our results demonstrated that the level of alanine transaminase and endotoxin in the plasma and lipid peroxides in the liver of chemically poisoned rats were reduced by hHSS to different extent at different periods of observation compared with the saline control group. The apparent recovery of liver function and the increase of 3H-TdR incorporation into hepatic DNA correlated with the morphologic changes observed under light and electron microscopes, showing that the damages inflicted on the cellular and subcellular structure in the liver of hHSS-treated rats were greatly alleviated and rapidly repaired. Therefore, hHSS, which can prevent liver deterioration and promote hepatocyte regeneration, may be a new hepatic stimulator factor readily available for clinical use.
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PMID:Hepatic stimulator substance from human fetal liver for treatment of experimental hepatic failure. 145 72

The relation among the blood clearance of 99mTc-phytate (99mTc-P), the hepatic uptake of 99mTc-P and the severity of hepatic injury was investigated by using the rats with carbon tetrachloride (CCl4), D-galactosamine (Gal N), alpha-naphthylisothiocyanate (ANIT) or DL-ethionine (EthN) induced hepatic injury. After the administration of CCl4, GalN or ANIT, serum GPT activity increased significantly with the increase of dose level, and the degree of this increase was in the order: GalN greater than CCl4 greater than ANIT. However, the mild increase in serum GPT activity was observed after EthN administration. The blood clearance rate of 99mTc-P and the hepatic uptake ratio of 99mTc-P decreased with the increase of dose level after CCl4, GalN or ANIT administration, but significant changes were not found after EthN administration. The degree of decrease in the blood clearance rate of 99mTc-P was in the order: GalN not equal to CCl4 greater than ANIT, and the degree of decrease in the hepatic uptake ratio of 99mTc-P was in the order: GalN not equal to CCl4 greater than ANIT. These results suggest that the disorder in the hepatocytes may be one of causes for inducing the decrease in the hepatic uptake of 99mTc-P, and the consequence of this decrease may induce the decrease in the blood clearance of 99mTc-P.
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PMID:Relation between blood clearance and hepatic uptake of 99mTc-phytate in rats with hepatic injury. 281 59

Studies by Liehr et al. suggest that endotoxins are important in the pathogenesis of galactosamine hepatitis (Gal-N hepatitis) in rats. Lactulose (9.1 gm per kg per day) prevents hepatic lesions induced by Gal-N; an antiendotoxin effect of lactulose is postulated. However, commercial preparations of lactulose are contaminated with galactose, which shows a competitive action to Gal-N. To analyze the effect of galactose, male Wistar rats were pretreated with lactulose (Duphalac, 9.1 gm per kg per day) and given Gal-N (375 mg per kg i.p.). After 24 hr, serum was analyzed for glutamic pyruvate transaminase, glutamate dehydrogenase, and sorbitol dehydrogenase activities. Pretreatment with Duphalac, even 1 hr before Gal-N, abolished toxicity. Duphalac contains 10 gm galactose per 100 ml. Galactose was given in a similar concentration and similar inhibition occurred. Pretreatment with purified lactulose (9.1 gm per kg for 5 days) diminished the effects of Gal-N but did not normalize enzyme concentrations. Because small doses of galactose (80 and 300 mg per kg) showed similar inhibitory effects, we conclude that the protective effect of commercial lactulose preparations is mainly due to galactose contamination and not to an antiendotoxin effect.
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PMID:Galactosamine hepatitis, endotoxemia, and lactulose. 683 15

Hongning Gantai has a remarkable counteraction on the elevation of ALT activity of mice and rats induced by chemical damages with CCl4 and D-Gal. It can decrease the BSP-retention. The result of pathologic examination indicates that Hongning Gantai can alleviate liver damages of mice and rats and thus has liver-protecting and ALT-lowering actions.
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PMID:[Liver-protecting and alanine aminotransferase lowering actions of hongning gantai]. 749 64

To study the effect of cyclic AMP on liver dysfunction, dibutyryl cyclic AMP (DBcAMP, 15 mg/kg) was given to rats with acute hepatic failure induced by D-galactosamine (D-Gal; 500 mg/kg) and lipopolysaccharide (i.e., endotoxin) (Et; 0.5 mg/kg). The survival rate was only 7% for rats given D-Gal and Et (control group), while it was 100% for rats given seven doses of DBcAMP, and 53% for rats given two doses. The ALT level was high at 3475 +/- 488 KU in group III, while it was 242 +/- 69 KU in group I, and 376 +/- 49 KU in group II. The hepaplastin test level was decreased at 24 hr in all groups except group I, in which it was high at 55 +/- 11%. The serum tumor necrosis factor (TNF) level was 155 +/- 42 IU/ml in group I, 463 +/- 30 IU/ml in group II, and 1334 +/- 328 IU/ml in group III. The results of the blood biochemistry and liver tissue blood flow studies were better in the DBcAMP-treated groups, and the serum TNF levels were also lower in the treated groups. Histological examination of the liver showed extensive necrosis in the control group, but mild necrosis and inflammatory cell infiltration in the DBcAMP-treated groups. Therefore, treatment with DBcAMP suppressed acute hepatic failure induced by D-Gal and Et, resulting in a significant increase in the survival rate.
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PMID:Protective effects of dibutyryl cyclic AMP on acute hepatic failure in rats. 895 35

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E(1)(PGE(1)) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. First poly-L-lysine (PLL) and poly-L-glutamic acid (PLGA) with an ethylenediamine (ED) spacer were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated derivatives. After intravenous injection in mice, Gal-ED-PLGA was selectively taken up by the liver parenchymal cells via receptor-mediated endocytosis, while Gal-PLL accumulated in the liver as well as PLL mostly due to electrostatic interaction. Although Gal-ED-PLGA showed good targeting efficacy, its PGE(1) conjugate synthesized with activated PGE(1) by carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE(1) during conjugation and lack of release in the tissue. In order to overcome these problems, we next conjugated PGE(1) to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) in which PGE(1) was easily coupled to Gal-HZ-PLGA via a hydrazone bond in weak acidic solution (pH 5) at room temperature. The PGE(1)-Gal-HZ-PLGA conjugate labeled with [(111)In] or [(3)H]PGE(1) rapidly accumulated in the liver parenchymal cells. In addition, the PGE(1) conjugate effectively inhibited the increase of the GPT level in plasma, while free PGE(1) indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE(1) to hepatocyte utilizing galactose recognition.
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PMID:Design of polymeric prodrugs of prostaglandin E(1) having galactose residue for hepatocyte targeting. 1051 58

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E1 (PGE1) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. Although galactosylated poly-L-glutamic acid with a ethylene diamine (ED) spacer (Gal-ED-PLGA) showed good targeting efficacy in mice, its PGE1 conjugate synthesized by the carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE1 during conjugation and lack of release in the tissue. In order to overcome these problems, PGE1 was conjugated to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) via hydrazone bond. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1 rapidly accumulated in the liver parenchymal cells after intravenous injection. In addition, PGE1 conjugate effectively inhibited the increase of GPT level in plasma, while free PGE1 indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE1 to hepatocyte utilizing galactose recognition.
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PMID:Design of polymeric prodrugs of PGE1 for cell-specific hepatic targeting. 1075 41

Prostaglandin E(1) (PGE(1) ) was incorporated in galactosylated liposomes containing cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiogalactosyle thyl)amino)b utyl)formamide (Gal-C4-Chol) intended for hepatocyte-selective delivery. Liposomes composed of distearoylphosphatidylcholine (DSPC)/cholesterol (Chol)/Gal-C4-Chol (60∶35∶5) were prepared and compared with DSPC/Chol (60∶40) liposomes. After intravenous injection of [(3) H]-labeled PGE(1) or cholesteryl hexadecyl ether (CHE) with the liposomal formulation, mice were sacrificed at a series of times, and the radioactivity in tissues was determined. Up to about 80% of [(3) H]CHE in galactosylated liposomes had accumulated in the liver 10 min after intravenous injection and the liver accumulation of the incorporated [(3) H]PGE(1) was significantly higher than that in control liposomes during the entire test period. The pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. Intravenous injection of PGE(1) incorporated in DSPC/Chol/Gal-C4-Chol (60∶35∶5) liposomes significantly suppressed the GPT increase, whereas PGE(1) (dissolved in saline) and PGE(1) incorporated in DSPC/Chol (60∶40) liposomes had little effect.
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PMID:Targeted delivery of prostaglandin E1 to hepatocytes using galactosylated liposomes. 1093 23

Neutrophils can cause parenchymal cell injury in the liver during ischemia-reperfusion and endotoxemia. Neutrophils relevant for the injury accumulate in sinusoids, transmigrate, and adhere to hepatocytes. To investigate the role of E- and L-selectin in this process, C3Heb/FeJ mice were treated with 700 mg/kg galactosamine and 100 microgram/kg endotoxin (Gal/ET). Immunogold labeling verified the expression of E-selectin on sinusoidal endothelial cells 4 hours after Gal/ET injection. In addition, Gal/ET caused up-regulation of Mac-1 (CD11b/CD18) and shedding of L-selectin from circulating neutrophils. Gal/ET induced hepatic neutrophil accumulation (422 +/- 32 polymorphonuclear leukocytes [PMN]/50 high power fields [HPF]) and severe liver injury (plasma alanine transaminase [ALT] activities: 4,120 +/- 960 U/L; necrosis: 44 +/- 3%) at 7 hours. Treatment with an anti-E-selectin antibody (3 mg/kg, intravenously) at the time of Gal/ET administration did not significantly affect hepatic neutrophil accumulation and localization. However, the anti-E-selectin antibody significantly attenuated liver injury as indicated by reduced ALT levels (-84%) and 43% less necrotic hepatocytes. In contrast, animals treated with an anti-L-selectin antibody or L-selectin gene knock out mice were not protected against Gal/ET-induced liver injury. However, E-, L-, and P-selectin triple knock out mice showed significantly reduced liver injury after Gal/ET treatment as indicated by lower ALT levels (-65%) and reduced necrosis (-68%). Previous studies showed that circulating neutrophils of E-selectin-overexpressing mice are primed and activated similar to neutrophils adhering to E-selectin in vitro. Therefore, we conclude that blocking E-selectin or eliminating this gene may have protected against Gal/ET-induced liver injury in vivo by inhibiting the full activation of neutrophils during the transmigration process.
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PMID:Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice. 1105 49

Excessive apoptotic cell death is implicated in a growing number of acute and chronic disease states. Caspases are critical for the intracellular signaling pathway leading to apoptosis. The aim of this investigation was to evaluate the efficacy and the mechanism of action of the novel caspase inhibitor CV1013 in a well-characterized model of TNF-induced apoptosis. Administration of 700 mg/kg galactosamine/100 microg/kg endotoxin (Gal/ET) induced hepatocellular apoptosis in C3Heb/FeJ mice as indicated by increased caspase-3 activity (706% above controls) and enhanced DNA fragmentation (3400% above controls) at 6 h. In addition, apoptosis was aggravated by the neutrophil-induced injury at 7 h (ALT activities: 4220 +/- 960 U/L and 48 +/- 4% necrosis). All animals died 8-12 h after Gal/ET treatment from shock and liver failure. A dose of 10 or 1 mg/kg of CV1013 administered three times (3, 4.5, and 5.5 h after Gal/ET) effectively prevented caspase-3 activation and parenchymal cell apoptosis at 6 h as well as the subsequent neutrophil-induced aggravation of the injury at 7 h after Gal/ET treatment. Animals treated with 10 mg/kg CV1013 survived for 24 h without liver injury. CV1013 reduced the processing of caspase-3 and caspase-8. This suggests that CV1013 may have inhibited the small amount of active caspase-8 generated at the receptor level. Because of the multiple amplification loops used to activate the entire caspase cascade, blocking the initial intracellular signal by CV1013 was highly effective in preventing apoptotic cell death. CV1013 has therapeutic potential for disease states with excessive apoptosis.
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PMID:Protection against TNF-induced liver parenchymal cell apoptosis during endotoxemia by a novel caspase inhibitor in mice. 1107 99


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