Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A selective deficiency of uridine triphosphate (UTP) was induced in AS-30D rat ascites hepatoma cells by the synergistic action of D-galactosamine and 6-azauridine. The resistance of these hepatoma cells to low concentrations of D-galactosamine (less than 2 mM) was due to their active de novo pyrimidine synthesis which compensated the trapping of uridylate in the form of uridine diphosphate-amino sugars derived from D-galactosamine. The additional blockage of de novo pyrimidine synthesis led to noncompensated uridylate trapping with a UTP content of less than 0.05 mmole/kg of cell wet weight as compared to the control level of 0.66 mmole/kg. The induction of UTP deficiency by incubating the cells with low concentrations of D-galactosamine and 6-azauridine (0.5 mM each) was not accompanied by significant changes in the content of adenine and guanine nucleotides, uridine diphosphate glucose, and uridine diphosphate galactose. The depletion of UTP pools could be reversed within 10 min by the addition of uridine; orotate or uracil were completely ineffective in these hepatoma cells. A UTP content in the range of 0.1 to 0.4 mmole/kg, induced by either 6-azauridine or D-galactosamine, was associated with a reversible depression of cell growth in suspension culture. A UTP content below 0.05 mmole/kg led to irreversible growth inhibition and to necrocytosis in culture, as well as to a loss of transplantability in vivo. Uridine reversal studies indicated that the percentage of cells able to resume growth in culture decreased with an increasing time period of UTP deficiency. The deficiency period required for irreparable or lethal damage in these hepatoma cells ranged from 3 to 20 hr. The principle of noncompensated uridylate trapping can be extended to other inhibitors of nucleotide synthesis combined with various nucleotide-trapping sugar analogs. Noncompensated nucleotide trapping may be useful for an induction of selective nucleotide deficiencies in tumor cells.
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PMID:Uridine triphosphate deficiency, growth inhibition, and death in ascites hepatoma cells induced by a combination of pyrimidine biosynthesis inhibition with uridylate trapping. 18 18

Behavioral and electrophysiological evidence implicating the GABA-benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy was obtained using an improved rat model of hepatic encephalopathy caused by thioacetamide-induced fulminant hepatic failure. After the administration of thioacetamide together with supportive therapy, acute hepatocellular failure developed in rats as a result of massive hepatocellular necrosis without evidence of renal failure or hypoglycemia. The evolution of hepatic encephalopathy in this model was sufficiently slow to readily permit the staging of the syndrome. Prominent features of the encephalopathy include a marked reduction in open field activity and an abnormal visual evoked response. Both the deficits in spontaneous motor function and visual evoked response abnormalities of rats in stages III to IV hepatic encephalopathy were significantly improved after the administration of the benzodiazepine receptor ligands flumazenil or Ro 15-4513. Doses of flumazenil or Ro 15-4513 that produced these effects in rats with hepatic encephalopathy had no detectable action on either the behavior or the visual evoked responses of normal rats. The ability of benzodiazepine receptor ligands to ameliorate both the behavioral depression and the visual evoked response abnormalities associated with hepatic encephalopathy in the thioacetamide-induced rat model suggest an involvement of the GABA/benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy. In addition, the similarity of these observations to those in rabbits with hepatic encephalopathy caused by galactosamine-induced fulminant hepatic failure is compatible with the hypothesis that the mechanisms of hepatic encephalopathy in these two distinct models share a common final pathway, the allosteric enhancement of GABAergic tone through the benzodiazepine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reversal of the behavioral and electrophysiological abnormalities of an animal model of hepatic encephalopathy by benzodiazepine receptor ligands. 215 65

Several glycosyltransferases participating in ganglioside biosynthesis were measured in Golgi-rich fractions from rat liver. Addition of those UDP-amino sugars to the enzyme assays which accumulate in liver after treatment of rats with D-galactosamine inhibited the transferases to different degrees. The simultaneous presence of UDP-GalN, UDP-GalNAc, UDP-GlcN, and UDP-GlcNAc in concentrations resembling their overall content in livers 6 h after D-galactosamine administration led to an inhibition of the glycolipid galactosyltransferases, GL2 and GM1 synthases of 44 and 64%, respectively. GM2 synthase was moderately inhibited whereas the sialyltransferases (GM3, GD3, and GD1a synthases) were almost unimpaired. Induction of liver cell damage by D-galactosamine did not cause any change of glycosyltransferase activities as determined in rat liver homogenates and Golgi-rich fractions. These results indicate a possible role for UDP-amino sugars in the depression of ganglioside biosynthesis observed in vivo after GalN administration.
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PMID:Ganglioside biosynthesis in rat liver: effect of UDP-amino sugars on individual transfer reactions. 296 46

A new approach to pathogenetic study of hepatic encephalopathy was recently undertaken in order to identify the neurological alterations of the brain which characterize the coma. In this study attention was firstly addressed to a correct and objective evaluation of the comatose state in rats with fulminant hepatic failure induced by galactosamine. For this purpose visual evoked potentials were utilized since this electrophysiological test proved reliable and sensitive on the basis of an extensive pharmacological study. Two different stages of coma were identified in the rat and they were named mild and severe. Receptor binding studies performed on brain membranes of these rats show in the mild stage an increased number of low and high affinity GABA receptors and a decreased affinity of dopamine receptors. The severe stage is characterized by the persistence of only high affinity GABA receptors and a reduced number of dopamine receptors. This imbalance between inhibitory and excitatory receptor systems may explain the generalized central nervous system depression which characterizes the hepatic encephalopathy while the increased number of benzodiazepine receptors found in both stages of coma may account for the brain supersensitivity to sedative administration of patients with liver disease and for the sedative-induced episodes of coma. These receptor alterations may be attributed to a disuse and/or a partial degeneration of nerve terminals due to peripheral neurotoxins (i.e., ammonia, mercaptans, short chain fatty acids) and the decrease of glutamate decarboxylase activity and of zinc levels in brain tissues seems to be respectively a direct and an indirect demonstration of this phenomenon. Bearing in mind the supersensitivity of the GABA-benzodiazepine receptor system and their reciprocal interaction, a benzodiazepine antagonist was administered to rats in mild stage of encephalopathy. Electrophysiological and benzodiazepine binding studies demonstrated that this treatment can temporarily counteract some of the neurological disturbances of the earlier stage of coma and act as antidote of the sedative-induced episodes of coma.
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PMID:Hepatic encephalopathy. Experimental studies in a rat model of fulminant hepatic failure. 299 24

As shown by light and electron microscopy, and by biochemical investigation, D-galactosamine-induced hepatocellular injury in the rat can be prevented by giving fructose simultaneously. However, when injected 3 h after D-galactosamine, fructose has no protective effect. It is suggested that rapid fructose phosphorylation, with the consequent marked depression of the hepatocellular ATP pool, inhibits the more prolonged D-galactosamine phosphorylation and with it the injurious effects of D-galactosamine metabolism.
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PMID:The pattern of D-galactosamine-induced hepatocellular injury modified by simultaneous application of D (--)-fructose. 611 37

Following the administration of D-galactosamine the utilization of [2-14C] orotic acid for the synthesis of the cytidine components of the acid-soluble extract and liver RNA cytosine is markedly decreased. The depression of the specific activity of the cytidine components takes place after application of low doses of the drug which do not interfere with the specific activity of the uridine components of the acid-soluble extract or of liver RNA uracil. Simultaneously the administration of [U-14C]cytidine paralleled by its enhanced liver uptake. The total amount of uridine as well as cytidine components of the acid-soluble extract following the administration of D-galactosamine increases; however, the molar ratio of both pyrimidines does not change. The alterations of the cytidine metabolism after the administration of the drug are accompanied by the increased level of microsomal cytochrome P-450.
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PMID:Biosynthesis of cytidine nucleotides in rat liver after administration of D-galactosamine. 616 66

Many polar fishes synthesize a group of eight glycopeptides that exhibit a non-colligative lowering of the freezing point of water. These glycopeptides range in molecular weight between 2600 and 33 700. The largest glycopeptides [1-5] lower the freezing point more than the small ones on a weight basis and contain only two amino acids, alanine and threonine, with the disaccharide galactose-N-acetyl-galactosamine attached to threonine. The small glycopeptides, 6, 7, and 8, also lower the freezing point and contain proline, which periodically substitutes for alanine. Glycopeptides with similar antifreeze properties isolated from the saffron cod and the Atlantic tomcod contain an additional amino acid, arginine, which substitutes for threonine in glycopeptide 6. In this study we address the question of whether differences in amino acid composition or molecular weight between large and small glycopeptides are responsible for the reduced freezing point depressing capability of the low molecular weight glycopeptides. The results indicate that the degree of amino acid substitutions that occur in glycopeptides 6-8 do not have a significant effect on the unusual freezing point lowering and that the observed decrease in freezing point depression with smaller glycopeptides can be accounted for on the basis of molecular weight.
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PMID:Relationship of amino acid composition and molecular weight of antifreeze glycopeptides to non-colligative freezing point depression. 711 72

Dichloroacetate has been shown to have therapeutic effects on sepsis and endotoxin shock and to reduce liver damage in rats intoxicated with ethanol or carbon tetrachloride. In this study, the effect of dichloroacetate on endotoxin hepatitis was investigated. Endotoxin hepatitis was induced by an intraperitoneal coadministration of 50 micrograms/kg lipopolysaccharide from Escherichia coli, and 200 mg/kg D-galactosamine in starved, male Wistar rats. This treatment induced the following changes within 24 hr: an increase in the serum aminotransferase activity, histological alterations of the liver including focal necrosis of liver cells and inflammatory infiltrates, an increase in blood pyruvate and alanine concentrations, and inhibition of starvation ketosis. The intraperitoneal administration of 250 mg/kg dichloroacetate 30 min after the administration of the toxins partially counteracted all of these changes. The administration of dichloroacetate might be useful in coping with hepatic damage as well as lacticemia and cardiovascular depression induced by endotoxins.
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PMID:The limiting effect of dichloroacetate on endotoxin-induced liver damage in starved rats. 814 37

Plasma hyaluronan (HA) concentration and the rate of HA uptake by the isolated, perfused liver were measured in rats treated with saline, D-galactosamine (GaI-NH2, 50 mg/100 g body wt), gadolinium chloride (GdCl3) (0.5 mg/100 g body wt), and GdCl3 + GaI-NH2. GdCl3 was given 24 hr before GaI-NH2 or saline. Plasma L-alanine:2-oxoglutarate aminotransferase (EC 2.6.1.2), a marker for hepatocyte damage, was increased by 8 hr and remained elevated for 24 hr after GaI-NH2 injection. GdCl3 did not affect plasma enzyme levels when given alone or in association with, but prior to, GaI-NH2. Plasma HA levels were increased (200%) within 24 hr after GaI-NH2 administration. A plateau was reached at 8 hr, which was maintained for at least 24 hr. Although GdCl3 alone did not affect plasma HA levels, it slightly delayed the increase in HA concentration in GaI-NH2-treated rats. Livers, isolated 24 hr after GaI-NH2 treatment, exhibited a severe depression (approximately 67%) of HA uptake. GdCl3 did not prevent this suppression. The data presented indicate that: (1) one of the sinusoidal endothelial cell-dependent functions of the liver, i.e. removal of HA from the blood stream, is profoundly impaired during galactosamine-induced hepatitis, and (2) the adverse effect of GaI-NH2 on this sinusoidal endothelial cell function may not be dependent on CdCl3-suppressible Kupffer cell functions.
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PMID:Association of galactosamine-induced hepatitis in the rat with hyperhyaluronanaemia and decreased hyaluronan uptake by the isolated, perfused liver. 836 40

The protective effects of a new, selective, plant-derived platelet-activating factor (PAF) antagonist, yangambin, on the cardiovascular alterations and mortality due to endotoxic shock were investigated in anaesthetized rats. We also studied the involvement of PAF in the induction of the vascular and cardiac hyporesponsiveness to adrenergic stimulation observed during endotoxaemia. The animals were sensitized to the lethal effects of Escherichia coli lipopolysaccharide (LPS) with D(+)-galactosamine (50 mg/kg, i.v.) 15 min before LPS injection. LPS (3 mg/kg, i.v.) induced a progressive and marked decrease in mean arterial blood pressure from 85+/-4 to 30+/-3 mmHg and a reduction of cardiac output (CO) from 180+/-7 to 37+/-3 ml/min (120 min) accompanied by a maintenance of systemic vascular resistance, suggesting that cardiovascular collapse resulted mainly from myocardial depression. The maximum pressor responses to noradrenaline (0.3-3.0 microg/kg, i.v.) fell from 72+/-9 (control) to 5+/-1 mmHg (LPS) while the CO responses decreased from 81+/-5 to 8+/-3 ml/min. Pre-treatment with yangambin (30 mg/kg, i.v.) or with WEB 2086 (5 mg/kg, i.v.), a reference PAF receptor antagonist, completely prevented the LPS-induced cardiovascular collapse and abolished the sharp reductions of the arterial blood pressure and CO responses to noradrenaline observed during endotoxaemia. Post-treatment with yangambin 90 min after LPS administration did not reverse the arterial hypotension, cardiac failure or cardiovascular hyporesponsiveness to catecholamines. Finally, the acute (150 min) survival rates of endotoxic shock increased from 0% (LPS group) to 100% in the groups pretreated with either yangambin or WEB 2086. The long-term (7-day) survival also increased from 0% (LPS group) to 85% (yangambin pre-treatment group). In conclusion, these data suggest a role for PAF in the pathogenesis of endotoxin-induced vascular and cardiac hyporesponsiveness to catecholamines and confirm its involvement in the complex cascade of multiple mediators released during endotoxic/septic shock. Yangambin proved to be an effective pharmacological agent against cardiovascular collapse and mortality in endotoxin shock.
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PMID:Protective effects of yangambin on cardiovascular hyporeactivity to catecholamines in rats with endotoxin-induced shock. 1128 40


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