Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA, which are caused by reactive oxygen species (ROS). Here we investigate the effects of the PARS inhibitors 3-aminobenzamide (3-AB), nicotinamide and 1,5-dihydroxyisoquinoline (ISO) on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat. 2 Haemorrhage (sufficient to lower mean arterial blood pressure to 50 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure to 66+/-4 mmHg (control, n=13). This circulatory failure was not affected by administration (5 min prior to resuscitation) of 3-AB (10 mg kg-1 i.v., n=7), nicotinamide (10 mg kg-1 i.v., n=6) or ISO (3 mg kg-1 i.v., n=6). 3 Haemorrhage and resuscitation also resulted in rises in the serum levels of urea and creatinine. This renal dysfunction was attenuated by 3-AB and nicotinamide, but not by nicotinic acid (n=7), an inactive analogue of nicotinamide. Although ISO (n=6) also attenuated the renal dysfunction caused by haemorrhage and resuscitation, its vehicle (10% DMSO, n=4) had the same effect. 4 Haemorrhagic shock resulted in enhanced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lipase, indicating the development of hepatocellular and pancreatic injury, respectively. Similarly, haemorrhagic shock also resulted in an increase in the serum levels of creatine kinase (CK) indicating the development of neuromuscular injury. This was attenuated by 3-AB and nicotinamide, but not by nicotinic acid. Although ISO also attenuated the liver, pancreatic and neuromuscular injury caused by haemorrhagic shock, its vehicle had the same effect. 5 Thus, activation of PARS contributes to the organ injury and dysfunction caused by haemorrhage and resuscitation in the rat.
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PMID:Effects of inhibitors of the activity of poly (ADP-ribose) synthetase on the organ injury and dysfunction caused by haemorrhagic shock. 1057 50

The vitamin B-6 status of Indonesian children was evaluated by determining their dietary vitamin B-6 intakes, erythrocyte alanine aminotransferase activity coefficients and plasma pyridoxal phosphate (PLP) concentrations. Thirty-eight third-grade elementary school children (ages = 8-9 y) in rural and 39 in urban areas of Bogor, West Java, Indonesia, voluntarily served as subjects. The subjects included 39 male and 38 female students. The mean vitamin B-6 intake of the subjects was 0.57 mg/d. Fifty-five percentage of the children reported consuming <0.5 mg/d of vitamin B-6 (the 1998 Estimated Average Requirement for those 4-8 y). Erythrocyte alanine aminotransferase activity coefficients >/= 1.25 were observed in 30%, and plasma PLP concentrations </= 30 nmol/L were observed in 25%; these values are considered indicative of vitamin B-6 inadequacy. Similar percentages of male and female subjects had inadequate vitamin B-6 status. Significantly more (P < 0.05) rural children than urban had inadequate vitamin B-6 status as assessed by the three indices. Vitamin B-6 inadequacy was found to be prevalent among these Indonesian children, especially those living in rural areas.
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PMID:Vitamin B-6 inadequacy is prevalent in rural and urban Indonesian children. 1070 84

In a prospective, randomized, double-blind therapeutic trial, 191 patients with non-alcoholic steatohepatitis were treated for 8 weeks daily b.i.d. orally either with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate (Ietepar) (96 patients) or with undistinguishable placebo capsules (95 patients). The verum treatment effectively reduced by 25% hepatic steatosis (p < 0.01) and by 6% hepatomegaly (p < 0.05), while placebo did not significantly reduce the disorders. Verum was also more effective than placebo on discomfort in abdominal upper right quadrant. The global efficacy of treatment was rated by the doctor "very good" or "good" in 48% of verum treated patients and only in 17% after placcbo (P of difference = 9 x 10(-6)). 52% of patients self-rated efficacy as "very good" or "good" after verum and only 34% after placebo (P of difference = 0.017). The verum treatment provoked a significant reduction of the increased liver transaminases (ALT, AST and gamma-GT) while placebo was ineffective. Adverse events were recorded in 10% of verum-treated patients and in 7% under placebo (no significant difference). In both groups the adverse events were mild and transient, did not require treatment discontinuation and were undistinguishable from common symptoms of liver disorders. In conclusion, the 8-week treatment with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate was found effective in non-alcoholic steatohepatitis, a disorder for which the hitherto pharmacological interventions were poorly and inconsistently effective.
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PMID:Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. 1099 56

Acetaminophen (AAP), the analgesic hepatotoxicant, is a powerful inducer of oxidative stress, DNA fragmentation, and apoptosis. The anti-apoptotic oncogene bcl-XL, and the pro-apoptotic oncogene p53 are two key regulators of cell cycle progression and/or apoptosis subsequent to DNA damage in vitro and in vivo. This study investigated the effect of AAP on the expression of these oncogenes and whether agents that modulate DNA fragmentation (chlorpromazine, CPZ) and DNA repair through poly(ADP-Ribose) polymerase (PARP) activity (4-AB: 4-aminobenzamide) can protect against AAP-induced hepatotoxicity by inhibiting oxidative stress, DNA fragmentation, and/or by altering the expression of bcl-XL and p53. In addition, the protective effect of supplemental nicotinamide (NICO), known to be depleted in cells with high PARP activity during DNA repair, is similarly evaluated. Male ICR mice (3 months old) were administered vehicle alone; nontoxic doses of 4-AB (400 mg/kg, ip), NICO (250 mg/kg, ip) or CPZ (25 mg/kg, ip), hepatotoxic dose of AAP alone (500 mg/kg, ip), or AAP plus one of the protective agents 1 h later. All animals were sacrificed 24 h following AAP administration. Serum alanine aminotransferase activity (ALT), hepatic histopathology and lipid peroxidation, DNA damage, and expression of bcl-XL and p53 (western blot analysis) were compared in various groups. All of the three agents significantly prevented AAP-induced liver injury, lipid peroxidation, DNA damage, and associated apoptotic and necrotic cell deaths, 4-AB being the most effective and NICO the least. Compared to control, there was a considerable decrease in bcl-XL expression, and an increase in p53 expression in AAP-exposed livers. The effect of AAP on bcl-XL was antagonized and that on p53 was synergized by the PARP-modulator 4-AB as well as NICO, whereas the endonuclease inhibitor CPZ was without effect on either bcl-XL or p53 expression. These results suggest that the hepatotoxic effect of AAP involves multiple mechanisms including oxidative stress, upregulation of endonuclease (or caspase-activated DNAse) and alteration of pro- and anti-apoptotic oncogenes. The observed antagonism of AAP-induced hepatocellular apoptosis and/or necrosis by modulators of multiple processes including DNA repair suggests the likelihood that a more effective therapy against AAP intoxication should involve a combination of antidotes.
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PMID:Ca(2+)-calmodulin antagonist chlorpromazine and poly(ADP-ribose) polymerase modulators 4-aminobenzamide and nicotinamide influence hepatic expression of BCL-XL and P53 and protect against acetaminophen-induced programmed and unprogrammed cell death in mice. 1146 65

The Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) of vitamin B-6 for children were recently estimated by extrapolating from adult values because of limited available information. To determine vitamin B-6 requirements and provide recommendations for intakes, vitamin B-6 intake, nutritional status and anthropometry of 168 healthy children (79 boys and 89 girls) were studied in Tainan, Taiwan. Direct and indirect vitamin B-6 status indicators were measured in plasma, erythrocytes and urine. Anthropometric data of children in this study were similar to those of the first Nutrition and Health Survey in Taiwan (NAHSIT) conducted in 1993-1996. The plasma pyridoxal phosphate (PLP) concentration of each child was >/=30 nmol/L, indicating an adequate vitamin B-6 status. Daily dietary vitamin B-6 intakes of boys and girls were 0.80 +/- 0.16 and 0.74 +/- 0.16 mg/d, respectively. Daily dietary vitamin B-6 intakes of children who had adequate urinary 4-pyridoxic acid (4-PA) (>3.0 micro mol/L), erythrocyte alanine aminotransferase activity coefficient (EALT-AC) (<1.25) and aspartate aminotransferase activity coefficient (EAST-AC) (<1.8) were not different from those of children who had adequate plasma PLP, although the percentages of adequacy for urinary 4-PA, EALT-AC and EAST-AC ranged from 20 to 91%. Vitamin B-6 status indicators were strongly correlated with vitamin B-6 intake. Adequate values of PLP, EALT-AC, EAST-AC and urinary 4-PA were used to determine the EAR according to Dietary Reference Intake (DRI) committee methodology. We determined the vitamin B-6 EAR (RDA) for boys and girls aged 7-12 y to be 0.84 (1.01) and 0.75 (0.89) mg/d, respectively.
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PMID:Determination of vitamin B-6 estimated average requirement and recommended dietary allowance for children aged 7-12 years using vitamin B-6 intake, nutritional status and anthropometry. 1236 6

Alcoholic extract of the stems of Coscinium fenestratum, a medicinal plant indigenous to India and Sri Lanka used in ayurveda and siddha medicine for treating diabetes, was studied for its carbohydrate metabolism effect and antioxidant status in streptozotocin-nicotinamide induced type 2 diabetic rats. Oral administration of C. fenestratum stem extract in graded doses caused a significant increase in enzymatic antioxidants such as catalase, superoxide dismutase, glutathione synthetase, peroxidase, and glutathione peroxidase and in the nonenzymatic antioxidants ascorbic acid, ceruloplasmin and tocopherol. Effects of alcoholic extract on glycolytic enzymes such as glucose-6-phosphate dehydrogenase, lactate dehydrogenase and hexokinase showed a significant increase in their levels, whereas a significant decrease was observed in the levels of gluconeogenic enzyme, glucose-6-phosphatase and alanine aminotransferase in treated diabetic rats. Serum creatinine and urea levels also declined significantly. This investigation demonstrates significant antidiabetic activity of C. fenestratum.
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PMID:Alcoholic stem extract of Coscinium fenestratum regulates carbohydrate metabolism and improves antioxidant status in streptozotocin-nicotinamide induced diabetic rats. 1613 16

The serum concentrations of Unsaturated Vitamin B(12) binding (UBBC) capacity and the three individual transcobalamins were measured in 34 malnourished children aged 9 months-5 y. Levels of serum vitamin B12, aspartate aminotransferase, alanine aminotransferase, albumin and total proteins were also estimated. The serum UBBC, Transcobalamin I (TC I), Transcobalamin III (TC III), vitamin B12 and the enzyme activities were significantly higher in the kwashiorkor children when compared with both the marasmic and control children. There was also a marked reduction of serum Transcobalamin II (TC II), albumin and total proteins in the kwashiorkor children. In contrast with kwashiorkor, there was a slight increase of serum TC II in the marasmic children. Their serum UBBC, TC I, TC III and B12 were also raised but not as high as in kwashiorkor. These results are discussed in the light of the hepatic dysfunction in kwashiorkor affecting the production of TC II in the liver, while the elevated serum B12 in Protein-energy malnutrition (PEM) may be due to both hepatic damage and intensified release of TC I as a result of infection.
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PMID:Clinical significance of serum transcobalamins in protein-energy malnutrition. 1682 16

The tricarboxylic acid (TCA) cycle is the major final common pathway for oxidation of carbohydrates, lipids and some amino acids, which produces reducing equivalents in the form of nicotinamide adenine dinucleotide and flavin adenine dinucleotide that result in production of large amounts of adenosine triphosphate (ATP) via oxidative phosphorylation. Although regulated primarily by the products of ATP hydrolysis, in particular adenosine diphosphate, the rate of delivery of reducing equivalents to the electron transport chain is also a potential regulatory step of oxidative phosphorylation. The TCA cycle is responsible for the generation of approximately 67% of all reducing equivalents per molecule of glucose, hence factors that influence TCA cycle flux will be of critical importance for oxidative phosphorylation. TCA cycle flux is dependent upon the supply of acetyl units, activation of the three non-equilibrium reactions within the TCA cycle, and it has been suggested that an increase in the total concentration of the TCA cycle intermediates (TCAi) is also necessary to augment and maintain TCA cycle flux during exercise. This article reviews the evidence of the functional importance of the TCAi pool size for oxidative metabolism in exercising human skeletal muscle. In parallel with increased oxidative metabolism and TCA cycle flux during exercise, there is an exercise intensity-dependent 4- to 5-fold increase in the concentration of the TCAi. TCAi concentration reaches a peak after 10-15 minutes of exercise, and thereafter tends to decline. This seems to support the suggestion that the concentration of TCAi may be of functional importance for oxidative phosphorylation. However, researchers have been able to induce dissociations between TCAi pool size and oxidative energy provision using a variety of nutritional, pharmacological and exercise interventions. Brief periods of endurance training (5 days or 7 weeks) have been found to result in reduced TCAi pool expansion at the start of exercise (same absolute work intensity) in parallel with either equivalent or increased oxidative energy provision. Cycloserine inhibits alanine aminotransferase, which catalyses the predominant anaplerotic reaction in exercising human muscle. When infused into contracting rat hindlimb muscle, TCAi pool expansion was reduced by 25% with no significant change in oxidative energy provision or power output. Glutamine supplementation has been shown to enhance TCAi pool expansion at the start of exercise with no increase in oxidative energy provision. In summary, there is a consistent dissociation between the extent of TCAi pool expansion at the onset of exercise and oxidative energy provision. At the other end of the spectrum, the parallel loss of TCAi, glycogen and adenine nucleotides and accumulation of inosine monophosphate during prolonged exercise has led to the suggestion that there is a link between muscle glycogen depletion, reduced TCA cycle flux and the development of fatigue. However, analysis of serial biopsies during prolonged exercise demonstrated dissociation between muscle TCAi content and both muscle glycogen content and muscle oxygen uptake. In addition, the delay in fatigue development achieved through increased carbohydrate availability does not attenuate TCAi reduction during prolonged exercise. Therefore, TCAi concentration in whole muscle homogenate does not seem to be of functional importance. However, TCAi content can currently only be measured in whole muscle homogenate rather than the mitochondrial subfraction where TCA cycle reactions occur. In addition, anaplerotic flux rather than TCAi content per se is likely to be of greater importance in determining TCA cycle flux, since TCAi content is probably merely reflective of anaplerotic substrate concentration. Methodological advances are required to allow researchers to address the questions of whether oxidative phosphorylation is limited by mitochondrial TCAi content and/or anaplerotic flux.
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PMID:Tricarboxylic acid cycle intermediate pool size: functional importance for oxidative metabolism in exercising human skeletal muscle. 1802 94

Vitamin B(12) contains a cobalt complex and accumulates at high levels in the liver. Vitamin B(12) was examined for its hepatoprotective effect on dimethylnitrosamine-induced liver injury in mice. Vitamin B(12) decreased the blood levels of aspartate aminotransferase and alanine aminotransferase, and clearly inhibited the overaccumulation of collagen fibrils. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the liver showed that the gene expression of alpha-smooth muscle actin and heat-shock protein 47, which are markers of fibrosis, were suppressed by vitamin B(12) administration. Our findings indicate that vitamin B(12) could be an effective hepatoprotective agent.
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PMID:Hepatoprotective effect of vitamin B12 on dimethylnitrosamine-induced liver injury. 1823 93

Resveratrol is a polyphenolic phytoalexin produced in appreciable amounts as a secondary metabolite in grapevines in response to fungal infections. Based on the present knowledge, it appears to be a promising bioactive natural molecule with potential applications in phytotherapy or pharmacology. The present study was aimed to evaluate the antidiabetic properties of resveratrol in streptozotocin-nicotinamide induced experimental diabetes in rats. The diabetic rats orally treated with resveratrol (5 mg kg(-)(1)b.w d(-)(1)) for 30 days resulted in significant (p<0.05) decrease in the levels of blood glucose, glycosylated hemoglobin, blood urea, serum uric acid, serum creatinine and diminished activities of pathophysiological enzymes such as aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). The antihyperglycemic nature of resveratrol is also evidenced from the improvement in the levels of plasma insulin and hemoglobin. Further, the results are comparable with glyclazide, an oral standard drug. Thus, the present findings suggest that resveratrol may be considered as an effective therapeutic agent for the treatment of diabetes mellitus.
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PMID:Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. 1867 32


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