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)

The ability to document the extent of hepatic injury and predict the outcome of fulminant hepatic failure would be helpful in identifying those patients who might benefit from liver transplantation. The aim of the present study was to determine whether in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS) accurately assesses the severity of liver damage and is of prognostic value in a D-galactosamine (D-galN)-induced model of acute liver failure. Adult male Sprague-Dawley rats (n = 36) received an intraperitoneal dose of D-galN (1.0 g/kg), and MRS examinations were performed at peak (48 hours) and in subsequent experiments, just prior to peak (30 hours) hepatic injury. Rats not exposed to D-galN served as controls. The concentration of hepatic phosphorylated metabolites decreased in proportion to the severity of liver injury at 48 hours. Significant correlations were detected between hepatic adenosine triphosphate (ATP) and serum aspartate aminotransferase, bilirubin, and percentage of hepatocyte necrosis identified histologically (r = -.91, -.74, and -.92, respectively; p < .001). Prior to peak hepatic injury (30 hours), 31P MRS was able to predict with 100% accuracy those rats that would survive (ATP > 2.3 mM) and those that would not (ATP < 1.5 mM). When an intermediate cutoff value of 2.0 mM was selected, ATP levels were able to correctly predict survival and death with 80% and 60% accuracy, respectively. These findings indicate that hepatic ATP levels as measured by 31P MRS provide a noninvasive indication of the severity of liver damage and serve as a useful prognostic indicator of outcome in this model of acute liver failure.
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PMID:Utility of hepatic phosphorus-31 magnetic resonance spectroscopy in a rat model of acute liver failure. 1258 Mar 20

HP-1 a herbal formulation comprising of Phyllanthus niruri and extracts of Terminalia belerica, Terminalia chebula, Phyllanthus emblica and Tinospora cordifolia has been evaluated for hepatoprotective activity against carbon tetrachloride (CCl4) induced toxicity. Results show that HP-1 reversed the leakage of lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) and prevented the depletion of glutathione (GSH) levels in a primary monolayer culture of rat hepatocytes (in vitro). HP-1 attenuated the serum toxicity as manifested in elevated levels of transaminases (glutamate oxaloacetate transaminase (GOT), and GPT) The antioxidative enzymes in liver (catalase and superoxide dismutase (SOD)) were restored to normal values after the oral administration of HP-1. HP-1 suppressed the formation of the superoxide anion radical and reduced CCl4 mediated lipid peroxidation (LPO). Silymarin and antioxidants (ascorbic acid, beta-carotene and alpha-tocopherol) were used for comparison. The present study showed that HP-1 is a potential hepatoprotective formulation with an additional attribute of being anti-peroxidative.
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PMID:Hepatocurative and antioxidant profile of HP-1, a polyherbal phytomedicine. 1499 25

Many enzymes catalyze fast exchange between a small pool and a large pool in vivo. For example, aspartate aminotransferase catalyzes fast exchanges between alpha-ketoglutarate and glutamate and between oxaloacetate and aspartate, which can be detected using in vivo(13)C MRS while saturating alpha-carbons of the keto acids. Unlike in the traditional saturation transfer experiments studied using (31)P MRS, the tricarboxylic acid cycle intermediates alpha-ketoglutarate and oxaloacetate are below the detection limit of in vivo NMR. In this work, a theoretical analysis of the saturation transfer between alpha-ketoglutarate and glutamate catalyzed by aspartate aminotransferase was presented to examine the requirements for complete saturation of the rapidly turning over alpha-ketoglutarate pool without affecting the longitudinal magnetization of glutamate. The fast turnover of the small alpha-ketoglutarate pool also allows a quasi-steady-state approximation of its dynamic longitudinal relaxation. The theoretical analysis provides a useful guide for designing experimental methods to characterize saturation transfer processes associated with fast turning over small pools in vivo.
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PMID:Theoretical analysis of carbon-13 magnetization transfer for in vivo exchange between alpha-ketoglutarate and glutamate. 1652 Oct 93

The role of A3 adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-alpha 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5'N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
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PMID:A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis. 1677 64

Malate dehydrogenase catalyzes rapid interconversion between dilute metabolites oxaloacetate and malate. Both oxaloacetate and malate are below the detection threshold of in vivo MRS. Oxaloacetate is also in rapid exchange with aspartate catalyzed by aspartate aminotransferase, the latter metabolite is observable in vivo using (13)C MRS. We hypothesized that the rapid turnover of oxaloacetate can effectively relay perturbation of magnetization between malate and aspartate. Here, we report indirect observation of the malate dehydrogenase reaction by saturating malate C2 resonance at 71.2 ppm and detecting a reduced aspartate C2 signal at 53.2 ppm due to relayed magnetization transfer via oxaloacetate C2 at 201.3 ppm. Using this strategy the rate of the cerebral malate dehydrogenase reaction was determined to be 9+/-2 micromol/g wet weight/min (means+/-SD, n=5) at 11.7 Tesla in anesthetized adult rats infused with [1,6-(13)C(2)]glucose.
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PMID:Relayed (13)C magnetization transfer: detection of malate dehydrogenase reaction in vivo. 1712 47

Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) and lactate in ALF and associate the results with other liver function parameters. Five pediatric patients with ALF-related encephalopathy and five controls, examined after successful liver transplantation, were examined by brain MRI/MRS. ALF patients had higher Glx and lactate concentrations in brain white matter than controls (Glx + 125%: P < 0.01; lactate + 33%, P < 0.05) and higher Glx in grey matter (Glx + 125%: P < 0.01). Within the group of ALF patients positive correlations were found between grey or white matter lactate concentration and serum ammonia (P < 0.05), and negative correlations between grey or white matter Glx and venous pH (P < 0.001). This is the first study presenting evidence of high Glx levels in both white and grey matter brain tissue in ALF-related encephalopathy. The elevations in CNS Glx and lactate concentrations appear to relate to hepatic detoxification (ammonia, venous pH), rather than to liver parenchymal integrity (aspartate aminotransferase, alanine aminotransferase) or biliary cholestasis (bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase).
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PMID:Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure. 1849 80

Mitochondrial functions are intimately associated with neurological symptoms. Various clinical and biological features are suggestive of energy depletion diseases, such as Leigh syndrome, Alpers syndrome, epilepsy (including myoclonic seizures and status epilepticus), stroke-like episodes, and acute cerebellar ataxia with high lactate peaks on magnetic resonance spectroscopy. Magnetic resonance imaging (MRI) discloses abnormalities in over 90% of the cases presenting with neurological symptoms. Basal ganglionic involvement, the most frequent imaging sign, can be isolated or combined with subtentorial atrophy of both the cerebellum and brainstem. MRS monovoxel proton spectroscopy is useful to reveal high lactate spikes if placed in the putamen and the cerebellar dentate nucleus. Lactate and pyruvate levels are required to exclude pyruvate dehydrogenase deficiency. However, lactate may be normal in the CSF. Clinical and biochemical investigations guide molecular studies, with two major heredities: mtDNA point mutations and autosomal recessive defects that program the majority of respiratory chain subunits. Muscle biopsy is the first test demonstrating the histochemical and ultrastructural alterations in mitochondria, even in diseases in which myopathy is not clinically prominent, and is also a good tissue for biochemical analysis, as the biopsy is not dangerous for the patient. Negative results in skeletal muscle do not exclude respiratory chain deficiency, and a liver biopsy may be necessary whatever the blood AST and ALT levels, to perform biochemical and molecular investigations. Only the identification of nuclear or mitochondrial mutation confirms the diagnosis.
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PMID:Respiratory chain deficiencies. 2362 86

In patients suffering from stress-related pathologies and depression, frontal cortex GABA and glutamate contents are reported to decrease and increase, respectively. This suggests that the GABA and/or glutamate content may participate in pathological phenotype expression. Whether differences in frontal cortex GABA and glutamate contents would be associated with specific behavioral and neurobiological patterns remains unclear, especially in the event of exposure to moderate stress. We hypothesized that an increase in prefrontal cortex GABA/glutamate ratio would be associated with a blunted prefrontal cortex activation, an enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activation and changes in behavior. Rats being restrained for 1-h were then tested in an open-field test in order to assess their behavior while under stress, and were sacrificed immediately afterward. The GABA/glutamate ratio was assessed by (1)H high-resolution magic angle spinning magnetic resonance spectroscopy ((1)H-HRMAS-MRS). The neurobiological response was evaluated through prefrontal cortex mRNA expression and plasma corticosterone levels. The stressed rats were distributed into two subgroups according to their high (H-G/g) or low (L-G/g) GABA/glutamate ratio. Compared to the L-G/g rats, the H-G/g rats exhibited a decrease in c-fos, Arc, Npas4, Nr4a2 mRNA expression suggesting blunted prefrontal cortex activation. They also showed a more pronounced stress with an enhanced rise in corticosterone, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine kinase (CK) and lactate dehydrogenase (LDH) levels, as well as behavioral disturbances with decreased locomotion speed. These changes were independent from prefrontal cortex energetic status as mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathway activities were similar in both subpopulations. The differences in GABA/glutamate ratio in the frontal cortex observed in the stressed animals may participate in shaping individual differences in psychophysiological reactions.
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PMID:Differences in prefrontal cortex GABA/glutamate ratio after acute restraint stress in rats are associated with specific behavioral and neurobiological patterns. 2545 Dec 75

Objective: Type 2 diabetes mellitus (T2DM) is a risk factor for nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the effect of T2DM on nonalcoholic steatohepatitis (NASH) and advanced fibrosis. Methods: A total of 221 NAFLD patients who had undergone a liver biopsy were included in this study. Subjects were divided into a non-T2DM group and a T2DM group based on glycemic control. NASH was diagnosed by the joint presence of steatosis, ballooning, and lobular inflammation. The steatosis, activity, and fibrosis (SAF) score and NAFLD activity score (NAS) were used to evaluate the severity of NAFLD. The severity of liver fibrosis was evaluated based on the fibrosis stage. Results: The total percentages of NASH and advanced fibrosis in this study were 95.0% and 50.2%, respectively. The percentages of NASH and advanced fibrosis in NAFLD patients with T2DM were 96.1% and 56.5%, respectively, which were higher than those in the non-T2DM group. SAF score (especially activity and fibrosis stage) and NAS (especially ballooning) were higher in NAFLD patients with T2DM than in NAFLD patients without T2DM. Glycemic control and insulin resistance were positively associated with SAF, NAS, and fibrosis stage. Additionally, T2DM elevated the risk of a high NAS and advanced fibrosis. Conclusion: T2DM increases the risk of serious NASH and advanced fibrosis in patients with NAFLD. Liver biopsy can be performed in NAFLD patients with T2DM to confirm the stage of NAFLD. Screening of NASH and advanced fibrosis in NAFLD patients with T2DM is needed. Abbreviations: ALT = alanine aminotransferase; APO = apolipoprotein; AST = aspartate aminotransferase; BMI = body mass index; CI = confidence interval; FPG = fasting plasma glucose; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HDL-c = high-density-lipoprotein cholesterol; 1H-MRS = proton magnetic resonance spectroscopy; HOMA-IR = homeostasis model assessment of insulin resistance; 2hPG = postprandial plasma glucose at 2 hours; LDL-c = low-density-lipoprotein cholesterol; LFC = liver fat content; NAFLD = nonalcoholic fatty liver disease; NAS = NAFLD activity score; NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; OR = odds ratio; T2DM = type 2 diabetes mellitus; TC = total cholesterol; TG = triglyceride; SAF = steatosis, activity, and fibrosis; US-FLI = ultrasonographic fatty liver indicator.
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PMID:IMPACT OF TYPE 2 DIABETES ON NONALCOHOLIC STEATOHEPATITIS AND ADVANCED FIBROSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE. 3196 97

The impact of ultramarathon (UM) runs on the organs of competitors, especially elite individuals, is poorly understood. We tested a 36-year-old UM runner before, 1-2 days after, and 10-11 days after winning a 24-h UM as a part of the Polish Championships (258.228 km). During each testing session, we performed an electrocardiogram (ECG), transthoracic echocardiography (TTE), cardiac magnetic resonance imaging (MRI), cardiac 31P magnetic resonance spectroscopy (31P MRS), and blood tests. Initially, increased cholesterol and low-density lipoprotein cholesterol (LDL-C) levels were identified. The day after the UM, increased levels of white blood cells, neutrophils, fibrinogen, alanine aminotransferase, aspartate aminotransferase, creatine kinase, C-reactive protein, and N-terminal type B natriuretic propeptide were observed. Additionally, decreases in hemoglobin, hematocrit, cholesterol, LDL-C, and hyponatremia were observed. On day 10, all measurements returned to normal levels, and cholesterol and LDL-C returned to their baseline abnormal values. ECG, TTE, MRI, and 31P MRS remained within the normal ranges, demonstrating physiological adaptation to exercise. The transient changes in laboratory test results were typical for the extreme efforts of the athlete and most likely reflected transient but massive striated muscle damage, liver cell damage, activation of inflammatory processes, effects on the coagulation system, exercise-associated hyponatremia, and cytoprotective or growth-regulatory effects. These results indicated that many years of intensive endurance training and numerous UMs (including the last 24-h UM) did not have a permanent adverse effect on this world-class UM runner's body and heart. Transient post-competition anomalies in laboratory test results were typical of those commonly observed after UM efforts.
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PMID:Heart of the World's Top Ultramarathon Runner-Not Necessarily Much Different from Normal. 3201 17


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