Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On expression of the cDNA encoding the precursor of chicken mitochondrial aspartate aminotransferase (pmAspAT) in Escherichia coli, the bulk of pmAspAT was found to be associated with the 70-kDa heat-shock protein DnaK which is closely related to mitochondrial 70-kDa heat-shock protein (HSP70). Purification protocols for the DnaK/pmAspAT complex and its individual components were elaborated. The complex dissociated on treatment with MgATP or at pH 5.5. Like the mature enzyme, pmAspAT is a dimer (2 x 47 kDa) and exhibits about a third of its enzyme activity. In the DnaK/pmAspAT complex, one DnaK molecule is bound to each subunit of pmAspAT; this tetramer may further aggregate to an octamer. The complex is catalytically almost as active as free pmAspAT. It could be reconstituted from isolated DnaK and pmAspAT. No complex was formed with mAspAT. Apparently, DnaK binds to the solvent-exposed presequence of folded pmAspAT without significantly changing the structure and functional properties of its mature moiety.
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PMID:Precursor of mitochondrial aspartate aminotransferase synthesized in Escherichia coli is complexed with heat-shock protein DnaK. 139 76

Metabolism of the common industrial gas tetrafluoroethylene in mammals results in the formation of S-(1,1,2,2)-tetrafluoroethyl-L-cysteine (TFEC), which can be bioactivated by a mitochondrial C-S lyase commonly referred to as beta-lyase. The resultant "reactive intermediate", difluorothioacetyl fluoride (DFTAF), is a potent thioalkylating and protein-modifying species. Previously, we have identified mitochondrial HSP70, HSP60, aspartate aminotransferase, and the E2 and E3 subunits of the alpha-ketoglutarate dehydrogenase (alphaKGDH) complex as specific proteins structurally modified during this process. Moreover, functional alterations to the alphaKGDH complex were also detected and implicated in the progression of injury. We report here the identification, by tandem mass spectrometry, and functional characterization of the final remaining major protein species modified by DFTAF, previously designated as P99(unk), as mitochondrial aconitase. Aconitase activity was maximally inhibited by 56.5% in renal homogenates after a 6 h exposure to TFEC. In comparison to alphaKGDH, aconitase inhibition (up to 79%) in a cell culture model for TFEC-mediated cytotoxicity was greater and preceded alphaKGDH inhibition, indicating that aconitase modification may constitute an early event in TFEC-mediated mitochondrial damage and cell death. These findings largely define the initial lesion of TFEC-mediated cell death and also have implications for the modeling of mitochondrial enzymatic architecture and the localization and identity of renal mitochondrial cysteine S-conjugate beta-lyase.
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PMID:Mitochondrial aconitase modification, functional inhibition, and evidence for a supramolecular complex of the TCA cycle by the renal toxicant S-(1,1,2,2-tetrafluoroethyl)-L-cysteine. 1202 83

Mercury is a highly toxic metal which induces oxidative stress. Metallothionein and heat shock protein 70 (HSP70) are stress proteins involved in response to different stimuli. In the present study rats were administered per oral application by gavage, a single daily dose (0.1 mg/kg) of HgCl(2) for 3 consecutive days. To find a relation between these two stress proteins and mercury, parameters of liver injury, redox state of the cells, and the expression and protein levels of HSP70 and metallothionein by Northern and Western blot analysis were assayed either in blood or in liver. HgCl(2) at the doses of 0.1 mg/kg induced liver injury detected by a slight increase in serum aspartate aminotransferase and alkaline phosphatase activities and by the enhanced levels of bilirubin. Oxidative stress was detected by a significant decrease in protein-SH and an increase in thiobarbituric acid reactive substances in liver following one dose of mercury. mRNA and protein levels of both metallothionein and HSP70 increased progressively from first to third doses of mercury. We conclude that against low doses of mercury that produce a slight liver injury and oxidative stress, the liver rapidly responds by inducing the expression of metallothionein and HSP70. We suggest that metallothionein induction attenuates the decrease in protein-SH induced by the first dose of mercury, since metallothionein increases the pool of thiol groups in the cytosol eliminating oxygen radicals and inhibiting lipid peroxidation. From these results we can suggest that the changes observed in these stress proteins by the effect of mercury appear to be a response rapidly induced at transcriptional and at translational levels.
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PMID:Relationship between expression of HSP70 and metallothionein and oxidative stress during mercury chloride induced acute liver injury in rats. 1281 12

Tetrafluoroethylcysteine (TFEC), a metabolite of the industrial gas tetrafluoroethylene, can cause both nephrotoxicity and limited hepatotoxicity in animal models, and this is associated with the covalent modification of specific intramitochondrial proteins including heat shock protein 60 (HSP60), mitochondrial HSP70 (mtHSP70), aspartate aminotransferase (AST), aconitase, and alpha-ketoglutarate dehydrogenase (alphaKGDH). Using the murine TAMH cell line as a useful in vitro model for TFEC toxicity, we demonstrate a rapid and sustained induction of Nrf2, a member of the "cap-and-collar" transcription factor family, following exposure to cytotoxic concentrations of TFEC. A functional correlate was also established with the rapid translocation of cytosolic Nrf2 into the nucleus. In addition, transcriptional and translational upregulation of known Nrf2 regulated genes including glutamate cysteine ligase (GCL), both catalytic and modulatory subunits, heme oxygenase-1, and glutathione S-transferase (GST) isoforms were detected. While Nrf2 activation is often linked to perturbation of cellular thiol status and/or oxidative stress, we were unable to detect any significant depletion of cellular glutathione or oxidation of mitochondrial membrane cardiolipin or increases in reactive oxygen species (ROS). These data suggest Nrf2 activation is likely independent of classical oxidative stress or, at best, a result of a transient, low-level redox stress. Moreover, supporting evidence indicates an early endoplasmic reticular (ER) stress response after TFEC treatment, with a time-dependent upregulation of the ER responsive genes gadd34, gadd45, gadd153, and ndr1 . These findings suggest an alternative pathway for Nrf2 activation, i.e., Nrf2 phosphorylation through ER-mediated protein kinases such as PKR-like endoplasmic reticular kinase (PERK). Overall, the results implicate a role for Nrf2 in the cellular response to TFEC toxicity and suggest a previously unrecognized role for the ER in this model of mitochondrially initiated cytotoxicity.
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PMID:Nrf2 activation involves an oxidative-stress independent pathway in tetrafluoroethylcysteine-induced cytotoxicity. 1590 13

The present study was performed to determine whether melatonin protects mouse liver against severe damage induced by acetaminophen (APAP) administration and where melatonin primarily functions in the metabolic pathway of APAP to protect mouse liver against APAP-induced injury. Treatment of mice with melatonin (50 or 100 mg/kg, p.o.) 8 or 4 hr before APAP administration (750 mg/kg, p.o.) suppressed the increase in plasma alanine aminotransferase and aspartate aminotransferase activities in a dose- and a time-dependent manner. Melatonin treatment (100 mg/kg, p.o.) 4 hr before APAP administration remarkably inhibited centrilobular hepatic necrosis with inflammatory cell infiltration and increases in hepatic lipid peroxidation and myeloperoxidase activity, an index of tissue neutrophil infiltration, as well as release of nitric oxide and interleukin-6 into blood circulation at 9 hr after APAP administration. However, melatonin neither affected hepatic reduced glutathione (GSH) content nor spared hepatic GSH consumption by APAP treatment. Moreover, pretreatment with melatonin 4 hr before APAP administration did not influence the induction of hepatic heat shock protein 70 (HSP70) by APAP and melatonin alone did not induce HSP70 in mouse liver. These results indicate that exogenously administered melatonin exhibits a potent hepatoprotective effect against APAP-induced hepatic damage probably downstream of the activity of cytochrome P450 2E1, which works upstream of GSH conjugation in the pathway of APAP metabolism, via its anti-nitrosative and anti-inflammatory activities in addition to its antioxidant activity.
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PMID:Mechanisms of protection by melatonin against acetaminophen-induced liver injury in mice. 1694 81

Increased hepatic abnormality has been observed in patients with systemic lupus erythematosus (SLE) and contributes to the elevated apoptosis that results in severe disease activity. Since cystamine has been demonstrated to be beneficial for NZB/W F1 mice, this study investigates the effects of cystamine on various inflammatory and stress-related proteins in liver from NZB/W F1 mice. Nephelometric analyses and immunoblots were conducted to detect aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP), p53, p21, Gadd45, heat shock protein 70 (HSP70) and cyclooxygenase-2 (COX-2). AST and ALT were reduced in NZB/W F1 mice that were given cystamine and CRP, p53, p21, Gadd45, HSP70 and COX-2 proteins in the liver were reduced in NZB/W F1 mice that were treated with cystamine. Moreover, cystamine has no obvious effect on BALB/c mice. These findings suggest that cystamine reduces the inflammation in liver of NZB/W F1 mice and provide a clue in treatment of SLE with liver abnormality.
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PMID:Transglutaminase inhibitor cystamine alleviates the abnormality in liver from NZB/W F1 mice. 1803 33

Heat shock proteins (HSPs) are the best-known endogenous factors that protect against cell injury under various pathological conditions and that can be induced by various physical, chemical, and biological stressors. New research seeks to discover a compound that is clinically safe and can induce the accumulation of HSPs in patients. This paper reports that the oral administration of three doses of bicyclol, a novel antihepatitis drug, induced hepatic HSP27 and HSP70 expression in a time- and dose-dependent manner, and that bicyclol treatment stimulated heat shock factor 1 (HSF1) activation in mice. The inducing effects of bicyclol on HSP27, HSP70 and HSF1 were all blocked by quercetin, an inhibitor of HSP biosynthesis. The cytoprotective effect of HSP27/70 induced by bicyclol against hepatotoxicity of acetaminophen (AP) was assessed in mice. The prior administration of bicyclol markedly suppressed AP-induced liver injury as indicated by the reduction in the elevation of serum alanine aminotransferase and aspartate aminotransferase, in liver necrosis, in the release of cytochrome c and apoptosis-inducing factor from mitochondria, as well as in hepatic deoxyribonucleic acid fragmentation in mice. However, all the above actions of bicyclol against AP-induced mouse liver injuries were significantly attenuated by quercetin. This is the first report to show that bicyclol induces hepatic HSP27/70 expression via activation of HSF1 and that the cytoprotective action of bicyclol against liver injury is mediated by its induction of HSP27/70. These results provide new evidence for elucidating the mechanism of the hepatoprotective action of bicyclol in animals and patients.
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PMID:Bicyclol: a novel antihepatitis drug with hepatic heat shock protein 27/70-inducing activity and cytoprotective effects in mice. 1839 51

Endotoxemia caused by LPS is a life-threatening and inflammatory condition contributing to multiple organ failure. Viruses or bacteria require sialic acid (SA) for target-cell binding. We suggest that exogenous SA through masking or mediating the binding of LPS to the target cells may attenuate LPS-induced liver dysfunction and cecal ligation and puncture-induced shock. We found that SA can directly scavenge O2-, H2O2, and NO activity by a chemiluminescence analyzer and bind to LPS with high affinity using surface plasmon resonance. Intravenous SA significantly increased plasma SA concentration within 4 h. We then assessed the potential effect of SA on LPS-induced acute endotoxemia in the rat. Intravenous LPS (10-50 mg/kg) dose-dependently increased plasma endotoxin and reactive oxygen species in the blood, bile, and liver and increased plasma alanine aminotransferase and aspartate aminotransferase levels as well as TNF-alpha, monocyte chemoattractant protein 1, tissue inhibitor of metalloproteinase 1, IL-1beta, and IL-6 levels in the rats. Thirty minutes after LPS stimulation, SA decreased LPS-enhanced endotoxin level, oxidative stress, alanine aminotransferase and aspartate aminotransferase levels, and cytokine concentration and ameliorated histopathologic alteration in the liver. We found that SA increased LPS-depressed Mn-superoxide dismutase, CuZn-superoxide dismutase, and heat shock protein 70 and decreased LPS-enhanced iNOS and proapoptotic Bax protein expression in the liver by Western blot. Sialic acid was given after treatment to rats subjected to cecal ligation and puncture, and the hypotensive effect was blunted for 6 h. In conclusion, SA treatment can counteract LPS-enhanced acute endotoxemia and oxidative injury via a direct scavenging reactive oxygen species activity and neutralization potential.
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PMID:Sialic acid reduces acute endotoxemia-induced liver dysfunction in the rat. 1906 Jul 86

Heat shock protein (HSP) expression is an adaptive mechanism against the disruption of cell homeostasis during exercise. Several antioxidant supplementation strategies have been used to enhance tissue protection. In this study, we examined the effects of a redox modulator, alpha-lipoic acid (LA) on HSP responses in six standardbred trotters following intense aerobic exercise. DL-LA supplementation (25 mg kg(-1) d(-1)) for five weeks increased the resting levels of HSP90 (1.02+/-0.155 in control and 1.26+/-0.090 after supplementation in arbitrary units) and the recovery levels of inducible HSP70 (0.89+/-0.056 in control and 1.05+/-0.089 after supplementation in arbitrary units) in skeletal muscle. Furthermore, LA increased skeletal muscle citrate synthase activity at rest and lowered the blood lactate concentration during exercise without any changes in the heart rate. LA had no effect on concentrations of HSP60, HSP25 or GRP75 in skeletal muscle. LA decreased the exercise-induced increases in plasma aspartate aminotransferase and creatine kinase concentrations during recovery. Our results suggest that LA supplementation may enhance tissue protection and increase oxidative capacity of the muscle in horse.
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PMID:alpha-Lipoic acid supplementation enhances heat shock protein production and decreases post exercise lactic acid concentrations in exercised standardbred trotters. 1942 59

The benefit of gaseous oxygenation during storage of liver grafts from donors after cardiac death should be investigated as applied either during the whole period of preservation or only for the last 2 h prior to reperfusion. Rat livers were explanted 30 min after cardiac arrest of the donor and cold-stored (CS) for 20 h. Some grafts were subjected to venous systemic oxygen persufflation (VSOP) either for 20 h or for only 2 h subsequent to 18 h of CS. Viability of the livers was assessed thereafter by warm reperfusion in vitro. Twenty hours VSOP and 18 h CS + 2 h VSOP prevented mitochondrial protein breakdown of mitochondrial heat shock protein 70 and promoted a significant and approximately twofold increase in hepatic oxygen consumption, bile production, and energetic recovery upon warm reperfusion. No differences were seen whether VSOP was performed for 20 h or for only 2 h prior to reperfusion. Both techniques significantly abrogated parenchymal enzyme loss (alanine aminotransferase, aspartate aminotransferase) upon reperfusion compared with simple 20 h CS. An increase in perfusate levels of the mitochondrial enzyme glutamate dehydrogenase was observed only in the 20 h VSOP group. In conclusion, viability of donation after cardiac death liver grafts can still be augmented, similarly to continuous aerobic storage, by only endischemic reconditioning, both protocols preventing initial mitochondrial dysfunction and subsequent tissue injury.
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PMID:Donation after cardiac death: dynamic graft reconditioning during or after ischemic preservation? 2131 36


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