Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysosomal degradation of intracellular proteins during serum withdrawal is stimulated by a member of the 70-kDa heat shock protein (hsp70) family (Chiang, H.-L., Terlecky, S. R., Plant, C. P., and Dice, J. F. (1989) Science 246, 382-385). This hsp70, isolated by affinity chromatography with RNase S-peptide-Sepharose, is referred to as the 73-kDa peptide recognition protein (prp73). We now report that prp73 binds to several proteins and peptides whose degradative rates are increased during serum withdrawal. prp73 also binds to the pentapeptide, KFERQ, and more weakly to most modified RNase S-peptide derivatives with a single amino acid substitution within the KFERQ sequence. Taken together, these results suggest that prp73 binds to a variety of proteins at peptide regions biochemically related to KFERQ. Three lines of evidence indicate that prp73 is the heat shock cognate protein of 73 kDa (hsc73): (a) among five hsp70s tested, hsc73 binds to RNase S-peptide most avidly, (b) both prp73 and hsc73 also bind to RNase A and aspartate aminotransferase but not to ovalbumin, lysozyme, or ubiquitin, and (c) both prp73 and hsc73 promote uptake and degradation of [3H] RNase S-peptide by lysosomes in vitro, while three other hsp70s are without activity in this assay.
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PMID:Protein and peptide binding and stimulation of in vitro lysosomal proteolysis by the 73-kDa heat shock cognate protein. 157 55

The hemodynamic effects of sepsis have been attributed in part to increased nitric oxide (NO) production and activation of guanylate cyclase, resulting in increased cGMP and relaxation of vascular smooth muscle. Heme oxygenase-1 (HO-1), a heat shock protein, has been shown to increase intracellular cGMP levels by formation of carbon monoxide (CO). We hypothesized that HO may be an important mediator of the hepatic response to infection. Male Swiss Webster mice underwent standard cecal ligation and puncture (CLP, 18 gauge 2X) or sham operation, and received either normal saline (NS) or Zn protoporphyrin IX (ZN PP IX), a competitive HO inhibitor (n = 6-8/group). Hepatic tissue samples were collected at 3, 6, 12, and 24 hr from separate mice. Serum was collected at 3 and 24 hr. A semiquantitative reverse transcriptase polymerase chain reaction method was used to measure HO-1 mRNA levels. Hepatic cGMP levels were measured by ELISA. Groups were repeated (n = 10/group) to assess mortality. Serum was collected at 3 and 24 hr to measure serum aspartate aminotransferase (AST) levels. HO-1 mRNA expression increased significantly by 3 hr after CLP and with HO inhibition alone (P < 0.05 vs sham + NS). HO-1 mRNA remained elevated through 24 hr. CLP animals with HO inhibition showed a significant reduction of hepatic cGMP following CLP compared with CLP + saline at 24 hr (P < 0.05). Mortality was significantly increased in the CLP + ZN PP group at 24 hr (P < 0.05 CLP NS vs CLP ZN PP). CLP caused a marked increase in AST activity, which was increased further with HO inhibition. HO-1 mRNA expression was induced by CLP. AST levels following CLP were markedly increased with HO inhibition. HO-1 function appeared to contribute to elevation of hepatic cGMP during peritonitis and may be an important hepatic adaptive response to infection.
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PMID:Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis. 927 Dec 71

Heat shock proteins are ubiquitous intracellular proteins induced by various physiological stress-related events. A 72-kDa heat shock protein (HSP72) has been reported to be an endogenous cytoprotectant in variety of cells in vitro. In order to study the cytoprotective function of HSP72 in the liver, the effect of preinduction of HSP72 in rat liver by systemic hyperthermia on thioacetamide-induced hepatic injury was investigated in this study. Expression of HSP72 in the liver was investigated by immunoblot and densitometric analysis. Rats were injected with thioacetamide (100 mg/kg, subcutaneously) with or without preinduction of HSP72 by hyperthermia. Serum AST and ALT concentrations were measured before and after thioacetamide injection in both group. Histologic alteration of the liver was evaluated also. Systemic hyperthermia (42.5 degrees C, 20 min) significantly induced HSP72 in the liver. Thioacetamide-induced hepatic injury was clearly prevented by preinduction of HSP72 by hyperthermia. Prevention of hepatocyte damage was more clear in the area around central veins where HSP72 induction was apparent. Our findings might suggest that HSP72 has an important function in the liver with respect to cytoprotection. These results might be important for understanding the mechanism of "adaptive cytoprotection" in the liver mediated by the function of heat shock proteins as "molecular chaperons" as reported in vitro.
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PMID:Induction of a 72-kDa heat shock protein and cytoprotection against thioacetamide-induced liver injury in rats. 933 Nov 66

The nucleotide sequences (310 bp) of the groEL gene, which encode the 60-kDa heat shock protein GroEL from 31 reference strains of Borrelia were determined and compared. More than 92.3% similarity was observed among Borrelia burgdorferi sensu lato strains. In the phylogenetic tree constructed with the maximum-likelihood method, each species of B. burgdorferi sensu lato was differentiated as a distinct entity. We developed polymerase chain reaction-restriction fragment length polymorphism analysis using a specific single amino acid variation [N(213) (AAT)-->S (AGC or AGT)] between B. burgdorferi sensu stricto strains and the other B. burgdorferi sensu lato strains. These results showed that the groEL gene is useful for differentiation of B. burgdorferi sensu lato.
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PMID:Differentiation of Borrelia burgdorferi sensu lato through groEL gene analysis. 1275 46

We investigated whether longer-term cortisol exposure modified hepatic glucocorticoid receptor (GR) status and tissue responsiveness to cortisol stimulation in rainbow trout. Fish were given intraperitoneal implants of cortisol (50mg/kg body mass) and this led to elevated plasma cortisol levels mimicking chronically stressed salmonids. There was significantly higher hepatic GR mRNA abundance, despite a drop in GR protein content in the liver of cortisol-treated fish. The tissue responsiveness to cortisol stimulation was apparent from the higher plasma glucose concentration and liver glycogen content. Also, the higher phosphoenolpyruvate carboxykinase (PEPCK) mRNA abundance, a key glucocorticoid-responsive gene, by cortisol suggests activation of the GR signalling pathway. There was no significant effect of cortisol treatment on liver PEPCK, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase activities compared to the sham fish. The higher heat shock protein (hsp) 90 mRNA abundance and a corresponding elevation in this protein and constitutive hsp70 (hsc70) protein content in the cortisol-treated fish reflects a role for glucocorticoids in the hepatic stress response process. Taken together, the molecular and biochemical responses evident in the liver of trout imply changes favouring tissue responsiveness to glucocorticoids and may be a mechanism to offset GR protein downregulation evident with chronic cortisol stimulation in rainbow trout.
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PMID:Cortisol treatment affects glucocorticoid receptor and glucocorticoid-responsive genes in the liver of rainbow trout. 1281 73

The administration of glutamine before experimental ischemia/reperfusion (I/R) has been shown to protect intestinal, pulmonary, and myocardial tissue by inducing heat shock proteins (HSP). However, it is not known whether glutamine is protective for all organs. We therefore tested whether pretreatment with glutamine reduces injury following hepatic I/R in rats. Male lean Zucker rats were pretreated with either glutamine (0.75 g/kg intraperitoneally, n = 6) or saline (n = 6), 24 and 6 hours before ischemia. Seventy percent of the liver was exposed to 75 minutes of warm ischemia followed by 24 hours reperfusion. Liver enzymes, histology, neutrophil accumulation, survival, and heat shock protein (HSP) 70 induction were examined. Glutamine administration did not reduce liver injury. In both groups, 5 of 6 animals survived 24 hours of reperfusion. There was no difference in serum transaminase levels with AST 15113 +/- 4336 U/L (glutamine) vs. 17695 +/- 8531 U/L (control, P > 0.05), and ALT 7763 +/- 2524 (glutamine) U/L vs. 5884 +/- 2063 U/L (control, P > 0.05). The degree of neutrophil accumulation and necrosis was not different between groups at 24 hours of reperfusion. Pretreatment did not result in HSP70 upregulation in any of the groups. Pretreatment with glutamine did not reduce hepatic ischemia/reperfusion injury. The lack of protection was associated with an absence of HSP70 upregulation prior to ischemia.
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PMID:Glutamine does not protect against hepatic warm ischemia/reperfusion injury in rats. 1645 56

The final step of protein translocation across the mitochondrial inner membrane is mediated by a translocation motor composed of 1) the matrix-localized, ATP-hydrolyzing, 70-kDa heat shock protein mHsp70; 2) its anchor to the import channel, Tim44; 3) the nucleotide exchange factor Mge1; and 4) a J-domain-containing complex of co-chaperones, Tim14/Pam18-Tim16/Pam16. Despite its essential role in the biogenesis of mitochondria, the mechanism by which the translocation motor functions is still largely unknown. The goal of this work was to carry out a structure-function analysis of the mitochondrial translocation motor utilizing purified components, with an emphasis on the formation of the Tim44-mHsp70 complex. To this end, we purified Tim44 and monitored its interaction with other components of the motor using cross-linking with bifunctional reagents. The effects of nucleotides, the J-domain-containing components, and the P5 peptide (CALLSAPRR, representing part of the mitochondrial targeting signal of aspartate aminotransferase) on the formation of the translocation motor were examined. Our results show that only the peptide and nucleotides, but not J-domain-containing proteins, affect the Tim44-mHsp70 interaction. Additionally, binding of Tim44 to mHsp70 prevents the formation of a complex between the latter and Tim14/Pam18-Tim16/Pam16. Thus, mutually exclusive interactions between various components of the motor with mHsp70 regulate its functional cycle. The results are discussed in light of known models for the function of the mitochondrial translocation motor.
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PMID:The interplay between components of the mitochondrial protein translocation motor studied using purified components. 1788 57

Mitochondria are involved in the development of organ failure in critical care diseases. However, the mechanisms underlying mitochondrial dysfunction are not clear yet. Inducible hemoxygenase (HO-1), a member of the heat shock protein family, is upregulated in critical care diseases and considered to confer cytoprotection against oxidative stress. However, one of the products of HO-1 is Fe2+ which multiplies the damaging potential of reactive oxygen species catalyzing Fenton reaction. The aim of this study was to clarify the relevance of free iron metabolism to the oxidative damage of the liver in endotoxic shock and its impact on mitochondrial function. Endotoxic shock in rats was induced by injection of lipopolysaccharide (LPS) at a dose of 8 mg/kg (i.v.). We observed that the pro-inflammatory cytokine TNF-alpha and the liver necrosis marker aspartate aminotransferase were increased in blood, confirming inflammatory response to LPS and damage to liver tissue, respectively. The levels of free iron in the liver were significantly increased at 4 and 8 h after onset of endotoxic shock, which did not coincide with the decrease of transferrin iron levels in the blood, but rather with expression of the inducible form of heme oxygenase (HO-1). The proteins important for sequestering free iron (ferritin) and the export of iron out of the cells (ferroportin) were downregulated facilitating the accumulation of free iron in cells. The temporarily increased concentration of free iron in the liver correlated with the temporary impairment of both mitochondrial function and tissue ATP levels. Addition of exogenous iron ions to mitochondria isolated from control animals resulted in an impairment of mitochondrial respiration similar to that observed in endotoxic shock in vivo. Our data suggest that free iron released by HO-1 causes mitochondrial dysfunction in pathological situations accompanied by endotoxic shock.
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PMID:A novel endotoxin-induced pathway: upregulation of heme oxygenase 1, accumulation of free iron, and free iron-mediated mitochondrial dysfunction. 1798 71

Hydrogen sulfide (H(2)S) is an endogenously produced gaseous signaling molecule with diverse physiological activity. The potential protective effects of H(2)S have not been evaluated in the liver. The purpose of the current study was to investigate if H(2)S could afford hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R) injury. Hepatic injury was achieved by subjecting mice to 60 min of ischemia followed by 5 h of reperfusion. H(2)S donor (IK1001) or vehicle were administered 5 min before reperfusion. H(2)S attenuated the elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate aminotransferase (AST) by 70.8% compared with vehicle group. H(2)S-mediated cytoprotection was associated with an improved balance between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an attenuated formation of lipid hydroperoxides, and an increased expression of thioredoxin-1 (Trx-1). Furthermore, H(2)S inhibited the progression of apoptosis after I/R injury by increasing the protein expression of heat shock protein (HSP-90) and Bcl-2. These results indicate that H(2)S protects the murine liver against I/R injury through an upregulation of intracellular antioxidant and antiapoptotic signaling pathways.
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PMID:Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. 1856 6

We examined the effect of heat-killed Lactobacillus brevis (L. brevis) SBC8803 on the development of alcoholic liver disease using ethanol-containing diet-fed mice. Heat-killed L. brevis was orally administered at a dose of 100 or 500 mg/kg once a day for 35 days. Alcoholic liver injury was examined by measuring the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a serum, and the alcoholic fatty liver was assessed from the content of triglyceride (TG) and total cholesterol in the liver. Quantitative RT-PCR was used to examine mRNA expression of tumor necrosis factor (TNF)-alpha, sterol regulatory element-binding protein (SREBP)-1, SREBP-2, and peroxisome proliferator-activated receptor alpha (PPARalpha) in the liver, as well as E-cadherin, Zonula occludens 1 (ZO-1), and heat shock protein (Hsp) 25 in the small intestine. Oral administration of L. brevis significantly inhibited an increase in the level of serum ALT and AST, as well as the content of TG and total cholesterol in the liver caused by ethanol intake. L. brevis supplementation suppressed the overexpression of TNF-alpha, SREBP-1, and SREBP-2 mRNA in the liver induced by ethanol intake and up-regulated the expression of Hsp25 mRNA in the small intestine. These results suggest that L. brevis ameliorated the ethanol-induced liver injury and the fatty liver by suppressing the up-regulation of TNF-alpha and SREBPs in the liver. We speculate that the inhibition of TNF-alpha and SREBPs up-regulation by L. brevis is due to the inhibition of gut-derived endotoxin migration into the liver through the enhancement of intestinal barrier function by the induction of cytoprotective Hsps.
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PMID:Oral administration of heat-killed Lactobacillus brevis SBC8803 ameliorates alcoholic liver disease in ethanol-containing diet-fed C57BL/6N mice. 1897 29


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