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Author (up) Campbell, L.L.; Tyson, J.A.; Stackpole, E.E.; Hokenson, K.E.; Sherrill, H.; McKeon, J.E.; Kim, S.A.; Edmands, S.D.; Suarez, C.; Hall, A.C. file  url
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  Title Assessment of general anaesthetic cytotoxicity in murine cortical neurones in dissociated culture Type Journal Article
  Year 2011 Publication Toxicology Abbreviated Journal Toxicology  
  Volume 283 Issue 1 Pages 1-7  
  Keywords Anesthetics, General/*toxicity; Animals; Animals, Newborn; Cell Survival/drug effects; Cerebral Cortex/cytology/*drug effects/metabolism; Isoflurane/*toxicity; Ketamine/*toxicity; L-Lactate Dehydrogenase/metabolism; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Microtubule-Associated Proteins/metabolism; N-Methylaspartate/metabolism; Neurons/cytology/*drug effects/metabolism; Nitrous Oxide/*toxicity; gamma-Aminobutyric Acid/metabolism  
  Abstract General anaesthetics are proposed to cause unconsciousness by modulating neuronal excitability in the mammalian brain through mechanisms that include enhancement of inhibitory GABA(A) receptor currents and suppression of excitatory glutamate receptor responses. Both intravenous and volatile agents may produce neurotoxic effects during early postnatal rodent brain development through similar mechanisms. In the following study, we investigated anaesthetic cytotoxicity in primary cortical neurones and glia from postnatal day 2-8 mice. Cultures at 4-20 days in vitro were exposed to combinations of ketamine (100 muM to 3 mM), nitrous oxide (75%, v/v) and/or isoflurane (1.5-5%, v/v) for 6-12 h. Neuronal survival and cell death were measured via microtubule associated protein 2 immunoassay and lactate dehydrogenase release assays, respectively. Clinically relevant anaesthetic concentrations of ketamine, nitrous oxide and isoflurane had no significant neurotoxic effects individually or when given as anaesthetic cocktails, even with up to 12 h exposure. This lack of neurotoxicity was observed regardless of whether cultures were prepared from postnatal day 0-2 or day 8 mice, and was also unaffected by number of days in vitro (DIV 4-20). Significant neurotoxic effects were only observed at supraclinical concentrations (e.g. 1-3 mM ketamine). Our study suggests that neurotoxicity previously reported in vivo is not due to direct cytotoxicity of anaesthetic agents, but results from other impacts of the anaesthetised state during early brain development.  
  Call Number Serial 510  
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Author (up) Huang, Y.; Lu, Z.; Liu, N.; Chen, Y. file  url
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  Title Identification of important residues in diketoreductase from Acinetobacter baylyi by molecular modeling and site-directed mutagenesis Type Journal Article
  Year 2012 Publication Biochimie Abbreviated Journal Biochimie  
  Volume 94 Issue 2 Pages 471-478  
  Keywords 3-Hydroxyacyl CoA Dehydrogenases/chemistry/genetics/metabolism; Acinetobacter/*enzymology/genetics; Amino Acid Motifs; Amino Acid Substitution; Bacterial Proteins/*chemistry/genetics/metabolism; Binding Sites; Biocatalysis; Esters/*metabolism; Humans; Hydrogen-Ion Concentration; Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism; Kinetics; Molecular Dynamics Simulation; Molecular Sequence Data; Mutagenesis, Site-Directed; NAD/metabolism; Oxidation-Reduction; Oxidoreductases/*chemistry/genetics/metabolism; Protein Structure, Tertiary; Recombinant Proteins/chemistry/genetics/metabolism; Sequence Homology, Amino Acid; Stereoisomerism  
  Abstract Diketoreductase (DKR) from Acinetobacter baylyi exhibits a unique property of double reduction of a beta, delta-diketo ester with excellent stereoselectivity, which can serve as an efficient biocatalyst for the preparation of an important chiral intermediate for cholesterol lowering statin drugs. Taken the advantage of high homology between DKR and human heart 3-hydroxyacyl-CoA dehydrogenase (HAD), a molecular model was created to compare the tertiary structures of DKR and HAD. In addition to the possible participation of His-143 in the enzyme catalysis by pH profile, three key amino acid residues, Ser-122, His-143 and Glu-155, were identified and mutated to explore the possibility of involving in the catalytic process. The catalytic activities for mutants S122A/C, H143A/K and E155Q were below detectable level, while their binding affinities to the diketo ester substrate and cofactor NADH did not change obviously. The experimental results were further supported by molecular docking, suggesting that Ser-122 and His-143 were essential for the proton transfer to the carbonyl functional groups of the substrate. Moreover, Glu-155 was crucial for maintaining the proper orientation and protonation of the imidazole ring of His-143 for efficient catalysis.  
  Call Number Serial 1415  
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Author (up) Leskovac, V.; Trivic, S.; Anderson, B.M. file  url
openurl 
  Title Use of competitive dead-end inhibitors to determine the chemical mechanism of action of yeast alcohol dehydrogenase Type Journal Article
  Year 1998 Publication Molecular and Cellular Biochemistry Abbreviated Journal  
  Volume 178 Issue 1-2 Pages 219-227  
  Keywords yeast; alcohol; dehydrogenase; dead-end inhibitors; mechanism of action; dehydrogenases  
  Abstract In this work, we have postulated a comprehensive and unified chemical mechanism of action for yeast alcohol dehydrogenase (EC 1.1.1.1, constitutive, cytoplasmic), isolated from Saccharomyces cerevisiae. The chemical mechanism of yeast enzyme is based on the integrity of the proton relay system: His-51....NAD+....Thr-48....R.CH2OH(H2>O)....Zn<math>++, stretching from His-51 on the surface of enzyme to the active site zinc atom in the substrate-binding site of enzyme. Further, it is based on extensive studies of steady-state kinetic properties of enzyme which were published recently. In this study, we have reported the pH-dependence of dissociation constants for several competitive dead-end inhibitors of yeast enzyme from their binary complexes with enzyme, or their ternary complexes with enzyme and NAD+ or NADH; inhibitors include: pyrazole, acetamide, sodium azide, 2-fluoroethanol, and 2,2,2-trifluorethanol. The unified mechanism describes the structures of four dissociation forms of apoenzyme, two forms of the binary complex E.NAD+, three forms of the ternary complex E.NAD+.alcohol, two forms of the ternary complex E.NADH.aldehyde and three binary complexes E.NADH. Appropriate pKa values have been ascribed to protonation forms of most of the above mentioned complexes of yeast enzyme with coenzymes and substrates.  
  Call Number Serial 1414  
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Author (up) Narayana, N.; Matthews, D.A.; Howell, E.E.; Nguyen-huu, X. file  url
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  Title A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site Type Journal Article
  Year 1995 Publication Nature Structural Biology Abbreviated Journal Nat Struct Biol  
  Volume 2 Issue 11 Pages 1018-1025  
  Keywords Amino Acid Sequence; Binding Sites; Crystallography, X-Ray; Folic Acid Antagonists/chemistry/metabolism; Models, Molecular; Molecular Sequence Data; NADP/chemistry/metabolism; Plasmids/*genetics; Protein Conformation; Recombinant Proteins/chemistry; Tetrahydrofolate Dehydrogenase/*chemistry/genetics; Trimethoprim/chemistry/metabolism; Trimethoprim Resistance/*genetics  
  Abstract Bacteria expressing R67-plasmid encoded dihydrofolate reductase (R67 DHFR) exhibit high-level resistance to the antibiotic trimethoprim. Native R67 DHFR is a 34,000 M(r) homotetramer which exists in equilibrium with an inactive dimeric form. The structure of native R67 DHFR has now been solved at 1.7 A resolution and is unrelated to that of chromosomal DHFR. Homotetrameric R67 DHFR has an unusual pore, 25 A in length, passing through the middle of the molecule. Two folate molecules bind asymmetrically within the pore indicating that the enzyme's active site consists of symmetry related binding surfaces from all four identical units.  
  Call Number Serial 1208  
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Author (up) Semchyshyn, H.; Bagnyukova, T.; Lushchak, V. file  url
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  Title Involvement of soxRS regulon in response of Escherichia coli to oxidative stress induced by hydrogen peroxide Type Journal Article
  Year 2005 Publication Biochemistry. Biokhimiia Abbreviated Journal Biochemistry (Mosc)  
  Volume 70 Issue 11 Pages 1238-1244  
  Keywords Bacterial Proteins/*genetics; Escherichia coli/enzymology/*genetics/*physiology; Escherichia coli Proteins/*genetics; Glucosephosphate Dehydrogenase/metabolism; Glutathione Peroxidase/metabolism; Hydrogen Peroxide/*pharmacology; *Oxidative Stress; *Regulon; Superoxide Dismutase/metabolism; Trans-Activators/*genetics; Transcription Factors/*genetics  
  Abstract The effect of hydrogen peroxide on the activity of soxRS and oxyR regulon enzymes in different strains of Escherichia coli has been studied. Treatment of bacteria with 20 microM H2O2 caused an increase in catalase and peroxidase activities (oxyR regulon) in all strains investigated. It is shown for the first time that oxidative stress induced by hydrogen peroxide causes in some E. coli strains a small increase in activity of superoxide dismutase and glucose-6-phosphate dehydrogenase (soxRS regulon). This effect is cancelled by chloramphenicol, an inhibitor of protein synthesis in prokaryotes. The increase in soxRS regulon enzyme activities was not found in the strain lacking the soxR gene. These results provide evidence for the involvement of the soxRS regulon in the adaptive response of E. coli to oxidative stress induced by hydrogen peroxide.  
  Call Number Serial 348  
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Author (up) Tanaka, F.; Shiratori, Y.; Yokosuka, O.; Imazeki, F.; Tsukada, Y.; Omata, M. file  url
openurl 
  Title Polymorphism of alcohol-metabolizing genes affects drinking behavior and alcoholic liver disease in Japanese men Type Journal Article
  Year 1997 Publication Alcoholism, Clinical and Experimental Research Abbreviated Journal Alcohol Clin Exp Res  
  Volume 21 Issue 4 Pages 596-601  
  Keywords Adult; Alcohol Dehydrogenase/*genetics; Alcohol Drinking/*genetics/physiopathology; Alcoholism/*genetics/psychology; Aldehyde Dehydrogenase/*genetics; Alleles; Cytochrome P-450 CYP2E1/genetics; Ethanol/*pharmacokinetics; Ethnic Groups/*genetics/psychology; Flushing/enzymology/genetics; Gene Expression Regulation, Enzymologic; Humans; Japan; Liver Diseases, Alcoholic/enzymology/*genetics; Male; Middle Aged; Polymorphism, Genetic/*genetics  
  Abstract Alcohol is known to be mainly metabolized in the liver by alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2), and cytochrome P-450IIEI. The purpose of this study was to clarify the role of polymorphism of these ethanol-metabolizing enzymes in drinking behavior and the progression of alcoholic liver disease among Japanese men. Polymorphism of the ADH2, ALDH2, and P-45IIEI genes were determined by polymerase chain reaction, followed by restriction fragment-length polymorphism analysis in 189 normal Japanese men and 26 male patients with alcoholic liver disease. Drinking behavior was estimated by self-assessment according to DSM-III-R criteria. Facial flushing was reported in 91 subjects heterozygous for ALDH2*1/*2 and in two subjects homozygous for ALDH2*2/*2, but was not found in 96 subjects homozygous for ALDH2*1/*1. In contrast, polymorphism of ADH2 and P-450IIEI did not differ between flushers and nonflushers. Although the flushers only drank a small amount of alcohol (< 20 g of ethanol/day), the nonflushers were divided into a group of moderate drinkers (20 to 80 g/day; n = 54) and a group of heavy drinkers (> 80 g/day; n = 42). A high preponderance of heterozygosity for the ADH2*1/*2 genes (20/42; 60%) and a high frequency of the ADH2*1 allele were found in heavy drinkers, compared with moderate drinkers. However, cytochrome P-45IIEI gene polymorphism was similar among the moderate and heavy drinkers. Not only a high frequency of the ALDH2*1 and ADH2*1 alleles, but also a high frequency of the P-450IIEI c2 allele was found in the patients with alcoholic liver disease. From these results, the drinking behavior of Japanese men is strongly influenced by the ALDH2*1 allele, and the level of alcohol intake is affected by the ADH2*1 allele, but not by cytochrome P-45IIEI. However, progression to alcoholic liver disease among heavy drinkers may be affected by the cytochrome P-450IIEI c2 allele.  
  Call Number Serial 517  
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Author (up) Zaidi, P.H.; Rafique, S.; Singh, N.N. file  url
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  Title Response of maize (Zea mays L.) genotypes to excess soil moisture stress: morpho-physiological effects and basis of tolerance Type Journal Article
  Year 2003 Publication European Journal of Agronomy Abbreviated Journal European Journal of Agronomy  
  Volume 19 Issue 3 Pages 383-399  
  Keywords Excess soil moisture; Waterlogging; Growth; Alcohol dehydrogenase activity; Transpiration  
  Abstract Experiments were conducted during kharif (summer rainy) season in 1999 and 2000 under controlled environment (glass-house) followed by field condition to assess the effects of excess soil moisture (ESM) stress on maize (Zea mays L.), extent of genetic variability and to assess the morpho-physiological/metabolic basis of stress tolerance. Six genotypes, having different genetic background and known for their reactions to waterlogging stress, have been used in this study. Seedlings were raised in disposable plastic cups (250 cm3) under completely saturated soil conditions, transplanted in field 20 days after planting and again exposed to waterlogging stress at knee-high stage for 7 days. ESM stress severely affected growth, biochemical composition and metabolic activities, both at early stage and knee-high stage. There was good similarity in the response of genotypes to ESM stress at two growth stages. Genotypes with early adventitious rooting, partial stomatal closure, <5.0 days anthesis-silking interval, increased root NAD+-alcohol dehydrogenase activity and high starch accumulation in stem tissues showed good tolerance to ESM stress. Most of these morpho-physiological traits associated with ESM tolerance were common in both pre-existing and induced (pre-hypoxia/anoxia) tolerance. The results show that hypoxia/anoxia pre-treatment enhances tolerance to waterlogging conditions in maize. However, genetic heritability of such induced tolerance needs to be worked out. It may be concluded that ESM tolerance was mainly based on the stress avoidance mechanism by anaerobic metabolic and alternative arrangement like brace root development to avoid anoxia condition.  
  Call Number Serial 609  
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